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As the primary screening test, E6/E7 mRNA has shown similar sensitivity for CIN3+ and lower positivity rate than the HPV DNA test. Nevertheless, the overall mRNA positivity is too high for immediate colposcopy, making a triage test necessary. The aim was to estimate the mRNA performance as a primary test with different triage strategies. All HPV DNA-positives were tested for mRNA, cytology and p16/ki67. A sample of HPV DNA-negatives was also tested for mRNA to estimate test specificity. We included all CIN3+ histologically diagnosed within 24 months since recruitment. Of the 41 127 participants, 7.7% were HPV DNA-positive, of which 66.4% were mRNA-positive. Among the HPV DNA-negatives, 10/1108 (0.9%) were mRNA-positive. Overall, 97 CIN3+ were found. If mRNA was used as the primary test, it would miss about 3% of all CIN3+ with a 22% reduction of positivity compared with HPV DNA. The weighted specificity estimate forCIN2 was 94.5% (95% CI = 93.9%-94.9%) and sensitivity for CIN3+ was 96.9% (95% CI = 91.3%-99.1%). If all the weighted estimated 6.0% mRNA-positive women had been referred to colposcopy, PPV for CIN3+ would have been 4.2%. Cytology or p16/ki67 triage would decrease immediate referral to 1.7% and 2.0%, increasing PPV to 11.2% and 11.7%, respectively; total colposcopy referral would be 4.0% and 3.9%, respectively. As the primary screening test, the mRNA assay showed a positivity rate lower than that of HPV DNA, with a small number of CIN3+ missed. Triage with cytology or p16/ki67 would only marginally decrease overall colposcopy referral.

Birth cohorts vaccinated against human papillomavirus (HPV) are now entering cervical cancer screening. Assessment of (pre)cancer (CIN3+) risk is needed to assess the residual screening need in vaccinated women. We estimated the lifetime (screen‐detected) CIN3+ risk under five‐yearly primary HPV screening between age 30 and 60, using HPV genotyping and histology data of 21,287 women participating in a screening trial with two HPV‐based screening rounds, 5 years apart. The maximum follow‐up after an HPV‐positive test was 9 years. We re‐estimated the CIN3+ risk after projecting direct vaccine efficacy for the bivalent and the nonavalent HPV vaccines, assuming life‐long protection. The lifetime CIN3+ risk was 4.1% (95% confidence interval 3.5‐4.9) and declined by 53.5% and 70.5% after bivalent vaccination without and with cross‐protection, respectively, translating into a residual lifetime CIN3+ risk of 1.9% (1.4‐2.4) and 1.2% (0.9‐1.5). The CIN3+ risk declined by 88.5% after nonavalent vaccination, translating into a residual lifetime CIN3+ risk of 0.5% (0.2‐0.7). The latter risk increased to 1.6% when vaccine protection only lasted until the first screening round at age 30. Among HPV‐positive women with abnormal adjunct cytology, the nine‐year CIN3+ risk was 16.9% (8.7‐32.4) after nonavalent vaccination. In conclusion, HPV vaccination will lead to a strong decline in the lifetime CIN3+ risk and the remaining absolute CIN3+ risk will be very low. Primary HPV testing combined with adjunct cytology at five‐year intervals still seems feasible even after nonavalent vaccination, although unlikely to be cost‐effective. Our results support a de‐intensification of screening programs in settings with high vaccination coverage., What's new? Human papillomavirus (HPV)‐based screening and vaccination are key strategies for early detection and prevention of cervical intraepithelial neoplasia grade 3 and cancer (CIN3+). Here the authors estimated the lifetime screen‐detected CIN3+ risk expected under different HPV vaccination scenarios using a novel statistical, data‐driven approach that deals with multiple‐type HPV infections. The model estimated that the lifetime CIN3+ risks under five‐yearly primary HPV screening will become very low in vaccinated women, in particular when protection is life‐long and provided beyond genotypes 16 and 18. These CIN3+ risks are important when defining new extended screening intervals for vaccinated cohorts.

The aim of this study was to describe the compliance of the population-based cancer screening programmes in the European Union Member States to the invitation strategies enumerated in the European Guidelines and the impact of such strategies on the invitational coverage. Experts in screening programme monitoring from the respective countries provided data. Coverage by invitation was calculated as the proportion of individuals in the target age range receiving a screening invitation over the total number of annualized eligible population. The invitation strategies of 30 breasts, 25 cervical and 27 colorectal national or regional population-based screening programmes are described. Individual mail invitations are sent by 28 breasts, 20 cervical and 25 colorectal screening programmes. Faecal occult blood test kits are sent by post in 17 of the colorectal cancer screening programmes. The majority of programmes claimed to have a population registry, although some use health insurance data as the database for sending invitations. At least 95% invitation coverage was reached by 16 breast, six cervical and five colorectal screening programmes. Majority of the programmes comply with the invitation strategies enumerated in the European guidelines, although there is still scope for improvements. Coverage by invitation is below the desirable level in many population-based cancer screening programmes in European Union.

International variations in the prevalence of HPV infection derive from differences in sexual behaviors, which are also a key factor of the basic reproductive number (R0 ) of HPV infection in different populations. R0 affects the strength of herd protection and hence the impact of a vaccination program. Similar vaccination programs may therefore generate different levels of impact depending upon the population's pre-vaccination HPV prevalence. We used IARC's transmission model to estimate (i) the overall effectiveness of vaccination versus no vaccination in women aged 15-34 years measured as percent prevalence reduction (%PR) of HPV16 and (ii) the corresponding herd protection in populations with gender-equal or traditional sexual behavior and with different levels of sexual activity, corresponding to pre-vaccination HPV16 prevalence from 1 to 8% as observed worldwide. Between populations with different levels of gender-equal sexual activity, the highest difference in %PR under girls-only vaccination is observed at 40% coverage (91%PR vs. 48%PR for 1% and 8% pre-vaccination prevalence, respectively). HPV16 elimination is obtained with 55 and 97% coverage, respectively. To achieve desirable levels of HPV16 prevalence after vaccination, different levels of coverage are required in populations with different levels of pre-vaccination HPV16 prevalence, for example, in populations with gender-equal sexual behavior a decrease to 1/1000 HPV16 from pre-vaccination prevalence of 1 and 8% would require coverages of 37 and 96%, respectively. In traditional populations, corresponding coverages would need to be 28 and 93%, respectively. In conclusion, pre-vaccination HPV prevalence strongly influences herd immunity and helps predict the overall effectiveness of HPV vaccination.

Human papilloma virus (HPV) testing is more sensitive but less specific than cytology. We evaluated stand-alone genotyping as a possible triage method. During a multicentre randomised controlled trial comparing HPV testing to conventional cytology, HPV-positive women were referred to colposcopy and followed up if no high-grade lesion was detected. HPV-positive samples were genotyped by GP5+/GP6+ primed polymerase chain reaction followed by reverse line blot. Genotypes were hierarchically ordered by positive predictive value (PPV) for CIN grade 2 or more (CIN2+), and grouped by cluster analysis into three groups (A, B and C in decreasing order). Receiver operating characteristic curves were computed. Among 2,255 HPV-positive women with genotyping, 239 CIN2+ (including 113 CIN3+) were detected at baseline or during a 3-year follow-up. HPV33 had the highest PPV with CIN2+ and CIN3+ as the endpoint and when considering lesions detected at baseline or also during follow-up. HPV16 and HPV35 were the second and third, respectively. Cross-sectional sensitivity for CIN2+ at baseline was 67.3% (95% CI 59.7-74.2), 91.8% (95% CI 86.6-95.5) and 94.7% (95% CI 90.2-97.6), respectively, when considering as "positive" any of the HPV types in group A (33, 16 and 35), A or B (31, 52, 18, 59 and 58) and A or B or C (39, 51, 56, 45 and 68). The corresponding cross-sectional PPVs for CIN2+ were 15.8% 95% (CI 13.2-18.7), 12.0% (95% CI 10.3-13.9) and 9.6% (95% CI 8.2-11.1), respectively. HPV33, 16 and 35 confer a high probability of CIN2+ but this rapidly decreases when adding other genotypes.

Cervical cancer screening will rely, increasingly, on HPV testing as a primary screen. The requirement for triage tests which can delineate clinically significant infection is thus prescient. In this EUROGIN 2017 roadmap, justification behind the most evidenced triages is outlined, as are challenges for implementation. Cytology is the triage with the most follow-up data; the existence of an HR-HPV-positive, cytology-negative group presents a challenge and retesting intervals for this group (and choice of retest) require careful consideration. Furthermore, cytology relies on subjective skills and while adjunctive dual-staining with p16/Ki67 can mitigate inter-operator/-site disparities, clinician-taken samples are required. Comparatively, genotyping and methylation markers are objective and are applicable to self-taken samples, offering logistical advantages including in low and middle income settings. However, genotyping may have diminishing returns in immunised populations and type(s) included must balance absolute risk for disease to avoid low specificity. While viral and cellular methylation markers show promise, more prospective data are needed in addition to refinements in automation. Looking forward, systems that detect multiple targets concurrently such as next generation sequencing platforms will inform the development of triage tools. Additionally, multistep triage strategies may be beneficial provided they do not create complex, unmanageable pathways. Inevitably, the balance of risk to cost(s) will be key in decision making, although defining an acceptable risk will likely differ between settings. Finally, given the significant changes to cervical screening and the variety of triage strategies, appropriate education of both health care providers and the public is essential.

The role of non-coding RNAs in different biological processes and diseases is continuously expanding. Next-generation sequencing together with the parallel improvement of bioinformatics analyses allows the accurate detection and quantification of an increasing number of RNA species. With the aim of exploring new potential biomarkers for disease classification, a clear overview of the expression levels of common/unique small RNA species among different biospecimens is necessary. However, except for miRNAs in plasma, there are no substantial indications about the pattern of expression of various small RNAs in multiple specimens among healthy humans. By analysing small RNA-sequencing data from 243 samples, we have identified and compared the most abundantly and uniformly expressed miRNAs and non-miRNA species of comparable size with the library preparation in four different specimens (plasma exosomes, stool, urine, and cervical scrapes). Eleven miRNAs were commonly detected among all different specimens while 231 miRNAs were globally unique across them. Classification analysis using these miRNAs provided an accuracy of 99.6% to recognize the sample types. piRNAs and tRNAs were the most represented non-miRNA small RNAs detected in all specimen types that were analysed, particularly in urine samples. With the present data, the most uniformly expressed small RNAs in each sample type were also identified. A signature of small RNAs for each specimen could represent a reference gene set in validation studies by RT-qPCR. Overall, the data reported hereby provide an insight of the constitution of the human miRNome and of other small non-coding RNAs in various specimens of healthy individuals.

The second report on the implementation status of cancer screening in European Union (EU) was published in 2017. The report described the implementation status, protocols and organization (updated till 2016) and invitation coverage (for index year 2013) of breast, cervical and colorectal cancer screening in the EU. Experts in screening programme monitoring (N=80) from the EU Member States having access to requisite information in their respective countries provided data on breast, cervical and colorectal cancer screening through online questionnaires. Data was collected for screening performed in the framework of publicly mandated programmes only. Filled in questionnaires were received from 26 Member States for all three sites and from one Member State for breast cancer only. Substantial improvement in screening implementation using population-based approach was documented. Among the age-eligible women, 94.7% were residents of Member States implementing or planning population-based breast cancer screening in 2016, compared to 91.6% in 2007. The corresponding figures for cervical cancer screening were 72.3% and 51.3% in 2016 and 2007 respectively. Most significant improvement was documented for colorectal cancer screening with roll-out ongoing or completed in 17 Member States in 2016, compared to only five in 2007. So the access to population-based screening increased to 72.4% of the age-eligible populations in 2016 as opposed to only 42.6% in 2007. The invitation coverage was highly variable, ranging from 0.2%-111% for breast cancer, 7.6%-105% for cervical cancer and 1.8%-127% for colorectal cancer in the target populations. In spite of the considerable progress, much work remains to be done to achieve optimal effectiveness. Continued monitoring, regular feedbacks and periodic reporting are needed to ensure the desired impacts of the programmes. This article is protected by copyright. All rights reserved.

In Italy, the cohorts of women who were offered Human papillomavirus (HPV) vaccination in 2007/08 will reach the age (25years) for cervical cancer (CC) screening from 2017. The simultaneous shift from cytology-based screening to HPV test-based screening gives the opportunity for unprecedented reorganisation of CC prevention. The ONS (National Screening Monitoring Centre) Directive and the GISCi (Italian Group for Cervical Screening) identified the consensus conference as the most suitable method for addressing this topic. A summary of consensus recommendations is reported here. The main objective was to define the best screening methods in girls vaccinated against HPV and the knowledge required for defining evidence-based screening strategies. A Jury made recommendations about questions and proposals formulated by a panel of experts representative of Italian scientific societies involved in CC prevention and based on systematic reviews of literature and evidence. The Jury considered changing the screening protocols for girls vaccinated in their twelfth year as appropriate. Tailored screening protocols based on vaccination status could be replaced by "one size fits all" protocols only when a herd immunity effect has been reached. Vaccinated women should start screening at age 30, instead of 25, with HPV test. Furthermore, there is a strong rationale for applying longer intervals for re-screening HPV negative women than the currently recommended 5years, but research is needed to determine the optimal screening time points. For non-vaccinated women and for women vaccinated in their fifteenth year or later, the current protocol should be kept.

BACKGROUND The accumulation of cyclin-dependent kinase inhibitor 2A (p16ink4a) protein in a cell is associated with neoplastic progression in precancerous cervical lesions. Dual staining for p16ink4a and Ki-67 has been proposed as a triage test in cervical cancer screening for women who test positive for human papillomavirus DNA. In this study, interobserver reproducibility of the interpretation of this test was assessed. METHODS Forty-two immunostained, liquid-based cytology slides were divided into 2 sets and were interpreted by 17 to 21 readers from 9 different laboratories, yielding a total of 816 reports. Immunostaining results were classified as positive, negative, inconclusive, or inadequate. After evaluation of the first set of slides and before circulation of the second set, the results were discussed in a plenary meeting. The 10 slides with the most discordant results were evaluated again by selected expert cytopathologists. RESULTS The overall κ value was 0.612 (95% confidence interval [CI], 0.523-0.701), it was higher for the positive and negative categories (κ = 0.692 and κ = 0.641, respectively), and it was almost null for the inconclusive category (κ = 0.058). Considering only readers from laboratories with documented experience, the κ value was higher (κ = 0.747; 95% CI, 0.643-0.839) compared with nonexperienced centers (κ = 0.498; 95% CI, 0.388-0.616). The results were similar in both sets of slides (κ = 0.505 [95% CI, 0.358-0.642] and κ = 0.521 [95% CI, 0.240-0.698] for the first and second sets, respectively). Reinterpretation of the slides with the most discordant results did not provide any improvement (first evaluation, κ = 0.616 [95% CI, 0.384-0.866]; second evaluation, κ = 0.403 [95% CI, 0.182-0.643]). CONCLUSIONS Dual staining for p16 ink4a and Ki-67 demonstrated good reproducibility, confirming its robustness, which is a necessary prerequisite for its adoption as a triage test in cervical cancer screening programs that use human papillomavirus DNA as a primary test. Cancer Cytopathol 2017;125:212–220. © 2016 American Cancer Society.

Background The study presents cross-sectional accuracy of E6 and E7 (E6/E7) mRNA detection and p16/ki67 dual staining, alone or in combination with cytology and human papillomavirus (HPV)16/18 genotyping, as a triage test in HPV DNA-positive women and their impact on cervical intraepithelial neoplasia (CIN2+) overdiagnosis. Methods Women aged 25-64 years were recruited. HPV DNA-positive women were triaged with cytology and tested for E6/E7 mRNA and p16/ki67. Cytology positive women were referred to colposcopy, and negatives were randomly assigned to immediate colposcopy or to 1-year HPV retesting. Lesions found within 24 months since recruitment were included. All P values were 2-sided. Results 40 509 women were recruited, and 3147 (7.8%) tested HPV DNA positive; 174 CIN2+ were found: sensitivity was 61.0% (95% confidence interval [CI] = 53.6 to 68.0), 94.4% (95% CI = 89.1 to 97.3), and 75.2% (95% CI = 68.1 to 81.6) for cytology, E6/E7 mRNA, and p16/ki67, respectively. Immediate referral was 25.6%, 66.8%, and 28.3%, respectively. Overall referral was 65.3%, 78.3%, and 63.3%, respectively. Cytology or p16/ki67, when combined with HPV16/18 typing, reached higher sensitivity with a small impact on referral. Among the 2306 HPV DNA-positive and cytology-negative women, relative CIN2+ detection in those randomly assigned at 1-year retesting vs immediate colposcopy suggests a -28% CIN2+ regression (95% CI = -57% to +20%); regression was higher in E6/E7 mRNA-negatives (Pinteraction = .29). HPV clearance at 1 year in E6/E7 mRNA and in p16/ki67 negative women was about 2 times higher than in positive women (Pinteraction < .001 for both). Conclusions p16/ki67 showed good performance as a triage test. E6/E7 mRNA showed the highest sensitivity, at the price of too high a positivity rate to be efficient for triage. However, when negative, it showed a good prognostic value for clearance and CIN2+ regression.

The 2003 European Council recommendation urging the Member States to introduce or scale up breast, cervical and colorectal cancer screening through an organized population-based approach has had a remarkable impact. We argue that the recommendation needs to be updated for at least two sets of reasons. First, some of the current clinical guidelines include new tests or protocols that were not available at the time of the Council document. Some have already been adopted by organized screening programs, such as newly defined age ranges for mammography screening, Human Papillomavirus (HPV)-based cervical cancer screening, fecal immunochemical test (FIT) and sigmoidoscopy for colorectal cancer screening. Second, the outcomes of randomized trials evaluating screening for lung and prostate cancer have been published recently and the balance between harms and benefits needs to be pragmatically assessed. In the European Union, research collaboration and networking to exchange and develop best practices should be regularly supported by the European Commission. Integration between primary and secondary preventive strategies through comprehensive approaches is necessary not only to maximize the reduction in cancer burden but also to control the rising trend of other noncommunicable diseases sharing the same risk factors.

Objective To assess the 5-year risk of high-grade lesions in women with a transient high-risk HPV infection. Design Population-based cohort study. Setting HPV primary testing within population-based organised cervical cancer screening programmes. Population Italian women enrolled in seven pilot projects and attending the second round. Methods On the basis of the cytology triage performed on HPV-positive women, immediate colposcopy or HPV repeat at 12 months was recommended. Data were collected at the subsequent round 3-4 years after HPV infection clearance. Main outcome measures Rates of HPV infection, CIN2+ and CIN3+ detection at subsequent round after HPV clearance, and relative risks (RR) in comparison with HPV-negative women (with 95% confidence interval). Results Data on 1230 women (1027 aged 25-64 years and 203 aged 35-64 years) have been analysed. Overall compliance with repeat HPV testing was 84%. In comparison with HPV-negative women, those with a transient HPV infection had higher proportions of HPV positivity (15% versus 3.7%) and of CIN2+ lesions (0.87% versus 0.23%) in round two; most of these (7/10) were CIN2; no cancers were detected, and CIN3 occurred in 3/1230 (0.24%). Conclusions HPV-based protocols for cervical cancer screening allow long intervals for HPV-negative women; it is important to monitor the clinical outcome in the women with transient high-risk HPV infection. CIN3 detection is similar to that observed in routine European cytology-based screening programmes (CIN3+: 2.7‰); 5-year intervals may provide reasonable protection but longer intervals are not recommended. Tweetable abstract A screening interval of 5 years (but no longer) appears safe in women with transient HPV detection.

Nuclear grade is an important indicator of the biological behaviour of ductal carcinoma in situ (DCIS). De-escalation of treatment has been suggested for low-grade DCIS. Our aim is to estimate the relative rate of progression of DCIS by nuclear grade by analysing the distribution of nuclear grade by detection at initial or subsequent screening. We asked International Cancer Screening Network sites to complete, based on their screening and clinical databases, an aggregated data file on DCIS detection, diagnosis and treatment. Eleven screening programs reported 5068 screen-detected pure DCIS in nearly 7 million screening tests in women 50–69 years of age. For all programs combined, low-grade DCIS were 20.1% (range 11.4–31.8%) of graded DCIS, intermediate grade 31.0% and high grade 48.9%. Detection rates decreased more steeply from initial to subsequent screening in low compared to high-grade DCIS: the ratios of subsequent to initial detection rates were 0.39 for low grade, 0.51 for intermediate grade, and 0.75 for high grade (p

With the discovery that human papillomavirus (HPV) is the leading cause of cervical cancer development, it soon became clear that screening by HPV testing is much more sensitive, reproductive, and objective, but less specific for cervical cancer screening than cytology. To compensate for the lower specificity, triage tests for HPV positive women are needed. In this chapter we discuss the original studies underlining the evidence for the introduction of HPV-based screening. We highlight different collection techniques of cervicovaginal material for HPV and triage testing, including self-sampling, different triage tests to select HPV positive women for colposcopy referral, and describe developments, which may result into full molecular self-screening. Finally the implementation of HPV-based screening in some Western countries is highlighted.

In a project coordinated by the International Agency for Research on Cancer (IARC) 31 experts from 11 European countries and IARC have developed supplements to the current European guidelines for quality assurance in cervical cancer screening. The supplements take into account the potential of primary testing for human papillomavirus (HPV) and vaccination against HPV infection to improve cervical cancer prevention and control and will be published by the European Commission in book format. They include 62 recommendations or conclusions for which the strength of the evidence and the respective recommendations is graded. While acknowledging the available evidence for more efficacious screening using HPV primary testing compared to screening based on cytology, the authors and editors of the supplements emphasize that appropriate policy and programme organization remain essential to achieve an acceptable balance between benefit and harm of any screening or vaccination programme. A summary of the supplements and all of the graded recommendations are presented here in journal format to make key aspects of the updated and expanded guidelines known to a wider professional and scientific community. Keywords: Mass screening, Vaccination, Cervical neoplasms, Human papillomavirus, Evidence-based guidelines, Population-based programme

Background Invasive cervical cancer (ICC) is caused by high-risk human papillomavirus types (HR-HPVs) and is usually preceded by a long phase of intraepithelial neoplasia (CIN). Before invasion, (epi) genetic changes, potentially applicable as molecular markers within cervical screening, occur in HPV host cells. Epigenetic alterations, such as dysregulation of microRNA (miRNA) expression, are frequently observed in ICC. The mechanisms and role of miRNA dysregulation in cervical carcinogenesis are still largely unknown. Methods We provide an overview of the studies investigating miRNA expression in relation to ICC progression, highlighting their common outcomes and their weaknesses/strengths. To achieve this, we systematically searched through Pubmed database all articles between January 2010 and December 2017. Results From the 24 studies retrieved, miR-29a and miR-21 are the most frequently down- and up-regulated in ICC progression, respectively. Microarray-based studies show a small overlap, with miR-10a, miR-20b, miR-9, miR-16 and miR-106 found repeatedly dysregulated. miR-34a, miR-125 and miR-375 were also found dysregulated in cervical exfoliated cells in relation to cancer progression. Conclusions The pivotal role of miRNAs in ICC progression and initial development is becoming more and more relevant. Available studies are essentially based on convenience material, entailing possible selection bias, and frequently of small size: all these points still represent a limitation to a wide comprehension of miRNAs relevant for ICC. The targeted approach instead of a genome-wide investigation still precludes the identification of all the relevant miRNAs in the process. The implementation of deep sequencing on large scale population-based studies will help to discover and validate the relation between altered miRNA expression and CC progression for the identification of biomarkers. Optimally, once explored on a miRNome scale, small specific miRNA signatures maybe used in the context of screening. Electronic supplementary material The online version of this article (10.1186/s12885-018-4590-4) contains supplementary material, which is available to authorized users.

BACKGROUND The triage of human papillomavirus (HPV)-positive women is needed to avoid overreferral to colposcopy. p16INK4a immunostaining is an efficient triage method. p16INK4a/Ki-67 dual staining was introduced mainly to increase reproducibility and specificity compared with stand-alone p16INK4a staining. METHODS Within a pilot project, HPV-positive women were referred to colposcopy if cytology was abnormal or unsatisfactory or HPV testing was still positive after 1 year. For 500 consecutive women, a slide obtained during colposcopy was immunostained for p16INK4a/Ki-67 and independently interpreted by 7 readers without previous experience with dual staining. Four of these readers were experts in cervical pathology and 3 were not. Kappa values for multiple raters, sensitivity, and specificity for cervical intraepithelial neoplasia type 2-positive histology were computed. Because women with normal cytology were underrepresented, estimates for all HPV-positive women were obtained as weighted means of cytology-specific estimates. RESULTS The overall kappa for HPV-positive women was 0.70 (95% confidence interval [95% CI], 0.60-0.77). Kappa values were not found to be significantly different between expert and nonexpert readers with regard to cervical cytology but were significantly increased (P =. 0066) after consensus discussion. The overall specificity estimate for HPV-positive women was 64.0% (95% CI, 57.4%-70.2%): 66.7% (95% CI, 59.8%-73.0%) for experts and 60.5% (95% CI, 59.8%-73.0%) for nonexperts. Among women with abnormal cytology, the sensitivity was 85.5% (95% CI, 77.9%-90.8%): 85.8% (95% CI, 77.9%-91.2%) for experts and 85.1% (95% CI, 76.6%-90.9%) for nonexperts. CONCLUSIONS p16INK4a/Ki-67 immunostaining demonstrated good reproducibility and specificity when triaging HPV-positive women. Dual-staining interpretation can be performed, after short training, even by staff who are not experts in cervical cytology. This allows HPV-based screening with triage to be performed in settings in which such expert staff is not available. Cancer (Cancer Cytopathol) 2015;123:212–218. © 2014 American Cancer Society.

International variations in the prevalence of HPV infection derive from differences in sexual behaviors, which are also a key factor of the basic reproductive number (R0) of HPV infection in different populations. R 0 affects the strength of herd protection and hence the impact of a vaccination program. Similar vaccination programs may therefore generate different levels of impact depending upon the population's pre‐vaccination HPV prevalence. We used IARC's transmission model to estimate (i) the overall effectiveness of vaccination versus no vaccination in women aged 15–34 years measured as percent prevalence reduction (%PR) of HPV16 and (ii) the corresponding herd protection in populations with gender‐equal or traditional sexual behavior and with different levels of sexual activity, corresponding to pre‐vaccination HPV16 prevalence from 1 to 8% as observed worldwide. Between populations with different levels of gender‐equal sexual activity, the highest difference in %PR under girls‐only vaccination is observed at 40% coverage (91%PR vs. 48%PR for 1% and 8% pre‐vaccination prevalence, respectively). HPV16 elimination is obtained with 55 and 97% coverage, respectively. To achieve desirable levels of HPV16 prevalence after vaccination, different levels of coverage are required in populations with different levels of pre‐vaccination HPV16 prevalence, for example, in populations with gender‐equal sexual behavior a decrease to 1/1000 HPV16 from pre‐vaccination prevalence of 1 and 8% would require coverages of 37 and 96%, respectively. In traditional populations, corresponding coverages would need to be 28 and 93%, respectively. In conclusion, pre‐vaccination HPV prevalence strongly influences herd immunity and helps predict the overall effectiveness of HPV vaccination., What's new? Differences in sexual activity from one population to another account for up to a ten‐fold difference in HPV prevalence, which in turn affects cervical‐cancer risk. How do these factors impact the effectiveness of HPV‐vaccination programs? In this epidemiological study, the authors found that, in countries where sexual behavior is based on traditional norms and HPV prevalence remains low, an early introduction of HPV vaccination will anticipate any increase of HPV prevalence among young women due to the liberalization of social attitudes.

Cervical cancer screening will rely, increasingly, on HPV testing as a primary screen. The requirement for triage tests which can delineate clinically significant infection is thus prescient. In this EUROGIN 2017 roadmap, justification behind the most evidenced triages is outlined, as are challenges for implementation. Cytology is the triage with the most follow-up data; the existence of an HR-HPV-positive, cytology-negative group presents a challenge and retesting intervals for this group (and choice of retest) require careful consideration. Furthermore, cytology relies on subjective skills and while adjunctive dual-staining with p16/Ki67 can mitigate inter-operator/-site disparities, clinician-taken samples are required. Comparatively, genotyping and methylation markers are objective and are applicable to self-taken samples, offering logistical advantages including in low and middle income settings. However, genotyping may have diminishing returns in immunised populations and type(s) included must balance absolute risk for disease to avoid low specificity. While viral and cellular methylation markers show promise, more prospective data are needed in addition to refinements in automation. Looking forward, systems that detect multiple targets concurrently such as next generation sequencing platforms will inform the development of triage tools. Additionally, multistep triage strategies may be beneficial provided they do not create complex, unmanageable pathways. Inevitably, the balance of risk to cost(s) will be key in decision making, although defining an acceptable risk will likely differ between settings. Finally, given the significant changes to cervical screening and the variety of triage strategies, appropriate education of both health care providers and the public is essential.

Human papilloma virus (HPV) testing is more sensitive but less specific than cytology. We evaluated stand‐alone genotyping as a possible triage method. During a multicentre randomised controlled trial comparing HPV testing to conventional cytology, HPV‐positive women were referred to colposcopy and followed up if no high‐grade lesion was detected. HPV‐positive samples were genotyped by GP5+/GP6+ primed polymerase chain reaction followed by reverse line blot. Genotypes were hierarchically ordered by positive predictive value (PPV) for CIN grade 2 or more (CIN2+), and grouped by cluster analysis into three groups (A, B and C in decreasing order). Receiver operating characteristic curves were computed. Among 2,255 HPV‐positive women with genotyping, 239 CIN2+ (including 113 CIN3+) were detected at baseline or during a 3‐year follow‐up. HPV33 had the highest PPV with CIN2+ and CIN3+ as the endpoint and when considering lesions detected at baseline or also during follow‐up. HPV16 and HPV35 were the second and third, respectively. Cross‐sectional sensitivity for CIN2+ at baseline was 67.3% (95% CI 59.7–74.2), 91.8% (95% CI 86.6–95.5) and 94.7% (95% CI 90.2–97.6), respectively, when considering as “positive” any of the HPV types in group A (33, 16 and 35), A or B (31, 52, 18, 59 and 58) and A or B or C (39, 51, 56, 45 and 68). The corresponding cross‐sectional PPVs for CIN2+ were 15.8% 95% (CI 13.2–18.7), 12.0% (95% CI 10.3–13.9) and 9.6% (95% CI 8.2–11.1), respectively. HPV33, 16 and 35 confer a high probability of CIN2+ but this rapidly decreases when adding other genotypes., What's new? The Human papilloma virus (HPV) infection genotype is an early predictor of cervical lesions. The current focus lies on high‐risk genotypes 16 and 18, frequently found in cancers. Here the authors studied the predictive value of all carcinogenic types and identified infections with HPV16, but also HPV33 and 35, as conferring very high risk for the development of high‐grade cervical intraepithelial neoplasia (CIN2+). However, HPV genotyping alone did not reliably triage women, and combinations with other methods are recommended.

The identification of some types of human papillomavirus (HPV) as necessary, but not sufficient, cause of cervical cancer has suggested the use of HPV testing in cervical cancer prevention. A large number of studies has provided evidence supporting its application (1) as primary screening test, (2) for triaging borderline cytology, (3) for follow-up after positive primary test but no abnormal histology and (4) as a test of cure. They also allowed a reasonably good definition of the appropriate policies and protocols, leading to the delivery of evidence-based guidelines resulting from a systematic review of the literature. In this chapter, we present a critical analysis of the recommendations of the main European and North American guidelines relative to industrialised countries.

The second report on the implementation status of cancer screening in European Union (EU) was published in 2017. The report described the implementation status, protocols and organization (updated till 2016) and invitation coverage (for index year 2013) of breast, cervical and colorectal cancer screening in the EU. Experts in screening programme monitoring (N = 80) from the EU Member States having access to requisite information in their respective countries provided data on breast, cervical and colorectal cancer screening through online questionnaires. Data was collected for screening performed in the framework of publicly mandated programmes only. Filled in questionnaires were received from 26 Member States for all three sites and from one Member State for breast cancer only. Substantial improvement in screening implementation using population-based approach was documented. Among the age-eligible women, 94.7% were residents of Member States implementing or planning population-based breast cancer screening in 2016, compared to 91.6% in 2007. The corresponding figures for cervical cancer screening were 72.3 and 51.3% in 2016 and 2007, respectively. Most significant improvement was documented for colorectal cancer screening with roll-out ongoing or completed in 17 Member States in 2016, compared to only five in 2007. So the access to population-based screening increased to 72.4% of the age-eligible populations in 2016 as opposed to only 42.6% in 2007. The invitation coverage was highly variable, ranging from 0.2-111% for breast cancer, 7.6-105% for cervical cancer and 1.8-127% for colorectal cancer in the target populations. In spite of the considerable progress, much work remains to be done to achieve optimal effectiveness. Continued monitoring, regular feedbacks and periodic reporting are needed to ensure the desired impacts of the programmes.

Cervical cancer screening by human papillomavirus (HPV) DNA testing with cytology triage is more effective than cytology testing. Compared to cytology, the HPV DNA test's higher sensitivity, which allows better protection with longer intervals, makes it necessary to triage the women with a positive result to compensate its lower specificity. We are conducting a large randomized clinical trial (New Technologies for Cervical Cancer 2 [NTCC2]) within organized population-based screening programs in Italy using HPV DNA as the primary screening test to evaluate, by the Aptima HPV assay (Hologic), the use of HPV E6-E7 mRNA in a triage test in comparison to cytology. By the end of June 2016, data were available for 35,877 of 38,535 enrolled women, 2,651 (7.4%) of whom were HPV DNA positive. Among the samples obtained, 2,453 samples were tested also by Aptima, and 1,649 (67.2%) gave a positive result. The proportion of mRNA positivity was slightly higher among samples tested for HPV DNA by the Cobas 4800 HPV assay (Roche) than by the Hybrid Capture 2 (HC2) assay (Qiagen). In our setting, the observed E6-E7 mRNA positivity rate, if used as a triage test, would bring a rate of immediate referral to colposcopy of about 4 to 5%. This value is higher than that observed with cytology triage for both immediate and delayed referrals to colposcopy. By showing only a very high sensitivity and thus allowing a longer interval for HPV DNA-positive/HPV mRNA-negative women, a triage by this test might be more efficient than by cytology.

Summary The level of coverage and type-specific vaccine efficacy necessary to reduce or eliminate carcinogenic human papillomavirus (HPV) is chiefly determined by their propensity to persist. Therefore, HPV-16 infection and related cancers are the most difficult to eliminate through vaccination., Background Human papillomavirus (HPV) vaccination is still not reaching many high-risk populations. HPV16/18 vaccines offer cross-protection against other types, for example, HPV45. Both direct vaccine efficacy and indirect herd protection contribute to vaccination effectiveness. Methods We used a dynamic transmission model, calibrated to cervical screening data from Italy, to estimate vaccination effectiveness against HPV16 and HPV45 infection, assuming for HPV45 either 95% or lower cross-protection. Results Basic reproductive number was smaller (2.1 vs 4.0) and hence vaccine effectiveness and herd protection stronger for HPV45 than for HPV16. The largest difference in the reduction of infection prevalence in women

Cervical cancer screening test performance has been hampered by either lack of sensitivity of Pap cytology or lack of specificity of Human Papillomavirus (HPV) testing. This uncertainty can lead to unnecessary referral and treatment, which is disturbing for patients and increases costs for health care providers. The identification of p16(INK4a) as a marker for neoplastic transformation of cervical squamous epithelial cells by HPVs allows the identification of HPV-transformed cells in histopathology or cytopathology specimens. Diagnostic studies have demonstrated that the use of p16(INK4a) immunohistochemistry substantially improves the reproducibility and diagnostic accuracy of histopathologic diagnoses. p16(INK4a) cytology has substantially higher sensitivity for detection of cervical precancer in comparison to conventional Pap tests. Compared to HPV DNA tests, immunochemical detection of p16(INK4a) -stained cells demonstrates a significantly improved specificity with remarkably good sensitivity. About 15 years after the initial observation that p16(INK4a) is overexpressed in HPV-transformed cells we review the accumulated clinical evidence suggesting that p16(INK4a) can serve as a useful biomarker in the routine diagnostic work up of patients with HPV infections and associated lesions of the female anogenital tract.

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. Methods: 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. Findings: 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). Interpretation: 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. Funding: European Union, Belgian Foundation Against Cancer, KCE-Centre d'Expertise, IARC, The Netherlands Organisation for Health Research and Development, the Italian Ministry of Health.

Infection with human papillomavirus (HPV) is recognized as one of the major causes of infection-related cancer worldwide, as well as the causal factor in other diseases. Strong evidence for a causal etiology with HPV has been stated by the International Agency for Research on Cancer for cancers of the cervix uteri, penis, vulva, vagina, anus and oropharynx (including base of the tongue and tonsils). Of the estimated 12.7 million new cancers occurring in 2008 worldwide, 4.8% were attributable to HPV infection, with substantially higher incidence and mortality rates seen in developing versus developed countries. In recent years, we have gained tremendous knowledge about HPVs and their interactions with host cells, tissues and the immune system; have validated and implemented strategies for safe and efficacious prophylactic vaccination against HPV infections; have developed increasingly sensitive and specific molecular diagnostic tools for HPV detection for use in cervical cancer screening; and have substantially increased global awareness of HPV and its many associated diseases in women, men, and children. While these achievements exemplify the success of biomedical research in generating important public health interventions, they also generate new and daunting challenges: costs of HPV prevention and medical care, the implementation of what is technically possible, socio-political resistance to prevention opportunities, and the very wide ranges of national economic capabilities and health care systems. Gains and challenges faced in the quest for comprehensive control of HPV infection and HPV-related cancers and other disease are summarized in this review. The information presented may be viewed in terms of a reframed paradigm of prevention of cervical cancer and other HPV-related diseases that will include strategic combinations of at least four major components: 1) routine introduction of HPV vaccines to women in all countries, 2) extension and simplification of existing screening programs using HPV-based technology, 3) extension of adapted screening programs to developing populations, and 4) consideration of the broader spectrum of cancers and other diseases preventable by HPV vaccination in women, as well as in men. Despite the huge advances already achieved, there must be ongoing efforts including international advocacy to achieve widespread-optimally universal-implementation of HPV prevention strategies in both developed and developing countries. This article summarizes information from the chapters presented in a special ICO Monograph 'Comprehensive Control of HPV Infections and Related Diseases' Vaccine Volume 30, Supplement 5, 2012. Additional details on each subtopic and full information regarding the supporting literature references may be found in the original chapters. (C) 2013 Elsevier Ltd. All rights reserved.

Human papillomavirus (HPV) vaccination of a birth cohort of girls in the 9-13 age range is recommended as a priority, but decreases in HPV vaccine cost may make catch-up of a few additional cohorts more attractive not only in high-income countries. We assessed the reduction in HPV16 and 18 infections that could be achieved in a medium- (Poland) and a low-income (Guinea) country by adding one-time catch-up of 12- to 19-year-old girls to the vaccination of 11-year-old girls. According to our ad hoc adapted dynamic model of HPV infection transmission, the addition of catch-up was estimated to bring forward the 50% reduction of HPV16/18 prevalence due to vaccination in women ≤35 by as much as 5 years. Catch-up of 12- to 15-year olds reduced the cumulative probability of HPV16/18 infections by age 35 in the relevant cohorts by about 30% in both countries. Catch-up of 16- to 19-year-old girls added little. Regardless of the chosen catch-up strategy, 16 to 20% of HPV16/18 prevention from vaccination was attributable to herd immunity. Assuming a sufficiently low vaccine cost, the addition of a catch-up round is, therefore, worth considering in medium/low-income countries to extend vaccine benefits to less young adolescent girls whose future access to cervical screening is uncertain.

The identification of HPV as the cause of cervical cancer has changed the information required for surveillance. HPV prevalence and screening uptake worldwide are now necessary to describe the epidemiology of this cancer. In low-income countries cervical cancer incidence varies from low to very high levels and is strongly influenced by virus prevalence. In high-income countries, instead, incidence is low and little influenced by the virus prevalence, thanks to screening. The European Guidelines currently recommend Pap test every 3-5 years starting at age 22-30 and stopping at age 60-65. HPV testing is now limited to triage of borderline lesions? and to post-CIN follow up. Pilot studies evaluating HPV testing as primary test are recommended. Future governmental agency Guidelines in Europe will probably include HPV testing as viable for primary screening, with cytology triage for HPV-positive women (those positive to cytology will be directly referred to colposcopy, those negative will repeat HPV at one year. Persistence of HPV positivity will refer to colposcopy directly, clearance to regular screening). The interval after an HPV-negative test should be at least 5 years and starting age should be age 30/35. Pap test is still recommended for women under 30.

Cervical cancer screening underutilisation is documented among immigrants from poor countries and it is associated to an augmented risk for severe lesions. In a cohort of 1,410,364 Italian women and 200,491 immigrants from poor countries differences in screening participation and results were investigated. Participation rate was lower for immigrants than for Italians: 43.98% versus 48.59% (chi(1): p0.001). This gap increased with age (ptrend0.0001). Some socio-demographic factors negatively influenced immigrants' participation. Illiteracy (OR=0.75) versus secondary school, being single (OR=0.71) versus attached, first screens (OR=0.67) versus subsequent ones. Although the interaction between educational and professional levels showed that graduated immigrant women conducting an intellectual job have a higher inclination towards screening than their Italian peers (OR=1.43 vs OR=1.04). The Standardised Detection Ratio (SDR) suggested a frequency of severe lesions nearly double among immigrants in first screens (SDR=1.94; 95% CI: 1.82-2.08) and even higher (SDR=2.53; 95% CI: 2.35-2.73) for Central/Eastern Europeans. Multi-component interventions involving both patients and providers offer the greatest potential to increase cervical cancer screening uptake within foreign-born populations. So immigrant-specific interventions are needed for some immigrant groups, like Central/Eastern Europeans who are at higher risk of cervical lesions and, together with Asians and Africans, showed a poor attitude towards cancer prevention.

The accumulation of cyclin-dependent kinase inhibitor 2A (p16Forty-two immunostained, liquid-based cytology slides were divided into 2 sets and were interpreted by 17 to 21 readers from 9 different laboratories, yielding a total of 816 reports. Immunostaining results were classified as positive, negative, inconclusive, or inadequate. After evaluation of the first set of slides and before circulation of the second set, the results were discussed in a plenary meeting. The 10 slides with the most discordant results were evaluated again by selected expert cytopathologists.The overall κ value was 0.612 (95% confidence interval [CI], 0.523-0.701), it was higher for the positive and negative categories (κ = 0.692 and κ = 0.641, respectively), and it was almost null for the inconclusive category (κ = 0.058). Considering only readers from laboratories with documented experience, the κ value was higher (κ = 0.747; 95% CI, 0.643-0.839) compared with nonexperienced centers (κ = 0.498; 95% CI, 0.388-0.616). The results were similar in both sets of slides (κ = 0.505 [95% CI, 0.358-0.642] and κ = 0.521 [95% CI, 0.240-0.698] for the first and second sets, respectively). Reinterpretation of the slides with the most discordant results did not provide any improvement (first evaluation, κ = 0.616 [95% CI, 0.384-0.866]; second evaluation, κ = 0.403 [95% CI, 0.182-0.643]).Dual staining for p16

Human papillomavirus (HPV)-related screening technologies and HPV vaccination offer enormous potential for cancer prevention, notably prevention of cervical cancer. The effectiveness of these approaches is, however, suboptimal owing to limited implementation of screening programmes and restricted indications for HPV vaccination. Trials of HPV vaccination in women aged up to 55 years have shown almost 90% protection from cervical precancer caused by HPV16/18 among HPV16/18-DNA-negative women. We propose extending routine vaccination programmes to women of up to 30 years of age (and to the 45-50-year age groups in some settings), paired with at least one HPV-screening test at age 30 years or older. Expanding the indications for HPV vaccination and much greater use of HPV testing in screening programmes has the potential to accelerate the decline in cervical cancer incidence. Such a combined protocol would represent an attractive approach for many health-care systems, in particular, countries in Central and Eastern Europe, Latin America, Asia, and some more-developed parts of Africa. The role of vaccination in women aged >30 years and the optimal number of HPV-screening tests required in vaccinated women remain important research issues. Cost-effectiveness models will help determine the optimal combination of HPV vaccination and screening in public health programmes, and to estimate the effects of such approaches in different populations.

The EUROGIN 2011 roadmap reviews the current burden of human papillomavirus (HPV)-related morbidity, as well as the evidence and potential practice recommendations regarding primary and secondary prevention and treatment of cancers and other disease associated with HPV infection. HPV infection causes ~600,000 cases of cancer of the cervix, vulva, vagina, anus and oropharynx annually, as well as benign diseases such as genital warts and recurrent respiratory papillomatosis. Whereas the incidence of cervical cancer has been decreasing over recent decades, the incidence of anal and oropharyngeal carcinoma, for which there are no effective screening programs, has been rising over the last couple of decades. Randomized trials have demonstrated improved efficacy of HPV-based compared to cytology-based cervical cancer screening. Defining the best algorithms to triage HPV-positive women, age ranges and screening intervals are priorities for pooled analyses and further research, whereas feasibility questions can be addressed through screening programs. HPV vaccination will reduce the burden of cervical precancer and probably also of invasive cervical and other HPV-related disease in women. Recent trials demonstrated that prophylactic vaccination also protects against anogenital HPV infection, anogenital intraepithelial lesions and warts associated with vaccine types, in males; and anal HPV infection and anal intraepithelial neoplasia in MSM. HPV-related oropharyngeal cancer could be treated less aggressively because of better survival compared to cancers of the oropharynx unrelated to HPV. Key findings in the field of cervical cancer prevention should now be translated in cost-effective strategies, following an organized approach integrating primary and secondary prevention, according to scientific evidence but adapted to the local situation with particular attention to regions with the highest burden of disease.

The EUROGIN 2010 roadmap represents a continuing effort to provide and interpret updated information on cervical cancer screening and vaccination against the cause of the disease, high-risk human papillomavirus (HPV). Contrary to the two previous reports in 2008 and 2009, the present roadmap gives equal room to HPV-based screening and HPV vaccination, as a result of the recent strengthening of the evidence on the efficacy and feasibility of both approaches. The superiority of HPV testing in primary screening compared to cytology (in more developed countries) and to cytology or visual inspection methods (in less developed countries) has been demonstrated in several randomised trials. High vaccine efficacy has been confirmed up to 7 years after vaccination; school-based programmes in some countries have been able to reach over 70% coverage among adolescent girls. Demonstration projects have indicated that the delivery of HPV vaccines in less developed countries is feasible and favourably received by populations where cervical cancer is very common. HPV-based screening can diminish cervical cancer incidence more quickly than HPV vaccination, but vaccination can eventually facilitate screening efforts, especially if new vaccines against a greater number of HPV types are introduced. The availability of two highly complementary prevention tools such as HPV testing and HPV vaccination makes it possible to conceive integrated strategies for the elimination of cervical cancer that have no precedent in the cancer field. HPV tests and HPV vaccines remain, however, too expensive, and large-scale financing of screening and vaccination in less developed countries is sorely lacking.

A model representing carcinogenic HPV infection transmission dynamics and cervical cancer natural history was adapted to assess the consequences of introducing vaccination against HPV-16 infection. Alternative scenarios either allowing repeated infections with the HPV-16 (i.e. SIS scenario) or assuming that clearance of infection occurs through the development of a long lasting, specific immune response which protects against re-infection (i.e. SIR scenario) were investigated. The difference in reduction in lifetime cervical cancer achieved through vaccination of 12-year-old girls, between SIS and SIR scenarios, was up to 25% of expected cases in an unscreened population. This difference increased to 30% when vaccination of 12-year-old boys was also included as an intervention. The role of SIS or SIR dynamics should be accounted for in the assessment of model-based projections of the effectiveness of vaccination programmes, until available data about the transmission dynamics support the accuracy of model predictions.

Please cite this paper as: Castle P, Bulten J, Confortini M, Klinkhamer P, Pellegrini A, Siebers A, Ronco G, Arbyn M. Age-specific patterns of unsatisfactory results for conventional Pap smears and liquid-based cytology: data from two randomised clinical trials. BJOG 2010;117:1067–1073. Objective To investigate the rate of unsatisfactory cervical cell samples in liquid-based cytology (LBC) versus conventional cytology (CC) by age. Design Randomised clinical trials. Setting Population-based cervical cancer screening in the Netherlands and Italy. Population Asymptomatic women invited for screening enrolled in two randomised trials: Netherlands ThinPrep® versus conventional cytology (NETHCON; 39 010 CC, 46 064 LBC) and New Technologies in Cervical Cancer Screening (NTCC; 22 771 CC, 22 403 LBC). Methods Comparison of categorical variables using Pearson’s chi-square test, logistic regression and trend tests. Main outcome measures Proportion of unsatisfactory samples, ratio of LBC versus CC, and variation by 5-year group. Results In NETHCON, a lower percentage of LBC samples were judged to be unsatisfactory compared with CC samples (0.33 versus 1.11%). There was no significant trend in unsatisfactory results by age group for conventional cytology (Ptrend = 0.54), but there was a trend towards an increasing percentage of unsatisfactory results with increasing age for LBC (Ptrend

BACKGROUND: In the New Technologies for Cervical Cancer Screening (NTCC) randomized controlled trial, no significant increase in the sensitivity of liquid-based cytology (LBC) was observed compared with conventional cytology. Both were interpreted by cytologists who had limited previous LBC experience. The objective of the current study was to assess whether different results could be expected with experienced LBC interpreters. METHODS: A stratified, random sample of 818 LBC slides from the NTCC study was obtained. These slides were reviewed blindly and independently by 3 international experts who did not participate in the NTCC. The sensitivity and specificity of external experts were estimated for cervical intraepithelial neoplasia grade 2 or greater (CIN2+) and for CIN3+ histology, and the differences were compared with the sensitivity and specificity of the original cytologic interpretation using cutoffs of atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LSIL). RESULTS: With the endpoint of CIN2+ histology, the difference in sensitivity between external experts and the original interpretation was −5.3 (95% confidence interval [CI], −16.0 to 5.4) with ASCUS as the cutoff and 3.8 (95% CI, −8.2 to 15.8) with LSIL as the cutoff. External experts had slightly lower specificity using ASCUS as the cutoff (−3.4; 95% CI, −3.9 to −2.9) and LSIL as the cutoff (−0.7; 95% CI, −1.0 to −0.4). CONCLUSIONS: The accuracy of the external experts' interpretation was similar to that of the original interpretation. Therefore, the current results indicated that LBC is not expected to increase sensitivity even if it is used by interpreters who have extensive experience with this technique. Cancer (Cancer Cytopathol) 2010. © 2010 American Cancer Society.