Performance of HPV E6/E7 mRNA assay as primary screening test: Results from the NTCC2 trial.

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 for

Estimating the direct effect of human papillomavirus vaccination on the lifetime risk of screen-detected cervical precancer.

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.

Combined use of cytology, p16 immunostaining and genotyping for triage of women positive for high-risk human papillomavirus at primary screening.

Human papillomavirus (HPV) testing is very sensitive for primary cervical screening but has low specificity. Triage tests that improve specificity but maintain high sensitivity are needed. Women enrolled in the experimental arm of Phase 2 of the New Technologies for Cervical Cancer randomized controlled cervical screening trial were tested for high-risk HPV (hrHPV) and referred to colposcopy if positive. hrHPV-positive women also had HPV genotyping (by polymerase chain reaction with GP5+/GP6+ primers and reverse line blotting), immunostaining for p16 overexpression and cytology. We computed sensitivity, specificity and positive predictive value (PPV) for different combinations of tests and determined potential hierarchical ordering of triage tests. A number of 1,091 HPV-positive women had valid tests for cytology, p16 and genotyping. Ninety-two of them had cervical intraepithelial neoplasia grade 2+ (CIN2+) histology and 40 of them had CIN grade 3+ (CIN3+) histology. The PPV for CIN2+ was >10% in hrHPV-positive women with positive high-grade squamous intraepithelial lesion (61.3%), positive low-grade squamous intraepithelial lesion (LSIL+) (18.3%) and positive atypical squamous cells of undetermined significance (14.8%) cytology, p16 positive (16.7%) and, hierarchically, for infections by HPV33, 16, 35, 59, 31 and 52 (in decreasing order). Referral of women positive for either p16 or LSIL+ cytology had 97.8% sensitivity for CIN2+ and women negative for both of these had a 3-year CIN3+ risk of 0.2%. Similar results were seen for women being either p16 or HPV16/33 positive. hrHPV-positive women who were negative for p16 and cytology (LSIL threshold) had a very low CIN3+ rate in the following 3 years. Recalling them after that interval and referring those positive for either test to immediate colposcopy seem to be an efficient triage strategy. The same applies to p16 and HPV16.

Key issues that need to be considered while revising the current annex of the European Council Recommendation (2003) on cancer screening.

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.

Low-grade screen-detected ductal carcinoma in situ progresses more slowly than high-grade lesions: evidence from an international multi-centre study.

PURPOSE: 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. METHODS: 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. RESULTS: 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 < 0.001). CONCLUSIONS: These results suggest that the duration of the preclinical detectable phase is longer for low than for high-grade DCIS. The findings from this large multi-centre, international study emphasize that the management of low-grade DCIS should be carefully scrutinized in order to minimize overtreatment of screen-detected slow-growing or indolent lesions. The high variation by site in the proportion of low grade suggests that further pathology standardization and training would be beneficial.

Impacts of human papillomavirus vaccination for different populations: A modeling study.

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.

Eurogin roadmap 2017: Triage strategies for the management of HPV-positive women in cervical screening programs.

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.

Status of implementation and organization of cancer screening in The European Union Member States-Summary results from the second European screening report.

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.

Human papilloma virus genotyping for the cross-sectional and longitudinal probability of developing cervical intraepithelial neoplasia grade 2 or more.

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.

MicroRNAs as markers of progression in cervical cancer: a systematic review.

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.

Different Challenges in Eliminating HPV16 Compared to Other Types: A Modeling Study.

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 <35 years old was found at 70% coverage in girls-only vaccination programs (99% vs 83% for total protection for HPV45 and HPV16, respectively, mainly owing to stronger herd protection, ie, 37% vs 16%). In gender-neutral vaccination, the largest difference was at 40% coverage (herd protection, 54% vs 28% for HPV16 and HPV45, respectively). With ≥80% coverage, even 50% cross-protection would reduce HPV45 by ≥94%. Conclusions: The characteristics of individual high-risk HPV types strongly influence herd protection and determine the level of coverage and cross-protection required to reduce or eliminate the infection through HPV vaccination. HPV16 infection and related cancers are the most difficult to eliminate.

Determinants of Viral Oncogene E6-E7 mRNA Overexpression in a Population-Based Large Sample of Women Infected by High-Risk Human Papillomavirus Types.

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.

Cervical cancer screening in women vaccinated against human papillomavirus infection: Recommendations from a consensus conference.

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.

[Implementation of DNA-HPV primary screening in Italian cervical cancer screening programmes. Results of the MIDDIR Project]. / L'implementazione del DNA-HPV come test primario nei programmi italiani di screening del cervicocarcinoma. Risultati del Progetto MIDDIR.

OBJECTIVES: to obtain data on conversion paths to HPV testing as part of screening programmes and to harmonize the introduction of HPV testing in primary cervical cancer screening protocols of Italian programmes. DESIGN: survey by questionnaire on strategies adopted by screening programmes for transition to primary HPV testing; systematic review of the literature; discussion among experts. SETTING AND PARTICIPANT S: managers of Italian Regions' cervical cancer screening programmes. MAIN OUTCOME MEASURES: transition planning; activity volumes; modalities of centralization; criteria for dismissal; staff training; communication initiatives. RESULTS: nine cervical screening programmes responded to the survey. Most of them chose to schedule a transition of a few years to allow for adjustment of the volume of activity in the passage from the three-year screening interval to the five-year one. To select women to be given precedence, 7 programmes use the age, starting from the oldest. The liquid base is the choice by far preferred both for HPV test and for Pap test. The reading of HPV test "born" already centralized, but a centralization process is in place also for cytology. CONCLUSIONS: the survey on conversion strategies to primary HPV testing showed the opportunity to schedule a transition phase. For HPV test, cost, organization, and quality benefits of centralization are clear, thus the central organization should be preferred and managed immediately. Moreover, the need for a centralization of cytology is evident. The tariff scheme should be based on the whole process rather than on single performances. Dismissal strategies have to be tailored on peculiarities of single services, but some typologies can be outlined.

The clinical impact of using p16(INK4a) immunochemistry in cervical histopathology and cytology: an update of recent developments.

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.

Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials.

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 10(5) (1·1-12·1) and 8·7 per 10(5) (3·3-18·6) at 3·5 and 5·5 years, respectively, in the experimental arm, and 15·4 per 10(5) (7·9-27·0) and 36·0 per 10(5) (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.

Changes in cervical cancer incidence following the introduction of organized screening in Italy.

OBJECTIVE: To quantify the impact of organized cervical screening programs (OCSPs) on the incidence of invasive cervical cancer (ICC), comparing rates before and after activation of OCSPs. METHODS: This population-based investigation, using individual data from cancer registries and OCSPs, included 3557 women diagnosed with ICC at age 25-74years in 1995-2008. The year of full-activation of each OCSP was defined as the year when at least 40% of target women had been invited. Incidence rate ratios (IRRs) with 95% confidence intervals (95% CIs) were calculated as the ratios between age-standardized incidence rates observed in periods after full-activation of OCSPs vs those observed in the preceding quinquennium. RESULTS: ICC incidence rates diminished with time since OCSPs full-activation: after 6-8years, the IRR was 0.75 (95% CI: 0.67-0.85). The reduction was higher for stages IB-IV (IRR=0.68, 95% CI: 0.58-0.80), squamous cell ICCs (IRR=0.74, 95% CI: 0.64-0.84), and particularly evident among women aged 45-74years. Conversely, incidence rates of micro-invasive (stage IA) ICCs increased, though not significantly, among women aged 25-44years (IRR=1.34, 95% CI: 0.91-1.96). Following full-activation of OCSPs, micro-invasive ICCs were mainly and increasingly diagnosed within OCSPs (up to 72%). CONCLUSION(S): Within few years from activation, organized screening positively impacted the already low ICC incidence in Italy and favored down-staging.

Extension of organized cervical cancer screening programmes in Italy and their process indicators, 2011-2012 activity.

Italian national guidelines recommend regional implementation of organized screening programmes for cervical cancer. As we have been doing since 1998, we collected aggregated tables of data from Italian organized cervical screening programmes in order to centrally compute process indicators. Data on women invited during 2011 and 2012 and screened up to April of the subsequent year were considered. In 2012, the target population of Italian organized screening programmes included 14,497,207 women, corresponding to 87.3% of Italian women aged 25-64 years. Compliance to invitation was 41.2%in 2011 and 40.8%in 2012, with a strong decreasing North-South trend. However, it should be considered that many women are screened outside any organized programmes. In 2012, of the women screened, 3.5% were referred for repeat cytology and 71.1% of them complied; 2.4% of screened women were referred to colposcopy. Compliance with colposcopy referral was 85.3%among women referred because of ASC-US or more severe cytology and 90.4% among those referred because of HSIL or more severe cytology. The positive predictive value (PPV) of referral because of ASC-US or more severe cytology for CIN2 or more severe histology was 16.9%. The unadjusted detection rate of CIN2 or more severe histology was 3.4 per 1,000 screened women (3.6 standardized on the Italian population, truncated 25-64). CIN2 or more severe histology was detected in 64.6% of colposcopies classified as grade 2 or higher. Of all colposcopies during which a CIN2 or more severe histology was obtained, 33.6% were classified as grade 2 or higher. Follow-up only was recommended to 81.7% of women with CIN1. Excision by radio-frequency device was the most common treatment for women with CIN2 (52.8%) and CIN3 (57.0%). However 0.4% of all CIN2 and 2.3% of all CIN3 had hysterectomy.

A first survey of HPV-based screening in routine cervical cancer screening in Italy.

Pilot HPV-based cervical screening programmes have recently started in Italy, partly on the strength of a large randomized trial. The Ministry of Health recommended that regions shift toward HPV-based screening in early 2013 and provided guidelines for its application (stand-alone HPV testing by validated methods, cytological triage of HPV positives, beginning at age 30-35, 5-year intervals). A first survey on the 2012 activity was conducted in 2013. In 2012, 19 Italian organized cervical screening programmes from 10 regional programmes invited 311,856 women (8.0%of all women invited for cervical screening in 2012 in Italy) for HPV-based screening; 41.5% complied, with a decreasing North-South trend. Among screened women, 7.9% (range 4.3%-13.9%) were HPV positive, decreasing to 6.6% (range 4.0%-12.4%) when considering women aged 35-64 years. Among HPV positive women, 34.8%(with high variability between programmes: range 11.1%-59.3%) were judged to have ASC-US or more severe cytology (5.3%ASC-US, 26.6%L-SIL, 5.2% H-SIL). Out of all screened women, those referred to colposcopy based on HPV and cytology results were 2.9% (range 0.6%-4.8%), whereas they were 2.0% when considering only women aged 35-64 years.

[Introduction of a centralised system (Service) for collecting clinical data in cancer screening programmes in Piedmont (Northern Italy): a pre-post assessment of a hub&spoke model]. / L'introduzione di un sistema centralizzato (Service) per la raccolta dei dati clinici negli screening oncologici in Piemonte: valutazione pre-post di un modello hub&spoke.

OBJECTIVES: evaluation of a centralised collection of clinical data (Service) within cancer screening programmes in Piedmont based on a hub&spoke model and its impact on process indicators. DESIGN: assessment of an organisational intervention, through a non-controlled pre-post design. SETTING AND PARTICIPANTS: organised screening programmes within the Piedmont Region, divided into 9 departments. MAIN OUTCOME MEASURES: clinical data (extracted from medical charts for mammography screening and from excision histology reports for cervical screening) obtained through the Service were quantified and their completeness was assessed. The Service impact on the detection rate (DR) was evaluated, comparing the DR pre- (2005-2008) and post-Service (2009- 2012) within breast screening; the DR was computed through histological diagnosis made during colposcopy (pre-Service method) or through the worst diagnosis between the latter and that reported from excision histology (post-Service method) within cervical screening (data available for department 1, year 2013). Some hints on human resources employed in pre- and post-Service periods were reported. RESULTS: within mammography screening, the Service obtained 53.1% of extra-department medical charts and 45.8% of extra-region ones; the percentage of missing diagnoses changed from 5.5% (pre- Service) to 3.7% (post-Service). The age standardised DR for malignant tumours in the post-Service period is 1.3 times the DR of the pre-Service period per 1,000 screening tests. Within cervical screening, 51.7% of histological reports was recorded. Crude DR for high-grade lesions changed from 3.9 (pre-Service) to 4.7 (post-Service) per 1,000 screened women. The system centralisation did not imply an increase in the dedicated personnel. CONCLUSION: the Service is an operational core which coordinates the collection of clinical data, impacting on process indicators without an increase in human resources at departmental level.