Baseline Cell-Free DNA Can Predict Malignancy of Nodules Observed in the ITALUNG Screening Trial.

The role of total plasma cell-free DNA (cfDNA) in lung cancer (LC) screening with low-dose computed tomography (LDCT) is uncertain. We hypothesized that cfDNA could support differentiation between malignant and benign nodules observed in LDCT. The baseline cfDNA was measured in 137 subjects of the ITALUNG trial, including 29 subjects with screen-detected LC (17 prevalent and 12 incident) and 108 subjects with benign nodules. The predictive capability of baseline cfDNA to differentiate malignant and benign nodules was compared to that of Lung-RADS classification and Brock score at initial LDCT (iLDCT). Subjects with prevalent LC showed both well-discriminating radiological characteristics of the malignant nodule (16 of 17 were classified as Lung-RADS 4) and markedly increased cfDNA (mean 18.8 ng/mL). The mean diameters and Brock scores of malignant nodules at iLDCT in subjects who were diagnosed with incident LC were not different from those of benign nodules. However, 75% (9/12) of subjects with incident LC showed a baseline cfDNA ≥ 3.15 ng/mL, compared to 34% (37/108) of subjects with benign nodules (p = 0.006). Moreover, baseline cfDNA was correlated (p = 0.001) with tumor growth, measured with volume doubling time. In conclusion, increased baseline cfDNA may help to differentiate subjects with malignant and benign nodules at LDCT.

Cervical cancer prevention: Feasibility of self-sampling and HPV testing in rural and urban areas of Bolivia: An observational study.

BACKGROUND: Cervical cancer is a major health problem in Latin America. In 2019, the Italian Agency for Development Cooperation (La Paz regional site) conducted a pilot study to estimate the prevalence of high-risk human papillomavirus (HPV) and the feasibility of HPV screening in Bolivia through self-sampling and portable and transportable laboratory instruments for HPV testing in urban and rural areas. METHODS: Women aged 20-65 years from La Paz (urban area), Toro Toro (rural area), and Acasio (rural area) were enrolled in local public health centers between Dec 1, 2019, and June 30, 2021. Self-sampling was carried out with the Viba-Brush system (Rovers, Oss, Netherlands) and samples were preserved in ThinPrep containers (Hologic Corporation, San Diego, CA, USA). The GeneXpert system (Cepheid, Sunnyvale, CA, USA) for high-risk HPV testing detects HPV E6 and E7 DNA via real-time PCR in a mobile system of easy execution requiring minimal manual intervention. The system provides results in about 1 h. The hr- HPV prevalence data, overall and partial genotyping, were analyzed considering the following age groups: 20-34, 35-44, and 45-65 years old. FINDINGS: 2168 women were enrolled: 614 (28.3%) in La Paz, 743 (34.3%) in Toro Toro, and 811 (37.4%) in Acasio. Only one sample was collected from each participant. 2043 (94.2%) of 2168 samples were adequate for HPV testing. 255 (12.5%) samples were positive for high-risk HPV. Comparing the urban area (La Paz) versus rural combined areas (Acasio+Toro Toro), using a logistic model, the HPV total rate was statistically significantly higher in the city of La Paz (15.0% vs 11.4%; OR:1.37;95% CI: 1.04-1.80). Furthermore, the HPV prevalence was declining by age, and the urban/rural odds ratio was 1.50; (95% IC 1.13-19). The overall HPV 16 positivity was 2.7% (55/2043) and for HPV 18/45 was 1.8% (37/2043) without any statistically significant differences between the three BHU enrolling centers. Only the prevalence of HPV group '39/56/66/68' was significantly higher in La Paz (p<0,001) in comparison to Acasio and Toro Toro. INTERPRETATION: The total and age-adjusted prevalence of high-risk HPV infection in rural and urban areas in Bolivia, as measured with a validated test for screening, is similar to that observed in Europe and the USA. Our study shows that a screening protocol for HPV testing with self-sampling would be feasible in urban and rural areas in Bolivia, and that the reported high occurrence of cervical cancer in Bolivia is not related to a higher rate of high-risk HPV infections. Carrying out HPV tests locally avoids the issues associated with transportation and storage of the collected material and allows the participant to wait in the clinic for the test result, overcoming the very long response time for screening test in Bolivia.

Lung Cancer Screening with Low-Dose CT: What We Have Learned in Two Decades of ITALUNG and What Is Yet to Be Addressed.

The ITALUNG trial started in 2004 and compared lung cancer (LC) and other-causes mortality in 55-69 years-aged smokers and ex-smokers who were randomized to four annual chest low-dose CT (LDCT) or usual care. ITALUNG showed a lower LC and cardiovascular mortality in the screened subjects after 13 years of follow-up, especially in women, and produced many ancillary studies. They included recruitment results of a population-based mimicking approach, development of software for computer-aided diagnosis (CAD) and lung nodules volumetry, LDCT assessment of pulmonary emphysema and coronary artery calcifications (CAC) and their relevance to long-term mortality, results of a smoking-cessation intervention, assessment of the radiations dose associated with screening LDCT, and the results of biomarkers assays. Moreover, ITALUNG data indicated that screen-detected LCs are mostly already present at baseline LDCT, can present as lung cancer associated with cystic airspaces, and can be multiple. However, several issues of LC screening are still unaddressed. They include the annual vs. biennial pace of LDCT, choice between opportunistic or population-based recruitment. and between uni or multi-centre screening, implementation of CAD-assisted reading, containment of false positive and negative LDCT results, incorporation of emphysema. and CAC quantification in models of personalized LC and mortality risk, validation of ultra-LDCT acquisitions, optimization of the smoking-cessation intervention. and prospective validation of the biomarkers.

The 5-year risk of recurrence of grade 2/3 cervical intraepithelial neoplasia after treatment in a population screening programme by human papillomavirus status: A cohort study in central Italy.

OBJECTIVES: (a) To estimate the risk of recurrent cervical intraepithelial neoplasia, grade 2/3 or worse (CIN2+/CIN3+), lesions within 5 years of follow-up in human papillomavirus-negative/human papillomavirus-positive cohorts; (b) to assess whether certain risk factors can predict the recurrence of CIN2+/CIN3+ lesions; and (c) to provide recommendations for follow-up after treatment of cervical intraepithelial neoplasia, grade 2/3 to prevent cervical cancer. SETTING: Organized cervical cancer screening programme in Central Italy. METHODS: We included 1063 consecutive first excisional treatments performed between 2006 and 2014 for screening-detected cervical intraepithelial neoplasia, grade 2/3 lesions among women aged 25-65. The study population was divided into two groups according to the human papillomavirus test results performed 6 months after treatment: Human papillomavirus-negative and human papillomavirus-positive cohorts. The 5-year risk of developing cervical intraepithelial neoplasia, grade 2/3 or worse (CIN2+/CIN3+) was estimated using the Kaplan-Meier method and the Cox regression model. RESULTS: Among 829 human papillomavirus-negative and 234 human papillomavirus-positive women, six (0.72%; three cervical intraepithelial neoplasia, grade 2, three cervical intraepithelial neoplasia, grade 3) and 45 (19.2%; 15 cervical intraepithelial neoplasia, grade 2, 30 cervical intraepithelial neoplasia, grade 3), respectively, developed CIN2+ recurrence within 5 years of follow-up. The cumulative risks for CIN2+ and CIN3+ were 0.9% (95% confidence interval: 0.4%-2.0%) and 0.5% (95% confidence interval: 0.1%-1.4%), respectively, for the human papillomavirus-negative cohort, and 24.8% (95% confidence interval: 18.5%-32.7%) and 16.9% (95% confidence interval: 11.4%-24.5%), respectively, for the human papillomavirus-positive cohort. Risk factors associated with increased risk of recurrence were both margins positive for the human papillomavirus-negative cohort, and positive margins, cervical intraepithelial neoplasia, grade 3 lesions, high-grade cytology and high viral load for the human papillomavirus-positive cohort. CONCLUSIONS: Human papillomavirus testing can identify women at increased risk of recurrence and this supports a recommendation for its use in the post-treatment follow-up of cervical intraepithelial neoplasia, grade 2/3 lesions.

Cervical screening during the COVID-19 pandemic: optimising recovery strategies.

Disruptions to cancer screening services have been experienced in most settings as a consequence of the COVID-19 pandemic. Ideally, programmes would resolve backlogs by temporarily expanding capacity; however, in practice, this is often not possible. We aim to inform the deliberations of decision makers in high-income settings regarding their cervical cancer screening policy response. We caution against performance measures that rely solely on restoring testing volumes to pre-pandemic levels because they will be less effective at mitigating excess cancer diagnoses than will targeted measures. These measures might exacerbate pre-existing inequalities in accessing cervical screening by disregarding the risk profile of the individuals attending. Modelling of cervical screening outcomes before and during the pandemic supports risk-based strategies as the most effective way for screening services to recover. The degree to which screening is organised will determine the feasibility of deploying some risk-based strategies, but implementation of age-based risk stratification should be universally feasible.

Pool testing on random and natural clusters of individuals: Optimisation of SARS-CoV-2 surveillance in the presence of low viral load samples.

Facing the SARS-CoV-2 epidemic requires intensive testing on the population to early identify and isolate infected subjects. During the first emergency phase of the epidemic, RT-qPCR on nasopharyngeal (NP) swabs, which is the most reliable technique to detect ongoing infections, exhibited limitations due to availability of reagents and budget constraints. This stressed the need to develop screening procedures that require fewer resources and are suitable to be extended to larger portions of the population. RT-qPCR on pooled samples from individual NP swabs seems to be a promising technique to improve surveillance. We performed preliminary experimental analyses aimed to investigate the performance of pool testing on samples with low viral load and we evaluated through Monte Carlo (MC) simulations alternative screening protocols based on sample pooling, tailored to contexts characterized by different infection prevalence. We focused on the role of pool size and the opportunity to develop strategies that take advantage of natural clustering structures in the population, e.g. families, school classes, hospital rooms. Despite the use of a limited number of specimens, our results suggest that, while high viral load samples seem to be detectable even in a pool with 29 negative samples, positive specimens with low viral load may be masked by the negative samples, unless smaller pools are used. The results of MC simulations confirm that pool testing is useful in contexts where the infection prevalence is low. The gain of pool testing in saving resources can be very high, and can be optimized by selecting appropriate group sizes. Exploiting natural groups makes the definition of larger pools convenient and potentially overcomes the issue of low viral load samples by increasing the probability of identifying more than one positive in the same pool.

Prognostic selection and long-term survival analysis to assess overdiagnosis risk in lung cancer screening randomized trials.

OBJECTIVES: Overdiagnosis in low-dose computed tomography randomized screening trials varies from 0 to 67%. The National Lung Screening Trial (extended follow-up) and ITALUNG (Italian Lung Cancer Screening Trial) have reported cumulative incidence estimates at long-term follow-up showing low or no overdiagnosis. The Danish Lung Cancer Screening Trial attributed the high overdiagnosis estimate to a likely selection for risk of the active arm. Here, we applied a method already used in benefit and overdiagnosis assessments to compute the long-term survival rates in the ITALUNG arms in order to confirm incidence-excess method assessment. METHODS: Subjects in the active arm were invited for four screening rounds, while controls were in usual care. Follow-up was extended to 11.3 years. Kaplan-Meyer 5- and 10-year survivals of "resected and early" (stage I or II and resected) and "unresected or late" (stage III or IV or not resected or unclassified) lung cancer cases were compared between arms. RESULTS: The updated ITALUNG control arm cumulative incidence rate was lower than in the active arm, but this was not statistically significant (RR: 0.89; 95% CI: 0.67-1.18). A compensatory drop of late cases was observed after baseline screening. The proportion of "resected and early" cases was 38% and 19%, in the active and control arms, respectively. The 10-year survival rates were 64% and 60% in the active and control arms, respectively (p = 0.689). The five-year survival rates for "unresected or late" cases were 10% and 7% in the active and control arms, respectively (p = 0.679). CONCLUSIONS: This long-term survival analysis, by prognostic categories, concluded against the long-term risk of overdiagnosis and contributed to revealing how screening works.

Determinants of p16/Ki-67 adequacy and positivity in HPV-positive women from a screening population.

BACKGROUND: The objective of this study was to describe the determinants of adequacy and positivity of the p16/Ki-67 assay in a human papillomavirus (HPV)-positive screening population enrolled within the New Technologies for Cervical Cancer 2 (NTCC2) study. METHODS: ThinPrep slides were immunostained for p16/Ki-67; each slide had 3 reports from different laboratories. The authors included population-related, sampling-related/staining-related, and interpretation-related variables in the analyses. Adequacy and positivity proportions were stratified by variables of interest. Univariate and multivariate logistic models were used to identify determinants of adequacy and positivity. RESULTS: In total, 3100 consecutive HPV-positive cases were analyzed. Because every slide was interpreted by 3 centers, 9300 reports were obtained, including 905 (9.7%) that were inadequate and 2632 (28.3%) that were positive. The percentage of cases in which all 3 reports were inadequate increased with increasing age of the women and with inadequate cytology. The highest percentage of adequacy in all 3 reports and of cases with all 3 reports positive was observed in specimens from women who had grade ≥2 cervical intraepithelial neoplasia (CIN2+), atypical squamous cells of undetermined significance or more severe (ASC-US+) cytology, or mRNA positivity. The number of inadequate reports was significantly associated with increasing age, inadequate cytology, mRNA negativity, and scant cellularity. A positive p16/Ki-67 report was associated with an ASC-US+ result and with a positive mRNA result in cases both with and without CIN2+ but was associated with an HPV type 16 and/or 18 infection only in CIN2+ cases. The presence of CIN2+ was strongly associated with dual staining positivity. CONCLUSIONS: The interpretation of p16/Ki-67 results may be influenced by several different variables, all of which are part of the steps in the procedure, and by the characteristics of the screened population.

Interlaboratory concordance of p16/Ki-67 dual-staining interpretation in HPV-positive women in a screening population.

BACKGROUND: p16/Ki-67 dual staining is a candidate biomarker for triaging human papillomavirus (HPV)-positive women. Reproducibility is needed for adopting a test for screening. This study assessed interlaboratory reproducibility in HPV-positive women. METHODS: All women positive for HPV from the Italian New Technologies for Cervical Cancer 2 study, were included in this study. ThinPrep slides were immunostained for p16/Ki-67 in 4 laboratories and were interpreted in 7 laboratories. Each slide had 3 reports from different laboratories. Slides were classified as valuable or inadequate, and valuable slides were classified as positive (at least 1 double-stained cell) or negative. Interlaboratory reproducibility was evaluated with κ values. RESULTS: Overall, we obtained 9300 reports for 3100 cases; 905 reports (9.7%) were inadequate. The overall adequacy concordance was poor (κ = 0.224; 95% confidence interval [CI], 0.183-0.263). The overall positivity concordance was moderate (κ = 0.583; 95% CI, 0.556-0.610). Of the 176 cervical intraepithelial neoplasia 2+ (CIN-2+) lesions found in HPV DNA-positive women, 158 had a valid result: 107 were positive in all 3 reports (sensitivity for CIN-2+, 67.7%; 95% CI, 59.8%-74.9%), 23 were positive in 2 reports (sensitivity of the majority report, 82.3%; 95% CI, 75.4%-87.9%), and 15 were positive in 1 report (sensitivity of at least 1 positive result, 91.8%; 95% CI, 86.3%-95.5%). Thirteen CIN-2+ cases were negative in all 3 reports. The overall positivity concordance in CIN-2+ samples was κ = 0.487 (95% CI, 0.429-0.534), whereas in the non-CIN-2+ samples, it was κ = 0.558 (95% CI, 0.528-0.588). CONCLUSIONS: The p16/Ki-67 assay showed poor reproducibility for adequacy and good reproducibility for positivity comparable to that of cervical cytology. Nevertheless, the low reproducibility does not affect the sensitivity for CIN-2+.

Smoking Cessation in the ITALUNG Lung Cancer Screening: What Does "Teachable Moment" Mean?

BACKGROUND: Changes in smoking habits and predictors of smoking cessation were examined in the randomized ITALUNG lung cancer screening trial. METHODS: In three centers, eligible smokers or ex-smokers (55-69 years, ≥20 pack-years in the last 10 years) were randomized to receive annual invitation for low-dose computed tomography for 4 years or usual care. At invitation, subjects received written information for a free smoking cessation program. Quitting outcome was assessed at year 4. RESULTS: Among participants who completed baseline assessments and year 4 screening, higher quitting (20.8% vs. 16.7%, p = .029) and lower relapse (6.41% vs. 7.56%, p = .50) rates were observed in the active screening group as compared to the usual-care control group. Corresponding figures in the intention-to-treat analysis were as follows: 16.04% versus 14.64% (p = .059) and 4.88% versus 6.43% (p = .26). Quitting smoking was significantly associated to male gender, lower pack-years, and having pulmonary nodules at baseline. Center-specific analyses showed a threefold statistically significant higher probability to quit associated with participating in the smoking cessation program. A subsample of smokers of the scan group from one center showed higher quitting rates over 12-month follow-up as compared to matched controls from the general population who underwent the same smoking cessation program. CONCLUSIONS: Consistently with previous reports, in the ITALUNG trial, screened subjects showed significantly higher quit rates than controls, and higher quit rates were associated with both the presence of pulmonary nodules and participating in a smoking cessation program. Maximal effect on quitting outcome was observed with the participation in the smoking cessation program. IMPLICATIONS: Participating in lung cancer screening promotes smoking cessation. An effective "teachable moment" may be achieved when the smoking cessation intervention is structured as integral part of the screening clinical visits and conducted by a dedicated team of health care professionals. Standardized guidelines for smoking cessation interventions in lung cancer screening are needed.

Decreased cardiovascular mortality in the ITALUNG lung cancer screening trial: Analysis of underlying factors.

OBJECTIVES: In the ITALUNG lung cancer screening trial after 9.3 years of follow-up we observed an unexpected significant decrease of cardiovascular (CV) mortality in subjects invited for low-dose CT (LDCT) screening as compared to controls undergoing usual care. Herein we extended the mortality follow-up and analyzed the potential factors underlying such a decrease. MATERIALS AND METHODS: The following factors were assessed in screenes and controls: burden of CV disease at baseline, changes in smoking habits, use of CV drugs and frequency of planned vascular procedures after randomisation. Moreover, in the screenes we evaluated inclusion of presence of coronary artery calcification (CAC) in the LDCT report form that was transmitted to the participant and his/her General Practitioner. RESULTS: The 2-years extension of follow-up confirmed a significant decrease of CV mortality in the subjects of the active group compared to control subjects (15.6 vs 34.0 per 10,000; p = 0.001) that was not observed in the drops-out of the active group. None of the explaining factors we considered significantly differed between active and control group. However, the subjects of the active group with reported CAC experienced a not significantly lower CV mortality and showed a significantly higher use of CV drugs and frequency of planned vascular procedures than the control group. CONCLUSIONS: LDCT screening for lung cancer offers the opportunity for detection of CAC that is an important CV risk factor. Although the underlying mechanisms are not clear, our results suggest that the inclusion of information about CAC presence in the LDCT report may represent a candidate factor to explain the decreased CV mortality observed in screened subjects of the ITALUNG trial, possibly resulting in intervention for patient care to prevent CV deaths. Further studies investigating whether prospective reporting and rating of CAC have independent impact on such interventions and CV mortality are worthy.

Cost analysis of colorectal cancer screening with CT colonography in Italy.

OBJECTIVE: Unit costs of screening CT colonography (CTC) can be useful for cost-effectiveness analyses and for health care decision-making. We evaluated the unit costs of CTC as a primary screening test for colorectal cancer in the setting of a randomized trial in Italy. METHODS: Data were collected within the randomized SAVE trial. Subjects were invited to screening CTC by mail and requested to have a pre-examination consultation. CTCs were performed with 64- and 128-slice CT scanners after reduced or full bowel preparation. Activity-based costing was used to determine unit costs per-process, per-participant to screening CTC, and per-subject with advanced neoplasia. RESULTS: Among 5242 subjects invited to undergo screening CTC, 1312 had pre-examination consultation and 1286 ultimately underwent CTC. Among 129 subjects with a positive CTC, 126 underwent assessment colonoscopy and 67 were ultimately diagnosed with advanced neoplasia (i.e., cancer or advanced adenoma). Cost per-participant of the entire screening CTC pathway was €196.80. Average cost per-participant for the screening invitation process was €17.04 and €9.45 for the pre-examination consultation process. Average cost per-participant of the CTC execution and reading process was €146.08 and of the diagnostic assessment colonoscopy process was €24.23. Average cost per-subject with advanced neoplasia was €3777.30. CONCLUSIONS: Cost of screening CTC was €196.80 per-participant. Our data suggest that the more relevant cost of screening CTC, amenable of intervention, is related to CTC execution and reading process.

Multimodal lung cancer screening using the ITALUNG biomarker panel and low dose computed tomography. Results of the ITALUNG biomarker study.

Asymptomatic high-risk subjects, randomized in the intervention arm of the ITALUNG trial (1,406 screened for lung cancer), were enrolled for the ITALUNG biomarker study (n = 1,356), in which samples of blood and sputum were analyzed for plasma DNA quantification (cut off 5 ng/ml), loss of heterozygosity and microsatellite instability. The ITALUNG biomarker panel (IBP) was considered positive if at least one of the two biomarkers included in the panel was positive. Subjects with and without lung cancer diagnosis at the end of the screening cycle with LDCT (n = 517) were evaluated. Out of 18 baseline screen detected lung cancer cases, 17 were IBP positive (94%). Repeat screen-detected lung cancer cases were 18 and 12 of them positive at baseline IBP test (66%). Interval cancer cases (2-years) and biomarker tests after a suspect Non Calcific Nodule follow-up were investigated. The single test versus multimodal screening measures of accuracy were compared in a simulation within the screened ITALUNG intervention arm, considering screen-detected and interval cancer cases. Sensitivity was 90% at baseline screening. Specificity was 71 and 61% for LDCT and IBP as baseline single test, and improved at 89% with multimodal, combined screening. The positive predictive value was 4.3% for LDCT at baseline and 10.6% for multimodal screening. Multimodal screening could improve the screening efficiency at baseline and strategies for future implementation are discussed. If IBP was used as primary screening test, the LDCT burden might decrease of about 60%.

[Molecular biomarkers and early diagnosis of lung cancer: state of knowledge and future perspectives]. / Biomarcatori nella diagnosi precoce del tumore polmonare: stato delle conoscenze e prospettive future.

Lung cancer is the leading cause of cancer death worldwide and it would be essential to have effective tools to diagnose the disease in its early stages, to identify individuals at highest risk of developing the disease, and to set personalised therapies. The effectiveness of screening for lung cancer with low-dose CT (LDCT) in heavy smokers was demonstrated, in terms of reduction of cause-specific mortality, in recently published data by the study National Lung ScreeningTrial (NLST). In Europe, the introduction of LDCT as screening in individuals at risk is the object of a debate until the results of European randomized trials, expected in 2015-2016, are published. One problem is the high rate of calls for investigations when there is a noncalcified nodule, and it is therefore essential to be able to more accurately identify malignant nodules. The development of specific biomarkers appears to offer promising prospects. Recent advances in genetics and genomics have led to a series of studies aimed at the identification of molecular markers for the diagnosis, the assessment of the risk of developing lung cancer, the molecular characterisation of the different stages of the disease and the personalisation of therapy. Subjects enrolled in trials evaluating LCDT as a test for early detection of lung cancer represent the ideal population in which to study a combined bioinstrumental approach of screening (molecular test and LDCT). This paper reports on the state of knowledge on the possible use of biomarkers in the early detection of lung cancer and molecular analysis conducted within the project ITALUNG, a randomized controlled trial to assess the effect on tumour-specific mortality of LDCT, which provided a collection of biological materials from the subjects enrolled.

HPV testing for primary cervical screening: Laboratory issues and evolving requirements for robust quality assurance.

This review aims to highlight the importance of Quality Assurance for Laboratories performing HPV test for Cervical Cancer Screening. An HPV test, to be used as primary screening test, must be validated according to international criteria, based on comparison of its clinical accuracy to HC2 or GP5+/6+ PCR-EIA tests. The number of validated platforms is increasing and appropriate Quality Assurance Programs (QAPs) which can interrogate longitudinal robustness and quality are paramount. This document describes the following topics: (1) the characteristics of an HPV laboratory and the personnel training needs, to ensure an elevated quality of the entire process and the optimal use of the resources; (2) the Quality Assurance, as both internal (IQA) and external quality assessment (EQA) systems, to be implemented and performed, and the description of the existing EQAs, including limitations; (3) general considerations for an optimal EQA program for hrHPV primary screening Due to the importance of Quality Assurance for this field, international efforts are necessary to improve QA International Collaboration.

The diffusion of screening programmes in Italy, years 2011-2012.

In this report, we present the results of cancer screening programmes in Italy for the years 2011-2012. This report is produced by the National centre for screening monitoring (ONS), together with the Italian professional multidisciplinary screening groups: GISMa (Italian group for mammographic screening), GISCor (Italian group for colorectal screening), and GISCi (Italian group for cervical screening). Since 2004, ONS has been monitoring and supporting Italian screening programmes, in accordance with a decree issued by the Ministry of Health. Multidisciplinary groups work with ONS and provide the know-how required to promote the quality of public health programmes. The following is a brief outline of the Italian screening programme setting: screening programmes (cervical, mammographic, colorectal) have been a Basic Healthcare Parameter (livello essenziale di assistenza, LEA) since 2001; guidelines are provided by the Ministry of Health's Department of Prevention in agreement with regional governments; regional governments are responsible for the organization, management, and quality assurance of screening programmes; since 2004, ONS has been responsible for monitoring and promoting screening programmes nationwide; the results of the screening programmes of each region are evaluated annually by the Ministry of Health in terms of coverage and impact.

hr-HPV testing in the management of women with ASC-US+ and in the follow-up of women with cytological abnormalities and negative colposcopy. Recommendations of the Italian group for cervical cancer screening (GISCi).

Compared to spontaneous screening, an organized screening programme is characterized by the presence of protocols and recommendations for all stages including follow-up. Despite the availability of well-functioning screening programmes throughout the country, the follow-up protocol after an abnormal Pap test and negative colposcopy is not clearly defined in Italy, and there is no uniformity of indications. HPV testing for oncogenic human papillomavirus (hr-HPV) has a high negative predictive value (NPV) and high positive predictive value (PPV) for CIN2+ and its employment can reduce follow-up assessments. In order to provide indications about the management of women with ASC-US+ and the follow-up of women with cytological abnormalities and negative colposcopy, a literature analysis was carried out, taking into consideration European and American guidelines and good practice recommendations from the most important scientific associations and regulatory agencies. GISCi (Italian Group for Cervical Screening) drafted recommendations for the management of women with ASC-US, L-SIL, ASC-H, AGC, and H-SIL until their return to the routine screening interval. This protocol can be applied not only in the management of abnormal Pap smears in cytology-based programmes, but also in the management of abnormal Pap test triage after HPV positive test when HPV is the primary screening test. The protocols approved within the screening programmes must have an extensive consensus among all involved professionals, including any that women might meet outside the programme.

Clinical impact of the analytical specificity of the hybrid capture 2 test: data from the New Technologies for Cervical Cancer (NTCC) study.

The Hybrid Capture 2 (HC2) test targets 13 human papillomavirus (HPV) types. Here, cross-reactivity with non-HC2-targeted HPV types is described. We aimed to define the proportion of HC2-positive women who had negative results with HC2-targeted HPV types and estimate its determinants and impact on women's health management. The New Technologies for Cervical Cancer (NTCC) trial was followed in two predetermined phases. Women in the experimental arm were tested for the presence of HPV DNA by HC2 following a sample collection in PreservCyt (first phase) or Digene specimen transport medium (STM) (second phase). HPV genotyping was performed on DNA samples from HC2-positive women by PCR with GP5(+)/GP6(+) primers and reverse line blot (RLB) hybridization. Untyped samples were submitted to direct sequencing or restriction fragment length polymorphism. Multivariate logistic regression analysis estimated the adjusted odds ratios (ORs) between the presence of HC2-targeted types and age, viral load, and type of transport medium. Out of 2,920 HC2-positive samples, 2,310 (79.1%) were positive on RLB for HC2-targeted types, 396 were positive (13.6%) for only non-HC2-targeted types (mostly represented by HPV-53, HPV-66, and HPV-70), and in 214 (7.33%) samples, no HPV types were detected. The probability of detecting HC2-targeted types increased with increasing viral load expressed as the relative light unit/positive-control specimen ratio (RLU/PC) (OR for unitary increase of log RLU/PC, 1.35; 95% confidence interval [CI], 1.30 to 1.42) and with STM versus PreservCyt (OR, 1.56; 95% CI, 1.25 to 1.84). If only the samples containing HC2-targeted types tested positive, the positive predictive value (PPV) would have increased from 7.0% (95% CI, 6.1% to 8.0%) to 8.4% (95% CI, 7.3 to 9.6), although 4.9% (95% CI, 2.4% to 8.8%) of cervical intraepithelial neoplasia grade 2(+) (CIN2(+)) cases would have been missed. In conclusion, STM use and an increased cutoff would reduce the HC2 analytical false-positive rate and increase the positive predictive value for high-grade CIN. The gain in clinical sensitivity by detecting non-HC2-targeted HPV types is limited.

Four-year results of low-dose CT screening and nodule management in the ITALUNG trial.

INTRODUCTION: Recruitment and nodule management are critical issues of lung cancer screening with low-dose computed tomography (LDCT). We report subjects' compliance and results of LDCT screening and management protocol in the active arm of the ITALUNG trial. METHODS: Three thousand two hundred six smokers or former smokers invited by mail were randomized to receive four annual LDCT (n = 1613) or usual care (n = 1593). Management protocol included follow-up LDCT, 2-[18F]fluoro-2-deoxy-D glucose positron emission tomography (FDG-PET), and CT-guided fine-needle aspiration biopsy (FNAB). RESULTS: One thousand four hundred six subjects (87%) underwent baseline LDCT, and 1263 (79%) completed four screening rounds. LDCT was positive in 30.3% of the subjects at baseline and 15.8% subsequently. Twenty-one lung tumors in 20 subjects (1.5% detection) were found at baseline, and 20 lung tumors in 18 subjects (0.5% detection) in subsequent screening rounds. Ten of 18 prevalent (55%) and 13 of 17 incident (76%) non-small-cell cancers were in stage I. Interval growth enabled diagnosis of lung cancer in 16 subjects (42%), but at least one follow-up LDCT was obtained in 741 subjects (52.7%) over the screening period. FDG-PET obtained in 6.5% of subjects had 84% sensitivity and 90% specificity for malignant lesions. FNAB obtained in 2.4% of subjects showed 90% sensitivity and 88% specificity. Positivity of both FDG-PET and FNAB invariably predicted malignancy. Surgery for benign lesions was performed on four subjects (10% of procedures) but followed protocol violations on three subjects. CONCLUSIONS: High-risk subjects recruited by mail who entered LDCT screening showed a high and stable compliance. Efficacy of screening is, however, weakened by low detection rate and specificity. Adhesion to management protocol might lessen surgery for benign lesions.