Pulmonary emphysema and coronary artery calcifications at baseline LDCT and long-term mortality in smokers and former smokers of the ITALUNG screening trial.

OBJECTIVES: Cardiovascular disease (CVD), lung cancer (LC), and respiratory diseases are main causes of death in smokers and former smokers undergoing low-dose computed tomography (LDCT) for LC screening. We assessed whether quantification of pulmonary emphysematous changes at baseline LDCT has a predictive value concerning long-term mortality. METHODS: In this longitudinal study, we assessed pulmonary emphysematous changes with densitometry (volume corrected relative area below - 950 Hounsfield units) and coronary artery calcifications (CAC) with a 0-3 visual scale in baseline LDCT of 524 participants in the ITALUNG trial and analyzed their association with mortality after 13.6 years of follow-up using conventional statistics and a machine learning approach. RESULTS: Pulmonary emphysematous changes were present in 32.3% of subjects and were mild (6% ≤ RA950 ≤ 9%) in 14.9% and moderate-severe (RA950 > 9%) in 17.4%. CAC were present in 67% of subjects (mild in 34.7%, moderate-severe in 32.2%). In the follow-up, 81 (15.4%) subjects died (20 of LC, 28 of other cancers, 15 of CVD, 4 of respiratory disease, and 14 of other conditions). After adjusting for age, sex, smoking history, and CAC, moderate-severe emphysema was significantly associated with overall (OR 2.22; 95CI 1.34-3.70) and CVD (OR 3.66; 95CI 1.21-11.04) mortality. Machine learning showed that RA950 was the best single feature predictive of overall and CVD mortality. CONCLUSIONS: Moderate-severe pulmonary emphysematous changes are an independent predictor of long-term overall and CVD mortality in subjects participating in LC screening and should be incorporated in the post-test calculation of the individual mortality risk profile. KEY POINTS: • Densitometry allows quantification of pulmonary emphysematous changes in low-dose CT examinations for lung cancer screening. • Emphysematous lung density changes are an independent predictor of long-term overall and cardio-vascular disease mortality in smokers and former smokers undergoing screening. • Emphysematous changes quantification should be included in the post-test calculation of the individual mortality risk profile.

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.

[Early effects of attendance to the Friuli Venezia Giulia (Northern Italy) mammography screening programme on the incidence of advanced-stage breast cancer: a cohort study]. / Effetti precoci dell'adesione al programma di screening mammografico della Regione Friuli Venezia Giulia sull'incidenza del cancro della mammella in stadio avanzato: uno studio di coorte.

OBJECTIVES: to evaluate the incidence of advanced-stage breast cancer (BC) - an early surrogate indicator of effectiveness of mammography screening - among women who attended the Friuli Venezia Giulia (FVG) Region (Northern Italy) screening programme compared to women who did not attend. DESIGN: retrospective cohort study. Women invited to the first screening round (2006-2007) were identified from the database of the programme. The cohort was record-linked to the archive of women invited to the second round (2008-2009). The definition of attendance to screening was based on attendance to at least one of the two rounds. The incidence of BC was assessed through record linkage with the FVG cancer registry using an anonymous univocal identifier (end of follow-up: 31st December 2013). Three distinct definitions of advanced stage were used: pT2 or greater (pT2+), positive lymph nodes (pN+), and TNM stage II or greater (stage II+). SETTING AND PARTICIPANTS: organized mammography screening programme for women aged 50-69 years in the five regional healthcare districts. MAIN OUTCOME MEASURES: incidence rate ratio (IRR) between attenders and non-attenders, adjusted for age and deprivation index, with 95% confidence interval (95%CI). RESULTS: the cohort included 104,488 attenders and 49,839 non-attenders. During follow-up (median duration 84 months), 2,717 invasive BCs were diagnosed among attenders and 1,149 among non-attenders. Total incidence rate was 13% higher among attenders (IRR 1.13; 95%CI 1.05-1.21). These, conversely, had a 36% lower rate of pT2+ BC (IRR 0.64; 95%CI 0.56-0.72), a 13% lower rate of pN+ BC (IRR 0.87; 95%CI 0.78-0.98), a 22% lower rate of stage II+ BC (IRR 0.78; 95%CI 0.70-0.87), and a 32% lower rate of mastectomy (IRR 0.68; 95%CI 0.60-0.78). CONCLUSIONS: attenders had lower incidence rates of advanced-stage BC. This early effect is suggestive of a future impact of the screening programme on BC mortality.

Volumetric breast density and risk of advanced cancers after a negative screening episode: a cohort study.

BACKGROUND: We evaluated the association between volumetric breast density (BD) and risk of advanced cancers after a negative screening episode. METHODS: A cohort of 16,752 women aged 49-54 years at their first screening mammography in the Florence screening programme was followed for breast cancer (BC) incidence until the second screening round. Volumetric BD was measured using fully automated software. The cumulative incidence of advanced cancer after a negative screening episode (including stage II or more severe cancer during the screening interval - on average 28 months - and at the subsequent round) was calculated separately for Volpara density grade (VDG) categories. RESULTS: BC incidence gradually increased with the increas in BD: 3.7‰, 5.1‰, 5.4‰ and 9.1‰ in the VDG categories 1-4, respectively (p trend < 0.001). The risk of advanced cancers after a negative screening episode was 1.0‰, 1.3‰, 1.1‰, and 4.2‰ (p trend = 0.003). The highest BD category, compared with the other three together, has double the invasive BC risk (RR = 2.0; 95% CI 1.5-2.8) and almost fourfold risk of advanced cancer (RR = 3.8; 95% CI 1.8-8.0). CONCLUSION: BD has a strong impact on the risk of advanced cancers after a negative screening episode, the best early surrogate of BC mortality. Therefore, our results suggest that screening effectiveness is quite different among BD categories.

Monitoring vaccine and non-vaccine HPV type prevalence in the post-vaccination era in women living in the Basilicata region, Italy.

BACKGROUND: A large free-of-charge quadrivalent HPV (qHPV) vaccination program, covering four cohorts annually (women 11, 14, 17 and 24 years), has been implemented in Basilicata since 2007. This study evaluated vaccine and non-vaccine HPV prevalence 5-7 years post-vaccination program implementation in vaccinated and unvaccinated women. METHODS: This population-based, cross-sectional study was conducted in the public screening centers of the Local Health Unit in Matera between 2012 and 2014. Cervical samples were obtained for Pap and HPV testing (HC2, LiPA Extra® assay) and participants completed a sociodemographic and behavioral questionnaire. Detailed HPV vaccination status was retrieved from the official HPV vaccine registry. HPV prevalence was described overall, by type and vaccination status. The association between HPV type-detection and risk/protective factors was studied. Direct vaccine protection (qHPV vaccine effectiveness [VE]), cross-protection, and type-replacement were evaluated in cohorts eligible for vaccination, by analyzing HPV prevalence of vaccine and non-vaccine types according to vaccination status. RESULTS: Overall, 2793 women (18-50 years) were included, 1314 of them having been in birth cohorts eligible for the HPV vaccination program (18- to 30-year-old women at enrolment). Among the latter, qHPV vaccine uptake was 59% (at least one dose), with 94% completing the schedule; standardized qHPV type prevalence was 0.6% in vaccinated versus 5.5% in unvaccinated women (P <0.001); adjusted VE against vaccine type infections was 90% (95% CI: 73%-96%) for all fully vaccinated women and 100% (95% CI not calculable) in women vaccinated before sexual debut. No statistically significant difference in overall high-risk HPV, high-risk non-vaccine HPV, or any single non-vaccine type prevalence was observed between vaccinated and unvaccinated women. CONCLUSIONS: These results, conducted in a post-vaccine era, suggest a high qHPV VE and that a well-implemented catch-up vaccination program may be efficient in reducing vaccine-type infections in a real-world setting. No cross-protective effect or evidence of type-replacement was observed a few years after HPV vaccine introduction.

Mortality, survival and incidence rates in the ITALUNG randomised lung cancer screening trial.

BACKGROUND: ITALUNG is contributing to the European evaluation of low-dose CT (LDCT) screening for lung cancer (LC). METHODS: Eligible subjects aged 55-69 years, smokers or ex-smokers (at least 20 pack-years in the last 10 years), were randomised to receive an annual invitation for LDCT screening for 4 years (active group) or to usual care (control group). All participants were followed up for vital status and cause of death (at the end of 2014) and LC incidence (at the end of 2013). Pathological and clinical information was collected from the Tuscan Cancer Registry data. RESULTS: 1613 subjects were randomly assigned to the active group and 1593 to the control group. At the end of the follow-up period 67 LC cases were diagnosed in the active group and 71 in the control group (rate ratio (RR)=0.93; 95% CI 0.67 to 1.30). A greater proportion of stage I LC was observed in the active group (36% vs 11%, p<0.001). Non-significant reductions of 17% (RR=0.83; 95% CI 0.67 to 1.03) for overall mortality and 30% (RR=0.70; 95% CI 0.47 to 1.03) for LC-specific mortality were estimated. CONCLUSIONS: Despite the lack of statistical significance, the ITALUNG trial outcomes suggest that LDCT screening could reduce LC and overall mortality. Moreover, the comparison of the number of LC cases diagnosed in the two groups does not show overdiagnosis after an adequate follow-up period. A pooled analysis of all European screening trials is advocated to assess the benefit-to-harm ratio of LDCT screening and its implementation in public health settings. TRIAL REGISTRATION NUMBER: Results, NCT02777996.

Patterns and determinants of receipt of follow-up mammography and/or clinical examination in a cohort of Italian breast cancer survivors.

Information regarding the use of mammography by breast cancer survivors is limited. This study aimed at evaluating the compliance to surveillance mammography and/or clinical breast examination and the associated factors among patients living in northern Italy. A cancer registry-based cohort of 1304 patients living in the Health Care District of Forlì was followed up for 10 years. Eighty percent of patients had a mammogram and/or clinical breast examination during the first year after treatment. The proportion decreased to 67 % at 10 years of follow-up. Three demographic characteristics were independently associated with lower odds of having an annual mammogram and/or clinical breast examination: age at diagnosis [odds ratio (OR) 0.51, 95 % confidence interval (CI) 0.41-0.63 for patients aged 65-74 years; and OR 0.14, 95 % CI 0.11-0.18, for patients ≥75 years versus patients aged <64 year]; socio-economic status (OR 0.81, 95 % CI 0.65-1.00, for deprived patients versus patients of the reference class); and hospital travel time greater than 30 min (OR 0.44, 95 % CI 0.29-0.68 versus ≤15 min). With respect to clinical and disease characteristics, lower odds were observed for patients treated with mastectomy (OR 0.79, 95 % CI 0.65-0.97), for patients diagnosed with in situ breast cancer (OR 0.68, 95 % CI 0.46-0.99) as well as with stage II + breast cancer (OR 0.77, 95 % CI 0.63-0.94), and for patients with ≥3 Elixhauser comorbidities (OR 0.43, 95 % CI 0.26-0.71). Adherence to follow-up declined over time. Knowledge of associated factors may assist in improving access to care for breast cancer survivors.

Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up.

BACKGROUND: The European Randomised study of Screening for Prostate Cancer (ERSPC) has shown significant reductions in prostate cancer mortality after 9 years and 11 years of follow-up, but screening is controversial because of adverse events such as overdiagnosis. We provide updated results of mortality from prostate cancer with follow-up to 2010, with analyses truncated at 9, 11, and 13 years. METHODS: ERSPC is a multicentre, randomised trial with a predefined centralised database, analysis plan, and core age group (55-69 years), which assesses prostate-specific antigen (PSA) testing in eight European countries. Eligible men aged 50-74 years were identified from population registries and randomly assigned by computer generated random numbers to screening or no intervention (control). Investigators were masked to group allocation. The primary outcome was prostate cancer mortality in the core age group. Analysis was by intention to treat. We did a secondary analysis that corrected for selection bias due to non-participation. Only incidence and no mortality data at 9 years' follow-up are reported for the French centres. This study is registered with Current Controlled Trials, number ISRCTN49127736. FINDINGS: With data truncated at 13 years of follow-up, 7408 prostate cancer cases were diagnosed in the intervention group and 6107 cases in the control group. The rate ratio of prostate cancer incidence between the intervention and control groups was 1·91 (95% CI 1·83-1·99) after 9 years (1·64 [1·58-1·69] including France), 1·66 (1·60-1·73) after 11 years, and 1·57 (1·51-1·62) after 13 years. The rate ratio of prostate cancer mortality was 0·85 (0·70-1·03) after 9 years, 0·78 (0·66-0·91) after 11 years, and 0·79 (0·69-0·91) at 13 years. The absolute risk reduction of death from prostate cancer at 13 years was 0·11 per 1000 person-years or 1·28 per 1000 men randomised, which is equivalent to one prostate cancer death averted per 781 (95% CI 490-1929) men invited for screening or one per 27 (17-66) additional prostate cancer detected. After adjustment for non-participation, the rate ratio of prostate cancer mortality in men screened was 0·73 (95% CI 0·61-0·88). INTERPRETATION: In this update the ERSPC confirms a substantial reduction in prostate cancer mortality attributable to testing of PSA, with a substantially increased absolute effect at 13 years compared with findings after 9 and 11 years. Despite our findings, further quantification of harms and their reduction are still considered a prerequisite for the introduction of populated-based screening. FUNDING: Each centre had its own funding responsibility.

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.

Decreasing incidence of late-stage breast cancer after the introduction of organized mammography screening in Italy.

BACKGROUND: After the introduction of a mammography screening program, the incidence of late-stage breast cancer is expected to decrease. The objective of the current study was to evaluate variations in the total incidence of breast cancer and in the incidence of breast cancers with a pathologic tumor (pT) classification of pT2 through pT4 after the introduction of mammography screening in 6 Italian administrative regions. METHODS: The study area included 700 municipalities, with a total population of 692,824 women ages 55 to 74 years, that were targeted by organized mammography screening between 1991 and 2005. The year screening started at the municipal level (year 1) was identified. The years of screening were numbered from 1 to 8. The ratio of the observed 2-year, age-standardized (Europe) incidence rate to the expected rate (the incidence rate ratio [IRR]) was calculated. Expected rates were estimated assuming that the incidence of breast cancer was stable and was equivalent to that in the last 3 years before year 1. RESULTS: The study was based on a total of 14,447 incident breast cancers, including 4036 pT2 through pT4 breast cancers. The total IRR was 1.35 (95% confidence interval, 1.03-1.41) in years 1 and 2, 1.16 (95% confidence interval, 1.10-1.21) in years 3 and 4, 1.14 (95% confidence interval, 1.08-1.20) in years 5 and 6, and 1.14 (95% confidence interval, 1.08-1.21) in years 7 and 8. The IRR for pT2 through pT4 breast cancers was 0.97 (95% confidence interval, 0.90-1.04) in years 1 and 2, 0.81 (95% confidence interval, 0.75-0.88) in years 3 and 4, 0.79 (95% confidence interval, 0.73-0.87) in years 5 and 6, and 0.71 (95% confidence interval, 0.64-0.79) in years 7 and 8. CONCLUSIONS: A significant and stable decrease in the incidence of late-stage breast cancer was observed from the third year of screening onward, when the IRR varied between 0.81 and 0.71.

[Tailored Breast Screening Trial (TBST)]. / Tailored Breast Screening Trial (TBST).

BACKGROUND: mammography screening in premenopausal women is still the object of controversy and the cost and harms-benefit balance is lower than the one observed for women aged 50 years or more. The reasons are the lower screening sensitivity and the lower risk of occurrence of breast cancer at younger ages. For these reasons, an annual interval is suggested for this age group, and a lower positive predictive value of the recall rate is observed in screening practice. Harms of screening are false positive rates and overdiagnosis (that is an exceeding number of cases over the women's lifetime ascribable to early diagnosis). A tailored approach to screening could both contribute to a reduction of possible harms and reduce the costs of the service screening programmes, which started to offer screening mammography to 45- 49-year-old women also in Italy, according with the suggestions of the Italian Group for Mammography Screening. Higher breast density is considered a marker of risk and, at the same time, it brings about a masking effect that decreases the screening mammography sensitivity at younger ages. AIM: the Tailored Breast Screening Trial (TBST) is a population-based, non-inferiority randomised trial aimed at evaluating the impact of a change in the screening protocol in a service screening practice. "Tailored" means that the use of a breast density classification allocates women to a longer interval, decreasing the number of screening rounds in the 45- 50-year age range. Density of the breast at the baseline is considered as an indicator of risk and also as a masking factor. The aim of this study is to assess the impact of a longer interval and the reduction of side effects for women allocated to the intervention group. In this study, any further intervention is offered to high-density women who are followed-up according to the usual care interval, since the study aimed at decreasing the screening burden. METHODS: 45-year-old women resident in the screening centre catchment area will be invited to attend for mammography screening and will be asked for informed consent in order to be included in the study. After the enrolment, they will receive a high quality digital mammography; two views and breast density will be classified according with the BI-RADS classification. Women are randomly allocated either to an usual care group or to the intervention group. In the intervention group, women with a dense breast (3-4 categories in BI-RADS)will be invited again after 1 year, while the lower-density group in the intervention arm will be invited after 2 years. After the age of 50, all women will continue to be screened in the usual service screening programme. Density of the breast will be read by 2 readers, and controversies will be solved by a consensus. Allocation of women is blinded to the mammography readers. EXPECTED RESULTS: the outcomes are: A. cumulative incidence of interval-cancer cases by intention to treat (ITT) grouping and by density group, aimed at assessing the non inferiority of screening performance; B. cumulative incidence of T2+/node-positive status breast cancer cases between arms and by protocol. Screening performance parameters will be evaluated at each screening round. Interim and outcome analysis are expected at 3 and 6 years average follow- up, respectively, starting from the beginning of the screening. SAMPLE SIZE: the non-inferiority limit is derived from the accepted level of interval cancers in women 50-69 years, which was considered acceptable by the European Community Guidelines. Assuming a 70%BI-RADS 1-2 at the baseline on the basis of the digital mammography experience, the estimated sample size with a power of 90% is 16,596 women per arm. RESULTS OF THE FEASIBILITY STUDY: the background of the study, that uses data from cancer registries and screening centres, describes the most relevant characteristics of breast cancer occurring in the Italian regions where the study will be conducted. The description of stage distribution in the 40-54-year-old group and the coverage by spontaneous screening, as available by outpatient current data, showed the modification of stage at presentation, according with the implementation of service screening in women 50-54 years. In Emilia-Romagna and Piedmont Regions, service screening is already active for women aged 45 years and more, even though different invitation protocols were used. In Tuscany Region the extension of screening has already been planned for the next few years. Performance data are reported: they show the recall and the detection rates at first and at repeated screening rounds in Emilia-Romagna Region. In order to assess the feasibility and the interobserver reproducibility of breast density visual classification by BI-RADS, two testing sets of 80 digital mammograms for screened women aged 50-52 years were made available by the ISPO (Institute for oncological study and prevention) service screening tests. The test was performed by 11 radiologists, which are members of the working group. Concordance was moderate with a BI-RADS classification in 4 categories (kappa=0.46;95%CI 0.41-0.53), and substantial using 1-2 vs.3-4 (kappa=0.68;95%CI 0.59-0.79). The retest performed using the second mammography test did not change the results. CONCLUSION: the TBST was authorised by the Ethical Committee in Florence (Tuscany Region, Central Italy) and the recruitment is still in progress through the invitation of the target population in the participating screening centres. In Florence and Veneto Region, the first round is almost completed and it confirmed the feasibility of the study and of the randomisation process.

Accuracy and Reproducibility of Cytology Triage in a HPV-Based Primary Screening Setting: A Revision of 384 Pap Tests.

INTRODUCTION: After the transition toward the HPV-based screening protocol, which has led to an increase in sensitivity, and in order to bring the specificity back to acceptable values, cytology underwent a change of approach, becoming a triage test. For these reasons, in the Tuscany region (after the recommendations of the GISCi document), it was decided to reduce, as much as possible, the use of ASC-US category in cytology triage, classifying these morphological cases as negative for intraepithelial lesion or malignancies (NILM) or LSIL, basing on the grade of nuclear atypia. So, in Italy, in a cytology triage context (HPV primary screening), a modified Bethesda system (TBS) is currently used. The aim of this study was to evaluate the performance of the review activity of 384 cytology triage cases and of the cervical cancer screening indicators (sensitivity and specificity for CIN2+ lesions) using the TBS 2014 or the modified TBS. MATERIALS AND METHODS: 384 HPV positive cases at one-year recall (192 with a cytology result of NILM both at baseline and at one-year recall; 192 with a cytology result of NILM at baseline but abnormal at one-year recall), all with a histologically confirmed result (128 CIN2+, 256 ≤ CIN1), were selected, and their baseline Pap tests were reviewed in blind mode by 5 expert cytologists. RESULTS: The cytological results of NILM were confirmed for 92.5% and 83.8% of cases using TBS 2014 or modified TBS, respectively. 20/128 CIN2+ cases could have been reported at the baseline cytology triage, causing an anticipatory effect and an improvement in sensitivity of the screening protocol at baseline (+15.6%). Using TBS 2014, the number of false positives more than tripled with respect to the modified TBS 2014, with a significant increase in unnecessary colposcopies (+11.4%). CONCLUSION: This work demonstrated that a greater expertise of cytologists, acquired during the following 3 years of experience with cytological triage, and a strong IQC system could lead to the identification of a significant number of lesions reported to baseline rather than at one-year recall (diagnostic anticipation).

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.

Relationship Between Baseline Prostate-specific Antigen on Cancer Detection and Prostate Cancer Death: Long-term Follow-up from the European Randomized Study of Screening for Prostate Cancer.

BACKGROUND: The European Association of Urology guidelines recommend a risk-based strategy for prostate cancer screening based on the first prostate-specific antigen (PSA) level and age. OBJECTIVE: To analyze the impact of the first PSA level on prostate cancer (PCa) detection and PCa-specific mortality (PCSM) in a population-based screening trial (repeat screening every 2-4 yr). DESIGN, SETTING, AND PARTICIPANTS: We evaluated 25589 men aged 55-59 yr, 16898 men aged 60-64 yr, and 12936 men aged 65-69 yr who attended at least one screening visit in the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial (screening arm: repeat PSA testing every 2-4 yr and biopsy in cases with elevated PSA; control arm: no active screening offered) during 16-yr follow-up (FU). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We assessed the actuarial probability for any PCa and for clinically significant (cs)PCa (Gleason ≥7). Cox proportional-hazards regression was performed to assess whether the association between baseline PSA and PCSM was comparable for all age groups. A Lorenz curve was computed to assess the association between baseline PSA and PCSM for men aged 60-61 yr. RESULTS AND LIMITATIONS: The overall actuarial probability at 16 yr ranged from 12% to 16% for any PCa and from 3.7% to 5.7% for csPCa across the age groups. The actuarial probability of csPCa at 16 yr ranged from 1.2-1.5% for men with PSA <1.0 ng/ml to 13.3-13.8% for men with PSA ≥3.0 ng/ml. The association between baseline PSA and PCSM differed marginally among the three age groups. A Lorenz curve for men aged 60-61 yr showed that 92% of lethal PCa cases occurred among those with PSA above the median (1.21 ng/ml). In addition, for men initially screened at age 60-61 yr with baseline PSA <2 ng/ml, further continuation of screening is unlikely to be beneficial after the age of 68-70 yr if PSA is still <2 ng/ml. No case of PCSM emerged in the subsequent 8 yr (up to age 76-78 yr). A limitation is that these results may not be generalizable to an opportunistic screening setting or to contemporary clinical practice. CONCLUSIONS: In all age groups, baseline PSA can guide decisions on the repeat screening interval. Baseline PSA of <1.0 ng/ml for men aged 55-69 yr is a strong indicator to delay or stop further screening. PATIENT SUMMARY: In prostate cancer screening, the patient's baseline PSA (prostate-specific antigen) level can be used to guide decisions on when to repeat screening. The PSA test when used according to current knowledge is valuable in helping to reduce the burden of prostate cancer.

Balancing harms and benefits of service mammography screening programs: a cohort study.

INTRODUCTION: The use of screening mammography is still under debate within the medical community. The aim of this study is to define a balance sheet of benefits (breast cancer mortality reduction) and harms (overdiagnosis) for mammography screening programs. METHODS: We compared breast cancer incidence and mortality in two cohorts of women, defined as 'attenders' or 'non-attenders' on the basis of the individual attitudes towards screening, who were invited to the first round of the Florentine screening program. The effects of screening exposure on breast cancer incidence and mortality were evaluated by fitting Poisson regression models adjusted for age at entry, marital status and deprivation index. We performed a sensitivity analysis excluding 34 women not responding to the invitation with a breast cancer diagnosis in the following six months. RESULTS: In total, we included 51,096 women aged 50 to 69 years invited at the first screening round (1991 to 1993) and followed-up for breast cancer incidence and mortality until 31 December 2007 and 31 December 2008, respectively The estimate of mortality reduction varies from 45% among 50 to 59 year-old women up to 51% among 60 to 69 year-old women. The estimate of overdiagnosis, according to the cumulative-incidence method, is an additional 10% of all breast cancer cases among 60 to 69 year-old women screened. CONCLUSIONS: Comparing the breast cancer mortality and breast cancer incidence between attenders and non-attenders, we have determined that the overall cost to save one life corresponds to no more than one over-diagnosed tumor (from 0.6 to 1 depending on the selection criteria of the cohort), even if a residual self-selection bias cannot be excluded.

Breast cancer screening: are we seeing the benefit?

A decline in breast cancer mortality has been observed in western European Countries since the middle of the 1990s. Different methodological approaches, including case-control studies, incidence-based mortality studies, and trend studies, have been used to assess the effectiveness of mammography screening programmes in reducing breast cancer mortality. However, not all methods succeed in distinguishing the relative contributions of service screening and taking correctly into consideration the potential source of bias that might affect the estimate. Recently, a review of six case-control studies confirmed a breast cancer mortality reduction ranging from 38% to 70% among screened women. This figure is in accordance with the estimate obtained from incidence-based mortality studies if screening compliance is taken into account. We will describe the methodological constraints of mortality trend studies in predicting the impact of screening on mortality and the necessary caution that must be applied when interpreting the results of such studies. In conclusion, when appropriate methodological approaches are used, it is evident that mammographic screening programmes have contributed substantially to the observed decline in breast cancer mortality.

Single CT Appointment for Double Lung and Colorectal Cancer Screening: Is the Time Ripe?

Annual screening of lung cancer (LC) with chest low-dose computed tomography (CT) and screening of colorectal cancer (CRC) with CT colonography every 5 years are recommended by the United States Prevention Service Task Force. We review epidemiological and pathological data on LC and CRC, and the features of screening chest low-dose CT and CT colonography comprising execution, reading, radiation exposure and harm, and the cost effectiveness of the two CT screening interventions. The possibility of combining chest low-dose CT and CT colonography examinations for double LC and CRC screening in a single CT appointment is then addressed. We demonstrate how this approach appears feasible and is already reasonable as an opportunistic screening intervention in 50-75-year-old subjects with smoking history and average CRC risk. In addition to the crucial role Computer Assisted Diagnosis systems play in decreasing the test reading times and the need to educate radiologists in screening chest LDCT and CT colonography, in view of a single CT appointment for double screening, the following uncertainties need to be solved: (1) the schedule of the screening CT; (2) the effectiveness of iterative reconstruction and deep learning algorithms affording an ultra-low-dose CT acquisition technique and (3) management of incidental findings. Resolving these issues will imply new cost-effectiveness analyses for LC screening with chest low dose CT and for CRC screening with CT colonography and, especially, for the double LC and CRC screening with a single-appointment CT.

Overdiagnosis in breast cancer: design and methods of estimation in observational studies.

OBJECTIVES: In recent years observational epidemiological studies have been used to estimate overdiagnosis in breast cancer screening. These estimates vary widely. In this paper we present some of the methodological issues which explain the large variability of the reported findings. METHODS: Different types of observational studies were identified according to study design, definition of the population, adjustment for breast cancer risk and adjustment for lead time. RESULTS: The majority of observational studies that have estimated breast cancer overdiagnosis have analyzed temporal trends or geographical differences in breast cancer incidence. Estimates of overdiagnosis in a dynamic population vary widely, from 4% to 52%. Only a few studies have used the cohort approach and they found estimates varying from 1% to 5%. CONCLUSIONS: The cohort approach is preferable to the analysis of a dynamic population because it allows the follow-up of a group of women who have had the opportunity for screening and evaluates if there is sufficient follow-up after the last screen.

[End-of-life care and end-of-life medical decisions: the ITAELD study]. / Cure di fine vita e decisioni mediche: lo studio ITAELD.

OBJECTIVE: To describe the attitudes towards end of life care and the practice of end-of-life medical decisions with possible life-shortening effect among Italian physicians. DESIGN: Cross sectional study (last death among the assisted patients in the last 12 months was considered). SETTING AND PARTICIPANTS: In the year 2007, 5,710 GPs and 8,950 hospital physicians were invited all over Italy to participate in the ITAELDstudy through anonymous mail questionnaire. MAIN OUTCOME MEASURES: Proportion of agreement with statements on end-of-life care issues. Proportion of deaths with an end-of-life medical decision. RESULTS: The response rate was 19.2%. The 65% of respondents agreed with the duty to respect any non-treatment request of the competent patient, the 55% agreed with the same duty in case of advanced directives, the 39% in case of proxy's request. The 53% of respondents agreed with the ethical acceptability of active euthanasia in selected cases. Among 1,850 deaths the 57.7% did not receive any end-of-life medical decision. For a further 21.0% no decision was possible, being sudden and unexpected deaths. In the remaining 21.3% at least one end-of-life medical decision was reported: 0.8% was classified as physician assisted death, 20.5% as non-treatment decision. Among all deceased the 19.6% were reported to have been deeply sedated. Being favourable to the use of opioids in terminal patients was associated to non-treatment decisions with possible but non-intentional life shortening effect; agreeing with the duty to fully respect any actual non-treatment request of the competent patient was associated to end-of life medical decisions with intentional life-shortening effect (adjusted OR>10 in both cases). CONCLUSIONS: The life stance and ethical beliefs of physicians determine their behaviour at the end of life wherever specific statements of law are lacking. Therefore education and debate are needed on these issues.

[Cancer incidence in Italian natives and in first-generation immigrants to Italy]. / L'incidenza dei tumori in cittadini nati in Italia e in immigrati di prima generazione.

OBJECTIVE: The aim of this study was to evaluate differences in cancer incidence in populations born in different countries in the area covered by the Tuscan Cancer Registry. SETTING: We selected cancer cases diagnosed during the period 1998-2005 in the population resident in the provinces of Firenze and Prato. Each case was classified according to the place of birth: a) born in Italy, b) born in countries with high migration (PFPM), born in other highly developed countries (PSA).To compute incidence rates we used as denominator the health regional registry. MAIN OUTCOME MEASURES: We used the European standard population in computing standardized incidence rates (restricted to the age group 20-59 years) and the standardized rate ratio (SRR) in order to compare subjects born in different countries. RESULTS: During the period 1998-2005, 14 791 invasive cancers were diagnosed (non-melanoma skin excluded) in subjects aged 20-59 years old, 4.2% in subjects born in countries outside Italy (1.2% in other PSA e 3.0% in PFPM). Incidence in subjects born in PSA did not differ significantly from incidence in subjects born in Italy. Incidence rates among subjects born in PFPM were statistically lower, both in men (151.2 per 100 000) and women (199.3 per 100 000), than in subjects born in Italy (243.5 men e 337.5 women). On the contrary, liver and cervix uteri cancer incidence showed higher rates among subjects born in PFPM (liver: SRR=2.13, p=0.007; cervix uteri: SRR=1.88, p=0.0095). CONCLUSION: Subjects born in countries with high migration showed a level of incidence lower than subjects born in Italy (healthy migration effect). Incidence was higher among subjects born in PFPM only for liver and cervix uteri, cancers with a virological aetiology. The migration phenomena open new study prospectives, but also methodological questions (definition of immigrants and of reference populations).