Eugenio Paci

The ITALUNG trial (Italian Lung Cancer Screening Trial) is a randomised controlled trial that evaluated the efficacy of Low-Dose Computed Tomography (LDCT) for lung cancer screening of over 3100 high-risk individuals, smokers and ex-smokers, aged 55–69. ITALUNG was coordinated by the Institute for Cancer Prevention Research in Florence and carried out across Tuscany in three main screening centres: Florence, Pisa, and Pistoia. The ITALUNG study demonstrated lower long-term lung cancer (LC) and cardiovascular mortality in the screened groups, with notable benefits observed in women. When the performance of the ITALUNG biomarker panel, i.e., loss of heterozygosity and microsatellite instability (LOH/MSI) and circulating free DNA (cfDNA), was analysed in samples of blood and sputum from asymptomatic high-risk subjects screened for lung cancer, sensitivity (SE) was 90% at baseline screening. However, the respective roles of LDCT screening and fluid biomarkers in screening for lung cancer are not established, highlighting the need for biomarkers to be able to detect tumours not only at the time of diagnosis but also when tested in pre-diagnostic samples. Therefore, we evaluated the longitudinal changes in the performance of multiple biomarkers in the ITALUNG biomarker panel and/or its single components to identify LC patients in ITALUNG. The cohort consisted of 55 LC patients whose biological specimens were collected over several years before diagnosis. Good results were found in test specimens obtained close to the time of diagnosis; out of 21 LC cases, 20 were positive in the ITALUNG biomarker panel [95% SE; 95% C.I. 0.86–1.04], 18 for LOH/MSI (86% SE; 95% C.I. 0.71–1.01) and 17 for cfDNA (85% SE; 95% C.I. 0.70–1.00). The panel was able to identify over 80% of LC cases by analysing the pre-diagnostic samples collected within 3 years prior to diagnosis: out of six LC patients, five were positive in the ITALUNG biomarker panel (83% SE; 95% C.I. 0.53–1.13). In addition, over 67% of the early and resected cancer cases were detected by the multiple-biomarker panel when biomarker testing samples were obtained within 11 years prior to diagnosis. The positivity of the ITALUNG biomarker panel might be associated with both carcinogenic field effects and early tumour presence when using pre-diagnostic samples obtained several years before diagnosis.

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.

This article aims to present the results of a national, cross-sectional, voluntary, online survey on the presence and roles of associations of breast cancer patients and volunteers in Italian specialist breast centres. The survey was developed according to standard methods. The questionnaire was pre-tested by a random sample of three breast centres, loaded onto the SurveyMonkey platform, and piloted by one volunteer breast centre. The breast centre clinical leads were invited to participate via email. A link to the online instrument was provided. No financial incentives were offered. The results were reported using standard descriptive statistics. The response rate was 82/128 (65%). Members of associations were routinely present in 70% Italian breast centres. Breast centres most often reporting their presence were those certified by the European Society of Breast Cancer Specialists. Patient support (reception and information, listening, identification of needs, and psychological support) was the primary area where associations were reported to offer services. The magnitude of this phenomenon warrants a study to investigate the impact of the activities of associations on the quality of life of patients and on the cost–benefit ratio of the service, and the modes of their interactions with the nursing staff and the medical staff.

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 new EU Council Recommendation on cancer screening extends organized mammography screening to the 45-74 -year age group. Mammography screening in young women has been the subject of discussion since its inception almost forty years ago. Starting from the recent publication of the survival data for breast cancer of the regional programme for women aged 45-49 years, activated in the Emilia-Ro-magna Region (Northern Italy), it is here proposed to test, with a research and innovation practice, a new screening of-fer for the 45-54-year age group with a tailored approach, i.e., based on the risk level and breast density.

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-center 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 generation of rapid information has been an import-ant novelty in the COVID-19 pandemic and a challenge for epidemiology. The methodological frailty and uncertainty of rapid data use has been a consequence. We are talk-ing about an 'intermezzo' epidemiology between the event and the production of consolidated data that opens up great opportunities to the use epidemiology for rapid public health decisions, provided a careful work to be done before emergencies. In Italy, an ad hoc national COVID-19 information system producing daily data that quickly be-came essential for public decision-making. Total and all-cause mortality data are derived from the traditional information system of the Italian National Institute of Stat-istics (Istat), which, at the onset of the pandemic, was un-able to provide rapid total and all-causes mortality data at the national level and still produces them with a one-to two-month delay. National cause and place mortality data referred to the first epidemic wave (March and April 2020) was in May 2021 and recently updated (October 2022) for the whole year 2020. Nearly three years after the on-set of the epidemic, we have no nationwide rapid informa-tion on the distribution of deaths by place of death (hospit-als, nursing homes and other care facilities, home) neither on their breakdown in 'by COVID-19', 'with COVID-19', and 'non-COVID-19' deaths. The pandemic being still in progress, new problems arise (the long-term impact of COVID-19, the impact of lockdown policies, etcetera), whose solution cannot be postponed until peer reviewed papers are available. A fine-tuning of the rapid processing of interim data certainly requires the development of na-tional and regional information systems, but first of all a methodologically robust 'intermezzo' epidemiology.

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. 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. 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). This long-term survival analysis, by prognostic categories, concluded against the long-term risk of overdiagnosis and contributed to revealing how screening works.