Cytisine as a smoking cessation aid: Preliminary observations with a modified therapeutic scheme in real life.

INTRODUCTION: Cigarette smoke accounts for over 90,000 deaths each year in Italy. Tobacco dependence treatment guidelines suggest adopting an integrated pharmacological-behavioral model of intervention. Cytisine is a partial agonist of nicotinic receptors. Trials conducted to date have demonstrated its good efficacy in promoting smoking cessation. The cytisine scheme of treatment consists of 25 days of treatment. A 40-day regimen, with an escalating dose and an extended duration of the treatment, has been in use in many anti-smoking centers in Italy for several years, but to date there are no reports on the use of cytisine with this scheme. METHODS: A retrospective, real-life, observational study was conducted between January 2016 and September 2022. The 300 patients who had received at least one dose of study medication were selected. Continuous variables were compared by the Wilcoxon-Mann-Whitney test. Univariate and multivariate logistic regression models were implemented for self-reported seven-day point prevalence for abstinence at three, six and 12 months. RESULTS: The median age of the patients was 59 years, 57% were women. The median smoking exposure was 33.8 pack-years. Self-reported smoking abstinence at three, six and 12 months was 68.7%, 56.3% and 47.3% respectively. 84% completed the cytisine treatment, 31.3% reported adverse events and in 8.3% these led to dropping out of the treatment. CONCLUSION: Cytisine, administered with a novel therapeutic scheme in the real-life setting of a specialized anti-smoking center, significantly promotes smoking abstinence. However, more studies are needed to assess the tolerability and efficacy of this new regimen.

Long-term outcomes of lung cancer screening in males and females.

BACKGROUND: This study explored female and male overall mortality and lung cancer (LC) survival in two LC screening (LCS) populations, focusing on the predictive value of coronary artery calcification (CAC) at baseline low-dose computed tomography (LDCT). METHODS: This retrospective study analysed data of 6495 heavy smokers enrolled in the MILD and BioMILD LCS trials between 2005 and 2016. The primary objective of the study was to assess sex differences in all-cause mortality and LC survival. CAC scores were automatically calculated on LDCT images by a validated artificial intelligence (AI) software. Sex differences in 12-year cause-specific mortality rates were stratified by age, pack-years and CAC score. RESULTS: The study included 2368 females and 4127 males. The 12-year all-cause mortality rates were 4.1 % in females and 7.7 % in males (p < 0.0001), and median CAC score was 8.7 vs. 41 respectively (p < 0.0001). All-cause mortality increased with rising CAC scores (log-rank test, p < 0.0001) for both sexes. Although LC incidence was not different between the two sexes, females had lower rates of 12-year LC mortality (1.0 % vs. 1.9 %, p = 0.0052), and better LC survival from diagnosis (72.3 % vs. 51.7 %; p = 0.0005), with a similar proportion of stage I (58.1 % vs. 51.2 %, p = 0.2782). CONCLUSIONS: Our findings demonstrate that female LCS participants had lower rates of all-cause mortality at 12 years and better LC survival than their male counterparts, with similar LC incidence rates and stage at diagnosis. The lower CAC burden observed in women at all ages might contribute to explain their lower rates of all-cause mortality and better LC survival.

Routine perioperative blood tests predict survival of resectable lung cancer.

There is growing evidence that inflammatory, immunologic, and metabolic status is associated with cancer patients survival. Here, we built a simple algorithm to predict lung cancer outcome. Perioperative routine blood tests (RBT) of a cohort of patients with resectable primary lung cancer (LC) were analysed. Inflammatory, immunologic, and metabolic profiles were used to create a single algorithm (RBT index) predicting LC survival. A concurrent cohort of patients with resectable lung metastases (LM) was used to validate the RBT index. Charts of 2088 consecutive LC and 1129 LM patients undergoing lung resection were evaluated. Among RBT parameters, C-reactive protein (CRP), lymphocytes, neutrophils, hemoglobin, albumin and glycemia independently correlated with survival, and were used to build the RBT index. Patients with a high RBT index had a higher 5-year mortality than low RBT patients (adjusted HR 1.93, 95% CI 1.62-2.31). High RBT patients also showed a fourfold higher risk of 30-day postoperative mortality (2.3% vs. 0.5%, p 0.0019). The LM analysis validated the results of the LC cohort. We developed a simple and easily available multifunctional tool predicting short-term and long-term survival of curatively resected LC and LM. Prospective external validation of RBT index is warranted.

Fully automated calcium scoring predicts all-cause mortality at 12 years in the MILD lung cancer screening trial.

Coronary artery calcium (CAC) is a known risk factor for cardiovascular (CV) events and mortality but is not yet routinely evaluated in low-dose computed tomography (LDCT)-based lung cancer screening (LCS). The present analysis explored the capacity of a fully automated CAC scoring to predict 12-year mortality in the Multicentric Italian Lung Detection (MILD) LCS trial. The study included 2239 volunteers of the MILD trial who underwent a baseline LDCT from September 2005 to January 2011, with a median follow-up of 190 months. The CAC score was measured by a commercially available fully automated artificial intelligence (AI) software and stratified into five strata: 0, 1-10, 11-100, 101-400, and > 400. Twelve-year all-cause mortality was 8.5% (191/2239) overall, 3.2% with CAC = 0, 4.9% with CAC = 1-10, 8.0% with CAC = 11-100, 11.5% with CAC = 101-400, and 17% with CAC > 400. In Cox proportional hazards regression analysis, CAC > 400 was associated with a higher 12-year all-cause mortality both in a univariate model (hazard ratio, HR, 5.75 [95% confidence interval, CI, 2.08-15.92] compared to CAC = 0) and after adjustment for baseline confounders (HR, 3.80 [95%CI, 1.35-10.74] compared to CAC = 0). All-cause mortality significantly increased with increasing CAC (7% in CAC ≤ 400 vs. 17% in CAC > 400, Log-Rank p-value <0.001). Non-cancer at 12 years mortality was 3% (67/2239) overall, 0.8% with CAC = 0, 1.0% with CAC = 1-10, 2.9% with CAC = 11-100, 3.6% with CAC = 101-400, and 8.2% with CAC > 400 (Grey's test p < 0.001). In Fine and Gray's competing risk model, CAC > 400 predicted 12-year non-cancer mortality in a univariate model (sub-distribution hazard ratio, SHR, 10.62 [95% confidence interval, CI, 1.43-78.98] compared to CAC = 0), but the association was no longer significant after adjustment for baseline confounders. In conclusion, fully automated CAC scoring was effective in predicting all-cause mortality at 12 years in a LCS setting.

Ultra-low dose computed tomography protocols using spectral shaping for lung cancer screening: Comparison with low-dose for volumetric LungRADS classification.

PURPOSE: To compare Low-Dose Computed Tomography (LDCT) with four different Ultra-Low-Dose Computed Tomography (ULDCT) protocols for PN classification according to the Lung Reporting and Data System (LungRADS). METHODS: Three hundred sixty-one participants of an ongoing lung cancer screening (LCS) underwent single-breath-hold double chest Computed Tomography (CT), including LDCT (120kVp, 25mAs; CTDIvol 1,62 mGy) and one ULDCT among: fully automated exposure control ("ULDCT1"); fixed tube-voltage and current according to patient size ("ULDCT2"); hybrid approach with fixed tube-voltage ("ULDCT3") and tube current automated exposure control ("ULDCT4"). Two radiologists (R1, R2) assessed LungRADS 2022 categories on LDCT, and then after 2 weeks on ULDCT using two different kernels (R1: Qr49ADMIRE 4; R2: Br49ADMIRE 3). Intra-subject agreement for LungRADS categories between LDCT and ULDCT was measured by the k-Cohen Index with Fleiss-Cohen weights. RESULTS: LDCT-dominant PNs were detected in ULDCT in 87 % of cases on Qr49ADMIRE 4 and 88 % on Br49ADMIRE 3. The intra-subject agreement was: κULDCT1 = 0.89 [95 %CI 0.82-0.96]; κULDCT2 = 0.90 [0.81-0.98]; κULDCT3 = 0.91 [0.84-0.99]; κULDCT4 = 0.88 [0.78-0.97] on Qr49ADMIRE 4, and κULDCT1 = 0.88 [0.80-0.95]; κULDCT2 = 0.91 [0.86-0.96]; κULDCT3 = 0.87 [0.78-0.95]; and κULDCT4 = 0.88 [0.82-0.94] on Br49ADMIRE 3. LDCT classified as LungRADS 4B were correctly identified as LungRADS 4B at ULDCT3, with the lowest radiation exposure among the tested protocols (median effective doses were 0.31, 0.36, 0.27 and 0.37 mSv for ULDCT1, ULDCT2, ULDCT3, and ULDCT4, respectively). CONCLUSIONS: ULDCT by spectral shaping allows the detection and characterization of PNs with an excellent agreement with LDCT and can be proposed as a feasible approach in LCS.

Long term outcome of complex surgical resection and reconstruction for rare thoracic cancers.

BACKGROUND: Complex surgical resection and reconstruction for rare thoracic cancers (RTCs) represent a major challenge, given their very low frequency, extreme variability of presentation, multi-modality treatment options and inadequate outcome prediction. We analysed the experience of a tertiary referral centre on a consecutive series of patients with thoracic germ cell tumours, thymomas and sarcomas, with the aim of reporting the long-term outcome by cancer type and complexity of surgical procedures. METHODS: From Jan 2003 to Dec 2018, 768 surgical procedures were performed with curative intent on 644 RTC patients. Study endpoints were: post-operative hospital stay (Pod), 30-day and 90-day mortality, 5-year and 10-year overall survival (OS). Median follow-up of alive patients was 7.2 years. RESULTS: Median Pod was 7 days, with a 1.2% 30-day and 2.9% 90-day mortality. OS was 90.8% at one year, 74.2% at five years and 62.8% at 10 years. Ten-year OS was 73.0% in low, 65.3% in intermediate, and 55.6% in high complexity score (Log-rank tests p<0.0001); 66.6% in patients with one or two reconstructions and 46.4% in patients with three or more reconstructions (p<0.0001); 46.0% with vascular and 50.0% with chest wall reconstruction; 71.8% in germ cell tumours, 64.6% in thymoma and 51.3% in sarcoma (p<0.0001). CONCLUSION: Complex surgical resection and reconstruction was associated with acceptable 90-day mortality and good 10-year survival in all RTC types. A predictive score based on surgical complexity and cancer type can help the clinical decision making.

Automated Coronary Artery Calcium and Quantitative Emphysema in Lung Cancer Screening: Association With Mortality, Lung Cancer Incidence, and Airflow Obstruction.

PURPOSE: To assess automated coronary artery calcium (CAC) and quantitative emphysema (percentage of low attenuation areas [%LAA]) for predicting mortality and lung cancer (LC) incidence in LC screening. To explore correlations between %LAA, CAC, and forced expiratory value in 1 second (FEV 1 ) and the discriminative ability of %LAA for airflow obstruction. MATERIALS AND METHODS: Baseline low-dose computed tomography scans of the BioMILD trial were analyzed using an artificial intelligence software. Univariate and multivariate analyses were performed to estimate the predictive value of %LAA and CAC. Harrell C -statistic and time-dependent area under the curve (AUC) were reported for 3 nested models (Model survey : age, sex, pack-years; Model survey-LDCT : Model survey plus %LAA plus CAC; Model final : Model survey-LDCT plus selected confounders). The correlations between %LAA, CAC, and FEV 1 and the discriminative ability of %LAA for airflow obstruction were tested using the Pearson correlation coefficient and AUC-receiver operating characteristic curve, respectively. RESULTS: A total of 4098 volunteers were enrolled. %LAA and CAC independently predicted 6-year all-cause (Model final hazard ratio [HR], 1.14 per %LAA interquartile range [IQR] increase [95% CI, 1.05-1.23], 2.13 for CAC ≥400 [95% CI, 1.36-3.28]), noncancer (Model final HR, 1.25 per %LAA IQR increase [95% CI, 1.11-1.37], 3.22 for CAC ≥400 [95%CI, 1.62-6.39]), and cardiovascular (Model final HR, 1.25 per %LAA IQR increase [95% CI, 1.00-1.46], 4.66 for CAC ≥400, [95% CI, 1.80-12.58]) mortality, with an increase in concordance probability in Model survey-LDCT compared with Model survey ( P <0.05). No significant association with LC incidence was found after adjustments. Both biomarkers negatively correlated with FEV 1 ( P <0.01). %LAA identified airflow obstruction with a moderate discriminative ability (AUC, 0.738). CONCLUSIONS: Automated CAC and %LAA added prognostic information to age, sex, and pack-years for predicting mortality but not LC incidence in an LC screening setting. Both biomarkers negatively correlated with FEV 1 , with %LAA enabling the identification of airflow obstruction with moderate discriminative ability.

Evaluation of Simplified Diet Scores Related to C-Reactive Protein in Heavy Smokers Undergoing Lung Cancer Screening.

The aim of this study was to assess the relationship between adherence to a healthy diet, such as the Mediterranean diet (MedDiet), and C-reactive protein (CRP) in Italian heavy smokers undergoing an LDCT screening program (bioMILD trial), using scores calculated by simple questionnaires. Simple formats of food frequency questionnaires were administered to a sample of 2438 volunteers, and the adherence to a healthy diet was measured by the validated 14-point MEDAS and by two adaptations proposed by us: 17-item revised-MEDAS and 18-item revised-MEDAS. The OR of CRP ≥ 2 mg/L for 1-point increase in 14-point MEDAS score was 0.95 (95% CI 0.91-0.99), for 17-point score was 0.94 (95% CI 0.91-0.98), and for 18-point score was 0.92 (95% CI 0.88-0.97). These inverse associations remained statistically significant also after further adjustment for body mass index. These results showed the efficacy of simplified scores and their relationship with lower levels of CRP in a population of heavy smokers. This suggests that a targeted nutritional intervention might achieve a substantial reduction in CRP levels. The findings will be prospectively tested in a new randomized study on primary prevention during lung cancer screening.

Cytisine Therapy Improved Smoking Cessation in the Randomized Screening and Multiple Intervention on Lung Epidemics Lung Cancer Screening Trial.

INTRODUCTION: Cytisine, a partial agonist-binding nicotine acetylcholine receptor, is a promising cessation intervention. We conducted a single-center, randomized, controlled trial (RCT) in Italy to assess the efficacy and tolerability of cytisine as a smoking cessation therapy among lung cancer screening participants. METHODS: From July 2019 to March 2020, the Screening and Multiple Intervention on Lung Epidemics RCT enrolled 869 current heavy tobacco users in a low-dose computed tomography screening program, with a randomized comparison of pharmacologic intervention with cytisine plus counseling (N = 470) versus counseling alone (N = 399). The primary outcome was continuous smoking abstinence at 12 months, biochemically verified through carbon monoxide measurement. RESULTS: At the 12-month follow-up, the quit rate was 32.1% (151 participants) in the intervention arm and 7.3% (29 participants) in the control arm. The adjusted OR of continuous abstinence was 7.2 (95% confidence interval: 4.6-11.2). Self-reported adverse events occurred more frequently in the intervention arm (399 events among 196 participants) than in the control arm (230 events among 133 participants, p < 0.01). The most common adverse events were gastrointestinal symptoms, comprising abdominal swelling, gastritis, and constipation. CONCLUSIONS: The efficacy and safety observed in the Screening and Multiple Intervention on Lung Epidemics RCT indicate that cytisine, a very low-cost medication, is a useful treatment option for smoking cessation and a feasible strategy to improve low-dose computed tomography screening outcomes with a potential benefit for all-cause mortality.

Volumetric Measurements in Lung Cancer Screening Reduces Unnecessary Low-Dose Computed Tomography Scans: Results from a Single-Center Prospective Trial on 4119 Subjects.

This study aims to compare the low-dose computed tomography (LDCT) outcome and volume-doubling time (VDT) derived from the measured volume (MV) and estimated volume (EV) of pulmonary nodules (PNs) detected in a single-center lung cancer screening trial. MV, EV and VDT were obtained for prevalent pulmonary nodules detected at the baseline round of the bioMILD trial. The LDCT outcome (based on bioMILD thresholds) and VDT categories were simulated on PN- and screenee-based analyses. A weighted Cohen's kappa test was used to assess the agreement between diagnostic categories as per MV and EV, and 1583 screenees displayed 2715 pulmonary nodules. In the PN-based analysis, 40.1% PNs were included in different LDCT categories when measured by MV or EV. The agreements between MV and EV were moderate (κ = 0.49) and fair (κ = 0.37) for the LDCT outcome and VDT categories, respectively. In the screenee-based analysis, 46% pulmonary nodules were included in different LDCT categories when measured by MV or EV. The agreements between MV and EV were moderate (κ = 0.52) and fair (κ = 0.34) for the LDCT outcome and VDT categories, respectively. Within a simulated lung cancer screening based on a recommendation by estimated volumetry, the number of LDCTs performed for the evaluation of pulmonary nodules was higher compared with in prospective volumetric management.

Timeline of SARS-CoV-2 Spread in Italy: Results from an Independent Serological Retesting.

The massive emergence of COVID-19 cases in the first phase of pandemic within an extremely short period of time suggest that an undetected earlier circulation of SARS-CoV-2 might have occurred. Given the importance of this evidence, an independent evaluation was recommended by the World Health Organization (WHO) to test a subset of samples selected on the level of positivity in ELISA assays (positive, low positive, negative) detected in our previous study of prepandemic samples collected in Italy. SARS-CoV-2 antibodies were blindly retested by two independent centers in 29 blood samples collected in the prepandemic period in Italy, 29 samples collected one year before and 11 COVID-19 control samples. The methodologies used included IgG-RBD/IgM-RBD ELISA assays, a qualitative micro-neutralization CPE-based assay, a multiplex IgG protein array, an ELISA IgM kit (Wantai), and a plaque-reduction neutralization test. The results suggest the presence of SARS-CoV-2 antibodies in some samples collected in the prepandemic period, with the oldest samples found to be positive for IgM by both laboratories collected on 10 October 2019 (Lombardy), 11 November 2019 (Lombardy) and 5 February 2020 (Lazio), the latter with neutralizing antibodies. The detection of IgM and/or IgG binding and neutralizing antibodies was strongly dependent on the different serological assays and thresholds employed, and they were not detected in control samples collected one year before. These findings, although gathered in a small and selected set of samples, highlight the importance of harmonizing serological assays for testing the spread of the SARS-CoV-2 virus and may contribute to a better understanding of future virus dynamics.

Lung cancer screening by nodule volume in Lung-RADS v1.1: negative baseline CT yields potential for increased screening interval.

OBJECTIVES: The 2019 Lung CT Screening Reporting & Data System version 1.1 (Lung-RADS v1.1) introduced volumetric categories for nodule management. The aims of this study were to report the distribution of Lung-RADS v1.1 volumetric categories and to analyse lung cancer (LC) outcomes within 3 years for exploring personalized algorithm for lung cancer screening (LCS). METHODS: Subjects from the Multicentric Italian Lung Detection (MILD) trial were retrospectively selected by National Lung Screening Trial (NLST) criteria. Baseline characteristics included selected pre-test metrics and nodule characterization according to the volume-based categories of Lung-RADS v1.1. Nodule volume was obtained by segmentation with dedicated semi-automatic software. Primary outcome was diagnosis of LC, tested by univariate and multivariable models. Secondary outcome was stage of LC. Increased interval algorithms were simulated for testing rate of delayed diagnosis (RDD) and reduction of low-dose computed tomography (LDCT) burden. RESULTS: In 1248 NLST-eligible subjects, LC frequency was 1.2% at 1 year, 1.8% at 2 years and 2.6% at 3 years. Nodule volume in Lung-RADS v1.1 was a strong predictor of LC: positive LDCT showed an odds ratio (OR) of 75.60 at 1 year (p < 0.0001), and indeterminate LDCT showed an OR of 9.16 at 2 years (p = 0.0068) and an OR of 6.35 at 3 years (p = 0.0042). In the first 2 years after negative LDCT, 100% of resected LC was stage I. The simulations of low-frequency screening showed a RDD of 13.6-21.9% and a potential reduction of LDCT burden of 25.5-41%. CONCLUSIONS: Nodule volume by semi-automatic software allowed stratification of LC risk across Lung-RADS v1.1 categories. Personalized screening algorithm by increased interval seems feasible in 80% of NLST eligible. KEY POINTS: • Using semi-automatic segmentation of nodule volume, Lung-RADS v1.1 selected 10.8% of subjects with positive CT and 96.87 relative risk of lung cancer at 1 year, compared to negative CT. • Negative low-dose CT by Lung-RADS v1.1 was found in 80.6% of NLST eligible and yielded 40 times lower relative risk of lung cancer at 2 years, compared to positive low-dose CT; annual screening could be preference sensitive in this group. • Semi-automatic segmentation of nodule volume and increased screening interval by volumetric Lung-RADS v1.1 could retrospectively suggest a 25.5-41% reduction of LDCT burden, at the cost of 13.6-21.9% rate of delayed diagnosis.

Unexpected detection of SARS-CoV-2 antibodies in the prepandemic period in Italy.

There are no robust data on the real onset of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and spread in the prepandemic period worldwide. We investigated the presence of SARS-CoV-2 receptor-binding domain (RBD)-specific antibodies in blood samples of 959 asymptomatic individuals enrolled in a prospective lung cancer screening trial between September 2019 and March 2020 to track the date of onset, frequency, and temporal and geographic variations across the Italian regions. SARS-CoV-2 RBD-specific antibodies were detected in 111 of 959 (11.6%) individuals, starting from September 2019 (14%), with a cluster of positive cases (>30%) in the second week of February 2020 and the highest number (53.2%) in Lombardy. This study shows an unexpected very early circulation of SARS-CoV-2 among asymptomatic individuals in Italy several months before the first patient was identified, and clarifies the onset and spread of the coronavirus disease 2019 (COVID-19) pandemic. Finding SARS-CoV-2 antibodies in asymptomatic people before the COVID-19 outbreak in Italy may reshape the history of pandemic.

Comparison of ultra-low dose chest CT scanning protocols for the detection of pulmonary nodules: a phantom study.

PURPOSE: To test ultra-low-dose computed tomography (ULDCT) scanning protocols for the detection of pulmonary nodules (PN). METHODS: A chest phantom containing 19 solid and 11 subsolid PNs was scanned on a third-generation dual-source computed tomography (CT) scanner. Five ULDCT scans (Sn100kVp and 120, 70, 50, 30, and 20 reference mAs, using tube current modulation), reconstructed with iterative reconstruction (IR) algorithm at strength levels 2, 3, 4, and 5, were compared with standard CT (120kVp, 150 reference mAs, using tube current modulation). PNs were subjectively assessed according to a 4-point scale: 0, nondetectable nodule; 1, detectable nodule, very unlikely to be correctly measured; 2, detectable nodule, likely to be correctly measured; 3, PN quality equal to standard of reference. PN scores were analysed according to the Lung Imaging Reporting and Data System (Lung-RADS), simulating detection of nodules at baseline and incidence screening round. RESULTS: For the baseline round, there were 17 Lung-RADS 2, 4 Lung-RADS 3, 8 Lung-RADS 4A, and 1 Lung-RADS 4B PNs. They were detectable in any ULDCT protocol, with the exception of 1 nondetectable part-solid nodule in 1 scanning protocol (120 reference mAs; IR strength: 3). For the incidence round, there were 4 Lung-RADS 2, 14 Lung-RADS 3, 2 Lung-RADS 4A, and 10 Lung-RADS 4B PNs. Ten were nondetectable in at least one ULDCT dataset; however, they were at least detectable in ULDCT with 70 reference mAs (IR strength: 4 and 5). CONCLUSIONS: ULDCT scanning protocols allowing the detection of PNs can be proposed for the purpose of lung cancer screening.