Massimo Paolucci

Targeting α7-nicotinic receptor for the treatment of pleural mesothelioma

Human malignant pleural mesothelioma (MPM) is a dreadful disease and there is still no standard therapy available for a consistent therapeutic approach. This research is aimed at the evaluation of the potential therapeutic effect of a specific nicotinic receptor (nAChR) antagonist, namely alpha-Cobratoxin (alpha-CbT). Its effectiveness was tested in mesothelioma cell lines and in primary mesothelioma cells in vitro, as well as in vivo, in orthotopically xenotransplanted NOD/SCID mice. Cells showed alpha7-nAChR expression and their growth was significantly inhibited by alpha-CbT. Severe induction of apoptosis was observed after exposure to alpha-CbT [IC(80-90)]. Apoptosis was characterised by: change in mitochondrial potential, caspase-3 cleavage, down-regulation of mRNA and protein for survivin, XIAP, IAP1, IAP2 and Bcl-XL, inhibition by caspase-3 inhibitor. In vivo, the alpha-CbT acute LD(50) was 0.15 mg/kg. The LD(100) [0.24 mg/kg] induced fatal respiratory failure and massive kidney necrosis. Phase II experiments with 0.12 ng/kg alpha-CbT (1/1000 of LD(10)) were done in 53 xenotransplanted mice, inhibiting tumour development as confirmed by chest X-ray examinations, autopsy and microscopical findings. The growth of human proliferating T lymphocytes and of mesothelial cells in primary culture was not affected by alpha-CbT. Non-immunogenic derivatives of the alpha-CbT molecule need to be developed for possible human use.

Self-Selection Effects in Smokers Attending Lung Cancer Screening: A 9.5-Year Population-Based Cohort Study in Varese, Italy

Background: We hypothesize that mortality risk profile of participants and nonparticipants in nonrandomized lung cancer (LC) screening of smokers may be different. Methods: In 1997, a population-based cohort of 5815 smokers of Varese Province was invited to nonrandomized LC screening by annual chest x-ray examination for 4 years. LC risk factors and screening participation rate were recorded. Except for screening, the whole cohort received usual care. After 9.5-year observation, we compared mortality of participants versus nonparticipants by assessing age-standardized all-cause mortality rate ratio (MRR) and disease group-specific MRR with 95% confidence intervals (95% CI). Results: Self-selected screening participants were 21% of cohort. Participants were younger (p < 0.001), were more frequently current smokers (p = 0.019), had more pack-years of smoking (p < 0.0001), and had higher rate of LC family history (p < 0.0001) and of occupational LC risk (p < 0.0001) relative to nonparticipants. In logistic regression analysis familial LC, occupational risk and pack-years smoked were significant predictors of participation in screening and of developing LC. Participants displayed a healthy effect, as shown by all-cause MRR = 0.67 (95% CI, 0.53–0.84), all cancers except LC MRR = 0.61 (95% CI, 0.41–0.91), cardiovascular diseases MRR = 0.38 (95% CI, 0.22–0.63), and noncancer disease other than cardiovascular or respiratory MRR = 0.57 (95% CI, 0.34–0.92). The LC mortality (MRR = 1.40; 95% CI, 1.03–1.91) was higher in participants relative to nonparticipants (p = 0.031). Conclusion: The selection effect in LC screening participants was dual: healthy effect and higher LC mortality. In assessing the overall effectiveness of LC screening on a population level, a higher LC mortality risk in participants should be considered.

A population-based cohort study of chest x-ray screening in smokers: lung cancer detection findings and follow-up

BackgroundCase-control studies of mass screening for lung cancer (LC) by chest x-rays (CXR) performed in the 1990s in scarcely defined Japanese target populations indicated significant mortality reductions, but these results are yet to be confirmed in western countries. To ascertain whether CXR screening decreases LC mortality at community level, we studied a clearly defined population-based cohort of smokers invited to screening. We present here the LC detection results and the 10-year survival rates.MethodsThe cohort of all smokers of > 10 pack-years resident in 50 communities of Varese, screening-eligible (n = 5,815), in July 1997 was invited to nonrandomized CXR screening. Self-selected participants (21% of cohort) underwent screening in addition to usual care; nonparticipants received usual care. The cohort was followed-up until December 2010. Kaplan-Meier LC-specific survival was estimated in participants, in nonparticipants, in the whole cohort, and in an uninvited, unscreened population (control group).ResultsOver the initial 9.5 years of study, 67 LCs were diagnosed in screening participants (51% were screen-detected) and 178 in nonparticipants. The rates of stage I LC, resectability and 5-year survival were nearly twice as high in participants (32% stage I; 48% resected; 30.5% 5-year survival) as in nonparticipants (17% stage I; 27% resected; 13.5% 5-year survival). There were no bronchioloalveolar carcinomas among screen-detected cancers, and median volume doubling time of incidence screen-detected LCs was 80 days (range, 44-318), suggesting that screening overdiagnosis was minimal. The 10-year LC-specific survival was greater in screening participants than in nonparticipants (log-rank, p = 0.005), and greater in the whole cohort invited to screening than in the control group (log-rank, p = 0.001). This favourable long-term effect was independently related to CXR screening exposure.ConclusionIn the setting of CXR screening offered to a population-based cohort of smokers, screening participants who were diagnosed with LC had more frequently early-stage resectable disease and significantly enhanced long-term LC survival. These results translated into enhanced 10-year LC survival, independently related to CXR screening exposure, in the entire population-based cohort. Whether increased long-term LC-specific survival in the cohort corresponds to mortality reduction remains to be evaluated.Trial registration numberISRCTN90639073

Lung cancer screening in cigarette smokers in the province of Varese, Italy

For heavy cigarette smokers and recent former smokers who have accumulated a high risk of lung carcinoma, a primary objective is the early detection of that disease; this goal can be achieved by annual screening with one of the radiologic imaging methods available. While awaiting for the implementation of computed tomography or of other, more sensitive methods, it is quite reasonable to screen those who are at risk with annual chest X‐ray (CXR), an examination that is readily available at low cost. Indeed, with the annual CXR screening of heavy smokers, it is possible to detect about 50% of lung carcinomas in TNM Stage I. The 5‐year survival rate of patients with asymptomatic, screen‐detected Stage I disease after radical surgery is significantly greater than the survival rate of patients with symptomatic disease.