Is chest X-ray screening for lung cancer in smokers cost-effective? Evidence from a population-based study in Italy.

BACKGROUND: After implementation of the PREDICA annual chest X-ray (CXR) screening program in smokers in the general practice setting of Varese-Italy a significant reduction in lung cancer-specific mortality (18 %) was observed. The objective of this study covering July 1997 through December 2006 was to estimate the cost-effectiveness of this intervention. METHODS: We examined detailed information on lung cancer (LC) cases that occurred among smokers invited to be screened in the PREDICA study (Invitation-to-screening Group, n = 5815 subjects) to estimate costs and quality-adjusted life-years (QALYs) from LC diagnosis until death. The control group consisted of 156 screening-eligible smokers from the same area, uninvited and unscreened, who developed LC and were treated by usual care. We calculated the incremental net monetary benefit (INMB) by comparing LC management in screening participants (n = 1244 subjects) and in the Invitation-to-screening group versus control group. RESULTS: The average number of QALYs since LC diagnosis was 1.7, 1.49 and 1.07, respectively, in screening participants, the invitation-to-screening group, and the control group. The average total cost (screening + management) per LC case was higher in screening participants (€17,516) and the Invitation-to-screening Group (€16,167) than in the control group (€15,503). Assuming a maximum willingness to pay of €30,000/QALY, we found that the intervention was cost-effective with high probability: 79 % for screening participation (screening participants vs. control group) and 95 % for invitation-to-screening (invitation-to-screening group vs. control group). CONCLUSIONS: Based on the PREDICA study, annual CXR screening of high-risk smokers in a general practice setting has high probability of being cost-effective with a maximum willingness to pay of €30,000/QALY.

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

BACKGROUND: Case-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. METHODS: The 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). RESULTS: Over 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. CONCLUSION: In 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 NUMBER: ISRCTN90639073.

Inhibition of non-neuronal alpha7-nicotinic receptor reduces tumorigenicity in A549 NSCLC xenografts.

Nicotinic acetylcholine receptors (nAChR) are expressed on bronchial epithelial and non-small cell lung cancer cells and are involved in cell growth regulation. Nicotine (classical nAChR agonist) induced cell proliferation, whereas nAChR antagonists, d- tubocurarine or alpha-cobratoxin (alpha-CbT), induced cell death. In the current study, we further explored the antitumor potential mechanisms and activities of alpha-CbT. NOD/SCID mice were grafted intraperitoneally or orthotopically and treated with alpha-CbT. alpha-CbT treatment [0.04 ng/kg or 0.12 ng/kg] induced a strong reduction in tumor size ( approximately 90%) in comparison with mice treated with the vehicle alone. Tumor inhibition was related to severe induction of apoptosis. Moreover, neoangiogenesis was strongly inhibited (reduction of cells positive to vascular endothelial growth factor and CD31). Biochemical analyses of the cells, isolated by the primary lung tumor in alpha-CbT-treated mice, showed apoptosis features characterized by: (i) inhibition of BAD phosphorylation at Ser(112) and Ser(136); (ii) BAD dissociation from 14-3-3; (iii) BAD association with BCL-XL; and (iv) cleavage of caspase-9. Moreover, these cells were unable to grow in soft agar and develop tumor, when reinjected into mice. The small interfering RNA-mediated silencing of the alpha7-nAChR gene confirmed that alpha-CbT specifically inhibited the alpha7-nAChR-mediated survival pathway in A549 cells. Furthermore, the specificity of alpha-CbT is reinforced by the lack of effect of short chain toxin (Erabutoxin-a). Once more, the no effect of the low-affinity R33E-modified alpha-CbT strengthened the specificity of this inhibition. Although alpha7-nAChR antagonists, such as alpha-CbT, are unlikely to be a primary therapy, it may provide lead compounds for the design of clinically useful drugs.

Two new approaches for the bi-objective shortest path with a fuzzy objective applied to HAZMAT transportation.

This work proposes two algorithms to the Bi-objective Shortest Path (BSP) problem, considering a fuzzy objective. Such approaches originally extend two classic label setting algorithms to solve BSP, in particular, the first one using a modified Gandibleux revision of Martin's algorithm and the second one based on the A* algorithm acceleration technique. The proposed extensions differ from the previous classic approaches for two main aspects: the two methods solve BSP problems with a linear objective function and a min-max objective function; the max-min objective considered in the BSP is a fuzzy objective function. This latter aspect represents the main contribution of this paper. The proposed approaches, applied to the selection of paths for the road transport of hazardous materials, generate the set of Pareto optimal solutions among which the decision makers have to evaluate the trade-off between paths with minimum cost and paths with minimum (or min-max) risk. In this paper, a real life case study related to the delivery of petrol from a depot to refueling stations is finally illustrated to compare the effectiveness of the proposed approaches.

Multi-objective optimization of solid waste flows: environmentally sustainable strategies for municipalities.

An approach to sustainable municipal solid waste (MSW) management is presented, with the aim of supporting the decision on the optimal flows of solid waste sent to landfill, recycling and different types of treatment plants, whose sizes are also decision variables. This problem is modeled with a non-linear, multi-objective formulation. Specifically, four objectives to be minimized have been taken into account, which are related to economic costs, unrecycled waste, sanitary landfill disposal and environmental impact (incinerator emissions). An interactive reference point procedure has been developed to support decision making; these methods are considered appropriate for multi-objective decision problems in environmental applications. In addition, interactive methods are generally preferred by decision makers as they can be directly involved in the various steps of the decision process. Some results deriving from the application of the proposed procedure are presented. The application of the procedure is exemplified by considering the interaction with two different decision makers who are assumed to be in charge of planning the MSW system in the municipality of Genova (Italy).

A dynamic optimization model for solid waste recycling.

Recycling is an important part of waste management (that includes different kinds of issues: environmental, technological, economic, legislative, social, etc.). Differently from many works in literature, this paper is focused on recycling management and on the dynamic optimization of materials collection. The developed dynamic decision model is characterized by state variables, corresponding to the quantity of waste in each bin per each day, and control variables determining the quantity of material that is collected in the area each day and the routes for collecting vehicles. The objective function minimizes the sum of costs minus benefits. The developed decision model is integrated in a GIS-based Decision Support System (DSS). A case study related to the Cogoleto municipality is presented to show the effectiveness of the proposed model. From optimal results, it has been found that the net benefits of the optimized collection are about 2.5 times greater than the estimated current policy.

Assessment of lung cancer mortality reduction after chest X-ray screening in smokers: a population-based cohort study in Varese, Italy.

BACKGROUND: The effectiveness of screening for lung cancer (LC) in smokers on a population level, as distinct from the special circumstances that may apply in a randomized trial of selected volunteers, has not been thoroughly investigated. Here we evaluate by the standardized mortality ratio (SMR) indicator the impact of a chest X-ray (CXR) screening programme carried out at community level on LC mortality in smokers. METHODS: All smokers of >10 pack-years, of both genders, ages 45-75 years, resident in 50 communities of the Province of Varese, Italy, screening-eligible, in 1997 were invited by their National Health Service (NHS) general practitioner physicians to a nonrandomized programme of five annual CXR screenings. The entire invitation-to-screen cohort (n=5815 subjects) received NHS usual care, with the addition of CXR exams in volunteer participants (21% of invitees), and was observed through December 2006. To overcome participants' selection bias of LC mortality assessment, for the entire invitation-to-screen cohort we estimated the LC-specific SMR, based on the local reference population receiving the NHS usual care. RESULTS: Over the 8-year period 1999-2006, a total of 172 cumulative LC deaths were observed in the invitation-to-screen cohort; 210 were expected based on the reference population. Each year in the invited cohort the observed LC deaths were fewer than expected. The cumulative LC SMR was 0.82 (95% CI, 0.67-0.99; p=0.048), suggesting that LC mortality was reduced by 18% with CXR screening. CONCLUSION: Implementation of a CXR screening programme at community level was associated with a significant reduction of LC mortality in smokers.

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.

Targeting alpha7-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.