The Smokers Health Multiple ACtions (SMAC-1) Trial: Study Design and Results of the Baseline Round.

BACKGROUND: Lung cancer screening with low-dose helical computed tomography (LDCT) reduces mortality in high-risk subjects. Cigarette smoking is linked to up to 90% of lung cancer deaths. Even more so, it is a key risk factor for many other cancers and cardiovascular and pulmonary diseases. The Smokers health Multiple ACtions (SMAC-1) trial aimed to demonstrate the feasibility and effectiveness of an integrated program based on the early detection of smoking-related thoraco-cardiovascular diseases in high-risk subjects, combined with primary prevention. A new multi-component screening design was utilized to strengthen the framework on conventional lung cancer screening programs. We report here the study design and the results from our baseline round, focusing on oncological findings. METHODS: High-risk subjects were defined as being >55 years of age and active smokers or formers who had quit within 15 years (>30 pack/y). A PLCOm2012 threshold >2% was chosen. Subject outreach was streamlined through media campaign and general practitioners' engagement. Eligible subjects, upon written informed consent, underwent a psychology consultation, blood sample collection, self-evaluation questionnaire, spirometry, and LDCT scan. Blood samples were analyzed for pentraxin-3 protein levels, interleukins, microRNA, and circulating tumor cells. Cardiovascular risk assessment and coronary artery calcium (CAC) scoring were performed. Direct and indirect costs were analyzed focusing on the incremental cost-effectiveness ratio per quality-adjusted life years gained in different scenarios. Personalized screening time-intervals were determined using the "Maisonneuve risk re-calculation model", and a threshold <0.6% was chosen for the biennial round. RESULTS: In total, 3228 subjects were willing to be enrolled. Out of 1654 eligible subjects, 1112 participated. The mean age was 64 years (M/F 62/38%), with a mean PLCOm2012 of 5.6%. Former and active smokers represented 23% and 77% of the subjects, respectively. At least one nodule was identified in 348 subjects. LDCTs showed no clinically significant findings in 762 subjects (69%); thus, they were referred for annual/biennial LDCTs based on the Maisonneuve risk (mean value = 0.44%). Lung nodule active surveillance was indicated for 122 subjects (11%). Forty-four subjects with baseline suspicious nodules underwent a PET-FDG and twenty-seven a CT-guided lung biopsy. Finally, a total of 32 cancers were diagnosed, of which 30 were lung cancers (2.7%) and 2 were extrapulmonary cancers (malignant pleural mesothelioma and thymoma). Finally, 25 subjects underwent lung surgery (2.25%). Importantly, there were zero false positives and two false negatives with CT-guided biopsy, of which the patients were operated on with no stage shift. The final pathology included lung adenocarcinomas (69%), squamous cell carcinomas (10%), and others (21%). Pathological staging showed 14 stage I (47%) and 16 stage II-IV (53%) cancers. CONCLUSIONS: LDCTs continue to confirm their efficacy in safely detecting early-stage lung cancer in high-risk subjects, with a negligible risk of false-positive results. Re-calculating the risk of developing lung cancer after baseline LDCTs with the Maisonneuve model allows us to optimize time intervals to subsequent screening. The Smokers health Multiple ACtions (SMAC-1) trial offers solid support for policy assessments by policymakers. We trust that this will help in developing guidelines for the large-scale implementation of lung cancer screening, paving the way for better outcomes for lung cancer patients.

Surgical and Oncological Outcomes of En-Bloc Resection for Malignancies Invading the Thoracic Spine.

OBJECTIVE(S): There is still limited data in the literature concerning the survival of patients with tumors of the thoracic spine. In this study, we analyzed clinical features, perioperative and long-term outcomes in patients who underwent vertebrectomy for cancer. Furthermore, we evaluated the survival and surgical complications. METHODS: We retrospectively reviewed all cases of thoracic spinal tumors treated by the same team between 1998 and 2018. We divided them into three groups according to type of tumor (primary vertebral, primary lung and metastases) and compared outcomes. For each patient, Overall Survival (OS) and Cumulative Incidence of Relapse (CIR) were estimated. Complications and survival were analyzed using a logistic model. RESULTS: Seventy-two patients underwent thoracic spine surgery (40 in group 1, 16 in each group 2 and 3). Thirty patients died at the end of the observation at a mean follow up time of 60 months (41%). The 5-year overall survival was 72% (95% CI: 0.52-0.84), 20% (95% CI: 0.05-0.43) and 27% (95% CI: 0.05-0.56) for each group, respectively. CIR of group 3 was higher (HR 2.57, 95% CI: 1.22-5.45, p = 0.013). The logistic model revealed that age was related to complications (p = 0.04), while surgery for a type 3 tumor was related to mortality (p = 0.02). CONCLUSIONS: Although the cohort size was limited, primary vertebral tumors displayed the best 5-y-OS with an acceptable complications rate. The indication of surgery should be advised by a multidisciplinary team and only for selected cases. Finally, the use of a combined approach does not increase the risk of complications.

Perioperative Outcome of Robotic Approach Versus Manual Videothoracoscopic Major Resection in Patients Affected by Early Lung Cancer: Results of a Randomized Multicentric Study (ROMAN Study).

INTRODUCTION: We report the results of the first prospective international randomized control trial to compare the perioperative outcome and surgical radicality of the robotic approach with those of traditional video-assisted surgery in the treatment of early-stage lung cancer. METHODS: Patients with clinical stage T1-T2, N0-N1 non-small cell lung cancer (NSCLC) were randomly assigned to robotic-assisted thoracoscopic surgery (RATS) or video-assisted thoracic surgery (VATS) resection arms. The primary objective was the incidence of adverse events including complications and conversion to thoracotomy. The secondary objectives included extent of lymph node (LN) dissection and other indicators. RESULTS: This trial was closed at 83 cases as the probability of concluding in favor of the robot arm for the primary outcome was null according to the observed trend. In this study, we report the results of the analysis conducted on the patients enrolled until trial suspension. Thirty-nine cases were randomized in the VATS arm and 38 in the robotic arm. Six patients were excluded from analysis. Despite finding no difference between the two arms in perioperative complications, conversions, duration of surgery, or duration of postoperative stay, a significantly greater degree of LN assessment by the robotic technique was observed in regards to the median number of sampled LN stations [6, interquartile range (IQR) 4-6 vs. 4, IQR 3-5; p = 0.0002], hilar LNs (7, IQR 5-10 vs. 4, IQR 2-7; p = 0.0003), and mediastinal LNs (7, IQR 5-10 vs. 5, IQR 3-7; p = 0.0001). CONCLUSIONS: The results of this trial demonstrated that RATS was not superior to VATS considering the perioperative outcome for early-stage NSCLC, but the robotic approach allowed an improvement of LN dissection. Further studies are suggested to validate the results of this trial. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov, identifier NCT02804893.

Subpopulations of Circulating Cells with Morphological Features of Malignancy Are Preoperatively Detected and Have Differential Prognostic Significance in Non-Small Cell Lung Cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) frequently presents when surgical intervention is no longer feasible. Despite local treatment with curative intent, patients might experience disease recurrence. In this context, accurate non-invasive biomarkers are urgently needed. We report the results of a pilot study on the diagnostic and prognostic role of circulating tumor cells (CTCs) in operable NSCLC. METHODS: Blood samples collected from healthy volunteers (n = 10), nodule-negative high-risk individuals enrolled in a screening program (n = 7), and NSCLC patients (n = 74) before surgery were analyzed (4 mL) for the presence of cells with morphological features of malignancy enriched through the ISET® technology. RESULTS: CTC detection was 60% in patients, while no target cells were found in lung cancer-free donors. We identified single CTCs (sCTC, 46%) and clusters of CTCs and leukocytes (heterotypic clusters, hetCLU, 31%). The prevalence of sCTC (sCTC/4 mL ≥ 2) or the presence of hetCLU predicted the risk of disease recurrence within the cohort of early-stage (I-II, n = 52) or advanced stage cases (III-IVA, n = 22), respectively, while other tumor-related factors did not inform prognosis. CONCLUSIONS: Cancer cell hematogenous dissemination occurs frequently in patients with NSCLC without clinical evidence of distant metastases, laying the foundation for the application of cell-based tests in screening programs. CTC subpopulations are fine prognostic classifiers whose clinical validity should be further investigated in larger studies.

Quality of Life, Postoperative Pain, and Lymph Node Dissection in a Robotic Approach Compared to VATS and OPEN for Early Stage Lung Cancer.

We compare the perioperative course, postoperative pain, and quality-of-life (QOL) in patients undergoing anatomic resections of early-stage lung cancer by means of robotic surgery (RATS), video-assisted thoracic surgery (VATS), or muscle-sparing thoracotomy (OPEN); 169 consecutive patients with known/suspected lung cancer, candidates to anatomic resection, were enrolled in a single-center prospective study from April 2016 to December 2018. EORTC QLQ-C30 and QLQ-LC13 scores were obtained preoperatively and, at three time points, postoperatively. RATS and VATS groups were matched for ASA scores, while RATS and open surgery were matched for gender, ASA score, cancer stage, and tumor size; 58 patients underwent open surgery, 58 had VATS, and 53 had RATS. Hospital stay was shorter after RATS than OPEN (median 4.5 versus 5; p = 0.047). Comparing matched RATS and VATS groups, the number of hilar lymph nodes and nodal stations removed was significantly higher in the former approach (p = 0.01 vs. p < 0.0001); conversely, pain at 2 weeks was slightly lower after VATS (p = 0.004). No significant difference was observed in conversions, complications, duration of surgery, and postoperative hospitalization. The robotic approach was superior to OPEN in terms of QOL, pain, and length of postoperative stay and showed improved lymph node dissection compared to VATS.

Favorable incremental cost-effectiveness ratio for lung cancer screening in Italy.

OBJECTIVES: Lung cancer detection by low-dose computed tomographic screening reduces mortality. However, it is essential to assess cost-effectiveness. We present a cost-effectiveness analysis of screening in Italians at high risk of lung cancer, from the point of view of the Italian tax-payer. MATERIALS AND METHODS: We used a decision model to estimate the cost-effectiveness of annual screening for 5 years in smokers (≥30 pack-years) of 55-79 years. Patients diagnosed in the COSMOS study were the screening arm; patients diagnosed and treated for lung cancer in the Lombardy Region, Italy, constituted the usual care arm. Treatment costs were extracted from our hospital database. Lung cancer survival in screened patients was adjusted for 2-year lead-time bias. Life-years and quality-adjusted life-years were estimated by stage at diagnosis, from which incremental cost-effectiveness ratios per life-year and quality-adjusted life-year gained were estimated. RESULTS: Base-case incremental cost-effectiveness ratios were 3297 and 2944 euro per quality-adjusted life-year and life-year gained, respectively. Deterministic sensitivity analysis indicated that these values were particularly sensitive to lung cancer prevalence, screening sensitivity and specificity, screening cost, and treatment costs for stage I and IV disease. From the probabilistic sensitivity analysis incremental cost-effectiveness ratios had a 98 % probability of being <25,000 euro (widely-accepted threshold) and a 55 % probability of being <5000 euro. CONCLUSIONS: Low-dose computed tomographic screening is associated with an incremental cost of 2944 euro per life-year gained in high risk population, implying that screening can be introduced in Italy at contained cost, saving the lives of many lung cancer patients.

Low-dose computed tomography screening for lung cancer in people with workplace exposure to asbestos.

OBJECTIVES: Smoking is the main risk factor for lung cancer, but environmental and occupational exposure to carcinogens also increase lung cancer risk. We assessed whether extending low-dose computed tomography (LDCT) screening to persons with occupational exposure to asbestos may be an effective way reducing lung cancer mortality. MATERIALS AND METHODS: We conducted a nested case-control study within the COSMOS screening program, assessing past asbestos exposure with a questionnaire. LDCT scans of asbestos-exposed participants were reviewed to assess the presence of pulmonary, interstitial and pleural alterations in comparison to matched unexposed controls. We also performed an exhaustive review, with meta-analysis, of the literature on LDCT screening in asbestos-exposed persons. RESULTS: Exposure to asbestos, initially self-reported by 9.8% of COSMOS participants, was confirmed in 216 of 544 assessable cases, corresponding to 2.6% of the screened population. LDCT of asbestos-exposed persons had significantly more pleural plaques, diaphragmatic pleural thickening and pleural calcifications, but similar frequency of parenchymal and interstitial alterations to unexposed persons. From 16 papers, including this study, overall lung cancer detection rates at baseline were 0.81% (95% CI 0.50-1.19) in asbestos-exposed persons, 0.94% (95% CI 0.47-1.53) in asbestos-exposed smokers (12 studies), and 0.11% (95% CI 0.00-0.43) in asbestos-exposed non-smokers (9 studies). CONCLUSION: Persons occupationally exposed to asbestos should be monitored to gather more information about risks. Although LDCT screening is effective in the early detection lung cancer in asbestos-exposed smokers, our data suggest that screening of asbestos-exposed persons with no additional risk factors for cancer does is not viable due to the low detection rate.

Robotic resection of Stage III lung cancer: an international retrospective study.

OBJECTIVES: Minimally invasive surgery is accepted for early-stage lung cancer, but its role in locally advanced disease is controversial, especially using a robotic platform. The aim of this retrospective study was to assess the safety and effectiveness of robot-assisted resection in patients with Stage IIIA non-small-cell lung cancer (NSCLC) or carcinoid tumours in the series as a whole and in different subgroups according to adjuvant treatment. METHODS: This was a retrospective multicentre study of consecutive patients with clinically evident or occult N2 disease (210 NSCLC and 13 carcinoid) who, in 2007-2016, underwent robot-assisted resection at 7 high-volume centres. Perioperative outcomes, recurrences and overall survival were assessed. RESULTS: N2 disease was diagnosed preoperatively in 72 (32%) patients and intraoperatively in 151 (68%) patients. Surgical margins were negative in 98.4% of cases with available data. Thirty-four (15.2%) patients received neoadjuvant treatment, 140 (63%) patients received postoperative treatment, and 49 (22%) patients underwent surgery only. There were 22 (9.9%) conversions to thoracotomy, 23 (10.3%) had serious (Grades III-IV) postoperative morbidity and the mean hospital stay was 5.3 days. Complications and outcomes did not differ significantly between treatment groups. Of the 34 patients who were given neoadjuvant chemotherapy, all had R0 resection, 5 (15%) patients required conversion but none required conversion because of bleeding and 4 (12%) patients had Grade III or IV postoperative complications. After a median of 18 (interquartile range 8-33) months, 3-year overall survival in NSCLC patients was 61.2% and 60.3% (P = 0.6) of patients in the subgroup were given induction treatment. However, overall survival was significantly better (P = 0.012) in NSCLC patients with ≤2 positive nodes (vs >2). Nineteen (8.5%) patients developed local recurrence. CONCLUSIONS: Robot-assisted lobectomy is safe and effective in patients with Stage III NSCLC or carcinoid tumours with low conversions and complications. Among patients with NSCLC, including those who were given induction chemotherapy, survival was similar to that reported for open surgery.

Robotic surgery, video-assisted thoracic surgery, and open surgery for early stage lung cancer: comparison of costs and outcomes at a single institute.

BACKGROUND: Robotic surgery is increasingly used to resect lung cancer. However costs are high. We compared costs and outcomes for robotic surgery, video-assisted thoracic surgery (VATS), and open surgery, to treat non-small cell lung cancer (NSCLC). METHODS: We retrospectively assessed 103 consecutive patients given lobectomy or segmentectomy for clinical stage I or II NSCLC. Three surgeons could choose VATS or open, the fourth could choose between all three techniques. Between-group differences were assessed by Fisher's exact, two-way analysis of variance (ANOVA), and Wilcoxon-Mann-Whitney test. P values <0.05 were considered significant. RESULTS: Twenty-three patients were treated by robot, 41 by VATS, and 39 by open surgery. Age, physical status, pulmonary function, comorbidities, stage, and perioperative complications did not differ between the groups. Pathological tumor size was greater in the open than VATS and robotic groups (P=0.025). Duration of surgery was 150, 191 and 116 minutes, by robotic, VATS and open approaches, respectively (P<0.001). Significantly more lymph node stations were removed (P<0.001), and median length of stay was shorter (4, 5 and 6 days, respectively; P<0.001) in the robotic than VATS and open groups. Estimated costs were 82%, 68% and 69%, respectively, of the regional health service reimbursement for robotic, VATS and open approaches. DISCUSSION: Robotic surgery for early lung cancer was associated with shorter stay and more extensive lymph node dissection than VATS and open surgery. Duration of surgery was shorter for robotic than VATS. Although the cost of robotic thoracic surgery is high, the hospital makes a profit.

Pilot study on use of home telephoning to identify and recruit high-risk individuals for lung cancer screening.

Widespread lung cancer screening with low-dose computed tomography is urgently needed in Europe to identify lung cancers early and reduce lung cancer deaths. The most effective method of identifying high-risk individuals and recruiting them for screening has not been determined. In the present pilot study we investigated direct telephoning to families as a way of identifying high risk individuals and recruiting them to a screening/smoking cessation program, that avoided the selection bias of voluntary screening. Families in the province of Milan, Italy, were contacted by telephone at their homes and asked about family members over 50 years who were heavy smokers (30 or more pack-years). Persons meeting these criteria were contacted and asked to participate in the program. Those who agreed were given an appointment to undergo screening and receive smoking cessation counseling. Among the 1000 contacted families, involving 2300 persons, 44 (1.9%) were eligible for LDCT screening, and 12 (27%) of these participated in the program. The cost of this recruitment strategy pilot study was around 150 euro per screened subject. We obtained useful information on the proportion of the general population eligible for lung cancer screening and the proportion of those who responded. However the cost of home telephone calling is probably too high to be practicable as a method of recruiting high risk persons for screening. Alternative recruitment methods, possibly involving family physicians practitioners, need to be investigated.

Acylated and unacylated ghrelin protect MC3T3-E1 cells against tert-butyl hydroperoxide-induced oxidative injury: pharmacological characterization of ghrelin receptor and possible epigenetic involvement.

Increasing evidence suggests a role for oxidative stress in age-related decrease in osteoblast number and function leading to the development of osteoporosis. This study was undertaken to investigate whether ghrelin, previously reported to stimulate osteoblast proliferation, counteracts tert-butyl hydroperoxide (t-BHP)-induced oxidative damage in MC3T3-E1 osteoblastic cells as well as to characterize the ghrelin receptor (GHS-R) involved in such activity. Pretreatment with ghrelin (10(-7)-10(-11)M) significantly increased viability and reduced apoptosis of MC3T3-E1 cells cultured with t-BHP (250 µM) for three hours at the low concentration of 10(-9)M as shown by MTT assay and Hoechst-33258 staining. Furthermore, ghrelin prevented t-BHP-induced osteoblastic dysfunction and changes in the cytoskeleton organization evidenced by the staining of the actin fibers with Phalloidin-FITC by reducing reactive oxygen species generation. The GHS-R type 1a agonist, EP1572 (10(-7)-10(-11)M), had no effect against t-BHP-induced cytotoxicity and pretreatment with the selective GHS-R1a antagonist, D-Lys(3)-GHRP-6 (10(-7)M), failed to remove ghrelin (10(-9) M)-protective effects against oxidative injury, indicating that GHS-R1a is not involved in such ghrelin activity. Accordingly, unacylated ghrelin (DAG), not binding GHS-R1a, displays the same protective actions of ghrelin against t-BHP-induced cytotoxicity. Preliminary observations indicate that ghrelin increased the trimethylation of lys4 on histones H3, a known epigenetic mark activator, which may regulate the expression of some genes limiting oxidative damage. In conclusion, our data demonstrate that ghrelin and DAG promote survival of MC3T3-E1 cell exposed to t-BHP-induced oxidative damage. Such effect is independent of GHS-R1a and is likely mediated by a common ghrelin/DAG binding site.

Dietary tryptophan manipulation reveals a central role for serotonin in the anabolic response of appendicular skeleton to physical activity in rats.

Several studies support a serotonin role in the physiological control of bone mass. However, whether serotonin (5-HT) is involved in bone loss due to reduced mechanical stress or unloading is unknown. We investigated the effects of reduced 5-HT tone, induced by tryptophan-free diet, in movement-restraint osteopenia induced by housing mature rats, acclimatised in single cages with a floor area of 1,500 cm(2), in smaller size single cages where their motor activity was reduced. Tryptophan-deficiency significantly worsened movement-restraint-induced bone loss in both femoral metaphysis and diaphysis (DXA analysis) but not at lumbar vertebrae and impaired the mechanical properties of the femur by significantly reducing both cortical thickness and strength strain index (pQCT analysis). Such effects resulted from an impairment of bone turnover with bone resorption exceeding bone formation. Tryptophan-supplemented diet reversed the worsening effects of tryptophan-deficiency on movement-restraint osteopenia. The improvements of both bone mass and strength were associated with an increase of serum osteocalcin and IGF-I, markers of osteoblast activity. In vitro studies in primary cultures of rat osteoblasts suggest that the anabolic action of 5-HT involves the activation of the Wnt/ß-catenin pathway. Serotonin significantly increased the cytoplasmatic ß-catenin protein levels by the inhibition of the enzyme glycogen synthase kinase-3ß, that by phosphorylating ß-catenin promotes its degradation. Our data support a role for 5-HT in the anabolic response of the appendicular skeleton to mechanical loading. We suggest that serotonin might stimulate canonical Wnt/ß-catenin-dependent bone formation to occur.

Pharmacological characterization of the ghrelin receptor mediating its inhibitory action on inflammatory pain in rats.

Recent research suggests a role for ghrelin in the modulation of inflammatory disorders. However, the type of ghrelin receptor (GHS-R) involved in both the anti-inflammatory and anti-hyperalgesic actions of ghrelin remains to be characterized. In this study, we examined whether the inhibitory effect of ghrelin in the development of hyperalgesia and edema induced by intraplantar carrageenan administration depends on an interaction with GHS-R1a. Both central (1 nmol/rat, i.c.v.) and peripheral (40 nmol/kg, i.p.) administration of the selective GHS-R1a agonist EP1572 had no effect on carrageenan-induced hyperalgesia measured by Randall-Selitto test and paw edema. Furthermore, pre-treatment with the selective GHS-R1a antagonist, D-lys(3)-GHRP-6 (3 nmol/rat, i.c.v.) failed to prevent the anti-hyperalgesic and anti-inflammatory effects exerted by central ghrelin administration (1 nmol/rat), thus indicating that the type 1a GHS-R is not involved in these peptide activities. Accordingly, both central (1 and 2 nmol/rat, i.c.v.) and peripheral (40 and 80 nmol/kg, i.p.) administration of desacyl-ghrelin (DAG), which did not bind GHS-R1a, induced a significant reduction of the hyperalgesic and edematous activities of carrageenan. In conclusion, we have shown for the first time that DAG shares with ghrelin an inhibitory role in the development of hyperalgesia, as well as the paw edema induced by carrageenan and that a ghrelin receptor different from type 1a is involved in the anti-inflammatory activities of the peptide.