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Screening with low-dose computed tomography of high-risk individuals with a smoking history reduces lung cancer mortality. Current screening guidelines and eligibility criteria can miss more than 50% of lung cancers, and in some geographic areas, such as East Asia, a large proportion of the missed lung cancers are in never-smokers. Although randomized trials revealed the benefits of screening for people who smoke, these trials generally excluded never-smokers. Thus, the feasibility and effectiveness of lung cancer screening of individuals who never smoked are uncertain. Several known and suspected risk factors for lung cancers in never-smokers such as exposure to secondhand smoke, occupational carcinogens, radon, air pollution, and pulmonary diseases, such as chronic obstructive pulmonary disease and interstitial lung diseases, and intrinsic factors, such as age, are well noted. In this regard, knowledge of risk factors may make possible quantification and prediction of lung cancer risk in never smokers. It is worth considering if and how never smokers could be included in population-based screening programs. As the implementation of these programs is challenging in many countries owing to multiple factors and the epidemiologic differences by global regions, these issues will need to be evaluated in each country taking into account various factors, including accuracy of risk assessment and cost-effectiveness of screening in never smokers. This report aims to outline current knowledge on risk factors for lung cancer in never smokers to propose research strategies for this topic and initiate a broader discussion on lung cancer screening of never smokers. Similar considerations can be made in current and ex-smokers, which do not fulfill the current screening inclusion criteria, but otherwise are at increased risk. Although screening of never smokers may in the future be effectively conducted, current evidence to support widespread implementation of this practice is lacking.

Pleural mesothelioma (PM) is an aggressive malignancy with poor prognosis. Although histology and pathologic stage are important prognostic factors, better prognostic biomarkers are needed. The ribosomal protein S6 is a downstream target of the phosphatidylinositol 3-kinase (PI3K) pathway involved in protein synthesis and cell proliferation. In previous studies, low phosphorylated S6 (pS6) immunoreactivity was significantly correlated with longer progression-free survival (PFS) and overall survival (OS) in PM patients. We aimed to correlate pS6 expression to clinical data in a large multi-centre PM cohort as part of the European Thoracic Oncology Platform (ETOP) Mesoscape project. Tissue Micro Arrays (TMAs) of PM were constructed and expression of pS6 was evaluated by a semi-quantitatively aggregate H-score. Expression results were correlated to patient characteristics as well as OS/PFS. pS6 IHC results of 364 patients from 9 centres, diagnosed between 1999 and 2017 were available. The primary histology of included tumours was epithelioid (70.3%), followed by biphasic (24.2%) and sarcomatoid (5.5%). TMAs included both treatment-naïve and tumour tissue taken after induction chemotherapy. High pS6 expression (181 patients with H-score>1.41) was significantly associated with less complete resection. In the overall cohort, OS/PFS were not significantly different between pS6-low and pS6-high patients. In a subgroup analysis non-epithelioid (biphasic and sarcomatoid) patients with high pS6 expression showed a significantly shorter OS (p

Background: The accepted aim of radical surgery for malignant pleural mesothelioma (MPM) is the achievement of macroscopic complete resection (MCR) whilst reducing perioperative morbidity by preserving normal tissue. Whilst preservation of the lung by pleurectomy/decortication (PD) has become widely utilised, there remains debate regarding the management of the diaphragm. Muscle-sparing complete excision of the diaphragmatic pleura is technically challenging; thus, surgeons may proceed to extended PD with phrenectomy and possible increased morbidity or to preserve the diaphragmatic pleura at the expense of MCR with potential survival deficit. We aimed to evaluate the effects of an intentional change in protocol to diaphragm-sparing PD whilst maintaining MCR as the treatment of choice for MPM. Methods: In a series of 136 patients (111M:25F, median age 68(63–73) years) undergoing radical surgery for MPM, we identified 28 patients (22M:6F, median age 67(60–71) years) in whom MCR was achieved without phrenectomy (PD group). We compared their perioperative outcomes and survival with a historical control group of 18 patients (18M:0F, median age 69(57–78) years) in whom MCR had been achieved with phrenectomy (EPD group) but in whom there was no histological evidence of diaphragm muscle invasion and who, in retrospect, could have undergone muscle-sparing MCR if this procedure had been attempted. Results: There was no significant intergroup difference in demographics or tumour cell type; the majority of both groups were found to be epithelial (PD 85.7%, EPD 77.8%). The EPD group was found to be more locally advanced (T3 55.56%) than the PD group (T1 46.43%) (p = 0.03). All the following parameters were significantly reduced after PD compared to EPD: operative time (188 vs. 220 min, p = 0.007); duration of air leak (5 vs. 10 days, p = 0.001), duration of inotrope (p = 0.009) and post-operative hospital stay (8 vs. 13 days, p = 0.034). There were no significant differences (p = 0.123) in overall survival (OS) between the two groups, but the median survival in the PD group had not been reached at a median follow up of 33.9 (24.2–46) months. Conclusions: A surgical strategy of attempting to spare the diaphragm whilst still achieving MCR wherever possible is justified by improved perioperative outcomes without compromising OS.

Background Alectinib is a potent anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (TKI) which is currently used in the first-line setting of advanced ALK+ non-small cell lung cancer (NSCLC). Despite favorable results in the metastatic setting, the activity of alectinib in locally-advanced ALK+ NSCLC as a neoadjuvant treatment remains to be assessed. We report the case of a patient with stage IIIA ALK+ NSCLC (cT2aN2) who received alectinib as neoadjuvant treatment, achieving major pathological response (MPR) at pathologic examination. Hence we present the treatment rationale and study design of a phase II, open-label, single-arm, multicenter clinical trial (ALNEO study, EUDRACT number 2020-003432-25). Materials and Methods Patients with potentially resectable stage III ALK+ NSCLC (any T with N2, T4N0-1) will be registered to receive oral alectinib 600 mg twice daily for 2 cycles of 4 weeks each (8 weeks totally) during the neoadjuvant phase. After definitive surgery, patients will enter in the adjuvant setting, during which they will receive alectinib 600 mg twice daily for 24 cycles (96 weeks). The primary endpoint is MPR, defined as ≤10% residual viable tumor cells histologically detected in the resected primary tumor and all resected lymph nodes after surgery. Secondary endpoints include pathological complete response, objective response, event-free survival, disease-free survival, overall survival, adverse events. Conclusions Our case report supports the feasibility of alectinib as neoadjuvant treatment. ALNEO study will further explore the activity and safety of this novel treatment strategy.

Purpose Pulmonary hamartoma is the most common benign tumor of the lung. We analyzed a 20-year historical series of patients with pulmonary hamartoma undergoing surgical resection, aiming to evaluate the characteristics, the outcomes, and the association between hamartoma and lung cancer. Methods It was a retrospective multicenter study including the data of all consecutive patients with pulmonary hamartoma undergoing surgical resection. The end-points were to evaluate: (i) the characteristics of hamartoma, (ii) outcomes, and (iii) whether hamartoma was a predictive factor for lung cancer development Results Our study population included 540 patients. Upfront surgical or endoscopic resection was performed in 385 (71%) cases while in the remaining 155 (29%) cases, the lesions were resected 20 ± 3.5 months later due to increase in size. In most cases, lung sparing resection was carried out including enucleation (n = 259; 48%) and wedge resection (n = 230; 43%) while 5 (1%) patients underwent endoscopic resection. Only two patients (0, 2%) had major complications. One patient (0.23%) had recurrence after endoscopic resection, while no cases of malignant degeneration were seen (mean follow-up:103.3 ± 93 months). Seventy-six patients (14%) had associated lung cancer, synchronous in 9 (12%) and metachronous in 67 (88%). Only age > 70-year-old (p = 0.0059) and smokers > 20 cigarettes/day (p Conclusion PH was a benign tumor, with no evidence of recurrence and/or of malignant degeneration after resection. The association between hamartoma and lung cancer was a spurious phenomenon due to common risk factors.

Objective The presence of micropapillary and solid adenocarcinoma patterns leads to a worse survival and a significantly higher tendency to recur. This study aims to assess the impact of pT descriptor combined with the presence of high-grade components on long-term outcomes in early-stage lung adenocarcinomas. Methods We retrospectively collected data of consecutive resected pT1-T3N0 lung adenocarcinoma from nine European Thoracic Centers. All patients who underwent a radical resection with lymph-node dissection between 2014 and 2017 were included. Differences in Overall Survival (OS) and Disease-Free Survival (DFS) and possible prognostic factors associated with outcomes were evaluated also after performing a propensity score matching to compare tumors containing non-high-grade and high-grade patterns. Results Among 607 patients, the majority were male and received a lobectomy. At least one high-grade histological pattern was seen in 230 cases (37.9%), of which 169 solid and 75 micropapillary. T1a-b-c without high-grade pattern had a significant better prognosis compared to T1a-b-c with high-grade pattern (p = 0.020), but the latter had similar OS compared to T2a (p = 0.277). Concurrently, T1a-b-c without micropapillary or solid patterns had a significantly better DFS compared to those with high-grade patterns (p = 0.034), and it was similar to T2a (p = 0.839). Multivariable analysis confirms the role of T descriptor according to high-grade pattern both for OS (p = 0.024; HR 1.285 95% CI 1.033–1.599) and DFS (p = 0.003; HR 1.196, 95% CI 1.054–1.344, respectively). These results were confirmed after the propensity score matching analysis. Conclusions pT1 lung adenocarcinomas with a high-grade component have similar prognosis of pT2a tumors.

Objective:To identify histopathological and immunophenotypical features with potential predictive or prognostic value in patients undergoing pulmonary metastasectomy from renal cell carcinoma (RCC).Methods:We retrospectively collected all consecutive patients undergoing pulmonary metastasectomy from RCC after prior nephrectomy. Paired samples of primary tumors and corresponding pulmonary metastases were analyzed, revising histopathological features and testing C-MET, mTOR, and PD-L1 by immunohistochemistry.Results:A total of 25 patients were included. Median overall survival (mOS) from metastasectomy was 5.5 years (95% CI = 1.9–9.1). The laterality of metastases had a significant predictive value, with median relapse-free survival (mRFS) from metastasectomy not reached (NR) at mean follow-up (FU) of 60.8 months for left lung involvement, mRFS of 52.9 months (95% CI = 0–145.5) for the right lung and 6.4 months (95% CI = 1.7–11) for bilateral metastases ( p = 0.028). Primary RCC with positive expression of mTOR had higher mOS after metastasectomy than negative cases ( p < 0.001), NR at mean FU of 4.3 years versus mOS of 2 years (95% CI = 0.7–3.3), respectively. PD-L1 positivity on intra-tumor (TILs) and peri-tumor (RILs) infiltrating lymphocytes of metastases was related to higher OS, NR versus 2 years (95% CI = 1.2–2.7, p = 0.003), and NR versus 1.4 years (95% CI = 0.2–2.6, p = 0.012), respectively. The shorter was the surgical interval, the more probably the metastases had high c-MET expression (>70%) ( p = 0.007) and PD-L1 expression >10% on TILs ( p = 0.024).Conclusions:mTOR positivity on primary RCC could be a favorable prognostic factor to select patients for pulmonary metastasectomy. The positive impact of PD-L1 expression on immune cells is opposite to the well-known negative prognostic value of PD-L1 on tumor cells in RCC.

Backgrounds Oligometastatic Non-Small Cell Lung Cancer (NSCLC) patients represent a category without a standard therapeutic approach. However, in selected oligometastatic NSCLC, radical surgery seems to offer a good prognosis. This retrospective study aimed to analyse the long-term outcomes of synchronous oligometastatic patients treated with curative intent and identify the factors associated with better results and the proposal of a risk stratification system for classifying the synchronous oligometastatic NSCLC. Methods The medical records of patients from 18 centres with pathologically diagnosed synchronous oligometastatic NSCLC were retrospectively reviewed. The inclusion criteria were synchronous oligometastatic NSCLC, radical surgical treatment of the primary tumour with or without neoadjuvant/adjuvant therapy and radical treatment of all metastatic sites. The Kaplan – Meier method estimated survivals. A stratified backward stepwise Cox regression model was assessed for multivariable survival analyses. Results 281 patients were included. The most common site of metastasis was the brain, in 50.89 % patients. Median overall survival was 40 months (95 % CI: 29–53). Age ≤65 years (HR = 1.02, 95 % CI: 1.00–1.05; p = 0.019), single metastasis (HR = 0.71, 95 % CI: 0.45–1.13; p = 0.15) and presence of contralateral lung metastases (HR = 0.30, 95 % CI: 0.15 – 0.62; p = 0.001) were associated with a good prognosis. The presence of pathological N2 metastases negatively affected survival (HR = 2.00, 95 % CI: 1.21–3.32; p = 0.0065). These prognostic factors were used to build a simple risk classification scheme. Conclusions Treatment of selected synchronous oligometastatic NSCLC with curative purpose could be conducted safely and at acceptable 5-year survival levels, especially in younger patients with pN0 disease.

Benign metastasizing leiomyoma (BML) is a rare disease characterized by extrauterine benign leiomyomatosis in patients with a previous or concomitant history of uterine leiomyoma. Currently, there are no specific criteria to predict the metastasizing ability of the uterine leiomyoma and the risk of malignant degeneration of pulmonary BML, and these are the aims of this study. We analyzed 10 uterine (three leiomyomas, four leiomyomas that gave rise to lung BML, three healthy tissues) and 11 pulmonary tissue samples (eight lung BML, three healthy tissues). Interestingly, one of the BML lesions exceptionally evolved into a leiomyosarcoma (case 2). Uterine leiomyoma microvascular density (MVD) was higher in the patients with uterine leiomyomas that gave rise to lung BML, reaching a peak in case 2. Strong positivity for the estrogen (ER) and progesterone (PR) receptors and a low proliferation index (Ki67

PURPOSE: This study aimed to evaluate a potential relationship between the diffusing capacity of the lung for carbon monoxide(DLCO) and the aggressiveness of lung adenocarcinoma(ADC).METHODS: Patients who underwent radical surgery for lung ADC between 2001 and 2018 were retrospectively reviewed. DLCO values were dichotomized into DLCOlow(normal(≥80%).Relationships between DLCO and ADC histopathological features, clinical features, as well as with overall survival (OS), were evaluated. RESULTS: Four hundred and sixty patients were enrolled, of which 193(42%) were included in the DLCOlow group. DLCOlow was associated with smoking status, low FEV1, micropapillary and solid ADC, tumour grade 3,high tumour lymphoid infiltrate and presence of tumour desmoplasia. In addition, DLCO values were higher in low-grade ADC and progressively decreased in intermediate and high-grade ADC(p=0.024). After adjusting for clinical variables, at multivariable logistic regression analysis, DLCOlow still showed a significant correlation with high lymphoid infiltrate(p=0.017), presence of desmoplasia(p=0.065), tumour grade 3(p=0.062),micropapillary and solid ADC subtypes(p=0.008).To exclude the association between non-smokers and well-differentiated ADC, the relationship between DLCO and histopathological ADC patterns was confirmed in the subset of 377 former and current smokers(p=0.021).At univariate analysis, gender, DLCO, FEV1, ADC histotype, tumor grade, stage, pleural invasion, tumour necrosis, tumour desmoplasia, lymphatic and blood invasion were significantly related with OS. At multivariate analysis, only gender(pCONCLUSIONS: We found a relationship between DLCO and ADC patterns as well as with tumour grade, tumour lymphoid infiltrate and desmoplasia, suggesting that lung damage may be associated with tumour aggressiveness.

Background Phrenic nerve injury (PNI) during lung cancer surgery, without apparent nerve section or damage, is still not well-studied. The aim of our study is to find an easy and objective way to evaluate a significant diaphragm elevation (SDE) suggestive of inadvertent PNI and its incidence and impact on lung cancer patients undergone video-assisted thoracoscopic surgery (VATS) lobectomy. Methods Extent of diaphragm elevation was first examined on chest X-ray in a cohort of patients with invasive thymoma in whom phrenic nerve was intentionally transected. The result was then used as the criterion to diagnose a SDE suggestive of PNI in another cohort of VATS lobectomy patients. Fluoroscopy test was used to validate the results. Spirometry test was repeated to evaluate pulmonary function loss after surgery. Results Diaphragm elevation was 24.24%±6.2% in 22 invasive thymoma-patients, with 30% elevation adopted as the criterion to diagnose SDE suggestive of PNI. In 753 VATS lobectomy patients, 56 (7.4%) were diagnosed of SDE. On Fluoroscopy test, diaphragm movement was significantly less in patients with diaphragm elevation >30% than those without (5.0 vs. 11.0 mm, P=0.003), together with a significantly smaller diaphragm movement ratio on the operation (OP) side than on the contralateral side (17% vs. 42%, P=0.018). Although no difference in postoperative complications was found, reduction in FEV1, FVC, and DLCO was significantly greater in patients with a SDE than those without (P=0.009). Conclusions Patients with more than 30% diaphragm elevation after VATS lobectomy is highly likely to have PNI and should undergo fluoroscopic validation. Inadvertent PNI during VATS lobectomy is an underestimated phenomenon and is associated with significantly greater loss of pulmonary function.

In this paper, we analyze the wealth accumulation and saving behavior of the retired elderly in Italy using micro data from the “Survey of Italian Households’ Income and Wealth,” a panel survey of households conducted every two years by the Bank of Italy. We find that, on average, the retired elderly in Italy are decumulating their wealth (dissaving) but that their wealth decumulation rates are much slower than expected. Moreover, we also find that more than 40 percent of the retired elderly in Italy are continuing to accumulate wealth and that more than 80 percent are doing positive amounts of saving. Thus, the Wealth Decumulation Puzzle (the tendency of the retired elderly to decumulate their wealth more slowly than expected) appears to apply in the case of Italy, as it does in most other countries, before as well as after the Global Financial Crisis. Moreover, our regression analysis of the determinants of the wealth accumulation and saving behavior of the retired elderly in Italy suggests that the lower than expected wealth decumulation rates and dissaving of the retired elderly in Italy is due largely to intergenerational transfers (bequests and inter vivos transfers) and saving for precautionary purposes, especially the former. Institutional subscribers to the NBER working paper series, and residents of developing countries may download this paper without additional charge at www.nber.org.

Objective:To evaluate the prognostic role of maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) measured by FDG–positron emission tomography (PET)/computed tomography (CT) in patients with primary lung adenocarcinoma undergoing surgical resection.Methods:All consecutive patients undergoing curative surgery for primary lung adenocarcinoma at the Thoracic Surgery Unit of the University Hospital of Parma between January 2009 and December 2014 were retrospectively analyzed. The cutoff point of each continuous PET parameter was determined through receiver operating characteristic curve and Youden index, using overall survival (OS) as the classification status. Univariate and multivariate Cox proportional hazards models were applied to evaluate the association between OS and potential prognostic variables, including SUVmax, MTV, and TLG.Results:A total of 193 patients were considered eligible for this study. The mean 5-year OS rate was 70.5 ± 3.5%. Acinar and lepidic patterns were more frequently associated with absent or low (18F]FDG uptake. At univariate analysis, male sex, advanced stage, micropapillary and solid pattern, lymphatic, blood vessels and pleural invasion, high SUVmax, MTV, and TLG were significantly associated with poorer OS. Multivariate analyses revealed that only sex, stage, and TLG were independent factors for OS, with male sex, stage 3+4, and high TLG value ( p = 0.041) significantly associated with poorer OS.Conclusions:In this study, [18F]FDG PET/CT parameters SUVmax, MTV, and TLG were prognostic factors in patients with surgically resected lung adenocarcinoma, able to predict OS and helping to further stratify these patients into prognostic subsets. Elevated TLG was also an independent predictor for shorter OS.

Background Only a small number of studies have explored the clinicopathological features of pulmonary adenocarcinoma (PA) associated with 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) false-negative (FN) results. Herein, we investigated the FDG-PET diagnostic performance by stratifying PAs according to International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) classification. Methods From January 2002 to December 2016, all consecutive patients who underwent pulmonary resection for stage I PA at six thoracic surgery institutions were retrospectively reviewed. The diagnostic performance of FDG-PET was analysed according to IASLC/ATS/ERS classification and two validated subclassifications. Univariable and multivariable logistic analysis were used to identify predictors of FDG-PET FN results. Results Five hundred and fifty (550) patients with stage I PA were included in the analyses. Most of the patients were male (n=354 [64.4%]) and smokers (n=369 [67.1%]). Ninety-seven (n=97 [17.6%]) FN cases were observed at FDG-PET imaging. On multivariable analysis, a lepidic pattern was found to be independently associated with FDG-PET FN results (odds ratio [OR], 3.20; p Conclusions In our cohort, histopathological features were significantly associated with FDG uptake. In particular, some adenocarcinoma subtypes (mostly Lepidic pattern) have a tendency towards FN FDG-PET findings. The correlation between computed tomography findings, clinical characteristics, and FDG uptake is mandatory, in order to tailor the precise diagnostic and therapeutic pathway for each patient.

OBJECTIVES Lung cancer is increasingly diagnosed as a second cancer. Our goal was to analyse the characteristics and outcomes of early-stage resected lung adenocarcinomas in patients with previous cancers (PC) and correlations with adenocarcinoma subtypes. METHODS We retrospectively reviewed data of patients radically operated on for stage I–II lung adenocarcinoma in 9 thoracic surgery departments between 2014 and 2017. Overall survival (OS) and time to disease relapse were evaluated between subgroups. RESULTS We included 700 consecutive patients. PC were present in 260 (37.1%). Breast adenocarcinoma, lung cancer and prostate cancer were the most frequent (21.5%, 11.5% and 11.2%, respectively). No significant differences in OS were observed between the PC and non-PC groups (P = 0.378), with 31 and 75 deaths, respectively. Patients with PC had smaller tumours and were more likely to receive sublobar resection and to be operated on with a minimally invasive approach. Previous gastric cancer (P = 0.042) and synchronous PC (when diagnosed up to 6 months before lung adenocarcinoma; P = 0.044) were related, with a worse OS. Colon and breast adenocarcinomas and melanomas were significantly related to a lower incidence of high grade (solid or micropapillary, P = 0.0039, P = 0.005 and P = 0.028 respectively), whereas patients affected by a previous lymphoma had a higher incidence of a micropapillary pattern (P = 0.008). CONCLUSIONS In patients with PC, we found smaller tumours more frequently treated with minimally invasive techniques and sublobar resection, probably due to a more careful follow-up. The impact on survival is not uniform and predictable; however, breast and colon cancers and melanoma showed a lower incidence of solid or micropapillary patterns whereas patients with lymphomas had a higher incidence of a micropapillary pattern.

The authors make the argument that the so-calledtraditional risk factors for lung cancer (older age,male sex, heavy smoking status), apart from geneticand environmental factors, are no longer the only riskfactors one should consider when defifining high riskand organizing early detection programs with low-dosecomputed tomography (LDCT). In general, a worldwideapproach to perform early detection LDCTs in individuals without additional risk factors who neversmoked cannot be mandated. Despite the fact thatLDCT can detect early lung cancer in individuals whonever smoked, the risk-to-benefifit ratio without additional risk factors is currently not favorable either onthe individual or the population level.

Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) used both as the first-line treatment of EGFR-mutated non-small cell lung cancer patients and in second-line after T790M-positive disease progression to first- or second-generation TKIs. Unfortunately, patients unavoidably experience disease progression to osimertinib and the current research is focused on resistance mechanisms and the relative therapeutic strategy. We report the case of a patient with advanced EGFR-mutated (exon 19 deletion and T790M-positive) non-small cell lung cancer who developed disease progression to osimertinib characterized by the loss of T790M concurrently with the emergence of G724S EGFR mutation, which was tackled by subsequent afatinib treatment. Next-generation sequencing molecular study of rebiopsy at time of progression to osimertinib revealed the persistence of EGFR exon 19 deletion, loss of T790M with a new G724S EGFR mutation; other concomitant mechanisms were excluded. Retrospective analysis of cell-free DNA revealed the emergence of G724S EGFR mutation four months before the radiologically-proven disease progression. The patient, after chemotherapy, was treated with afatinib with clinical and radiological benefit. Our case report contributes to increase the knowledge on acquired resistance mechanisms to osimertinib treatment, and it shows, for the first time, the efficacy of afatinib in the case of T790M loss and emergence of G724S EGFR mutation.

A recent paper (Bove and Elia (2017)) argues that migrants' diversity, as captured by the indexes of both fractionalization and polarization, exerts a posive effect on GDP growth. In fact, by using the same dataset and method- ology, it can easily be shown that the impact of diversity cannot be distinguished from that of migration itself, due to the very high correlation among the corresponding variables. Also, if one disentangles migration from diversity, following Alesina et al. (2016), only migration maintains a positive impact on growth while diversity, as captured by fractionalization, turns out to be weakly and positively associated to growth, but limitedly to the 1980-2010 time span. Polarization, on the other hand, does not seem to exert any effect on growth. The question as to whether diversity is more or less beneficial in terms of economic growth remains therefore an intriguing one, and calls for more theoretical and empirical analyses, possibly based on less (geographically) aggregated data.

Objective: To evaluate the influence of lung adenocarcinoma second predominant pattern on the maximal standard uptake value (SUVmax) and its prognostic effect in different histologic groups. Methods: We retrospectively collected surgically resected pathologic stage I and II lung adenocarcinoma from nine European institutions. Only patients who underwent preoperative PET-CT and with available information regarding SUVmax of T (SUVmaxT) and N1 (SUVmaxN1) component were included. Results: We enrolled 344 patients with lung adenocarcinoma. SUVmaxT did not show any significant relation according to the second predominant pattern ( p = 0.139); this relationship remained nonsignificant in patients with similar predominant pattern. SUVmaxT influenced the disease-free survival in the whole cohort ( p = 0.002) and in low- and intermediate-grade predominant pattern groups ( p = 0.040 and p = 0.008, respectively). In the high-grade predominant pattern cohort and in the pathologic N1 cases, SUVmaxT lost its prognostic power. SUVmaxN1 did not show any significant correlation with predominant and second predominant patterns and did not have any prognostic impact on DFS. Conclusions: SUVmaxT is influenced only by the adenocarcinoma predominant pattern, but not by second predominant pattern. Concurrently, in high-grade predominant pattern and pN1 group the prognostic power of SUVmaxT becomes nonsignificant.

Background and objectives Adenocarcinoma patterns could be grouped based on clinical behaviors: low- (lepidic), intermediate- (papillary or acinar), and high-grade (micropapillary and solid). We analyzed the impact of the second predominant pattern (SPP) on disease-free survival (DFS). Methods We retrospectively collected data of surgically resected stage I and II adenocarcinoma. Selection criteria anatomical resection with lymphadenectomy and pathological N0. Pure adenocarcinomas and mucinous subtypes were excluded. Recurrence rate and factors affecting DFS were analyzed according to the SPP focusing on intermediate-grade predominant pattern adenocarcinomas. Results Among 270 patients, 55% were male. The mean age was 68.3 years. SPP pattern appeared as follows: lepidic 43.0%, papillary 23.0%, solid 14.4%, acinar 11.9%, and micropapillary 7.8%. The recurrence rate was 21.5% and 5-year DFS was 71.1%. No difference in DFS was found according to SPP (p = .522). In patients with high-grade SPP, the percentage of SPP, age, and tumor size significantly influenced DFS (p = .016). In patients with lepidic SPP, size, male gender, and lymph-node sampling (p = .005; p = .014; p = .038, respectively) significantly influenced DFS. Conclusions The impact of SPP on DFS is not homogeneous in a subset of patients with the intermediate-grade predominant patterns. The influence of high-grade SPP on DFS is related to its proportion in the tumor.

Background: In previous multicentre studies, the longest survival was observed in synchronous lung oligometastatic patients without pN2 disease. This paper aimed to identify preoperative favourable prognostic factors and propose a preoperative classification for categorising the synchronous oligometastatic non-small cell lung cancer (NSCLC). Methods: A retrospective review of prospectively collected patients was performed. The inclusion criteria were: synchronous oligometastatic NSCLC (≤5 extrapulmonary metastases), radical surgical treatment of the primary tumour and all metastatic sites (2005–2018). Exclusion criteria were: palliative surgery, recurrent lung cancer, low-performance status, follow-up information unavailable. The reverse Kaplan – Meier method estimated median overall survival (OS) and progression-free survival. A stratified backward stepwise Cox regression model was employed for multivariable survival analyses. A prognostic grouping considering all the relevant prognostic factors simultaneously was constructed, and a Receiver Operating Characteristic (ROC) curve was generated. Hosmer-Lemeshow χ statistics was used for measuring OS calibration within groups. Findings: 281 patients were included. Data from the Cox regression model were used to construct a prognostic risk classification. Four parameters (age ≤65 years, site of metastasis, clinical nodal status, and induction treatment) were used to build a risk classification. Group A: no risk factors (age ≤65 years, lung/brain metastasis, cN0, induction treatment); Group B: one risk factor (age >65 years or no lung/brain metastasis or cN1–2 or no induction treatment); Group C: two risk factors; Group D: ≥3 risk factors. The Area Under the Curve (AUC) was 0.56 (95% CI: 0.49–0.62), Hosmer-Lemeshow χ statistics was 21.3 (3 degrees of freedom, p=0.0042). Interpretations: Patient selection is critical in identifying the proper subsets of oligometastatic NSCLC. After clinical validation, this preoperative risk classification might support decision-making during the multidisciplinary team assessment and patient selection for enrolment in future randomised trials. Funding: This work was partially supported by the Italian Ministry of Health with Ricerca Corrente and 5 x 1000 funds. Declaration of Interest: All authors have no conflict of interest to declare. Ethical Approval: This research was carried out following the Helsinki Declaration 10. The Ethical Committee authorised the study (785/19).

Objective: Currently, unlike earlier years, patients affected by multiple primary malignancies (MPM) are significantly increased, thus representing a clinical-pathologic category worthy of attention. Their clinical features and prognosis still need to be studied thoroughly, and this is the aim of our study. Methods: Patients with MPM involving lung cancer admitted in our center between January 2006 and December 2016 were considered. Parametric and nonparametric testing was used for statistical comparisons. Univariate and multivariate analysis was used to evaluate the variables associated with a prognostic value. Results: MPM incidence was 19.8%. Among the 222 patients with MPM enrolled, 204 (91.8%) had two malignancies, while 18 (8.2%) had three malignancies, 38 (17.1%) were synchronous, 41 (18.5%) had lung cancer first (LCF) and 181 (81.5%) had other cancer first (OCF). A significant difference between the time of first cancer diagnosis to the second cancer diagnosis in the LCF vs OCF group was found (median 32 vs 51 months; p-value: 0.038). The most frequent anatomical sites of malignancies preceding or following lung cancer were prostate, colorectal, bladder, and larynx. Multivariate analysis revealed that sex, histologic pattern, and time and order of occurrence were independent factors for overall survival, with male sex, squamous cell lung carcinoma, synchronous and LCF MPM significantly associated with poorer overall survival. Conclusions: Prostate, colorectal, bladder, and larynx were the most frequent anatomical sites of malignancies preceding or following lung cancer. Male sex, squamous cell lung carcinoma, synchronous and LCF MPM might be associated with poorer prognosis.

Only a small number of studies have explored the clinicopathological features of pulmonary adenocarcinoma (PA) associated withFrom January 2002 to December 2016, all consecutive patients who underwent pulmonary resection for stage I PA at six thoracic surgery institutions were retrospectively reviewed. The diagnostic performance of FDG-PET was analysed according to IASLC/ATS/ERS classification and two validated subclassifications. Univariable and multivariable logistic analysis were used to identify predictors of FDG-PET FN results.Five hundred and fifty (550) patients with stage I PA were included in the analyses. Most of the patients were male (n=354 [64.4%]) and smokers (n=369 [67.1%]). Ninety-seven (n=97 [17.6%]) FN cases were observed at FDG-PET imaging. On multivariable analysis, a lepidic pattern was found to be independently associated with FDG-PET FN results (odds ratio [OR], 3.20; p0.001), while a solid pattern more commonly presented with a positive finding (OR, 0.40; p=0.066). According to Nakamura's classification, we observed an independent association between lepidic pattern and FDG-PET FN results (OR, 3.17; p0.001), while solid/micropapillary patterns were independently related with increased FDG uptake (OR, 0.35; p=0.021). According to Yoshizawa's classification, Intermediate-grade tumours were independently correlated with FN FDG-PET results (OR, 2.78; p=0.005).In our cohort, histopathological features were significantly associated with FDG uptake. In particular, some adenocarcinoma subtypes (mostly Lepidic pattern) have a tendency towards FN FDG-PET findings. The correlation between computed tomography findings, clinical characteristics, and FDG uptake is mandatory, in order to tailor the precise diagnostic and therapeutic pathway for each patient.

To evaluate the prognostic role of maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) measured by FDG-positron emission tomography (PET)/computed tomography (CT) in patients with primary lung adenocarcinoma undergoing surgical resection.All consecutive patients undergoing curative surgery for primary lung adenocarcinoma at the Thoracic Surgery Unit of the University Hospital of Parma between January 2009 and December 2014 were retrospectively analyzed. The cutoff point of each continuous PET parameter was determined through receiver operating characteristic curve and Youden index, using overall survival (OS) as the classification status. Univariate and multivariate Cox proportional hazards models were applied to evaluate the association between OS and potential prognostic variables, including SUVmax, MTV, and TLG.A total of 193 patients were considered eligible for this study. The mean 5-year OS rate was 70.5 ± 3.5%. Acinar and lepidic patterns were more frequently associated with absent or low (2.5) SUVmax values [In this study, [

This paper aims to fill the gaps in the analysis of risk‐sharing channels at the microlevel, both within and across households. Using data from the Bank of Italy's Survey on Household Income and Wealth covering the financial crisis, we are able to quantify in a unified and consistent framework several risk‐sharing mechanisms that so far have been documented separately. We find that Italian households were able to smooth on average about 85% of shocks to household head's earnings in both 2008–2010 and 2010–2012 spells. The most important smoothing mechanisms turn out to be self‐insurance through savings/dissavings (40% and 47% in 2008–2010 and 2010–2012, respectively), and within‐household risk‐sharing (16% and 14%). Interestingly, risk‐sharing through portfolio diversification and private transfers is rather limited, but the overall percentage of shock absorption occurring through private risk‐sharing channels hovers around four‐fifths, as opposed to around one‐fifth of a shock cushioned by taxes and public transfers, excluding pensions. In addition, by exploiting subjective expectations on the following year's household income, we find significant evidence of a lower degree of smoothing of persistent shocks. Household risk‐sharing precautionary savings consumption smoothing income smoothing C31 D12 E21

Background: Second cancer is the leading cause of death in lymphoma survivors, with lung cancer representing the most common solid tumor. Limited information exists about the treatment and prognosis of second lung cancer following lymphoma. Herein, we evaluated the outcome and prognostic factors of Lung Cancer in Lymphoma Survivors (the LuCiLyS study) to improve the patient selection for lung cancer treatment. Methods: This is a retrospective multicentre study including consecutive patients treated for lymphoma disease that subsequently developed non-small cell lung cancer (NSCLC). Data regarding lymphoma including age, symptoms, histology, disease stage, treatment received and lymphoma status at the time of lung cancer diagnosis, and data on lung carcinoma as age, smoking history, latency from lymphoma, symptoms, histology, disease stage, treatment received, and survival were evaluated to identify the significant prognostic factors for overall survival. Results: Our study population included 164 patients, 145 of which underwent lung cancer resection. The median overall survival was 63 (range, 58-85) months, and the 5-year survival rate 54%. At univariable analysis no-active lymphoma (HR: 2.19; P=0.0152); early lymphoma stage (HR: 1.95; P=0.01); adenocarcinoma histology (HR: 0.59; P=0.0421); early lung cancer stage (HR: 3.18; P

The administration of target inhibitors is paramount to grant the longest survival in patients with ALK-positive non-small cell lung cancer (NSCLC). The eventual resistance to tyrosine kinase inhibitors (TKI) is monitored clinically and radiologically for prompt molecule shift to further generation TKI, if available. However, the early radiological detection of progression pattern (e.g. nodule onset) should be regarded with caution because overlaps exist with non-tumor cell proliferation and/or accumulation. Here we report the case of a stage IV ALK-rearranged NSCLC patient exposed to serial crizotinib, brigatinib, ceritinib, and lorlatinib (this latter brought to complete brain and leptomeningeal disease response), in a period of more than five years. During lorlatinib, the appearance of solid pulmonary nodules was obviously interpreted as disease progression. However, surgical biopsies of the pulmonary nodules revealed features of sarcoid-like granulomatous lymphadenitis, namely without tumor cell. This invasive approach, besides documenting for the first time a sarcoid-like reaction to ALK inhibitors, allowed to revert the radiological diagnosis and maintain lorlatinib, for the best patient outcome. The pragmatic relevance of these findings suggests a careful attitude towards the interpretation of radiologic patterns of disease progression in patients under TKI.

Purpose: To describe a case of giant intercostal nerve schwannoma successfully resected in a patient with neurofibromatosis type 2. Methods: A 44-year-old woman, with a history of neurofibromatosis type 2, presented with chest discomfort and mild dyspnea. She had undergone a recent resection of a large frontal parasagittal benign meningioma. Radiologic examinations showed a large lesion (9×12×9 cm) of the left hemithorax causing a complete atelectasis of left upper lobe. Bronchoscopy did not show any endobronchial alterations, apart from an ab estriseco compression of the left upper bronchial tree. A transthoracic needle biopsy was then performed and microscopic examination revealed a mesenchymal tumor composed of spindle-like cells. Results: A video-assisted thoracoscopic surgery procedure was proposed. The tumor mass appeared to be tenaciously adherent to the parietal pleura in its anterolateral aspect, confirming the radiologic appearance. No invasion of the lung parenchyma or parietal pleural metastases were visible. Therefore, a left posterolateral thoracotomy at the fifth intercostal space was performed and a macroscopic complete resection was carried out. The recovery was uneventful and the patient was discharged on postoperative day 5. The histologic examination revealed a moderate cellular proliferation of spindle-shaped and oval to polygonal cells with frequent Verocay bodies; mitotic figures were rare. The tumor cells were strongly S-100 positive. The microscopic features were consistent with benign intercostal schwannoma. Eight years later, the patient is disease-free and asymptomatic. Conclusions: An unusual case of giant intercostal nerve schwannoma successfully resected in a patient with neurofibromatosis type 2 is described.

International risk sharing has been among the most actively researched areas of macroeconomics for the last two decades. Empirical contributions in this field make extensive use of so called "consumption insurance" tests evaluating the extent to which idiosyncratic shocks in income get transferred to consumption. A prerequisite of such a test is the isolation of country specific variation in the data. We show that the cross-sectional demeaning technique frequently used in the literature is in general inadequate to eliminate global factors from a panel data set, and can lead to misleading inference. We argue that international risk sharing tests should instead be based on a method that more reliably deals with global factors. We claim and illustrate in our empirical application that the fairly simple common correlated e ects estimator for cross-sectionally dependent panels introduced by Pesaran (2006), and Kapetanios et al. (2010) is a tool that satisfies this requirement.

Background: Pulmonary metastasectomy is considered a standard procedure in the treatment of metastatic colorectal cancer (CRC). Different prognostic factors including multiple metastatic nodules, the presence of extra-pulmonary metastases and BRAF mutation status have been associated with poor survival. The aim of this study was to evaluate which factors influenced survival in CRC patients undergoing pulmonary metastasectomy by studying primary tumors and pulmonary metastases. Methods: All patients treated for primary CRC who presented pulmonary metastases in a 10-year period were considered (group A). A control group treated for primary CRC who did not develop any pulmonary or extra-pulmonary metastases was taken for comparison (group B). Different prognostic factors including gender, age, tumor location, histological type, inflammatory infiltrate, BRAF, CDX2 and extra-pulmonary metastases were analyzed. Overall survival (OS) and patients’ survival after pulmonary metastasectomy were also considered. Results: Fifty-four patients were evaluated in group A and twenty-three in group B. In group A, BRAF immunohistochemistry did not significantly differ between primary tumors and pulmonary metastases; no difference of BRAF expression was found between group A and B. Even the expression of CDX2 was not significantly different in primary tumors and metastases. Similarly, in group B CDX2 did not significantly differ from primary CRC of group A. The most significant prognostic factor was the presence of extra-pulmonary metastases. Patients with extra-pulmonary metastases experienced a significant shorter survival compared to patients with pulmonary metastases alone (P=0.001 with log-rank test vs. P=0.003 with univariate Cox regression). Interestingly, patients with right pulmonary metastases presented a significant longer survival than those with left pulmonary metastases (P=0.027 with log-rank test vs. 0.04 with univariate Cox regression). Conclusions: The main prognostic factor associated with poor survival after lung resection of CRC metastases is a history of extra-pulmonary metastases. BRAF and CDX2 did not have a significant role in this small series of patients.

Primary neuroendocrine tumors (NETs) of the mediastinum are very rare. Prognosis is usually poor despite treatment options. We present the case of a primary atypical carcinoid tumor of the mediastinum successfully treated by multimodal approach. A 50-year-old man presented for asthenia, dyspnea, and substernal sense of weight for two weeks. A chest-CT scan revealed a tumor mass of 107×55×95 mm3 localized in the anterosuperior mediastinum compressing both brachiocephalic veins, the superior vena cava, the pericardium, and lungs. A FDG-PET demonstrated high FDG uptake only in the mediastinal mass; no metastases were seen. CT-guided needle biopsy revealed a NET; cells were immunoreactive for synaptophysin; Ki67 was 20%. After neoadjuvant chemotherapy, the chest CT-scan showed a significant reduction of the tumor. A surgical excision was proposed. The tumor was radically removed along with a partial resection of the vena cava and reconstruction with a bovine pericardium patch. The patient underwent 25 sessions of adjuvant radiotherapy. Microscopically the tumor showed clusters of medium-sized cells, eosinophilic cytoplasm with nuclear pleomorphism and small nucleoli, arranged in trabeculae, nests and lobules. No thymic tissue was found. Immunohistochemically the tumor cells were positive for CD117, synaptophysin, chromogranin, CD56, cytokeratin pool, epithelial membrane antigen (EMA), and negative for thyroid transcription factor-1 (TTF1), leukocyte common antigen (LCA), fibroblast-activation protein (FAP), prostate-specific antigen (PSA), P63, CD5 and CD99. Mitoses were found to be 8/10 HPF. The Ki67 was 10%. A diagnosis of primary NET of the mediastinum, intermediate grade (G2), atypical carcinoid according to WHO 2015, was formulated. Even in case of primary NE mediastinal tumor, a multimodal approach could lead to long-term survival.

Black hairy tongue (BHT) is a self-limiting disorder characterized by abnormal hypertrophy and elongation of filiform papillae on the surface of the tongue. The exact mechanism of drug-induced BHT is unknown. Several factors have been implicated and included smoking or chewing tobacco, drinking alcohol, poor oral hygiene and antibiotics such as tetracyclines and penicillins. We report a quite uncommon case of Linezolid-induced BHT in a patient with a long-lasting history of chest wall infection (www.actabiomedica.it)

OBJECTIVES Tumour-infiltrating lymphocytes (TILs) are critically implicated in the clinical outcome and response to immunotherapy in non-small-cell lung cancer (NSCLC) patients. The functional competence of lymphocyte subpopulations is strongly conditioned by their spatial arrangement within the tumour immune microenvironment. The aim of this study was to determine whether the tissue localization of specific TIL subpopulations might have an impact on the risk of recurrence in surgically resected NSCLC. METHODS High-speed scanning of whole slide images was performed on immunohistochemically stained tissue sections from 97 NSCLC patients to assess the number and ratio of CD3+, CD8+ and PD-1+ T-lymphocytes. TIL distribution was computed considering the intratumoural (proximal or distal) and peripheral (invasive margin) localization as well as their location within the fibrotic tissue (immune excluded). The tumour proliferative index was assessed by Ki67 labelling. The impact of TILs number and distribution on clinical-pathological characteristics and outcomes were statistically analysed. RESULTS High density and percentage of proximal CD8+ TILs and low PD-1-to-CD8 ratio had a positive impact on disease-free-survival (P = 0.03) and overall survival (P = 0.003). An inverse correlation was observed between the abundance of intratumoural CD8+ TILs carrying PD-1 inhibitory receptor and cancer cell proliferation. Cases with high compared to low fraction of immune excluded CD8+ TILs had significantly reduced 5-year overall survival (n events: 22 vs 12; P = 0.04) and disease-free survival (n events: 24 vs 16; P = 0.03) rates while the amount of CD3+ and CD8+ TILs located at the invasive margin had a favourable effect on the clinical course. CONCLUSIONS Mapping TIL subpopulations may implement the definition of prognostic parameters in surgically resected NSCLC.

Background: In last years, an increasing interest emerges on the role of sub-lobar resection and lobespecific lymph nodal dissection in the treatment of early-stage lung cancer. The aim of our study was to define the impact on cumulative incidence of recurrence (CIR) of type of surgical resection and type of nodal staging in this subset of patients. Furthermore, we evaluated the possible synergism between the different kinds of procedure. Methods: An analysis of 969 consecutive stage I pulmonary adenocarcinoma patients, operated in six Thoracic Surgery Institutions between 2001 and 2013, was conducted. Type of surgical resection included lobectomy and sub-lobar resection; while pneumonectomy and bilobectomy were excluded from the analysis. Nodal staging procedures were classified in nodal sampling (NS), lobe-specific lymph node dissection (LS-ND) and systematic lymph node dissection (SND). Multivariable-adjusted comparisons for CIR was performed using Fine and Grey model, taking into account of death by any cause as competing event. In order to evaluate synergism between the different procedures, the test of interaction between type of surgical resection and type of nodal staging was carried out and results presented in a stratified way. Results: Eight-hundred forty-six (87%) patients were submitted to lobectomy, while 123 (13%) to sublobar resection. Four-hundred fifty-five (47%) patients received SND, 98 (10%) LS-ND and 416 (43%) NS. Two-hundred forty-seven (26%) patients developed a local/distant recurrence with a 5-year CIR of 24.2%. Multivariable-adjusted comparisons showed an independent negative effect of sub-lobar resection (HR =1.52; 95% CI: 1.07–2.17), LS-ND (HR =1.74; 95% CI: 1.16–2.6) and NS (HR =1.49; 95% CI: 1.12–1.98) on CIR. Test of interaction showed a homogeneity of results among subgroups. Conclusions: Patients affected by stage I pulmonary adenocarcinoma and submitted to lobectomy presented a significant lower recurrence rate than those submitted to sub-lobar resection. Moreover, SND presented an independent positive effect on recurrence development than other lymph node assessment strategy. Finally, lobectomy in combination with systematic lymph nodal resection showed the best results in term of CIR.

Heterogeneity in risk attitudes, if not properly accounted for, may induce a bias on the income coefficient of standard consumption insurance regressions. We show that, extending the theoretical analysis and empirical findings in Schulhofer‐Wohl (Journal of Political Economy, 2011, 119, 925–958), the sign of the bias is ambiguous, and depends on cycle‐related variables and on the covariances of both aggregate and idiosyncratic risk with individual risk aversion.