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Background: Sleeve resection is currently the gold standard procedure for centrally located non-small cell lung cancer (NSCLC). Extended sleeve lobectomy (ESL) consists of an atypical bronchoplasty with resection of >1 lobe and carries several technical difficulties compared with simple sleeve lobectomy (SSL). Our study compared the outcomes of ESL and SSL for NSCLC., Methods: This multicenter, retrospective, cohort study included 1314 patients who underwent ESL (155 patients) or SSL (1159 patients) between 2000 and 2018. The primary end points were 30-day and 90-day mortality, overall survival (OS), disease-free survival (DFS), and complications., Results: No differences were found between the 2 groups in general characteristics and surgical and survival outcomes. In particular, there were no differences in early and late complication frequency, 30- and 90-day mortality, R status, recurrence, OS (54.26 ± 33.72 months vs 56.42 ± 32.85 months, P = .444), and DFS (46.05 ± 36.14 months vs 47.20 ± 35.78 months, P = .710). Mean tumor size was larger in the ESL group (4.72 ± 2.30 cm vs 3.81 ± 1.78 cm, P < .001). Stage IIIA was the most prevalent stage in ESL group (34.8%), whereas stage IIB was the most prevalent in SSL group (34.3%; P < .001). The multivariate analyses found nodal status was the only independent predictive factor for OS., Conclusions: ESL gives comparable short- and long-term outcomes to SSL. Appropriate preoperative staging and exclusion of metastases to mediastinal lymph nodes, as well as complete (R0) resection, are essential for good long-term outcomes., (Copyright © 2024 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Introduction: Tumor Inflammatory microenvironment (TIME) encompasses several immune pathways modulating cancer development and escape that are not entirely uncoded. The results achieved with immunotherapy elicited the scientific debate on TIME also in non-small cell lung cancer (NSCLC). We aimed to investigate whether TIME (in terms of PD-L1 expression and/or Tumor Infiltrating Lymphocytes - TILs) played a separate role in terms of survival (OS) in resected upstaged lung adenocarcinomas (ADCs), excluding other perioperative variables as confounders., Materials and Methods: This retrospective study included 50 patients with a clinically resectable lung ADC, undergoing surgery (lobectomy or segmentectomy) at the Thoracic Unit of Padova University Hospital between 2016 and 2022 and receiving an unexpected pathological upstaging (IIB or higher)., Results: Despite microscopical variables increasing from IIB to IIIB, survival was not significantly related to them. OS was better in TIME-active patients (defined as the presence of positive PD-L1 and/or TILs>10 %) than double negatives (PD-L1-/TILs-) (p = 0.01). In IIB or higher ADCs, TIME-active patients showed an improved survival compared to double negatives, merging the current TIME theories., Conclusion: TIME seems to be associated with survival independently from other microscopical parameter, even in case of resected upstaged adenocarcinomas., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Objective: The aim of this study is to describe characteristics and survival outcome of patients who underwent surgical treatment for distant thymoma relapse according to the definition of the International Thymic Malignancy Interest Group., Methods: Data of patients affected by thymoma recurrence from four different institutions were collected and retrospectively reviewed. Patients with locoregional metastases who underwent nonsurgical therapies and with incomplete data on follow-up were excluded. According to the International Thymic Malignancy Interest Group distant recurrence definition, patients with recurrence due to hematogenic localization were included. Clinical and pathologic characteristics were described using descriptive statistics, whereas survival outcome was calculated using Kaplan-Meier curves and Cox regression analysis., Results: The analysis was conducted on 40 patients. A single localization was present in 13 patients, the relapse was intrathoracic in 28 cases (70%), and lung involvement was found in 26 cases. The liver was operated in seven cases, whereas other kinds of abdominal involvement were detected in eight cases. Adjuvant treatment was administered in 22 cases (55%).Five- and 10-year overall survival (OS) were 67% and 30%, respectively. Univariable analysis identified as significant favorable factor a low-grade histology (A, B1, B2): five-year OS at 92.3% versus 53.3% in high-grade (B3-C) (p = 0.035). Site of recurrence and number of localization did not influence the prognosis, but in patients with adjuvant therapy administration, there was a survival advantage also if not statistically significant: five-year OS 84.8% versus 54.5% in patients without adjuvant therapy (p = 0.101).Multivariable analysis confirmed as independent prognostic factor low-grade histology: hazard ratio = 0.176, 95% confidence interval 0.042-0.744, p = 0.018., Conclusions: Our study revealed a good survival outcome in patients who underwent surgery for distant thymoma recurrence, independently from the number and site of the relapse localization. Patients with A, B1, or B2 histology presented a significantly better survival than patients with B3-C., Competing Interests: Disclosure All authors declare no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Objectives: This study aims to show the application of flexible statistical methods in real-world cost-effectiveness analyses applied in the cardiovascular field, focusing specifically on the use of proprotein convertase subtilisin-kexin type 9 inhibitors for hyperlipidemia., Methods: The proposed method allowed us to use an electronic health database to emulate a target trial for cost-effectiveness analysis using multistate modeling and microsimulation. We formally established the study design and provided precise definitions of the causal measures of interest while also outlining the assumptions necessary for accurately estimating these measures using the available data. Additionally, we thoroughly considered goodness-of-fit assessments and sensitivity analyses of the decision model, which are crucial to capture the complexity of individuals' healthcare pathway and to enhance the validity of this type of health economic models., Results: In the disease model, the Markov assumption was found to be inadequate, and a "time-reset" timescale was implemented together with the use of a time-dependent variable to incorporate past hospitalization history. Furthermore, the microsimulation decision model demonstrated a satisfying goodness of fit, as evidenced by the consistent results obtained in the short-term horizon compared with a nonmodel-based approach. Notably, proprotein convertase subtilisin-kexin type 9 inhibitors revealed their favorable cost-effectiveness only in the long-term follow-up, with a minimum willingness to pay of 39 000 Euro/life years gained., Conclusions: The approach demonstrated its significant utility in several ways. Unlike nonmodel-based or alternative model-based methods, it enabled to (1) investigate long-term cost-effectiveness comprehensively, (2) use an appropriate disease model that aligns with the specific problem under study, and (3) conduct subgroup-specific cost-effectiveness analyses to gain more targeted insights., Competing Interests: Author Disclosures Author disclosure forms can be accessed below in the Supplemental Material section., (Copyright © 2024. Published by Elsevier Inc.)

Background: Pulmonary antibody-mediated rejection is still a challenging diagnosis as C4d immunostaining has poor sensitivity. Previous studies have indicated that the phosphorylated S6 ribosomal protein, a component of the mammalian target of rapamycin (mTOR) pathway, is correlated with de novo donor-specific antibodies in lung transplantation. The objective of this study was to evaluate the phosphorylation of S6 ribosomal protein as a surrogate for antibody-mediated rejection diagnosis in lung transplant patients., Methods: This multicentre retrospective study analyzed transbronchial biopsies from 216 lung transplanted patients, 114 with antibody-mediated rejection and 102 without (19 with acute cellular rejection, 17 with ischemia/reperfusion injury, 18 with infection, and 48 without post-transplant complications). Immunohistochemistry was used to quantify phosphorylated S6 ribosomal protein expression in macrophages, endothelium, epithelium, and inter-pathologist agreement was assessed., Results: Median phosphorylated S6 ribosomal protein expression values were higher in antibody-mediated rejection cases than in controls for all cell components, with the highest sensitivity in macrophages (0.9) and the highest specificity in endothelial expression (0.8). The difference was mainly significant in macrophages compared to other post-lung transplantation complications. Inter-pathologist agreement was moderate for macrophages and endothelium, with higher agreement when phosphorylated S6 ribosomal protein expression was dichotomized into positive/negative. The inclusion of phosphorylated S6 ribosomal protein in the diagnostic algorithm could have increased antibody-mediated rejection certainty levels by 25%., Conclusions: The study supports the role of the mTOR pathway in antibody-mediated rejection-related graft injury and suggests that tissue phosphorylation of S6 ribosomal protein could be a useful surrogate for a more accurate pathological diagnosis of lung antibody-mediated rejection., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The role of video-assisted thoracoscopic surgery for oncological major pulmonary resections is now well established; however, the literature within pulmonary re-operations is still limited. The purpose of this study is to evaluate the safety and efficacy of redo thoracoscopic resections for ipsilateral pulmonary malignancy., Methods: Data from patients undergoing video-assisted thoracoscopic surgery at the Unit of Thoracic Surgery of Padua were analyzed, comparing the results between the first and second ipsilateral surgery. The retrospective study included patients who underwent 2 thoracoscopic surgeries for oncological reasons between 2015 and 2022. The variables considered included patients' baseline characteristics, pre, intra, and postoperative data., Results: The study enrolled 51 patients undergoing ipsilateral thoracoscopic re-operation. The statistical analysis showed that surgical time (95min vs 115min; p = 0.009), the presence of intrapleural adhesions at second surgery (30 % vs 76 %; p < 0.001), overall pleural fluid output (200 vs 560 ml; p = 0.003), time with pleural drainage (2 vs 3 days; p = 0.027), air leaks duration time (p = 0.004) and post-operative day of discharge (3 vs 4 days; p = 0.043) were significantly higher in the re-operation group. No statistical differences were observed between the 2 groups respect to R0 resection rate (90.2 % vs 89.1 %; p=>0.9) and complications (5.8 % vs 15.6 %; p = 0.11). The conversion rate to open surgery was 11.8 %., Conclusion: Although some differences emerged between the first and second intervention, they had minimal impact on the clinical course of the patients. Therefore, thoracoscopic surgery has been shown to be safe and effective in re-operations with satisfying perioperative outcomes. To achieve such results, these procedures should be reserved for experienced surgeons., Competing Interests: Declaration of competing interest None., (© 2023 Published by Elsevier Ltd.)

Background: Diaphragm ultrasound (DUS) has been extensively used in critically ill patients while data on outpatients with interstitial lung disease (ILD) are limited. We hypothesized that diaphragm function, assessed by ultrasound, could be impaired in patients with ILD, considering both Idiopathic Pulmonary Fibrosis (IPF) and Connective Tissue Disease (CTD-ILD), compared to healthy subjects. Moreover, this impairment could impact clinical and functional parameters., Methods: All consecutive CTD-ILD and IPF patients followed in our center (March-October 2020) were screened. Diaphragm displacement (DD), inspiratory thickness (Ti), expiratory thickness (Te), thickening fraction (TF), and respiratory functional parameters were collected. The prevalence of diaphragmatic dysfunction (TF <30%) was then recorded., Results: Eighty-two consecutive patients (41 CTD-ILD, 41 IPF) and 15 age- and sex-matched controls were enrolled. In the overall population, 24 out of 82 (29%) presented diaphragmatic dysfunction. In CTD-ILD, DD and Ti were lower as compared to IPF (p = 0.021 and p = 0.036, respectively); while diaphragmatic dysfunction was more prevalent compared to controls (37% vs 7%, p = 0.043). TF positively correlated to patients' functional parameters in the CTD-ILD group (FVC%pred: p = 0.003; r = 0.45), while not in the IPF group. Diaphragmatic dysfunction was associated with moderate/severe dyspnea in both CTD-ILD and IPF (p = 0.021)., Conclusion: The prevalence of diaphragmatic dysfunction was 29% in patients with ILD and was associated with moderate/severe dyspnea. CTD-ILD presented lower DD compared with IPF and a higher prevalence of diaphragmatic dysfunction (TF<30%) compared with controls. TF was associated with lung function only in CTD-ILD patients, suggesting its potential role in the comprehensive patient assessment., Competing Interests: Declaration of competing interest There is no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Air leak is the major factor that influences the permanence of the chest tube and the in-hospital length of stay (LOS) among patients undergoing lung resections. The aim of this study was to determine whether the use of digital chest drain systems, compared with traditional ones, reduced the duration of chest drainage and postoperative in-hospital LOS in patients undergoing video-assisted thoracoscopic (VATS) lobectomy., Methods: The study was a prospective, randomized, multicenter trial. Patients undergoing VATS lobectomy were randomized in 2 groups, receiving a digital drain system or a traditional one and managed accordingly to the protocol., Results: Among 503 patients who fulfilled inclusion criteria and were randomized, 38 dropped out after randomization. Finally, 465 patients were analyzed, of whom 204 used the digital device and 261 the traditional one. In the digital group, there was a significantly shorter median chest tube duration of 3 postoperative days (interquartile range [IQR], 2-4 days) vs 4 postoperative days (IQR, 3-4 days; P = .001) and postoperative in-hospital LOS of 4 days (IQR, 3-6 days) vs 5 days (IQR, 4-6 days; P = .035). Analysis of predictors for increased duration of air leaks showed a relationship with male sex (P = .039), forced expiratory volume in 1 second percentage (P = .004), forced vital capacity percentage (P = .03), and presence of air leaks at the end of surgery (P = .001)., Conclusions: In patients undergoing VATS lobectomy, the use of a digital drainage system allows an earlier removal of the chest drain compared with the traditional system, leading to a shorter in-hospital LOS., (Copyright © 2023 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Lung cancer (LC) is the leading cause of cancer-related death worldwide, mostly because the lack of a screening program so far. Although smoking cessation has a central role in LC primary prevention, several trials on LC screening through low-dose computed tomography (LDCT) in a high risk population showed a significant reduction of LC related mortality. Most trials showed heterogeneity in terms of selection criteria, comparator arm, detection nodule method, timing and intervals of screening and duration of the follow-up. LC screening programs currently active in Europe as well as around the world will lead to a higher number of early-stage Non Small Cell Lung Cancer (NSCLC) at the diagnosis. Innovative drugs have been recently transposed from the metastatic to the perioperative setting, leading to improvements in terms of resection rates and pathological responses after induction chemoimmunotherapy, and disease free survival with targeted agents and immune checkpoint inhibitors. The present review summarizes available evidence about LC screening, highlighting potential pitfalls and benefits and underlining the impact on the diagnostic therapeutic pathway of NSCLC from a multidisciplinary perspective. Future perspectives in terms of circulating biomarkers under evaluation for patients' risk stratification as well as a focus on recent clinical trials results and ongoing studies in the perioperative setting will be also presented., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: In recent decades, the incidence of multidrug-resistant (MDR) and extended-spectrum β-lactamase (ESBL) gram-negative (GN) bacteria has increased progressively among lung transplantation (LT) recipients. A prompt diagnosis, prevention, and management of these pathogens remain the cornerstone for successful organ transplantation., Research Question: What are the incidence of MDR and ESBL GN bacteria within the first 30 days after LT and related risk of in-hospital mortality? What are the potential clinical predictors of isolation of MDR and ESBL GN bacteria?, Study Design and Methods: All consecutive LT recipients admitted to the ICU of the University Hospital of Padua (February 2016-December 2021) were screened retrospectively. Only adult patients undergoing the first bilateral LT and not requiring invasive mechanical ventilation, extracorporeal membrane oxygenation, or both before surgery were included. MDR and ESBL GN bacteria were identified using in vitro susceptibility tests and were isolated from the respiratory tract, blood, urine, rectal swab, or surgical wound or drainage according to a routine protocol., Results: One hundred fifty-three LT recipients were screened, and 132 were considered for analysis. Median age was 52 years (interquartile range, 41-60 years) and 46 patients (35%) were women. MDR and ESBL GN bacteria were identified in 45 patients (34%), and 60% of patients demonstrated clinically relevant infection. Pseudomonas aeruginosa (n = 22 [49%]) and Klebsiella pneumoniae (n = 17 [38%]) were frequently isolated after LT from the respiratory tract (n = 21 [47%]) and multiple sites (n = 18 [40%]). Previous recipient-related colonization (hazard ratio [HR], 2.48 [95% CI, 1.04-5.90]; P = .04) and empirical exposure to broad-spectrum antibiotics (HR, 6.94 [95% CI, 2.93-16.46]; P < .01) were independent predictors of isolation of MDR and ESBL GN bacteria. In-hospital mortality of the MDR and ESBL group was 27% (HR, 6.38 [95% CI, 1.98-20.63]; P < .01)., Interpretation: The incidence of MDR and ESBL GN bacteria after LT was 34%, and in-hospital mortality was six times greater. Previous recipient-related colonization and empirical exposure to broad-spectrum antibiotics were clinical predictors of isolation of MDR and ESBL GN bacteria., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Glycated albumin (GA) reflects short-term glycemic control, but few data are available on its association with hard clinical outcomes. The purpose of this study is to evaluate the association between GA levels and all-cause and cardiovascular mortality in people with and without a previous diagnosis of diabetes., Methods and Results: Serum GA levels were measured in 12147 people from the general population (1319 with and 10828 without diabetes) that participated in the 1999-2004 cycles of the National Health and Nutrition Examination Survey (NHANES). We evaluated the association between GA and all-cause and cardiovascular mortality through December 2015 by linking NHANES data with data from the National Death Index. Associations were compared with those observed for hemoglobin A1c (HbA1c). After a median follow-up of 13 years, 2785 participants (619 with and 2166 without diabetes) died, 651 of cardiovascular causes. Multivariable-adjusted Cox proportional hazard models showed that higher baseline GA levels were significantly associated with a higher incidence of both outcomes in participants with (all-cause: HR 1.03, 95% CI 1.01-1.04; cardiovascular: HR 1.04, 95% CI 1.02-1.07) and without diabetes (all-cause: HR 1.05, 95% CI 1.03-1.08; cardiovascular: HR: 1.08, 95% CI 1.02-1.14); on the other hand, we found a trend for increased mortality with increasing HbA1c levels in patients with known diabetes, but not in participants without., Conclusions: For a novel measure of hyperglycemia to be considered useful, its association with hard, long term clinical outcomes is of great importance. We showed that GA is associated with mortality in the general population independently of a previous diagnosis of diabetes., Competing Interests: Conflict of interest All authors declare no conflicts of interest related to this study., (Copyright © 2022 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: The surgical treatment of advanced non-small-cell-lung-cancer (NSCLC) invading mediastinal organs and great vessels is still controversial. The aim of this multicentre study is to analyse oncological outcomes, surgical outcomes and prognostic factors of patients with NSCLC involving heart and great vessels., Methods: 362 patients treated surgically for locally advanced T4-NCSLC between 1990 and 2020 were retrospectively reviewed. Patients were divided into five subgroups: pulmonary artery(n = 129), left atrium(n = 82), superior vena cava(n = 80), aorta(n = 43), and multiple vascular structures(n = 28). Resection was complete in 327(90%) patients., Results: Overall 90-day mortality was 8.8%, influenced by poly-transfusions, pneumonectomy, bronchopleural fistula and previous cardiovascular disease (4.5HR.p = 0.03, 3.7HR p = 0.01, 14.0HR.p < 0.001 and 3.0HR p < 0.01). One-, 3- and 5-year survival rates were 75%, 43%, 33%, respectively and there were significant differences among the five groups(p < 0.001). Survival was significantly affected by induction radiotherapy, nodal status, pTNM-stage and radicality (3.8HR p = 0.03, 2.6HR p = 0.001, 1.6HR p < 0.05 and 1.6HR p < 0.05)., Conclusions: Surgery provided acceptable results in selected patients with T4-NSCLC with major vascular infiltration in expert centres. Nodal-status and radicality influenced the overall-survival and disease-free survival. Neoadjuvant chemotherapy appears to have a positive effect on long-term results, particularly in N2-patients., Competing Interests: Declaration of competing interest No conflict of interest to declare., (Copyright © 2022 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Prolonged air leaks (PAL) complicate 10% to 15% of lung resections, delaying chest tube removal and prolonging length of hospital stay. No consensus exists for managing this common complication, despite favorable results for autologous blood patch pleurodesis (ABPP) in the literature. The aim of this study was to evaluate the effectiveness and safety of ABPP., Methods: We retrospectively reviewed medical records of 510 patients with PAL after lobectomy in four centers between January 2010 and December 2019. They were divided into two groups: group A consisted of patients who received ABPP for PAL of more than 5 days; and group B was patients for whom no ABPP or other procedure was performed for PAL unless strictly necessary. Propensity score matched analysis was performed, and 109 patients were included in each group. Time to cessation of air leak and chest tube removal, length of hospital stay, reoperation, and complications rate were examined., Results: After the propensity score matching, ABPP significantly reduced the number of days before chest tube removal (8.12 vs 9.30, P = .004), and length of hospital stay (10 vs 11 days, P = .045) with fewer perioperative complications (6 vs 17, P = .015). Furthermore, ABPP was related to lower incidence of any additional invasive procedures (0 vs 9, P = .002) and reoperation (0 vs 4, P = .044). No patient in the ABPP group had long-term complications related to pleurodesis., Conclusions: Autologous blood patch pleurodesis is safe and effective in reducing length of hospital stay and leads to earlier chest tube removal without increasing complications., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Successful postoperative pain management after major lung resection surgery is mostly achieved through intravenous administration of analgesic drugs. This study explored the use of sublingual sufentanil cartridges (Zalviso) as a noninvasive alternative to postoperative analgesia., Methods: From July 2019 to April 2020, patients who underwent major thoracoscopic lung resection surgery were randomly allocated to receive either intravenous pain management, or patient-controlled analgesia by the Zalviso system. Pain assessment scores were collected for a 72-hour time window, and requests for additional medication due to insufficient pain control were recorded., Results: Of the 80 patients enlisted, 40 were assigned to the Zalviso group and 40 to the control group. The groups were not statistically different from each other. The difference in the mean pain scores reported was statistically significant in the first 24 hours in favor of the Zalviso group (P = .046), and the need for additional pain medication was significantly higher in the control group (P = .004)., Conclusions: Patient-controlled analgesia using sublingual sufentanil cartridges can provide effective pain relief for patients undergoing video-assisted thoracic surgery and can reduce the need for additional medication, offering a noninvasive alternative to traditional intravenous therapy., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Aortic invasion from non-small cell lung cancers (NSCLC) is a relative contraindication to surgery for oncological and technical reasons. Only a few studies have been published showing good results. Our aim was to evaluate short and long-term results of surgery for T4 NSCLC with aortic resection., Methods: This is a multicenter retrospective study including 47 patients (33 males and 14 females) who received a major lung resection with aortic surgery in our centers between January 2000 and December 2016., Results: Adenocarcinoma was diagnosed in 31 patients (66.0%). Induction therapy was used in 14 patients. Pneumonectomy was performed in 34 patients (72.3%). A subadventitial dissection with or without endovascular stent graft was carried out in 40 patients (85.1%), a cardiopulmonary bypass was used in 3 patients and left heart bypass in 4. Intraoperatively, two patients had bleeding (4.3%) and one ventricular fibrillation (2.1%). Twenty-three patients (48.9%) experienced at least one postoperative complication. A radical resection was achieved in 39 patients (83.0%). Thirty-day and 90-day mortality were 2.1% and 4.3%. One-, 3- and 5-year overall survival were 85.1%, 57.4% and 53.2%. Overall and disease-free survivals were significantly influenced by pathological lymph node status and R status that were independent predictive factors for poorer survival at the multivariate analyses., Conclusions: Aortic resection during surgery for NSCLC is a challenging situation. Nevertheless, oncologic outcomes may be favorable in selected cases justifying a risky procedure that should be performed in experienced hands., Competing Interests: Declaration of competing interest No conflict of interest to declare., (Copyright © 2021 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Objectives: This study aimed to assess the cost-effectiveness profile of adherence to recommendations for the community management of patients discharged with a diagnosis of acute coronary syndrome (ACS)., Methods: The cohort of 50 282 residents in the Lombardy Region (Italy) who were discharged with a diagnosis of ACS during 2011 to 2015 was followed up until 2018. Adherence to selected recommendations including drug therapies (DTs), outpatient controls, and rehabilitation, experienced during the first year after index discharge, was considered. Adherent and nonadherent cohort members were matched on high-dimensional propensity scores. Composite clinical outcomes (cardiovascular hospital admissions and all-cause mortality) and healthcare costs were assessed for a time horizon of 5 years. Cost-effectiveness profile of adherence to recommendations was measured through the incremental cost-effectiveness ratio, that is, the incremental cost for 1 day free from the composite clinical outcome., Results: Adherence to DTs, outpatient controls, and rehabilitation, respectively, regarded 39%, 81%, and 3% of cohort members. Compared with nonadherent patients, those adherent to DTs, outpatient controls, and rehabilitation had (1) a delay in the occurrence of the composite clinical outcome of 50, 43, and 73 days, respectively, and (2) lower (on average, €199 per year for DTs) and higher costs (€292 and €1024 for outpatient controls and rehabilitation). Cost-effectiveness profiles were better for patients with myocardial infarction than those with angina and for patients with more severe clinical complexity than those with milder conditions., Conclusions: Health-related and economic benefits are expected from improving adherence to international guidelines recommendations concerning outpatient treatments and monitoring of patients with ACS., (Copyright © 2021 ISPOR–The International Society for Pharmacoeconomics and Outcomes Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: Methodological challenges for investigating the changes in healthcare utilization during COVID-19 pandemic must be considered for obtaining unbiased estimates., Study Design and Setting: A population-based study in the Lombardy region (Italy) measured the association between the level of epidemic restrictions (increasing exposure during pre-epidemic, post-lockdown, and lockdown periods) and the recommended healthcare (outcome) for patients with schizophrenia, heart failure, chronic obstructive pulmonary disease, breast cancer, and pregnancy women. Two designs are applied: the self-controlled case series (SCCS) and the usual cohort design. Adjustments for between-patients unmeasured confounders and seasonality of medical services delivering were performed., Results: Compared with pre-epidemic, reductions in delivering recommended healthcare during lockdown up to 73% (95% confidence interval: 63%-80%) for timeliness of breast cancer surgery, and up to 20% (16%-23%) for appropriated gynecologic visit during pregnancy were obtained from SCCS and cohort design, respectively. Healthcare provision came back to pre-epidemic levels during the post-lockdown, with the exception of schizophrenic patients for whom the SCCS showed a reduction in continuity of care of 11% (11%-12%)., Conclusion: Strategies for investigating the changes in healthcare utilization during pandemic must be implemented. Recommendations for taking into account sources of systematic uncertainty are discussed and illustrated by using motivating examples., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: T4 tumours comprise a heterogeneous group of locally invasive non-small cell lung cancers (NSCLC). Intrapericardial and extrapericardial involvement of the pulmonary artery (PA) may have a different prognosis. We compared the short and long-term surgery outcomes for NSCLC of the PA with intrapericardial or extrapericardial involvement., Methods: This is a multicenter retrospective study that included 129 patients who received an anatomical resection with PA resection and reconstruction in our centres between January 2000 and December 2018. Extrapericardial group included 70 patients, while the intrapericardial included 59., Results: Differences in outcomes were found in terms of left side surgery (more common in extrapericardial, p = 0.010), type of lung resection (p < 0.001), Clavien-Dindo score (p = 0.012) and 90-day mortality (1.4 vs 16.9%, p = 0.002). Overall survival (OS, 91.11 ± 63.78 vs 63.78 ± 58.241 months, p = 0.008) and tumour-free survival (TFS, 68.17 ± 71.57 vs 45.44 ± 61.32 months, p = 0.007) were statistically different. OS stratification for performed pneumonectomy, pathological lymph node status and pattern of recurrence were statistically different (p = 0.017, 0.040, <0.001). Differences were found in terms of recurrence months stratified for recurrence pattern (p < 0.001)., Conclusions: According to our results, the difference between PA involvement is significant in terms of survival and complications. A T4 subset or a shift to T3 for extrapericardial involvement of the PA may lead to a change in staging and surgical approach for these patients., Competing Interests: Declaration of competing interest No conflict of interest to declare., (Copyright © 2021 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: The treatment of non-small cell lung cancer is based, when suitable, on surgical resection. Pneumonectomy has been considered the standard surgical procedure for locally advanced lung cancers but it is associated with high mortality and morbidity rates. Reconstruction of the pulmonary artery, associated with parenchyma-sparing techniques, is meant to be an alternative to pneumonectomy., Methods: This retrospective single-center study is based on a detailed and comprehensive analysis of the clinical and oncologic data of patients treated between 2004 and 2016 through pneumonectomy or lobectomy with reconstruction of the pulmonary artery. A propensity score weighting approach, based on the preoperative characteristics of two groups of 124 patients each was performed. The subsequent statistical analysis evaluated long-term and short-term clinical outcomes together with risk factors analysis., Results: The comparison between pneumonectomy and pulmonary artery reconstructions showed a higher 30-day (P = .02) and 90-day (P = .03) mortality rate in the pneumonectomy group, together with a higher incidence of major complications (P = .004). Long-term results have shown comparable outcomes, both in terms of 5-year disease-free survival (52.2% for pneumonectomy vs 46% for pulmonary artery reconstructions, P = .57) and overall 5-year survival (41.9% vs 35.6%, respectively; P = .57). Risk factors analysis showed that cancer-specific survival was related to lymph node status (P < .01) and absence of adjuvant therapy (P = .04). Lymph node status also influenced the risk of recurrence (P < .01)., Conclusions: Lobectomy with reconstruction of the pulmonary artery is a valuable and oncologically safe alternative to pneumonectomy, with lower short-term mortality and morbidity, without affecting long-term oncologic results., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background and Aims: To validate a set of indicators for monitoring the quality of care of patients with diabetes in 'real-life' practice through its relationship with measurable clinical outcomes and healthcare costs., Methods and Results: A population-based cohort study was carried out by including the 20,635 patients, residents in the Lombardy Region (Italy), who in the year 2012 were newly taken-in-care for diabetes. Adherence with clinical recommendations (i.e., controls for glycated haemoglobin, lipid profile, urine albumin excretion and serum creatinine) was recorded during the first year after the patient was taken-in-care, and categorized according whether he/she complied with none or almost none (0 or 1), just some (2) or all or almost all (3 or 4) the recommendations, respectively denoted as poor, intermediate and high adherence. Short- and long-term complications of diabetes, and healthcare cost incurred by the National Health Service, were assessed during follow-up. Compared with patients with poor adherence, those with intermediate and high adherence respectively showed (i) a delay in outcome occurrence of 13 days (95% CI, -2 to 27) and 23 days (9-38), and (ii) a lower healthcare cost of 54 € and 77 €. In average, a gain of 18 Euros and 15 Euros for each day free from diabetic complication by increasing adherence respectively from poor to intermediate and from poor to high were observed., Conclusion: Close control of patients with diabetes through regular clinical examinations must be considered the cornerstone of national guidance, national audits, and quality improvement incentive schemes., Competing Interests: Declaration of competing interest Giovanni Corrao received research support from the European Community (EC), the Italian Agency of Drug (AIFA), and the Italian Ministry of Education, University and Research (MIUR). He took part to a variety of projects that were funded by pharmaceutical companies (i.e., Novartis, GSK, Roche, AMGEN and BMS). He also received honoraria as member of Advisory Board from Roche. Giuseppe Mancia received honoraria for participation as speaker/chairman in national/international meetings from Bayer, Boehringer Ingelheim, CVRx, Daiichi Sankyo, Ferrer, Medtronic, Menarini Int., Merck, Novartis, Recordati and Servier. Other authors declare that they have no conflict of interest to disclose., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: Total lung-sparing tracheobronchial sleeve resections are a step forward in the treatment of low-grade bronchial tumors in which minimal resection margins are required to achieve complete control of the disease., Methods: This study retrospectively collected data on patients who underwent total lung-sparing procedures for low-grade tracheobronchial tumors at 2 thoracic surgical centers from January 1984 to October 2019., Results: The study included 98 patients, 46 -female (47%) and 52 -male (53%), with a median age of 39 years (range, 7 to 70 years). Thirty-four patients underwent operative endoscopy before surgery (32 had laser treatment, and 2 had endobronchial stenting). The surgical resections were as follows: 9 (9%), tracheal carina; 18 (18%), second carina; 31 (32%), left main bronchi; 25 (26%), right main bronchi; and 15 (15%), intermediate bronchus. The median length of the resected bronchus was 2.2 cm. The median postoperative in-hospital stay was 8 days, and no perioperative mortality was observed. Postoperative complications were recorded in 26-patients (27%). The final histologic classification was as follows: 37 typical carcinoids (38%); 10 atypical carcinoids (10%); 29 adenoid cystic carcinomas (30%); 15 mucoepidermoid carcinomas (15%); 6 inflammatory myofibroblastic tumors (6%); and 1 glomic tumor (1%). Twenty-two patients had positive resection margins and underwent adjuvant radiotherapy. Three patients with adenoid cystic carcinoma had recurrences (1 local and 2 systemic). After a median follow-up time of 54.5 months (range, 4 to 360 months), the overall actuarial 5-year survival was 97%., Conclusions: Total lung-sparing tracheobronchial sleeve resection for low-grade malignant disease requires advanced surgical skills, but the hospital morbidity and mortality are very low. This technique is adequate and safe for highly selected patients with low-grade endobronchial malignant diseases, and its use should be encouraged in experienced centers., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Reconstruction of the anterior chest wall defect after sternectomy is a challenge for cardiothoracic surgeons. In 2010, the Padua group published the first case of cadaveric sternum transplantation after sternectomy. This multicenter study reports the clinical indications and early and long-term results of sternal chondral allograft transplantation., Methods: This is a retrospective multicenter study from 7 academic centers. We collected demographic data, surgical indications, technical details, and early postoperative results. The complications, long-term stability, and tolerance of the allografts were also analyzed., Results: Between January 2008 and December 2019, 58 patients underwent sternectomy followed by reconstruction using cadaveric-cryopreserved sternochondral allografts. Thirty-two patients were male, median age 63.5 years (interquartile range, 50-72 years). Indications for sternectomy were secondary sternal tumors (n = 13), primary sternal tumors (n = 15), and nonneoplastic disease (n = 30). Thirty patients underwent total sternectomy, 16 lower-body sternectomy, and 12 upper-body manubrium resection. The 30-day mortality was 5%; overall morbidity was 31%. Six early reoperations were necessary because of bleeding (n = 1), titanium plate dislocation (n = 1), and resuture of the skin in the lower part of the incision (n = 4). Overall, 5-year survival was 74%. In all the survived patients, the reconstructions were stable and free from mechanical or infective complications., Conclusions: The main indications for sternal allograft implantation were complex poststernotomy dehiscence followed by primary or secondary tumor involvement of the sternum. The collected results demonstrate that sternochondral allograft transplantation is a safe and effective method in reconstructing the anterior chest wall after sternectomy. Further studies to demonstrate the integration of the bone grafts into the patients' sternal wall will be made., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objectives: Because observational studies often use imperfect measurements, results are prone to misclassification errors. We used as a motivating example the possible teratogenic risks of antiemetic agents in pregnancy since a large observational study recently showed that first-trimester exposure to doxylamine-pyridoxine was associated with significantly increased risk of congenital malformations as a whole, as well as central nervous system defects, and previous observational studies did not show such associations. A meta-analysis on this issue was carried out with the aim to illustrate how differential exposure and outcome misclassifications may lead to uncertain conclusions., Methods: Medline, searched to October 2019 for full text papers in English. Summary Odds Ratios (ORs) with confidence intervals (CIs) were calculated using random-effect models. Probabilistic sensitivity analyses were performed for evaluating the extension of differential misclassification required to account for the exposure-outcome association., Results: Summary ORs were 1.02 (95 % CI, 0.92-1.15), 0.99 (0.82-1.19) and 1.25 (1.08-1.44) for overall congenital, cardiocirculatory, and central nervous system malformations respectively. By assuming exposure and outcome bias factor respectively of 0.95 (i.e., newborns with congenital defects had exposure specificity 5% lower than healthy newborns) and 1.12 (i.e., exposed newborns had outcome sensitivity 12 % higher than unexposed newborns), summary OR of central nervous system defects became 1.13 (95 % CI, 0.99-1.29) and 1.17 (95 % CI, 0.99-1.38)., Conclusion: Observational investigations and meta-analyses of observational studies need cautious interpretations. Their susceptibility to several, often sneaky, sources of bias should be carefully evaluated., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Ischemia-reperfusion (IR) injury after lung transplantation is still today an important complication in up to 25% of patients. The Organ Care System (OCS) Lung, an advanced normothermic ex vivo lung perfusion system, was found to be effective in reducing primary graft dysfunction compared to standard organ care (SOC) but studies on tissue/molecular pathways that could explain these more effective clinical results are lacking. This observational longitudinal study aimed to investigate IR injury in 68 tissue specimens collected before and after reperfusion from 17 OCS and 17 SOC preserved donor lungs. Several tissue analyses including apoptosis evaluation and inducible nitric oxide synthase (iNOS) expression (by immunohistochemistry and real-time reverse transcriptase-polymerase chain reaction) were performed. Lower iNOS expression and apoptotic index were distinctive of OCS preserved tissues at pre- and post-reperfusion times, independently from potential confounding factors. Moreover, OCS recipients had lower acute cellular rejection at the first 6-month follow-up. In conclusion, IR injury, in terms of apoptosis and iNOS expression, was less frequent in OCS- than in SOC-preserved lungs, which could eventually explain a better clinical outcome. Further studies are needed to validate our data and determine the role of iNOS expression as a predictive biomarker of the complex IR injury mechanism., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Patients who experience a hospital admission for acute coronary syndromes (ACS) exhibit poor prognosis over the years. The purposes of this study were to evaluate the real-world patterns of out-of-hospital practice in the management of ACS patients and to assess their impact on the risk of selected outcomes., Methods: The cohort of 87,530 residents in the Lombardy Region (Italy) who were newly hospitalised for ACS during 2011-2015 was followed until 2018. Exposure to medical treatment including use of selected drugs, diagnostic procedures and laboratory tests was recorded. The main outcome of interest was re-hospitalisation for cardiovascular (CV) outcomes. Proportional hazards models were fitted to estimate hazard ratio, and 95% confidence intervals (CI), for the exposure-outcome association. Analyses were stratified according to the ACS type., Results: The cumulative incidence of re-hospitalisation for CV disease was 33%, 42% and 38% at 5 years after index discharge among STEMI, NSTEMI and unstable angina patients. Within one year from index discharge, between 70% and 80% of patients had at least a prescription of statins, beta-blockers and renin-angiotensin-system blocking agents, underwent ECG and lipid profile examination, and had a cardiologic examination. One patient in five underwent cardiac rehabilitation. Compared with patients who did not adhere to healthcare recommendations, the risk of CV hospital readmission was reduced from 10% (95% CI: 4%-10%) to 23% (12%-32%) among patients who underwent lipid profile examinations and who experienced cardiac rehabilitation., Conclusion: Close out-of-hospital healthcare must be considered the cornerstone for improving the long-term prognosis of ACS patients., Competing Interests: Declaration of Competing Interest Giovanni Corrao received research support from the European Community (EC), the Italian Agency of Drug (AIFA), and the Italian Ministry of Education, University and Research (MIUR). He took part to a variety of projects that were funded by pharmaceutical companies (i.e., Novartis, GSK, Roche, AMGEN and BMS). He also received honoraria as member of Advisory Board from Roche. For the remaining authors, nothing was declared., (Copyright © 2020. Published by Elsevier B.V.)

Background: A set of indicators to assess the quality of care for women operated for breast cancer was developed by an expert working group of the Italian Health Ministry in order to compare the Italian regions. A study to validate these indicators through their relationship with survival was carried out., Methods: The 16,753 women who were residents in three Italian regions (Lombardy, Emilia-Romagna and Lazio) and hospitalized for breast cancer surgery during 2011 entered the cohort and were followed until 2016. Adherence to selected recommendations (i.e., surgery timeliness, medical therapy timeliness, appropriateness of complementary radiotherapy and mammographic follow-up) was assessed. Multivariable proportional hazards models were fitted to estimate hazard ratios for the association between adherence with recommendations and the risk of all-cause mortality., Results: Adherence to recommendations was 53% for medical therapy timeliness, 73% for appropriateness of mammographic follow-up, 74% for surgery timeliness and 82% for appropriateness of complementary radiotherapy. Risk reductions of 26%, 62% and 56% were observed for adherence to recommendations on medical therapy timeliness, appropriateness of complementary radiotherapy and mammographic follow-up, respectively. There was no evidence that mortality was affected by surgery timeliness., Conclusions: Clinical benefits are expected from improvements in adherence to the considered recommendations. Close control of women operated for breast cancer through medical care timeliness and appropriateness of radiotherapy and mammographic monitoring must be considered the cornerstone of national guidance, national audits, and quality improvement incentive schemes., Competing Interests: Declaration of competing interest Giovanni Corrao received research support from the European Community (EC), the Italian Drugs Agency (AIFA), and the Italian Ministry of Education, University and Research (MIUR). He took part in a number of projects funded by pharmaceutical companies (i.e., Novartis, GSK, Roche, AMGEN and BMS). He also received honoraria from Roche as a member of the Advisory Board. For the remaining authors, nothing was declared., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Despite the invaluable efficacy of statins, adherence to therapy is extremely poor in clinical practice. Improvement interventions should be as personalized as possible, but it is necessary to know factors that most influence adherence, and sex seems to be a key determinant. Thus, we aimed at exploring potential areas of sex-differences in statin adherence in a real-world population. For this purpose, we assessed adherence (as proportion of days covered) on a wide cohort of new statin users aged >40 years, and we evaluated its association with several covariates through sex-stratified log-binomial regression models. In addition, to compare also the benefits of optimal statin adherence in primary prevention of cardiovascular disease between men and women, we implemented sex-stratified Cox proportional hazard models. Our study showed that women are more likely to stop or be less adherent to statin treatment than men. Moreover, we observed significant sex-differences on effect size of several factors associated with adherence that should be taken into consideration for the management of patients. Finally, we observed no significant difference between men and women regarding statin efficacy in terms of reduction of incident hospitalization for ischemic heart disease and/or non-haemorrhagic cerebrovascular disease. These results invoke the responsibility of physicians to a prompt and personalized intervention. Physicians should consider routine screening for non-adherence in their clinical practice, target patients at higher risk of non-adherence, and improved motivation and communication., Competing Interests: Declaration of Competing Interest EO, MTB, MC, ET, LM and FR report no disclosures. ALC received research funding and/or honoraria for advisory boards, consultancy or speaker bureau from Aegerion, Amgen, AstraZeneca, Eli Lilly, Genzyme, Mediolanum, Merck or MSD, Pfizer, Recordati, Rottapharm, Sanofi-Regeneron, Sigma-Tau. GC received research support from the European Community (EC), the Italian Agency of Drug (AIFA), and the Italian Ministry of Education, University and Research (MIUR). He took part in a variety of projects that were funded by pharmaceutical companies (i.e., Novartis, GSK, Roche, Amgen, and BMS). He also received honoraria as member of Advisory Board from Roche., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: This group previously reported on the repair of a wide tracheoesophageal fistula with a bioabsorbable patch. The current study describes a consecutive series of patients operated on using the same technique., Methods: Data of patients undergoing surgical closure of tracheoesophageal fistula at a single center from 2011 to 2018 were extracted and analyzed., Results: An absorbable patch was used in 8 of 23 patients (34.8%) operated on for tracheoesophageal fistula during the study period. Causes of the fistulae included postintubation injury (n = 6), mediastinal radiotherapy (n = 1), and a complication of lung resection (n = 1). The median fistula size was 27.5 mm (range, 15 to 45 mm). In 3 patients, the surgical approach was through cervicotomy and in 5 it was through right thoracotomy. Prosthetic materials consisted of Gore Bio-A (W.L. Gore & Associates, Inc, Newark, DE) tissue reinforcement in 6 patients and polyglactin 910 knitted mesh in 2 patients. In every case, the prosthesis was covered with a pedicled muscle flap. The esophageal defect was treated by primary closure in 7 patients and by esophageal exclusion in 1. Fistula recurrence and postoperative death occurred in 1 patient (12.5%), whereas 7 patients experienced postoperative complications (87.5%). Five patients resumed oral intake, and 3 breathed without a tracheal appliance. Compared with the other patients, in those who underwent repair of their fistula using a prosthesis, the median size of the airway defect was larger, morbidity was greater, and the rate of resumption of oral intake was lower., Conclusions: Repair of tracheoesophageal fistulae with synthetic prostheses is feasible and may be effective in complex cases. Further research is needed to identify the ideal prosthetic material., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: The Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) is a comprehensive instrument developed to accurately assess the main pretransplant psychosocial risk factors that may impact transplant outcomes., Objective: As neither established assessment procedures nor standardized tools designed to perform pretransplant psychosocial evaluation are currently available in Italy, the present study was designed to develop and preliminarily validate the Italian version of the SIPAT., Methods: First, our team developed the Italian version of the SIPAT, following standard forward-back translation procedures. Then, the Italian version of the SIPAT was retrospectively and blindly applied to 118 randomly selected transplant cases (40 heart, 40 lung, and 38 liver) by 2 independent examiners. Information about the patients' final transplant listing recommendation (i.e., listing vs. deferral) was independently collected from the respective transplant teams., Results: The inter-rater reliability of the Italian version of the SIPAT scores was substantial (Cohen's kappa = 0.77; P < 0.001). Moreover, the predictive value of the SIPAT ratings on the final transplant listing recommendation (i.e., listing vs. deferral) for each examiner was significant (both P < 0.05)., Conclusion: Current findings suggest that SIPAT is a promising and reliable instrument in its Italian version. Given these excellent psychometric characteristics, the use of the SIPAT as part of the pretransplant psychosocial evaluation in Italian medical settings is highly encouraged., (Copyright © 2019 Academy of Consultation-Liaison Psychiatry. Published by Elsevier Inc. All rights reserved.)

Pulmonary artery sling is a rare congenital anomaly of the origin and course of the left pulmonary artery. Patients with this condition typically present with respiratory failure in young infancy, and asymptomatic cases are uncommon. We describe the case of an adult patient with a lung adenocarcinoma of the right upper lobe, extending into the hilum and superior mediastinum, and with a previously unknown pulmonary artery sling anomaly. The local invasiveness of the tumor and the peculiar vascular anatomy contributed to a unique surgical scenario, wherein multiple reconstructive procedures were required., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to develop a new population-based risk stratification tool (Chronic Related Score [CReSc]) for predicting 5-year mortality and other outcomes., Study Design and Setting: The score included 31 conditions selected from a list of 65 candidates whose weights were assigned according to the Cox model coefficients. The model was built from a sample of 5.4 million National Health Service (NHS) beneficiaries from the Italian Lombardy Region and applied to the remaining 2.7 million NHS beneficiaries. Predictive performance was assessed by discrimination and calibration. CReSc ability in predicting secondary endpoints (i.e., hospital admissions and health care costs) was investigated. Finally, the relationship between CReSc and income was considered., Results: Among individuals aged 50-85 years, CReSc performance showed (1) an area under the receiver operating characteristic curve of 0.730, (2) an improved reclassification from 44% to 52% with respect to other scores, and (3) a remarkable calibration. A trend toward increasing rates of all the considered endpoints as CReSc increases was observed. Compared with individuals on low-intermediate income, NHS beneficiaries on high income showed better CReSc profile., Conclusion: We developed a risk stratification tool able to predict mortality, costs, and hospital admissions. The application of CReSc may generate clinically and operationally important effects., (Copyright © 2019 Elsevier Inc. All rights reserved.)

About 15% of patients with myasthenia gravis are affected by thymoma. Precise tumor staging is necessary to plan the appropriate operation. In early stages, complete surgical resection is the mainstay of treatment. Minimally invasive approaches can be safely performed by highly trained surgeons, and may be preferred in myasthenic patients because they can ensure optimal results from the oncological, neurologic, and surgical point of views, avoiding the complications of open approach. For advanced stage thymoma in myasthenic patients, a careful, multidisciplinary planning of the therapeutic approach must be undertaken, particularly for extended resections involving the lung and great vessels., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Incidence and prognostic impact of heart failure (HF) progression has been not well addressed., Methods: From 2009 until 2015, consecutive ambulatory HF patients were recruited. HF progression was defined by the presence of at least two of the following criteria: step up of ≥1 New York Heart Association (NYHA) class; decrease LVEF ≥ 10 points; association of diuretics or increase ≥ 50% of furosemide dosage, or HF hospitalization., Results: 2528 met study criteria (mean age 76; 42% women). Of these, 48% had ischemic heart disease, 18% patients with LVEF ≤ 35%. During a median follow-up of 2.4 years, overall mortality was 31% (95% CI: 29%-33%), whereas rate of HF progression or death was 57% (95% CI: 55%-59%). The 4-year incidence of HF progression was 39% (95% CI: 37%-41%) whereas the competing mortality rate was 18% (95% CI: 16%-19%). Rates of HF progression and death were higher in HF patients with LVEF ≤ 35% vs >35% (HF progression: 42% vs 38%, p = 0.012; death as a competing risk: 22% vs 17%, p = 0.002). HF progression identified HF patients with a worse survival (HR = 3.16, 95% CI: 2.75-3.72). In cause-specific Cox models, age, previous HF hospitalization, chronic obstructive pulmonary disease, chronic kidney disease, anemia, sex, LVEF ≤ 35% emerged as prognostic factors of HF progression., Conclusions: Among outpatients with HF, at 4 years 39% presented a HF progression, while 18% died before any sign of HF progression. This trend was higher in patients with LVEF ≤ 35%. These findings may have implications for healthcare planning and resource allocation., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Thymic epithelial tumors (TETs) are a heterogenous group of rare tumors, with a complex histopatological classification. Furthermore, the recent introduction of the first TNM staging system, that is scheduled to replace the Masaoka-Koga system, may create further difficulties in TET management, that remains challenging. Several guidelines for treatment of TETs are available and provide recommendations based mainly on non randomized trials and retrospective or limited series. Often the lack of evidence leads to formulation of indications based on expert opinions. As for other rare cancers it is crucial to create networks to coordinate the work among centres involved in treatment of these diseases in order to offer the best diagnostic and therapeutic tools. For this purpose, in 2014 a network named TYME (ThYmic MalignanciEs), was founded in Italy with the aim of improving care and research in TETs. In September 2017 a panel of multidisciplinary experts from TYME network and from other Italian centres strongly involved in TET diagnosis and treatment convened a first Italian Expert meeting together with representatives of association for patients affected by rare thoracic cancers Tu.To.R, to explore how these tumors are managed in the different centres of Italy compared to ESMO guidelines. In this paper we summarize the issues discussed during that meeting and we propose recommandations based on Masaoka Koga and the new TNM staging system., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: A pathologic grading system (PGS) for malignant pleural mesothelioma (MPM) is warranted to better identify different risk categories of patients, plan therapeutic options, and activate clinical trials., Methods: A series of 940 patients with MPM (328 in a training set and 612 in a validation set) that was diagnosed between October 1980 and June 2015 at the participant institutions was retrospectively assembled. A PGS was constructed by attributing to each histologic parameter, independent at multivariate analysis with excellent reproducibility (κ > 0.75), different scores based on the increase in corresponding hazard ratios. The relevant PGS score thus ranged from 0 to 8 points for individual patients with MPM., Conclusions: The PGS was constructed by taking into consideration the histological subtyping of MPM (epithelioid/biphasic = 0 points; sarcomatoid = 2 points), necrosis (absent = 0 points versus present = 1 point), mitotic count per 1 mm 2 (cutoffs as follows: 1-2 = 0 points, 3-5 = 1 point, 6-9 = 2 points, or ≥10 = 4 points), and Ki-67 labeling index based on 2000 cells (<30% = 0 points versus ≥30 = 1 point), all of which are independent factors in both patient sets after adjustment for stage and age at diagnosis. No heterogeneity was seen across the validation centers (p = 0.19). Epithelioid/biphasic MPM patterning and biopsy versus resection did not affect survival, whereas the PGS outperformed mitotic count and Ki-67 LI in both the training (area under the curve receiver operating characteristic = 0.76) and validation sets (area under the curve receiver operating characteristic = 0.73) (p < 0.01). Patient survival progressively deteriorated from a score of 0 (median times of 26.3 and 26.9 months) to a score 1 to 3 (median times of 12.8 and 14.4 months) and a score of 4 to 8 (median times of 3.7 and 7.7 months) in both sets of patients, with the hazard ratio for a 1-point increase in score being 1.46 (95% confidence interval: 1.36-1.56) in the training set and 1.28 (95% confidence interval: 1.22-1.34) in the validation set (after adjustment for age and [when available] tumor stage). The PGS was effective even in subgroup analysis (epithelioid, biphasic, and sarcomatoid tumors)., Discussion: A simple and reproducible multiparametric PGS effectively predicted survival in patients with MPM., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Several gray areas and controversies exist concerning the management of pulmonary ground-glass opacities (GGOs), and there is a lack of consensus among clinicians on this topic. One of the main aims of the Italian Society of Thoracic Surgery is to promote education and research, so we decided to perform a survey on this topic to estimate current trends in practice in a large sample of thoracic surgeons., Methods: A total of 160 thoracic surgeons responded, namely, completed our questionnaire (response rate, 53%; 160 of 302). The survey was composed of 36 questions divided into six subsections: (1) demographic characteristics of the respondents; (2) terminology and taxonomy; (3) radiologic and radiometabolic evaluation; (4) diagnostic approach and indications for surgery; (5) surgical management; and (6) radiologic surveillance., Results: We observed some divergence of opinion regarding the definition of mixed GGOs, the role of 18F fluorodeoxyglucose positron emission tomography and computed tomography scans, indications for nonsurgical biopsy, intraoperative techniques for localizing GGOs, indications for surgery, extension of lung resection and lymph node dissection according to the radiologic scenario, use of intraoperative frozen section analysis, and radiologic surveillance of pure GGOs., Conclusions: This topic warrants more investigation in the future. An upcoming consensus conference of Italian Society of Thoracic Surgery experts (also open to experts in other specialties) could provide updated indications for GGO management based on the literature, expert opinions, and the results of the present survey., (Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: The deficiency of α 1 -antitrypsin (AAT) is secondary to misfolding and polymerization of the abnormal Z-AAT in liver cells and is associated with lung emphysema. Alveolar macrophages (AMs) produce AAT; however, it is not known whether Z-AAT can polymerize in AMs, further decreasing lung AAT and promoting lung inflammation. Our intention was to investigate whether AAT polymerizes in human AMs and to study the possible relation between polymerization and degree of lung inflammation., Methods: Immunohistochemical analysis with 2C1 monoclonal antibody specific for polymerized AAT was performed in sections of the following: nine lungs from individuals with AAT deficiency (AATD) and severe COPD; 35 smokers with normal AAT levels, of whom 24 had severe COPD and 11 did not have COPD; and 13 nonsmokers. AMs positive for AAT polymers were counted and expressed as the percentage of total AMs in the lungs., Results: AAT polymerization was detected in 27% (4%-67%) of AMs from individuals with AATD but also in AMs from smokers with normal AAT with (24% [0%-70%]) and without (24% [0%-60%]) COPD, but not in AMs from nonsmokers (0% [0%-1.5%]) (P < .0001). The percentage of AMs with polymerized AAT correlated with pack-years smoked (r = 0.53, P = .0001), FEV 1 /FVC (r = -0.41, P = .005), small airways disease (r = 0.44, P = .004), and number of CD8 + T cells and neutrophils in alveolar walls (r = 0.51, P = .002; r = 0.31, P = .05, respectively)., Conclusions: Polymerization of AAT in alveolar macrophages occurs in the lungs of individuals with AATD but also in smokers with normal AAT levels with or without COPD. Our findings highlight the similarities in the pathophysiology of COPD in individuals with and without AATD, adding a potentially important step to the mechanism of COPD., (Copyright © 2018 American College of Chest Physicians. All rights reserved.)

Background: Severe primary graft dysfunction (PGD) of grade 3 (PGD3) is a common serious complication following lung transplantation. We aimed to assess physiological donor lung preservation using the Organ Care System (OCS) Lung device compared with cold static storage., Methods: In this non-inferiority, randomised, controlled, open-label, phase 3 trial (INSPIRE) recipients were aged 18 years or older and were registered as standard criteria primary double lung transplant candidates. Eligible donors were younger than 65 years old with a ratio of partial pressure of oxygen in arterial blood to the fraction of inspired oxygen of more than 300 mm Hg. Transplant recipients were randomly assigned (1:1) with permuted blocks, stratified by centre, to receive standard criteria donor lungs preserved in the OCS Lung device (OCS arm) or cold storage at 4°C (control arm). The composite primary effectiveness endpoint was absence of PGD3 within the first 72 h after transplant and 30-day survival in the per-protocol population, with a stringent 4% non-inferiority margin. Superiority was tested upon meeting non-inferiority. The primary safety endpoint was the mean number of lung graft-related serious adverse events within 30 days of transplant. We did analyses in the per-protocol and intention-to-treat populations. This trial is registered with ClinicalTrials.gov, number NCT01630434., Findings: Between Nov 17, 2011, and Nov 24, 2014, we randomly assigned 370 patients, and 320 (86%) underwent transplantation (n=151 OCS and n=169 control); follow-up was completed in Nov 24, 2016. The primary endpoint was met in 112 (79·4%) of 141 patients (95% CI 71·8 to 85·8) in the OCS group compared with 116 (70·3%) of 165 patients (62·7 to 77·2) in the control group (non-inferiority point estimate -9·1%; 95% CI -∞ to -1·0; p=0·0038; and superiority test p=0·068). Patient survival at day 30 post-transplant was 135 (95·7%) of 141 patients (95% CI 91·0-98·4) in the OCS group and 165 patients (100%; 97·8-100·0) in the control group (p=0·0090) and at 12 months was 126 (89·4%) of 141 patients (83·1-93·9) for the OCS group compared with 146 (88·1%) of 165 patients (81·8-92·8) for the control group. Incidence of PGD3 within 72 h was reported in 25 (17·7%) of 141 patients in the OCS group (95% CI 11·8 to 25·1) and 49 (29·7%) of 165 patients in the control group (22·8 to 37·3; superiority test p=0·015). The primary safety endpoint was met (0·23 lung graft-related serious adverse events in the OCS group compared with 0·28 events in the control group [point estimate -0·045%; 95% CI -∞ to 0·047; non-inferiority test p=0·020]). In the intention-to-treat population, causes of death at 30 days and in hospital were lung graft failure or lung infection (n=2 for OCS vs n=7 for control), cardiac causes (n=4 vs n=1), vascular or stroke (n=3 vs n=0), metabolic coma (n=0 vs n=2), and generalised sepsis (n=0 vs n=1)., Interpretation: The INSPIRE trial met its primary effectiveness and safety endpoints. Although no short-term survival benefit was reported, further research is needed to see whether the reduced incidence of PGD3 within 72 h of a transplant might translate into earlier recovery and improved long-term outcomes after lung transplantation., Funding: TransMedics Inc., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: Combining multiple health-care databases (DBs) allows comparing the effects of a wide variety of health-care services. There is a growing interest in methods for combining the results from multiple DBs. We attempted to learn lessons about the performance of one- and two-stage approaches from the reanalysis of data drawn from two studies of pharmacoepidemiology based on multiple DBs., Study Design and Setting: Two nested case-control studies were carried out for estimating the tricyclic antidepressants (TCAs)-arrhythmia and etoricoxib-heart failure associations, respectively, from the Italian Group for Appropriate Drug Prescription in the Elderly and the European Safety of Non-Steroidal Anti-Inflammatory programs. The associations of interest were modeled by conditional logistic regression for matched case-control sets, fitting fixed-effect and random-effect models with both one- and two-stage approaches., Results: One- and two-stage approaches gave very similar results, showing uncertainty of TCA-arrhythmia association (random-effect odds ratios [ORs], 95% confidence interval [CI], 1.26, 0.71-2.24, and 1.30, 0.66-2.55, respectively) and statistical evidence for etoricoxib-heart failure association (fixed-effect OR, 95% CI, 1.53, 1.41-1.66, and 1.54, 1.42-1.66, respectively)., Conclusion: Our study offers further evidence that two-stage approach generates estimates very similar as those from one-stage approach, even in the case of between-DB exposure heterogeneity and when several covariates must be concurrently considered. As current rules limit the free movement of electronic health data, our findings open the door of treating data within the country where they are generated and then to apply conventional techniques for summarizing estimates, which is the two-stage approach for meta-analysis using individual participant data., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Patients with acute heart failure (AHF) have high rates of attendance to emergency departments (EDs), with significant health care costs., Objectives: We aimed to describe the clinical characteristics of patients attending Italian EDs for AHF and their diagnostic and therapeutic work-up., Methods: We carried out a retrospective analysis on 2683 cases observed in six Italian EDs for AHF (January 2011 to June 2012)., Results: The median age of patients was 84 years (interquartile range 12), with females accounting for 55.8% of cases (95% confidence interval [CI] 53.5-57.6%). A first episode of AHF was recorded in 55.3% (95% CI 55.4-57.2%). Respiratory disease was the main precipitating factor (approximately 30% of cases), and multiple comorbidities were recorded in > 50% of cases (history of acute coronary syndrome, chronic obstructive pulmonary disease, diabetes, chronic kidney disease, valvular heart disease). The treatment was based on oxygen (69.7%; 67.9-71.5%), diuretics (69.2%; 67.9-71.5%), nitroglycerin (19.7%; 18.3-21.4%), and noninvasive ventilation (15.2%; 13.8-16.6%). Death occurred within 6 h in 2.5% of cases (2.0-3.1%), 6.4% (5.5-7.3%) were referred to the care of their general practitioners within a few hours from ED attendance or after short-term (< 24 h) observation 13.9% (12.6-15.2%); 60.4% (58.5-62.2%) were admitted to the hospital, and 16.8% (15.4-18.3%) were cared for in intensive care units according to disease severity., Conclusions: Our study reporting the "real-world" clinical activity indicates that subjects attending the Italian EDs for AHF are rather different from those reported in international registries. Subjects are older, with a higher proportion of females, and high prevalence of cardiac and noncardiac comorbidities., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Surgical excision with wide margins, prevention of respiratory impairment, and protection of surrounding organs are primary goals in resection and reconstruction of the chest wall. We describe our experience of the use of cadaveric cryopreserved sternal allograft., Methods: Eighteen patients underwent surgery. Indications for sternectomy were sternal metastases (n = 9), primary chondrosarcoma (n = 4), sternal dehiscence (n = 2), soft tissue sarcoma (n = 1), malignant solitary fibrous tumor (n = 1), and direct involvement of thymic carcinoma (n = 1). The defect was reconstructed using a cadaveric sternal allograft harvested aseptically, treated with antibiotic solution, and cryopreserved (-80°C). The graft was tailored to fit the defect and fixed in place with titanium plates and screws., Results: Four patients underwent a total sternectomy, 8 a partial lower sternectomy, and 6 a partial upper sternectomy. In 14 patients, muscle flaps were positioned to cover the graft. During the postoperative course, 1 patient died of pulmonary embolism, 1 had systemic Candida infection, and 1 had surgical revision for bleeding at the site of muscle flap. One patient required removal of a screw on the clavicle 4 months after operation because of partial dislocation. At a median follow-up of 36 months, neither infection nor rejection of the graft occurred; 13 patients are alive without disease, and 4 patients had died. None had local tumor relapse., Conclusions: Sternal replacement with cadaveric allograft is safe and effective, providing optimal stability of the chest wall and protection of the surrounding organs, even after extensive chest wall resections. The allograft was biologically well tolerated, allowing a perfect integration into the host., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Introduction: Nodal categories for malignant pleural mesothelioma are derived from the lung cancer staging system and have not been adequately validated. The International Association for the Study of Lung Cancer developed a multinational database to generate evidence-based recommendations to inform the eighth edition of the TNM classification of malignant pleural mesothelioma., Methods: Data from 29 centers were entered prospectively (n = 1566) or by transfer of retrospective data (n = 1953). Survival according to the seventh edition N categories was evaluated using Kaplan-Meier survival curves and Cox proportional hazards regression analysis. Survival was measured from the date of diagnosis., Results: There were 2432 analyzable cases: 1603 had clinical (c) staging, 1614 had pathologic (p) staging, and 785 had both. For clinically staged tumors there was no separation in Kaplan-Meier curves between cN0, cN1 or cN2 (cN1 versus cN0 hazard ratio [HR] = 1.06, p = 0.77 and cN2 versus cN1 HR = 1.04, p = 0.85). For pathologically staged tumors, patients with pN1 or pN2 tumors had worse survival than those with pN0 tumors (HR = 1.51, p < 0.0001) but no survival difference was noted between those with pN1 and pN2 tumors (HR = 0.99, p = 0.99). Patients with both pN1 and pN2 nodal involvement had poorer survival than those with pN2 tumors only (HR = 1.60, p = 0.007) or pN0 tumors (HR = 1.62, p < 0.0001)., Conclusions: A recommendation to collapse both clinical and pN1 and pN2 categories into a single N category comprising ipsilateral, intrathoracic nodal metastases (N1) will be made for the eighth edition staging system. Nodes previously categorized as N3 will be reclassified as N2., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Acquired nonmalignant tracheoesophageal fistula (TEF) is a rare condition that requires proper treatment. We present the case of a 55-year-old woman with a 4.5-cm recurrent TEF, which had developed after an attempted surgical repair. After closure of the esophageal defect in two layers, a tracheoplasty technique was used to repair the tracheal membranous wall with a synthetic bioabsorbable patch (Gore Bio-A tissue reinforcement) covered with an intercostal muscle flap. The use of Gore Bio-A tissue reinforcement is an innovative and effective method to close a wide tracheal defect while achieving a scaffold for epithelial colonization., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)