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Epigenetic drugs induce ATP depletion, promoting a glycolysis-to-oxidative phosphorylation (OXPHOS) shift which sometimes favors tumor growth by promoting necroptosis over apoptosis. To restore effective apoptosis in tumors, we propose that the administration of citrate could inhibit ATP production, activate caspase-8 (a key necroptosis inhibitor), and downregulate key anti-apoptotic proteins (Bcl-xL and MCL1). [ABSTRACT FROM AUTHOR]

Simple Summary: We propose that PFK1 promotes a positive feedback loop with PI3K/AKT and YAP/TAZ signaling pathways in cancer cells. Therefore, targeting PFK1 (or its product F-1,6-BP) could improve the efficacy of PI3K and YAP/TAZ inhibitors currently tested in clinical trials. To this aim, we suggest the use of citrate, which is a physiologic and potent inhibitor of PFK1. PI3K/AKT is one of the most frequently altered signaling pathways in human cancers, supporting the activation of many proteins sustaining cell metabolism, proliferation, and aggressiveness. Another important pathway frequently altered in cancer cells is the one regulating the YAP/TAZ transcriptional coactivators, which promote the expression of genes sustaining aerobic glycolysis (such as WNT, MYC, HIF-1), EMT, and drug resistance. Of note, the PI3K/AKT pathway can also regulate the YAP/TAZ one. Unfortunately, although PI3K and YAP inhibitors are currently tested in highly resistant cancers (both solid and hematologic ones), several resistance mechanisms may arise. Resistance mechanisms to PI3K inhibitors may involve the stimulation of alternative pathways (such as RAS, HER, IGFR/AKT), the inactivation of PTEN (the physiologic inhibitor of PI3K), and the expression of anti-apoptotic Bcl-xL and MCL1 proteins. Therefore, it is important to improve current therapeutic strategies to overcome these limitations. Here, we want to highlight how the glycolytic enzyme PFK1 (and its product F-1,6-BP) promotes the activation of both PI3K/AKT and YAP/TAZ pathways by several direct and indirect mechanisms. In turn, PI3K/AKT and YAP/TAZ can promote PFK1 activity and F-1,6-BP production in a positive feedback loop, thus sustaining the Warburg effect and drug resistance. Thus, we propose that the inhibition of PFK1 (and of its key activator PFK2/PFKFB3) could potentiate the sensitivity to PI3K and YAP inhibitors currently tested. Awaiting the development of non-toxic inhibitors of these enzymes, we propose to test the administration of citrate at a high dosage, because citrate is a physiologic inhibitor of both PFK1 and PFK2/PFKFB3. Consistently, in various cultured cancer cells (including melanoma, sarcoma, hematologic, and epithelial cancer cells), this "citrate strategy" efficiently inhibits the IGFR1/AKT pathway, promotes PTEN activity, reduces Bcl-xL and MCL1 expression, and increases sensitivity to standard chemotherapy. It also inhibits the development of sarcoma, pancreatic, mammary HER+ and lung RAS-driven tumors in mice without apparent toxicities. [ABSTRACT FROM AUTHOR]

We propose that fructose-1,6-bisphosphate (F-1,6-BP) promotes a feedback loop between phosphofructokinase-1 (PFK1), phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), and PFK2/PFKFB3, which enhances aerobic glycolysis and sustains effector T (T eff) cell activation, while oxidative metabolism is concomitantly downregulated. This regulation, promoted by low citrate and mitochondrial ATP synthesis, also sustains the Warburg effect in cancer cells. [ABSTRACT FROM AUTHOR]

Significant aspects of COVID-19 pandemic remain obscure. Angiotensin converting enzyme 2 (ACE2), a component of the renin-angiotensin system, whose expression dominates on lung alveolar epithelial cells, is the human cell receptor of SARS-CoV-2, the causative agent of COVID-19. We strongly encourage the concept that thorough considerations of receptor-ligand interactions should be kept at the heart of scientific debate on infection. In this idea, the whole renin-angiotensin system has to be evaluated. We hypothesize that factors related to ethnicity, environment, behaviors, associated illness, and medications involving this complex system are probably responsible for situations regarded as anomalous from both an epidemiological and a clinical point of view, but, taken together, such factors may explain most of the aspects of current outbreak. We decided to use the analogy of a play and speculate about the possible impact in this tragedy of 1) air pollution via the interference of nitrogen dioxide on ACE2 expression; 2) the dual role of nicotine; 3) the hypothetical involvement of ACE2 polymorphisms, the relationships of which with ethnic factors and susceptibility to cardiovascular disease seems intriguing; 4) the impact on the severity of infection of hypertension and related medications acting on the renin/angiotensin system, and, finally, 5) the possible helpful role of chloroquine, thanks to its capacity of modifying ACE2 affinity to the viral spike protein by altering glycosylation. This hypothesis paper is an urgent call for the development of research programs that aim at questioning whether the putative protagonists of this tragedy are real-life actors in COVID-19. • Significant aspects of COVID-19 pandemic remain obscure. • Angiotensin converting enzyme 2 (ACE2) is the human cell receptor of SARS-CoV-2. • Receptor-ligand interactions, should be kept at the heart of scientific debate. • Ethnicity, environment, and behaviors factors interfere with these interactions. • Associated illness, and medications also interfere in a possibly dual manner. [ABSTRACT FROM AUTHOR]

Surgery is still the best treatment option of lung cancer but only one third of patients are operable and prognosis remains mediocre in operated patients, with the exception of initial stages. Medical treatment is fast moving toward new frontiers. New insights in the biology of cancer development led to discovery of new drugs, which are more effective as compared to conventional platinum based chemotherapy. A new approach to immunotherapy based on immune-check point represents a remarkable innovation in lung cancer treatment. Initial trials with anti PD-1 antibodies in metastatic patients provided results never observed with previously known drug categories. Several key question need to be answered to identify patients most likely to respond to anti PD-1/anti PD-L1 treatments, to assess the role of combined treatment modalities including immune check point receptor block (associations with surgery, chemotherapy, ITKs), and to boost host immune response, possibly by lowering his systemic inflammation and improving nutritional status. [ABSTRACT FROM AUTHOR]

Background: Hypothesizing that nutritional status, systemic inflammation and tumoral immune microenvironment play a role as determinants of lung cancer evolution, the purpose of this study was to assess their respective impact on long-term survival in resected non-small cell lung cancers (NSCLC). Methods and Findings: Clinical, pathological and laboratory data of 303 patients surgically treated for NSCLC were retrospectively analyzed. C-reactive protein (CRP) and prealbumin levels were recorded, and tumoral infiltration by CD8+ lymphocytes and mature dendritic cells was assessed. We observed that factors related to nutritional status, systemic inflammation and tumoral immune microenvironment were correlated; significant correlations were also found between these factors and other relevant clinical-pathological parameters. With respect to outcome, at univariate analysis we found statistically significant associations between survival and the following variables: Karnofsky index, American Society of Anesthesiologists (ASA) class, CRP levels, prealbumin concentrations, extent of resection, pathologic stage, pT and pN parameters, presence of vascular emboli, and tumoral infiltration by either CD8+ lymphocytes or mature dendritic cells and, among adenocarcinoma type, tumor grade (all p<0.05). In multivariate analysis, prealbumin levels (Relative Risk (RR): 0.34 [0.16–0.73], p = 0.0056), CD8+ cell count in tumor tissue (RR = 0.37 [0.16–0.83], p = 0.0162), and disease stage (RR 1.73 [1.03–2.89]; 2.99[1.07–8.37], p = 0.0374- stage I vs II vs III-IV) were independent prognostic markers. When taken together, parameters related to systemic inflammation, nutrition and tumoral immune microenvironment allowed robust prognostic discrimination; indeed patients with undetectable CRP, high (>285 mg/L) prealbumin levels and high (>96/mm2) CD8+ cell count had a 5-year survival rate of 80% [60.9–91.1] as compared to 18% [7.9–35.6] in patients with an opposite pattern of values. When stages I-II were considered alone, the prognostic significance of these factors was even more pronounced. Conclusions: Our data show that nutrition, systemic inflammation and tumoral immune contexture are prognostic determinants that, taken together, may predict outcome. [ABSTRACT FROM AUTHOR]

BACKGROUND Catamenial pneumothorax and thoracic endometriosis (TE) are still under diagnosed. The purpose of this study is to increase the diagnostic accuracy for these conditions in patients with spontaneous pneumothorax and to identify their risk factors. METHODS We conducted a retrospective study on all consecutive women of reproductive age referred to our Centre for surgical treatment of spontaneous pneumothorax between July 2000 and January 2009. RESULTS The study population comprised 156 premenopausal women of whom 49 (31.4%) had catamenial and/or TE-related pneumothorax. Over a quarter of these 49 patients had a previous history of recurrent thoracic or scapular catamenial pain. They experienced their first pneumothorax episode at an older age (mean ± SD) (34.0 years ± 6.7) than women with idiopathic pneumothorax (28.7 ± 6.1 years, P < 0.001). Pelvic endometriosis was found in 51% of women with catamenial and/or TE-related pneumothorax. After adjustment for confounding factors by multiple logistic regression analysis, the results show that, infertility [odd ratio (OR) = 4.21, 95% confidence interval (CI) = 1.28–13.88] and a history of pelvic surgery with a uterine procedure and/or uterine scraping (OR = 2.85, 95% CI = 1.12–7.26) were the strongest predictors of catamenial and/or TE-related pneumothorax. CONCLUSIONS Infertility and uterine procedures are significantly associated with catamenial and/or TE-related pneumothorax. Scapular or thoracic pain during menses often precedes the occurrence of pneumothorax and is highly specific for the diagnosis of TE. Our results suggest that in women with pelvic endometriosis, these symptoms should be systematically investigated for an earlier diagnosis of TE. [ABSTRACT FROM AUTHOR]

Abstract: Malignant pleural mesothelioma is a frequently fatal disease and the impact of available treatments is globally poor. Identification of new prognostic factors would help in the understanding of disease progression and, possibly, patient management. Here, we evaluate the prognostic impact of the neurotensin (NTS) and its cognate receptor (NTSR1) known for mediating cellular proliferation, survival, invasiveness, and mobility. We studied a series of 52 consecutive patients with epithelioid malignant mesothelioma undergoing management with curative intent, by immunohistochemistry for the expression of NTS and NTSR1. Specimens were scored as 0, 1, or 2 for less than 10%, between 10 and 50%, or more than 50% of NTS positive staining in tumor cells, respectively. Immunohistochemistry revealed that NTS and NTSR1 expression was found in 71.1% and 90.4% of malignant mesotheliomas, respectively. Using univariate analysis, expression of NTS was significantly (p = 0.015) related with a poor prognosis, with median survivals of 11.0 months, 18.4 months, and 29.8 months in patients showing expression scored as 2, 1, and 0, respectively. Multivariate analysis showed that expression of NTS (p = 0.007) and non-surgical therapy (p = 0.004) were independent predictors of poor prognosis. In order to evaluate the role of NTS/NTSR1 complex in mesothelioma progression, in vitro cell invasion assays and wound healing were performed on the mesothelioma cell line, MSTO-211H, and showed that inhibition of the NTS system resulted in a significant reduction of both migration and collagen invasion of mesothelioma cells. The expression of NTS is identified as a prognostic marker in patients with malignant pleural mesothelioma (Patent EP 08305971.7). [Copyright &y& Elsevier]

The article presents information on a study on the relationship between occurrence of idiopathic spontaneous pneumothorax (ISP) and climatic conditions. The study was conducted on all cases of ISP that were hospitalized between January 1, 2000 and December 31, 2004 in Bolonga, Italy. The metrological data of the area for each of the 1,4161 days of the study period were investigated. The study showed that pneumothorax is associated with fall in atmospheric pressure and storm.

Background: There are no recommendations about admission to an ICU after a major lung resection and there are considerable differences among institutions in this respect. Objectives: To audit the practice of admission to an ICU after a major lung resection and evaluate factors predicting the need for intensive care. Methods: Clinicalrecords of all patients who underwent major pulmonary resections in a 14-month period were reviewed retrospectively. The criteria for postoperative admission to the ICU were: (1) standard pneumonectomy if comorbidity index (CI) >0 and/or ASA score >1, and/or abnormal spirometry or arterial gas analysis; (2) extended pneumonectomy; (3) lobectomy if CI ≥4 and/or ASA ≥3; (4) lobectomy if FEV1 <60% of predicted; (5) lobectomy if FEV1 is between 60 and 80% and hypercapnia. Results: Among the 49 patients postoperatively admitted to the surgical ward, only 1 needed late intensive care. Among the 55 patients admitted to the ICU, 25 did not require specific intensive care and were discharged 24 h postoperatively, whereas the remaining 30 patients required specific intensive care. Multivariate analysis identified ASA score, predictive postoperative DLCO, and predictive postoperative product (PPP) as independent predictors of a need for admission to an ICU. Conclusion: This empirical protocol was useful in identifying patients not likely to need admission to the ICU. ASA score, predictive postoperative DLCO, and PPP are independent predictors of a need for admission to an ICU. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Examines whether low-molecular-weight heparin can improve the outcome of patients with operable non-small cell lung cancer. Surgery and therapeutic advances; Impact on survival of adjuvant platinum-based chemotherapy; Effectiveness of heparins in both prevention and treatment of venous thromboembolism (VTE); Effects on cellular growth; Effects on blood coagulation pathway and platelet aggregation.

Reports on a study of clinical characteristics, treatment modalities and outcome of patients with superior sulcus tumors who underwent surgery. Method of the surgical approaches; Types of the pulmonary resection and pathologic stages; Association of major illness with survival.

Evaluates the incidence of catamenial pneumothorax among women referred for the surgical treatment of spontaneous pneumothorax. Investigation of possible temporal relationship between pneumothorax and menses; Identification of blebs and origin of possible air leaks; Signs of thoracic endometriosis.

Objective: The aim of this paper is to study clinical characteristics, surgical treatment and outcome of patients with solitary fibrous tumor of the pleura operated in our institutions in a 20-year period. Methods: Clinical records of all patients operated for solitary fibrous tumors of the pleura between 1981 and 2000 were reviewed retrospectively. Tumors were classified as malignant in the presence of at least one of the following criteria: (1) high mitotic activity; (2) high cellularity with crowding and overlapping of nuclei; (3) presence of necrosis; (4) pleomorphism; otherwise they were considered as benign. Results: Sixty patients (mean age 55 years) were operated in this period. None had asbestos exposure. Symptoms were present in 31 cases. Surgical approaches included thoracotomy (n=53), video-assisted thoracoscopy (n=6), and median sternotomy (n=1). Tumors originated from visceral pleura in 48 cases, from parietal, mediastinal or diaphragmatic pleura in seven, two and three cases, respectively; their mean diameter was 8.5 cm. Tumors could be resected with their implantation basis in 49 patients. In the remaining 11, extended resections were performed, including lung parenchyma (lobectomy, n=4, pneumonectomy, n=2), osteomuscular chest wall structures (n=2), diaphragm (n=2), and pericardium (n=1). Two postoperative deaths (due to myocardial infarction and pulmonary embolism, respectively) occurred. Tumors were pathologically benign in 38 cases and malignant in 22 cases. Mean follow-up was 88 months. Resection was complete in all the patients with benign tumors and no recurrence occurred. Resection was considered as complete in 21/22 malignant tumors. Local recurrence was observed in two cases. Both could be successfully managed by iterative exeresis (no extended resection had been initially performed). Metastatic disease (responsible for patient''s death) was observed following the only incomplete resection. Actuarial 5- and 10-year survival rates were 97% for benign tumors and 89% for malignant ones. Conclusions: Surgical resection provided cure in all the patients with benign tumors. As insufficiency of exeresis is associated with all recurrences in malignant tumors, completeness of resection is in our experience the best prognostic factor in these forms. [Copyright &y& Elsevier]

Simple Summary: It is commonly believed that obesity increases the risk of cancers and lowers the possibility of cure of patients with proven cancers. In recent years, this traditional view has been challenged by the hypothesis of an 'obesity paradox', which refers to a better prognosis in obese patients with some specific cancers, compared to normal/underweight patients. In this study, we assessed, in a nationwide dataset, the prognostic role of preoperative BMI on postoperative outcomes in patients undergoing curative lung resection for non-small-cell lung cancer (NSCLC) and found that BMI is a strong and independent predictor of long-term survival. Obesity could have a protective effect in patients with lung cancer. We assessed the prognostic role of preoperative BMI on survival in patients who underwent lung resection for NSCLC. A total of 54,631 consecutive patients with resectable lung cancer within a 15-year period were extracted from Epithor (the French Society of Thoracic and Cardiovascular Surgery database). Patient subgroups were defined according to body mass index (BMI): underweight (BMI < 18.5 kg/m2), normal weight (18.5 ≤ BMI < 25 kg/m2), overweight (25 ≤ BMI < 30 kg/m2), and obese (BMI ≥ 30 kg/m2). Underweight was associated with lower survival (unadjusted HRs 1.24 (1.16–1.33)) compared to normal weight, whereas overweight and obesity were associated with improved survival (0.95 (0.92–0.98) and 0.88 (0.84–0.92), respectively). The impact of BMI was confirmed when stratifying for sex or Charlson comorbidities index (CCI). Among patients with obesity, a higher BMI was associated with improved survival. After adjusting for period of study, age, sex, WHO performance status, CCI, side of tumor, extent of resection, histologic type, and stage of disease, the HRs for underweight, overweight, and obesity were 1.51 (1.41–1.63), 0.84 (0.81–0.87), and 0.80 (0.76–0.84), respectively. BMI is a strong and independent predictor of survival in patients undergoing surgery for NSCLC. [ABSTRACT FROM AUTHOR]

Studies carried out in the last ten years have shown that the metabolites made up from the gut microbiota are essential for multiple functions, such as the correct development of the immune system of newborns, interception of pathogens, and nutritional enrichment of the diet. Therefore, it is not surprising that alteration of the gut microbiota is the starting point of gastrointestinal infection, obesity, type 2 diabetes, inflammatory bowel disease, colorectal cancer, and lung cancer. Diet changes and antibiotics are the major factors damaging the gut microbiota. Early exposure of the newborns to antibiotics may prevent their correct development of the immune system, exposing them to pathogen infections, allergies, and chronic inflammatory diseases. We already know much on how host genes, microbiota, and the environment interact, owing to experiments in several model animals, especially in mice; advances in molecular technology; microbiota transplantation; and comparative metagenomic analysis. However, much more remains to be known. Longitudinal studies on patients undergoing to therapy, along with the identification of bacteria prevalent in responding patients may provide valuable data for improving therapies. [ABSTRACT FROM AUTHOR]

OBJECTIVES To determine safety and survival outcomes associated with lobectomy, segmentectomy and wedge resection for early-stage lung cancer by quiring the French population-based registry EPIdemiology in THORacic surgery (EPITHOR). METHODS Retrospective analysis of 19 452 patients with stage c IA lung carcinoma who underwent lobectomy, segmentectomy or wedge resection between 2016 and 2022 with curative-intent. Main outcome measures were 90-day mortality and 5-year overall survival estimates. Proportional hazards regression and propensity score matching were used to adjust outcomes for key patient, tumour and practice environment factors. RESULTS The treatment distribution was 72.2% for lobectomy, 21.5% for segmentectomy and 6.3% for wedge. Unadjusted 90-day mortality rates were 1.6%, 1.2% and 1.1%, respectively (P  = 0.10). Unadjusted 5-year overall survival estimates were 80%, 78% and 70%, with significant inter-group survival curves differences (P  < 0.0001). Multivariable proportional hazards regression showed that wedge was associated with worse overall survival [adjusted hazard ratio (AHR), 1.23 (95% confidence interval 1.03–1.47); P  = 0.021] compared with lobectomy, while no significant difference was disclosed when comparing segmentectomy to lobectomy (1.08 [0.97–1.20]; P  = 0.162). The three-way propensity score analyses confirmed similar 90-day mortality rate for wedge resection and segmentectomy compared with lobectomy (hazard ratio: 0.43; 95% confidence interval 0.16–1.11; P  = 0.081 and 0.99; 0.48–2.10; P  = 0.998, respectively), but poorer overall survival (1.45; 1.13–1.86; P  = 0.003 and 1.31; 1–1.71; P  = 0.048, respectively). CONCLUSIONS Wedge resection was associated with comparable 90-day mortality but lower overall survival when compared to lobectomy. Overall, all types of sublobar resections may not offer equivalent oncologic effectiveness in real-world settings. [ABSTRACT FROM AUTHOR]

Simple Summary: The role of autophagy in lung cancers is still controversial, mainly because the visualization of autophagy levels in patients remains challenging. One interesting approach consists of studying autophagy at the transcriptomic level. In this line, many transcriptomics analyses performed on autophagy genes focused on the discovery of new biomarkers to predict the efficiency of antitumor therapies. However, the majority of these studies were based on global transcriptomic analysis of the whole tumor microenvironment, and few investigations have been performed on malignant cells themselves. The goal of this study was not to determine another new predictive signature based on autophagy-related genes. Instead, we investigated the expression of autophagy genes to understand the involvement of this process in lung cancer homeostasis. Specifically, we discovered a new autophagy signature that correlates with the metabolic and immunogenic status of malignant cells, supporting the relationship between autophagy and tumor growth in lung cancer patients. Autophagy is a self-degradative mechanism involved in many biological processes, including cell death, survival, proliferation or migration. In tumors, autophagy plays an important role in tumorigenesis as well as cancer progression and resistance to therapies. Usually, a high level of autophagy in malignant cells has been associated with tumor progression and poor prognostic for patients. However, the investigation of autophagy levels in patients remains difficult, especially because quantification of autophagy proteins is challenging in the tumor microenvironment. In this study, we analyzed the expression of autophagy genes in non-small cell lung (NSCLC) cancer patients using public datasets and revealed an autophagy gene signature for proliferative and immune-checkpoint-expressed malignant cells in lung adenocarcinoma (LUAD). Analysis of autophagy-related gene expression profiles in tumor and adjacent tissues revealed differential signatures, namely signature A (23 genes) and signature B (12 genes). Signature B correlated with a bad prognosis and poor overall and disease-specific survival. Univariate and multivariate analyses revealed that this signature was an independent factor for prognosis. Moreover, patients with high expression of signature B exhibited more genes related to proliferation and fewer genes related to immune cells or immune response. The analysis of datasets from sorted fresh tumor cells or single cells revealed that signature B is predominantly represented in malignant cells, with poor expression in pan-immune population or in fibroblast or endothelial cells. Interestingly, autophagy was increased in malignant cells exhibiting high levels of signature B, which correlated with an elevated expression of genes involved in cell proliferation and immune checkpoint signaling. Taken together, our analysis reveals a novel autophagy-based signature to define the metabolic and immunogenic status of malignant cells in LUAD. [ABSTRACT FROM AUTHOR]

• AI increases the radiologists' sensitivity for the preoperative detection of lung nodules (92.4 % versus 80.4 %, p < 0.001), at a cost a few false positive detections. • AI detects lung nodules earlier than the radiologists in up to 50% of patients having multiple preoperative CT scans. • Vascular contact is associated with non-detection by radiologists (OR: 0.32[0.19, 0.54], p < 0.001), whilst cavitation (OR: 0.26[0.13, 0.54], p < 0.001) or pleural contact (OR: 0.10[0.04, 0.22], p < 0.001) is associated non-detection by AI. To evaluate the performance of artificial intelligence (AI) in the preoperative detection of lung metastases on CT. Patients who underwent lung metastasectomy in our institution between 2016 and 2020 were enrolled, their preoperative CT reports having been performed before an AI solution (Veye Lung Nodules, version 3.9.2, Aidence) became available as a second reader in our department. All CT scans were retrospectively processed by AI. The sensitivities of unassisted radiologists (original CT radiology reports), AI reports alone and both combined were compared. Ground truth was established by a consensus reading of two radiologists, who analyzed whether the nodules mentioned in the pathology report were retrospectively visible on CT. Multivariate analysis was performed to identify nodule characteristics associated with detectability. A total of 167 patients (men: 62.9 %; median age, 59 years [47–68]) with 475 resected nodules were included. AI detected an average of 4 nodules (0–17) per CT, of which 97 % were true nodules. The combination of radiologist plus AI (92.4 %) had significantly higher sensitivity than unassisted radiologists (80.4 %) (p < 0.001). In 27/57 (47.4 %) patients who had multiple preoperative CT scans, AI detected lung nodules earlier than the radiologist. Vascular contact was associated with non-detection by radiologists (OR:0.32[0.19, 0.54], p < 0.001), whilst the presence of cavitation (OR:0.26[0.13, 0.54], p < 0.001) or pleural contact (OR:0.10[0.04, 0.22], p < 0.001) was associated with non-detection by AI. AI significantly increases the sensitivity of preoperative detection of lung metastases and enables earlier detection, with a significant potential benefit for patient management. [ABSTRACT FROM AUTHOR]

Catamenial pneumothorax is an uncommon disease whose management is not consensual. We report the case of a patient who experienced several episodes of pneumothorax. She was initially treated by repair of diaphragmatic defects and hormonal treatment. During the therapeutic amenorrhea, no recurrence occurred. However, each cessation of medical therapy was followed by recurrence. Finally, talc pleurodesis and tubal ligature were performed without any recurrence in the subsequent 12 months. This report outlines the great difficulties that can be encountered in the management of patients with catamenial pneumothorax. [ABSTRACT FROM AUTHOR]

The described case is of a 15-year-old boy who presented with a persistent hiccup and repeated episodes of left-sided chest pain. At computed tomography scan an exostosis originating from the costo-chondral junction of the left 4th rib was seen. The tip of the exostosis reached the external surface of the pericardium. Removal of a 2 cm rib segment including the implantation basis of the exostosis was achieved by video-assisted thoracic surgery. Symptoms disappeared after surgery. This report shows an exceptional symptom of costal exostosis. [Copyright &y& Elsevier]

We report a case of postpneumonectomy syndrome in a 75-year-old man operated on for right lung cancer 18 months previously. The patient had a pre-existing severe thoracic scoliosis. Treatment involved positioning of an expandable silastic prosthesis in the postpneumonectomy cavity. A favorable outcome was observed. We think that a pre-existing scoliosis could be considered as a potentially predisposing factor to the development of the syndrome. [Copyright &y& Elsevier]

Myasthenia gravis (MG) is an autoimmune disease characterized by muscle fatigability due to acetylcholine receptor (AChR) autoantibodies. To better characterize juvenile MG (JMG), we analyzed 85 pre- and 132 post-pubescent JMG (with a cutoff age of 13) compared to 721 adult MG patients under 40 years old using a French database. Clinical data, anti-AChR antibody titers, thymectomy, and thymic histology were analyzed. The proportion of females was higher in each subgroup. No significant difference in the anti-AChR titers was observed. Interestingly, the proportion of AChR+ MG patients was notably lower among adult MG patients aged between 30 and 40 years, at 69.7%, compared to over 82.4% in the other subgroups. Thymic histological data were examined in patients who underwent thymectomy during the year of MG onset. Notably, in pre-JMG, the percentage of thymectomized patients was significantly lower (32.9% compared to more than 42.5% in other subgroups), and the delay to thymectomy was twice as long. We found a positive correlation between anti-AChR antibodies and germinal center grade across patient categories. Additionally, only females, particularly post-JMG patients, exhibited the highest rates of lymphofollicular hyperplasia (95% of cases) and germinal center grade. These findings reveal distinct patterns in JMG patients, particularly regarding thymic follicular hyperplasia, which appears to be exacerbated in females after puberty. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article regarding the multidisciplinary management of necrotizing pneumonia in adults.

A letter to the editor is presented in response to the article "Low-Molecular-Weight Heparin and Outcomes" published in the previous issue.

Purpose: Respiratory complications are the leading causes of morbidity and mortality after lung cancer surgery. We hypothesized that oropharyngeal and nasopharyngeal decontamination with chlorhexidine gluconate (CHG) would be an effective method to reduce these complications as reported in cardiac surgery.Methods: In this multicenter parallel-group randomized double-blind placebo-controlled trial, we enrolled consecutive adults scheduled for anatomical pulmonary resection for lung cancer. Perioperative decontamination consisted in oropharyngeal rinse solution (0.12% CHG) and nasopharyngeal soap (4% CHG) or a placebo. The primary outcome measure was the proportion of patients requiring postoperative invasive and/or noninvasive mechanical ventilation (MV). Secondary outcome measures included occurrence of respiratory and non-respiratory healthcare-associated infections (HAIs) and outcomes within 90 days.Results: Between July 2012 and April 2015, 474 patients were randomized. Of them, 24 had their surgical procedure cancelled or withdrew consent. The remaining 450 patients were included in a modified intention-to-treat analysis: 226 were allocated to CHG and 224 to the placebo. Proportions of patients requiring postoperative MV were not significantly different [CHG 14.2%; placebo 15.2%; relative risks (RRs) 0.93; 95% confidence interval (CI) 0.59-1.45; P = 0.76]. Neither of the proportions of patients with respiratory HAIs were different (CHG 13.7%; placebo 12.9%; RRs 1.06; 95% CI 0.66-1.69; P = 0.81). The CHG group had significantly decreased incidence of bacteremia, surgical-site infection and overall Staphylococcus aureus infections. However, there were no significant between-group differences for hospital stay length, change in tracheal microbiota, postoperative antibiotic utilization and outcomes by day 90.Conclusions: CHG decontamination decreased neither MV requirements nor respiratory infections after lung cancer surgery. Additionally, CHG did not change tracheal microbiota or postoperative antibiotic utilization.Trial Registration: This study is registered on ClinicalTrials.gov, number NCT01613365. [ABSTRACT FROM AUTHOR]

Simple Summary: Systemic inflammation and changes in the inflammatory status are frequent features of lung cancer. There is a close interconnection between cancer development and the clinical, general, and inflammatory status of patients. In this paper, we evaluate a large panel of inflammatory indexes in patients who underwent lung resection for NSCLC lung cancer; we show that pre-operative inflammatory status strongly influences long-term prognosis in patients affected by NSCLC and undergoing surgery. Background (1): Our goal was to investigate if and how pre-operative inflammatory status can influence the long-term prognosis of patients undergoing lung surgery for cancer. Materials and Methods (2): This prospective observational study includes the agreement of all operable patients to the study, who were referred to our department between 1 January 2017 and 30 December 2018. The inflammatory pre-operative status of the patients was investigated by calculating albumin, CPR (c-protein reactive), complete blood count (neutrophils, lymphocytes, platelets, hemoglobin), and some other indexes referring to inflammatory status, namely the HALP amalgamated index, platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocytes ratio (NLR), systemic immune-inflammation index (SII), and advanced lung cancer inflammation Index (ALI). The follow-up ended in November 2021. Patient overall survival was assessed using the Kaplan–Meier method. The log-rank test was used to compare survival rates. Variables significantly associated with survival at univariate analysis were entered int Cox multivariate analysis (stepwise mode) to assess their independent character. Hazard ratios and their 95% confidence intervals were calculated. Variables associated with p < 0.05 were considered significative. Results (3): We enrolled 257 patients in our study. The overall survival of the cohort was as follows: 1 year, 96.1%; 3 year, 81.3%; and 4 year, 74.2%. Univariate analysis showed risk factors for overall survival as follows: Thoracoscore ≥ 2 (p = 0.002); histology (p = 0.002); HALP < 32.2 (p = 0.0002); SII ≥ 808.9 (p = 0.0004); ALI < 34.86 (p = 0.0005); NLr ≥ 2.29 (p = 0.01); hemoglobin < 13 g/dl (p = 0.01); PLR ≥ 196.1 (p = 0.005); pN+ (p < 0.0001); pleural invasion (p = 0.0002); and presence of vascular or lymphatic tumor emboli (p = 0.0002). Multivariate Cox analysis (stepwise model) identified Thoracoscore ≥ 2 (p = 0.02); histology, HALP < 32.2 (p = 0.004), and pN (p < 0.0001) as independent predictors of death. Conclusion (4): Pre-operative inflammatory status strongly influences long-term prognosis in patients affected by NSCLC and undergoing surgery. [ABSTRACT FROM AUTHOR]

• Management of non-bulky/non-infiltrative N2 disease is controversial. • With increasing N2 disease extent, there is a trend towards chemoradiotherapy followed by consolidation immunotherapy as first-line therapy. • Multidisciplinary decision-making is important in this challenging patient population. The optimal management of patients with non-bulky/non-infiltrative stage IIIA N2 non-small cell lung cancer (NSCLC) remains controversial. In this modified Delphi study from France, we aimed to generate agreement through multidisciplinary decision-making on the clinical management of patients with non-bulky/non-infiltrative N2 NSCLC. An expert panel of 30 physicians from different specialities completed two Delphi rounds of a 76-item questionnaire, pertaining to: pathological confirmation of N2 disease; initial treatment approach; treatment approach in case of disease progression/stability following neoadjuvant chemotherapy; treatment approach taking into account various patient and tumour characteristics. Each questionnaire item was scored using a 9-point Likert scale. Consensus in agreement was achieved if ≥ 80 % of responses to a questionnaire item were scored between 7 and 9 and if the median value of the score to the item was ≥ 7. Regarding the pathologic confirmation of N2 disease, agreement (up to 100 %) was reached on endobronchial ultrasound/endoscopic ultrasound as the preferred method of initial mediastinal staging for paratracheal lymph nodes. There was also panellist agreement (up to 93 %) on the adoption as first-line treatment of surgery and (neo)adjuvant chemotherapy in patients with single-station disease, and of concurrent chemoradiotherapy followed by adjuvant immunotherapy in those with multi-station N2 disease. Panellists further agreed on the use of a non-surgical strategy, i.e., concurrent chemoradiotherapy with adjuvant immunotherapy, in patients with single-station N2 disease in case of: involvement of ≥ 2 mediastinal lymph nodes; disease progression following neoadjuvant chemotherapy; compromised cardiopulmonary function if compatible with radiotherapy; anticipated right pneumonectomy. This Delphi study reinforces the importance of multidisciplinary discussions leading to the best individual approach to the clinical management of patients with non-bulky/non-infiltrative N2 NSCLC, a challenging heterogeneous population. [ABSTRACT FROM AUTHOR]

Acetylcholine receptor (AChR) myasthenia gravis (MG) is a chronic autoimmune disease characterized by muscle weakness. The AChR+ autoantibodies are produced by B-cells located in thymic ectopic germinal centers (eGC). No therapeutic approach is curative. The inflammatory IL-23/Th17 pathway is activated in the thymus as well as in the blood and the muscle, contributing to the MG pathogenic events. We aimed to study a potential new therapeutic approach that targets IL-23p19 (IL-23) in the two complementary preclinical MG models: the classical experimental MG mouse model (EAMG) based on active immunization and the humanized mouse model featuring human MG thymuses engrafted in NSG mice (NSG-MG). In both preclinical models, the anti-IL-23 treatment ameliorated MG clinical symptoms. In the EAMG, the treatment reduced IL-17 related inflammation, anti-AChR IgG2b antibody production, activated transduction pathway involved in muscle regeneration and ameliorated the signal transduction at the neuromuscular junction. In the NSG-MG model, the treatment reduced pathogenic Th17 cell population and expression of genes involved in eGC stabilization and B-cell development in human MG thymus biopsies. Altogether, these data suggest that a therapy targeting IL-23p19 may promote significant clinical ameliorations in AChR+ MG disease due to concomitant beneficial effects on the thymus and skeletal muscle defects. [ABSTRACT FROM AUTHOR]

Objective: To elucidate the pathophysiology of catamenial pneumothorax (CP) due to thoracic endometriosis and support the theory of the transdiaphragmatic passage of air from the genital tract through diaphragmatic perforations caused by endometrial implants. Design: Three case reports. Setting: Academic hospital. Patient(s): Three women with pneumoperitoneum concomitant to CP. Intervention(s): Thoracic/abdominal computed tomography scans and chest x-rays. Main Outcome Measure(s): Presence of pneumoperitoneum coexisting with CP. Result(s): The observation of pneumoperitoneum associated with CP supports the theory of the transdiaphragmatic passage of air, which implies the occurrence of a pneumoperitoneum as an intermediate step. Conclusion(s): Our three cases strongly support the theory of the transdiaphragmatic passage of air in the pathogenesis of CP. [ABSTRACT FROM AUTHOR]

On one hand, regulatory T cells (Tregs) play an immunosuppressive activity in most solid tumors but not all. On the other hand, the organization of tumor-infiltrating immune cells into tertiary lymphoid structures (TLS) is associated with long-term survival in most cancers. Here, we investigated the role of Tregs in the context of Non-Small Cell Lung Cancer (NSCLC)-associated TLS. We observed that Tregs show a similar immune profile in TLS and non-TLS areas. Autologous tumor-infiltrating Tregs inhibit the proliferation and cytokine secretion of CD4+ conventional T cells, a capacity which is recovered by antibodies against Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4) and Glucocorticoid-Induced TNFR-Related protein (GITR) but not against other immune checkpoint (ICP) molecules. Tregs in the whole tumor, including in TLS, are associated with a poor outcome of NSCLC patients, and combination with TLS-dendritic cells (DCs) and CD8+ T cells allows higher overall survival discrimination. Thus, Targeting Tregs especially in TLS may represent a major challenge in order to boost anti-tumor immune responses initiated in TLS. Regulatory T cells (Tregs) have similar immune profiles in tertiary lymphoid structures of lung cancer and non-TLS areas, with tumor-infiltrating Tregs found to inhibit the proliferation and cytokine secretion of CD4 + conventional T cells. [ABSTRACT FROM AUTHOR]

• Loss of BRG1/SMARCA4-deficient carcinoma is found in 5–10% of NSCLC. • SMARCA4-deficient lung carcinomas are associated with poor clinical outcome. • SMARCA4-deficient carcinomas are highly infiltrated in FOXP3+ cells and neutrophils. • Non-response to anti-PD1 could be related to the immunosuppressive tumor environment. SMARCA4/BRG1 loss of expression occurs in 5–10% of non-small cell lung carcinomas (NSCLC). We investigated the pathological, molecular and immune environment characteristics of this deficiency among NSCLC, its impact on overall survival (OS) of resected patients and the sensitivity to anti-PD1 inhibitors in metastatic patients. BRG1 expression was assessed by immunohistochemistry to identify SMARCA4-deficient NSCLC (SD-NSCLC) from the cancer tissue collection of Cochin Hospital (Paris, France). Molecular profiles were analyzed by targeted NGS covering 28 genes in 63 resected SD-NSCLC. The balance of immune cells between CD8+, FOXP3+ cells and neutrophils (CD66b+) was characterized by multiplex immunohistochemistry and compared to non-SD NSCLC. Clinical outcome after anti–PD-1 therapy was evaluated in 7 SD-NSCLC out of 77 NSCLC patients. SD-NSCLCs were more commonly found in TTF1-negative high-grade adenocarcinomas and pleomorphic carcinomas. They were associated with few targetable alterations (KRAS G12C and MET amplification). Their immune environment was characterized by an increased of FOXP3+ cell and neutrophil densities, but not of CD8+ T cells, compared to non-SD NSCLC. SD-NSCLC patients had a significantly shorter OS in early stages of resected patients and in metastatic patients treated by anti-PD1 treatment. BRG1-loss in NSCLC confers a poor prognosis and is associated with an immunosuppressive environment that could be responsible of limited efficacy to anti-PD1 inhibitors. The identification of SD-NSCLC by BRG1 immunohistochemistry is desirable for an optimal management of NSCLC patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Incidence of lung carcinoids is rapidly increasing, but the correct management of these patients is still debated. Although their clinical behaviour differs from Non-Small Cell Lung Cancer, the same staging system is used for these tumors, even if it presents limitations in prognosis prediction and overlapping curves especially regarding sub-stages. For these reasons, in recent years, ad hoc scores have been constructed aiming to better stratify prognosis and indicate appropriate treatment options. In particular, a score including the node ration as nodal factor was proposed, although external validation was not possible. The aim of this study is to validate this score, for the possibility of identifying a specific class of patients that may benefit from specific follow-up schedules or post-operative treatments. Background: A prognostic score including T-dimension, age, histology and lymph node ratio was previously proposed in absence of an external validation dataset. The aim of the current study was to validate the proposed prognostic score using an independent dataset. Methods: Data of patients with lung carcinoids, who underwent surgical resection and lymphadenectomy in five institutions from 1 January 2005 to 31 December 2019, were retrospectively analyzed. Two risk groups were created based on the following data: age, histology, node ratio and pT for disease-free survival (DFS); age, sex, node ratio and pT for overall survival (OS). The previously proposed score was validated, identifying two groups of patients: a high risk (HRG) and low risk (LRG) group. Results: The final analysis was conducted on 283 patients. Regarding DFS, 230 (81.3%) patients were assigned to the LRG and 53 (18.7%) to the HRG. Considering OS, 268 (94.7%) were allocated in the LRG and 15 (5.3%) in the HRG. The 5-year DFS was 92.7% in the LRG vs. 67% in the HRG (p < 0.001) while the 5-year OS was 93.6% in the LRG vs. 86.2% in the HRG (p = 0.29) with clear curve separation. Conclusion: Our analysis confirmed the validity of the composite score for DFS in lung carcinoids. Regarding OS, statistical significance was not reached because of a low number of deaths and patients in the HRG. [ABSTRACT FROM AUTHOR]

Simple Summary: Enhanced Recovery Pathways (ERP) have been scarcely assessed in lung cancer surgery. We performed a two-step audit for our experience: the first dealing with our initial experience focusing on patients undergoing segmentectomies and lobectomies, the second including all subsequent consecutive patients undergoing all kind of lung resections for NSCLC. The first step aimed at auditing results of ERP on occurrence of postoperative complications and at assessing which ERP components were associated with improved short-term outcomes. We also audited late results by assessing long-term survival of patients in the first step of our study. The second step aimed at auditing on large-scale short-term results of the ERP in a real-life setting. In total, 166 patients were included in the first period. No postoperative death occurred. The overall adverse events rate was 30%. In multivariate analyzes, the only element associated with reduced adverse postoperative events was chest tube withdrawal within POD2. The 1-, 3- and 5-year survival rates were 97%, 86.1%, and 76.3%, respectively. In the second period, 1077 patients were included; 11 patients died during the postoperative period. The overall postoperative adverse event rate was 30.3%. Thoracoscore independently predicted postoperative death, the occurrence of complications (all-kind, minor, major, or respiratory ones). We conclude that compliance to ERP procedures and early chest tube removal are associated with reduced postoperative events in patients with lung resection surgery. Thoracoscore is a useful tool in predicting mortality and postoperative adverse events. Introduction: In spite of increasing diffusion, Enhanced Recovery Pathways (ERP) have been scarcely assessed in large scale programs of lung cancer surgery. The aim of this study was auditing our practice. Methods: A two-step audit program was established: the first dealing with our initial ERP experience in patients undergoing non-extended anatomical segmentectomies and lobectomies, the second including all consecutive patients undergoing all kind of lung resections for NSCLC. The first step aimed at auditing results of ERP on occurrence of postoperative complications and at assessing which ERP components are associated with improved short-term outcomes. We also audited late results by assessing long-term survival of patients in the first step of our study. The second step aimed at auditing on large-scale short-term results of the ERP in a real-life setting. Results: Over a one-year period, 166 patients were included. The median number of ERP procedures per patient was three (IQR 3–4). No postoperative death occurred. The overall adverse events rate was 30%. In multivariate analyzes, the only element associated with reduced adverse postoperative events was chest tube withdrawal within POD2 (OR = 0.21, 95% CI (0.10–0.46)). The 1-, 3-, and 5-year survival rates were 97%, 86.1%, and 76.3%, respectively. In the second period, 1077 patients were included in our ERP; 11 patients died during the postoperative period or within 30 days of operation (1.02%). The overall postoperative adverse event rate was 30.3%, major complication occurring in 134 (12.4%), and minor ones in 192 (17.8%). Respiratory complications occurred in 64 (5.9%). Thoracoscore independently predicted postoperative death, the occurrence of complications (all-kind, minor, major, or respiratory ones). Conclusions: Compliance to ERP procedures and early chest tube removal are associated with reduced postoperative events in patients with lung resection surgery. In a large setting scale, ERP can be applied with satisfactory results in terms of mortality and morbidity. Thoracoscore is a useful tool in predicting mortality and postoperative adverse events. [ABSTRACT FROM AUTHOR]

• The prognosis of MPM is strongly and negatively influenced by systemic inflammation. • Advanced Lung cancer inflammation Index can be used as prognostic indicator in MPM. • Inflammation-related indexes and hemoglobin are independent predictors of survival. • Age, histology and CRP are independently associated with "long survival" in MPM. Prediction of prognosis is a key step of malignant pleural mesothelioma (MPM) management and treatment assignment. Aim of this study was to identify simple prognostic factors, focusing on inflammation-related parameters. Baseline clinical and laboratory data were extracted from a single-center 20-year cohort of consecutive patients exhibiting a proven MPM. Inflammation-related ratios and composite scores were evaluated as prognostic indicators. 468 patients were identified. Mean age and BMI were 73.0 years and 25.1 kg/m2. The histologic subtype was epithelioid, sarcomatoid, or biphasic in 80.3%, 6.2%, and 13.5% of cases, respectively. Mean Neutrophil to Lymphocyte Ratio (NLR), systemic Inflammation Index (SII) and Advanced Lung cancer inflammation Index (ALI) were 5.8, 1,836.6, and 29.6. Median survival was 13.0 months. Univariate analyses revealed that age > 70 years, persistent asthenia, hemoglobin < 13 g/dL, and non-epithelioid histologic type were associated with poorer survival, as well as the following high-inflammation-related criteria: CRP > 25 mg/L, white blood cell count (WBC) > 109/dL, NLR > 5, SII > 1,270, and ALI < 18. Multivariate regression showed that age, histology, hemoglobin, and WBC were independent predictors of survival. Also, the inflammation-related factors ALI and NLR were independently associated with survival. Interestingly, hemoglobin was statistically significant predictor of survival in all multivariate models. We found higher proportion of survival > 18 months (66th percentile) in patients exhibiting SII < 2,000 and NLR < 5. The prognosis of MPM is strongly influenced by systemic inflammation and patients exhibiting higher NLR, SII and lower ALI have shorter survival, which strengthens the level of evidence about the major role played by inflammation in MPM. [ABSTRACT FROM AUTHOR]

Background Activating epidermal growth factor receptor (EGFR) mutations characterize a subgroup of non-small-cell lung cancer that benefit from first line EGFR tyrosine kinase inhibitors (EGFR-TKI). However, the existence of polyclonal cell populations may hinder personalized-medicine strategies as patients' screening often depends upon a single tumorbiopsy sample. The purpose of this study is to clarify and to validate in clinical testing conditions the accuracy of EGFR genotyping using different tumor sites and various types of samples (transthoracic, surgical or endoscopic biopsies and cytology specimens). Methods We conducted a retrospective review of 357 consecutive patients addressed for EGFR mutation screening in accordance with the directive of the European Medicines Agency (stage IV NSCLC). Fifty-seven samples were EGFR mutated and 40 had adequate tumor specimens for analysis on multiple spatially separated sites. Ten wild type samples were also analyzed. A total of 153 and 39 tumor fragments, from mutated and non-mutated cases respectively, were generated to analyze tumor heterogeneity or primary-metastatic discordances. After histological review of all fragments, EGFR genotyping was assessed using the routine diagnostic tools: fragment analysis for insertions and deletions and allele specific TaqMan probes for point mutations. EGFR copy number (CN) was evaluated by qPCR using TaqMan probes. Results The identification of EGFR mutations was independent of localization within primary tumor, of specimen type and consistent between primary and metastases. At the opposite, for half of the samples, tumor loci showed different EGFR copy number that may affect mutation detection cut-off. Conclusions This is the largest series reporting multiple EGFR testing in Caucasians. It validates the accuracy of EGFR mutation screening from single tumor-biopsy samples before first line EGFR-TKI. The unpredictable variability in EGFR CN and therefore in EGFR wild type/mutant allelic ratio justifies the implementation of sensitive methods to identify patients with EGFR mutated tumors. [ABSTRACT FROM AUTHOR]

OBJECTIVES Large cell neuroendocrine carcinoma (LCNEC) represents a relatively rare and poorly studied entity whose management is not clearly established. The aim of this study was to assess clinico-pathological characteristics, treatment modalities and outcomes of LCNEC. METHODS A retrospective study of patients operated on for LCNEC between 2000 and 2010 was carried out. RESULTS Sixty-three patients (49 men, median age 64 years) with pathologically confirmed LCNEC of the lung were operated on between 2000 and 2010. Neoadjuvant chemotherapy was administered in 16 cases. Standard lobectomy, sleeve lobectomy, bilobectomy and pneumonectomy were performed in 63.5%, 9.5%, 1.6% and 15.8% of cases. There were two cases of extended resection. Sublobar resections were performed in four patients. Postoperative mortality was 1.6%. Postoperative staging was IA, IB, IIA, IIB, IIIA, IIIB and IV in 15.9%, 19%, 20.6%, 4.8%, 34.9%, 4.8% and 0% of cases, respectively. Adjuvant treatments were administered in 70% of cases. Overall 5-, and 8- year survival rates were 49.2% (37–61.6%) and 42% (28.8–56.4%), respectively. Multivariate analysis, including age >64 years, cumulative tobacco consumption, size of tumour, pT and pN parameters showed that only age (P = 0.05, RR 2.1 [0.99–4.43]) and pT parameter (P = 0.0078, RR 2.93[1.33–6.46]) were independent predictors of survival. CONCLUSIONS Surgery may achieve satisfactory results in terms of survival, in spite of the similarities of LCNEC with small cell lung cancer. Multimodality management seems necessary. [ABSTRACT FROM AUTHOR]

A single prospective randomized study found that, in selected patients with acute respiratory failure (ARF) following lung resection, noninvasive ventilation (NIV) decreases the need for endotracheal mechanical ventilation and improves clinical outcome. We prospectively evaluated early NIV use for ARF after lung resection during a 4-year period in the setting of a medical and a surgical ICU of a university hospital. We documented demographics, initial clinical characteristics and clinical outcomes. NIV failure was defined as the need for tracheal intubation. Among 690 patients at risk of severe complications following lung resection, 113 (16.3%) experienced ARF, which was initially supported by NIV in 89 (78.7%), including 59 with hypoxemic ARF (66.3%) and 30 with hypercapnic ARF (33.7%). The overall success rate of NIV was 85.3% (76/89). In-ICU mortality was 6.7% (6/89). The mortality rate following NIV failure was 46.1%. Predictive factors of NIV failure in univariate analysis were age ( P = 0.046), previous cardiac comorbidities ( P = 0.0075), postoperative pneumonia ( P = 0.0016), admission in the surgical ICU ( P = 0.034), no initial response to NIV ( P < 0.0001) and occurrence of noninfectious complications ( P = 0.037). Only two independent factors were significantly associated with NIV failure in multivariate analysis: cardiac comorbidities (odds ratio, 11.5; 95% confidence interval, 1.9–68.3; P = 0.007) and no initial response to NIV (odds ratio, 117.6; 95% confidence interval, 10.6–1305.8; P = 0.0001). This prospective survey confirms the feasibility and efficacy of NIV in ARF following lung resection. [ABSTRACT FROM AUTHOR]

Background: The neurotensin (NTS) and its specific high affinity G protein coupled receptor, the NT1 receptor (NTSR1), are considered to be a good candidate for one of the factors implicated in neoplastic progression. In breast cancer cells, functionally expressed NT1 receptor coordinates a series of transforming functions including cellular migration and invasion. Methods and Results: we investigated the expression of NTS and NTSR1 in normal human breast tissue and in invasive ductal breast carcinomas (IDCs) by immunohistochemistry and RT-PCR. NTS is expressed and up-regulated by estrogen in normal epithelial breast cells. NTS is also found expressed in the ductal and invasive components of IDCs. The high expression of NTSR1 is associated with the SBR grade, the size of the tumor, and the number of metastatic lymph nodes. Furthermore, the NTSR1 high expression is an independent factor of prognosis associated with the death of patients. Conclusion: these data support the activation of neurotensinergic deleterious pathways in breast cancer progression. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to assess the usefulness of combined video-assisted mediastinoscopy (VM) and video-assisted thoracoscopy (VT) in the management of patients with lung cancer. Methods: A prospective observational study was performed over a 5-year period. Indications for combined VM and VT included inconclusive findings from imaging techniques concerning locoregional extension and resectability; possible involvement of different structures not accessible to a single procedure; and failure to obtain a histologic diagnosis with a single technique. Results: An indication for combined exploration was established in 30 patients, representing 2.6% of all the patients referred to us for diagnosis, staging, and/or resection of lung cancer. Combined VM and VT was completed in 28 patients, as pleural carcinosis was found at VT in 2 cases. There was no mortality or morbidity in our series. Histologic diagnosis was obtained in 12/13 patients without preoperative histologic typing. In all the evaluated patients, combined VM and VT was useful in clinical decision-making, leading to immediate surgery (n = 10), induction treatments (n = 8), or nonsurgical therapy (n = 12). Among the patients who underwent immediate surgery, combined VM and VT never failed to assess the T factor. The N factor was correctly evaluated in 8/10 patients, and in 2 patients it failed to recognize a minimal N2 disease. Conclusion: Combined VM and VT is a safe and useful tool in the management of selected patients with lung neoplasms. Both the extent of primary tumor and the possible intrathoracic spread can be thoroughly evaluated. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To study clinical characteristics, surgical treatment modalities, early and long-term outcome of patients with severe ventilatory impairment undergoing lung resection for NSCLC. Methods: We performed a retrospective review of clinical records of all patients with severe chronic ventilatory impairment (FEV1 and/or FVC≤50% of predicted values) operated on for NSCLC in a 21-year period (1983–2003). Results: One hundred and six patients were operated on. Mean FEV1 and FVC were 40% (range 23–50%) and 69% (17–117%), respectively. An obstructive pattern was observed in 87 cases (82%). Extent of maximal exeresis was based on the assessment of predicted post-operative FEV1 (ppoFEV1). Major resections were contraindicated if ppoFEV1 was lower than 30%. Sixteen pneumonectomies, 73 lobectomies and 17 sublobar resections were carried out. Pathologic stages were I, II, IIIA and IIIB in 58, 26, 18 and 4 cases, respectively. Resection was complete in 104 patients. Operative mortality and morbidity were 8.5% (n=9) and 70% (n=74), respectively. Twenty-two patients needed prolonged (>48h) mechanical ventilation. Overall mean ppoFEV1 loss was 9.1% (0–34%). If ppoFEV1 loss was >15%, the morbidity rate was 100%. Mean PaCO2 and ppoFEV1 loss were higher among patients who died (41mmHg versus 37mmHg, P=0.02 and 13.2% versus 8.5%, P=0.025, respectively) as compared with operative survivors. Among patients with PaCO2>39mmHg and ppoFEV1 loss>15% (n=9), mortality rate was 33%. Overall 1-year and 5-year survival rates were 82 and 33%, respectively. Respiratory failure was the cause of late death in 2 patients. Among patients available at follow-up (n=85), respiratory function was considered subjectively improved, stable and worsened in 6 (7%), 62 (73%) and 17 (20%) cases, respectively. Eleven patients needed continuous oxygen therapy. Conclusions: Lung resection should not be denied a priori in patients with severe ventilatory impairment. Evaluation of predicted post-operative function often allows major resections, which are functionally economic, at the price of a high operative morbidity. Operative mortality, long-term survival and respiratory function are acceptable in the absence of a valid therapeutic alternative. [Copyright &y& Elsevier]

COVID-19 pandemic has been characterized by a pattern of consecutive declines and regrowth in European countries in 2020. After being partially regressed during the summer, the reappearance of the infection during fall 2020 in many temperate countries strongly suggests that temperature and cold may play a role in influencing the infectivity and virulence of SARS-CoV-2. While promoting medicine as an art, Hippocrates interpreted with logical reasoning the occurrence of diseases such as epidemics, as a consequence of environmental factors, in particular climatic variations. During the Renaissance, Sanctorius was one of the first to perform quantitative measurements, and Harvey discovered the circulation of blood by performing experimental procedures in animals. We think that a reasoning mixing various observations, measurements and experiments is fundamental to understand how cold increases infectivity and virulence of SARS-CoV-2. By this review, we provide evidence linking cold, angiotensin-II, vasoconstriction, hypoxia and aerobic glycolysis (the Warburg effect) to explain how cold affects the epidemiology of COVID-19. Also, a low humidity increases virus transmissibility, while a warm atmosphere, a moderate airway humidity, and the production of vasodilator angiotensin 1-7 by ACE2 are less favorable to the virus entry and/or its development. The meteorological and environmental parameters impacting COVID-19 pandemic should be reintegrated into a whole perspective by taking into account the different factors influencing transmissibility, infectivity and virulence of SARS-CoV-2. To understand the modern enigma represented by COVID-19, an interdisciplinary approach is surely essential. • The influence of climate on COVID-19 pandemic is suspected but largely enigmatic. • Cold may increase viral infectivity by paralyzing airway defense barriers. • Angiotensin II-mediated vasoconstriction induced by cold promotes hypoxia in cells. • Hypoxia activates aerobic glycolysis promoting SARS-CoV-2 replication. • This cascade may have favored the spread of COVID-19 in European countries in 2020. [ABSTRACT FROM AUTHOR]

• Lung carcinoid tumors associated with DIPNECH is a rare condition. • The rate of atypical carcinoid tumors subtype is significantly higher in patients with DIPNECH compared to others. • Mediastinal lymph-nodes (pN2+) invasion is more frequently associated to resected carcinoid tumors in DIPNECH patients. Diffuse Idiopathic Pulmonary NeuroEndocrine Cell Hyperplasia (DIPNECH) is a rare disease often associated with carcinoid tumors. We aimed at evaluating the impact of DIPNECH on characteristics and prognosis of patients who underwent radical treatment of pulmonary carcinoid tumors. We reviewed all patients operated on for curative-intent resection of carcinoid tumor in our department from 2001 to 2020. Cases exhibiting both pathological and radiological features of DIPNECH, as assessed by respective thoracic expert physicians, were analyzed separately. 172 cases of resected carcinoid tumors were identified, including 25 (14.5 %) harboring pathological criteria of DIPNECH and radiologic features like mosaic attenuation (92.0 %), multiple nodules < 5 mm (76.0 %), and mucoid impactions (32 %). In DIPNECH patients, major pulmonary resections were usually performed (92.0 %) and resected tumors were mostly classified as pT1 (92 %). Mean Ki67 staining was 3.7 ± 5.2 %. The early postoperative period was mostly uneventful (96.0 %) and 5-year survival was 92.9 ± 6.9 %. Compared to non-DIPNECH cases, we found that patients were older (mean 65.6 ± 9.3 versus 54.1 ± 17.9, p = 0.002), more frequently female (84.0 % versus 56.5 %, p = 0.009), and exhibiting diabetes mellitus (45.8 % versus 18.5 %, p < 0.001) or hypertension (45.8 % versus 24.1 %, p = 0.039). The rate of atypical carcinoid tumors was significantly higher in DIPNECH patients (40.0 % versus 19.9 %, p = 0.027), as well as rate of mediastinal lymph-nodes involvement (pN2+) (36.0 % versus 4.1 %, p < 0.001). At multivariate analysis, only DIPNECH pattern and atypical histology were independent factors of pN2 invasion which was the only predictor of poorer prognosis on Log-Rank test. Carcinoid tumors with proven DIPNECH are associated with negative pathological features and may deserve a dedicated perioperative management. [ABSTRACT FROM AUTHOR]

Current mortality due to the Covid-19 pandemic (approximately 1.2 million by November 2020) demonstrates the lack of an effective treatment. As replication of many viruses - including MERS-CoV - is supported by enhanced aerobic glycolysis, we hypothesized that SARS-CoV-2 replication in host cells (especially airway cells) is reliant upon altered glucose metabolism. This metabolism is similar to the Warburg effect well studied in cancer. Counteracting two main pathways (PI3K/AKT and MAPK/ERK signaling) sustaining aerobic glycolysis inhibits MERS-CoV replication and thus, very likely that of SARS-CoV-2, which shares many similarities with MERS-CoV. The Warburg effect appears to be involved in several steps of COVID-19 infection. Once induced by hypoxia, the Warburg effect becomes active in lung endothelial cells, particularly in the presence of atherosclerosis, thereby promoting vasoconstriction and micro thrombosis. Aerobic glycolysis also supports activation of pro-inflammatory cells such as neutrophils and M1 macrophages. As the anti-inflammatory response and reparative process is performed by M2 macrophages reliant on oxidative metabolism, we speculated that the switch to oxidative metabolism in M2 macrophages would not occur at the appropriate time due to an uncontrolled pro-inflammatory cascade. Aging, mitochondrial senescence and enzyme dysfunction, AMPK downregulation and p53 inactivation could all play a role in this key biochemical event. Understanding the role of the Warburg effect in COVID-19 can be essential to developing molecules reducing infectivity, arresting endothelial cells activation and the pro-inflammatory cascade. • Enhanced aerobic glycolysis supports replication of many viruses including MERS-CoV. • PI3K/AKT and MAPK/ERK inhibitors arrest MERS-CoV replication. • This metabolism likely sustains SARS-CoV-2 replication in host cells, in particular airway cells. • The Warburg effect also supports activation of endothelial cells and pro-inflammatory cells. [ABSTRACT FROM AUTHOR]

There is increasing evidence that ACE2 gene polymorphism can modulate the interaction between ACE2 and the SARS-CoV-2 spike protein affecting the viral entry into the host cell, and/or contribute to lung and systemic damage in COVID-19. Here we used in silico molecular docking to predict the effects of ACE2 missense variants on the interaction with the spike protein of SARS-CoV-2. HDOCK and FireDock simulations identified 6 ACE2 missense variants (I21T, A25T, K26R, E37K, T55A, E75G) with higher affinity for SARS-CoV-2 Spike protein receptor binding domain (RBD) with respect to wild type ACE2, and 11 variants (I21V, E23K, K26E, T27A, E35K, S43R, Y50F, N51D, N58H, K68E, M82I) with lower affinity. This result supports the hypothesis that ACE2 genetic background may represent the first "genetic gateway" during the disease progression. • Significant aspects of SARS-CoV-2 infectivity remain obscure. • Host-pathogen interactions are determinants of infectivity and clinical course. • Host genetics might explain heterogeneity in disease susceptibility and severity. • ACE2 polymorphisms might account for differences in receptor-ligand affinity. • We show in silico evidence of ACE2 polymorphisms with higher Spike affinity. [ABSTRACT FROM AUTHOR]

• Sarcopenia is associated with short-term outcome in pneumonectomy. • Similarly, right side of pneumonectomy was associated with short-term outcome. • Muscle surface measurements after fat-suppression are the most distinctive factor. Sarcopenia is associated with poor outcome in cancer-patients. However, the methods to define sarcopenia are not entirely standardized. We compared several morphometric measurements of sarcopenia and their prognostic value in short-term-outcome prediction after pneumonectomy. Consecutive lung-cancer patients undergoing pneumonectomy from January 2007 to December 2015 and having a pre-operative computed tomography (CT) scan were retrospectively included. Sarcopenia was assessed by the following CT-based parameters measured at the level of the third lumbar vertebra: cross-sectional Total Psoas Area (TPA), cross-sectional Total Muscle Area (TMA), and Total Parietal Muscle Area (TPMA), defined as TMA without TPA. Measures were obtained for entire muscle surface, as well as by excluding fatty infiltration based on CT attenuation. Findings were stratified for gender, and a threshold of 33rd percentile was set to define sarcopenia. Acute Respiratory Failure (ARF), Acute Respiratory Distress Syndrome (ARDS), and 30-day mortality were assessed as parameters of short-term-outcome. Two hundred thirty-four patients with pneumonectomy (right, n = 107; left, n = 127) were analysed. Postoperative mortality rate was 9.0 % (21/234), 17.1 % of patients (40/234) experienced ARF requiring re-intubation, and 10.3 % (24/234) had ARDS. All parameters describing sarcopenia gave significant results; the best discriminating parameter was TMA after excluding fat (p < 0.001). While right sided pneumonectomy and sarcopenia were independently associated to the three short-term outcome parameters, Charlson Comorbidity Index only independently predicted ARF. Sarcopenia defined as the sex-related 33rd percentile of fat-excluded TMA at the level of the third lumbar vertebra is the most discriminating parameter to assess short-term-outcome in patients undergoing pneumonectomy. [ABSTRACT FROM AUTHOR]