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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]

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]

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]

La prise en charge pathologique des pièces de résections chirurgicales de cancer du poumon après thérapie néo- adjuvante a eu récemment un regain d'intérêt avec l'émergence d'essais évaluant l'efficacité de l'immunothérapie en situation néoadjuvante. Dans ce contexte, l' international association for the study of lung cancer (IASLC) a publié des recommandations sur la prise en charge macroscopique et l'évaluation microscopique de ces pièces opératoires, s'appliquant à tous les types de traitements néoadjuvants. Une approche standardisée est nécessaire pour évaluer les pourcentages de surface tumorale occupée par la tumeur viable, la nécrose et le stroma (incluant fibrose et inflammation) dont la somme est égale à 100 %. Seul le pourcentage de tumeur viable est associée à la survie des patients et correspond à la réponse pathologique. La réponse pathologique majeure est définie par un pourcentage de tumeur viable inférieur à 10 %. Le but est de présenter les recommandations pour la prise en charge des pièces de résection de cancer du poumon après thérapie néoadjuvante, permettant d'obtenir la réponse pathologique. La standardisation de cette prise en charge est essentielle pour améliorer la reproductibilité entre pathologistes et pour l'évaluation des essais thérapeutiques en néoadjuvant. The pathological management of resected lung cancer specimens after neoadjuvant therapy has recently gained renewed interest with the emergence of trials evaluating the efficacy of immunotherapy in neoadjuvant settings. In this context, the International Association for the Study of Lung Cancer (IASLC) has published recommendations on the macroscopic management and microscopic evaluation of these surgical specimens, applicable to all systemic therapies. A standardized approach is needed to assess the percentages of viable tumor, necrosis and stroma (including fibrosis and inflammation), with a total adding up to 100%. Only the percentage of viable tumor is associated with patient survival and corresponds to the pathological response. The major pathological response is defined as a percentage of viable tumor less than 10%. The aim of this article is to outline recommendations for the management of resected lung cancer specimens after neoadjuvant therapy, to determine pathological response. Standardization of this management is essential to improve reproducibility between pathologists and for the evaluation of neoadjuvant therapeutic trials. [ABSTRACT FROM AUTHOR]

Purpose: The widespread use of Nivolumab results in an increasing number of side effects and adverse events. Herein, we evaluated the impact of Nivolumab on crude and normalized pulmonary artery diameter (PAD).Methods: We analyzed clinical, morphometric, pathological and radiological data of lung cancer patients treated by Nivolumab in an 18-month period. Blinded radiological evaluation was performed, by three observers measuring axial PAD and Aorta diameter (AoD) in secondarily matched pre- and post-Nivolumab CT-scans. Correlation between ΔPAD and clinicopathological data was investigated.Results: 59 patients receiving Nivolumab for treatment of advanced lung carcinoma were identified. Pre-and post-Nivolumab comparison of CT-scan measures revealed that mean PAD was 26.3 ± 2.8 mm versus 28.0 ± 3.0 mm (p < 0.001), and mean PAD/AoD ratio was 0.82 ± 0.09 versus 0.87 ± 0.11 (p <  0.001), respectively. Median ΔPAD was 0.05 [0.01-0.122] was significantly higher in hypometabolic patients exhibiting low Rest Energy Expenditure (p = 0.03). Patients exhibiting ΔPAD > 1% had significantly lower serum albumin level (p = 0.03), and higher nutritional risk (p = 0.02), compared to others. Unlike Nivolumab therapy, there was no increase of PAD after chemotherapy in the same cohort of patients with available scans (n = 45, 25.9 ± 2.9 mm pre-chemotherapy versus 25.7 ± 2.4 mm post-chemotherapy, p = 0.51). Anti-PD-1 treatment was associated with immune-related adverse events in 11 (18.6%) cases including 2 cases of life-threatening acute pulmonary hypertension, both exhibiting post-treatment PAD/AoD ratio > 1.Conclusion: Nivolumab is associated to PAD enlargement, a potential marker of pulmonary hypertension, sometimes leading to lethal adverse events. Careful CT-scan and echocardiographic evaluation of PAD should be part of the therapeutic work-up of patients receiving Nivolumab, especially those suffering cancer-associated malnutrition. [ABSTRACT FROM AUTHOR]

The tumor suppressor gene neurofibromin 1 (NF1) is a major regulator of the RAS‐MAPK pathway. NF1 mutations occur in lung cancer but were not extensively explored. We hypothesized that NF1‐mutated tumors could define a specific population with a distinct clinical and molecular profile. We performed NF1 sequencing using next generation sequencing (NGS) in 154 lung adenocarcinoma surgical specimens with known KRAS, EGFR, TP53, BRAF, HER2, and PIK3CA status, to evaluate the molecular and clinical specificities of NF1‐mutated lung cancers. Clinical data were retrospectively collected, and their associations with molecular profiles assessed. In this series, 24 tumors were NF1 mutated (17.5%) and 11 were NF1 deleted (8%). There was no mutation hotspot. NF1 mutations were rarely associated with other RAS‐MAPK pathway mutations. Most of patients with NF1 alterations were males (74.3%) and smokers (74.3%). Overall survival and disease‐free survival were statistically better in patients with NF1 alterations (N = 34) than in patients with KRAS mutations (N = 30) in univariate analysis. Our results confirm that NF1 is frequently mutated and represents a distinct molecular and clinical subtype of lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Abstract Objective Post-pneumonectomy acute respiratory failure leading to invasive mechanical ventilation carries a severe prognosis especially when acute respiratory distress syndrome occurs. The aim of this study was to describe risk factors and outcome of acute respiratory failure. Methods We retrospectively reviewed clinical files of all patients who underwent pneumonectomy in a single center between 2005 and 2015. Risk factors and outcome of acute respiratory failure were assessed in univariate and multivariate analysis. Results Among the 543 patients who underwent pneumonectomy in the period of study, 89 (16.4%) needed reintubation within the 30th postoperative day and 60 of these (11% of all pneumonectomies) developed acute respiratory distress syndrome. In multivariate analysis, right-side of pneumonectomy (odds ratio [OR], 2.29; 95% confidence interval [CI], 1.24-4.22), chronic cardiac disease (OR, 2.15; 95% CI, 1.08-4.25), Charlson Comorbidity Index (OR, 1.35; 95% CI, 1.14-1.61), carinal resection (OR, 3.23; 95% CI, 1.26-8.29), and extrapleural pneumonectomy (OR, 8.36; 95% CI, 3.31-21.11) were identified as independent risk factors of reintubation. Thirty-day mortality was 7.7% for all pneumonectomies, 41.6% (37/89) in the invasive ventilation group, and 53.3% (32/60) in patients with acute respiratory distress syndrome. In non-reintubated patients, 30-day mortality was 1.1% (5/454). In reintubated patients, 5-year survival was 27.1% (95% CI, 17.8-41.4). Conclusions Early acute respiratory failure requiring reintubation remains a severe complication of pneumonectomy with a poor outcome. [ABSTRACT FROM AUTHOR]

Rationale: Patients with chronic obstructive pulmonary disease (COPD) have a higher prevalence of lung cancer. The chronic inflammation associated with COPD probably promotes the earliest stages of carcinogenesis. However, once tumors have progressed to malignancy, the impact of COPD on the tumor immune microenvironment remains poorly defined, and its effects on immune-checkpoint blockers' efficacy are still unknown.Objectives: To study the impact of COPD on the immune contexture of non-small cell lung cancer.Methods: We performed in-depth immune profiling of lung tumors by immunohistochemistry and we determined its impact on patient survival (n = 435). Tumor-infiltrating T lymphocyte (TIL) exhaustion by flow cytometry (n = 50) was also investigated. The effectiveness of an anti-PD-1 (programmed cell death-1) treatment (nivolumab) was evaluated in 39 patients with advanced-stage non-small cell lung cancer. All data were analyzed according to patient COPD status.Measurements and Main Results: Remarkably, COPD severity is positively correlated with the coexpression of PD-1/TIM-3 (T-cell immunoglobulin and mucin domain-containing molecule-3) by CD8 T cells. In agreement, we observed a loss of CD8 T cell-associated favorable clinical outcome in COPD+ patients. Interestingly, a negative prognostic value of PD-L1 (programmed cell death ligand 1) expression by tumor cells was observed only in highly CD8 T cell-infiltrated tumors of COPD+ patients. Finally, data obtained on 39 patients with advanced-stage non-small cell lung cancer treated by an anti-PD-1 antibody showed longer progression-free survival in COPD+ patients, and also that the association between the severity of smoking and the response to nivolumab was preferentially observed in COPD+ patients.Conclusions: COPD is associated with an increased sensitivity of CD8 tumor-infiltrating T lymphocytes to immune escape mechanisms developed by tumors, thus suggesting a higher sensitivity to PD-1 blockade in patients with COPD. [ABSTRACT FROM AUTHOR]

OBJECTIVES: The aim of this study was to evaluate, in a predominantly white population, correlations between radiological and pathological diagnoses based on the latest classifications of pulmonary adenocarcinomas. METHODS: We analysed data from patients undergoing lung resection for ground glass nodules (GGNs) less than 3 cm and whose solid component was <50%, over a 6-year period. Computed tomography scans were reviewed independently by two senior radiologists. Pathological slides were reviewed and adenocarcinomas re-classified according to the current World Health Organization classification. RESULTS: There were 72 patients with a mean age of 64.7 (±9.4) years; 58.3% were women and 70.8% were smokers. GGNs were classified as pure, dense or part-solid in 27 (37.5%), 14 (19.4%) and 31 (43.1%) cases, respectively. The median (first and third quartiles) diameter of the whole nodule was 19.8 [12.9-23.0] mm. The solid component was measurable on the mediastinal window in 23 cases. Segmentectomy, lobectomy and wedge resection were performed in 33 (45.8%), 30 (41.7%) and 9 (12.5%) cases, respectively. Adenocarcinomas (n = 70) were classified as early-phase (in situ or minimally invasive) or invasive in 28 (40.0%) and 42 (60.0%) cases, respectively. Early-phase adenocarcinomas occurred in the pure, dense or part-solid radiological group in 16 (61.5%), 7 (50.0%) and 5 (16.7%) patients, respectively (P = 0.001), and were significantly smaller compared to invasive adenocarcinomas [14.3mm (11.0-20.8) vs 21.8mm (17.0-25.0), P < 0.001]. CONCLUSION: Among a predominantly white population of operated patients, almost all resected GGNs were adenocarcinomas including a majority of invasive lesions. Radiological features and analysis may be improved to predict invasiveness. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to determine the efficacy of alginate staple-line reinforcement of fissure openings as compared with stapling alone, with or without tissue sealant or glue, in reducing the incidence and duration of air leakage after pulmonary lobectomy for malignancy. Summary Background Data: No randomized trial evaluating alginate staple-line reinforcement has been performed to date. Methods: The Staple-line Reinforcement for Prevention of Pulmonary Air Leakage study was a multicenter randomized trial, with blinded evaluation of endpoints. Patients over 18 years of age scheduled for elective open lobectomy or bilobectomy for malignancy were eligible for enrollment. At thoracotomy, patients were deemed ineligible if an unanticipated pneumonectomy was indicated, or if air leakage occurred after the liberation of pleural adhesions. Otherwise, if the fissure was incomplete or the lung had an emphysematous appearance, patients were randomized to either standard management or interventional procedure consisting of fissure opening with linear cutting staplers buttressed with paired alginate sleeves (FOREseal). The number of eligible patients necessary in each randomization arm was estimated to be 190, and an outcomes analysis was performed on an intention-to-treat basis. Results: Of the 611 patients consented to study enrollment, 380 met the inclusion criteria and were randomized. Based on an intention-to-treat analysis, the primary endpoint of air leak duration was not different between the 2 groups: 1 day (range: 0–2 d) in the FOREseal group and 1 day (range: 0–3 d) in the control group (P = 0.8357). In addition, the 2 groups were similar in terms of the proportion of patients presenting with prolonged air leakage (7.8% in the FOREseal group vs 11.3% in the control group, P = 0.264) and the average duration of chest drainage (P = 0.107). Procedure costs were comparable for both groups. Conclusions: FOREseal did not demonstrate a significant advantage over standard treatment alone. [ABSTRACT FROM AUTHOR]

T cells play a key role in the battle against cancer. To perform their antitumor activities, T cells need to adequately respond to tumor antigens by establishing contacts with either malignant cells or antigen-presenting cells. These latter functions rely on a series of migratory steps that go from entry of T cells into the tumor followed by their locomotion in the tumor stroma. Our knowledge of how T cells migrate within tumors mainly comes from experiments performed in mouse models. Whereas such systems have greatly advanced our understanding, they do not always faithfully recapitulate the disease observed in cancer patients. We previously described a technique based on tissue slices that enables to track with real-time imaging microscopy the motile behavior of fluorescent T cells plated onto fresh sections of human lung tumors. We have now refined this approach to monitor the locomotion of resident tumor-infiltrating CD8 T cells labeled with fluorescently coupled antibodies. Using this approach, our findings reveal that CD8 T cells accumulate in the stroma of ovarian and lung carcinomas but move slowly in this compartment. Conversely, even though less populated, tumors islets were found to be zones of faster migration for resident CD8 T cells. We also confirm the key role played by collagen fibers, which, by their orientation, spacing and density, control the distribution and migration of resident CD8 T cells within the tumor stroma. We have subsequently demonstrated that, under some physical tissue constraints, CD8 T cells exhibited a mode of migration characterized by alternate forward and backward movements. In sum, using an ex vivo assay to track CD8 T cells in fresh human tumor tissues, we have identified the extracellular matrix as a major stromal component in influencing T cell migration, thereby impacting the control of tumor growth. This approach will aid in the development and testing of novel immunotherapy strategies to promote T cell migration in tumors. [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]

OBJECTIVES Nutritional assessment is not included yet as a major recommendation in lung cancer guidelines. The purpose of this study was thus to assess the influence on surgical outcome of the nutritional status of patients with primary lung cancer undergoing lobectomy. METHODS We queried Epithor, the national clinical database of the French Society of Thoracic and Cardiovascular Surgery, and identified a retrospective cohort of 19 635 patients having undergone lobectomy for a primary lung cancer in the years 2005–11. Their nutritional status was categorized according to the WHO definition: underweight (BMI < 18.5): 857 patients (4.4%), normal (18.5 ≤ BMI < 25): 9391 patients (47.8%), overweight (25 ≤ BMI < 30): 6721 patients (34.2%), obese (BMI ≥ 30): 2666 patients (13.6%). Operative mortality, pulmonary, cardiovascular, infectious and surgical complications rates were collected and analysed for these various BMI groups. RESULTS In the normal-weight category, operative mortality, pulmonary, surgical, cardiovascular and infectious complications rates were 2.7, 14.6, 13.8, 5.5 and 4.1%, respectively. When compared with that of normal BMI patients, adjusted operative mortality was significantly lower in overweight (2.3%; odd ratio (OR): 0.72 [95% confidence interval (CI): 0.59–0.89]; P = 0.002) and obese patients (1.9%, OR: 0.54 [95% CI: 0.40–0.74]; P < 0.001), and significantly higher in underweight patients (4.1%, OR: 1.89 [95% CI: 1.30–2.75]; P = 0.001). Underweight patients experienced significantly more pulmonary (21.1%; P < 0.001), surgical (23.2%; P < 0.001) and infectious (5.1%; P = 0.05) complications (P < 0.0001). Among surgical complications, prolonged air leaks (17.6%; P < 0.001) and bronchial stump dehiscence (1.5%; P = 0.001) were significantly more frequent in underweight patients than in normal BMI patients. Obesity was not associated with increased incidence of postoperative complications, except for arrhythmia (5.6%; P < 0.05), deep venous thrombosis and pulmonary embolism (1.5%; P = 0.005). Moreover, a statistical protective effect of obesity was observed regarding surgical complications (7.1%; P < 0.001). CONCLUSIONS Despite having an increased risk of some postoperative cardiovascular complications, obese patients should undergo surgical standard of care therapy for appropriately stage-specific lung cancer. In underweight patients, in addition to preoperative rehabilitation including a nutritional program, attention should be given to aggressive prophylactic respiratory therapy in the perioperative period, and specific intraoperative actions to prevent prolonged air leaks and bronchial stump dehiscence. [ABSTRACT FROM AUTHOR]

Simple Summary: Surgery is the mainstay treatment of non-small-cell lung cancer, but its impact on survival beyond 15 years has never been reported so far. We studied retrospectively clinical characteristics and short and long-term survival of a single-institution patient population whose baseline data were prospectively collected. All patients underwent major lung resection between June 2001 and December 2002. Vital status was obtained by checking INSEE database and verifying if reported as "non-death" by the hospital administrative database and direct phone interviews with patients of families. A total of 345 patients were analyzed; 15-year and 20-year overall survival rates were 12.2% and 5.7%, respectively. At univariate analysis, predictors of worse survivals were increasing age at surgery, lower BMI, weight loss, higher baseline C-reactive protein, pathological stage, and, among patients with adenocarcinoma, higher grade. Increasing age, cumulative smoking, lower BMI, and pathological stage were independent predictors of long-term survival at Cox multivariate analysis. We conclude that very-long-term survivals can be achieved after surgery of NSCLC, and factors classically predicting 5- and 10-years survival also determines longer outcomes suggesting that both initial tumor aggressiveness and host characteristics act beyond the period usually taken into account in oncology. Surgery is the mainstay treatment of non-small-cell lung cancer (NSCLC), but its impact on very-long-term survival (beyond 15 years) has never been evaluated. Methods: All patients operated on for major lung resection (Jun. 2001–Dec. 2002) for NSCL in the Thoracic Surgery Department at Paris-Hôtel-Dieu-University-Hospital were included. Patients' characteristics were prospectively collected. Vital status was obtained by checking INSEE database and verifying if reported as "non-death" by the hospital administrative database and direct phone interviews with patients of families. Results: 345 patients were included. The 15- and 20-year survival rates were 12.2% and 5.7%, respectively. At univariate analysis, predictors of worse survivals were: increasing age at surgery (p = 0.0042), lower BMI (p = 0.009), weight loss (p = 0.0034), higher CRP (p = 0.049), pathological stage (p = 0.00000042), and, among patients with adenocarcinoma, higher grade (p = 0.028). Increasing age (p = 0.004), cumulative smoking (p = 0.045), lower BMI (0.046) and pathological stage (p = 0.0026), were independent predictors of long-term survival at Cox multivariate analysis. In another model, increasing age (p = 0.013), lower BMI (p = 0.02), chronic bronchitis (p = 0.03), lower FEV1% (p = 0.00019), higher GOLD class of COPD (p = 0.0079), and pathological stage (p = 0.000024), were identified as independent risk factors. Conclusions: Very-long-term survivals could be achieved after surgery of NSCLC, and factors classically predicting 5- and 10-years survival also determined longer outcomes suggesting that both initial tumor aggressiveness and host's characteristics act beyond the period usually taken into account in oncology. [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]

Background: Resection of tumors with carinal involvement remains a challenge because of specific problems of operative technique and airway management. We reviewed our experience with carinal resection and studied factors influencing postoperative course and long-term survival. Methods: Between 1983 and 2002, 65 patients underwent a carinal resection for non–small-cell lung cancers involving the carina (54 squamous cell carcinomas and 11 adenocarcinomas). Results: Fifty-eight right sleeve pneumonectomies and 2 left sleeve pneumonectomies were performed. In addition, five tracheocarinal resections with double bronchial reimplantation (no lung resection) were also performed. The intraoperative airway management consisted of high-frequency jet ventilation in 83% of patients and intermittent conventional ventilation through the operative field in the remaining 17% of patients. Operative mortality was 7.7%. Resection was complete in 61 patients. The overall 5-year and 10-year survival rates were 26.5% and 10.6%, respectively. Patients with N0 or N1 disease had a 5-year survival of 38% compared with 5.3% for those with N2 disease (p < 0.01). At multivariate analysis only nodal status (N0, N1 versus N2; p = 0.0046) had a significant impact on long-term survival. Conclusions: Carinal resection provides acceptable results in terms of operative mortality and long-term survival rates. Patients should be carefully selected and probably enrolled in a multimodality treatment program in case of anticipated mediastinal lymph node involvement. [Copyright &y& Elsevier]

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]

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.

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]

Simple Summary: Lung cancer continues to be one of the leading cause of cancer-related deaths. In multimodality management of non-small cell lung cancer, surgery remains the mainstay, and in particular, pneumonectomy remains the only possible surgical procedure in patients with centrally located lesions. However, despite improvements in technique and perioperative management, it continues to be associated with significant postoperative mortality. Thus, identifying patients at high postoperative risk is of paramount importance to select surgical candidates, but identifying patients more likely to achieve definitive cure after surgery is at least as important. Among all the evaluated parameters, we found that being sarcopenic at both psoas and parietal muscles is an independent negative prognostic factor of overall survival. The whole muscular area had the best predictive value among all of the tested factors evaluating sarcopenia. There is no standardization in methods to assess sarcopenia; in particular the prognostic significance of muscular fatty infiltration in lung cancer patients undergoing surgery has not been evaluated so far. We thus performed several computed tomography (CT)-based morphometric measurements of sarcopenia in 238 consecutive non-small cell lung-cancer patients undergoing pneumonectomy from 1 January 2007 to 31 December 2015. Sarcopenia was assessed by the following CT-based parameters: 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 performed at the level of the third lumbar vertebra and were obtained for the entire muscle surface, as well as by excluding fatty infiltration based on CT attenuation. Findings were stratified for gender, and a threshold of the 33rd percentile was set to define sarcopenia. Furthermore, we assessed the possibility of being sarcopenic at both the TPA and TPMA level, or not, by taking into account of not fatty infiltration. Five-year survival was 39.1% for the whole population. Lower TPA, TMA, and TPA were associated with lower survival at univariate analysis; taking into account muscular fatty infiltration did not result in more powerful discrimination. Being sarcopenic at both psoas and parietal muscle level had the optimum discriminating power. At the multivariable analysis, being sarcopenic at both psoas and parietal muscles (considering the whole muscle areas, including muscular fat), male sex, increasing age, and tumor stage, as well as Charlson Comorbidity Index (CCI), were independently associated with worse long-term outcomes. We conclude that sarcopenia is a powerful negative prognostic factor in patients with lung cancer treated by pneumonectomy. [ABSTRACT FROM AUTHOR]

A large interindividual variability has been observed in anti Programmed cell Death 1 (anti-PD1) therapies efficacy. The aim of this study is to assess the correlation of soluble PD-1 (sPD-1), soluble Programmed cell Death Ligand 1 (sPD-L1), Vascular Endothelial Growth Factor A (VEGFA), soluble CD40 ligand (sCD40L) and soluble CD44 (sCD44), with survival in nivolumab-treated metastatic non-small cell lung cancer (NSCLC) patients. Plasma biomarkers were assayed at baseline and after two cycles of nivolumab. A cut-off of positivity for sPD-1, sPD-L1 and sCD40L expressions was defined as a plasma level above the lower limit of quantification. Baseline sPD-1 and sPD-L1 levels were subsequently analyzed in a control group of EGFR-mutated (Epidermal Growth Factor Receptor) NSCLC patients. Association between survival and biomarkers was investigated using Cox proportional hazard regression model. Eighty-seven patients were included (51 nivolumab-treated patients, 36 in EGFR-mutated group). In nivolumab group, baseline sPD-1, sPD-L1 and sCD40L were positive for 15(29.4%), 27(52.9%) and 18(50%) patients, respectively. We defined a composite criteria (sCombo) corresponding to sPD-1 and/or sPD-L1 positivity for each patient. In nivolumab group, baseline sCombo positivity was associated with shorter median progression-free survival (PFS) (78 days 95%CI (55–109) vs. 658 days (222-not reached); HR: 4.12 (1.95–8.71), p = 0.0002) and OS (HR: 3.99(1.63–9.80), p = 0.003). In multivariate analysis, baseline sCombo independently correlated with PFS (HR: 2.66 (1.17–6.08), p = 0.02) but not OS. In EGFR-mutated group, all patients were baseline sCombo positive; therefore this factor was not associated with survival. After two cycles of nivolumab, an increased or stable sPD-1 level independently correlated with longer PFS (HR: 0.49, 95%CI (0.30–0.80), p = 0.004) and OS (HR: 0.39, 95%CI (0.21–0.71), p = 0.002). VEGFA, sCD40L and sCD44 did not correlate with survival. We propose a composite biomarker using sPD-1and sPDL-1 to predict nivolumab efficacy in NSCLC patients. A larger validation study is warranted. [ABSTRACT FROM AUTHOR]

Lower pre-surgery Body Mass Index (BMI) and low muscle mass impact negatively long-term survival of non-small cell lung cancer (NSCLC). We investigated their influence on survival after major lung resection for NSCLC. Methods: A retrospective analysis of a prospectively collected database was made on 304 consecutive patients. Results: Underweight, normal, overweight and obese patients represented 7.6%, 51.6%, 28.6%, and 12.6% of the pre-disease population. Weight loss and gain were recorded in 44.4% and 5% of patients, respectively. Low muscle mass was more frequently associated with BMI < 25 kg/m2 (p < 0.000001). Overall survival was positively affected by pre-disease (p = 0.036) and pre-surgery (p = 0.017) BMI > 25 kg/m2, and, even more, in case of BMI > 25 kg/m2 and increasing weight (p = 0.012). Long-term outcome was negatively influenced by low muscle mass (p = 0.042) and weight loss (p = 0.0052) as well as age (p = 0.017), ASA categories (p = 0.025), extent of resection (p = 0.0001), pleural invasion (p = 0.0012) and higher pathologic stage (p < 0.0001). Three stepwise multivariable models confirmed the independent favorable prognostic value of higher pre-disease (RR 0.66[0.49–0.89], p = 0.006) and pre-surgery BMI (RR 0.72[0.54–0.98], p = 0.034), and the absence of low muscle mass (RR 0.56[0.37–0.87], p = 0.0091). Conclusions: Body reserves assessed by simple clinical markers impact survival of surgically treated NSCLC. Strategies improving body fat and muscular mass before surgery should be considered. [ABSTRACT FROM AUTHOR]

Background: The 18-gene tumor inflammation signature (TIS) is a clinical research assay that enriches for clinical benefit to immune checkpoint blockade. We evaluated its ability to predict clinical benefit of immunotherapy in cancer patients treated with PD-1 checkpoint inhibitors in routine clinical care.Methods: The CERTIM cohort is a prospective cohort which includes patients receiving immune checkpoint inhibitors in Cochin University hospital. RNA extracted from 58 archival formalin fixed paraffin embedded tumor blocks (including 38 lung cancers, 5 melanomas, 10 renal carcinomas, 4 urothelial carcinomas and 1 colon carcinoma) was hybridized to a beta version of the NanoString® PanCancer IO360™ CodeSet using nCounter® technology. Gene expression signatures were correlated with tumor responses (by RECIST criteria) and overall survival. PD-L1 immunostaining on tumor cells was assessed in 37 non-small cell lung cancer (NSCLC) samples and tumor mutational burden (TMB) measured by whole exome sequencing in 19 of these.Results: TIS scores were significantly associated with complete or partial response to anti-PD-1 treatment in the whole cohort (odds ratio = 2.64, 95% CI [1.4; 6.0], p = 0.008), as well as in the NSCLC population (odds ratio = 3.27, 95% CI [1.2; 11.6], p = 0.03). Patients whose tumor had a high TIS score (upper tertile) showed prolonged overall survival compared to patients whose tumor had lower TIS scores, both in the whole cohort (hazard ratio = 0.37, 95% CI [0.18, 0.76], p = 0.005) and in the NSCLC population (hazard ratio = 0.36, 95% CI [0.14, 0.90], p = 0.02). In the latter, the TIS score was independent from either PD-L1 staining on tumor cells (spearman coefficient 0.2) and TMB (spearman coefficient - 0.2).Conclusions: These results indicate that validated gene expression assay measuring the level of tumor microenvironment inflammation such as TIS, are accurate and independent predictive biomarkers and can be easily implemented in the clinical practice. [ABSTRACT FROM AUTHOR]

Abstract Objective Postpneumonectomy acute respiratory failure leading to invasive mechanical ventilation carries a severe prognosis, especially when acute respiratory distress syndrome develops. The aim of this study was to describe the risk factors, management, and outcome of postpneumonectomy acute respiratory distress syndrome. Methods We retrospectively reviewed the clinical files of patients undergoing pneumonectomy in a single center between 2005 and 2015. Risk factors for acute respiratory distress syndrome, management characteristics, and short- and long-term outcomes were assessed. Results Among the 543 patients undergoing pneumonectomy, 89 (16.4%) needed reintubation within the 30th postoperative day, including 60 (11%) who developed acute respiratory distress syndrome. At multivariate analysis, right-side pneumonectomy (odds ratio [OR], 2.75; 95% confidence interval [CI], 1.51-5.02; P =.0009) and higher Charlson Comorbidity Index (OR, 1.26; 95% CI, 1.07-1.49; P =.007) were identified as independent risk factors for acute respiratory distress syndrome. Operative mortality was 8.1% for all pneumonectomies, 43.8% (n = 39/89) in intubated patients, and 56.7% (34/60) in patients with acute respiratory distress syndrome. Mortality was higher in severe (25/36, 69.4%) than in mild or moderate acute respiratory distress syndrome (9/24, 37.5%, P =.014). Logistic regression identified 3 independent predictors of operative mortality in patients with acute respiratory distress syndrome: age (OR, 1.08; 95% CI, 1.01-1.15; P =.02), right pneumonectomy (OR, 5.97; 95% CI, 1.33-26.71; P =.02), and severe acute respiratory distress syndrome (OR, 7.19; 95% CI, 1.74-29.73; P =.006). Five-year survival was 17.6% for patients with acute respiratory distress syndrome. Conclusions Acute respiratory distress syndrome is a severe early complication of pneumonectomy with a poor outcome. The low survival underlines the need for novel management strategies. [ABSTRACT FROM AUTHOR]

Co-stimulatory and inhibitory receptors expressed by immune cells in the tumor microenvironment modulate the immune response and cancer progression. Their expression and regulation are still not fully characterized and a better understanding of these mechanisms is needed to improve current immunotherapies. Our previous work has identified a novel ligand/receptor pair, LLT1/CD161, that modulates immune responses. Here, we extensively characterize its expression in non-small cell lung cancer (NSCLC). We show that LLT1 expression is restricted to germinal center (GC) B cells within tertiary lymphoid structures (TLS), representing a new hallmark of the presence of active TLS in the tumor microenvironment. CD161-expressing immune cells are found at the vicinity of these structures, with a global enrichment of NSCLC tumors in CD161+ CD4+ and CD8+ T cells as compared to normal distant lung and peripheral blood. CD161+ CD4+ T cells are more activated and produce Th1-cytokines at a higher frequency than their matched CD161-negative counterparts. Interestingly, CD161+ CD4+ T cells highly express OX40 co-stimulatory receptor, less frequently 4-1BB, and display an activated but not completely exhausted PD-1-positive Tim-3-negative phenotype. Finally, a meta-analysis revealed a positive association of CLEC2D (coding for LLT1) and KLRB1 (coding for CD161) gene expression with favorable outcome in NSCLC, independently of the size of T and B cell infiltrates. These data are consistent with a positive impact of LLT1/CD161 on NSCLC patient survival, and make CD161-expressing CD4+ T cells ideal candidates for efficient anti-tumor recall responses. [ABSTRACT FROM AUTHOR]

There is now growing evidence that the immune contexture influences cancer progression and clinical outcome of patients with non-small cell lung cancer (NSCLC). If chemotherapy is widely used to treat patients with advanced-stage NSCLC, it remains unclear how it could modify the immune contexture and impact its prognostic value. Here, we analyzed two retrospective cohorts, respectively composed of 122 stage III-N2 NSCLC patients treated with chemotherapy before surgery and 39 stage-matched patients treated by surgery only. In patients treated with neoadjuvant chemotherapy, the histological characteristics, the expression of PD-L1 protein, and the tumor immune microenvironment (CD8+T cells, DC-LAMP+mature dendritic cells, and CD68+macrophages) were evaluated and their prognostic value assessed together with standard clinical parameters. By analyzing pre- and post-treatment specimens, we did not find any changes in the PD-L1 expression. We also found that the tumor immune contexture in patients treated with neoadjuvant chemotherapy exhibited a similar pattern that the one found in chemotherapy-naive patients, with comparable densities of tumor-infiltrating CD8+and DC-LAMP+cells and a similar spatial organization. The percentage of residual viable tumor cells and the immune pattern (CD8+and DC-LAMP+cell densities) were significantly associated with the clinical outcome and allowed the identification of short- and long-term survivors, respectively. In multivariate analysis, the immune pattern was found to be the strongest independent prognostic factor. In conclusion, this study decrypts the complex interplay between cancer and immune cells in patients undergoing chemotherapy and supports potential beneficial synergistic effect of immunotherapy and chemotherapy. [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]

The number of clinical protocols testing combined therapies including immune check-point inhibitors and platinum salts is currently increasing in lung cancer treatment, however preclinical studies and rationale are often lacking. Here, we evaluated the impact of cisplatin treatment on PD-L1 expression analyzing the clinicopathological characteristics of patients who received cisplatin-based neoadjuvant chemotherapy followed by surgery and showed that cisplatin-based induction treatment significantly increased PD-L1 staining in both tumor and immune cells from the microenvironment. Twenty-two patients exhibited positive PD-L1 staining variation after neoadjuvant chemotherapy; including 9 (23.1%) patients switching from <50% to ≥50% of stained tumor-cells. We also confirmed the up-regulation of PD-L1 by cisplatin, at both RNA and protein levels, in nude and immunocompetent mice bearing tumors grafted with A549, LNM-R, or LLC1 lung cancer cell lines. The combined administration of anti-PD-L1 antibodies (3 mg/kg) and cisplatin (1 mg/kg) to mice harboring lung carcinoma significantly reduced tumor growth compared to single agent treatments and controls. Overall, these results suggest that cisplatin treatment could synergize with PD-1/PD-L1 blockade to increase the clinical response, in particular through early and sustainable enhancement of PD-L1 expression. [ABSTRACT FROM AUTHOR]

Overall survival of patients with metastatic non-small cell lung cancer (NSCLC) has significantly improved with platinum-based salt treatments and recently with targeted therapies and immunotherapies. However, treatment failure occurs due to acquired or emerging tumor resistance. We developed a monoclonal antibody against the proform of neurotensin (LF-NTS mAb) that alters the homeostasis of tumors overexpressing NTSR1. Neurotensin is frequently overexpressed along with its high affinity receptor (NTSR1) in tumors from epithelial origins. This ligand/receptor complex contributes to the progression of many tumor types by activation of the cellular effects involved in tumor progression (proliferation, survival, migration, and invasion). We demonstrate that LF-NTS mAb operates on the plasticity of tumor cells overexpressing NTSR1 and lowers their aggressiveness. The mAb enables the restoration of platinum-based therapies responsiveness, while also decreasing metastatic processes. Efficacy dosage with long-term treatment showed no obvious adverse events, while demonstrating improvement in the performance status. Our data suggests that LF-NTS mAb is an ideal candidate to be safely added to the conventional standard of care in order to improve its efficacy. [ABSTRACT FROM AUTHOR]

Introduction Pulmonary Sarcomatoid Carcinoma (PSC) is a rare subset of NSCLC, associated with worse prognosis and resistant to platinum-based regimens. Recent investigations have shown high levels of PD-L1 expression in PSC, providing a rationale for the potential use of immunotherapy. In this study, we investigated whether the PD-L1 expression was related to clinico-pathologic and molecular characteristics. Materials and methods Fortythree surgically-resected PSCs were selected from 2006 to 2014 and clinical information retrieved. PD-L1 expression was analyzed by immunohistochemistry and correlated with the clinic-pathologic features and driver gene mutations analyzed by Next-Generation-Sequencing. Correlation of clinical, pathological and genetic variants with PD-L1 expression positivity were tested by Fisher’s exact test analysis. Results About 25% of PSCs showed a significant expression of PD-L1 (positive staining defined as staining in ≥10% of tumor cells). PD-L1 expression was associated with aggressive pathological features of PSCs including N2-involvement (PD-L1 positive in 83.3% of N2-PSCs vs in 16.2% of N0/N1-PSCs, p = 0.003) and presence of either local (p = 0.038) and distant metastases (p = 0.022). Furthermore, PD-L1 expression was significantly associated with the overall mutational load of the tumors (PD-L1 positivity only in PSCs with at least one mutational event) and in particular with the presence of KRAS mutation (PD-L1 positive in 44.4% of KRAS -Mut PSCs vs 12.0% in KRAS -Wild PSCs). The correlation between PD-L1 expression and KRAS -mutation were found at univariate analysis (p = 0.031), even considering PD-L1 as a continuous variable (p = 0.018), and confirmed at multivariate analysis (p = 0.035). The mutational status of the other genes explored in the NGS-panel ( EGFR, APC, PTEN, PIK3CA, TP53 and STK11) did not correlate with PD-L1 expression. Conclusions PD-L1 expression significantly correlates with overall mutational load and KRAS mutational status in pulmonary sarcomatoid carcinomas. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To assess computed tomography (CT) evaluation of mediastinal nodes in non-small cell lung cancer to predict metastatic involvement by measurement of their axis and surface area in the coronal plane, as compared to standard short-axis measures in the axial plane. Methods: Evaluation of mediastinal nodes was retrospectively performed on CT scans of 100 patients before thoracotomy. In all patients, mediastinal dissection was performed in the appropriate stations (n =264) according to the side (59 right, 41 left) of the tumor. Measurements of short axis and surface area of the largest node in each dissected station were performed on axial and coronal planes. Results: By using the standard threshold of axial short axis ≥10mm, sensitivity and specificity were 25% and 98%, respectively. Areas under receiver operating characteristic curves were 0.828 and 0.821 for axial short axis and axial surface area data. For comparison, areas under receiver operating characteristic curves were 0.843 and 0.845 for coronal short axis and coronal surface area data, respectively. So, for a specificity of 98%, sensitivity was 29% for coronal short axis ≥11mm and 33% for coronal surface area ≥123mm2. When using axial short axis ≥10mm or coronal surface area ≥120mm2, sensitivity was 45%, whereas specificity remained at 96%. Conclusion: Coronal measurements of mediastinal nodes give a slightly albeit non-significant improvement of diagnostic accuracy over axial ones. If both axial short axis and coronal surface area are taken into account, accuracy is improved. [Copyright &y& Elsevier]

De novo formation of tertiary lymphoid structures (TLS) has been described in lung cancers. Intratumoral TLS seem to be functional and are associated with a long-term survival for lung cancer patients, suggesting that they epresent an activation site for tumor-specific T cells. Here, we characterized T-cell recruitment to TLS in human lung cancer to identify the adhesion molecules and chemoattractants orchestrating this migration. We found hat most TLS T cells were CD62L+ and mainly of CD4+ memory phenotype, but naive T cells were highly enriched in these structures as compared with the rest of the tumor. A specific gene expression signature associated with T cell presence was identified in TLS, which included chemokines (CCL19, CCL21, CXCL13, CCL17, CCL22, and IL16), adhesion molecules (ICAM-2, ICAM-3, VCAM-1, and MAdCAM-1) and integrins alphaL, alpha4, and alphaD). The presence of the corresponding receptors on TLS T cells was confirmed. ntratumoral PNAd+ high endothelial venules also were exclusively associated with TLS and colocalized with CD62L+ lymphocytes. Together, these data bring new insights into the T-cell recruitment to intratumoral TLS and suggest that blood T cell enter into TLS via high endothelial venules, which represent a new gateway for T cells to the tumor. Findings identify the molecules that mediate migration of tumor-specific T cells into TLS where T cell priming occurs, suggesting new strategies to enhance the efficacy of cancer immunotherapies. [ABSTRACT FROM AUTHOR]

Both the innate and adaptive immune systems contribute to tumor immunosurveillance in mice and humans; however, there is a paucity of direct evidence of a role for natural killer (NK) cells in this important process. In this study, we investigated the intratumoral phenotypic profile and functions of NK cells in primary human tumor specimens of non--small cell lung carcinoma (NSCLC). We used methods to quantify and localize in situ NK cells using the NKp46 marker and we characterized their phenotype in blood, tumoral, and nontumoral samples of NSCLC patients. Intratumoral NK cells displayed a profound and coordinated alteration of their phenotype, with a drastic reduction of NK cell receptor expression specifically detected in the tumoral region. According to their altered phenotype, intratumoral NK cells exhibited profound defects in the ability to activate degranulation and IFN- production. We found that the presence of NK cells did not impact the clinical outcome g of patients with NSCLC. Finally, we showed that tumor cells heterogeneously express ligands for both activating and inhibitory NK receptors. Taken together, our results suggest that the NSCLC tumor microenvironment locally impairs NK cells, rendering them less tumorcidal and thereby supportive to cancer progression. Cancer Res; 71(16); 5412-22. ©2011 AACR. [ABSTRACT FROM AUTHOR]