Prognostic impact of PD-1 and PD-L1 expression in malignant pleural mesothelioma: an international multicenter study.

BACKGROUND: Programmed cell death 1/programmed death ligand 1 (PD-1/PD-L1) immune-checkpoint blockade is a promising new therapeutic strategy in cancer. However, expression patterns and prognostic significance of PD-L1 and PD-1 are still controversial in human malignant pleural mesothelioma (MPM). METHODS: Formalin-fixed paraffin-embedded (FFPE) tumor samples from 203 MPM patients receiving standard treatment without immunotherapy were collected from 5 European centers. PD-L1 and PD-1 expression of tumor cells (TCs) and tumor-infiltrating lymphocytes (TILs) were measured by immunohistochemistry and correlated with clinical parameters and long-term outcome. RESULTS: High (>10%) PD-L1 TC and PD-1 TILs expressions were found in 18 (8%) and 39 (24%) patients, respectively. PD-L1 was rarely expressed by TILs [≥1%, n=13 (8%); >10%, n=1]. No significant associations were found between the PD-L1 or PD-1 expression of TCs or TILs and clinicopathological parameters such as stage or histological subtype. Notably, patients with high (>10%) TC-specific PD-L1 expression exhibited significantly worse median overall survival (OS) (6.3 vs. 15.1 months of those with low TC PD-L1 expression; HR: 2.51, P<0.001). In multivariate cox regression analysis adjusted for clinical parameters, high TC PD-L1 expression (>10%) proved to be an independent negative prognostic factor for OS (HR: 2.486, P=0.005). There was no significant correlation between PD-L1 or PD-1 expression of TILs and OS. CONCLUSIONS: In this multicenter cohort study, we demonstrate that high (>10%) PD-L1 expression of TCs independently predicts worse OS in MPM. Further studies are warranted to investigate the value of PD-L1/PD-1 expression as a marker for treatment response in MPM patients receiving immunotherapy.

Giant lung metastasis of NRAS-mutant melanoma in a 24-year-old patient with a history of BRAF-mutant conventional melanoma harboring Spitzoid morphology: a case report.

BACKGROUND: Spitzoid melanocytic lesions represent a heterogeneous group of proliferations with ambiguous and overlapping terminology. The exact distinction of a Spitz nevus from a Spitzoid melanoma can be very difficult or, in some cases, impossible. Among the Spitzoid lesions, there is a lesion termed an atypical Spitz tumour (AST) that has intermediate histopathologic features between those of a Spitz nevus and a Spitzoid melanoma and thus uncertain malignant potential. There are several rare cases of patients with a Spitzoid melanoma initially misdiagnosed as a Spitz nevus or an AST with fatal consequences. It is, therefore, advised to perform a molecular characterization in cases where uncertain skin lesions are presented, as it may provide extended set of information with a possible impact on the treatment options. Furthermore, preventive measures, such as regular physical and skin examinations, as well as thorough scheduling of individual follow-up visits, are essential in patients with potentially malignant skin nevi. CASE REPORT: We report a case of a young adult female with a history of AST excision with a negative sentinel lymph node biopsy (SLNB) and insufficient follow-up. Four years after the primary dermatological diagnosis, she presented with a giant tumour in the right hemithorax. Radical en bloc resection of the tumour with right pneumonectomy and resection of the pericardium with reconstruction of the pericardium using mesh was performed. A definitive histopathological examination revealed a metastatic melanoma. The association of the previously diagnosed AST and subsequent appearance of melanoma metastases led to a retrospective re-evaluation of the initial lesion. The suspected diagnosis of Spitzoid melanoma, however, was not confirmed. Moreover, the molecular examination revealed a major discordance between the initial lesion and the lung tumour, which most likely excluded the possible association of the lung metastasis with the initial skin lesion. The initial skin lesion was a BRAF-mutant melanoma with Spitzoid features and termed as AST, while the giant lung metastasis was NRAS-mutant melanoma. The subsequent postoperative course was complicated by the appearance of brain metastases that were stereotactically irradiated. Nevertheless, despite complex specialised medical care, the patient's clinical condition rapidly deteriorated. By this time, no active oncological treatment was possible. The patient was delegated to local hospice for palliative care six months after the surgery and died three weeks later. CONCLUSIONS: Our patient was surgically treated at the age of 20 for AST and died four years later of metastatic NRAS-mutant melanoma most likely of different occult origin. Molecular characterization, as well as the close clinical follow-up should be always precisely performed in patients with uncertain skin lesions, such as AST.

Genetic control of CCL24, POR, and IL23R contributes to the pathogenesis of sarcoidosis.

Sarcoidosis is a genetically complex systemic inflammatory disease that affects multiple organs. We present a GWAS of a Japanese cohort (700 sarcoidosis cases and 886 controls) with replication in independent samples from Japan (931 cases and 1,042 controls) and the Czech Republic (265 cases and 264 controls). We identified three loci outside the HLA complex, CCL24, STYXL1-SRRM3, and C1orf141-IL23R, which showed genome-wide significant associations (P < 5.0 × 10-8) with sarcoidosis; CCL24 and STYXL1-SRRM3 were novel. The disease-risk alleles in CCL24 and IL23R were associated with reduced CCL24 and IL23R expression, respectively. The disease-risk allele in STYXL1-SRRM3 was associated with elevated POR expression. These results suggest that genetic control of CCL24, POR, and IL23R expression contribute to the pathogenesis of sarcoidosis. We speculate that the CCL24 risk allele might be involved in a polarized Th1 response in sarcoidosis, and that POR and IL23R risk alleles may lead to diminished host defense against sarcoidosis pathogens.

Chronotropic incompetence could negatively influence post-operative risk assessment in patients before lung cancer surgery.

BACKGROUND: Cardiopulmonary exercise testing (CPET) is a standard part of preoperative evaluation in patients before lung surgical resection. According to current guidelines the risk of such a procedure is estimated according to maximum oxygen consumption (VO2max). Chronotropic incompetence (CI) is a prevalent condition which could possibly influence cardiopulmonary fitness. The aim of this study was to assess the prevalence of CI in patients before surgical lung resections and its influence on CPET results. METHODS: This study enrolled 154 patients (97 men) of average age 66.4±8.3 with newly diagnosed lung cancer indicated for surgical lung resections. All patients underwent CPET (cycle ergometry). Age predicted maximal HR was calculated using the traditional equation (220 - age). Three levels of CI were defined as, 85% HRpred, 80% HRpred and 70% HRpred. The influence of CI on CPET results was evaluated. RESULTS: CI was present in the following ratios: 85% HRpred-48.7%; 80% HRpred-39.6% and 70% HRpred-16.9%. A significant negative correlation was also found between VO2max, maximal heart rate (HR) and maximal work load among all CI groups (P<0.0001). The presence of CI significantly correlated with beta-blocker treatment (P<0.0001). CONCLUSIONS: CI significantly decreases VO2max in patients before lung cancer surgery. It is strongly associated with beta-blocker treatment which could negatively influence risk assessment. It is thus a matter for future discussion, as to whether the evaluation of CI should be part of preoperative care guidelines.

Prognostic value of tumor-infiltrating lymphocytes (TILs) and their association with PD-L1 expression and DNA repair protein RAD51 in patients with resected non-small cell lung carcinoma.

OBJECTIVES: DNA repair proteins have emerged as potential predictors for immunotherapy response alongside PD-L1 expression, tumor-infiltrating lymphocytes (TILs) and tumor mutational burden. We analyzed expression of PD-L1, TILs count and expression of the homologous recombination (HR) protein RAD51, as potential prognostic factors in patients with resected non-small-cell lung carcinoma (NSCLC). MATERIALS AND METHODS: Discovery set included 96 NSCLC patients from the University Hospital Olomouc (Czech Republic) and a replication set included 1109 NSCLC patients from University Hospital Zurich (Switzerland). Tissue microarrays (TMAs) were stained using the automated staining platform Ventana Benchmark Ultra with antibodies against RAD51,CD3, CD8, CD68 and PD-L1. RESULTS: Loss of nuclear RAD51 protein was associated with high TILs (r=-0.25, p = 0.01) and PD-L1 status (10.6 vs. 2.4 %, p = 0.012) in patients receiving neoadjuvant chemo-/radiotherapy (CT/RT). In silico analysis from the TCGA data set showed a negative relationship between RAD51 mRNA expression and CD45 (r = ‒0.422, p < 0.0001), CD68 (r = ‒0.326, p < 0.001), CD3 (r = ‒0.266, p < 0.001) and CD8 (r = ‒0.102, p < 0.001). RAD51 low/PD-L1 high patients were clustered as separate entity in the replication set and in TCGA dataset. High TILs status was significantly associated with improved OS in the replication set (unadjusted HR = 0.57, 95 % CI 0.42-0.76, p < 0.001). Similar results have been seen for CD3, CD8 and CD68. CONCLUSIONS: In conclusion, RAD51 nuclear loss is weakly associated with increased TILs and high PD-L1 at the time of surgery in curatively resected NSCLC and after prior exposure to neoadjuvant chemo- or radiotherapy. Both high TILs and RAD51 nuclear loss were confirmed as independent prognostic factors in curatively resected NSCLC.

Drug induced lung toxicity by nitrofurantoin

We present the clinical case of the patient with nitrofurantoin (FUR) lung toxicity. Diagnosis was made from detailed history of the patient and by studying CT images before the start of FUR treatment. An extensive interstitial changes were evident on HRCT scan at the presentation at our clinic. The definitive diagnosis was supported by negative microbiology and autoantibody screening and almost complete regression of changes after FUR treatment withdrawal. There was no need for corticosteroid treatment or immunosuppressive medication.

Efficacy and analgesic use during the therapy of iatrogenic pneumothorax using Pleuralvent™ and Chest Tube (ASPIRATE): A randomised controlled trial protocol.

BACKGROUND: Iatrogenic pneumothorax is a common complication of various diagnostic and therapeutic procedures such as transbronchial lung biopsies. The classical mode of treatment is chest tube insertion. Pneumothorax devices are now available on the market but there is a dearth of data on their efficacy to treat iatrogenic pneumothorax. It is important to provide such data as the pathophysiology of iatrogenic pneumothorax is different in comparison with spontaneous pneumothorax for which some data is available. METHODS: This is a randomized, non-blinded, actively controlled trial of effectivity of iatrogenic pneumothorax treatment using the Pleuralvent™ device and chest tube insertion (16F). The secondary aim is to compare the overall pain level and the need for analgesic treatment in both treatment arms. We are planning to enrol 126 patients (63 in each treatment arm). DISCUSSION: Preliminary results showed similar effectivity of the Pleuralvent™ system compared to large bore chest tube insertion. This randomized clinical trial should confirm these results and prove that the Pleuralvent™ system is an effective way of treatment of patients with iatrogenic pneumothorax. If Pleuralvent™ proves to have the same level of efficacy, it may become the standard of care of patients with iatrogenic pneumothorax. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03700554.

Randomized Phase II Study of Paclitaxel plus Alisertib versus Paclitaxel plus Placebo as Second-Line Therapy for SCLC: Primary and Correlative Biomarker Analyses.

INTRODUCTION: We assessed the Aurora A kinase inhibitor, alisertib, plus paclitaxel (henceforth referred to as alisertib/paclitaxel) as second-line treatment for SCLC. METHODS: In this double-blind study, patients with relapsed or refractory SCLC were stratified by relapse type (sensitive versus resistant or refractory) and brain metastases and randomized 1:1 to alisertib/paclitaxel or placebo plus paclitaxel (henceforth referred to as placebo/paclitaxel) in 28-day cycles. The primary end point was progression-free survival (PFS). Associations of c-Myc expression in tumor tissue (prespecified) and genetic alterations in circulating tumor DNA (retrospective) with clinical outcome were evaluated. RESULTS: A total of 178 patients were enrolled (89 in each arm). The median PFS was 3.32 months with alisertib/paclitaxel versus 2.17 months with placebo/paclitaxel (hazard ratio [HR] = 0.77, 95% confidence limit [CI]: 0.557-1.067, p = 0.113 in the intent-to-treat population versus HR = 0.71, 95% CI: 0.509-0.985, p = 0.038 with corrected analysis applied). Among 140 patients with genetic alternations, patients with cell cycle regulator mutations (cyclin-dependent kinase 6 gene [CDK6], retinoblastoma-like 1 gene [RBL1], retinoblastoma-like 2 gene [RBL2], and retinoblastoma 1 gene [RB1]) had significantly improved PFS with alisertib/paclitaxel versus with placebo/paclitaxel (3.68 versus 1.80 months, respectively [HR = 0.395, 95% CI: 0.239-0.654, p = 0.0003]), and overall survival (7.20 versus 4.47 months, respectively [HR = 0.427, 95% CI: 0.259-0.704, p = 0.00085]). A subset of patients with c-Myc expression showed significantly improved PFS with alisertib/paclitaxel. The incidence of grade 3 or higher drug-related adverse events was 67% (58 patients) with alisertib/paclitaxel versus 22% (25 patients) with placebo/paclitaxel. Twelve patients (14%) versus 11 (12%) died on study, including four versus zero treatment-related deaths. CONCLUSIONS: Efficacy signals were seen with alisertib/paclitaxel in relapsed or refractory SCLC. c-Myc expression and mutations in cell cycle regulators may be potential predictive biomarkers of alisertib efficacy; further prospective validations are warranted.

Dabrafenib monotherapy in BRAF+ non-small cell lung cancer - our experience.

BACKGROUND: Activating BRAF mutations result in constitutive activation of the MAP kinase signaling cascade, stimulating cell proliferation. BRAF mutations are typical for malignant melanoma, but occur less frequently in other tumors, including in 1-2% cases of non-small cell lung cancer (NSCLC) [1,2]. CASE: We present two case reports of BRAF+ NSCLC patients, treated with 3rd line dabrafenib monotherapy on our department, and also brief review of available information about dabrafenib and its use in monotherapy of BRAF+ NSCLC. CONCLUSION: Monotherapy with BRAF inhibitors presents a viable alternative for BRAF+ NSCLC patients, incapable of combined therapy with trametinib. The lack of proper indication and reimbursement for NSCLC cases remains a problem, and individual treatment approval is required.

Non-small Cell Lung Cancer as a Chronic Disease - A Prospective Study from the Czech TULUNG Registry.

AIM: To compare survival outcomes in patients with non-small cell lung cancer (NSCLC) treated with modern-era drugs (antifolates, antiangiogenics, tyrosine kinase and anaplastic lymphoma kinase inhibitors, immunotherapy) with treatment initiation in 2011-12 and 2015-16, respectively. PATIENTS AND METHODS: Prospective data from Czech TULUNG Registry (960 patients from 2011-12 and 512 patients from 2015-16) were analyzed. Kaplan-Meier analysis was used to estimate overall survival (OS) and progression-free survival (PFS); Cox proportional hazards model to assess factors associated with 2-year survival. RESULTS: Survival at 2 years was more frequent in cohort 2015-16 compared to cohort 2011-12 (43.2% vs. 24% for adenocarcinoma; p<0.001 and 28.7% vs. 11.8% for squamous-cell lung carcinoma; p=0.002). Assignment to cohort 2015-16 and treatment multilinearity (two or more lines in sequence) were associated with higher probability of 2-year survival (hazard ratio=0.666 and hazard ratio=0.597; p<0.001). Comparison of 2-year survivors from both cohorts showed no differences. CONCLUSION: Survival at 2 years probability in stage IIIB-IV NSCLC doubled between 2011-12 and 2015-16; advanced-stage NSCLC may be considered a chronic disease in a large proportion of patients.

Neurogenic pulmonary oedema as a rare complication of epileptic seizures.

INTRODUCTION: Neurogenic pulmonary oedema (NPE) is avery rare complication of epileptic seizures, which could potentially increase mortality. MATERIAL AND METHODS: The case of a66-year-old male patient with NPE caused by repeated epileptic seizures is reported. Rapid resolution of pulmonary oedema is well documented by X-ray and computed tomography images. CONCLUSIONS: Neurogenic pulmonary oedema could potentially increase mortality, and thus, it is important to perform achest X-ray in all patients presenting with seizures and dyspnoea.

Helsinki by nature: The Nature Step to Respiratory Health.

BACKGROUND: The Nature Step to Respiratory Health was the overarching theme of the 12th General Meeting of the Global Alliance against Chronic Respiratory Diseases (GARD) in Helsinki, August 2018. New approaches are needed to improve respiratory health and reduce premature mortality of chronic diseases by 30% till 2030 (UN Sustainable Development Goals, SDGs). Planetary health is defined as the health of human civilization and the state of the natural systems on which it depends. Planetary health and human health are interconnected, and both need to be considered by individuals and governments while addressing several SDGs. RESULTS: The concept of the Nature Step has evolved from innovative research indicating, how changed lifestyle in urban surroundings reduces contact with biodiverse environments, impoverishes microbiota, affects immune regulation and increases risk of NCDs. The Nature Step calls for strengthening connections to nature. Physical activity in natural environments should be promoted, use of fresh vegetables, fruits and water increased, and consumption of sugary drinks, tobacco and alcohol restricted. Nature relatedness should be part of everyday life and especially emphasized in the care of children and the elderly. Taking "nature" to modern cities in a controlled way is possible but a challenge for urban planning, nature conservation, housing, traffic arrangements, energy production, and importantly for supplying and distributing food. Actions against the well-known respiratory risk factors, air pollution and smoking, should be taken simultaneously. CONCLUSIONS: In Finland and elsewhere in Europe, successful programmes have been implemented to reduce the burden of respiratory disorders and other NCDs. Unhealthy behaviour can be changed by well-coordinated actions involving all stakeholders. The growing public health concern caused by NCDs in urban surroundings cannot be solved by health care alone; a multidisciplinary approach is mandatory.

Comparison of lymphocyte immune phenotypes in bronchoalveolar lavage of non-smoking patients with sarcoidosis and other interstitial lung diseases.

BACKGROUND: Bronchoalveolar lavage (BAL) as complementary method is still used as ancillary tool in diagnosis of interstitial lung diseases. Tobacco smoking has been described to affect the BAL lavage cellular profile. To our knowledge, only few reports have so far investigated CD3+CD4+ and CD3+CD8+ lymphocyte subsets in non-smoking sarcoidosis patients additionally stratified according to CXR stage, and compared them to other non-smoking patients with interstitial lung diseases (ILDs). METHODS: We compared lymphocytes immune phenotypes, subsets, with CD3+, CD3+CD4+ and CD3+CD8+ cell markers, in the non-smoking subjects (n=297) including the patients with pulmonary sarcoidosis (S), idiopathic pulmonary fibrosis (IPF) (n=22), hypersensitivity pneumonitis (HP) (n=15), other interstitial idiopathic pneumonias (OIIPs) (n=39). According to prognosis, the patients with S were divided into four groups: 18 patients with Löfgren's syndrome (LS) in chest X-ray (CXR) ≤1 stage, 64 patients without LS in CXR ≤1 stage, 113 patients in CXR 2 stage and 26 patients with advanced CXR ≥3 stage. RESULTS: After the use of false discovery rate (FDR) correction, relative numbers (%) of CD3+, CD3+CD4+, CD3+CD8+ and CD3+CD4/CD3+CD8 ratio showed the most significant differences between the non-smokers with S (both with/without LS) and the non-smokers with other ILDs (IPF, OIIPs, HP). These lymphocytes subsets were further altered in the non-smokers with CXR stage 2 compared to the non-smokers with other ILDs (IPF, OIIPs, HP). We did not observe any differences in these lymphocyte subsets and CD3+CD4+/CD3+CD8+ ratio between the non-smokers with advanced sarcoidosis stage (CXR ≥3) and the non-smokers with IPF. CONCLUSIONS: Our data on the non-smokers confirmed the presence of the typical BAL cellular profile in sarcoidosis. The BAL cellular profile was helpful namely for differentiation of less advanced sarcoidosis. Its definite diagnostic utility should be the subject of further clinical studies with large numbers of the well characterized patients taking into consideration other clinical factors influencing BAL cellular profile, such as smoking or treatment.

Sphingosine kinase-1 predicts overall survival outcomes in non-small cell lung cancer patients treated with carboplatin and navelbine.

Sphingosine 1-phosphate (S1P) is a bioactive lipid metabolite associated with cancer cell proliferation, survival, migration and regulation of tumor angiogenesis in various cellular and animal models. Sphingosine kinase-1 (SphK1) and S1P lyase are the main enzymes that respectively control the synthesis and degradation of S1P. The present study analyzed the prognostic and predictive value of SphK1 and S1P lyase expression in patients with non-small cell lung cancer (NSCLC), treated with either surgery alone or in combination with adjuvant carboplatin and navelbine. Formalin-fixed, paraffin-embedded tissue samples from 176 patients with NSCLC were stained immunohistochemically using antibodies against SphK1 and S1P lyase, and their expression was correlated with all available clinicopathological factors. Increased expression of SphK1 was significantly associated with shorter overall and disease free survival in patients treated with adjuvant platinum-based chemotherapy. No prognostic relevance for S1P lyase expression was observed. Collectively, the results suggest that the immunohistochemical detection of SphK1 may be a promising predictive marker in NSCLC patients treated with adjuvant platinum-based chemotherapy.

Limited ambulatory night sleep testing in patients with a suspicion of sleep apnoea syndrome: Is its indication tenable?

INTRODUCTION: Ambulatory sleep testing is nowadays an available diagnostic method, measuring air flow and blood oxygen saturation in patients with a suspicion of obstructive sleep apnoea syndrome (OSAS). It can be performed by either a general practitioner or an ambulatory specialist in various fields. Using this simple screening method it is possible to exclude subjects without OSAS, who therefore do not require further sleep testing at a sleep laboratory. There is no published data regarding the use of ambulatory sleep testing by sleep laboratories in the Czech Republic. The aim of this study was to evaluate the proportion of patients examined by ambulatory sleep testing and to determine the factors influencing its indication. MATERIAL AND METHODS: The study involved 497 patients (363 males) with an average age of 55.5 ± 12.3 years. These patients were tested by the sleep laboratory at University Hospital Olomouc with a suspicion of OSAS. The clinical complaints of the patients were evaluated (e.g. excessive daytime sleepiness, microsleeps, etc.) along with a basic examination, including anthropometric parameter measurements, on admission to the ward. Whilst admitted, night sleep testing using respiratory polygraphy or videopolysomnography was performed in all patients. Furthermore, the number of patients that underwent ambulatory sleep testing prior to admission to the sleep laboratory and the number of patients with an indication for positive airway pressure therapy (PAP) (apnoea-hypopnea index > 15) was assessed. The results were processed using the software IBM SPSS Statistics v22. RESULTS: Ambulatory sleep testing was performed in only 96 patients (19.3 %). Among these patients, 76 (79.0 %) were diagnosed with OSAS with an indication for PAP. In the 401 patients who did not undergo ambulatory sleep tests, 227 (53.9 %) were diagnosed with OSAS with an indication for PAP. Patients who underwent ambulatory sleep tests and those who did not differed only in age (p = 0.03). There were no significant differences in other parameters (sex, height, weight, BMI, circumference of neck, waist and hips, ESS), including sleepiness (p = 0.605) and microsleeps (p = 0.74). CONCLUSION: Ambulatory sleep testing is performed in only a small proportion of patients. Its use can reduce healthcare costs as well as waiting times for sleep laboratory tests.

Tumor autophagy is associated with survival outcomes in patients with resected non-small cell lung cancer.

OBJECTIVES: LC3A protein is associated with autophagosomes, and LC3A immunohistochemistry (IHC) is used for the detection of autophagy activity. The aim of this study was to assess the prognostic value of LC3A expression in patients with resected non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: We used tissue microarrays (TMAs) constructed from 116 resected stage IB-III NSCLC patients. Standard immunohistochemistry was performed on formalin-fixed paraffin-embedded tissue sections using antibody against LC3A autophagic potein. Stained slides were scanned by Olympus dotSlide Digital Virtual Microscopy System (Japan) and the LC3A staining was evaluated digitally. Groups were compared using the Mann Whitney U test, and correlations were assessed using Spearman's rank test. Survival was calculated using Kaplan-Meier analysis. Primary study endpoint was overall survival (OS), secondardy study endpoint disease-free survival (DFS). Cut-off optimization for LC3A prognostic value was performed using the "cut-off finder' 'software (Charite, Berlin, Germany). In addition, the Kaplan Meier plotter (KmPlot) was used to assess the relationship between LC3A mRNA expression and clinical outcome (OS and DFS) in patients with NSCLC. RESULTS: From 116 patients, 88 tissue samples were available for final examination. No significant association was found between LC3A staining and other clinicopathological variables, including tumor grade, stage and histological subtype. A higher number of LC3A stone-like structures (SLSs) (>20), was significanly associated with poor OS (HR = 2.27, p = 0.011) and DFS (HR = 2.27, p = 0.003). A significant association between high LC3A mRNA and both a worse OS and worse DFS was found by KMPlot analysis in patients with stage I-III NSCLC. CONSLUSION: This retrospective study suggests that SLSs as assessed by LC3A IHC as well as LC3A mRNA expression has a clinically relevant negative prognostic value in patients with resected NSCLC, and should be further investigated.

Effect of pirfenidone on lung function decline and survival: 5-yr experience from a real-life IPF cohort from the Czech EMPIRE registry.

INTRODUCTION: Pirfenidone, an antifibrotic drug, slows-down the disease progression in idiopathic pulmonary fibrosis (IPF) over 12 months, however limited data on the decline of lung function and overall survival (OS) in real-world cohorts on longer follow-up exists. PATIENTS/METHODS: Of the enrolled Czech IPF patients (n = 841) from an EMPIRE registry, 383 (45.5%) received pirfenidone, 218 (25.9%) no-antifibrotic treatment and 240 (28.5%) were excluded (missing data, nintedanib treatment). The 2- and 5-yrs OS and forced vital capacity (FVC) and diffusing lung capacity for carbon monoxide (DLCO) were investigated at treatment initiation and 6, 12, 18 and 24 months' follow-up. RESULTS: During a 2-yr follow-up, less than a quarter of the patients progressed on pirfenidone as assessed by the decline of ≥10% FVC (17.0%) and ≥ 15% DLCO (14.3%). On pirfenidone, the DLCO (≥10%) declines at 6, 12, 18 and 24 months' and DLCO (≥15%) declines at 6, 18 and 24 months' follow-up were associated with increased mortality. The DLCO decline showed higher predictive value for mortality than FVC decline. In patients with no-antifibrotics, FVC and DLCO declines were not predictive for mortality. Pirfenidone increased 5-yrs OS over no-antifibrotic treatment (55.9% vs 31.5% alive, P = 0.002). CONCLUSION: Our study observed the 2-yrs sustained effect of pirfenidone on the decline of lung function and survival in the real-world patient's IPF cohort. DLCO decline of ≥10% shows a potential as a mortality predictor in IPF patients on pirfenidone, and should be routinely evaluated during follow-up examinations.

Epicardial fat in patients with chronic obstructive pulmonary disease as a marker of high cardiovascular risk - review.

Chronic obstructive pulmonary disease (COPD) and cardiovascular diseases (CVD) are commonly interconnected, and this coincidence negatively influences patients' mortality and morbidity. On the basis of the current available data originating mainly from cardiovascular studies epicardial fat (EF) has been proposed as a marker of cardiovascular risk. This review is focused on a potential role of epicardial fat as a new biomarker for risk stratification of COPD patients. Epicardial fat may present an important link between chronic obstructive pulmonary disease and cardiovascular diseases, mainly coronary artery disease.

Chronic Inflammation as a Potential Predictive Factor of Nivolumab Therapy in Non-small Cell Lung Cancer.

AIM: To investigate potential associations between clinical and standard peripheral blood biomarkers and clinical outcome in patients with non-small cell lung cancer (NSCLC) treated with nivolumab. PATIENTS AND METHODS: A total of 120 patients with advanced NSCLC treated at seven comprehensive cancer care centers were analyzed in this national retrospective study. Survival statistics were evaluated using the Kaplan-Meier method and Cox analysis. RESULTS: Among clinical parameters, histology was significantly associated with progression-free survival. Univariate Cox-proportional hazards model indicated prognostic and predictive role of a panel of laboratory parameters reflecting chronic inflammatory pattern (elevated neutrophil count, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, C-reactive protein and decrease in hemoglobin and albumin). Higher serum calcium concentration was also associated with nivolumab treatment effect. CONCLUSION: Tumor histology was the only clinical parameter predicting the outcome of nivolumab treatment. Among the laboratory parameters, our analysis identified a laboratory panel reflecting chronic inflammation as a potential predictive marker of nivolumab treatment.

Expression analysis of extracellular microRNA in bronchoalveolar lavage fluid from patients with pulmonary sarcoidosis.

BACKGROUND AND OBJECTIVE: MicroRNA (miRNA) are transcriptional regulators implicated in pulmonary sarcoidosis and packaged in extracellular vesicles (EV) during cellular communication. We characterized EV and investigated miRNA expression in bronchoalveolar lavage (BAL) fluid from sarcoidosis patients. METHODS: EV were characterized for size(s) using dynamic light scattering and transmission electron microscopy (TEM) analysis and protein markers by immunoblotting. Twelve extracellular and 5 cellular miRNA were investigated in BAL from 16 chest X-ray stage-I (CXR-I) and 17 CXR stage-II (CXR-II) sarcoidosis patients. Associations between miRNA and disease characteristics (extrapulmonary involvement, pulmonary function and BAL cell profile) were statistically analysed. RESULTS: BAL from sarcoidosis patients contained exosomes and microvesicles (MV) as EV. In these EV, expression of miR-146a (P = 0.007), miR-150 (P = 0.003) and BAL cellular miR-21 (P = 0.01) was increased in CXR-II compared with CXR-I. Other detected EV (miR-21 and miR-26a) and cellular (miR-31, miR-129-3p, miR-146a and miR-452) miRNA were not differentially expressed. The investigated miRNA did not reflect extrapulmonary involvement, but EV miR-146a and miR-150 were negatively correlated with pulmonary function (miR-146a with vital capacity (VC; Spearman's correlation coefficient (rs ), P = -0.657, 0.007), percent predicted forced expiratory volume in 1 s (FEV1 ; -0.662, 0.006) and FEV1 /forced vital capacity (FVC) ratio (-0.649, 0.008); miR-150 correlated negatively with VC (-0.584, 0.019) and FEV1 /FVC ratio (-0.746, 0.001) in CXR-II cases). CONCLUSION: Our data provide evidence that exosomes and microvesicles as extracellular vesicles are present in the bronchoalveolar space of sarcoidosis patients and they differentially express EV miRNA (miR-146a and miR-150), the expression of which correlates negatively with pulmonary function indices. The significance of these findings for disease pathophysiology and clinical course require further investigation.