Comprehensive molecular and clinical insights into non-small cell lung cancer transformation to small cell lung cancer with an illustrative case report.

Histologic transformation to small cell lung cancer (tSCLC) is a rare but increasingly recognised mechanism of acquired resistance to tyrosine kinase inhibitors (TKI) in patients with epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC). Beyond its acknowledged role in TKI resistance, histologic transformation to SCLC might be an important, yet under-recognised, mechanism of resistance in NSCLC treated with immunotherapy. Our review identified 32 studies that investigated tSCLC development in patients with EGFR-mutated NSCLC treated with TKI therapy and 16 case reports of patients treated with immunotherapy. It revealed the rarity of tSCLC, with a predominance of EGFR exon 19 mutations and limited therapeutic options and outcomes. Across all analysed studies in EGFR-mutated NSCLC treated with TKI therapy, the median time to tSCLC development was ∼17 months, with a median overall survival of 10 months. Histologic transformation of EGFR-mutated NSCLC to SCLC is a rare, but challenging clinical problem with a poor prognosis. A small number of documented cases of tSCLC after immunotherapy highlight the need for rebiopsies at progression to diagnose this potential resistance mechanism. Further research is needed to better understand the mechanisms underlying this phenomenon and to develop more effective treatment strategies for patients with tSCLC.

High burden of clonal mast cell disorders and hereditary α-tryptasemia in patients who need Hymenoptera venom immunotherapy.

BACKGROUND: In patients who require venom immunotherapy (VIT), there is a need to identify underlying mast cell (MC) disorders since these may affect the risk and severity of future sting reactions and the long-term effectiveness of VIT. METHODS: 1319 individuals with Hymenoptera venom allergy (HVA) who needed VIT from referral centers in Slovenia, Austria, Croatia, and Poland underwent examination for KIT p.D816V in peripheral blood leukocytes (PBL) using a highly sensitive PCR test and tryptase genotyping by digital droplet PCR. We also included 183 control individuals with large local reactions (LLRs) to Hymenoptera stings and with asymptomatic sensitization to Hymenoptera venoms. RESULTS: 285 of 1319 individuals recommended for VIT (21.6%) were positive for KIT p.D816V in PBL, preferably those who present with severe reaction (33.9% [n = 207 of 610] with Ring-Messmer grade 3-4 vs. 11% [n = 78 of 709] with Grade 1-2; p < .0001), whereas only 1.3% (n = 2 of 152) of controls with LLR and none with asymptomatic sensitization (n = 31) had KIT p.D816V. KIT p.D816V allelic burden was higher in those with severe reaction (median 0.018% [n = 207] in Grade 3-4 vs. 0.001% [n = 78] in Grade 1-2; p < .0001), and the majority had normal baseline serum tryptase levels (69% [n = 196 of 285]). All KIT p.D816V-positive individuals (n = 41) who underwent bone marrow (BM) biopsy were found to have underlying clonal diseases, principally BM mastocytosis. HαT was also associated with severe HVA and symptoms (p < .01), and remarkably, 31.0% (n = 31 of 100) were found to have concomitant KIT p.D816V. Concomitant HαT and KIT p.D816V showed an additive effect, and having both was associated with the highest risk for severe HVA, even higher than having either HαT or KIT p.D816V alone (OR = 3.8; p < .01). CONCLUSIONS: By employing prospective universal tryptase genotyping and examination for KIT p.D816V in PBL in large HVA populations, we have demonstrated a high burden of clonal MC disorders and HαT in patients who require VIT.

Transcriptomic Profiling for Prognostic Biomarkers in Early-Stage Squamous Cell Lung Cancer (SqCLC).

Squamous cell lung carcinoma (SqCLC) is associated with high mortality and limited treatment options. Identification of therapeutic targets and prognostic biomarkers is still lacking. This research aims to analyze the transcriptomic profile of SqCLC samples and identify the key genes associated with tumorigenesis, overall survival (OS), and a profile of the tumor-infiltrating immune cells. Differential gene expression analysis, pathway enrichment analysis, and Gene Ontology analysis on RNA-seq data obtained from FFPE tumor samples (N = 23) and healthy tissues (N = 3) were performed (experimental cohort). Validation of the results was conducted on publicly available gene expression data using TCGA LUSC (N = 225) and GTEx healthy donors' cohorts (N = 288). We identified 1133 upregulated and 644 downregulated genes, common for both cohorts. The most prominent upregulated genes were involved in cell cycle and proliferation regulation pathways (MAGEA9B, MAGED4, KRT, MMT11/13), while downregulated genes predominately belonged to immune-related pathways (DEFA1B, DEFA1, DEFA3). Results of the survival analysis, conducted on the validation cohort and commonly deregulated genes, indicated that overexpression of HOXC4 (p < 0.001), LLGL1 (p = 0.0015), and SLC4A3 (p = 0.0034) is associated with worse OS in early-stage SqCLC patients. In contrast, overexpression of GSTZ1 (p = 0.0029) and LILRA5 (p = 0.0086) was protective, i.e., associated with better OS. By applying a single-sample gene-set enrichment analysis (ssGSEA), we identified four distinct immune subtypes. Immune cell distribution suggests that the memory T cells (central and effector) and follicular helper T cells could serve as important stratification parameters.

Body composition, pulmonary function tests, exercise capacity, and quality of life in chronic obstructive pulmonary disease patients with obesity.

PURPOSE OF THE STUDY: Larger proportions of chronic obstructive pulmonary disease (COPD) patients are currently overweight or with obesity than underweight, and the combination of COPD and obesity is increasing. The purpose of this study was to investigate differences in the body composition, pulmonary function tests, exercise capacity, and health-related quality of life among normal weight, overweight, and obese patients with COPD. STUDY DESIGN: A total of 514 patients with COPD were included in the study. According to the World Health Organization criteria for body mass index, the patients were classified as normal weight, overweight, and obese. Evaluations included fat-free mass, fat-free mass index, phase angle, pulmonary function tests, and 6-minute walk test. Dyspnea was assessed using the modified Medical Research Council dyspnea scale, and the health-related quality of life was evaluated using COPD Assessment Test and St. George's Respiratory Questionnaire. Values were compared among the three groups. RESULTS: There were 315 male and 199 female patients, with a mean age of 66.7 ± 8.4 years. Fat-free mass, fat-free mass index, and phase angle values were significantly higher in COPD patients with obesity than in other patients (P < .001, P < .001, P < .001). Forced expiratory volume in 1 s, forced expiratory volume in 1 s/forced vital capacity, and diffusing capacity of lung for carbon monoxide value in pulmonary function tests were significantly higher in COPD patients with obesity than in other patients (P = .046, P < .001, P < .001), while the forced vital capacity values were similar in all groups. Exercise capacity (6-min walk test distance), dyspnea symptoms (modified Medical Research Council scale), and health-related quality of life (COPD Assessment Test and St. George's Respiratory Questionnaire) did not differ significantly between groups. CONCLUSIONS: According to our study, obesity has no negative effect on pulmonary function tests, dyspnea perception, exercise capacity, and health-related quality of life.

Nintedanib treatment for bleomycin-induced lung injury - First report.

Although the antineoplastic agent bleomycin is known for more than 50 years, its exact pharmacological and side-effect mechanisms remain incompletely understood. The major limitation of bleomycin therapy is the risk of pulmonary toxicity which can be diverse, and potentially fatal in 10% of patients. The optimal treatment for bleomycin lung toxicity has not been established and no clinical trials have been performed. Here we present first successful case report of nintedanib therapy in a patient with bleomycin-induced lung injury (BILI). The prevention, early diagnosis, and management of bleomycin pulmonary toxicities are essential, clinical trials are needed in this area.

Efficacy and safety of nintedanib and docetaxel in patients with previously treated lung non-squamous non-small cell lung cancer: a multicenter retrospective real-world analysis.

BACKGROUND: The standard first-line systemic treatment for patients with non-oncogene addicted advanced nonsquamous non-small cell lung cancer (NSCLC) is immunotherapy with immune checkpoint inhibitors (ICI) and/or chemotherapy (ChT). Therapy after failing ICI +/- ChT remains an open question, and docetaxel plus nintedanib represent a valid second line option. PATIENTS AND METHODS: A multicenter retrospective trial of real-life treatment patterns and outcomes of patients with advanced lung adenocarcinoma treated with docetaxel plus nintedanib after the failure of ICI and/or ChT was performed. Patients from 2 Slovenian and 1 Croatian oncological center treated between June 2014 and August 2022 were enrolled. We assessed objective response (ORR), disease control rate (DCR), median progression free survival (PFS), median overall survival (OS), and safety profile of treatment. RESULTS: There were 96 patients included in the analysis, with ORR of 18.8%, DCR of 57.3%, median PFS of 3.0 months (95% CI: 3.0-5.0 months), and a median OS of 8.0 months (95% CI: 7.0-10.0 months). The majority of patients (n = 47,49%) received docetaxel plus nintedanib as third-line therapy. The ORR for this subset of patients was 19.1%, with a DCR of 57.4%. The highest response rate was observed in patients who received second-line docetaxel plus nintedanib after first-line combination of ChT-ICI therapy (n = 24), with an ORR of 29.2% and DCR of 66.7% and median PFS of 4.0 months (95% CI: 3.0-8.0 months). Fifty-three patients (55.2%) experienced adverse events (AEs), most frequently gastrointestinal; diarrhea (n = 29, 30.2%), and increased liver enzyme levels (n = 17, 17.7%). CONCLUSIONS: The combination of docetaxel and nintedanib can be considered an effective therapy option with an acceptable toxicity profile for patients with advanced NSCLC after the failure of ICI +/- ChT.

Differences in nutritional status of patients with chronic obstructive pulmonary disease between Mediterranean and non-Mediterranean regions in Croatia.

The nutritional status of patients with chronic obstructive pulmonary disease (COPD) is a significant factor that influences the prognosis of the disease. This observational study aimed to analyse the nutritional status of COPD patients and assess the associations between nutritional status, disease severity, and exercise capacity in four different regions of Croatia. In this multicentre study, 534 COPD patients were recruited and evaluated concerning fat-free mass (FFM), fat-free mass index (FFMI), skeletal muscle mass index (SMMI), phase angle (PhA), pulmonary function tests, and the 6-minute walk test (6MWT). There were 325 (60.9%) male and 209 (39.1%) female patients with a mean age of 66.7±8.4 years. Most patients (73.2%) exhibited a moderate to severely abnormal obstructive pattern and had a reduced 6MWT distance (396.5±110.8 m). Among the participants, 32.8% were overweight and 22.3% were obese, and they had satisfactory values for nutritional status variables (FFM, FFMI, SMMI, PhA). There were no statistical differences between the centres in terms of nutritional status variables. There was a significantly positive correlation of FEV1 with BMI (r=0.148, p=0.001), PhA (r=0.256, p=0.00), FFM (r=0.365, p=0.00), and SMMI (r=0.238, p=0.00). However, there was no significant correlation of the 6MWT with BMI (r=-0.049, p=0.254), FFM (r=0.065, p=0.133), and SMMI (r=-0.007, p=0.867). The data analysis demonstrated that our patients were not underweight and that there was no significant difference between the centres in terms of BMI, FFM, FFMI, SMMI, and PhA. This lack of significant difference was observed even though one of the regions studied was Mediterranean.

Small Cell Lung Carcinoma: Current Diagnosis, Biomarkers, and Treatment Options with Future Perspectives.

Small cell lung cancer (SCLC) is an aggressive malignancy characterized by rapid proliferation, early dissemination, acquired therapy resistance, and poor prognosis. Early diagnosis of SCLC is crucial since most patients present with advanced/metastatic disease, limiting the potential for curative treatment. While SCLC exhibits initial responsiveness to chemotherapy and radiotherapy, treatment resistance commonly emerges, leading to a five-year overall survival rate of up to 10%. New effective biomarkers, early detection, and advancements in therapeutic strategies are crucial for improving survival rates and reducing the impact of this devastating disease. This review aims to comprehensively summarize current knowledge on diagnostic options, well-known and emerging biomarkers, and SCLC treatment strategies and discuss future perspectives on this aggressive malignancy.

The Challenges and Opportunities of the Implementation of Comprehensive Genomic Profiling in Everyday Clinical Practice with Non-Small Cell Lung Cancer: National Results from Croatia.

Non-small cell lung cancer (NSCLC) has become the best example of precision oncology's impact on outcomes in everyday clinical practice, significantly changing the expectations of all stakeholders, including medical professionals, society, and most importantly, patients. Consequently, the implementation of the precision oncology concept in medical systems, in order to achieve optimal and proven curative effects in NSCLC, is imperative. In this study, we investigated the development, challenges, and results associated with the implementation of precision oncology in NSCLC on a national level in Croatia. We conducted a multicenter, retrospective, cross-sectional analysis on the total population of Croatian patients with metastatic lung cancer, on whose tumors specimen comprehensive genomic profiling (CGP) testing was performed during 2020 and 2021. A total of 48 patients were included in the study. CGP revealed clinically relevant genomic alterations (CRGA) in 37 patients (79%), with a median of 2 (IQR 1-3) CRGA per patient. From the panel of recommended tests, KRAS, MET, and EGFR were the most common alterations, detected in 16 (34%), 5 (11%), and 3 (6%) patients, respectively. CGP revealed additional targetable mutations in 29 (60%) patients who would not have been tested (and consequently, whose mutations would not have been detected) according to the existing everyday standard of practice in Croatia. The tumor mutational burden was reported as high (≥10 Muts/Mb) in 19 patients (40%). CGP analysis reported some kind of targeted therapy for 34 patients (72%). CGP revealed other potentially targetable mutations, and it also determined TMB to be high in a significant number of patients. In conclusion, when possible, CGP should be used as an upfront backbone diagnostic and treatment-oriented work-up in patients with NSCLC.

Germline variants of the genes involved in NF-kB activation are associated with the risk of COPD and lung cancer development.

Chronic obstructive pulmonary disease (COPD) and lung cancer (LC) are closely related diseases associated with smoking history and dysregulated immune response. However, not all smokers develop the disease, indicating that genetic susceptibility could be important. Therefore, the aim of this study was to search for the potential overlapping genetic biomarkers, with a focus on single nucleotide polymorphisms (SNPs) located in the regulatory regions of immune-related genes. Additionally, the aim was to see if an identified SNP has potentially an effect on proinflamma-tory cytokine concentration in the serum of COPD patients. We extracted summary data of variants in 1511 immune-related genes from COPD and LC genome-wide association studies (GWAS) from the UK Biobank. The LC data had 203 cases, patients diagnosed with LC, and 360 938 controls, while COPD data had 1 897 cases and 359 297 controls. Assuming 1 association/gene, SNPs with a p-value < 3.3 × 10-5 were considered statistically significantly associated with the disease. We identified seven SNPs located in different genes (BAG6, BTNL2, TNF, HCP5, MICB, NCR3, ABCF1, TCF7L1) to be associated with the COPD risk and two with the LC risk (HLA-C, HLA-B), with statistical significance. We also identified two SNPs located in the IL2RA gene associated with LC (rs2386841; p = 1.86 × 10-4) and COPD (rs11256442; p = 9.79 × 10-3) but with lower significance. Functional studies conducted on COPD patients showed that RNA expression of IL2RA, IFNγ and related proinflammatory cytokines in blood serum did not correlate with a specific genotype. Although results presented in this study do not fully support our hypothesis, it is worth to mention that the identified genes/SNPs that were associated with either COPD or LC risk, all were involved in the activation of the NF-κB transcription factor which is closely related to the regulation of the inflammatory response, a condition associated with both pathologies.

Platelet Serotonin (5-HT) Concentration, Platelet Monoamine Oxidase B (MAO-B) Activity and HTR2A, HTR2C, and MAOB Gene Polymorphisms in Asthma.

The complex role of the serotonin system in respiratory function and inflammatory diseases such as asthma is unclear. Our study investigated platelet serotonin (5-HT) levels and platelet monoamine oxidase B (MAO-B) activity, as well as associations with HTR2A (rs6314; rs6313), HTR2C (rs3813929; rs518147), and MAOB (rs1799836; rs6651806) gene polymorphisms in 120 healthy individuals and 120 asthma patients of different severity and phenotypes. Platelet 5-HT concentration was significantly lower, while platelet MAO-B activity was considerably higher in asthma patients; however, they did not differ between patients with different asthma severity or phenotypes. Only the healthy subjects, but not the asthma patients, carrying the MAOB rs1799836 TT genotype had significantly lower platelet MAO-B activity than the C allele carriers. No significant differences in the frequency of the genotypes, alleles, or haplotypes for any of the investigated HTR2A, HTR2C and MAOB gene polymorphisms have been observed between asthma patients and healthy subjects or between patients with various asthma phenotypes. However, the carriers of the HTR2C rs518147 CC genotype or C allele were significantly less frequent in severe asthma patients than in the G allele carriers. Further studies are necessary to elucidate the involvement of the serotonergic system in asthma pathophysiology.

Important steps towards a big change for lung health: a joint approach by the European Respiratory Society, the European Society of Radiology and their partners to facilitate implementation of the European Union's new recommendations on lung cancer screening.

Enormous progress has been made on the epic journey towards implementation of lung cancer screening in Europe. A breakthrough for lung health has been achieved with the EU proposal for a Council recommendation on cancer screening. https://bit.ly/3J4O0Jb.

Tracheal complications of mechanical ventilation for COVID-19: a plot twist for survivors.

Tracheal complications should be suspected in mechanically ventilated COVID-19 survivors with respiratory symptoms. Treatment requires a multimodal approach of interventional bronchoscopy and surgery with tight follow-up due to a high rate of restenosis. https://bit.ly/3iw05xQ.

Tranexamic Acid vs Adrenaline for Controlling Iatrogenic Bleeding During Flexible Bronchoscopy: A Double-Blind Randomized Controlled Trial.

BACKGROUND: The most commonly used topical hemostatic agents during flexible bronchoscopy (FB) are cold saline and adrenaline. Data on use of other agents such as tranexamic acid (TXA) for this purpose are limited. RESEARCH QUESTION: Is TXA effective and safe in controlling iatrogenic bleeding during FB compared with adrenaline? STUDY DESIGN AND METHODS: We conducted a cluster-randomized, double-blind, single-center trial in a tertiary teaching hospital. Patients were randomized in weekly clusters to receive up to three applications of TXA (100 mg, 2 mL) or adrenaline (0.2 mg, 2 mL, 1:10000) after hemostasis failure after three applications of cold saline (4 ° C, 5 mL). Crossover was allowed (for up to three further applications) before proceeding with other interventions. Bleeding severity was graded by the bronchoscopist using a visual analog scale (VAS; 1 = very mild, 10 = severe). RESULTS: A total of 2,033 FBs were performed and 130 patients were randomized successfully to adrenaline (n = 65) or TXA (n = 65), whereas 12 patients had to be excluded for protocol violations (two patients from the adrenaline arm and 10 patients from TXA arm). Bleeding was stopped in 83.1% of patients (54/65) in both groups (P = 1). The severity of bleeding and number of applications needed for bleeding control were similar in both groups (adrenaline: mean VAS score, 4.9 ± 1.3 [n = 1.8 ± 0.8]; TXA: mean VAS score, 5.3 ± 1.4 [n = 1.8 ± 0.8]). Both adrenaline and TXA were more successful in controlling moderate bleeding (86.7% and 88.7%, respectively) than severe bleeding (40% and 58.3%, respectively; P = .008 and P = .012, respectively) and required more applications for severe bleeding (3.0 ± 0 and 2.4 ± 0.5, respectively) than moderate bleeding (1.7 ± 0.8 and 1.7 ± 0.8, respectively) control (P = .006 and P = .002, respectively). We observed no drug-related adverse events in either group. INTERPRETATION: We found no significant difference between adrenaline and TXA for controlling noncatastrophic iatrogenic endobronchial bleeding after cold saline failure, adding to the body of evidence that TXA can be used safely and effectively during FB. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT04771923; URL: www. CLINICALTRIALS: gov.

Delphi-Based Consensus on Interstitial Lung Disease Screening in Patients with Connective Tissue Diseases (Croatian National-Based Study).

The aim of this study was to develop a Croatian Delphi-based expert consensus for screening interstitial lung disease (ILD) associated with connective tissue disease (CTD). A systematic literature review was conducted on risk factors for the development of ILD, prevalence and incidence of ILD, diagnostic and screening methods for ILD, and prognosis of ILD in idiopathic inflammatory myopathy (IIM), mixed connective tissue disease (MCTD), primary Sjögren's syndrome (pSS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc) were performed. Based on the evidence found, experts developed questionnaires for screening and monitoring ILD in each CTD, which were provided via an online survey. Following the electronic survey, two screening algorithms were developed based on the consensus opinions. The detection strategy for ILD included high-resolution computed tomography (HRCT) in addition to pulmonary function testing for IIM, MCTD, and SSc. and pulmonary function testing for newly diagnosed pSS, RA and SLE. However, in patients with identified risk factors for ILD HRCT, these tests should also be performed. A screening strategy for early identification of patients with various CTD-ILD was first developed by a multidisciplinary team of rheumatologists, pulmonologists, and radiologists to identify early CTD patients at risk of ILD, a severe extra-articular manifestation of CTD.

The Interplay of Lung Cancer, COVID-19, and Vaccines.

Patients with cancer are more susceptible to a higher risk of coronavirus infection and its severe complications than the general population. In addition, these patients were not included in the pivotal clinical trials for COVID-19 vaccines. Therefore, considerable uncertainty remains regarding the management of cancer patients during the COVID-19 pandemic and the safety of COVID-19 vaccinations in cancer patients. In this review, we summarize the current knowledge generated from the beginning of the COVID-19 pandemic on the vulnerability of cancer patients to the coronavirus disease, as well as the effectiveness of COVID-19 vaccines in this population. We also discuss the available data on the effects of anticancer treatment with immune checkpoint inhibitors on the immune responses to SARS-CoV-2 in cancer patients. Special attention in this review will be given to patients with lung cancer, as such patients are at an increased risk for severe effects from COVID-19.

Significance of the Lung Immune Prognostic Index for Assessment of the Reliability of the Clinical Treatment Outcome for Advanced Non-Small-Cell Lung Cancer in Patients with COVID-19 Infection.

Introduction: Lung cancer is one of the most diagnosed malignancies with increasing incidence worldwide. Immunotherapy is the main oncological treatment for advanced non-small cell lung cancer (NSCLC), for which the discovery of new efficient biomarkers is crucial. Scientific evidence points to the importance of the Lung Immune Prognostic Index (LIPI), but its predictive significance is unclear. Aim: The aim of this study was to investigate the clinical significance and predictive role of LIPI in patients with advanced NSCLC and PD-L1 mutation who are eligible for immunotherapy in combination with chemotherapy. In addition, to our knowledge, this is the first time that the association between COVID-19 infection and the course and outcome of oncologic treatment of NSCLC has been investigated. Patients and Methods: Patients were divided into four study groups according to strictly defined clinical parameters, therapeutic approach, and COVID-19 infection. LIPI was determined and its predictive power was evaluated in all studied groups, as well as overall survival (OS), progression-free survival (PFS), and disease control rate (DCR). Results: This study confirmed the understudied and uncertain predictive power and clinical relevance of LIPI as a biomarker in patients with advanced NSCLC. Patients infected with COVID-19 had a higher survival rate than uninfected patients despite the therapeutic approach, which may be attributed to their hospitalization and intensive medical management during the pandemic. Conclusions: Findings obtained in this study may help to determine treatment options according to the clinical condition of the patient by using LIPI values as a non-invasive, readily available and economically acceptable predictive biomarker in lung oncology.

TLR5 Variants Are Associated with the Risk for COPD and NSCLC Development, Better Overall Survival of the NSCLC Patients and Increased Chemosensitivity in the H1299 Cell Line.

Chronic obstructive pulmonary disease (COPD) is considered as the strongest independent risk factor for lung cancer (LC) development, suggesting an overlapping genetic background in both diseases. A common feature of both diseases is aberrant immunity in respiratory epithelia that is mainly regulated by Toll-like receptors (TLRs), key regulators of innate immunity. The function of the flagellin-sensing TLR5 in airway epithelia and pathophysiology of COPD and LC has remained elusive. We performed case−control genetic association and functional studies on the importance of TLR5 in COPD and LC development, comparing Caucasian COPD/LC patients (n = 974) and healthy donors (n = 1283). Association analysis of three single nucleotide polymorphisms (SNPs) (rs725084, rs2072493_N592S, and rs5744174_F616L) indicated the minor allele of rs2072493_N592S to be associated with increased risk for COPD (OR = 4.41, p < 0.0001) and NSCLC (OR = 5.17, p < 0.0001) development and non-small cell LC risk in the presence of COPD (OR = 1.75, p = 0.0031). The presence of minor alleles (rs5744174 and rs725084) in a co-dominant model was associated with overall survival in squamous cell LC patients. Functional analysis indicated that overexpression of the rs2072493_N592S allele affected the activation of NF-κB and AP-1, which could be attributed to impaired phosphorylation of p38 and ERK. Overexpression of TLR5N592S was associated with increased chemosensitivity in the H1299 cell line. Finally, genome-wide transcriptomic analysis on WI-38 and H1299 cells overexpressing TLR5WT or TLR5N592S, respectively, indicated the existence of different transcription profiles affecting several cellular pathways potentially associated with a dysregulated immune response. Our results suggest that TLR5 could be recognized as a potential biomarker for COPD and LC development with functional relevance.

Expression of phosphorylated ribosomal protein S6 in mesothelioma patients - correlation with clinico-pathological characteristics and outcome: results from the European Thoracic Oncology Platform (ETOP) Mesoscape project.

Pleural mesothelioma (PM) is an aggressive malignancy with poor prognosis. Although histology and pathologic stage are important prognostic factors, better prognostic biomarkers are needed. The ribosomal protein S6 is a downstream target of the phosphatidylinositol 3-kinase (PI3K) pathway involved in protein synthesis and cell proliferation. In previous studies, low phosphorylated S6 (pS6) immunoreactivity was significantly correlated with longer progression-free survival (PFS) and overall survival (OS) in PM patients. We aimed to correlate pS6 expression to clinical data in a large multi-centre PM cohort as part of the European Thoracic Oncology Platform (ETOP) Mesoscape project. Tissue Micro Arrays (TMAs) of PM were constructed and expression of pS6 was evaluated by a semi-quantitatively aggregate H-score. Expression results were correlated to patient characteristics as well as OS/PFS. pS6 IHC results of 364 patients from 9 centres, diagnosed between 1999 and 2017 were available. The primary histology of included tumours was epithelioid (70.3%), followed by biphasic (24.2%) and sarcomatoid (5.5%). TMAs included both treatment-naïve and tumour tissue taken after induction chemotherapy. High pS6 expression (181 patients with H-score>1.41) was significantly associated with less complete resection. In the overall cohort, OS/PFS were not significantly different between pS6-low and pS6-high patients. In a subgroup analysis non-epithelioid (biphasic and sarcomatoid) patients with high pS6 expression showed a significantly shorter OS (p < 0.001, 10.7 versus 16.9 months) and PFS (p < 0.001, 6.2 versus 10.8 months). In subgroup analysis, in non-epithelioid PM patients high pS6 expression was associated with significantly shorter OS and PFS. These exploratory findings suggest a clinically relevant PI3K pathway activation in non-epithelioid PM which might lay the foundation for future targeted treatment strategies.