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BACKGROUND Neoadjuvant or adjuvant immunotherapy can improve outcomes in patients with resectable non-small-cell lung cancer (NSCLC). Perioperative regimens may combine benefits of both to improve long-term outcomes. METHODS We randomly assigned patients with resectable NSCLC (stage II to HIB [N2 node stage] according to the eighth edition of the AJCC Cancer Staging Manual) to receive platinum-based chemotherapy plus durvalumab or placebo administered intravenously every 3 weeks for 4 cycles before surgery, followed by adjuvant durvalumab or placebo intravenously every 4 weeks for 12 cycles. Randomization was stratified according to disease stage (II or III) and programmed death ligand 1 (PD-L1) expression (>l°/o or <1%). Primary end points were event-free survival (defined as the time to the earliest occurrence of progressive disease that precluded surgery or prevented completion of surgery, disease recurrence [assessed in a blinded fashion by independent central review], or death from any cause) and pathological complete response (evaluated centrally). RESULTS A total of 802 patients were randomly assigned to receive durvalumab (400 patients) or placebo (402 patients). The duration of event-free survival was significantly longer with durvalumab than with placebo; the stratified hazard ratio for disease progression, recurrence, or death was 0.68 (95% confidence interval [CI], 0.53 to 0.88; P=0.004) at the first interim analysis. At the 12-month landmark analysis, event-free survival was observed in 73.4% of the patients who received durvalumab (95% CI, 67.9 to 78.1), as compared with 64.5% of the patients who received placebo (95% CI, 58.8 to 69.6). The incidence of pathological complete response was significantly greater with durvalumab than with placebo (17.2% vs. 4.3% at the final analysis; difference, 13.0 percentage points; 95% CI, 8.7 to 17.6; PcO.OOl at interim analysis of data from 402 patients). Event-free survival and pathological complete response benefit were observed regardless of stage and PD-L1 expression. Adverse events of maximum grade 3 or 4 occurred in 42.4% of patients with durvalumab and in 43.2% with placebo. Data from 62 patients with documented EGFR or ALK alterations were excluded from the efficacy analyses in the modified intention-to-treat population. CONCLUSIONS In patients with resectable NSCLC, perioperative durvalumab plus neoadjuvant chemotherapy was associated with significantly greater event-free survival and pathological complete response than neoadjuvant chemotherapy alone, with a safety profile that was consistent with the individual agents. (Funded by AstraZeneca; AEGEAN ClinicalTrials.gov number, NCT03800134). [ABSTRACT FROM AUTHOR]

Background: Advanced-stage non-small cell lung cancer (NSCLC) poses treatment challenges, with immune checkpoint inhibitors (ICIs) as the main therapy. Emerging evidence suggests the gut microbiome significantly influences ICI efficacy. This study explores the link between the gut microbiome and ICI outcomes in NSCLC patients, using metatranscriptomic (MTR) signatures., Methods: We utilized a de novo assembly-based MTR analysis on fecal samples from 29 NSCLC patients undergoing ICI therapy, segmented according to progression-free survival (PFS) into long (> 6 months) and short (≤ 6 months) PFS groups. Through RNA sequencing, we employed the Trinity pipeline for assembly, MMSeqs2 for taxonomic classification, DESeq2 for differential expression (DE) analysis. We constructed Random Forest (RF), Support Vector Machine (SVM), and Extreme Gradient Boosting (XGBoost) machine learning (ML) algorithms and comprehensive microbial profiles., Results: We detected no significant differences concerning alpha-diversity, but we revealed a biologically relevant separation between the two patient groups in beta-diversity. Actinomycetota was significantly overrepresented in patients with short PFS (vs long PFS, 36.7% vs. 5.4%, p < 0.001), as was Euryarchaeota (1.3% vs. 0.002%, p = 0.009), while Bacillota showed higher prevalence in the long PFS group (66.2% vs. 42.3%, p = 0.007), when comparing the abundance of corresponding RNA reads. Among the 120 significant DEGs identified, cluster analysis clearly separated a large set of genes more active in patients with short PFS and a smaller set of genes more active in long PFS patients. Protein Domain Families (PFAMs) were analyzed to identify pathways enriched in patient groups. Pathways related to DNA synthesis and Translesion were more enriched in short PFS patients, while metabolism-related pathways were more enriched in long PFS patients. E. coli-derived PFAMs dominated in patients with long PFS. RF, SVM and XGBoost ML models all confirmed the predictive power of our selected RNA-based microbial signature, with ROC AUCs all greater than 0.84. Multivariate Cox regression tested with clinical confounders PD-L1 expression and chemotherapy history underscored the influence of n = 6 key RNA biomarkers on PFS., Conclusion: According to ML models specific gut microbiome MTR signatures' associate with ICI treated NSCLC outcomes. Specific gene clusters and taxa MTR gene expression might differentiate long vs short PFS., Competing Interests: Declarations Ethics approval and consent to participate In the current study, we adhered to the Helsinki Declaration’s study criteria established by the World Medical Association. The study was formally approved by the national ethics committee, specifically the Hungarian Scientific and Research Ethics Committee of the Medical Research Council (ETTTUKEB- 50302-2/2017/EKU). Participation in the study was contingent upon the provision of permission by all patients involved. To maintain confidentiality, patient IDs were removed after the collection of clinicopathological data, thereby preventing direct or indirect identification of patients. Consent for publication All authors agree to submit the article for publication. Competing interests The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024. The Author(s).)

Current proteomic technologies focus on the quantification of protein levels, while little effort is dedicated to the development of system approaches to simultaneously monitor proteome variability and abundance. Protein variants may display different immunogenic epitopes detectable by monoclonal antibodies. Epitope variability results from alternative splicing, posttranslational modifications, processing, degradation, and complex formation and possesses dynamically changing availability of interacting surface structures that frequently serve as reachable epitopes and often carry different functions. Thus, it is highly likely that the presence of some of the accessible epitopes correlates with function under physiological and pathological conditions. To enable the exploration of the impact of protein variation on the immunogenic epitome first, here, we present a robust and analytically validated PEP technology for characterizing immunogenic epitopes of the plasma. To this end, we prepared mAb libraries directed against the normalized human plasma proteome as a complex natural immunogen. Antibody producing hybridomas were selected and cloned. Monoclonal antibodies react with single epitopes, thus profiling with the libraries is expected to profile many epitopes which we define by the mimotopes, as we present here. Screening blood plasma samples from control subjects (n = 558) and cancer patients (n = 598) for merely 69 native epitopes displayed by 20 abundant plasma proteins resulted in distinct cancer-specific epitope panels that showed high accuracy (AUC 0.826-0.966) and specificity for lung, breast, and colon cancer. Deeper profiling (≈290 epitopes of approximately 100 proteins) showed unexpected granularity of the epitope-level expression data and detected neutral and lung cancer-associated epitopes of individual proteins. Biomarker epitope panels selected from a pool of 21 epitopes of 12 proteins were validated in independent clinical cohorts. The results demonstrate the value of PEP as a rich and thus far unexplored source of protein biomarkers with diagnostic potential., Competing Interests: Conflict of interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Due to the high variance in response rates concerning anti-PD1 immunotherapy (IT), there is an unmet need to discover innovative biomarkers to predict immune checkpoint inhibitor (ICI)-efficacy. Our study included 62 Caucasian advanced-stage non-small cell lung cancer (NSCLC) patients treated with anti-PD1 ICI. Gut bacterial signatures were evaluated by metagenomic sequencing and correlated with progression-free survival (PFS), PD-L1 expression and other clinicopathological parameters. We confirmed the predictive role of PFS-related key bacteria with multivariate statistical models (Lasso- and Cox-regression) and validated on an additional patient cohort ( n  = 60). We find that alpha-diversity showed no significant difference in any comparison. However, there was a significant difference in beta-diversity between patients with long- (>6 months) vs. short (≤6 months) PFS and between chemotherapy (CHT)-treated vs. CHT-naive cases. Short PFS was associated with increased abundance of Firmicutes (F) and Actinobacteria phyla, whereas elevated abundance of Euryarchaeota was specific for low PD-L1 expression. F/Bacteroides (F/B) ratio was significantly increased in patients with short PFS. Multivariate analysis revealed an association between Alistipes shahii, Alistipes finegoldii, Barnesiella visceriola, and long PFS. In contrast, Streptococcus salivarius, Streptococcus vestibularis, and Bifidobacterium breve were associated with short PFS. Using Random Forest machine learning approach, we find that taxonomic profiles performed superiorly in predicting PFS (AUC = 0.74), while metabolic pathways including Amino Acid Synthesis and Fermentation were better predictors of PD-L1 expression (AUC = 0.87). We conclude that specific metagenomic features of the gut microbiome, including bacterial taxonomy and metabolic pathways might be suggestive of ICI efficacy and PD-L1 expression in NSCLC patients., Competing Interests: GJW: is a current employee of SOTIO Biotech Inc., a former employee of Unum Therapeutics; reports personal fees from Imaging Endpoints II, MiRanostics Consulting, Paradigm, International Genomics Consortium, Angiex, GLG Council, Guidepoint Global, Genomic Health, Oncocare, Rafael Pharmaceuticals, Gossamer Bio, and SPARC, Harvest Integrated Research Organization-all outside this submitted work; has ownership interest in Unum Therapeutics (now Cogent Biosciences), MiRanostics Consulting, Exact Sciences, Moderna, Agenus, Aurinia Pharmaceuticals, and Circulogene-outside the submitted work; and has issued patents: PCT/US2008/072787, PCT/US2010/043777, PCT/US2011/020612, and PCT/US2011/037616-all outside the submitted work., (© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Candida species overgrowth in the human gut is considered a prerequisite for invasive candidiasis, but our understanding of gut bacteria promoting or restricting this overgrowth is still limited. By integrating cross-sectional mycobiome and shotgun metagenomics data from the stool of 75 male and female cancer patients at risk but without systemic candidiasis, bacterial communities in high Candida samples display higher metabolic flexibility yet lower contributional diversity than those in low Candida samples. We develop machine learning models that use only bacterial taxa or functional relative abundances to predict the levels of Candida genus and species in an external validation cohort with an AUC of 78.6-81.1%. We propose a mechanism for intestinal Candida overgrowth based on an increase in lactate-producing bacteria, which coincides with a decrease in bacteria that regulate short chain fatty acid and oxygen levels. Under these conditions, the ability of Candida to harness lactate as a nutrient source may enable Candida to outcompete other fungi in the gut., (© 2023. The Author(s).)

The tissue distribution and prognostic relevance of subtype-specific proteins (ASCL1, NEUROD1, POU2F3, YAP1) present an evolving area of research in small-cell lung cancer (SCLC). The expression of subtype-specific transcription factors and P53 and RB1 proteins were measured by immunohistochemistry (IHC) in 386 surgically resected SCLC samples. Correlations between subtype-specific proteins and in vitro efficacy of various therapeutic agents were investigated by proteomics and cell viability assays in 26 human SCLC cell lines. Besides SCLC-A (ASCL1-dominant), SCLC-AN (combined ASCL1/NEUROD1), SCLC-N (NEUROD1-dominant), and SCLC-P (POU2F3-dominant), IHC and cluster analyses identified a quadruple-negative SCLC subtype (SCLC-QN). No unique YAP1-subtype was found. The highest overall survival rates were associated with non-neuroendocrine subtypes (SCLC-P and SCLC-QN) and the lowest with neuroendocrine subtypes (SCLC-A, SCLC-N, SCLC-AN). In univariate analyses, high ASCL1 expression was associated with poor prognosis and high POU2F3 expression with good prognosis. Notably, high ASCL1 expression influenced survival outcomes independently of other variables in a multivariate model. High POU2F3 and YAP1 protein abundances correlated with sensitivity and resistance to standard-of-care chemotherapeutics, respectively. Specific correlation patterns were also found between the efficacy of targeted agents and subtype-specific protein abundances. In conclusion, we investigated the clinicopathological relevance of SCLC molecular subtypes in a large cohort of surgically resected specimens. Differential IHC expression of ASCL1, NEUROD1, and POU2F3 defines SCLC subtypes. No YAP1-subtype can be distinguished by IHC. High POU2F3 expression is associated with improved survival in a univariate analysis, whereas elevated ASCL1 expression is an independent negative prognosticator. Proteomic and cell viability assays of human SCLC cell lines revealed distinct vulnerability profiles defined by transcription regulators. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

Impaired exercise tolerance and lung function is a marker for increased mortality in lung cancer patients undergoing lung resection surgery. Recent data suggest that the gut-lung axis regulates systemic metabolic and immune functions, and microbiota might alter exercise tolerance. Here, we aimed to evaluate the associations between gut microbiota and outcomes in lung cancer patients who underwent lung resection surgery. We analysed stool samples, from 15 early-stage lung cancer patients, collected before and after surgical resection using shotgun metagenomic and Internal Transcribed Spacer (ITS) sequencing. We analysed microbiome and mycobiome associations with post-surgery lung function and cardiopulmonary exercise testing (CPET) to assess the maximum level of work achieved. There was a significant difference, between pre- and post-surgical resection samples, in microbial community functional profiles and several species from Alistipes and Bacteroides genus, associated with the production of SCFAs, increased significantly in abundance. Interestingly, an increase in VO2 coincides with an increase in certain species and the "GABA shunt" pathway, suggesting that treatment outcome might improve by enriching butyrate-producing species. Here, we revealed associations between specific gut bacteria, fungi, and their metabolic pathways with the recovery of lung function and exercise capacity., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: GJW reports personal fees and ownership interest from Circulogene, personal fees from Paradigm, personal fees from Angiex, personal fees from Gossamer Bio, personal fees from Genomic Health, ownership interest from Exact Sciences, personal fees from GLG Council, personal fees and ownership interest from MiRanostics Consulting, personal fees from Guidepoint Global, personal fees from Imaging Endpoints II, personal fees from Spring Bank Pharmaceuticals, personal fees from IBEX Medical Analytics, travel and lodging fees from GlaxoSmithKline, personal fees from SOTIO US, outside the submitted work. In addition, GJW is a former employee and stockholder of Unum Therapeutics, an employee of SOTIO US, and has a patent PCT/US2011/020612 issued. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The remaining authors declare no competing interests.

Cachexia is associated with decreased survival in cancer patients and has a prevalence of up to 80%. The etiology of cachexia is poorly understood, and limited treatment options exist. Here, we investigated the role of the human gut microbiome in cachexia by integrating shotgun metagenomics and plasma metabolomics of 31 lung cancer patients. The cachexia group showed significant differences in the gut microbial composition, functional pathways of the metagenome, and the related plasma metabolites compared to non-cachectic patients. Branched-chain amino acids (BCAAs), methylhistamine, and vitamins were significantly depleted in the plasma of cachexia patients, which was also reflected in the depletion of relevant gut microbiota functional pathways. The enrichment of BCAAs and 3-oxocholic acid in non-cachectic patients were positively correlated with gut microbial species Prevotella copri and Lactobacillus gasseri, respectively. Furthermore, the gut microbiota capacity for lipopolysaccharides biosynthesis was significantly enriched in cachectic patients. The involvement of the gut microbiome in cachexia was further observed in a high-performance machine learning model using solely gut microbial features. Our study demonstrates the links between cachectic host metabolism and specific gut microbial species and functions in a clinical setting, suggesting that the gut microbiota could have an influence on cachexia with possible therapeutic applications., (© 2021. The Author(s).)

The survivin protein contributes to the development and progression of tumors. Protein expression and mRNA levels correlate with clinicopathological parameters and survival of cancer patients. Our purpose was to evaluate whether circulating survivin levels have any diagnostic or predictive value in lung cancer. 118 patients with advanced stage lung cancer participated in our study. 53 suffered from adenocarcinoma (ADC), 33 from squamous cell carcinoma (SqCC), and 32 from small cell lung cancer (SCLC). We also enrolled 21 control subjects. Blood samples were collected before and after two cycles of chemotherapy. We measured survivin concentrations with ELISA. Non-parametric tests were used for analysis. We did not find significant difference in survivin levels between patients and control subjects (17.19/0-829.74/vs. 49.13/0-165.92/pg/ml; p = 0.07). We found lower survivin concentrations in patients with SqCC (0/0-171.24/pg/ml) than in those with ADC (24.94/0-626.46 pg/ml) and SCLC (45.51/0-829.74/pg/ml) (ADC vs. SqCC p < 0.0001, ADC vs. SCLC p = 0.0405, SqCC vs. SCLC p < 0.0001). Survivin levels were higher in stage IV patients than in patients without distant metastases ( p = 0.0061), and concentrations were progressively higher with increasing number of metastatic organ sites ( p = 0.04). We observed a decrease in survivin levels in ADC patients after platinum plus pemetrexed chemotherapy (26.22/0-626.46/pg/ml before vs. 0/0-114.36/pg/ml after; p = 0.01). Neither progression-free nor overall survival correlated with survivin levels at baseline. Our data imply that survivin may be involved in the development of metastases and it might be used as a biomarker of disease progression. However, circulating survivin concentrations do not predict survival of patients with lung cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Puskas, Bikov, Horvath, Lazar, Kunos, Nagy, Pinter and Galffy.)

Small cell lung cancer (SCLC; accounting for approximately 13%-15% of all lung cancers) is an exceptionally lethal malignancy characterized by rapid doubling time and high propensity to metastasize. In contrast to the increasingly personalized therapies in other types of lung cancer, SCLC is still regarded as a homogeneous disease and the prognosis of SCLC patients remains poor. Recently, however, substantial progress has been made in our understanding of SCLC biology. Advances in genomics and development of new preclinical models have facilitated insights into the intratumoral heterogeneity and specific genetic alterations of this disease. This worldwide resurgence of studies on SCLC has ultimately led to the development of novel subtype-specific classifications primarily based on the neuroendocrine features and distinct molecular profiles of SCLC. Importantly, these biologically distinct subtypes might define unique therapeutic vulnerabilities. Herein, we summarize the current knowledge on the molecular profiles of SCLC subtypes with a focus on their potential clinical implications., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Background: Although lung adenocarcinoma (LADC) with sensitizing mutations of the epidermal growth factor receptor ( EGFR ) is highly sensitive to EGFR tyrosine kinase inhibitors (EGFR-TKIs), in most cases disease progression inevitably occurs. Our aim was to investigate the predictive and prognostic significance of adjusted tumoral EGFR variant allele frequency (EGFR-aVAF) in the above setting., Methods: Eighty-nine Caucasian advanced-stage LADC patients with known exon-specific EGFR mutations undergoing EGFR-TKI treatment were included. The correlations of EGFR-aVAF with clinicopathological variables including progression-free and overall survival (PFS and OS, respectively) were retrospectively analyzed., Results: Of 89 EGFR -mutant LADC patients, 46 (51.7%) had exon 19 deletion, while 41 (46.1%) and 2 (2.2%) patients had exon 21- and exon 18-point mutations, respectively. Tumoral EGFR-aVAF was significantly higher in patients harboring EGFR exon 19 mutations than in those with exon 21-mutant tumors (P<0.001). Notably, patients with EGFR exon 19 mutant tumors demonstrated significantly improved PFS (P=0.003) and OS (P=0.02) compared to patients with exon 21 mutations. Irrespective of specific exon mutations, a statistically significant positive linear correlation was found between EGFR-aVAF of tumoral tissue and PFS (r=0.319; P=0.002). High (≥70%) EGFR-aVAF was an independent predictor of longer PFS [ vs. low (<70%) EGFR-aVAF; median PFSs were 52 vs. 26 weeks, respectively; P<0.001]. Additionally, patients with high EGFR-aVAF also had significantly improved OS than those with low EGFR-aVAF (P=0.011)., Conclusions: Our study suggests that high (≥70%) EGFR-aVAF of tumoral tissue predicts benefit from EGFR-TKI treatment in advanced LADC and, moreover, that exon 19 EGFR mutation is associated with high EGFR-aVAF and improved survival outcomes., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-20-814). The authors have no conflicts of interest to declare., (2021 Translational Lung Cancer Research. All rights reserved.)

Background: Treatment of non-small cell lung cancer (NSCLC) improved substantially in the last decades. Novel targeted and immune-oncologic drugs were introduced into routine treatment. Despite accelerated development and subsequent drug registrations by the European Medicinal Agency (EMA), novel drugs for NSCLC are poorly accessible in Central and Eastern European (CEE) countries., Material and Methods: The Central European Cooperative Oncology Group conducted a survey among experts from 10 CEE countries to provide an overview on the availability of novel drugs for NSCLC and time from registration to reimbursement decision in their countries., Results: Although first-generation epidermal growth factor receptor tyrosine kinase inhibitors were reimbursed and available in all countries, for other registered therapies-even for ALK inhibitors and checkpoint inhibitors in first-line-there were apparent gaps in availability and/or reimbursement. There was a trend for better availability of drugs with longer time from EMA marketing authorization. Substantial differences in access to novel drugs among CEE countries were observed. In general, the availability of drugs is not in accordance with the Magnitude of Clinical Benefit Scale (MCBS), as defined by the European Society for Medical Oncology (ESMO). Time spans between drug registrations and national decisions on reimbursement vary greatly, from less than 3 months in one country to more than 1 year in the majority of countries., Conclusion: The access to novel drugs for NSCLC in CEE countries is suboptimal. To enable access to the most effective compounds within the shortest possible time, reimbursement decisions should be faster and ESMO MCBS should be incorporated into decision making., (© 2019 The Authors. The Oncologist published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

The anti-aging factor, klotho has been identified as a tumor suppressor in various human cancers, including lung cancer. In vitro studies provided evidence that klotho expression influences the characteristics of lung cancer cells, however, in vivo results are lacking. The aim of our study was to evaluate whether circulating klotho protein might serve as a potential biomarker of lung cancer. Blood samples were taken from 45 newly diagnosed lung cancer patients (31 NSCLC, 14 SCLC) and 43 control subjects. Plasma klotho concentration was measured using ELISA. No difference in plasma klotho values was detected between patients and control subjects (366.3 (257.9-486.8) vs. 383.5 (304.6-489.7) pg/ml respectively (median (IQR)); p > 0.05). Plasma klotho levels in patients with distant metastasis did not differ from less advanced stage disease (354.2 (306.9-433.3 vs. 328.5 (242.5-419.7) pg/ml, p > 0.05). In contrast, analyzed with one-way ANOVA, significant difference (p = 0.04) was found between the examined histological types of lung cancer: adenocarcinoma (353 (329.4-438.5) pg/ml), squamous cell carcinoma (308 (209.6-348.1) pg/ml) and small cell lung cancer (388.8 (289.9-495.4) pg/ml). However, Tukey's post hoc test did not reveal significant difference between any pairs of histological groups. There was no difference between any histological subtype and health either. Our results suggest that circulating klotho protein cannot be considered as a biomarker for lung cancer. Further studies are warranted in order to examine the relationship between klotho expression in lung tissue and circulating levels of the protein, and to explore its mechanism of action in lung cancer.

Purpose: Lung cancer may be associated with airway acidification due to enhanced airway inflammation and oxidative stress. Exhaled breath condensate (EBC) pH is a non-invasive indicator of airway acidity; however, it is still unclear how EBC pH changes in lung cancer. The aim of the study was to investigate EBC pH in lung cancer together with clinical variables., Methods: Thirty-five patients with lung cancer and 37 control subjects (21 patients with stable COPD and 16 non-COPD smokers) were enrolled. EBC was collected for pH, which was determined with the argon-purging method, compared among the groups and correlated with clinical variables of patients with lung cancer., Results: No difference was found in EBC pH between patients with lung cancer and control subjects. However, endobronchial tumour localisation, squamous-cell carcinoma subtype and gastro-oesophageal reflux were associated with low EBC pH values. No relationship was observed between EBC pH and the presence of COPD, lung function variables or smoking history., Conclusions: Although, EBC pH is unchanged in lung cancer, lower EBC pH values are associated with distinct phenotypes. Our findings could facilitate further research on airway acidity in lung cancer.

Objectives: Erlotinib is an epidermal growth factor receptor tyrosine-kinase inhibitor (EGFR-TKI), used for the treatment of non-small cell lung cancer. As the clinical significance of KRAS mutational status has not yet been clearly determined in this setting, our aim was to investigate the efficacy of erlotinib in advanced KRAS mutation-negative lung adenocarcinoma patients., Materials and Methods: MOTIVATE is an open-label, multicenter, observational trial with Tarceva(®) (erlotinib) monotherapy. Enrolled patients with advanced (stage IIIB/IV) KRAS wild type (WT) lung adenocarcinoma refractory to one or two courses of prior chemotherapy were treated with erlotinib at 150mg/day. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS) and best tumor response rate (RR)., Results and Conclusion: In total, 327 patients were included. Median PFS and OS were 3.3 and 14.4 months, respectively. Three patients (1.2%) had complete response, 51 patients (20.2%) had partial response and 123 patients (48.8%) had SD. Significantly longer median PFS and OS were observed in Eastern Oncology Cooperative Group Performance Status (ECOG PS) 0-1 patients, as compared to ECOG PS 2-3 patients. The longest median OS (20.5 months) was found in patients with ECOG PS 0-1 who received erlotinib as a second-line therapy. There was no difference in median OS in cohorts stratified to disease stage and smoking status. Female patients had both longer median PFS and OS. Disease control rate was 70.2%. Our results suggest that erlotinib represents a valid treatment option for patients with KRAS WT lung adenocarcinoma and, moreover, that KRAS mutation analysis could help to identify clinically relevant subgroups of NSCLC patients that may benefit from EGFR-TKI therapy., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background and Objective: Exercise-induced bronchoconstriction (EIB) is the temporary narrowing of the airways caused by physical exercise. Its exact pathophysiology is unclear; however, acute changes in airways pH may play a role. Exhaled breath condensate (EBC) pH was suggested as a surrogate indicator for airway acid-base status, but its value is also affected by volatile molecules and respiratory droplet dilution. The aim of the study was to assess changes in EBC pH during EIB., Methods: Twenty-two asthmatics who reported breathlessness following exercise and 16 healthy individuals participated in the study. Lung function test was performed and exhaled breath samples were collected for pH, dilution factor and volatile compound pattern measurements (Cyranose 320) pre-exercise and at 0, 10, 20 and 30 min after physical exercise challenge. Fractional exhaled nitric oxide was measured before exercise., Results: EIB developed in 13 asthmatic subjects. In these participants, but not in the EIB-negative asthmatics (P = 0.51), EBC pH reduced significantly during exercise (P = 0.01). In addition, changes in EBC pH were related to the degree of bronchospasm in the EIB-positive group (P = 0.01, r = 0.68). Exhaled volatile pattern became altered (P < 0.05) during exercise in all subjects (asthmatics and controls). EBC pH changes were not related to EBC dilution or volatile compound pattern alterations (P > 0.05)., Conclusions: The development of EIB was related to acute changes of EBC pH, which suggest the role of airway pH decrease in the pathophysiology of EIB. Exercise-induced changes in exhaled biomarkers suggest methodological precautions to avoid physical exercise before performing exhaled breath tests., (© 2014 The Authors. Respirology © 2014 Asian Pacific Society of Respirology.)

Several studies support that airway acid stress plays a role in the pathophysiology of asthma. Exhaled breath condensate pH (EBC pH) was suggested as a surrogate marker of airway acidification. The dilution of airway lining fluid (ALF) acids and bases by alveolar water may influence condensate pH, but it has not been studied yet. The aim of our study was to investigate the relationship between EBC pH and ALF dilution in EBC samples obtained from asthmatic and healthy subjects. EBC was collected from 55 asthmatic and 57 healthy subjects for pH and conductivity measurements. Fractional exhaled nitric oxide (FE(NO)) and lung function tests were also performed in asthmatic patients. EBC pH was determined after 10 min of argon deareation and the dilution was estimated by the measurement of conductivity in vacuum-treated samples. There was no difference either in EBC pH or dilution between the two groups. However, a significant relationship was found between EBC pH and dilution in both groups (p < 0.05, r = -0.35 and r = -0.29, asthmatic and healthy groups, respectively). Our results suggest important methodological aspect indicating that EBC pH is affected by respiratory droplet dilution, and this effect should be taken into consideration when interpreting EBC pH data.

Pleural injury results in the death of mesothelial cells and denudation of the mesothelial basement membrane. Repair of the mesothelium without fibrosis requires proliferation and migration of mesothelial cells into the injured area. We hypothesized that monocyte chemoattractant protein-1 (MCP-1) induces proliferative and haptotactic responses in pleural mesothelial cells (PMCs) and that the MCP-1 binding receptor CCR2 mediates the pleural repair process. We demonstrate that PMCs exhibited MCP-1-specific immunostaining on injury. MCP-1 induced proliferative and haptotactic responses in PMCs. PMCs express CCR2 in a time-dependent manner. Fluorescence-activated cell sorting analysis demonstrated that interleukin (IL)-2 upregulated CCR2 protein expression in PMCs, whereas lipopolysaccharide (LPS) downregulated the response at the initial period compared with that in resting PMCs. However, the inhibitory potential of LPS was lost after 12 h and showed a similar response at 24 and 48 h. Haptotactic migration was upregulated in PMCs that were cultured in the presence of IL-2. The increased haptotactic capacity of mesothelial cells in the presence of IL-2 correlated with increased CCR2 mRNA expression. PMCs cultured in the presence of LPS showed decreased haptotactic activity to MCP-1. Blocking the CCR2 with neutralizing antibodies decreased the haptotactic response of PMCs to MCP-1. These results suggest that the haptotactic migration of mesothelial cells in response to MCP-1 are mediated through CCR2, which may play a crucial role in reepithelialization of the denuded basement membrane at the site of pleural injury and may thus contribute to the regeneration of the mesothelium during the process of pleural repair.

Pleurodesis with talc is an accepted method for the treatment of symptomatic pleural effusions secondary to mesotheliomas. Patients with mesothelioma who have talc-induced pleurodesis have a lower morbidity than do those who do not have pleurodesis. The mechanisms whereby talc mediated these effects were considered to be secondary to a decrease or absence of a pleural effusion. The possibility that talc may directly affect malignant cells was not considered. The present study was designed to evaluate if talc directly effects cell death of malignant mesothelioma cells (MMC) or normal pleural mesothelial cells (PMC). Three confluent MMC and PMC were exposed to talc for 24, 48, and 72 h. In parallel experiments, glass beads similar in size to talc were included as control. Apoptosis was determined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) and DNA electrophoresis. Our results demonstrated that talc at a therapeutically achievable concentration (6 microg/cm(2)) induces significant apoptosis in MMC. Talc-induced maximum apoptosis in MMC (39.50 +/- 2.55%, 31.87 +/- 4.69%, and 15.10 +/- 3.93% in CRL-2081, CRL-5820, and CRL-5915, respectively) at 48 h, which was significantly (p < 0.05) greater than that in control cells. Electrophoresis of DNA isolated from talc-exposed MMC demonstrated the typical ladder pattern of internucleosomal DNA cleavage. Talc did not induce apoptosis in PMC, and glass beads did not cause significant apoptosis in either MMC or PMC. The present study has demonstrated that talc induces apoptosis in MMC without affecting normal mesothelial cells of the pleura.

Interleukin 8 (IL-8) is a potent chemokine that also has a direct growth-potentiating effect on certain tumors. In the present study, we determined IL-8 levels in human malignant mesothelioma (MM) effusions and congestive heart failure pleural fluids. We also investigated antigenic IL-8 production by different MM cell lines, and we describe the role of IL-8 in the autocrine growth regulation of MMs. Mesothelial (CRL-9444 = MC) and MM (CRL-2081 = MM-1, CRL-5915 = MM-2, and CRL-5820 = MM-3) cell lines were grown using standard culture methods. The bioactive IL-8 levels were measured in supernatants of cultured cells by ELISA, and the expression of cell-associated immunoreactive IL-8 was observed by immunohistochemistry. The proliferative activity was determined by thymidine ([3H]thymidine) incorporation and also by direct cell counts after incubation with varying concentrations of IL-8 in the presence/absence of specific polyclonal IL-8 antibody. We found significantly higher levels of IL-8 in mesothelioma pleural fluids than congestive heart failure and a time-dependent increase in IL-8 levels in MM-1 and MM-2 cell supernatants during 96 h of incubation. IL-8 levels were nearly undetectable in MM-3 and MC cell line supernatants. In MM-1 and MM-2 cells, IL-8 caused a dose-dependent increase of [3H]thymidine incorporation to maximal levels of 46.3 +/- 3.6% and 12.3 +/- 1.6% (P < 0.001), respectively, when compared with serum-free medium as control. Neutralization of IL-8 significantly decreased proliferative activity of MM-1 and MM-2. IL-8 did not induce proliferative activity in MM-3 and MC cells. We conclude that IL-8 had a direct growth-potentiating activity in MMs.

Malignant pleural mesothelioma (MPM), despite current therapeutic strategies, is still an aggressive tumor with a very poor prognosis. Interleukin-8 (IL-8), a proinflammatory and angiogenic cytokine, has an important role in tumor-related neovascularization. IL-8 has also been described to function as an autocrine growth factor. The purpose of this study was to evaluate the effect of IL-8 antibody (IL-8 Ab) on progression of MPM in vivo. Athymic nude mice (n = 65) were injected intrapleurally with human MPM cells (CRL-2081), equally divided into three groups (IL-8 Ab, control Ab, untreated), and received IP injection of IL-8 Ab, control Ab, or no treatment, respectively, every 48 h up to 15 days. Pleural fluid and serum IL-8 levels, and tumor and body weight of mice were measured following 5, 10, and 15 days of tumor injection. We found that both pleural fluid and serum IL-8 levels were significantly (P < 0.0001) lower in mice that received IL-8 Ab when compared to the other groups. In this group, lower IL-8 levels were associated with a decreased rate of tumor growth. There was a significant and direct correlation between pleural fluid IL-8 levels and tumor weight of all animals enrolled in this study (P < 0.0001, r = 0.88). We demonstrate that antibody treatment against IL-8 decreased human MPM progression. Our results suggest that treatments targeting the decrease of MPM-associated IL-8 levels or the effects of this protein may inhibit mesothelioma growth.

Following a first field trial in the year 1966 a second field trial was carried out in the Pediatric Clinic of the University of Vienna in the years 1967 und 1968, in which 420 children were vaccinated against measles by various methods. Apart from the observations of the clinical reactions the chief purpose of the examination was to establish the height of the antibodies achieved, how long they persisted and whether the primary vaccination with split-vaccine had any influence on the level and persistance of antibodies. The results following the combined vaccination were compared with those following with Schwarz-strain alone, whereby no significant differences appeared. The serological follow-up examinations were made after a month, a year, after 3 and finally after 7 years. Whilst in the first year the combined vaccinated children showed an average higher titre, the average antibody titre following single live vaccination were somewhat higher after 7 years and showed a lesser degree of scatter. The values of antibody titres are impart so high that one has to assume a silent booster effect since none of the examined children were taken ill with measles. The single live vaccination by means of Schwarz-vaccine has thus been proved outstanding, is to be regarded as the general method of choice and should be applied as widely as possible since the morbidity risk of measles is considerably high and vaccination is not dangereous. The use of split-vaccine is indicated only with chronically ill children for instance with leukaemia, mucoviscidosis etc. and in infants in the first year of life, if one wants to protect them against measles. If we reach our aim of through-vaccination of the population against measles, infants will no longer be in danger and a prevaccination in the first year of life will not be indicated.