Association of the advanced lung cancer inflammation index (ALI) with immune checkpoint inhibitor efficacy in patients with advanced non-small-cell lung cancer.

BACKGROUND: The advanced lung cancer inflammation index [ALI: body mass index × serum albumin/neutrophil-to-lymphocyte ratio (NLR)] reflects systemic host inflammation, and is easily reproducible. We hypothesized that ALI could assist guidance of non-small-cell lung cancer (NSCLC) treatment with immune checkpoint inhibitors (ICIs). PATIENTS AND METHODS: This retrospective study included 672 stage IV NSCLC patients treated with programmed death-ligand 1 (PD-L1) inhibitors alone or in combination with chemotherapy in 25 centers in Greece and Germany, and a control cohort of 444 stage IV NSCLC patients treated with platinum-based chemotherapy without subsequent targeted or immunotherapy drugs. The association of clinical outcomes with biomarkers was analyzed with Cox regression models, including cross-validation by calculation of the Harrell's C-index. RESULTS: High ALI values (>18) were significantly associated with longer overall survival (OS) for patients receiving ICI monotherapy [hazard ratio (HR) = 0.402, P < 0.0001, n = 460], but not chemo-immunotherapy (HR = 0.624, P = 0.111, n = 212). Similar positive correlations for ALI were observed for objective response rate (36% versus 24%, P = 0.008) and time-on-treatment (HR = 0.52, P < 0.001), in case of ICI monotherapy only. In the control cohort of chemotherapy, the association between ALI and OS was weaker (HR = 0.694, P = 0.0002), and showed a significant interaction with the type of treatment (ICI monotherapy versus chemotherapy, P < 0.0001) upon combined analysis of the two cohorts. In multivariate analysis, ALI had a stronger predictive effect than NLR, PD-L1 tumor proportion score, lung immune prognostic index, and EPSILoN scores. Among patients with PD-L1 tumor proportion score ≥50% receiving first-line ICI monotherapy, a high ALI score >18 identified a subset with longer OS and time-on-treatment (median 35 and 16 months, respectively), similar to these under chemo-immunotherapy. CONCLUSIONS: The ALI score is a powerful prognostic and predictive biomarker for patients with advanced NSCLC treated with PD-L1 inhibitors alone, but not in combination with chemotherapy. Its association with outcomes appears to be stronger than that of other widely used parameters. For PD-L1-high patients, an ALI score >18 could assist the selection of cases that do not need addition of chemotherapy.

Safety and efficacy of a CXCR2 antagonist in patients with severe asthma and sputum neutrophils: a randomized, placebo-controlled clinical trial.

BACKGROUND: Increased numbers of neutrophils are reported in the airways of patients with severe asthma. It is not clear if they contribute to the lack of control and severity. There are currently no strategies to investigate this by decreasing neutrophil numbers in the airways. OBJECTIVE: To investigate the safety and efficacy of SCH527123, a selective CXCR2 receptor antagonist, in patients with severe asthma and increased number of neutrophils in sputum. METHODS: In a randomized, double-blind, parallel study, patients with severe asthma and sputum total cell count < 10 × 10(6) /g and neutrophils > 40% were randomized to SCH527123, 30 mg daily PO (n = 22) or placebo (n = 12) for 4 weeks. Primary end-points were safety and change in sputum and blood neutrophil counts. Secondary end-points were change in asthma control questionnaire (ACQ) score, minor and major exacerbations, spirometry and sputum neutrophil activation markers. RESULTS: The SCH 527123 caused a mean reduction of 36.3% in sputum neutrophil percentage compared to a 6.7% increase in the placebo arm (P = 0.03). The mean absolute neutrophil count in blood was reduced by 14% at the end of 4 weeks, but recovered by the 5th week. There were no differences in the overall rates of adverse events among the groups. There were fewer mild exacerbations (1.3 vs. 2.25, P = 0.05) and a trend towards improvement in the ACQ score (mean difference between groups of 0.42 points, P = 0.053). No statistically significant changes were observed in forced expiratory volume in 1 s (FEV (1)), sputum myeloperoxidase, IL8 or elastase. CONCLUSIONS: The SCH527123 is safe and reduces sputum neutrophils in patients with severe asthma. CLINICAL RELEVANCE: This new treatment provides an opportunity to investigate the role of neutrophils in severe asthma with potential clinical benefits. Larger studies of longer duration are needed to evaluate the impact on other outcomes of asthma including exacerbations.

Multiple tuberculous abscesses and mediastinal lymphadenitis with no pulmonary involvement in an immunocompetent patient.

Tubercular cold abscesses secondary to neighbouring bone involvement are a well-known clinical manifestation of extra-pulmonary tuberculosis. However, primary soft tissue tuberculous abscesses with no pulmonary involvement in immuno-competent patients are very uncommon. A rare case of multiple primary intrathoracic and extraperitoneal soft tissue tuberculous abscesses and mediastinal lymph node tuberculosis with no pulmonary involvement is reported. This case demonstrates the need for a high index of suspicion for such rare presentations of extra-pulmonary tuberculosis in patients from endemic areas.

Osteopontin expression and relation to disease severity in human asthma.

Recent studies have associated osteopontin (OPN) with allergic inflammation; however, its role in human asthma remains unclear. The aim of this study was to measure OPN levels in the serum, bronchoalveolar lavage fluid (BALF) and bronchial tissue of healthy controls and asthmatics, identify cellular sources of OPN and examine possible correlations between OPN expression, disease severity and airway remodelling. Serum samples were obtained from 35 mild-to-moderate asthmatics, 19 severe asthmatics and 17 healthy controls in the steady state and in cases of exacerbation. Of these subjects, 29 asthmatics and nine controls underwent bronchoscopy with endobronchial biopsy and BALF collection. OPN expression was determined by ELISA and immunohistochemistry/immunofluorescence. Reticular basement membrane thickness and goblet cell hyperplasia were also determined. Serum and BALF OPN levels were significantly increased in all asthmatics in the steady state, whereas serum levels decreased during exacerbations. OPN was upregulated in the bronchial tissue of all patients, and expressed by epithelial, airway and vascular smooth muscle cells, myofibroblasts, T-lymphocytes and mast cells. OPN expression correlated with reticular basement membrane thickness and was more prominent in subepithelial inflammatory cells in severe compared to mild-to-moderate asthma. OPN expression is upregulated in human asthma and associated with remodelling changes, and its subepithelial expression correlates with disease severity.

Differences in microsatellite DNA level between asthma and chronic obstructive pulmonary disease.

Previous studies have shown that microsatellite (MS) DNA instability (MSI) is detectable in sputum cells in chronic obstructive pulmonary disease (COPD) and asthma. The aim of the present study was to investigate whether asthma and COPD could be distinguished at the MS DNA level. DNA was extracted from sputum cells and white blood cells from 63 COPD patients, 60 non-COPD smokers, 36 asthmatics and 30 healthy nonsmokers. Ten MS markers located on chromosomes 2p, 5q, 6p, 10q, 13q, 14q and 17q were analysed. No MSI was detected in non-COPD smokers or healthy nonsmokers. A significantly higher proportion of COPD patients exhibited MSI (49.2%) compared to asthmatics (22.2%). MSI was detected even in the mild stages of COPD (33.3%) and asthma (22.2%). No relationship was found between MSI and COPD severity. The most frequently affected marker was D14S588 (17.5% in COPD and 2.7% in asthma). The markers D6S344, G29802 and D13S71 showed alterations only in COPD, and G29802 was associated with a significantly decreased forced expiratory volume in one second FEV1 (% predicted), whereas MSI in D6S344 was associated with a significantly higher FEV1 (% pred). The frequency of microsatellite instability was higher in chronic obstructive pulmonary disease than in asthma, and microsatellite instability in three workers showed chronic obstructive pulmonary disease specificity. However, further studies are needed to verify the differences between chronic obstructive pulmonary disease and asthma at the microsatellite level.

Risk factors and characteristics associated with severe and difficult to treat asthma phenotype: an analysis of the ENFUMOSA group of patients based on the ECRHS questionnaire.

BACKGROUND: Severe and difficult to treat asthma impairs health status and accounts for about half of asthma expenditure. In 1994, a European Network For Understanding Mechanisms of Severe Asthma (ENFUMOSA) was formed. A large group of patients from nine European countries has been selected. OBJECTIVE: To examine the risk factors and symptoms associated with a phenotype of severe/difficult to treat asthma. METHODS: The present report presents data assessed through the use of the European Community Respiratory Health Survey (ECRHS) Questionnaire in 148 mild-moderate controlled and 155 severe asthmatics from the ENFUMOSA group. RESULTS: There is a negative association of severe asthma with reported allergy and with a family history of allergy (Odds ratio (OR)=0.45). Sharing a bedroom before the age of five is associated with a higher risk of severe asthma (OR=1.5) while childhood infections, play school attendance and exposure to allergens or animals are not. A larger proportion of severe asthma patients report symptoms at work (OR=2.7) or have to change jobs (OR=4.3) and fewer severe than mild patients are currently employed (OR=0.39). Smoking and exposure to smoke is similar in mild and severe asthma. Dietary habits do not differ between the groups, but severe asthmatics report eating less savoury snacks and there is a trend for lower intake of sweets. CONCLUSIONS: Analysis of the ECRHS questionnaire in the ENFUMOSA study shows that severe asthma patients experience more symptoms and their health status is impaired by their inability to work and perhaps eat freely. Personal and maternal history of allergy is associated with mild but not severe asthma. Other than sharing a bedroom before the age of 5 years, no childhood exposure risk factors associated with severe asthma could be identified from this analysis.

Emissions of regulated pollutants from a spark ignition engine. Influence of fuel and air/fuel equivalence ratio.

A spark ignition engine is used to determine the influence of fuel composition and air/fuel equivalence ratio on the exhaust emissions of regulated pollutants. Two specific fuel matrices are used: the first contains eight hydrocarbons and the second contains four oxygenated compounds. A specific experimental design is used for these tests. Fuel aromatics increase the exhaust CO, HC, and NOx at stoichiometry, lean and rich conditions. Lambda is more important than fuel composition in the case of CO and HC. At stoichiometry, the addition of oxygenated compounds can decrease exhaust CO, HC, and NOx up to 30%, 50%, and 60%, respectively. Under these conditions, the addition of 5% of 2-propanol is the most effective for the reduction of CO, the addition of 20% of ethanol forthe reduction of HC, and this of 5% of methyl tributyl ester (MTBE) for the NOx. The addition of oxygenated compounds can decrease CO by 30% at lean conditions, while no decrease is observed at rich ones; HC and NOx can decrease up to 30% and 80%, respectively, under lean conditions and 50% under rich ones. At all lambda tested, exhaust NOx increases with the addition of 20% of 2-propanol.

Emission of alcohols and carbonyl compounds from a spark ignition engine. Influence of fuel and air/fuel equivalence ratio.

A spark ignition engine was used to study the impact of fuel composition and of the air/fuel equivalence (lambda) ratio on exhaust emissions of alcohols and aldehydes/ketones. Fuel blends contained eight hydrocarbons (n-hexane, 1-hexene, cyclohexane, n-octane, isooctane, toluene, o-xylene, and ethylbenzene (ETB)) and four oxygenated compounds (methanol, ethanol, 2-propanol, and methyl tert butyl ether (MTBE)). Exhaust methanol is principally produced from fuel methanol and MTBE but also from ethanol, 2-propanol, isooctane, and hexane. Exhaust ethanol and 2-propanol are produced only from the respective fuel compounds. Exhaust formaldehyde is mainly produced from fuel methanol, acetaldehyde from fuel ethanol, and propionaldehyde from straight-chain hydrocarbons. Exhaust acroleine comes from fuel 1-hexene, acetone from 2-propanol, n-hexane, n-octane, isooctane, and MTBE. Exhaust crotonaldehyde comes from fuel 1-hexene, cyclohexane, n-hexane, and n-octane, methacroleine from fuel isooctane, and benzaldehyde from fuel aromatics. Light pollutants (C1-C2) are most likely formed from intermediate species which are quite independent of the fuel composition. An increase in A increases the exhaust concentration of acroleine, crotonaldehyde, methacroleine, and decreases these of the three alcohols for the alcohol-blended fuels. The concentration of methanol, formaldehyde, propionaldehyde, and benzaldehyde is a maximum atstoichiometry. The exhaust concentration of acetaldehyde and acetone presents a complex behavior: it increases in some cases, decreases in others, or presents a maximum at stoichiometry. The concentration of four aldehydes (formaldehyde, acetaldehyde, propionaldehyde, and benzaldehyde) is also linked with the exhaust temperature and fuel H/C ratio.

C1-C5 organic acid emissions from an SI engine: influence of fuel and air/fuel equivalence ratio.

A spark ignition engine is used to study the impact of fuel composition and of the air/fuel equivalence ratio on exhaust emissions of organic acids. Fuel blends are composed from eight hydrocarbons (n-hexane, 1-hexene, cyclohexane, n-octane, 2,2,4-trimethylpentane, toluene, o-xylene, and ethylbenzene) and four oxygenated compounds (methanol, ethanol, 2-propanol, and MTBE). Exhaust formic acid is slightly enhanced from aromatics and oxygenated compounds; acetic acid is slightly enhanced from the oxygenated fuel components; propionic acid comes from fuel aromatic compounds, and butyric acid originates from fuel o-xylene. Acrylic and isovaleric acids are also detected in lower concentrations. It is unlikely that oxygenated compounds are precursors to the formation of organic acids, but they facilitate their formation because they facilitate the oxidation of other fuel components. Exhaust concentration of formic acid is also related to exhaust oxygen and exhaust temperature. Air/fuel equivalence ratio increases the exhaust concentration of formic, acetic acid (for the fuels without oxygenated compounds), and acrylic acid and decreases the concentration of isovaleric acid. The acetic (for the oxygenated fuels), propionic, and butyric acids are at a maximum at stoichiometry.

Magnesium levels in plasma and erythrocytes before and after histamine challenge.

Previous studies have assessed the protective effect of nebulized magnesium sulphate on bronchial hyperreactivity. This study investigated the effect of histamine challenge on intracellular (erythrocytes) and extracellular (plasma) levels of magnesium and the possible relationship between degree of bronchial hyperreactivity and levels of Mg in plasma and erythrocytes. The authors studied 42 mildly asthmatic patients (10 on inhaled steroids) and 20 healthy subjects. Histamine challenge was performed by the dosimeter method and provocative dose causing a 20% fall in forced expiratory volume in one second (PD20) (FEV1) was calculated. Mg levels were measured with a calmagite colourimetric assay, both at baseline and when FEV1 had fallen by 20%. The results showed that Mg levels in plasma did not significantly change after histamine challenge (from 2.06+/-0.02 mg x dL(-1) to 2.08+/-0.02 mg x dL(-1) respectively, p=0.14). Conversely there was a statistically significant decrease in Mg levels in erythrocytes between these two time points (from 1.84+/-0.02 fmmol x cell to 1.78+/-0.02 fmmol x cell p<0.0001). Similar results were observed when the subgroups were studied separately. There was no significant correlation between PD20, the difference in both magnesium concentrations (baseline-PD20 time) or the initial values of Mg levels in erythrocytes and plasma. To conclude, histamine challenge reduces magnesium levels in erythrocytes while plasma levels remain unchanged. This histamine-induced decrease in magnesium levels occurs regardless of the diagnosis of asthma, and it is not correlated with the degree of bronchial hyperreactivity.

The Influence of Gasoline Formulation on Specific Pollutant Emissions.

Many recent works have dealt with the influence of fuel composition on regulated and specific pollutant emissions from spark ignition engines. While many qualitative correlations have been already proposed, only a few quantitative ones are known (benzene remains an exception). This paper describes qualitative and quantitative correlations between fuel composition and specific pollutant emissions (individual hydrocarbons, aldehydes, ketones, alcohols, and organic acids) of a spark ignition engine. The aim of this work was to find the precursors of the main specific pollutants. Then, for each of them, a multilinear equation has been calculated, illustrating the correlation between its concentration in exhaust gases and its content in the fuel. The results of these calculations point out which initial compound favors the formation of a determined pollutant. As lean conditions are probably going to be used in future commercial engines, the fuel effect has been studied for a broad range of equivalence ratios (from 0.8 to 1.2).

Using recurrent neural networks for adaptive communication channel equalization.

Nonlinear adaptive filters based on a variety of neural network models have been used successfully for system identification and noise-cancellation in a wide class of applications. An important problem in data communications is that of channel equalization, i.e., the removal of interferences introduced by linear or nonlinear message corrupting mechanisms, so that the originally transmitted symbols can be recovered correctly at the receiver. In this paper we introduce an adaptive recurrent neural network (RNN) based equalizer whose small size and high performance makes it suitable for high-speed channel equalization. We propose RNN based structures for both trained adaptation and blind equalization, and we evaluate their performance via extensive simulations for a variety of signal modulations and communication channel models. It is shown that the RNN equalizers have comparable performance with traditional linear filter based equalizers when the channel interferences are relatively mild, and that they outperform them by several orders of magnitude when either the channel's transfer function has spectral nulls or severe nonlinear distortion is present. In addition, the small-size RNN equalizers, being essentially generalized IIR filters, are shown to outperform multilayer perceptron equalizers of larger computational complexity in linear and nonlinear channel equalization cases.