A phase II open-label trial of avelumab plus axitinib in previously treated non-small-cell lung cancer or treatment-naïve, cisplatin-ineligible urothelial cancer.

BACKGROUND: We hypothesized that avelumab plus axitinib could improve clinical outcomes in patients with advanced non-small-cell lung cancer (NSCLC) or urothelial carcinoma (UC). PATIENTS AND METHODS: We enrolled previously treated patients with advanced or metastatic NSCLC, or untreated, cisplatin-ineligible patients with advanced or metastatic UC. Patients received avelumab 800 mg every 2 weeks (Q2W) and axitinib 5 mg orally two times daily. The primary endpoint was objective response rate (ORR). Immunohistochemistry was used to assess programmed death-ligand 1 (PD-L1) expression (SP263 assay) and the presence of CD8+ T cells (clone C8/144B). Tumor mutational burden (TMB) was assessed by whole-exome sequencing. RESULTS: A total of 61 patients were enrolled and treated (NSCLC, n = 41; UC, n = 20); 5 remained on treatment at data cut-off (26 February 2021). The confirmed ORR was 31.7% in the NSCLC cohort and 10.0% in the UC cohort (all partial responses). Antitumor activity was observed irrespective of PD-L1 expression. In exploratory subgroups, ORRs were higher in patients with higher (≥median) CD8+ T cells in the tumor. ORRs were higher in patients with lower TMB (

Size distribution and relationship of airborne SARS-CoV-2 RNA to indoor aerosol in hospital ward environments.

Aerosol particles proved to play a key role in airborne transmission of SARS-CoV-2 viruses. Therefore, their size-fractionated collection and analysis is invaluable. However, aerosol sampling in COVID departments is not straightforward, especially in the sub-500-nm size range. In this study, particle number concentrations were measured with high temporal resolution using an optical particle counter, and several 8 h daytime sample sets were collected simultaneously on gelatin filters with cascade impactors in two different hospital wards during both alpha and delta variants of concern periods. Due to the large number (152) of size-fractionated samples, SARS-CoV-2 RNA copies could be statistically analyzed over a wide range of aerosol particle diameters (70-10 µm). Our results revealed that SARS-CoV-2 RNA is most likely to exist in particles with 0.5-4 µm aerodynamic diameter, but also in ultrafine particles. Correlation analysis of particulate matter (PM) and RNA copies highlighted the importance of indoor medical activity. It was found that the daily maximum increment of PM mass concentration correlated the most with the number concentration of SARS-CoV-2 RNA in the corresponding size fractions. Our results suggest that particle resuspension from surrounding surfaces is an important source of SARS-CoV-2 RNA present in the air of hospital rooms.

Severe exacerbations and mortality in COPD patients: A retrospective analysis of the database of the Hungarian National Health Insurance Fund.

INTRODUCTION: COPD is one of the most common pulmonary diseases and one of the leading causes of death worldwide. Exacerbations of COPD include acute worsening that could lead to hospitalization and death. In this study, our objective was to investigate the natural course of moderate and severe exacerbations (SAE) and mortality in the Hungarian population in the past decade. METHODS: A retrospective financial database analysis was performed to examine the risk of additional SAEs and death after the first ever SAE in COPD patients, using the financial database of the Hungarian National Health Insurance Fund (NHIF). Patients were enrolled between 2009.01.01. and 2019.12.31. if they had received at least one inhaled drug (LABA, LAMA, ICS or SABA/SAMA) and had been hospitalized for a COPD exacerbation (ICD-10 code J44). RESULTS: A total of 63,037 patients with COPD were enrolled after their first SAE. Of them, 27,095 patients suffered at least one subsequent SAE, and 32,120 patients died during the 10-year follow-up. The median survival was 4.7 years. The risk of subsequent hospitalizations increased significantly after each SAE, with hazard ratios ranging from 1.65 to 5.01. The risk for mortality was increased after each SAE, but did not increase further with the number of SAEs. Moreover, the risk for subsequent SAE and death increased with moderate exacerbations; however, this risk did not increase further with each event. CONCLUSIONS: Despite a relevant improvement in COPD treatment, the natural course of exacerbations remained unchanged. This result highlights the importance of preventing exacerbations and the need for more research to better predict them.

Circulating P-Selectin Glycoprotein Ligand 1 and P-Selectin Levels in Obstructive Sleep Apnea Patients.

PURPOSE: Obstructive sleep apnea (OSA) is characterized by chronic intermittent hypoxia which induces inflammation in blood vessels leading to the development of cardiovascular comorbidities. Several studies implicated the role of P-selectin in vascular inflammation of OSA. P-selectin glycoprotein ligand 1 (PSGL-1) is the main activator for P-selectin and is involved in immune cell trafficking. However, PSGL-1 has not been analyzed in OSA. The aim of the study was to investigate plasma PSGL-1 and P-selectin levels to have a deeper understanding on their interaction in obstructive sleep apnea. METHODS: Fifty-one untreated patients with OSA and 42 non-OSA controls were recruited. Plasma PSGL-1 levels were determined in evening and morning samples, P-selectin levels were analyzed in morning samples using commercially available ELISA kits. Polysomnography was performed in all participants. OSA was defined by an apnea-hypopnea index ≥ 5/h. RESULTS: PSGL-1 levels did not differ between controls and OSA patients either in the evening or in the morning. Although, there was no difference between controls (16.9/6.8-40.8 ng/ml) and patients with OSA (19.6/8.4-56.8, p = 0.24), patients with severe OSA had increased plasma P-selectin levels (25.6/8.4-56.8 ng/ml) compared to mild OSA patients (14.1/8.5-35.3 ng/ml, p = 0.006) and controls (p = 0.03). CONCLUSIONS: P-selectin expression relates to disease severity suggesting a pathophysiological role in endothelial cell activation. PSGL-1 levels are unaltered in OSA, suggesting an alternative activation pathway for P-selectin in OSA.

Trends in prevalence and risk factors of allergic rhinitis symptoms in primary schoolchildren six years apart in Budapest

Background: Few data are available concerning the time trends and risk factors associated with allergic rhinitis (AR) in schoolchildren in Hungary. Methods: At an interval of six years, parents of 6–12-year-old children completed identical ISAAC-based and additional questionnaires related to possible risk factors. Results: Response rate was 62.8% with 6335 questionnaires distributed in 2007, and 52.9% with 6441 questionnaires in 2013. The prevalence of current AR symptoms (subjects presenting clinical symptoms of AR in the past 12 months, but had yet to be diagnosed by physician) increased significantly from 14.9% to 23.5% (p < 0.001). There was no significant change in the prevalence of physician-diagnosed AR (11.6–11.2%). In multivariate analysis, gender (OR 0.733; CI 0.642–0.931), a family history of atopy (OR 2.017; CI 1.669–2.436), frequent upper respiratory tract infections (OR 2.033; CI 1.659–2.492), long-lasting disease before the appearance of the allergy (OR 2.119; CI 1.311–3.428), feather bedding (OR 0.773; CI 0.599–0.996) and living in a green area (OR 1.367; CI 1.133–1.650) were found to be significant risk factors of cumulative AR in 2013. In both of the groups with (p < 0.000) or without (p < 0.003) AR the families with a history of atopy used feather bedding less frequently than families without atopy. Conclusion: Although the prevalence of physician-diagnosed AR has not shown significant changes during the studied interval, the significant increase of the current AR symptoms suggests growing prevalence of AR among children in Budapest. Our results revealed new aspects of bedding customs in atopic families (AU)

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Trends in prevalence and risk factors of allergic rhinitis symptoms in primary schoolchildren six years apart in Budapest.

BACKGROUND: Few data are available concerning the time trends and risk factors associated with allergic rhinitis (AR) in schoolchildren in Hungary. METHODS: At an interval of six years, parents of 6-12-year-old children completed identical ISAAC-based and additional questionnaires related to possible risk factors. RESULTS: Response rate was 62.8% with 6335 questionnaires distributed in 2007, and 52.9% with 6441 questionnaires in 2013. The prevalence of current AR symptoms (subjects presenting clinical symptoms of AR in the past 12 months, but had yet to be diagnosed by physician) increased significantly from 14.9% to 23.5% (p<0.001). There was no significant change in the prevalence of physician-diagnosed AR (11.6-11.2%). In multivariate analysis, gender (OR 0.733; CI 0.642-0.931), a family history of atopy (OR 2.017; CI 1.669-2.436), frequent upper respiratory tract infections (OR 2.033; CI 1.659-2.492), long-lasting disease before the appearance of the allergy (OR 2.119; CI 1.311-3.428), feather bedding (OR 0.773; CI 0.599-0.996) and living in a green area (OR 1.367; CI 1.133-1.650) were found to be significant risk factors of cumulative AR in 2013. In both of the groups with (p<0.000) or without (p<0.003) AR the families with a history of atopy used feather bedding less frequently than families without atopy. CONCLUSION: Although the prevalence of physician-diagnosed AR has not shown significant changes during the studied interval, the significant increase of the current AR symptoms suggests growing prevalence of AR among children in Budapest. Our results revealed new aspects of bedding customs in atopic families.

MCP-1 in pleural injury: CCR2 mediates haptotaxis of pleural mesothelial cells.

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.

Talc induces apoptosis in human malignant mesothelioma cells in vitro.

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.

Inhibition of interleukin-8 reduces human malignant pleural mesothelioma propagation in nude mouse model.

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.

Interleukin 8: an autocrine growth factor for malignant mesothelioma.

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.

[Prevention of acute respiratory infections in healthy young adults by using oral immunomodulators]. / Akut légúti fertözések megelözése egészséges, fiatal felnött közösségben oralis immunmoduláns preventív alkalmazásával.

It is a general experience at army posts that right after the joining up period the number of airway infections suddenly increases. The upper and lower airway infections are especially facilitated by the confinement of military barracks, and the high number of smokers among soldiers. In the winter of 1995/96 at an army post of the Hungarian National Defense Forces authors treated 68 healthy, young recruits, aged between 18-23 preventively with an immunomodulant which contains lyophilized bacterial extracts, and placebo. The aim was to try this medicine on healthy adults to prevent or influence acute respiratory infections. In one third of the nine-month long follow-up period, a blind study was carried out, and two thirds of it were spent with a double blind one. The number of airway infections and off duty days was reduced by more than 40% in the group which was treated with the immunomodulant. In case of airway infection the complains and the signs were also milder in this group. Furthermore the medicine consumption decreased too. All of these indicate that the tried immunomodulant can be used in the primary prevention of airway infections among healthy adults even in a markedly infective environment.

[Long-term-follow-up-study after measles-vaccination (author's transl)]. / Langzeitstudie nach Masernimpfung

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.