Favorable impact of PD1/PD-L1 antagonists on bone remodeling: an exploratory prospective clinical study and ex vivo validation.

BACKGROUND: Skeletal morbidity in patients with cancer has a major impact on the quality of life, and preserving bone health while improving outcomes is an important goal of modern antitumor treatment strategies. Despite their widespread use in early disease stages, the effects of immune checkpoint inhibitors (ICIs) on the skeleton are still poorly defined. Here, we initiated a comprehensive investigation of the impact of ICIs on bone health by longitudinal assessment of bone turnover markers in patients with cancer and by validation in a novel bioengineered 3D model of bone remodeling. METHODS: An exploratory longitudinal study was conducted to assess serum markers of bone resorption (C-terminal telopeptide, CTX) and formation (procollagen type I N-terminal propeptide, PINP, and osteocalcin, OCN) before each ICI application (programmed cell death 1 (PD1) inhibitor or programmed death-ligand 1 (PD-L1) inhibitor) for 6 months or until disease progression in patients with advanced cancer and no evidence of bone metastases. To validate the in vivo results, we evaluated osteoclast (OC) and osteoblast (OB) differentiation on treatment with ICIs. In addition, their effect on bone remodeling was assessed by immunohistochemistry, confocal microscopy, and proteomics analysis in a dynamic 3D bone model. RESULTS: During the first month of treatment, CTX levels decreased sharply but transiently. In contrast, we observed a delayed increase of serum levels of PINP and OCN after 4 months of therapy. In vitro, ICIs impaired the maturation of preosteoclasts by inhibiting STAT3/NFATc1 signaling but not JNK, ERK, and AKT while lacking any direct effect on osteogenesis. However, using our bioengineered 3D bone model, which enables the simultaneous differentiation of OB and OC precursor cells, we confirmed the uncoupling of the OC/OB activity on exposure to ICIs by demonstrating impaired OC maturation along with increased OB differentiation. CONCLUSION: Our study indicates that the inhibition of the PD1/PD-L1 signaling axis interferes with bone turnover and may exert a protective effect on bone by indirectly promoting osteogenesis.

Determinants of immunoglobulin G responses to respiratory syncytial virus and rhinovirus in children and adults.

Introduction: Exposure to respiratory viruses is a significant cause of morbidity and affects virus-specific antibody levels. Little is known about determinants associated with immune response to these viruses. We aimed to investigate the determinants of respiratory syncytial virus (RSV)- and rhinovirus (RV)- specific IgG responses in both children and adults. Methods: The study is based on the EGEA cohort, composed of 530 samples of children in EGEA1 (1991-95) and 1241 samples of adults in EGEA2 (2003-07). Cumulative RV-specific IgG levels (species A, B and C) and IgG levels to RSV-G protein were measured by using micro-array technoloy. Multiple linear mixed models (random effect to account for familial dependence) were performed to assess associations between age, sex, body mass index (BMI), tobacco smoke exposure and season of blood sampling with RSV-and RV-specific IgG levels. Results: In children (11.1 ± 2.8 years old, 57% boys), higher RV-specific IgG levels were associated with older age (only for RV-B), female sex and lower BMI, while only older age was associated with higher RSV-specific IgG levels. In adults (43.5 ± 16.7 years old, 48% men), younger age, female sex, lower BMI, active smoking and all seasons except summer were associated with higher RV-specific IgG levels. Older age, active smoking and all seasons except summer were associated with higher RSV-specific IgG levels. Conclusion: Personal and seasonal determinants of RSV- and RV-specific IgG levels seem to vary according to the respiratory virus type and between children and adults, suggesting different patterns of responses along the life course.

Cumulative IgE-levels specific for respiratory allergens as biomarker to predict efficacy of anti-IgE-based treatment of severe asthma.

Molecular therapies, including anti-IgE, biologicals and small molecules are increasingly used for treatment of asthma. The effectiveness of these therapies may be increased with biomarkers. Aim of this study was to assess the value of measuring cumulative IgE levels specific for respiratory allergens to increase the efficacy of anti-IgE therapy for severe bronchial asthma. One hundred and thirty seven patients with severe asthma were recruited from 2016 to 2022. Standard empirical allergy diagnosis (i.e., anamnesis, skin testing, allergen-specific IgE measurement), blood eosinophil counting, measurement of total IgE and of cumulative IgE-specific for respiratory allergens by Phadiatop™ were performed. Thirty four patients with severe allergic asthma, for whom all three diagnostic methods were performed, were then used to analyze the efficacy of anti-IgE treatment in patients stratified in two groups according to cumulative IgE levels specific for respiratory allergens determined by Phadiatop™. Group #1 patients (n = 8) had cumulative specific IgE values ≥ 0.35 and < 1.53 PAU/l while in group #2 patients (n = 26) they were ≥ 1.53 PAU/l. Treatment with Omalizumab was performed for at least 12 months. The level of asthma control (ACT questionnaire), the number of asthma exacerbations, the quality of life (AQLQ questionnaire), the need for systemic corticosteroids, and the respiratory function (FEV1) was determined by "before-after" analysis for each group, followed by a comparison of the dynamics between groups. In group 2 patients with an initial allergen-specific IgE level ≥ 1.53 kUA/L, the efficacy of Omalizumab treatment was better regarding asthma control, number of exacerbations, and quality of life than in group 1 patients. Our study provides evidence that measuring cumulative levels of IgE specific for respiratory allergens could be a useful screening method for detecting an allergic phenotype of severe asthma and may serve as biomarker to enhance the success of IgE-targeted therapy.

Microarray-Based Analyses of Rhinovirus Species-Specific Antibody Responses in Exacerbated Pediatric Asthma in a German Pediatric Cohort.

Rhinoviruses (RV) account for a significant number of asthma exacerbations, and RV species C may be associated with a severe course in vulnerable patient groups. Despite important evidence on the role of RV reported by clinicians and life scientists, there are still unanswered questions regarding their influence on asthma exacerbation in young patients. Thus, we measured the RVspecies-specific IgG titers in our German pediatric exacerbation cohort using a microarray-based technology. For this approach, human sera of patients with exacerbated asthma and wheeze, as well as healthy control subjects (n = 136) were included, and correlation analyses were performed. Concordantly with previously published results, we observed significantly higher cumulative levels of RV species A-specific IgG (p = 0.011) and RV-C-specific IgG (p = 0.051) in exacerbated asthma group compared to age-matched controls. Moreover, atopic wheezers had increased RV-specific IgG levels for species A (p = 0.0011) and species C (p = 0.0009) compared to non-atopic wheezers. Hypothesizing that bacterial infection positively correlates with immune memory against RV, we included nasopharyngeal swab results in our analyses and detected limited correlations. Interestingly, the eosinophil blood titer positively correlated with RV-specific IgG levels. With these observations, we add important observations to the existing data regarding exacerbation in pediatric and adolescent medicine. We propose that scientists and clinicians should pay more attention to the relevance of RV species in susceptible pediatric patients.

Identification of Epitopes on Rhinovirus 89 Capsid Proteins Capable of Inducing Neutralizing Antibodies.

Rhinoviruses (RVs) are major causes of the common cold, but they can also trigger exacerbations of asthma. More than 160 different RV strains exist and can be classified into three genetic species (RV-A, RV-B and RV-C) which bind to different receptors on human cells including intracellular adhesion molecule 1 (ICAM-1), the low-density lipoprotein receptor (LDLR) or the cadherin-related family member 3 (CDHR3). Epitopes located in the RV capsid have mainly been determined for RV2, a minor-group RV-A strain binding to LDLR, and for RV14, a major-group RV-B strain binding to ICAM-1. In order to study epitopes involved in the neutralization of RV89, an ICAM-1-binding RV-A strain which is highly different from RV2 and RV14 in terms of receptor specificity and sequence, respectively, we analyzed the specificity and epitopes of a highly neutralizing antiserum using recombinantly produced RV89 capsid proteins (VP1, VP2, VP3 and VP4), recombinant fragments and synthetic overlapping peptides thereof. We found that the antiserum which neutralized in vitro RV89 infection up to a dilution of 1:24,000 reacted with the capsid proteins VP1 and VP2 but not with VP3 and VP4. The neutralizing antibodies recognized recombinant fragments comprising approximately 100 amino acids of the N- and C-terminus of VP1 and the middle part of VP2, in particular, three peptides which, according to molecular modeling based on the three-dimensional structure of RV16, were surface-exposed on the viral capsid. Two recombinant fusion proteins containing the identified peptides fused to hepatitis B (HBV)-derived preS as a carrier protein induced upon immunization of rabbits antibodies capable of neutralizing in vitro RV89 infections. Interestingly, the virus-neutralizing epitopes determined for RV89 corresponded to those determined for minor-group RV2 binding to LDL and major-group RV14 belonging to the RV-B species, which are highly different from RV89. Our results indicate that highly different RV strains, even when reacting with different receptors, seem to engage similar parts of their capsid in the infection process. These results may be important for the design of active and passive immunization strategies for RV.

Lymph but Not Blood Vessel Invasion Is Independent Prognostic in Lung Cancer Patients Treated by VATS-Lobectomy and Might Represent a Future Upstaging Factor for Early Stages.

Lung cancer is the most frequent cause of cancer-related death worldwide. The patient's outcome depends on tumor size, lymph node involvement and metastatic spread at the time of diagnosis. The prognostic value of lymph and blood vessel invasion, however, is still insufficiently investigated. We retrospectively examined the invasion of lymph vessels and blood vessels separately as two possible prognostic factors in 160 patients who underwent a video-assisted thoracoscopic lobectomy for non-small-cell lung cancer at our institution between 2014 and 2019. Lymph vessel invasion was significantly associated with the UICC stage, lymph node involvement, tumor dedifferentiation, blood vessel invasion and recurrence. Blood vessel invasion tended to be negative prognostic, but missed the level of significance (p = 0.108). Lymph vessel invasion, on the other hand, proved to be a prognostic factor for both histological subtypes, adenocarcinoma (p < 0.001) as well as squamous cell carcinoma (p = 0.018). After multivariate analysis apart from the UICC stage, only lymph vessel invasion remained independently prognostic (p = 0.018). Remarkably, we found analogue survival curve progressions of patients with stage I, with lymph vessel invasion, compared to stage II non-small-cell lung cancer. After further validation in prospective studies, lymph vessel invasion might be considered as an upstaging factor in resectable lung cancer. Especially in the early-stage of the disease, it might represent an additional risk factor to consider adjuvant therapy after surgical resection.

Transbronchial lung cryobiopsy: prospective safety evaluation and 90-day mortality after a standardized examination protocol.

BACKGROUND: Transbronchial lung cryobiopsy (TBLC) is a new method of bronchoscopic tissue sampling in patients with unclear diffuse parenchymal lung disease (DPLD). While not the gold standard, TBLC has a good diagnostic correlation with surgical lung biopsy, and retrospective analyses of peri-interventional complications and mortality are promising. However, prospective reports on 90-day mortality are lacking. OBJECTIVES: This study addresses morbidity and 30- and 90-day mortality in TBLC after a standardized protocol. METHODS: In this prospective study, 75 patients with DPLD requiring tissue sampling were included. A standardized protocol (including prophylactic use of an endobronchial balloon, postinterventional observation, and minimum sampling requirements) was used in all patients. Adverse events (pneumothorax, bronchial bleeding, premature discontinuation, prolonged monitoring at ICU, and fatal outcome) and 30- and 90-day mortality rates were recorded. RESULTS: A total of 308 cryobiopsies were performed in 75 patients. Peri- and postinterventional pneumothorax were observed in 20% (9.3% mild and 10.7% moderate with the necessity of chest drainage), and bronchial bleeding was found in 29.3% (22.7% moderate and 6.7% severe). Total lung capacity below normal value was associated with the risk of pneumothorax (p = 0.009), and diffusion limitation for carbon monoxide below normal value was associated with the risk of bronchial bleeding (p = 0.044). No fatal events were observed within 30 days, and the 90-day mortality rate was 1.3%, but not related to the procedure itself. CONCLUSION: As it gradually becomes the invasive procedure of choice in unclear DPLD, TBLC is a safe procedure with a low 30- and 90-day mortality.Trial registration ID: DRKS00026746 (German Clinical Trial Register).

Evaluation of Antibody Responses to COVID-19 Vaccines among Solid Tumor and Hematologic Patients.

Vaccination is the primary public health strategy to cope with the COVID-19 pandemic. Although solid tumor and hematologic patients are at higher risk of serious COVID-19-related complications, data on immune responses to COVID-19 vaccines in this patient cohort are particularly scarce. The present study, therefore, aimed at the standardized determination of anti-SARS-CoV-2 spike protein antibody titers among non-vaccinated versus vaccinated solid tumor and hematologic patients who are under clinical observation or under treatment at the University Hospital Krems. Standardized anti-SARS-CoV-2 S antibody titers of a total of 441 patients were retrospectively analyzed. Our results show that antibody titers against the SARS-CoV-2 spike protein are significantly higher in solid tumor versus hematologic patients. While SARS-CoV-2 antibody titers were equal among sexes, an age-dependent decrease was observed. Of note, our studies additionally show that complete vaccination represents a valuable predictor for high anti-SARS-CoV-2 antibody responses in solid tumor and hematologic patients. In summary, to date, this is one of the largest studies to comprehensively evaluate the impact of various COVID-19 vaccines on anti-SARS-CoV-2 S antibody production in solid tumor and hematologic patients. Our findings aim to support future vaccination strategies in these highly vulnerable patients, including vaccination booster programs and alternative protective approaches.

Microarray Technology May Reveal the Contribution of Allergen Exposure and Rhinovirus Infections as Possible Triggers for Acute Wheezing Attacks in Preschool Children.

Allergen exposure and rhinovirus (RV) infections are common triggers of acute wheezing exacerbations in early childhood. The identification of such trigger factors is difficult but may have therapeutic implications. Increases of IgE and IgG in sera, were shown against allergens and the N-terminal portion of the VP1 proteins of RV species, respectively, several weeks after allergen exposure or RV infection. Hence, increases in VP1-specific IgG and in allergen-specific IgE may serve as biomarkers for RV infections or allergen exposure. The MeDALL-allergen chip containing comprehensive panels of allergens and the PreDicta RV chip equipped with VP1-derived peptides, representative of three genetic RV species, were used to measure allergen-specific IgE levels and RV-species-specific IgG levels in sera obtained from 120 preschool children at the time of an acute wheezing attack and convalescence. Nearly 20% of the children (22/120) showed specific IgE sensitizations to at least one of the allergen molecules on the MeDALL chip. For 87% of the children, increases in RV-specific IgG could be detected in the follow-up sera. This percentage of RV-specific IgG increases was equal in IgE-positive and -negative children. In 10% of the children, increases or de novo appearances of IgE sensitizations indicative of allergen exposure could be detected. Our results suggest that, in the majority of preschool children, RV infections trigger wheezing attacks, but, in addition, allergen exposure seems to play a role as a trigger factor. RV-induced wheezing attacks occur in IgE-sensitized and non-IgE-sensitized children, indicating that allergic sensitization is not a prerequisite for RV-induced wheeze.

Somatic Copy-Number Alterations in Plasma Circulating Tumor DNA from Advanced EGFR-Mutated Lung Adenocarcinoma Patients.

BACKGROUND: To assess the clinical relevance of genome-wide somatic copy-number alterations (SCNAs) in plasma circulating tumor DNA (ctDNA) from advanced epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma patients. METHODS: We included 43 patients with advanced EGFR T790M-positive lung adenocarcinoma who were treated with osimertinib after progression under previous EGFR-TKI therapy. We performed genomic profiling of ctDNA in plasma samples from each patient obtained pre-osimertinib and after patients developed resistance to osimertinib. SCNAs were detected by shallow whole-genome plasma sequencing and EGFR mutations were assessed by droplet digital PCR. RESULTS: SCNAs in resistance-related genes (rrSCNAs) were detected in 10 out of 31 (32%) evaluable patients before start of osimertinib. The presence of rrSCNAs in plasma before the initiation of osimertinib therapy was associated with a lower response rate to osimertinib (50% versus 81%, p = 0.08) and was an independent predictor for shorter progression-free survival (adjusted HR 3.33, 95% CI 1.37-8.10, p = 0.008) and overall survival (adjusted HR 2.54, 95% CI 1.09-5.92, p = 0.03). CONCLUSIONS: Genomic profiling of plasma ctDNA is clinically relevant and affects the efficacy and clinical outcome of osimertinib. Our approach enables the comprehensive assessment of SCNAs in plasma samples of lung adenocarcinoma patients and may help to guide genotype-specific therapeutic strategies in the future.

Detection of EGFR Activating and Resistance Mutations by Droplet Digital PCR in Sputum of EGFR-Mutated NSCLC Patients.

BACKGROUND: Proof of the T790M resistance mutation is mandatory if patients with EGFR-mutated non-small cell lung cancer (NSCLC) progress under first- or second-generation tyrosine kinase inhibitor therapy. In addition to rebiopsy, analysis of plasma circulating tumor DNA is used to detect T790M resistance mutation. We studied whether sputum is another feasible specimen for detection of EGFR mutations. METHODS: Twenty-eight patients with advanced EGFR-mutated NSCLC were included during stable and/or progressive disease. The initial activating EGFR mutations (exon 19 deletions or L858R mutations) at stable disease and at progressive disease (together with T790M) were assessed in simultaneously collected plasma and sputum samples and detected by droplet digital polymerase chain reaction (ddPCR). RESULTS: Activating EGFR mutations were detected in 47% of the plasma samples and 41% of sputum samples during stable disease, and in 57% of plasma samples and 64% of sputum samples during progressive disease. T790M was detected in 44% of the plasma samples and 66% of the sputum samples at progressive disease. In ddPCR T790M-negative results for both specimens (plasma and sputum), negativity was confirmed by rebiopsy in 5 samples. Concordance rate of plasma and sputum for T790M was 0.86, with a positive percent agreement of 1.0 and a negative percent agreement of 0.80. CONCLUSIONS: We demonstrated that EGFR mutation analysis with ddPCR is feasible in sputum samples. Combination of plasma and sputum analyses for detection of T790M in NSCLC patients with progressive disease increases the diagnostic yield compared with molecular plasma analysis alone.

Later-Line Treatment with Lorlatinib in ALK- and ROS1-Rearrangement-Positive NSCLC: A Retrospective, Multicenter Analysis.

In clinical practice, patients with anaplastic lymphoma kinase (ALK)-rearrangement-positive non-small-cell lung cancer commonly receive sequential treatment with ALK tyrosine kinase inhibitors. The third-generation agent lorlatinib has been shown to inhibit a wide range of ALK resistance mutations and thus offers potential benefit in later lines, although real-world data are lacking. This multicenter study retrospectively investigated later-line, real-world use of lorlatinib in patients with advanced ALK- or ROS1-positive lung cancer. Fifty-one patients registered in a compassionate use program in Austria, who received second- or later-line lorlatinib between January 2016 and May 2020, were included in this retrospective real-world data analysis. Median follow-up was 25.3 months. Median time of lorlatinib treatment was 4.4 months for ALK-positive and 12.2 months for ROS-positive patients. ALK-positive patients showed a response rate of 43.2%, while 85.7% percent of the ROS1-positive patients were considered responders. Median overall survival from lorlatinib initiation was 10.2 and 20.0 months for the ALK- and ROS1-positive groups, respectively. In the ALK-positive group, lorlatinib proved efficacy after both brigatinib and alectinib. Lorlatinib treatment was well tolerated. Later-line lorlatinib treatment can induce sustained responses in patients with advanced ALK- and ROS1-positive lung cancer.

Diagnostic accuracy of two commercially available rapid assays for detection of IgG and IgM antibodies to SARS-CoV-2 compared to ELISA in a low-prevalence population.

Background: New commercially available point-of-care (POC) immunodiagnostic tests are appearing, which may yield rapid results for anti-SARS-CoV-2 antibodies. The aim of this study was to evaluate the diagnostic accuracy of rapid antibody detection tests compared to a validated laboratory-based enzyme-linked immunosorbent assay (ELISA) and to investigate infections amongst healthcare workers (HCWs) after unprotected close contact to COVID-19 patients. Methods: Blood serum and whole blood of 130 participants were tested with NADAL® COVID-19 IgG/IgM rapid test and mö-screen 2019-NCOV coronavirus test against a validated ELISA test. Infection status was evaluated using real-time polymerase-chain-reaction. Results: Acute COVID-19 infection was detected in 2.4% of exposed HCWs. Antibody tests showed an overall frequency of IgG and IgM in 5.3%, with 1.6% asymptomatic infections. The NADAL® test showed a sensitivity (IgM/IgG) of 100% (100%/100%), a specificity (IgM/IgG) of 98.8% (97.6%/100 %), a PPV of 76.9% (57.1%/100%), an NPV of 100% (100%/100%), and a diagnostic accuracy of 98.8% (97.7%/100%). The mö-screen test had a sensitivity (IgM/IgG) of 90.9% (80%/100%), a specificity (IgM/IgG) of 98.8% (97.6%/100%), a PPV of 76.9% (57.1%/100%), an NPV of 99.6% (99.2%/100%), and a diagnostic accuracy of 98.5% (96.9%/100%). Conclusions: The frequency of COVID-19 infections in HCWs after unprotected close contact is higher than in the general population of a low-prevalence country. Both POC tests were useful for detecting IgG, but did not perform well for IgM, mainly due to false positive results.

Results of the Austrian National Lung Cancer Audit.

OBJECTIVES: The Austrian Lung Cancer Audit (ALCA) is a pilot study to evaluate clinical and organizational factors related to lung cancer care across Austria. MATERIALS AND METHODS: The ALCA is a prospective, observational, noninterventional cohort study conducted in 17 departments in Austria between September 2013 and March 2015. Participating departments were selected based on an annual case load of >50 patients with lung cancer. RESULTS: The ALCA included 745 patients, representing 50.5% of all newly diagnosed cancer cases during that time period. In 75.8% of patients, diagnosis was based on histology, and in 24.2% on cytology; 83.1% had non-small-cell lung cancer, 16.9% small-cell lung cancer; and only 4.6% had to be classified as not otherwise specified cancers. The median time elapsed between first presentation at hospital and diagnosis was 8 days (interquartile range [IQR]: 4-15; range: 0-132); between diagnosis and start of treatment it was 15 days for chemotherapy (IQR: 9-27; range: 0-83), 21 days (IQR: 10-35; range: 0-69) for radiotherapy, and 24 days (IQR: 11-36; range: 0-138) for surgery, respectively. In 150 patients undergoing surgical treatment, only 3 (2.0%; n = 147, 3 missings) were seen with postoperative restaging indicating unjustified surgery. One-year follow-up data were available for 723 patients, indicating excellent 49.8% survival; however, a wide range of survival between departments (range: 37.8-66.7) was seen. CONCLUSIONS: The ALCA conducted in high case load departments indicated management of lung cancer in accordance with international guidelines, and overall excellent 1-year survival.

Infraglottic versus supraglottic jet-ventilation for endobronchial ultrasound-guided transbronchial needle aspiration: A randomised controlled trial.

BACKGROUND: For endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) under general anaesthesia, both rigid bronchoscopy and laryngeal masks (LMAs) with superimposed high-frequency jet ventilation can be used. Despite the fact that in Europe rigid bronchoscopy for EBUS-TBNA is still widely used, an increasing number of centres use jet ventilation via the LMA for this procedure. To our knowledge no clinical trials have ever been made to compare these two methods. This trial aimed to evaluate whether patients recover from the procedure more quickly when a LMA is used for ventilation compared with rigid bronchoscopy where muscle relaxants and deep anaesthesia are required. OBJECTIVES: We wanted to test the hypothesis that there is no difference in the postoperative recovery of patients in the postanaesthesia care unit (PACU) after EBUS-TBNA with jet ventilation via a rigid bronchoscope and a LMA. Secondary outcomes were the difference of duration of anaesthesia, the diagnostic outcome of the procedure and drug quantities for both groups. DESIGN: Prospective randomised single blinded two centre controlled trial. SETTING: Two centres in Austria participated. Patients were enrolled from December 2016 until January 2018. PATIENTS: Ninety patients for elective EBUS-TBNA were enrolled and assigned to one of two intervention groups. Two patients were excluded before and eleven patients were excluded after EBUS-TBNA. Seventy-seven were analysed. INTERVENTIONS: Patients assigned to group 1 were ventilated with a LMA; those assigned to group 2 were ventilated via a rigid bronchoscope. Vital signs, drug dosage, duration of anaesthesia, recovery, PACU stay and Aldrete score at the PACU were recorded. MAIN OUTCOME MEASURES: The primary endpoint was an integral over time of a modified Aldrete score. Secondary endpoints were the durations of the interventions, the recovery from anaesthesia and PACU stay, initial and mean Aldrete values at PACU, the effect site concentration of Propofol according to the Schnider pharmacokinetic model, the peak ultiva rates and the diagnostic outcome. RESULTS: We were not able to show any significant difference regarding the postoperative recovery criteria based on the Aldrete score, the durations measured and the diagnostic outcomes. Vital signs remained stable and in an equal range in both groups. There were no differences in the mean effect site propofol concentration and the peak ultiva rates. CONCLUSION: EBUS-TBNA under general anaesthesia using a LMA with SHJV is equal to rigid bronchoscopy with superimposed high-frequency jet ventilation for the variables analysed. TRIAL REGISTRATION: ISRCTN (ISRCTN58911367).

Tumour cell PD-L1 expression is prognostic in patients with malignant pleural effusion: the impact of C-reactive protein and immune-checkpoint inhibition.

Malignant pleural effusion (MPE) confers dismal prognosis and has limited treatment options. While immune-checkpoint inhibition (ICI) proved clinical efficacy in a variety of malignancies, data on the prognostic role of PD-L1 in MPE is scarce. We retrospectively studied PD-L1 tumour proportion score and Ki-67 index in pleural biopsies or cytologies from 123 patients (69 lung cancer, 25 mesothelioma, and 29 extrathoracic primary malignancies). Additionally, the impact of C-reactive protein (CRP) and platelet count was also analysed. Median overall survival (OS) after MPE diagnosis was 9 months. Patients with PD-L1 positive tumours (≥1%) had significantly shorter OS than patients with negative PD-L1 status (p = 0.031). CRP and Ki-67 index were also prognostic and remained independent prognosticators after multivariate analysis. Interestingly, Ki-67 index and CRP influenced the prognostic power of PD-L1. Finally, patients receiving ICI tended to have a longer median OS and CRP - but not PD-L1 - was a significant prognosticator in this subgroup. In summary, histological and circulating biomarkers should also be taken into account as potential biomarkers in ICI therapy and they may have an impact on the prognostic power of PD-L1. Our findings might help personalizing immune-checkpoint inhibition for patients with MPE and warrant further prospective validation.

Toward personalization of asthma treatment according to trigger factors.

Asthma is a severe and chronic disabling disease affecting more than 300 million people worldwide. Although in the past few drugs for the treatment of asthma were available, new treatment options are currently emerging, which appear to be highly effective in certain subgroups of patients. Accordingly, there is a need for biomarkers that allow selection of patients for refined and personalized treatment strategies. Recently, serological chip tests based on microarrayed allergen molecules and peptides derived from the most common rhinovirus strains have been developed, which may discriminate 2 of the most common forms of asthma, that is, allergen- and virus-triggered asthma. In this perspective, we argue that classification of patients with asthma according to these common trigger factors may open new possibilities for personalized management of asthma.

Ratio of carcinoembryonic antigen in pleural fluid and serum for the diagnosis of malignant pleural effusion.

BACKGROUND: Tumour markers in pleural fluid and their diagnostic value are subject to debate. Although there are several studies on this topic, standardized cut-off values do not exist. In this study we investigated the potential of a ratio of carcinoembryonic antigen (CEA) in pleural fluid and serum, serving as an individual marker for pleural cancer manifestation. METHODS: A total of 201 consecutive patients with unclear pleural effusion were included in the study; 98 were diagnosed with malignant pleural effusion and 103 had an effusion due to other, benign reasons. CEA levels in pleural fluid and serum were measured. RESULTS: By using receiver operating characteristics analysis, at the cut-off of 1.0, the CEA ratio showed a specificity of 92% and sensitivity of 85%, with a positive predictive value of 91% and a negative predictive value of 87%. These results are higher than in previous investigations on different pleural tumour markers and their combination. CONCLUSIONS: The CEA ratio is a useful tool in predicting pleural carcinosis. Elevated results in cytology-negative patients should lead to further investigations, such as repeated cytological examination or thoracoscopy.

Cell-Free Plasma DNA-Guided Treatment With Osimertinib in Patients With Advanced EGFR-Mutated NSCLC.

INTRODUCTION: Osimertinib is standard treatment for patients with advanced EGFR T790M-mutated non-small-cell lung cancer who have been pre-treated with EGFR-tyrosine kinase inhibitors (TKIs). We studied whether cell-free plasma DNA for T790M detection can be used to select patients for osimertinib treatment in the clinical routine. METHODS: From April 2015 to November 2016, we included 119 patients with advanced EGFR-mutated non-small-cell lung cancer who had progressed under treatment with an EGFR-TKI. The T790M mutation status was assessed in cell-free plasma DNA by droplet digital polymerase chain reaction in all patients and by tissue analyses in selected patients. RESULTS: T790M mutations were detected in 85 (93%) patients by analyses of cell-free plasma DNA and in 6 (7%) plasma-negative patients by tumor re-biopsy. Eighty-nine of 91 T790M-positive patients received osimertinib. Median progression-free survival (PFS) was 10.1 months (95% confidence interval [CI]: 8.1-12.1). Median survival was not reached and the 1-year survival was 64%. The response rate was 70% in T790M-positive patients (n = 91) in the intention-to-treat population. PFS trended to be shorter in patients with high T790M copy number (≥10 copies/mL) compared to those with low T790M copy number (<10 copies/mL) (hazard ratio for PFS = 1.72, 95% CI: 0.92-3.2, p = 0.09). A comparable trend was observed for overall survival (hazard ratio for overall survival = 2.16, 95% CI: 0.89-5.25, p = 0.09). No difference in response rate was observed based on T790M copy numbers. CONCLUSION: Plasma genotyping using digital polymerase chain reaction is clinically useful for the selection of patients who had progressed during first-line EGFR-TKI therapy for treatment with osimertinib.

Fever after bronchoscopy: serum procalcitonin enables early diagnosis of post-interventional bacterial infection.

BACKGROUND: The aim of this study was to differentiate unspecific and self-limiting fever after bronchoscopy from fever due to infection by using serum procalcitonin, C-reactive protein and neutrophil count. Furthermore, frequency of fever after bronchoscopy and procedures as possible risk factors were evaluated. METHODS: Three hundred and fourteen consecutive patients were included. All bronchoscopies were performed using jet-ventilation and general anesthesia. Patients were analyzed according to interventions performed during bronchoscopy and laboratory results. Microbiological assessment was done in patients who developed fever to prove or rule out a bacterial infection. RESULTS: Forty-four patients showed fever within 24 h following bronchoscopy (14%). A bacterial infection was proven in 11 patients with fever (3.5%). Procalcitonin, neutrophil count and C-reactive protein were significantly higher in patients with fever after bronchoscopy compared to non-fever patients. To predict bacterial infection in the receiver operating analysis, procalcitonin had the highest area under the curve (0.942; 95% confidence interval [CI], 0.768 to 1.000; p = <0.001), followed by neutrophil count (AUC, 0.804; 95% CI, 0.606 to 0.946; p = 0.005), whereas CRP levels where not statistically significant. Endoscopic airway recanalization was the only intervention that induced fever more frequently than all other interventions (OR 13.629). CONCLUSIONS: Fever is frequently seen after bronchoscopy and in some cases caused by bacterial infection. Procalcitonin might be useful to distinguish a bacterial infection from unspecific self-limiting fever. Airway recanalization is a procedure that seems to induce fever significantly more often than other bronchoscopic interventions.