Health Outcomes with Curative and Palliative Therapies in Real World: Role of the Quality of Life Summary Score in Thoracic Oncology Patients.

BACKGROUND: For patients receiving therapy with curative or palliative intent for a thoracic malignancy, prediction of quality of life (QOL), once therapy starts, remains challenging. The role of health assessments by the patient instead of the doctor herein remains ill-defined. AIMS: To assess the evolution of QOL in patients with thoracic malignancies treated with curative and palliative intent, respectively. To identify factors that determine QOL one year after the start of cancer therapy. To identify factors that affect survival. METHODS: We prospectively included consecutive patients with a thoracic malignancy who were starting anti-cancer therapy and measured QOL with QLQ-C30 before the start of therapy, and thereafter at regular intervals for up to 12 months. A multivariate regression analysis of the global health score (GHS) and QOL summary scores (QSS) one year after the start of therapy was conducted. A proportional hazards Cox regression was conducted to investigate the effects of case-mix variables on survival. RESULTS: Of 587 new patients, 375 started different forms of therapy. Most had non-small cell lung cancer (n = 298), 35 had small cell lung cancer, and 42 had other thoracic malignancies or were diagnosed on imaging alone. There were 203 who went for a curative intent and 172 for a palliative intent strategy. The WHO score of 0-1 was more prevalent in the former group (p = 0.02), and comorbidities were equally distributed. At baseline, all QOL indices were better in the curative group (p < 0.05). The curative group was characterized by a significant worsening of GHS and QSS (p < 0.05). The palliative group was characterized by an improvement in GHS and emotional health (p < 0.05), while other dimensions of functioning remained stable. GHS at 12 months was estimated in a multivariate linear regression model (R2 = 0.23-p < 0.001) based on baseline GHS, QSS, and comorbidity burden. QSS at 12 months was estimated (R2 = 0.31-p < 0.001) by baseline QSS and therapeutic intent strategy (curative vs. palliative). The prognostic factors for overall survival were the type of therapy (curative vs. palliative intent, p < 0.001) and occurrence of early toxicity-related hospitalization (grade ≥ 3, p = 0.001). CONCLUSION: Patients with thoracic malignancies treated with curative intent experience a worsening of their QOL in the first year, whereas those receiving palliative anti-cancer therapy do not. QOL one year after the start of therapy depends on the baseline health scores as determined by the patient, comorbidity burden, and therapeutic strategy. Survival depends on therapeutic strategy and early hospitalization due to toxicity.

EBUS versus EUS-B for diagnosing sarcoidosis: The International Sarcoidosis Assessment (ISA) randomized clinical trial.

BACKGROUND AND OBJECTIVE: Endosonography with intrathoracic nodal sampling is proposed as the single test with the highest granuloma detection rate in suspected sarcoidosis stage I/II. However, most studies have been performed in limited geographical regions. Studies suggest that oesophageal endosonographic nodal sampling has higher diagnostic yield than endobronchial endosonographic nodal sampling, but a head-to-head comparison of both routes has never been performed. METHODS: Global (14 hospitals, nine countries, four continents) randomized clinical trial was conducted in consecutive patients with suspected sarcoidosis stage I/II presenting between May 2015 and August 2017. Using an endobronchial ultrasound (EBUS) scope, patients were randomized to EBUS or endoscopic ultrasound (EUS)-B-guided nodal sampling, and to 22- or 25-G ProCore needle aspiration (2 × 2 factorial design). Granuloma detection rate was the primary study endpoint. Final diagnosis was based on cytology/pathology outcomes and clinical/radiological follow-up at 6 months. RESULTS: A total of 358 patients were randomized: 185 patients to EBUS-transbronchial needle aspiration (EBUS-TBNA) and 173 to EUS-B-fine-needle aspiration (FNA). Final diagnosis was sarcoidosis in 306 patients (86%). Granuloma detection rate was 70% (130/185; 95% CI, 63-76) for EBUS-TBNA and 68% (118/173; 95% CI, 61-75) for EUS-B-FNA (p = 0.67). Sensitivity for diagnosing sarcoidosis was 78% (129/165; 95% CI, 71-84) for EBUS-TBNA and 82% (115/141; 95% CI, 74-87) for EUS-B-FNA (p = 0.46). There was no significant difference between the two needle types in granuloma detection rate or sensitivity. CONCLUSION: Granuloma detection rate of mediastinal/hilar nodes by endosonography in patients with suspected sarcoidosis stage I/II is high and similar for EBUS and EUS-B. These findings imply that both diagnostic tests can be safely and universally used in suspected sarcoidosis patients.

A Randomized Open-Label Phase III Trial Evaluating the Addition of Denosumab to Standard First-Line Treatment in Advanced NSCLC: The European Thoracic Oncology Platform (ETOP) and European Organisation for Research and Treatment of Cancer (EORTC) SPLENDOUR Trial.

INTRODUCTION: Receptor activator of NF-kB ligand stimulates NF-kB-dependent cell signaling and acts as the primary signal for bone resorption. Retrospective analysis of a large trial comparing denosumab versus zoledronic acid in bone metastatic solid tumors suggested significant overall survival (OS) advantage for patients with lung cancer with denosumab (p = 0.01). The randomized open-label phase III SPLENDOUR trial was designed to evaluate whether the addition of denosumab to standard first-line platinum-based doublet chemotherapy improved OS in advanced NSCLC. METHODS: Patients with stage IV NSCLC were randomized in a 1:1 ratio to either chemotherapy with or without denosumab (120 mg every 3-4 wks), stratified by the presence of bone metastases (at diagnosis), Eastern Cooperative Oncology Group performance status, histology, and region. To detect an OS increase from 9 to 11.25 months (hazard ratio [HR] = 0.80), 847 OS events were required. The trial closed prematurely owing to decreasing accrual rate. RESULTS: A total of 514 patients were randomized, with 509 receiving one or more doses of the assigned treatment (chemotherapy: 252, chemotherapy-denosumab: 257). The median age was 66.1 years, 71% were men, and 59% were former smokers. Bone metastases were identified in 275 patients (53%). Median OS (95% confidence interval [CI]) was 8.7 (7.6-11.0) months in the control arm versus 8.2 (7.5-10.4) months in the chemotherapy-denosumab arm (HR = 0.96; 95% CI: 0.78-1.19; one-sided p = 0.36). For patients with bone metastasis, HR was 1.02 (95% CI: 0.77-1.35), whereas for those without, HR was 0.90 (95% CI: 0.66-1.23). Adverse events grade 3 or greater were observed in 40.9%, 5.2%, 8.7% versus 45.5%, 10.9%, 10.5% of patients. Conditional power for OS benefit was less than or equal to 10%. CONCLUSIONS: Denosumab was well-tolerated without unexpected safety concerns. There was no OS improvement for denosumab when added to chemotherapy in the intention-to-treat population and the subgroups with and without bone metastases. Our data do not provide evidence of a clinical benefit for denosumab in patients with NSCLC without bone metastases.

Health Outcomes for Definite Concurrent Chemoradiation in Locally Advanced Non-Small Cell Lung Cancer: A Prospective Study.

BACKGROUND: In patients with locally advanced lung cancer treated with concurrent chemoradiation, outcome measurements have been mostly limited to survival. OBJECTIVES: We aimed to measure outcomes that matter to these patients beyond survival in a general clinical practice. METHODS: In a prospective single-centre study, consecutive patients with locally advanced non-small cell lung cancer reported their own outcomes using the EORTC Quality of Life Questionnaire Core 30 at baseline, during therapy, at therapy stop and till 1 year after therapy end every 3 months. Survival, complications, quality of death and case-mix variables were measured. RESULTS: There were 32 consecutive patients included prospectively from June 2013 until September 2016. Median overall survival was 24.3 months (95% CI 12.7-35.9). Severe toxicity (grade III-IV) was frequent (haematologic toxicity III-IV in 59%). Patient-reported outcomes (PROs) documented the burden on global health status and on functional domains (physical, role, social, emotional and cognitive functioning). Deterioration was pronounced during and after treatment with drops over 20 up to 40% points from baseline for physical, role and social functioning. Clinically meaningful negative effects did persist up to 6 and 9 months for physical and role functioning. Fifty-six percent of the deceased patients died in hospital. CONCLUSIONS: The assault on health-related quality of life during concurrent chemoradiation for locally advanced lung cancer is considerable. Loss of physical and role functioning persists up to 6 and 9 months after therapy end, respectively. Measuring PROs can help to identify issues for improvement of the value of care delivered.

Systematic and combined endosonographic staging of lung cancer (SCORE study).

Guidelines recommend endosonography for mediastinal nodal staging in patients with resectable nonsmall cell lung cancer (NSCLC). We hypothesise that a systematic endobronchial ultrasound (EBUS) evaluation combined with an oesophageal investigation using the same EBUS bronchoscope (EUS-B) improves mediastinal nodal staging versus the current practice of targeted positron emission tomography (PET)-computed tomography (CT)-guided EBUS staging alone.A prospective, multicentre, international study (NCT02014324) was conducted in consecutive patients with (suspected) resectable NSCLC. After PET-CT, patients underwent systematic EBUS and EUS-B. Node(s) suspicious on CT, PET, EBUS and/or EUS-B imaging and station 4R, 4L and 7 (short axis ≥8 mm) were sampled. For patients without N2/N3 disease determined on endosonography, surgical-pathological staging was the reference standard.229 patients were included in this study. The prevalence of N2/N3 disease was 103 out of 229 patients (45%). A PET-CT-guided targeted approach by EBUS identified 75 patients with N2/N3 disease (sensitivity 73%, 95% CI 63-81%; negative predictive value (NPV) 81%, 95% CI 74-87%). Four additional patients with N2/N3 disease were found by systematic EBUS (sensitivity 77%, 95% CI 67-84%; NPV 84%, 95% CI 76-89%) and five more by EUS-B (84 patients total; sensitivity 82%, 95% CI 72-88%; NPV 87%, 95% CI 80-91%). Additional clinical relevant staging information was obtained in 23 out of 229 patients (10%).Systematic EBUS followed by EUS-B increased sensitivity for the detection of N2/N3 disease by 9% compared to PET-CT-targeted EBUS alone.

Does nivolumab for progressed metastatic lung cancer fulfill its promises? An efficacy and safety analysis in 20 general hospitals.

OBJECTIVES: In patients with refractory or recurrent non-small-cell lung cancer (NSCLC) after first line chemotherapy, phase III trials showed superiority of nivolumab, an IgG4 programmed death-1 immune-checkpoint-inhibitor antibody, over docetaxel. We evaluated case mix, effectiveness and safety of nivolumab upon implementation in general practice. MATERIALS AND METHODS: In 20 general hospitals, all consecutive NSCLC patients treated with nivolumab within the medical need program (inclusion period 12 months) in Flanders - Belgium were evaluated. RESULTS: There were 267 patients, Eastern Cooperative Oncology Group (ECOG) score was 2 in 24% and 0-1 in 76%. In 48%, two or more systemic regimens were given before nivolumab. The median overall survival was 7.8 months (95% confidence interval (CI) 6.3-9.3). At one year, the overall survival rate was 36.5±0.34%. Median progression-free survival was 3.7 months (95% CI 2.9-4.5). An objective response was obtained in 23.2%. ECOG score 2 and presence of liver metastasis strongly correlated with worse survival (p<0.00001). Treatment related adverse events grade 3 or 4 were reported in 21%, colitis (4%) and pneumonitis (7%) were most frequent. CONCLUSION: Upon implementation of nivolumab therapy in general hospitals, the case mix was characterized by a more heavily pretreated population with a substantial fraction of patients with ECOG score 2. The median overall survival is slightly inferior to what was published in the randomized phase III trials. An ECOG score 2 and the presence of liver metastasis correlated strongly with a worse survival. We report a high prevalence of serious adverse events.

Pro- and Anti-Inflammatory Role of ChemR23 Signaling in Pollutant-Induced Inflammatory Lung Responses.

Inhalation of traffic-related particulate matter (e.g., diesel exhaust particles [DEPs]) is associated with acute inflammatory responses in the lung, and it promotes the development and aggravation of allergic airway diseases. We previously demonstrated that exposure to DEP was associated with increased recruitment and maturation of monocytes and conventional dendritic cells (DCs), resulting in TH2 polarization. Monocytes and immature DCs express the G-protein coupled receptor chemR23, which binds the chemoattractant chemerin. Using chemR23 knockout (KO) and corresponding wild-type (WT) mice, we determined the role of chemR23 signaling in response to acute exposure to DEPs and in response to DEP-enhanced house dust mite (HDM)-induced allergic airway inflammation. Exposure to DEP alone, as well as combined exposure to DEP plus HDM, elevated the levels of chemerin in the bronchoalveolar lavage fluid of WT mice. In response to acute exposure to DEPs, monocytes and monocyte-derived DCs accumulated in the lungs of WT mice, but this response was significantly attenuated in chemR23 KO mice. Concomitant exposure to DEP plus HDM resulted in allergic airway inflammation with increased eosinophilia, goblet cell metaplasia, and TH2 cytokine production in WT mice, which was further enhanced in chemR23 KO mice. In conclusion, we demonstrated an opposing role for chemR23 signaling depending on the context of DEP-induced inflammation. The chemR23 axis showed proinflammatory properties in a model of DEP-induced acute lung inflammation, in contrast to anti-inflammatory effects in a model of DEP-enhanced allergic airway inflammation.

Endosonography for lung cancer staging: predictors for false-negative outcomes.

OBJECTIVES: Non-small cell lung cancer (NSCLC) guidelines recommend endosonography (endobronchial [EBUS] and/or transesophageal ultrasound [EUS]) as the initial step for mediastinal tissue staging. Identifying predictors for false negative results could help establish which patients should undergo confirmatory surgical staging. MATERIALS AND METHODS: 775 NSCLC patients staged negative by EBUS, EUS or combined EUS/EBUS were retrospectively analyzed. Predictors of false-negative outcomes were identified by logistic regression analysis. RESULTS AND CONCLUSION: Three predictors for false-negative outcomes were identified: central location of the lung tumor (OR 3.7/4.5/3.6 for EBUS, EUS and EUS/EBUS respectively, p<0.05), nodal enlargement on CT (OR 3.2/2.5/4.9 for EBUS, EUS and EUS/EBUS respectively, p<0.05) and FDG-avidity of N2/N3 lymph node stations on PET (OR 4.2/4.0/7.5 for EBUS, EUS and EUS/EBUS respectively, p<0.05). One subgroup (peripheral lung tumor, nodal enlargement on CT without FDG-avidity for N2/N3) had a low predicted probability (7.8%) for false-negative EUS. For combined EUS/EBUS, two subgroups were identified: peripheral located tumor with nodal enlargement on CT but without FDG-avidity for N2/N3 (predicted probability 4.7%) and centrally located tumor without affected lymph nodes on CT or PET (predicted probability 3.4%). In conclusion, for specific well-defined subsets of NSCLC patients the low predicted probability of metastasis after negative endosonography might justify omitting confirmatory surgical staging.

Endosonography for mediastinal nodal staging of clinical N1 non-small cell lung cancer: a prospective multicenter study.

BACKGROUND: Patients with clinical N1 (cN1) lung cancer based on imaging are at risk for malignant mediastinal nodal involvement (N2 disease). Endosonography with a needle technique is suggested over surgical staging as a best first test for preoperative invasive mediastinal staging. The addition of a confirmatory mediastinoscopy seems questionable in patients with a normal mediastinum on imaging. This prospective multicenter trial investigated the sensitivity of preoperative linear endosonography and mediastinoscopy for mediastinal nodal staging of cN1 lung cancer. METHODS: Consecutive patients with operable and resectable cN1 non-small cell lung cancer underwent a lobe-specific mediastinal nodal staging by endosonography. The primary study outcome was sensitivity to detect N2 disease. The secondary end points were the prevalence of N2 disease, the negative predictive value (NPV) of both endosonography and endosonography with confirmatory mediastinoscopy, and the number of patients needed to detect one additional N2 disease with mediastinoscopy. RESULTS: Of the 100 patients with cN1 on imaging, 24 patients were diagnosed with N2 disease. Invasive mediastinal nodal staging with endosonography alone has a sensitivity of 38%, which can be increased to 73% by adding a mediastinoscopy. NPV was 81% and 91%, respectively. Ten mediastinoscopies are needed to detect one additional N2 disease missed by endosonography. CONCLUSIONS: Endosonography alone has an unsatisfactory sensitivity to detect mediastinal nodal metastasis in cN1 lung cancer, and the addition of a confirmatory mediastinoscopy is of added value. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01456429; URL: www.clinicaltrials.gov.

Cost effectiveness of endosonography versus surgical staging in potentially resectable lung cancer: a health economics analysis of the ASTER trial from a European perspective.

In the ASTER study, mediastinal staging was more accurate for patients randomised to combined endobronchial and endoscopic ultrasound, followed by surgical staging if endoscopy was negative, versus surgical staging alone. Here, we report survival, quality of life and cost effectiveness up to 6 months, for the UK, The Netherlands and Belgium, separately. Survival in the two arms of the study was similar. In all three countries, the endosonography strategy had slightly higher quality-adjusted life years over 6 months, and was cheaper. Therefore, based on clinical accuracy and cost effectiveness, we conclude that mediastinal staging should commence with endosonography.

Endosonography vs conventional bronchoscopy for the diagnosis of sarcoidosis: the GRANULOMA randomized clinical trial.

IMPORTANCE: Tissue verification of noncaseating granulomas is recommended for the diagnosis of sarcoidosis. Bronchoscopy with transbronchial lung biopsies, the current diagnostic standard, has moderate sensitivity in assessing granulomas. Endosonography with intrathoracic nodal aspiration appears to be a promising diagnostic technique. OBJECTIVE: To evaluate the diagnostic yield of bronchoscopy vs endosonography in the diagnosis of stage I/II sarcoidosis. DESIGN, SETTING, AND PATIENTS: Randomized clinical multicenter trial (14 centers in 6 countries) between March 2009 and November 2011 of 304 consecutive patients with suspected pulmonary sarcoidosis (stage I/II) in whom tissue confirmation of noncaseating granulomas was indicated. INTERVENTIONS: Either bronchoscopy with transbronchial and endobronchial lung biopsies or endosonography (esophageal or endobronchial ultrasonography) with aspiration of intrathoracic lymph nodes. All patients also underwent bronchoalveolar lavage. MAIN OUTCOMES AND MEASURES: The primary outcome was the diagnostic yield for detecting noncaseating granulomas in patients with a final diagnosis of sarcoidosis. The diagnosis was based on final clinical judgment by the treating physician, according to all available information (including findings from initial bronchoscopy or endosonography). Secondary outcomes were the complication rate in both groups and sensitivity and specificity of bronchoalveolar lavage in the diagnosis of sarcoidosis. RESULTS: A total of 149 patients were randomized to bronchoscopy and 155 to endosonography. Significantly more granulomas were detected at endosonography vs bronchoscopy (114 vs 72 patients; 74% vs 48%; P < .001). Diagnostic yield to detect granulomas for endosonography was 80% (95% CI, 73%-86%); for bronchoscopy, 53% (95% CI, 45%-61%) (P < .001). Two serious adverse events occurred in the bronchoscopy group and 1 in the endosonography group; all patients recovered completely. Sensitivity of the bronchoalveolar lavage for sarcoidosis based on CD4/CD8 ratio was 54% (95% CI, 46%-62%) for flow cytometry and 24% (95% CI, 16%-34%) for cytospin analysis. CONCLUSION AND RELEVANCE: Among patients with suspected stage I/II pulmonary sarcoidosis undergoing tissue confirmation, the use of endosonographic nodal aspiration compared with bronchoscopic biopsy resulted in greater diagnostic yield. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00872612.

Short cigarette smoke exposure facilitates sensitisation and asthma development in mice.

Epidemiological studies indicate that cigarette smoke exposure is a risk factor for increased sensitisation and asthma development. The aim of this study was to examine the impact of cigarette smoke on sensitisation and allergic airway inflammation in response to a low dose of house dust mite (HDM), and to obtain potential mechanistic insights. Mice were exposed to low doses of HDM extract combined with air or cigarette smoke exposure, either during allergen sensitisation or during the development of allergic airway disease. Mice concomitantly exposed to low-dose HDM, combined with cigarette smoke for 3 weeks, demonstrated an asthmatic phenotype with significantly increased airway eosinophilia, goblet cell metaplasia, airway hyperresponsiveness and a rise in HDM-specific serum immunoglobulin G1, compared to sole HDM or cigarette smoke exposure. In addition, short cigarette smoke inhalation, during the initial contact with HDM allergens, was sufficient to facilitate sensitisation and development of a complete asthmatic phenotype after rechallenge with HDM. Mechanistically, short cigarette smoke exposure amplified dendritic cell-mediated transport of fluorescein isothiocyanate-labelled HDM allergens to the intrathoracic lymph nodes and generated a local T-helper cell type 2 response. Short cigarette smoke exposure is sufficient to facilitate allergic sensitisation and the development of low-dose HDM-induced allergic asthma, possibly by affecting dendritic cell function.

Mediastinal staging of lung cancer: novel concepts.

Clinical TNM staging is the standard method used to decide treatment for patients with non-small-cell lung cancer. Although integrated fluorodeoxyglucose (FDG) PET CT increases the accuracy of staging, it only guides direct tissue sampling. Histological assessment of mediastinal lymph nodes has traditionally been done with mediastinoscopy, a surgical procedure. Endobronchial and oesophageal ultrasound-guided lymph node sampling have been assessed as additions or alternatives to mediastinoscopy. We review endosonography and surgical staging, and show that both have a place in the mediastinal staging of lung cancer. We conclude that mediastinal tissue staging should preferentially start with a complete endosonographic assessment. A surgical mediastinoscopy should be reserved for those in whom the endosonography result is negative. Further refinement of this recommendation is likely in the near future because data suggest that the confirmatory mediastinoscopy is particularly useful for patients with enlarged or FDG-avid lymph nodes.

Monocyte-derived dendritic cell recruitment and allergic T(H)2 responses after exposure to diesel particles are CCR2 dependent.

BACKGROUND: The inhalation of diesel exhaust particles (DEPs) is associated with increased sensitization toward inhaled allergens. Dendritic cells (DCs) are important mediators in immune regulation. We previously showed that the inhalation of DEPs increased the accumulation of DCs in the lung and enhanced the T(H)2 response in the mediastinal lymph node. OBJECTIVE: We hypothesized that CC chemokine receptors CCR2, CCR5, and CCR6 critically mediate the DC recruitment upon exposure to DEPs and that these CC chemokine receptors are important in the DEP-induced T(H)2 response. METHODS: We exposed CCR2 knockout, CCR5 knockout, CCR6 knockout, and wild-type mice to DEPs and examined the pulmonary monocyte and DC accumulation. By an adoptive transfer experiment, we assessed the direct involvement of CCR2 and CCR6 in the recruitment of blood monocytes toward the lung upon exposure to DEPs. We also examined the T(H)2 cytokine production in the mediastinal lymph nodes of DEP-exposed CCR2 knockout and CCR6 knockout mice. RESULTS: We observed that the DEP-induced monocyte and monocyte-derived DC recruitment was completely abolished in CCR2 knockout mice. CCR6 knockout mice also showed impaired monocyte recruitment upon exposure to DEPs. In contrast, monocyte and DC recruitment was comparable between DEP-exposed wild-type and CCR5 knockout mice. The impaired monocyte-derived DC recruitment in DEP-exposed CCR2 knockout, not CCR6 knockout, mice resulted in an abolished T(H)2 response in the mediastinal lymph node. CONCLUSION: These data suggest that monocyte-derived DCs, recruited in a CCR2-dependent manner, are critical in inducing T(H)2 responses upon inhalation of DEPs.

NLRP3/caspase-1-independent IL-1beta production mediates diesel exhaust particle-induced pulmonary inflammation.

Inhalation of diesel exhaust particles (DEP) induces an inflammatory reaction in the lung; however, the mechanisms are largely unclear. IL-1ß/IL-1RI signaling is crucial in several lung inflammatory responses. Typically, caspase-1 is activated within the NLRP3 inflammasome that recognizes several damage-associated molecular patterns, which results in cleavage of pro-IL-1ß into mature IL-1ß. In this study, we hypothesized that the NLRP3/caspase-1/IL-1ß pathway is critical in DEP-induced lung inflammation. Upon DEP exposure, IL-1RI knockout mice had reduced pulmonary inflammation compared with wild-type mice. Similarly, treatment with rIL-1R antagonist (anakinra) and IL-1ß neutralization impaired the DEP-induced lung inflammatory response. Upon DEP exposure, NLRP3 and caspase-1 knockout mice, however, showed similar IL-1ß levels and comparable pulmonary inflammation compared with wild-type mice. In conclusion, these data show that the DEP-induced pulmonary inflammation acts through the IL-1ß/IL-1RI axis. In addition, DEP initiates inflammation independent of the classical NLRP3/caspase-1 pathway, suggesting that other proteases might be involved.

EUS-FNA for the detection of left adrenal metastasis in patients with lung cancer.

In patients with lung cancer, enlarged or (18)Fluoro-deoxyglucose positron emission tomography ((18)FDG-PET) positive left adrenal glands are suspected for distant metastases and require tissue confirmation for a definitive assessment. The aim of this study was to assess the sensitivity of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) for left adrenal metastases in lung cancer patients with a suspect adrenal gland based on imaging. EUS-FNA findings of patients with (suspected) lung cancer and CT enlarged or (18)FDG-PET positive left adrenal glands were retrospectively evaluated. In the absence of metastases at EUS, clinical and radiological follow-up was obtained. In 85 patients, EUS-FNA demonstrated left adrenal metastases of lung cancer in 53 (62%), benign adrenal tissue in 25 (29%), a metastasis from colon carcinoma in 1 (1%) and a primary adrenocortical carcinoma in 1 (1%) patient. In five patients (5.9%), the aspirates contained non-representative material. EUS outcomes were false negative in two patients. Sensitivity and negative predictive value (NPV) for EUS-FNA of the left adrenal gland were at least 86% (95% CI 74-93%) and 70% (95% CI 50-85%). No complications occurred. EUS-FNA is a sensitive, safe and minimally invasive technique to provide tissue proof of left adrenal metastases in patients with (suspected) lung cancer and enlarged or (18)FDG-PET positive adrenal glands. Therefore, EUS-FNA qualifies as the staging test of choice for patients with lung cancer with suspected left adrenal metastases.

Inflammatory signatures for eosinophilic vs. neutrophilic allergic pulmonary inflammation reveal critical regulatory checkpoints.

Contrary to the T-helper (Th)-2 bias and eosinophil-dominated bronchial inflammation encountered in most asthmatic subjects, other patients may exhibit neutrophil-predominant asthma subphenotypes, along with Th-1 and Th-17 cells. However, the etiology of many neutrophil-dominated asthma subphenotypes remains ill-understood, in part due to a lack of appropriate experimental models. To better understand the distinct immune-pathological features of eosinophilic vs. neutrophilic asthma types, we developed an ovalbumin (OVA)-based mouse model of neutrophil-dominated allergic pulmonary inflammation. Consequently, we probed for particular inflammatory signatures and checkpoints underlying the immune pathology in this new model, as well as in a conventional, eosinophil-dominated asthma model. Briefly, mice were OVA sensitized using either aluminum hydroxide (alum) or complete Freund's adjuvants, followed by OVA aerosol challenge. T-cell, granulocyte, and inflammatory mediator profiles were determined, along with alveolar macrophage genomewide transcriptome profiling. In contrast to the Th-2-dominated phenotype provoked by alum, OVA/ complete Freund's adjuvants adjuvant-based sensitization, followed by allergen challenge, elicited a pulmonary inflammation that was poorly controlled by dexamethasone, and in which Th-1 and Th-17 cells additionally participated. Analysis of the overall pulmonary and alveolar macrophage inflammatory mediator profiles revealed remarkable similarities between both models. Nevertheless, we observed pronounced differences in the IL-12/IFN-γ axis and its control by IL-18 and IL-18 binding protein, but also in macrophage arachidonic acid metabolism and expression of T-cell instructive ligands. These differential signatures, superimposed onto a generic inflammatory signature, denote distinctive inflammatory checkpoints potentially involved in orchestrating neutrophil-dominated asthma.