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Background: In recent decades, asthma-related quality of life questionnaires have joined objective clinical indicators as important outcome measures. In this study, we sought to investigate the predictors of asthma-related quality of life in a large cohort of patients recruited from a secondary care center., Methods: We conducted a cross-sectional study on asthmatics ( N  = 1301) recruited from the Liège University Hospital asthma clinic (Belgium). After performing a descriptive analysis highlighting the distribution of scores from the Mini Asthma Quality of Life Questionnaire (Mini AQLQ) and its four dimensions (symptoms, activity limitation, emotional function, and environmental stimuli), we did multiple regression analysis to identify the independent predictors of AQLQ., Results: Multiple regression beta analysis showed that AQLQ and its four dimensions were primarily associated with asthma control ( p  < 0.0001 in all instances). Female gender was associated with a lower score for the AQLQ's activity and environmental dimensions ( p  < 0.05 for both), while current smokers had a higher score on the AQLQ's environmental dimension ( p  < 0.0001). The burden of asthma treatment was associated with a lower score for the AQLQ's emotional ( p  < 0.05) and environmental ( p  < 0.05) dimensions. BMI was associated with a lower score in the AQLQ's activity dimension ( p  < 0.0001), while the opposite was true for the FeNO test ( p  < 0.0001). Sputum neutrophils were inversely related to the score for the AQLQ's symptom dimension ( p  < 0.05), whereas post-bronchodilator FEV 1 showed a positive relationship for that same dimension ( p  < 0.05)., Conclusion: Asthma control is the main predictor of AQLQ score and impacts all its dimensions, but demographic, functional, and airway inflammatory parameters may also influence some dimensions of the AQLQ., Competing Interests: Outside of this submitted work, RL received unrestricted research grants from GSK, AstraZeneca, Novartis and Chiesi and lecture or adboard fees from GSK, AZ, Novartis and Sanofi. Outside of this submitted work, FS received lecture or adboard fees from Chiesi, AZ, GSK, and Novartis. The remaining authors declare that they have no relevant conflicts of interest., (© 2021 The Authors. Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.)

Background: Eosinophilic inflammation has long been associated with asthma. Looking at systemic and airway eosinophilia, we have recently identified a group of patients exhibiting diffuse eosinophilic inflammation. Among the mechanisms governing eosinophilic inflammation, IgE-mediated mast cell activation is a key event leading to eosinophilia in atopic asthmatics., Methods: We conducted a retrospective study on our asthma clinic database containing more than 1500 patients and identified 205 asthmatics with successful sputum induction and concordant eosinophilic phenotype. This phenotype was defined as a sputum eosinophil count≥3% and a blood eosinophils concentration≥400cells/mm 3 . IgE-high atopic phenotype was characterized by the presence of at least one positive specific IgE (>0.35kU/L) to common aeroallergens and a raised total serum IgE (≥113kU/L)., Results: The largest group of asthmatics displaying concordant eosinophilic phenotype had a raised total serum IgE and atopy (45%). IgE-low non-atopic concordant eosinophilic asthma was a predominantly late onset disease, exhibited a more intense airway eosinophilic inflammation (P<0.05), required more often maintenance treatment with oral corticosteroids (P<0.05) but, surprisingly, had a reduced level of bronchial hyperresponsiveness to methacholine (P<0.05) despite similar baseline airway calibre impairment., Conclusion: The more severe airway eosinophilic inflammation in IgE-low non-atopic asthmatics despite similar treatment with ICS and a higher burden of OCS points to a certain corticosteroid resistance in this asthma phenotype., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Chlamydia pneumoniae and Mycoplasma pneumoniae have been implicated in the pathogenesis of asthma and are responsible for chronic inflammation when host immune system fails to eradicate the bacteria., Method: We performed a prospective study on 410 patients who underwent a visit at the asthma clinic of CHU of Liege between June 2016 and June 2018 with serology testing for C. pneumoniae and M. pneumoniae., Results: 65% of our asthmatic population had serum IgA and/or IgG towards C. pneumoniae, while only 12.6% had IgM and/or IgG against M. pneumoniae. Compared to seronegative asthmatics, asthmatics with IgA+ and IgG+ against C. pneumoniae were more often male and older with a higher proportion of patients with smoking history. They received higher doses of inhaled corticosteroids (ICS) and displayed lower FEV 1 /FVC ratio, higher RV/TLC ratio and lower conductance. They had higher levels of fibrinogen, though in the normal range and had lower sputum eosinophil counts. Patients with IgA- and IgG+ against C. pneumoniae were older and had higher blood monocyte counts and alpha-1-antitrypsin levels as compared to seronegative patients. Patients with IgM and/or IgG towards M. pneumoniae were more often males than seronegative asthmatics. In a subpopulation of 14 neutrophilic asthmatics with Chlamydia pneumoniae IgA + /IgG + treated with macrolides, we found a significant decrease in blood neutrophils and normalization of sputum neutrophil count but no effect on asthma quality of life and exacerbations., Conclusion: Positive Chlamydia serologic test is more common than positive Mycoplasma serology. Asthmatics with IgA and IgG against C. pneumoniae have more severe disease with increased airway obstruction, higher doses of ICS, more signs of air trapping and less type-2 inflammation.

Competing Interests: Prof. Dr Renaud Louis reports grants and/or personal fees from GSK, AZ, Novartis, Chiesi, and Sanofi, outside the submitted work. The authors report no other conflict of interest with this work.

Background & Aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress, and novel therapeutic response in PC to develop a biomarker-driven therapeutic strategy targeting DDR and replication stress in PC., Methods: We interrogated the transcriptome, genome, proteome, and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient-derived xenografts and human PC organoids., Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors, including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, cosegregates with response to platinum (P < .001) and PARP inhibitor therapy (P < .001) in vitro and in vivo. We generated a novel signature of replication stress that predicts response to ATR (P < .018) and WEE1 inhibitor (P < .029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < .001) but was not associated with DDR deficiency., Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR-proficient PC and after platinum therapy., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Asthmatics and patients with chronic obstructive pulmonary disease (COPD) have more severe outcomes with viral infections than people without obstructive disease., Objective: To evaluate if obstructive diseases are risk factors for intensive care unit (ICU) stay and death due to coronavirus disease 2019 (COVID19)., Methods: We collected data from the electronic medical record from 596 adult patients hospitalized in University Hospital of Liege between March 18 and April 17, 2020, for severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection. We classified patients into 3 groups according to the underlying respiratory disease, present before the COVID19 pandemic., Results: Among patients requiring hospitalization for COVID19, asthma and COPD accounted for 9.6% and 7.7%, respectively. The proportions of asthmatics, patients with COPD, and patients without obstructive airway disease hospitalized in the ICU were 17.5%, 19.6%, and 14%, respectively. One-third of patients with COPD died during hospitalization, whereas only 7.0% of asthmatics and 13.6% of patients without airway obstruction died due to SARS-CoV2. The multivariate analysis showed that asthma, COPD, inhaled corticosteroid treatment, and oral corticosteroid treatment were not independent risk factors for ICU admission or death. Male gender (odds ratio [OR]: 1.9; 95% confidence interval [CI]: 1.1-3.2) and obesity (OR: 8.5; 95% CI: 5.1-14.1) were predictors of ICU admission, whereas male gender (OR 1.9; 95% CI: 1.1-3.2), older age (OR: 1.9; 95% CI: 1.6-2.3), cardiopathy (OR: 1.8; 95% CI: 1.1-3.1), and immunosuppressive diseases (OR: 3.6; 95% CI: 1.5-8.4) were independent predictors of death., Conclusion: Asthma and COPD are not risk factors for ICU admission and death related to SARS-CoV2 infection., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Objective: Airway remodeling, as many other factors, may lead to lung function decline and irreversible airflow obstruction (IRAO) in asthma. This study was undertaken in order to highlight predictors of incomplete reversibility of airflow obstruction in adult asthmatics to identify patients with poorer prognosis and improve their care, and decrease morbidity., Methods: A retrospective study was conducted in 973 asthmatics recruited from the University Asthma Clinic of Liege. Patients with IRAO (post-BD FEV 1 /FVC<0.7 & FEV 1 <80% predicted) were compared to patients with reversible airway obstruction (RAO) (post-BD FEV 1 /FVC≥0.7 & FEV 1 ≥80% predicted). TGF-β was measured in sputum supernatant of 85 patients., Results: Seventeen percent of asthmatics presented with IRAO. These patients were significantly older, more smokers, with a lower proportion of female, a longer disease duration, were more poorly controlled with a lower quality of life. This sub-population of asthmatics also showed more often elevated blood and sputum eosinophils and neutrophils, and higher exacerbation and hospitalisation rates in the previous year. The multivariable analysis revealed male gender, longer disease duration, cigarette smoking, ACQ score, sputum eosinophils and neutrophils, ICS dose and OCS maintenance, BMI, and asthma onset as variables independently linked to IRAO. Total TGF-β levels appeared higher in patients with IRAO (n = 38) compared to patients with RAO (n = 47)., Conclusion: These data show that risk factors for IRAO are male gender, smoking, a longer disease duration, uncontrolled asthma, eosinophilic or neutrophilic airway inflammation, lower BMI, and later asthma onset. Moreover, TGF-β levels are higher in IRAO., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Chronic obstructive pulmonary disease (COPD) is a complex, multidimensional and heterogeneous disease. The main purpose of the present study was to identify clinical phenotypes through cluster analysis in adults suffering from COPD. A retrospective study was conducted on 178 COPD patients in stable state recruited from ambulatory care at University hospital of Liege. All patients were above 40 years, had a smoking history of more than 20 pack years, post bronchodilator FEV1/FVC <70% and denied any history of asthma before 40 years. In this study, the patients were described by a total of 84 mixed sets of variables with some missing values. Hierarchical clustering on principal components (HCPC) was applied on multiple imputation. In the final step, patients were classified into homogeneous distinct groups by consensus clustering. Three different clusters, which shared similar smoking history were found. Cluster 1 included men with moderate airway obstruction ( n  = 67) while cluster 2 comprised men who were exacerbation-prone, with severe airflow limitation and intense granulocytic airway and neutrophilic systemic inflammation ( n  = 56). Cluster 3 essentially included women with moderate airway obstruction ( n  = 55). All clusters had a low rate of bacterial colonization (5%), a low median FeNO value (<20 ppb) and a very low sensitization rate toward common aeroallergens (0-5%). CAT score did not differ between clusters. Including markers of systemic airway inflammation and atopy and applying a comprehensive cluster analysis we provide here evidence for 3 clusters markedly shaped by sex, airway obstruction and neutrophilic inflammation but not by symptoms and T2 biomarkers.

Background: Omalizumab arose as a therapeutic option in patients suffering from moderate to severe refractory allergic asthma. It acts as a humanized monoclonal antibody neutralizing circulating IgE antibodies. Randomized clinical trials and real life clinical studies have already confirmed benefits, cost-effectiveness and applicability of the medication., Method: Our study retrospectively reports on the clinical outcomes and airway inflammation in 157 severe allergic asthmatics who were initiated with omalizumab between 2007 and 2019., Results: After 4 months of therapy, 76% of the patients were judged to have benefited from omalizumab and were admitted to prolonged treatment. During follow-up, we observed an improvement in asthma control, quality of life and spirometric performance. There was also a sustained reduction in exacerbation rate over the years. As for T2 biomarkers, FeNO significantly decreased and, in a subgroup of patients who had repeated sputum inductions, there was also significant reduction in sputum eosinophils but no change in blood eosinophil count. Lastly, we found a correlation between high FeNO levels at baseline and reduction in ACQ scores at 1 year., Conclusion: We conclude that omalizumab shows effectiveness in severe allergic asthma in a real life setting, by reducing exacerbation rate, improving patient perspective outcomes and airway calibre, together with reducing type-2 airway inflammation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Demonstration of bronchial hyperresponsiveness is a key feature in asthma diagnosis. Methacholine challenge has proved to be a highly sensitive test to diagnose asthma in patients with chronic respiratory symptoms and preserved baseline lung function (FEV1 > 70% pred.) but is time consuming and may sometimes reveal unpleasant to the patient. We conducted a retrospective study on 270 patients recruited from the University Asthma Clinic of Liege. We have compared the values of several lung function indices and fractional exhaled nitric oxide (FeNO) in predicting a provocative methacholine concentration ≤16 mg/ml on a discovery cohort of 129 patients (57 already on ICS) and on a validation cohort of 141 patients (66 already on ICS). In the discovery study (n = 129), 85 patients (66%) had a positive methacholine challenge with PC20M ≤ 16 mg/ml. Those patients had lower baseline % predicted FEV1 (92% vs. 100%; p < 0.01), lower FEV1/FVC ratio (79% vs. 82%; p < 0.05), higher RV/TLC ratio (114% vs. 100%; p < 0,0001), lower SGaw (specific conductance) (0.76 vs. 0.95; p < 0,001) and higher FeNO (29 ppb vs. 19 ppb; p < 0,01). When performing ROC curve the RV/TLC ratio provided the greatest AUC (0.74, p < 0.001), sGAW had intermediate AUC of 0.69 (p < 0.001) while FeNO, FEV1 and FEV1/FVC ratio were modestly predictive (AUC of 0.65 (p < 0.05), 0,67 (p < 0.001) and 0,63 (p < 0.001). These results were confirmed in the validation study (n = 141). Based on a logistic regression analysis, significant variables associated with positive methacholine challenge were FeNO and RV/TLC (% Pred). A combined application of FeNO and RV/TLC (% Pred) for predicting the PC20M had a specificity of 85%, a sensitivity of 59% and an AUC of 0.79. In the validation study, three variables (RV/TLC, FeNO and FEV1) were independently associated with positive methacholine challenge and the combination of these three variables yielded a specificity of 77%, a sensitivity of 39% and an AUC of 0.77. The RV/TLC ratio combined to FeNO may be of interest to predict significant methacholine bronchial hyperresponsiveness., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Asthma in obese subjects is poorly understood. According to GINA guidelines, pulmonologists increase ICS in case of poor asthma control but lung volume restriction may also worsen respiratory symptoms in obese asthmatics leading to overtreatment in this subpopulation., Methods: We conducted a retrospective study on 1217 asthmatics recruited from University Hospital of Liege. 92 patients with a BMI ≥30 came at least two times at the asthma clinic (mean interval: 335 days). In this obese population, we identified predictors of good (decrease in ACQ ≥0.5) versus poor response (rise in ACQ ≥0.5) to ICS step-up therapy., Results: Obese asthmatics had a poorer asthma control and quality of life as compared to non-obese and exhibited reduced FVC, higher levels of blood leucocytes and markers of systemic inflammation. The proportion of asthma inflammatory phenotypes was similar to that observed in a general population of asthmatics. Among uncontrolled obese asthmatics receiving ICS step-up therapy, 53% improved their asthma control while 31% had a worsening of their asthma. Uncontrolled obese asthmatics showing a good response to increase in ICS had higher ACQ, lower CRP levels, higher sputum eosinophil counts and higher FeNO levels at visit 1. Uncontrolled obese asthmatics that worsened after increasing the dose of ICS had lower FVC, lower sputum eosinophil counts and higher sputum neutrophil counts., Conclusion: We observed poorer asthma control in obese asthmatics despite similar bronchial inflammation. Managing obese asthmatics according to ACQ alone seems to underestimate asthma control and the contribution of restriction to dyspnea. Increasing the dose of ICS in the absence of sputum eosinophilic inflammation or in the presence of restriction or bronchial neutrophilia led to poorer asthma control. In those patients, management of obesity should be the first choice., (Copyright © 2020 Elsevier Inc. All rights reserved.)

T2 biomarkers lack the accuracy to make an asthma diagnosis in patients with suggestive symptoms https://bit.ly/3hYnnHu., Competing Interests: Conflict of interest: H. Nekoee has nothing to disclose. Conflict of interest: E. Graulich has nothing to disclose. Conflict of interest: F. Schleich reports lecture and advisory board fees from GSK, AZ, Chiesi and Novartis, outside the submitted work. Conflict of interest: F. Guissard has nothing to disclose. Conflict of interest: V. Paulus has nothing to disclose. Conflict of interest: M. Henket has nothing to disclose. Conflict of interest: A.F. Donneau has nothing to disclose. Conflict of interest: R. Louis reports an educational grant and lecture fees from GSK, a research grant and advisory board fees from AZ, a research grant from Chiesi and a research grant and advisory board fees from Novartis, outside the submitted work., (Copyright ©ERS 2020.)

Background: Randomized control trials performed in selected populations of severe eosinophilic asthmatics have shown that mepolizumab, an anti-IL5 therapy, was able to reduce exacerbations and OCS maintenance dose and in some studies, to improve asthma control and lung function., Objective: The aim of this study was to confirm the results of the RCTs in real-life in a population of 116 severe eosinophilic asthmatics treated with mepolizumab and who were followed up at the asthma clinic every month for at least 18 months. Severe asthmatics underwent FENO, lung function, asthma control and quality of life questionnaires, sputum induction and gave a blood sample at baseline, after 6 months and then every year., Results: We found a significant reduction in exacerbations by 85% after 6 months (P < .0001), which was maintained over time. We also found a significant and maintained reduction by 50% in the dose of oral corticosteroids (P < .001). Patients improved their ACT (+5.31pts, p<0.0001) ACQ (-1.13pts, P < .0001) and their AQLQ score (+1.24, P < .0001) at 6 months and this was maintained during follow-up. Only 37% reached asthma control (ACQ <1.5, ACT> 20). We observed a progressive increase in post-BD FEV1 that reached significance after 18 months (190ml or 11%, P < .01). Patients improving their FEV1had higher baseline sputum eosinophils than those not improving airway caliber. We found a significant reduction in sputum eosinophil counts by 60% after 6 months (P < .01) and a maintained reduction in blood eosinophil counts by 98% (P < .0001)., Conclusion: In our real-life study, we confirm the results published in the RCTs showing a sharp reduction in exacerbation and oral corticosteroids dose and an improvement in asthma control and quality of life., Clinical Relevance: Mepolizumab is efficient in severe eosinophilic asthma in real life., (© 2020 John Wiley & Sons Ltd.)

Pancreatic ductal adenocarcinoma (PDAC) can be divided into transcriptomic subtypes with two broad lineages referred to as classical (pancreatic) and squamous. We find that these two subtypes are driven by distinct metabolic phenotypes. Loss of genes that drive endodermal lineage specification, HNF4A and GATA6, switch metabolic profiles from classical (pancreatic) to predominantly squamous, with glycogen synthase kinase 3 beta (GSK3β) a key regulator of glycolysis. Pharmacological inhibition of GSK3β results in selective sensitivity in the squamous subtype; however, a subset of these squamous patient-derived cell lines (PDCLs) acquires rapid drug tolerance. Using chromatin accessibility maps, we demonstrate that the squamous subtype can be further classified using chromatin accessibility to predict responsiveness and tolerance to GSK3β inhibitors. Our findings demonstrate that distinct patterns of chromatin accessibility can be used to identify patient subgroups that are indistinguishable by gene expression profiles, highlighting the utility of chromatin-based biomarkers for patient selection in the treatment of PDAC., Competing Interests: Declaration of Interests A.V.B. receives grant funding from Celgene and AstraZeneca and is a consultant for or on advisory boards of AstraZeneca, Celgene, Elstar Therapeutics, Clovis Oncology, and Roche. S.T.B. is an AstraZeneca employee and shareholder. C.J.L. receives research funding from AstraZeneca, Merck KGaA, and Artios; received consultancy, SAB membership, or honoraria payments from Syncona, Sun Pharma, GLG, Merck KGaA, Vertex, AstraZeneca, Tango, 3rd Rock, Ono Pharma, and Artios; and has stock in Tango and Ovibio. A.A. is co-founder of Tango Therapeutics, Azkarra Therapeutics, and Ovibio Corporation; is a consultant for SPARC, Bluestar, TopoRx, ProLynx, Earli, and Cura; is a member of the SAB of Genentech and GLAdiator; receives grant/research support from SPARC and AstraZeneca; and holds patents on the use of PARP inhibitors held jointly with AstraZeneca, which he has benefitted from financially (and may do so in the future) through the ICR Rewards to Inventors Scheme., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Asthma is a chronic heterogeneous airway disease. There are different asthma inflammatory phenotypes with various responses to treatment and different disease severities. When asthma requires chronic systemic corticosteroids or hospitalizations despite maximal inhaled therapies in asthmatic patients in whom comorbidities have been managed and who are considered as compliant, the pulmonologist may propose biological treatment to reduce exacerbations and the dose of systemic corticosteroids. During the last ten years, the number of biologics for the management of type-2 severe asthma has increased. Anti-IgE monoclonal antibodies (omalizumab) are available for more than ten years and recommended in severe allergic asthma. New biologics are now available to block IL-5 (mepolizumab, reslizumab) or its receptor (benralizumab). These treatments allow a reduction of exacerbations and of the dose of systemic corticosteroids, an improvement in asthma control, in asthma quality of life and for some of them, an increase in lung function. New biologics will soon be available in Belgium for the management of severe asthma. In addition to the improvement of asthma control in severe asthma, biological treatments have improved the understanding of the mechanisms leading to severe asthma.

Background: Methacholine bronchial challenge and bronchodilation to salbutamol are key tests in clinical practice to make asthma diagnosis., Objective: To assess the concordance between the 2 tests and to see whether they actually identify the same population of asthmatics., Method: We conducted a retrospective study using our asthma clinic database to see how methacholine bronchial challenge compared to bronchodilation to salbutamol in untreated patients with recurrent or chronic symptoms suspicious of asthma. We identified 194 untreated patients with baseline forced expiratory volume in 1 second (FEV 1 ) ≥70% predicted who had both a bronchodilation test with salbutamol and a methacholine bronchial challenge 7 to 14 days apart. A positive bronchial challenge was a provocative concentration of methacholine causing a 20% fall in FEV 1 ≤16 mg/mL, whereas a positive bronchodilation test was a reversibility to 400 μg inhaled salbutamol ≥12% from baseline and 200 mL., Results: Overall, asthma diagnosis was confirmed in 91% of cases leaving 9% of subjects with double negative tests. Isolated positive methacholine challenge was found in 71% of subjects, double positive tests in 17%, whereas isolated significant bronchodilation to salbutamol was rare (3%). There was no correlation between provocative concentration of methacholine causing a fall in FEV 1 of 20% (PC20M) and the magnitude of salbutamol reversibility (P = .10). Baseline FEV 1 /forced vital capacity ratio inversely correlated with reversibility to salbutamol (P < .001) but not with PC20M (P = .1). No difference was found between the groups regarding demographic and immunoinflammatory features, including the proportion of eosinophilic asthma., Conclusion: We conclude that methacholine challenge outperforms reversibility to salbutamol to diagnose asthma without selecting patients with distinct inflammatory profile. Baseline airway obstruction predicts magnitude of reversibility but not hyperresponsiveness., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction In the treatment of prolapse and incontinence, the choice of surgical procedure often depends not only on the clinical findings but also on the age of the patient. Uncertainty exists at present regarding the effect of patient age on treatment outcomes for both vaginal and laparoscopic procedures. The aim of this study is therefore to compare both the anatomical outcome after prolapse surgery and the functional outcome after incontinence surgery in the context of the treatment of stress urinary incontinence in older and younger patients. Patients/Methods This is a retrospective single-centre study conducted at a university site. Over the study period, a total of 407 women underwent surgery, 278 of whom were < 70 and 129 ≥ 70 years of age. They were assigned to one of three treatment groups (prolapse surgery, incontinence surgery or a combination of both types of surgery) and were then subjected to statistical analysis after assessment of the anatomical and functional outcome after 3 - 6 months. Results The most common form of prolapse among the 407 evaluated patients was in the anterior and middle compartment, with a higher degree of severity being diagnosed in the older patients. Grade 4 prolapse according to the Baden-Walker system was thus present in the anterior compartment in 15.6 vs. 28.8% (p = 0.033) and in the middle compartment in 5.7 vs. 23.7% (p < 0.001) of cases. Younger women underwent vaginal mesh implantation less frequently and laparoscopic sacropexy more frequently for this overall. The proportion of cases of combined prolapse and incontinence surgery was the same in both groups. Overall, high success rates were observed in both younger and older patients following prolapse and incontinence surgery. These rates were 93.5 vs. 84.8% (p = 0.204) after prolapse surgery and 92.8 vs. 84.2% (p = 0.261) after incontinence surgery. A significant disadvantage for the older patients was the persistence of stress urinary incontinence after prolapse surgery alone (19.6 vs. 50%, p = 0.030) and the rate of occult (de novo) stress urinary incontinence (7.4 vs. 20%, p = 0.030). Conclusion Our data show that both pelvic organ prolapse and stress urinary incontinence can be treated with surgery with good results in women aged ≥ 70 years. It was thus possible to show for the first time in a large patient population that older women should not be denied appropriate surgery but can be offered the same range of surgical options as younger patients.

Rationale: Analysis of exhaled breath for asthma phenotyping using endogenously generated volatile organic compounds (VOCs) offers the possibility of noninvasive diagnosis and therapeutic monitoring. Induced sputum is indeed not widely available and markers of neutrophilic asthma are still lacking. Objectives: To determine whether analysis of exhaled breath using endogenously generated VOCs can be a surrogate marker for recognition of sputum inflammatory phenotypes. Methods: We conducted a prospective study on 521 patients with asthma recruited from the University Asthma Clinic of Liege. Patients underwent VOC measurement, fraction of exhaled nitric oxide (Fe NO ) spirometry, sputum induction, and gave a blood sample. Subjects with asthma were classified in three inflammatory phenotypes according to their sputum granulocytic cell count. Measurements and Main Results: In the discovery study, seven potential biomarkers were highlighted by gas chromatography-mass spectrometry in a training cohort of 276 patients with asthma. In the replication study ( n  = 245), we confirmed four VOCs of interest to discriminate among asthma inflammatory phenotypes using comprehensive two-dimensional gas chromatography coupled to high-resolution time-of-flight mass spectrometry. Hexane and 2-hexanone were identified as compounds with the highest classification performance in eosinophilic asthma with accuracy comparable to that of blood eosinophils and Fe NO . Moreover, the combination of Fe NO , blood eosinophils, and VOCs gave a very good prediction of eosinophilic asthma (area under the receiver operating characteristic curve, 0.9). For neutrophilic asthma, the combination of nonanal, 1-propanol, and hexane had a classification performance similar to Fe NO or blood eosinophils in eosinophilic asthma. Those compounds were found in higher levels in neutrophilic asthma. Conclusions: Our study is the first attempt to characterize VOCs according to sputum granulocytic profile in a large population of patients with asthma and provide surrogate markers for neutrophilic asthma.

Background: Asthma is associated with accelerated rate of lung function (FEV 1 ) decline., Objective: To determine predictive factors associated with FEV 1 decline in adult asthma., Methods: A retrospective study was conducted in 229 asthmatics recruited from the University Asthma Clinic of Liege. Subjects had at least two visits with post-bronchodilation (post-BD) FEV 1 and minimum one year between them. A multivariable linear regression analysis was conducted in order to come up with factors associated with lung function decline., Results: Post-BD FEV 1 decline in % predicted. y -1 was 0.2 (95%CI -2.0 to 2.8) in the overall population. Our population was made up of mild to moderate asthmatics [1] for 58%, aged 50 (41-60) years old, 62% were female and 59% were atopic. Median ICS dose was 1000 μg beclomethasone equivalent (CFC)/day with 81% treated at baseline. Time between visits was 46.8 ± 32.1 months. The univariate linear regression analysis revealed a negative association between % predicted FEV 1 decline and baseline ACQ (p < 0.0001) and blood eosinophils (% and/mm 3 ) (p < 0.0001 and p < 0.0001). A positive association was found between % predicted FEV 1 decline and baseline pre-BD FEV1 (mL) values (p = 0.001), blood neutrophils (%) (p = 0.02), change in blood eosinophils (%) (p < 0.0001), time between visits (months) (p < 0.0001). The predictive variables for accelerated decline highlighted by the multivariable analysis (r 2  = 0.39) were change in blood eosinophils (%) over time (p = 0.002) and time between visits (months) (p < 0.0001)., Conclusion: These findings highlight a new value for blood eosinophil counts as their increase over time predicts greater lung function decline in asthma., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

As treating severe forms of asthma represents a medical and economical challenge, research for new therapies in this area is extensive and expansive. Recently, bronchial thermoplasty (BT) - ie. bronchoscopic procedure delivering a thermic form of energy through radiofrequency to the bronchi, in order to interfere with the components of the smooth muscle layer - arose as a promising technique. Our study followed the path of 10 patients from CHU Liège (University Hospital), who underwent this procedure in a context of severe asthma. We compared clinical and spirometric and treatment data in patients at 0 - 6 and 12 months post-procedural intervals, in order to determine whether thermoplasty had been improving asthma. Overall, we observed a stabilization and possibly a clinical improvement while reducing the total amount of exacerbation rate, and the burden of maintenance oral corticoids.

Background: While non-eosinophilic asthmatics are usually considered poorly responsive to inhaled corticosteroids (ICSs), studies assessing a step-down of ICS in this specific population are currently lacking., Objectives: To assess the proportion of non-eosinophilic asthmatics in whom ICS may be withdrawn without any clinical degradation and to determine the predictive markers of a failure to stop treatment with ICS., Methods: This prospective study was completed by 36 non-eosinophilic asthmatics, defined by sputum eosinophils <3% and blood eosinophils <400/μL. In these patients, whichever the baseline asthma control level, the dose of ICS was gradually reduced every 3 months until they met the failure criteria or successfully discontinued ICS for 6 months. The failure criteria were an ACQ score ≥1.5 with an increase from baseline >0.5 or a number of severe exacerbations during the study which was greater than the number during the year prior to the baseline visit. Receiver-operating characteristic (ROC) curves were constructed to assess predictors of a failure to stop ICS. This study is registered with ClinicalTrials.gov, number NCT02169323., Results: In 14 patients (39%), ICSs were completely withdrawn, and in 10 further patients (28%), ICS were stepped-down to a reduced ICS dose without any deterioration of asthma control and exacerbation rate. Baseline predictors of a failure to stop ICS were a greater age (area under ROC curve [ROC AUC] and [95% CI]: 0.77 [0.62-0.93]) and elevated blood eosinophils (ROC AUC [95% CI]: 0.77 [0.61-0.93]). After the first step-down of ICS, the best predictor was an elevated blood eosinophil count (ROC AUC [95% CI]: 0.85 [0.72-0.99])., Conclusions & Clinical Relevance: Withdrawing or reducing the dose of ICS is feasible in two-thirds of non-eosinophilic asthmatics irrespective of baseline asthma control. An elevated blood eosinophil count may predict the failure to stop ICS., (© 2018 John Wiley & Sons Ltd.)

The technique of sputum induction and processing is a recognized non-invasive method allowing the collection and analysis of cells from the airways, which is interesting in various respiratory diseases like asthma, chronic obstructive pulmonary disease (COPD), chronic cough, or idiopathic pulmonary fibrosis. This technique is well tolerated, safe and non-invasive, but is currently limited to research services and specialized centers in clinical practice because it is technically demanding, time-consuming, and requires trained staff. The success rate of sputum induction and analysis is about 80%. Here, we describe the induction and laboratory processing of sputum samples. Sputum is induced by inhalation of hypertonic or isotonic saline with salbutamol. For the processing, we use the whole sputum technique. Dithiothreitol (DTT) is used to allow mucolysis of sputum samples. The primary aim of sputum processing is to obtain a differential cell count to study the cell types present in the airway lumen. Additional analyses may also be performed on sputum supernatant and sputum cells, which may allow further investigation into inflammatory processes and immune mechanisms. Examples include studying mediators in sputum supernatant and performing a large spectrum of analysis on sputum cells such as flow cytometry, genomics, or proteomics. Finally, representative results of sputum analysis in healthy controls, asthmatics, and COPD patients are presented.

Objective: Transcribed-ultraconserved regions (T-UCR) are long non-coding RNAs which are conserved across species and are involved in carcinogenesis. We studied T-UCRs downstream of the Wnt/β-catenin pathway in liver cancer., Design: Hypomorphic Apc mice ( Apcfl/fl ) and thiocetamide (TAA)-treated rats developed Wnt/β-catenin dependent hepatocarcinoma (HCC) and cholangiocarcinoma (CCA), respectively. T-UCR expression was assessed by microarray, real-time PCR and in situ hybridisation., Results: Overexpression of the T-UCR uc.158- could differentiate Wnt/β-catenin dependent HCC from normal liver and from β-catenin negative diethylnitrosamine (DEN)-induced HCC. uc.158- was overexpressed in human HepG2 versus Huh7 cells in line with activation of the Wnt pathway. In vitro modulation of β-catenin altered uc.158- expression in human malignant hepatocytes. uc.158- expression was increased in CTNNB1 -mutated human HCCs compared with non-mutated human HCCs, and in human HCC with nuclear localisation of β-catenin. uc.158- was increased in TAA rat CCA and reduced after treatment with Wnt/β-catenin inhibitors. uc.158- expression was negative in human normal liver and biliary epithelia, while it was increased in human CCA in two different cohorts. Locked nucleic acid-mediated inhibition of uc.158- reduced anchorage cell growth, 3D-spheroid formation and spheroid-based cell migration, and increased apoptosis in HepG2 and SW1 cells. miR-193b was predicted to have binding sites within the uc.158- sequence. Modulation of uc.158- changed miR-193b expression in human malignant hepatocytes. Co-transfection of uc.158- inhibitor and anti-miR-193b rescued the effect of uc.158- inhibition on cell viability., Conclusions: We showed that uc.158- is activated by the Wnt pathway in liver cancers and drives their growth. Thus, it may represent a promising target for the development of novel therapeutics., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

While the use of bioluminescent proteins for molecular imaging is a powerful technology to further our understanding of complex processes, fluorescent labeling with visible light fluorescent proteins such as GFP and RFP suffers from poor tissue penetration and high background autofluorescence. To overcome these limitations, we generated an inducible knock-in mouse model of iRFP713. This model was used to assess Cre activity in a Rosa Cre-ER background and quantify Cre activity upon different tamoxifen treatments in several organs. We also show that iRFP can be readily detected in 3D organoid cultures, FACS analysis and in vivo tumour models. Taken together we demonstrate that iRFP713 is a progressive step in in vivo imaging and analysis that widens the optical imaging window to the near-infrared spectrum, thereby allowing deeper tissue penetration, quicker image acquisition without the need to inject substrates and a better signal to background ratio in genetically engineered mouse models (GEMMs).

Concomitant chemotherapy with cisplatin (100 mg/m every 3 weeks) improves outcome for high-risk patients in the postoperative setting and for inoperable disease. Toxicity is increased. Other schemes of potentiation are sometimes used to reduce toxicity, but efficiency is diminished. Cetuximab also improves outcome, but there has been no direct comparison with cisplatin. Immunotherapy is currently being evaluated in association with radiation therapy. Trials are ongoing to evaluate the impact of de-escalation for human papillomavirus-positive patients. The association of docetaxel, cisplatin, and 5-fluorouracil is the standard of induction; it is also the standard treatment for laryngeal preservation. Many trials have attempted to compare the concomitant approach with the sequential treatment; none have managed to show a difference between the two. After induction chemotherapy, there is still no standard of potentiation of radiotherapy.

Chemotherapy is the only option of treatment for most patients presenting with a recurrent and/or metastatic head and neck squamous cell carcinoma. The triple association of cisplatin, 5-fluorouracile, and cetuximab is still the current standard for fit patients. Other schemes are currently being compared with this protocol in ongoing trials and the association of cisplatin, docetaxel, and cetuximab appears to be the most efficient. The human papilloma virus is very likely a favorable prognostic factor. Immunotherapy with nivolumab or pembrolizumab is now a new standard of treatment in second line after yielding an improvement in overall survival, but predictive markers of efficacy are needed to refine the selection of patients. The combination of paclitaxel and buparlisib appears to be promising.

Introduction: Angiogenesis is critical for tumor growth, proliferation and metastasis with the crucial role of Vascular Endothelial Growth factor (VEGF) pathway. Ramucirumab is a monoclonal antibody that specifically targets the extracellular domain of Vascular Endothelial Growth Factor Receptor 2. Areas covered: We performed a search on Medline to browse the current literature on Ramucirumab and anti-angiogenic agents, for the treatment of NSCLC. The REVEL study demonstrated a significant improvement of response rate, progression-free survival and overall survival by adding ramucirumab to docetaxel compared to docetaxel plus a placebo in second-line treatment of advanced non-small cell lung cancer, irrespective of histology, with an acceptable safety profile. This article has for objective to summarize efficacy and safety data of the use of ramucirumab in combination with docetaxel in second line in NSCLC. Expert commentary: REVEL constitutes the first significant advance in second-line setting for patients eligible to anti-angiogenic therapy. The landscape of post-platinum therapy in NSCLC is considerably evolving and the role of ramucirumab or other anti-angiogenic agents as nintedanib in this setting has to be discussed for each patient with other available treatment options, among which immune checkpoints inhibitors, as well as the best treatment sequence.

Background: The technique of induced sputum has allowed to subdivide asthma patients into inflammatory phenotypes according to their level of granulocyte airway infiltration. There are very few studies which looked at detailed sputum and blood cell counts in a large cohort of asthmatics divided into inflammatory phenotypes. The purpose of this study was to analyze sputum cell counts, blood leukocytes and systemic inflammatory markers in these phenotypes, and investigate how those groups compared with healthy subjects., Methods: We conducted a retrospective cross-sectional study on 833 asthmatics recruited from the University Asthma Clinic of Liege and compared them with 194 healthy subjects. Asthmatics were classified into inflammatory phenotypes., Results: The total non-squamous cell count per gram of sputum was greater in mixed granulocytic and neutrophilic phenotypes as compared to eosinophilic, paucigranulocytic asthma and healthy subjects (p < 0.005). Sputum eosinophils (in absolute values and percentages) were increased in all asthma phenotypes including paucigranulocytic asthma, compared to healthy subjects (p < 0.005). Eosinophilic asthma showed higher absolute sputum neutrophil and lymphocyte counts than healthy subjects (p < 0.005), while neutrophilic asthmatics had a particularly low number of sputum macrophages and epithelial cells. All asthma phenotypes showed an increased blood leukocyte count compared to healthy subjects (p < 0.005), with paucigranulocytic asthmatics having also increased absolute blood eosinophils compared to healthy subjects (p < 0.005). Neutrophilic asthma had raised CRP and fibrinogen while eosinophilic asthma only showed raised fibrinogen compared to healthy subjects (p < 0.005)., Conclusions: This study demonstrates that a significant eosinophilic inflammation is present across all categories of asthma, and that paucigranulocytic asthma may be seen as a low grade inflammatory disease.

Systemic and airway eosinophilia are recognised features of asthma. There are, however, patients who exhibit discordance between local and systemic eosinophilia. In this study, we sought to determine the prevalence and characteristics of patients with concordant and discordant systemic and bronchial eosinophilia. We conducted a retrospective study on 508 asthmatics with successful sputum induction. We assessed the relationship between blood and sputum eosinophils by breaking down the population into four groups according to blood (≥400 cells per mm3) and sputum (≥3%) eosinophils. Then, we prospectively reassessed the link between eosinophils and asthma control (Asthma Control Questionnaire (ACQ)) and exacerbation rate in a new cohort of 250 matched asthmatics. In our retrospective cohort, asthmatics without eosinophilic inflammation were the largest group (49%). The group with isolated sputum eosinophilia (25%) was, compared with noneosinophilic asthma, associated with lower forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity ratio and higher bronchial hyperresponsiveness and exhaled nitric oxide fraction (FeNO). Asthmatics exhibiting isolated systemic eosinophilia (7%) had similar characteristics as noneosinophilic asthmatics. The group with concordant systemic and airway eosinophilia (19%) showed remarkable male predominance, and had the lowest airway calibre, asthma control and quality of life, and the highest bronchial hyperresponsiveness, FeNO and exacerbation rate. The prospective cohort confirmed the different subgroup proportions and the higher ACQ and exacerbation rates in cases of diffuse eosinophilia compared with noneosinophilic asthmatics. Concomitant systemic and bronchial eosinophilic inflammation contribute to poor asthma control., (© ERS 2014.)

Anchorage independent growth is one of the hallmarks of oncogenic transformation. Here we show that infrared fluorescent protein (iRFP) based assays allow accurate and unbiased determination of colony formation and anchorage independent growth over time. This protocol is particularly compatible with high throughput systems, in contrast to traditional methods which are often labor-intensive, subjective to bias and do not allow further analysis using the same cells. Transformation in a single layer soft agar assay could be documented as early as 2 to 3 days in a 96 well format, which can be easily combined with standard transfection, infection and compound screening setups to allow for high throughput screening to identify therapeutic targets.

MicroRNA deregulation is frequent in human colorectal cancers (CRCs), but little is known as to whether it represents a bystander event or actually drives tumor progression in vivo. We show that miR-135b overexpression is triggered in mice and humans by APC loss, PTEN/PI3K pathway deregulation, and SRC overexpression and promotes tumor transformation and progression. We show that miR-135b upregulation is common in sporadic and inflammatory bowel disease-associated human CRCs and correlates with tumor stage and poor clinical outcome. Inhibition of miR-135b in CRC mouse models reduces tumor growth by controlling genes involved in proliferation, invasion, and apoptosis. We identify miR-135b as a key downsteam effector of oncogenic pathways and a potential target for CRC treatment., (Copyright © 2014 Elsevier Inc. All rights reserved.)

FoxO transcription factors play critical roles in cell cycle control and cellular stress responses, and abrogation of FoxO function promotes focus formation by Myc in vitro. Here we show that stable introduction of a dominant-negative FoxO moiety (dnFoxO) into Emu-myc transgenic hematopoietic stem cells accelerates lymphoma development in recipient mice by attenuating Myc-induced apoptosis. When expressed in Emu-myc; p53(+/-) progenitor cells, dnFoxO alleviates the pressure to inactivate the remaining p53 allele in upcoming lymphomas. Expression of the p53 upstream regulator p19(Arf) is virtually undetectable in most dnFoxO-positive Myc-driven lymphomas. We find that FoxO proteins bind to a distinct site within the Ink4a/Arf locus and activate Arf expression. Moreover, constitutive Myc signaling induces a marked increase in nuclear FoxO levels and stimulates binding of FoxO proteins to the Arf locus. These data demonstrate that FoxO factors mediate Myc-induced Arf expression and provide direct genetic evidence for their tumor-suppressive capacity.