La thermoplastie bronchique dans le traitement de l'asthme sévère de l'adulte.
; ; et al
in Revue des maladies respiratoires (2014)
Bronchial thermoplasty is a recent endoscopic technique for the treatment of severe asthma. It is an innovative treatment whose clinical efficacy and safety are beginning to be better understood. Since ... [more ▼]
Bronchial thermoplasty is a recent endoscopic technique for the treatment of severe asthma. It is an innovative treatment whose clinical efficacy and safety are beginning to be better understood. Since this is a device-based treatment, the evaluation procedure of risks and benefits is different that for pharmaceutical products; safety aspects, regulatory requirements, study design and the assessment of the magnitude of effects may all be different. The mechanism of action and optimal patient selection need to be assessed further in rigorous clinical and scientific studies. This technique is in harmony with the development of personalised medicine in the 21st century. It should be developed further in response to the numerous challenges and needs not yet met in the management of severe asthma. [less ▲]Detailed reference viewed: 20 (2 ULg)
First-line crizotinib versus chemotherapy in ALK-positive lung cancer.
; ; et al
in The New England journal of medicine (2014), 371(23), 2167-77
BACKGROUND: The efficacy of the ALK inhibitor crizotinib as compared with standard chemotherapy as first-line treatment for advanced ALK-positive non-small-cell lung cancer (NSCLC) is unknown. METHODS: We ... [more ▼]
BACKGROUND: The efficacy of the ALK inhibitor crizotinib as compared with standard chemotherapy as first-line treatment for advanced ALK-positive non-small-cell lung cancer (NSCLC) is unknown. METHODS: We conducted an open-label, phase 3 trial comparing crizotinib with chemotherapy in 343 patients with advanced ALK-positive nonsquamous NSCLC who had received no previous systemic treatment for advanced disease. Patients were randomly assigned to receive oral crizotinib at a dose of 250 mg twice daily or to receive intravenous chemotherapy (pemetrexed, 500 mg per square meter of body-surface area, plus either cisplatin, 75 mg per square meter, or carboplatin, target area under the curve of 5 to 6 mg per milliliter per minute) every 3 weeks for up to six cycles. Crossover to crizotinib treatment after disease progression was permitted for patients receiving chemotherapy. The primary end point was progression-free survival as assessed by independent radiologic review. RESULTS: Progression-free survival was significantly longer with crizotinib than with chemotherapy (median, 10.9 months vs. 7.0 months; hazard ratio for progression or death with crizotinib, 0.45; 95% confidence interval [CI], 0.35 to 0.60; P<0.001). Objective response rates were 74% and 45%, respectively (P<0.001). Median overall survival was not reached in either group (hazard ratio for death with crizotinib, 0.82; 95% CI, 0.54 to 1.26; P=0.36); the probability of 1-year survival was 84% with crizotinib and 79% with chemotherapy. The most common adverse events with crizotinib were vision disorders, diarrhea, nausea, and edema, and the most common events with chemotherapy were nausea, fatigue, vomiting, and decreased appetite. As compared with chemotherapy, crizotinib was associated with greater reduction in lung cancer symptoms and greater improvement in quality of life. CONCLUSIONS: Crizotinib was superior to standard first-line pemetrexed-plus-platinum chemotherapy in patients with previously untreated advanced ALK-positive NSCLC. (Funded by Pfizer; PROFILE 1014 ClinicalTrials.gov number, NCT01154140.). [less ▲]Detailed reference viewed: 18 (1 ULg)
Heterogeneity of phenotypes in severe asthmatics. The Belgian Severe Asthma Registry (BSAR).
SCHLEICH, FLorence ; ; Louis, Renaud et al
in Respiratory medicine (2014), 108(12), 1723-32
The Belgian severe asthma registry is a web-based registry encompassing demographic, clinical, functional and inflammatory data of severe asthmatics (SA), aiming at improving awareness, knowledge on its ... [more ▼]
The Belgian severe asthma registry is a web-based registry encompassing demographic, clinical, functional and inflammatory data of severe asthmatics (SA), aiming at improving awareness, knowledge on its natural history and subphenotypes, and offering tools to optimize care of this asthma population. METHODS: The cross-sectional analyses of this registry included 350 SA as defined by the ATS (2000) from 9 Belgian centres, with at least one year follow up. RESULTS: Mean age was 55 +/- 14 yrs. SA were more frequently female (57%) and atopic (70%). Late-onset asthma (>/=40 yr) was observed in 31% of SA. Current smokers represented 12% while 31% were ex-smokers. In addition to high doses ICS + LABA, 65% of patients were receiving LTRA, 27% anti-IgE and 24% maintenance oral corticosteroids (8 mg (Interquartile range-IQR:4-8) methylprednisolone). Despite impaired airflow (median FEV1:67%; IQR: 52-81) only 65% had a post-bronchodilator FEV1/FVC ratio <70%. The median blood eosinophil count was 240/mm(3). The median FENO was 26 ppb (IQR: 15-43) and 22% of SA had FENO >/= 50 ppb. Induced sputum was successful in 86 patients. Eosinophilic asthma (sputum Eos >/= 3%) was the predominant phenotype (55%) while neutrophilic (sputum Neu >/= 76%) and paucigranulocytic asthma accounted for 22% and 17% respectively. Comorbidities included rhinitis and chronic rhinosinusitis (49%), nasal polyposis (19%), oesophageal reflux (36%), overweight and obesity (47%) and depression (19%). In addition, 8% had aspirin-induced asthma and 3% ABPA. Asthma was not well-controlled in 83% according to ACT < 20 and 77% with ACQ > 1.5. CONCLUSION: In this cohort of patients with severe asthma, the majority displayed indices of persistent airflow limitation and eosinophilic inflammation despite high-dose corticosteroids, suggesting potential for eosinophil-targeted biotherapies. [less ▲]Detailed reference viewed: 11 (0 ULg)
Bronchial thermoplasty: a new therapeutic option for the treatment of severe, uncontrolled asthma in adults.
; ; et al
in European respiratory review : an official journal of the European Respiratory Society (2014), 23(134), 510-8
Bronchial thermoplasty is a young yet promising treatment for severe asthma whose benefit for long-term asthma control outweighs the short-term risk of deterioration and hospitalisation in the days ... [more ▼]
Bronchial thermoplasty is a young yet promising treatment for severe asthma whose benefit for long-term asthma control outweighs the short-term risk of deterioration and hospitalisation in the days following the treatment. It is an innovative treatment whose clinical efficacy and safety are beginning to be better understood. Since this is a device-based therapy, the overall evaluation of risk-benefit is unlike that of pharmaceutical products; safety aspects, regulatory requirements, study design and effect size assessment may be unfamiliar. The mechanisms of action and optimal patient selection need to be addressed in further rigorous clinical and scientific studies. Bronchial thermoplasty fits in perfectly with the movement to expand personalised medicine in the field of chronic airway disorders. This is a device-based complimentary asthma treatment that must be supported and developed in order to meet the unmet needs of modern severe asthma management. The mechanisms of action and the type of patients that benefit from bronchial thermoplasty are the most important challenges for bronchial thermoplasty in the future. [less ▲]Detailed reference viewed: 10 (2 ULg)
Sputum cytokines levels in patients undergoing hematopoietic SCT (HSCT) and comparison with healthy subjects and COPD: a pilot study
MOERMANS, Catherine ; BONNET, Christophe ; WILLEMS, Evelyne et al
in Bone Marrow Transplantation (2014), 49(11), 1382-1388
Patients undergoing hematopoietic stem cell transplantation (HSCT) display an airway neutrophilic inflammation before the transplantation that persists over the years. In this study, we have investigated ... [more ▼]
Patients undergoing hematopoietic stem cell transplantation (HSCT) display an airway neutrophilic inflammation before the transplantation that persists over the years. In this study, we have investigated the cytokine profile over a period of one year in sputum supernatant of patients who underwent HSCT. We have measured sputum supernatant levels of TNF-α, TGF-β1, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, IL-17, and IFN-γ in 49 HSCT patients and compared the results with those found in 40 COPD and 54 healthy subjects matched for age. Compared to healthy subjects, before the transplantation, HSCT patients exhibited raised levels of IL-6 (p<0.001) and IL-8 (p<0.05) while the other cytokines were generally poorly detectable. This picture was rather similar to what is seen in COPD even if cytokine levels were much greater in the latter with IL-8 being significantly greater in COPD than in HSCT patients (p<0.0001). In the 1 year following the transplantation, sputum IL-6 and IL-8 did not differ any longer compared to healthy subjects. Overall in HSCT patients, sputum IL-8 and IL-6 correlated with sputum neutrophil counts (r=0.4, p<0.0001; r=0.42, p<0.0001, respectively). In conclusion, sputum IL-6 and IL-8 may play a role in neutrophilic airway inflammation seen in patients undergoing HSCT. [less ▲]Detailed reference viewed: 39 (17 ULg)
Time for reasoning ICS prescription in obstructive airway diseases.
Louis, Renaud ; Demarche, Sophie
in International journal of clinical practice (2014), 68(10), 1176-8Detailed reference viewed: 3 (0 ULg)
Increased of exhaled breath condensate neutrophil chemotaxis in acute exacerbation of COPD.
Corhay, Jean-Louis ; MOERMANS, Catherine ; HENKET, Monique et al
in Respiratory research (2014), 15
BACKGROUND: Neutrophils have been involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). Underlying mechanisms of neutrophil accumulation in the airways of stable and exacerbated ... [more ▼]
BACKGROUND: Neutrophils have been involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). Underlying mechanisms of neutrophil accumulation in the airways of stable and exacerbated COPD patients are poorly understood. The aim of this study was to assess exhaled breath condensate (EBC) neutrophil chemotactic activity, the level of two chemoattractants for neutrophils (GRO-alpha and LTB4) during the course of an acute exacerbation of COPD (AECOPD). METHODS: 50 ex smoking COPD patients (33 with acute exacerbation and 17 in stable disease) and 20 matched ex smoking healthy controls were compared. EBC was collected by using a commercially available condenser (EcoScreen(R)). EBC neutrophil chemotactic activity (NCA) was assessed by using Boyden microchambers. Chemotactic index (CI) was used to evaluate cell migration. LTB4 and GROalpha levels were measured by a specific enzyme immunoassay in EBC. RESULTS: Stable COPD and outpatients with AECOPD, but not hospitalized with AECOPD, had raised EBC NCA compared to healthy subjects (p < 0.05 and p < 0.01 respectively). In outpatients with AECOPD EBC NCA significantly decreased 6 weeks after the exacerbation. Overall EBC NCA was weakly correlated with sputum neutrophil counts (r = 0.26, p < 0.05). CONCLUSIONS: EBC NCA rose during acute exacerbation of COPD in ambulatory patients and decreased at recovery. While LTB4 seems to play a role both in stable and in exacerbated phase of the disease, the role of GRO-alpha as a chemotactic factor during AECOPD is not clearly established and needs further investigation. [less ▲]Detailed reference viewed: 16 (0 ULg)
Mepolizumab treatment in patients with severe eosinophilic asthma.
; ; et al
in The New England journal of medicine (2014), 371(13), 1198-207
BACKGROUND: Some patients with severe asthma have frequent exacerbations associated with persistent eosinophilic inflammation despite continuous treatment with high-dose inhaled glucocorticoids with or ... [more ▼]
BACKGROUND: Some patients with severe asthma have frequent exacerbations associated with persistent eosinophilic inflammation despite continuous treatment with high-dose inhaled glucocorticoids with or without oral glucocorticoids. METHODS: In this randomized, double-blind, double-dummy study, we assigned 576 patients with recurrent asthma exacerbations and evidence of eosinophilic inflammation despite high doses of inhaled glucocorticoids to one of three study groups. Patients were assigned to receive mepolizumab, a humanized monoclonal antibody against interleukin-5, which was administered as either a 75-mg intravenous dose or a 100-mg subcutaneous dose, or placebo every 4 weeks for 32 weeks. The primary outcome was the rate of exacerbations. Other outcomes included the forced expiratory volume in 1 second (FEV1) and scores on the St. George's Respiratory Questionnaire (SGRQ) and the 5-item Asthma Control Questionnaire (ACQ-5). Safety was also assessed. RESULTS: The rate of exacerbations was reduced by 47% (95% confidence interval [CI], 29 to 61) among patients receiving intravenous mepolizumab and by 53% (95% CI, 37 to 65) among those receiving subcutaneous mepolizumab, as compared with those receiving placebo (P<0.001 for both comparisons). Exacerbations necessitating an emergency department visit or hospitalization were reduced by 32% in the group receiving intravenous mepolizumab and by 61% in the group receiving subcutaneous mepolizumab. At week 32, the mean increase from baseline in FEV1 was 100 ml greater in patients receiving intravenous mepolizumab than in those receiving placebo (P=0.02) and 98 ml greater in patients receiving subcutaneous mepolizumab than in those receiving placebo (P=0.03). The improvement from baseline in the SGRQ score was 6.4 points and 7.0 points greater in the intravenous and subcutaneous mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 4 points), and the improvement in the ACQ-5 score was 0.42 points and 0.44 points greater in the two mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 0.5 points) (P<0.001 for all comparisons). The safety profile of mepolizumab was similar to that of placebo. CONCLUSIONS: Mepolizumab administered either intravenously or subcutaneously significantly reduced asthma exacerbations and was associated with improvements in markers of asthma control. (Funded by GlaxoSmithKline; MENSA ClinicalTrials.gov number, NCT01691521.). [less ▲]Detailed reference viewed: 11 (0 ULg)
NEXThaler, an innovative dry powder inhaler delivering an extrafine fixed combination of beclometasone and formoterol to treat large and small airways in asthma.
; ; et al
in Expert opinion on drug delivery (2014), 11(9), 1497-506
INTRODUCTION: Airway inflammation and remodelling in asthma occur in the large airways and also in the small airways. The small airways are those < 2 mm in diameter and are significant sites of chronic ... [more ▼]
INTRODUCTION: Airway inflammation and remodelling in asthma occur in the large airways and also in the small airways. The small airways are those < 2 mm in diameter and are significant sites of chronic asthmatic inflammation. It is important, therefore, to target the small as well as the large airways in any strategy for effective treatment of this disease. AREAS COVERED: The present review deals with the recently developed fixed dose drug combination of beclometasone dipropionate/formoterol fumarate that emits extrafine particles when delivered from an innovative dry powder inhaler (DPI), NEXThaler(R). The aim is to present the technical and clinical aspects of aerosolized drug delivery to the lungs. EXPERT OPINION: The data show that the NEXThaler DPI is an efficient device for the management of persistent asthma. The evaluation of the inhalation profiles through the NEXThaler DPI demonstrates that device activation and consistent dose delivery occurs at patient achievable inhalation flow rates, and supports the broad utility of the NEXThaler DPI in patients with asthma. Overall, all the effectiveness, efficiency and satisfaction outcomes demonstrate the NEXThaler DPI is easy to use. [less ▲]Detailed reference viewed: 12 (0 ULg)
Thermoplastie bronchique : une réelle avancée dans le traitement de l'asthme
HEINEN, Vincent ; SCHLEICH, FLorence ; DUYSINX, Bernard et al
in Revue Médicale Suisse (2014), 10(439), 1544-1548
New treatments are needed to improve the care of severe asthmatic patients. Bronchial thermoplasty aims to lessen the airway smooth muscles via the heating of bronchial walls by radiofrequency. The ... [more ▼]
New treatments are needed to improve the care of severe asthmatic patients. Bronchial thermoplasty aims to lessen the airway smooth muscles via the heating of bronchial walls by radiofrequency. The preliminary studies showed a good tolerance and some good efficacy. Randomized controlled trials have been undertaken on moderate to severe asthmatic patients, demonstrating an improvement in quality of life, rate of severe exacerbations and unscheduled medical visits. The main side-effects consist of asthma exacerbations, atelectasis and infections. Bronchial thermoplasty is an innovative treatment with good efficacy and acceptable tolerance for moderate to severe asthmatic patients. More studies are needed to better understand its mechanism of action and more clearly delineate the precise indications of this innovative technique. [less ▲]Detailed reference viewed: 18 (5 ULg)
Integrated care pathways for airway diseases (AIRWAYS-ICPs).
; ; et al
in The European respiratory journal (2014), 44(2), 304-23
The objective of Integrated Care Pathways for Airway Diseases (AIRWAYS-ICPs) is to launch a collaboration to develop multi-sectoral care pathways for chronic respiratory diseases in European countries and ... [more ▼]
The objective of Integrated Care Pathways for Airway Diseases (AIRWAYS-ICPs) is to launch a collaboration to develop multi-sectoral care pathways for chronic respiratory diseases in European countries and regions. AIRWAYS-ICPs has strategic relevance to the European Union Health Strategy and will add value to existing public health knowledge by: 1) proposing a common framework of care pathways for chronic respiratory diseases, which will facilitate comparability and trans-national initiatives; 2) informing cost-effective policy development, strengthening in particular those on smoking and environmental exposure; 3) aiding risk stratification in chronic disease patients, using a common strategy; 4) having a significant impact on the health of citizens in the short term (reduction of morbidity, improvement of education in children and of work in adults) and in the long-term (healthy ageing); 5) proposing a common simulation tool to assist physicians; and 6) ultimately reducing the healthcare burden (emergency visits, avoidable hospitalisations, disability and costs) while improving quality of life. In the longer term, the incidence of disease may be reduced by innovative prevention strategies. AIRWAYSICPs was initiated by Area 5 of the Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing. All stakeholders are involved (health and social care, patients, and policy makers). [less ▲]Detailed reference viewed: 17 (0 ULg)
Phenotypes de la broncho-pneumopathie chronique obstructive.
Corhay, Jean-Louis ; SCHLEICH, FLorence ; Louis, Renaud
in Revue medicale de Liege (2014), 69(7-8), 415-21
Chronic Obstructive Pulmonary Disease (COPD) is a multi-dimensional disorder with multiple phenotypes. The GOLD guidelines, used for the diagnosis, staging and treatment of COPD, do not fully reflect the ... [more ▼]
Chronic Obstructive Pulmonary Disease (COPD) is a multi-dimensional disorder with multiple phenotypes. The GOLD guidelines, used for the diagnosis, staging and treatment of COPD, do not fully reflect the heterogeneous nature of the disease. Historically, the two most recognized clinical phenotypes of COPD are emphysema and chronic bronchitis. Most COPD patients encountered in practice actually share, both of these features. Genetic background, clinical presentation, variation in the response to treatment and propensity to exacerbations may also identify other phenotypes. Recently, using a mathematical approach, such as cluster analysis, which is based on pre-selected parameters, other interesting phenotypes were identified. A precise definition of COPD phenotypes should lead to a more targeted therapeutic approach based on these phenotypes. The purpose of this article is to point out that COPD is a heterogeneous disease and to summarize the current data available about the phenotypes of this disease. [less ▲]Detailed reference viewed: 16 (0 ULg)
Exhaled Air Analysis for Early Detection of Lung Cancer
Pesesse, Romain ; Stefanuto, Pierre-Hugues ; SCHLEICH, FLorence et al
Poster (2014, May 23)Detailed reference viewed: 35 (6 ULg)
Le cas clinique du mois. Maladie de Carrington: pneumopathie chronique idiopathique à eosinophiles.
; FRUSCH, Nicolas ; DUYSINX, Bernard et al
in Revue medicale de Liege (2014), 69(3), 126-31
Idiopathic Chronic Eosinophilic Pneumonia (ICEP) or Carrington's disease is a rare disease, exclusively pulmonary, and of an unknown origin. Connective tissues of the lungs are infiltrated by eosinophilic ... [more ▼]
Idiopathic Chronic Eosinophilic Pneumonia (ICEP) or Carrington's disease is a rare disease, exclusively pulmonary, and of an unknown origin. Connective tissues of the lungs are infiltrated by eosinophilic cell elements. This illness is progressive, consisting of dyspnea, cough and thoracic pain. In addition, the general condition is impaired. The average delay between onset of symptoms and discovery of chest radiographic opacities is often longer than 3-4 months. Symptoms and chest X-ray quickly improve under corticosteroid treatment. In the future, new research could lead to alternative treatments. We report the case of a woman with ICEP. We shall discuss the diagnostic approach, envisage the potential complications and describe the treatment of the disease. [less ▲]Detailed reference viewed: 11 (0 ULg)
Usage of inhalation devices in asthma and chronic obstructive pulmonary disease: a Delphi consensus statement.
; ; Louis, Renaud et al
in Expert opinion on drug delivery (2014), 11(3), 313-23
OBJECTIVES: The study aimed to assess usage of inhalation devices in asthma and chronic obstructive pulmonary disease (COPD). METHODS: In this two-round Delphi survey, 50 experts in asthma and COPD ... [more ▼]
OBJECTIVES: The study aimed to assess usage of inhalation devices in asthma and chronic obstructive pulmonary disease (COPD). METHODS: In this two-round Delphi survey, 50 experts in asthma and COPD completed a 13-item, Internet-based, self-administered questionnaire about choice of inhalation device, training and monitoring of inhalation techniques, the interchangeability and the role of costs in the selection of inhalation devices. For each item, the median (central tendency) and interquartile ranges (degree of consensus) were calculated. RESULTS: Experts considered that the choice of inhalation device was as important as that of active substance (very good consensus) and should be driven by ease of use (good to very good consensus) and teaching (very good consensus). Experts recommended giving oral and visual instructions (good consensus) and systematic monitoring inhalation techniques. Pulmonologists and paramedics have predominantly educational roles (very good consensus). Experts discouraged inhalation device interchangeability (good consensus) and switching for cost reasons (good to very good consensus) without medical consultation (good consensus). CONCLUSIONS: The results of this survey thus suggested that inhalation devices are as important as active substances and training and monitoring are essential in ensuring effective treatment of asthma and COPD. Inhalation device switching without medical consultation should be avoided. [less ▲]Detailed reference viewed: 20 (0 ULg)
Lipid-lowering drug therapies and chronic obstructive pulmonary disease: lung failure or just heart failure?
; Louis, Renaud
in International journal of clinical practice (2014), 68(2), 144-51Detailed reference viewed: 5 (0 ULg)
Adrenomedullin refines mortality prediction by the BODE index in COPD - The "BODE-A" index.
; ; et al
in European Respiratory Journal (2014)
The BODE index is well-validated for mortality prediction in COPD. Concentrations of plasma proadrenomedullin, a surrogate for mature adrenomedullin, independently predicted 2-year mortality among ... [more ▼]
The BODE index is well-validated for mortality prediction in COPD. Concentrations of plasma proadrenomedullin, a surrogate for mature adrenomedullin, independently predicted 2-year mortality among inpatients with COPD exacerbation.We compared accuracy of initial proadrenomedullin level, BODE, and BODE components, alone or combined, in predicting 1-year or 2-year all-cause mortality in a multicenter, multinational observational cohort with stable, moderate to very severe COPD.Proadrenomedullin was significantly associated (P<0.001) with 1-year mortality (4.7%) and 2-year mortality (7.8%), and comparably predictive to BODE regarding both (C statistics: 0.691 vs. 0.745, 0.635 vs. 0.679). Relative to using BODE alone, adding proadrenomedullin significantly improved 1-year and 2-year mortality prognostication (C statistics: 0.750, 0.818; both P<0.001). Proadrenomedullin plus BOD was more predictive than was the original BODE including 6-minute-walk distance. In multivariable analysis, proadrenomedullin (LR X2 13.0, P<0.001), body mass index (8.5, P=0.004), and 6-minute-walk distance (7.5, P=0.006), but not modified MMRC dyspnoea score (2.2, P=0.14) or FEV1 % predicted (0.3, P=0.60), independently foretold 2-year survival.Proadrenomedullin plus BODE better predicts mortality in COPD patients than does BODE alone; proadrenomedullin may substitute for 6-minute-walk distance in BODE when 6-minute-walk testing is unavailable. [less ▲]Detailed reference viewed: 15 (3 ULg)
Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial.
; ; et al
in The Lancet. Oncology (2014), 15(1), 59-68
BACKGROUND: Effective maintenance therapies after chemoradiotherapy for lung cancer are lacking. Our aim was to investigate whether the MUC1 antigen-specific cancer immunotherapy tecemotide improves ... [more ▼]
BACKGROUND: Effective maintenance therapies after chemoradiotherapy for lung cancer are lacking. Our aim was to investigate whether the MUC1 antigen-specific cancer immunotherapy tecemotide improves survival in patients with stage III unresectable non-small-cell lung cancer when given as maintenance therapy after chemoradiation. METHODS: The phase 3 START trial was an international, randomised, double-blind trial that recruited patients with unresectable stage III non-small-cell lung cancer who had completed chemoradiotherapy within the 4-12 week window before randomisation and received confirmation of stable disease or objective response. Patients were stratified by stage (IIIA vs IIIB), response to chemoradiotherapy (stable disease vs objective response), delivery of chemoradiotherapy (concurrent vs sequential), and region using block randomisation, and were randomly assigned (2:1, double-blind) by a central interactive voice randomisation system to either tecemotide or placebo. Injections of tecemotide (806 mug lipopeptide) or placebo were given every week for 8 weeks, and then every 6 weeks until disease progression or withdrawal. Cyclophosphamide 300 mg/m(2) (before tecemotide) or saline (before placebo) was given once before the first study drug administration. The primary endpoint was overall survival in a modified intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00409188. FINDINGS: From Feb 22, 2007, to Nov 15, 2011, 1513 patients were randomly assigned (1006 to tecemotide and 507 to placebo). 274 patients were excluded from the primary analysis population as a result of a clinical hold, resulting in analysis of 829 patients in the tecemotide group and 410 in the placebo group in the modified intention-to-treat population. Median overall survival was 25.6 months (95% CI 22.5-29.2) with tecemotide versus 22.3 months (19.6-25.5) with placebo (adjusted HR 0.88, 0.75-1.03; p=0.123). In the patients who received previous concurrent chemoradiotherapy, median overall survival for the 538 (65%) of 829 patients assigned to tecemotide was 30.8 months (95% CI 25.6-36.8) compared with 20.6 months (17.4-23.9) for the 268 (65%) of 410 patients assigned to placebo (adjusted HR 0.78, 0.64-0.95; p=0.016). In patients who received previous sequential chemoradiotherapy, overall survival did not differ between the 291 (35%) patients in the tecemotide group and the 142 (35%) patients in the placebo group (19.4 months [95% CI 17.6-23.1] vs 24.6 months [18.8-33.0], respectively; adjusted HR 1.12, 0.87-1.44; p=0.38). Grade 3-4 adverse events seen with a greater than 2% frequency with tecemotide were dyspnoea (49 [5%] of 1024 patients in the tecemotide group vs 21 [4%] of 477 patients in the placebo group), metastases to central nervous system (29 [3%] vs 6 [1%]), and pneumonia (23 [2%] vs 12 [3%]). Serious adverse events with a greater than 2% frequency with tecemotide were pneumonia (30 [3%] in the tecemotide group vs 14 [3%] in the placebo group), dyspnoea (29 [3%] vs 13 [3%]), and metastases to central nervous system (32 [3%] vs 9 [2%]). Serious immune-related adverse events did not differ between groups. INTERPRETATION: We found no significant difference in overall survival with the administration of tecemotide after chemoradiotherapy compared with placebo for all patients with unresectable stage III non-small-cell lung cancer. However, tecemotide might have a role for patients who initially receive concurrent chemoradiotherapy, and further study in this population is warranted. FUNDING: Merck KGaA (Darmstadt, Germany). [less ▲]Detailed reference viewed: 12 (2 ULg)
Impact of cotransplantation of mesenchymal stem cells on lung function after unrelated allogeneic hematopoietic stem cell transplantation following non-myeloablative conditioning
MOERMANS, Catherine ; LECHANTEUR, Chantal ; BAUDOUX, Etienne et al
in Transplantation (2014), 98(3), 348-353
Background: In the context of hematopoietic stem cell transplantation (HSCT), mesenchymal stem cells (MSC) have been used to promote engraftment and prevent graft- versus-host-disease. However, in animal ... [more ▼]
Background: In the context of hematopoietic stem cell transplantation (HSCT), mesenchymal stem cells (MSC) have been used to promote engraftment and prevent graft- versus-host-disease. However, in animal models, MSC were shown to cause pulmonary alterations after systemic administration. The impact of MSC infusion on lung function has not been studied in humans. The objective of the study was to investigate the impact of MSC co-infusion on lung function and airway inflammation as well as on the incidence of pulmonary infections and cytomegalovirus (CMV) reactivation after HSCT. Methods: We have prospectively followed 30 patients who underwent unrelated HSCT with MSC co-infusion after non-myeloablative conditioning (NMA). Each patient underwent detailed lung function testing (FEV1, FVC, FEV1/FVC, RV, TLC, DLCO and KCO) and measurement of exhaled nitric oxide before HSCT and 3, 6 and 12 months posttransplant. The incidence of pulmonary infections and CMV reactivation were also monitored. This group was compared with another group of 28 patients who underwent the same type of transplantation but without MSC co-infusion. Results: Lung function tests did not show important modifications over time and did not differ between the MSC and control groups. There was a higher 1-year incidence of infection, particularly of fungal infections, in patients having received a MSC co-infusion. There was no difference between groups regarding the 1-year incidence of CMV reactivation. Conclusions: MSC co-infusion does not induce pulmonary deterioration 1 year after HSCT with NMA conditioning. MSC appear to be safe for the lung but close monitoring of pulmonary infections remains essential. [less ▲]Detailed reference viewed: 60 (28 ULg)
Development of recombinant stable house dust mite allergen Der p 3 molecules for component-resolved diagnosis and specific immunotherapy.
; ; et al
in Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology (2014)
BACKGROUND: The allergen Der p 3 is underrepresented in house dust mite (HDM) extracts probably due to autolysis. Recombinant stable molecule of the allergen is thus needed to improve the diagnosis of ... [more ▼]
BACKGROUND: The allergen Der p 3 is underrepresented in house dust mite (HDM) extracts probably due to autolysis. Recombinant stable molecule of the allergen is thus needed to improve the diagnosis of allergy and the safety and efficacy of immunotherapy. OBJECTIVE: The current study reports the immunological characterization of two recombinant molecules of the HDM allergen Der p 3 as useful tools for diagnosis and immunotherapy. METHODS: Recombinant mature (rDer p 3) and immature (proDer p 3) Der p 3 and their corresponding S196A mutants were produced in Pichia pastoris and purified. The stability, IgE-binding capacity and allergenicity of the different proteins were analyzed and compared with those of the major mite allergen Der p 1 used as a reference. Additionally, the immunogenicity of the different allergens was evaluated in a murine model of Der p 3 sensitization. RESULTS: Compared to the IgE reactivity to recombinant and natural Der p 3 (nDer p 3), the mean IgE binding of patient's sera to rDer p 3-S196A (50 %) was higher. The poorly binding to nDer p 3 or rDer p 3 was due to autolysis of the allergen. Contrary to Der p 3, proDer p 3 displayed very weak IgE reactivity, as measured by sandwich ELISA and competitive inhibition, RBL degranulation and human basophil activation assays. Moreover, proDer p 3 induced a TH 1-biased immune response that prevented an allergic response in mice but retained Der p 3-specific T cell reactivity. CONCLUSION: rDer p 3-S196A should be used for the diagnosis of HDM allergy elicited by Der p 3, and proDer p 3 may represent a hypoallergen of Der p 3. This article is protected by copyright. All rights reserved. [less ▲]Detailed reference viewed: 6 (2 ULg)