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Despite successful introduction of NK-based cellular therapy in the treatment of myeloid leukemia, the potential use of NK alloreactivity in solid malignancies is still elusive. We performed a phase I clinical trial to assess the safety and efficacy of in situ delivery of allogeneic NK cells combined with cetuximab in liver metastasis of gastrointestinal origin. The conditioning chemotherapy was administrated before the allogeneic NK cells injection via hepatic artery. Three escalating doses were tested (3.106, 8.106 and 12.106 NK cells/kg) following by a high-dose interleukin-2 (IL-2). Cetuximab was administered intravenously every week for 7 weeks. Nine patients with liver metastases of colorectal or pancreatic cancers were included, three per dose level. Hepatic artery injection was successfully performed in all patients with no report of dose-limiting toxicity. Two patients had febrile aplasia requiring a short-term antibiotherapy. Grade 3/4 anemia and thrombopenia were also observed related to the chemotherapy. Objective clinical responses were documented in 3 patients and among them 2 occurred in patients injected with cell products harboring two KIR ligand mismatches and one in a patient with one KIR ligand mismatch. Immune monitoring revealed that most patients presented an increase but transient of IL-15 and IL-7 cytokines levels one week after chemotherapy. Furthermore, a high expansion of FoxP3+regulatory T cells and PD-1+ T cells was observed in all patients, related to IL-2 administration. Our results demonstrated that combining allogeneic NK cells transfer via intra-hepatic artery, cetuximab and a high-dose IL-2 is feasible, well tolerated and may result in clinical responses.

Alexis Dupuis,1 Aurore Thierry,2 Jeanne-Marie Perotin,1,3 Julien Ancel,1,3 Valérian Dormoy,3 Sandra Dury,1 Gaëtan Deslée,1,3 Claire Launois1,3 1Department of Respiratory Diseases, University Hospital of Reims, Reims, France; 2Université de Reims Champagne-Ardenne, VieFra, CHU Reims, Unité d’Aide Méthodologique, Reims, F-51100, France; 3University of Reims Champagne-Ardenne (URCA), Inserm UMR-S 1250, SFR Cap-Santé, Reims, FranceCorrespondence: Claire Launois, Service des Maladies Respiratoires, 45, Rue Cognacq Jay, Reims Cedex, Reims, 51092, France, Tel +33 3 26 78 76 14, Fax +33 3 26 06 03 19, Email claunois@chu-reims.frBackground: The role of obesity on dyspnea in chronic obstructive pulmonary disease (COPD) patients remains unclear. We aimed to provide an assessment of dyspnea in COPD patients according to their Body Mass Index (BMI) and to investigate the impact of obesity on dyspnea according to COPD severity.Methods: One hundred and twenty seven COPD patients with BMI ≥ 18.5 kg/m² (63% male, median (interquartile range) post bronchodilator forced expiratory volume of 1 second (post BD FEV1) at 51 (34– 66) % pred) were consecutively included. Dyspnea was assessed by mMRC (Modified medical research council) scale. Lung function tests were recorded, and emphysema was quantified on CT-scan (computed tomography-scan).Results: Twenty-five percent of the patients were obese (BMI ≥ 30kg/m²), 66% of patients experienced disabling dyspnea (mMRC ≥ 2). mMRC scores did not differ depending on BMI categories (2 (1– 3) for normal weight, 2 (1– 3) 1 for overweight and 2 (1– 3) for obese patients; p = 0.71). Increased mMRC scores (0– 1 versus 2– 3 versus 4) were associated with decreased post BD-FEV1 (p < 0.01), higher static lung hyperinflation (inspiratory capacity/total lung capacity (IC/TLC), p < 0.01), reduced DLCO (p < 0.01) and higher emphysema scores (p < 0.01). Obese patients had reduced static lung hyperinflation (IC/TLC p < 0.01) and lower emphysema scores (p < 0.01) than non-obese patients. mMRC score increased with GOLD grades (1– 2 versus 3– 4) in non-obese patients but not in obese patients, in association with a trend towards reduced static lung hyperinflation and lower emphysema scores.Conclusion: By contrast with non-obese patients, dyspnea did not increase with spirometric GOLD grades in obese patients. This might be explained by a reduced lung hyperinflation related to the mechanical effects of obesity and a less severe emphysema in severe COPD patients with obesity.Keywords: chronic obstructive pulmonary disease, obesity, dyspnea, lung function, pulmonary emphysema

Jeanne-Marie Perotin,1,2 Anaëlle Muggeo,3 Quentin Lecomte-Thenot,3 Audrey Brisebarre,1 Sandra Dury,2 Claire Launois,1,2 Julien Ancel,1,2 Valérian Dormoy,1 Thomas Guillard,3 Gaëtan Deslee1,2 1Université de Reims Champagne-Ardenne, INSERM UMR-S 1250, P3Cell, Reims, France; 2CHU de Reims, Service des Maladies Respiratoires, Reims, France; 3Université de Reims Champagne-Ardenne, INSERM UMR-S 1250, P3Cell, CHU de Reims, Laboratoire de bactériologie-Virologie-Hygiène hospitalière-Parasitologie-Mycologie, Reims, FranceCorrespondence: Jeanne-Marie Perotin, Service des Maladies Respiratoires, CHU Maison Blanche, Inserm UMR-S 1250, 45 Rue Cognacq-Jay, Reims cedex, 51092, France, Email jmperotin-collard@chu-reims.frPurpose: The heterogeneity of clinical features in COPD at stable state has been associated with airway microbiota. Blood eosinophil count (BEC) represents a biomarker for a pejorative evolution of COPD, including exacerbations and accelerated FEV1 decline. We aimed to analyse the associations between BEC and airway microbiota in COPD at stable state.Patients and Methods: Adult COPD patients at stable state (RINNOPARI cohort) were included and characterised for clinical, functional, biological and morphological features. BEC at inclusion defined 2 groups of patients with low BEC < 300/mm3 and high BEC ≥ 300/mm3. Sputa were collected and an extended microbiological culture was performed for the identification of viable airway microbiota.Results: Fifty-nine subjects were included. When compared with the low BEC (n=40, 67.8%), the high BEC group (n=19, 32.2%) had more frequent exacerbations (p< 0.001) and more pronounced cough and sputum (p< 0.05). The global composition, the number of bacteria per sample and the α-diversity of the microbiota did not differ between groups, as well as the predominant phyla (Firmicutes), or the gender repartition.Conclusion: In our study, high BEC in COPD at stable state was associated with a clinical phenotype including frequent exacerbation, but no distinct profile of viable airway microbiota compared with low BEC.Keywords: COPD, eosinophil, sputum, microbiota

Abstract Background Severe asthma is characterized by frequent exacerbations, altered lung function, and impaired quality of life. Tailored patient education allows for the improvement of both asthma management and quality of life. Our study aimed to assess the needs of severe asthma patient in therapeutic education, according to previous therapeutic patient education background and asthma phenotype. Methods Consecutive patients monitored for severe asthma in a tertiary referral center were considered for inclusion and answered a questionnaire detailing their patient education needs and the topics they would like to discuss. Asthma history, clinical and biological data, and lung function results were recorded. Results Fifty-three patients were included and 47 (88.7%) expressed at least one need. The most frequently selected topics were “life with asthma” (83%), “treatment use” (68%), and “exacerbation management” (60%), independent of previous participation in a patient education program dedicated to asthma. Patients of older age at inclusion, uncontrolled asthma, and T2-high phenotypes were associated with different profiles of patient education needs. Conclusion Our study identified frequent and various patient educational needs among severe asthmatics, highlighting the importance of an in-depth assessment of severe asthmatics expectations and the crucial need for the development of dedicated educational tools.

Abstract Background Bronchiectasis is a chronic airway disease characterized by permanent and irreversible abnormal dilatation of bronchi. Several studies have reported the development of bronchiectasis after renal transplantation (RT), but no prospective study specifically assessed bronchiectasis in this population. This study aimed to compare features of patients with bronchiectasis associated with RT to those with idiopathic bronchiectasis. Methods Nineteen patients with bronchiectasis associated with RT (RT-B group) and 23 patients with idiopathic bronchiectasis (IB group) were prospectively included in this monocentric cross-sectional study. All patients underwent clinical, functional, laboratory, and CT scan assessments. Sputum was collected from 25 patients (n = 11 with RT-B and n = 14 with IB) and airway microbiota was analyzed using an extended microbiological culture. Results Dyspnea (≥ 2 on mMRC scale), number of exacerbations, pulmonary function tests, total bronchiectasis score, severity and prognosis scores (FACED and E-FACED), and quality of life scores (SGRQ and MOS SF-36) were similar in the RT-B and IB groups. By contrast, chronic cough was less frequent in the RT-B group than in the IB group (68% vs. 96%, p = 0.03). The prevalence and diversity of the airway microbiota in sputum were similar in the two groups. Conclusion Clinical, functional, thoracic CT scan, and microbiological characteristics of bronchiectasis are overall similar in patients with IB and RT-B. These results highlight that in RT patients, chronic respiratory symptoms and/or airway infections should lead to consider the diagnosis of bronchiectasis. Further studies are required to better characterize the pathophysiology of RT-B including airway microbiota, its incidence, and impact on therapeutic management.

Abstract Background Cough and sputum are major symptoms in cystic fibrosis (CF) that contribute to the impairment of quality of life. Methods This prospective single centre cross-sectional pilot study aimed to evaluate the results of a self-administered questionnaire assessing cough and sputum symptoms (2 domains), and their impact (2 domains) on daily activities in the previous week, named the Cough and Sputum Assessment Questionnaire (CASA-Q) in CF adult patients at stable state, and to analyse associations with clinical, functional, microbiological, radiological data, and two quality of life scales: the Cystic Fibrosis Questionnaire Revised (CFQ-R) and the Saint George Respiratory Questionnaire (SGRQ). Results Forty-eight patients were included in this analysis (69% men; median age of 27.8 ± 8.1 years; median body mass index of 21.8 + 3.3 kg/m²; mean FEV1 of 64 ± 30% of the predicted value). The mean values of the CASA-Q domains were 58 ± 23 for cough symptoms, 77 ± 24 for cough impact, 62 ± 25 for sputum symptoms and 84 ± 21 for sputum impact. Impairment in CASA-Q cough and sputum domains was associated with dyspnea mMRC scale (p

Cilia are organelles emanating from the cell surface, consisting of an axoneme of microtubules that extends from a basal body derived from the centrioles. They are either isolated and nonmotile (primary cilia), or grouped and motile (motile cilia). Cilia are at the centre of fundamental sensory processes and are involved in a wide range of human disorders. Pulmonary cilia include motile cilia lining the epithelial cells of the conductive airways to orchestrate mucociliary clearance, and primary cilia found on nondifferentiated epithelial and mesenchymal cells acting as sensors and cell cycle keepers. Whereas cilia are essential along the airways, their regulatory molecular mechanisms remain poorly understood, resulting in a lack of therapeutic strategies targeting their structure or functions. This review summarises the current knowledge on cilia in the context of lung homeostasis and COPD to provide a comprehensive overview of the (patho)biology of cilia in respiratory medicine with a particular emphasis on COPD.

Lung cancer remains the first cause of cancer-related death despite many therapeutic innovations, including immune checkpoint inhibitors (ICI). ICI are now well used in daily practice at late metastatic stages and locally advanced stages after a chemo-radiation. ICI are also emerging in the peri-operative context. However, all patients do not benefit from ICI and even suffer from additional immune side effects. A current challenge remains to identify patients eligible for ICI and benefiting from these drugs. Currently, the prediction of ICI response is only supported by Programmed death-ligand 1 (PD-L1) tumor expression with perfectible results and limitations inherent to tumor-biopsy specimen analysis. Here, we reviewed alternative markers based on liquid biopsy and focused on the most promising biomarkers to modify clinical practice, including non-tumoral blood cell count such as absolute neutrophil counts, platelet to lymphocyte ratio, neutrophil to lymphocyte ratio, and derived neutrophil to lymphocyte ratio. We also discussed soluble-derived immune checkpoint-related products such as sPD-L1, circulating tumor cells (detection, count, and marker expression), and circulating tumor DNA-related products. Finally, we explored perspectives for liquid biopsies in the immune landscape and discussed how they could be implemented into lung cancer management with a potential biological–driven decision.

Abstract Background Obesity is a risk factor for dyspnea. However, investigations of daily living obesity-related dyspnea are limited and its mechanisms remain unclear. We conducted a cross-sectional study to analyze the relationships between dyspnea in daily living, lung function, and body composition in patients with obesity. Methods One-hundred and thirty patients (103 women/27 men), candidate for bariatric surgery, with a mean ± SD Body Mass Index (BMI) of 44.8 ± 6.8 kg/m2 were included. Dyspnea was assessed by the modified Medical Research Council (mMRC) scale. Comorbidities, laboratory parameters, pulmonary function tests, arterial blood gases, six-minute walk test (6MWT), handgrip strength, and DXA body composition were analyzed. Results Thirty-one percent of patients exhibited disabling dyspnea in daily living (mMRC ≥ 2). Compared with patients without disabling dyspnea (mMRC

Concerns about the numerous health problems associated with unhealthy snacks prompted recommendations to steer individuals toward healthier eating habits. One such recommendation advises limiting unhealthy snacks and replacing them with more fruits and vegetables with significant health benefits. This study investigates US consumers' perceptions and preferences for healthy (vegetable-based) snacks/beverages. An online survey was designed to estimate consumer perception and willingness-to-pay (WTP) for vegetable-based crackers, spreads, and beverages. A sampling company sent the survey to its national consumer panels in 2020, resulting in a sample of 402 US consumers. Eligible participants were adults, primary grocery shoppers who consumed crackers, spreads, and beverages. Consumer WTP for healthy snacks/beverages, the dependent variable, was elicited using a payment card method. Independent variables include personality traits (Innovativeness and Extraversion) and the important factors affecting healthy snack purchases, health consciousness, and demographic variables. Results show that consumers' preferences for healthy snacking vary by product, even when the products have similar health benefits. Significant positive associations exist between WTP for healthy snacks/beverages and personality traits, health consciousness, and some demographics. This study provides critical insights to policymakers and informs marketing campaigns to promote healthy snacking in the US more effectively.

This article discusses a study that examines the relationship between cilia dysregulation and asthma phenotypes and endotypes. The researchers analyzed the transcriptomic signature of cilia-associated genes in the bronchial airway epithelial cells of patients with asthma and healthy individuals. The results showed that patients with high cilia dysregulation had severe asthma characteristics, including high total IgE, eosinophil counts, and low FEV1. The study suggests that dysregulation of cilia may contribute to inflammation and epithelial remodeling in asthma. Further research is needed to fully understand the implications of these findings. [Extracted from the article]