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OBJECTIVES A lung transplant is the final treatment option for end-stage lung disease. We evaluated the individual risk of 1-year mortality at each stage of the lung transplant process. METHODS This study was a retrospective analysis of patients undergoing bilateral lung transplants between January 2014 and December 2019 in 3 French academic centres. Patients were randomly divided into development and validation cohorts. Three multivariable logistic regression models of 1-year mortality were applied (i) at recipient registration, (ii) the graft allocation and (iii) after the operation. The 1-year mortality was predicted for individual patients assigned to 3 risk groups at time points A to C. RESULTS The study population consisted of 478 patients with a mean (standard deviation) age of 49.0 (14.3) years. The 1-year mortality rate was 23.0%. There were no significant differences in patient characteristics between the development (n = 319) and validation (n = 159) cohorts. The models analysed recipient, donor and intraoperative variables. The discriminatory power (area under the receiver operating characteristic curve) was 0.67 (0.62–0.73), 0.70 (0.63–0.77) and 0.82 (0.77–0.88), respectively, in the development cohort and 0.74 (0.64–0.85), 0.76 (0.66–0.86) and 0.87 (0.79 – 0.95), respectively, in the validation cohort. Survival rates were significantly different among the low- (< 15%), intermediate- (15%–45%) and high-risk (> 45%) groups in both cohorts. CONCLUSIONS Risk prediction models allow estimation of the 1-year mortality risk of individual patients during the lung transplant process. These models may help caregivers identify high-risk patients at times A to C and reduce the risk at subsequent time points.

RationaleChronic obstructive pulmonary disease (COPD) is a prevalent respiratory disease lacking effective treatment. Focusing on the early stage of COPD should help to discover disease modifying therapies.ObjectivesIn this study, we examined the role of the CXCL12/CXCR4 axis in both a mouse model of early COPD and in human samples from COPD patients.MethodsTo generate the early COPD model, mice were exposed to cigarette smoke (CS) for 10 weeks and intranasal instillations of polyinosinic–polycytidylic acid (poly(I:C)) for 5 weeks to mimic exacerbations.Measurements and Main ResultsExposed mice presented mild airway obstruction, peri-bronchial fibrosis and right heart remodeling. CXCR4 expressing cells number was increased in the blood of exposed mice, as well as in the blood of patients with COPD. Lung CXCL12 expression was higher in both exposed mice and early COPD patients. The density of fibrocytes expressing CXCR4 was increased in the bronchial submucosa of exposed mice. Conditional inactivation of CXCR4 at adult stage as well as pharmacological inhibition of CXCR4 with plerixafor injections improved lung function, reduced inflammation and protected against CS and poly-(I:C)-induced airway and cardiac remodeling. CXCR4-/-and plerixafor-treated mice also had less CXCR4-expressing circulating cells and a lower density of peri-bronchial fibrocytes.ConclusionsWe demonstrate that targeting CXCR4 has beneficial effects in an animal model of early COPD and provide a framework to translate these preclinical findings to clinical settings within a drug repurposing approach.

Summary Objectives Lung lobectomy or segmentectomy is the first-line treatment for stage 1 or 2 non-small cell lung carcinoma (NSCLC) or selected metastasectomy. The development of thoracoscopy represents a major advancement in minimally invasive surgery but requires the use of highly specialised medical devices. The goal of this study was to provide an objective cost analysis for a surgical thoracic department to identify the most cost-effective surgical practices and to highlight actions for potential cost adjustments. Methods Retrospective analysis of all consecutive patients undergoing lung resections for cancer in the first half of 2019. All costs were based on a micro-costing method or calculated following standard analytical principles, after which the final reimbursement was calculated, and the relative financial outcomes were determined. Results A total of 162 patients were included in this study, of which 67 underwent thoracotomy and 95 underwent thoracoscopy. The overall cost of patient care was 2,135,547.80€, with a final reimbursement of 1,927,498.06€, for an overall loss of 208,049.74€. The cost differential was significantly worse for patients with hospitalisation severity levels 1 and 2 (P Conclusion Treatment of major pulmonary resections appears to be a net-financial loss for medical institutions. The evaluation of surgical practices with respect to the overall financial implications is an important step to ensure adequate compensation for patient care.

Bronchi of chronic obstructive pulmonary disease (COPD) are the site of extensive cell infiltration, allowing persistent contacts between resident cells and immune cells. Tissue fibrocytes interaction with CD8+T cells and its consequences were investigated using a combination ofin situ,in vitroexperiments and mathematical modeling. We show that fibrocytes and CD8+T cells are found in vicinity in distal airways and that potential interactions are more frequent in tissues from COPD patients compared to those of control subjects. Increased proximity and clusterization between CD8+T cells and fibrocytes are associated with altered lung function. Tissular CD8+T cells from COPD patients promote fibrocyte chemotaxis via the CXCL8-CXCR1/2 axis. Live imaging shows that CD8+T cells establish short-term interactions with fibrocytes, that trigger CD8+T cell proliferation in a CD54– and CD86-dependent manner, pro-inflammatory cytokines production, CD8+T cell cytotoxic activity against bronchial epithelial cells and fibrocyte immunomodulatory properties. We defined a computational model describing these intercellular interactions and calibrated the parameters based on our experimental measurements. We show the model’s ability to reproduce histological ex vivo characteristics, and observe an important contribution of fibrocyte-mediated CD8+T cell proliferation in COPD development. Using the model to test therapeutic scenarios, we predict a recovery time of several years, and the failure of targeting chemotaxis or interacting processes. Altogether, our study reveals that local interactions between fibrocytes and CD8+T cells could jeopardize the balance between protective immunity and chronic inflammation in bronchi of COPD patients.

Rib-sternal osteoradionecrosis is a rare but serious complication of chest radiotherapy. No consensus-based method of managing deep sternal wounds that develop after radiotherapy is available. Usually patients require long-term antibiotics. The surgical placement of a muscle, an omental flap, or a prosthesis is described. We report, in pictures, four successful omental flap placements. Between March 2015 and July 2018, four women with deep sternal wound injuries that developed after radiation therapy to treat breast cancer underwent rib-sternal reconstruction with omental flap placement. The first signs of infected radionecrosis developed 28.5 years after radiotherapy. Despite prolonged antibiotic treatment, surgery was necessary. The mean age at surgery was 76 years (range: 62–86 years). All necrotic tissue was excised and debridement was performed before the placement of a pedicled omental flap dissected along the transverse colon and raised through a subcutaneous tunnel. No skin graft or osteosynthesis was required. After surgery, lubricated bandages were applied daily, and antibiotics were prescribed for a few weeks. Complete healing was obtained after surgery without clinical complication. Our experience suggests that a pedicled omental flap is an affordable, simple, and very useful option for reconstructing deep rib-sternal wounds caused by radiation.

OBJECTIVES Chest wall sarcomas are rare, aggressive malignancies, the management of which mainly revolves around surgery. Radical tumour excision with free margins represents the optimal treatment for loco-regional clinically resectable disease. The objective of this study was to review our 11-year experience with chest wall resection for primary and metastatic sarcomas, focusing on surgical techniques and strategies for reconstruction. METHODS Retrospective analysis of a comprehensive database of patients who underwent chest wall resection for primary or secondary sarcoma at our Institute from January 2009 to December 2019. RESULTS Out of 26 patients, 21 (81%) suffered from primary chest wall sarcoma, while 5 (19%) had recurring disease. The median number of resected ribs was 3. Sternal resection was performed in 6 cases (23%). Prosthetic thoracic reconstruction was deemed necessary in 24 cases (92%). Tumour recurrence was observed in 15 patients (58%). The median overall survival was 73.6 months. Primary and secondary tumours showed comparable survival (P = 0.49). At univariate analysis, disease recurrence and infiltrated margins on pathological specimens were associated with poorer survival (P = 0.014 and 0.022, respectively). In patients with primary sarcoma, the median progression-free survival was 13.3 months. Associated visceral resections were significantly associated to postoperative complications (P = 0.02). CONCLUSIONS Chest wall resection followed by prosthetic reconstruction is feasible in carefully selected patients and should be performed by experienced surgeons with the aim of achieving free resection margins, resulting in improved long-term outcomes.

Chest wall resections for lung cancer treatment remain difficult to plan using standard 2-dimensional computed tomography. Although virtual reality headsets have been used in many medical contexts, they have not been used in chest wall resection planning.We compared preoperative planning of a chest wall surgical resection for lung cancer treatment between senior and resident surgeons who used an immersive virtual reality device and a 2-dimensional computed tomography.Chest wall resection planning was more accurate when surgeons used virtual reality vs computed tomography analysis (28.6% vs 18.3%, P = .018), and this was particularly true in the resident surgeon group (27.4% vs 8.3%, P = .0025). Predictions regarding the need for chest wall substitutes were also more accurate when they were made using virtual reality vs computed tomography analysis in all groups (96% vs 68.5%, P.0001). Other studied parameters were not affected by the use of the virtual reality tool.Virtual reality may offer enhanced accuracy for chest wall resection and reconstruction planning for lung cancer treatment.

Triple-negative breast cancer (TNBC) patients have an increased risk of developing visceral metastases and other primary nonbreast cancers, particularly lung cancer. The differential diagnosis of TNBC metastases and primary cancers from other organs can be difficult due to lack of a TNBC standard immunoprofile. We analyzed the diagnostic value of estrogen receptor, progesterone receptor, human epidermal growth factor receptor, thyroid transcription factor-1 (TTF1), Napsin A, mammaglobin, gross cystic disease fluid protein 15 (GCDFP15), Sry-related HMg-Box gene 10 (SOX10), GATA-binding protein 3 (GATA3), and androgen receptor in a series of 207 TNBC and 152 primary lung adenocarcinomas (LA). All tested TNBCs were TTF1 and Napsin A-negative. When comparing TNBC and TTF1-positive or negative LA, SOX10 had the best sensitivity (62.3%) and specificity (100%) as a marker in favor of TNBC compared with LA, irrespective of TTF1 status (P

Lung cancer remains the leading cause of cancer death. In 2008, 2,206,771 new cases and 1,796,144 deaths were reported worldwide [1]. At diagnosis, approximately one third of the patients have a potentially resectable tumor that is confined to the chest without clinical evidence of mediastinal lymphadenopathy (clinical stages I and II). Nevertheless, even after complete surgical resection, the overall survival in such patients with early-stage disease remains disappointing. The 5-year survival rate even for patients with stage IA or IB non-small cell lung cancer (NSCLC) is 73% and 56%, respectively [2]. Besides, the 5-year risks of local or regional recurrence after surgery alone for non-small cell lung cancer for stages IA, IB, IIA, IIB, and IIIA are also high (16%, 23%, 37%, 39%, and 30%, respectively [3]). The 5-year survival of small cell lung cancer (SCLC) patients with early-stage resected disease (T1,2 N0M0) is roughly similar, around 50% [4]. Relapse of the disease at distant sites, despite complete removal of all macroscopic lesions, is the main cause of treatment failure [5–8]. The presence of micro-metastatic disease at resection is the likely reason for such relapse. However, the mechanisms involved in micro-metastases propagation remains to be clarified. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Henrot has nothing to disclose.Dr. Henrot reports non-financial support from Avad, outside the submitted work. Conflict of interest: Dr. Beaufils reports personal fees and non-financial support from Novartis, personal fees and non-financial support from Chiesi, personal fees and non-financial support from AstraZeneca, outside the submitted work. Conflict of interest: Dr. Thumerel has nothing to disclose. Conflict of interest: Dr. Eyraud has nothing to disclose. Conflict of interest: Dr. Boudoussier has nothing to disclose. Conflict of interest: Dr. BEGUERET has nothing to disclose. Conflict of interest: Dr. Maurat has nothing to disclose. Conflict of interest: Dr. Girodet reports grants, personal fees and non-financial support from AstraZeneca, personal fees and non-financial support from Chiesi, personal fees and non-financial support from GlaxoSmithKline, personal fees and non-financial support from Novartis, personal fees and non-financial support from Sanofi, outside the submitted work. Conflict of interest: Dr. Marthan has nothing to disclose. Conflict of interest: Dr. Berger reports grants, personal fees and non-financial support from AstraZeneca, personal fees and non-financial support from Chiesi, personal fees and non-financial support from GlaxoSmithKline, personal fees and non-financial support from Novartis, personal fees and non-financial support from Sanofi, outside the submitted work. Conflict of interest: Dr. Dupin reports grants from Fondation Bordeaux Universite, during the conduct of the study; In addition, Dr. Dupin has a patent (EP N°15152886.6 i.e. New compositions and methods of treating and/or preventing Chronic Obstructive Pulmonary Disease) pending. Conflict of interest: Dr. Zysman reports grants and personal fees from Astra Zeneca, personal fees from GSK, personal fees from Boehringer Ingelheim, personal fees from CSL Behring, personal fees from Chiesi, outside the submitted work.

Bronchi from COPD are an area of extensive immune cell infiltration and changes in tissue structures, allowing persistent contacts between resident and immune cells. We investigate whether tissue fibrocytes, recently evidenced around COPD bronchi lung, can interact with CD8+ T cells, and whether the contact between both cell types could alter the balance between tissue repair and destruction. Using co-immunostaining of bronchial specimens, we show that fibrocytes and CD8+ T cells are found within close proximity in distal airways of COPD patients, and that indirect and direct interactions are more frequent in tissue from COPD patients compared to those of control subjects. The density of interacting cells is negatively associated with lung function parameters, such as FEV1/FVC. Transcriptome analysis indicates that the attractive capacity of tissular CD8+ T cells is greater in COPD patients than in control subjects. Using in vitro assay based on autologous co-culture with fibrocytes and CD8+ T cells isolated from blood samples of COPD patients, we demonstrate that direct contact between both cell types trigger CD8+ T cell proliferation in a CD11a-dependent manner, and IFN-ɣ, TNF-α and granzyme B production. From these results, we defined a stochastic and computational model, based on local intercellular interactions, with the objective to predict the distributions of the two cell types, depending on whether the subject is healthy or ill. Altogether, this study reveals that local intercellular interactions between fibrocytes and CD8+ T cells can occur in vivo and could result in increased destruction and inappropriate repair in the lung of COPD patients.

Rhinovirus (RV) infection of the bronchial epithelium is implicated in the vast majority of severe asthma exacerbations. Interestingly, the susceptibility of bronchial epithelium to RV infection is increased in persons with asthma. Bronchial smooth muscle (BSM) remodeling is an important feature of severe asthma pathophysiology, and its reduction using bronchial thermoplasty has been associated with a significant decrease in the exacerbation rate. We hypothesized that asthmatic BSM can play a role in RV infection of the bronchial epithelium. Using an original co-culture model between bronchial epithelium and BSM cells, we show that asthmatic BSM cells increase RV replication in bronchial epithelium following RV infection. These findings are related to the increased production of CCL20 by asthmatic BSM cells. Moreover, we demonstrate an original downregulation of the activity of the epithelial protein kinase RNA-activated (PKR) antiviral pathway. Finally, we identify a direct bottom-up effect of asthmatic BSM cells on bronchial epithelium susceptibility to RV infection.

International audience; Metabolic reprogramming is a common hallmark of cancer, but a large variability in tumor bioenergetics exists between patients. Using high-resolution respirometry on fresh biopsies of human lung adenocarcinoma, we identified 2 subgroups reflected in the histologically normal, paired, cancer-adjacent tissue: high (OX+) mitochondrial respiration and low (OX-) mitochondrial respiration. The OX+ tumors poorly incorporated [F-18]fluorodeoxy-glucose and showed increased expression of the mitochondrial trifunctional fatty acid oxidation enzyme (MTP; HADHA) compared with the paired adjacent tissue. Genetic inhibition of MTP altered OX+ tumor growth in vivo. Trimetazidine, an approved drug inhibitor of MTP used in cardiology, also reduced tumor growth and induced disruption of the physical interaction between the MTP and respiratory chain complex I, leading to a cellular redox and energy crisis. MTP expression in tumors was assessed using histology scoring methods and varied in negative correlation with [F-18]fluorodeoxy-glucose incorporation. These findings provide proof-of-concept data for preclinical, precision, bioenergetic medicine in oxidative lung carcinomas.

Bronchial smooth muscle (BSM) remodeling has an important prognostic value in asthma. BSM cell hyperplasia has been related to an increased proliferation of asthmatic BSM cells in vitro and ex vivo. We demonstrated that this increase was related to an increased number of mitochondria in the BSM of severe asthmatic patients. However, the impact of this increased mitochondrial mass on asthmatic BSM cell metabolism remains to be elucidated. We then enrolled 18 asthmatic patients from the COBRA cohort, and 27 control subjects. Asthmatic patients were similar to control subjects in terms of sex ratio, age and BMI but presented a lower FEV-1. Energetic metabolism was modified in asthmatic BSM cells, since oxygen consumption was increased and less lactate was produced than in control with no difference in glucose consumption. Then, we explored the TCA cycle intermediates and highlighted a significant increased level of pyruvate, succinate and malate in asthmatic BSM cells. Those results indicated that asthmatic BSM cells shifted their metabolism for oxidative phosphorylation. Large-scale proteomic confirmed an altered expression of oxidative enzymes, and in particular an upregulation of CPT2, underlying this metabolic shift in asthmatic BSM cells. Moreover, we showed a significant increased fatty acid internalization in asthmatic BSM cells, demonstrating the importance of fatty acid consumption in asthmatic BSM. Finally, inhibition of CPT2, significantly decreased asthmatic BSM cell proliferation. Taken together asthmatic BSM cells shifted their metabolism and CPT2 enzyme was crucial for asthmatic BSM cell proliferation. Then CPT2 could be a new therapeutic target against BSM remodeling in asthma.

Resume L’hamartochondrome endobronchique est une tumeur benigne rare qui se differencie de la forme parenchymateuse par la symptomatologie mais aussi par le traitement qui sera le plus possible conservateur. La localisation enbobronchique est exceptionnelle. Nous presentons ici les cas de deux patients presentant des hamartochondromes endobronchiques avec retentissement clinique, respectivement des douleurs thoraciques et des infections pulmonaires a repetition. Le diagnostic a ete formellement porte apres realisation d’un scanner, d’un TEP-SCAN et d’une analyse histologique. Apres discussion des dossiers en reunion de concertation pluridisciplinaire, le traitement a ete conservateur dans les deux cas.

Introduction Chronic obstructive pulmonary disease (COPD) is a frequent respiratory disease with chronic inflammation, in which CD8+ T cells play a key role. Since circulating and tissue fibrocytes are associated with mortality and bronchial obstruction, respectively, we investigated whether tissue fibrocytes can interact with CD8+ T cells, and whether the contact between both cell types could be a cause of chronic immune activation. Methods Using co-immunostaining of bronchial specimens obtained from surgery in 17 COPD patients and 25 control subjects, and specific image analysis methods, we quantified the relative distribution of fibrocytes and CD8+ T cells. Direct and indirect co-cultures of fibrocytes and CD8+ T cells, isolated from blood samples of COPD patients, were performed to test fibrocyte effect on CD8+ T cell proliferation and cytokines secretion profile. We defined a computational model with intercellular interactions which fits to experimental measurements and explains the macroscopic properties of cell populations in situ. Results The density of fibrocytes in contact with CD8+ T cells and the minimal distance between both cell types were respectively higher and lower in tissue specimens from COPD patients compared with those of control subjects. We also demonstrated that direct contact between both cell types triggered in vitro naive and memory CD8+ T cell differential proliferation and IFN-ɣ and TNF-α production. Computer modelling predicted that modification in local intercellular interactions induced changes in cell repartitions similar to those measured in situ. Conclusion This study reveals that direct intercellular interactions between fibrocytes and CD8+ T cells can occur in vivo and could potentiate the inflammatory response in lungs from COPD patients.

Introduction Asthma is the most common chronic respiratory disease. In severe patients, one of the main feature of the physiopathology is the increased bronchial smooth muscle (BSM) mass, which is related to frequency and severity of asthma exacerbations. Exacerbations are mainly triggered by rhinovirus infection of the epithelium. In addition, histology analysis has shown that distance between BSM cells and epithelium decrease proportionally to the severity of the disease. We thus hypothesis that rhinovirus infection of the epithelium increase the migration of asthmatic BSM cells. Methods Primary BSM cells from control and asthmatic patients were obtained from bronchial biopsies. Epithelial cells were cultivated in an air-liquid Interface. After complete differentiation, epithelium were exposed to RVA-16 (MOI 0,1) and epithelium supernatant were collected 24 h post infection. BSM migration was assessed in response to epithelium supernatant in a chemotaxis assay for 24 h using live microscopy. Transcriptomics and ELISA were used to analysed chemokine content within the epithelial supernatant. Immunohistochemistry and flow cytometry were used to quantify CXCR3 isoforms distribution (i.e CXCR3 A and B). Finally, western blot, cAMP assay and Ca2+ fluorometric probes were used to assess CXCR3 activation pathway. Results BSM cells from asthmatics migrates towards RV-infected epithelium whereas such a chemotactic effect was not observed in control BSM cells. Analysis of epithelium supernatant show that CXCL9 and CXCL10 were both induced by RVA-16. Interestingly, blocking of CXCR3 receptor, which is activated, by both CXCL9 and 10 abolished asthmatic BSM migration. They are two main isoforms of CXCR3 (A and B) which are described as activator and inhibitor of cell migration reciprocally. Interestingly, CXCR3-B expression and activation pathway through PKC and cAMP are increased in control BSM cells whereas CXCR3-A signalling pathway through calcium and Raf-1 activation are increase in asthmatic BSM cells. Conclusion Asthmatic BSM cells specifically migrate toward RV-infected epithelium through the activation of CXCR3-A. This new mechanism could be a new therapeutic target against BSM remodelling in asthma.

International audience; Circulating tumor cell (CTC) detection and numeration are becoming part of the common clinical practice, especially for breast, colon, and prostate cancer. However, their paucity in peripheral blood samples is an obstacle for their identification. Several groups have tried to improve CTC recovery rate by developing highly sensitive cellular and molecular detection methods. However, CTCs are still difficult to detect in peripheral blood. Therefore, their recovery rate could be increased by obtaining blood samples from vessels close to the drainage territories of the invaded organ, when the anatomical situation is favorable. This approach has been tested mostly during tumor resection surgery, when the vessels nearest to the tumor are easily accessible. Moreover, radiological (including echo-guided based and endovascular techniques) and/or endoscopic routes could be utilized to obtain CTC samples close to the tumor in a less invasive way than conventional biopsies. The purpose of this article is to summarize the available knowledge on CTC recovery from blood samples collected close to the tumor (i.e., in vessels located in the drainage area of the primary tumor or metastases). The relevance of such an approach for diagnostic and prognostic evaluations will be discussed, particularly for pancreatic ductal adenocarcinoma, colorectal adenocarcinoma, hepatocellular carcinoma, and non-small-cell lung cancer.

BackgroundBronchial smooth muscle (BSM) remodelling in asthma is related to an increased mitochondrial biogenesis and enhanced BSM cell proliferation in asthma. Since mitochondria produce the highest levels of cellular energy and fatty acid β-oxidation is the most powerful way to produce ATP, we hypothesised that, in asthmatic BSM cells, energetic metabolism is shifted towards the β-oxidation of fatty acids.ObjectivesWe aimed to characterise BSM cell metabolism in asthma both in vitro and ex vivo to identify a novel target for reducing BSM cell proliferation.Methods21 asthmatic and 31 non-asthmatic patients were enrolled. We used metabolomic and proteomic approaches to study BSM cells. Oxidative stress, ATP synthesis, fatty acid endocytosis, metabolite production, metabolic capabilities, mitochondrial networks, cell proliferation and apoptosis were assessed on BSM cells. Fatty acid content was assessed in vivo using matrix-assisted laser desorption/ionisation spectrometry imaging.ResultsAsthmatic BSM cells were characterised by an increased rate of mitochondrial respiration with a stimulated ATP production and mitochondrial β-oxidation. Fatty acid consumption was increased in asthmatic BSM both in vitro and ex vivo. Proteome remodelling of asthmatic BSM occurred via two canonical mitochondrial pathways. The levels of carnitine palmitoyl transferase (CPT)2 and low-density lipoprotein (LDL) receptor, which internalise fatty acids through mitochondrial and cell membranes, respectively, were both increased in asthmatic BSM cells. Blocking CPT2 or LDL receptor drastically and specifically reduced asthmatic BSM cell proliferation.ConclusionThis study demonstrates a metabolic switch towards mitochondrial β-oxidation in asthmatic BSM and identifies fatty acid metabolism as a new key target to reduce BSM remodelling in asthma.

This work aimed at estimating the kinetic parameters, and hence cumulated activity (AC), of a diagnostic/therapeutic convergence radiopharmaceutical, namely 64Cu-/177Lu-labeled antibody (64Cu-/177Lu-cetuximab), that acts as anti-epidermal growth factor receptor. Methods: In mice bearing esophageal squamous cell carcinoma tumors, to estimate uptake (K), release rate constant (kR), and hence AC, a kinetic model analysis was applied to recently published biodistribution data of immuno-PET imaging with 64Cu-cetuximab and of small-animal SPECT/CT imaging with 177Lu-cetuximab, including blood and TE-8 tumor. Results: K, kR, and AC were estimated to be 0.0566/0.0593 g⋅h-1⋅g-1, 0.0150/0.0030 h-1, and 2.3 × 1010/4.1 × 1012 disintegrations (per gram of TE-8 tumor), with an injected activity of 3.70/12.95 MBq, for 64Cu-/177Lu-cetuximab, respectively. Conclusion: A model is available for comparing kinetic parameters and AC of the companion diagnostic/therapeutic 64Cu-/177Lu-cetuximab that may be considered as a step for determining whether one can really use the former to predict dosimetry of the latter.

The remodelling mechanism and cellular players causing persistent airflow limitation in COPD remain largely elusive. We have recently demonstrated that circulating fibrocytes, a rare population of fibroblast-like cells produced by the bone marrow stroma, are increased in COPD patients during an exacerbation. We aimed to quantify fibrocyte density in situ in bronchial specimens from both control subjects and COPD patients, to define associations with relevant clinical, functional and computed tomography (CT) parameters, and to investigate the effect of the epithelial microenvironment on fibrocyte survival in vitro (“Fibrochir” study).A total of 17 COPD patients and 25 control subjects, all requiring thoracic surgery, were recruited. Using co-immunostaining and image analysis, we identified CD45+ FSP1+ cells as tissue fibrocytes, and quantified their density in distal and proximal bronchial specimens. Fibrocytes, cultured from the blood samples of six COPD patients, were exposed to primary bronchial epithelial cell secretions from control subjects or COPD patients.We demonstrate that fibrocytes are increased in both distal and proximal tissue specimens of COPD patients. The density of fibrocytes is negatively correlated with lung function parameters and positively correlated with bronchial wall thickness as assessed by CT scan. A high density of distal bronchial fibrocytes predicts the presence of COPD with a sensitivity of 83% and a specificity of 70%. Exposure of fibrocytes to COPD epithelial cell supernatant favours cell survival.Our results thus demonstrate an increased density of fibrocytes within the bronchi of COPD patients, which may be promoted by epithelial-derived survival-mediating factors.

BackgroundThe remodeling mechanism and cellular players causing persistent airflow limitation in chronic obstructive pulmonary disease (COPD) remain largely elusive. We have recently demonstrated that circulating fibrocytes, a rare population of fibroblast-like cells produced by the bone marrow stroma, are increased in COPD patients during an exacerbation. It remains, however, unclear, whether fibrocytes are present in bronchial tissue of COPD patients.ObjectiveWe aimed to quantify fibrocytes density in bronchial specimens from both control subjects and COPD patients, and to define associations with clinical, functional and computed tomography relevant parameters.Methods17 COPD patients and 25 control subjects with normal lung function testing and no chronic symptoms, all of them requiring thoracic surgery, were recruited. LFT and CT-scan were performed before surgery. Using co-immunostaining and image analysis, we identify CD45+ FSP1+ cells as tissue fibrocytes and quantify their density in distal and proximal bronchial specimens from the whole series.ResultsHere, we demonstrate that fibrocytes are increased in both distal and proximal tissue specimens of COPD patients, compared to those of controls. The density of fibrocytes is negatively correlated with lung function parameters, such as FEV1 and FEV1/FVC, and positively with bronchial wall thickness assessed by CT scan. High density of distal bronchial fibrocytes predicts presence of COPD with a sensitivity of 83% and a specificity of 70%.ConclusionsOur results thus suggest that recruitment of fibrocytes in the bronchi may participate to lung function decline during COPD progression.Clinical ImplicationsHigh density of tissue fibrocytes is associated with a deteriorated lung function and an increase in airway wall thickness. A low density tissue fibrocytes virtually eliminates the presence of COPD.Capsule summaryBlood fibrocytes assessed during exacerbation is a predictor of mortality in COPD. This study shows an increase of bronchial fibrocytes, that is associated with lower lung function, increased bronchial thickness and air trapping in COPD.

Severe asthma is a major public health issue throughout the world. Increased bronchial smooth muscle (BSM) mass, a characteristic feature of airway remodeling in severe asthma, is associated with resistance to high-intensity treatment and poor prognosis. In vitro, the Ca(2+)-channel blocker gallopamil decreased the proliferation of BSM cells from patients with severe asthma.We conducted a double-blind, randomized, placebo-controlled study to evaluate the effect of gallopamil on airway remodeling in patients with severe asthma.Subjects received either gallopamil (n = 16) or placebo (n = 15) for 1 year and were monitored for an additional 3-month period. Airway remodeling was analyzed at baseline and after treatment phase using both fiberoptic bronchoscopy and computed tomography scan. The primary end point was the BSM area. Secondary end points included normalized BSM thickness and frequency of asthma exacerbations.BSM area was reduced in the gallopamil group (baseline vs. end of treatment) but was unchanged in the placebo group. Between-group differences in BSM area were not significantly different in gallopamil versus placebo groups. By contrast, between-group differences in normalized BSM thickness were significantly different between the two groups. The mean number of exacerbations per month was not different during the treatment phase in gallopamil versus placebo group but was significantly lower in patients previously treated with gallopamil during the follow-up period. There were no differences between the groups with respect to overall side effects.Gallopamil treatment for 12 months reduces BSM remodeling and prevents the occurrence of asthma exacerbations. Clinical trial registered with www.clinicaltrials.gov (NCT 00896428).

IntroductionSince July 2007, the French high emergency lung transplantation (HELT) allocation procedure prioritises available lung grafts to waiting patients with imminent risk of death. The relative impacts of donor, recipient and matching on the outcome following HELT remain unknown. We aimed at deciphering the relative impacts of donor, recipient and matching on the outcome following HELT in an exhaustive administrative database.MethodsAll lung transplantations performed in France were prospectively registered in an administrative database. We retrospectively reviewed the procedures performed between July 2007 and December 2015, and analysed the impact of donor, recipient and matching on overall survival after the HELT procedure by fitting marginal Cox models.ResultsDuring the study period, 2335 patients underwent lung transplantation in 11 French centres. After exclusion of patients with chronic obstructive pulmonary disease/emphysema, 1544 patients were included: 503 HELT and 1041 standard lung transplantation allocations. HELT was associated with a hazard ratio for death of 1.41 (95% CI 1.22–1.64; pConclusionsThis exhaustive French national study suggests that HELT is associated with an adverse outcome compared with regular allocation. This adverse outcome is mainly related to the severity status of the recipients rather than donor or matching characteristics.

Objectives During sequential double-lung transplantation (DLT), the newly implanted first lung receives the entire cardiac output during the implantation of the second one. This may be responsible for the increased hydrostatic pressure that causes severe interstitial and alveolar edema that can lead to allograft dysfunction. The authors tested the hypothesis that CPB started after first graft implantation and before second recipient lung removal should improve post-transplantation oxygenation and clinical outcomes. Design Observational during 2 consecutive 1-year periods. Setting University hospital. Participants Nine consecutive patients undergoing sequential DLT with CPB started after first graft implantation and before second recipient lung removal were compared to controls, who were 10 consecutive patients who underwent sequential DLT but without CPB the year before. Measurements and Main Results Oxygenation after transplantation was assessed. The use of CPB during the implantation of the second lung was associated with an increased mean postoperative ratio of PaO 2 to the fraction of inspired oxygen at 1 hour (363±51 v 240±113, p = 0.01) and 6 hours (430±111 v 280±103, p = 0.03). The mean duration of CPB was 111±19 min. The occurrence of primary graft dysfunction and the need for extracorporeal membrane oxygenation tended to be lower, but did not reach significance. Similarly, mortality rate was comparable between both groups, as was the rate of blood transfusions. Conclusions The authors' results suggest that the use of CPB started after first graft implantation and before second recipient lung removal appears to benefit oxygenation and reduces the occurrence of severe pulmonary edema in the first transplanted lung.

This work aimed at estimating the kinetic parameters, and hence cumulated activity (A

This retrospective study was carried out to evaluate the indications for and outcomes of the hemiclamshell (HCS) approach (longitudinal partial sternotomy with antero-lateral thoracotomy) in patients undergoing mass resection in thoracic surgery. All patients (50) who underwent a HCS procedure in our department, between July 1996 and July 2005, were studied retrospectively, analyzing the indications, morbidity and outcome (pain, neurological or shoulder defects, mortality) at one month and one year. The main indications were apical tumours (38%), tumours of the cervicothoracic junction (46%) and chest wall (10%), and 'bulky' tumours (6%). One-month mortality was 6%. Two patients suffered from a chylothorax and one from phrenic paralysis. The postoperative analgesic requirements were similar to those after other thoracic surgery approaches. Twelve percent of patients suffered pain at one month and 6% at one year. Shoulder dysfunction was observed in 10% of patients at one month and 6% at one year. In conclusion, the HCS surgical approach was associated with an uncomplicated postoperative course. This anterior approach is suitable for apical tumours, tumours of the cervicothoracic junction and 'bulky' lung tumours, providing good access for control of the large vessels and radical mediastinal clearance.

Increased bronchial smooth muscle (BSM) mass is a key feature of airway remodeling that classically distinguishes severe from nonsevere asthma. Proliferation of BSM cells involves a specific mitochondria-dependent pathway in individuals with severe asthma. However, BSM remodeling and mitochondrial biogenesis have not been examined in nonsevere asthma.We aimed to assess whether an increase in BSM mass was also implicated in nonsevere asthma and its relationship with mitochondria and clinical outcomes.We enrolled 34 never-smoker subjects with nonsevere asthma. In addition, we recruited 56 subjects with nonsevere asthma and 19 subjects with severe asthma as comparative groups (COBRA cohort [Cohorte Obstruction Bronchique et Asthme; Bronchial Obstruction and Asthma Cohort; sponsored by the French National Institute of Health and Medical Research, INSERM]). A phenotypic characterization was performed using questionnaires, atopy and pulmonary function testing, exhaled nitric oxide measurement, and blood collection. Bronchial biopsy specimens were processed for immunohistochemistry and electron microscopy analysis. After BSM remodeling assessment, subjects were monitored over a 12-month period.We identified characteristic features of remodeling (BSM area26.6%) and increased mitochondrial number within BSM in a subgroup of subjects with nonsevere asthma. The number of BSM mitochondria was positively correlated with BSM area (r = 0.78; P0.001). Follow-up analysis showed that subjects with asthma with high BSM had worse asthma control and a higher rate of exacerbations per year compared with subjects with low BSM.This study reveals that BSM remodeling and mitochondrial biogenesis may play a critical role in the natural history of nonsevere asthma (Mitasthme study). Clinical trial registered with www.clinicaltrials.gov (NCT00808730).

Rationale: Proliferation of bronchial smooth muscle (BSM) cells involves a specific mitochondria-dependent pathway in severe asthmatic patients. However, BSM remodeling and mitochondrial biogenesis have not been assessed in non-severe asthma. We aimed to assess whether a high BSM mass is implicated in non-severe asthma. Methods: We enrolled 30 never smokers subjects, with non-severe asthma. A phenotypic characterization was performed using questionnaires, atopy and pulmonary function testing, exhaled nitric oxide and blood collection. Bronchial-biopsy specimens obtained by fiberoptic bronchoscopy were processed for optic microscopy, immunohistochemistry and electron microscopy analysis. Following BSM remodeling assessment, participants were monitored over a 12 months period. Results: We identified characteristic features of BSM remodeling and mitochondrial biogenesis in non-severe asthmatics. Baseline characteristics were similar in patients with BSM remodeling (“high BSM group”) and subjects without remodeling (“low BSM group”). However, 12 months follow-up showed that Juniper asthma control score and the number of exacerbations were increased in asthmatics with high BSM as compared to low BSM patients. Furthermore, the number of BSM mitochondria was positively correlated to BSM area in non-severe asthma (r = 0.78; P Conclusions: This study reveals that BSM remodeling and mitochondrial biogenesis may play a key role in natural history of non-severe asthma (“Mitasthme” study; ClinicalTrials.gov number, NCT00808730).

Background Increase of bronchial smooth muscle (BSM) mass is a crucial feature of asthma remodeling. The mechanisms of such an increased BSM mass are complex but involve enhanced mitochondrial biogenesis, leading to increased proliferation of BSM cells in asthmatic patients. The major tumor suppressor protein p53 is a key cell regulator involved in cell proliferation and has also been implicated in mitochondrial biogenesis. However, the role of p53 in BSM cell proliferation and mitochondrial biogenesis has not been investigated thus far. Objective We sought to evaluate the role of p53 in proliferation of BSM cells in asthmatic patients and mitochondrial biogenesis. Methods The expression of p53 was assessed both in vitro by using flow cytometry and Western blotting and ex vivo by using RT-PCR after laser microdissection. The role of p53 was assessed with small hairpin RNA lentivirus in both asthmatic patients and control subjects with BSM cell proliferation by using 5-bromo-2′-deoxyuridine and cell counting and in the expression of p21, BCL2-associated X protein, mitochondrial transcription factor A (TFAM), and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α). Results Twenty-nine patients with moderate-to-severe asthma and 26 control subjects were enrolled in the study. p53 expression was increased in BSM from asthmatic patients both ex vivo and in vitro , with a decreased interaction with mouse double minute 2 homolog (Mdm2) and an increased phosphorylation of serine 20. p53 did not inhibit the transcription of both TFAM and PGC-1α in BSM cells from asthmatic patients. As a consequence, p53 is unable to slow the increased mitochondrial biogenesis and hence the subsequent increased proliferation of BSM cells in asthmatic patients. Conclusion This study suggests that p53 might act as a new potential therapeutic target against BSM remodeling in asthmatic patients.

Asthma is a frequent airway disease, and asthma control determinants have been associated with indoor allergen sensitization. The most frequent allergens are house dust mites (HDM), which act in vivo on the bronchial epithelial layer. Severe asthma has also been associated with bronchial remodeling and more specifically with increased mass of bronchial smooth muscle (BSM). However, the relationship between HDM stimulation of the bronchial epithelial layer and BSM remodeling is unknown.To evaluate whether epithelial stimulation with HDM induces BSM cell proliferation in subjects with severe asthma.A total of 22 subjects with severe asthma and 27 subjects with no asthma were recruited. We have developed an in vitro culture model combining an epithelium layer in air-liquid interface (ALI) interacting with BSM. We assessed BSM proliferation using BrdU incorporation. We explored the role of epithelium-derived mediators using reverse-transcriptase polymerase chain reaction (RT-PCR) and ELISA in vitro and in vivo. Finally, leukotrienes receptor expression was assessed in vitro by flow cytometry and RT-PCR and ex vivo by laser microdissection and RT-PCR.We found that epithelial stimulation by HDM selectively increased the proliferation of asthmatic BSM cells and not that of nonasthmatic cells. The mechanism involved epithelial protease-activated receptor-2-dependent production of leukotrienes C4 associated with an overexpression of leukotrienes receptor CysLTR1 by asthmatic BSM cells in vitro and ex vivo.This work demonstrates the selective role of HDM on BSM remodeling in patients with severe asthma and points out different therapeutic targets at epithelial and smooth muscle levels.

Dear Editor, Extracorporeal membrane oxygenation (ECMO) is used in severe ARDS but also in case of primary graft dysfunction (PGD) after lung transplantation [1, 2]. ECMO in ARDS patients ventilated for more than 7 days is associated with poor outcome [3]. This could be the consequence of post-aggressive fibrosis. Bedside open lung biopsy (OLB) has been proposed for patients with unresolving ARDS despite a well-conducted therapy and seems to be contributive when the etiology remains unknown or when pulmonary fibrosis is suspected [4]. However, such a strategy may lead to severe complications under the systemic anticoagulation required by ECMO. We report here five consecutive patients treated with ECMO requiring bedside OLB. The procedure was carried out at the bedside in the ICU. All patient were ventilated with pressure-controlled ventilation using a driving pressure of 12 cmH2O, a PEEP of 12 cmH2O, and a respiratory frequency of 12 cycles min. ECMO blood flow was between 4.5 and 5.5 l min. Heparin was stopped 6 h before OLB was performed. A 10–15 cm right anterolateral thoracotomy was performed by a thoracic surgeon and a biopsy of the mid lobe was obtained with a stapler (Covidien, Elancourt, France). Chest drainage was ensured by two tubes. Characteristics are summarized in Table 1. In transplanted patients (n = 3), OLB confirmed severe acute rejection and all patients were discharged alive from our hospital. For ARDS patients, OLB confirmed irreversible fibrosis and patients died after prolonged ECMO ([30 days). Regarding mechanical complications of OLB, none of the five patients exhibited air leaks. Two patients presented bleeding requiring allogenic transfusion (table). No heparin was used until bleeding stopped and we did not have any complication on the ECMO circuit. No patients required reoperation and no death was related to bleeding. In transplanted patients, OLB confirmed acute rejection before initiation of immunosuppressive therapy. In patients with ARDS, OLB identified fibrosis and thus suggested poor outcome. Whatever the underlying disease, the OLB was clinically relevant and helped in decision making. The major complication was hemothorax treated with chest tubes. However, bleeding was limited in volume and lasted 2 days. The use of a heparin-coated ECMO circuit allowed a reduction or transitory interruption of heparin therapy without any complications. A retrospective study found 30 % of air leaks after OLB in ARDS patients; this finding was associated with high peak airway pressure [5]. Mechanical complications might also be associated with high minute ventilation [4]. None of our five patients under ECMO had air leaks after OLB. This might be explained by the extremely low thoracopulmonary compliance of these patients on the day of OLB. Lungs were poorly aerated with extremely low tidal volume and a limited plateau pressure. At the same time respiratory frequency was low and therefore minute ventilation was significantly reduced. This ventilatory strategy under ECMO probably protects from air leaks after OLB. Although these results may be considered encouraging, we have to point out that this report included only five patients and involved trained staff because of the lung transplant activity.

OBJECTIVES: The high mortality rate observed on the regular waiting list (RWL) before lung transplantation (LTx) prompted the French organ transplantation authorities to set up in 2007 a dedicated graft allocation strategy, the so-called ‘high-emergency waiting list’ (HEWL), for patients with an abrupt worsening of their respiratory function. This study reports on the early results of this new allocation system. METHODS: Among 11 active French LTx programmes, 7 were able to provide full outcome data by 31 December 2011. The medical records of 101 patients who were listed on the HEWL from July 2007 to December 2011 were reviewed for an intention-to-treat analysis. RESULTS :N inety-five patients received LTx within a median waiting time on the HEWL of 4 days (range 1–26), and 6 died before transplantation. Conditions were cystic fibrosis (65.2%), pulmonary fibrosis (24.8%), emphysema (5%) and miscellaneous (5%). The median age of the recipient was 30 years (range 16–66). Patients listed on the HEWL came from the RWL in 48.5% of the cases and were new patients in 51.5%. Forty-nine were placed under invasive ventilation and, in 26 cases, extracorporeal membrane oxygenation (ECMO) prior to transplantation was necessary as a complementary treatment. ECMO for non-intubated patients was performed in 6 cases. Eighty-one bilateral and 14 single LTx were performed, with an overall in-hospital mortality rate of 29.4%. One- and 3-year survival rates were 67.5 and 59%, respectively. Multivariate analysis shows that the use of ECMO prior to transplantation was the sole independent mortality risk factor (hazard ratio = 2.77 [95% CI 1.26–6.11]). CONCLUSIONS: The new allocation system aimed at lowering mortality on the RWL, but also offered an access to LTx for new patients with end-stage respiratory failure. The HEWL increased the likelihood of mortality after LTx, but permitted acceptable mid-term survival rates. The high mortality associated with the use of ECMO should be interpreted cautiously.

We report a case of metastatic chondrosarcoma to the lung that invaded the right inferior pulmonary vein with massive cardiac extension and presented with an acute heart failure. CT scan showed a large mass of the right lower lobe which invaded and filled almost all the left atrium with an extension into left ventricle through the mitral valve. Surgical resection was performed in emergency. The patient is still alive 4 months after development of cardiac symptoms and surgery.

Background Chronic obstructive pulmonary disease (COPD) is characterized by peribronchial fibrosis. The chronic course of COPD is worsened by recurrent acute exacerbations. Objective The aim of the study was to evaluate the recruitment of blood fibrocytes in patients with COPD during exacerbations and, subsequently, to identify potential mechanisms implicated in such recruitment. Methods Using flow cytometry, we quantified circulating fibrocytes and characterized their chemokine receptor expression in 54 patients with COPD examined during an acute exacerbation (V1) and 2 months afterward (V2) and in 40 control subjects. The role of the chemokines CXCL12 and CCL11 in fibrocyte migration was investigated by using a chemotaxis assay. Patients were followed for up to 3 years after V1. Results We demonstrated a significantly increased number of circulating fibrocytes at V1 compared with control subjects. The number of circulating fibrocytes decreased at V2. A high percentage of circulating fibrocytes during exacerbation was associated with increased risk of death. The percentage of fibrocytes at V2 was negatively correlated with FEV 1 , forced vital capacity, FEV 1 /forced vital capacity ratio, transfer lung capacity of carbon monoxide, and Pao 2 . Fibrocytes highly expressed CXCR4 and CCR3, the chemokine receptors for CXCL12 and CCL11, respectively. Fibrocytes collected from patients with COPD at V1 had increased chemotactic migration in response to CXCL12 but not to CCL11 compared with those from control subjects. Plerixafor, a CXCR4 antagonist, decreased fibrocyte migration to plasma from patients with exacerbating COPD. Conclusion Blood fibrocytes are recruited during COPD exacerbations and related to mortality and low lung function. The CXCL12/CXCR4 axis is involved in such fibrocyte recruitment (Firebrob study; ClinicalTrials NCT01196832).