High risk of lung cancer in surfactant-related gene variant carriers.

RATIONALE: Several rare surfactant-related genes variants associated with interstitial lung disease are suspected to be associated with lung cancer, but data are missing. OBJECTIVES: We aimed to study the epidemiology and phenotype of lung cancer in an international cohort of surfactant-related gene (SRG) variant carriers. METHODS: We conducted a cross-sectional study of all adults with SRG variants in the OrphaLung network and compared lung cancer risk with telomerase-related gene (TRG) variant carriers. RESULTS: We identified 99 SRG adult variant carriers (SFTPA1 [n=18], SFTPA2 [n=31], SFTPC [n=24], ABCA3 [n=14] and NKX2-1 [n=12]), including 20 (20.2%) with lung cancer (SFTPA1 [n=7]; SFTPA2 [n=8], SFTPC [n=3], NKX2-1 [n=2] and ABCA3 [n=0]). Among SRG variant carriers, the odds of lung cancer was associated with age (odds ratio [OR] 1.04 [95% CI 1.01-1.08]), smoking (OR 20.7 [6.60-76.2]) and SFTPA1/SFTPA2 variants (OR 3.97 [1.39-13.2]). Adenocarcinoma was the only histological type reported, with PDL1 expression≥1% of tumor cells in 3 cases. Cancer staging was localized (I/II) in 8 (40%) individuals, locally advanced (III) in 2 (10%) and metastatic (IV) in 10 (50%). We found no somatic variant eligible for targeted therapy. Seven cancers were surgically removed, 10 received systemic therapy, and 3 received the best supportive care according to their stage and performance status. The median overall survival was 24 months, with stage I/II cancers showing better survival. We identified 233 TRG variant carriers. The comparative risk (subdistribution hazard ratio) for lung cancer in SRG patients versus TRG patients was 18.1 [7.1-44.7]. CONCLUSION: The high risk of lung cancer among SRG variant carriers suggests specific screening and diagnostic and therapeutic challenges. The benefit of regular CT scan follow-up should be evaluated.

Evaluation of computed tomography in the diagnosis of ultrasound-proven diaphragm dysfunction.

INTRODUCTION: Computed tomography (CT) is routinely employed on the evaluation of dyspnea, yet limited data exist on its assessment of diaphragmatic muscle. This study aimed to determine the capability of CT in identifying structural changes in the diaphragm among patients with ultrasound-confirmed diaphragmatic dysfunction. METHODS: Diaphragmatic ultrasounds conducted between 2018 and 2021 at our center in Marseille, France, were retrospectively collected. Diaphragmatic pillars were measured on CT scans at the L1 level and the celiac artery. Additionally, the difference in height between the two diaphragmatic domes in both diaphragmatic dysfunction cases and controls was measured and compared. RESULTS: A total of 65 patients were included, comprising 24 with diaphragmatic paralysis, 13 with diaphragmatic weakness, and 28 controls. In the case group (paralysis and weakness) with left dysfunctions (n = 24), the CT thickness of the pillars at the level of L1 and the celiac artery was significantly thinner compared with controls (2.0 mm vs. 7.4 mm and 1.8 mm vs. 3.1 mm, p < 0.001 respectively). Significantly different values were observed for paralysis (but not weakness) in the right dysfunction subgroup (n = 15) (2.6 mm vs. 7.4 mm and 2.2 mm vs. 3.8 mm, p < 0.001 respectively, for paralysis vs. controls). Regardless of the side of dysfunction, a significant difference in diaphragmatic height was observed between cases and controls (7.70 cm vs. 1.16 cm and 5.51 cm vs. 1.16 cm, p < 0.001 for right and left dysfunctions, respectively). Threshold values determined through ROC curve analyses for height differences between the two diaphragmatic domes, indicative of paralysis or weakness in the right dysfunctions, were 4.44 cm and 3.51 cm, respectively. Similarly for left dysfunctions, the thresholds were 2.70 cm and 2.48 cm, respectively, demonstrating good performance (aera under the curve of 1.00, 1.00, 0.98, and 0.79, respectively). CONCLUSION: In cases of left diaphragmatic dysfunction, as well as in paralysis associated with right diaphragmatic dysfunction, CT revealed thinner pillars. Additionally, a notable increase in the difference in diaphragmatic height demonstrated a strong potential to identify diaphragmatic dysfunction, with specific threshold values.

Outcome of lung transplantation for adults with interstitial lung disease associated with genetic disorders of the surfactant system.

Background: Interstitial lung disease associated with genetic disorders of the surfactant system is a rare entity in adults that can lead to lung transplantation. Our objective was to describe the outcome of these patients after lung transplantation. Methods: We conducted a retrospective, multicentre study, on adults who underwent lung transplantation for such disease in the French lung transplant centres network, from 1997 to 2018. Results: 20 patients carrying mutations in SFTPA1 (n=5), SFTPA2 (n=7) or SFTPC (n=8) were included. Median interquartile range (IQR) age at diagnosis was 45 (40-48) years, and median (IQR) age at lung transplantation was 51 (45-54) years. Median overall survival after transplantation was 8.6 years. Two patients had a pre-transplant history of lung cancer, and two developed post-transplant lung cancer. Female gender and a body mass index <25 kg·m-2 were significantly associated with a better prognosis, whereas transplantation in high emergency was associated with a worst prognosis. Conclusions: Lung transplantation in adults with interstitial lung disease associated with genetic disorders of surfactant system may be a valid therapeutic option. Our data suggest that these patients may have a good prognosis. Immunosuppressive protocol was not changed for these patients, and close lung cancer screening is needed before and after transplantation.

Ultrasound evaluation of diaphragmatic function in patients with idiopathic pulmonary fibrosis: a retrospective observational study.

INTRODUCTION: The diaphragm function assessed by ultrasound has been well-studied in COPD, asthma, and intensive care. However, there are only a few studies on diffuse interstitial lung disease, while dyspnea and quality of life are major issues in the management that may depend on the diaphragm. METHODS: We retrospectively included idiopathic pulmonary fibrosis (IPF) patients followed in our center (Marseille, France) between January 2020 and February 2023 who underwent diaphragmatic ultrasound. Our objectives were to describe the diaphragmatic function of IPFs compared to healthy controls and to correlate with clinical, functional, and lung density on CT-scan. RESULTS: 24 IPF patients and 157 controls were included. The diaphragmatic amplitude in IPF was increased at rest (median of 2.20 cm vs 1.88 cm on the right, p < 0.007, and 2.30 cm vs 1.91 cm on the left, p < 0.03, in IPF and controls respectively) and decreased in deep breathing (median of 4.85 cm vs 5.45 cm on the right, p < 0.009, and 5.10 cm vs 5.65 cm on the left, p < 0.046, in IPF and controls respectively). Diaphragmatic thickness was significantly reduced at rest on the right side (median of 1.75 mm vs 2.00 mm, p < 0.02, in IPF and controls respectively) and in deep breathing on both sides compared to controls (mean of 3.82 mm vs 4.15 mm on the right, p < 0.02, and 3.53 mm vs 3.94 mm, on the left, p < 0.009, in IPF and controls respectively). Diaphragmatic amplitude in deep breathing was moderate to strongly correlated with FVC, DLCO, and 6MWT and negatively correlated with the dyspnea and lung density on CT scan. CONCLUSION: The diaphragmatic amplitude and thickness were impaired in IPF compared to controls. Diaphragmatic amplitude is the parameter best correlated with clinical, functional, and lung density criteria. Further studies are needed to determine if diaphragmatic amplitude can be a prognostic factor in IPF.

Change in diaphragmatic morphology in single-lung transplant recipients: a computed tomographic study.

Introduction: The influence of lung disease on the diaphragm has been poorly studied. The study aimed to evaluate the diaphragm morphology (height and thickness) in single-lung transplantation (SLTx), using computed tomography (CT), by assessing the evolution of the hemidiaphragm of the transplanted and the native side. Methods: Patients who underwent single lung transplantation in our center (Marseille, France) between January 2009 and January 2022 were retrospectively included. Thoracic or abdominal CT scans performed before and the closest to and at least 3 months after the surgery were used to measure the diaphragm crus thickness and the diaphragm dome height. Results: 31 patients mainly transplanted for emphysema or pulmonary fibrosis were included. We demonstrated a significant increase in diaphragm crus thickness on the side of the transplanted lung, with an estimated difference of + 1.25 mm, p = <0.001, at the level of the celiac artery, and + 0.90 mm, p < 0.001, at the level of the L1 vertebra while no significant difference was observed on the side of the native lung. We showed a significant reduction in the diaphragm height after SLTx on the transplanted side (-1.20 cm, p = 0.05), while no change on the native side (+0.02 cm, p = 0.88). Conclusion: After a SLTx, diaphragmatic morphology significantly changed on the transplanted lung, while remaining altered on the native lung. These results highlights that an impaired lung may have a negative impact on its diaphragm. Replacement with a healthy lung can promote the recovery of the diaphragm to its anatomical morphology, reinforcing the close relationship between these two organs.

Early chest CT abnormalities to predict the subsequent occurrence of chronic lung allograft dysfunction.

INTRODUCTION: Chronic lung allograft dysfunction (CLAD) can take two forms: bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS). The aim was to determine if chest-CT abnormalities after lung transplantation (LTx) could predict CLAD before respiratory functional deterioration. MATERIALS AND METHODS: This monocentric retrospective study analyzed consecutive patients who underwent LTx from January 2015 to December 2018. Initial CT post-LTx (CTi) and a follow-up CT at least 9 months post-LTx (CTf) were reviewed. CLAD was defined as a persistent respiratory functional decline (> 20% of basal FEV1) outside acute episode. A Cox regression was performed in univariate, then in multivariate analysis (including features with p < 0.01 in univariate or of clinical importance) to determine risk factors for CLAD. Subgroup analyses were made for BOS, RAS, and death. RESULTS: Among 118 LTx patients (median (min-max) 47 (18-68) years), 25 developed CLAD during follow-up (19 BOS). The median time to CLAD since LTx was 570 days [150-1770]. Moderate pulmonary artery stenosis (30-50%) was associated with the occurrence of CLAD on CTi (hazard ratio HR = 4.6, CI [1.6-13.2]) and consolidations and pleural effusion on CTf (HR = 2.6, CI [1.3-4.9] and HR = 4.5, CI [1.5-13.6] respectively). The presence of mosaic attenuation (HR = 4.1, CI [1.4-12.5]), consolidations (HR = 2.6, CI [1.3-5.4]), and pleural effusions (p = 0.01, HR = 5.7, CI [1.4-22.3]) were risk factors for BOS on CTf. The consolidations (p = 0.029) and pleural effusions (p = 0.001) were risk factors for death on CTf. CONCLUSIONS: CTi and CTf in the monitoring of LTx patients could predict CLAD. Moderate pulmonary artery stenosis, mosaic pattern, parenchyma condensations, and pleural effusions were risk factors for CLAD. CRITICAL RELEVANCE STATEMENT: There is a potential predictive role of chest CT in the follow-up of LTx patients for chronic lung allograft dysfunction (CLAD). Early chest CT should focus on pulmonary artery stenosis (risk factor for CLAD in this study). During the follow-up (at least 9 months post-LTx), parenchymal consolidations and pleural effusions were shown to be risk factors for CLAD, and death in subgroup analyses. KEY POINTS: • Pulmonary artery stenosis (30-50%) on initial chest-CT following lung transplantation predicts CLAD HR = 4.5; CI [1.6-13.2]. • Pleural effusion and consolidations 1 year after lung transplantation predict CLAD and death. • Early evaluation of lung transplanted patients should evaluate pulmonary artery anastomosis.

Impact of targeted pulmonary arterial hypertension therapies in severe pulmonary hypertension in chronic lung diseases.

Research questions: Patients with severe pulmonary hypertension associated with chronic lung disease have a poor prognosis. Targeted pulmonary arterial hypertension therapies might improve exercise capacity and outcome, but there are no guidelines on treatments which are not recommended because of an unproven benefit, with discordant results from few studies in this context. The aim of our study was to evaluate targeted pulmonary arterial hypertension therapies for severe group 3 pulmonary hypertension patients. Study design and methods: We conducted an observational retrospective monocentre study on patients with severe group 3 pulmonary hypertension diagnosed on right heart catheterisation treated with targeted therapies. Primary outcome was an improvement of the distance on 6-min walk test of ≥30 m. Secondary end-points included changes in haemodynamics (pulmonary vascular resistance (PVR) and mean pulmonary arterial pressure (mPAP)) and identification of potential predictive factors of therapeutic response. Results: 139 patients were enrolled. Most patients had monotherapy with phosphodiesterase 5 inhibitors (n=128; 92%). Mean change in 6-min walk distance was +1.5 m after treatment (p=0.59). Forced expiratory volume in 1 s and forced vital capacity were not predictive factors for response. We found a significant improvement of PVR and mPAP of -1.0 Wood Units (p<0.001) and -4 mmHg (p<0.001), respectively, under treatment. 18% of patients had to withdraw treatment for intolerance. Treatment duration <3 months was associated with poor survival (hazard ratio 2.75, p=0.0005). Conclusion: Oral targeted pulmonary arterial hypertension therapies do not improve exercise capacity in patients with severe pulmonary hypertension associated with chronic lung disease, but could improve haemodynamic parameters.

Refractory Pseudomonas aeruginosa Bronchopulmonary Infection After Lung Transplantation for Common Variable Immunodeficiency Despite Maximal Treatment Including IgM/IgA-Enriched Immunoglobulins and Bacteriophage Therapy.

Recipients transplanted for bronchiectasis in the context of a primary immune deficiency, such as common variable immunodeficiency, are at a high risk of severe infection in post-transplantation leading to poorer long-term outcomes than other transplant indications. In this report, we present a fatal case due to chronic Pseudomonas aeruginosa bronchopulmonary infection in a lung transplant recipient with common variable immunodeficiency despite successful eradication of an extensively drug-resistant (XDR) strain with IgM/IgA-enriched immunoglobulins and bacteriophage therapy. The fatal evolution despite a drastic adaptation of the immunosuppressive regimen and the maximal antibiotic therapy strategy raises the question of the contraindication of lung transplantation in such a context of primary immunodeficiency.

Rituximab and mycophenolate mofetil combination in patients with interstitial lung disease (EVER-ILD): a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Standard of care for interstitial lung disease (ILD) with a nonspecific interstitial pneumonia (NSIP) pattern proposes mycophenolate mofetil (MMF) as one of the first-step therapies while rituximab is used as rescue therapy. METHODS: In a randomised, double-blind, two-parallel group, placebo-controlled trial (NCT02990286), patients with connective tissue disease-associated ILD or idiopathic interstitial pneumonia (with or without autoimmune features) and a NSIP pattern (defined on NSIP pathological pattern or on integration of clinicobiological data and a NSIP-like high-resolution computed tomography pattern) were randomly assigned in a 1:1 ratio to receive rituximab (1000 mg) or placebo on day 1 and day 15 in addition to MMF (2 g daily) for 6 months. The primary end-point was the change in percent predicted forced vital capacity (FVC) from baseline to 6 months analysed by a linear mixed model for repeated measures analysis. Secondary end-points included progression-free survival (PFS) up to 6 months and safety. FINDINGS: Between January 2017 and January 2019, 122 randomised patients received at least one dose of rituximab (n=63) or placebo (n=59). The least-squares mean change from baseline to 6 months in FVC (% predicted) was +1.60 (se 1.13) in the rituximab+MMF group and -2.01 (se 1.17) in the placebo+MMF group (between-group difference 3.60, 95% CI 0.41-6.80; p=0.0273). PFS was better in the rituximab+MMF group (crude hazard ratio 0.47, 95% CI 0.23-0.96; p=0.03). Serious adverse events occurred in 26 (41%) patients of the rituximab+MMF group and in 23 (39%) of the placebo+MMF group. Nine infections were reported in the rituximab+MMF group (five bacterial infections, three viral infections, one other) and four bacterial infections in the placebo+MMF group. INTERPRETATION: Combination of rituximab and MMF was superior to MMF alone in patients with ILD and a NSIP pattern. The use of this combination must take into consideration the risk of viral infection.

Lung transplantation for interstitial lung disease in idiopathic inflammatory myositis: A cohort study.

In patients with interstitial lung disease (ILD) complicating classical or amyopathic idiopathic inflammatory myopathy (IIM), lung transplantation outcomes might be affected by the disease and treatments. Here, our objective was to assess survival and prognostic factors in lung transplant recipients with IIM-ILD. We retrospectively reviewed data for 64 patients who underwent lung transplantation between 2009 and 2021 at 19 European centers. Patient survival was the primary outcome. At transplantation, the median age was 53 [46-59] years, 35 (55%) patients were male, 31 (48%) had classical IIM, 25 (39%) had rapidly progressive ILD, and 21 (33%) were in a high-priority transplant allocation program. Survival rates after 1, 3, and 5 years were 78%, 73%, and 70%, respectively. During follow-up (median, 33 [7-63] months), 23% of patients developed chronic lung allograft dysfunction. Compared to amyopathic IIM, classical IIM was characterized by longer disease duration, higher-intensity immunosuppression before transplantation, and significantly worse posttransplantation survival. Five (8%) patients had a clinical IIM relapse, with mild manifestations. No patient experienced ILD recurrence in the allograft. Posttransplantation survival in IIM-ILD was similar to that in international all-cause-transplantation registries. The main factor associated with worse survival was a history of muscle involvement (classical IIM). In lung transplant recipients with idiopathic inflammatory myopathy, survival was similar to that in all-cause transplantation and was worse in patients with muscle involvement compared to those with the amyopathic disease.

CD146 at the Interface between Oxidative Stress and the Wnt Signaling Pathway in Systemic Sclerosis.

CD146 involvement was recently described in skin fibrosis of systemic sclerosis through its regulation of the Wnt pathway. Because the interaction between Wnt and ROS signaling plays a major role in fibrosis, we hypothesized that in systemic sclerosis, CD146 may regulate Wnt/ROS crosstalk. Using a transcriptomic and western blot analysis performed on CD146 wild-type or knockout mouse embryonic fibroblasts, we showed a procanonical Wnt hallmark in the absence of CD146 that is reversed when CD146 expression is restored. We found an elevated ROS content in knockout cells and an increase in DNA oxidative damage in the skin sections of knockout mice compared with those of wild-type mice. We also showed that ROS increased CD146 and its noncanonical Wnt ligand, WNT5A, only in wild-type cells. In humans, fibroblasts from patients with systemic sclerosis presented higher ROS content and expressed CD146, whereas control fibroblasts did not. Moreover, CD146 and its ligand were upregulated by ROS in both human fibroblasts. The increase in bleomycin-induced WNT5A expression was abrogated when CD146 was silenced. We showed an interplay between Wnt and ROS signaling in systemic sclerosis, regulated by CD146, which promotes the noncanonical Wnt pathway and prevents ROS signaling, opening the way for innovative therapeutic strategies.

Chest computed tomography improvement in patients with cystic fibrosis treated with elexacaftor-tezacaftor-ivacaftor: Early report.

RATIONALE AND OBJECTIVES: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have revolutionised the treatment of cystic fibrosis (CF). Chest computed tomography (CT) is key in the diagnosis and follow-up of anatomical damage to the lungs. Our study aimed to evaluate changes on lung CT scans of patients with CF after receiving elexacaftor-tezacaftor-ivacaftor (ETI) therapy for one year. MATERIALS AND METHODS: We conducted a retrospective, observational, single-centre study between 2018 and 2021 on adult patients with CF administered ETI. We reviewed chest CT scans before and at least one year after starting ETI. The Brody-II score (BSII) was measured by two experienced radiologists who were blinded to the treatment. Paranasal sinus CT scans and clinical and functional data were also compared. Wilcoxon tests were used to compare differences, and Spearman's correlation coefficient was used to evaluate changes in forced expiratory volume in one second (FEV1) and total BSII. RESULTS: In the period, 63 patients were given ETI, and 12 met the criteria for analysis. The inter-observer reproducibility of BSII was satisfactory (intraclass correlation coefficient = 0.83, 95% confidence interval 0.57-0.91). The BSII decreased after one year of treatment (-18 ±â€¯16, p = 0.002) due to lower mucous plugging (-7 ±â€¯4, p < 0.001) and peribronchial thickening (-9 ±â€¯10, p = 0.002) scores. Bronchial, parenchymal, and hyperinflation scores were unchanged. Clinical and functional parameters were significantly improved, except for total lung capacity. The correlation between ΔFEV1 and Δtotal BSII was strong (r = 0.88, p < 0.001). The paranasal sinus CT score significantly improved with ETI treatment. CONCLUSIONS: ETI decreased pulmonary and sinus morphological abnormalities after one year of treatment.

Angiographic and histopathological study on bronchial-to-pulmonary vascular anastomoses on explants from patients with cystic fibrosis after bronchial artery embolisation.

LABELLED BACKGROUND: Haemoptysis is a life-threatening complication of cystic fibrosis (CF). One treatment is bronchial artery embolisation (BAE) using embolic-microspheres (EMs). During BAE, pulmonary arteries can be seen on digital subtracted angiography while iodine containing contrast material injection is performed in the bronchial artery. This suggests that EMs could go from bronchial to nontarget pulmonary arteries. The aim was to evaluate if EMs could be found inside pulmonary arteries on lung explants after BAE in transplanted CF patients. METHODS: Retrospective observational study including patients with CF who underwent lung transplantation and had previously needed BAE. Clinical, chest CT angiography, and angiographic data were reviewed from medical records. Pathology examination of lung explants was performed to analyze the EMs anatomical localisation. RESULTS: Eight patients were included between 2013 and 2015, four males with a mean age of 29 (19-45) years. All patients had bronchial artery hypertrophy on CT and bronchial-to-pulmonary artery shunting during BAE. On pathology examination, EM ≤800 µm were found in the pulmonary arteries in all patients and were responsible for distal branch occlusions. Two pulmonary infarcts were observed on CT angiography after BAE and confirmed histopathologically. CONCLUSIONS: EM migration from the bronchial to pulmonary arteries is a common occurrence after BAE in patients with advanced stage CF. Although BAE is a highly effective means of controlling haemoptysis in CF, studies on the optimal particle size are needed to preserve pulmonary artery circulation, because these results suggest that low size EMs could lead to nontarget embolisation.

Quantification of Antifibrillarin (anti-U3 RNP) Antibodies: A New Insight for Patients with Systemic Sclerosis.

BACKGROUND: The detection of additional autoantibodies is of great concern in systemic sclerosis (SSc) when those included in the ACR/EULAR classification are negative. In this context, the interest of antifibrillarin (anti-U3RNP) autoantibodies (AFAs) in the routine evaluation of SSc remains unclear. We aimed to assess the relevance of AFAs and their clinical association in SSc patients. METHODS: In a multicenter observational retrospective study, we collected immunological and clinical data associated with AFA positivity in SSc (n = 42) and non-SSc patients (n = 13). Patients with SSc negative for AFAs (n = 83) were considered as a control group. AFAs were detected by indirect immunofluorescence (IIF) using HEp-2 cells, EliA or immunoblot techniques. RESULTS: We confirmed a typical nuclear IIF pattern and showed that AFAs are mostly exclusive towards SSc conventional autoantibodies. Although also observed in non-SSc patients, high levels of AFAs with the ELiA technique allowed the diagnosis of SSc. Compared to AFA-negative SSc patients, AFA-positive SSc patients more frequently exhibited visceral involvements. They more frequently suffered from the diffuse cutaneous form and had a higher global severity of the disease. CONCLUSIONS: We demonstrate the usefulness of quantifying AFAs in the immunological exploration of SSc, especially when patients are seronegative for SSc conventional autoantibodies and display a typical IIF pattern. AFAs might constitute an interesting marker of SSc severity.

CD146/sCD146 in the Pathogenesis and Monitoring of Angiogenic and Inflammatory Diseases.

CD146 is a cell adhesion molecule expressed on endothelial cells, as well as on other cells such as mesenchymal stem cells and Th17 lymphocytes. This protein also exists in a soluble form, whereby it can be detected in biological fluids, including the serum or the cerebrospinal fluid (CSF). Some studies have highlighted the significance of CD146 and its soluble form in angiogenesis and inflammation, having been shown to contribute to the pathogenesis of many inflammatory autoimmune diseases, such as systemic sclerosis, mellitus diabetes, rheumatoid arthritis, inflammatory bowel diseases, and multiple sclerosis. In this review, we will focus on how CD146 and sCD146 contribute to the pathogenesis of the aforementioned autoimmune diseases and discuss the relevance of considering it as a biomarker in these pathologies.

Functional assessment and phenotypic heterogeneity of SFTPA1 and SFTPA2 mutations in interstitial lung diseases and lung cancer.

INTRODUCTION: Interstitial lung diseases (ILDs) can be caused by mutations in the SFTPA1 and SFTPA2 genes, which encode the surfactant protein (SP) complex SP-A. Only 11 SFTPA1 or SFTPA2 mutations have so far been reported worldwide, of which five have been functionally assessed. In the framework of ILD molecular diagnosis, we identified 14 independent patients with pathogenic SFTPA1 or SFTPA2 mutations. The present study aimed to functionally assess the 11 different mutations identified and to accurately describe the disease phenotype of the patients and their affected relatives. METHODS: The consequences of the 11 SFTPA1 or SFTPA2 mutations were analysed both in vitro, by studying the production and secretion of the corresponding mutated proteins and ex vivo, by analysing SP-A expression in lung tissue samples. The associated disease phenotypes were documented. RESULTS: For the 11 identified mutations, protein production was preserved but secretion was abolished. The expression pattern of lung SP-A available in six patients was altered and the family history reported ILD and/or lung adenocarcinoma in 13 out of 14 families (93%). Among the 28 SFTPA1 or SFTPA2 mutation carriers, the mean age at ILD onset was 45 years (range 0.6-65 years) and 48% underwent lung transplantation (mean age 51 years). Seven carriers were asymptomatic. DISCUSSION: This study, which expands the molecular and clinical spectrum of SP-A disorders, shows that pathogenic SFTPA1 or SFTPA2 mutations share similar consequences for SP-A secretion in cell models and in lung tissue immunostaining, whereas they are associated with a highly variable phenotypic expression of disease, ranging from severe forms requiring lung transplantation to incomplete penetrance.

Lung involvement associated with anti-NXP2 autoantibodies in inflammatory myopathies: a French monocenter series.

BACKGROUND: Inflammatory myopathies (IM) are characterized by muscular inflammation that can be associated with systemic disorders including lung. Anti-NXP2 antibody (Ab) is a rare myositis-specific antibody and its association with pulmonary involvement is still unknown. In this study, we investigated the characteristics of lung disease in patients with IM associated with anti-NXP2 Ab. METHODS: Adult patients with confirmed IM and positive anti-NXP2 antibodies were recruited in our University departments (Assistance Publique- Hôpitaux de Marseille, France), between 2015 and 2019 to perform a retrospective study. RESULTS: Seven patients were identified. Mean age was 55 ± 13 years, with a predominance of females (71%). Two patients (29%) had respiratory symptoms. CT-scan shows abnormalities in three patients (organizing pneumonia, nonspecific interstitial pneumonia, and bilateral pleural effusion). An altered diffusing capacity for carbon monoxide was found in four patients. CONCLUSION: We observed that subclinical lung involvement is not rare in patients with IM associated with positive anti-NXP2 Ab, with various radiological patterns and a significant lung function defect. Such data deserve to be known by the pulmonologist in order to perform a complete lung screening in all patients with positive anti-NXP2 antibody and to detect earlier a concomitant lung impairment.

Association Between Immune-related Adverse Events and Efficacy of Immune Checkpoint Inhibitors in Non-small-cell Lung Cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are available for first- and further lines of treatment of patients with advanced non-small-cell lung cancer (NSCLC). These treatments are associated with adverse events called immune-related adverse events (IRAEs). The incidence, diagnosis, and treatment of IRAEs are quite acknowledged; however, the link between IRAEs and the efficacy of ICIs requires further clarification. The objectives of this study were to assess the association between IRAEs incidence and severity and ICIs efficacy in patients with advanced NSCLC. METHODS: In this retrospective study, clinical, biological, treatment, and outcome data were collected from patients with advanced NSCLC who received at least 1 cycle of ICIs from April 2013 to February 2017. The primary endpoint was to assess the association of IRAEs incidence with overall survival (OS). Secondary endpoints were the association of IRAEs with progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). RESULTS: Overall, 270 patients were studied. The median OS was 14 months, median PFS was 2.6 months, ORR was 13%, and DCR was 51%. OS, PFS, and ORR were significantly better for patients with IRAEs compared with patients with no IRAEs, translating to median OS not reached versus 8.21 months, respectively (hazard ratio, 0.29; 95% confidence interval [CI], 0.18-0.46; P < .001); PFS was 5.2 versus 1.97 months (hazard ratio, 0.42; 95% CI, 0.32-0.57; P < .001); and ORR was 212.9% versus 5.7% (odds ratio, 4.9; 95% CI, 2.18-11.05; P < .001). CONCLUSIONS: This report presents the largest case series showing longer OS and PFS and better ORR when IRAEs occurred in a population of patients with advanced NSCLC treated with ICIs. The biological background for this phenomenon is being explored prospectively.