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.

Phenotypes and outcome of diffuse pulmonary non-amyloid light chain deposition disease.

BACKGROUND: Light chain deposition disease (LCDD) is a very rare entity. Clinical manifestations of LCDD vary according to the organs involved. Data on pulmonary LCDD are scarce and limited to small series or case reports. This study aimed to describe the characteristics and outcome of diffuse pulmonary non-amyloid LCDD localized to the lungs. STUDY DESIGN AND METHODS: A multicenter retrospective cohort study was conducted. Clinical characteristics were collected, and chest CTs were centrally reviewed. The diagnosis of pulmonary non-amyloid LCDD was confirmed by immunohistochemistry. RESULTS: Thirty-one cases were identified (68% female), with a median age at diagnosis of 50 years (IQR 20). Baseline FEV1/FVC was < 0.70 in 45% of patients. Mean (± SD) FEV1 and DLCO were 86% ± 26.2 and 52% ± 23.9, respectively. CT revealed peculiar patterns of thin-walled cysts (58%) and thin-walled cystic bronchiectases (27%). Increased serum kappa light chain was found in 87% of patients. Histological analysis showed kappa light chain deposits in all patients, except one with lambda chain deposits. Median annual FEV1 decline was 127 ml (IQR 178) and median DLCO decline was 4.3% (IQR 4.3). Sixteen patients received immunomodulatory treatment or chemotherapy; serum light chain levels decreased in 9 cases (75%), without significant improvement in FEV1 (p = 0.173). Overall, 48% of patients underwent bilateral lung transplantation. Transplant-free survival at 5 and 10 years were 70% and 30%, respectively. An annual FEV1 decline greater than 127 ml/year was associated with increased risk of death or transplantation (p = 0.005). CONCLUSIONS: Diffuse pulmonary LCDD is characterised by female predominance, a peculiar imaging pattern with bronchiectasis and/or cysts, progressive airway obstruction and severe DLCO impairment, and poor outcome. Lung transplantation is a treatment of choice.

Chronic interstitial lung disease associated with systemic lupus erythematosus: A multicentric study of 89 cases.

BACKGROUND AND OBJECTIVE: Chronic interstitial lung disease (ILD) occurs rarely with systemic lupus erythematosus (SLE) as compared with other connective tissue diseases. This multicentric retrospective study of patients with SLE-ILD from the OrphaLung and French SLE networks during 2005-2020 aimed to describe the characteristics of patients with SLE-ILD and analyse factors associated with prognosis. METHODS: We analysed data for 89 patients with SLE-ILD (82 women, 92.1%) (median age at SLE diagnosis: 35 years [interquartile range 27-47]). All patients met the 2019 EULAR/ACR criteria for the diagnosis of SLE. RESULTS: Forty two (47.2%) patients were positive for anti-ribonuclear protein antibodies and 45 (50.6%) for anti SSA/Ro antibodies. A total of 58 (65.2%) patients had another connective tissue disease: Sjögren's syndrome (n = 33, 37.1%), systemic sclerosis (n = 14, 15.7%), inflammatory myopathy (n = 6, 6.7%), or rheumatoid arthritis (n = 6, 6.7%). ILD was diagnosed along with SLE in 25 (28.1%) patients and at a median of 6 (0-14) years after the SLE diagnosis. The most frequent CT pattern was suggestive of non-specific interstitial pneumonia (n = 41, 46.0%) with or without superimposed organizing pneumonia. After a median follow-up of 86.5 [39.5-161.2] months, 18 (20.2%) patients had died and 6 (6.7%) underwent lung transplantation. The median 5-year and 10-year transplantation-free survival were 96% (92-100) and 87% (78-97). In total, 44 (49.4%) patients showed ILD progression. Cutaneous manifestations and Raynaud's phenomenon were associated with better survival. Only forced vital capacity was significantly associated with survival and ILD progression. CONCLUSION: ILD is a rare manifestation of SLE with good overall prognosis but with possible risk of ILD progression. Patients with SLE-ILD frequently have another connective tissue disease.

HRCT imaging of pulmonary involvement in granulomatosis with polyangiitis and microscopic polyangiitis at disease onset and during follow-up.

BACKGROUND: The pulmonary involvement in patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) is well known at disease onset but data during follow-up (after the induction regimen and when the first relapse occurs) are limited. Our goal was to analyze chest high-resolution computed tomography (HRCT) findings of (ANCA)-associated vasculitis patients. METHOD: All consecutive unselected AAV patients over eighteen with positive ANCA status and with HRCT chest performed at the diagnosis were retrospectively enrolled between 2004 and 2019 at the Toulouse University Hospital (France). Two experienced pulmonologists and one expert respiratory radiologist reviewed independently HRCT chest scans. RESULTS: A total of 157 AAV patients were included in the study. Two-thirds of AAV patients had pulmonary involvement at diagnosis. Diffuse alveolar hemorrhage (DAH) was observed in 31.2 % of cases, nodules and masses in 18.5 %, bronchial airway involvement in 13.4 %, and interstitial involvement in 12.7 %. Following the induction regimen, chest HRCT scans over a two-year period demonstrated significant improvement in DAH and nodular manifestations, whereas bronchial airway involvement exhibited variability and half of cases of interstitial lung disease (ILD) had progressive course. Outcomes and survival rates are better for nodular and bronchial involvement. DAH was the most frequent cause of deaths. Progressive fibrotic changes in ILD over time could impact prognosis despite AAV remission. CONCLUSION: Employing a pattern-based approach with HRCT chest scans to assess lung involvement could be valuable in predicting treatment response, relapse, mortality, and could improved the management of AAV patients.

Role of bronchoscopy for respiratory involvement in granulomatosis with polyangiitis and microscopic polyangiitis.

Objectives: This study describes data from bronchoscopy performed at the diagnosis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Methods: We conducted a retrospective study between 2004 and 2019 in patients aged >18 years with a diagnosis of microscopic polyangiitis (MPA) or granulomatosis with polyangiitis (GPA) who underwent bronchoscopy at onset of the disease. We collected bronchoalveolar lavage (BAL) and histological findings obtained during bronchoscopy. Results: 274 patients with AAV were identified. Among 92 bronchoscopies, 62 were performed at diagnosis, and 58 procedures were finally analysed. Cough was more frequent in patients with MPA than GPA (p=0.02). The presence of endobronchial lesions (24.1%) was found to be significantly associated with GPA (p<0.0001) and proteinase 3-ANCA (p=0.01). The most frequent endobronchial lesions were inflammation and hyperaemia of the bronchial mucosa (50%), followed by stenoses (28%), ulcerations (21%) and mass-like granulomatosis (7%). The diagnostic yield of bronchial biopsies was useful for visible lesions (66.6% versus 0%; p=0.006). On BAL, diffuse alveolar haemorrhage (DAH) was detected in 31 (53.4%) patients and was more frequent in MPA patients (70.4% versus 38.7%; p=0.016). In 16.1% of DAH cases, BAL confirmed the diagnosis despite the absence of clinical or biological arguments. The incidence of microbial infections on BAL (38%) was similar between MPA and GPA (p=0.54). Conclusion: Bronchoscopy is an informative procedure at the onset of AAV disease in patients with respiratory manifestations. Endobronchial lesions are more frequently found in GPA and should be biopsied. BAL can be used to confirm DAH or diagnose superadded infection.

Infections in autoimmune pulmonary alveolar proteinosis: a large retrospective cohort.

BACKGROUND: Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease, predisposing to an increased risk of infection. A complete picture of these infections is lacking. RESEARCH QUESTION: Describe the characteristics and clinical outcomes of patients diagnosed with aPAP, and to identify risk factors associated with opportunistic infections. METHODS: We conducted a retrospective cohort including all patients diagnosed with aPAP between 2008 and 2018 in France and Belgium. Data were collected using a standardised questionnaire including demographics, comorbidities, imaging features, outcomes and microbiological data. RESULTS: We included 104 patients, 2/3 were men and median age at diagnosis was 45 years. With a median follow-up of 3.4 years (IQR 1.7-6.6 years), 60 patients (58%), developed at least one infection, including 23 (22%) with opportunistic infections. Nocardia spp was the main pathogen identified (n=10). Thirty-five (34%) patients were hospitalised due to infection. In univariate analysis, male gender was associated with opportunistic infections (p=0.04, OR=3.88; 95% CI (1.02 to 22.06)). Anti-granulocyte macrophage colony-stimulating factor antibody titre at diagnosis was significantly higher among patients who developed nocardiosis (1058 (316-1591) vs 580 (200-1190), p=0.01). Nine patients had died (9%), but only one death was related to infection. INTERPRETATION: Patients with aPAP often presented with opportunistic infections, especially nocardiosis, which highlights the importance of systematic search for slow-growing bacteria in bronchoalveolar lavage or whole lung lavage.

Hypomorphic pathogenic variant in SFTPB leads to adult pulmonary fibrosis.

Biallelic pathogenic variants in the surfactant protein (SP)-B gene (SFTPB) have been associated with fatal forms of interstitial lung diseases (ILD) in newborns and exceptional survival in young children. We herein report the cases of two related adults with pulmonary fibrosis due to a new homozygous SFTPB pathogenic variant, c.582G>A p.(Gln194=). In vitro transcript studies showed that this SFTPB synonymous pathogenic variant induces aberrant splicing leading to three abnormal transcripts with the preservation of the expression of a small proportion of normal SFTPB transcripts. Immunostainings on lung biopsies of the proband showed an almost complete loss of SP-B expression. This hypomorphic splice variant has thus probably allowed the patients' survival to adulthood while inducing an epithelial cell dysfunction leading to ILD. Altogether, this report shows that SFTPB pathogenic variants should be considered in atypical presentations and/or early-onset forms of ILD particularly when a family history is identified.

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.

French recommendations for the diagnosis and management of lymphangioleiomyomatosis.

BACKGROUND: The present article is an English-language version of the French National Diagnostic and Care Protocol, a pragmatic tool to optimize and harmonize the diagnosis, care pathway, management and follow-up of lymphangioleiomyomatosis in France. METHODS: Practical recommendations were developed in accordance with the method for developing a National Diagnosis and Care Protocol for rare diseases of the Haute Autorité de Santé and following international guidelines and literature on lymphangioleiomyomatosis. It was developed by a multidisciplinary group, with the help of patient representatives and of RespiFIL, the rare disease network on respiratory diseases. RESULTS: Lymphangioleiomyomatosis is a rare lung disease characterised by a proliferation of smooth muscle cells that leads to the formation of multiple lung cysts. It occurs sporadically or as part of a genetic disease called tuberous sclerosis complex (TSC). The document addresses multiple aspects of the disease, to guide the clinicians regarding when to suspect a diagnosis of lymphangioleiomyomatosis, what to do in case of recurrent pneumothorax or angiomyolipomas, what investigations are needed to make the diagnosis of lymphangioleiomyomatosis, what the diagnostic criteria are for lymphangioleiomyomatosis, what the principles of management are, and how follow-up can be organised. Recommendations are made regarding the use of pharmaceutical specialties and treatment other than medications. CONCLUSION: These recommendations are intended to guide the diagnosis and practical management of pulmonary lymphangioleiomyomatosis.

Serum and Pulmonary Expression Profiles of the Activin Signaling System in Pulmonary Arterial Hypertension.

BACKGROUND: Activins are novel therapeutic targets in pulmonary arterial hypertension (PAH). We therefore studied whether key members of the activin pathway could be used as PAH biomarkers. METHODS: Serum levels of activin A, activin B, α-subunit of inhibin A and B proteins, and the antagonists follistatin and follistatin-like 3 (FSTL3) were measured in controls and in patients with newly diagnosed idiopathic, heritable, or anorexigen-associated PAH (n=80) at baseline and 3 to 4 months after treatment initiation. The primary outcome was death or lung transplantation. Expression patterns of the inhibin subunits, follistatin, FSTL3, Bambi, Cripto, and the activin receptors type I (ALK), type II (ACTRII), and betaglycan were analyzed in PAH and control lung tissues. RESULTS: Death or lung transplantation occurred in 26 of 80 patients (32.5%) over a median follow-up of 69 (interquartile range, 50-81) months. Both baseline (hazard ratio, 1.001 [95% CI, 1.000-1.001]; P=0.037 and 1.263 [95% CI, 1.049-1.520]; P=0.014, respectively) and follow-up (hazard ratio, 1.003 [95% CI, 1.001-1.005]; P=0.001 and 1.365 [95% CI, 1.185-1.573]; P<0.001, respectively) serum levels of activin A and FSTL3 were associated with transplant-free survival in a model adjusted for age and sex. Thresholds determined by receiver operating characteristic analyses were 393 pg/mL for activin A and 16.6 ng/mL for FSTL3. When adjusted with New York Heart Association functional class, 6-minute walk distance, and N-terminal pro-B-type natriuretic peptide, the hazard ratios for transplant-free survival for baseline activin A <393 pg/mL and FSTL3 <16.6 ng/mL were, respectively, 0.14 (95% CI, 0.03-0.61; P=0.009) and 0.17 (95% CI, 0.06-0.45; P<0.001), and for follow-up measures, 0.23 (95% CI, 0.07-0.78; P=0.019) and 0.27 (95% CI, 0.09-0.78, P=0.015), respectively. Prognostic values of activin A and FSTL3 were confirmed in an independent external validation cohort. Histological analyses showed a nuclear accumulation of the phosphorylated form of Smad2/3, higher immunoreactivities for ACTRIIB, ALK2, ALK4, ALK5, ALK7, Cripto, and FSTL3 in vascular endothelial and smooth muscle layers, and lower immunostaining for inhibin-α and follistatin. CONCLUSIONS: These findings offer new insights into the activin signaling system in PAH and show that activin A and FSTL3 are prognostic biomarkers for PAH.

Ethnographic survey of patients and caregiver's life journey in idiopathic pulmonary fibrosis.

OBJECTIVES: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease associated with high mortality. The IPF journey affects patients' and caregivers' quality of life, this should be taken into account as an important parameter for a better disease management. An ethnographic study was conducted between December 2019 and January 2020 to explore social disease representations, patients' and cargivers' experiences in the disease journey and consequences in their daily life, to identify the means of actions permitting a quality of life (QoL) improvement. PATIENTS/CAREGIVERS: Twenty respondents, twelve patients aged 43 to 84 years old and eight caregivers in four French regions were met. Eleven patients were diagnosed with IPF between 2013 and 2017 and one patient in 1988 (at 12 years old). The lung function reported by patients ranged as follows: forced vital capacity from 112% to 40% and diffusing capacity of the lungs for carbon monoxide (DLCO) from 66% to <20%. RESULTS: The survey included patients diagnosed at least three years ago. Collected data comprised disease representation, patients'/caregivers' experience of the disease, healthcare journey, and consequences for their daily life. The first signs identified by the patient or their caregiver may not have been taken seriously by the primary care physician. The pre-diagnosis period was considered particularly traumatic for most patients. The biopsy performed in 8 cases was experienced as violent by 4/8 patients, some of whom still feel pain. Patients/caregivers knew how to define their disease and spontaneously gave severe representations of the disease such as "Rare, incurable disease", "an organ being destroyed". DISCUSSION: This study highlighted patients'/caregivers' common needs at each stage of the disease. The lack of disease knowledge from frontline practitioners (general physicians, community pulmonologists) can lead to significant diagnostic error. Patients require psychological support and more information on daily aspects in disease management, such as food good practices and importance of physical activity, along with information about disease progression. The fear caused by these shortages can be reduced through contact with patients' associations. CONCLUSIONS: Numerous essential data were identified and should be considered for supporting actions that could allow to improve the QoL of patients with IPF.

French practical guidelines for the diagnosis and management of idiopathic pulmonary fibrosis - 2021 update. Full-length version.

BACKGROUND: Since the latest 2017 French guidelines, knowledge about idiopathic pulmonary fibrosis has evolved considerably. METHODS: Practical guidelines were drafted on the initiative of the Coordinating Reference Center for Rare Pulmonary Diseases, led by the French Language Pulmonology Society (SPLF), by a coordinating group, a writing group, and a review group, with the involvement of the entire OrphaLung network, pulmonologists practicing in various settings, radiologists, pathologists, a general practitioner, a health manager, and a patient association. The method followed the "Clinical Practice Guidelines" process of the French National Authority for Health (HAS), including an online vote using a Likert scale. RESULTS: After a literature review, 54 guidelines were formulated, improved, and then validated by the working groups. These guidelines addressed multiple aspects of the disease: epidemiology, diagnostic procedures, quality criteria and interpretation of chest CT scans, lung biopsy indication and procedures, etiological workup, methods and indications for family screening and genetic testing, assessment of the functional impairment and prognosis, indication and use of antifibrotic agents, lung transplantation, management of symptoms, comorbidities and complications, treatment of chronic respiratory failure, diagnosis and management of acute exacerbations of fibrosis. CONCLUSION: These evidence-based guidelines are intended to guide the diagnosis and practical management of idiopathic pulmonary fibrosis.

Cytokines as prognostic biomarkers in pulmonary arterial hypertension.

BACKGROUND: Risk stratification and assessment of disease progression in patients with pulmonary arterial hypertension (PAH) are challenged by the lack of accurate disease-specific and prognostic biomarkers. To date, brain natriuretic peptide (BNP) and/or its N-terminal fragment (NT-proBNP) are the only markers for right ventricular dysfunction used in clinical practice, in association with echocardiographic and invasive haemodynamic variables to predict outcome in patients with PAH. METHODS: This study was designed to identify an easily measurable biomarker panel in the serum of 80 well-phenotyped PAH patients with idiopathic, heritable or drug-induced PAH at baseline and at first follow-up. The prognostic value of identified cytokines of interest was secondly analysed in an external validation cohort of 125 PAH patients. RESULTS: Among the 20 biomarkers studied with the multiplex Ella platform, we identified a three-biomarker panel composed of ß-NGF, CXCL9 and TRAIL that were independently associated with prognosis both at the time of PAH diagnosis and at the first follow-up after initiation of PAH therapy. ß-NGF and CXCL9 were predictors of death or transplantation, whereas high levels of TRAIL were associated with a better prognosis. Furthermore, the prognostic value of the three cytokines was more powerful for predicting survival than usual non-invasive variables (New York Heart Association Functional Class, 6-min walk distance and BNP/NT-proBNP). The results were validated in a fully independent external validation cohort. CONCLUSION: The monitoring of ß-NGF, CXCL9 and TRAIL levels in serum should be considered in the management and treatment of patients with PAH to objectively guide therapeutic options.

2022 Update of indications and contraindications for lung transplantation in France.

Lung transplantation (LTx) is a steadily expanding field. The considerable developments have been driven over the years by indefatigable work conducted at LTx centers to improve donor and recipient selection, combined with multifaceted efforts to overcome challenges raised by the surgical procedure, perioperative care, and long-term medical complications. One consequence has been a pruning away of contraindications over time, which has, in some ways, complicated the patient selection process. The Francophone Pulmonology Society (Société de Pneumology de Langue Française, SPLF) set up a task force to produce up-to-date working guidelines designed to assist pulmonologists in managing end-stage respiratory insufficiency, determining which patients may be eligible for LTx, and appropriately timing LTx-center referral. The task force examined the most recent literature and evaluated the risk factors that limit patient survival after LTx. Ideally, the objectives of LTx are to prolong life while also improving quality of life. The guidelines developed by the task force apply to a limited resource and are consistent with the ethical principles described below.

Clinical and molecular analysis of lung cancers associated with fibrosing interstitial lung disease.

BACKGROUND: Interstitial lung disease is a heterogeneous group of diseases, some of which are known to present an independent risk factor for lung cancer. Its pathophysiological mechanism has not been fully elucidated and therapeutic management is also complex. We aim to both describe a cohort of patients with lung cancer associated with pre-existing fibrosing interstitial lung disease and to characterize their molecular profile. METHODS: We conducted a retrospective, single centre cohort study, at Toulouse University Hospital. Immuno-histochemical (PD-L1, CD8) and molecular analysis was performed on archived tumour sample. Molecular signalling pathways involved were analysed with the Reactome Pathway Database. RESULTS: Forty-nine patients were analysed. Most common histology was adenocarcinoma (65,3%), followed by squamous cell carcinoma (30.6%). Idiopathic pulmonary fibrosis (30,6%) and interstitial lung disease associated with connective tissue disease (22,4%) were mostly diagnosed. Usual interstitial pneumonia dominated the scans patterns. A high proportion of early tumour stages was observed and overall survival was 34,5 months. In metastatic stages response rate to first line chemotherapy was 38% and overall survival was 11,2 months. Main cause of death was complex cancer progression. PD-L1 expression (n=23) was low (0%) to intermediate (1-49%). Tumour mutational burden was low in 69,2% of analysed cases (n=12) and microsatellite status was stable in all cases (n=13). Sample genotyping (n=14) showed frequent involvement of the TP53 gene and the implication of signalling pathways common to fibrotic processes such as TGFß and PI3K/AKT. CONCLUSIONS: We suggest a particular phenotype of lung cancer associated with fibrosing interstitial lung disease that could provide the basis for specific therapeutic strategies.

Impact of pulmonary hypertension on lung cancer management.

INTRODUCTION: The diagnosis and management of lung cancer is challenging among patients followed-up for pulmonary hypertension (PH). Many interventional procedures are not suitable for severely ill patients, thus limiting the diagnosis and treatment of cancer. We report on patients diagnosed with both conditions in our Institution. METHODS: We conducted a retrospective observational cohort study at Toulouse University Hospital. We analysed both management and outcome for patients followed-up for precapillary PH following diagnosis of primary lung cancer. RESULTS: Out of 764 patients followed-up for PH, 25 went on to develop bronchopulmonary neoplasia. The median age was 69 years with a predominance of males (56%) and smokers (92%). Fifty-two percent had group 1 PH and 36% severe group 3 PH. The comorbidity burden was high and 76% were oxygen-dependent. Twenty-eight percent of patients were considered ineligible for tissue biopsy, the diagnosis being made by a multidisciplinary team (MDT) based on radio-clinical presentation. Fifty-four percent of patients did not benefit from any treatment. Sixteen percent of pulmonary diagnostic procedures were associated with complications (severe hypoxaemia, intra-alveolar hemorrhage, haemothorax). Patients were undertreated compared to disease stage guidelines (2 surgical procedures for 9 localised stages). Median survival after cancer diagnosis was 6 months. CONCLUSION: The management of lung cancer is complex in PH patients. The high rate of complications during the diagnosis and therapy steps coupled with very poor patient outcome for both conditions should prompt physicians to thoroughly discuss the benefit/risk benefit in each case.

Balloon pulmonary angioplasty versus riociguat for the treatment of inoperable chronic thromboembolic pulmonary hypertension (RACE): a multicentre, phase 3, open-label, randomised controlled trial and ancillary follow-up study.

BACKGROUND: Riociguat and balloon pulmonary angioplasty (BPA) are treatment options for inoperable chronic thromboembolic pulmonary hypertension (CTEPH). However, randomised controlled trials comparing these treatments are lacking. We aimed to evaluate the efficacy and safety of BPA versus riociguat in patients with inoperable CTEPH. METHODS: In this phase 3, multicentre, open-label, parallel-group, randomised controlled trial done in 23 French centres of expertise for pulmonary hypertension, we enrolled treatment-naive patients aged 18-80 years with newly diagnosed, inoperable CTEPH and pulmonary vascular resistance of more than 320 dyn·s/cm5. Patients were randomly assigned (1:1) to BPA or riociguat via a web-based randomisation system, with block randomisation (block sizes of two or four patients) without stratification. The primary endpoint was change in pulmonary vascular resistance at week 26, expressed as percentage of baseline pulmonary vascular resistance in the intention-to-treat population. Safety analyses were done in all patients who received at least one dose of riociguat or had at least one BPA session. Patients who completed the RACE trial continued into an ancillary 26-week follow-up during which symptomatic patients with pulmonary vascular resistance of more than 320 dyn·s/cm5 benefited from add-on riociguat after BPA or add-on BPA after riociguat. This trial is registered at ClinicalTrials.gov, NCT02634203, and is completed. FINDINGS: Between Jan 19, 2016, and Jan 18, 2019, 105 patients were randomly assigned to riociguat (n=53) or BPA (n=52). At week 26, the geometric mean pulmonary vascular resistance decreased to 39·9% (95% CI 36·2-44·0) of baseline pulmonary vascular resistance in the BPA group and 66·7% (60·5-73·5) of baseline pulmonary vascular resistance in the riociguat group (ratio of geometric means 0·60, 95% CI 0·52-0·69; p<0·0001). Treatment-related serious adverse events occurred in 22 (42%) of 52 patients in the BPA group and five (9%) of 53 patients in the riociguat group. The most frequent treatment-related serious adverse events were lung injury (18 [35%] of 52 patients) in the BPA group and severe hypotension with syncope (two [4%] of 53 patients) in the riociguat group. There were no treatment-related deaths. At week 52, a similar reduction in pulmonary vascular resistance was observed in patients treated with first-line riociguat or first-line BPA (ratio of geometric means 0·91, 95% CI 0·79-1·04). The incidence of BPA-related serious adverse events was lower in patients who were pretreated with riociguat (five [14%] of 36 patients vs 22 [42%] of 52 patients). INTERPRETATION: At week 26, pulmonary vascular resistance reduction was more pronounced with BPA than with riociguat, but treatment-related serious adverse events were more common with BPA. The finding of fewer BPA-related serious adverse events among patients who were pretreated with riociguat in the follow-up study compared with those who received BPA as first-line treatment points to the potential benefits of a multimodality approach to treatment in patients with inoperable CTEPH. Further studies are needed to explore the effects of sequential treatment combining one or two medications and BPA in patients with inoperable CTEPH. FUNDING: Programme Hospitalier de Recherche Clinique of the French Ministry of Health and Bayer HealthCare. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Clinical impact and prognosis of cryoglobulinemia and cryofibrinogenemia in systemic sclerosis.

INTRODUCTION: An association of systemic sclerosis (SSc) with cryoglobulin and/or cryofibrinogenemia has been described. However, clinical, biological, morphological and prognostic implications are unknown. The objective of this study was to describe the phenotype and evaluate the prognosis of cryoglobulinemia and/or cryofibrinogenemia in the progression of SSc. MATERIALS AND METHODS: Patients were included from the Systemic Scleroderma Toulouse Cohort (SSTC), between June 1, 2005 and May 31, 2018, and underwent a measurement of a cryoglobulin and/or cryofibrinogen in immunology laboratory at the Toulouse University Hospital Center. Patients with and without cryoglobulinemia >50 mg/l and patients with and without cryofibrinogenemia were compared to identified the impact of cryoprcipitate on the phenotype. Mortality based on cryoprecipitate was explored. RESULTS: 166 patients were included in the study. 43.3% and 46.6% had a cryoglobulinemia >50 mg/l and cryofibrinogenemia, respectively. Cryoglobulin >50 mg was not associated with microvascular damage. Cryoglobulin does not influence the phenotype. 5-and 10-years survival were 97.6% and 88.8% respectively in patients with cryoglobulinemia >50 mg/l versus 91.9% and 78.4% in patients without cryoglobulin>50 mg/l. 10-years survival was better for patients with cryoglobulinemia >50 mg/l (log-rank 0.0363). Cryofibrinogenemia was not associated with neoplasia, any clinical (in particular ischemic damage), biological or morphological features. Cryofibrinogenemia had no influence on the mortality of these patients. CONCLUSION: Cryoglobulinemia and cryofibrinogenemia are frequent in SSc. The presence of cryoprecipitate (cryoglobulin or cryofibrinogen) not influence the phenotype and has not associated with a poor survival.