[Sotorasib treatment in KRAS G12C-mutated non-small cell lung cancer: Experience in the Tours university hospital]. / Traitement par sotorasib en autorisation d'accès précoce dans le cancer pulmonaire non à petites cellules mutées KRAS G12C : expérience du centre hospitalier régional universitaire de Tours.

Following the CodeBreak 100 study, since 2021 sotorasib has been available in France, with authorization for early access in treatment of non-small cell lung cancer with a KRAS G12C mutation. Our retrospective observational study was designed to determine the efficacy and safety of sotorasib under real-life conditions in patients treated at the Tours CHRU. Our study of 15 patients showed sotorasib to be effective in 47% of cases, with overall survival of 4 months and median progression-free survival of 5.5 months for responders. Tumor control was achieved in 7/8 (87%) of patients with PS of 0 or 1 and in 1/7 (14%) of patients with a PS of 2 or greater. Grade 3 acute hepatitis occurred in 3/15 patients (20%). While sotorasib is an interesting therapeutic option, with efficacy that seems better in patients in good general condition, it entails a possible risk of drug-induced hepatitis, which remains to be specified in dedicated studies.

[Secondary pulmonary alveolar proteinosis in a transplant patient]. / Protéinose pulmonaire secondaire chez un patient greffé.

INTRODUCTION: Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by alveolar accumulation of lipoproteinaceous material, caused by a macrophagic clearance disorder. We present a case of PAP in a patient taking the immunosuppressant drug mycophenolate mofetil (MMF) in the context of invasive pulmonary aspergillosis, of which we discuss the pathophysiology and treatment as reported in the literature. CASE REPORT: A 43-year-old man with cardiomyopathy received a heart transplant and was treated by MMF, tacrolimus and corticosteroids. Three months after the transplant, he presented with acute oxygen-dependent respiratory failure. The diagnosis of PAP seemed likely on the CT scan and was confirmed by bronchoalveolar lavage, as was the diagnostic of invasive pulmonary aspergillosis (IPA). However, GM-CSF autoantibodies were not found. As there existed a suspicion of MMF imputability, the treatment was discontinued and an antifungal treatment was started. The patient was reassessed one month after discontinuation of MMF and found to have clinically and radiologically improved. Four other cases of MMF-induced PAP have been reported in the literature. CONCLUSIONS: MMF and IPA could be predisposing cofactors for the occurrence of secondary PAP.

[French practical guidelines for the diagnosis and management of IPF - 2021 update, full version]. / Recommandations pratiques pour le diagnostic et la prise en charge de la fibrose pulmonaire idiopathique ­ Actualisation 2021. Version intégrale.

BACKGROUND: Since the previous French guidelines were published in 2017, substantial additional knowledge about idiopathic pulmonary fibrosis has accumulated. METHODS: Under the auspices of the French-speaking Learned Society of Pulmonology and at the initiative of the coordinating reference center, practical guidelines for treatment of rare pulmonary diseases have been established. They were elaborated by groups of writers, reviewers and coordinators with the help of the OrphaLung network, as well as pulmonologists with varying practice modalities, radiologists, pathologists, a general practitioner, a head nurse, and a patients' association. The method was developed according to rules entitled "Good clinical practice" in the overall framework of the "Guidelines for clinical practice" of the official French health authority (HAS), taking into account the results of an online vote using a Likert scale. RESULTS: After analysis of the literature, 54 recommendations were formulated, improved, and validated by the working groups. The recommendations covered a wide-ranging aspects of the disease and its treatment: epidemiology, diagnostic modalities, quality criteria and interpretation of chest CT, indication and modalities of lung biopsy, etiologic workup, approach to familial disease entailing indications and modalities of genetic testing, evaluation of possible functional impairments and prognosis, indications for and use of antifibrotic therapy, lung transplantation, symptom management, comorbidities and complications, treatment of chronic respiratory failure, diagnosis and management of acute exacerbations of fibrosis. CONCLUSION: These evidence-based guidelines are aimed at guiding the diagnosis and the management in clinical practice of idiopathic pulmonary fibrosis.

[Primary pleural epithelioid hemangioendothelioma, an often-misdiagnosed rare tumor]. / Hémangioendothéliome épithélioïde pleural, une tumeur rare de diagnostic difficile : à propos d'un cas et revue de la littérature.

INTRODUCTION: Epithelioid hemangioendothelioma (EHE) is a rare vascular tumor that develops in various organs. Primary pleural epithelioid hemangioendothelioma is an exceptional occurrence, with only forty cases reported in the literature. On account of its rarity, pleural EHE is difficult to diagnose. Differential diagnoses such as malignant pleural mesothelioma or lung carcinoma are often initially suspected. METHODS: We herein describe the case of a 52-year-old man presenting with a primary pleural epithelioid hemangioendothelioma revealed by thoracic pain and having evolved for three months. Having reviewed the literature, we consider the clinical presentation and diagnosis modalities of this rare tumor. RESULTS: After an initial diagnosis of lung carcinoma, an ultrasound-guided biopsy was performed, confirming the diagnosis of pleural EHE in our patient. Ours is the first case of pleural EHE to be diagnosed with ultrasound-guided echography. Presentation of pleural EHE is often clinically and radiologically nonspecific. Most diagnoses are obtained by thoracoscopy, which allows for targeted biopsies and evacuation of pleural effusion. CONCLUSION: The diagnostic process for this rare tumor must be rigorous. Ultrasound-guided biopsy may be considered, provided that the lesions are accessible.

[French practical guidelines for the diagnosis and management of IPF - 2021 update, short version]. / Recommandations pratiques pour le diagnostic et la prise en charge de la fibrose pulmonaire idiopathique ­ Actualisation 2021. Version courte.

BACKGROUND: Since the previous French guidelines were published in 2017, substantial additional knowledge about idiopathic pulmonary fibrosis has accumulated. METHODS: Under the auspices of the French-speaking Learned Society of Pulmonology and at the initiative of the coordinating reference center, practical guidelines for treatment of rare pulmonary diseases have been established. They were elaborated by groups of writers, reviewers and coordinators with the help of the OrphaLung network, as well as pulmonologists with varying practice modalities, radiologists, pathologists, a general practitioner, a head nurse, and a patients' association. The method was developed according to rules entitled "Good clinical practice" in the overall framework of the "Guidelines for clinical practice" of the official French health authority (HAS), taking into account the results of an online vote using a Likert scale. RESULTS: After analysis of the literature, 54 recommendations were formulated, improved, and validated by the working groups. The recommendations covered a wide-ranging aspects of the disease and its treatment: epidemiology, diagnostic modalities, quality criteria and interpretation of chest CT, indication and modalities of lung biopsy, etiologic workup, approach to familial disease entailing indications and modalities of genetic testing, evaluation of possible functional impairments and prognosis, indications for and use of antifibrotic therapy, lung transplantation, symptom management, comorbidities and complications, treatment of chronic respiratory failure, diagnosis and management of acute exacerbations of fibrosis. CONCLUSION: These evidence-based guidelines are aimed at guiding the diagnosis and the management in clinical practice of idiopathic pulmonary fibrosis.

Nebulised liposomal amphotericin-B as maintenance therapy in allergic bronchopulmonary aspergillosis: a randomised, multicentre trial.

BACKGROUND: In allergic bronchopulmonary aspergillosis (ABPA), prolonged nebulised antifungal treatment may be a strategy for maintaining remission. METHODS: We performed a randomised, single-blind, clinical trial in 30 centres. Patients with controlled ABPA after 4-month attack treatment (corticosteroids and itraconazole) were randomly assigned to nebulised liposomal amphotericin-B or placebo for 6 months. The primary outcome was occurrence of a first severe clinical exacerbation within 24 months following randomisation. Secondary outcomes included the median time to first severe clinical exacerbation, number of severe clinical exacerbations per patient, ABPA-related biological parameters. RESULTS: Among 174 enrolled patients with ABPA from March 2015 through July 2017, 139 were controlled after 4-month attack treatment and were randomised. The primary outcome occurred in 33 (50.8%) out of 65 patients in the nebulised liposomal amphotericin-B group and 38 (51.3%) out of 74 in the placebo group (absolute difference -0.6%, 95% CI -16.8- +15.6%; OR 0.98, 95% CI 0.50-1.90; p=0.95). The median (interquartile range) time to first severe clinical exacerbation was longer in the liposomal amphotericin-B group: 337 days (168-476 days) versus 177 days (64-288 days). At the end of maintenance therapy, total immunoglobulin-E and Aspergillus precipitins were significantly decreased in the nebulised liposomal amphotericin-B group. CONCLUSIONS: In ABPA, maintenance therapy using nebulised liposomal amphotericin-B did not reduce the risk of severe clinical exacerbation. The presence of some positive secondary outcomes creates clinical equipoise for further research.

Expectations about treatment of idiopathic pulmonary fibrosis: Comparative survey of patients, carers and physicians (the RESPIR French survey).

CONTEXT: Idiopathic pulmonary fibrosis (IPF) is a severe chronic disease during which anxiety and depression are frequent comorbidities. Better knowledge of patients' expectations is needed to inform an action plan to improve medical care. AIM: To describe feelings and expectations of patients suffering from IPF and of their carers about antifibrotic therapy and compare them to what is perceived by their pulmonologist. METHODS: National prospective study on practices and perceptions. Specific questionnaires were e-mailed to all 3276 pulmonologists in France who, in turn, invited patients and carers to participate in a survey. RESULTS: 147 pulmonologists, 161 patients and 144 carers participated in the survey. The role of the carer was evaluated as "important" or "very important" by more than 90% of participants, i.e. pulmonologists, patients or carers. Inconsistencies between how patients felt and how pulmonologists perceived them were identified: 88% of patients responded that they understood quite well what IPF is (vs. 75% of patients according to pulmonologists); 85.5% of patients said they were determined to fight the disease (vs. 68.0%); 61.7% of patients wanted to be kept informed of potential complications before they occurred (vs. 69.6%) and 81.2% wanted to be involved in therapeutic decisions (vs. 43.1%). Globally, patients had a more positive view of antifibrotic therapies than expected by pulmonologists: 41.5% evaluated their advantages superior to what they had expected (vs. 29.1% of patients according to pulmonologists) and 76.5% had a positive image of the benefits/disadvantages ratio (vs. 62.4%). Although pulmonologists had the impression that they were keeping their patients well-informed about exacerbations, hospital stays and the possible negative evolution of the disease despite antifibrotic therapies, 34.0%, 42.0% and 22.0% of patients respectively declared not being aware of these aspects. CONCLUSION: The feelings of patients suffering from IPF regarding their disease and treatment globally proved more positive compared with how pulmonologists perceived them. Taking into account the expectations and needs of patients may allow healthcare professionals to better address their needs and priorities.

Evaluation of efficacy and safety of rituximab in combination with mycophenolate mofetil in patients with nonspecific interstitial pneumonia non-responding to a first-line immunosuppressive treatment (EVER-ILD): A double-blind placebo-controlled randomized trial.

INTRODUCTION: Nonspecific interstitial pneumonia (NSIP) are rare but severe diseases, with high mortality and morbidity, with no effective pharmacological treatment allowing for long-term remission, and therefore no clear therapeutic recommendations. Classic immunosuppressants are used as first-line treatment, with only one third of patients being responders and no clear recommendations exist for the choice of the second-line therapy. The EvER-ILD study is the first one to prospectively evaluate the efficacy and safety of rituximab and mycophenolate mofetil (MMF) versus placebo and MMF in a broad range of NSIP patients that did not respond to a first-line therapy. A pharmacokinetic-pharmacodynamic analysis based on rituximab serum concentrations will allow identification of potential factors associated with therapeutic response and/or adverse effects. METHODS: EvER-ILD study is a French multicenter, prospective, randomized, double blind, placebo-controlled, superiority trial. Patients with severe and progressive NSIP non-responding to a first line immunosuppressive treatment will be randomized in 2 groups of treatment: one course of rituximab plus 6 months MMF (RTX-MMF group) and one course of placebo plus 6 months MMF (Placebo-MMF group). The primary outcome is the change in Forced Vital Capacity (FVC, % of predicted) from baseline to 6 months. Several clinical, biological, and quality of life secondary outcomes will be measured at 3, 6 and 12 months. A sample size of 122 patients (61 patients per group) would allow to show a point difference between groups in the change of FVC at 6 months, based on a common standard deviation for FVC change of 8% with a power of 90%, alpha 5% two-sided, and anticipating an extreme 10% drop-out rate. ETHICS AND DISSEMINATION: The protocol was approved by the French Research Ethics Committee (CPP Tours Ouest 1 2016-R28) on November 10, 2016, and by the French competent authority (ANSM, reference 160771A-22) on December 1st, 2016. This article refers to protocol V2, dated November 18, 2016. An independent data safety monitoring board will review safety and tolerability data for the duration of the trial. Results will be disseminated via peer reviewed publication and presentation at international conferences. TRIAL REGISTRATION NUMBER: NCT02990286 (clinicaltrials.gov), EudraCT 2016-003026-16 (European Medicines agency).

Lung function in Birt-Hogg-Dubé syndrome: a retrospective analysis of 96 patients.

BACKGROUND: Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominant disorder caused by mutations in the FLCN gene coding for folliculin. Its clinical expression includes cutaneous fibrofolliculomas, renal tumors, multiple pulmonary cysts, and recurrent spontaneous pneumothoraces. Data on lung function in BHD are scarce and it is not known whether lung function declines over time. We retrospectively assessed lung function at baseline and during follow-up in 96 patients with BHD. RESULTS: Ninety-five percent of BHD patients had multiple pulmonary cysts on computed tomography and 59% had experienced at least one pneumothorax. Mean values of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, and total lung capacity were normal at baseline. Mean (standard deviation) residual volume (RV) was moderately increased to 116 (36) %pred at baseline, and RV was elevated > 120%pred in 41% of cases. Mean (standard deviation) carbon monoxide transfer factor (DLco) was moderately decreased to 85 (18) %pred at baseline, and DLco was decreased < 80%pred in 33% of cases. When adjusted for age, gender, smoking and history of pleurodesis, lung function parameters did not significantly decline over a follow-up period of 6 years. CONCLUSIONS: Cystic lung disease in BHD does not affect respiratory function at baseline except for slightly increased RV and reduced DLco. No significant deterioration of lung function occurs in BHD over a follow-up period of 6 years.

[Diagnostic difficulties of chronic pulmonary berylliosis in France]. / Difficultés diagnostiques de la bérylliose pulmonaire chronique en France.

INTRODUCTION: The epidemiology of chronic beryllium disease (CBD) in France is poorly understood. The aim of this study was to determine the number of prevalent cases of CBD in France between 2010 and 2014. METHODS: We conducted a national survey using a specific questionnaire distributed by the professional pathology services. RESULTS: In total, 33 CBD cases were reported in France, with a diagnosis established between 1982 and 2014. 85% (28/33) of CBD cases resulted from professional exposure and mostly concerned foundry workers (39%). A definite diagnosis defined by the association of an abnormal beryllium lymphocyte proliferation test and of a granulomatous inflammatory response in the lung, was obtained in 29/33 cases (88%). The other cases were probable CBD, defined by a granulomatous lung disease with a beryllium exposure, but without evidence of beryllium sensitisation. The diagnosis of granulomatous disease was confirmed a mean of 4 years after the end of exposure. The median delay between diagnosis of a granulomatous disease and diagnosis of CBD was 2 years (range 0-38 years). A genetic predisposition was found in 14 of 17 tested patients (82%). CONCLUSION: In this study, we report 33 cases of CBD followed in France between 2010 and 2014. The poor understanding of CBD and the exposure leading to it, the late development after the end of exposure, the complexity of the diagnosis and the similarities with sarcoidosis may explain the small number of cases reported.

[Hypersensitivity pneumonitis and abscess reaction to nontuberculous mycobacteria acquired form jacuzzi aerosol]. / Pneumopathie d'hypersensibilité à mycobactéries atypiques se compliquant d'un abcès à Mycobacterium intracellulare.

INTRODUCTION: Mycobacterium avium complex can be responsible for a number of different radio-clinical presentations, ranging from invasive infections to hypersensitivity pneumonitis due to repeated inhalation of antigens. The diagnosis of hypersensitivity pneumonitis is clinical, radiological, biological and microbiological. CASE REPORT: A 61-year-old male developed a hypersensitivity pneumonitis reaction to non-tuberculous mycobacteria, following the repeated use of his own spa, which later evolved into chronic respiratory failure. The diagnosis was made via an environmental analysis. Immunosuppressive treatment comprising corticosteroids and methotrexate led to moderate improvement, but may also have been responsible for the development of a M. intracellulare abscess. Despite 12 months of well-conducted antibiotic treatment, the evolution was unfavourable, with a relapse of a M. intracellulare infection three months after the end of treatment, followed by the patient's death. CONCLUSION: Hypersensitivity pneumonitis reaction to non-tuberculous mycobacteria should be considered in patients who have their own spa. In the absence of microbiological identification, environmental analysis may guide the diagnosis. A fatal evolution of PHS is infrequent but prognosis may depend on the degree of associated fibrosis.

[Osteochondroplastic tracheobronchopathy: About three cases]. / Trachéobronchopathie ostéochondroplastique : à propos de 3 cas.

INTRODUCTION: Osteochondroplastic tracheobronchopathy (OCTB) is a rare disorder of unknown cause that affects the tracheobronchial tree. It is characterized by multiple cartilaginous formations or bone nodules projecting into the tracheal or proximal bronchial lumen. It is usually asymptomatic because of the slow progression of the nodules. However, chronic cough, recurrent hemoptysis or recurrent respiratory infections have been reported. OBSERVATIONS: We describe the cases of three patients with symptomatic OCTB: two men and one woman consulting for bronchial infections or pneumonia with sputum difficulties (2 cases) or simply for chronic cough (1 case). In all three cases, the diagnosis was suspected because of irregularities of the tracheal or bronchial wall with calcification seen on imaging and confirmed at bronchoscopy with biopsy specimens. No specific therapy was initiated in these patients except for the treatment of associated complications or comorbidities. CONCLUSION: OCTB is a benign pathology which can lead to bronchial symptoms ranging from mild cough to severe airway obstruction due to tracheobronchial stenosis. A key to diagnosis, limiting non-essential examinations and biopsies, is to consider OCTB based on CT scan or bronchoscopy based on irregularities of the tracheal or bronchial wall with calcification.

[The pentoxifylline, a corticosteroid sparing in the treatment of sarcoidosis: A case report]. / La pentoxifylline, un épargneur de corticoïdes dans le traitement de la sarcoïdose : à propos d'une observation.

INTRODUCTION: The pentoxifylline seems to have some effects on immune cells by inhibiting tumor necrosis factor alpha (TNFα). Its role as a sparing corticosteroids in the treatment of sarcoidosis remains to be defined. CLINICAL CASE: We present the case of a patient with sarcoidosis corticodependent despite the use of azathioprine. It was finally improved clinically, functionally and by a thoracic computed tomography with addition of pentoxifylline. CONCLUSION: When the tolerance of the pentoxifylline is good and there is not a bleeding risk, the benefit-risk in the long term might be interesting in some patients with sarcoidosis corticodependent.

[Relationships between COPD and nontuberculous mycobacteria pulmonary infections]. / Relations entre la BPCO et les infections à mycobactéries non tuberculeuses.

Nontuberculous mycobacteria (NTM) pulmonary infections are increasingly frequent in pneumological practice. The diagnosis is based on an association of clinical, microbiological and radiological criteria. Some risk factors for NTM disease have been described, including chronic respiratory diseases, but without specific focus on chronic obstructive pulmonary disease (COPD). COPD patients have more risk to be infected by NTM than patients with the main other chronic respiratory diseases (except cystic fibrosis) (odds ratio [OR] at 15.7 in a case-control study). This NTM pulmonary infection is associated with a greater decline in forced expiratory volume in one second (FEV1) and an increased exacerbation rate. Inhaled corticosteroids (ICS) increase the risk of COPD patients developing an NTM infection (OR at 16.9), especially if ICS are still used at the time of diagnosis. Chronic macrolide treatment could possibly select resistant NTM strains and so could make the treatment clearly more difficult as macrolides are the cornerstone NTM treatment. NTM infections in patients with COPD are probably underestimated and should be kept in mind, particularly when patients have frequent exacerbations and display accelerated respiratory function decline, before implementing ICS or macrolides.