RESUMEN
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.
Asunto(s)
Fibrosis Pulmonar Idiopática , Trasplante de Pulmón , Neumología , Biopsia , Humanos , Fibrosis Pulmonar Idiopática/diagnóstico , Fibrosis Pulmonar Idiopática/epidemiología , Fibrosis Pulmonar Idiopática/terapia , Pulmón/patologíaRESUMEN
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.
Asunto(s)
Fibrosis Pulmonar Idiopática , Trasplante de Pulmón , Neumología , Humanos , Fibrosis Pulmonar Idiopática/diagnóstico , Fibrosis Pulmonar Idiopática/epidemiología , Fibrosis Pulmonar Idiopática/terapia , Pulmón/patología , NeumólogosRESUMEN
INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a common condition that may initially look simple but may conceal other diseases capable of accelerating its natural history or even simulating it. We describe four cases presenting as COPD with emphysema that were reclassified on the basis of certain clinical characteristics and the radiological pattern. CASE REPORTS: A 52 year old never smoking woman presenting with emphysema was eventually diagnosed as having lymphangioleiomyomatosis on the basis of an abdominal CT scan showing kidney angiomyolipomas. A 44 years old smoker presenting with rapidly evolving emphysema was eventually diagnosed as having Langerhans cell histiocytosis on the basis of a previous chest CT (four years earlier) showing cavitating nodules. An airport refueler, 73 years old, with severe emphysema despite never having smoked, was eventually diagnosed as suffering from alpha-1 antitrypsin deficiency. The last patient was a 54 year old man, a never smoker, who presented with severe airflow limitation and multilobar hyperlucency, with bronchiectasis in the same areas. He was eventually diagnosed as having a severe form of the Swyer-James-MacLeod syndrome. CONCLUSION: These four case reports underline the importance of questioning the diagnosis of COPD when certain particular phenotypic characteristics are identified.
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Histiocitosis de Células de Langerhans/diagnóstico , Neoplasias Pulmonares/diagnóstico , Pulmón Hiperluminoso/diagnóstico , Linfangioleiomiomatosis/diagnóstico , Enfisema Pulmonar/diagnóstico , Deficiencia de alfa 1-Antitripsina/diagnóstico , Adulto , Anciano , Bronquiectasia/complicaciones , Bronquiectasia/diagnóstico , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfisema Pulmonar/complicacionesRESUMEN
INTRODUCTION: Immunotherapy aims to promote the immune system's activity against malignant cells by stimulating the response to several tumor antigens. STATE OF THE ART: Immunosurveillance may adjust the immunogenicity of tumors. To be effective, immunity must induce the specific activation of CD4+ and CD8+ T lymphocytes, as well as activation of innate immunity. Activator and inhibitory costimulatory molecules regulate T lymphocyte activation at immunity checkpoints such as PD-1/PD-L1 and CTLA-4. Adaptive immune resistance confers tumour resistance to immunosurveillance through these immune checkpoints. PERSPECTIVES: Approaches involving the combination of several immunotherapies with each other or with chemotherapy and radiotherapy and antibodies against other molecules of costimulation are under development. The development of biomarkers, which can select a targeted population and predict therapeutic response, represents a major challenge. Tumour high-throughput sequencing could refine "immunoscore". Intratumoral T cell receptor seems to represent a promising biomarker. CONCLUSIONS: Numerous challenges still remain in developing research approaches for the development of immunotherapies.
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Inmunoterapia/estadística & datos numéricos , Neoplasias/terapia , Anticuerpos Monoclonales/uso terapéutico , Antígeno B7-H1/fisiología , Humanos , Sistema Inmunológico/fisiología , Vigilancia Inmunológica/fisiología , Inmunoterapia/métodos , Neoplasias/inmunología , Receptor de Muerte Celular Programada 1/fisiología , Escape del Tumor/fisiologíaRESUMEN
Background: Expression of PD-L1 in tumor cells and tumor-infiltrating immune cells has been associated with improved efficacy to anti-PD-1/PD-L1 inhibitors in patients with advanced-stage non-small-cell lung cancer (NSCLC) and emerged as a potential biomarker for the selection of patients to cancer immunotherapies. We investigated the utility of circulating tumor cells (CTCs) and circulating white blood cells (WBCs) as a noninvasive method to evaluate PD-L1 status in advanced NSCLC patients. Patients and methods: CTCs and circulating WBCs were enriched from peripheral blood samples (ISET® platform; Rarecells) from 106 NSCLC patients. PD-L1 expression on ISET filters and matched-tumor tissue was evaluated by automated immunostaining (SP142 antibody; Ventana), and quantified in tumor cells and WBCs. Results: CTCs were detected in 80 (75%) patients, with levels ranging from 2 to 256 CTCs/4 ml, and median of 60 CTCs/4 ml. Among 71 evaluable samples with matched-tissue and CTCs, 6 patients (8%) showed ≥1 PD-L1-positive CTCs and 11 patients (15%) showed ≥1% PD-L1-positive tumor cells in tumor tissue with 93% concordance between tissue and CTCs (sensitivity = 55%; specificity = 100%). From 74 samples with matched-tissue and circulating WBCs, 40 patients (54%) showed ≥1% PD-L1-positive immune infiltrates in tumor tissue and 39 patients (53%) showed ≥1% PD-L1 positive in circulating WBCs, with 80% concordance between blood and tissue (sensitivity = 82%; specificity = 79%). We found a trend for worse survival in patients receiving first-line cisplatin-based chemotherapy treatments, whose tumors express PD-L1 in CTCs or immune cells (progression-free and overall survival), similar to the effects of PD-L1 expression in matched-patient tumors. Conclusions: These results demonstrated that PD-L1 status in CTCs and circulating WBCs correlate with PD-L1 status in tumor tissue, revealing the potential of CTCs assessment as a noninvasive real-time biopsy to evaluate PD-L1 expression in patients with advanced-stage NSCLC.
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Antígeno B7-H1/sangre , Carcinoma de Pulmón de Células no Pequeñas/sangre , Leucocitos/metabolismo , Neoplasias Pulmonares/sangre , Células Neoplásicas Circulantes/metabolismo , Antígeno B7-H1/biosíntesis , Carcinoma de Pulmón de Células no Pequeñas/patología , Hemofiltración/métodos , Humanos , Neoplasias Pulmonares/patología , Estadificación de NeoplasiasAsunto(s)
Fibrosis Pulmonar Idiopática/diagnóstico , Fibrosis Pulmonar Idiopática/terapia , Neumología/métodos , Neumología/tendencias , Algoritmos , Biopsia , Diagnóstico Diferencial , Práctica Clínica Basada en la Evidencia/normas , Práctica Clínica Basada en la Evidencia/tendencias , Francia , Humanos , Pulmón/patología , Neumología/normas , Radiografía Torácica , Tomografía Computarizada por Rayos XAsunto(s)
Fibrosis Pulmonar Idiopática/diagnóstico , Fibrosis Pulmonar Idiopática/terapia , Neumología/métodos , Neumología/tendencias , Algoritmos , Biopsia , Lavado Broncoalveolar , Diagnóstico Diferencial , Práctica Clínica Basada en la Evidencia/normas , Práctica Clínica Basada en la Evidencia/tendencias , Francia , Humanos , Pulmón/patología , Neumología/normas , Radiografía Torácica , Tomografía Computarizada por Rayos XAsunto(s)
Fibrosis Pulmonar Idiopática/diagnóstico , Fibrosis Pulmonar Idiopática/terapia , Neumología/métodos , Neumología/tendencias , Algoritmos , Biopsia , Lavado Broncoalveolar , Diagnóstico Diferencial , Práctica Clínica Basada en la Evidencia/normas , Práctica Clínica Basada en la Evidencia/tendencias , Francia , Humanos , Pulmón/patología , Neumología/normas , Radiografía Torácica , Tomografía Computarizada por Rayos XRESUMEN
Immunotherapy aims to amplify the anticancer immune response through reactivation of the lymphocytic response raised against several tumor neo-antigens. To obtain an effective immune response, this therapeutic approach requires that a number of immunological checkpoints be passed, such as the activation of excitatory costimulatory signals or the avoidance of coinhibitory molecules. Among the immune checkpoints, the interaction of the membrane-bound ligand PD-1 and its receptor PD-L1 has received much attention because of remarkable efficacy in numerous clinical trials for various cancer types, including non-small cell lung cancer (NSCLC). However, several limitations exist with these therapeutic agents when used as monotherapy, with objective responses observed in only 30-40% of patients, with the majority of patients demonstrating innate resistance, and approximately 25% of responders later demonstrating disease progression. Recent developments in the understanding of cancer immunology have the potential to identify mechanisms of innate and acquired resistance to immune checkpoint inhibitors through translational research in human samples. This review focuses on the biological basic principles for immunological checkpoint blockade, and highlights the current status and the perspectives of this therapeutic approach in NSCLC patients.
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Anticuerpos Monoclonales/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Inmunoterapia , Neoplasias Pulmonares/tratamiento farmacológico , Antígeno B7-H1/inmunología , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Humanos , Neoplasias Pulmonares/inmunología , PronósticoRESUMEN
BACKGROUND: High expression of programmed death ligand-1 (PD-L1) on tumor cells (TC) and/or on tumor-infiltrating immune cells (IC) is associated with a high response rate in patients with advanced nonsmall-cell lung cancer (NSCLC) treated with PD-L1 inhibitors. The use of a PD-L1 immunohistochemical (IHC) test in determining the responsiveness to immunotherapy has raised the question of the reliability and reproducibility of its evaluation in lung biopsies compared with corresponding resected surgical specimens. PATIENTS AND METHODS: PD-L1 expression in TC and IC was assessed in 160 patients with operable NSCLC on both whole surgical tissue sections and matched lung biopsies, by using a highly sensitive SP142 IHC assay. The specimens were scored as TC 0-3 and IC 0-3 based on increasing PD-L1 expression. RESULTS: PD-L1 expression was frequently discordant between surgical resected and matched biopsy specimens (the overall discordance rate = 48%; 95% confidence interval 4.64-13.24) and κ value was equal to 0.218 (poor agreement). In all cases, the biopsy specimens underestimated the PD-L1 status observed on the whole tissue sample. PD-L1-positive IC tumors were more common than PD-L1-positive TC tumors on resected specimens. The discrepancies were mainly related to the lack of a PD-L1-positive IC component in matched biopsies. CONCLUSIONS: Our results indicate relatively poor association of the PD-L1 expression in TC and IC between lung biopsies and corresponding resected tumors. Although these results need to be further validated in larger cohorts, they indicate that the daily routine evaluation of the PD-L1 expression in diagnostic biopsies can be misleading in defining the sensitivity to treatment with PD-L1 targeted therapy.
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Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Neoplasias Pulmonares/metabolismo , Pulmón/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Femenino , Humanos , Pulmón/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/cirugía , Masculino , Persona de Mediana EdadRESUMEN
KRAS mutations are detected in over one third of lung adenocarcinomas, most frequently in Caucasian and smoker patients. The impact of KRAS mutations on lung adenocarcinoma prognosis is currently subject to debate, as is their impact on the response to chemotherapy and EGFR tyrosine kinase inhibitors. The different methods for KRAS status assessment, based on histological and cytological samples or biological fluids, offer varying sensitivities. Since no treatments are available in clinical routine for KRAS-mutated lung cancer patients, one of the current major challenges in thoracic oncology is developing new dedicated strategic therapies. Different molecules can be developed that act on a post-transcriptional KRAS protein level, blocking its cytoplasmic membrane recruitment. The efficacy of these molecules' targeting of the different signaling pathways activated by the KRAS mutation (such as the MEK and BRAF pathways) is related to the particular KRAS mutation subtype. New therapeutic strategies are currently focused on certain genes linked with KRAS inducing a synthetic lethal interaction. The purpose of this work is to provide an overview of i) the recent epidemiological and molecular findings concerning KRASmutated lung adenocarcinoma, ii) the prognostic impact of KRAS mutations, in particular during response to treatment, iii) the available methods for detecting this mutation, and iv) the current molecules under development for new therapeutic strategies and the clinical trials targeting this genomic alteration.
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Adenocarcinoma/genética , Neoplasias Pulmonares/genética , Mutación , Proteínas Proto-Oncogénicas p21(ras)/genética , Adenocarcinoma/diagnóstico , Adenocarcinoma/epidemiología , Adenocarcinoma/terapia , Adenocarcinoma del Pulmón , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunoterapia/métodos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/terapia , Técnicas de Diagnóstico Molecular , Terapia Molecular Dirigida , Pronóstico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Factores de RiesgoRESUMEN
Acute respiratory distress syndrome (ARDS) in humans is characterized by the infiltration of polymorphonuclears in the alveolar spaces. However, the role of T-cells in ARDS is unknown. Our aim was to characterize the T-cell phenotype in bronchoalveolar lavage (BAL) during the early phase of acute lung infection(ALI)/ARDS-infected patients in comparison to a control group (CG). BAL lymphocyte phenotypes of two ALI, 16 ARDS, and eight CG were examined by flow cytometry. ALI/ARDS showed a significant increase in CD4 and CD8 T-cell activation as compared to CG. Moreover, a significant level of proliferation was observed using the Ki67 marker in ARDS patients as compared to controls (median): 37 versus 6 % for CD4 T-cells (p = 0.022) and 34 versus 2 % for CD8 T-cells (p = 0.009). In contrast, the percentage of T-regulatory cells and apoptotic T-cells were similar in both groups. Among costimulatory molecules, we observed an overexpression of CTLA-4/CD152 on CD4 T-cells in ALI/ARDS as compared to CG: 30 versus 7 %, respectively (p = 0.063). In further characterizing T-cell subsets expressing high levels of CD152, we found the presence of IL-17 secreting CD4 T-cells in ALI/ARDS. In humans, ALI/ARDS due to infection is associated with a high level of T-cell activation and proliferation, along with the presence of Th17 cells, which are known to attract polymorphonuclears.
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Proliferación Celular , Activación de Linfocitos , Neumonía/patología , Alveolos Pulmonares/patología , Síndrome de Dificultad Respiratoria/patología , Subgrupos de Linfocitos T/patología , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD/análisis , Líquido del Lavado Bronquioalveolar/citología , Femenino , Citometría de Flujo , Humanos , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Adulto JovenRESUMEN
BACKGROUND: Patients with advanced lung adenocarcinomas expressing ALK rearrangements are highly responsive to crizotinib, a dual ALK/c-MET inhibitor. Immunohistochemistry (IHC) is an easy clinically and routinely applicable cost-effective assay for ALK, c-MET and ROS1 protein expression for potential treatment with crizotinib. The purpose of this study was to evaluate the percentage and the pattern of ALK-rearranged cells, the variation in the native ALK copy number, as well as ALK, c-MET and ROS1 protein expression, and their significance on outcome of crizotinib-treated lung adenocarcinoma patients. PATIENTS AND METHODS: Consecutive lung adenocarcinoma specimens (n = 176) 'double-negative' (wild-type EGFR and KRAS) were tested for ALK rearrangements/copy number alterations and for ALK, c-MET and ROS1 protein expression using automated standardized protocols. Preliminary data on the outcome of crizotinib-treated patients were recorded. RESULTS: FISH analysis identified 26/176 (15%) cases with ALK rearrangements. Seven cases had discordant results between the ALK FISH and IHC. Five cases with discordant FISH-positive/IHC-negative revealed FISH 'borderline' positivity (15%-20%). Three cases overexpressed c-MET and responded to crizotinib, and two cases with ALK-'borderline' rearranged cells only, not associated with c-MET expression, progressed under crizotinib. Two cases with discordant FISH-negative/IHC-positive revealed ALK gene amplification without associated c-MET or ROS1 protein expression. CONCLUSIONS: The discrepancies observed between the IHC and FISH data revealed unexpected biological events, rather than technical issues, which potentially can have a strong impact on the therapeutic strategy with crizotinib.
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Adenocarcinoma/genética , Técnica del Anticuerpo Fluorescente/métodos , Hibridación Fluorescente in Situ/métodos , Neoplasias Pulmonares/genética , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/análisis , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/mortalidad , Adenocarcinoma del Pulmón , Adulto , Anciano , Anciano de 80 o más Años , Quinasa de Linfoma Anaplásico , Crizotinib , Femenino , Dosificación de Gen/genética , Reordenamiento Génico , Variación Genética/genética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/análisis , Proteínas Proto-Oncogénicas/análisis , Proteínas Proto-Oncogénicas c-met/análisis , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Pirazoles/uso terapéutico , Piridinas/uso terapéutico , Proteínas Tirosina Quinasas Receptoras/genéticaRESUMEN
Interest in biomarkers in the field of thoracic oncology is focused on the search for new robust tests for diagnosis (in particular for screening), prognosis and theragnosis. These biomarkers can be detected in tissues and/or cells, but also in biological fluids, mainly the blood. In this context, there is growing interest in the detection of circulating tumor cells (CTCs) in the blood of lung cancer patients since CTC identification, enumeration and characterization may have a direct impact on diagnosis, prognosis and theragnosis in the daily clinical practice. Many direct and indirect methods have been developed to detect and characterize CTCs in lung cancer patients. However, these different approaches still hold limitations and many of them have demonstrated unequal sensitivity and specificity. Indeed, these methods hold advantages but also certain disadvantages. Therefore, despite the promises, it is currently difficult and premature to apply this methodology to the routine care of lung cancer patients. This situation is the consequence of the analysis of the methodological approaches for the detection and characterization of CTCs and of the results published to date. Finally, the advent of targeted cancer therapies in thoracic oncology has stimulated considerable interest in non-invasive detection of genomic alterations in tumors over time through the analysis of CTCs, an approach that may help clinicians to optimize therapeutic strategies for lung cancer patients. We describe here the main methods for CTC detection, the advantages and limitations of these different approaches and the potential usefulness and value of CTC characterization in the field of thoracic oncology.