RESUMEN
N-myristoyltransferases (NMTs) catalyze essential acylations of N-terminal alpha or epsilon amino groups of glycines or lysines. Here, we reveal that peptides tightly fitting the optimal glycine recognition pattern of human NMTs are potent prodrugs relying on a single-turnover mechanism. Sequence scanning of the inhibitory potency of the series closely reflects NMT glycine substrate specificity rules, with the lead inhibitor blocking myristoylation by NMTs of various species. We further redesigned the series based on the recently recognized lysine-myristoylation mechanism by taking advantage of (1) the optimal peptide chassis and (2) lysine side chain mimicry with unnatural enantiomers. Unlike the lead series, the inhibitory properties of the new compounds rely on the protonated state of the side chain amine, which stabilizes a salt bridge with the catalytic base at the active site. Our study provides the basis for designing first-in-class NMT inhibitors tailored for infectious diseases and alternative active site targeting.
RESUMEN
BACKGROUND: One of the major challenges in managing allergic bronchopulmonary aspergillosis remains consistent and reproducible assessment of response to treatment. RESEARCH QUESTION: What are the most relevant changes in CT scan parameters over time for assessing response to treatment? STUDY DESIGN AND METHODS: In this ancillary study of a randomized clinical trial (NebuLamB), patients with asthma with available CT scan and without exacerbation during a 4-month allergic bronchopulmonary aspergillosis exacerbation treatment period (corticosteroids and itraconazole) were included. Changed CT scan parameters were assessed by systematic analyses of CT scan findings at initiation and end of treatment. CT scans were assessed by two radiologists anonymized to the clinical data. Radiologic parameters were determined by selecting those showing significant changes over time. Improvement of at least one, without worsening of the others, defined the radiologic response. Agreement between radiologic changes and clinical and immunologic responses was likewise investigated. RESULTS: Among the 139 originally randomized patients, 132 were included. We identified five CT scan parameters showing significant changes at end of treatment: mucoid impaction extent, mucoid impaction density, centrilobular micronodules, consolidation/ground-glass opacities, and bronchial wall thickening (P < .05). These changes were only weakly associated with one another, except for mucoid impaction extent and density. No agreement was observed between clinical, immunologic, and radiologic responses, assessed as an overall response, or considering each of the parameters (Cohen κ, -0.01 to 0.24). INTERPRETATION: Changes in extent and density of mucoid impaction, centrilobular micronodules, consolidation/ground-glass opacities, and thickening of the bronchial walls were found to be the most relevant CT scan parameters to assess radiologic response to treatment. A clinical, immunologic, and radiologic multidimensional approach should be adopted to assess outcomes, probably with a composite definition of response to treatment. TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT02273661; URL: www. CLINICALTRIALS: gov).
Asunto(s)
Antifúngicos , Aspergilosis Broncopulmonar Alérgica , Asma , Itraconazol , Tomografía Computarizada por Rayos X , Humanos , Aspergilosis Broncopulmonar Alérgica/diagnóstico por imagen , Aspergilosis Broncopulmonar Alérgica/tratamiento farmacológico , Masculino , Femenino , Tomografía Computarizada por Rayos X/métodos , Asma/diagnóstico por imagen , Asma/tratamiento farmacológico , Adulto , Persona de Mediana Edad , Itraconazol/uso terapéutico , Antifúngicos/uso terapéutico , Resultado del Tratamiento , Corticoesteroides/uso terapéuticoRESUMEN
Introduction: Inflammatory lesions after Influenza A viruses (IAV) are potential therapeutic target for which better understanding of post-infection immune mechanisms is required. Most studies to evaluate innate immune reactions induced by IAV are based on quantitative/functional methods and anatomical exploration is most often non-existent. We aimed to study pulmonary damage and macrophage recruitment using two-photon excitation microscopy (TPEM) after IAV infection. Methods: We infected C57BL/6 CD11c+YFP mice with A/Puerto Ricco/8/34 H1N1. We performed immune cell analysis, including flow cytometry, cytokine concentration assays, and TPEM observations after staining with anti-F4/80 antibody coupled to BV421. We adapted live lung slice (LLS) method for ex-vivo intravital microscopy to analyze cell motility. Results: TPEM provided complementary data to flow cytometry and cytokine assays by allowing observation of bronchial epithelium lesions and spreading of local infection. Addition of F4/80-BV421 staining allowed us to precisely determine timing of recruitment and pulmonary migration of macrophages. Ex-vivo LLS preserved cellular viability, allowing us to observe acceleration of macrophage motility. Conclusion: After IAV infection, we were able to explore structural consequences and successive waves of innate immune cell recruitment. By combining microscopy, flow cytometry and chemokine measurements, we describe novel and precise scenario of innate immune response against IAV.
Asunto(s)
Alphainfluenzavirus , Subtipo H1N1 del Virus de la Influenza A , Virus de la Influenza A , Gripe Humana , Animales , Ratones , Humanos , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Inmunidad Innata , Microscopía Fluorescente , CitocinasRESUMEN
N-terminal myristoylation is an essential eukaryotic modification crucial for cellular homeostasis in the context of many physiological processes. Myristoylation is a lipid modification resulting in a C14 saturated fatty acid addition. This modification is challenging to capture due to its hydrophobicity, low abundance of target substrates, and the recent discovery of unexpected NMT reactivity including myristoylation of lysine side chains and N-acetylation in addition to classical N-terminal Gly-myristoylation. This chapter details the high-end approaches developed to characterize the different features of N-myristoylation and its targets through in vitro and in vivo labeling.
Asunto(s)
Aciltransferasas , Ácidos Grasos , Aciltransferasas/metabolismo , Ácido Mirístico/metabolismo , LisinaRESUMEN
N-myristoyltransferases (NMTs) are members of the large family of GCN5-related N-acetyltransferases (GNATs). NMTs mainly catalyze eukaryotic protein myristoylation, an essential modification tagging protein N-termini and allowing successive subcellular membrane targeting. NMTs use myristoyl-CoA (C14:0) as major acyl donor. NMTs were recently found to react with unexpected substrates including lysine side-chains and acetyl-CoA. This chapter details the kinetic approaches that have allowed the characterization of the unique catalytic features of NMTs in vitro.
Asunto(s)
Aciltransferasas , Secuencia de Aminoácidos , Aciltransferasas/químicaRESUMEN
OBJECTIVE: To identify characteristics of granulomatosis with polyangiitis (GPA) associated with induction failure, describe salvage therapies and their efficacy. METHODS: We conducted a nationwide retrospective case-control study of GPA with induction failure between 2006 and 2021. Each patient with induction failure was randomly paired to three controls matched for age, sex and induction treatment. RESULTS: We included 51 patients with GPA and induction failure (29 men and 22 women). At induction therapy, median age was 49 years. Twenty-seven patients received intravenous cyclophosphamide (ivCYC) and 24 rituximab (RTX) as induction therapy. Patients with ivCYC induction failure more frequently had PR3-ANCA (93% vs 70%, P = 0.02), relapsing disease (41% vs 7%, P < 0.001) and orbital mass (15% vs 0%, P < 0.01) compared with controls. Patients with disease progression despite RTX induction therapy more frequently had renal involvement (67% vs 25%, P = 0.02) with renal failure (serum creatinine >100 µmol/l in 42% vs 8%, P = 0.02) compared with controls. After salvage therapy, remission was achieved at 6 months in 35 (69%) patients. The most frequent salvage therapy was switching from ivCYC to RTX (or vice versa), showing an efficacy in 21/29 (72%). Remission was achieved in nine (50%) patients with inappropriate response to ivCYC, while in patients with progression after RTX induction, remission was achieved in four (100%) who received ivCYC (with or without immunomodulatory therapy), but only in three (50%) after adding immunomodulatory therapy alone. CONCLUSION: In patients with induction failure, characteristics of GPA, salvage therapies and their efficacy vary according to induction therapy and failure modality.
Asunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Granulomatosis con Poliangitis , Masculino , Humanos , Femenino , Persona de Mediana Edad , Granulomatosis con Poliangitis/complicaciones , Granulomatosis con Poliangitis/tratamiento farmacológico , Estudios Retrospectivos , Estudios de Casos y Controles , Resultado del Tratamiento , Rituximab/uso terapéutico , Ciclofosfamida/uso terapéutico , Factores de Riesgo , Inducción de RemisiónRESUMEN
N-myristoyltransferases (NMTs) catalyze protein myristoylation, a lipid modification crucial for cell survival and a range of pathophysiological processes. Originally thought to modify only N-terminal glycine α-amino groups (G-myristoylation), NMTs were recently shown to also modify lysine ε-amino groups (K-myristoylation). However, the clues ruling NMT-dependent K-myristoylation and the full range of targets are currently unknown. Here we combine mass spectrometry, kinetic studies, in silico analysis, and crystallography to identify the specific features driving each modification. We show that direct interactions between the substrate's reactive amino group and the NMT catalytic base promote K-myristoylation but with poor efficiency compared to G-myristoylation, which instead uses a water-mediated interaction. We provide evidence of depletion of proteins with NMT-dependent K-myristoylation motifs in humans, suggesting evolutionary pressure to prevent this modification in favor of G-myristoylation. In turn, we reveal that K-myristoylation may only result from post-translational events. Our studies finally unravel the respective paths towards K-myristoylation or G-myristoylation, which rely on a very subtle tradeoff embracing the chemical landscape around the reactive group.
Asunto(s)
Aciltransferasas , Glicina , Lisina , Ácido Mirístico , Procesamiento Proteico-Postraduccional , Humanos , Aciltransferasas/química , Catálisis , Glicina/química , Cinética , Lisina/química , Ácido Mirístico/químicaRESUMEN
Protein N-acetyltransferases (NATs) belong to the general control non-repressible 5 (Gcn5)-related N-acetyltransferases (GNATs) superfamily. GNATs catalyze the transfer of acetyl from acetyl-CoA to the reactive amine moiety of a wide range of acceptors. NAT sequences are difficult to distinguish from other members of the GNAT superfamily and there are many uncharacterized GNATs. To facilitate the discovery and characterization of new GNATs, we have developed a new continuous, non-radioactive assay. This assay is virtually independent of the substrate and can be used to get substrate specificity hints. We validated first the assay with the well-characterized Schizosaccharomyces pombe NatA (SpNatA). The SpNatA kinetic parameters were determined with various peptides confirming the robustness of the new assay. We reveal that the longer the peptide substrate the more efficient the enzyme. As a proof of concept of the relevance of the new assay, we characterized a NAA90 member from rice (Oryza sativa), OsGNAT2. We took advantage of an in vivo medium-scale characterization of OsGNAT2 specificity to identify and then validate in vitro several specific peptide substrates. With this assay, we reveal long-range synergic effects of basic residues on OsGNAT2 activity. Overall, this new, high-throughput assay allows better understanding of the substrate specificity and activity of any GNAT.
RESUMEN
OBJECTIVES: The diagnosis of interstitial lung disease is based on clinical and biological analysis associated with computed tomography (CT) pattern after discussion in multidisciplinary discussion. Lung transbronchial cryobiopsy has emerged with acceptable diagnostic reliability and low morbidity and mortality. The goal of our work is to describe our experience with lung cryobiopsy. METHODS: This is monocentric and retrospective analysis of prospectively collected data on epidemiological, clinical, biological, CT, respiratory and histological features of patients with lung transbronchial cryobiopsy between January 1st, 2017, and July 1st, 2020. RESULTS: Lung transbronchial cryobiopsy has been done for 23 patients with sex ratio M/F of 1.1, majority of smoker/former smoker. Thirty-nine percent of procedures were complicated by pneumothorax. On the haemorrhagic level, we reported 1 grade 2 bleeding (no serious bleeding). An histological diagnosis was obtained for 19 patients (82%). Only 4 patients needed to discuss surgical lung biopsy: 2 (8.6%) surgical lung biopsy, 1 refused surgical lung biopsy and 1 patient lost to follow-up. CONCLUSION: Our results suggest that transbronchial lung cryobiopsy may be considered the first diagnostic modality instead of surgical lung biopsy for interstitial lung disease in appropriate patients. Larger studies are, however, needed to confirm our observations.
RESUMEN
BACKGROUND: The use of cyclophosphamide in patients with acute exacerbation of idiopathic pulmonary fibrosis (IPF) is unknown. Our study was designed to evaluate the efficacy and safety of four cyclophosphamide pulses in addition to high-dose methylprednisolone in this population. METHODS: In this double-blind, placebo-controlled trial done in 35 departments across 31 hospitals in France, adult patients (≥18 years) with acute exacerbation of IPF and those with suspected acute exacerbation of IPF were randomly assigned in a 1:1 ratio using a web-based system to receive either intravenous pulses of cyclophosphamide (600 mg/m2) plus uromitexan as haemorrhagic cystitis prophylaxis (200 mg/m2) at the time of cyclophosphamide administration and then again, 4 h later, or placebo at days 0, 15, 30, and 60. Random assignment was stratified according to the severity of IPF and was block-balanced with variable block sizes of four or six patients. Patients receiving mechanical ventilation, with active infection, with active cancer, or who were registered on the lung transplant waiting list were excluded. All patients received standardised high-dose glucocorticoids. The investigators, patients, and the sponsor were masked to the treatment assignments. The primary endpoint was 3-month all-cause mortality, analysed by a χ2 test adhering to an intention-to-treat principle. The trial is now complete and registered with ClinicalTrials.gov, NCT02460588. FINDINGS: Between Jan 22, 2016, and July 19, 2018, 183 patients were assessed for eligibility, of whom 120 patients were randomly assigned and 119 patients (62 [52%] with severe IPF) received at least one dose of cyclophosphamide (n=60) or placebo (n=59), all of whom were included in the intention-to-treat analysis. The 3-month all-cause mortality was 45% (27/60) in patients given cyclophosphamide compared with 31% (18/59) in the placebo group (difference 14·5% [95% CI -3·1 to 31·6]; p=0·10). Similar results were found after adjustment by IPF severity (odds ratio [OR] 1·89 [95% CI 0·89-4·04]). The risk of death at 3 months, independent of the treatment received, was higher with severe than non-severe IPF (OR 2·62 [1·12-6·12]) and was lower with the use of antifibrotic therapy (OR 0·33 [0·13-0·82]). Adverse events were similar between groups by 6 months (25 [42%] in the cyclophosphamide group vs 30 [51%] in the placebo group) and their proportion, including infections, did not differ. Overall infection was the main adverse event and occurred in 20 (33%) of 60 patients in the cyclophosphamide group versus 21 (36%) of 59 patients in the placebo group. INTERPRETATION: In patients with acute exacerbation of IPF, adding intravenous cyclophosphamide pulses to glucocorticoids increased 3-month mortality. These findings provide evidence against the use of intravenous cyclophosphamide in such patients. FUNDING: Programme Hospitalier de Recherche Clinique of the French Ministry of Health (PHRC 2014-502), Roche Pharmaceuticals.
Asunto(s)
Glucocorticoides , Fibrosis Pulmonar Idiopática , Adulto , Ciclofosfamida/efectos adversos , Método Doble Ciego , Glucocorticoides/efectos adversos , Humanos , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Resultado del TratamientoRESUMEN
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 6â months. The primary outcome was occurrence of a first severe clinical exacerbation within 24â 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.
Asunto(s)
Aspergilosis Broncopulmonar Alérgica , Anfotericina B/efectos adversos , Antifúngicos/uso terapéutico , Aspergilosis Broncopulmonar Alérgica/tratamiento farmacológico , Aspergillus , Humanos , Método Simple CiegoRESUMEN
Haematopoietic stem cell transplantation (HSCT) recipients are at risk for severe respiratory syncytial virus (RSV) infection. Two prognostic scores have been proposed to predict the risk of progression from upper respiratory tract infection (URTI) to lower respiratory tract infection (LRTI) and death. This was a multicentre study of allogeneic HSCT recipients diagnosed with an RSV infection between 2010 and 2019 who were retrospectively stratified by the immunodeficiency scoring index (ISI) and the severe immunodeficiency (SID) score. Endpoints were overall survival, RSV-attributable mortality and progression to LRTI after URTI. Prognostic analyses were performed using Cox regression models. We included 147 consecutive patients, including 94 (63.9%) initially diagnosed with URTI and 53 (36.1%) with LRTI. At 90 days, 14 patients had died (survival rate, 90.5%; 95% CI: 85.9-95.3), and nine deaths were attributable to RSV (attributable mortality rate, 5.4%; 95% CI: 2.5-10.0). The cumulative 90-day incidence of LRTI after URTI was 13.8% (95% CI: 7.8-21.6). Neither score showed prognostic value for mortality, while the ISI allowed the prediction of progression to LRTI (p = 0.0008). Our results do not fully replicate the results previously reported in cohorts of HSCT recipients. This may reflect the recent epidemiology of RSV infections in this HSCT cohort.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Infecciones por Virus Sincitial Respiratorio , Infecciones del Sistema Respiratorio , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Pronóstico , Infecciones por Virus Sincitial Respiratorio/diagnóstico , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Results of previous studies demonstrated that high-intensity end-of-life (EOL) care improves neither cancer patients' survival nor quality of life. Our objective was to assess the incidence of and factors associated with aggressiveness of care during the last 30 days of life (DOL) of lung cancer (LC) patients and the impacts of aggressiveness of care in EOL-care costs. PATIENTS AND METHODS: Using French national hospital database, all patients with LC who died between January 1, 2010, and December 31, 2011, or between January 1, 2015, and January 31, 2016, were included. EOL-care aggressiveness was assessed using the following criteria: chemotherapy administered within the last 14 DOL; more than one hospitalization within the last 30 DOL; admission to the intensive care unit within the last 30 DOL; and palliative care initiated < 3 days before death. Expenditures were limited to direct costs, from a health care payer's perspective. RESULTS: Among 79,746 adult LC patients identified; 57% had at least one indicator of EOL-care aggressiveness (49% repeated hospitalizations, 12% intensive care unit admissions, 9% chemotherapy, 5% palliative care). It increased significantly between the 2 periods (56% vs. 58%, P < .001). Young age, male sex, shorter time since diagnosis, comorbidities, no malnutrition, type of care facility other than general hospital, social deprivation, and low-density population were independently associated with having one or more indicator of aggressive EOL care. The mean EOL cost was 8152 ± 5117 per patient, but the cost was significantly higher for patients with at least one EOL-care aggressiveness criterion (9480 vs. 6376, P < .001). CONCLUSION: In France, a majority of LC patients had at least one criterion of aggressive EOL care that had a major economic impact on the health care system.
Asunto(s)
Costos de la Atención en Salud/estadística & datos numéricos , Neoplasias Pulmonares/terapia , Cuidados Paliativos/estadística & datos numéricos , Cuidado Terminal/métodos , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Bases de Datos Factuales , Femenino , Francia , Hospitalización/economía , Hospitalización/estadística & datos numéricos , Humanos , Unidades de Cuidados Intensivos/economía , Unidades de Cuidados Intensivos/estadística & datos numéricos , Neoplasias Pulmonares/economía , Masculino , Persona de Mediana Edad , Cuidados Paliativos/economía , Estudios Retrospectivos , Factores Sexuales , Cuidado Terminal/economía , Adulto JovenAsunto(s)
Infecciones por Coronavirus/complicaciones , Neumonía Viral/complicaciones , Tuberculosis Pulmonar/complicaciones , Adulto , Anciano , Antituberculosos/uso terapéutico , Antivirales/uso terapéutico , Azitromicina/uso terapéutico , Betacoronavirus , COVID-19 , Prueba de COVID-19 , Técnicas de Laboratorio Clínico , Estudios de Cohortes , Coinfección , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/tratamiento farmacológico , Combinación de Medicamentos , Emigrantes e Inmigrantes , Femenino , Humanos , Hidroxicloroquina/uso terapéutico , Lopinavir/uso terapéutico , Pulmón/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Mortalidad , Pandemias , Neumonía Viral/diagnóstico , Neumonía Viral/tratamiento farmacológico , Ritonavir/uso terapéutico , SARS-CoV-2 , Tomografía Computarizada por Rayos X , Tuberculosis/complicaciones , Tuberculosis/diagnóstico , Tuberculosis/tratamiento farmacológico , Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/tratamiento farmacológico , Tratamiento Farmacológico de COVID-19RESUMEN
The promising drug target N-myristoyltransferase (NMT) catalyses an essential protein modification thought to occur exclusively at N-terminal glycines (Gly). Here, we present high-resolution human NMT1 structures co-crystallised with reactive cognate lipid and peptide substrates, revealing high-resolution snapshots of the entire catalytic mechanism from the initial to final reaction states. Structural comparisons, together with biochemical analysis, provide unforeseen details about how NMT1 reaches a catalytically competent conformation in which the reactive groups are brought into close proximity to enable catalysis. We demonstrate that this mechanism further supports efficient and unprecedented myristoylation of an N-terminal lysine side chain, providing evidence that NMT acts both as N-terminal-lysine and glycine myristoyltransferase.
Asunto(s)
Aciltransferasas/química , Aciltransferasas/metabolismo , Glicina/metabolismo , Lisina/metabolismo , Aciltransferasas/genética , Catálisis , Dominio Catalítico , Coenzima A/química , Coenzima A/genética , Coenzima A/metabolismo , Cristalografía por Rayos X , Humanos , Cinética , Mutación , Ácido Mirístico/metabolismo , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
OBJECTIVES: Despite recent advances in thoracic oncology, most patients with metastatic lung cancer die within months of diagnosis. Aggressiveness of their end-of-life (EOL) care has been the subject of numerous studies. This study was undertaken to evaluate the literature on aggressive inpatient EOL care for lung cancer and analyse the evolution of its aggressiveness over time. METHODS: A systematic international literature search restricted to English-language publications used terms associated with aggressiveness of care, EOL and their synonyms. Two independent researchers screened for eligibility and extracted all data and another a random 10% sample of the abstracts. Electronic Medline and Embase databases were searched (2000-20 September 2018). EOL-care aggressiveness was defined as follows: 1) chemotherapy administered during the last 14 days of life (DOL) or new chemotherapy regimen during the last 30 DOL; 2) >2 emergency department visits; 3) >1 hospitalisation during the last 30 DOL; 4) ICU admission during the last 30 DOL and 5) palliative care started <3 days before death. RESULTS: Among the 150 articles identified, 42 were retained for review: 1 clinical trial, 3 observational cohorts, 21 retrospective analyses and 17 administrative data-based studies. The percentage of patients subjected to aggressive therapy seems to have increased over time. Early management by palliative care teams seems to limit aggressive care. CONCLUSIONS: Our analysis indicated very frequent aggressive EOL care for patients with lung cancer, regardless of the definition used. The extent of that aggressiveness and its impact on healthcare costs warrant further studies.
Asunto(s)
Neoplasias Pulmonares/terapia , Cuidado Terminal , Humanos , Pacientes Internos , Cuidados PaliativosRESUMEN
PURPOSE: The IFCT-GFPC-0701 MAPS phase III trial highlighted significant improvement in overall survival from adding bevacizumab to the standard first-line chemotherapy regimen [cisplatin plus pemetrexed (PC)] in advanced malignant pleural mesothelioma (MPM). We present the results of health-related quality of life (HRQoL), a secondary endpoint of MAPS. PATIENTS AND METHODS: HRQoL was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire QLQ-C30 and the lung cancer-specific module QLQ-LC13 at randomization and then every 9 weeks until disease progression.HRQoL deterioration-free survival (QFS), used to analyze longitudinal HRQoL data, was defined as the interval between randomization and the occurrence of the first clinically relevant definitive deterioration compared with the HRQoL score at baseline, or death. RESULTS: A total of 448 patients were included in the MAPS trial between 2008 and 2014. At baseline, 425 patients (94.8%) completed the HRQoL questionnaire. We report that adding bevacizumab to cisplatin and pemetrexed (PCB) significantly improved QFS for the peripheral neuropathy dimension, with a median QFS of 12.09 months [95% confidence interval (CI), 9.59-13.67] in the PCB arm versus 7.59 months (95% CI, 6.57-8.61) in the PC arm [HR (PCB vs. PC) = 0.74; 95% CI, 0.61-0.91; P = 0.004]. QFS was also longer in the PCB arm for the pain dimension (HR = 0.84; 95% CI, 0.69-1.02; P = 0.08). CONCLUSIONS: This study demonstrated that adding bevacizumab to standard chemotherapy in patients with advanced MPM had no negative impact on HRQoL. A significant improvement in the peripheral neuropathy and pain HRQoL dimensions was even observed.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/psicología , Mesotelioma/tratamiento farmacológico , Mesotelioma/psicología , Anciano , Bevacizumab/administración & dosificación , Cisplatino/administración & dosificación , Femenino , Humanos , Estudios Longitudinales , Masculino , Mesotelioma Maligno , Dimensión del Dolor/efectos de los fármacos , Pemetrexed/administración & dosificación , Enfermedades del Sistema Nervioso Periférico/prevención & control , Calidad de Vida , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
BACKGROUND: Mycobacterium canettii forms part of the Mycobacterium tuberculosis complex. Mycobacterium canettii infections are mainly described in the Horn of Africa. The permanent presence of French soldiers in Djibouti raises the question of the risk of being infected with M. canettii. Here, we describe M. canettii infections among French military and their families between 1998 and 2015. METHODS: This retrospective study relied on 3 sources of data: the reference center for mycobacteria in the Biology Department at Percy Military Hospital in Paris, the French Military Center for Epidemiology and Public Health, and the scientific literature. After an exhaustive census of the strains, we studied the epidemiological data on 20 cases among French soldiers and their families. RESULTS: Twenty cases of M. canettii infections are reported, including 5 unpublished cases. Adenitis predominates (n = 15), especially in the cervico facial area and among children; 1 case was observed 1 month after dental care in Djibouti. The pulmonary forms were less frequent (n = 6), and 3 atypical forms are described. All patients had stayed in Djibouti. CONCLUSIONS: Cases of M. canettii infection among the French military consisted mainly of adenitis; disseminated forms were possible with immunodeficiency. Their evolution under specific treatments was comparable to that of tuberculosis. The presumed origin of the infection seemed to be environmental, possibly a water reservoir, and not due to human-to-human contagion.
Asunto(s)
Infecciones por Mycobacterium/diagnóstico , Infecciones por Mycobacterium/microbiología , Mycobacterium/patogenicidad , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Personal Militar/estadística & datos numéricos , Estudios Retrospectivos , Tuberculosis/microbiología , Adulto JovenRESUMEN
Epidemiological data on late-onset noninfectious pulmonary complications (LONIPCs) following allogeneic haematopoietic stem cell transplantation (HSCT) are derived exclusively from retrospective studies and are conflicting. We aimed to evaluate prospectively the incidence, risk factors and outcomes for LONIPCs.All consecutive patients scheduled to receive allogeneic HSCT between 2006 and 2008 at a university teaching hospital in France were screened for inclusion in the study. Eligible patients were those surviving at day 100. Among 243 screened patients, 198 patients were included in the analysis. The median (interquartile range) follow-up was 72.3 (15.2-88.5)â months. 55 LONIPCs were diagnosed in 43 patients. Bronchiolitis obliterans syndrome (n=22) and interstitial lung disease (n=12) were the most common LONIPCs. At 36â months after inclusion, the estimated cumulative incidence of LONIPCs was 19.8% (95% CI 14.2-25.3%). The estimated median survival after the diagnosis of LONIPCs was 78.5â months (95% CI 20.0-not reached). Based on a multivariate Cox model, a history of chest irradiation anytime prior to HSCT, a history of pneumonia within 100 days post-HSCT and a low mean forced expiratory flow at 25-75% of forced vital capacity at day 100 were associated with the development of LONIPCs.Our data provide clues to identify patients at high risk of developing LONIPCs. These patients should be targeted for close monitoring to provide earlier LONIPC treatment or prophylactic treatment.