Deregulated immune cell recruitment orchestrated by c-MET impairs pulmonary inflammation and fibrosis.

BACKGROUND: Pulmonary fibrosis (PF) represents the pathologic end stage of several interstitial lung diseases (ILDs) associated with high morbidity and mortality rates. However, current treatments can only delay disease progression rather than provide a cure. The role of inflammation in PF progression is well-established, but new insights into immune regulation are fundamental for developing more efficient therapies. c-MET signaling has been implicated in the migratory capacity and effector functions of immune cells. Nevertheless, the role of this signaling pathway in the context of PF-associated lung diseases remains unexplored. METHODS: To determine the influence of c-MET in immune cells in the progression of pulmonary fibrosis, we used a conditional deletion of c-Met in immune cells. To induce pulmonary fibrosis mice were administered with bleomycin (BLM) intratracheally. Over the course of 21 days, mice were assessed for weight change, and after euthanasia at different timepoints, bronchoalveolar lavage fluid cells and lung tissue were assessed for inflammation and fibrosis. Furthermore, c-MET expression was assessed in cryobiopsy sections, bronchoalveolar lavage fluid cells samples and single cell RNA-sequencing dataset from human patients with distinct interstitial lung diseases. RESULTS: c-MET expression was induced in lung immune cells, specifically in T cells, interstitial macrophages, and neutrophils, during the inflammatory phase of BLM-induced PF mouse model. Deletion of c-Met in immune cells correlated with earlier weight recovery and improved survival of BLM-treated mice. Moreover, the deletion of c-Met in immune cells was associated with early recruitment of the immune cell populations, normally found to express c-MET, leading to a subsequent attenuation of the cytotoxic and proinflammatory environment. Consequently, the less extensive inflammatory response, possibly coupled with tissue repair, culminated in less exacerbated fibrotic lesions. Furthermore, c-MET expression was up-regulated in lung T cells from patients with fibrosing ILD, suggesting a potential involvement of c-MET in the development of fibrosing disease. CONCLUSIONS: These results highlight the critical contribution of c-MET signaling in immune cells to their enhanced uncontrolled recruitment and activation toward a proinflammatory and profibrotic phenotype, leading to the exacerbation of lung injury and consequent development of fibrosis.

The impact of nintedanib and pirfenidone on lung function and survival in patients with idiopathic pulmonary fibrosis in real-life setting.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, fibrosing interstitial pneumonia of unknown cause that is associated with radiological and/or histological features of usual interstitial pneumonia (UIP). A mean survival of 2-5 years was reported previously to the advent of antifibrotics. According to clinical trials, nintedanib and pirfenidone induce a significant delay in functional decline, with a favorable impact on survival. METHODS: A real-life retrospective and longitudinal study was conducted to assess the efficacy and tolerability of antifibrotics in IPF patients, between January 2014 and December 2020. Two groups (under nintedanib or pirfenidone) were analyzed at diagnosis through their clinical features and radiological patterns. Lung function was assessed at diagnosis (time 0) and after 6, 12 and 24 months of treatment. We also compared this antifibrotic cohort with an older naïve antifibrotic cohort, mainly treated with immunosuppressive drugs and/or N- acetylcysteine. Survival was analyzed and prognostic features were also studied. Statistical analysis was performed with IBM® SPSS®. RESULTS: A cohort of 108 patients under antifibrotics (nintedanib n = 54; pirfenidone n = 54) was assessed. Lung function analysis showed an overall stabilization in FVC and DLCO mean predicted percentages at 6, 12 and 24 months of treatment. The mean decline in FVC and DLCO, at 12 months, was -40.95 ± 438.26 mL and -0.626 ± 1.31 mL/min/mmHg, respectively. However, during this period, 34.2% of the patients died mostly due to acute exacerbation associated with a poorer lung function at diagnosis. Mean survival in the naïve antifibrotic cohort was significantly lower than in the antifibrotic cohort (39.9 months versus 58.2 months; p < 0.005). Regarding lung function evolution and survival, we found no differences between definitive or probable UIP radiological patterns, both on patients under nintedanib and pirfenidone (p = 0.656). CONCLUSIONS: In this real-life observational study, the positive impact of antifibrotic therapy on the IPF clinical course and on survival was corroborated. Regarding efficacy, there was no difference between patients taking nintedanib or pirfenidone. The need for an early treatment was also demonstrated, since a worse outcome is clearly associated with lower lung volumes and lower diffusing capacity at diagnosis.

Efficacy and Safety of Indwelling Catheter for Malignant Pleural Effusions Related to Timing of Cancer Therapy: A Systematic Review

Introduction: To compare the efficacy and safety of indwelling pleural catheters (IPC) in relation with the timing of systemic cancer therapy (SCT) (i.e., before, during, or after SCT) in patients with malignant pleural effusion (MPE). Methods: Systematic review of randomized controlled trials (RCT), quasi-controlled trials, prospective and retrospective cohorts, and case series of over 20 patients, in which the timing of IPC insertion in relation to that of SCT was provided. Medline (via PubMed), Embase, and Cochrane Library were systematically searched from inception to January 2023. The risk of bias was assessed using the Cochrane Risk of Bias (ROB) tool for RCTs and the ROB in non-randomized studies of interventions (ROBINS-I) for non-randomized designs. Results: Ten studies (n=2907 patients; 3066 IPCs) were included. Using SCT while the IPC was in situ decreased overall mortality, increased survival time, and improved quality-adjusted survival. Timing of SCT had no effect on the risk of IPC-related infections (2.85% overall), even in immunocompromised patients with moderate or severe neutropenia (relative risk 0.98 [95%CI: 0.93–1.03] for patients treated with the combination of IPC and SCT). The inconsistency of the results or the lack of analysis of all outcome measures in relation to the SCT/IPC timing precluded drawing solid conclusions about time to IPC removal or need of re-interventions. Conclusions: Based on observational evidence, the efficacy and safety of IPC for MPE does not seem to vary depending on the IPC insertion timing (before, during, or after SCT). The data most likely support early IPC insertion. (AU)

Efficacy and Safety of Indwelling Catheter for Malignant Pleural Effusions Related to Timing of Cancer Therapy: A Systematic Review.

INTRODUCTION: To compare the efficacy and safety of indwelling pleural catheters (IPC) in relation with the timing of systemic cancer therapy (SCT) (i.e., before, during, or after SCT) in patients with malignant pleural effusion (MPE). METHODS: Systematic review of randomized controlled trials (RCT), quasi-controlled trials, prospective and retrospective cohorts, and case series of over 20 patients, in which the timing of IPC insertion in relation to that of SCT was provided. Medline (via PubMed), Embase, and Cochrane Library were systematically searched from inception to January 2023. The risk of bias was assessed using the Cochrane Risk of Bias (ROB) tool for RCTs and the ROB in non-randomized studies of interventions (ROBINS-I) for non-randomized designs. RESULTS: Ten studies (n=2907 patients; 3066 IPCs) were included. Using SCT while the IPC was in situ decreased overall mortality, increased survival time, and improved quality-adjusted survival. Timing of SCT had no effect on the risk of IPC-related infections (2.85% overall), even in immunocompromised patients with moderate or severe neutropenia (relative risk 0.98 [95%CI: 0.93-1.03] for patients treated with the combination of IPC and SCT). The inconsistency of the results or the lack of analysis of all outcome measures in relation to the SCT/IPC timing precluded drawing solid conclusions about time to IPC removal or need of re-interventions. CONCLUSIONS: Based on observational evidence, the efficacy and safety of IPC for MPE does not seem to vary depending on the IPC insertion timing (before, during, or after SCT). The data most likely support early IPC insertion.

Mortality risk prediction with ILD-GAP index in a fibrotic hypersensitivity pneumonitis cohort.

BACKGROUND: Fibrotic hypersensitivity pneumonitis (fHP) is associated with significant morbidity and mortality. Interstitial lung disease-gender-age-physiology (ILD-GAP) performance in fHP outside the initial cohort was never performed. AIM: To assess the ILD-GAP index's ability to predict mortality in a Portuguese cohort of patients with fHP and analyse whether other clinical variables add value. METHODS: Retrospective analysis of fHP cohort in two Portuguese ILD centres. The baseline ILD-GAP index was calculated. Survival was analysed in months; mortality was the primary outcome. Univariate and multivariate analyses to identify mortality risk factors were performed. RESULTS: A total of 141 patients were included. Fifty-three patients (37.6%) died during the follow-up. The usual interstitial pneumonia (UIP) pattern was found in 49.6%, and their survival was inferior to non-UIP [32 months (interquartile range, IQR = 19, 60) versus 52 months (IQR = 28, 98), p = 0.048]. Patients with an ILD-GAP index higher than three double their risk of mortality [hazard ratio (HR) = 6.48, 95% confidence interval (CI) = (3.03-13.96)] when compared with the patients with an index between 2 and 3 [HR = 3.04, 95% CI = (1.62-5.71)] adjusting for acute exacerbation history. Even though UIP patients had worse survival, it did not reach statistical significance when UIP pattern was added to this model. Acute exacerbation history was an independent risk factor for mortality; however, ILD-GAP still predicted mortality after adjusting for this factor. PaO2 and 6-minute walk test desaturation were not significant risk factors. CONCLUSION: ILD-GAP index is a good predictor for mortality in fHP, even after adjusting for other mortality risk factors.

Diagnostic yield and safety of transbronchial lung cryobiopsy and surgical lung biopsy in interstitial lung diseases: a systematic review and meta-analysis.

INTRODUCTION: Transbronchial lung cryobiopsy (TBLC) is increasingly being used as an alternative to video-assisted thoracoscopic surgery (VATS) biopsy to establish the histopathologic pattern in interstitial lung disease (ILD). METHODS: A systematic literature search of the PubMed and Embase databases, from October 2010 to October 2020, was conducted to identify studies that reported on diagnostic yield or safety of VATS or TBLC in the diagnosis of ILD. RESULTS: 43 studies were included. 23 evaluated the diagnostic yield of TBLC after multidisciplinary discussion, with a pooled diagnostic yield of 76.8% (95% confidence interval (CI) 70.6-82.1), rising to 80.7% in centres that performed ≥70 TBLC. 10 studies assessed the use of VATS and the pooled diagnostic yield was 93.5% (95% CI 88.3-96.5). In TBLC, pooled incidences of complications were 9.9% (95% CI 6.8-14.3) for significant bleeding (6.9% for centres with ≥70 TBLC), 5.6% (95% CI 3.8-8.2) for pneumothorax treated with a chest tube and 1.4% (95% CI 0.9-2.2) for acute exacerbation of ILD after TBLC. The mortality rates were 0.6% and 1.7% for TBLC and VATS, respectively. CONCLUSIONS: TBLC has a fairly good diagnostic yield, an acceptable safety profile and a lower mortality rate than VATS. The best results are obtained from more experienced centres.

Predictive value of common genetic variants in idiopathic pulmonary fibrosis survival.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial pneumonia of unknown etiology. The role of genetic risk factors has been the focus of numerous studies probing for associations of genetic variants with IPF. We aimed to determine whether single-nucleotide polymorphisms (SNPs) of four candidate genes are associated with IPF susceptibility and survival in a Portuguese population. A retrospective case-control study was performed with 64 IPF patients and 74 healthy controls. Ten single-nucleotide variants residing in the MUC5B, TOLLIP, SERPINB1, and PLAU genes were analyzed. Single- and multi-locus analyses were performed to investigate the predictive potential of specific variants in IPF susceptibility and survival. Multifactor dimensionality reduction (MDR) was employed to uncover predictive multi-locus interactions underlying IPF susceptibility. The MUC5B rs35705950 SNP was significantly associated with IPF: T allele carriers were significantly more frequent among IPF patients (75.0% vs 20.3%, P < 1.0 × 10-6). Genotypic and allelic distributions of TOLLIP, PLAU, and SERPINB1 SNPs did not differ significantly between groups. However, the MUC5B-TOLLIP T-C-T-C haplotype, defined by the rs35705950-rs111521887-rs5743894-rs5743854 block, emerged as an independent protective factor in IPF survival (HR = 0.37, 95% CI 0.17-0.78, P = 0.009, after adjustment for FVC). No significant multi-locus interactions correlating with disease susceptibility were detected. MUC5B rs35705950 was linked to an increased risk for IPF, as reported for other populations, but not to disease survival. A haplotype incorporating SNPs of the MUC5B-TOLLIP locus at 11p15.5 seems to predict better survival and could prove useful for prognostic purposes and IPF patient stratification. KEY MESSAGES : The MUC5B rs35705950 minor allele is associated with IPF risk in the Portuguese. No predictive multi-locus interactions of IPF susceptibility were identified by MDR. A haplotype defined by MUC5B and TOLLIP SNPs is a protective factor in IPF survival. The haplotype may be used as a prognostic tool for IPF patient stratification.

Pentraxin 3 Inhibits Complement-driven Macrophage Activation to Restrain Granuloma Formation in Sarcoidosis.

Rationale: Sarcoidosis is a multisystemic inflammatory disease characterized by the formation of granulomas in response to persistent stimuli. The long pentraxin PTX3 (pentraxin 3) has emerged as a component of humoral innate immunity with essential functions in the resolution of inflammation, but its role during granuloma formation is unknown. Objectives: To evaluate PTX3 as a modulator of pathogenic signals involved in granuloma formation and inflammation in sarcoidosis. Methods: Peripheral blood mononuclear cells obtained from patients with sarcoidosis harboring loss-of-function genetic variants and gene-deleted mice were used to assess the role of PTX3 in experimental models of granuloma formation in vitro and in vivo. The identified mechanisms of granulomatous inflammation were further evaluated in tissue and BAL samples and correlated with the disease course. Measurements and Main Results: We have identified a molecular link between PTX3 deficiency and the pathogenic amplification of complement activation to promote granuloma formation. Mechanistically, PTX3 deficiency licensed the complement component C5a-mediated activation of the metabolic checkpoint kinase mTORC1 (mammalian target of rapamycin complex 1) and the reprogramming of macrophages toward increased glycolysis to foster their proliferation and aggregation. This process sustained the further recruitment of granuloma-promoting immune cells and the associated proinflammatory microenvironment and influenced the clinical course of the disease. Conclusions: Our results identify PTX3 as a pivotal molecule that regulates complement-mediated signaling cues in macrophages to restrain granulomatous inflammation and highlight the therapeutic potential of this signaling axis in targeting granuloma formation in sarcoidosis.

Pleuroparenchymal fibroelastosis as a complication of chemotherapy: A case report.

Pleuroparenchymal fibroelastosis (PPFE) is a rare and recently described distinct pattern of lung apical fibrosis involving the upper lobe parenchyma and pleural dome. PPFE has definable and reproducible clinical, radiological and histopathological criteria, which allowed its classification as an independent interstitial lung disease. Several factors have been associated with PPFE, such as chemotherapy, especially with alkylating agents. The authors present a case of a 34-year-old female with previous history of Hodgkin lymphoma treated with first line chemotherapy (doxorubicin, bleomycin, vinblastine and dacarbazine). The patient had no other known comorbidities or relevant exposure to lung irritants. A total of 2 years after completing cancer treatment, the patient developed clinical and radiological features of PPFE. Given their previous history of malignancy, a biopsy of the lesion was obtained, which confirmed the diagnosis of PPFE. The authors present this case to raise awareness of this disease and to demonstrate that PPFE can develop months to years following chemotherapy treatment. Moreover, to date, none of these chemotherapy agents have been associated with the development of PPFE.

The Role of Ultrasonography in the Diagnosis and Decision Algorithm for the Management of Pneumothorax after Transbronchial Lung Cryobiopsy.

BACKGROUND: Pneumothorax is one of the main complications of transbronchial lung cryobiopsy (TBLC). Chest ultrasound (CUS) is a radiation-free alternative method for pneumothorax detection. OBJECTIVE: We tested CUS diagnostic accuracy for pneumothorax and assessed its role in the decision algorithm for pneumothorax management. Secondary objectives were to evaluate the post-procedure pneumothorax occurrence and risk factors. METHODS: Eligible patients underwent TBLC, followed by chest X-ray (CXR) evaluation 2 h after the procedure, as our standard protocol. Bedside CUS was performed within 30 min and 2 h after TBLC. Pneumothorax by CUS was defined by the absence of lung sliding and comet-tail artefacts and confirmed with the stratosphere sign on M-mode. Pneumothorax size was determined through lung point projection on CUS and interpleural distance on CXR and properly managed according to clinical status. RESULTS: Sixty-seven patients were included. Nineteen pneumothoraces were detected at 2 h after the procedure, of which 8 (42.1%) were already present at the first CUS evaluation. All CXR-detected pneumothoraces had a positive CUS detection. There were 3 discordant cases (κ = 0.88, 95% CI: 0.76-1.00, p < 0.001), which were detected by CUS but not by inspiration CXR. We calculated a specificity of 97.5% (95% CI: 86.8-99.9) and a sensitivity of 100% (95% CI: 87.2-100) for CUS. Pneumothorax rate was higher when biopsies were taken in 2 lobes and if histology had pleural representation. Final diagnosis was achieved in 79.1% of patients, with the most frequent diagnosis being hypersensitivity pneumonitis. Regarding patients with large-volume pneumothorax needing drainage, the rate of detection was similar between CUS and CRX. CONCLUSION: CUS can replace CXR in detecting the presence of pneumothorax after TBLC, and the lung point site can reliably indicate its size. This useful method optimizes time spent at the bronchology unit and allows immediate response in symptomatic patients, helping to choose optimal treatment strategies, while preventing ionizing radiation exposure.

Pulmonary Emphysema Regional Distribution and Extent Assessed by Chest Computed Tomography Is Associated With Pulmonary Function Impairment in Patients With COPD.

Objective: This study aimed to evaluate how emphysema extent and its regional distribution quantified by chest CT are associated with clinical and functional severity in patients with chronic obstructive pulmonary disease (COPD). Methods/Design: Patients with a post-bronchodilator forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) < 0.70, without any other obstructive airway disease, who presented radiological evidence of emphysema on visual CT inspection were retrospectively enrolled. A Quantitative Lung Imaging (QUALI) system automatically quantified the volume of pulmonary emphysema and adjusted this volume to the measured (EmphCTLV) or predicted total lung volume (TLV) (EmphPLV) and assessed its regional distribution based on an artificial neural network (ANN) trained for this purpose. Additionally, the percentage of lung volume occupied by low-attenuation areas (LAA) was computed by dividing the total volume of regions with attenuation lower or equal to -950 Hounsfield units (HU) by the predicted [LAA (%PLV)] or measured CT lung volume [LAA (%CTLV)]. The LAA was then compared with the QUALI emphysema estimations. The association between emphysema extension and its regional distribution with pulmonary function impairment was then assessed. Results: In this study, 86 patients fulfilled the inclusion criteria. Both EmphCTLV and EmphPLV were significantly lower than the LAA indices independently of emphysema severity. CT-derived TLV significantly increased with emphysema severity (from 6,143 ± 1,295 up to 7,659 ± 1,264 ml from mild to very severe emphysema, p < 0.005) and thus, both EmphCTLV and LAA significantly underestimated emphysema extent when compared with those values adjusted to the predicted lung volume. All CT-derived emphysema indices presented moderate to strong correlations with residual volume (RV) (with correlations ranging from 0.61 to 0.66), total lung capacity (TLC) (from 0.51 to 0.59), and FEV1 (~0.6) and diffusing capacity for carbon monoxide DLCO (~0.6). The values of FEV1 and DLCO were significantly lower, and RV (p < 0.001) and TLC (p < 0.001) were significantly higher with the increasing emphysema extent and when emphysematous areas homogeneously affected the lungs. Conclusions: Emphysema volume must be referred to the predicted and not to the measured lung volume when assessing the CT-derived emphysema extension. Pulmonary function impairment was greater in patients with higher emphysema volumes and with a more homogeneous emphysema distribution. Further studies are still necessary to assess the significance of CTpLV in the clinical and research fields.

Management of Coronavirus Disease 2019 Patients With Lung Cancer: Experience From a Thoracic Oncology Center.

BACKGROUND: Cancer patients appear to be at a higher risk of complications from coronavirus disease 2019 (COVID-19). Specific data related to lung cancer (LC) patient management, active treatment, and/or recent diagnosis are still very limited. Here, we aimed to investigate the clinical presentation, baseline features, and clinical outcomes of LC patients with COVID-19. METHODS: A retrospective case study was performed at Centro Hospitalar Universitário de São Joao, a tertiary hospital in the North of Portugal. Data from LC patients diagnosed with COVID-19 were collected during the first 10 months of the COVID-19 pandemic (March 2020-January 2021). RESULTS: Twenty-eight patients with active LC were diagnosed with COVID-19, being adenocarcinoma the most common histological type present (n = 13, 46.4%). Sixteen patients had metastatic stage IV LC (61.5%). Twenty-five patients (89.3%) had relevant comorbidities including hypertension (39.3%) and chronic obstructive pulmonary disease (32.1%). For patients undergoing antineoplastic treatment, the median time from the last chemotherapy administration to COVID-19 diagnosis was of 16 days (interquartile range = 13-41 days). Half of patients were previously on corticosteroid therapy. Twenty patients (71.4%) needed hospitalization, 18 received oxygen therapy (64.3%), 3 (10.7%) of them received high-flow nasal cannula with good tolerability, and 1 (3.6%) needed non-invasive ventilation. Hydroxychloroquine and antibiotics were given to 4 (14.3%) and 12 (42.9%) patients, respectively. Seven patients (25%) died at a median time of 5 days following COVID-19 diagnosis. CONCLUSION: This is one of the first studies reporting the adverse outcomes associated with COVID-19 in LC patients at same time that adds evidence regarding the need to create protocols and guidelines to reduce the infection risk in such patients.

Heterogeneous Streptomycin Resistance Level Among Mycobacterium tuberculosis Strains From the Same Transmission Cluster.

Widespread and frequent resistance to the second-line tuberculosis (TB) medicine streptomycin, suggests ongoing transmission of low fitness cost streptomycin resistance mutations. To investigate this hypothesis, we studied a cohort of 681 individuals from a TB epidemic in Portugal. Whole-genome sequencing (WGS) analyses were combined with phenotypic growth studies in culture media and in mouse bone marrow derived macrophages. Streptomycin resistance was the most frequent resistance in the cohort accounting for 82.7% (n = 67) of the resistant Mycobacterium tuberculosis isolates. WGS of 149 clinical isolates identified 13 transmission clusters, including three clusters containing only streptomycin resistant isolates. The biggest cluster was formed by eight streptomycin resistant isolates with a maximum of five pairwise single nucleotide polymorphisms of difference. Interestingly, despite their genetic similarity, these isolates displayed different resistance levels to streptomycin, as measured both in culture media and in infected mouse bone marrow derived macrophages. The genetic bases underlying this phenotype are a combination of mutations in gid and other genes. This study suggests that specific streptomycin resistance mutations were transmitted in the cohort, with the resistant isolates evolving at the cluster level to allow low-to-high streptomycin resistance levels without a significative fitness cost. This is relevant not only to better understand transmission of streptomycin resistance in a clinical setting dominated by Lineage 4 M. tuberculosis infections, but mainly because it opens new prospects for the investigation of selection and spread of drug resistance in general.

Resistance Profile of Osimertinib in Pre-treated Patients With EGFR T790M-Mutated Non-small Cell Lung Cancer.

Background: Osimertinib efficacy in pre-treated patients with epidermal growth factor receptor (EGFR) T790M-mutated non-small cell lung cancer (NSCLC) has been demonstrated in clinical trials, but real-world data, particularly regarding resistance profile, remains limited. This study aims to analyze the resistance mechanisms acquired after treatment with Osimertinib. Methods: Clinical outcomes and molecular results from re-biopsies at the time of osimertinib progression of EGFR T790M-mutated NSCLC patient were analyzed. Results: Twenty-one patients with stage IV adenocarcinoma were included [median 69 years; 57.1% female; 85.7% never-smokers; 23.8% ECOG performance status (PS) ≥2]. Median PFS and OS were 13.4 (95% CI: 8.0-18.9) and 26.4 (95% IC: 8.9-43.8) months, respectively. At the time of analysis, 10 patients had tumor progression (47.6%). T790M loss occurred in 50%, being associated with earlier progression (median PFS 8.1 vs. 21.4 months, p = 0.011). Diverse molecular alterations were identified, including C797S mutation (n = 1), PIK3CA mutation (n = 2), MET amplification (n = 1), CTNNB1 mutation (n = 1), and DCTN1-ALK fusion (n = 1). Histological transformation into small cell carcinoma occurred in one patient. Conclusions: This real-world life study highlights the relevance of re-biopsy at the time of disease progression, contributing to understand resistance mechanisms and to guide treatment strategies.

Modified Glasgow Prognostic Score predicts survival among advanced non-small cell lung carcinoma patients treated with anti-PD1 agents.

Immune checkpoint inhibitors were approved for advanced nonsmall cell lung cancer (NSCLC) treatment. Despite improved survival, not all patients benefit from these agents. Here, the prognostic impact of pretreatment modified Glasgow Prognostic Score (mGPS) and neutrophil-to-lymphocyte ratio (NLR) was assessed. From 77 patients included, 83.2% received at least one prior systemic therapy. Immune-related adverse events (irAE) occurred in 20 patients. A lower mGPS was associated with higher median overall survival (OS), and a lower Eastern Cooperative Oncology Group (ECOG), irAE and fewer metastatic sites with better survival. A trend towards greater OS and progression-free survival (PFS) was stated among patients with NLR <5. mGPS 0 was associated with better survival; ≥3 metastatic sites with worse PFS and OS; ECOG >2 with worse OS and irAE with better survival. Pretreatment mGPS seems to be useful for predicting survival among advanced NSCLC patients treated with anti-programmed cell death 1 drugs, with ECOG performance status, irAE occurrence, and number of metastatic sites acting as survival predictors.

Insights on chronic hypersensitivity pneumonitis' treatment: Factors associated with a favourable response to azathioprine.

BACKGROUND: The use of immunosuppressive and antifibrotic agents for the treatment of chronic hypersensitivity pneumonitis (CHP) appears promising, but there is still no evidence supporting the clinical decision regarding the implementation of each specific pharmacological strategy. METHODS: Patients diagnosed with CHP and treated with azathioprine (AZA) were retrospectively selected from a single centre for Interstitial Lung Diseases. Baseline clinical data, as well as functional, imaging, bronchoalveolar lavage (BAL) and histology features were assessed. Longitudinal data on functional parameters were collected and comparatively analysed with patients' characteristics. RESULTS: In this cohort of 80 patients, of those who reached 12 months of treatment, 78.3% presented a preserved forced vital capacity, with 59 being eligible to be classified as AZA responders (n = 36) or non-responders (n = 23). BAL lymphocytosis was associated with a favourable response to AZA treatment (OR 1.051; 95% CI 1.015-1.089), although it didn't identify all responders. CONCLUSIONS: AZA revealed to be effective in disease stabilisation in most patients, while ineffective for a subset. BAL lymphocytosis appears as a potentially valuable strategy to identify AZA responders, although with limited accuracy. Further studies are needed to clarify other response markers to immunosuppressive agents, in order to optimize the therapeutic options for this condition.

Predictors of survival and technical success of bronchoscopic interventions in malignant airway obstruction.

BACKGROUND: Malignant airway obstruction (MAO) leads to quality of life impairment and increased mortality. Interventional bronchoscopy allows airway patency restoring, leading to a better survival. We investigated predictors of survival and successful bronchoscopic intervention among MAO patients. METHODS: This observational prospective study enrolled 100 patients who were newly diagnosed with MAO. Survival was estimated with Kaplan-Meier method and curves compared by log-rank test. Multivariate analyses were performed using Cox proportional hazard models. Univariate and multivariate logistic regression were used for odds ratio calculation. RESULTS: A proportion of 73% of the patients were male with a median age was 62.5 years (range, 21-88 years). Lung cancer was the most common primary malignancy (74%). The majority had single (61%), endoluminal (62%) lesions and were classified as grade III in Myer Cotton scale (57%). The most used techniques comprised mechanical debulking (n=81) and laser therapy (n=68). Twenty-two airway stents were placed. While eleven patients were considered untreatable, technical success was achieved in 78%. Haemorrhage was the most common acute complication (16%). No deaths occurred as a result of the procedure. Median global survival was 8 months. Adjusting for age and Eastern Cooperative Oncology Group Performance Status (ECOG), extrinsic compression or mixed airway obstructions [hazard ratio (HR) =2.075; P=0.012], successful bronchoscopic intervention (HR =0.468; P=0.025) and initiation of cancer treatment (HR =0.373; P=0.006) were independent predictors of survival. The absence of distal airway patency on thoracic CT was independently associated with failure of the intervention [odds ratio (OR) =0.013; P<0.001]. CONCLUSIONS: Interventional bronchoscopy has proven to be an efficient and safe strategy to manage MAO patients. The patients who benefit the most in terms of survival are those with purely endoluminal lesions, in whom technical success was achieved and those whose cancer-specific treatment was initiated. Distal airway patency on thoracic CT predicts the technical success of bronchoscopic intervention.