The Impact of Switching to a Second Antifibrotic in Patients With Idiopathic Pulmonary Fibrosis: A Retrospective Multicentre Study From the EMPIRE Registry

Introduction Most patients with idiopathic pulmonary fibrosis (IPF) treated with antifibrotics (AF) have progressive disease despite treatment. A switch of AF may improve survival, but evidence from randomised controlled trials is missing. We aimed to evaluate the efficacy of an AF switch on survival and FVC decline in patients from the European MultiPartner IPF registry (EMPIRE). Methods The study included 612 patients who discontinued the first antifibrotic therapy. Patients were grouped and analysed from two perspectives: (1) whether they had received a second antifibrotic treatment after the discontinuation of the first therapy, and (2) a reason for discontinuation of the first AF – “lack of efficacy” (LE) and “intolerance” (INT). Results While 263 (43%) of 612 patients received no second AF (“non-switched”), 349 (57%) patients switched. Overall survival was higher in patients who received a second AF (median 50 vs. 29 months; adjusted HR 0.64, P=0.023). Similarly, the annual FVC decline was significantly reduced in switched patients: −98ml/y in switched and −172ml/y in non-switched patients (P=0.023), respectively. The switched patients had similar risk for mortality in both LE and INT groups (adjusted HR 0.95, P=0.85). The high impact of switching on survival was demonstrated in LE patients (adjusted HR 0.27, P<0.001). Conclusion The patients without a second AF had significantly shorter overall survival. Our analysis suggests the importance of switching patients with an ineffective first AF therapy to a second AF therapy (AU)

The Impact of Switching to a Second Antifibrotic in Patients With Idiopathic Pulmonary Fibrosis: A Retrospective Multicentre Study From the EMPIRE Registry.

INTRODUCTION: Most patients with idiopathic pulmonary fibrosis (IPF) treated with antifibrotics (AF) have progressive disease despite treatment. A switch of AF may improve survival, but evidence from randomised controlled trials is missing. We aimed to evaluate the efficacy of an AF switch on survival and FVC decline in patients from the European MultiPartner IPF registry (EMPIRE). METHODS: The study included 612 patients who discontinued the first antifibrotic therapy. Patients were grouped and analysed from two perspectives: (1) whether they had received a second antifibrotic treatment after the discontinuation of the first therapy, and (2) a reason for discontinuation of the first AF - "lack of efficacy" (LE) and "intolerance" (INT). RESULTS: While 263 (43%) of 612 patients received no second AF ("non-switched"), 349 (57%) patients switched. Overall survival was higher in patients who received a second AF (median 50 vs. 29 months; adjusted HR 0.64, P=0.023). Similarly, the annual FVC decline was significantly reduced in switched patients: -98ml/y in switched and -172ml/y in non-switched patients (P=0.023), respectively. The switched patients had similar risk for mortality in both LE and INT groups (adjusted HR 0.95, P=0.85). The high impact of switching on survival was demonstrated in LE patients (adjusted HR 0.27, P<0.001). CONCLUSION: The patients without a second AF had significantly shorter overall survival. Our analysis suggests the importance of switching patients with an ineffective first AF therapy to a second AF therapy.

Physical Activity, Depression and Quality of Life in COPD - Results from the CLARA II Study.

Background: Symptoms of depression, pain and limitations in physical activity may affect quality of life in COPD patients independent from their respiratory burden. We aimed to analyze the associations of these factors in outpatients with COPD in Austria in a stable phase of disease. Methods: We conducted a national, cross-sectional study among patients with COPD. For depression, the Patient Health Questionnaire-9 (PHQ-9) and for respiratory symptoms the St. George's Respiratory Questionnaire for COPD patients (SGRQ-C) were used along with 10-point scales for physical activity and pain. Results: After exclusion of 211 patients due to non-obstructive spirometry or missing data, 630 patients (62.5% men; mean age 66.8 ± 8.6 (SD) years; mean FEV1%pred. 54.3 ± 16.5 (SD)) were analyzed. Of these, 47% reported one or more exacerbations in the previous year, 10.4% with hospitalization. A negative depression score was found in 54% and a score suggesting severe depression (PHQ-9 score ≥ 15) in 4.7%. In a multivariate linear regression model, self-reported pain, dyspnea, and number of exacerbations were predictors for higher PHQ-9-scores. A negative pain score was found in 43.8%, and a score suggesting severe pain in 2.9% (8-10 points of 10-point scale). Patients reporting severe pain were more often female, had more exacerbations, and reported more respiratory and depressive symptoms, a lower quality of life, and less physical activity. About 46% of patients rated their physical activity as severely impaired. These patients were significantly older, had more exacerbations, concomitant heart disease, a higher pain and depression score, and a lower quality of life (SGRQ-C - total score and all subscores). Conclusions: In Austria, nearly half of stable COPD outpatients reported symptoms of depression, which were associated with lower levels of self-reported physical activity, more pain, and respiratory symptoms. The associations were particularly strong for depression with SGRQ-C.

The Impact of Exercise Training and Supplemental Oxygen on Peripheral Muscles in Chronic Obstructive Pulmonary Disease: A Randomized Controlled Trial.

OBJECTIVE: Exercise training is a cornerstone of the treatment of chronic obstructive pulmonary disease, whereas the related interindividual heterogeneity in skeletal muscle dysfunction and adaptations are not yet fully understood. We set out to investigate the effects of exercise training and supplemental oxygen on functional and structural peripheral muscle adaptation. METHODS: In this prospective, randomized, controlled, double-blind study, 28 patients with nonhypoxemic chronic obstructive pulmonary disease (forced expiratory volume in 1 second, 45.92% ± 9.06%) performed 6 wk of combined endurance and strength training, three times a week while breathing either supplemental oxygen or medical air. The impact on exercise capacity, muscle strength, and quadriceps femoris muscle cross-sectional area (CSA) was assessed by maximal cardiopulmonary exercise testing, 10-repetition maximum strength test of knee extension, and magnetic resonance imaging, respectively. RESULTS: After exercise training, patients demonstrated a significant increase in functional capacity, aerobic capacity, exercise tolerance, quadriceps muscle strength, and bilateral CSA. Supplemental oxygen affected significantly the training impact on peak work rate when compared with medical air (+0.20 ± 0.03 vs +0.12 ± 0.03 W·kg -1 , P = 0.047); a significant increase in CSA (+3.9 ± 1.3 cm 2 , P = 0.013) was only observed in the training group using oxygen. Supplemental oxygen and exercise-induced peripheral desaturation were identified as significant opposing determinants of muscle gain during this exercise training intervention, which led to different adaptations of CSA between the respective subgroups. CONCLUSIONS: The heterogenous functional and structural muscle adaptations seem determined by supplemental oxygen and exercise-induced hypoxia. Indeed, supplemental oxygen may facilitate muscular training adaptations, particularly in limb muscle dysfunction, thereby contributing to the enhanced training responses on maximal aerobic and functional capacity.

The association of spirometric small airways obstruction with respiratory symptoms, cardiometabolic diseases, and quality of life: results from the Burden of Obstructive Lung Disease (BOLD) study.

BACKGROUND: Spirometric small airways obstruction (SAO) is common in the general population. Whether spirometric SAO is associated with respiratory symptoms, cardiometabolic diseases, and quality of life (QoL) is unknown. METHODS: Using data from the Burden of Obstructive Lung Disease study (N = 21,594), we defined spirometric SAO as the mean forced expiratory flow rate between 25 and 75% of the FVC (FEF25-75) less than the lower limit of normal (LLN) or the forced expiratory volume in 3 s to FVC ratio (FEV3/FVC) less than the LLN. We analysed data on respiratory symptoms, cardiometabolic diseases, and QoL collected using standardised questionnaires. We assessed the associations with spirometric SAO using multivariable regression models, and pooled site estimates using random effects meta-analysis. We conducted identical analyses for isolated spirometric SAO (i.e. with FEV1/FVC ≥ LLN). RESULTS: Almost a fifth of the participants had spirometric SAO (19% for FEF25-75; 17% for FEV3/FVC). Using FEF25-75, spirometric SAO was associated with dyspnoea (OR = 2.16, 95% CI 1.77-2.70), chronic cough (OR = 2.56, 95% CI 2.08-3.15), chronic phlegm (OR = 2.29, 95% CI 1.77-4.05), wheeze (OR = 2.87, 95% CI 2.50-3.40) and cardiovascular disease (OR = 1.30, 95% CI 1.11-1.52), but not hypertension or diabetes. Spirometric SAO was associated with worse physical and mental QoL. These associations were similar for FEV3/FVC. Isolated spirometric SAO (10% for FEF25-75; 6% for FEV3/FVC), was also associated with respiratory symptoms and cardiovascular disease. CONCLUSION: Spirometric SAO is associated with respiratory symptoms, cardiovascular disease, and QoL. Consideration should be given to the measurement of FEF25-75 and FEV3/FVC, in addition to traditional spirometry parameters.

Chemo-Radio-Immunotherapy for NSCLC III: ESR/ATS Thresholds for DLCO Correlate with Radiation Dosimetry and Pneumonitis Rate.

INTRODUCTION: Durvalumab following chemoradiotherapy (CRT) for non-small cell lung cancer stage III has become the standard of care (SoC) in the past few years. With this regimen, 5-year overall survival (OS) has risen to 43%. Therefore, adequate pulmonary function (PF) after treatment is paramount in long-term survivors. In this respect, carbon monoxide diffusing capacity (DLCO), which represents the alveolar compartment, seems to be a suitable measure for residual lung capacity. The aim of the current analysis was to correlate DLCO with pneumonitis and radiation dose. PATIENTS AND METHODS: One hundred and twelve patients with histologically confirmed NSCLC III treated between 2015/10 and 2022/03 were eligible for this study. Patients received two cycles of platinum-based induction chemotherapy followed by high-dose radiotherapy (RT). As of 2017/09, durvalumab maintenance therapy was administered for one year. The clinical endpoints were based on the thresholds jointly published by the European Respiratory Society (ERS) and the American Thoracic Society (ATS). Pre-treatment DLCO of 60% was correlated to the incidence of pneumonitis, whereas the post-treatment DLCO decline of 10% was related to radiation dose. RESULTS: Patients with a pre-treatment DLCO < 60% had a higher probability of pneumonitis (n = 98; r = 0.175; p-value 0.042), which could be reproduced in the subgroup of patients who did not receive durvalumab (n = 40; r = 0.288; p-value 0.036). In these individuals, the decline in DLCO ≥ 10% depended significantly on the size of the lung volume receiving between 45% and 65% (V65-45%) of the total radiation dose (r = 0.354; p-value = 0.020) and V20 Total Lung (r = 0.466; corrected p-value = 0.042). CONCLUSIONS: The current analysis revealed that DLCO is a predictor for clinically relevant pneumonitis and a monitoring tool for post-treatment lung function as it correlates with radiation dose. This underlines the importance of peri-treatment lung function testing.

Association of respiratory symptoms and lung function with occupation in the multinational Burden of Obstructive Lung Disease (BOLD) study.

BACKGROUND: Chronic obstructive pulmonary disease has been associated with exposures in the workplace. We aimed to assess the association of respiratory symptoms and lung function with occupation in the Burden of Obstructive Lung Disease study. METHODS: We analysed cross-sectional data from 28 823 adults (≥40 years) in 34 countries. We considered 11 occupations and grouped them by likelihood of exposure to organic dusts, inorganic dusts and fumes. The association of chronic cough, chronic phlegm, wheeze, dyspnoea, forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1)/FVC with occupation was assessed, per study site, using multivariable regression. These estimates were then meta-analysed. Sensitivity analyses explored differences between sexes and gross national income. RESULTS: Overall, working in settings with potentially high exposure to dusts or fumes was associated with respiratory symptoms but not lung function differences. The most common occupation was farming. Compared to people not working in any of the 11 considered occupations, those who were farmers for ≥20 years were more likely to have chronic cough (OR 1.52, 95% CI 1.19-1.94), wheeze (OR 1.37, 95% CI 1.16-1.63) and dyspnoea (OR 1.83, 95% CI 1.53-2.20), but not lower FVC (ß=0.02 L, 95% CI -0.02-0.06 L) or lower FEV1/FVC (ß=0.04%, 95% CI -0.49-0.58%). Some findings differed by sex and gross national income. CONCLUSION: At a population level, the occupational exposures considered in this study do not appear to be major determinants of differences in lung function, although they are associated with more respiratory symptoms. Because not all work settings were included in this study, respiratory surveillance should still be encouraged among high-risk dusty and fume job workers, especially in low- and middle-income countries.

Small airways obstruction and its risk factors in the Burden of Obstructive Lung Disease (BOLD) study: a multinational cross-sectional study.

BACKGROUND: Small airways obstruction is a common feature of obstructive lung diseases. Research is scarce on small airways obstruction, its global prevalence, and risk factors. We aimed to estimate the prevalence of small airways obstruction, examine the associated risk factors, and compare the findings for two different spirometry parameters. METHODS: The Burden of Obstructive Lung Disease study is a multinational cross-sectional study of 41 municipalities in 34 countries across all WHO regions. Adults aged 40 years or older who were not living in an institution were eligible to participate. To ensure a representative sample, participants were selected from a random sample of the population according to a predefined site-specific sampling strategy. We included participants' data in this study if they completed the core study questionnaire and had acceptable spirometry according to predefined quality criteria. We excluded participants with a contraindication for lung function testing. We defined small airways obstruction as either mean forced expiratory flow rate between 25% and 75% of the forced vital capacity (FEF25-75) less than the lower limit of normal or forced expiratory volume in 3 s to forced vital capacity ratio (FEV3/FVC ratio) less than the lower limit of normal. We estimated the prevalence of pre-bronchodilator (ie, before administration of 200 µg salbutamol) and post-bronchodilator (ie, after administration of 200 µg salbutamol) small airways obstruction for each site. To identify risk factors for small airways obstruction, we performed multivariable regression analyses within each site and pooled estimates using random-effects meta-analysis. FINDINGS: 36 618 participants were recruited between Jan 2, 2003, and Dec 26, 2016. Data were collected from participants at recruitment. Of the recruited participants, 28 604 participants had acceptable spirometry and completed the core study questionnaire. Data were available for 26 443 participants for FEV3/FVC ratio and 25 961 participants for FEF25-75. Of the 26 443 participants included, 12 490 were men and 13 953 were women. Prevalence of pre-bronchodilator small airways obstruction ranged from 5% (34 of 624 participants) in Tartu, Estonia, to 34% (189 of 555 participants) in Mysore, India, for FEF25-75, and for FEV3/FVC ratio it ranged from 5% (31 of 684) in Riyadh, Saudi Arabia, to 31% (287 of 924) in Salzburg, Austria. Prevalence of post-bronchodilator small airways obstruction was universally lower. Risk factors significantly associated with FEV3/FVC ratio less than the lower limit of normal included increasing age, low BMI, active and passive smoking, low level of education, working in a dusty job for more than 10 years, previous tuberculosis, and family history of chronic obstructive pulmonary disease. Results were similar for FEF25-75, except for increasing age, which was associated with reduced odds of small airways obstruction. INTERPRETATION: Despite the wide geographical variation, small airways obstruction is common and more prevalent than chronic airflow obstruction worldwide. Small airways obstruction shows the same risk factors as chronic airflow obstruction. However, further research is required to investigate whether small airways obstruction is also associated with respiratory symptoms and lung function decline. FUNDING: National Heart and Lung Institute and Wellcome Trust. TRANSLATIONS: For the Dutch, Estonian, French, Icelandic, Malay, Marathi, Norwegian, Portuguese, Swedish and Urdu translations of the abstract see Supplementary Materials section.

Survival and lung function decline in patients with definite, probable and possible idiopathic pulmonary fibrosis treated with pirfenidone.

BACKGROUND: There is no clear evidence whether pirfenidone has a benefit in patients with probable or possible UIP, i.e. when idiopathic pulmonary fibrosis (IPF) is diagnosed with a lower degree of diagnostic certainty. We report on outcomes of treatment with pirfenidone in IPF patients diagnosed with various degrees of certainty. METHODS AND FINDINGS: We followed patients in the multi-national European MultiPartner IPF Registry (EMPIRE) first seen between 2015 and 2018. Patients were assessed with HRCT, histopathology and received a multi-disciplinary team (MDT) IPF diagnosis. Endpoints of interest were overall survival (OS), progression-free survival (PFS) and lung function decline. RESULTS: A total of 1626 patients were analysed, treated with either pirfenidone (N = 808) or receiving no antifibrotic treatment (N = 818). When patients treated with pirfenidone were compared to patients not receiving antifibrotic treatment, OS (one-, two- and three-year probability of survival 0.871 vs 0.798; 0.728 vs 0.632; 0.579 vs 0.556, P = 0.002), and PFS (one-, two- and three-year probability of survival 0.597 vs 0.536; 0.309 vs 0.281; 0.158 vs 0.148, P = 0.043) was higher, and FVC decline smaller (-0.073 l/yr vs -0.169 l/yr, P = 0.017). The benefit of pirfenidone on OS and PFS was also seen in patients with probable or possible IPF. CONCLUSIONS: This EMPIRE analysis confirms the favourable outcomes observed for pirfenidone treatment in patients with definitive IPF and indicates benefits also for patients with probable or possible IPF.

Durvalumab after Sequential High Dose Chemoradiotherapy versus Standard of Care (SoC) for Stage III NSCLC: A Bi-Centric Trospective Comparison Focusing on Pulmonary Toxicity.

Introduction: The standard of care (SoC) for unresectable stage III non-small-cell lung cancer (NSCLC) is durvalumab maintenance therapy after concurrent chemoradiation in patients with PD-L1 > 1%. However, the concurrent approach is only amenable for about one-third of patients due to co-morbidities. Although sequential regimens are usually not regarded as curative, these schedules applied in a dose-escalated manner may be similarly radical as SoC. As combining high-dose radiation and durvalumab remains a question of debate this retrospective bi-center study aims to evaluate pulmonary toxicity after high-dose chemoradiotherapy beyond 70 Gy compared to SoC. Patients and Methods: Patients with NSCLC stage III received durvalumab after either sequential high-dose chemoradiation or concomitant SoC. Chemotherapy consisted of platinum combined with either pemetrexed, taxotere, vinorelbine, or gemcitabine. The primary endpoint was short-term pulmonary toxicity occurring within six months after the end of radiotherapy (RT). Results: A total of 78 patients were eligible for this analysis. 18F-FDG-PET-CT, cranial MRT, and histological/cytological verification were mandatory in the diagnostic work-up. The high-dose and SoC group included 42/78 (53.8%) and 36/78 (46.2%) patients, respectively, which were matched according to baseline clinical variables. While the interval between the end of RT and the start of durvalumab was equal in both groups (p = 0.841), more courses were administered in the high-dose cohort (p = 0.031). Pulmonary toxicity was similar in both groups (p = 0.599), whereas intrathoracic disease control was better in the high-dose group (local control p = 0.081, regional control p = 0.184). Conclusion: The data of this hypothesis-generating study suggest that sequential high-dose chemoradiation followed by durvalumab might be similar to SoC in terms of pulmonary toxicity and potentially more effective with respect to intra-thoracic disease control. Larger trials with a prospective design are warranted to validate these results.

Real-world experience with capmatinib in MET exon 14-mutated non-small cell lung cancer (RECAP): a retrospective analysis from an early access program.

Background: Patients with non-small cell lung cancer (NSCLC) presenting with mesenchymal-epithelial transition (MET) exon 14 skipping mutation have an unfavorable prognosis with standard treatments. Capmatinib is a selective MET inhibitor, which showed promising efficacy in this patient population in early trials. Methods: We performed a retrospective, international, multicenter efficacy and safety analysis in patients with NSCLC treated with capmatinib in an early access program between March 2019 and December 2021. Results: Data from 81 patients with advanced MET exon 14 mutated NSCLC treated with capmatinib in first- or later-line therapy were analyzed. Median age was 77 years (range, 48-91), 56% were women, 86% had stage IV disease, and 27% had brain metastases. For all patients, the objective response rate (ORR) to capmatinib was 58% (95% CI, 47-69), whereas it was 68% (95% CI, 50-82) in treatment-naïve and 50% (95% CI, 35-65) in pretreated patients. The median progression-free survival was 9.5 months (95% CI, 4.7-14.3), whereas it was 10.6 months (95% CI, 5.5-15.7) in first-line and 9.1 months (95% CI, 3.1-15.1) in pretreated patients. After a median follow-up of 11.0 months, the median overall survival was 18.2 months (95% CI, 13.2-23.1). In patients with measurable brain metastases (n = 11), the intracranial ORR was 46% (95% CI, 17-77). Capmatinib showed a manageable safety profile. Grade ⩾ 3 treatment-related adverse events included peripheral edema (13%), elevated creatinine (4%), and elevated liver enzymes (3%). Conclusion: In patients with MET exon 14 skipping mutation, capmatinib showed durable systemic and intracranial efficacy and a manageable safety profile. This analysis confirms previously reported phase II data in a real-world setting.

Comorbidity burden and survival in patients with idiopathic pulmonary fibrosis: the EMPIRE registry study.

BACKGROUND: Patients with idiopathic pulmonary fibrosis (IPF) frequently have multiple comorbidities, which may influence survival but go under-recognised in clinical practice. We therefore report comorbidity, antifibrotic treatment use and survival of patients with IPF observed in the multi-national EMPIRE registry. METHODS: For this prospective IPF cohort, demographics, comorbidities, survival and causes of death were analysed. Comorbidities were noted by the treating physician based on the patient's past medical history or as reported during follow-up. Comorbidities were defined as prevalent when noted at enrolment, or as incident when recorded during follow-up. Survival was analysed by Kaplan-Meier estimates, log-rank test, and Cox proportional hazards models. Hazard ratios (HR) were adjusted for gender, age, smoking status and FVC at enrolment. RESULTS: A population of 3,580 patients with IPF from 11 Central and Eastern European countries was followed every 6 months for up to 6 years. At enrolment, 91.3% of patients reported at least one comorbidity, whereas more than one-third (37.8%) reported four or more comorbidities. Five-year survival was 53.7% in patients with no prevalent comorbidities, whereas it was 48.4%, 47.0%, 43.8% and 41.1% in patients with 1, 2, 3 and ≥ 4 comorbidities, respectively. The presence of multiple comorbidities at enrolment was associated with significantly worse survival (log-rank test P = 0.007). Adjusted HRs indicate that risk of death was increased by 44% in patients with IPF reporting ≥ 4 comorbidities at baseline compared with no comorbidity (P = 0.021). The relationship between number of comorbidities and decreased survival was also seen in patients receiving antifibrotic treatment (63% of all patients; log-rank test P < 0.001). Comorbidity as cause of death was identified in at least 26.1% of deaths. CONCLUSIONS: The majority of patients with IPF demonstrate comorbidities, and many have comorbidity-related deaths. Increasing numbers of comorbidities are associated with worse survival; and this pattern is also present in patients receiving antifibrotic therapy.

Carbon Monoxide Diffusing Capacity (DLCO) Correlates with CT Morphology after Chemo-Radio-Immunotherapy for Non-Small Cell Lung Cancer Stage III.

Introduction: Curatively intended chemo-radio-immunotherapy for non-small cell lung cancer (NSCLC) stage III may lead to post-therapeutic pulmonary function (PF) impairment. We hypothesized that the decrease in global PF corresponds to the increase in tissue density in follow-up CTs. Hence, the study aim was to correlate the dynamics in radiographic alterations to carbon monoxide diffusing capacity (DLCO) and FEV1, which may contribute to a better understanding of radiation-induced lung disease. Methods: Eighty-five patients with NSCLC III were included. All of them received two cycles of platinum-based induction chemotherapy followed by high dose radiation. Thereafter, durvalumab was administered for one year in 63/85 patients (74%). Pulmonary function tests (PFTs) were performed three months and six months after completion of radiotherapy (RT) and compared to baseline. At the same time points, patients underwent diagnostic CT (dCT). These dCTs were matched to the planning CT (pCT) using RayStation® Model Based Segmentation and deformable image registration. Differential volumes defined by specific isodoses were generated to correlate them with the PFTs. Results: In general, significant correlations between PFTs and differential volumes were found in the mid-dose range, especially for the volume of the lungs receiving between 65% and 45% of the dose prescribed (V65−45%) and DLCO (p<0.01). This volume range predicted DLCO after RT (p-value 0.03) as well. In multivariate analysis, DLCO (p-value 0.040) and FEV1 (p-value 0.014) predicted pneumonitis. Conclusions: The current analysis revealed a strong relation between the dynamics of DLCO and CT morphology changes in the mid-dose range, which convincingly indicates the importance of routinely used PFTs in the context of a curative treatment approach.

Restricted spirometry and cardiometabolic comorbidities: results from the international population based BOLD study.

BACKGROUND: Whether restricted spirometry, i.e. low Forced Vital Capacity (FVC), predicts chronic cardiometabolic disease is not definitely known. In this international population-based study, we assessed the relationship between restricted spirometry and cardiometabolic comorbidities. METHODS: A total of 23,623 subjects (47.5% males, 19.0% current smokers, age: 55.1 ± 10.8 years) from five continents (33 sites in 29 countries) participating in the Burden of Obstructive Lung Disease (BOLD) study were included. Restricted spirometry was defined as post-bronchodilator FVC < 5th percentile of reference values. Self-reports of physician-diagnosed cardiovascular disease (CVD; heart disease or stroke), hypertension, and diabetes were obtained through questionnaires. RESULTS: Overall 31.7% of participants had restricted spirometry. However, prevalence of restricted spirometry varied approximately ten-fold, and was lowest (8.5%) in Vancouver (Canada) and highest in Sri Lanka (81.3%). Crude odds ratios for the association with restricted spirometry were 1.60 (95% CI 1.37-1.86) for CVD, 1.53 (95% CI 1.40-1.66) for hypertension, and 1.98 (95% CI 1.71-2.29) for diabetes. After adjustment for age, sex, education, Body Mass Index (BMI) and smoking, the odds ratios were 1.54 (95% CI 1.33-1.79) for CVD, 1.50 (95% CI 1.39-1.63) for hypertension, and 1.86 (95% CI 1.59-2.17) for diabetes. CONCLUSION: In this population-based, international, multi-site study, restricted spirometry associates with cardiometabolic diseases. The magnitude of these associations appears unattenuated when cardiometabolic risk factors are taken into account.

High Dose Thoracic Re-Irradiation and Chemo-Immunotherapy for Centrally Recurrent NSCLC.

INTRODUCTION: Thoracic re-irradiation for recurrent lung cancer dates back four decades, when the first small series on 29 patients receiving palliative doses was published. With 5-year overall survival rates of 57% in PDL-1 positive patients after primary chemo-radio-immunotherapy, the number of patients who experience loco-regional relapse will increase in the near future. In this context, centrally recurring lung tumors pose a major treatment challenge. Hence, the aim of the current review is to compile the available evidence on curatively intended thoracic re-irradiation for this special clinical situation. METHODS: A systematic literature search according to the PRISMA guidelines was performed. A study was included when the following criteria were met: (1) 66% of the patients had NSCLC, (2) a total dose of 50 Gy in the second course and/or a biologically effective dose of at least 100 Gy in both treatment courses was administered, (3) re-irradiation was administered with modern radiation techniques, (4) 50% or more of the patients had a centrally located relapse, (5) the minimum cohort size was 30 patients. RESULTS: Of the initial 227 studies, 11 were analyzed, 1 of which was prospective. Median overall survival (OS) was 18.1 months (range 9.3-25.1), median progression free survival (PFS) was nine months (range 4.5-16), and median loco-regional control (LRC) was 12.1 months (range 6.5-20). Treatment-related mortality rates ranged from 2% to 14%. The total dose at re-irradiation correlated with both LRC (p-value = 0.012) and OS (p-value = 0.007) with a close relation between these two clinical endpoints (p-value = 0.006). The occurrence of acute toxicity grade 1 to 4 depended on the PTV size at re-irradiation (p-value = 0.033). CONCLUSION: The evidence regarding curative re-irradiation for centrally recurrent NSCLC is primarily based on scarce retrospective data, which are characterized by a high degree of heterogeneity. The OS in this clinically challenging situation is expected to be around 1.5 years after re-treatment. Patients with a good performance score, younger age, small tumors, and a longer interval to recurrence potentially benefit most from re-irradiation. In this context, prospective trials are warranted to achieve substantial advances in the field.

Re-Irradiation for Locally Recurrent Lung Cancer: A Single Center Retrospective Analysis.

The treatment of locally recurrent lung cancer is a major challenge for radiation-oncologists, especially with data on high-dose reirradiation being limited to small retrospective studies. The aim of the present study is to assess overall survival (OS) for patients with locally recurrent lung cancer after high-dose thoracic reirradiation. Thirty-nine patients who were re-irradiated for lung cancer relapse between October 2013 and February 2019 were eligible for the current retrospective analysis. All patients were re-irradiated with curative intent for in-field tumor recurrence. The diagnostic work-up included a mandatory 18F-FDG-PET-CT scan and-if possible-histological verification. The ECOG was ≤2, and the interval between initial and second radiation was at least nine months. Thirty patients (77%) had non-small cell lung cancer (NSCLC), eight (20%) had small cell lung cancer (SCLC), and in one patient (3%) histological confirmation could not be obtained. More than half of the patients (20/39, 51%) received re-treatment with dose differentiated accelerated re-irradiation (DART) at a median interval of 20.5 months (range: 6-145.3 months) after the initial radiation course. A cumulative EQD2 of 131 Gy (range: 77-211 Gy) in a median PTV of 46 mL (range: 4-541 mL) was delivered. Patients with SCLC had a 3 mL larger median re-irradiation volume (48 mL, range: 9-541) compared to NSCLC patients (45 mL, range: 4-239). The median cumulative EQD2 delivered in SCLC patients was 84 Gy (range: 77-193 Gy), while NSCLC patients received a median cumulative EQD2 of 135 Gy (range: 98-211 Gy). The median OS was 18.4 months (range: 0.6-64 months), with tumor volume being the only predictor (p < 0.000; HR 1.007; 95%-CI: 1.003-1.012). In terms of toxicity, 17.9% acute and 2.6% late side effects were observed, with a toxicity grade >3 occurring in only one patient. Thoracic high dose reirradiation plays a significant role in prolonging survival, especially in patients with small tumor volume at recurrence.

Chronic airflow obstruction and ambient particulate air pollution.

Smoking is the most well-established cause of chronic airflow obstruction (CAO) but particulate air pollution and poverty have also been implicated. We regressed sex-specific prevalence of CAO from 41 Burden of Obstructive Lung Disease study sites against smoking prevalence from the same study, the gross national income per capita and the local annual mean level of ambient particulate matter (PM2.5) using negative binomial regression. The prevalence of CAO was not independently associated with PM2.5 but was strongly associated with smoking and was also associated with poverty. Strengthening tobacco control and improved understanding of the link between CAO and poverty should be prioritised.