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Aim: To analyze immune cell populations in non-small-cell lung cancer (NSCLC) tumors and matched tumor-bearing and non-tumor-bearing lymph nodes (ntbLNs) to predict prognosis. Patients & methods: 71 patients with long-term disease-free survival and 80 patients with relapse within 3 years were included in this study. We used Cox regression to identify factors associated with overall survival (OS) and progression-free survival (PFS). Results: Sinus histiocytosis and tumor-infiltrating lymphocyte density in the tumor were positively associated with PFS and OS. CD4 expression in node 1 (hazard ratio = 0.72; p = 0.02) and node 2 (hazard ratio = 0.91; p = 0.04) ntbLNs were positively correlated with OS and PFS, respectively. Discussion: Immunological markers in ntbLNs could be used to predict survival in NSCLC.

Background: Long-term outcome of lung transplantation (LTx) recipients is limited by chronic lung allograft dysfunction (CLAD). In this setting of new onset respiratory failure, the amount of oxygenated hemoglobin (OxyHem; hemoglobin (Hb) concentration × fractional oxygen saturation) may provide valuable information. Objective: We hypothesized that OxyHem predicts survival of LTx recipients at the onset of CLAD. Methods: Data from 292 LTx recipients with CLAD were analyzed. After excluding patients with missing data or supplemental oxygen, the final population comprised 218 patients. The relationship between survival upon CLAD and OxyHem was analyzed by Cox regression analyses and ROC curves. Results: Among the 218 patients (102 males, 116 females), 128 (58.7%) died, median survival time after CLAD onset being 1,156 days. Survival was significantly associated with type of transplantation, time to CLAD, CLAD stage at onset, and OxyHem, which was superior to Hb or oxygen saturation. The risk for death after CLAD increased by 14% per reduction of OxyHem by 1 g/dL, and values below 11 g/dL corresponded to an 80% increase in mortality risk. Conclusion: Thus, OxyHem was identified as an independent predictor of mortality after CLAD onset. Whether it is useful in supporting therapeutic decisions and potentially home monitoring in the surveillance of lung transplant recipients has to be studied further.

Introduction: Interstitial lung diseases (ILDs) are associated with a high economic burden, yet prospective data of the German healthcare system are sparse. Objective: We assessed average ILD-related costs of pharmacological and non-pharmacological (hospitalizations, outpatient, rehabilitation, physiotherapy, and medical aids) interventions in ILD. Methods: We used data from the multicenter, observational, prospective Exploring Clinical and Epidemiological Characteristics of Interstitial Lung Diseases registry to evaluate adjusted per capita costs and cost drivers for ILD-related healthcare costs over 4 years, using generalized estimating equation regression models. Results: Idiopathic pulmonary fibrosis (IPF) had the highest annual pharmacological costs >EUR 21,000, followed by connective tissue disease-associated ILD (CTD-ILD) averaging EUR 6,000. Other idiopathic interstitial pneumonias and hypersensitivity pneumonitis averaged below EUR 2,400 and sarcoidosis below EUR 400. There were no significant differences in pharmacological costs over time. Trends in non-pharmacological costs were statistically significant. At year 1, CTD-ILD had the highest costs (EUR 7,700), while sarcoidosis had the lowest (EUR 2,547). By year 4, these declined to EUR 3,218 and EUR 232, respectively. Regarding cost drivers, the ILD subtype had the greatest impact with 75 times higher pharmacological costs in IPF and 4 times higher non-pharmacological costs in CTD-ILD, compared to the reference. Pulmonary hypertension (PH) and gastroesophageal reflux disease (GERD) triggered higher pharmacological costs, and higher values of forced vital capacity % predicted were associated with lower pharmacological and non-pharmacological costs. Conclusion: Stabilizing lung function and reducing the impact of PH and GERD are crucial in reducing the economic burden of ILD. There is an urgent need for effective treatment options, especially in CTD-ILD.

ZusammenfassungIdiopathische interstitielle Pneumonien sind mit einer deutlichen Minderung der Lebensqualität (LQ) assoziiert. Es existiert in Deutschland lediglich der Lebensqualitätsfragebogen für Patienten mit interstitiellen Lungenerkrankungen (K-BILD; 1) und eine deutsche Validierung von Kreuter et al. 2 Dieser Fragebogen ist jedoch in der präzisen Erfassung der Lebensqualität (LQ) für Fibrosepatienten eingeschränkt. Daher wurde ein Fragebogen zur Lebensqualität von Patienten mit idiopathischer Lungenfibrose und nicht-spezifischer interstitieller Pneumonie (Fibrose-Fragebogen, FFB) entwickelt und sprachlich validiert. Methode Die linguistische Validierung des FFB erfolgte in einem mehrstufigen Prozess durch enge Zusammenarbeit der Entwickler des Fragebogens mit bilingualen, professionellen Übersetzern durch Hin- und Rückübersetzung, um eine deutsche und englische Version zu erstellen. Ein Vergleich mit dem St. Georges Respiratory Questionnaire (SGRQ) wurde durchgeführt. Ergebnisse Es wurden eine deutsche und eine englische Version des FFB linguistisch validiert. Die Fragen umfassen 5 Skalen und 23 Items mit Aussagen zur Befindlichkeit, Beeinträchtigung und Fragen zu Symptomen wie Atemnot und Husten sowie eine visuelle Analog-Skala zum allgemeinen Gesundheitszustand. Schlussfolgerung Die deutsche und die englische Version des FFB erlauben den klinischen und wissenschaftlichen Einsatz bei Patienten mit progressiver Lungenfibrose wie der idiopathischen Lungenfibrose (IPF) und der idiopathischen nicht-spezifischen Lungenfibrose (iNSIP), um die Lebensqualität zuverlässig bestimmen zu können. Im Verlauf der Erkrankung kann der Einsatz dieses Fragebogens hilfreich sein.

BACKGROUND: The prognostic value of improvement endpoints that have been used in clinical trials of treatments for pulmonary arterial hypertension (PAH) needs to be further investigated. METHODS: Using the COMPERA database, we evaluated the prognostic value of improvements in functional class (FC) and absolute or relative improvements in 6-min walking distance (6MWD) and N-terminal fragment of pro-brain natriuretic peptide (NT-proBNP). In addition, we investigated multicomponent endpoints based on prespecified improvements in FC, 6MWD and NT-proBNP that have been used in recent PAH trials. Finally, we assessed the predictive value of improvements determined by risk stratification tools. The effects of changes from baseline to first follow-up (3-12 months after initiation of PAH therapy) on consecutive survival were determined by Kaplan-Meier analysis with Log-Rank testing and Cox proportional hazard analyses. RESULTS: All analyses were based on 596 patients with newly diagnosed PAH for whom complete data were available at baseline and first follow-up. Improvements in FC were associated with improved survival, whereas absolute or relative improvements in 6MWD had no predictive value. For NT-proBNP, absolute declines conferred no prognostic information while relative declines by ≥35% were associated with better survival. Improvements in multicomponent endpoints were associated with improved survival and the same was found for risk stratification tools. CONCLUSION: While sole improvements in 6MWD and NT-proBNP had minor prognostic relevance, improvements in multicomponent endpoints and risk stratification tools based on FC, 6MWD, and NT-proBNP were associated with improved survival. These tools should be further explored as outcome measures in PAH trials. ispartof: JOURNAL OF HEART AND LUNG TRANSPLANTATION vol:41 issue:7 pages:971-981 ispartof: location:United States status: published

BackgroundRisk stratification plays an essential role in the management of patients with pulmonary arterial hypertension (PAH). The current European guidelines propose a three-stratum model to categorise risk as low, intermediate or high, based on the expected 1-year mortality. However, with this model, most patients are categorised as intermediate risk. We investigated a modified approach based on four risk categories, with intermediate risk subdivided into intermediate-low and intermediate-high risk.MethodsWe analysed data from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA), a European pulmonary hypertension registry, and calculated risk at diagnosis and first follow-up based on World Health Organization functional class, 6-min walk distance (6MWD) and serum levels of brain natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP), using refined cut-off values. Survival was assessed using Kaplan–Meier analyses, log-rank testing and Cox proportional hazards models.ResultsData from 1655 patients with PAH were analysed. Using the three-stratum model, most patients were classified as intermediate risk (76.0% at baseline and 63.9% at first follow-up). The refined four-stratum risk model yielded a more nuanced separation and predicted long-term survival, especially at follow-up assessment. Changes in risk from baseline to follow-up were observed in 31.1% of the patients with the three-stratum model and in 49.2% with the four-stratum model. These changes, including those between the intermediate-low and intermediate-high strata, were associated with changes in long-term mortality risk.ConclusionsModified risk stratification using a four-stratum model based on refined cut-off levels for functional class, 6MWD and BNP/NT-proBNP was more sensitive to prognostically relevant changes in risk than the original three-stratum model.

BACKGROUND: A diagnosis of idiopathic pulmonary arterial hypertension (IPAH) is frequently made in elderly patients who present with comorbidities, especially hypertension, coronary heart disease, diabetes mellitus, and obesity. It is unknown to what extent the presence of these comorbidities affects the response to PAH therapies and whether risk stratification predicts outcome in patients with comorbidities. METHODS: We assessed the database of COMPERA, a European pulmonary hypertension registry, to determine changes after initiation of PAH therapy in WHO functional class (FC), 6-minute walking distance (6MWD), brain natriuretic peptide (BNP) or N-terminal fragment of probrain natriuretic peptide (NT-pro-BNP), and mortality risk assessed by a 4-strata model in patients with IPAH and no comorbidities, 1-2 comorbidities and 3-4 comorbidities. RESULTS: The analysis was based on 1,120 IPAH patients (n = 208 [19%] without comorbidities, n = 641 [57%] with 1-2 comorbidities, and n = 271 [24%] with 3-4 comorbidities). Improvements in FC, 6MWD, BNP/NT-pro-BNP, and mortality risk from baseline to first follow-up were significantly larger in patients with no comorbidities than in patients with comorbidities, while they were not significantly different in patients with 1-2 and 3-4 comorbidities. The 4-strata risk tool predicted survival in patients without comorbidities as well as in patients with 1-2 or 3-4 comorbidities. CONCLUSIONS: Our data suggest that patients with IPAH and comorbidities benefit from PAH medication with improvements in FC, 6MWD, BNP/NT-pro-BNP, and mortality risk, albeit to a lesser extent than patients without comorbidities. The 4-strata risk tool predicted outcome in patients with IPAH irrespective of the presence of comorbidities. ispartof: JOURNAL OF HEART AND LUNG TRANSPLANTATION vol:42 issue:1 pages:102-114 ispartof: location:United States status: published

Kirsten rat sarcoma virus (KRAS)-mutant cancers are frequent, metastatic, lethal, and largely undruggable. While interleukin (IL)-1β and nuclear factor (NF)-κB inhibition hold promise against cancer, untargeted treatments are not effective. Here, we show that human KRAS-mutant cancers are addicted to IL-1β via inflammatory versican signaling to macrophage inhibitor of NF-κB kinase (IKK) β. Human pan-cancer and experimental NF-κB reporter, transcriptome, and proteome screens reveal that KRAS-mutant tumors trigger macrophage IKKβ activation and IL-1β release via secretory versican. Tumor-specific versican silencing and macrophage-restricted IKKβ deletion prevents myeloid NF-κB activation and metastasis. Versican and IKKβ are mutually addicted and/or overexpressed in human cancers and possess diagnostic and prognostic power. Non-oncogene KRAS/IL-1β addiction is abolished by IL-1β and TLR1/2 inhibition, indicating cardinal and actionable roles for versican and IKKβ in metastasis.

Background Anti-IL-5 antibodies represent an established therapy for severe eosinophilic asthma (SEA), but some patients show inadequate response. The objective of this study was to assess the effects of a switch to anti-IL-5Rα therapy in patients with inadequate response to anti-IL-5 therapy. Methods In this retrospective multi-centre, real-life study, we analysed all SEA patients switched from anti-IL-5 to anti-IL-5Rα therapy due to inadequate response or intolerability. Pulmonary function tests, blood gas analyses, asthma control tests (ACT) and oral corticosteroid (OCS) usage were analysed and compared at three timepoints: baseline (BL, before anti-IL-5 therapy), timepoint 1 (T1, under anti-IL-5 therapy) and timepoint 2 (T2, under anti-IL-5Rα therapy). Results Of 665 patients treated with anti-IL-5 antibodies, 70 were switched to anti-IL-5Rα and 60 were included in the analysis. Median treatment duration was 8 months [IQR 5; 15] for anti-IL-5 and 5 months [IQR 4; 6] for anti-IL-5Rα therapy. FEV1 was 61% of predicted at BL [IQR 41; 74], 61% [IQR 43; 79] at T1 and 68% [IQR 49; 87] at T2 (pT1-T2=0.011). ACT score was 10 [IQR 8; 13], 16 [IQR 10; 19] and 19 [IQR 14; 22], respectively (both p

Background: Recombinant human erythropoietin (rHuEPO), a hormone regulating the proliferation and differentiation of erythroid cells, is one of the prescription drugs used to treat cancer-associated anemia. However, administration of rHuEPO to cancer patients has been reported to be associated with decreased survival, and the mechanism by which it acts remains controversial. The present study aimed to investigate the expression of the EPO-receptor in lung cancer cell lines and whether rHuEPO treatment affected its growth and migration. Moreover, the angiogenic effects of rHuEPO were also explored in vivo. Methods: Expression of the EPO-receptor in lung cancer cell lines was measured by Western blotting and enzyme linked immunosorbent assays (ELISAs). Proliferation of the lung cancer cells was monitored in the presence of rHuEPO. Human umbilical vein endothelial cells (HUVECs) were used for tube formation assays in vitro, and transwell migration assays were performed to detect migration under rHuEPO treatment. Matrigel plug technology was employed to observe the angiogenic effects in both nude mice and Matrigel-containing lung cancer cell lines H838 or H1975. Microvessel density (MVD) was measured using CD31 Immunohistochemistry (IHC) staining. Results: EPO-receptor (EPO-R) was only detected in the cell lines H838 and H1339 by ELISA. However, the EPO-R protein was detected in all cell lines by Western blotting, which is in contradiction to the ELISA results. Proliferation and migration were not affected by rHuEPO treatment. However, rHuEPO promoted HUVEC tube formation in vitro and significantly induced the formation of new blood vessels in vivo. Furthermore, rHuEPO did not antagonize the inhibitory effects of Afatinib (epidermal growth factor receptor-tyrosine kinase inhibitor; EGFR-TKI) in simultaneous treatment with rHuEPO. In a 3D cell co-culture model, rHuEPO did not enhance the secretion of vascular endothelial growth factor (VEGF) in lung cancer cells or human lung fibroblast cell line MRC-5. Conclusions: We have shown that the role of EPO goes beyond erythropoiesis, also playing a strong role in angiogenesis by participating in new blood vessel formation in lung cancer models. Thus, rHuEPO may raise the risk of thrombosis and metastasis in vivo. Additionally, our results suggest that studies using commercially available EPO-R antibodies should be reexamined; some of these antibodies may not in fact recognize EPO-R.

BackgroundSince 2015, the European pulmonary hypertension guidelines recommend the use of combination therapy in most patients with pulmonary arterial hypertension (PAH). However, it is unclear to what extent this treatment strategy is adopted in clinical practice and if it is associated with improved long-term survival.MethodsWe analysed data from COMPERA, a large European pulmonary hypertension registry, to assess temporal trends in the use of combination therapy and survival of patients with newly diagnosed PAH between 2010 and 2019. For survival analyses, we looked at annualised data and at cumulated data comparing the periods 2010–2014 and 2015–2019.ResultsA total of 2531 patients were included. The use of early combination therapy (within 3 months after diagnosis) increased from 10.0% in patients diagnosed with PAH in 2010 to 25.0% in patients diagnosed with PAH in 2019. The proportion of patients receiving combination therapy 1 year after diagnosis increased from 27.7% to 46.3%. When comparing the 2010–2014 and 2015–2019 periods, 1-year survival estimates were similar (89.0% (95% CI 87.2–90.9%) and 90.8% (95% CI 89.3–92.4%), respectively), whereas there was a slight but nonsignificant improvement in 3-year survival estimates (67.8% (95% CI 65.0–70.8%) and 70.5% (95% CI 67.8–73.4%), respectively).ConclusionsThe use of combination therapy increased from 2010 to 2019, but most patients still received monotherapy. Survival rates at 1 year after diagnosis did not change over time. Future studies need to determine if the observed trend suggesting improved 3-year survival rates can be confirmed.

The COVID-19 pandemic has caused acute lung injury in millions of individuals worldwide. Some patients develop COVID-related acute respiratory distress syndrome (CARDS) and cannot be liberated from mechanical ventilation. Others may develop post-COVID fibrosis, resulting in substantial disability and need for long-term supplemental oxygen. In both of these situations, treatment teams often inquire about the possibility of lung transplantation. In fact, lung transplantation has been successfully employed for both CARDS and post-COVID fibrosis in a limited number of patients worldwide. Lung transplantation after COVID infection presents a number of unique challenges that transplant programs must consider. In those with severe CARDS, the inability to conduct proper psychosocial evaluation and pretransplantation education, marked deconditioning from critical illness, and infectious concerns regarding viral reactivation are major hurdles. In those with post-COVID fibrosis, our limited knowledge about the natural history of recovery after COVID-19 infection is problematic. Increased knowledge of the likelihood and degree of recovery after COVID-19 acute lung injury is essential for appropriate decision-making with regard to transplantation. Transplant physicians must weigh the risks and benefits of lung transplantation differently in a post-COVID fibrosis patient who is likely to remain stable or gradually improve in comparison with a patient with a known progressive fibrosing interstitial lung disease (fILD). Clearly lung transplantation can be a life-saving therapeutic option for some patients with severe lung injury from COVID-19 infection. In this review, we discuss how lung transplant providers from a number of experienced centers approach lung transplantation for CARDS or post-COVID fibrosis.

BACKGROUND: Among patients meeting diagnostic criteria for idiopathic pulmonary arterial hypertension (IPAH), there is an emerging lung phenotype characterised by a low diffusion capacity for carbon monoxide (DLCO) and a smoking history. The present study aimed at a detailed characterisation of these patients. METHODS: We analysed data from two European pulmonary hypertension registries, COMPERA (launched in 2007) and ASPIRE (from 2001 onwards), to identify patients diagnosed with IPAH and a lung phenotype defined by a DLCO of less than 45% predicted and a smoking history. We compared patient characteristics, response to therapy, and survival of these patients to patients with classical IPAH (defined by the absence of cardiopulmonary comorbidities and a DLCO of 45% or more predicted) and patients with pulmonary hypertension due to lung disease (group 3 pulmonary hypertension). FINDINGS: The analysis included 128 (COMPERA) and 185 (ASPIRE) patients with classical IPAH, 268 (COMPERA) and 139 (ASPIRE) patients with IPAH and a lung phenotype, and 910 (COMPERA) and 375 (ASPIRE) patients with pulmonary hypertension due to lung disease. Most patients with IPAH and a lung phenotype had normal or near normal spirometry, a severe reduction in DLCO, with the majority having no or a mild degree of parenchymal lung involvement on chest computed tomography. Patients with IPAH and a lung phenotype (median age, 72 years [IQR 65-78] in COMPERA and 71 years [65-76] in ASPIRE) and patients with group 3 pulmonary hypertension (median age 71 years [65-77] in COMPERA and 69 years [63-74] in ASPIRE) were older than those with classical IPAH (median age, 45 years [32-60] in COMPERA and 52 years [38-64] in ASPIRE; p

Since December 2020, the COVID-19 pandemic in Germany was influenced by two new major factors: detection of new virus Variants of Concern (VOC) and the start of the vaccination campaign...

Bronchiolitis obliterans; Clinical research; Lung transplantation Bronquiolitis obliterante; Investigación clínica; Trasplante de pulmón Bronquiolitis obliterant; Recerca clínica; Trasplantament de pulmó Long-term survival after lung transplantation is limited by chronic allograft dysfunction. The aim of this study was to investigate the effect of locally augmented immunosuppression with liposomal cyclosporine A for inhalation (L-CsA-i) for the prevention of bronchiolitis obliterans syndrome (BOS). In a randomized, double-blind, placebo-controlled, multi-center Phase 3 study, 180 LT recipients in BOS grade 0 were planned to receive L-CsA-i or placebo in addition to triple-drug immunosuppression. L-CsA-i was administered twice daily via an Investigational eFlow nebulizer to recipients of single (SLT) and bilateral lung transplants (BLT) within 6–32 weeks posttransplant, and continued for 2 years. The primary endpoint was BOS-free survival. 130 patients were enrolled before the study was prematurely terminated for business reasons. Despite a 2-year actuarial difference in BOS-free survival of 14.1% in favor of L-CsA-i in the overall study population, the primary endpoint was not met (p = .243). The pre-defined per protocol analysis of SLT recipients (n = 24) resulted in a treatment difference of 58.2% (p = .053). No difference was observed in the BLT (n = 48) subpopulation (p = .973). L-CsA-i inhalation was well tolerated. Although this study failed to meet its primary endpoint, the results warrant additional investigation of L-CsA-i in lung transplant recipients. The study was funded by PARI Pharma GmbH. Open access funding enabled and organized by ProjektDEAL.

BackgroundSurvival after curative resection of early-stage lung adenocarcinoma (LUAD) varies and prognostic biomarkers are urgently needed.MethodsLarge-format tissue samples from a prospective cohort of 200 patients with resected LUAD were immunophenotyped for cancer hallmarks TP53, NF1, CD45, PD-1, PCNA, TUNEL and FVIII, and were followed for a median of 2.34 (95% CI 1.71–3.49) years.ResultsUnsupervised hierarchical clustering revealed two patient subgroups with similar clinicopathological features and genotype, but with markedly different survival: “proliferative” patients (60%) with elevated TP53, NF1, CD45 and PCNA expression had 50% 5-year overall survival, while “apoptotic” patients (40%) with high TUNEL had 70% 5-year survival (hazard ratio 2.23, 95% CI 1.33–3.80; p=0.0069). Cox regression and machine learning algorithms including random forests built clinically useful models: a score to predict overall survival and a formula and nomogram to predict tumour phenotype. The distinct LUAD phenotypes were validated in The Cancer Genome Atlas and KMplotter data, and showed prognostic power supplementary to International Association for the Study of Lung Cancer tumour–node–metastasis stage and World Health Organization histologic classification.ConclusionsTwo molecular subtypes of LUAD exist and their identification provides important prognostic information.

The mechanisms tumor cells use to hijack the immune system are largely uncharted. Here we used bioluminescent nuclear factor (NF)-κB reporter mice and macrophages to discover that metastatic tumors trigger NF-κB activation in host macrophages, dependent on mutant KRAS signaling and delivered via secretory versican. Versican activates NF-κB in tumor-associated macrophages via inhibitor of NF-κB kinase (IKK) β, resulting in release of interleukin (IL)-1β into the tumor microenvironment. Versican silencing in cancer cells or conditional IKKβ deletion in macrophages prevents myeloid NF-κB activation and metastasis. Versican is overexpressed and/or mutated in human cancers and metastatic effusions with KRAS mutations, predicts poor survival, can aid in the development of diagnostic platforms for pleural metastasis, and is druggable via toll-like receptor (TLR) 1/2 inhibition. The data indicate a cardinal role for tumor-derived versican in establishing cross-talk with macrophage IKKβ during metastasis and may foster the development of new therapies and diagnostic tools.

While there is a good knowledge of the natural course of lung function in interstitial lung diseases (ILD) like idiopathic lung fibrosis (IPF), many ambiguities remain in patients with asbestosis. Therefore, we evaluated the change in lung function in asbestos exposed subjects with pleural plaques and asbestosis and analysed corresponding morphology of computer tomography of the thorax. Methods 93 asbestos exposed subjects with pleural plaques and asbestosis were analysed retrospectively at the Klinikum Bergmannsheil of the Ruhr-University of Bochum. Parameters of lung function were obtained at least twice and annual changes of FVC, TLC and DLCOsb were calculated. In addition, we assessed the predominant pattern in high-resolution computer tomography of the thorax (HRCT) and differentiated three phenotypes: p (pleural) –type, f (fibrosis) -type and m (mixed) –type. Results FU data are available in 56/93 (60.2%) patients. The annual deterioration (Mean ± SEM) of FVC is −31.46 ± 17.34 ml, of TLC -55.55 ± 25.67 ml, of DLCOsb −0.38 ± 0.07 mmol/min/kPa and of DLCOva −0.05 ± 0.01 mmol/min/kPa/L. A categorical change of FVC > −100 ml was found in 12/56 (21.4%) and 18/56 (32.1%) patients showed an annual loss of TLC > −100 ml. The greatest annual decline of FVC was observed in patients with the fibrotic phenotype on HRCT (−76.76 ± 66.43 ml) and the mixed phenotype (−81.52 ± 24.79 ml), while the pleural phenotype was less affected (−10.52 ± 25.07 ml). Conclusion More than 20% of our cohort have a progressive disease with an annual loss of FVC > −100 ml. Patients with the fibrotic-phenotype or mixed-phenotype on HRCT are particularly at risk.

Background In the SARS-CoV-2 pandemic, viral genomes are available at unprecedented speed, but spatio-temporal bias in genome sequence sampling precludes phylogeographical inference without additional contextual data. Aim We applied genomic epidemiology to trace SARS-CoV-2 spread on an international, national and local level, to illustrate how transmission chains can be resolved to the level of a single event and single person using integrated sequence data and spatio-temporal metadata. Methods We investigated 289 COVID-19 cases at a university hospital in Munich, Germany, between 29 February and 27 May 2020. Using the ARTIC protocol, we obtained near full-length viral genomes from 174 SARS-CoV-2-positive respiratory samples. Phylogenetic analyses using the Auspice software were employed in combination with anamnestic reporting of travel history, interpersonal interactions and perceived high-risk exposures among patients and healthcare workers to characterise cluster outbreaks and establish likely scenarios and timelines of transmission. Results We identified multiple independent introductions in the Munich Metropolitan Region during the first weeks of the first pandemic wave, mainly by travellers returning from popular skiing areas in the Alps. In these early weeks, the rate of presumable hospital-acquired infections among patients and in particular healthcare workers was high (9.6% and 54%, respectively) and we illustrated how transmission chains can be dissected at high resolution combining virus sequences and spatio-temporal networks of human interactions. Conclusions Early spread of SARS-CoV-2 in Europe was catalysed by superspreading events and regional hotspots during the winter holiday season. Genomic epidemiology can be employed to trace viral spread and inform effective containment strategies.

Malignant pleural mesothelioma (MPM) arises from mesothelial cells lining the pleural cavity of asbestos-exposed individuals and rapidly leads to death. MPM harbors loss-of-function mutations in BAP1, NF2, CDKN2A, and TP53, but isolated deletion of these genes alone in mice does not cause MPM and mouse models of the disease are sparse. Here, we show that a proportion of human MPM harbor point mutations, copy number alterations, and overexpression of KRAS with or without TP53 changes. These are likely pathogenic, since ectopic expression of mutant KRAS(G12D) in the pleural mesothelium of conditional mice causes epithelioid MPM and cooperates with TP53 deletion to drive a more aggressive disease form with biphasic features and pleural effusions. Murine MPM cell lines derived from these tumors carry the initiating KRAS(G12D) lesions, secondary Bap1 alterations, and human MPM-like gene expression profiles. Moreover, they are transplantable and actionable by KRAS inhibition. Our results indicate that KRAS alterations alone or in accomplice with TP53 alterations likely play an important and underestimated role in a proportion of patients with MPM, which warrants further exploration., European Union (EU); Horizon 2020; European Research Council 2010 Starting Independent Investigator; ERC Proof of Concept 2015 (ERC-PoC-2015); German Research Society; ALTERNATIVE; German Ministry for Education and Research; German Center for Lung Research Translational Research Grant; Greek State Scholarship Foundation Program; European Union (EU); European Union Social Fund; Greek National Fund; Reinforcement of Postdoctoral Researchers-1 stand 2nd cycles; General Secretariat for Research and Innovation; Hellenic Foundation for Research and Innovation; REPSIRE European Respiratory Society Fellowship; Institut National de la Sante et de la Recherche Medicale (INSERM); Centre National de la Recherche Scientifique (CNRS); Institut de Recherche en Sante Respiratoire des Pays de la Loire; National Research Agency Programme d' Investissements d' Avenir; Pays de la Loire Region Research Program; Ligue Contrele Cancer; Chancellerie des Universites de Paris; Projekt DEAL

The term idiopathic pulmonary arterial hypertension (IPAH) is used to categorize patients with pre-capillary pulmonary hypertension of unknown origin. There is considerable variability in the clinical presentation of these patients. Using data from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension, we performed a cluster analysis of 841 patients with IPAH based on age, sex, diffusion capacity of the lung for carbon monoxide (DLCO

Malignant pleural mesothelioma (MPM) arises from mesothelial cells lining the pleural cavity of asbestos-exposed individuals and rapidly leads to the development of pleural effusion and death. MPM harbours loss-of-function mutations in genes likeBAP1, NF2, CDKN2A, andTP53, but isolated deletion of these genes alone in mice does not cause MPM and mouse models of the disease are sparse. Here we show that a significant proportion of human MPM harbour point mutations and copy number alterations in theKRASproto-oncogene. These mutations are likely pathogenic, since ectopic expression of mutantKRASG12Din the pleural mesothelium of conditional mice causes MPM. Murine MPM cell lines derived from these tumours carry the initiatingKRASG12Dlesions, secondaryBap1alterations, and human MPM-like gene expression profiles. Moreover, they are transplantable and actionable by KRAS inhibition. Our results indicate thatKRASmutations likely play an important and underestimated role in MPM, which warrants further exploration.

Background: Riociguat in Patients with Symptomatic Pulmonary Hypertension associated with Idiopathic Interstitial Pneumonias (RISE-IIP), a randomized, controlled, phase 2b trial of riociguat for pulmonary hypertension associated with idiopathic interstitial pneumonia, was terminated early due to increased mortality in riociguat-treated patients. Baseline characteristics of enrolled patients demonstrated a low diffusing capacity of the lung for carbon monoxide (DLCO) with preserved lung volumes at baseline, suggesting the presence of combined pulmonary fibrosis and emphysema (CPFE) in some patients. This post hoc analysis of RISE-IIP was undertaken to explore lung morphology, assessed by high-resolution computed tomography, and associated clinical outcomes. Methods: Available baseline/pre-baseline high-resolution computed tomography scans were reviewed centrally by 2 radiologists. The extent of emphysema and fibrosis was retrospectively scored and combined to provide the total CPFE score. Results: Data were available for 65/147 patients (44%), including 15/27 fatal cases (56%). Of these, 41/65 patients (63%) had CPFE. Mortality was higher in patients with CPFE (12/41; 29%) than those without (3/24; 13%). Fourteen patients with CPFE had emphysema > fibrosis (4 died). No relationship was observed between CPFE score, survival status, and treatment assignment. A low DLCO, short 6-min walking distance, and high forced vital capacity:DLCO ratio at baseline also appeared to be risk factors for mortality. Conclusions: High parenchymal lung disease burden and the presence of more emphysema than fibrosis might have predisposed patients with pulmonary hypertension associated with idiopathic interstitial pneumonia to poor outcomes in RISE-IIP. Future studies of therapy for group 3 pulmonary hypertension should include centrally adjudicated imaging for morphologic phenotyping and disease burden evaluation during screening. © 2021 The Authors, Ikaria Sanofi Inova Health System Roche University of Texas Southwestern Medical Center Gilead Sciences AstraZeneca Boehringer Ingelheim, BI Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, SNF United Therapeutics Corporation Merck Sharp and Dohme, MSD Novartis Sunovion Actelion Pharmaceuticals Pfizer National Institutes of Health, NIH GlaxoSmithKline, GSK National Heart, Lung, and Blood Institute, NHLBI Lunge Zürich Bayer Merck Sharp and Dohme, MSD, The authors have reported to the Journal of Heart and Lung Transplantation the following: S. D. Nathan reports consultation fees and Inova Fairfax Hospital receiving research funding for work pertaining to the RISE-IIP study from Bayer AG. V. Cottin reports grants from Actelion, Boehringer Ingelheim, GSK, Pfizer, and Roche, and personal fees from Bayer AG, Biogen Idec, Boehringer Ingelheim, Gilead, GSK, Intermune, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Sanofi. J. Behr reports receiving personal fees from Actelion, Bayer AG, Biogen, BMS, Boehringer Ingelheim, Galapagos, and Roche for consulting and lectures. M. M. Hoeper reports consultancy fees from Actelion, Bayer AG, and Pfizer, and personal fees from Actelion, Bayer AG, Pfizer, and Merck Sharp & Dohme. F. J. Martinez reports grants from National Institutes of Health and National Heart, Lung and Blood Institute, and support from Academic CME, Amgen, Annenberg, AstraZeneca, ATS, Axon, Axon Communication, Biogen, Bioscale, Boehringer Ingelheim, California Society for Allergy and Immunology, Carden Jennings, Centocor, CME Incite, CSA Medical, Falco, Forest, Genentech, Genzyme, GSK, Gilead, Inova Health System, Haymarket Communications, Ikaria, Informa, Integritas, InThought, Ikaria/Bellerophon, Janssen, Johnson & Johnson, Kadmon, MedScape, Merck, Miller Medical, National Association for Continuing Education, Novartis, Nycomed/Takeda, Paradigm, Pearl, Peer Voice, Pfizer, Promedior, Roche, Spectrum Health System, St John's Hospital, St Mary's Hospital, Sunovion, Theravance, University of Texas Southwestern, Unity Biotechnology, UpToDate, Western Society of Allergy and Immunology, Vertex, and Veracyte. T. J. Corte reports grants and personal fees from Boehringer Ingelheim and Roche, grants from Bayer AG, Gilead, and Intermune, and personal fees from AstraZeneca. A. M. Keogh reports grants and personal fees from Bayer AG. H. Leuchte reports personal fees from Actelion, Bayer AG, GSK, Merck Sharp & Dohme, and Pfizer, and nonfinancial support from Bayer AG. N. Mogulkoc reports receiving personal fees from Boehringer Ingelheim, Roche, Actelion, Bayer AG, and Nobel for consulting and lectures. S. Ulrich reports personal fees from Actelion and Bayer AG, and grants from Swiss National Science Foundation, United Therapeutics, and Zurich Lung League. W. A. Wuyts reports grants from Boehringer Ingelheim, FWO Flanders, Roche, and National Institutes of Health. Z. Yao was an employee of Bayer AG during the conduct of the RISE-IIP study. J. Ley-Zaporozhan reports consultation fees from Bayer AG and Boehringer Ingelheim. U. G. Müller-Lisse reports no conflicts of interest. F-D. Scholle, G. Brüggenwerth, and S. Nikkho were employees of Bayer AG during the conduct of the RISE-IIP study. D. Busse was an employee of Chrestos Concept GmbH & Co. during the development of this manuscript. A. U. Wells reports personal fees from Bayer AG, Roche, and Boehringer Ingelheim., The RISE-IIP study was funded by Bayer AG, Berlin, Germany, and Merck Sharp & Dohme Corp. , a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. D.B. performed statistical analyses, funded by Bayer AG, Berlin, Germany.

The hemodynamic criteria for pulmonary hyperension (PH) has been recently changed according to the recommendation of the 6th world conference of PH 2018. The impact of the new haemodynamic criteria on PAH diagnosis in e.g. systemic sclerosis has been shown to be minimal (1). In the newly established Pulmonary Hypertension service at the Lung Center Munich-Gauting, 369 patients (118 female, mean age 69 (10) years) have undergone evaluation for suspected PH inculding right heart catheter. In 273 patients (77 female, mean age 70 (10) years) a manifest PH (mPAP >25 mmHg) was diagnosed. According to the new hemodynamic criteria (mPAP > 20 mmHg), the number of patients with manifest PH increased by 52 to 325 patients ( 19% increase), among them 231 patients with precapillary PH, 59 patients with postcapillary PH and 35 patients with combined pre-/postcapillary PH. In respect to the underlying diseases, the major increase was seen in PH due to left heart disease (Claas II PH, 32% increase) and PH in lung disease (class III PH, 19% increase) and in CTEPH (class IV, 13% increase), while PAH remained nearly stable. In our cohort, the new haemodynamic classification led to an increase of PH diagnosis of about 19%, mostly in PH due to left heart disease and PH due to lung disease. 1 Jaafar S, et al Eur Respir J. 2019;54(2):1900586.