Centrilobular emphysema has significantly worse remodelling of pulmonary arteries than panlobular emphysema, suggesting distinct pathological phenotypes in COPD, a concept that might improve the understanding of the disease https://bit.ly/4oZtm09.

Extracellular Vesicles (EVs), released by all cell types and detectable in biological samples, carry a variety of biological molecules. These molecules mediate communication and signaling with both local and distant cells, potentially playing a role in the pathogenesis of diseases, including Interstitial Lung Diseases and, more specifically, Idiopathic Pulmonary Fibrosis. To better understand the role of EVs in IPF, a systematic search was performed in PubMed, Scopus, and Ovid databases. These searches were conducted from January 1st, 2019, the period during which the MISEV 2018 guidelines were published, to August 31st, 2024. The SANRA scale was used for quality assessment. A total of 691 papers were screened, and 16, in the end, were definitively enrolled for our evaluation. The studies were reviewed in the following steps: 1) the nomenclature used to define EVs; 2) conformity with the MISEV 2018 guidelines; 3) the biological samples used to isolate EVs; 4) the main conclusion of each manuscript. There was significant heterogeneity among the publications in all the aforementioned steps, such as the type and source of EVs and the analysis of EVs content, primarily a wide array of different miRNAs in the various publications. Despite these differences, the emerging role of EVs and their potential usefulness both in therapies and clinical practice is of growing interest.

Depending on local cues, macrophages can polarize into classically activated (M1) or alternatively activated (M2) phenotypes. This study investigates the impact of polarized macrophage-derived Extracellular Vesicles (EVs) (M1 and M2) and their cargo of miRNA-19a-3p and miRNA-425-5p on TGF-β production in lung fibroblasts. EVs were isolated from supernatants of M0, M1, and M2 macrophages and quantified using nanoscale flow cytometry prior to fibroblast stimulation. The concentration of TGF-β in fibroblast supernatants was measured using ELISA assays. The expression levels of miRNA-19a-3p and miRNA-425-5p were assessed via TaqMan-qPCR. TGF-β production after stimulation with M0-derived EVs and with M1-derived EVs increased significantly compared to untreated fibroblasts. miRNA-425-5p, but not miRNA-19a-3p, was significantly upregulated in M2-derived EVs compared to M0- and M1-derived EVs. This study demonstrates that EVs derived from both M0 and M1 polarized macrophages induce the production of TGF-β in fibroblasts, with potential regulation by miRNA-425-5p.

Background: Recent literature has shown the presence of B cells and autoantibodies in idiopathic pulmonary fibrosis (IPF) which would imply the presence of tertiary lymphoid structures (TLS, sites where the immune response is triggered), yet TLS are not considered features of the histological characteristics of IPF. Aim: This study aims to quantify the presence, size, and degree of activation of TLS in biopsied and explanted lungs from patients with early- and late-IPF, never treated with antifibrotics, and relate their presence and activity to the clinical course, disease progression, and lung inflammation. Methods: Immunohistochestry for B cells and CD4, CD8, and CD45 cells was performed in lung tissue from IPF patients: 18 at diagnosis (early), 39 explanted (end-stage), and 12 smoking controls. TLS activation was assessed by CD40 expression. Spirometry along 31 (12-72) months of follow-up was used to characterize end-stage IPF as slow progressors or rapid progressors. Results: B cells, along with other inflammatory cells, were higher in early- and end-stage IPF than in controls (p < 0.001). In rapid progressors, all inflammatory cells were higher than in slow progressors (p < 0.05). TLS were present in 100% of early- and end-stage IPF and in 50% of controls. In end-stage IPF, the TLS area and activation score were higher than in early IPF (p < 0.0001; p = 0.005) and controls (p < 0.04; p < 0.002). TLS activation score correlated with FVC decline during follow-up in rapid progressors (r = 0.73; p = 0.007) but not in slow progressors. Conclusions: A prominent B-cell infiltration, along with the presence of TLS, the activity of which correlates with FVC decline, is an important component of IPF from the beginning of the disease, likely playing an important role on its mechanism and progression.

BackgroundThe family of Suppressor of Cytokine Signaling (SOCS) acts as a controller of the duration and intensity of cytokine function by negatively regulating the JAK-STAT signaling pathway. SOCS’ role in inflammatory diseases in animal models is well demonstrated. However, its role in the development of human disease is still under investigation. SOCS3 plays an important role in tumor development where its downregulation has been implicated in the pathogenesis of various solid tumors such as triple-negative breast cancer.AimThe aim of this work was to study (1) the expression of SOCS3 in smokers’ lungs and its relation to the degree of inflammation and (2) SOCS3 regulation by microRNA (miRNA) in alveolar-macrophage (AM)-derived extracellular vesicles (EVs) in bronchoalveolar lavage (BAL).MethodsGroup A: 35 smokers’ [19 with COPD (SC) and 16 without COPD (S)] and 9 nonsmokers (NS); SOCS3, TNFα in AM, and CD8+ T cells were quantified by immunohistochemistry, in lung tissue. Group B: additional 9 SC, 11 S, and 5 NS; AM-EVs expressing SOCS3 (CD14+SOCS3+) and SOCS3 suppressors miRNA-19a-3p and 221-3p in EVs were quantified by flow cytometry and PCR, in BAL.ResultsThe percentage of SOCS3+ AM was higher in SC [68 (6.6–99)%] and S [48 (8–100)%] than in NS [9.6 (1.9–61)%; p = 0.002; p = 0.03] and correlated with % of TNFα+AM (r = 0.48; p = 0.0009) and CD8+ T cells (r = 0.44; p = 0.0029). In BAL, the CD14+SOCS3+ EVs/μL were increased in SC [33 (21–74)] compared to S [16 (8–37); p = 0.03] and NS [9 (7–21); p = 0.003]. Conversely, miRNA-19a-3p and miRNA-221-3p expression were increased in S when compared to SC [19 (2–53) vs. 3 (0.6–8); p = 0.03 and 3 (0.005–9.6) vs. 0.2 (0.08–0.7); p = 0.05].ConclusionsThe suppressor function of SOCS3 in COPD seems to be overridden by other factors and does not follow the animal-model paradigm. Expression of SOCS3 in BAL macrophage-derived EVs might be useful to assess the degree of inflammation and possible progression of COPD. Downregulation of SOCS3, by miRNA, in smokers without COPD might contribute to the risk of developing cancer in these patients.

BackgroundThe local, extravascular, activation of the coagulation system in response to injury is a key factor mediating the resulting inflammatory response. Coagulation Factor XIIIA (FXIIIA) found in alveolar macrophages (AM) and dendritic cells (DC), by influencing fibrin stability, might be an inflammatory modifier in COPD. AimsTo study the expression of FXIIIA in AM and Langerin+DC (DC-1) and their relation to the inflammatory response and disease progression in COPD. MethodsIn 47 surgical lungs, 36 from smokers (22 COPD and 14 no-COPD) and 11 from non-smokers we quantified by immunohistochemistry FXIIIA expression in AM and DC-1 along with numbers of CD8+Tcells and CXCR3 expression in lung parenchyma and airways. Lung function was measured prior to surgery. ResultsThe percentage of AM expressing FXIII (%FXIII+AM) was higher in COPD than no-COPD and non-smokers. DC-1 expressed FXIIIA and their numbers were higher in COPD than no-COPD and non-smokers. DC-1 positively correlated with %FXIII+AM (r=0.43; p<0.018). CD8+Tcells, which were higher in COPD than in no-COPD, were correlated with DC-1 (p<0.01) and %FXIII+AM. CXCR3+ cells were increased in COPD and correlated with %FXIII+AM (p<0.05). Both %FXIII+AM (r=-0.6; p=0.001) and DC-1 (r=-0.7; p=0.001) correlated inversely with FEV1. ConclusionFXIIIA, an important link between the extravascular coagulation cascade and inflammatory response, is significantly expressed in alveolar macrophages and dendritic cells of smokers with COPD, suggesting that it could play an important role in the adaptive inflammatory reaction characteristic of the disease.

Cell-derived extracellular vesicles (EVs) found in the circulation and body fluids contain biomolecules that could be used as biomarkers for lung and other diseases. EVs from bronchoalveolar lavage (BAL) might be more informative of lung abnormalities than EVs from blood, where information might be diluted. To compare EVs’ characteristics in BAL and blood in smokers with and without COPD. Same-day BAL and blood samples were obtained in 9 nonsmokers (NS), 11 smokers w/o COPD (S), and 9 with COPD (SCOPD) (FEV1: 59 ± 3% pred). After differential centrifugation, EVs (200–500 nm diameter) were identified by flow cytometry and labeled with cell-type specific antigens: CD14 for macrophage-derived EVs, CD326 for epithelial-derived EVs, CD146 for endothelial-derived EVs, and CD62E for activated-endothelial-derived EVs. In BAL, CD14-EVs were increased in S compared to NS [384 (56–567) vs. 172 (115–282) events/μL; p = 0.007] and further increased in SCOPD [619 (224–888)] compared to both S (p = 0.04) and NS (p < 0.001). CD326-EVs were increased in S [760 (48–2856) events/μL, p < 0.001] and in SCOPD [1055 (194–11,491), p < 0.001] when compared to NS [15 (0–68)]. CD146-EVs and CD62E-EVs were similar in the three groups. In BAL, significant differences in macrophage and epithelial-derived EVs can be clearly detected between NS, S and SCOPD, while these differences were not found in plasma. This suggests that BAL is a better medium than blood to study EVs in lung diseases.

The term pulmonary hypertension (PH) refers to different conditions, all characterized by increased pressure and resistance in the pulmonary arterial bed. PH has a wide range of causes (essentially, cardiovascular, pulmonary, or connective tissue disorders); however, idiopathic (i.e., without a clear cause) PH exists. This chronic, progressive, and sometimes devastating disease can finally lead to right heart failure and eventually death, through pulmonary vascular remodeling and dysfunction. The exact nature of PH pathophysiology is sometimes still unclear. Extracellular vesicles (EVs), previously known as apoptotic bodies, microvesicles, and exosomes, are small membrane-bound vesicles that are generated by almost all cell types and can be detected in a variety of physiological fluids. EVs are involved in intercellular communication, thus influencing immunological response, inflammation, embryogenesis, aging, and regenerative processes. Indeed, they transport chemokines, cytokines, lipids, RNA and miRNA, and other biologically active molecules. Although the precise functions of EVs are still not fully known, there is mounting evidence that they can play a significant role in the pathophysiology of PH. In this review, after briefly recapping the key stages of PH pathogenesis, we discuss the current evidence on the functions of EVs both as PH biomarkers and potential participants in the distinct pathways of disease progression.

Background: Programmed Death Ligand 1 (PD-L1) is crucial in regulating the immunological tolerance in non-small cell lung cancer (NSCLC). PD-L1 behavior in COPD (a chronic lung adaptive inflammation with possible dysregulated immune tolerance) and how it could affect NSCLC is not clear. Aim: To investigate PD-L1 expression in smokers with COPD (SCOPD), without COPD (noCOPD) and non-smokers (NS) with NSCLC and its relation to clinical and inflammatory features. Methods: PD-L1 expression was quantified in lung tissue samples from 71 patients with NSCLC. Medical history, pulmonary function and blood cell counts were obtained. The possible relations of clinical data to PD-L1 values were investigated. Results: 35 of the 71 NSCLC patients were SCOPD (FEV1 67±16%), 21 noCOPD (99±12%) and 15 NS (100±17%). PD-L1 tissue expression was higher in SCOPD (20 [5-56]%) than in smokers noCOPD (2 [0-21]%; p=0.05) and NS (1 [0-21]%; p=0.05). Squamous cell carcinoma was more common in SCOPD than NS (14/35 vs 1/15; p=0.02). PD-L1 expression was similar among cancer histotypes, genders, and cancer stage (advanced: 28±31%, early: 18±26%). PD-L1 was not related to pack-years, blood cell counts, or lung function. Overall, patients with FEV1<67% of predicted (25° percentile) had lower circulating lymphocytes (19±6 vs 26±8%; p=0.01) and higher NLR (4±3 vs 3±2; p=0.01) than those with higher FEV1. Conclusions: PD-L1 was strikingly higher in smokers with NSCLC and COPD than in those without COPD, suggesting that dysregulation of adaptive immune response in COPD contributes to PD-L1 expression and might have beneficial therapeutic effects.

BACKGROUND:Asthma can present in early childhood or de novo in adulthood. Our understanding of the burden of comorbidities in adult asthmatic patients stratified by age at onset is incomplete. OBJECTIVES:To evaluate how different comorbidities may affect symptom control in two distinct groups of patients with early- and late-onset asthma (EOA and LOA, respectively) and to explore whether reported comorbidities are associated with lung function and inflammatory parameters. METHODS:We conducted a cross-sectional study of 175 adult asthmatic patients (aged 57.5 ± 17.1 years) recruited at our university asthma clinic. We defined EOA as asthma onset less than 12 years, and LOA as onset greater than 40 years. The primary outcome was symptom control and main comorbidities evaluated were rhinitis, gastroesophageal reflux, obesity, cardiovascular conditions, and bronchiectasis. We used multivariable regression analysis to identify potential predictors of poor control in EOA and LOA. RESULTS:Of 175 subjects, 77 had EOA (44%), 98 had LOA (56%), and comorbidities had a differential impact in the two groups. Rhinitis was more frequent in EOA (76 vs 53%; P = .02) and was associated with uncontrolled asthma (P < .001), reduced FEV1/FVC (P = .01), increased eosinophils (P = .003) and total IgE (P < .01). Conversely, in LOA, rhinitis was associated with more controlled asthma and higher FEV1/FVC (both P < .01). In EOA, only, IgE levels were directly related to blood eosinophils (r = 0.42; P <.001) and inversely to FEV1/FVC (r = -0.35; P = .002). Obesity was present in 20% of patients in both groups, but only in LOA was it associated with uncontrolled disease (P = .009), reduced FEV1/FVC (P = .009), and blood neutrophils (P = .03). In multivariable regression analysis, rhinitis in EOA and obesity in LOA were the risk factors most closely associated with poor control. Gastroesophageal reflux, cardiovascular comorbidities, and bronchiectasis did not affect control. CONCLUSIONS:Early-onset persistent asthma and late-onset asthma are distinct phenotypes with different underlying inflammatory patterns and different comorbidities affecting symptom control.

Background. Chronic bronchitis (CB) importantly affects outcomes in smokers with COPD, but the effects on smokers without COPD are less well known and less emphasized. The aim of our study was to investigate the possible effects of CB on clinical outcomes in smokers without COPD (noCOPD) and compare them with the effects in smokers with COPD (COPD). Methods. For that purpose, we studied 511 smokers, 302 with and 209 without COPD, followed for 10 years in an academic COPD ambulatory setting. Chronic bronchitis was defined as the presence of cough and sputum production for at least 3 months in each of two consecutive years. All subjects underwent clinical and functional examination with spirometry, diffusion capacity (DLco), 6-min walking test (6MWT), mMRC Dyspnoea Scale, COPD Assessment Test (CAT), and recording of annual frequency of exacerbations. All-cause mortality during follow-up was recorded. Results. 27% of noCOPD and 45% of COPD had CB. noCOPD with CB had lower FEV1 and DLco, worse 6MWT, more dyspnoea, a higher number of exacerbations and lower survival than noCOPD without CB. CB did not affect FEV1 decline in noCOPD but it significantly did in COPD. Conclusions. The presence of chronic bronchitis in smokers without COPD will significantly affect symptoms, quality of life, and survival, underlining the importance of recognizing the condition and managing it accordingly.

The pathogenesis of chronic obstructive pulmonary disease (COPD) is characterized by complex cellular and molecular mechanisms, not fully elucidated so far. It involves inflammatory cells (monocytes/macrophages, neutrophils, lymphocytes), cytokines, chemokines and, probably, new players yet to be clearly identified and described. Chronic local and systemic inflammation, lung aging and cellular senescence are key pathological events in COPD development and progression over time. Extracellular vesicles (EVs), released by virtually all cells both as microvesicles and exosomes into different biological fluids, are involved in intercellular communication and, therefore, represent intriguing players in pathobiological mechanisms (including those characterizing aging and chronic diseases); moreover, the role of EVs as biomarkers in different diseases, including COPD, is rapidly gaining recognition. In this review, after recalling the essential steps of COPD pathogenesis, we summarize the current evidence on the roles of EVs collected in different biological mediums as biomarkers in COPD and as potential players in the specific mechanisms leading to disease development. We will also briefly review the data on EV as potential therapeutic targets and potential therapeutic agents.

Background:COPD is a major health problem, mainly due to cigarette smoking. Most studies in COPD are dedicated to fully developed COPD in older subjects, even though development of COPD may start soon after smoking initiation. Therefore, there is a need to diagnose this "early disease" by detecting the initial events responsible for ultimate development of COPD. Methods:Measurement of maximum mid expiratory flow between 25 and 75% of vital capacity (MMEF) in a routine spirometry, which detects small airways disease, was used to investigate if MMEF abnormalities in smokers without COPD (noCOPD) would relate to respiratory symptoms and identify smokers that might progress to COPD. For this purpose we studied 511 smokers, 302 COPD and 209 noCOPD, followed long term with spirometry including MMEF, diffusing capacity of the lung for carbon monoxide (D LCO), 6-min walk test (6MWT), Medical Research Council Dyspnoea Scale and COPD Assessment Test. Three spirometries V1,V2 and V3 (5±2.5 and 10±4 years apart from V1) were performed to assess functional decline and development of COPD. Results:65% of noCOPD had an abnormal MMEF (<80%) and 38% an abnormal D LCO. The NoCOPD with MMEF <80% group performed worse in the 6MWT (p=0.01), was more dyspnoeic (p=0.01) and had higher prevalence of chronic bronchitis than the noCOPD with MMEF>80% group (p=0.04). 21% of noCOPD with MMEF <80% and 2.7% with MMEF>80% developed COPD by V3 (p=0.0004). Conclusions:The MMEF, a functional test available in a routine spirometry, can detect early lung abnormalities and identify the subset of symptomatic smokers with pathological changes that might lead to COPD.

Background: Due to pre-existing lung abnormalities and abnormal immune responses, the possible impact of COVID-19 in COPD is of real concern. Aim: To investigate the prevalence of COVID-19 in a cohort of properly diagnosed and precisely characterized COPD patients and to evaluate the possible risk and prognostic factors predicting the clinical outcome. Methods: Study cohort:370 subjects followed in outpatient COPD clinics. The characteristics of COPD patients with COVID-19 (COPD/COVID+) were compared to a sex and age-matched COPD/COVID- group randomly selected from our cohort. The characteristics of COPD/COVID+ patients needing high (HighIC) or low (LowIC) intensity care were compared. Results: From Feb to Nov2020, 22(5.9%) patients had molecular-confirmed diagnosis of COVID-19. Hypertension [100 vs 68%;p=0.008] and dyslipidemia [59 vs 27%;p=0.03] were more prevalent in COPD/COVID+ than in COPD/COVID-. Pulmonary function was similar in the 2 groups. The 10 of 22 (45%) COPD/COVID+ patients requiring HighIC had a higher prevalence of dyslipidemia [90 vs 41%;p=0.03] and metabolic syndrome [70 vs 16%; p=0.02] than LowIC, obesity and type 2 diabetes were similar. Degree of airflow obstruction was similar in the 2 groups, but low DLCO [32 vs 88%pred;p=0.02] and CT emphysema [89 vs 36%;p=0.028] were more prevalent in HighIC than in LowIC. Conclusions: The COVID-19 prevalence in our COPD cohort was 5.9%. Cardiometabolic, but not respiratory parameters, were risk factors for the infection while cardiometabolic comorbidities and lung parenchyma damage (emphysema and low DLCO) were prognostic factors for worse outcomes in COPD/COVID+ patients. Identification of these factors is essential to plan better strategies to protect fragile COPD patients.

Background: Age of asthma onset may have significant pathogenetic implications. While early and late phenotypes have been well studied, intermediate onset-asthma is not well understood. Aim: To investigate the impact of comorbidities, smoking history and inflammatory phenotypes on asthma control (GINA) in patients stratified by age of onset. Methods: In a cohort of 250 patients(54±16 yr) followed at the asthma clinic 3 clusters were defined: early-onset asthma(EA)<12 yr; intermediate asthma(IA) 12-40 yr; late-onset asthma(LA)>40 yr. Results: 77/250 (30%) subjects had EA, 76 (30%) IA and 98 (39%) LA. EA was different from LA, with more rhinitis (76vs53%, p=0.02) which was associated to worse asthma control (p=0.01) and lower FEV1/FVC (74±10vs83±7%;p=0.01); EA also had more eosinophils (0.36±0.3 vs 0.14±0.1 x109/L;p<0.01) and IgE (441±635vs71±76KU/L;p<0.01). LA patients had more neutrophils (4.2±1.5vs3.3±1.1x109/L;p=0.01) particularly when obese. Obesity in LA was associated to worse control (p=0.009) and lower FEV1/FVC (73±9vs80±10;p=0.009). IA was an intermediate phenotype, with both eosinophilic (0.31±0.3x109/L) and neutrophilic (4±1.4x109/L) patterns. In IA obesity, but not rhinitis, was associated to worse control (p=0.003), lower FEV1/FVC (71±10vs79±10; p=0.03) and neutrophilic inflammation. Of note, smoking history and environmental exposure were associated to worse control in IA (p<0.001, p=0.04) but not in EA and LA. Conclusions: Early, intermediate and late-onset asthma are distinct phenotypes. In our population IA showed a combination of EA and LA features and a mixed eosinophilic/neutrophilic pattern. Differently from EA and LA, in IA asthma control is influenced by smoking and environmental exposure.

Background: Increasing evidence suggests that an immune dysregulation may be involved in the progression of IPF. The presence of lymphoid follicles (LF) (sites where the immune response is triggered) in earlyIPF and their evolution with the progression of the disease, have never been caracterized as part of the natural history of IPF. Aim: 1) To investigate the presence of LF in earlyIPF(EIPF) and end-stage late IPF(LIPF) 2) To quantify LF numbers, dimensions and state of activation and their evolution from EIPF to LIPF. Methods: LF immunostained for B-lymphocytes were counted and measured in 15 EIPF (surgical biopsies), 42 LIPF (explanted lungs) and 9 smokers controls (SC)(surgical resection). Immunostaining for CD40, a costimulatory molecule expressed by B lymphocytes, was used to study the degree of LF activation in EIPF and LIPF. Results: LF were present in 100% of EIPF and LIPF and in 44% of SC (p<0.0001). LF number was higher in EIPF than in LIPF [9(3-36) vs 6(1–19)/cm2;p=0.02] and SC [0(0-20) cm2;p=0.0007], while LF area was increased in LIPF compared to EIPF [27,97(2,97-63,26) vs 14,41(8,97-23,21) μm2; p<0.0001) and similar to SC [23,51(14,57-43,72)μm2;p=0.58]. Both the percentage of activated LF(CD40+) (86%vs50%;p=0.04) and their absolute number [7(0-20)/cm2 vs 2(0-8)/cm2;p=0.04] in the lung were higher in LIPF than in EIPF. Conclusions: The large number of Lymphoid Follicles found in EIPF and the increase in LF volume and degree of immune activation as the disease progresses, suggest that an immune response has an important role in driving the progressive damage characteristic of the IPF course.

Introduction: Acute cellular rejection (ACR) and infection are significant causes of morbidity and mortality in transplanted recipients. The use of scheduled post-transplant biopsies (SPB) remains controversial because of its risk-benefit ratio compared to biopsies on clinical demand. Cystic fibrosis (CF) recipients have a higher risk of early immunological complications (ACR and antibody mediated rejection) compared to other diseases. Few studies have evaluated the effectiveness and safety of SPB in CF, with special regard to the time period elapsed from lung transplantation (LTx). Aim: To investigate the incidence of ACR and microbial infection in CF recipients, the safety and adequacy of SPB in detecting ACR and whether the time after LTx may influence these results. Methods: A single-centre retrospective analysis was performed on CF patients who underwent SPB for LTx between January 2019 and December 2020. The time after LTx was recorded in each patient. Results: 92 SPB were performed with a median time after LTx of 24 months (range 1-148). 89(97%) had adequate samples, and ACR was diagnosed in 13 procedures (11%). 3(3.2%) pneumothorax and 3(3.2%) major bleeding were reported. ACR and complication incidence were similar when considering the different time period elapsed from LTx (0-1, 1-2, 2-3, 3-4 and >4 years). CF transplanted from >2 years had a significantly higher number of ACR that required treatment [8/8(100%) vs 2/5(46%), p=0.03] and a lower incidence of infections [5/46(11%) vs 14/46(30%), p=0.03] than those transplanted <2 years. Conclusions: In CF recipients, SPB is a safe and accurate procedure to identify ACR that should be routinely performed in transplant recipient follow-up.

Introduction: Malignant pleural effusion (PE) is a common complication of advanced malignancy, especially lung and breast cancer (BC). The incidence of pleural metastasis in BC is known to be higher within the first years from diagnosis and rarer after 10-12 years. Aim: To evaluate the incidence of ultra-late pleural metastasis in patients with breast cancer-related PE, and whether clinical aspects may be associated with this late recurrence. Methods: A single-centre retrospective study of all patients that underwent medical thoracoscopy for suspected malignant PE from 2013 to 2019 was performed. Ultra-late metastasis were defined as recurrence appearing later than 10 years from BC diagnosis. Data regarding BC histotype (Luminal A, Luminal B, HER2+ and triple negative), macroscopic pleural appearance (nodules or diffuse thickening), amount of PE (litres) and side of PE compared to primary BC were recorded. Results: Of the 491 patients evaluated, 40 (8%) had BC pleural involvement. Four (10%) had a first diagnosis of BC after thoracoscopy. Of the other 36 patients, 19 (52%) had BC diagnosed more than 10 years before, and 7 of them even more than 20. The amount of PE, macroscopic appearance, side of PE involvement and histotype were similar between those < or >10 years from BC. There was a significantly higher time to recurrence (months) in Luminal B compared to triple negative (166±101 vs 76±74; p=0.02) and a trend in diffuse pleural involvement compared to nodules (175.6±105.6 vs 114.3±84.5; p=0.08). Conclusions: Ultra-late pleural BC metastasis are not uncommon in our cohort of patients with breast cancer-related PE. Longer time to recurrence was found in Luminal B histotype and in diffuse pleural involvement.