OBJECTIVES:Pulmonary artery sarcoma (PAS) is a rare and aggressive malignancy often mimicking pulmonary embolism, leading to diagnostic delays and poor outcomes. This study aims to describe the clinical characteristics, diagnostic pathways, treatment modalities, and outcomes of PAS patients in a multicentre cohort. METHODS:This retrospective cohort study included patients from 7 institutions between 1994 and 2024. Clinical, radiological, histological, and treatment data were collected via a standardized REDCap-based platform. All patients underwent either multimodal treatment or single therapy approach, including systemic therapy, surgery, and/or radiotherapy. Kaplan-Meier survival analysis and log-rank testing were performed to assess overall survival (OS) and progression-free survival (PFS). RESULTS:84 patients from 7 international centres were analysed. The mean age was 54.4 years, and 43.8% of patients were female. The most common presenting symptoms were dyspnoea (81.2%) and chest pain (50.0%). Pulmonary embolism was the most frequent initial misdiagnosis (49.1%). Histologically, PAS was diagnosed in 46 cases. Tumours were bilateral in 58.1% of patients with surgery only. Most commonly, endarterectomy was performed in 59.5%. After a median follow-up time of 39 months, 19 were excluded as they either had no treatment information or received monotherapy only. Additionally, 11 patients were excluded due to missing date of diagnosis and 17 due to missing overall follow-up date. There was moderate evidence that OS differed between treatment groups (75th quantile: 34 months for multimodal [95% CI, 26 to not reached] vs 11 months for surgery only [95% CI, 7-21]; log-rank P = .022). There was no evidence that PFS differed between treatment groups (median 19 months for multimodal [95% CI, 14-39] vs 16 months surgery only [95% CI, 11-21]; log-rank P = .69). CONCLUSIONS:This study represents the largest reported PAS cohort to date and underscores the diagnostic challenges and poor prognosis associated with this disease. Our findings offer evidence that multimodal treatment provides significant prognostic benefits. However, further prospective studies are warranted to establish standardized diagnostic and therapeutic protocols.

BACKGROUND:Tumor size was recently proposed as a prognosticator in thymic tumors. The aim of this study is to investigate the prognostic role of tumor size in the different thymic tumor histologies. METHODS:Clinical and pathologic data of patients from the European Society of Thoracic Surgeons thymic database who underwent surgery for thymic epithelial tumors from January 2000 to December 2022 were reviewed, analyzed, and correlated to overall survival and disease-free survival using Kaplan-Meier curves. The log-rank test was used to assess differences between subgroups. RESULTS:The final analysis was conducted on 2,556 patients. Histology results showed thymoma in 2,231 (87.3%), thymic carcinoma in 271 (10.6%), and neuroendocrine tumors in 54 (2.1%) cases. In 1,518 (59.4%) cases, size was >5 cm. The survival difference was significant considering thymoma and thymic carcinoma/neuroendocrine tumor. The 5-and 10-year disease-free survival rates were 85.4% and 78.1% vs 77.6% and 62.4% in ≤5 cm vs >5 cm thymomas (P < .001), and 5- and 10-year overall survival rates were 92.4% and 79.4% vs 88% and 74.5% in ≤5 cm vs >5 cm thymomas (P = .002). For thymic carcinoma/neuroendocrine tumor, the disease-free survival rate in the ≤5 cm group was 61.3% at both 5 and 10 years, compared with 53.3% and 46.9% in the >5 cm group, respectively (P = .042), whereas 5- and 10-year overall survival rates were 84.9% and 79.4% vs 74.9% and 64.9% in ≤5 cm vs >5 cm groups (P = .002). CONCLUSION:Tumor size was a significant prognosticator in thymic epithelial tumor, thymoma, and thymic carcinoma/neuroendocrine tumor, confirming its validity in prognosis prediction of these tumors.

BACKGROUND:Characterizing the immune landscape of thymic epithelial tumors (TETs) is essential for patient stratification for emerging immunotherapeutic approaches and for optimizing follow-up strategies. In this study, we examined the expression patterns and clinical significance of five immune-related markers in a large cohort of TETs. MATERIAL AND METHODS:Expression of TIM3, OX40L, GTF2I, XPO1, and GITR was assessed by immunohistochemistry (IHC) in the epithelial and lymphocytic compartments of 137 surgically resected TETs and correlated with clinicopathological parameters and patient outcomes. Tumors were grouped according to their immune profile using cluster analysis. RESULTS:TIM3, GTF2I, and XPO1 showed high and consistent expression in the epithelial compartment of TETs across histological subgroups, whereas GITR expression was mostly absent. In the lymphocytic compartment, only XPO1 was highly expressed, with no significant differences between TET subtypes. Epithelial and lymphocytic OX40L expressions were significantly higher in patients with myasthenia gravis (vs. those without this autoimmune disorder; p = 0.004 and p = 0.045, respectively). Importantly, hierarchical clustering identified four distinct TET subgroups based on their combined immune marker expression profiles, which displayed widely divergent survival outcomes (p < 0.0001). Among these, the subgroup characterized by elevated epithelial expression of GTF2I, XPO1, and TIM3 showed worse survival in our multivariate model (HR 6.37; p = 0.025). CONCLUSIONS:TIM3, GTF2I, and XPO1 are highly expressed in the epithelial compartment of TETs, providing a rationale for therapeutic targeting in future immunotherapy trials. Differential IHC expression of TIM3, OX40L, GTF2I, XPO1, and GITR defines distinct TET subtypes with independent prognostic relevance, enabling more accurate risk assessment in these highly heterogeneous thoracic malignancies.

Background Tumor size is recently proposed as prognosticator in thymic tumors. The aim of this study is to investigate the prognostic role of tumor size in the different thymic tumor histologies. Methods Clinical and pathological data of patients from ESTS thymic database underwent surgery for TETs from 1/2000 to 12/2022 were reviewed, analyzed and correlated to overall survival (OS) and Disease free Survival (DFS) using Kaplan Meier curves. The log-rank test was used to assess differences between subgroups. Results The final analysis was conducted on 2.556 patients. Histology results showed thymoma in 2.231(87.3%), thymic carcinoma in 271(10.6%) and neuroendocrine tumors (NET) in 54 (2.1%) cases. In 1.518 (59.4%) size resulted > 5 cm.The survival difference was significant considering thymoma and thymic carcinoma/NET. The 5-and 10-year DFS of 85.4% and 78.1% versus 77.6% and 62.4% in ≤ 5 cm vs > 5 cm thymomas (p<0.001) and a 5- and 10-year OS of 92.4% and 79.4% versus 88% and 74.5% in ≤ 5 cm versus > 5 cm thymomas (p=0.002). For thymic carcinoma/NET, the DFS rate in the ≤ 5 cm group was 61.3% at both 5 and 10 years, compared to 53.3% and 46.9% in the > 5 cm group, respectively (p=0.042), while 5- and 10-year OS were 84.9% and 79.4% versus 74.9% and 64.9% in ≤ 5 cm versus > 5 cm groups (p=0.002). Conclusions Tumor size resulted a significant prognosticator in TET, thymoma and thymic carcinoma/NET, confirming its validity in prognosis prediction of these tumors.

The human thymus plays a key role in the development of the adaptive immune system. Its development and pathologic aberrations with missing involution occupy the scientific world for years. Here, we present a comprehensive single-cell RNA sequencing (scRNA-seq) analysis of 453,727 cells across 53 datasets derived from healthy prenatal, pediatric, and adult thymic tissues, as well as six pathological conditions, including thymic hyperplasia and thymic epithelial tumors (types A, AB, B, C, and micronodular thymoma). We created a high-resolution cellular atlas revealing disease-specific cellular populations and transcriptional programs, particularly within fibroblast subsets and thymic epithelial cells. Comparative analysis uncovers distinct intercellular communication patterns and identifies transcriptional alterations associated with thymic pathology. Integration with published bulk RNA-seq datasets supports the robustness and translational relevance of our findings. This study provides a foundational resource for understanding the cellular and molecular landscape of thymic development and disease, offering avenues for diagnostic and therapeutic innovations.

Background/Objectives: Soluble ST2 (sST2) has gained recognition as a clinically relevant biomarker across a spectrum of inflammatory, cardiovascular, and respiratory conditions. However, the lack of assay standardization raises concerns about result comparability across platforms and studies. Methods: This study systematically evaluated serum sST2 concentrations measured with two ELISA systems-DuoSet and Quantikine-produced by the same manufacturer (R&D Systems, Minneapolis, MN, USA). Results: Using archived serum samples from healthy volunteers and marathon runners, we identified marked discrepancies: serum sST2 concentrations using the DuoSet recombinant standard were on average 4.3-fold higher than those using Quantikine (median 308.3 [106.6-608.6] vs. 71.5 [41.8-115.6] ng/mL). On the pre-coated Quantikine plate, using the DuoSet recombinant standard increased calculated concentrations 4.3-fold compared with the native Quantikine standard (median 308.3 [106.6-608.6] vs. 71.5 [41.8-115.6] ng/mL). On the manually coated DuoSet plate, the DuoSet standard yielded higher medians than the Quantikine standard (8.0 [5.6-11.3] vs. 5.0 [3.7-7.4] ng/mL). Furthermore, between-lot variability within the same ELISA platform resulted in concentration shifts from 0.09 [0.07-0.10] ng/mL (2016) to 1.17 [0.81-3.23] ng/mL (2023) using the same sample. Previously published studies also exhibited wide inter-study variability among healthy cohorts. Conclusions: These findings emphasize that current ELISA systems for sST2 are not standardized and that cross-study comparisons should be interpreted with caution. Until universal standardization is implemented, sST2 should primarily be used for within-study comparisons. This variability may limit the reliability of longitudinal sST2 assessment even in clinical settings.

Marathon running exerts physical stress and may lead to transient immune dysregulation, increasing susceptibility to airway inflammation and exercise-induced bronchoconstriction (EIB). This study investigated systemic levels of antimicrobial peptides in athletes and their association with EIB. Serum concentrations of angiogenin, human beta-defensin 2 (hBD-2), major basic protein (MBP), S100A8, and S100A8/A9 were measured in 34 marathoners and 36 half-marathoners at baseline, immediately after a race, and seven days postrace using enzyme-linked immunosorbent assays and compared with 30 sedentary controls. Lung function was assessed by spirometry to identify bronchoconstriction. Levels of hBD-2 and S100A8/A9 were significantly elevated postrace in runners compared to baseline and controls, returning to baseline during recovery. During recovery, S100A8 levels remained slightly elevated in marathoners with EIB. Similarly, human beta-defensin 2 was modestly increased in runners who developed bronchoconstriction. Notably, S100A8 levels correlated negatively with lung function parameters, including forced expiratory volume and mid-expiratory flows. These findings suggest that endurance running induces systemic inflammatory responses and modulates innate immune peptides, particularly in individuals prone to bronchoconstriction. These peptides may serve as biomarkers of respiratory stress and help guide personalized strategies in endurance sports.

OBJECTIVE:The 9thTNM proposal for thymic epithelial tumours (TETs) introduced size as category in stage I, confirming tumour infiltration type as descriptor for the other stages. Aim of this study is to evaluate the role of tumour size in TETs considering different possible cut-offs also among different subgroups. MATERIAL AND METHODS:Clinical and pathological data of patients from ESTS thymic database who underwent surgery for TETs from1/2000 to 12/2022 were reviewed and analysed. Patients clinical data, tumour characteristics, size and organs infiltration were collected and correlated to overall survival (OS), Disease free Survival (DFS) and Cancer specific Survival (CSS) using Kaplan Meier curves. The log-rank test was used to assess differences between subgroups. A multivariable model was built using Cox-regression analysis including clinical relevant variables resulting significant at univariable (p-value < 0.05). RESULTS:The final analysis was conducted on 2146 patients. Most patients presented tumours size >5 cm(59 %)and without surrounding structures infiltrations (51.3 %). During FUP, a recurrence occurred in 235 (11%) patients, 199 (9.3%) died, 38 due to tumour progression. Multivariable confirmed as independent negative prognostic factors age (p < 0.001), carcinoma/NETT histology (p < 0.001),TETs size >5 cm (p < 0.001, HR 2.16; 95 %CI 1.32-3.50), and infiltration (p = 0.04) for OS; advanced TNM STAGE 9th edition (p < 0.001) and carcinoma/NETT (p = 0.001) for DFS; infiltration presence (p < 0.001) and carcinoma/NETT (p < 0.001) for CSS. Significant differences in OS, DFS and CSS were present considering size cut-off 5 cm (p < 0.001, p < 0.001 and p = 0.001, respectively), while using 3 cm cut-off only DFS (p < 0.001) and CSS (p = 0.001) resulted statistically significant. Significant differences in OS, DFS and CSS were present considering surrounding organ infiltration in TETs ≤ 5 cm (p = 0.004, p < 0.001 and p = 0.001) and in TETs > 5 cm (p = 0.024, p < 0.001 and p < 0.001). CONCLUSIONS:Tumour size resulted a significant prognosticator in TETs, and its associations with infiltration permits to identify different prognostic groups.

The lung can experience different oxygen concentrations, low as in hypoxia, high as under supplemental oxygen therapy, or oscillating during intermittent hypoxia as in obstructive sleep apnea or intermittent hypoxia/hyperoxia due to cyclic atelectasis in the ventilated patient. This study aimed to characterize the oxygen-condition-specific protein composition of extracellular vesicles (EVs) released from human pulmonary microvascular endothelial cells in vitro to decipher their potential role in biotrauma using quantitative proteomics with bioinformatic evaluation, transmission electron microscopy, flow cytometry, and non-activated thromboelastometry (NATEM). The release of vesicles enriched in markers CD9/CD63/CD81 was enhanced under intermittent hypoxia, strong hyperoxia and intermittent hypoxia/hyperoxia. Particles with exposed phosphatidylserine were increased under intermittent hypoxia. A small portion of vesicles were tissue factor-positive, which was enhanced under intermittent hypoxia and intermittent hypoxia/hyperoxia. EVs from treatment with intermittent hypoxia induced a significant reduction of Clotting Time in NATEM analysis compared to EVs isolated after normoxic exposure, while after intermittent hypoxia/hyperoxia, tissue factor in EVs seems to be inactive. Gene set enrichment analysis of differentially expressed genes revealed that EVs from individual oxygen conditions potentially induce different biological processes such as an inflammatory response under strong hyperoxia and intermittent hypoxia/hyperoxia and enhancement of tumor invasiveness under intermittent hypoxia.

Sepsis is characterized by a dysfunctional host response to infection culminating in life-threatening organ failure that requires complex patient management and rapid intervention. Timely diagnosis of the underlying cause of sepsis is crucial, and identifying those at risk of complications and death is imperative for triaging treatment and resource allocation. Here, we explored the potential of explainable machine learning models to predict mortality and causative pathogen in sepsis patients. By using a modelling pipeline employing multiple feature selection algorithms, we demonstrate the feasibility of identifying integrative patterns from clinical parameters, plasma biomarkers, and extensive phenotyping of blood immune cells. While no single variable had sufficient predictive power, models that combined five and more features showed a macro area under the curve (AUC) of 0.85 to predict 90-day mortality after sepsis diagnosis, and a macro AUC of 0.86 to discriminate between Gram-positive and Gram-negative bacterial infections. Parameters associated with the cellular immune response contributed the most to models predictive of 90-day mortality, most notably, the proportion of T cells among PBMCs, together with expression of CXCR3 by CD4+ T cells and CD25 by mucosal-associated invariant T (MAIT) cells. Frequencies of Vδ2+ γδ T cells had the most profound impact on the prediction of Gram-negative infections, alongside other T-cell-related variables and total neutrophil count. Overall, our findings highlight the added value of measuring the proportion and activation patterns of conventional and unconventional T cells in the blood of sepsis patients in combination with other immunological, biochemical, and clinical parameters.

BACKGROUND:The role of the number of involved structures (NIS) in thymic epithelial tumors (TETs) has been investigated for inclusion in future staging systems, but large cohort results still are missing. This study aimed to analyze the prognostic role of NIS for patients included in the European Society of Thoracic Surgeons (ESTS) thymic database who underwent surgical resection. METHODS:Clinical and pathologic data of patients from the ESTS thymic database who underwent surgery for TET from January 2000 to July 2019 with infiltration of surrounding structures were reviewed and analyzed. Patients' clinical data, tumor characteristics, and NIS were collected and correlated with CSS using Kaplan-Meier curves. The log-rank test was used to assess differences between subgroups. A multivariable model was built using logistic regression analysis. RESULTS:The final analysis was performed on 303 patients. Histology showed thymoma for 216 patients (71.3%) and NET/thymic carcinoma [TC]) for 87 patients (28.7%). The most frequently infiltrated structures were the pleura (198 cases, 65.3%) and the pericardium in (185 cases, 61.1%), whereas lung was involved in 96 cases (31.7%), great vessels in 74 cases (24.4%), and the phrenic nerve in 31 cases (10.2%). Multiple structures (range, 2-7) were involved in 183 cases (60.4%). Recurrence resulted in the death of 46 patients. The CSS mortality rate was 89% at 5 years and 82% at 10 years. In the univariable analysis, the favorable prognostic factors were neoadjuvant therapy, Masaoka stage 3, absence of metastases, absence of myasthenia gravis, complete resection, thymoma histology, and no more than two NIS. Patients with more than two NIS presented with a significantly worse CSS than patients with no more than two NIS (CSS 5- and 10-year rates: 9.5% and 83.5% vs 93.2% and 91.2%, respectively; p = 0.04). The negative independent prognostic factors confirmed by the multivariable analysis were incomplete resection (hazard ratio [HR] 2.543; 95% confidence interval [CI] 1.010-6.407; p = 0.048) and more than two NIS (HR 1.395; 95% CI 1.021-1.905; p = 0.036). CONCLUSIONS:The study showed that more than two involved structures are a negative independent prognostic factor in infiltrative thymic epithelial tumors that could be used for prognostic stratification.

Direct interaction between T-cells exerts a major influence on tissue immunity and inflammation across multiple body sites including the human gut, which is highly enriched in 'unconventional' lymphocytes such as γδ T-cells. We previously reported that microbial activation of human Vγ9/Vδ2+ γδ T-cells in the presence of the mucosal damage-associated cytokine IL-15 confers the ability to promote epithelial barrier defence, specifically via induction of IL-22 expression in conventional CD4+ T-cells. In the current report, we assessed whether other cytokines enriched in the gut milieu also functionally influence microbe-responsive Vγ9/Vδ2 T-cells. When cultured in the presence of IL-21, Vγ9/Vδ2 T-cells acquired the ability to induce expression of the immunoregulatory cytokine IL-10 in both naïve and memory CD4+ T-cells, at levels surpassing those induced by monocytes or monocyte-derived DCs. These findings identify an unexpected influence of IL-21 on Vγ9/Vδ2 T-cell modulation of CD4+ T-cell responses. Further analyses suggested a possible role for CD30L and/or CD40L reverse signalling in mediating IL-10 induction by IL-21 conditioned Vγ9/Vδ2 T-cells. Our findings indicate that the local microenvironment exerts a profound influence on Vγ9/Vδ2 T-cell responses to microbial challenge, leading to induction of distinct functional profiles among CD4+ T-cells that may influence inflammatory events at mucosal surfaces. Targeting these novel pathways may offer therapeutic benefit in disorders such as inflammatory bowel disease.

Purpose of review Thymectomy has long been used in the treatment of patients with myasthenia gravis and antibodies against the acetylcholine receptor. However, its effectiveness has only been proven a few years ago in a randomized controlled trial in patients under the age of 65. Here, we review the current literature focusing on patient subgroups, potential biomarkers for outcome prediction and the choice of surgical approach. Recent findings Long-term follow-up studies after thymectomy confirmed that the benefits regarding clinical outcome parameters and a reduced need for immunosuppressive treatment persist. Nevertheless, a substantial proportion of patients in real-world cohorts do not reach complete stable remission after thymectomy indicating that the underlying autoimmune process is sustained in the periphery. Our understanding of the responsible mechanisms has improved with recent studies. Presently, outcome data after thymectomy in several patient subgroups, such as those aged over 50 years, those with juvenile onset or those with purely ocular symptoms are limited and have been the focus of recent research activities. Similarly, biomarkers guiding an appropriate patient selection for thymectomy are under investigation. A number of cohort studies demonstrated that minimal invasive surgical techniques such as extended robotic thymectomy lead to similar positive outcomes as a transsternal approach with potentially fewer short-term adverse effects. Summary Thymectomy is an effective treatment option in adult patients with early onset acetylcholine-receptor positive myasthenia gravis but uncertainty remains with regard to certain patient subgroups.

Infection with severe acute respiratory syndrome coronavirus 2 associates with diverse symptoms, which can persist for months. While antiviral antibodies are protective, those targeting interferons and other immune factors are associated with adverse coronavirus disease 2019 (COVID-19) outcomes. Here we discovered that antibodies against specific chemokines were omnipresent post-COVID-19, were associated with favorable disease outcome and negatively correlated with the development of long COVID at 1 yr post-infection. Chemokine antibodies were also present in HIV-1 infection and autoimmune disorders, but they targeted different chemokines compared with COVID-19. Monoclonal antibodies derived from COVID-19 convalescents that bound to the chemokine N-loop impaired cell migration. Given the role of chemokines in orchestrating immune cell trafficking, naturally arising chemokine antibodies may modulate the inflammatory response and thus bear therapeutic potential.