RESUMEN
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.
RESUMEN
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.
Asunto(s)
Bases de Datos Factuales , Neoplasias Glandulares y Epiteliales , Neoplasias del Timo , Humanos , Neoplasias del Timo/patología , Neoplasias del Timo/cirugía , Neoplasias del Timo/mortalidad , Masculino , Femenino , Persona de Mediana Edad , Neoplasias Glandulares y Epiteliales/patología , Neoplasias Glandulares y Epiteliales/cirugía , Neoplasias Glandulares y Epiteliales/mortalidad , Pronóstico , Tasa de Supervivencia , Estudios de Seguimiento , Anciano , Estudios Retrospectivos , Adulto , Estadificación de Neoplasias , Timoma/patología , Timoma/cirugía , Timoma/mortalidad , Pleura/patología , Pleura/cirugía , Invasividad NeoplásicaRESUMEN
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.
Asunto(s)
Sepsis , Humanos , Sepsis/inmunología , Sepsis/microbiología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Biomarcadores/sangre , Receptores CXCR3/metabolismo , Aprendizaje Automático , Subunidad alfa del Receptor de Interleucina-2/sangre , Subunidad alfa del Receptor de Interleucina-2/inmunología , Inmunidad Celular , Linfocitos T CD4-Positivos/inmunología , Linfocitos T/inmunología , Pronóstico , Infecciones por Bacterias Gramnegativas/inmunologíaRESUMEN
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.
Asunto(s)
Vesículas Extracelulares , Hiperoxia , Humanos , Oxígeno/farmacología , Oxígeno/metabolismo , Hiperoxia/metabolismo , Proteoma/metabolismo , Células Endoteliales/patología , Tromboplastina/metabolismo , Pulmón/patología , Hipoxia/metabolismo , Vesículas Extracelulares/metabolismo , Endotelio/patologíaRESUMEN
INTRODUCTION: R0 resection and radiation therapy have been associated with improved overall survival (OS) in patients with thymic carcinoma (TC). Here, we analyzed which subgroups of patients derive the greatest benefit from postoperative radiation therapy (PORT). METHODS: Clinical, pathologic, treatment, and survival information of 462 patients with TC from the International Thymic Malignancy Interest Group/European Society of Thoracic Surgeons database were analyzed. Variables included age, sex, continent of treatment, paraneoplastic syndrome, carcinoma subtype, tumor size, pathologic Masaoka stage, resection status, and use of chemotherapy. OS was the primary end point using the Kaplan-Meier method. Time to recurrence (TTR) was the secondary end point using a competing risk analysis. A 3-month landmark analysis was performed. RESULTS: PORT was associated with a significant OS benefit (5-y OS 68% versus 53%, p = 0.002). In patients with R0 resection, PORT was associated with increased OS for advanced (stages III-IV, p = 0.04), but not early (stages I-II, p = 0.14) stage TC. In patients with an R1/2 resection of advanced-stage TC, PORT was associated with significantly longer OS (5-y OS 53% versus 38%; p < 0.001). Subset analyses did not reveal clear associations of PORT with TTR. On multivariable analysis, lower pathologic stage, PORT, and R0 resection status were associated with an OS benefit, whereas only higher age and lower pathologic stage had an association with longer TTR. CONCLUSIONS: In the largest individual patient data set on patients with TC reported to date, PORT was associated with a meaningful OS benefit in patients with advanced-stage TC after an R0 or R1/2 resection.
Asunto(s)
Neoplasias Pulmonares , Cirujanos , Timoma , Neoplasias del Timo , Humanos , Timoma/radioterapia , Timoma/cirugía , Opinión Pública , Estadificación de Neoplasias , Neoplasias Pulmonares/patología , Neoplasias del Timo/radioterapia , Neoplasias del Timo/cirugía , Estudios RetrospectivosRESUMEN
Objectives: Data on anesthetic proceedings during cardiac implantable electronic device (CIED) implant procedures are scarce and it remains unclear whether anesthetic care is still required in selected patients. Methods: In this retrospective, single center study we assessed the prevalence of intraoperative anesthetic management comprising anesthetic standby, sedation or general anesthesia as well as anesthetic and procedural complications. We analyzed pre-existing and perioperative risk factors related to procedure-related adverse outcome such as perioperative cardiopulmonary resuscitation (CPR) and 30-day mortality in a uni- and multivariable analysis. Results: In total, PM and ICD insertion were performed in up to 85% and 58% under anesthetic standby, with an increasing tendency over time.Overall, Cardiopulmonary resuscitation (CPR) was required in 59 patients. Acute heart failure (AHF) was the only independent pre-existing risk factor for CPR and for 30-day mortality. Sedation and general anesthesia had a significantly increased odds ratio for CPR compared to anesthetic standby. The risk for CPR significantly decreased during the study period. Conclusions: Over the years anesthetic practice during CIED implant procedures shifted from mixed anesthetic proceedings to mainly standby duties. The prevalence of complications and emergency measures is low, however not uncommon. Accordingly, the presence of an anesthesiologist should be further guaranteed when sedatives were titrated and in AHF patients. However, in patients receiving local anesthetic infiltration only, it seems safe to perform CIED implant procedures without anesthetic standby.
RESUMEN
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 50âyears, 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.
Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Miastenia Gravis , Adulto , Humanos , Persona de Mediana Edad , Timectomía , Miastenia Gravis/cirugía , Anticuerpos , Inmunosupresores , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
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.
Asunto(s)
COVID-19 , Humanos , SARS-CoV-2 , Autoanticuerpos , Síndrome Post Agudo de COVID-19 , QuimiocinasRESUMEN
BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by obstruction of major pulmonary arteries with organized thrombi. Clinical risk factors for pulmonary hypertension due to left heart disease including metabolic syndrome, left-sided valvular heart disease, and ischemic heart disease are common in CTEPH patients. OBJECTIVES: The authors sought to investigate prevalence and prognostic implications of elevated left ventricular filling pressures (LVFP) in CTEPH. METHODS: A total of 593 consecutive CTEPH patients undergoing a first diagnostic right and left heart catheterization were included in this study. Mean pulmonary arterial wedge pressure (mPAWP) and left ventricular end-diastolic pressure (LVEDP) were utilized for assessment of LVFP. Two cutoffs were applied to identify patients with elevated LVFP: 1) for the primary analysis mPAWP and/or LVEDP >15 mm Hg, as recommended by the current pulmonary hypertension guidelines; and 2) for the secondary analysis mPAWP and/or LVEDP >11 mm Hg, representing the upper limit of normal. Clinical and echocardiographic features, and long-term mortality were assessed. RESULTS: LVFP was >15 mm Hg in 63 (10.6%) and >11 mm Hg in 222 patients (37.4%). Univariable logistic regression analysis identified age, systemic hypertension, diabetes, atrial fibrillation, calcific aortic valve stenosis, mitral regurgitation, and left atrial volume as significant predictors of elevated LVFP. Atrial fibrillation, calcific aortic valve stenosis, mitral regurgitation, and left atrial volume remained independent determinants of LVFP in adjusted analysis. At follow-up, higher LVFPs were measured in patients who had meanwhile undergone pulmonary endarterectomy (P = 0.002). LVFP >15 mm Hg (P = 0.021) and >11 mm Hg (P = 0.006) were both associated with worse long-term survival. CONCLUSIONS: Elevated LVFP is common, appears to be due to comorbid left heart disease, and predicts prognosis in CTEPH.
Asunto(s)
Fibrilación Atrial , Hipertensión Pulmonar , Hipertensión , Insuficiencia de la Válvula Mitral , Estenosis de la Válvula Mitral , Humanos , Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/epidemiología , Hipertensión Pulmonar/etiología , Función Ventricular Izquierda , Presión Esfenoidal Pulmonar , Presión VentricularRESUMEN
The investigation of biomarkers associated with undesired outcome following lung transplantation (LuTX) is essential for a better understanding of the underlying pathophysiology, an earlier identification of susceptible recipients and the development of targeted therapeutic options. We therefore determined the longitudinal perioperative course of putative cytokines related to neutrophil activation (chemokine CC motif ligand 4 (CCL-4), interleukin (IL)-23 and Lipocalin 2 (LCN2)) and a cytokine that has been implicated in graft-versus-host disease (Follistatin-like 1 (FSTL1)) in 42 consecutive patients undergoing LuTX. We plotted receiver-operating curves (ROC) to assess the predictive power of the measured cytokines for short-term outcomes namely primary graft dysfunction (PGD), early complications requiring extracorporeal membrane oxygenation (ECMO), and a high postoperative sequential organ failure assessment (SOFA). All cytokines increased immediately after surgery. ROC analyses determined significant associations between CCL4 and a high SOFA score (area under the curve (AUC) 0.74 (95%CI:0.5−0.9; p < 0.05), between LCN2 and postoperative ECMO support (AUC 0.73 (95%CI:0.5−0.9; p < 0.05), and between FSTL1 and PGD (AUC 0.70 (95%CI:0.5−0.9; p < 0.05). The serum concentrations of the neutrophil-derived cytokines LCN2 and CCL4 as well as FSTL1 were all related to poor outcome after LuTX. The specific predictive power, however, still has to be assessed in larger trials. The potential role of FSTL1 as a biomarker in the development of PGD could be of great interest particularly since this protein appears to play a crucial role in allograft tolerance.
RESUMEN
Pulmonary hypertension (PH) is a risk factor for morbidity and mortality in patients undergoing surgery and anesthesia. This document represents the first international consensus statement for the perioperative management of patients with pulmonary hypertension and right heart failure. It includes recommendations for managing patients with PH being considered for surgery, including preoperative risk assessment, planning, intra- and postoperative monitoring and management strategies that can improve outcomes in this vulnerable population. This is a comprehensive document that includes common perioperative patient populations and surgical procedures with unique considerations.
Asunto(s)
Insuficiencia Cardíaca , Hipertensión Pulmonar , Consenso , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/cirugía , Humanos , Hipertensión Pulmonar/epidemiología , Hipertensión Pulmonar/cirugía , Medición de Riesgo , Factores de RiesgoRESUMEN
Objectives: The ratio of pulmonary artery (PA) and ascending aorta (AA) diameters has recently been shown to be a useful indicator for disease severity and predictor of outcome in patients with pulmonary hypertension and heart failure. This study aimed at evaluating the applicability of this ratio for perioperative risk assessment of patients with chronic thromboembolic pulmonary hypertension undergoing pulmonary endarterectomy. Methods: In this retrospective cohort study on 149 patients undergoing pulmonary endarterectomy between 2013 and 2020, the preoperative PA to AA ratio was analyzed on axial computed tomography. Variables of pulmonary hemodynamic status were assessed during preoperative right heart catheterization and postoperative Swan-Ganz catheter measurements. Perioperative survival was analyzed by Kaplan-Meier method and log-rank tests. Results: Preoperative computed tomography measurements showed a median AA diameter of 31 mm (range, 19-47 mm), and a median PA diameter of 36 mm (range, 25-55 mm). The calculated median PA to AA ratio was 1.13 (range, 0.79-1.80). PA to AA ratio correlated positively with PA pressure (systolic, r = 0.352 [P < .001]; diastolic, r = 0.406 [P < .001]; mean, r = 0.318 [P < .001]) and inversely with age (r = -0.484 [P < .001]). Univariable Cox regression analysis identified PA diameter (P = .008) as a preoperative parameter predictive of survival. There was a significant difference (log-rank P = .037) in 30-day survival probability for patients with lower PA to AA ratios (<1.136; survival probability, 97.4%) compared with patients with higher ratios (>1.136; survival probability, 88.9%). Conclusions: PA to AA ratio shows a correlation with other variables associated with pulmonary hypertension. In addition, patients with higher PA to AA ratios have lower survival probabilities after PEA. Further analysis of PA to AA ratio on the selection of chronic thromboembolic pulmonary hypertension for different treatment modalities-pulmonary endarterectomy, medical therapy, and or balloon pulmonary angioplasty-is warranted.
RESUMEN
This series of 15 articles (4 original articles and 11 reviews) is presented by international leaders in chemokine research [...].
RESUMEN
Background: Thymic carcinoma is a rare and highly malignant tumor with a dismal prognosis, which occasionally coexists with myasthenia gravis (MG). This study aims to investigate the MG incidence on a surgical cohort of patients with thymic carcinoma and to explore its influence on long-term survival. Methods: the prospectively collected data from the ESTS database on thymic epithelial tumors were reviewed. Clinical, pathological, and survival information on thymic carcinoma were analyzed. Results: the analysis was conducted on 203 patients, with an equal gender distribution (96 males and 107 females). MG was detected in 22 (10.8%) patients, more frequently elderly (>60 years, p = 0.048) and male (p = 0.003). Induction therapy was performed in 22 (10.8%) cases. After surgery, 120 (59.1%) patients had a Masaoka stage II−III while complete resection (R0) was achieved in 158 (77.8%). Adjuvant therapy was performed in 68 cases. Mean follow-up was 60 (SD = 14) months. The 3-year, 5-year and 10-year survival rates were 79%, 75% and 63%, respectively. MG did not seem to influence long-term survival (5-year survival in non-MG−TCs 78% vs. 50% in MG−TCs, p = ns) as age < 60 years, female gender, early Masaoka stage, and postoperative radiotherapy did, conversely. Conclusions: myasthenia occurred in about 10% of thymic carcinomas and it did not seem to affect significantly the long-term prognosis in surgically treated thymic carcinoma-patients.
RESUMEN
BACKGROUND: The spatial distribution of tumour-infiltrating lymphocytes (TILs) is a novel descriptor characterising the tumour immune microenvironment (TIME). The aim of our study was to assess whether a specific TIME of surgically resected thymic carcinoma (TC) can predict tumour invasiveness, recurrence or survival. METHODS: Digital microscopy was performed on 39 TCs immunohistochemically stained to investigate the activation of the immune checkpoint pathway (PD-L1/PD-1), along with density and spatial distribution of TILs phenotypes (CD3+, CD4+, CD8+, FOXP3+, CD56+). The impact of PD-L1 and TIL density considering the intratumoural (iTILs) and stromal (sTILs) distribution on pathological characteristics and clinical outcomes were analysed. RESULTS: In early TC stages, we observed a higher total density of CD3+ (p = 0.05) and CD8+ (p = 0.02) TILs. PD-L1 was expressed in 71.8% of TCs. In advanced TC stages, we observed a lower density of CD3+ (p = 0.04) and CD8+ (p = 0.01) iTILs compared to early stages. Serum concentrations of PD-L1 were significantly higher in TCs compared to healthy controls: 134.43 ± 18.51 vs. 82.01 ± 6.34 pg/ml (p = 0.001), respectively. High densities of stromal CD4+ TILs (54 vs. 32%, p = 0.043) and CD8+ TILs (65 vs. 17%, p = 0.048) were associated with improved freedom from recurrence (FFR) and cause-specific survival (CSS). High density of FoxP3+ TILs were associated with improved FFR (p = 0.03) and CSS (p = 0.003). DISCUSSION: Mapping TIL subpopulations complement the armamentarium for prognostication of TC outcomes. The improved outcome in patients with high density of TILs supports the use of immune checkpoint inhibitors in TC patients.