Larger pulmonary artery to ascending aorta ratios are associated with decreased survival of patients undergoing pulmonary endarterectomy.

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.

Tumour immune microenvironment in resected thymic carcinomas as a predictor of clinical outcome.

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.

The Roles of S100A4 and the EGF/EGFR Signaling Axis in Pulmonary Hypertension with Right Ventricular Hypertrophy.

Pulmonary hypertension (PH) is characterized by increased pulmonary arterial pressure caused by the accumulation of mesenchymal-like cells in the pulmonary vasculature. PH can lead to right ventricular hypertrophy (RVH) and, ultimately, heart failure and death. In PH etiology, endothelial-to-mesenchymal transition (EndMT) has emerged as a critical process governing the conversion of endothelial cells into mesenchymal cells, and S100A4, EGF, and EGFR are implicated in EndMT. However, a potential role of S100A4, EGF, and EGFR in PH has to date not been elucidated. We therefore quantified S100A4, EGF, and EGFR in patients suffering from chronic thromboembolic pulmonary hypertension (CTEPH) and idiopathic pulmonary arterial hypertension (iPAH). To determine specificity for unilateral heart disease, the EndMT biomarker signature was further compared between PH patients presenting with RVH and patients suffering from aortic valve stenosis (AVS) with left ventricular hypertrophy. Reduced S100A4 concentrations were found in CTEPH and iPAH patients with RVH. Systemic EGF was increased in CTEPH but not in iPAH, while AVS patients displayed slightly diminished EGF levels. EGFR was downregulated in all patient groups when compared to healthy controls. Longitudinal data analysis revealed no effect of surgical therapies on EndMT markers. Pulmonary thrombo-endarterectomized samples were devoid of S100A4, while S100A4 tissue expression positively correlated with higher grades of Heath-Edwards histopathological lesions of iPAH-derived lung tissue. Histologically, EGFR was not detectable in CTEPH lungs or in iPAH lesions. Together, our data suggest an intricate role for S100A4 and EGF/EGFR in PH with right heart pathology.

Transient perioperative inflammation following lung transplantation and major thoracic surgery with elective extracorporeal support: a prospective observational study.

BACKGROUND: The clinical relevance of inflammation induced by elective perioperative extracorporeal membrane oxygenation (ECMO) usage as an integral part of modern lung transplantation (LUTX) remains elusive. The aim of this study was to determine the perioperative cytokine response accompanying major thoracic surgery employing different extracorporeal devices comprising ECMO, cardiopulmonary bypass (CPB), or no extracorporeal circulation in relation to inflammation, clinically tangible as increased sequential organ failure assessment (SOFA) score, called SOFA. METHODS: In this prospective, observational pilot study 42 consecutive patients with end-stage pulmonary disease undergoing LUTX; 15 patients with chronic thromboembolic pulmonary hypertension (CTEPH) undergoing pulmonary endarterectomy and 15 patients with lung cancer undergoing major lung resections were analysed. Cytokine serum concentrations and SOFA were determined before, at end of surgery and in the following postoperative days. RESULTS: LUTX on ECMO and pulmonary endarterectomy (PEA) on CPB triggered an immediate increase in cytokine serum concentrations at end of surgery: IL-6: 66-fold and 71-fold, IL-10: 3-fold and 2.5-fold, ST2/IL-33R: 5-fold and 4-fold and SOFA: 10.5±2.8 and 10.7±1.7, that decreased sharply to baseline levels from postoperative day 1-5. Despite low perioperative mortality (3 patients, 4.1%) extremely high SOFA ≥13 was associated with mortality after LUTX. Delta-SOFA distinguished survivors from non-survivors: -4.5±3.2 vs. -0.3±1.5 (P=0.001). Increased IL-6 serum concentrations were predictive for increased SOFA (sensitivity: 97%, specificity: 80%). Peak cytokine serum concentrations correlated with ECC duration, maximal lactate, transfusion of red-blood-cells, fresh-frozen-plasma, and catecholamine support. CONCLUSIONS: LUTX and PEA on extracorporeal circulation with an excellent outcome triggered an immediate rise and concomitant fall of inflammation as observed in cytokine serum concentrations and SOFA. High absolute SOFA in the presence of an uncomplicated postoperative course may pertain to specific management strategies rather than organ failure.

Heat shock protein 90α in thymic epithelial tumors and non-thymomatous myasthenia gravis.

Background: Thymic epithelial tumors (TETs) are rare malignancies with unique association to the autoimmune disease myasthenia gravis (MG). Heat shock proteins (HSPs) harbor great potential as cancer biomarkers and HSP inhibitors approach clinical cancer therapy. Methods: To explore HSP pathophysiology, we assessed sera (immunoassays) and tissues (immunohistochemistry) of TETs (and thymic tissues) for HSP27, phosphorylated (p)HSP27, HSP70 and HSP90α expression in 114 TETs and 26 non-thymomatous MG patients undergoing extended thymectomy. Results: Serum concentrations of HSP90α were significantly increased in patients with thymic carcinomas, thymomas, thymic neuroendocrine tumors and non-thymomatous MG compared to patients who underwent thymectomy revealing regular thymic morphology or controls. In thymoma patients, high serum HSP90α represented a significantly worse prognostic factor for free-from-recurrence, and complete tumor resection led to decreased levels. The expression of HSP90 in nuclei and cytoplasm of tumor cells and non-neoplastic lymphocytes varied with WHO histological subtype. HSP90 was expressed in centroblasts of thymic germinal centers in MG patients. Higher pHSP27 serum concentrations were observed in seropositive MG and those not treated with steroids. Conclusions: HSP data suggest high potential for HSPs as TET cancer biomarkers or as candidates for targeted therapy. Caution is warranted in TET patients with associated MG overexpressing HSPs.

Clinical prognostic scores for patients with thymic epithelial tumors.

Several inflammation-based prognostic scores emerged in various types of cancer to predict clinical outcomes. So far, no accurate pre-treatment scoring systems exist for patients with thymic epithelial tumors (TETs), comprising thymomas and thymic carcinomas (TCs). Therefore, we sought to test the prognostic value of different clinical composite scores and their components, identify optimal cut-off values for TETs as well as combine predictive components to new suitable prognostic scores. One hundred eighty-four patients with TETs undergoing surgical tumor resection were analyzed. A significant advantage in Freedom-from-Recurrence and/or Cause-specific survival (CSS) was evident for patients with high Advanced-Lung- Cancer-Inflammation-Index, low CRP-Fibrinogen-Score (CFS), low Glasgow-Prognostic-Score (GPS), low high-sensitivity-modified GPS, low TET-adapted GPS (TET-aGPS) and low Systemic-Immune-Inflammation Index. On multivariable analysis high TET-aGPS (HR = 14.9;p = 0.001), incomplete resection status (HR = 13.5;p = 0.001) and TC (HR = 26.0;p = 0.001) were significant independent prognostic factors for worse CSS. The CFS had the highest coefficient of determination (R2 = 0.188) to predict tumor recurrence of all composite scores, comprising CRP (R2 = 0.141) and fibrinogen (R2 = 0.158), the best single factor predictors. Inflammation-based prognostic scores and selected components are suitable to predict survival and/or tumor recurrence in TET patients undergoing primary surgery. Due to excellent long-term survival and frequent tumor recurrence, cut-off values were tailored to increase prognostic power.