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Cutaneous angiosarcoma (CAS) is a malignant sarcoma with poor prognosis. Programmed cell death-1 (PD-1)/programmed cell death-1 ligand-1 (PD-L1) expression reflects antitumor immunity, and is associated with patient prognosis in various cancers. The purpose of this study is to investigate the relationship between PD-1/PD-L1 expression and CAS prognosis. CAS cases (n D 106) were immunohistochemically studied for PD-L1 and PD-1 expression, and the correlation with patient prognosis was analyzed. PD-L1 expression was assessed by flow cytometry on three CAS cell lines with or without IFNg stimulation. A total of 30.2% of patients' samples were positive for PD-L1, and 17.9% showed a high infiltration of PD-1-positive cells. Univariate analysis showed a significant relationship between a high infiltration of PD-1-positive cells with tumor site PD-L1 expression and favorable survival in stage 1 patients (p D 0.014, log-rank test). Multivariable Cox-proportional hazard regression analysis also showed that patients with a high infiltration of PD-1-positive cells with tumor site PD-L1 expression were more likely to have favorable survival, after adjustment with possible confounders (hazard ratio (HR) D 0.38, p D 0.021, 95% confidence interval (CI) 0.16-0.86). Immunofluorescence staining of CAS samples revealed that PD-L1-positive cells were adjacent to PD-1-positive cells and/or tumor stroma with high IFNg expression. In vitro stimulation with IFNg increased PD-L1 expression in two out of three established CAS cell lines. Our results suggest that PD-1/PD-L1 expression is related to CAS progression, and the treatment with anti-PD-1 antibodies could be a new therapeutic option for CAS.

Objective-The response-to-tissue-injury theory is currently the favorite paradigm to investigate valve pathology. To the best of our knowledge, there are currently no in vivo valve injury models. There are few calcific aortic valve stenosis (AVS) models that develop hemodynamically significant stenosis. Here, we investigated the effect of direct mechanical injury on aortic valves in vivo and developed a novel mouse model of calcific AVS. Approach and Results-Aortic valve injury was created by inserting and moving a spring guidewire under echocardiographic guidance into the left ventricle of male C57/BL6 mice via right common carotid artery. Serial echocardiographic measurements revealed that aortic velocity was increased 1 week after injury and persistently increased until 16 weeks after injury. AVS mice showed a higher heart weight/body weight ratio and decreased left ventricular fractioning shortening 4 weeks after injury, compared with sham mice. We found remarkable proliferation of valve leaflets 4 weeks after injury. Proliferative valves showed increased production of reactive oxygen species and expression of inflammatory cytokines and osteochondrogenic factors. Alizarin red staining showed valvular calcification 12 weeks after injury. Conclusions-We report a novel calcific AVS model to support the response-to-tissue-injury theory. This model may be a valuable tool for analyzing the mechanism of AVS and assessing therapeutic options. Materials and MethodsMaterials and Methods are available in the online-only Supplement. Results Aortic Valve InjuryThe surgical procedure time, including anesthesia, needed for aortic valve injury was 21.0±5.1 minutes. Seven of 132 mice died during the operation due to sudden cardiac arrest (5 mice) and bleeding (2 mice). In the sham group, 1 of 63 mice died as a result of bleeding. After aortic valve injury, 25 of 125 mice died during the next 16 weeks. Survival curves showed that 18.7% of mice with aortic valve injury died <4 weeks, whereas none in the sham-operated mice died ( Figure 2A). The causes of death after aortic valve injury were congestive heart failure with pleural effusion at autopsy (5) and unknown causes (20), most likely attributable to cardiac arrhythmia or heart failure without obvious effusion. Valve and Ventricular FunctionImmediately after injury, aortic regurgitation was not observed on 2-dimensional color Doppler and pulse-wave Doppler imaging, and aortic velocity did not increase. Mice with aortic valve injury had significantly higher aortic velocity and smaller aortic valve area compared with sham-operated mice 1 week after surgery. The elevated velocity persisted for 16 weeks without improvement. Left ventricular outflow tract velocity was not significantly increased at all time points. Left ventricular fractional shortening was significantly decreased 4 weeks after surgery, and left ventricular end-diastolic diameter was increased 8 weeks after injury (see Table). Heart weight/body weight ratio gradually increased ( Figure 2C). Additionally, real-t...

BackgroundVarious adipokines are reported to be associated with the development of heart failure (HF) through insulin resistance and chronic inflammation. Omentin-1 is a novel adipokine and is associated with incident coronary artery disease. However, it remains unclear whether serum omentin-1 levels are associated with cardiac prognosis in patients with HF.MethodsWe measured serum omentin-1 levels at admission in 136 consecutive patients with HF, and 20 control subjects without signs of significant heart disease. We prospectively followed patients with HF to endpoints of cardiac death or re-hospitalization for worsening HF.ResultsSerum omentin-1 levels were markedly lower in HF patients with cardiac events compared with to without. The patients who were in New York Heart Association (NYHA) functional class IV showed significantly lower serum omentin-1 levels compared to those in class II and III, whereas serum omentin-1 levels did not correlate with serum brain natriuretic peptide levels (r = 0.217, P = 0.011). We divided the HF patients into three groups based on the tertiles of serum omentin-1 level (low T1, middle T2, and high T3). Multivariate Cox hazard analysis showed that the lowest serum omentin-1 level (T1) was independently associated with cardiac events after adjustment for confounding factors (hazard ratio 5.78, 95% confidence interval 1.20-12.79). We divided the HF patients into two groups according to the median serum omentin-1 levels. Kaplan-Meier analysis revealed that the patients with low serum omentin-1 levels had a higher risk of cardiac events compared with those with high serum omentin-1 levels (log-rank test p < 0.001).ConclusionDecreased serum omentin-1 levels were associated with a poor cardiac outcome in patients with HF.