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Metastatic Ewing Sarcoma carries a poor prognosis, and novel therapeutics to prevent and treat metastatic disease are greatly needed. Recent evidence demonstrates that tumor-associated macrophages in Ewing Sarcoma are associated with more advanced disease. While some macrophage phenotypes (M1) exhibit anti-tumor activity, distinct phenotypes (M2) may contribute to malignant progression and metastasis. In this study, we show that M2 macrophages promote Ewing Sarcoma invasion and extravasation, pointing to a potential target of anti-metastatic therapy. CNI-1493 is a selective inhibitor of macrophage function and has shown to be safe in clinical trials as an anti-inflammatory agent. In a xenograft mouse model of metastatic Ewing Sarcoma, CNI-1493 treatment dramatically reduces metastatic tumor burden. Furthermore, metastases in treated animals have a less invasive morphology. We show in vitro that CNI-1493 decreases M2-stimulated Ewing Sarcoma tumor cell invasion and extravasation, offering a functional mechanism through which CNI-1493 attenuates metastasis. These data indicate that CNI-1493 may be a safe and effective adjuvant agent for the prevention and treatment of metastatic Ewing Sarcoma.

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BACKGROUND Extracorporeal life support utilizing extracorporeal membrane oxygenation (ECMO) techniques has been used in the pediatric population for numerous indications, but its use in trauma has been understudied. We sought to examine the indications, characteristics, and outcomes of children placed on ECMO for trauma and hypothesized that outcomes would be equivalent to those of patients placed on ECMO for other indications. METHODS We performed a retrospective review of all pediatric trauma patients in the Extracorporeal Life Support Organization registry from 1989 to 2018. Patient characteristics, indications for ECMO, pre- and post-ECMO ventilator settings and blood chemistry, complications, and survival rates were examined. Categories were stratified by mode: venovenous (VV), veno-arterial (VA), or conversion. Data were analyzed using SPSS software, with significance considered at p value less than 0.05. RESULTS We identified 573 patients with a median age of 4.82 years. The majority of patients (62.3%) were male and on VA support (54.5%). Drowning (38.7%) was the most common mechanism, followed by burns (21.1%) and thoracic trauma (17.8%). Complication rates were high (81.9%), with the most frequent types being cardiovascular, mechanical, and hemorrhagic. Incidences of complications (overall and by type) were similar to those reported in other Extracorporeal Life Support Organization cohorts. Overall survival was 55.3% and was significantly higher (p = 0.00) for patients on VV (74.3%) compared with those on VA (41.7%), even when controlling for mechanism. CONCLUSION Survival and complication rates of pediatric trauma patients on ECMO are comparable to those reported for other indications. Trauma should not be considered a contraindication for ECMO. LEVEL OF EVIDENCE Therapeutic, level V.

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