The Macrophage Inhibitor CNI-1493 Blocks Metastasis in a Mouse Model of Ewing Sarcoma through Inhibition of Extravasation.

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.

Neonatal esophageal perforation: nonoperative management.

BACKGROUND: Esophageal perforation is a rare complication of enteric instrumentation in neonates. Enteric tube placement in micro-preemies poses a particular hazard to the narrow lumen and thin wall of the developing esophagus. The complication may be difficult to recognize or misdiagnosed as esophageal atresia, and is associated with considerable mortality. Historically, management of this life-threatening iatrogenic disease was operative, but trends have shifted toward nonoperative treatment. Here, we review neonatal esophageal perforation at our own institution for management techniques, risk factors, and outcomes. MATERIALS AND METHODS: Seven neonatal patients with esophageal perforation were identified and charts reviewed for demographics, comorbidities, etiology of perforation, diagnostic modalities, management decisions, complications, and outcomes. RESULTS: Mean gestational age was 27.2 ± 4.0 wk, and weight at diagnosis was 892 ± 674 g. All seven patients had esophageal perforation resulting from endotracheal or enterogastric intubation and were managed nonoperatively. Treatment included removal of the offending tube, nil per os, and antibiotics. Five patients required additional interventions: four tube thoracostomies for pneumothoraces and one peritoneal drain for pneumoperitoneum. Three patients died because of sequelae of prematurity (intraventricular hemorrhage, necrotizing enterocolitis, and sepsis). One patient was diagnosed as having esophageal atresia; esophagoscopy before surgical repair established the correct diagnosis. CONCLUSIONS: Neonates, particularly those under 1500 g, are at substantial risk for iatrogenic esophageal perforation during enterogastric intubation. Nonoperative management may be a safe initial strategy in the neonatal setting, but more aggressive interventions may ultimately be required. Despite recent improvement in early recognition of this injury, misdiagnosis still occurs.

Celecoxib inhibits Ewing sarcoma cell migration via actin modulation.

BACKGROUND: Ewing sarcoma (ES) is an aggressive childhood solid tumor in which 30% of cases are metastatic at presentation, and subsequently carry a poor prognosis. We have previously shown that treatment with celecoxib significantly reduces invasion and metastasis of ES cells in a cyclooxygenase-2-independent fashion. Celecoxib is known to downregulate ß-catenin independently of cyclooxygenase-2. Additionally, the actin cytoskeleton is known to play an important role in tumor micrometastasis. We hypothesized that celecoxib's antimetastatic effect in ES acts via modulation of one of these two targets. METHODS: ES cells were treated with celecoxib, and the levels of ß-catenin and total actin were examined by Western blot and quantitative polymerase chain reaction. Cells were transfected with small interfering RNA targeting ß-catenin, and invasion assays were performed. Immunofluorescence staining for ß-catenin and F-actin was performed on treated and untreated cells. Additionally, cells were subjected to a wound healing assay to assess migration. RESULTS: Celecoxib had no effect on the messenger RNA or protein levels of ß-catenin but did significantly decrease the amount of total actin within ES cells. Reduction of ß-catenin by small interfering RNA had no effect on invasion, and celecoxib treatment of the ß-catenin depleted cells continued to inhibit invasion. Immunofluorescence staining demonstrated no change in ß-catenin with treatment but did show a significant reduction in the amount of F-actin, as well as morphologic changes of the cells. Wound healing assays demonstrated that celecoxib significantly inhibited migration. CONCLUSIONS: Celecoxib does not exert its antimetastatic effects in ES through alteration of ß-catenin but does significantly modulate the actin cytoskeleton.

Recent trends in the operative experience of junior pediatric surgical attendings: a study of APSA applicant case logs.

PURPOSE: Pediatric surgical education and workforce have changed significantly in the past decade. To document trends in the operative experiences of junior pediatric surgeons, we examined case logs submitted by applicants for membership to APSA. METHODS: Case logs for 164 APSA membership applicants from 2006 to 2013 were reviewed. Total case volume, categories, and specific operations were analyzed. Negative binomial regression assessed for significant associations between the number of cases and the application year, presence of a pediatric surgery training program, region of the country, and years since fellowship completion. RESULTS: Overall case numbers decreased initially after 2006/2007, but have remained stable since. Decreasing trends were seen in a number of specific cases/categories. The number of newborn cases did not change. Significant variations in operative experience were identified depending upon region, presence of a pediatric surgery training program, and years since fellowship completion. Median reported value for several important cases was ≤4 per year, and for some was zero. CONCLUSION: These data describing the experience of young pediatric surgeons supplement recent observations regarding pediatric surgery fellows and general surgery residents. The limited exposure of surgeons to particularly rare conditions appears to be an unresolved problem. This information will be useful in developing future workforce proposals.