Targeting the contact system in a rabbit model of extracorporeal membrane oxygenation.

Previous studies suggested that contact pathway factors drive thrombosis in mechanical circulation. We used a rabbit model of veno-arterial extracorporeal circulation (VA-ECMO) to evaluate the role of factors XI and XII in ECMO-associated thrombosis and organ damage. Factors XI and XII (FXI, FXII) were depleted using established antisense oligonucleotides before placement on a blood-primed VA-ECMO circuit. Decreasing FXII or FXI to < 5% of baseline activity significantly prolonged ECMO circuit lifespan, limited the development of coagulopathy, and prevented fibrinogen consumption. Histological analysis suggested that FXII depletion mitigated interstitial pulmonary edema and hemorrhage whereas heparin and FXI depletion did not. Neither FXI nor FXII depletion was associated with significant hemorrhage in other organs. In vitro analysis showed that membrane oxygenator fibers (MOFs) alone are capable of driving significant thrombin generation in a FXII- and FXI-dependent manner. MOFs also augment thrombin generation triggered by low (1 pM) or high (5 pM) tissue factor concentrations. However, only FXI elimination completely prevented the increase in thrombin generation driven by MOFs, suggesting MOFs augment thrombin-mediated FXI activation. Together, these results suggest that therapies targeting FXII or FXI limit thromboembolic complications associated with ECMO. Further studies are needed to determine the contexts wherein targeting FXI and FXII, either alone or in combination, would be most beneficial in ECMO. Moreover, studies are also needed to determine the potential mechanisms coupling FXII to end-organ damage in ECMO.

A Murine Model of Veno-Arterial Extracorporeal Membrane Oxygenation.

The mechanisms driving the pathologic state created by extracorporeal membrane oxygenation (ECMO) remain poorly defined. We developed the first complete blood-primed murine model of veno-arterial ECMO capable of maintaining oxygenation and perfusion, allowing molecular studies that are unavailable in larger animal models. Fifteen C57BL/6 mice underwent ECMO by cannulating the left common carotid artery and the right external jugular vein. The mean arterial pressure was measured through cannulation of the femoral artery. The blood-primed circuit functioned well. Hemodynamic parameters remained stable and blood gas analyses showed adequate oxygenation of the animals during ECMO over a 1-hour timeframe. A significant increase in plasma-free hemoglobin was observed following ECMO, likely secondary to hemolysis within the miniaturized circuit components. Paralleling clinical data, ECMO resulted in a significant increase in plasma levels of multiple proinflammatory cytokines as well as evidence of early signs of kidney and liver dysfunction. These results demonstrate that this novel, miniature blood-primed ECMO circuit represents a functional murine model of ECMO that will provide unique opportunities for further studies to expand our knowledge of ECMO-related pathologies using the wealth of available genetic, pharmacological, and biochemical murine reagents not available for other species.

Ingested Foreign Bodies Can Cause Appendicitis and Perforation: A Multi-Institutional Case Series.

INTRODUCTION: Appendicular foreign bodies are a rare, under-described cause of appendicitis. We performed this study to determine the varied causes and consequences of foreign-body appendicitis. METHODS: On retrospective review of the pathology archives of seven institutions, we identified 56 appendix specimens containing a foreign body (defined as ingested, non-digestible material). We recorded the type of foreign body, patient age and sex, and other findings, as available. RESULTS: Mean patient age was 7.7 years (range: 1 day-18 years). The foreign bodies included hair, plant material, magnets, other metallic material, BB pellets, foreign material not otherwise specified, and other miscellaneous objects. Of 48 cases with available clinical information, 31 patients presented with abdominal pain, and 22 were preoperatively diagnosed as having appendicitis/appendicular inflammation. Seven patients had appendiceal perforation (13%). The foreign body was grossly identified in 34/47 cases with available gross descriptions. Twenty-seven cases had an identifiable foreign body microscopically; 10 were associated with giant cell reaction. DISCUSSION: Hair and plant materials were the most common foreign objects found in the appendix; they often cause mucosal damage and giant cell reaction. Metallic objects were less common. Although appendicular foreign bodies in children are rare and sometimes asymptomatic, they may lead to perforation.

Immuno-transcriptomic profiling of extracranial pediatric solid malignancies.

We perform an immunogenomics analysis utilizing whole-transcriptome sequencing of 657 pediatric extracranial solid cancer samples representing 14 diagnoses, and additionally utilize transcriptomes of 131 pediatric cancer cell lines and 147 normal tissue samples for comparison. We describe patterns of infiltrating immune cells, T cell receptor (TCR) clonal expansion, and translationally relevant immune checkpoints. We find that tumor-infiltrating lymphocytes and TCR counts vary widely across cancer types and within each diagnosis, and notably are significantly predictive of survival in osteosarcoma patients. We identify potential cancer-specific immunotherapeutic targets for adoptive cell therapies including cell-surface proteins, tumor germline antigens, and lineage-specific transcription factors. Using an orthogonal immunopeptidomics approach, we find several potential immunotherapeutic targets in osteosarcoma and Ewing sarcoma and validated PRAME as a bona fide multi-pediatric cancer target. Importantly, this work provides a critical framework for immune targeting of extracranial solid tumors using parallel immuno-transcriptomic and -peptidomic approaches.

Isolated Upper Extremity Posttransplant Lymphoproliferative Disorder in a Child.

Posttransplant lymphoproliferative disorder (PTLD) is a well-described complication of solid organ and bone marrow transplants. The most common presentation is intra-abdominal lymphadenopathy or single or multiple intraparenchymal masses involving the liver, spleen, or kidneys. Here we describe the imaging and pathology findings of an unusual case of PTLD appearing as an intramuscular forearm lesion in a pediatric male. The manifestation of PTLD as an isolated upper extremity mass in a pediatric patient has to our knowledge not been described.