Hemangioma of infancy is the most common neoplasm of childhood. While hemangiomas are classic examples of angiogenesis, the angiogenic factors responsible for hemangiomas are not fully understood. Previously, we demonstrated that malignant endothelial tumors arise in the setting of autocrine loops involving vascular endothelial growth factor (VEGF) and its major mitogenic receptor vascular endothelial growth factor receptor 2. Hemangiomas of infancy differ from malignant endothelial tumors in that they usually regress, or can be induced to regress by pharmacologic means, suggesting that angiogenesis in hemangiomas differs fundamentally from that of malignant endothelial tumors. Here, we demonstrate constitutive activation of the endothelial tie-2 receptor in human hemangioma of infancy and, using a murine model of hemangioma, bEnd.3 cells; we show that bEnd.3 hemangiomas produce both angiopoietin-2 (ang-2) and its receptor, tie-2, in vivo. We also demonstrate that inhibition of tie-2 signaling with a soluble tie-2 receptor decreases bEnd.3 hemangioma growth in vivo. The efficacy of tie-2 blockade suggests that either tie-2 activation or ang-2 may be required for in vivo growth. To address this issue, we used tie-2-deficient bEnd.3 hemangioma cells, which, surprisingly, were fully proficient in in vivo growth. Previous studies from our laboratory and others have implicated reactive oxygen-generating nox enzymes in the angiogenic switch, so we examined the effect of nox inhibitors on ang-2 production in vitro and on bEnd.3 tumor growth in vivo. We then inhibited ang-2 production pharmacologically using novel inhibitors of nox enzymes and found that this treatment nearly abolished bEnd.3 hemangioma growth in vivo. Signal-transduction blockade targeting ang-2 production may be useful in the treatment of human hemangiomas in vivo.

Purpose Melanoma is a solid tumor that is notoriously resistant to chemotherapy, and its incidence is rapidly increasing. Recently, several signaling pathways have been demonstrated to contribute to melanoma tumorigenesis, including constitutive activation of MAP kinase, Akt and Stat-3. The activation of multiple pathways may account in part for the difficulty in treatment of melanoma. In a recent screen of compounds, we found that an organopalladium compound, tris (dibenzylideneacetone) dipalladium (Tris DBA), demonstrated significant antiproliferative activity against melanoma cells. Studies were carried out to determine the mechanism of action of Tris DBA Experimental Design Tris DBA was tested on efficacy on proliferation of human and murine melanoma cells. In order to find the mechanism of action of Tris DBA, we performed Western Blot analysis and gene array analysis. The ability of Tris DBA to block tumor growth in vivo was assessed. Results (Tris DBA), has activity against B16 murine and A375 human melanoma in vivo. Tris DBA inhibits several signaling pathways including activation of MAP kinase, Akt, Stat-3 and S6 kinase activation, suggesting an upstream target. Tris DBA was found to be a potent inhibitor of N-myristoyltransferase 1 (NMT-1), which is required for optimal activity of membrane based signaling molecules. Tris DBA demonstrated potent antitumor activity in vivo against melanoma. Conclusion Tris DBA is thus a novel inhibitor of NMT-1 with significant antitumor activity and is well tolerated in vivo. Further preclinical evaluation of Tris DBA and related complexes is warranted.

Melanoma is a common malignancy which is poorly responsive to chemotherapy and radiation. One of the major reasons melanoma responds poorly to these modalities is constitutive expression of Akt, which protects against apoptosis. The antidepressant sertraline was found to be a potent cytotoxic agent against A375 human melanoma. To determine the mechanism by which sertraline kills melanoma cells, Western blot analysis of signaling molecules, including phosphorylated Akt, caspase 9 and phospho-p70 S6 kinase was performed. Finally, the effects of sertraline on A375 xenografts in mice were assessed. Sertaline potently inhibited the phosphorylation of Akt, and caused cell death through induction of endoplasmic reticulum in vitro. Sertraline monotherapy demonstrated activity against A375 xenografts in vivo. Akt is a major cause of resistance of melanoma to current therapy. Antidepressants are commonly used to prevent interferon-induced depression. Use of antidepressants that decrease Akt may improve the efficacy of interferon and other therapies against melanoma. Further studies are needed to elucidate whether sertraline acts as an Akt inhibitor in melanoma.

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Background: While ventriculoperitoneal shunt (VPS) is the most commonly performed surgical procedure for treating hydrocephalus, complications following shunt placement are associated with a high mortality rate. Preoperative medical optimization and surgery are the primary means of correcting shunt migration. We present the case of an 11-week-old patient who underwent emergent surgical intervention for transrectal VPS migration and associated infection. Case Report: An 11-week-old female presented with VPS tubing protruding from her rectum. The patient had a history of grade III intraventricular hemorrhage complicated by hydrocephalus status post VPS placement at age 3 weeks. Shunt tap demonstrated gross infection, and she was started prophylactically on broad-spectrum antibiotics. She was taken emergently to the operating room (OR) for VPS externalization and exploratory minilaparotomy. VPS tubing was removed, and the patient was transferred to the pediatric intensive care unit for postoperative management. Cultures confirmed methicillinresistant Staphylococcus aureus, and the patient was treated according to infectious disease recommendations. On postoperative day (POD) 5, the patient had a full component VPS replacement. On POD 23, computed tomography scan of the head obtained for lethargy demonstrated a new midline shift, and she was returned to the OR for another VPS replacement. A small abscess was discovered and drained; postoperative cerebrospinal fluid laboratory values normalized after drainage. Once the infectious process cleared, the VPS was internalized on POD 33, and the patient was discharged home on POD 35. Conclusion: Few case reports detail the appropriate anesthetic considerations for cases of VPS migration. This report describes shunt migration pathophysiology and patient assessment with a focus on anesthetic preparation and management for this rare complication.