Treatment of superficial vascular anomalies with topical sirolimus: A multicenter case series.

BACKGROUND: Systemic sirolimus (rapamycin) has recently been found effective in treating complex vascular anomalies by reducing the size and associated complications. Many vascular anomalies have a cutaneous component, and thus, we sought to determine whether topical administration of sirolimus may be an effective therapy, as data on the use of topical sirolimus are limited. OBJECTIVE: We reviewed the efficacy and tolerability of topical formulations of sirolimus in the treatment of various simple and combined vascular malformations and tumors. METHODS: Eighteen patients with any vascular anomaly treated exclusively with topical sirolimus were retrospectively reviewed. RESULTS: Eleven patients had combined venous lymphatic malformations, three had tufted angiomas, two had a lymphatic malformation, one had a venous malformation, and one had a verrucous venous malformation. All (100%) patients reported some degree of improvement and 50% of patients reported marked improvement in one or more symptoms, most commonly blebs and lymphatic drainage, and bleeding. LIMITATIONS: The retrospective nature, small number of patients, and differences in topical preparations limit the broad application of the results. CONCLUSION: Topical sirolimus appears to be a safe and useful non-invasive therapy that is well-tolerated in the treatment of the cutaneous portion of a variety of vascular anomalies.

Ponatinib Combined With Rapamycin Causes Regression of Murine Venous Malformation.

Objective- Venous malformations (VMs) arise from developmental defects of the vasculature and are characterized by massively enlarged and tortuous venous channels. VMs grow commensurately leading to deformity, obstruction of vital structures, bleeding, and pain. Most VMs are associated with the activating mutation L914F in the endothelial cell (EC) tyrosine kinase receptor TIE2. Therapeutic options for VM are limited and ineffective while therapy with the mammalian target of rapamycin inhibitor rapamycin shows moderate efficacy. Here, we investigated novel therapeutic targets promoting VM regression. Approach and Results- We performed an unbiased screen of Food and Drug Administration-approved drugs in human umbilical vein ECs expressing the TIE2-L914F mutation (HUVEC-TIE2-L914F). Three ABL (Abelson) kinase inhibitors prevented cell proliferation of HUVEC-TIE2-L914F. Moreover, c-ABL, common target of these inhibitors, was highly phosphorylated in HUVEC-TIE2-L914F and VM patient-derived ECs with activating TIE2 mutations. Knockdown of c-ABL/ARG in HUVEC-TIE2-L914F reduced cell proliferation and vascularity of murine VM. Combination treatment with the ABL kinase inhibitor ponatinib and rapamycin caused VM regression in a xenograft model based on injection of HUVEC-TIE2-L914F. A reduced dose of this drug combination was effective in this VM murine model with minimal side effects. The drug combination was antiproliferative, enhanced cell apoptosis and vascular channel regression both in vivo and in a 3-dimensional fibrin gel assay. Conclusions- This is the first report of a combination therapy with ponatinib and rapamycin promoting regression of VM. Mechanistically, the drug combination enhanced AKT inhibition compared with single drug treatment and reduced PLCγ (phospholipase C) and ERK (extracellular signal-regulated kinase) activity.

Magnetic resonance imaging signatures of vascular pathology in multiple sclerosis.

Venous vascular contributing factors to multiple sclerosis (MS) have been known for some time. Only recently has the scope of their potential role become more apparent with the theory of chronic cerebrospinal venous insufficiency (CCSVI). As research expands to further explore the role of vascular pathology in the MS population, it is expedient to review the evidence from an imaging perspective. In this paper, we review the current state-of-the-art methods using magnetic resonance imaging (MRI) as applied to imaging MS patients and CCSVI. This includes evaluating imaging signatures of vascular structure and flow as well as brain iron content. Upon review of the literature, we find that extracranial venous anomalies including stenosis, venous malformations, and collateralization of flow in the major veins of the neck have been observed to be prevalent in the MS population. Abnormal flow has been reported in MS patients both in major vessels using phase-contrast flow quantification and in the brain using perfusion-weighted imaging. We discuss the role of quantitative flow imaging and its potential in assessing possible biomarkers for abnormal flow. Finally, it has been suggested that the presence of high iron content may indirectly indicate progression of existing vascular pathology. To that end, we review the use of susceptibility-weighted imaging in monitoring iron in the thalamus, basal ganglia, and MS lesions.