Vascular endothelial growth factor

We report on the feasibility, safety, and efficacy of performing therapeutic plasmapheresis (TPE) in parallel with extracorporeal membrane oxygenation (ECMO) to alleviate antibody mediated rejection (AMR) after heart transplantation. Two pediatric and one adult patient presented with severe congestive heart failure and respiratory distress after heart transplantation and required ECMO support. TPE was initiated to treat AMR while patients remained on ECMO. Each patient received three to five procedures either every day or every other day. One equivalent total plasma volume (TPV) was processed for each procedure (patient TPV + ECMO extracorporeal TPV). A total of 13 TPE procedures were performed with 12 procedures completed without complications or adverse events; one procedure was terminated before completion because of cardiac arrhythmia. Anti-HLA antibody titers decreased after TPE in all three patients. Ventricular function improved and ECMO was discontinued in 2 of 3 patients. Performing large volume TPE with a processed volume up to 2.5 times the patient's TPV is well tolerated in both pediatric (< or = 10 kg) and adult patients. TPE in parallel with ECMO is feasible, safe, and may be measurably effective at reducing anti-HLA antibodies and should be considered as part of the treatment for patients with early AMR after heart transplantation.

No abstract

Approval of the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab by the FDA in 2004 reflected the success of this vascular targeting strategy in extending survival in patients with advanced cancers. However, consistent with previous reports that experimental tumors can grow or recur during VEGF blockade, it has become clear that many patients treated with VEGF inhibitors will ultimately develop progressive disease. Previous studies have shown that disruption of VEGF signaling in tumors induces remodeling in surviving vessels, and link increased expression of angiopoietin-1 (Ang-1) with this process. However, overexpression of Ang-1 in different tumors has yielded divergent results, restricting angiogenesis in some systems while promoting it in others. These data raise the possibility that effects of Ang-1/Tie-2 may be context-dependent. Expression of an Ang-1 construct (Ang1*) did not significantly change tumor growth in our model prior to treatment, although vessels exhibited changes consistent with increased Tie-2 signaling. During inhibition of VEGF, however, both over-expression of Ang1* and administration of an engineered Ang-1 agonist (Bow-Ang1) strikingly protected tumors and vasculature from regression. In this context, Ang-1/Tie-2 activation limited tumor hypoxia, increased vessel caliber, and promoted recruitment of mural cells. Thus, these studies support a model in which activation of Tie-2 is important for tumor and vessel survival when VEGF-dependent vasculature is stressed. Understanding such mechanisms of adaptation to this validated form of therapy may be important in designing regimens that make the best use of this approach.

Small animal imaging systems now allow researchers to non-invasively monitor the progression of diseases in living small animals and study the efficacy of drugs and treatment protocols. Magnetic resonance imaging (MRI) is an established imaging modality capable of obtaining high resolution anatomical images which are sensitive to blood volume, blood flow, and metabolic rate of oxygen. Optical tomography, on the other hand, is an emerging imaging modality, which, while much lower in spatial resolution and insensitive to blood flow, can separate the effects of oxyhemoglobin, deoxyhemoglobin, and blood volume with high temporal resolution. We illustrate how these imaging modalities can supplement each other and cross validation can be performed by applying both modalities to imaging of tumors growth & regression in mice that are treated with a vascular endothelial growth factor (VEGF) antagonist.