Simultaneous breast and lymphatic reconstruction is an ideal option for patients who suffer from lymphedema after mastectomy and axillary dissection.

Background— Lymphedema after surgery, infection, or radiation therapy is a common and often incurable problem. Application of lymphangiogenic growth factors has been shown to induce lymphangiogenesis and to reduce tissue edema. The therapeutic effect of autologous lymph node transfer combined with adenoviral growth factor expression was evaluated in a newly established porcine model of limb lymphedema. Methods and Results— The lymphatic vasculature was destroyed within a 3-cm radius around an inguinal lymph node. Lymph node grafts and adenovirally (Ad) delivered vascular endothelial growth factor (VEGF)-C (n=5) or VEGF-D (n=9) were used to reconstruct the lymphatic network in the inguinal area; AdLacZ (β-galactosidase; n=5) served as a control. Both growth factors induced robust growth of new lymphatic vessels in the defect area, and postoperative lymphatic drainage was significantly improved in the VEGF-C/D–treated pigs compared with controls. The structure of the transferred lymph nodes was best preserved in the VEGF-C–treated pigs. Interestingly, VEGF-D transiently increased accumulation of seroma fluid in the operated inguinal region postoperatively, whereas VEGF-C did not have this side effect. Conclusions— These results show that growth factor gene therapy coupled with lymph node transfer can be used to repair damaged lymphatic networks in a large animal model and provide a basis for future clinical trials of the treatment of lymphedema.

Lymphangiogenic growth factors improve lymphatic vessel regeneration and lymph node function after lymph node transfer. The perinodal route of delivery provides a basis for future clinical trials in lymphedema patients.

Our results show that VEGF-C provides the preferred alternative for growth factor therapy of lymphedema when compared to VEGF-C156S, due to the superior lymphangiogenic response and minor blood vessel effects. Furthermore, these observations suggest that activation of both VEGFR-2 and VEGFR-3 might be needed for efficient lymphangiogenesis.

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Transfer of the metabolically inactive (epididymal) fat into a new environment modulated the metabolic activity of the fat grafts to resemble the situation in the recipient site. These novel findings support the clinical use of free fat grafts in various anatomical regions and tissue types. Proangiogenic VEGF-A therapy enhanced the vascularization and survival of the free fat grafts.

The presence of lymphatic vessels has been known for centuries, but the key players regulating the lymphatic vessel growth and function have only been discovered during the recent decade. The lymphatic vasculature is essential for maintenance of normal fluid balance and for the immune response. Hypoplasia or dysfunction of the lymphatic vessels can lead to lymphedema. Currently, lymphedema is treated primarily by physiotherapy, compression garments, and occasionally by surgery, but the means to reconstitute the collecting lymphatic vessels and cure the condition are limited. Specific growth factor therapy has been used in experimental models to regenerate lymphatic capillaries and collecting vessels after surgical damage. Recent results provide a new concept of combining growth factor therapy with lymph node transplantation as a rationale for treating secondary lymphedema. Lymphatic vessels are also involved in lymph node and systemic metastasis of cancer cells; our understanding of mechanisms of lymphatic metastasis has increased remarkably.

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