• Athanasios Bramos, David Perrault, Sara Yang, Eunson Jung, Young Kwon Hong, and Alex K Wong.
• *Department of Surgery, Division of Plastic and Reconstructive Surgery, Keck School of Medicine of University of Southern California, Los Angeles, CA†Department of Surgery and Biochemistry & Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine of University of Southern California, Los Angeles, CA.aCo-corresponding authors.
• Ann. Surg. 2016 Aug 1; 264 (2): 353-61.

ObjectiveTo determine the effect of 9-cis retinoic acid (9-cis RA) on postsurgical lymphedema.Background9-cis RA promotes lymphangiogenesis in vitro and in vivo and has promise as a therapeutic agent to limit the development of postsurgical lymphedema.MethodsLymphedema was induced in the right hind limb after a single fraction of 20 Gy radiation, popliteal lymphadenectomy, and lymphatic vessel ablation. Postoperatively, mice were randomly divided in to 2 groups that received daily intraperitoneal injections of either (1) an oil-based vehicle solution (control) or (2) 0.08 mg/kg of 9-cis RA dissolved in a vehicle solution. Outcome measures included paw thickness, lymphatic drainage, and lymphatic vessel density as measured by podoplanin immunohistochemistry and whole mount skin analysis.ResultsUsing our combined injury protocol, postsurgical lymphedema was observed 89% of the time. 9-cis RA-treated animals had less early postsurgical edema and significantly less paw lymphedema compared with vehicle-treated animals at all time-points (P < 0.001). 9-cis RA-treated animals had significantly faster lymphatic drainage as measured by indocyanine green clearance and increased lymphatic vessel density as measured by podoplanin immunohistochemistry (P < 0.001) and whole mount skin analysis (P < 0.05).ConclusionsWe have developed a highly reproducible model of secondary lymphedema and have demonstrated that 9-cis RA significantly prevents postsurgical lymphedema. Treatment with 9-cis RA is associated with increased lymphatic clearance and lymphangiogenesis. Because 9-cis RA (alitretinoin) is already approved for clinical use by the US Food and Drug Administration for other conditions, it has the potential to be repurposed as a preventative agent for postsurgical lymphedema in humans.

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