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Short Duration 9-cis-Retinoic Acid Mitigates Postoperative Lymphedema in the Mouse Hindlimb Model
Maxwell Johnson, M.S., Daniel Gardner, M.S., Athanasios Bramos, M.D., Brandon Pang, B.S., Kian Banks, B.S., Young Jin Seong, B.A., Eunson Jung, M.A., Young-Kwon Hong, Ph.D., Alex K. Wong, M.D..
Keck School of Medicine of USC, Los Angeles, CA, USA.

PURPOSE:Lymphedema is an incurable disease that can occur after lymphadenectomy for the management of malignant tumors. We have previously shown that retinoic acids (RA) induce lymphangiogenesis in vitro and in vivo, and that continuous daily treatment with 9-cis-retinoic acid (9cisRA) for 45 days prevents secondary lymphedema in a mouse hindlimb model. To limit potential toxicity and side effects, we sought to identify the minimum effective duration of 9cisRA treatment.
METHODS:Ten week old Balb/c mice were radiated with 20 Gy in the right hindlimb. Ten days later, popliteal lymphadenectomy was performed. Animals were randomized to receive either 0.8mg/kg 9cisRA or vehicle control via daily intraperitoneal injection for 14 days after surgery. Change in paw thickness relative to the unoperated hindlimb was measured every 5 days for 45 days.
RESULTS:Gross swelling and increased paw thickness was observed in all animals by postoperative day (POD) five. Animals receiving 9cisRA for 14 days had 11.9% less paw thickness relative to the unoperated hindlimb than controls at POD 40 (p < 0.05). Paw skin from 9cisRA treated animals showed significant increase in podoplanin-positive lymphatics relative to untreated controls (p < 0.05).
CONCLUSION:This study demonstrates that 14 days of 9cisRA is effective in reducing postoperative lymphedema in the mouse hindlimb model. Reduced toxicity and side effects make 9cisRA a viable therapy for prevention of secondary lymphedema.


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