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Orally Administered 9-cis Retinoid Acid Improves Functional Lymphatic Drainage In Post-surgical Lymphedema
Roy P. Yu, BS, Anjali C. Raghuram, BA, Jingxin Yao, BS, Andrea Y. Lo, BS, Haig L. Manoukian, Sarah X. Wang, Sun Young Park, MS, Wan Jiao, MD, PhD, Alex K. Wong, MD.
Keck School of Medicine, Los Angeles, CA, USA.

PURPOSE: We have previously shown that daily intraperitoneal administration of 9-cis Retinoic Acid (9-cis RA) is associated with increased lymphangiogenesis and lymphatic clearance in a mouse tail model of lymphedema. Since an oral dosing regimen would have higher clinical translatability, we sought to determine if orally administered 9-cis RA was similarly effective in preventing lymphedema.
METHODS: In a mouse tail model, secondary lymphedema was induced by excising 5 mm of skin circumferentially and obliterating all remaining lymphatics utilizing injection of methylene blue and the operative microscope. Twenty-five sex-matched FVB mice aged weighing between 20 and 30 grams were assigned to one of three groups: control (n=8), low-dose 9-cis RA (n=8), and high-dose 9-cis RA (n=9). 9-cis retinoic acid was dissolved in soybean oil, and vehicle control consisted of soybean oil. Low-dose 9-cis RA mice and high-dose 9-cis RA mice received doses of 10 mg/kg and 30 mg/kg respectively, and each mouse was given 0.15 mL of solution via oral gavage daily. The tail images were taken every week for 6 weeks and analyzed with ImageJ software. On POD42, mice tails were injected intradermally with indocyanine green (ICG), and fluorescence was captured and quantified via NOVADAQ Spy Fluorescence Imaging at 0, 1, 3, 6, 12, 24, 48, 72, and 96 hours. Lastly, a comprehensive metabolic panel was performed on the blood serum of each mouse.
RESULTS: The percentage change in tail volume of the low 9-cis RA group was statistically lower than the control group at all time points beginning on POD14 (p < 0.05). At POD14, the mean change in tail volume for the low 9-cis RA group and control groups were 18.11% and 69.26% respectively (p < 0.001). The percentage change in fluorescence from hour 1 post-ICG injection was significantly different between low-dose 9-cis RA group and the control group at 72, 96, and 120 hours (p < 0.05). The high-dose 9-cis RA group did not show a significant difference in tail volume change or fluorescence change relative to the control group. In addition, the high-dose 9-cis RA group demonstrated mild cutaneous irritation in the perioral and throat regions while these adverse events were not observed in the low-dose 9-cis RA group. The chemistry panel results showed no significant differences between control and both 9-cis RA groups, and there was no significant difference in weights for any groups at any time point.
CONCLUSION: Treatment with orally administered 9-cis RA at an oral dose of 10 mg/kg attenuates the volume change associated with lymphedema and improves lymphatic drainage in a mouse tail model. These findings offer a potential preventative treatment for patients at risk of developing secondary lymphedema.


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