Development of New Serum Biomarkers for Early Lymphedema Detection

Andre´sA. Herrada, PhD, Camila Mej´ıas, Rodrigo Lazo-Amador, Alexandra Olate-Briones, Danitza Lara, and Noelia Escobedo, PhD. Lymphatic Research and Biology 2019.

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Development of New Serum Biomarkers for Early Lymphedema Detection

Andre´sA.Herrada ,PhD, Camila Mej´ıas, RodrigoLazo-Amador, Alexandra Olate-Briones, Danitza Lara, and Noelia Escobedo, PhD. Lymphatic Research and Biology 2019

Background: Early lymphedema detection may reduce the symptoms and improve clinical outcomes. However, the lack of reliable serum biomarkers capable of predicting lymphedema development is a current medical problem. In this study, we investigated if serum levels of hyaluronic acid (HA) and leukotriene B4 (LTB4), two molecules involved in lymphedema development, may work as predictors of this condition.

Methods and Results: A mouse model of acquired lymphedema was generated through ablation of tail dermal lymphatic network. Tail diameter was measured daily, and HA and LTB4 serum levels were analyzed before and during the development of lymphedema. We found increased serum levels of HA and reduced levels of LTB4 at early days before the appearance of lymphedema signs. Similar results were observed in the lymphedema tissue. Increased local and systemic inflammation was also detected at early time points. Moreover, the ratio LTB4/HA arises as the strongest predictor for lymphedema development. In fact, we found an inverse correlation in our model, where reduced LTB4/HA levels showed increased lymphedema signs.

Conclusions: These findings suggest that serum ratio of LTB4/HA may be a useful biomarker to predict acquired lymphedema development, with potential to be used in clinical conditions such as breast cancer patients.

Main findings

  • These results suggest that serum HA by itself is not a good biomarker capable of predicting acquired lymphedema development.
  • Serum levels of LTB4 can be a good biomarker candidate to predict the development of acquired lymphedema.
  • A reduction of LTB4 levels in the lymphedema tissue can be found at early days postsurgery.
  • All these results showed increased local and systemic inflammation at early days postsurgery and suggest that changes in HA or LTB4 levels in the serum or in the lymphedematous tissue could contribute to this increased immune response.
  • These results suggest that serum ratio of LTB4/HA is the strongest predictor of acquired lymphedema development in mice.
  • The LTB4/HA ratio is not only able to predict the development of acquired lymphedema but also can give us information about how it will be the severity of lymphedema, with potential in clinical diagnostics.
  • In summary, our observations indicate that serum ratio of LTB4/HA can work as a novel biomarker to predict the development and the severity of acquired lymphedema. Because of the importance of these molecules in modulating immune responses, our results highlight the role of inflammatory responses in the development of lymphedema. The use of HA and LTB4 as biomarkers could facilitate the identification of patients with high risk to develop lymphedema. Further clinical studies are needed to validate these biomarkers as predictors of acquired lymphedema inpatients.