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Quantification of Chronic Lymphedema in a Revised Mouse Model

Jørgensen, Mads Gustaf, BSc*; Toyserkani, Navid Mohammadpour, MD*; Hansen, Christian Rønn, MSc†‡; Hvidsten, Svend, MSc§; Baun, Christina, MSc§; Hejbøl, Eva Kildall, MSc; Schrøder, Henrik Daa, MD, DMSc; Sørensen, Jens Ahm, MD, PhD*

doi: 10.1097/SAP.0000000000001537

Background Lymphedema is a common and debilitating complication following cancer treatment with surgical lymph node excision and radiotherapy. Currently there are no curative treatments for lymphedema. Animal models that intended to replicate the disease have been inadequate, making a troublesome transition from experimental therapeutic studies into the clinic. It is therefore imperative to establish an experimental animal model that can reliably replicate clinical lymphedema.

Methods To discover the optimal method of lymphedema induction, surgical lymph ablation and irradiation or silicone splint emplacement were combined in 8 experimental groups (n = 4). In total, 32 mice served in this study and were followed for 8 weeks after surgery. Outcomes included micro–computed tomography hind limb volumetry, lymphatic clearance measured with technetium Tc 99m (99mTc) human serum albumin lymphoscintigraphy and lymph vessel ectasia quantified with LYVE-1 immunohistochemistry.

Results All trialed models but one resulted in only transient lymphedema or lasting lymphedema with adverse morbidity. Combined surgical lymph obstruction with 2 fractions of 10-Gy irradiation successfully induced lasting lymphedema without adverse events. Over the 8 weeks' follow-up, limb volumes were significantly increased at all time points (P < 0.001), lymph drainage was impaired (P < 0.001), and lymph vessels were ectatic (P < 0.001), when compared with the unoperated limbs.

Conclusions The presented model of acquired lymphedema is a reduction and refinement of previous works and can transpose to future observational and interventional studies. In addition, it is shown how 99mTc-HSA lymphoscintigraphy can quantify lymphatic clearance, which can prove insightful in therapeutic studies aiming to enhance lymphatic drainage.

From the *Department of Plastic Surgery and

Laboratory of Radiation Physics, Odense University Hospital;

Institute of Clinical Research, University of Southern Denmark; and

Departments of §Nuclear Medicine and

Pathology, Odense University Hospital, Odense, Denmark.

Received January 23, 2018, and accepted for publication, after revision April 27, 2018.

This study was funded by unrestricted grants from Karen A. Tholstrups Foundation, Timber Merchant Vilhelm Bangs Foundation, Dagmar Marshalls Foundation, A. J Andersen and Wife Foundation, and Vissing Foundation supporting independent research.

Conflicts of interest and sources of funding: none declared.

Reprints: Jens Ahm Sørensen, MD, PhD, Department of Plastic Surgery, Odense University Hospital, Sdr. Boulevard 29, 5000 Odense C, Denmark. E-mail:

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