Acquired Lymphedema: An Urgent Need for Adequate Animal Models

Hadamitzky, Catarina; Pabst, Reinhard

doi:10.1158/0008-5472.can-07-2454

Cited by 50 publications

(33 citation statements)

References 18 publications

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“…The removal of the LN damages the axillary lymphatic system and impairs lymph drainage. As described by Hadamitzky and Pabst, adequate models to study lymphedema development are missing, although there is an urgent need for such animal models [1]. In the present study we showed that lymphadenectomy results in a development of lymph vessel collaterals and dermal backflow in minipigs 8 months later.…”

Section: Discussionsupporting

confidence: 67%

“…On the way through the body the lymph fluid is screened for foreign agents and particles are filtered in the various LN before leaving the lymph vessel and entering the venous system. The pathophysiology of lymphedema development is very complex and not entirely clear [1]. Surgical removal of LN often leads to an impaired lymph flow, because of the damage to the lymphatic network.…”

Section: Introductionmentioning

confidence: 99%

“…Liposuction can reduce the volume in upper extremity lymphedema, especially in combination with compression garments, although the lymph flow is not cured [5,17]. The urgent need for adequate animal models to prevent lymphedema, has been stressed recently [1]. Studies with LN transplantation alone and in combination with growth factor therapy showed an improvement of lymphedema after lymphadenectomy in mice [18].…”

Section: Introductionmentioning

confidence: 99%

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Effects of autotransplanted lymph node fragments on the lymphatic system in the pig model

Blum

Hadamitzky

Gratz

et al. 2009

Breast Cancer Res Treat

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Secondary lymphedema often develops after removal of lymph nodes in combination with radiation therapy, in particular in patients with breast cancer, inguinal cancer, cervical cancer and melanoma. No convincing treatment for the prevention and therapy of acquired lymphedema exists so far, therefore we wanted to show the reintegration of transplanted avascular lymph node fragments in the lymphatic system and positive effects of the transplanted fragments on the restoration of the lymphatic flow in this study. A total of 26 minipigs underwent lymphadenectomy of both groins. A minimum of one lymph node was retransplanted. The lymph nodes were cut into small pieces and retransplanted in the left groin (n = 17) or in both groins (n = 9). Different retransplantation techniques were investigated, transplantation of large versus small fragments, with and without capsule. The lymph flow was evaluated 5 and 8 months after surgery, using SPECT/CT and Berlin Blue. The results were confirmed by dissection. The lymph node transplants were assessed histologically. In contrast to the lymph flow in the transplanted groin, the lymph flow in the non-transplanted groin was often malfunctioning. Large lymph node fragments were found reintegrated in the lymphatic system more often than small slices of lymph node fragments. About 5 months after surgery impairment of lymph flow was seen especially after retransplantation of small slices of lymph node fragments. In seven out of eight minipigs a dermal backflow developed in the non-transplanted groin, 8 months after surgery. Only one minipig of these groups developed dermal backflow in both groins. All lymph node fragments showed an organized structure histologically. Autologous lymph node transplantation has positive effects on the regeneration of lymph vessels and restoration of lymph flow after lymphadenectomy.

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Section: Discussionsupporting

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of autotransplanted lymph node fragments on the lymphatic system in the pig model

Blum

Hadamitzky

Gratz

et al. 2009

Breast Cancer Res Treat

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“…The lack of large animal models that better recapitulate conditions in human lymphedema has limited experimental research of lymphedema. 28 Previously used canine models were complex and would be considered unethical today. We present here a novel large animal model of lymphatic vessel damage and lymph node transfer.…”

Section: Discussionmentioning

confidence: 99%

Growth Factor Therapy and Autologous Lymph Node Transfer in Lymphedema

et al. 2011

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Background— Lymphedema after surgery, infection, or radiation therapy is a common and often incurable problem. Application of lymphangiogenic growth factors has been shown to induce lymphangiogenesis and to reduce tissue edema. The therapeutic effect of autologous lymph node transfer combined with adenoviral growth factor expression was evaluated in a newly established porcine model of limb lymphedema. Methods and Results— The lymphatic vasculature was destroyed within a 3-cm radius around an inguinal lymph node. Lymph node grafts and adenovirally (Ad) delivered vascular endothelial growth factor (VEGF)-C (n=5) or VEGF-D (n=9) were used to reconstruct the lymphatic network in the inguinal area; AdLacZ (β-galactosidase; n=5) served as a control. Both growth factors induced robust growth of new lymphatic vessels in the defect area, and postoperative lymphatic drainage was significantly improved in the VEGF-C/D–treated pigs compared with controls. The structure of the transferred lymph nodes was best preserved in the VEGF-C–treated pigs. Interestingly, VEGF-D transiently increased accumulation of seroma fluid in the operated inguinal region postoperatively, whereas VEGF-C did not have this side effect. Conclusions— These results show that growth factor gene therapy coupled with lymph node transfer can be used to repair damaged lymphatic networks in a large animal model and provide a basis for future clinical trials of the treatment of lymphedema.

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“…Many surgical methods with curative aims have been proposed, but no long lasting effective methods have been established. Recently, it has been summarized that adequate animal models to study lymphedema development and treatment are missing, although there is an urgent need for such models (Hadamitzky and Pabst, 2008).…”

mentioning

confidence: 99%

Improved Regeneration of Autologous Transplanted Lymph Node Fragments by VEGF‐C Treatment

Sommer

Büettner

Bruns

et al. 2012

The Anatomical Record

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Secondary lymphedema is a common complication after removal of lymph nodes in combination with radiation therapy in the treatment of breast cancer, cervical cancer, and melanomas. Only symptomatic therapies are available at the moment, and lymphedema is for most patients a lifelong condition involving psychological and physical disabilities. Animal models exist to study the pathophysiology of lymphedema but not to study surgical treatments. The aim of this study was to show that regeneration of autologous transplanted lymph node fragments is possible in rats that were irradiated previously locally in the groin and to examine the effects of vascular endothelial growth factor (VEGF)-C injections on the rate of regeneration of transplanted lymph nodes. In all of the animals, inguinal and popliteal lymph nodes and adjacent lymphatic vessels were unilaterally removed and the inguinal region irradiated by a single dose of 15 Gy. Afterward, lymph node fragments were transplanted subcutaneously in the irradiated region. Half of the animals were treated by local VEGF-C injections after transplantation. Four weeks after transplantation, drainage of the leg was tested by injection of blue dye, and the transplanted fragments were removed and examined immunohistologically. We could show that regeneration of autologous transplanted lymph node fragments is possible in areas treated with radiotherapy in the rat. We also documented that transplants can achieve a connection to the lymphatic collectors of the leg. The results suggest that the outcome of regeneration can be improved by injection of VEGF-C in the transplantation area. Thus, lymph node fragment regeneration may be relevant for lymphedema prevention and therapy. Anat Rec, 295:786-791, 2012. V C 2012 Wiley Periodicals, Inc.

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Acquired Lymphedema: An Urgent Need for Adequate Animal Models

Cited by 50 publications

References 18 publications

Effects of autotransplanted lymph node fragments on the lymphatic system in the pig model

Effects of autotransplanted lymph node fragments on the lymphatic system in the pig model

Growth Factor Therapy and Autologous Lymph Node Transfer in Lymphedema

Improved Regeneration of Autologous Transplanted Lymph Node Fragments by VEGF‐C Treatment

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