Lymphangiogenesis and Lymphangiogenic Growth Factors

Lymphedema is a progressive disease caused by damage to the lymphatic network. Recent development in the fields of preclinical growth factor research and lymphedema microsurgery promise new hope for lymphedema patients. In this article, we review the latest results on basic research and highlight the role of specific growth factors in normal lymphatic development and several disease states. Lymph node transfer, a new promising method in reconstructive lymphatic microsurgery, is also dependent on the lymphatic vascular regrowth and lymphangiogenic growth factors. We discuss the scientific basis of lymph node transfer and therapeutic potential of lymphangiogenic growth factors in the treatment of lymphedema.Peer reviewe

Phase 1 Lymfactin (R) Study : Short-term Safety of Combined Adenoviral VEGF-C and Lymph Node Transfer Treatment for Upper Extremity Lymphedema

Objective: To study the safety and tolerability of Lymfactin (R) treatment combined with microvascular lymph node transfer surgery in patients with upper limb lymphedema. Background: Upper limb lymphedema is a common clinical challenge after breast cancer surgery and/or radiotherapy. Lymfactin (R) is an adenovirus type 5-based gene therapy involving expression of human vascular endothelial growth factor C (VEGF-C) in the damaged tissue. It aims to correct deficient lymphatic flow by promoting the growth and repair of lymphatic vessels. Methods: In Phase I, Lymfactin (R) was combined with microvascular lymph node transfer surgery to study the safety and tolerability of Lymfactin (R) and the biodistribution of the viral vector in patients with upper limb lymphedema. Results: Fifteen patients with breast cancer-associated secondary lymphedema of the upper arm were recruited between December 2016 and February 2018. Three patients received a lower dose (1 x 10(10)) and 12 a higher dose (1 x 10(11)) of viral particles, respectively. No dose-limiting toxicities were observed, and the study was completed with the pre-determined maximum dose. Commonly reported adverse events during the 12-month follow-up were common cold, fever, gastroenteritis, pain in the operation area, headache, muscle ache and elevated liver enzymes. Serious adverse events consisted of two erysipelas infections in the lymphedema arm (requiring hospitalization) and one hematoma of the flap donor site. Conclusions: After 12 months' follow-up, results indicate that Lymfactin (R) is well tolerated. The study continues with a 36-months efficacy and 5 years safety follow-up of the patients. The oncological safety aspects of Lymfactin (R) will require a longer follow-up period. (c) 2020 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Pub-lished by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/)Peer reviewe

Short duration of upper extremity lymphedema correlates with a favorable cytokine response after lymph node transfer surgery

Vascularized lymph node transfer surgery (VLNT) can provide benefit to lymphedema patients. Cytokines mayplaya role in the development oflymphedema and in the regeneration oflymphatic vessels after VLNT. Ourprimary aim was to investigate whether the VLNTpatients have a specific cytokine profile. Our secondary aim was to see whether the preoperative lymphedema or severity affects the postoperative cytokine response. Wound exudate was gathered from 18 patients undergoing VLNT on the first and sixth postoperative day (POD). The concentrations of IL-10, TNF-alpha, TGF-beta 1 and VEGF-C were analyzed using enzyme-inked immune-sorbent assays. A general score was generated to assess the benefit ofthe surgery. The changes in cytokine concentrations (1(st) POD-6th POD) were correlated with the pre- andpostoperative lymphedema related factors. A shorter duration oflymphedema preoperatively correlated with an increase in the concentration of IL-10 and TNF-beta during the first six PODs (IL-10: r=0.495, p=0.051; TNF-alpha: p=0.006) and a decrease in the concentration of 7VF-111 (r= p=0.020). The increase ofthe concentration of TNF-alpha during the first six PODs also correlated with a greater total general score (r=0.775, p=0.005) and hence indicated a better response to the surgery. The patients with a shorter duration oflymphedema preoperatively had a more favorable cytokine response during the first six PODs after VLNT

Anti-inflammatory effects of flap and lymph node transfer

Background: Transfer of healthy tissue is commonly used in the treatment of complicated wounds and in reconstruction of tissue defects. Recently, microvascular lymph node transfer (LN) has been used to improve the lymphatic function in lymphedema patients. To elucidate the biological effects of flap transfer (with and without lymph nodes), we have studied the postoperative production of proinflammatory, anti-inflammatory, prolymphangiogenic and antilymphangiogenic cytokines, and growth factors (interleukin 1 alpha [IL-1 alpha], IL-1 beta, tumor necrosis factor alpha [TNF-alpha], IL-10, transforming growth factor beta 1 [TGF-beta 1], IL-4 and IL-13, and vascular endothelial growth factor C [VEGF-C] and VEGF-D) in postoperative wound exudate samples. Methods: Axillary wound exudate samples were analyzed from four patient groups: axillary lymph node dissection (ALND), microvascular breast reconstruction (BR), LN, and combined LN and BR (LN-BR). Results: The concentration of proinflammatory cytokines was low in all the flap transfer groups as opposed to the ALND group, which showed an extensive proinflammatory response. The level of anti-inflammatory and antifibrotic cytokine IL-10 was increased in the LN-BR group samples compared with the ALND and BR groups. In the LN and LN-BR groups, the cytokine profile showed an anti-inflammatory response. Conclusions: Transfer of healthy tissue hinders the proinflammatory response after surgery, which may explain the beneficial effects of flap transfer in various patient groups. In addition, flap transfer with lymph nodes seems to also promote an antifibrotic effect. The clinical effects of LN in lymphedema patients may be mediated by the increased production of prolymphangiogenic growth factor (VEGF-C) and antifibrotic cytokine (IL-10). (C) 2015 Elsevier Inc. All rights reserved.Peer reviewe

Phase 1 LymfactinⓇ Study: Short-term Safety of Combined Adenoviral VEGF-C and Lymph Node Transfer Treatment for Upper Extremity Lymphedema

Objective: To study the safety and tolerability of LymfactinⓇ treatment combined with microvascular lymph node transfer surgery in patients with upper limb lymphedema.Background: Upper limb lymphedema is a common clinical challenge after breast cancer surgery and/or radiotherapy. LymfactinⓇ is an adenovirus type 5–based gene therapy involving expression of human vascular endothelial growth factor C (VEGF-C) in the damaged tissue. It aims to correct deficient lymphatic flow by promoting the growth and repair of lymphatic vessels.Methods: In Phase I, LymfactinⓇ was combined with microvascular lymph node transfer surgery to study the safety and tolerability of LymfactinⓇ and the biodistribution of the viral vector in patients with upper limb lymphedema.Results: Fifteen patients with breast cancer–associated secondary lymphedema of the upper arm were recruited between December 2016 and February 2018. Three patients received a lower dose (1 × 1010) and 12 a higher dose (1 × 1011) of viral particles, respectively. No dose-limiting toxicities were observed, and the study was completed with the pre-determined maximum dose. Commonly reported adverse events during the 12-month follow-up were common cold, fever, gastroenteritis, pain in the operation area, headache, muscle ache and elevated liver enzymes. Serious adverse events consisted of two erysipelas infections in the lymphedema arm (requiring hospitalization) and one hematoma of the flap donor site.Conclusions: After 12 months’ follow-up, results indicate that LymfactinⓇ is well tolerated. The study continues with a 36-months efficacy and 5 years safety follow-up of the patients. The oncological safety aspects of LymfactinⓇ will require a longer follow-up period.</p

Long-term Results of Microvascular Lymph Node Transfer: Correlation of Preoperative Factors and Operation Outcome

Background: Our objective was to analyze whether a correlation could be observed between preoperative factors and microvascular lymph node transfer outcome after long-term follow-up.Methods: We included 67 patients in this retrospective case series. The incidence of cellulitis, the difference of arm circumference, the use of the compression garments both preoperatively and postoperatively, and subjective symptoms, such as pain, were analyzed. Volumetry and lymphoscintigraphy results were also analyzed in a subgroup of patients. We correlated preoperative factors with postoperative results.Results: After 70 +/- 17 months of follow-up, 42% of the patients were able to discontinue the use of compression garments. The subjective pain symptoms were reduced in 75% of the patients. The incidence of cellulitis was reduced from preoperative 0.20 +/- 0.55/y to postoperative 0.02 +/- 0.08/y. As a novel finding, the patients with preoperative cellulitis were more likely to continue the use of the compression garments.Conclusions: The surgery is beneficial to most studied lymphedema patients, although it is not the cure for all patients. The incidence of cellulitis was reduced, and further, the presence of preoperative cellulitis seems to affect the outcome of the operation.</p

Phase 1 Lymfactin® Study: 24-month Efficacy and Safety Results of Combined Adenoviral VEGF-C and Lymph Node Transfer Treatment for Upper Extremity Lymphedema

BACKGROUNDLymphedema is a common problem after breast cancer treatment. Lymfactin® is a prolymphangiogenic growth factor vector inducing the expression of human vascular endothelial growth factor C (VEGF-C). It promotes growth and repair of lymphatic vessels.METHODSLymfactin® was combined with microvascular lymph node transfer surgery (VLNT) to study the safety and efficacy of the treatment in breast cancer-related upper limb lymphedema (BCRL) patients. This is a continuation study with a 3 year efficacy and 5 year safety follow-up.RESULTSFifteen patients were recruited in the study between June 2016 and February 2018. Three patients received a lower dose (1 × 1010 viral particles (vp)), and 12 patients received a higher dose (1 × 1011 vp) of Lymfactin®, respectively. In the higher dose group, the reduction of excess arm volume was on average 46% after the 12 month follow-up, and the transport index was improved in 7/12 patients. At baseline, removal of the compression garment for 7 days resulted in significant arm swelling (105.7±161.0 ml, p=0.0253). However, at 12 months, there was less and not significant swelling after removal of the garment (84.4±143.0 ml, p=0.0682). Lymphedema Quality of Life Inventory (LQOLI or LyQLI) questionnaire showed significant and sustained improvement of quality of life.CONCLUSIONSDuring 24 months' of follow-up, the results indicate that Lymfactin® is well tolerated. The most promising findings were a 46% reduction in excess arm volume and a nonsignificant volume increase after garment removal at 12 months, suggesting that there is potential for the reduction of lymphedema.</p

Phase 1 Lymfactin (R) Study : 24-month Efficacy and Safety Results of Combined Adenoviral VEGF-C and Lymph Node Transfer Treatment for Upper Extremity Lymphedema

BACKGROUND: Lymphedema is a common problem after breast cancer treatment. Lymfactin (R) is a prolymphangiogenic growth factor vector inducing the expression of human vascular endothelial growth factor C (VEGF-C). It promotes growth and repair of lymphatic vessels.METHODS: Lymfactin (R) was combined with microvascular lymph node transfer surgery (VLNT) to study the safety and efficacy of the treatment in breast cancer-related upper limb lymphedema (BCRL) patients. This is a continuation study with a 3 year efficacy and 5 year safety follow-up.RESULTS: Fifteen patients were recruited in the study between June 2016 and February 2018. Three patients received a lower dose (1 x 10 10 viral particles (vp)), and 12 patients received a higher dose (1 x 10 11 vp) of Lymfactin (R), respectively. In the higher dose group, the reduction of excess arm volume was on average 46% after the 12 month follow-up, and the transport index was improved in 7/12 patients. At baseline, removal of the compression garment for 7 days resulted in significant arm swelling (105.7 +/- 161.0 ml, p = 0.0253). However, at 12 months, there was less and not significant swelling after removal of the garment (84.4 +/- 143.0 ml, p = 0.0682). Lymphedema Quality of Life Inventory (LQOLI or LyQLI) questionnaire showed significant and sustained improvement of quality of life.CONCLUSIONS: During 24 months' of follow-up, the results indicate that Lymfactin (R) is well tol-erated. The most promising findings were a 46% reduction in excess arm volume and a nonsignif-icant volume increase after garment removal at 12 months, suggesting that there is potential for the reduction of lymphedema.(c) 2022 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Pub-lished by Elsevier Ltd. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )Peer reviewe