Lymphedema is a chronic disease that results in swelling and decreased function due to abnormal lymphatic fluid clearance and chronic inflammation. In Western countries, lymphedema most commonly develops following an iatrogenic injury to the lymphatic system during cancer treatment. It is estimated that as many as 10 million patients suffer from lymphedema in the United States alone. Current treatments for lymphedema are palliative in nature, relying on compression garments and physical therapy to decrease interstitial fluid accumulation in the affected extremity. However, recent discoveries have increased the hopes of therapeutic interventions that may promote lymphatic regeneration and function. The purpose of this review is to summarize current experimental pharmacological strategies in the treatment of lymphedema.

Penile amputation is a surgical emergency where practical and timely perioperative management is crucial for ensuring a successful outcome. Tenuous viability of penile and scrotal skin has been well described in the literature, with a putative mechanism attributed to the transection of distal branches of the external pudendal artery. Although the perforasomes critical to penile replantation have been debated, this case report details a patient who successfully recovered sensation and function with minimal necrosis after penile replantation. Surgically, this was facilitated by intentional drain placement, aggressive debridement beyond the zone of injury, and planned redundancies with dorsal artery/vein anastomoses via interposition grafts of the dorsal penile vessels alone.

Purpose: TGF-B1-a growth factor that regulates inflammation and fibrosis—is a key regulator of secondary lymphedema development. Angiotensin-converting enzyme (ACE) activity regulates TGF-B1 signaling in other organ systems; however, it is not known if ACE signaling plays an important role in lymphedema. The purpose of this study was therefore to analyze the expression of ACE in clinical samples, and determine if ACE inhibition is effective for treating the disease in a mouse model. Methods: Matched upper extremity biopsies were collected from patients with unilateral breast cancer-related lymphedema (BCRL) and analyzed using immunofluorescence and qPCR. In addition, we used mouse models to analyze fibrosis, inflammation, lymphatic pumping, and lymphangiogenesis in animals treated with a topical formulation of Captopril, an ACE inhibitor. Results: ACE expression was significantly increased in lymphedematous tissues of patients and in mouse models of lymphedema. Topical Captopril markedly decreased lymphedematous changes in the mouse tail by decreasing TGF-B1 expression and decreasing swelling, fibro adipose deposition, and inflammation. Captopril-treated animals also had significantly increased lymphatic collecting vessel pumping and collateral lymphatic formation. Conclusions: Topical Captopril significantly attenuates the pathological changes of lymphedema in a preclinical model. The use of topical formulations may help avoid systemic effects and holds promise in the clinical setting.

Traumatic lip amputation is a devastating injury. No other tissue replicates its unique histology, often limiting the reconstructive outcome. Replantation is a technically challenging procedure, requiring extensive postoperative optimization, including systemic anticoagulation, leech therapy, significant blood loss, and antibiosis. Given the rarity of replantation in the context of pregnancy, there are no documented accounts of lip replantation in pregnant patients. We report a case of a 25-year-old pregnant woman who sustained an avulsion injury of the right upper lip from a dog bite. The patient presented with the amputated lip and emergent microvascular replantation was performed. Postoperative course consisted of management of controlled yet significant blood loss through leech therapy and close collaboration with obstetric colleagues. The patient was ultimately discharged with successful cosmetic and functional outcome and, importantly, with maintenance of a healthy pregnancy.

PURPOSE: TGF-B1-a growth factor that regulates inflammation and fibrosis—is a key regulator of secondary lymphedema development. Angiotensin-converting enzyme (ACE) activity regulates TGF-B1 signaling in other organ systems; however, it is not known if ACE signaling plays an important role in lymphedema. The purpose of this study was therefore to analyze the expression of ACE in clinical samples, and determine if ACE inhibition is effective for treating the disease in a mouse model. METHODS: Matched upper extremity biopsies were collected from patients with unilateral breast cancer-related lymphedema (BCRL) and analyzed using immunofluorescence and qPCR. In addition, we used mouse models to analyze fibrosis, inflammation, lymphatic pumping, and lymphangiogenesis in animals treated with a topical formulation of Captopril, an ACE inhibitor. RESULTS: ACE expression was significantly increased in lymphedematous tissues of patients and in mouse models of lymphedema. Topical Captopril markedly decreased lymphedematous changes in the mouse tail by decreasing TGF-B1 expression and decreasing swelling, fibroadipose deposition, and inflammation. Captopril-treated animals also had significantly increased lymphatic collecting vessel pumping and collateral lymphatic formation. CONCLUSION: Topical Captopril significantly attenuates the pathological changes of lymphedema in a preclinical model. The use of topical formulations may help avoid systemic effects and holds promise in the clinical setting.

T cell-mediated responses have been implicated in the development of fibrosis, impaired lymphangiogenesis, and lymphatic dysfunction in secondary lymphedema. Here we show that CD4(+) T cells are necessary for lymphedema pathogenesis by utilizing adoptive transfer techniques in CD4 knockout mice that have undergone tail skin and lymphatic excision or popliteal lymph node dissection. We also demonstrate that T cell activation following lymphatic injury occurs in regional skin-draining lymph nodes after interaction with antigen-presenting cells such as dendritic cells. CD4(+) T cell activation is associated with differentiation into a mixed T helper type 1 and 2 phenotype, as well as upregulation of adhesion molecules and chemokines that promote migration to the skin. Most importantly, we find that blocking T cell release from lymph nodes using a sphingosine-1-phosphate receptor modulator prevents lymphedema, suggesting that this approach may have clinical utility.

Secondary lymphedema, a life-long complication of cancer treatment, currently has no cure. Lymphedema patients have decreased quality of life and recurrent infections with treatments limited to palliative measures. Accumulating evidence indicates that T cells play a key role in the pathology of lymphedema by promoting tissue fibrosis and inhibiting lymphangiogenesis. Here using mouse models, we show that topical therapy with tacrolimus, an anti-T-cell immunosuppressive drug, is highly effective in preventing lymphedema development and treating established lymphedema. This intervention markedly decreases swelling, T-cell infiltration and tissue fibrosis while significantly increasing formation of lymphatic collaterals with minimal systemic absorption. Animals treated with tacrolimus have markedly improved lymphatic function with increased collecting vessel contraction frequency and decreased dermal backflow. These results have profound implications for lymphedema treatment as topical tacrolimus is FDA-approved for other chronic skin conditions and has an established record of safety and tolerability.

Background: Angioinvasive mold infections (AMIs) are among the most serious infections a patient can acquire. These infections carry high mortality and are difficult to cure. Methods: Report of case series of five patients with AMIs and review of pertinent English-language literature. Results: Five cases of AMIs developed in the surgical and burn intensive care units (ICUs) of a single center over a three-year period; four patients were female. The mean age was 48 y. One patient had advanced breast cancer and four had large total body surface area (TBSA; average 59%) burns. Among the burn patients, AMIs developed on average 25 d after burn injury (range, 18–35 d). Four of the AMIs reported here were polymicrobial; four patients had Candida spp., three had Aspergillus spp., two had Fusarium spp., two had Trichosporon asahii, two had Mucor spp., and one had Purpureocillium lilacinus. Four patients were treated with intravenous voriconazole, two with intravenous amphotericin B (amB), and one was treated with enteral posaconazole. Adjunctive topical anti-fungal therapy consisted of silver nitrate solution (n=4), 0.5% sodium hypochlorite (Dakin) solution (n=3), and topical amB (n=1). Conclusion: Three patients were cured of their infections (one of whom succumbed to a bacterial infection later in the hospitalization) and two died of the AMI, for an overall mortality rate of 60%. A majority of AMIs were polymicrobial, which has not been reported previously. To our knowledge, this is the first case report of P. lilacinus AMI in a burn patient.

Introduction Secondary lymphedema is a common complication of cancer treatment and recent studies have demonstrated that lymph node transplantation (LNT) can decrease swelling, as well as the incidence of infections. However, although these results are exciting, the mechanisms by which LNT improves these pathologic findings of lymphedema remain unknown. Using a transgenic mouse model of lymphedema, this study sought to analyze the effect of LNT on lymphatic regeneration and T cell-mediated immune responses. Methods We used a mouse model in which the expression of the human diphtheria toxin receptor is driven by the FLT4 promoter to enable the local ablation of the lymphatic system through subdermal hindlimb diphtheria toxin injections. Popliteal lymph node dissection was subsequently performed after a two-week recovery period, followed by either orthotopic LNT or sham surgery after an additional two weeks. Hindlimb swelling, lymphatic vessel regeneration, immune cell trafficking, and T cell-mediated immune responses were analyzed 10 weeks later. Results LNT resulted in a marked decrease in hindlimb swelling, fibroadipose tissue deposition, and decreased accumulation of perilymphatic inflammatory cells, as compared to controls. In addition, LNT induced a marked lymphangiogenic response in both capillary and collecting lymphatic vessels. Interestingly, the resultant regenerated lymphatics were abnormal in appearance on lymphangiography, but LNT also led to a notable increase in dendritic cell trafficking from the periphery to the inguinal lymph nodes and improved adaptive immune responses. Conclusions LNT decreases pathological changes of lymphedema and was shown to potently induce lymphangiogenesis. Lymphatic vessels induced by LNT were abnormal in appearance, but were functional and able to transport antigen-presenting cells. Animals treated with LNT have an increased ability to mount T cell-mediated immune responses when sensitized to antigens in the affected hindlimb.

Key points Obesity induces lymphatic leakiness, decreases initial lymphatic vessel density, impairs collecting vessel pumping and decreases transport of macromolecules. Obesity results in perilymphatic inducible nitric oxide synthase (iNOS) expression and accumulation of T cells and macrophages. Deleterious effects of obesity on the lymphatic system correlate with weight gain. Weight loss restores lymphatic function in obese animals and decreases perilymphatic iNOS and inflammatory cell accumulation. AbstractAlthough clinical and experimental studies have shown that obesity results in lymphatic dysfunction, it remains unknown whether these changes are permanent or reversible with weight loss. In the current study, we used a mouse model of diet‐induced obesity to identify putative cellular mechanisms of obesity‐induced lymphatic dysfunction, determine whether there is a correlation between these deleterious effects and increasing weight gain, and finally examine whether lymphatic dysfunction is reversible with diet‐induced weight loss. We report that obesity is negatively correlated with cutaneous lymphatic collecting vessel pumping rate (r = –0.9812, P < 0.0005) and initial lymphatic vessel density (r = –0.9449, P < 0.005). In addition, we show a significant positive correlation between weight gain and accumulation of perilymphatic inflammatory cells (r = 0.9872, P < 0.0005) and expression of inducible nitric oxide synthase (iNOS; r = 0.9986, P < 0.0001). Weight loss resulting from conversion to a normal chow diet for 8 weeks resulted in more than a 25% decrease in body weight and normalized cutaneous lymphatic collecting vessel pumping rate, lymphatic vessel density, lymphatic leakiness, and lymphatic macromolecule clearance (all P < 0.05). In addition, weight loss markedly decreased perilymphatic inflammation and iNOS expression. Taken together, our findings show that obesity is linearly correlated with lymphatic dysfunction, perilymphatic inflammation and iNOS expression, and that weight loss via dietary modification effectively reverses these deleterious effects.

AMERICAN SOCIETY OF PLASTIC SURGEONS PLASTIC & RECONSTRUCTIVE SURGERY PRS GLOBAL OPEN ASPS EDUCATION NETWORK AMERICAN SOCIETY OF PLASTIC SURGEONS PLASTIC & RECONSTRUCTIVE SURGERY PRS GLOBAL OPEN ASPS EDUCATION NETWORK

Objective: The objective of this study was to determine the contribution of lymphatic tissue to heterotopic ossification (HO).Background: HO is the pathologic development of ectopic bone within soft tissues often following severe trauma. Characterization of the tissue niche supporting HO is critical to identifying therapies directed against this condition. Lymphangiogenesis is upregulated during incidents of trauma, thereby coincident with the niche supportive of HO. We hypothesized that lymphatic tissues play a critical role in HO formation.Methods: Mice underwent hindlimb Achilles' tendon transection and dorsal burn injury (burn/tenotomy) to induce HO. The popliteal and inguinal lymph nodes were excised ipsilateral to the tenotomy site. Flow cytometry and immunostaining were used to quantify and localize lymphoendothelium. MicroCT was used to quantify HO.Results: Enrichment of mature lymphatic tissues was noted 2 weeks after injury at the tendon transection sites when compared with the contralateral, intact tendon based on LYVE1+ tubules (10.9% vs 0.8%, P < 0.05). Excision of the inguinal and popliteal nodes with draining popliteal lymphatic vessel significantly decreased the presence of mature lymphoendothelium 2 weeks after injury (10.9% vs 3.3%, P < 0.05). Bone-cartilage-stromal progenitor cells (CD105+/AlphaV+/Tie2-/CD45-/CD90-/BP1-) were also significantly decreased after lymph node excision (10.2% vs 0.5%, P < 0.05). A significant decrease was noted in the volume of de novo HOpresent within the soft tissues (0.12 mm(3) vs 0.02 mm(3)).Conclusion: These findings suggest that lymphatic vessels are intimately linked with the de novo formation bone within soft tissues following trauma, and their presence may facilitate bone formation.

Development of novel treatments for lymphedema has been limited by the fact that the pathophysiology of this disease is poorly understood. It remains unknown, for example, why limb swelling resulting from surgical injury resolves initially, but recurs in some cases months or years later. Finding answers for these basic questions has been hampered by the lack of adequate animal models. In the current study, we used Cre-lox mice that expressed the human diphtheria toxin receptor (DTR) driven by a lymphatic-specific promoter in order to noninvasively ablate the lymphatic system of the hind limb. Animals treated in this manner developed lymphedema that was indistinguishable from clinical lymphedema temporally, radiographically, and histologically. Using this model and clinical biopsy specimens, we show that the initial resolution of edema after injury is dependent on the formation of collateral capillary lymphatics and that this process is regulated by M2-polarized macrophages. In addition, we show that despite these initial improvements in lymphatic function, persistent accumulation of CD4+ cells inhibits lymphangiogenesis and promotes sclerosis of collecting lymphatics, resulting in late onset of edema and fibrosis. Our findings therefore provide strong evidence that inflammatory changes after lymphatic injury play a key role in the pathophysiology of lymphedema.

Background/Objectives: High-fat diet (HFD)-induced obesity has significant negative effects on lymphatic function, but it remains unclear whether this is a direct effect of HFD or secondary to adipose tissue deposition. Methods: We compared the effects of HFD on obesity-prone and obesity-resistant mice and analyzed lymphatic function in vivo and in vitro . Results: Only obesity-prone mice had impaired lymphatic function, increased perilymphatic inflammation and accumulation of lipid droplets surrounding their lymphatic endothelial cells (LECs). LECs isolated from obesity-prone mice, in contrast to obesity-resistant animals, had decreased expression of VEGFR-3 and Prox1. Exposure of LECs to a long-chain free fatty acid increased cellular apoptosis and decreased VEGFR-3 expression, while inhibition of intracellular inhibitors of VEGFR-3 signaling pathways increased cellular viability. Conclusions: Collectively, our studies suggest that HFD-induced obesity decreases lymphatic function by increasing perilymphatic inflammation and altering LEC gene expression. Reversal of diminished VEGFR-3 signaling may rescue this phenotype and improve lymphatic function.

Background Communication, particularly transmission of information between the surgical and nursing teams, has been identified as one of the most crucial determinants of patient outcomes. Nonetheless, transfer of information among and between the physician and nursing teams in the immediate postoperative period is often informal, verbal, and inconsistent.Methods An iterative process of multidisciplinary information gathering was undertaken to create a novel postoperative communication system (the "Pop-form"). Once developed, nurses were surveyed on multiple measures regarding the perceived likelihood that it would improve their ability to provide directed patient care. Data were quantified using a Likert scale (0-10), and statistically analyzed.Results The Pop-form records and transfers operative details, specific anatomic monitoring parameters, and senior physician contact information. Sixty-eight nurses completed surveys. The perceived usefulness of different components of the Pop-form system was as follows: 8.9 for the description of the procedure; 9.3 for the operative diagram; 9.4 for the monitoring details and parameters; and 9.4 for the direct contact information for the appropriate surgical team member. All respondents were in favor of widespread adoption of the Pop-form.Conclusion This uniform, visual communication system requires less than 1 minute to compose, yet formalizes and standardizes inter-team communication, and therefore shows promise for improving outcomes following microvascular free tissue transfer. We believe that this simple, innovative communication tool has the potential to be more broadly applied to many other health care settings.

PURPOSE: Lymphedema is characterized by fibrosis, and there is accumulating evidence that this process plays a key role in the pathology of the disease. We have previously shown that the expression of the profibrotic growth factor transforming growth factor (TGF)-β is increased in lymphedematous tissues. The purpose of this study was to evaluate the efficacy of this topical compound for prevention and treatment of lymphedema.

Although recent studies have shown that obesity decreases lymphatic function, the cellular mechanisms regulating this response remain unknown. In the current study, we show that obesity results in perilymphatic accumulation of inflammatory cells and that local inhibition of this response with topical tacrolimus, an inhibitor of T cell differentiation, increases lymphatic vessel density, decreases perilymphatic iNOS expression, increases lymphatic vessel pumping frequency, and restores lymphatic clearance of interstitial fluid to normal levels. Although treatment of obese mice with 1400W, a selective inhibitor of iNOS, also improved lymphatic collecting vessel contractile function, it did not completely reverse lymphatic defects. Mice deficient in CD4(+) cells fed a high fat diet also gained weight relative to controls but were protected from lymphatic dysfunction. Taken together, our findings suggest that obesity-mediated lymphatic dysfunction is regulated by perilymphatic accumulation of inflammatory cells and that T cell inflammatory responses are necessary to initiate this effect.

Key pointsObesity results in perilymphatic inflammation and lymphatic dysfunction.Lymphatic dysfunction in obesity is characterized by decreased lymphatic vessel density, decreased collecting lymphatic vessel pumping frequency, decreased lymphatic trafficking of immune cells, increased lymphatic vessel leakiness and changes in the gene expression patterns of lymphatic endothelial cells.Aerobic exercise, independent of weight loss, decreases perilymphatic inflammatory cell accumulation, improves lymphatic function and reverses pathological changes in gene expression in lymphatic endothelial cells.AbstractAlthough previous studies have shown that obesity markedly decreases lymphatic function, the cellular mechanisms that regulate this response remain unknown. In addition, it is unclear whether the pathological effects of obesity on the lymphatic system are reversible with behavioural modifications. The purpose of this study, therefore, was to analyse lymphatic vascular changes in obese mice and to determine whether these pathological effects are reversible with aerobic exercise. We randomized obese mice to either aerobic exercise (treadmill running for 30 min per day, 5 days a week, for 6 weeks) or a sedentary group that was not exercised and analysed lymphatic function using a variety of outcomes. We found that sedentary obese mice had markedly decreased collecting lymphatic vessel pumping capacity, decreased lymphatic vessel density, decreased lymphatic migration of immune cells, increased lymphatic vessel leakiness and decreased expression of lymphatic specific markers compared with lean mice (allP < 0.01). Aerobic exercise did not cause weight loss but markedly improved lymphatic function compared with sedentary obese mice. Exercise had a significant anti‐inflammatory effect, resulting in decreased perilymphatic accumulation of inflammatory cells and inducible nitric oxide synthase expression. In addition, exercise normalized isolated lymphatic endothelial cell gene expression of lymphatic specific genes, includingVEGFR‐3andProx1. Taken together, our findings suggest that obesity impairs lymphatic function via multiple mechanisms and that these pathological changes can be reversed, in part, with aerobic exercise, independent of weight loss. In addition, our study shows that obesity‐induced lymphatic endothelial cell gene expression changes are reversible with behavioural modifications.

Gardenier, Jason C. MD; Huang, Jung-Ju; Hespe, Geoffrey E.; Nores, Gabriela Garcia; Yu, Jessie Z. MD; Savetsky, Ira L. MD; Kataru, Raghu; Mehrara, Babak J. MD, FACS Author Information

PURPOSE: Diet-induced obesity is a known risk factor for lymphedema. However, although it is clear that obesity is associated with lymphatic dysfunction, it remains unclear whether this is because of increased subcutaneous adipose deposition or dietary toxins. Therefore, the purpose of this study was to evaluate the independent effects of high-fat diet or obesity on lymphatic function in obesity-prone and obesity-resistant mice.