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A diagnosis of lymphedema comes with a lifetime requirement for careful self-care and treatment to control skin deterioration and the consequences of excessive fluid and protein buildup leading to abnormal limb volume and an increased risk of infection. The burden of care and psychosocial aspects of physical disfiguration and loss of function are associated with compromised quality of life (QoL). The current standard therapeutic intervention is complex decongestive therapy with manual lymph drainage and frequent wearing of compression garments. With insurance limitations on therapy visits and the time and travel required, additional home treatment options are needed. Pneumatic compression pumps that mimic the manual massage pressure and pattern are sometimes prescribed, but these are bulky, difficult to apply, and require immobility during treatment. An open-label pilot study in 40 subjects was performed to evaluate the QoL and limb volume maintenance efficacy of a novel wearable compression system (Dayspring™) that is low profile, easy to use, and allows for mobility during treatment. After 28 days of use, subjects had a statistically significant 18% (

Objective Lymphatic malformations (LM) are common congenital vascular lesions, most often diagnosed at birth. They deform local anatomy and can be life-threatening if they compress the aerodigestive tract or other vital structures. Significant progress has been made in the treatment of LMs in the past 20 years. We conducted a systematic review of the literature on the management of LMs. Methods On September 21, 2020, we searched PubMed/MEDLINE for studies published from 2000 to 2020 reporting outcomes of invasive and pharmacologic treatment of LMs. Results A total of 251 studies met the eligibility criteria. Surgery has continued to be a mainstay in the management of LMs, especially in the treatment of microcystic and mixed lesions. Sclerotherapy has emerged as a first-line treatment of macrocystic LMs and as an adjunctive therapy used in combination with surgery for other lesions. Sirolimus, a strong inhibitor of mTOR (mechanistic target of rapamycin), has shown tremendous promise in the treatment of LMs, as both an oral and a topical agent. Recent investigations have shown the potential of targeted small molecule modulators of cellular pathways in the treatment of LMs. Conclusions Multiple invasive and pharmacologic therapies have been shown to be effective in the treatment of LMs. Future research should focus on rigorous, prospective comparisons of these treatment modalities.

Lymphedema is a common, complex, and inexplicably underappreciated human disease. Despite a history of relative neglect by health care providers and by governmental health care agencies, the last decade has seen an explosive growth of insights into, and approaches to, the problem of human lymphedema. The current review highlights the significant advances that have occurred in the investigative and clinical approaches to lymphedema, particularly over the last decade. This review summarizes the progress that has been attained in the realms of genetics, lymphatic imaging, and lymphatic surgery. Newer molecular insights are explored, along with their relationship to future molecular therapeutics. Growing insights into the relationships among lymphedema, obesity, and other comorbidities are important to consider in current and future responses to patients with lymphedema.

The lymphatic system was first described in the 17th century independently by Olaus Rudbeck and Thomas Bartholin. Since then, there has been deep-seated fascination with its development, function, and dysfunction.

Background: Lymphatic disease patients make up a significant proportion of the US and world populations. Due to inadequate medical school training and underestimation of the impact of lymphatic circulation, lymphatic disease patients often have difficulty finding competent diagnosis and care. Methods and Results: The Lymphatic Education & Research Network has initiated a Centers of Excellence program to designate institutions that provide services for lymphatic disease patients. Committees of experts drafted standards for five types of Centers of Excellence. Conclusions: The Centers of Excellence program is now launched, and the description of the formation process herein could provide other organizations guidance for similar ventures.

Advanced pneumatic compression devices (APCDs) have been shown to be an effective intervention for lymphedema when used as part of a self-care maintenance treatment regimen. However, adherence to self-care has been poor, and APCDs require patients to be immobile during treatment. We evaluated the safety and efficacy of a novel nonpneumatic compression device (NPCD) for treating lymphedema vs an APCD.A randomized, crossover head-to-head investigation was performed at five U.S. sites in 2021. The patients had been randomized to either the NPCD or a commercially available APCD. The patients used the randomly assigned initial device for 28 days with a 4-week washout period before a comparable 28-day use of the second device.Data from 50 adult women with unilateral breast cancer-related lymphedema were analyzed. Compared with the APCD, the NPCD was associated with a greater mean reduction in the limb edema volume (64.6% vs 27.7%; P .001), significantly greater mean improvements in quality of life scores, greater adherence (95.6% vs 49.8%; P .001), and greater satisfaction with the device (90% vs 14%; P .001). The patients indicated that use of the NPCD facilitated exercise and was convenient for travel. No adverse events were reported.The results have shown that the novel NPCD is an effective maintenance treatment for reducing the limb volume in patients with breast cancer-related lymphedema. The NPCD device was more effective than an APCD and resulted in greater adherence to self-care interventions and greater patient satisfaction.

Pathologic lymphatic remodeling in lymphedema evolves during periods of tissue inflammation and hypoxia through poorly defined processes. In human and mouse lymphedema, there is a significant increase of hypoxia inducible factor 1 α (HIF-1α), but a reduction of HIF-2α protein expression in lymphatic endothelial cells (LECs). We questioned whether dysregulated expression of these transcription factors contributes to disease pathogenesis and found that LEC-specific deletion of Hif2α exacerbated lymphedema pathology. Even without lymphatic vascular injury, the loss of LEC-specific Hif2α caused anatomic pathology and a functional decline in fetal and adult mice. These findings suggest that HIF-2α is an important mediator of lymphatic health. HIF-2α promoted protective phosphorylated TIE2 (p-TIE2) signaling in LECs, a process also replicated by upregulating TIE2 signaling through adenovirus-mediated angiopoietin-1 (Angpt1) gene therapy. Our study suggests that HIF-2α normally promotes healthy lymphatic homeostasis and raises the exciting possibility that restoring HIF-2α pathways in lymphedema could mitigate long-term pathology and disability.

The lymphatics are essential for the maintenance of tissue fluid homeostasis. Accordingly, lymphatic dysfunction contributes to lymphedema. In development, lymphangiogenesis often requires lymphatic endothelial cell (LEC) lineage specification from the venous ECs and subsequent LEC proliferation and migration, all of which are regulated by the VEGFC/VEGFR3 signaling. Cholesterol is essential for proper cell functions and organ development, yet the molecular mechanism by which cholesterol metabolism controls lymphangiogenesis is unknown. We show that the secreted protein, ApoA1 binding protein (AIBP), dictates lymphatic vessel formation by accelerating cholesterol efflux. Loss of Aibp2, the human paralog in zebrafish, impairs LEC progenitor specification and impedes lymphangiogenesis. Mechanistically, we found that caveolin-1 (CAV-1) suppresses VEGFR3 activation in LECs, and that AIBP-regulated cholesterol efflux disrupts lipid rafts/caveolae and reduces CAV-1 bioavailability, which abolishes the CAV-1 inhibition of VEGFR3 signaling, thereby augmenting VEGFR3 activation and increasing lymphangiogenesis. Enhancement of cholesterol efflux with ApoA1 overexpression or inhibition of cholesterol biosynthesis using atorvastatin restores proper lymphangiogenesis in Aibp2 mutant zebrafish. Loss of Cav-1 increases LEC progenitor specification in zebrafish, and rescues lymphangiogenesis in Aibp2-deficient animals. Recombinant AIBP supplement confers profound LEC fate commitment in the mouse embryonic stem cells (mESC) to LEC differentiation model. Furthermore, enhancement of AIBP-CAV-1-VEGFR3 signaling axis promotes VEGFC-engaged adult lymphangiogenesis in mice. Consistent with these data, AIBP expression is reduced in the epidermis of human lymphedematous skin. These studies identify that AIBP-mediated cholesterol efflux is a critical contributor for lymphangiogenesis. Our studies will provide a new therapeutic avenue for the treatment of lymphatic dysfunctions. One Sentence Summary Our studies identify that AIBP-CAV-1-VEGFR3 axis enhances VEGFC-elicited lymphangiogenesis, which will guide a new therapeutic strategy for the treatment of lymphatic dysfunctions.

Background: Lymphatic endothelium plays significant roles in lymph transport and maintaining a barrier between the lymph and interstitial compartments. Lymphatic endothelial dysfunction is suspected to be a key factor in the pathogenesis of lymphatic diseases such as lymphedema. Sigma receptor-1 (σ1) was recently identified to promote endothelial-dependent production of nitric oxide and relaxation of collecting lymphatic vessels. In this study, we investigated the potential role of σ1 in lymphatic endothelial barrier function. Methods and Results: Cultured adult human dermal lymphatic endothelial cells (HDLEC) were grown into confluent monolayers. Transendothelial electrical resistance (TER) served as an index of barrier function. Glycolytic rate of HDLEC was determined with the Agilent Seahorse system. The σ1-selective agonist PRE-084 was used to test the impact of σ1 on HDLEC monolayer barrier function and endothelial bioenergetics, whereas the contribution of basal σ1 activity was assessed with small interfering RNA (siRNA)-mediated knockdown of σ1 expression. The ability of σ1 activation to counteract interleukin (IL)-1β-induced barrier dysfunction was also tested. The results show that PRE-084 increases HDLEC TER in a concentration-dependent manner, whereas reducing σ1 expression with siRNA decreases HDLEC TER. PRE-084 also enhances glycolytic rate parameters in HDLEC. Moreover, PRE-084 treatment partially counteracts IL-1β-induced HDLEC monolayer barrier dysfunction. Conclusions: Collectively, the results suggest that σ1 contributes to basal lymphatic endothelial barrier function, potentially through its ability to enhance glycolytic energy production. Our work also highlights the therapeutic potential of σ1 agonists for preventing lymphatic barrier dysfunction caused by inflammatory mediators.

Phlebolymphedema (chronic venous insufficiency-related lymphedema) is a common and costly condition. Nevertheless, there is a dearth of evidence comparing phlebolymphedema therapeutic interventions. This study sought to examine the medical resource utilization and phlebolymphedema-related cost associated with Flexitouch (FLX; Tactile Medical, Minneapolis, Minn) advanced pneumatic compression devices (APCDs) relative to conservative therapy (CONS) alone, simple pneumatic compression devices (SPCDs), and other APCDs in a representative U.S. population of phlebolymphedema patients.This was a longitudinal matched case-control analysis of deidentified private insurance claims. The study used administrative claims data from Blue Health Intelligence for the complete years 2012 through 2016. Patients were continuously enrolled for at least 18 months, diagnosed with phlebolymphedema, and received at least one claim for CONS either alone or in addition to pneumatic compression (SPCDs or APCDs). The main outcomes included direct phlebolymphedema- and sequelae-related medical resource utilization and costs.After case matching, the study included 86 patients on CONS (87 on FLX), 34 on SPCDs (23 on FLX), and 69 on other APCDs (67 on FLX). Compared with CONS, FLX was associated with 69% lower per patient per year total phlebolymphedema- and sequelae-related costs net of any pneumatic compression device-related costs ($3839 vs $12,253; P = .001). This was driven by 59% fewer mean annual hospitalizations (0.13 vs 0.32; P .001) corresponding to 82% lower inpatient costs and 55% lower outpatient hospital costs. FLX was also associated with 52% lower outpatient physical therapy and occupational therapy costs and 56% lower other outpatient-related costs. Compared with SPCDs, FLX was associated with 85% lower total costs ($1153 vs $7449; P = .008) driven by 93% lower inpatient costs ($297 vs $4215; P = .002), 84% lower outpatient hospital costs ($368 vs $2347; P = .020), and 85% lower other outpatient-related costs ($353 vs $2313; P = .023). Compared with APCDs, FLX was associated with 53% lower total costs ($3973 vs $8436; P = .032) because of lower outpatient costs and lower rates of cellulitis (22.4% vs 44.9% of patients; P = .02).This analysis indicates significant benefits attributable to FLX compared with alternative compression therapies that can help reduce the notable economic burden of phlebolymphedema.

The lymphatics are essential for the maintenance of tissue fluid homeostasis. Accordingly, lymphatic dysfunction contributes to lymphedema. In development, lymphangiogenesis often requires lymphatic endothelial cell (LEC) lineage specification from the venous ECs and subsequent LEC proliferation and migration, all of which are regulated by the VEGFC/VEGFR3 signaling. Cholesterol is essential for proper cell functions and organ development, yet the molecular mechanism by which cholesterol metabolism controls lymphangiogenesis is unknown. We show that the secreted protein, ApoA1 binding protein (AIBP), dictates lymphatic vessel formation by accelerating cholesterol efflux. Loss of Aibp2, the human paralog in zebrafish, impairs LEC progenitor specification and impedes lymphangiogenesis. Mechanistically, we found that caveolin-1 (CAV-1) suppresses VEGFR3 activation in LECs, and that AIBP-regulated cholesterol efflux disrupts lipid rafts/caveolae and reduces CAV-1 bioavailability, which abolishes the CAV-1 inhibition of VEGFR3 signaling, thereby augmenting VEGFR3 activation and increasing lymphangiogenesis. Enhancement of cholesterol efflux with ApoA1 overexpression or inhibition of cholesterol biosynthesis using atorvastatin restores proper lymphangiogenesis in Aibp2 mutant zebrafish. Loss of Cav-1 increases LEC progenitor specification in zebrafish, and rescues lymphangiogenesis in Aibp2-deficient animals. Recombinant AIBP supplement confers profound LEC fate commitment in the mouse embryonic stem cells (mESC) to LEC differentiation model. Furthermore, enhancement of AIBP-CAV-1-VEGFR3 signaling axis promotes VEGFC-engaged adult lymphangiogenesis in mice. Consistent with these data, AIBP expression is reduced in the epidermis of human lymphedematous skin. These studies identify that AIBP-mediated cholesterol efflux is a critical contributor for lymphangiogenesis. Our studies will provide a new therapeutic avenue for the treatment of lymphatic dysfunctions.One Sentence SummaryOur studies identify that AIBP-CAV-1-VEGFR3 axis enhances VEGFC-elicited lymphangiogenesis, which will guide a new therapeutic strategy for the treatment of lymphatic dysfunctions.

Leukotrienes are biologically active eicosanoid lipid mediators that originate from oxidative metabolism of arachidonic acid. Biosynthesis of leukotrienes involves a set of soluble and membrane-bound enzymes that constitute a machinery complex primarily expressed by cells of myeloid origin. Leukotrienes and their synthetic enzymes are critical immune modulators for leukocyte migration. Increased concentrations of leukotrienes are implicated in a number of inflammatory disorders. More recent work indicates that leukotrienes may also interact with a variety of tissue cells, contributing to the low-grade inflammation of cardiovascular, neurodegenerative, and metabolic conditions, as well as that of cancer. Leukotriene signaling contributes to the active tumor microenvironment, promoting tumor growth and resistance to immunotherapy. This review summarizes recent insights into the intricate roles of leukotrienes in promoting tumor growth and metastasis through shaping the tumor microenvironment. The emerging possibilities for pharmacological targeting of leukotriene signaling in tumor metastasis are considered.

Genetic or acquired defects of the lymphatic vasculature often result in disfiguring, disabling, and, occasionally, life-threatening clinical consequences. Advanced forms of lymphedema are readily diagnosed clinically, but more subtle presentations often require invasive imaging or other technologies for a conclusive diagnosis. On the other hand, lipedema, a chronic lymphatic microvascular disease with pathological accumulation of subcutaneous adipose tissue, is often misdiagnosed as obesity or lymphedema; currently there are no biomarkers or imaging criteria available for a conclusive diagnosis. Recent evidence suggests that otherwise-asymptomatic defective lymphatic vasculature likely contributes to an array of other pathologies, including obesity, inflammatory bowel disease, and neurological disorders. Accordingly, identification of biomarkers of lymphatic malfunction will provide a valuable resource for the diagnosis and clinical differentiation of lymphedema, lipedema, obesity, and other potential lymphatic pathologies. In this paper, we profiled and compared blood plasma exosomes isolated from mouse models and from human subjects with and without symptomatic lymphatic pathologies. We identified platelet factor 4 (PF4/CXCL4) as a biomarker that could be used to diagnose lymphatic vasculature dysfunction. Furthermore, we determined that PF4 levels in circulating blood plasma exosomes were also elevated in patients with lipedema, supporting current claims arguing that at least some of the underlying attributes of this disease are also the consequence of lymphatic defects.

Key Clinical Points Lymphedema after Breast Cancer Treatment Breast cancer–related lymphedema is the most common form of lymphedema in the United States and other developed nations. Axillary lymph-...

Thoracic duct injury can be a devastating injury with disruption of lymphatic flow leading to potentially chylothorax and/or severe lymphedema. Standard treatment modalities include thoracic duct ligation or embolization for chylothorax, but treatment options to date are few for resultant lymphedema. In this case report, we describe lymphaticovenous bypass of the thoracic duct to the jugular venous system in a 21-year-old male with secondary lymphedema after iatrogenic thoracic duct injury. The patient experienced improvement of lymphedema symptoms including decreased weight and limb girth as well as normalization of serum markers indicating improved lymphatic delivery to the venous system. Lymphangiogram at 3 months post op demonstrated patency of the lymphaticovenous anastomoses. At 6-month follow-up, the patient had returned to his preoperative level of activity and showed continued improvement of his lymphedema symptoms. Lymphovenous bypass of the thoracic duct may be an effective technique to treat secondary lymphedema from thoracic duct obstruction, though further studies are required to determine long-term efficacy.

For a century-old problem, edema and its treatment have gone remarkably unnoticed by the biomedical community. Given the prevalence of lymphedema and its debilitating repercussions, there is an acute need for both efficacy-based measures and clinical standards to guide compression garment design and therapeutic application. This review outlines the current state of the art in compression treatment and suggests an integrated biomedical engineering approach going forward. Characterizing the pressure gradient profiles of commercial compression sleeves is necessary to better understand the role of compression treatment in the mitigation of swelling. Integration of pressure sensor technologies with advanced materials design and manufacture provides a critical path not only to elucidate the mechanisms of but also to improve on current compression-based therapies and associated therapeutic devices.

The lymphatic system is essential for the maintenance of tissue fluid homeostasis, gastrointestinal lipid absorption, and immune trafficking. Whereas lymphatic regeneration occurs physiologically in wound healing and tissue repair, pathological lymphangiogenesis has been implicated in a number of chronic diseases such as lymphedema, atherosclerosis, and cancer. Insight into the regulatory mechanisms of lymphangiogenesis and the manner in which uncontrolled inflammation promotes lymphatic dysfunction is urgently needed to guide the development of novel therapeutics: These would be designed to reverse lymphatic dysfunction, either primary or acquired. Recent investigation has demonstrated the mechanistic role of leukotriene B4 (LTB4) in the molecular pathogenesis of lymphedema. LTB4, a product of the innate immune response, is a constituent of the eicosanoid inflammatory mediator family of molecules that promote both physiological and pathological inflammation. Here we provide an overview of lymphatic development, the pathophysiology of lymphedema, and the role of leukotrienes in lymphedema pathogenesis.

Patients who suffer from lymphedema have impaired immunity and, as a result, are at an increased risk for infections. Furthermore, previous studies have shown that lymphadenectomy impairs acquisition of adaptive immune responses and antibody production in response to foreign antigens. Although it is clear that antigen presentation in lymph nodes plays a key role in adaptive immunity, the cellular mechanisms that regulate impaired immune responses in patients with lymphedema or following lymphatic injury remain unknown. We have previously found that axillary lymph node dissection (ALND), both clinically and in a mouse model, results in a marked increase in the number of T-regulatory cells (Tregs) in the ipsilateral limb. In this study, we focus on the role of Tregs in immunosuppression and show that Treg proliferation in tissues distal to site of lymphatic injury contributes to impaired innate and adaptive immune responses. More importantly, using Foxp3-diptheria toxin receptor (Foxp3-DTR) transgenic mice, we show that depletion of Tregs in the setting of lymphatic injury restores these critical immune-mediated responses. These findings provide additional evidence that immune responses following lymphatic injury play a key role in mediating the pathology of lymphedema.

Background Patients with lymphedema suffer lifelong swelling and recurrent cellulitis despite use of complete decongestive therapy. Pneumatic compression devices (PCDs), including non-programmable and programmable devices that meet individual patient needs, support long term self-care in the home. Yet, to date, no direct comparison of their relative benefits has been available. Objective Patients who acquired either a non-programmable device (NP-PCD) or a dynamic pressure programmable device (P-PCD; Flexitouch®) were evaluated to compare associated clinical and health utilization outcomes pre/post-device acquisition. Methods Retrospective analysis of de-identified administrative claims from 2007 through 2013 of a large United States insurer. The study populations were defined pre hoc as distinct cancer- and non-cancer-related lymphedema cohorts. Outcome variables included rates of lymphedema-related cellulitis, manual therapy use, outpatient services, and inpatient hospitalizations. Multivariate regression analysis was performed to: (1) compare outcomes for the 12 months pre- and post-device acquisition and (2) compare these two device types for their treatment-associated benefits. Results The sample consisted of 1,013 NP-PCD and 718 P-PCD recipients. Compared with the NP-PCD group, P-PCD patients’ baseline cellulitis rate was higher, while their post-device cellulitis rate was lower. In the cancer cohort, the NP-PCD group had a 53% reduction in episodes of cellulitis (from 17.9% to 8.5%), compared to a greater 79% reduction in the P-PCD group (from 23.7% to 5.0%) (p