The Role of Inflammation in Lymphedema: A Narrative Review of Pathogenesis and Opportunities for Therapeutic Intervention.

Lymphedema is a chronic and progressive disease of the lymphatic system characterized by inflammation, increased adipose deposition, and tissue fibrosis. Despite early hypotheses identifying lymphedema as a disease of mechanical lymphatic disruption alone, the progressive inflammatory nature underlying this condition is now well-established. In this review, we provide an overview of the various inflammatory mechanisms that characterize lymphedema development and progression. These mechanisms contribute to the acute and chronic phases of lymphedema, which manifest clinically as inflammation, fibrosis, and adiposity. Furthermore, we highlight the interplay between current therapeutic modalities and the underlying inflammatory microenvironment, as well as opportunities for future therapeutic development.

Proposed Framework for Research Case Definitions of Lipedema.

Background: Our aim is to propose a framework for the development of a research case definition of lipedema, based on current available literature and those observations that can be applied to future lipedema research with the intent to standardize and strengthen the scientific evidence base. Methods and Results: We conducted a narrative review of the literature, and identified consensus characteristics and disputed characteristics that could be included in a research case definition of lipedema. After considering the strength of the evidence and how each characteristic might be measured in a research study, we recommended an approach for the development of a research case definition of lipedema that would be based on consideration of five agreed-upon characteristics, and five disputed, or less substantiated, characteristics as additional evidence to enhance specificity. Conclusions: We present a case definition framework for lipedema drawn from the scientific literature that can be applied to future studies on lipedema. Utilizing this framework should help to increase the sensitivity and specificity of case definition and provide an opportunity for meta-analysis of clinical studies and facilitate future research intercomparisons.

Genetic causes of lymphatic disorders: recent updates on the clinical and molecular aspects of lymphatic disease.

PURPOSE OF REVIEW: The lymphatic system facilitates several key functions that limit significant morbidity and mortality. Despite the impact and burden of lymphatic disorders, there are many remaining disorders whose genetic substrate remains unknown. The purpose of this review is to provide an update on the genetic causes of lymphatic disorders, while reporting on newly proposed clinical classifications of lymphatic disease. RECENT FINDINGS: We reviewed several new mutations in genes that have been identified as potential causes of lymphatic disorders including: MDFIC, EPHB 4 , and ANGPT2. Furthermore, the traditional St. George's Classification system for primary lymphatic anomalies has been updated to reflect the use of genetic testing, both as a tool for the clinical identification of lymphatic disease and as a method through which new sub-classifications of lymphatic disorders have been established within this framework. Finally, we highlighted recent clinical studies that have explored the impact of therapies such as sirolimus, ketoprofen, and acebilustat on lymphatic disorders. SUMMARY: Despite a growing body of evidence, current literature demonstrates a persistent gap in the number of known genes responsible for lymphatic disease entities. Recent clinical classification tools have been introduced in order to integrate traditional symptom- and time-based diagnostic approaches with modern genetic classifications, as highlighted in the updated St. George's classification system. With the introduction of this novel approach, clinicians may be better equipped to recognize established disease and, potentially, to identify novel causal mutations. Further research is needed to identify additional genetic causes of disease and to optimize current clinical tools for diagnosis and treatment.

Various Therapies for Lymphedema and Chronic Venous Insufficiency, Including a Multimodal At-Home Nonpneumatic Compression Treatment.

ABSTRACT: Lymphedema and chronic venous insufficiency (CVI) affect millions of people and require lifelong management. Many compression options exist for the long-term management of these conditions; however, limitations in patient mobility and adherence are common. Current options for care often present challenges with adherence because they are time-intensive and cumbersome. Innovation is needed to improve compression options for patients with chronic edematous conditions, particularly because lymphedema and CVI benefit from combination interventions. In this narrative review, the authors focus on long-term management strategies for lymphedema and CVI and highlight a nonpneumatic compression device designed for ease of use in the management of lymphedema and CVI. Using a nonpneumatic compression device that combines multiple treatment modalities demonstrates improved efficacy, quality of life, and patient adherence.

Effectiveness of a Nonpneumatic Active Compression Device in Older Adults with Breast Cancer-Related Lymphedema: A Subanalysis of a Randomized Crossover Trial.

Background: A recently completed clinical trial compared a novel nonpneumatic compression device (NPCD) with a traditional advanced pneumatic compression device (APCD) for the treatment of breast cancer-related lymphedema (BCRL); the study revealed that the NPCD produced superior clinical and quality-of-life (QOL) outcomes. In this subanalysis, we sought to examine these results within the subset of trial subjects aged ≥65 years. Methods: A randomized crossover head-to-head trial was conducted to compare the NPCD with a commercially available APCD. Patients were randomly assigned to one or the other device for 28 days of use, followed by a 4-week washout period before a comparable 28-day utilization of the alternate device. Limb edema, adherence to daily device use, and QOL measures were collected at day 0 and 28 of each period. Results: A total of 14 subjects were aged ≥65. During NPCD use, subjects experienced a mean decrease in limb edema of 100.3% (p = 0.0082) as well as improvements in mean overall and subscale scores of the Lymphedema Quality of Life Questionnaire (LYMQOL). By comparison, during APCD use limb edema decreased by a mean of 2.9% (p = 0.8899) with no significant changes in any LYMQOL scores. Mean adherence was significantly higher during NPCD use (96.6%) than during APCD use (58.3%, p < 0.0001). Conclusions: The novel NPCD produced superior clinical and QOL outcomes in older subjects with BCRL. ClinicalTrials.gov ID: NCT04908254.

Abnormal Lymphatic Sphingosine-1-Phosphate Signaling Aggravates Lymphatic Dysfunction and Tissue Inflammation.

BACKGROUND: Lymphedema is a global health problem with no effective drug treatment. Enhanced T-cell immunity and abnormal lymphatic endothelial cell (LEC) signaling are promising therapeutic targets for this condition. Sphingosine-1-phosphate (S1P) mediates a key signaling pathway required for normal LEC function, and altered S1P signaling in LECs could lead to lymphatic disease and pathogenic T-cell activation. Characterizing this biology is relevant for developing much needed therapies. METHODS: Human and mouse lymphedema was studied. Lymphedema was induced in mice by surgically ligating the tail lymphatics. Lymphedematous dermal tissue was assessed for S1P signaling. To verify the role of altered S1P signaling effects in lymphatic cells, LEC-specific S1pr1-deficient (S1pr1LECKO) mice were generated. Disease progression was quantified by tail-volumetric and -histopathologic measurements over time. LECs from mice and humans, with S1P signaling inhibition, were then cocultured with CD4 T cells, followed by an analysis of CD4 T-cell activation and pathway signaling. Last, animals were treated with a monoclonal antibody specific to P-selectin to assess its efficacy in reducing lymphedema and T-cell activation. RESULTS: Human and experimental lymphedema tissues exhibited decreased LEC S1P signaling through S1P receptor 1 (S1PR1). LEC S1pr1 loss-of-function exacerbated lymphatic vascular insufficiency, tail swelling, and increased CD4 T-cell infiltration in mouse lymphedema. LECs, isolated from S1pr1LECKO mice and cocultured with CD4 T cells, resulted in augmented lymphocyte differentiation. Inhibiting S1PR1 signaling in human dermal LECs promoted T-helper type 1 and 2 (Th1 and Th2) cell differentiation through direct cell contact with lymphocytes. Human dermal LECs with dampened S1P signaling exhibited enhanced P-selectin, an important cell adhesion molecule expressed on activated vascular cells. In vitro, P-selectin blockade reduced the activation and differentiation of Th cells cocultured with shS1PR1-treated human dermal LECs. P-selectin-directed antibody treatment improved tail swelling and reduced Th1/Th2 immune responses in mouse lymphedema. CONCLUSIONS: This study suggests that reduction of the LEC S1P signaling aggravates lymphedema by enhancing LEC adhesion and amplifying pathogenic CD4 T-cell responses. P-selectin inhibitors are suggested as a possible treatment for this pervasive condition.

Abnormal lymphatic S1P signaling aggravates lymphatic dysfunction and tissue inflammation.

BACKGROUND: Lymphedema is a global health problem with no effective drug treatment. Enhanced T cell immunity and abnormal lymphatic endothelial cell (LEC) signaling are promising therapeutic targets for this condition. Sphingosine-1-phosphate (S1P) mediates a key signaling pathway required for normal LEC function, and altered S1P signaling in LECs could lead to lymphatic disease and pathogenic T cell activation. Characterizing this biology is relevant for developing much-needed therapies. METHODS: Human and mouse lymphedema was studied. Lymphedema was induced in mice by surgically ligating the tail lymphatics. Lymphedematous dermal tissue was assessed for S1P signaling. To verify the role of altered S1P signaling effects in lymphatic cells, LEC-specific S1pr1 -deficient ( S1pr1 LECKO ) mice were generated. Disease progression was quantified by tail-volumetric and -histopathological measurements over time. LECs from mice and humans, with S1P signaling inhibition, were then co-cultured with CD4 T cells, followed by an analysis of CD4 T cell activation and pathway signaling. Finally, animals were treated with a monoclonal antibody specific to P-selectin to assess its efficacy in reducing lymphedema and T cell activation. RESULTS: Human and experimental lymphedema tissues exhibited decreased LEC S1P signaling through S1PR1. LEC S1pr1 loss-of-function exacerbated lymphatic vascular insufficiency, tail swelling, and increased CD4 T cell infiltration in mouse lymphedema. LECs, isolated from S1pr1 LECKO mice and co-cultured with CD4 T cells, resulted in augmented lymphocyte differentiation. Inhibiting S1PR1 signaling in human dermal LECs (HDLECs) promoted T helper type 1 and 2 (Th1 and Th2) cell differentiation through direct cell contact with lymphocytes. HDLECs with dampened S1P signaling exhibited enhanced P-selectin, an important cell adhesion molecule expressed on activated vascular cells. In vitro , P-selectin blockade reduced the activation and differentiation of Th cells co-cultured with sh S1PR1 -treated HDLECs. P-selectin-directed antibody treatment improved tail swelling and reduced Th1/Th2 immune responses in mouse lymphedema. CONCLUSION: This study suggests that reduction of the LEC S1P signaling aggravates lymphedema by enhancing LEC adhesion and amplifying pathogenic CD4 T cell responses. P-selectin inhibitors are suggested as a possible treatment for this pervasive condition. Clinical Perspective: What is New?: Lymphatic-specific S1pr1 deletion exacerbates lymphatic vessel malfunction and Th1/Th2 immune responses during lymphedema pathogenesis. S1pr1 -deficient LECs directly induce Th1/Th2 cell differentiation and decrease anti-inflammatory Treg populations. Peripheral dermal LECs affect CD4 T cell immune responses through direct cell contact.LEC P-selectin, regulated by S1PR1 signaling, affects CD4 T cell activation and differentiation.P-selectin blockade improves lymphedema tail swelling and decreases Th1/Th2 population in the diseased skin.What Are the Clinical Implications?: S1P/S1PR1 signaling in LECs regulates inflammation in lymphedema tissue.S1PR1 expression levels on LECs may be a useful biomarker for assessing predisposition to lymphatic disease, such as at-risk women undergoing mastectomyP-selectin Inhibitors may be effective for certain forms of lymphedema.

Lymphedema self-care: economic cost savings and opportunities to improve adherence.

BACKGROUND: Breast cancer-related lymphedema (BCRL) imposes a significant economic burden on patients, providers, and society. There is no curative therapy for BCRL, but management through self-care can reduce symptoms and lower the risk of adverse events. MAIN BODY: The economic burden of BCRL stems from related adverse events, reductions in productivity and employment, and the burden placed on non-medical caregivers. Self-care regimens often include manual lymphatic drainage, compression garments, and meticulous skin care, and may incorporate pneumatic compression devices. These regimens can be effective in managing BCRL, but patients cite inconvenience and interference with daily activities as potential barriers to self-care adherence. As a result, adherence is generally poor and often worsens with time. Because self-care is on-going, poor adherence reduces the effectiveness of regimens and leads to costly treatment of BCRL complications. CONCLUSION: Novel self-care solutions that are more convenient and that interfere less with daily activities could increase self-care adherence and ultimately reduce complication-related costs of BCRL.

Development of a rat model of lymphedema and the implantation of a collagen-based medical device for therapeutic intervention.

Secondary lymphedema is a common condition among cancer survivors, and treatment strategies to prevent or treat lymphedema are in high demand. The development of novel strategies to diagnose or treat lymphedema would benefit from a robust experimental animal model of secondary lymphedema. The purpose of this methods paper is to describe and summarize our experience in developing and characterizing a rat hindlimb model of lymphedema. Here we describe a protocol to induce secondary lymphedema that takes advantage of micro computed tomography imaging for limb volume measurements and visualization of lymph drainage with near infrared imaging. To demonstrate the utility of this preclinical model for studying the therapeutic benefit of novel devices, we apply this animal model to test the efficacy of a biomaterials-based implantable medical device.

Acupuncture Treatment for Breast Cancer-Related Lymphedema: A Randomized Pilot Study.

Background: Methods of conservative management for breast cancer-related lymphedema (BCRL) are burdensome in terms of time, cost, and convenience. In addition, many patients are not candidates for surgical treatment. Preliminary results have demonstrated possible beneficial effects of acupuncture for patients with BCRL. In this small pilot study, we examined the safety and feasibility of an acupuncture randomized control trial (RCT) in this patient cohort, utilizing a battery of standardized clinical and patient-centered outcome measures. Methods and Results: Patients with BCRL were randomized 2:1 to the acupuncture (n = 10) or the control (n = 4) group. Patients received acupuncture to the unaffected extremity biweekly for 6 weeks. Feasibility was defined as enrollment ≥80%, completion of ≥9 of 12 acupuncture sessions per person, and ≥75% completion of three of three measurement visits. To inform a future adequately powered RCT, we describe within-group changes in patient-centered outcomes, including circumferential measurements, bioimpedance spectroscopy, perometry, cytokine levels, and patient quality of life. Adverse events were systematically tracked. Fourteen patients completed the study. Of those who received acupuncture (n = 10), 8 completed all 12 acupuncture sessions, and 2 patients completed 11 sessions. Ninety-three percent of all participants completed all three measurement visits. There was no consistent improvement in arm volumes. Inflammatory marker levels had inconclusive fluctuations among both groups. All patients receiving acupuncture demonstrated an improvement in their functional quality-of-life score. No severe adverse events occurred. Conclusions: A randomized controlled study of acupuncture for BCRL is feasible. The acupuncture intervention is acceptable in this population, without safety concerns in a small sample and warrants further investigation.