Lymphedema Research Articles

Angiosarcoma of the Breast: Case Report

Angiosarcoma is a rare and aggressive tumor of the breast arising from endothelial cells. It is usually associated with chronic lymphedema or radiation therapy. The diagnosis is made by biopsy and there is no specific finding on mammography. In this study, we report a 59-year-old woman with a history of radiotherapy for invasive ductal carcinoma who subsequently developed primary angiosarcoma of the breast. Angiosarcoma of the breast was first documented in 1887 and is classified as primary and secondary. While surgical R0 resection is recommended for the treatment of these tumors with unclear etiology, the significance of axillary lymph node dissection remains uncertain. Adjuvant radiotherapy has been shown to reduce the local recurrence rate, but adjuvant chemotherapy and radiotherapy have no significant effect on 5-year survival. Although there is no consensus on treatment regimens, it is concluded that more comprehensive studies should be conducted in a larger sample.

Adjustable compression wraps: back to the future

Adjustable Compression Wraps (ACWs) are used to treat a variety of conditions, in particular venous leg ulcers, edema and lymphedema. Publications on the use of these devices are ultimately few and far between, with limitations or biases (small sample sizes, methodological weaknesses, non-comparative studies, lack of interface pressures). A development model like that used in the study of a drug could be more rational. We propose five phases: phase 1) discovery and development, phase 2) in vitro testing, phase 3) clinical trials, phase 4) real-life data analysis, medico-economic investigation using Artificial Intelligence (AI), and phase 5) preparation of regulatory dossiers. This lack of coherence in development could be an obstacle to widespread clinical use. Using AI to analyse large quantities of data could reduce the cost and number of clinical trials needed to generate more robust evidence. This would make it possible to better define the clinical effects of ACWs in specific situations (e.g., leg wounds in the elderly, diabetic wounds, mixed leg ulcers, secondary lymphedema of the upper limb, efficacy, and comfort...) and to compare treatment costs between bandages and ACWs. If we don't explore the future with AI, we'll never know what will be useful for the present - hence the title “Back to the Future”.

Abstract 4136884: Incidence and Characteristics of Peri-Procedural Complications of Cardiac Implantable Electrical Devices in Breast Cancer Survivors

Introduction: Breast cancer (BC) is the most common non-cutaneous cancer in women. Several BC treatments increase the risk of conduction abnormalities and heart failure, potentially requiring cardiac implantable electrical devices (CIEDs). Due to vascular access devices, surgical management, and chest wall radiation, these patients are subject to upper extremity vascular alterations. There is limited data regarding CIED use in this population. Research question: Do patients with BC and CIEDs have different procedural approaches or complications compared to the general population? Aims: This study aimed to evaluate CIED placement and periprocedural complications in patients with a history of BC. Methods: This was a retrospective study of CIEDs placed at our institution between 2005 and 2023. Patients with a diagnosis of BC prior to time of placement were included. Complications included those within 30 days of the procedure. Results: We analyzed 109 female patients (median age of 73 years, IQR 66-80) who received pacemaker (PPM, 58.7%), cardiac resynchronization therapy defibrillator (CRT-D, 22%), implantable cardioverter defibrillator (ICD, 16.5%), or cardiac resynchronization therapy pacemaker (CRT-P, 2.8%). The median time from cancer diagnosis to device placement was 13 years (IQR 7-21). Oncologic therapies are included in Figure 1. In patients with unilateral cancer, most devices (78.4%) were placed contralaterally, with 32% of all devices being right sided. Anatomy related to chemotherapy port altered intraoperative approach in 2 cases and bilateral lymph node dissection necessitated subcutaneous ICD in 1 case. Complications were noted in 12 patients (11%) and included hematoma, lead revision, upper extremity DVT, pericardial effusion, stress cardiomyopathy, perforation, site infection, and worsening of chronic lymphedema. Conclusions: BC survivors undergoing CIED placement appear to be at higher risk of periprocedural complications when compared to the general population. They are more likely to undergo right sided device placement to avoid vascular access ipsilateral to prior surgery or radiation. Further studies are required to understand the long-term outcomes of CIED placement in this cohort of patients.

Assessing and managing lower limb oedema: a clinical review.

Lower limb oedema is a common condition in clinical practice, frequently affecting the distal lower limbs. Whereas benign causes such as prolonged sitting or standing are typical, oedema can also indicate serious systemic diseases such as cardiac failure, liver disease, or renal impairment. Identifying the cause is crucial to prevent irreversible skin and tissue changes. This clinical review aims to increase the knowledge of advanced clinical practitioners (ACPs) and generalist practitioners, including practice and community nurses, by providing an overview of how to approach patients with lower limb oedema, encompassing history-taking, examinations, investigations, and management plans. The main focus is on lymphoedema, which can be primary or secondary. Primary lymphoedema results from genetic abnormalities, while secondary lymphoedema arises from acquired defects due to factors such as obesity, infections, neoplasms, and trauma. Effective management includes addressing the underlying cause, ensuring proper skin care, recommending appropriate exercises, and the use of compression garments. Referral to a lymphoedema specialist is recommended for patient education on managing and treating the condition when required. Additionally, the article discusses the importance of regular skin inspections, minor injury management, environmental considerations, and the critical role of compression garments in lymphoedema management. This comprehensive approach aims to enhance patient outcomes and provide a thorough strategy for ACPs and generalist practitioners.

Ultrasound Irradiation as a Candidate Procedure to Improve the Transdermal Drug Delivery to the Tail Edema of a Mouse Model

Drug therapy for secondary lymphedema has not yet been established. Conventional oral and intravenous administration is difficult to administer in sufficient doses due to adverse events. Therefore, it is necessary to develop a transdermal delivery system that can deliver high concentrations of drugs to the edema area. In this study, we examined the efficacy of transdermal drug delivery in a mouse model of tail edema using ultrasound irradiation (sonication method). Ultrasound irradiation can deliver high-molecular-weight substances subcutaneously, and the percutaneous administration of clobetasol propionate to the mouse tail edema model prevented the enlargement of lymphatic vessels with reduced tail volume. Therefore, steroid administration utilizing ultrasound irradiation is effective in decreasing tail swelling in a mouse tail edema model. Thus, ultrasound irradiation could have the potential to innovate the treatment of secondary lymphedema by directly administering the drug to the edema.

The effects of lumbar sympathetic ganglion block therapy on secondary lower limb lymphedema among patients with gynecologic cancer surgery

The effects of lumbar sympathetic ganglion block therapy on secondary lower limb lymphedema among patients with gynecologic cancer surgery

Effect of scapular and shoulder strengthening exercises on prevention of upper limb lymphedema – a pilot study

Background. The most frequent type of cancer among women is breast cancer. According to the report published by Indian Council for Medical Research (ICMR, 2019), there are 1.5 lakh new instances of breast cancer nationwide and around 70,000 people in India die from breast cancer each year. Secondary lymphedema (SL) following breast cancer surgery can occur due to the removal of lymph nodes during breast cancer surgery. Objective. This pilot study was done with the objectives to improve the strength of scapular and shoulder muscles, increase the shoulder range of motion, prevent the development of upper limb lymphedema, to reduce shoulder pain and disability and to improve the quality of life among women who underwent breast cancer surgery. Methodology. Ten patients with a mean age of 49.9 ± 8.6 and mean Body mass index (BMI) of 28.4 ± 3.9 were included according to the inclusion and exclusion criteria. They were randomized into interventional group (Group A n = 5) and conventional group (Group B n = 5). The interventional group performed the routine exercises prescribed along with the scapular and shoulder muscle strengthening exercises, while the conventional group performed only the routine exercises for 12 weeks. Result. The mean change score values of the outcome variables of both the groups were analyzed using Independent ‘t’ test. Discussion. Arm circumference measurement, shoulder pain, disability and quality of life measures showed significant difference between groups at p < 0.05. Shoulder range of motion, muscle strength and arm volumetry did not show much difference between groups indicating the need for long term continuation of the exercises to produce improvement in those parameters. Conclusion. Long term effect of strengthening exercises will have an effect on improvement of shoulder range of motion, arm volume and muscle strength among the women following breast cancer surgery. Strengthening exercises should be recommended as a part of breast cancer rehabilitation protocol to prevent secondary lymphedema and other postsurgical complications.

Exercise benefits following breast cancer surgery – a narrative review

One of the most common cancer diseases among women is breast cancer. Treatment following breast cancer surgery leads to many complications. Exercises play an important role from the immediate post operative period which could help in preventing post-surgical complications. Prevention of complications improves the quality of life of women. Though women feel that performing exercises following treatment are difficult there are many positive effects of exercises. This current study was done with an objective to analyse the various effects of exercises especially on the resisted exercises in preventing Secondary lymphedema (SL) and to focus light on the benefits of the exercises during and after chemotherapy. Literature search of PubMed, Clinical Key and Google scholar was performed. For women recovering from breast cancer surgery, resisted exercises, either by themselves or in combination with aerobic exercises, were safe and effective. These exercises improved upper body strength, increased endurance, decreased adipose tissue, decreased waist and hip circumferences, increased lean body mass, improved cardiovascular fitness, improved self-esteem, and decreased depression. Women with breast cancer related lymphedema had a considerable improvement in pain after performing deep breathing exercises combined with upper limb movements. Exercise can help mitigate the negative effects of chemotherapy and helps to overcome cancer related fatigue. Along with conventional exercises including range of motion exercises and aerobic exercises, moderate-intensity upper body resistance exercises are recommended to be a part of exercise protocol prescribed and educated to the women following breast cancer surgery for them to lead a better quality of life.

Chronic infection and severe mitral regurgitation: first of all, do not harm.

techniques of mitral valve repair has improved in the last decades. Percutaneous approach is now a reliable and safe therapy in those patients with high surgical risk. However, the presence of an implanted prothesis increases the risk of endocarditis. we describe a case of a 75-year-old man with medical history of recurrent cellulitis due to chronic lymphedema, who had percutaneous edge-to-edge mitral valve treatment. After three months he developed fever without any specific symptoms. Emocolture were positive for Staphilococcus lugdunensis. Transesophageal echocardiogram demonstrated a huge vegetation at the level of Edwards Pascal device. Patients was then referred to cardiac surgery for mitral valve replacement with bioprothesis. in patients needing a prothesis implantation the management and treatment of chronic infection is of paramount importance to reduce the risk of prothesis infection procedure. Endocarditis after percutaneous edge-to-edge mitral valve treatment represents a rare but a life-threatening condition.

Successful Surgical Treatment of Coronavirus Disease 2019 (COVID-19) Vaccination Related Upper Extremity Lymphedema : Case Report

Lymphedema is rare adverse effect of COVID-19 vaccination which was reported at several literatures. We present a case of surgically treated secondary lymphedema after the COVID-19 vaccination. The patient presented lymphedema at the upper extremity with no specific history except the COVID-19 vaccination 18 months before the visit. LVA and liposuction for the posterolateral aspect of forearm and upper arm was performed. The volume of the affected arm was reduced to more than 54 percent at the postoperative 8 months. With precise surgical planning, secondary lymphedema occurred after the COVID-19 vaccination could be successfully treated surgically.

Effects of Short-Term Educational Hospitalization with Multidisciplinary Approach for Lymphedema on Limb Circumference and Quality of Life.

Background: Lymphedema is an intractable disease requiring lifelong treatment. Daily self-care by the patient is essential; however, establishing care is often difficult. Our hospital offers a short-term educational hospitalization program that involves intensive, multidisciplinary intervention to develop self-care. This study aimed to evaluate the effectiveness of this program. Methods and Results: Among the patients diagnosed with primary or secondary lymphedema who underwent educational hospitalization, 31 cases (33 limbs) were included in this study. The upper extremity lymphedema (UEL) index and lower extremity lymphedema (LEL) index were used for objective evaluation, and the Lymphedema Quality of Life Questionnaire was used for subjective evaluation. The therapeutic effects of educational hospitalization were examined before admission, at discharge, and at 6 months postdischarge. The UEL/LEL index significantly decreased for both the upper and lower limbs after educational hospitalization. In addition, the UEL/LEL index change rate from prehospitalization to 6 months postdischarge was compared between the continued and discontinued exercise groups; the former index showed significantly more improvement than the latter. Comparing the quality of life (QOL) assessments pre- and posthospitalization, statistically significant improvements were observed in all categories, including function, appearance, symptoms, and psychological state. Conclusions: Short-term educational hospitalization led to a sustained reduction in the circumference of lymphedema-affected limbs and an improvement in the QOL. The multidisciplinary approach resulted in improved self-efficacy and established daily self-care.

Improved lymphangiogenesis around vascularized lymph node flaps by periodic injection of hyaluronidase in a rodent model

Vascularized lymph node transfer (VLNT) is an advanced surgical approach for secondary lymphedema (SLE) treatment, but tissue fibrosis around the lymph node flap (VLNF) inhibiting lymphangiogenesis is the biggest challenge undermining its therapeutic efficacy. This study explored the effects of periodic hyaluronidase (HLD) injection in reducing fibrosis and promoting lymphangiogenesis in 52 Sprague–Dawley rats with a VLNF over 13 weeks. The results demonstrated that HLD administration significantly enhanced swelling reduction, lymphatic drainage efficiency, and lymphatic vessel regeneration, with up to a 26% decrease in tissue fibrosis around the VLNF. These findings suggest that combining VLNT with periodic injections of HLD could substantially improve SLE treatment outcomes in clinical settings. It offers a promising direction for future therapeutic strategies and drug development aimed at increasing the efficacy of surgical treatment for SLE patients.

Cancer and lymphatic marker FOXC2 drives wound healing and fibrotic tissue formation.

The FOXC2 transcription factor has been tied to a wide range of disease states, serving as a promising prognostic biomarker associated with aggressive basal-like human breast cancers (increased cancer invasion and metastasis). Dysregulation of FOXC2 expression has also been found to promote defects in lymphatic remodeling and hyperplastic lymphedema-distichiasis (LD). Since chronic lymphedema is a forerunner of several malignancies and cancers have been known to arise from poorly healing chronic wounds (e.g., Marjolin ulcers), we examined the effect of Foxc2 dysfunction on skin wound healing. We used our splinted excisional wounding model that mimics human-like wound healing on wildtype and Foxc2+/- mice (n = 4), which demonstrate incomplete lymphatic vasculature and lymphatic dysfunction. Wound size was measured over the course of 18days. Tissue was explanted from both groups at post-operative day (POD) 14 and 18 and stained with Masson's Trichrome to assess scar formation, Picrosirius Red for dermal integrity, or immunofluorescence to assess lymphatic (LYVE1) cell populations. Wildtype mice completely healed by POD 14, while Foxc2+/-mice did not completely heal until POD18. Scar area of healed Foxc2+/-mice (POD 18) was larger than that of healed wild-type mice (POD 14; p = 0.0294). At POD 14, collagen "bers in the scars of Foxc2+/-mice to be narrower (p = 0.0117) and more highly aligned (p = 0.0110), indicating signi"cantly more "brosis in these mice. Collagen "bers in both groups became longer (p = 0.0116) and wider (p = 0.0020) from POD 14 to 18, indicating a temporal evolution of "brosis. Foxc2+/-mice also had lower numbers of LYVE1+, F4/80+ and CD4+ cells compared to wildtype mice. Individuals over 65 years old are more likely to develop cancer and are highly susceptible to developing chronic wounds. Here, we found that FOXC2, which is tied to cancer metastasis and lymphatic dysregulation, also impairs wound healing and promotes "brotic tissue architecture. With FOXC2 proposed as a potential therapeutic target for cancer metastasis, its downstream systemic effects should be considered against the increased chance of developing nonhealing wounds. Further delineation of the microenvironment, cellular events, and molecular signals during normal and Foxc2-associated abnormal wound healing will improve clinical therapies targeting this important marker.

The influence of non-cancer-related risk factors on the development of cancer-related lymphedema: a rapid review.

Extensive research supports an evidence-base for cancer treatment-related risk factors, including extent of lymph node dissection and use of radiotherapy, as contributing to secondary lymphedema. Additionally, comorbidities, such as higher body mass index, and vascular-related conditions are identified to further augment risk. While social determinants of health (SDOH) and socioeconomic factors are widely regarded as influencing an individual's healthcare outcomes, including cancer risk and survival, these factors have not been explored as risk factors for developing secondary lymphedema. A rapid literature review explored the current evidence for SDOH as risk factors for lymphedema. Studies that were published over the last 10years and that specifically analyzed social factors as variables associated with lymphedema were included. Studies that only characterized the social determinants of the study population were not included. Forty-nine studies were identified through a rapid literature review, and 13 studies that expressly analyzed social determinants as risk factors for secondary lymphedema were reviewed and extracted. All studies were conducted in patients with breast cancer-related lymphedema. Social risk factors included race, educational level, insurance type, and income level. These are consistent with the socioeconomic inequalities related to cancer survival. SDOH may influence the risk of developing cancer treatment-related health conditions like secondary lymphedema. Research trials studying cancer treatment-related conditions should collect consistent and robust data across social, behavioral, environmental, and economic domains and should analyze these variables to understand their contribution to study endpoints. Risk prediction modeling could be a future pathway to better incorporate social determinants, along with medical and co-morbidity data, to holistically understand lymphedema risk.

Consensus statement on non-cancer-related risk factors for development of secondary lymphedema.

Non-cancer-related risk factors for secondary lymphedema were defined across four categories: co-morbidity, social determinants of health, behavioral factors, and environmental effectors. Based on rapid reviews of the literature and presentations at the ACS/LANA Lymphedema Summit, this working group categorized these risk factors according to the strength of evidence. Consensus agreement on level of evidence was achieved through one face-to-face working session and three follow-up virtual meetings. Findings elucidate strong evidence for co-morbidities, such as cardio/metabolic and vascular factors contributing to the risk for lymphedema. Evidence is low-to-moderate for social and behavioral factors and is lacking for environmental factors. Panel recommendations suggest a tailored approach to prospective surveillance when monitoring for secondary lymphedema that includes social determinants of health considering the growing awareness and evidence of these factors' influence on cancer and cancer-related morbidity.

Multi-omics characterization of lymphedema-induced adipose tissue resulting from breast cancer-related surgery.

Secondary lymphedema (LE) following breast cancer-related surgery is a life-long complication, which currently has no cure. LE induces significant regional adipose tissue deposition, requiring liposuction as a treatment. Here, we aimed to elucidate the transcriptional, metabolomic, and lipidomic signature of the adipose tissue developed due to the surgery-induced LE in short- and long-term LE patients and compared the transcriptomic landscape of LE adipose tissue to the obesity-induced adipose tissue. Adipose tissue biopsies were obtained from breast cancer-operated females with LE from the affected and non-affected arms (n = 20 patients). To decipher the molecular properties of the LE adipose tissue, we performed RNA sequencing, metabolomics, and lipidomics combined with bioinformatics analyses. Differential gene expression data from a cohort of lean and obese patients without LE was used for comparisons. Integrative analysis of functional genomics revealed that inflammatory response, cell chemotaxis, and angiogenesis were upregulated biological processes in the LE arm, indicating a sustained inflammation in the edematous adipose tissue; whereas, epidermal differentiation, cell-cell junction organization, water homeostasis, and neurogenesis were downregulated in the LE arm. Surprisingly, only a few genes were found to be the same in the LE-induced and the obesity-induced adipose tissue expansion, indicating a different type of adipose tissue development in these two conditions. In metabolomics analysis, we found reduced levels of a branched-chain amino acid valine in the LE arm and downregulation of the mRNA levels of its transporter SLC6A15. Lipidomics analyses did not show any significant differences between the LE and non-LE arms, suggesting that other factors affect the lipid composition of the adipose tissue more than the LE in these patients. Our results provide a detailed molecular characterization of adipose tissue in secondary LE after breast cancer-related surgery. We also show distinct differences in transcriptomic signatures between LE-induced adipose tissue and obesity-induced adipose tissue, but only minor differences in metabolome and lipidome between the LE and the non-LE arm.

The Usefulness of Portable Echo in the Preoperative Mapping of Lymphaticovenular Anastomosis.

This study evaluated the effectiveness of a pocket-sized ultrasound device in preoperative planning for lymphaticovenular anastomosis (LVA) to enhance lymphedema treatment outcomes. A retrospective analysis was performed on 24 patients who underwent LVA for secondary upper extremity lymphedema between June 2020 and August 2022. Patients were categorized into two groups: the ultrasound group, which used a pocket-sized device (Vscan Air), for preoperative vein identification, and a control group that did not. Preoperative lymphatic mapping was performed using indocyanine green lymphography, and suitable veins for anastomosis were identified using ultrasound. Upper extremity lymphedema index and incision length were compared. Participants in the ultrasound group had a shorter average incision length (2.85 ± 0.48 cm) than those in the control group (3.23 ± 0.78 cm, p = 0.038), indicating a more targeted and minimally invasive approach. Although volume reduction rates were not significantly different, the pocket ultrasound device facilitated more precise vein selection, enhancing surgical planning. Pocket-sized ultrasound devices provide a cost-effective and practical solution for vein identification during LVA, particularly in resource-limited settings. While high-frequency ultrasound offers superior resolution, portable devices could become standard tools for lymphatic surgery with continued technological advancement.

Cross-Sectional Analysis of Patients Referred to a Tertiary Lymphatic Surgery Center.

Secondary lymphedema has become an increasingly common reason for referral to plastic surgery. Understanding referral patterns for lymphedema patients is crucial to optimizing care. Patients referred to plastic surgery for lymphedema at a lymphatic surgery center between January 2016 and 2023 were identified. Primary outcomes of interest included clinical lymphedema staging and characteristics, patient demographics, and referral sources. Secondary outcomes were prior lymphedema treatment, agreement between referring provider and plastic surgeon's diagnosis, and patient disposition after surgical evaluation. Descriptive statistics and multivariate logistic regression analysis were performed. A total of 285 patients with extremity edema were referred to plastic surgery; 60.0% of patients had prior malignancy, 45.6% of patients had undergone a prior lymph node procedure, and 40% had received radiation, while 56.8% of patients had previously seen occupational therapy. Body mass index (BMI, OR 1.09, p = 0.013), age (OR 1.25, p = 0.005), and prior physical oroccupational therapy (OR 1.23, p = 0.011) were associated with later stages of lymphedema upon presentation, while prior radiation (OR 0.79, p = 0.006) and malignancy (OR 0.85, p = 0.034) were associated with earlier stages of lymphedema. Self-referral (27.4%), primary care (17.9%), and medical oncology (14.7%) were the most common referral sources. Lymphedema was confirmed in 68.1% of referrals, and 28.5% of these patients proceeded to surgery. Patients were more likely to be operative candidates if referred by primary care (RR 2.1, p = 0.006) or occupational therapy (RR 4.6, p = 0.010). Referred patients ultimately undergo lymphedema surgery at relatively low rates, indicating that most referred patients are not ideal surgical candidates. Optimizing referral patterns through multidisciplinary education may enhance the referral process and improve access to lymphedema surgery.

Progress in lymphedema.

A century ago, the first description of secondary lymphedema resulting from mastectomy was published in the medical literature. For most of the remaining twentieth century, evidence about cancer treatment related lymphedema grew slowly, and mostly through clinicians who wished to understand its causes, natural-history, and post-treatment risks, as well as from clinicians involved with its treatment. In the late 1990s, there was growing recognition that there were large gaps in our understanding of predisposing and post-treatment risks of onset, the near and long-term prevalence of lymphedema, andhow to educate patients. Moreover, there was no consensus on best practices for treating lymphedema, and how to ensure the quality of treatment. In 1998, with support from the Longaberger Company®, the American Cancer Society began a long-standing commitment to address enduring challenges associated with lymphedema. This commitment began with a landmark international workshop on lymphedema that was held in New York City in February 1998, millions of dollars in research funding, support to establish the Lymphology Association of North America (LANA), a second workshop convened in February 2011 on the prospective surveillance model for rehabilitation for women with breast cancer, and most recently, the 2023 Lymphedema Summit: Forward momentum; Future Steps in Lymphedema Management, co-sponsored with the LANA, Washington University School of Medicine in St. Louis, and the Stryker Corporation. This editorial introduces the papers and expert consensus statements from that Summit.

Adherence to Hygiene Protocols and Doxycycline Therapy in Ameliorating Lymphatic Filariasis Morbidity in an Endemic Area Post-Interruption of Disease Transmission in Ghana.

Filarial lymphedema (LE) remains a significant global problem despite the progress made toward elimination of lymphatic filariasis (LF). In Ghana, the main approach to LF is preventive chemotherapy, but this has minimal impact on individuals who have already developed LE. In 2018-2020, a 24-month randomized, double-blind, placebo-controlled trial was conducted to evaluate the efficacy of stringent hygiene measures using the Essential Package of Care with or without additional administration of doxycycline (DOX) to improve filarial leg LE. This study enrolled 356 participants with LE stages 1-3 from two districts in the Upper East Region of Ghana. In addition to regular training on appropriate care for their affected legs, participants were randomized to receive 6 weeks of either 200 mg/day DOX (n = 117), 100 mg/day DOX (n = 120), or matching placebo (n = 119). Participants were seen every 2 months, with clinical measurements done at 6, 12, 18, and 24 months to assess the status of affected legs. There was a trend toward later appearance of acute attacks after DOX, but surprisingly, DOX showed no effect on LE stage progression. In all groups, leg LE improvement was more common (DOX 200 mg: n = 23 [20%]; DOX 100 mg: n = 23 [19.5%]; placebo: n = 32 [27.4%]) than LE worsening (DOX 200 mg: n = 2 [1.7%]; DOX 100 mg: n = 3 [2.5%]; placebo: n = 2 [1.7%]). Overall, these data show a strong benefit from adherence to a strict hygiene protocol, with some added potential benefit for DOX in preventing acute attacks.