Evidence for the clinical effectiveness of decongestive lymphoedema treatment for breast cancer-related arm lymphoedema, a systematic review.

PURPOSE: Early treatment is advised for breast cancer-related arm lymphoedema (BCRL), a common sequelae of breast cancer treatment. Expert guidance recommends two-phase decongestive lymphoedema treatment (DLT), although evidence is lacking for current treatment protocols and UK women are routinely offered self-treatment with hosiery. This systematic review considered evidence regarding treatment of early BCRL, that is, within 12 months of developing BCRL. METHODS: A systematic review of evidence for clinical effectiveness of DLT for women with less than 12-month BCRL duration (early BCRL) was undertaken using the Joanna Briggs Institute (JBI) method. Studies included women with < 12-month or mean < 9-month BCRL duration; some studies reported only one eligible group. The original search was conducted in 2016 and updated in 2018 and 2022. Methodological quality of identified studies was assessed using JBI critical appraisal instruments. Outcomes of interest were extracted with eligible results displayed in narrative and tabular format. Strength of evidence was rated using the GRADE system. RESULTS: Seven trials and three descriptive studies provided weak evidence (grade B) for effectiveness of DLT for early BCRL. Heterogeneous protocols limited comparison of findings. There was no evidence for the most effective treatment or treatment combination or optimal frequency or duration of treatment. CONCLUSION: There is no evidence to justify change in current lymphoedema treatment, whether self-treatment with hosiery (UK) or two-phase DLT (other countries). Further research for the early BCRL population is required. IMPLICATIONS FOR CANCER SURVIVORS: Women with early BCRL require early and effective treatment although this updated review shows there is still no evidence for what that treatment should be.

Feasibility of implementing a remote system for lymphoedema conservative therapy: a case study.

BACKGROUND: Poor access to lymphoedema specialists and communication between them and patients prevents appropriate lymphoedema management. Therefore, development and dissemination of remote systems is necessary to improve care in rural areas with limited medical personnel or access to medical coordination. AIMS: The authors evaluated the elements required for providing patient education on conservative therapy for lymphoedema, to determine the feasibility of remote management. METHODS: The study involved connecting a health professional in a local clinic (point A) treating a patient with lymphoedema, who was present alongside the clinician, with a specialist certified lymphoedema therapist (CLT) located remotely in a university (point B). FINDINGS: The CLT was able to greet, interview and provide guidance to the patient on conservative therapy. Direct contact with the patient was not possible, which limited visualisation, palpation, leg circumference measurement, and lymphatic drainage management. CONCLUSION: The findings suggest that remote a lymphoedema management approach involving conservative therapy benefits both patients and health professionals, particularly in rural regions. Future studies are needed to confirm the effectiveness of this approach to confirm adequate treatment.

Obesity-related pubis lymphedema enclosing genitalia: An atypical case of genital reconstruction.

Massive localized lymphoedema (MLL) is a rare complication of morbid obesity and has been scarcely reported in the literature, especially in the pubic area and genitalia. It is associated to BMI more than 40 kg/m2. We report the case of a 37-year-old patient known for morbid obesity with 68.8 kg/m2 BMI and hypogonadism-obesity syndrome presenting an unusually voluminous scrotal MLL mass. Malignancy was ruled out before surgery. In total a 7.5 kg scrotal mass was resected. Surgery was performed with minor complications without requiring additional surgery.

The effect of exercise and educational programs for breast cancer patients on the development of breast cancer-related lymphoedema: secondary endpoint from a randomized controlled trial in the Setouchi Breast Project-10.

BACKGROUND: Although the association between higher physical activity and preventive effect on breast-cancer-related lymphoedema (BCRL) has been reported, it is unclear what intervention is optimal. We aimed to investigate the effect of exercise and educational programs on BCRL development. METHODS: This study was a secondary endpoint analysis from a prospective randomized controlled trial. We enrolled patients with stage 0-III breast cancer from March 2016 to March 2020 and randomly assigned them to the control (n = 111), education (n = 115), or exercise (n = 104) group. As secondary endpoint, we assessed the incidence of and preventive effect on BCRL at 12 months post-intervention. RESULTS: There were no significant differences in the incidence of BCRL at 12 months post-intervention between the exercise and control groups (9.8% and 10.8%, P = 0.83) and the education and control groups (11.6% and 10.8%, P = 1.00). There were no significant differences in time to BCRL onset from the day of surgery between the exercise and control groups (event rate at 12 months: 20.7% and 17.2%, log-rank, P = 0.54) and the education and control groups (18.8% and 17.2%, log-rank, P = 0.57). The multivariable analyses indicated that axillary dissection and obesity significantly increased the risk of BCRL [hazard ratio (HR): 2.36, 95% confidence interval (CI) 1.52-3.67 and HR: 1.68, 95% CI 1.07-2.63, respectively]. CONCLUSIONS: The intervention did not decrease the risk of BCRL, and axillary dissection and obesity were the risk factors of BCRL. TRIAL REGISTRATION NUMBER: UMIN000020595 at UMIN Clinical Trial Registry.

The lymphedema patient experience within the healthcare system: a cross-sectional epidemiologic assessment.

Lymphedema is a progressive lymphatic disease that potentiates physical and psychosocial distress. Despite its impact, patients reportedly encounter lymphatic ignorance throughout the healthcare system. This cross-sectional study aims to summarize clinical characteristics and interactions of lymphedema patients within the healthcare system. Two lymphedema patient cohorts were included: The Global Registry Analysis Cohort included lymphedema patients who contributed to an international digital lymphatic registry and the Interactions Cohort included patients who initiated a questionnaire about interactions with the medical system. The global registry was used to obtain demographic and clinical characteristics from affiliated lymphedema patients. A 23-item online questionnaire on healthcare experiences and satisfaction with lymphatic healthcare was then distributed to the Interactions Cohort. Complete responses were obtained from 2474 participants. Participants were a mean age of 57.5 ± 16.1 years and 51.4% had a cancer history. Participants reported substantial delays in diagnosis and treatment. Cancer-related and non-cancer-related lymphedema patients reported similar levels of perceived physician disinterest in their lymphedema; however, non-cancer-related lymphedema patients reported more care dissatisfaction. Ultimately, patients continue to face delays in lymphedema diagnosis and treatment. We developed an evidence-based model highlighting areas of reform needed to improve lymphatic education and healthcare.

Potential therapeutic effect of a ketogenic diet for the treatment of lymphoedema: Results of an exploratory study.

BACKGROUND: Lymphoedema is a chronic and progressive disease characterised by excessive accumulation of lymph in the interstitial compartment, leading to tissue swelling and fibroadipose deposition. Lymphangiogenesis is partly regulated by ketone body oxidation, and a ketogenic diet (KD) has shown therapeutic efficacy in a preclinical mouse tail lymphoedema model. Therefore, we aimed to investigate the potential therapeutic effect of a KD in patients with secondary lymphoedema. METHODS: Nine patients with unilateral stage 2 lymphoedema secondary to lymphadenectomy were included in this quasi-experimental exploratory study consisting of a short run-in phase to gradually induce ketosis, followed by a classic KD (CKD) and modified Atkins diet (MAD) phase during which patients consumed a CKD and MAD, respectively. Lymphatic function and oedema volume, the primary outcomes, were assessed at baseline and at the end of both the CKD and MAD phase. Secondary outcomes included health-related and lymphedema-specific quality of life (QoL). RESULTS: Seven out of nine patients completed the study protocol. Lymphatic function was improved upon consumption of both a CKD (dermal backflow score [mean ± SD]: 7.29 ± 2.98 vs. 10.86 ± 2.19 at baseline; p = 0.03) and MAD (6.71 ± 2.06; p = 0.02), whereas oedema volume did not decrease during the course of the study (excess limb volume [mean ± SD]: 20.13 ± 10.25% at end of CKD and 24.07 ± 17.77% at end of MAD vs. 20.79 ± 12.96% at baseline; p > 0.99 and p > 0.30, respectively). No changes were observed in health-related, nor lymphoedema-specific QoL at the end of CKD and MAD. CONCLUSIONS: The consumption of a KD improved lymphatic function and was associated with a clinically meaningful reduction in oedema volume in some patients (3/7 at end of CKD, 2/7 at end of MAD) with unilateral stage 2 secondary lymphoedema. These results highlight the potential of a KD to improve lymphatic function in patients with lymphoedema. However, further studies are required to substantiate our findings.

Panniculectomy for a Rare End-Stage Complication of Severe Obesity and Increasing Surgical Phenomenon.

Panniculus morbidus (PM) is a presentation of severe chronic abdominal lymphoedema associated with obesity resulting in oedema and chronic fibrosis. It is a multifaceted condition with significant clinical and psychosocial implications. A 29-year-old female weighing 260 kg with a body mass index of 95 kg/m2 had recurrent infections and sepsis associated with an abdominal pannus extending to her knees and an area of ulceration. The pannus was indurated with extensive fibrosis that significantly affected her quality of life (QOL) requiring assistance for all activities of daily living (ADLs). A panniculectomy was performed with a negative pressure skin dressing over the skin wound. She was discharged after two days. Two months postoperatively, she reported significant improvement in QOL and can now mobilise and perform ADLs independently with no recurrent admissions. The global prevalence of obesity is reaching pandemic proportions and so will its complications. It can be functionally debilitating and worsen obesity. Surgical resection is indicated to restore mobility and function, prevent recurrent infections, improve QOL, and reduce economic burden. Patients report high satisfaction rates following surgery. Panniculectomy is an effective treatment to alleviate morbidity in severe obesity and should be considered in patients with recurrent infections and a significant impact on QOL.

FLT4 causes developmental disorders of the cardiovascular and lymphovascular systems via pleiotropic molecular mechanisms.

AIMS: Rare, deleterious genetic variants in FLT4 are associated with Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease (CHD). Distinct genetic variants in FLT4 are also an established cause of Milroy disease, the most prevalent form of primary hereditary lymphoedema. Phenotypic features of these two conditions are non-overlapping, implying pleiotropic cellular mechanisms during development. METHODS AND RESULTS: Here, we show that FLT4 variants identified in TOF patients, when expressed in primary human endothelial cells, cause aggregation of FLT4 protein in the perinuclear endoplasmic reticulum, activating proteostatic and metabolic signalling, whereas lymphoedema-associated FLT4 variants and wildtype FLT4 do not. FLT4 TOF variants display characteristic gene expression profiles in key developmental signalling pathways, revealing a role for FLT4 in cardiogenesis distinct from its role in lymphatic development. Inhibition of proteostatic signalling abrogates these effects, identifying potential avenues for therapeutic intervention. Depletion of flt4 in zebrafish caused cardiac phenotypes of reduced heart size and altered heart looping. These phenotypes were rescued with coinjection of wildtype human FLT4 mRNA, but incompletely or not at all by mRNA harbouring FLT4 TOF variants. CONCLUSIONS: Taken together, we identify a pathogenic mechanism for FLT4 variants predisposing to TOF that is distinct from the known dominant negative mechanism of Milroy-causative variants. FLT4 variants give rise to conditions of the two circulatory subdivisions of the vascular system via distinct developmental pleiotropic molecular mechanisms. TRANSLATIONAL PERSPECTIVE: Proteostatic dysfunction, if confirmed as a mechanism of CHD pathogenesis for other predisposing genes, may identify pathways to therapeutic interventions. Distinguishing mechanistically how variants in FLT4 give rise to CHD may have potential to individualise genetic counselling in affected families.

BE-WEL trial (breast: evaluation of weight and exercise for lymphoedema) testing weight control and exercise programmes for women with breast cancer related lymphoedema: a feasibility trial.

PURPOSE: A combined body weight loss and upper body/arm exercise programme is a potential strategy for managing Breast cancer related lymphoedema (BCRL), but there is limited data on the best method for delivery or its potential efficacy. METHODS: Fifty-seven women with overweight/obesity and BCRL were randomised to a 12 week supervised (n = 12) or home-based combined weight loss and upper body/arm exercise programme (n = 16), a home-based upper-body arm exercise only programme (n = 17) or standard care (n = 12). Primary outcomes were uptake, retention and changes in weight and change in Relative Arm Volume Increase (RAVI) using analysis of covariance (ANCOVA). RESULTS: Sixteen percent of women invited joined the study and 49 completed the trial (85% retention). Reductions in weight occurred in the supervised and home-based weight control and exercise programmes; Mean (95% CI) change compared to standard care - 1.68 (- 4.36 to - 1.00), - 2.47(- 4.99 to - 0.04) Kg. Reductions in perometer assessed RAVI were seen in the supervised and home-based combined weight control and arm exercise groups and the weight stable home-based arm exercise only group: mean (95% CI) change compared to standard care - 2.4 (- 5.0 to + 0.4),- 1.8 (- 4.3 to + 0.7), - 2.5(- 4.9 to - 0.05)%. CONCLUSION: Women with BCRL and overweight and obesity engaged in diet and exercise weight loss programmes. Both weight loss/arm exercise programmes led to modest changes in weight and BCRL. Comparable reductions in BCRL were reported in the weight stable group undertaking arm exercise only. The independent and combined effects of weight loss and exercise on BCRL need further study. TRIAL REGISTRATION: ISRCTN86789850 https://doi.org/10.1186/ISRCTN86789850 , registered 2011.

Reducing the burden: managing lymphoedema and its complications.

Lymphoedema effects approximately 200 000 people in UK. It is a chronic condition without a cure but there is much that can be done to ease and manage these complications. This article looks at the eight most common complications, providing advise on how to manage them, derived from the literature and the author's own experience. It also presents advise on how nurses can promote self-management of these complications, promoting patients' self-care.

Pathogenic variants in HGF give rise to childhood-to-late onset primary lymphoedema by loss of function.

Developmental and functional defects in the lymphatic system are responsible for primary lymphoedema (PL). PL is a chronic debilitating disease caused by increased accumulation of interstitial fluid, predisposing to inflammation, infections and fibrosis. There is no cure, only symptomatic treatment is available. Thirty-two genes or loci have been linked to PL, and another 22 are suggested, including Hepatocyte Growth Factor (HGF). We searched for HGF variants in 770 index patients from the Brussels PL cohort. We identified ten variants predicted to cause HGF loss-of-function (six nonsense, two frameshifts, and two splice-site changes; 1.3% of our cohort), and 14 missense variants predicted to be pathogenic in 17 families (2.21%). We studied co-segregation within families, mRNA stability for non-sense variants, and in vitro functional effects of the missense variants. Analyses of the mRNA of patient cells revealed degradation of the nonsense mutant allele. Reduced protein secretion was detected for nine of the 14 missense variants expressed in COS-7 cells. Stimulation of lymphatic endothelial cells with these 14 HGF variant proteins resulted in decreased activation of the downstream targets AKT and ERK1/2 for three of them. Clinically, HGF-associated PL was diverse, but predominantly bilateral in the lower limbs with onset varying from early childhood to adulthood. Finally, aggregation study in a second independent cohort underscored that rare likely pathogenic variants in HGF explain about 2% of PL. Therefore, HGF signalling seems crucial for lymphatic development and/or maintenance in human beings and HGF should be included in diagnostic genetic screens for PL.

Outcomes from a proof-of-concept specialist lymphoedema clinic in the community.

The Health and Safety Execultive lymphoedema model of care was published in 2018 highlighting the lack of dedicated lymphoedema services in Ireland. This led to the introduction of a proof-of-concept primary care specialist lymphoedema clinic. The clinic was responsible for all patients from their county. A comprehensive dataset was gathered which included the patient's history for 1 year prior to their presentation at clinic and then 6 monthly. A quality of life tool (LymQoL) and a patient satisfaction survey were completed. Completed 1-year data showed a significant reduction in GP and public health nurse visits as well as a reduction in the occurrence of cellulitis and associated hospital admissions. All areas of quality of life were improved and patient satisfaction was either excellent (89%) or very good (11%). The 1-year findings strongly support the roll-out of specialist clinics to all regional health areas.

Integrated lymphoedema and tissue viability service: improving patient and wound outcomes.

This article will focus on the integration of tissue viability and lymphoedema services to improve outcomes for patients with leg ulceration. It will highlight why there is a need for lymphoedema specialist knowledge within the care of patients with leg ulceration and how the services are closely aligned. Lymphoedema can adversely affect wound healing and the article will provide case studies that highlight how developing a hybrid tissue viability and lymphoedema clinician or integration of the specialists can provide effective patient-centred care at reduced cost. The article offers potential strategies and suggestions on how to address inequalities in care and how to improve service provision.

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.

Limb Volume Measurements: A Comparison of Circumferential Techniques and Optoelectronic Systems against Water Displacement.

BACKGROUND: Accurate measurements of limb volumes are important for clinical reasons. We aimed to assess the reliability and validity of two centimetric and two optoelectronic techniques for limb volume measurements against water volumetry, defined as the gold standard. METHODS: Five different measurement methods were executed on the same day for each participant, namely water displacement, fixed-height (circumferences measured every 5 (10) cm for the upper (lower limb) centimetric technique, segmental centimetric technique (circumferences measured according to proportional height), optoelectronic plethysmography (OEP, based on a motion analysis system), and IGOODI Gate body scanner technology (which creates an accurate 3D avatar). RESULTS: A population of 22 (15 lower limbs, 11 upper limbs, 8 unilateral upper limb lymphoedema, and 6 unilateral lower limb lymphoedema) participants was selected. Compared to water displacement, the fixed-height centimetric method, the segmental centimetric method, the OEP, and the IGOODI technique resulted in mean errors of 1.2, 0.86, -16.0, and 0.71%, respectively. The corresponding slopes (and regression coefficients) of the linear regression lines were 1.0002 (0.98), 1.0047 (0.99), 0.874 (0.94) and 0.9966 (0.99). CONCLUSION: The centimetric methods and the IGOODI system are accurate in measuring limb volume with an error of <2%. It is important to evaluate new objective and reliable techniques to improve diagnostic and follow-up possibilities.

Management of Lymphoedema and Lymphorrhoea with Wrap around Compression in Breast Secondary to Carcinoma Breast: A Case Report.

Lymphoedema secondary to breast cancer is one of the most unfortunate outcomes, and lymphoedema secondary to breast cancer in the ipsilateral upper extremity and its management, has been described in the literature. We are reporting a case of lymphoedema and lymphorrhoea in the breast itself, managed by compression bandaging with limited resources and the use of active pharmacological agents in the palliative care unit of a tertiary care hospital. Lymphoedema and lymphorrhoea in the breast are not very common to see in clinics, but management of this case even though no protocol available, was done by modification of bandaging techniques available for limb lymphoedema management.

Bilateral axillary web syndrome in a patient with primary lymphoedema of upper limbs and non-Hodgkin lymphoma.

Primary lymphoedema, axillary web syndrome (AWS) and yellow nail syndrome may be related. Mr B is a 66-year-old gentleman with genital lymphoedema and lymphoedema of all four extremities. In 2023, he was diagnosed with non-Hodgkin lymphoma and also underwent cardiac surgery. In November 2023, he completed an inpatient rehabilitation at the Földi clinic in Germany, where he received intensive treatment for his lymphoedema and was also diagnosed with bilateral AWS. The presence of AWS in a patient with primary lymphoedema and no history of axillary surgery is unique. Although AWS typically presents after axillary surgery, this case highlights that it can also occur in patients without lymph node surgery. While the precise cause of this presentation of AWS is not known, it may be connected to yellow nail syndrome or potentially the recent chemotherapy treatment. This article will describe the clinical case, highlighting the need for further research on AWS present in primary lymphoedema.

Lymphoedema specialists embedded into community nurse and wound services: impacts and outcomes.

BACKGROUND: Lymphoedema is a progressive condition causing significant alterations to life, exerting pressures on unscheduled care from complications including cellulitis and wounds. An on the ground education programme (OGEP) was implemented to raise knowledge, competence and confidence in lymphoedema management in community clinical services. The aim of this study was to explore the impact and outcomes of the OGEP intervention. METHODS: Data were captured before and after OGEP on 561 lymphoedema patients in the community setting. Data recorded included resource use, costs and outcomes (EQ-5D-5L and LYMPROM). RESULTS: Data demonstrated statistically significant reductions in resource allocations including staff visits (P<0.001), cellulitis admissions (P<0.001), compression consumables and wound dressing costs (P<0.001). Overall, the total mean per patient cost decreased from £1457.10 to £964.40 (including intervention) with outcomes significantly improved in EQ-5D-5L/LYMPROM scores. CONCLUSION: The analysis suggests the OGEP intervention may offer reductions in resource costs and improvements in patient outcomes. OGEP may therefore provide an innovative solution in future care delivery.

Comparison of fluid and body composition measures in women with lipoedema, lymphoedema, and control participants.

Lipoedema is the disproportionate accumulation of adipose tissue in the lower body, often associated with hormonal changes in women. Lipoedema is commonly misdiagnosed as lymphoedema or obesity due to similarities in appearance. The aim of this study is to compare body composition and fluid measures of women with lipoedema, lymphoedema, and matched control participants, to determine differences that may help distinguish between each condition. One hundred and eleven participants aged over 18, who presented with the complaint of leg swelling and underwent indocyanine green lymphography were included in this study. Our analysis showed that the individuals with lymphoedema had a significantly higher overall total body water (lymphoedema: 9.6 ± 4.2 L, lipoedema: 7.4 ± 2.3 L, control: 7.5 ± 1.8 L; p < .001) and extracellular fluid (lymphoedema: 4.6 ± 1.6, lipoedema: 3.4 ± 1.0 L, control: 3.5 ± 0.7 L; p < .001) in the legs when compared to individuals with lipoedema and matched control participants. Individuals with lipoedema had a significantly higher overall fat mass as a percentage of body weight when compared to individuals with lymphoedema (lymphoedema: 33.1% ± 9.5%, lipoedema: 39.4% ± 6.5%; p = .003). We are unable to distinguish between individuals with lipoedema and control participants, therefore further research needs to be conducted to help reduce misdiagnosis.