Reply to Bourgeois, P. Comment on "Devoogdt et al. The Effectiveness of Fluoroscopy-Guided Manual Lymph Drainage as Part of Decongestive Lymphatic Therapy on the Superficial Lymphatic Architecture in Patients with Breast Cancer-Related Lymphoedema: A Randomised Controlled Trial. Cancers 2023, 15, 1545".

We appreciate the commentary by Pierre Bourgeois [...].

The Effectiveness of Fluoroscopy-Guided Manual Lymph Drainage as Part of Decongestive Lymphatic Therapy on the Superficial Lymphatic Architecture in Patients with Breast Cancer-Related Lymphoedema: A Randomised Controlled Trial.

The objective of this trial was to investigate the effectiveness of fluoroscopy-guided manual lymph drainage (MLD), as part of decongestive lymphatic therapy (DLT), on the superficial lymphatic architecture in patients with chronic mild to moderate breast cancer-related lymphoedema (BCRL). This trial was a multicentre, double-blind, randomised controlled trial involving 194 participants with BCRL. Participants were randomised into (1) DLT with fluoroscopy-guided MLD (intervention group), (2) DLT with traditional MLD (control group), or (3) DLT with placebo MLD (placebo group). Superficial lymphatic architecture was evaluated as a secondary outcome, visualised by ICG lymphofluoroscopy at the baseline (B0), post-intensive (P), and post-maintenance phases (P6). Variables were (1) number of efferent superficial lymphatic vessels leaving the dermal backflow region, (2) total dermal backflow score, and (3) number of superficial lymph nodes. The traditional MLD group showed a significant decrease in the number of efferent superficial lymphatic vessels at P (p = 0.026), and of the total dermal backflow score at P6 (p = 0.042). The fluoroscopy-guided MLD and placebo group showed significant decreases in the total dermal backflow score at P (p < 0.001 and p = 0.044, respectively) and at P6 (p < 0.001 and p = 0.007, respectively); the placebo MLD group showed a significant decrease in the total number of lymph nodes at P (p = 0.008). However, there were no significant between-group differences for the changes in these variables. In conclusion, based on lymphatic architecture outcomes, the added value of MLD, in addition to the other parts of DLT, could not be demonstrated in patients with chronic mild to moderate BCRL.

Use of fluorescence imaging during lymphatic surgery: A Delphi survey of experts worldwide.

BACKGROUND: Fluorescence imaging with indocyanine green is increasingly used during lymphedema patient management. However, to date, no guidelines exist on when it should and should not be used or how it should be performed. Our objective was to have an international panel of experts identify areas of consensus and nonconsensus in current attitudes and practices in fluorescence imaging with indocyanine green use during lymphedema surgery patient management. METHODS: A 2-round Delphi study was conducted involving 18 experts in the use of fluorescence imaging during lymphatic surgery, all asked to vote on 49 statements on patient preparation and contraindications (n = 7 statements), indocyanine green dosing and administration (n = 10), fluorescence imaging uses and potential advantages (n = 16), and potential disadvantages and training needs (n = 16). RESULTS: Consensus ultimately was reached on 40/49 statements, including consistent consensus regarding the value of fluorescence imaging with indocyanine green in almost all facets of lymphedema patient management, including early detection, assessing disease extent, preoperative work-up, surgical planning, intraoperative guidance, monitoring short- and longer-term outcomes, quality control, and resident training. All experts felt it was very safe, while 94% felt it should be part of routine care and that indocyanine green was superior to colored dyes and ultrasound. Nonetheless, there also was consensus that limited high-quality evidence remains a barrier to its widespread use and that patients should still be provided with specific information and asked to sign specific consent for both fluorescence imaging and indocyanine green. CONCLUSION: Fluorescence imaging with or without indocyanine green appears to have several roles in lymphedema prevention, diagnosis, assessment, and treatment.

Does Manual Lymphatic Drainage Add Value in Reducing Suprafascial Fluid Accumulation and Skin Elasticity in Patients With Breast Cancer-Related Lymphedema?

OBJECTIVE: The purpose of this study was to investigate the effectiveness of fluoroscopy-guided manual lymph drainage (MLD) versus that of traditional and placebo MLD, when added to decongestive lymphatic therapy (DLT) for the treatment of breast cancer-related lymphedema (BCRL) (EFforT-BCRL trial), on the suprafascial accumulation of lymphatic fluid and skin elasticity. METHODS: In this multicenter, 3-arm, double-blind, randomized controlled trial (EFforT-BCRL trial), 194 participants (mean age = 61 [SD = 10] years) with unilateral BCRL were recruited. All participants received standardized DLT (education, skin care, compression therapy, exercises) and were randomized to fluoroscopy-guided, traditional, or placebo MLD. Participants received 60 min/d of treatment during the 3-week intensive phase and 18 sessions of 30 minutes during the 6-month maintenance phase. During this phase, participants were instructed to wear a compression garment, to perform exercises, and to perform a self-MLD procedure once daily. This study comprises secondary analyses of the EFforT-BCRL trial. Outcomes were the amount of fluid accumulation in the suprafascial tissues (local tissue water, extracellular fluid, and thickness of the skin and subcutaneous tissue) and skin elasticity at the level of the arm and trunk. Measurements were performed at baseline; after intensive treatment; after 1, 3, and 6 months of maintenance treatment; and after 6 months of follow-up. RESULTS: At the level of the arm, there was a significant improvement over time in the 3 groups for most of the outcomes. At the level of the trunk, no remarkable improvement was noted within the individual groups. No significant interaction effects (between-group differences) were present. Only skin elasticity at the level of the arm, evaluated through palpation, showed a significant interaction effect. CONCLUSION: All 3 groups showed similar improvements in response to DLT regardless of the type of MLD that was added. The effect of the addition of MLD to other components of DLT for reducing local tissue water and extracellular fluid or skin thickness and for improving skin elasticity and fibrosis in participants with chronic BCRL was limited. IMPACT: Although MLD has been applied all over the world for many years, evidence regarding its added value in reducing arm volume in patients with BCRL is lacking. These results show that adding MLD to other components of DLT has limited value in reducing local tissue water and extracellular fluid or skin thickness and in improving skin elasticity and fibrosis in patients with chronic BCRL. To date, there is no clinical indication to continue including time-consuming MLD in physical therapist sessions for patients with chronic BCRL.

Manual lymphatic drainage with or without fluoroscopy guidance did not substantially improve the effect of decongestive lymphatic therapy in people with breast cancer-related lymphoedema (EFforT-BCRL trial): a multicentre randomised trial.

QUESTIONS: When added to decongestive lymphatic therapy (DLT), what is the effect of fluoroscopy-guided manual lymphatic drainage (MLD) versus traditional MLD or placebo MLD for the treatment of breast cancer-related lymphoedema (BCRL)? DESIGN: Multicentre, three-arm, randomised controlled trial with concealed allocation, intention-to-treat analysis and blinding of assessors and participants. PARTICIPANTS: At five hospitals in Belgium, 194 participants with unilateral chronic BCRL were recruited. INTERVENTION: All participants received standard DLT (education, skin care, compression therapy and exercises). Participants were randomised to also receive fluoroscopy-guided MLD (n = 65), traditional MLD (n = 64) or placebo MLD (n = 65). Participants received 14 sessions of physiotherapy during the 3-week intensive phase and 17 sessions during the 6-month maintenance phase. Participants performed self-management on the other days. OUTCOME MEASURES: All outcomes were measured: at baseline; after the intensive phase; after 1, 3 and 6 months of maintenance phase; and after 6 months of follow-up. The primary outcomes were reduction in excess volume of the arm/hand and accumulation of excess volume at the shoulder/trunk, with the end of the intensive phase as the primary endpoint. Secondary outcomes included daily functioning, quality of life, erysipelas and satisfaction. RESULTS: Excess lymphoedema volume decreased after 3 weeks of intensive treatment in each group: 5.3 percentage points of percent excessive volume (representing a relative reduction of 23.3%) in the fluoroscopy-guided MLD group, 5.2% (relative reduction 20.9%) in the traditional MLD group and 5.4% (relative reduction 24.8%) in the placebo MLD group. The effect of fluoroscopy-guided MLD was very similar to traditional MLD (between-group difference 0.0 percentage points, 95% CI -2.0 to 2.1) and placebo MLD (-0.2 percentage points, 95% CI -2.1 to 1.8). Fluid accumulated at the shoulder/trunk in all groups. The average accumulation with fluoroscopy-guided MLD was negligibly less than with traditional MLD (-3.6 percentage points, 95% CI -6.4 to -0.8) and placebo MLD (-2.4 percentage points, 95% CI -5.2 to 0.4). The secondary outcomes also showed no clinically important between-group differences. CONCLUSION: In patients with chronic BCRL, MLD did not provide clinically important additional benefit when added to other components of DLT. REGISTRATION: NCT02609724.

CDH5, a Possible New Candidate Gene for Genetic Testing of Lymphedema.

Background: Expressed by endothelial cells, CDH5 is a cadherin involved in vascular morphogenesis and in the maintenance of vascular integrity and lymphatic function. The main purpose of our study was to identify distinct variants of the CDH5 gene that could be associated with lymphatic malformations and predisposition for lymphedema. Methods and Results: We performed Next Generation Sequencing of the CDH5 gene in 235 Italian patients diagnosed with lymphedema but who tested negative for variants in known lymphedema genes. We detected six different variants in CDH5 five missense and one nonsense. We also tested available family members of the probands. For family members who carried the same variant as the proband, we performed lymphoscintigraphy to detect any lymphatic system abnormalities. Variants were modeled in silico. The results showed that CDH5 variants may contribute to the onset of lymphedema, although further in vitro studies are needed to confirm this hypothesis. Conclusions: Based on our findings, we propose CDH5 as a new gene that could be screened in patients with lymphedema to gather additional evidence.

Cross-cultural validation of the French version of the Lymphedema Functioning, Disability and Health Questionnaire for Upper Limb Lymphedema (Lymph-ICF-UL).

PURPOSE: Upper limb lymphedema is a vexing morbidity that can occur after the treatment for breast cancer. The Lymphedema Functioning, Disability and Health Questionnaire for Upper Limb Lymphedema (Lymph-ICF-UL) is a valid and reliable tool assessing problems in functioning in patients with breast cancer-related lymphedema. Until now, a French-language version was lacking. The aim of this study was to perform a cross-cultural validation of the French version of the Lymph-ICF-UL questionnaire. METHODS: A forward-backward translation process between the original language (Dutch) and the target language (French) was performed. Psychometric properties of this final French version were examined in 50 participants. RESULTS: Intraclass correlation coefficients for test-retest reliability ranged from 0.66 to 0.95. Cronbach's alpha coefficients for internal consistency were higher than 0.77. Face and content validity were very good because the scoring system was clear for all participants (100%), questions were understandable (100%), and all complaints due to BCRL were mentioned by 78% of the participants. Construct validity was moderate. Convergent validity was established since 3 out of 5 expected domains of the Lymph-ICF-UL showed a moderate correlation with expected domains of the 36-item Short-Form Health Survey. There was satisfactory divergent validity as 6 out of 9 hypotheses assessing divergent validity were accepted. CONCLUSION: The French version of the Lymph-ICF-UL is a reliable and valid questionnaire and ready for use in clinical as well as in scientific practice.Implications for rehabilitationSince the introduction of more effective treatment modalities increasing the number of breast cancer survivors, the amount of patients dealing with lymphedema is rising likewise up to a pooled incidence rate of more than 16% of the women treated for breast cancer.The French version of the Lymph-ICF-UL is a reliable and valid questionnaire for assessing problems in functioning of patients with breast cancer-related lymphedema of the arm and/or hand.As the questionnaire provides patient information in the different domains of the International Classification of Functioning, Disability and Health, it facilitates evaluating the impact of breast cancer-related lymphedema on daily functioning.Based on the outcomes of the Lymph-ICF-UL treatment goals can be set, where after the questionnaire can be used to monitor long-term results of this treatment and self-care.

What is the best method to determine excessive arm volume in patients with breast cancer-related lymphoedema in clinical practice? Reliability, time efficiency and clinical feasibility of five different methods.

OBJECTIVE: To investigate the reliability, time efficiency and clinical feasibility of five commonly used methods for assessing excessive arm volume in patients with breast cancer-related lymphoedema (BCRL). DESIGN: Cross-sectional study. SETTING: University Hospitals Leuven, Belgium. SUBJECTS: 30 participants with unilateral BCRL. METHODS: Excessive arm volume was determined by five different methods: traditional volumetry with overflow, volumetry without overflow, inverse volumetry, optoelectronic volumetry and calculated volume based on circumference measurements. To investigate intra- and inter-rater reliability, measurements were performed twice by the same assessor and once by a different assessor. Intraclass correlation coefficients (ICCs), standard errors of the measurement (SEMs) and systematic changes between the means were calculated. To determine time efficiency, the mean setup time, execution time and total time were examined for each method. Furthermore, 12 limitations regarding clinical feasibility were listed and scored for each method. Finally, an overall ranking score was determined between the methods. RESULTS: Mean age was 65 (±8) years and mean body mass index was 28 (±4) kg/m2. Intra- and inter-rater reliability ranged between strong and very strong. Calculated arm volume based on circumferences (mean excessive arm volume: assessor A: 477 (±367) mL; assessor B: 470 (±367) mL; assessor A (second time): 493 (±362) mL) showed the highest intra- and inter-rater ICCs of .987 and .984, respectively. Optoelectronic volumetry was the fastest method, representing a mean total time of 1 minute and 43 (±26) seconds for performing a bilateral measurement. The least limitations were reported on the calculated volume based on the circumference method (3 out of 12 limitations). CONCLUSION: Calculated volume based on arm circumferences is the best measurement method for evaluating excessive arm volume over time in terms of reliability, low error rate, low cost, few limitations and the time spent.

Protocol of a randomised controlled trial regarding the effectiveness of fluoroscopy-guided manual lymph drainage for the treatment of breast cancer-related lymphoedema (EFforT-BCRL trial).

OBJECTIVES: Lymphoedema is a dreadful complication following breast cancer therapy. According to the International Society of Lymphology, the consensus treatment for breast cancer-related lymphoedema (BCRL) is the decongestive lymphatic therapy. This is a two-phase treatment and combines different treatment modalities including skin care, manual lymphatic drainage (MLD), compression therapy and exercise. However, the additional effect of MLD is debated since pooled data only demonstrated a limited non-significant additional value. A possible explanation is that in previous studies MLD has been applied blind, without knowledge of patient-specific lymphatic routes of transport. In addition, the MLD hand manoeuvres used by the therapists in previous studies, possibly did not optimally stimulate lymphatic transport. Recently, near-infrared fluorescence imaging has been introduced to visualise the superficial lymphatic network which allows MLD at the most needed location. The aim of the present study is to determine the effectiveness of the fluoroscopy-guided MLD, additional to the other parts of the decongestive lymphatic therapy and compared to the traditional or a placebo MLD, in the treatment of BCRL. STUDY DESIGN: A three-arm double-blinded randomised controlled trial will be conducted in different university hospitals in Belgium. Based on a sample size calculation, 201 participants with chronic BCRL stage 1 or 2 of the arm or hand, with at least 5% difference between both sides (corrected for hand dominance) need to be recruited. All participants receive the standard treatment: skin care, compression therapy and exercises. The intervention group additionally receives fluoroscopy-guided MLD. One control group additionally receives the traditional 'blind' MLD and a second control group receives a placebo MLD. All subjects receive 3 weeks of daily intensive treatments and 6 months of maintenance treatment. Follow-up period is 6 months. The primary outcomes are the reduction in lymphoedema volume of the arm/hand and the change in stagnation of lymph fluid at level of the shoulder/trunk.

Near-Infrared Fluorescence Lymphatic Imaging to Reconsider Occlusion Pressure of Superficial Lymphatic Collectors in Upper Extremities of Healthy Volunteers.

BACKGROUND: There are very little scientific data on occlusion pressure for superficial lymphatic collectors. Given its importance in determining the transport capacity of lymphatic vessels, it is crucial to know its value. The novel method of near-infrared fluorescence lymphatic imaging (NIRFLI) can be used to visualize lymphatic flow in real time. The goal of this study was to see if this method could be used to measure the lymphatic occlusion pressure. METHODS: We observed and recorded lymph flow in the upper limb of healthy volunteers through a transparent cuff using near-infrared fluorescence lymphatic imaging. After obtaining a baseline of the lymph flow without pressure inside the cuff, the cuff was inflated by increments of 10 mm Hg starting at 30 mm Hg. A NIRFLI guided manual lymphatic drainage technique named "Fill & Flush Drainage Method" was performed during the measurement to promote lymph flow. Lymphatic occlusion pressure was determined by observing when lymph flow stopped under the cuff. RESULTS: We measured the lymphatic occlusion pressure on 30 healthy volunteers (11 men and 19 women). Mean lymphatic occlusion pressure in the upper limb was 86 mm Hg (CI ±3.7 mm Hg, α = 0.5%). No significant differences were found between age groups (p = 0.18), gender (p = 0.12), or limb side (p = 0.85). CONCLUSIONS: NIRFLI, a transparent sphygmomanometer cuff and the "Fill and Flush" manual lymphatic drainage method were used to measure the lymphatic occlusion pressure in 30 healthy humans. That combination of these techniques allows the visualization of the lymph flow in real time, while ensuring the continuous filling of the lymph collectors during the measurement session, reducing false negative observations. The measured occlusion pressures are much higher than previously described in the medical literature.

Excessive pressure in multichambered cuffs used for sequential compression therapy.

BACKGROUND AND PURPOSE: Pneumatic compression devices, used as part of the therapeutic strategy for lymphatic drainage, often have cuffs with multiple chambers that are inflated sequentially. The purpose of this study was to investigate (1) the relationship between cuff chamber pressure (P(chamber)) and the pressure on the cuff-skin interface (P(interface)) and (2) the mechanical interaction of cuff chambers and consequences for device control. SUBJECTS AND METHODS: In this study, we used 3 cylindrical (60-, 80-, and 100-mm-diameter) model limbs and 1 ellipsoidal model of the arm to test a commercially available pressure controller using "target pressures," indicated by the controller, of 30, 60, 80, and 100 mm Hg. We studied the time course of P(chamber) and P(interface) during the inflation sequence and the effect of local curvature on P(interface). RESULTS: Our data indicated that, overall, P(interface) is of the same order of magnitude as P(chamber). There was some effect of model diameter and shape, with the smaller curvatures yielding the highest P(interface). Cuff chamber interaction led to P(chamber) and P(interface) values in the most distal (first inflated) chamber that were up to 80% higher than the target pressure. For the 80-mm cylindrical model, for instance, pressure in this chamber reached 54, 98, 121, and 141 mm Hg, respectively, instead of the 30, 60, 80, and 100 mm Hg indicated by the controller. DISCUSSION AND CONCLUSION: The discrepancy between the target pressure, indicated by the controller, and the pressure measured inside the cuff chambers undermines the therapeutic control and efficacy of the pneumatic compression devices. Because the measured pressures were far beyond the pressure level indicated by the controller, it is recommended that pneumatic compression devices be used at much lower target pressures (<30 mm Hg) than those applied in clinical practice.