Lymphat Res Biol
· 2024 Jun · PMID 38608242
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Breast cancer-related lymphedema (BCRL) is the most prevalent comorbidity that occurs following breast cancer treatments and has negative impact on the patients' quality of life (QoL). The Lymphedema Functioning, Disabil...Breast cancer-related lymphedema (BCRL) is the most prevalent comorbidity that occurs following breast cancer treatments and has negative impact on the patients' quality of life (QoL). The Lymphedema Functioning, Disability, and Health Questionnaire for Upper Limb Lymphedema (Lymph-ICF-UL) is a valid and reliable instrument in assessing the QoL of patients with BCRL. However, the Bahasa Malaysia (BM) version is not available yet. This study aimed to translate the Lymph-ICF-UL into BM and to evaluate its validity and reliability. A forward-backward translation was performed based on Sousa's guideline, and then, the face, content, construct validity, internal consistency, and test-retest reliability were tested. Face validity was assessed by five patients, and content validity was evaluated by six experts. Then, construct validity and internal validity were assessed in 107 patients. Finally, test-retest reliability was analyzed in 21 patients. Two items were eliminated following suggestions from the patients and experts. All patients found the scoring system and items clear and relevant. The results showed sufficient content validity index and modified kappa statistics value. Confirmatory factor analysis showed acceptable fit indices. Cronbach's alpha values ranged from 0.67 to 0.95, intraclass correlation coefficient ranged from 0.88 to 0.99, standard error measurement was 2.29-6.15, and the Bland-Altman plot showed an agreement between two test occasions. These results suggested that the Lymph-ICF-UL BM has good validity and reliability in evaluating the QoL of patients with BCRL in Malaysia.
In advanced lymphedema of lower limbs, stage III bandaging under the routinely applied pressure of 40-60 mmHg remains largely ineffective. This is caused by skin and subcutaneous tissue stiffness due to fibrosis. Edema f...In advanced lymphedema of lower limbs, stage III bandaging under the routinely applied pressure of 40-60 mmHg remains largely ineffective. This is caused by skin and subcutaneous tissue stiffness due to fibrosis. Edema fluid accumulates deep in the subcutaneous tissue. Evacuating this fluid requires a high external compression force to overcome the resistance of fibrous tissue. We aimed to investigate the effectiveness of the compression method, with high pressure lasting for 3 days. Twenty-one patients with lower limb lymphedema, stage III, of the postinflammatory type were included. Patients with acute inflammatory symptoms, venous thrombosis, profuse varicose veins, diabetes, and cardiac insufficiency with edema were excluded. A 10-cm-wide rubber bandage was applied to the foot and calf. The interface pressure measured using PicoPress ranged from 58 to 120 mmHg. Skin and deep tissue tonometry, skin water concentration, leg circumference, and drop of interface pressure were measured. Ultrasound examination was done before and after each compression session. The calf circumference decreased by 15.9 ± 5.4%, deep tissue stiffness by 58.9 ± 18.9%, skin stiffness by 69.6 ± 13.5%, and skin water concentration by 43.8 ± 11.5%. Interface pressure dropped to 66.3 mmHg (28-110 mmHg); ultrasonography images showed less fluid in the tissue. High-pressure 30-minute leg compression can remove excess edema fluid within 3 days and enable adjustment of nonstretch compression stockings. This method is more effective in advanced lymphedema at the beginning of therapy than the standard 30-50-mmHg bandaging as it provides an immediate effect.
Indocyanine green (ICG) lymphography, a key diagnostic tool for lymphedema, is influenced by the dilution process of ICG dye, impacting patient experience. In our study, we assessed three different ICG diluents-water fo...Indocyanine green (ICG) lymphography, a key diagnostic tool for lymphedema, is influenced by the dilution process of ICG dye, impacting patient experience. In our study, we assessed three different ICG diluents-water for injection (WFI), normal saline (NS), and Dextrose plus human albumin-in five healthy volunteer individuals undergoing superficial lymphography of the upper limb over 3 weeks. Results indicated that NS, as a diluent for ICG, caused the least discomfort during injection, in contrast to WFI, which led to the highest levels of discomfort. Transport time of ICG from the injection site to the axillary lymph nodes was notably shorter in intradermal injections than in subdermal injections. Our findings advocate for using NS as the optimal and cost-effective diluent for ICG, enhancing patient experience.
We aimed to determine the course of arm swelling caused by the use of taxanes and to identify valid predictors of persistent swelling. A total of 15 patients with unilateral arm swelling that developed during the course...We aimed to determine the course of arm swelling caused by the use of taxanes and to identify valid predictors of persistent swelling. A total of 15 patients with unilateral arm swelling that developed during the course, or within 3 months after termination, of postoperative taxane-based chemotherapy were included in the present study. The patients attended follow-up appointments every 3-6 months for 24 months after their initial visit. Their arm circumference was measured at each follow-up appointment, while ultrasonography of the skin and subcutaneous tissues was performed at the 0-, 6-, 12-, and 24-month follow-ups. Of the 15 patients, 12 (80%) saw their taxane-induced arm swelling resolved within a median of 12 months (range, 3-29 months) after their final taxane administration. Of the 12 patients whose swelling resolved, 9 did not use compression sleeves; however, their course of resolution did not differ from the other 3 patients who regularly used compression sleeves. In the three patients with persistent swelling, the excess subcutaneous thickness in the medial upper arm (median, 283%) was significantly greater than that in the patients whose swelling resolved (120%; < 0.05) during their initial visits. Of the 15 patients included in the present study, 80% saw their taxane-induced arm swelling resolve within a median of 12 months after their final taxane administration, independent of the use of compression therapy. Persistent swelling may be predicted during the initial visit based on subcutaneous thickening of the medial upper arm.
Mestre S, Vignes S, Malloizel-Delaunay J
… +5 more, Abba S, Villet S, Picolet A, Vicaut E, Quéré I
Lymphat Res Biol
· 2024 Apr · PMID 38563697
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Genital lymphedema is a chronic debilitating condition associated with highly impaired health-related quality of life (QoL). This prospective multicenter study evaluated the use of a new compressive garment in patients w...Genital lymphedema is a chronic debilitating condition associated with highly impaired health-related quality of life (QoL). This prospective multicenter study evaluated the use of a new compressive garment in patients with secondary and primary genital lymphedema. Thirty-two patients prospectively enrolled were advised to wear the compressive garment for 12 weeks (day and night). The primary endpoint was change in patient-reported QoL at 12 weeks via the patient global impression of change (PGI-C) instrument. Secondary outcomes included change in other QoL measures at 12 weeks (visual analog scale, Lymphedema Quality of Life Inventory [LyQLI], and EQ-5D questionnaires), lymphedema severity (genital lymphedema score [GLS]), and physician assessment (Clinical Global Impression-Improvement [CGI-I]). Safety and tolerability were also assessed. After 12 weeks, improvement was reported in 78.6% of patients (PGI-C). Physician assessment (CGI-I) indicated clinical improvement in 82.8% of patients. Patient assessment of lymphedema symptoms showed a significant decrease in discomfort ( = 0.02) and swelling ( = 0.01). Significant declines in the mean global GLS ( < 0.0001), and in the proportion of patients reporting heaviness, tightness, swelling, or urinary dysfunction ( < 0.05 for all), were also observed. LyQLI scores decreased (indicating improved QoL) in each of the physical, psychosocial ( = 0.05), and practical domains. The compressive garment was well tolerated with high compliance, and adverse events (due to swelling or discomfort) led to permanent discontinuation in only three patients. The use of a new genital compression garment over 12 weeks improves the QoL and clinical measures in patients with genital lymphedema (ClinicalTrials.gov ID: NCT04602559; Registration: October 20, 2020).
Keith L, Seo C, Wahi MM
… +7 more, Huggins S, Carmody M, Faerber G, Forner-Cordero I, Michelini S, Rapprich S, Rockson SG
Lymphat Res Biol
· 2024 Apr · PMID 38546398
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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 inten...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. 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. 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.
Morgan S, Reid I, Bendon C
… +5 more, Ishaq M, Shayan R, Pope B, Park D, Karnezis T
Lymphat Res Biol
· 2024 Apr · PMID 38407896
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Lipedema is a progressive condition involving excessive deposition of subcutaneous adipose tissue, predominantly in the lower limbs, which severely compromises quality of life. Despite the impact of lipedema, its molecul...Lipedema is a progressive condition involving excessive deposition of subcutaneous adipose tissue, predominantly in the lower limbs, which severely compromises quality of life. Despite the impact of lipedema, its molecular and genetic bases are poorly understood, making diagnosis and treatment difficult. Historical evaluation of individuals with lipedema indicates a positive family history in 60%-80% of cases; however, genetic investigation of larger family cohorts is required. Here, we report the largest family-based sequencing study to date, aimed at identifying genetic changes that contribute to lipedema. DNA samples from 31 individuals from 9 lipedema families were analyzed to reveal genetic variants predicted to alter protein function, yielding candidate variants in 469 genes. We did not identify any individual genes that contained likely disease-causing variants across all participating families. However, gene ontology analysis highlighted vasopressin receptor activity, microfibril binding, and patched binding as statistically significantly overrepresented categories for the set of candidate variants. Our study suggests that lipedema is not caused by a single exomic genetic factor, providing support for the hypothesis of genetic heterogeneity in the etiology of lipedema. As the largest study of its kind in the lipedema field, the results advance our understanding of the disease and provide a roadmap for future research aimed at improving the lives of those affected by lipedema.
Lymphedema and lipedema are debilitating conditions with no proven drug or surgical therapy. Effective treatment requires self-management through movement and compression to reduce limb volume and the incidence of cellul...Lymphedema and lipedema are debilitating conditions with no proven drug or surgical therapy. Effective treatment requires self-management through movement and compression to reduce limb volume and the incidence of cellulitis. The addition of personalized everyday physical activity (PA) could be transformative, increasing the therapy window to include all waking hours per week and enabling an increased dose of PA. This service evaluation aimed to determine the feasibility of LymphActiv as a treatment option for lymphedema and lipedema patients. This service evaluation followed an open observational cohort design, including 55 patients who participated in LymphActiv over 24 weeks. Patients wore an objective PA monitor and interacted with their data in an online dashboard, alongside remote mentor support. Primary outcomes were changes to PA, body weight, limb volume and quality of life. Clinical assessments occurred at baseline and after the 24-week program. Noncompleters were used as a quasi-control group for comparison. Thirty-seven patients completed, of which 81% improved PA. On average, completers reduced their right and left lower limb volumes by -1.8% and -2.1%, respectively. Completers also experienced small average weight losses of -1.2 kg. Noncompleters experienced small average increases in each of these outcome measures. These results establish the value of LymphActiv, providing benefit to patients who might otherwise have deteriorated. For services, this could lead to substantial cost-savings through reduced admissions, greater patient independence, and less need for community health care input. The next step is to undertake a randomized, controlled trial comparing the intervention with standard care.
Breast cancer-related lymphedema (BCRL) remains a significant postcancer treatment challenge with no definitive cure. Recent supermicrosurgical treatments, such as lymphovenous anastomosis (LVA), have shown promise but l...Breast cancer-related lymphedema (BCRL) remains a significant postcancer treatment challenge with no definitive cure. Recent supermicrosurgical treatments, such as lymphovenous anastomosis (LVA), have shown promise but lack established objective indicators for outcome evaluation. We investigated the utility of Technetium-99m (Tc-99m) lymphoscintigraphy, an imaging technique providing objective information on lymphatic fluid flow, for assessing LVA surgical outcomes. A retrospective cohort analysis of patients undergoing LVA for BCRL was conducted. Lymphoscintigraphy images pre- and 1-year postsurgery were compared to determine changes in lymphatic fluid flow of 18 patients based on newly defined parameters "uptake ratio" and "washout rates." Statistically significant reduction in the uptake ratio was observed in the forearm at 30 and 60 minutes postinjection phases. In addition, the forearm showed higher washout rate, indicating an improved lymphatic function in the forearm. Tc-99m lymphoscintigraphy can provide valuable objective data for evaluating LVA surgical outcomes in BCRL patients. However, site-specific differences in outcomes highlight the need for individualized surgical planning. Further large-scale studies are necessary to validate these preliminary findings and develop a standardized approach for LVA assessment.
Cagliyan Turk A, Erden E, Eker Buyuksireci D
… +2 more, Umaroglu M, Borman P
Lymphat Res Biol
· 2024 Feb · PMID 38127646
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The aim of this study was to determine the frequency of fibromyalgia syndrome (FMS) in patients with lipedema and to evaluate the effects of FMS on anxiety, depression, and quality of life (QoL) in this patient group. P...The aim of this study was to determine the frequency of fibromyalgia syndrome (FMS) in patients with lipedema and to evaluate the effects of FMS on anxiety, depression, and quality of life (QoL) in this patient group. Patients with lipedema were invited to participate in a Survey-Monkey questionnaire (according to inclusion and exclusion criteria) that was announced on the facebook page of the lipedema patient community. The demographic and clinical properties, including age, body mass index (BMI), education, marital status, and types and stage of lipedema, were collected. Presence of fibromyalgia was assessed by the questions based on American College of Rheumatology 2016 FMS diagnostic criteria. The Hospital Anxiety and Depression Scale and Short Form-12 (SF-12) were used to assess the anxiety and depression, and QoL respectively. The demographic and clinical characteristics, as well as anxiety/depression level and QoL of lipedema patients were evaluated in regard to the presence (Group 1) and absence (Group 2) of FMS. A total of 354 participants with a mean age of 43.18 ± 9.53 years and BMI of 30.61 ± 6.86 were included. The majority of them were married and had university education. Most of the patients had types 1, 2 and commonly stages 1 and 2 lipedema. One hundred twenty-four patients (35%) satisfied FMS criteria. The demographic characteristics except pain intensity were similar between the groups. The mean anxiety and depression scores of Group 1 were significantly higher compared with Group 2 (13.11 ± 4.2 vs. 9.87 ± 4.65, 10.23 ± 3.79 vs. 8.26 ± 4.15, respectively, < 0.001). The mental and physical subgroup scores of SF-12 (35.37 ± 8.59 vs. 42.55 ± 10.15, 35.27 ± 8.49 vs. 40.38 ± 11.36, respectively) were significantly lower in Group 1 than in Group 2 ( < 0.001). More than every 3 lipedema patient may have FMS. This comorbidity may increase depression and anxiety, and impair QoL. Therefore, FMS must be kept in mind especially in the assessment of painful lipedema patients to decrease anxiety/depression and enhance the QoL of them.
Fujino A, Kuniyeda K, Nozaki T
… +20 more, Ozeki M, Ohyama T, Sato I, Kamibeppu K, Tanaka A, Uemura N, Kanmuri K, Nakamura K, Kobayashi F, Suenobu S, Nomura T, Hayashi A, Nagao M, Kato A, Aramaki-Hattori N, Imagawa K, Ishikawa K, Ochi J, Horiuchi S, Nagabukuro H
Lymphat Res Biol
· 2024 Feb · PMID 38112724
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The natural history of venous malformation (VM) and Klippel-Trenaunay Syndrome (KTS) has not been quantitatively studied. To obtain benchmarks to guide designing clinical trials to assess safety and efficacy of novel dru...The natural history of venous malformation (VM) and Klippel-Trenaunay Syndrome (KTS) has not been quantitatively studied. To obtain benchmarks to guide designing clinical trials to assess safety and efficacy of novel drug candidates, the clinical course of the patients was followed for 6 months. This is a multicenter prospective observational study evaluating the change rate in lesion volume from baseline with magnetic resonance images, as the primary endpoint. In addition, disease severities, performance status (PS), pain visual analog scale (VAS) score, quality of life (QoL), infections, and coagulation markers were also evaluated. Thirty-four patients (VM = 17, KTS = 17, 1-53 of age; median 15.9 years) with measurable lesion volume were analyzed. There was no statistically significant difference in the lesion volume between baseline and day 180, and the mean change rate (standard deviation) was 1.06 (0.28). There were no baseline characteristics that affected the change in lesion volume over 6 months. However, there were patients who showed more than 20% volume change and it was suggested that the lesion volume was largely impacted by local infection. There were no statistically significant changes in pain VAS score, severity, PS, QoL score, D-dimer, and platelet count over 6 months within all patients analyzed. The results showed the representative natural course of VM and KTS for a 6-month period with objective change of lesion volume and other factors, suggesting that it is scientifically reasonable to conduct a Phase 2 proof-of-concept study without a placebo arm, using the results of this study as the control. NCT04285723, NCT04589650.
Grigorean A, Lindenblatt N, Luchsinger I
… +5 more, Hobohm L, Konstantinides SV, Münzel T, Barco S, Keller K
Lymphat Res Biol
· 2024 Feb · PMID 38029369
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Deep venous thrombosis (DVT) poses a substantial disease burden. Lymphedema may present with similar symptoms making the diagnosis process more difficult. Data on the epidemiology of lymphedema are lacking. The German n...Deep venous thrombosis (DVT) poses a substantial disease burden. Lymphedema may present with similar symptoms making the diagnosis process more difficult. Data on the epidemiology of lymphedema are lacking. The German nationwide inpatient sample served to analyze all patients hospitalized owing to DVT and/or thrombophlebitis (referred to as DVT) of the legs in Germany between 2005 and 2020. We stratified these patients for additional lymphedema and analyzed the impact of lymphedema on adverse in-hospital events. Overall, 1,136,574 hospitalizations related to DVT were recorded in Germany during 2005-2020 (53.3% women; 51.3% aged ≥70 years). Lymphedema was coded in 9974 (0.9%) patient-cases (82.0% not elsewhere classified, 17.7% secondary lymphedema). Annual numbers of hospitalizations with lymphedema among DVT patients increased from 450 (2005) to 613 (2016) (β 0.57; 95% confidence interval [CI]: 0.48-0.66], < 0.001) and decreased thereafter. Despite similar age, DVT patients with lymphedema had higher prevalence of cardiovascular diseases, chronic organ failure, and all types of investigated cancer. Prevalence of pulmonary embolism (PE) with shock/CPR (4.1% vs. 1.5%), acute renal failure (6.7% vs. 2.5%), and stroke (5.2% vs. 4.2%) was higher in DVT patients with lymphedema than without. Lymphedema was independently associated with PE with shock/CPR (OR: 2.1; 95% CI: 1.9-2.3) as well as death (OR: 1.3; 95% CI: 1.2-1.4). Comorbidity conditions like cancer, obesity, and cardiovascular risk factors, and also infectious complications, were more prevalent in DVT patients with lymphedema than in those without. Lymphedema was independently associated with severe in-hospital complications, particularly when its genesis was related to severe comorbidities.
Lymphat Res Biol
· 2024 Feb · PMID 37971868
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We previously devised an ultrasonographic evaluation to calculate subcutaneous tissue cross-sectional area (△CSA). The reliability and accuracy of this method were demonstrated in healthy individuals and in patients with...We previously devised an ultrasonographic evaluation to calculate subcutaneous tissue cross-sectional area (△CSA). The reliability and accuracy of this method were demonstrated in healthy individuals and in patients with lymphedema. The purpose of this study was to estimate the optimal cut-off value of the ratio of the △CSA of the involved side (lesion side) to the contralateral side for detecting breast cancer-related lymphedema (BCRL) using ultrasonography. Ultrasonographic measurements were performed 290 times in 150 patients. BCRL was defined as a confirmed difference of >2 cm in arm circumference. BCRL confirmed by a clinician (BCRL) was defined as the patient group that included not only BCRL but also patients with subcutaneous thickening and abnormal findings on lymphoscintigraphy, even if the difference in arm circumference was <2 cm. The △CSAs of both upper arms and forearms were calculated by measuring the thickness of the subcutaneous tissue at four locations using ultrasonography (superior, medial, inferior, lateral) at 10 cm above the elbow and 10 cm below the elbow. With a 1.35 △CSA ratio as the cut-off value for detecting BCRL, the sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were 0.88, 0.87, and 0.95, respectively. With a 1.20 △CSA ratio as the cut-off value for detecting BCRL, the sensitivity, specificity, and AUC were 0.92, 0.89, and 0.97, respectively. Our findings suggest that a 1.20 △CSA ratio as determined using ultrasonography, corresponding to a tape measurement of 1.05 cm, can be considered as a diagnostic criterion for lymphedema.
Lymphat Res Biol
· 2024 Feb · PMID 37851985
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Bioimpedance spectroscopy (BIS) measurements are conventionally performed in supine position with a lead device attached to gel-backed electrodes, and more recently, with a stand-on device that uses fixed stainless-steel...Bioimpedance spectroscopy (BIS) measurements are conventionally performed in supine position with a lead device attached to gel-backed electrodes, and more recently, with a stand-on device that uses fixed stainless-steel electrodes under the hands and feet. The aim of this study was to assess and compare BIS measurements made in supine, sitting, and standing positions using lead and stand-on impedance devices in participants with and without unilateral leg lymphedema. Participants with self-ascribed unilateral leg lymphedema ( = 24) and healthy controls ( = 71) were recruited using a cross-sectional study design. Triplicate BIS measurements were taken for each device in each position. Impedance measurements with either device were reliable with coefficient of variation of 0.6% or lower. The magnitude of mean differences in absolute impedance values between devices were between 1% and 6% dependent on condition. L-Dex scores between the two devices were highly correlated ( = 0.82) and ∼70% of participants in the lymphedema group were classified as having lymphedema using the recommended cut-off with either device. There was no significant interleg difference of controls using the lead device; however, small, but significant differences ( = 0.0001) were found when using the stand-on device. The findings demonstrate that reliable impedance measurements of the legs can be made with either device in lying, sitting, or standing positions. However, data between the devices were not directly interchangeable. Although the risk of misidentification was small, reference ranges appropriate to the device and measurement position should be used when converting data to L-Dex scores.
Arends CR, van der Molen L, van den Brekel MWM
… +1 more, Stuiver MM
Lymphat Res Biol
· 2024 Feb · PMID 37815799
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Lymphedema measurement is vital to select appropriate treatment and monitor its progress. Quantifying lymphedema in the head and neck area is challenging. The use of tissue dielectric constant (TDC) measurements has show...Lymphedema measurement is vital to select appropriate treatment and monitor its progress. Quantifying lymphedema in the head and neck area is challenging. The use of tissue dielectric constant (TDC) measurements has shown promising results in other body areas. This study aims to determine the test-retest reliability of a TDC measurement protocol developed for the head and neck area. A detailed measurement protocol, including eight measurement points per side, was developed. Subsequently, the reliability of the protocol was tested in a sample of healthy participants ( = 50, 28 males). Using the LymphScanner (Delfin, Finland), participants were subjected to two measurement sessions. Each measurement point was measured three times per session. Test-retest reliability for each point was evaluated using intraclass correlation coefficients (ICCs) and standard errors of measurement (SEMs). Using the average of three measurements, reliability was good to excellent for all points (ICCs 0.81-0.95), with small measurement errors (SEMs 1.51-2.86). The reliability of a single measurement was moderate to excellent for all measurement points (ICCs 0.58-0.87), with larger, but still small, measurement errors (SEMs 1.65-3.39). When using single measurements, the lowest ICCs were found for the temporal (left 0.73 and right 0.67) and submandibular (left 0.58 and right 0.77) locations. Measurements with the LymphScanner, taken according to the developed protocol, are reliable in healthy participants. We recommend using the average of three measurements to optimize reliability. The protocol is fit for further testing in patient populations and for determining normal values in a larger scale study with healthy subjects.