Hot off the Press July 2022
We have collated some great articles and material published over the last month. Click on the links below to read the abstract or download the full paper.
Anatomy / Physiology /Pathophysiology
Clinical Significance of Serum Collagen Type IV and Procollagen Type III N-Peptide Levels in Diagnosis and Differential Diagnosis of Lymphedema - click for abstract
Clinical Significance of Serum Collagen Type IV and Procollagen Type III N-Peptide Levels in Diagnosis and Differential Diagnosis of Lymphedema
Lymphatic endothelial cells production or modification were closely related to the extracellular matrix (ECM) molecules. The serum hyaluronic acid (HA), laminin (LN), procollagen type III N-peptide (PIIINP), and collagen type IV (CGIV) levels were researched to explore the clinical significance of serum ECM proteins in the diagnosis and differentiation of lymphedema. Methods: Fifty-five patients were enrolled. They were divided into primary lymphedema (PLE), secondary lymphedema (SLE), and venous edema (VE) groups. Twenty-two healthy controls were also recruited as normal control (NC). Serum HA, LN, PIIINP, and CGIV levels of all subjects were assessed using chemiluminescence immunoassay. Statistical analysis and receiver operating characteristic (ROC) curves were used to data analysis. Results: The serum levels of CGIV were significantly decreased in both PLE and SLE groups compared with those in the NC group. Reduced serum CGIV levels were associated with the severity of lymphedema. The serum levels of CGIV and PIIINP were identified decreased in both PLE and SLE groups compared with those in the VE group. However, the levels of serum HA and LN were not observed significantly changed in both PLE and SLE groups than those in NC or VE group. Furthermore, ROC curve indicated that serum CGIV and PIIINP were capable of providing good diagnostic and differential diagnostic efficacy at the most appropriate cutoff point value. Conclusion: The serum levels of CGIV may have clinical significance in the diagnosis of lymphedema. CGIV and PIIINP may play a role in the differentiation of lymphedema from VE.
Lower Limb Lipedema-Superficial Lymph Flow, Skin Water Concentration, Skin and Subcutaneous Tissue Elasticity- click for abstract
Lower Limb Lipedema-Superficial Lymph Flow, Skin Water Concentration, Skin and Subcutaneous Tissue Elasticity
Lipedema of lower limbs is characterized by bilateral accumulations of excess adipose tissue starting from the ankle to the hips and buttocks. The studies with lymphoscintigraphy (LSC) and magnetic resonance (MR) lymphography show altered transport index and enlarged lymphatic vessels (LVs). Our studies aimed to investigate the superficial lymph flow, water accumulation, skin and subcutaneous tissue elasticity, and the possibility of using this information to diagnose lipedema. Methods and Results: Fifty patients with lipedema and 50 control subjects (women) were included. The Indocyanine Green (ICG) lymphography, LSC, skin water measurement, skin durometry, and deep tissue tonometry were done in all participants. ICG lymphography revealed: (1) Slower lymph flow in lipedema patients; after 3 minutes of feet movement in a horizontal position, the ICG-dyed lymph reached the upper calf level in 8% of lipedema patients compared with 56% in the control group (p ˂ 0.0001). (2) More than three LVs were noticed more often in lipedema patients. (3) The higher number of abnormal LV images at all limb levels and during each observation stage with a statistically significant number of foggy and dilated. (4) Statistically significant higher fluorescent intensity in all limb levels. Skin water concentration was higher in the feet in lipedema (p = 0.000189). Conclusion: Our studies have shown the differences in superficial lymph flow and water concentration between lipedema and normal limbs. Data proove the usefulness of ICG lymphography, skin water concentration and skin and subcutaneous tissue elasticity measurements in diagnosing lipedema.
Retrograde Lymph Flow in the Lymphatic Vessels in Limb Lymphedema - click for abstract
Retrograde Lymph Flow in the Lymphatic Vessels in Limb Lymphedema
Objective: Retrograde movement of lymph owing to damaged and/or incompetent valves in the lymphatic vessels has been considered a pathological feature of lymphedema. This study aimed to determine the prevalence of retrograde lymph flow and the characteristics of patients with this condition using indocyanine green (ICG) lymphography.
Methods: An audit of 679 patients with upper or lower limb swelling who underwent ICG lymphography was undertaken over a 4-year period. Harvey’s technique was applied to identify retrograde flow in the lymph collecting vessel during ICG lymphography. The characteristics of patients with retrograde lymph flow were recorded.
Results: Twenty-one patients (3.7%; lower limb, n ¼ 19; upper limb, n ¼ 2) were identified as having retrograde flow in lymph collecting vessels out of 566 confirmed lymphedema patients (lower limb, n ¼ 275; upper limb, n ¼ 291). Of the two patients with upper limb lymphedema (ULLE), one had a short segment of retrograde lymph flow in the forearm. The other patient with ULLE and one patient with lower limb lymphedema (LLLE) were previously diagnosed with lymphedema-distichiasis syndrome. Of the remaining 18 patients with LLLE and retrograde lymph flow, nine had initiating insect bites with lymphangitis and three had palpable benign enlarged inguinal lymph nodes evident before lower limb swelling onset. None had cancer-related LLLE.
Conclusions: Retrograde lymph flow with valve incompetence in the lymph-collecting vessels was a rare finding in ULLE and a relatively uncommon finding in LLLE, contradicting the conventional understanding of pathological changes in lymphedema. ICG lymphography identified anticipated retrograde lymph flow in two patients with lymphedema distichiasis. In the remaining patients, retrograde lymph flow may have resulted from toxic or asymptomatic lymphangitis but there was no association with secondary cancer-related lymphedema. These findings have implication for conservative management as well as lymphovenous anastomosis surgery where both ends of a transected lymph collecting vessel would be potential targets for anastomoses.
Single-cell RNA sequencing of subcutaneous adipose tissues identifies therapeutic targets for cancer-associated lymphedema
May-Thurner Syndrome and Lymphedema Reconstruction
Current Mechanistic Understandings of Lymphedema and Lipedema: Tales of Fluid, Fat, and Fibrosis
Prevalence and Risk Factors
Relationship of Adjuvant Radiation and the Lymphedema Index: A Valuable Trend to Follow Subclinical Lymphedema in Patients After Immediate Lymphatic Reconstruction - click for abstract
Relationship of Adjuvant Radiation and the Lymphedema Index: A Valuable Trend to Follow Subclinical Lymphedema in Patients After Immediate Lymphatic Reconstruction
BACKGROUND: Immediate lymphaticovenular bypass (immediate lymphatic reconstruction [ILR]) at the time of axillary lymph node dissection has emerged as a preventative paradigm to decrease the incidence of breast cancer-related lymphedema in high-risk patients. These patients are often treated with adjuvant therapies, including radiation. Bioimpedance spectroscopy is a validated tool for trending breast cancer-related lymphedema and identifying subclinical disease. Lymphedema Index (LDEX) values are commonly obtained in ILR patients; however, postoperative trends and relationships with adjuvant treatments are yet to be reported in the literature.
METHODS: After International Review Board approval, 100 consecutive patients underwent axillary lymph node dissection with axillary reverse lymphatic mapping and ILR at a tertiary cancer center. These patients were then followed prospectively in a multidisciplinary lymphedema clinic at 3-month intervals with clinical examination, circumferential limb girth measurements and bioimpedance spectroscopy (LDEX).
RESULTS: Seventy-two patients met inclusion for analysis at 3 months, 60 at 6 months, 51 at 9 months, 45 at 12 months, 41 at 15 months, and 22 at 18 months. A majority of the patients included underwent adjuvant radiation. Average LDEX score for patients who developed lymphedema was 3.02 at 3 months, at 29.1 months, 17.8 at 9 months, 15.05 at 12 months, 18.75 at 15 months, and 7.7 at 18 months. Patients who went on to develop lymphedema had a higher LDEX score at 6 months (29.1 vs 3.20, P = 0.1329), which reached a significant difference beginning at 9 months (17.8 vs 3.19, P = 0.0004). All patients who went on to develop lymphedema received adjuvant radiation.
CONCLUSIONS: These data provide valuable insight guiding follow-up after ILR. Six-month LDEX is much higher in patients who developed lymphedema, all of which underwent adjuvant radiation therapy, which correlates with the time of completion of their treatment. Average LDEX value after this remains significantly higher in this population. Patients who demonstrate this increase in LDEX and received adjuvant radiation are at highest risk to develop lymphedema despite ILR. All patients who developed lymphedema despite ILR had adjuvant radiation, and this is likely a contributing factor. Injury from adjuvant radiation and its impact after ILR is not insignificant and warrants further studies
Does Venipuncture Increase Lymphedema by Triggering Inflammation or Infection? An Experimental Rabbit Ear Lymphedema Model Study - click for abstract
Does Venipuncture Increase Lymphedema by Triggering Inflammation or Infection? An Experimental Rabbit Ear Lymphedema Model Study
Recent guidelines recommend avoiding venipuncture to prevent lymphedema for breast cancer patients. This study investigated whether single or multiple sterile venipuncture procedures develop a systemic inflammation or infection and increase lymphedema in the rabbit ear lymphedema model. Methods and Results: Eighteen New Zealand white female rabbits were included. The right ear lymphedema model was created by surgical procedure; then, rabbits were divided into three randomized groups. Single and multiple venipuncture procedures were applied at least the 60th day after surgery for Group I and II, respectively. Group III was a control group. C-reactive protein (CRP) and procalcitonin (PCT) levels were analyzed to determine inflammation and infection. Ear thickness measurements were applied using a vernier caliper to assess the differences in lymphedema between the ears. All rabbits were euthanized on the 90th day after surgery. Histopathological analysis was performed to evaluate lymphedema by measuring tissue thicknesses. Ear thickness measurements showed that ear lymphedema was developed and maintained with surgical operation in all groups (p < 0.05). There was no difference in the ear thickness measurements between and within-groups results (p > 0.05). CRP and PCT levels were below the lower detection levels in all groups. According to the differences of histopathological ear distances, there were significant differences within-groups for all groups (p < 0.05), and no differences were identified between groups (p > 0.05). Conclusion: This experimental study demonstrated that single or multiple sterile venipuncture procedures did not trigger infection or inflammation and did not exacerbate ear lymphedema in the rabbit ear lymphedema model.
Risk Factors and Racial and Ethnic Disparities in Patients With Breast Cancer-Related Lymphedema - click for abstract
Risk Factors and Racial and Ethnic Disparities in Patients With Breast Cancer-Related Lymphedema
IMPORTANCE: Risk factors for breast cancer-related lymphedema (BCRL) after axillary lymph node dissection (ALND) are poorly understood.
OBJECTIVE: To evaluate rates of and risk factors associated with BCRL in a prospective cohort of women treated with ALND.
DESIGN, SETTING, AND PARTICIPANTS: This prospective BCRL screening study performed at a tertiary cancer center enrolled women with breast cancer 18 years and older undergoing breast surgery and unilateral ALND in the primary setting or after sentinel lymph node biopsy.
EXPOSURES: Risk of BCRL during the first 2 years after ALND and radiotherapy.
MAIN OUTCOMES AND MEASURES: Patients were prospectively evaluated with arm volume (perometer) measurements, and BCRL was defined as a relative volume change of 10% or greater from baseline. Cumulative incidence of BCRL was assessed using competing risk analysis. Risk factors for BCRL were assessed on univariate and multivariable analyses.
RESULTS: From November 2016 to March 2020, 304 patients were enrolled; 276 had at least 1 longitudinal measurement. Median (IQR) age was 48 (40-57) years; median (IQR) body mass index, calculated as weight in kilograms divided by height in meters squared, was 26.4 (22.5-31.2). Of the 276 patients included in the analysis, 29 (11%) self-identified as Asian, 55 (20%) as Black, 16 (6%) as Hispanic, 166 (60%) as White, and 10 (3%) as unknown race and ethnicity; 70% received neoadjuvant chemotherapy (NAC); 93% received nodal irradiation. The 24-month BCRL rate was 23.8% (95% CI, 17.9%-29.8%), with significant variation by race and ethnicity (24-month rate: 37.2% [Black], 27.7% [Hispanic], 22.5% [Asian], and 19.8% [White]; P = .004). The BCRL rates were also higher among patients receiving NAC vs up-front surgery (24-month rate: 29.3% vs 11.1%; P = .01). On multivariable analysis, Black race and Hispanic ethnicity (compared with White race) (odds ratio [OR], 3.88; 95% CI, 2.14-7.08 and OR, 3.01; 95% CI, 1.10-7.62, respectively; P < .001 for each), receipt of NAC (compared with up-front surgery) (OR, 2.10; 95% CI, 1.16-3.95; P = .01), older age (OR, 1.04; 95% CI, 1.02-1.07 per 1-year increase; P = .001), and a longer follow-up interval (OR, 1.57; 95% CI, 1.30-1.90 per 6-month increase; P < .001) were independently associated with an increased risk of BCRL, while ERBB2-positive subtype was associated with a decreased risk of BCRL (compared with hormone receptor positive/ERBB2 negative): OR, 0.50; 95% CI, 0.23-0.99; P = .04).
CONCLUSION AND RELEVANCE: In this cohort study, Black race, Hispanic ethnicity, NAC receipt, older age, and longer follow-up were independently associated with risk of BCRL. Studies are warranted to evaluate the biologic mechanisms behind racial and ethnic disparities in BCRL development and alternatives to NAC to avoid ALND in tumor subtypes unlikely to achieve nodal pathologic complete response.
Assessment
Assessment of Measures of Head and Neck Lymphedema Following Head and Neck Cancer Treatment: A Systematic Review - click for abstract
Assessment of Measures of Head and Neck Lymphedema Following Head and Neck Cancer Treatment: A Systematic Review
Purpose: Head and neck lymphedema is a common condition following head and neck cancer (HNC) treatment, with substantial functional morbidity. This systematic review aimed to (1) identify tools used to assess head and neck lymphedema in HNC patients and (2) determine their validity and reliability.
Methods: Electronic and hand searches of Prospero, MEDLINE, Cochrane Library, and Embase were searched from their inception until April 2021, and hand searches were independently screened by two reviewers. Studies were included if they were available in English and measured lymphedema in adult HNC patients (aged ≥18 years). Data including psychometric characteristics were extracted and synthesized narratively, with the Quality Assessment of Diagnostic Accuracy Studies-2 and the COnsensus-based Standards for the selection of health Measurement INstruments checklists used to assess risk of bias.
Results: Thirty-three studies, reporting 38 assessment tools, were included. Assessments included clinician rating scales, symptom inventories, size measures, measures of internal edema, radiographic and ultrasonographic measures, and quality-of-life measures. Of the 38 measures cited, only 11 had any degree of validation and reliability testing. Risk of bias varied among the different assessment tools.
Conclusion: While many tools are used in the assessment of head and neck lymphedema, the majority of these tools lack validation and reliability data. Only one tool, the Head and Neck Lymphedema and Fibrosis Symptom Inventory, met criteria for strong quality assessment. Further efforts to establish a core set of metrics for this complex condition are warranted
The Clinical Usefulness of Ultrasonographic Measurement Technique in Patients with Lower Extremity Lymphedema - click for abstract
The Clinical Usefulness of Ultrasonographic Measurement Technique in Patients with Lower Extremity Lymphedema
A previous study reported a new ultrasonography (US) measurement technique to evaluate the cross-sectional area (ΔCSA) of lymphedema in the upper extremity. This ΔCSA correlated well with parameters, such as the circumference, volumetry, and bioimpedance analysis (BIA) in healthy people and upper extremity lymphedema patients. This study examined whether a US measurement technique is clinically useful in patients with lymphedema in the lower extremity. Methods and Results: Forty patients diagnosed with unilateral lower extremity lymphedema were enrolled in this study. The subjects’ leg circumference, BIA, isokinetic strength, and ΔCSA were examined on the same day. The leg circumference was measured at 15 cm above the knee (AK) and below the knee (BK) crease using a tape measure. BIA was performed by a trained physical therapist, and the data of impedance (Z) at 1 and 5 kHz of each side of the lower limbs and extracellular water (ECW) were used. A fully experienced physician measured soft tissue thickness, the distance between the skin and the fascia of the muscle, three times each at the anterior, medial, posterior, and lateral aspects of the bilateral legs by US at 15 cm AK and BK. The amount of soft tissue in the ΔCSA was calculated using the designed formula from the mean values of the thicknesses. Each parameter was calculated as the ratio of the sound side to the lesion side. The Pearson and Spearman correlation coefficients were used to assess the significance of these parameters. The ratio of ΔCSA measured at 15 cm AK and BK showed strong positive correlations with the circumference difference at the same level (rho = 0.790, p = 0.000, and rho = 0.882, p = 0.000, respectively). In addition, it showed moderate or strong correlations with the ratio of Z at 5 and 1 kHz in the BIA of the lower limbs (AK15, r = -0.511, p = 0.001 and r = -0.497, p = 0.001; BK15, r = -0.780, p = 0.000 and r = -0.756, p = 0.000, respectively). Although ECW and body mass index showed weak positive correlations with the ratio of ΔCSA measured at 15 cm BK, there was no significant correlation between the ratio of ΔCSA and the isokinetic muscle strength. Conclusion: The ΔCSA results showed moderate-to-strong correlations with other conveniently used methods except for the isokinetic muscle strength. As the US ΔCSA technique could measure lymphedema status with a structural consideration, it could also be recommended as a conventional measurement method in patients with upper and lower extremity lymphedema.
Management Strategies
What Should We Focus on When Managing Breast Cancer-Related Lymphedema to Improve Quality of Life? - click for abstract
What Should We Focus on When Managing Breast Cancer-Related Lymphedema to Improve Quality of Life?
Breast cancer-related lymphedema (BCRL) is correlated with poor quality of life (QOL). The effects of the management of lymphedema on QOL remain controversial. We analyzed the changes in QOL and identified factors associated with its improvement to improve the care of patients with BCRL. Methods and Results: A total of 194 patients with BCRL were recruited, and their medical records were reviewed regarding type of surgery, chemotherapy, and radiation. Patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires, and the volume and circumference of lymphedema were measured. Significant improvements in physical, emotional, cognitive, social, and role functioning, and future perspective were observed after BCRL management. However, the change in the size of lymphedema was not correlated with the change in QOL parameters. Conclusion: The management of BCRL has a beneficial effect on QOL. However, changes in the size of lymphedema did not reflect changes in QOL. Therefore, a comprehensive approach for the management of BCRL beyond reducing the size of lymphedema is recommended to improve QOL.
Safety and Efficacy of a Mobiderm Compression Bandage During Intensive Phase of Decongestive Therapy in Patients with Breast Cancer-Related Lymphedema: A Randomized Controlled Trial - click for abstract
Safety and Efficacy of a Mobiderm Compression Bandage During Intensive Phase of Decongestive Therapy in Patients with Breast Cancer-Related Lymphedema: A Randomized Controlled Trial
Lymphat Res Biol. 2022 Jun 8.
Breast cancer-related lymphedema (BCRL) after primary therapy is a common condition, causing physical and psychological distress. Decongestive lymphedema therapy (DLT) using multi-layered compression bandages is an effective treatment. We conducted a randomized controlled trial evaluating the use of a specific mobilizing bandage (Mobiderm®) on lymphedema volume reduction during the intensive phase of DLT.
Methods and Results: Fifty female BCRL patients were randomized to receive either conventional multi-layered bandages or mobilizing bandaging by using Mobiderm. Affected limb volume and excess volume were evaluated at baseline (D0) and after 15 days. The primary outcome was change in affected limb volume after adjustment for baseline. Symptom scores were evaluated by visual analogue scale (VAS); safety and tolerability were also assessed. Baseline characteristics were comparable. Affected limb volume reduction was observed in both study groups after 15 days: by 19.0% in the Mobiderm arm and 8.6% in controls (adjusted values). The between-group mean difference in adjusted volume reduction at day 15 was 256 mL (95% confidence interval [CI], 92.5 to 421.3 mL; p = 0.003) favoring Mobiderm. Reductions in excess volume of 57.3% (Mobiderm) and 25.1% (controls) were observed (adjusted values); with between-group mean difference in adjusted excess volume of 220.2 mL (95% CI, 69.3 to 371.3 mL; p = 0.006) favoring Mobiderm. Pain/heaviness VAS scores fell significantly in both groups, with mean reductions of 1.84 (Mobiderm) versus 0.83 (control; p = 0.001). Both regimens were well tolerated.
Conclusion: The use of Mobiderm in multilayer compression bandaging shows benefit in lymphedema reduction and in alleviating functional symptoms/pain in patients with BRCL
Experiences of breast cancer survivors with lymphedema self-management: a systematic review of qualitative studiesl - click for abstract
Experiences of breast cancer survivors with lymphedema self-management: a systematic review of qualitative studies
PURPOSE: This study systematically identified, evaluated, and synthesized qualitative literature on the experiences of breast cancer survivors with lymphedema self-management.
METHODS: This systematic review followed the Joanna Briggs Institute meta-aggregation approach and was guided by the ENTREQ, graded according to the ConQual approach, and evaluated using the Joanna Briggs Institute Qualitative Assessment and Review Instrument (JBI-QARI). Qualitative studies related to the experiences in lymphedema self-management among breast cancer survivors conducted until March 9, 2022, were searched. The selected studies were reviewed independently, and the data were synthesized collaboratively into core themes.
RESULTS: A total of 24 studies were included, and 85 findings resulted in three synthesis findings: (a) breast cancer survivors face challenges in lymphedema self-management, (b) breast cancer survivors are entangled in rebuilding a new balance between different roles, and (c) breast cancer survivors seek internal and external resources to regulate negative emotions.
CONCLUSIONS: Lymphedema self-management is a lifetime commitment and a challenge for breast cancer survivors, who find it difficult to adhere to self-management and cope with their problems. They require timely and continuous effective self-management education, and instrumental and emotional support from others, particularly healthcare providers and family members.
IMPLICATIONS FOR CANCER SURVIVORS: Timely self-management education and access to lymphedema treatment and related resources are important for survivors to prevent and manage lymphedema. Breast cancer survivors should develop coping skills, and family members should participate in survivors’ lymphedema self-management.
