Hot off the Press March 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

Lymphatic Pain in Breast Cancer Survivors

Katie Fitzgerald Jones, Mei R. Fu, Melissa L McTernan, Eunjung Ko, Simay Yazicioglu, Deborah Axelrod, Amber A Guth, Christine Miaskowski, Yvette P Conley, Lisa J Wood, Yao Wang. Lymphat Res Biol. 2021 Dec 3
Background: Breast cancer survivors who report chronic pain in the affected ipsilateral upper limb or body are nearly twice as likely to develop lymphedema. Little is known about lymphatic pain, defined as co-occurring pain and swelling in the affected ipsilateral upper limb or body. The study aimed to examine the predictors and effects of lymphatic pain on breast cancer survivors’ activities of daily living (ADLs).
Materials and Methods: A sample of 568 patients was recruited in a metropolitan cancer center in the United States. Demographic and clinical data were collected. Body mass index (BMI) and limb volume were measured using infra-red perometer. Lymphatic pain and ADLs were measured by the Lymphedema and Breast Cancer Symptom Experience Index. Parametric and nonparametric tests and generalized linear models were used to analyze data.
Results: Lymphatic pain affected 33% of survivors. Significant predictors of lymphatic pain included younger age, higher BMI, financial hardship, and a diagnosis of lymphedema. Patients with a diagnosis of lymphedema had 9.68 odds (confidence interval [CI]: 5.78-16.63; p < 0.001) and those with financial hardship had 4.64 odds (CI: 1.99-11.32; p = 0.001) of experiencing lymphatic pain. Patients with lymphatic pain had more impairments in ADLs (p < 0.001) compared to patients with only pain, only swelling, and no symptoms. Significantly more patients with lymphatic pain had a limb volume difference of >5% and >10% compared to patients with only pain and no symptom.
Conclusion: This study is the first to report that in a large sample of patients, 33.1% experienced lymphatic pain and that lymphatic pain was associated with significant impairments in ADLs. Findings suggest that lymphatic pain may be due to abnormal accumulation of lymph fluid. Research is needed to ascertain the physiological mechanisms that underlie lymphatic pain and determine whether strategies to prevent and treat lymphedema can decrease lymphatic pain.

Control of the extracellular matrix by hypoxic lymphatic endothelial cells: Impact on the progression of lymphedema?

Jörg Wilting, Gunther Felmerer, Jürgen Becker. Dev Dyn. 2022 Feb 8
BACKGROUND: Initial lymphatic vessels do not have a continuous basement membrane. Therefore, the ability of lymphatic endothelial cells (LECs) to produce extracellular matrix (ECM) has received little attention. Untreated lymphedema is a chronic disease that progresses to massive fibrosclerosis in advanced stages. Expansion of the intercellular space and fibrosclerosis cause hypoxia, which also affects the LECs.
RESULTS: We studied expression of genes in human LECs in vitro by RNA sequencing, analyzed the effects of hypoxia (1% O2 ) vs. normoxia (21%O2 ), and focused on ECM genes. LECs express fibrillin-1 and many typical components of a basement membrane such as type IV, VIII and XVIII collagen, laminin β1, β2, and α4, perlecan and fibronectin. Under hypoxia, we found significant upregulation of expression of genes controlling hydroxylation of procollagen (PLOD2, P4HA1), and also cross-linking, bundling and stabilization of collagen fibrils and fibers. Also striking was the highly significant downregulation of elastin expression, whereas fibulin-5, which controls assembly of tropoelastin monomers, was upregulated under hypoxia. In dermis from genital lymphedema, we observed significant PLOD2 expression in initial lymphatics.
CONCLUSIONS: Overall, hypoxia results in the picture of a dysregulated ECM production of LECs, which might be partly responsible for the progression of fibrosclerosis in lymphedema.

Prevalence and Risk Factors

Investigation of the Association Between Breast Cancer-Related Lymphedema and the Side Effects of Taxane-Based Chemotherapy Using Indocyanine Green Lymphography

Hideki Tokumoto, Shinsuke Akita, Rikiya Nakamura, Naohito Yamamoto, Yoshitaka Kubota, Nobuyuki Mitsukawa. Lymphat Res Biol. 2022 Jan 28
Breast cancer-related lymphedema (BCRL) is a common complication. Docetaxel (DOC) and paclitaxel (PTX) have been used in taxane-based chemotherapy for breast cancer and to induce fluid retention. The purpose of this study was to investigate the association between lymphatic functionality and the side effects of taxane-based chemotherapy using indocyanine green (ICG) lymphography.
Methods and Results: One hundred and eighty breast cancer cases who underwent full-dose taxane-based chemotherapy (DOC or PTX) and complained of upper extremity edema were enrolled in this study. BCRL was diagnosed exclusively on the basis of ICG lymphography results. The characteristics (age, body mass index, laterality, surgery type, regional lymph node irradiation, hormone therapy, and chemotherapy type) of patients diagnosed with BCRL (+) and BCRL (-; fluid retention only) were compared. The side effects were compared in eight categories (neutropenia, skin toxicity, nail changes, myalgia/arthralgia, peripheral neuropathy, stomatitis, dysgeusia, and digestive disease). BCRL (+) consisted of 116 patients and BCRL (-) consisted of 64 patients. BCRL (+) had significantly higher rates of axillary lymph node dissection (98.3%), lymph node irradiation (68.1%), neoadjuvant chemotherapy (14.7%), and DOC (62.9%) than BCRL (-) patients (56.3%, 20.3%, 3.1%, and 34.4%, respectively; p = 0.002 for neoadjuvant rate, p < 0.001 for the other rates). BCRL (+) patients had significantly higher rates of peripheral neuropathy (60.3%) than BCRL (-) patients (40.6%; p = 0.01).
Conclusions: The occurrence rate of BCRL increased for the patients with peripheral neuropathy induced by taxane-based chemotherapy. This implies that peripheral neuropathy can induce

Assessment

A Comparison of Bioimpedance Spectroscopy or Tape Measure Triggered Compression Intervention in Chronic Breast Cancer Lymphedema Prevention

Sheila H Ridner, Mary S Dietrich, John Boyages, Louise Koelmeyer, Elisabeth Elder, T Michael Hughes, James French, Nicholas Ngui, Jeremy Hsu, Vandana G Abramson, Andrew Moore, Chirag Shah
Lymphat Res Biol. 2022 Jan 28.
Background: This study compared rates of progression to chronic breast cancer-related lymphedema (defined as ≥ 10% arm volume change from baseline requiring complex decongestive physiotherapy [CDP]) following an intervention for subclinical lymphedema (S-BCRL) triggered by bioimpedance spectroscopy (BIS) or by tape measurement (TM).   
Methods and Results: This stratified, randomized, international trial enrolled new breast cancer patients undergoing: mastectomy/partial mastectomy, axillary treatment (dissection, sentinel lymph node biopsy [SLNB] >6 nodes or radiation), radiation therapy (chest wall/breast, supraclavicular fossa), or taxane-based chemotherapy. Following postsurgery eligibility reassessment, centralized, 1:1 randomization to prospective surveillance by BIS or TM occurred. S-BCRL detection triggered a 4-week, 12-hour per day, compression sleeve, and gauntlet intervention. The primary outcome (n = 209), rates of postintervention progression to CDP, was assessed over 3 years. Between June 24, 2014 and September 11, 2018, 1200 patients were enrolled, 963 randomized (BIS n = 482; TM n = 481) and 879 analyzed (BIS n = 442; TM n = 437). Median follow-up was 32.9 months (interquartile range = 22, 35). BIS patients triggered an intervention at a lower rate than TM patients (20.1%, n = 89 vs. 27.5%, n = 120, p = 0.011). Median months to trigger were longer with BIS than TM (9.7; 95% confidence interval [CI], 8.2-12.6 vs. 3.9; 95% CI, 2.8-4.5, p = 0.001). Overall, 14.4% (n = 30) progressed post-intervention, with reduced likelihood for BIS patients than TM patients (7.9%, n = 7 vs. 19.2%, n = 23; relative risk = 0.41; 95% CI, 0.13-0.81; absolute reduction 11.3%; 95% CI, 2.3-20.3; p = 0.016).
Conclusions: Compared to TM, BIS provides a more precise identification of patients likely to benefit from an early compression intervention.

Validation of a nomogram for predicting the risk of lymphedema following contemporary treatment for breast cancer: a large multi-institutional study (KROG 20-05)

Hwa Kyung Byun, Jae Sik Kim, Jee Suk Chang, Yeona Cho, Sung-Ja Ahn, Jung Han Yoon, Haeyoung Kim, Nalee Kim, Euncheol Choi, Hyeli Park, Kyubo Kim, Shin-Hyung Park, Chai Hong Rim, Hoon Sik Choi, Yoon Kyeong Oh, Ik Jae Lee, Kyung Hwan Shin, Yong Bae Kim. Breast Cancer Res Treat. 2022 Feb 2.
PURPOSE: We previously constructed a nomogram for predicting the risk of arm lymphedema following contemporary breast cancer treatment. This nomogram should be validated in patients with different background characteristics before use. Therefore, we aimed to externally validate the nomogram in a large multi-institutional cohort.
METHODS: Overall, 8835 patients who underwent breast cancer surgery during 2007-2017 were identified. Data of variables in the nomogram and arm lymphedema were collected. The nomogram was validated externally using C-index and integrated area under the curve (iAUC) with 1000 bootstrap samples and by calibration plots.
RESULTS: Overall, 1377 patients (15.6%) developed lymphedema. The median time from surgery to lymphedema development was 11.4 months. Lymphedema rates at 2, 3, and 5 years were 11.2%, 13.1%, and 15.6%, respectively. Patients with lymphedema had significantly higher body mass index (median, 24.1 kg/m2 vs. 23.4 kg/m2) and a greater number of removed nodes (median, 17 vs. 6) and more frequently underwent taxane-based chemotherapy (85.7% vs. 41.9%), total mastectomy (73.1% vs. 52.1%), conventionally fractionated radiotherapy (71.9% vs. 54.2%), and regional nodal irradiation (70.7% vs 22.4%) than those who did not develop lymphedema (all P < 0.001). The C-index of the nomogram was 0.7887, and iAUC was 0.7628, indicating good predictive accuracy. Calibration plots confirmed that the predicted lymphedema risks were well correlated with the actual lymphedema rates.
CONCLUSION: This nomogram, which was developed using factors related to multimodal breast cancer treatment and was validated in a large multi-institutional cohort, can well predict the risk of breast cancer-related lymphedema.

Impedance of Extracellular Fluid, Volume, and Local Tissue Water Can Be Reliably Measured in People with Lower Limb Lymphedema

Charlotta Jönsson, Karin Johansson, Maria Bjurberg, Christina Brogårdh. Phys Ther. 2022 Feb 28
OBJECTIVE: Lower limb lymphedema (LLL) is a chronic condition. To be able to evaluate changes of LLL over time and effects of interventions reliable measurement methods are important. Currently, there is limited knowledge of the reliability of commonly used measurement methods in LLL. The study objective was to evaluate the test-retest (intrarater) reliability of impedance of extracellular fluid, volume, and local tissue water measurements in people with unilateral or bilateral LLL and measurement errors both for a group of people and for a single individual.
METHODS: Forty-two people with mild to moderate unilateral or bilateral, primary or secondary LLL were measured twice, 2 weeks apart. Impedance of extracellular fluid was measured by bioimpedance spectroscopy and calculated as arm-to-leg ratio, volume with circumference measurements every 4 cm, and local tissue water with tissue dielectric constant at 14 points. Test-retest reliability was evaluated using the ICC(2,1), changes in the mean, standard error of measurement in relative terms (SEM%), and the smallest real difference in relative terms (SRD%).
RESULTS: For the impedance ratio, the reliability was high [ICC(2,1) = 0.79 to 0.90] and the measurement errors were acceptable (SEM% = 5.0%-5.2%; SRD% = 14.0%-14.4%). For volume, the reliability was high (ICC = 0.99) and the measurement errors were low (SEM% = 1.1%-1.7%; SRD% = 3.1%-4.6%). For the tissue dielectric constant, the reliability was fair to excellent [ICC(2,1) = 0.68 to 0.96] and the measurement errors were acceptable (SEM% = 4.2%-9.7%; SRD% = 11.7%-26.8%).
CONCLUSIONS: Impedance of extracellular fluid, volume, and local tissue water are reliable in people with mild to moderate LLL. The measurement errors were acceptable in all 3 methods indicating that real, clinical changes in lymphedema can be measured both for a group of people and a single individual.

Three-dimensional analysis of dermal backflow in cancer-related lymphedema using photoacoustic lymphangiography

Anna Oh, Hiroki Kajita, Nobuaki Imanishi, Hisashi Sakuma, Yoshifumi Takatsume, Keisuke Okabe, Sadakazu Aiso, Kazuo Kishi. Arch Plast Surg. 2022 Jan;49(1):99-107.

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The efficacy of change in limb volume on functional mobility, health-related quality of life, social appearance anxiety, and depression in patients with lower extremity lymphedema

Ertan Şahinoğlu, Gülbin Ergin, Didem Karadibak. Phlebology. 2022 Feb 27

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Management Strategies

Prophylactic Use of Compression Sleeves Reduces the Incidence of Arm Swelling in Women at High Risk of Breast Cancer-Related Lymphedema: A Randomized Controlled Trial

Vincent S Paramanandam, Elizabeth Dylke, Gary M Clark, Anuradha A Daptardar, Ajeeta M Kulkarni, Nita S Nair, Rajendra A Badwe, Sharon L Kilbreath. J Clin Oncol. 2022 Feb 2
PURPOSE: To determine whether prophylactic use of compression sleeves prevents arm swelling in women who had undergone axillary lymph node dissection for breast cancer surgery.
METHODS: Women (n = 307) were randomly assigned to either a compression or control group. In addition to usual postoperative care, the compression group received two compression sleeves to wear postoperatively until 3 months after completing adjuvant treatments. Arm swelling was determined using bioimpedance spectroscopy (BIS) thresholds and relative arm volume increase (RAVI). Incidence and time free from arm swelling were compared using Kaplan-Meier analyses. Hazard ratios (HRs) were estimated from Cox regression models for BIS and RAVI thresholds independently. In addition, time to documentation of the first minimally important difference (MID) in four scales of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the breast cancer-specific (BR23) questionnaire was analyzed.
RESULTS: The HR for developing arm swelling in the compression group relative to the control group was 0.61 (95% CI, 0.43 to 0.85; P = .004) on the basis of BIS and 0.56 (95% CI, 0.33 to 0.96; P = .034) on the basis of RAVI. The estimated cumulative incidence of arm swelling at 1 year was lower in the compression group than the control group on the basis of BIS (42% v 52%) and RAVI (14% v 25%). HRs for time from baseline to the first change of the minimally important difference were not statistically significant for any of the four scales of EORTC QLQ-30 and BR23 questionnaires.
CONCLUSION: Prophylactic use of compression sleeves compared with the control group reduced and delayed the occurrence of arm swelling in women at high risk for lymphedema in the first year after surgery for breast cancer.

A 24-hour interval compression plan for managing chronic oedema: part 1-the science and theory behind the concept

Karen Bock, Jeanette Muldoon. J Wound Care. 2022 Feb 1;31(Sup2):S4-S9
Compression, skin care, manual lymph drainage and exercise form the mainstays of treatment of chronic limb oedema. The compression aspect of the regimen is often prescribed and used without conscious concern for the patient’s ability for self-adjustment and skin hygiene. This article will focus on the action of compression therapy using a new concept of encouraging patients to apply and reapply an adjustable compression garment or multiple garment types during a 24-hour interval. The benefits of this focus on interval compression therapy on all aspects of care will be explained and case studies presented.

The 24-hour interval compression plan: part 2-lifestyle and therapeutic regimens to manage chronic oedema case series

Karen Bock, Suzie Ehmann, Jeanette Muldoon. J Wound Care. 2022 Mar 2;31

OBJECTIVE: The aim of this case series was to retrospectively assess the impact on volume control and patients’ quality of life (QOL) when a night-time garment was added to their previous compression regimen for a full 24-hour interval compression plan.

METHOD: Patients who had a history of chronic oedema presented to one of two oedema management centres in the US for treatment for oedema exacerbation and/or suboptimal performance of their current garments. Objective data examined were circumferential limb volume (cm3) measurements and QOL measured with the Lymphoedema QOL Tool (LYMQOL-Leg and LYMQOL-Arm). Subjective comments on functional abilities and perception of improvement with a compression plan that comprised a 24-hour interval were documented.

RESULTS: All three patients presented in this case series had a reduction in limb volume and improvement in QOL when their daytime regimen of garments was updated and new night-time garments were added. Their subjective comments indicated improvement in activities of daily living and ease of controlling daytime oedema with a 24-hour interval compression plan.

CONCLUSION: This case series illustrates the need for clinicians to create a partnership with the patient to promote concordance and adherence as part of their individual 24-hour interval compression plan. This partnership allows the plan to be uniquely changed and adjusted to allow each patient to feel in control of refreshing their mood, their skin and their garments.

Running a weight-management programme with a psychological focus within a lymphoedema service

Paula Lawrence. Br J Nurs. 2022 Feb 10;31(3):114-118.
Weight management and psychological health are intertwined. Patients in this context are often mindful of how to eat healthily and what they need to do to lose weight, but frequently self-sabotage, with external influences often impact any attempted weight-loss approach. Consequently, any form of lymphoedema management is also thwarted and vicious cycles between success and rebound occur. This article describes a 6-week weight-management programme that took place before the COVID-19 pandemic. The programme focused exclusively on the expectation that, if a patient’s psychological health could be improved, weight reduction would occur as a result, and, in turn, any positive effects on adherence with lymphoedema treatments could be observed.

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Pharmacological Treatment of Secondary Lymphedema
Stav Brown, Joseph H Dayan, Michelle Coriddi, Adana Campbell, Kevin Kuonqui, Jinyeon Shin, Hyeung Ju Park, Babak J Mehrara, Raghu P Kataru. Front Pharmacol. 2022 Jan 25;13:828513.
Lymphedema is a chronic disease that results in swelling and decreased function due to abnormal lymphatic fluid clearance and chronic inflammation. In Western countries, lymphedema most commonly develops following an iatrogenic injury to the lymphatic system during cancer treatment. It is estimated that as many as 10 million patients suffer from lymphedema in the United States alone. Current treatments for lymphedema are palliative in nature, relying on compression garments and physical therapy to decrease interstitial fluid accumulation in the affected extremity. However, recent discoveries have increased the hopes of therapeutic interventions that may promote lymphatic regeneration and function. The purpose of this review is to summarize current experimental pharmacological strategies in the treatment of lymphedema.

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The International Lipoedema AssociationThe PREVENT Trial – randomised clinical trial to assess lymphoedema p...