Hot off the Press April 2023

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

Synthesis and Physiological Remodeling of CD34 Cells in the Skin following the Reversal of Fibrosis through Intensive Treatment for Lower Limb Lymphedema: A Case Report

Jose Maria Pereira de Godoy, Ana Carolina Pereira de Godoy, Maria de Fatima Guerreiro Godoy, Dalisio de Santi Neto. Dermatopathology (Basel). 2023 Mar 9;10(1):104-111. doi: 10.3390/dermatopathology10010016.

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Phospholipase A2 (PLA2) injured lymphatic endothelial cells leading to progression of secondary lymphoedema

Zimin Zhao, Wanchun Su, Hanchen Li, Xin Liu, Jianfeng Xin, Song Xia, Yuguang Sun, Qi Yao, Wenbin Shen, Nengwei Zhang
Biotechnol Genet Eng Rev. 2023 Mar 27:1-24. doi: 10.1080/02648725.2023.2195082.
Secondary lymphoedema is one of the common complications after lymph node dissection for gynecologic malignancies and breast cancer. In this study, the relationship between PLA2 and postoperative lymphoedema in cancer at the molecular level has been explored through transcriptomics and metabolomic assays. Transcriptome sequencing technology, as well as metabolomic assays, were utilized to explore the expression of PLA2 in lymphoedema patients, and search for potential pathways in the pathogenesis and exacerbation mechanism of lymphoedema. The effect of sPLA2 on human lymphatic endothelial cells was investigated by culturing human lymphatic endothelial cells. Secretory phospholipases A2 (sPLA2) showed high expression levels in lymphoedema tissues, however, cytoplasmic phospholipases A2 (cPLA2), showed low expression in lymphoedema, as demonstrated by RT-qPCR. By culturing human lymphatic vascular endothelial cells, the study found that sPLA2 causes HLEC vacuolization and has an inhibitory effect on HLEC proliferation and migration. By detecting sPLA2 in the serum of lymphoedema patients and analyzing clinical data, it was found that sPLA2 was positively correlated with the severity of lymphoedema. Secretory Phospholipase A2 (sPLA2) is highly expressed in lymphoedema tissue, damages lymphatic vessel endothelial cells, is strongly associated with disease severity, and can be used as a potential predictor of disease severity.
The Prevalence of the Axillo-Inguinal Lymphatic Pathway in Lymphedema of the Extremities and Potential Therapeutic Implications
Helen Mackie, Belinda Thompson, Asha Heydon-White, Hiroo Suami, Robbie Blackwell, Louise Koelmeyer. Lymphat Res Biol. 2023 Mar 23.
 
The axillo-inguinal (or inguino-axillary) is a compensatory lymphatic drainage pathway regularly utilized by lymphedema therapists when applying manual lymphatic drainage (MLD) for upper and lower extremity lymphedema. However, there is limited evidence of the frequency of this pathway and the characteristics of patients with lymphedema in which this pathway is present. Indocyanine green (ICG) lymphography is an imaging technique that has the capability to identify lymphatic drainage pathways in lymphedema when combined with MLD. In this study, we used ICG lymphography in patients with upper and lower extremity lymphedema to investigate the presence of this pathway and its clinical characteristics. Methods and Results: A retrospective cohort audit of 563 patients with lymphedema (285 with upper extremity and 278 with lower extremity) who underwent ICG lymphography was conducted in combination with MLD. Compensatory lymphatic drainage was investigated. Patients demonstrating the axillo-inguinal pathway were identified, and their clinical characteristics were recorded. The axillo-inguinal pathway was not demonstrated in any patient with upper extremity and only five patients with lower extremity lymphedema. Of these five patients, all were female with a history of secondary cancer-related lymphedema following gynecological cancer. The majority (four) had bilateral lymphedema extending to the lower abdomen and presented with a greater severity of lymphedema. Conclusions: These findings suggest that the axillo-inguinal pathway is an infrequent compensatory drainage pathway in lower extremity lymphedema and rare in upper extremity lymphedema. Our findings have clinical implications for lymphedema management, in particular, the sequence in which MLD is applied.

Prevalence and Risk Factors

Under recognition and treatment of lymphedema in head and neck cancer survivors – a database study

Michael D Stubblefield, Derek Weycker. Support Care Cancer. 2023 Mar 23;31(4):229. doi: 10.1007/s00520-023-07698-3.
PURPOSE: Head and neck cancer (HNC) will be diagnosed in approximately 54,000 Americans in 2022 with more than 11,000 dying as a result. The treatment of HNC often involves aggressive multimodal therapy including surgery, radiotherapy, and systemic therapy. HNC and its treatments are associated with multiple painful and function-limiting neuromusculoskeletal and visceral long-term and late effects. Among these is head and neck lymphedema (HNL), the abnormal accumulation of protein rich fluid, in as many as 90% of survivors. Though HNL is common and potentially contributory to other function-limiting issues in this population, it is notoriously understudied, underrecognized, underdiagnosed, and undertreated. This study seeks to determine the incidence of HNC-related lymphedema diagnosis and treatment in a large US healthcare claims repository database.
METHODS: A retrospective observational cohort design and data from an integrated US healthcare claims repository-the IBM MarketScan Commercial Claims and Encounters (CCAE) and Medicare Supplemental and Coordination of Benefits (MDCR) Databases spanning the period April 1, 2012 through March 31, 2020.
RESULTS: Of the 16,654 HNC patients eligible for evaluation, 1,082 (6.5%) with a diagnosis of lymphedema were identified based on eligibility criteria. Of the 521 HNC patients evaluated for lymphedema treatment, 417 (80.0%) patients received 1.5 courses of MLD, 71 (13.6%) patients were prescribed compression garments, and 45 (8.6%) patients received an advanced pneumatic compression device.
CONCLUSION: HNL in this population of HNC survivors was underdiagnosed and treated compared with contemporary assessments HNL incidence.

Weight management barriers and facilitators after breast cancer in Australian women: a national survey

Carolyn Ee1* , Adele Elizabeth Cave1, Dhevaksha Naidoo1, Kellie Bilinski1 and John Boyages2. BMC Women’s Health (2020) 20:140.

Background: Breast cancer is the most common cancer in women worldwide. Weight gain after breast cancer is associated with poorer health outcomes. The aim of this study was to describe how Australian breast cancer survivors are currently managing their weight.

Methods: Online cross-sectional survey open to any woman living in Australia who self-identified as having breast cancer, between November 2017 and January 2018.

Results: We received 309 responses. Most respondents described their diet as good/excellent and reported moderate-high levels of weight self-efficacy. Despite this, the proportion of overweight/obesity increased from 47% at time of diagnosis to 67% at time of survey. More than three quarters of respondents did not receive any advice on weight gain prevention at the time of diagnosis. 39% of women reported being less active after cancer diagnosis, and and few weight loss interventions were perceived to be effective. Facilitators were structured exercise programs, prescribed diets, and accountability to someone else, while commonly cited barriers were lack of motivation/willpower, fatigue, and difficulty maintaining weight. Women who cited fatigue as a barrier were almost twice as likely to be doing low levels of physical activity (PA) or no PA than women who did not cite fatigue as a barrier.

Conclusions: We report high levels of concern about weight gain after BC and significant gaps in service provision around weight gain prevention and weight management. Women with BC should be provided with support for weight gain prevention in the early survivorship phase, which should include structured PA and dietary changes in combination with behavioural change and social support. Weight gain prevention or weight loss programs should address barriers such as fatigue. More research is required on the effectiveness of diet and exercise interventions in BC survivors, particularly with regard to weight gain prevention.

Early Disturbance of Lymphatic Transport as a Risk Factor for the Development of Breast-Cancer-Related Lymphedema

Sarah Thomis, Nele Devoogdt, Beate Bechter-Hugl, Inge Fourneau. Cancers (Basel). 2023 Mar 15;15(6):1774. doi: 10.3390/cancers15061774

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Assessment

Test-Retest Reliability of Local Tissue Water and Circumference Measurements in the Head and Neck Area of Healthy Women and Men

Agneta Hagren, Christina Brogårdh, Karin Johansson, Johanna Sjövall, Eva Ekvall Hansson. Lymphat Res Biol. 2023 Mar 10
Background: Measurements of local tissue water and circumferences are methods to evaluate lymphedema. Knowledge about reference values and reproducibility needs, however, to be determined for the head and neck (HN) area of healthy persons before it can be used in persons with HN lymphedema. The objective of this study was to evaluate the test-retest reliability including measurement errors of local tissue water and neck circumference measurements (CM) in the HN area in a healthy cohort.
Methods and Results: Thirty-one women and 29 men were measured on 2 occasions, 14 days apart. The percentage of tissue water content (PWC) were calculated in four facial points and neck CM at three levels. Intraclass correlation coefficient (ICC), changes in mean, standard error of measurement (SEM%), and smallest real difference (SRD%) were calculated. Reliability for PWC was fair to excellent for both women (ICC 0.67-0.89) and men (ICC 0.71-0.87). Measurement errors were acceptable in all points in both women (SEM% 3.6%-6.4%, SRD% 9.9%-17.7%) and men (SEM% 5.1%-10.9%, SRD% 14.2%-30.3%). For the CM, ICCs were excellent both for women (ICC 0.85-0.90) and men (ICC 0.92-0.94), and measurement errors were low (SEM% for women 1.9%-2.1%, SRD% 5.1%-5.9%; SEM% for men 1.6%-2.0%, SRD% 4.6%-5.6%). Most of the lowest values were found close to bone and vessels.
Conclusion: Measurements for PWC and CM in the HN area are reliable in healthy women and men, with acceptable to low measurement errors. PWC points close to bony structures and vessels should, however, be used with caution.

Screening for Breast Cancer-Related Lymphedema Development Using Extracellular Water Ratio

Yoshichika Yasunaga, Yuto Kinjo, Saeko Kondoh, Daisuke Yanagisawa, Shunsuke Yuzuriha, Shoji Kondoh. Lymphat Res Biol. 2023 Mar 23. doi: 10.1089/lrb.2022.0060.
This case-control retrospective study examined whether the extracellular water ratio (%ECW) of the upper extremity, as measured through bioelectrical impedance analysis (BIA), could be an indicator of the development and severity of breast cancer-related lymphedema (BCRL). Methods and Results: BIA was used to evaluate the changes in %ECW due to BCRL development, with the %ECW measured in female patients with unilateral BCRL and healthy controls. Receiver operating characteristic (ROC) analysis was performed to assess the diagnostic ability of %ECW to distinguish BCRL patients from controls. Twenty female patients, who were eligible for inclusion, and 20 healthy control volunteers were included. The %ECW of the affected arm correlated with the water volume difference between the affected and unaffected arms (R2 = 0.7183). ROC analysis showed that %ECW had a high diagnostic ability as a screening tool for BCRL development (area under the ROC curve = 0.982). A cutoff %ECW value of 38.5% could predict the presence of BCRL with a sensitivity of 91.7% and specificity of 97.9%. Conclusions: This study confirmed that %ECW could assess the presence and severity of BCRL in a single measurement noninvasively in a shorter amount of time. The %ECW value strongly correlated with excess arm body water volume, an indicator of the severity of unilateral arm lymphedema. The cutoff %ECW value could predict the presence of BCRL with high accuracy.

Early Detection of Breast Cancer-Related Lymphedema: Accuracy of Indocyanine Green Lymphography Compared with Bioimpedance Spectroscopy and Subclinical Lymphedema Symptoms

Atilla Soran, Fuat Baris Bengur, Wendy Rodriguez, Maria Z Chroneos, Efe Sezgin. Lymphat Res Biol. 2023 Mar 22. doi: 10.1089/lrb.2022.0066
Introduction: The reported incidences of breast cancer-related lymphedema (LE) affecting the arms vary greatly. Reason for this variability includes different diagnostic techniques used across studies. In the current study, we compared the accuracy of indocyanine green lymphography (ICG_L) and bioimpedance spectroscopy (BIS) in detecting LE before presentation of clinical signs.
Methods and Results: Patients with no initial detectable signs of clinical LE of their arms after axillary lymph node dissection or removal of >5 lymph nodes on sentinel lymph node biopsy were included. Subclinical LE was defined as BIS values outside the normal range [(≥7 units (or >10 units)] or a 7-unit (or 10 unit) change between two measurements. We tracked ICG_L and BIS measurements for 133 potentially affected arms (n = 123). ICG_L detected signs of lymphatic flow disruption in 63 arms (47%). Based on the BIS value of 7 units, 60 arms (45%) had values outside the normal range. When using ICG_L-identified LE cases as true positives, BIS had a 54% accuracy (area under the curve [AUC] = 0.54) in detecting LE. Accuracy was 61% for subclinical LE symptoms when compared with ICG_L (AUC = 0.62). Both BIS and subclinical LE symptoms had <0.70 AUC-receiver characteristic operator curve, suggesting that BIS and development of subclinical LE symptoms are not adequate for identifying patients with subclinical LE.
Conclusion: ICG_L is a reliable diagnostic tool for detecting early signs of lymphatic flow disruption in subclinical LE. Utilizing ICG_L to diagnose subclinical LE followed by a personalized treatment plan may provide patients the best chance of preventing disease progression.

Cross-sectional validity and specificity of comprehensive measurement in lymphedema and lipedema of the lower extremity: a comparison of five outcome instruments

Angst F, Lehmann S, Aeschlimann A, Sandòr PS, Wagner S. Health Qual Life Outcomes. 2020 Jul 22;18(1):245

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Improving the Assessment and Diagnosis of Breast Lymphedema after Treatment for Breast Cancer

Katie Riches, Kwok-Leung Cheung, Vaughan L. Keeley. Cancers (Basel). 2023 Mar 14;15(6):1758

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Management Strategies

The efficacy and safety of acupuncture and moxibustion for breast cancer lymphedema: a systematic review and network meta-analysis

Shiheng Wang, Fengxia Zhang, Hanqing Tang, Wanling Ning. Gland Surg. 2023 Feb 28;12(2):215-224. doi: 10.21037/gs-22-767.

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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

Nele Devoogdt, Sarah Thomis, An De Groef, An-Kathleen Heroes, Ines Nevelsteen, Nick Gebruers, Wiebren A A Tjalma, Jean-Paul Belgrado, Chris Monten, Marianne Hanssens, Tessa De Vrieze. Cancers (Basel). 2023 Feb 28;15(5):1545. doi: 10.3390/cancers15051545

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Evaluating telehealth for the education and monitoring of lymphoedema and shoulder dysfunction after breast cancer surgery

Leonie Naumann, Hildegard Reul-Hirche, Tracy Comans, Clare L Burns, Jenny Paratz, Michelle Cottrell
Support Care Cancer. 2023 Mar 28;31(4):239. doi: 10.1007/s00520-023-07693-8.
 

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YouTube as a Source of Information on Lipedema: Property, Quality, and Reliability Assessment

Elif Esen Özdemir, Pinar Borman, Gül Mete Civelek, Mümtaz Mutlu Umaroğlu. Lymphat Res Biol. 2023 Mar 16. doi: 10.1089/lrb.2022.0028.
Background/Aim: YouTube provides information on several health-conditions including lipedema. The aim of this study was to investigate the properties, quality, and quantity of YouTube videos on lipedema.
Methods: We explored YouTube using the key word lipedema and the initial top 50 videos were included to review. The properties comprising informers, target, and domains of videos covering number of views, likes, dislikes, duration, viewing rate (VR), and video power index (VPI) were recorded. A modified DISCERN tool and global quality scale (GQS) were used to assess the reliability and quality of videos, respectively.
Results: The top 50 videos had a mean of 35,805 views, 282 likes, 12 dislikes, and 30 comments. The mean VPI (96.4) and VR (63.8%) were high. The videos were generally uploaded by health professionals for patient/public and health professional targets with the same ratio (50%). The majority of video contents was related to general information (68%) followed by surgical treatment (62%). Only a small ratio of their content (22%) was about nonsurgical management. The reliability and quality of the videos were intermediate to low. The median DISCERN and GQS scores were higher in the videos uploaded by health professional group compared with nonhealth professionals, but the number of views, VPI, and VR were similar between the groups with regard to the source.
Conclusion: YouTube videos on lipedema are mostly provided by health professionals targeting both public/patients and health care providers but the content is limited and the quality and reliability of them were low to intermediate. Therefore, the lipedema specialists are suggested to work together to create up-to-date, high-quality, accessible online educational content to meet the needs of both patients/public and the health professionals. In addition, control mechanisms and careful peer reviewing of the videos informed by nonhealth professionals are warranted to avoid misleading information.
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