Hot off the Press April 2024

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

Proposed Framework for Research Case Definitions of Lipedema

Leslyn Keith, Catherine Seo, Monika M. Wahi, Siobhan Huggins, Matthew Carmody, Gabriele Faerber, Isabel Forner-Cordero, Sandro Michelini, Stefan Rapprich, Stanley G. Rockson. Lymphat Res Biol. 2024 Mar 28

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The Arteria Lymphatica and Lymphatic Microperforators: A Dedicated Blood Supply to Collecting Lymphatics and Their Potential Implications in Lymphedema: Anatomical Description

Bendon, Charlotte L. MA(Oxon), BM, BCh*,†; Hanssen, Eric PhD‡; Nowell, Cameron MSc§; Karnezis, Tara BSc, PhD*,†; Shayan, Ramin MB BS, PhD, FRACS*,†,¶. Plastic & Reconstructive Surgery-Global Open 12(1):p e5547, January 2024. 

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Pacemaking in the lymphatic system.- click for abstract

Pacemaking in the lymphatic system.

Davis, M. J., & Zawieja, S. D. (2024).The Journal of Physiology. https://doi.org/10.1113/JP284752

Lymphatic collecting vessels exhibit spontaneous phasic contractions that are critical for lymph propulsion and tissue fluid homeostasis. This rhythmic activity is driven by action potentials conducted across the lymphatic muscle cell (LMC) layer to produce entrained contractions. The contraction frequency of a lymphatic collecting vessel displays exquisite mechanosensitivity, with a dynamic range from<1to>20 contractions per minute. A myo-genic pacemaker mechanism intrinsic to the LMCs was initially postulated to account for pressure-dependent chronotropy. Further interrogation into the cellular constituents of the lymphatic vessel wall identified non-muscle cell populations that shared some characteristics with interstitial cells of Cajal, which have pacemaker functions in the gastrointestinal and lower urinary tracts, thus raising the possibility of a non-muscle cell pacemaker. However, recent genetic knockout studies in mice support LMCs and a myogenic origin of the pacemaker activity. LMCs exhibit stochastic, but pressure-sensitive, sarcoplasmic reticulum calcium release (puffs and 2M. J. Davis and S. D. ZawiejaJ Physiol0.0waves) from IP3R1 receptors, which couple to the calcium-activated chloride channel Anoctamin1, causing depolarisation. The resulting electrical activity integrates across the highly coupled lymphatic muscle electrical syncytia through connexin 45 to modulate diastolic depolarisation. However, multiple other cation channels may also contribute to the ionic pacemaking cycle. Upon reaching threshold, a voltage-gated calcium channel-dependent action potential fires, resulting in a nearly synchronous calcium global calcium flash within the LMC layer to drive an entrained contraction. This review summarizes the key ion channels potentially responsible for the pressure-dependent chronotropy of lymphatic collecting vessels and various mechanisms of IP3R1 regulation that could contribute to frequency tuning.

Prevalence and Risk Factors

Determining risk and predictors of head and neck cancer treatment-related lymphedema: A clinicopathologic and dosimetric data mining approach using interpretable machine learning and ensemble feature selection

P. Troy Teo, Kevin Rogacki, Mahesh Gopalakrishnan, Indra J. Das, Mohamed E. Abazeed, Bharat B. Mittal, Michelle Gentile. Clin Transl Radiat Oncol. 2024 Feb 28. May

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Predictors of Unilateral Arm Lymphedema in Non-obese Locoregionally Advanced Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy, Modified Radical Mastectomy, and Postoperative Irradiation

Surjeet Dwivedi, Amiy Arnav, Varun Kumar Agarwal, S.K. Deshpande, Rohit Sharma, Naresh Saidha. Eur J Breast Health. 2024 Apr 1. Apr.

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Leg Lymphoedema After Inguinal and Ilio-Inguinal Lymphadenectomy for Melanoma: Results from a Prospective, Randomised Trial - click for abstract

Leg Lymphoedema After Inguinal and Ilio-Inguinal Lymphadenectomy for Melanoma: Results from a Prospective, Randomised Trial

T.S. Lee, I Li, B Peric, R.P.M. Saw, J.P. Duprat, E Bertolli, J.B. Spillane, B.L. van Leeuwen, M Moncrieff, A Sommariva, C.P. Allan, J.H.W. de Wilt, R. Pritchard- Jones, J.L.C. Geh, J.R. Howle, A.J. Spillane. Ann Surg Oncol. 2024 Mar 17.

BACKGROUND: The Evaluation of Groin Lymphadenectomy Extent for Melanoma (EAGLE FM) study sought to address the question of whether to perform inguinal (IL) or ilio-inguinal lymphadenectomy (I-IL) for patients with inguinal nodal metastatic melanoma who have no clinical or imaging evidence of pelvic disease. Primary outcome measure was disease-free survival at 5 years, and secondary endpoints included lymphoedema.
METHODS: EAGLE FM was designed to recruit 634 patients but closed with 88 patients randomised because of slow recruitment and changes in melanoma management. Lymphoedema assessments occurred preoperatively and at 6, 12, 18, and 24 months postoperatively. Lymphoedema was defined as Inter-Limb Volume Difference (ILVD) > 10%, Lymphoedema Index (L-Dex®) > 10 or change of L-Dex® > 10 from baseline.
RESULTS: Prevalence of leg lymphoedema between the two groups was similar but numerically higher for I-IL at all time points in the first 24 months of follow-up; highest at 6 months (45.9% IL [CI 29.9-62.0%], 54.1% I-IL [CI 38.0-70.1%]) and lowest at 18 months (18.8% IL [CI 5.2-32.3%], 41.4% I-IL [CI 23.5-59.3%]). Median ILVD at 24 months for those affected by lymphoedema was 14.5% (IQR 10.6-18.7%) and L-Dex® was 12.6 (IQR 9.0-17.2). There was not enough statistical evidence to support associations between lymphoedema and extent of surgery, radiotherapy, or wound infection.
CONCLUSIONS: Despite a trend for patients who had I-IL to have greater lymphoedema prevalence than IL in the first 24 months after surgery, our study’s small sample did not have the statistical evidence to support an overall difference between the surgical groups.:10.1245

Lymphadenectomy After Melanoma-A National Analysis of Recurrence Rates and Risk of Lymphedema - click for abstract

Lymphadenectomy After Melanoma-A National Analysis of Recurrence Rates and Risk of Lymphedema

Chen Shen, Jennifer K. Shah, Priscila Cevallos, Rahim Nazerali, Joseph M. Rosen. Ann Plast Surg. 2024 Apr 1.S Suppl 2):.

INTRODUCTION: Treatment for melanoma after a positive sentinel lymph node biopsy includes nodal observation or lymphadenectomy. Important considerations for management, however, involve balancing the risk of recurrence and the risk of lymphedema after lymphadenectomy.
METHODS: From the Merative MarketScan Research Databases, adult patients were queried from 2007 to 2021. International Classification of Disease, Ninth (ICD-9) and Tenth (ICD-10) Editions, diagnosis codes and Current Procedural Terminology codes were used to identify patients with melanoma diagnoses who underwent an index melanoma excision with a positive sentinel lymph node biopsy (SLNB). Main outcomes were completion lymph node dissection (CLND) utilization after a positive SLNB, developing lymphedema with or without CLND, and nodal basin recurrence 3 months or more after index excision. Subanalyses stratified by index excision year (2007-2017 and 20.-2021) and propensity score matched were additionally conducted. Demographics and comorbidities (measured by Elixhauser index) were recorded.
RESULTS: A total of 153,085,453 patients were identified. Of those, 359,298 had a diagnosis of melanoma, and 202,456 patients underwent an excision procedure. The study cohort comprised 3717 patients with a melanoma diagnosis who underwent an excision procedure and had a positive SLNB. The mean age of the study cohort was 49 years, 57% were male, 41% were geographically located in the South, and 24% had an Elixhauser index of 4+. Among the 350 patients who did not undergo CLND, 10% experienced recurrence and 22% developed lymphedema. A total of 3367 patients underwent CLND, of which 8% experienced recurrence and 20% developed lymphedema. Completion lymph node dissection did not significantly affect risk of recurrence [odds ratio (OR), 1.370, P = 0.090] or lymphedema (OR, 1.114, P = 0.438). After stratification and propensity score matching, odds of experiencing lymphedema (OR, 1.604, P = 0.058) and recurrence (OR, 1.825, P = 0.058) after CLND were not significantly affected. Rates of CLND had significantly decreased (P < 0.001) overtime, without change in recurrence rate (P = 0.063).
CONCLUSIONS: Electing for nodal observation does not increase the risk of recurrence or reduce risk of lymphedema. Just as CLND does not confer survival benefit, its decreased utilization has not increased recurrence rate.:10.1097

Assessment

Comparison of fluid and body composition measures in women with lipoedema, lymphoedema, and control participants

Rhiannon Stellmaker, Belinda Thompson, Helen Mackie, Louise Koelmeyer. Clin Obes. 2024 Mar 2. 

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Estimation of Hand Function Impairment in Breast Cancer Survivors with Lymphedema

Sandeep B. Shinde, Pooja P. Jain, Diksha S. Jagwani, Sanjay K. Patil, Anand Gudur, Ravindra V. Shinde. South Asian Journal of Cancer. https://doi.org/10.1055/s-0044-1779301

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Development of a core set of outcome measures to be applied toward breast cancer-related lymphedema core outcome domains

Doubblestein, David ; Koehler, Linda ; Anderson, Elizabeth ; Scheiman, Nicole ; Stewart, Paula ; Schaverien, Mark ; Armer, Jane. Breast cancer research and treatment, 2024-03

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Digital volumetric measurements based on 3D scans of the lower limb: A valid and reproducible method for evaluation in lymphedema therapy - click for abstract

Digital volumetric measurements based on 3D scans of the lower limb: A valid and reproducible method for evaluation in lymphedema therapy

Daniel Schiltz, Sophia Theresa Diesch, Natalie Kiermeier, Dominik Eibl, Gunther Felmerer, Stephan Schreml, Niklas Biermann, Lukas Prantl, Christian D. Taeger. Ann Vasc Surg. 2024 Apr.

INTRODUCTION: Exact quantification of volumetric changes of the extremities is difficult and often error prone. The aim of this study was to establish a standardized method based on 3D scans. Furthermore, this study tests the method in terms of reproducibility and evaluates volume changes after surgical therapy in patients suffering from lymphedema on the lower extremity.
METHODS: 3D-scans of the lower limb were performed with a mobile 3D-scanner. “repeatability” and “inter-observer reliability” of digital volumetry were tested. Furthermore, the method was applied on 31 patients suffering from chronic lymphedema.
RESULTS: Calculations of repeatability of the volume based on 20 3D-scans of the same lower leg showed a mean volume of 2.488 ± 0,011 liters (range: 2.470 – 2.510). The mean volume of the different examiners did not differ significantly (F(2,18) = 1.579, p = .233). The paired t-Test showed a significant mean volume decrease of 375ml (95% CI = 245/505ml) between pre and post treatment (t (30) =5.892, p < .001).
CONCLUSIONS: 3D-Volumetry is a noninvasive, easy and quick method to assess volume changes of the lower leg. Other than the low costs, it is reproducible and precise and therefore ideal for evolution of therapy in lymphedema.:10.1016/j.avsg.2024.01.011

Management Strategies

Acupuncture in cancer care: recommendations for safe practice (peer-reviewed expert opinion)

Beverley A. de Valois, Teresa Young, Catherine Zollman, Ian Appleyard, Eran Ben-Arye, Mike Cummings, Ruth Green, Caroline Hoffman, Judith Lacey, Felicity Moir, Rachel Peckham, Jacqui Stringer, Susan Veleber, Matthew Weitzman, Kathrin Wode. Support Care Cancer. 2024 Mar 14

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Use of compression therapy for cellulitis

Mia Nielsen, Mette Midttun. Dan Med J. 2024 Feb 29.A08230530.

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Impact of risk factors, early rehabilitation and management of lymphedema associated with breast cancer: a retrospective study of breast Cancer survivors over 5 years

Slobodan Tomić, Goran Malenković, Ermina Mujičić, Armin Šljivo, Sanja D. Tomić. BMC Womens Health. 2024 Apr 6

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Therapist versus Machine—Immediate Effects of Manual versus Mechanical Lymphatic Drainage in Patients with Secondary Lymphedema.

Schiltz D, Eibl D, Mueller K, Biermann N, Prantl L, Taeger CD. Journal of Clinical Medicine. 2024; 13(5):1277.

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LymphActiv: A Digital Physical Activity Behavior Intervention for the Treatment of Lymphedema and Lipedema - click for abstract

LymphActiv: A Digital Physical Activity Behavior Intervention for the Treatment of Lymphedema and Lipedema

Peter S. Mortimer, Mark Pearson, Patryk Gawrysiak, Katie Riches, Vaughan L. Keeley, Kirstie F. Tew, Ewan J. Cranwell. Lymphat Res Biol. 2024 Feb 23.

Background: 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. Aim: This service evaluation aimed to determine the feasibility of LymphActiv as a treatment option for lymphedema and lipedema patients. Methods: 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. Results: 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. Discussion: 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.:10.1089.0033

Head and Neck Lymphedema: Treatment Response to Single and Multiple Sessions of Advanced Pneumatic Compression Therapy - click for abstract

Head and Neck Lymphedema: Treatment Response to Single and Multiple Sessions of Advanced Pneumatic Compression Therapy

Gutierrez, Carolina ; Karni, Ron J. ; Naqvi, Syed ; Aldrich, Melissa B. ; Zhu, Banghe ; Morrow, J. Rodney ; Sevick-Muraca, Eva M. ; Rasmussen, John C. Otolaryngology-head and neck surgery, 2019-04, Vol.160 (4), p.622-626

Ten head and neck cancer survivors diagnosed with head and neck lymphedema (HNL) were imaged using near infrared fluorescence lymphatic imaging (NIRFLI) prior to and immediately after an initial advance pneumatic compression device treatment and again after 2 weeks of daily at home use. Images assessed the impact of pneumatic compression therapy on lymphatic drainage. Facial composite measurement scores assessed reduction/increase in external swelling, and survey results were obtained. After a single pneumatic compression treatment, NIRFLI showed enhanced lymphatic uptake and drainage in all subjects. After 2 weeks of daily treatment, areas of dermal backflow disappeared or were reduced in 6 of 8 subjects presenting with backflow. In general, reductions in facial composite measurement scores tracked with reductions in backflow and subject-reported improvements; however, studies are needed to determine whether longer treatment durations can be impactful and whether advanced pneumatic compression can be used to ameliorate backflow characteristic of HNL.