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A promising new treatment for lymphedema

Surgical options at Mayo Clinic

Mayo Clinic is a leader in surgical options to reverse the damage from lymphedema. Dr. Forte specializes in lymphovenous bypass, a microsurgery done under powerful microscopes that are magnified 20 to 25 times. Through an incision no larger than a paper cut, the surgery connects tiny lymphatic vessels smaller than a strand of hair to tiny veins, creating a type of detour around the damaged area. The new vessel connections restore the body's ability to drain lymphatic fluids.

"When you remove that fluid, we don't know why, but the body is able to reverse these chronic changes in the tissue. In a way, what we're trying to do is reverse the damage that was done by the accumulation of the lymphatic fluid," says Dr. Forte. "It is a regenerative approach because not only do you restore function, but you actually heal the tissues."

Like a ton of bricks

Rebecca, who asked that her last name not be used, was diagnosed with triple-negative breast cancer in 2009. She prayed she'd live long enough to see her two youngest sons graduate college.

The Savannah, Georgia, resident waged a grueling battle that included chemotherapy, mastectomy and lymph node removal. She emerged victorious and was able to not only attend her sons' graduations, but also their weddings. However, a noxious side effect surfaced four years after her cancer treatment. Lymphedema developed in her right arm, causing swelling and fibrous tissue that progressively got harder.

"I felt as if I was dragging a ton of bricks everywhere I went. I could not go away to visit family without being sure I had all materials and compression garments with me. I had to make a checklist to include everything I needed to care for myself anywhere I went," she says.

Occupational therapy, compression wraps and a disciplined exercise regimen helped control her lymphedema, but it never really went away. A devastating reality set in when she realized that no matter how closely she followed medical advice, the lymphedema would not be cured.

9 was the lucky number

By luck, coincidence or maybe even a miracle, Rebecca discovered a new path to treatment while at the ninth green of the Players Championship at TPC Sawgrass in Ponte Vedra Beach, Florida. She and her family had gathered at the ninth green to watch a golfer sink a putt. Rebecca's right hand had swollen during the day.

"I had left my compression glove at home," she says.

She decided to stand in the shade and rest her hand on a tree to see if the swelling would go down. While standing there, with her right hand above her head resting on an ancient live oak tree, a nearby spectator noticed the compression sleeve.

"She said: 'Excuse me. I see you are a lymphedema patient. Did you know that Mayo Clinic offers lymphovenous bypass surgery?' This woman turned out to be a plastic surgery nurse practitioner at Mayo Clinic in Florida. I had not heard about the surgery until our chance meeting," says Rebecca.

Despite her initial apprehension, preparations for surgery started falling in place. Dr. Forte examined her and found the procedure to be a suitable match, and her insurance approved. One year after lymphovenous bypass surgery, Rebecca says the fluid has drained and her right arm is nearly normal.

"I can now feel the bone in my elbow. I hadn't felt that bone in three years," she says. "This surgery has taken a weight, ball and chain and a ton of bricks off my life. Resentment, fear and worry also have been removed. I truly do not have words to express the depth of gratitude and appreciation I have for Dr. Forte and his nurse practitioner. I weep with private tears of joy and relief."

While surgery relieved Rebecca's symptoms, Dr. Forte says there is a chance it might not work the same for others. However, he believes lymphovenous bypass is a safe and low-risk procedure.

"I love the bypass because the morbidity is so low that there's little downside to the procedure. If lymphovenous surgery doesn't relieve fluid buildup, then all you have to heal from is small incisions similar to paper cuts. If it does work, it's life-changing," he says.

By better understanding how each patient responds to the surgery, Dr. Forte hopes to improve the success rate. He also hopes to learn whether a targeted drug or complementary treatment might lead to quicker recovery.

A version of this story originally appeared on the Mayo Clinic Center for Regenerative Medicine blog .

Learn more about lymphedema .

Find a lymphedema clinical trial at Mayo Clinic .

Mayo Clinic's Center for Individualized Medicine is funding research to identify new biomarkers that could predict which patients are most likely to respond to this regenerative surgery.

New Mayo Clinic research represents a promising step toward identifying biological signals or biomarkers that may aid in early detection.

Study results showed significantly higher survival rates when blinatumomab was added to chemotherapy for people with B-cell acute lymphoblastic leukemia.

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Study identifies potential drug target for lymphedema

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The human lymphatic system consists of a vast network of vessels that drain protein-rich fluid in tissues and transport it to lymph nodes. When the machinery goes awry and the lymphatic vessels don't drain properly, the fluid accumulates in the tissues, leading to painful swelling known as lymphedema .

A Cornell-led collaboration built a 3D in-vitro model of a functional human lymphatic vessel that revealed a surprising mechanism that can jam up the necessary drainage: a protein expressed in lymphatic endothelial cells called rho-associated protein kinase 2 (ROCK2).

The researchers demonstrated that by inhibiting ROCK2 they can reverse the effects of lymphedema, creating a potential treatment for a condition that is estimated to affect up to 150 million people worldwide.

The team's paper, "A 3D Biomimetic Model of Lymphatics Reveals Cell-Cell Junction Tightening and Lymphedema Via a Cytokine-Induced ROCK2/JAM-A Complex," published Oct. 2 in Proceedings of the National Academy of Sciences . The paper's lead author is Esak (Isaac) Lee, Meinig Family Investigator in the Life Sciences and assistant professor of biomedical engineering at Cornell Engineering.

Lymphedema has so many patients in the world. Doctors usually suggest you wear a compression garment or do some physical therapy, like massage, to pump out all these fluids from your arms and legs. Unfortunately, there's no FDA-approved drug because we don't understand the mechanism of this disease." Esak (Isaac) Lee, Meinig Family Investigator in the Life Sciences and assistant professor of biomedical engineering at Cornell Engineering

Attempts to locate that mechanism in humans have been thwarted by the fact that the lymphatic system is entangled with the central nervous system, muscle movements, and a raft of other bodily processes.

Working with researchers from Boston University (BU) and Harvard Medical School who were led by co-lead author Christopher Chen of BU, Lee set out to create an in-vitro model – or "lymphatics-on-a-chip" – that could isolate several biological and biophysical factors, such as inflammatory cytokines, ROCK2 signal and interstitial fluid pressure, while mimicking the drainage.

The transparent, thumb-sized device realistically reproduced the "button-like" lymphatic junction – the borderline between the endothelial cells that line the lymphatic vessels – with two hollow channels in 3D collagen. In the first channel, the team seeded these human cells, which were then pressurized by interstitial fluid loaded in the second channel. High fluid pressure opened the junctions of the engineered lymphatics, and the uptake of fluid closed them. The researchers could then measure how much of the fluid drained through the system.

"Demonstrating this button-like junction is so crucial to recapitulate lymphatic function, which has not been successful in vitro before our study," Lee said. "The most important challenge was to make the right conditions: the size of the vessels, the distance between two channels, growth factors used, and the size of interstitial fluid pressure. All these things are really affecting button junctions, so we wanted to make sure they all are realistically mimicking the human biology."

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The Future of Lymphedema: Potential Therapeutic Targets for Treatment

Affiliation.

1 Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065 USA.
PMID: 37359311
PMCID: PMC10233555
DOI: 10.1007/s12609-023-00491-5

Purpose of review: This review aims to summarize the current knowledge regarding the pharmacological interventions studied in both experimental and clinical trials for secondary lymphedema.

Recent findings: Lymphedema is a progressive disease that results in tissue swelling, pain, and functional disability. The most common cause of secondary lymphedema in developed countries is an iatrogenic injury to the lymphatic system during cancer treatment. Despite its high incidence and severe sequelae, lymphedema is usually treated with palliative options such as compression and physical therapy. However, recent studies on the pathophysiology of lymphedema have explored pharmacological treatments in preclinical and early phase clinical trials.

Summary: Many potential treatment options for lymphedema have been explored throughout the past two decades including systemic agents and topical approaches to decrease the potential toxicity of systemic treatment. Treatment strategies including lymphangiogenic factors, anti-inflammatory agents, and anti-fibrotic therapies may be used independently or in conjunction with surgical approaches.

Keywords: ACE inhibitors; CD4 +; Captopril; Doxycycline; Lymphedema; NSAID; Non-steroidal anti-inflammatory drugs; Pirfenidone; TGFB; TH2 cells; Tacrolimus; Tetracyclines; VEGF-C; Vascular endothelial growth factor C.

© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

PubMed Disclaimer

Conflict of interest statement

Conflict of InterestBabak J. Mehrara, MD, is the recipient of investigator-initiated research grants from PureTech and Regeneron and has received royalty payments from PureTech; he also has served as a consultant for Pfizer Corp. Joseph H. Dayan, MD, is a paid consultant for the Stryker Corporation, has intellectual property rights with Elucida Oncology and equity interest in Welwaze Medical, LLC, and has a royalty agreement with Springer Publishers for Multimodal Management of Upper and Lower Extremity Lymphedema. All other authors report no potential conflicts of interest.

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Advances and challenges in treating lymphedema: A Q and A with Dhruv Singhal, M. D.

Intra Operative photo of Dr. Singhal M.D.

Q: How do problems with the lymphatic system end up causing lymphedema?

A: Normally as blood flows through the body, fluid seeps out of blood vessels and into the body’s tissues. This fluid drains into the lymphatic vessels, then moves to the lymph nodes to be filtered. Eventually the fluid returns to the veins and back into circulation. In lymphedema, however, the lymphatic system fails to keep up with the leaking fluid. That’s because the lymphatic vessels – the places where they’d normally drain – have been damaged. As a result, this fluid builds up and causes swelling, typically in an arm or a leg, and can result in chronic inflammation. Damage to the lymphatic vessels most commonly occurs because of cancer treatment. A surgeon will often remove the lymph nodes near a tumor to prevent the spread of cancer. In that process, lymphatic vessels get severed, and this is what can start the problem.

Q: What do you find most interesting about the lymphatic system?

A: One of the most interesting things about the lymphatic system is its scale, which is remarkably small compared to the blood vascular system (arteries and veins). To give you an idea, the largest artery, the aorta, is about 2 centimeters (cm). So is the largest vein, the inferior vena cava. But the largest lymphatic vessel, the thoracic duct, is only about 2 millimeters (mm), or 10 times smaller. The lymphatic system can almost seem invisible. If you cut yourself and damage an artery or vein, red blood comes out. If you cut 10 lymphatic vessels, you might not even notice, though it would slowly leak clear fluid. Yet the lymphatic system transports as much as 12 liters of fluid a day, whereas the arteries and veins hold only about 5 liters. So really, the lymphatic system is this vast network containing much of the body’s vascular fluid, but often we don’t notice it until something goes wrong.

Q: How is lymphedema treated, and is there a cure?

A: There is currently no cure for lymphedema. The standard treatment is called compression. A patient wears a pressurized sleeve over the arm or leg to compress it, and that helps the fluid drain. The problem is that it’s not feasible to wear these sleeves 24/7. And you can imagine it’s not very comfortable to wear them when you live in places like Florida, or anywhere during the summer. Of course, there are medicines and other approaches that can help. We can also do lymphatic reconstructive surgery, like a lymph node transplant. In that process we take lymph nodes from other parts of the body and transplant them into the affected region. But I think the most promising approach going forward will be prevention.

Q: What kind of prevention do you think is possible, and what will it take to put those approaches into practice broadly?

A: One of the biggest challenges to prevention and treatment of lymphedema is that we don’t fully understand the risk factors. Of four patients undergoing lymph node removal during cancer treatment, only one will develop lymphedema; the risk is about 26-33%. We think part of the answer lies in the small, but different ways lymphatic vessels form in one person to the next. We think this variability may protect some patients from developing lymphedema. A key to this approach will be understanding what normal lymphatic anatomy looks like. If we can accurately map the lymphatic vessels in healthy individuals as well as in patients before and after surgery, we may be able to identify patterns in lymphatic structure that are more likely to lead to lymphedema.

The second major hurdle in treating this disease is the lack of an objective measurement of lymphatic function. One of the biggest things holding back lymphatic care is that there is nothing we can do right now to get a quick assessment of the lymphatic system. If you have chest pain, within an hour we can have sophisticated measurements of heart function. Nothing like that exists right now for measuring lymphatic function. Measuring limb circumference is often used as an indicator of lymphedema, but this can be complicated by other factors and doesn’t give real-time information about lymphatic function. Techniques using radioactive tracers or magnetic resonance imaging (MRI) can be used to measure lymphatic function and structure, but they require specialized instruments and result in poor resolution (ability to see detail). These techniques are also difficult to use at the point of surgery, which would be ideal for determining whether a patient needs immediate intervention or not.

Q: How is your research group tackling these problems, and what do your results mean for lymphedema treatment going forward?

A: Firstly, we think it’s critical to take a step back and try to understand what normal lymphatic anatomy is. I often get asked, “Why not just study the patients who have lymphedema?” But very little has been done to look at lymphatic anatomy in healthy people. Once we’ve done that, we want to know how the anatomy changes in those who do and do not develop lymphedema after lymph nodes have been removed. In those patients who have lymph node damage but don’t develop lymphedema, if we can map how they are able to compensate, perhaps we can come up with a solution for those who do get lymphedema.

We also want to develop better tools and methods for evaluating lymphatic function. We’re working with Dr. Hak Soo Choi in the Gordon Center for Medical Imaging at Massachusetts General Hospital to develop dyes that are specific to the lymphatic system. We could then inject these dyes into the body to see and measure how the dye is being carried away by the lymphatic vessels. This would give us a readout of the efficiency of lymphatic drainage. It would also give us a measurement that we can use to evaluate surgical and medical interventions, and then objectively say which ones improved lymphatic function and which did not.

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Published: 21 October 2021

Primary lymphoedema

Pascal Brouillard 1 ,
Marlys H. Witte ORCID: orcid.org/0000-0001-5505-934X 2 ,
Robert P. Erickson 3 ,
Robert J. Damstra 4 ,
Corinne Becker 5 ,
Isabelle Quéré ORCID: orcid.org/0000-0002-1492-9764 6 &
Miikka Vikkula ORCID: orcid.org/0000-0002-6236-338X 1 , 7 , 8

Nature Reviews Disease Primers volume 7 , Article number: 77 ( 2021 ) Cite this article

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Disease genetics
Vascular diseases

Lymphoedema is the swelling of one or several parts of the body owing to lymph accumulation in the extracellular space. It is often chronic, worsens if untreated, predisposes to infections and causes an important reduction in quality of life. Primary lymphoedema (PLE) is thought to result from abnormal development and/or functioning of the lymphatic system, can present in isolation or as part of a syndrome, and can be present at birth or develop later in life. Mutations in numerous genes involved in the initial formation of lymphatic vessels (including valves) as well as in the growth and expansion of the lymphatic system and associated pathways have been identified in syndromic and non-syndromic forms of PLE. Thus, the current hypothesis is that most cases of PLE have a genetic origin, although a causative mutation is identified in only about one-third of affected individuals. Diagnosis relies on clinical presentation, imaging of the structure and functionality of the lymphatics, and in genetic analyses. Management aims at reducing or preventing swelling by compression therapy (with manual drainage, exercise and compressive garments) and, in carefully selected cases, by various surgical techniques. Individuals with PLE often have a reduced quality of life owing to the psychosocial and lifelong management burden associated with their chronic condition. Improved understanding of the underlying genetic origins of PLE will translate into more accurate diagnosis and prognosis and personalized treatment.

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Lymphatic vessel: origin, heterogeneity, biological functions, and therapeutic targets

Lower extremity lymphatic function predicted by body mass index: a lymphoscintigraphic study of obesity and lipedema

A new severity classification of lower limb secondary lymphedema based on lymphatic pathway defects in an indocyanine green fluorescent lymphography study

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Acknowledgements

M.V.’s laboratories were financially supported by the Fonds de la Recherche Scientifique – FNRS Grants T.0026.14 and T.0247.19, the Fund Generet managed by the King Baudouin Foundation (Grant 2018-J1810250-211305), and by la Région wallonne dans le cadre du financement de l’axe stratégique FRFS-WELBIO (WELBIO-CR-2019C-06). M.V. has also received funding from the MSCA-ITN network V. A. Cure No. 814316 and the Lymphatic Malformation Institute, USA. M.H.W. has received research support from the University of Arizona Health Sciences Translational Imaging Program Projects Stimulus (TIPPS) Award and National Institutes of Health NHLBI R25HL108837 for diverse undergraduate research trainees (Luis Luy, Jasmine Jones, Reginald Myles); she is also Secretary-General, International Society of Lymphology, Tucson, AZ, USA, and Zurich, Switzerland. The authors are grateful to Grace Wagner and Juan Ruiz for programmatic assistance and to Liliana Niculescu for expert secretarial assistance.

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Brouillard, P., Witte, M.H., Erickson, R.P. et al. Primary lymphoedema. Nat Rev Dis Primers 7 , 77 (2021). https://doi.org/10.1038/s41572-021-00309-7

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Study finds first possible drug treatment for lymphedema

Collaboration between two Stanford labs has resulted in the discovery of a molecular cause for lymphedema and the first possible drug treatment for it.

May 10, 2017 - By Tracie White

Woman standing in front of her garden and home

Tracey Campbell suffers from lymphedema and is participating in a clinical trial of a drug to determine whether it can treat the painful condition. Mark Williams

Tracey Campbell has lived for seven years with lymphedema, a chronic condition that causes unsightly swelling in her left leg.

The disease, which stems from a damaged lymphatic system, can lead to infections, disfigurement, debilitating pain and disability. There is no cure. The only available treatment is to wear compression garments or use massage to suppress the swelling, which can occur throughout the body in some cases. Campbell — who had two quarts of excess water in her left leg by the time she was diagnosed — has for years worn restrictive garments 24 hours a day and has spent an hour each night massaging the lymph fluid out of her leg.

Lymphedema is uncomfortable, exhausting and dangerous if left uncontrolled. As many as 10 million Americans and hundreds of millions of people worldwide suffer from the condition, many from the after-effects of cancer therapy treatments.

“There’s this extra layer of emotional burden,” said Campbell, who added that she has to be constantly vigilant to protect against infection. “All you want to be is normal.”

Now there’s new hope for a possible pharmaceutical treatment for patients like Campbell. A study led by scientists at the Stanford University School of Medicine has uncovered for the first time the molecular mechanism responsible for triggering lymphedema, as well as a drug with the potential for inhibiting that process.

The study was published May 10 in Science Translational Medicine .

“We figured out that the biology behind what has been historically deemed the irreversible process of lymphedema is, in fact, reversible if you can turn the molecular machinery around,” said Stanley Rockson , MD, professor of cardiovascular medicine and the Allan and Tina Neill Professor of Lymphatic Research and Medicine at Stanford. Rockson shares senior authorship of the study with Mark Nicolls , MD, professor of pulmonary and critical care medicine. Stanford research scientists Wen “Amy” Tian, PhD, and Xinguo Jiang, MD, PhD, share lead authorship of the study and are also affiliated with the Veterans Affairs Palo Alto Health Care System .

‘Fundamental new discovery’

“This is a fundamental new discovery,” said Nicolls, who is also a researcher at the VA Palo Alto.

Stanley Rockson

The researchers found that the buildup of lymph fluid is actually an inflammatory response within the tissue of the skin, not merely a “plumbing” problem within the lymphatic system, as previously thought.

Working in the lab, scientists discovered that a naturally occurring inflammatory substance known as leukotriene B4, or LTB4, is elevated in both animal models of lymphedema and in humans with the disease, and that at elevated levels it causes tissue inflammation and impaired lymphatic function.

Further research in mice showed that by using pharmacological agents to target LTB4, scientists were able to induce lymphatic repair and reversal of the disease processes.

“There is currently no drug treatment for lymphedema,” Tian said. Based on results of the study, the drug bestatin, which is not approved for use in the United States but which has been used for decades in Japan to treat cancer, was found to work well as an LTB4 inhibitor, with no side effects, she said.

Based on the research, bestatin (also known as ubenimex), is being tested in a clinical trial that started in May 2016 — known as ULTRA — as a treatment for secondary lymphedema, which occurs because of damage to the lymphatic system from surgery, radiation therapy, trauma or infection. Primary lymphedema, on the other hand, is hereditary. The results of the research pertain to both types.

Rockson is principal investigator for this multisite phase-2 clinical trial.

“The cool thing about this story — which you almost never see — is that a clinical trial testing the therapy has already started before the basic research was even published,” Nicolls said. “This is the first pharmaceutical company-sponsored trial for a medical treatment of lymphedema, a condition that affects millions.”

Nicolls and Tian are co-founders of Eiccose LLC. Eiccose is now part of Eiger BioPharmaceuticals, which gets the drug from Nippon Kayaku in Japan. Eiger is sponsoring the clinical trial. Nicolls and Rockson are both scientific advisers to the company.

Two labs, two diseases

The study, which got underway about four years ago, began somewhat uniquely as a collaboration between two labs that were studying two completely different diseases. At the time, the Nicolls lab, where Tian works, was studying pulmonary hypertension. The Rockson lab was conducting lymphedema research.

Mark Nicolls

The two teams met through SPARK , a Stanford program designed to help scientists translate biomedical research into treatments for patients.

“I was in a privileged position of seeing two faculty conducting important research and recognizing the possible link in causality,” said Kevin Grimes , MD, associate professor of chemical and systems biology and co-founder of SPARK. “It occurred to me that both diseases affected vascular tissues and had strong inflammatory components.”

“He blind-dated us,” Nicolls said. “When Amy Tian and I looked at the data from Stan’s research, Amy said, ‘It looks like it could be the same molecular process.’”

“It was an arranged marriage between us and Stan which worked out great,” Tian said.

At the time, Rockson had begun to suspect that lymphedema was an inflammatory disease. This led to his team’s discovery that the anti-inflammatory drug ketoprofen successfully helped to relieve lymphedema symptoms, although it wasn’t a perfect drug; side effects were a concern, and it remained unclear how the drug worked at the molecular level.

Meanwhile, the Nicolls lab had discovered that LTB4 was part of the cycle of inflammation and injury that keeps pulmonary hypertension progressing. When researchers blocked LTB4 in rats with the disease, their symptoms lessened and blood vessels became less clogged, lowering blood pressure in the lungs.

“When we became aware of Mark’s work, we began to realize that we were both possibly dealing with the activation of steps downstream of the 5-LO [5-lipoxygenase] pathway,” Rockson said . “This became intriguing and formed the basis of our relationship.”

Joining forces

The two teams joined forces to figure out the mechanism that triggered lymphedema, hopefully revealing a target for drug treatment in humans. After determining that ketoprofen was primarily working on the 5-LO pathway, the researchers began blocking the various endpoint pathways after 5-LO activation in mouse models of lymphedema, Rockson said.

“It turned out that, in fact, we were both dealing with the same branch, which is LTB4,” Rockson said.

When all of the sudden one of your limbs begins to swell, you want to understand what the heck is going on.

“So now it became clear we really were dealing with a very similar biological process in two different diseases,” he said. “Because of Mark’s work in pulmonary hypertension, we knew that we had an ideal form of therapy that we could try in lymphedema as well.”

The Nicolls lab had used the drug bestatin, which blocks the enzyme that generates LTB4, to reverse pulmonary hypertension disease processes. When researchers tested bestatin in the mouse lymphedema model, it worked to reverse symptoms of that disease.

“I’m still in awe,” Rockson said. “There are few situations where you take a problem at the bedside, and go into the lab, and then take discoveries back to the bedside. It’s amazingly gratifying.”

Campbell, who is now participating in the double-blinded, placebo-controlled bestatin trial at Stanford, remains hopeful.

“When all of the sudden one of your limbs begins to swell, you want to understand what the heck is going on,” she said. “It’s a tough condition that few people seem to care about, even though millions and millions suffer with it. We’re hoping for something that gives some relief.”

Other Stanford authors are research associate Jeanna Kim; former medical students Adrian Begaye, MD, and Abdullah Feroze, MD; Roham Zamanian , MD, associate professor of medicine and director of the Adult Pulmonary Hypertension Service; Gundeep Dhillon , MD, associate professor of medicine and medical director of the Stanford Lung Transplant Program; and research assistants Eric Shuffle and Allen Tu. Shuffle and Tu are affiliated with both Stanford and the VA Palo Alto.

Researchers at the Georgia Institute of Technology, Virginia Commonwealth University, the University of Michigan Health Systems and the University of Illinois at Chicago are also co-authors.

Eiger BioPharmaceuticals has licensed intellectual property developed by Tian, Rockson, Jiang, Kim and Nicolls involving the targeting of LTB4 for the treatment of lymphedema.

Stanford’s Department of Medicine supported the work.

About Stanford Medicine

Stanford Medicine is an integrated academic health system comprising the Stanford School of Medicine and adult and pediatric health care delivery systems. Together, they harness the full potential of biomedicine through collaborative research, education and clinical care for patients. For more information, please visit med.stanford.edu .

The majestic cell

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Stanford Medicine magazine: Majestic cell

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Published: 20 November 2021

Cell therapy as a treatment of secondary lymphedema: a systematic review and meta-analysis

Hector Lafuente 1 na1 ,
Ibon Jaunarena 2 , 3 na1 ,
Eukene Ansuategui 4 ,
Arantza Lekuona 2 , 3 &
Ander Izeta ORCID: orcid.org/0000-0003-1879-7401 1 , 5

Stem Cell Research & Therapy volume 12 , Article number: 578 ( 2021 ) Cite this article

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Lymphedema, the accumulation of interstitial fluid caused by poor lymphatic drainage, is a progressive and permanent disease with no curative treatment. Several studies have evaluated cell-based therapies in secondary lymphedema, but no meta-analysis has been performed to assess their efficacy.

We conducted a systematic review and meta-analysis of all available preclinical and clinical studies, with assessment of their quality and risk of bias.

A total of 20 articles using diverse cell types were selected for analysis, including six clinical trials and 14 pre-clinical studies in three species. The meta-analysis showed a positive effect of cell-based therapies on relevant disease outcomes (quantification of edema, density of lymphatic capillaries, evaluation of the lymphatic flow, and tissue fibrosis). No significant publication bias was observed.

Cell-based therapies have the potential to improve secondary lymphedema. The underlying mechanisms remain unclear. Due to relevant heterogeneity between studies, further randomized controlled and blinded studies are required to substantiate the use of these novel therapies in clinical practice.

As knowledge on the diverse lymphatic vasculature roles in health and disease progresses, it increases the lymphatic vessel relevance in understanding the physiopathology of a number of diseases [ 1 ]. Lymphedema is a chronic edema, lasting more than three months, due to the accumulation of interstitial fluid caused by poor lymphatic drainage [ 2 ]. Secondary lymphedema is due to obstruction or infiltration of the lymphatic vessels by tumors, infections (recurrent lymphangitis), obesity, surgery or overload and saturation of the lower limb venous system [ 3 ]. The most frequent cause in undeveloped countries is filariasis, while in developed countries, it is iatrogenic due to radiotherapy or surgery related to the management of malignant neoplasms (breast cancer, malignant melanoma, gyneco-urological cancer) [ 4 ]. Approximately, 30% of women with breast cancer and 20% of melanoma patients who have axillary and inguinal lymph nodes removed, develop lymphedema [ 5 , 6 ].

The accumulation of lymph in the interstitial tissue leads to remodeling of the skin and subcutaneous tissue and the accumulation of fibroadipose tissue [ 7 ]. The chronic form of lymphedema is characterized by swelling, fibrosis, accumulation of adipose tissue and infiltration of immune cells. Clinically, it can be classified into four stages: in stage 0, the condition is considered subclinical; swelling is not present. In stage I, edema is mild; fluid accumulates throughout the day but resolves overnight. In stage II, lymphedema is always present, but varies in severity. Stage III disease is characterized by persistent moderate-to-severe edema in the affected limb [ 8 ].

Lymphedema is a progressive and permanent disease for which there is no curative treatment. The standard treatment is physiotherapy (lymphatic drainage and compression bandaging) [ 9 ], although other treatments used include pharmacotherapy and surgery. More recently, reconstructive microsurgery (lympho-venous anastomosis, lymphatic vessel transplantation and autologous lymph node transplantation) has been proposed as an alternative [ 10 , 11 , 12 ].

Other potential therapies are still in development, e.g., the therapeutic potential of different growth factors, which would facilitate the regrowth of damaged, dysfunctional or obliterated lymphatics, has been investigated [ 13 , 14 ]. Among them, the role of vascular endothelial growth factor VEGF-C as a stimulant of lymphangiogenesis and mediator of lymphatic endothelial cell growth and viability has been studied [ 15 ], as well as fibroblast growth factor-2 and hepatocyte growth factor [ 16 ]. Also, the use of gene therapy via adenovirus, plasmids or even direct application of recombinant VEGF-C has been described to reduce edema in different preclinical models [ 17 , 18 , 19 ]. However, there are currently many unresolved questions, such as the lifespan of recombinant proteins, the time-limited action of gene therapy, as well as the side effects of growth factors on the blood vasculature and on the development of new tumors [ 18 , 20 ].

In the last decade, cell therapy with differentiated or progenitor cells has emerged as a new research target in the therapy of secondary lymphedema [ 21 , 22 ]. Although the cellular pathways through which stem cell therapy could help lymphedema patients are unclear, in vitro studies indicate that stem cells may differentiate into lymphatic endothelial-like cells under in vitro culture conditions and can improve interstitial fluid drainage when injected in vivo [ 13 ]. Stem cells have a wide range of therapeutic effects in terms of anti-inflammation, anti-fibrosis, anti-oxidative stress, as well as promoting the regeneration of different tissues. These properties could promote the regeneration of lymphatic vessels, rebuild lymphatic circulation and successfully treat lymphedema. Currently, several clinical and preclinical studies have evaluated the therapeutic potential of using lymphatic endothelial progenitor cells (LEPCs), embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) or mesenchymal stromal cells (MSCs) in the regeneration of lymphatic vessels. These results suggest that stem cell therapy is feasible and may promote recovery in patients with secondary lymphedema. However, stem cell transplantation has not been fully evaluated for the treatment of secondary lymphedema in clinical settings. In the present study, a meta-analysis of the available data was performed to evaluate the safety and efficacy of stem cell therapy for the treatment of secondary lymphedema.

We conducted a systematic review according to the Cochrane method [ 23 ] and SYRCLE guideline [ 24 ], and the results are reported in accordance with PRISMA guidelines [ 25 ]. The protocol for this review was registered on the International prospective register of systematic reviews website ( https://www.crd.york.ac.uk/prospero/ ) with two separate IDs (CRD42020180348 for preclinical studies and CRD42019130951 for clinical studies).

Search strategy and literature selection

Studies of cell therapy as a treatment of secondary lymphedema were identified from Medline, Web of Science, EMBASE, and The Cochrane library with no language or time restrictions using these search terms: lymphedema, lymphoedema, lymphangiogenesis, lymphatic diseases, lymphatic vessels, lymph nodes, stem cells, stromal cells, mesenchymal stem cells, cell- and tissue-based therapy, cell transplantation, and regenerative medicine. We identified all relevant studies or trials regardless of language or publication status (published, unpublished, in press, and ongoing). Two independent searches were conducted on January 2021, one with the inclusion criteria: pre-clinical studies and all animal models, and the other one with the inclusion criteria: clinical trials and prospective controlled studies in human.

After developing a search strategy for each database and collecting the citations, the search results were combined. The first selection was made using only the title and abstract of the studies. To avoid biases in the selection process, two observers independently screened articles for relevance. The criteria used for the first screening were based on the search components: (SC1) intervention (only cell therapies were included); (SC2) disease of interest (secondary lymphedema); (SC3) type of study (only pre-clinical studies, randomized controlled clinical trials and prospective controlled studies were included. The ex vivo studies, in vitro studies, or in silico studies were not included. Non-intervention studies, no control group, co-intervention studies and studies with other outcomes were not included); and (SC4) publication types (reviews and conference abstracts were not included). Only clearly irrelevant citations were removed. Citations resulting from the first screening underwent a second screening based on the predefined inclusion and exclusion criteria. Throughout the potentially relevant article selection process, the reasons for the removal of citations were documented and reported to facilitate transparency and to independently examine the accuracy of the study removal. Two independent reviewers performed all stages of the review process. Discrepancies were resolved by consensus. The flow diagram of search strategy and literature selection is shown in Fig. 1 for preclinical studies and in Fig. 2 for clinical studies.

PRISMA flow diagram of search strategy and literature selection for preclinical studies

PRISMA flow diagram of search strategy and literature selection for clinical studies

Assessment of study quality and risk of bias

Quality and risk of bias was assessed for clinical trials by use of Cochrane's risk of bias tool [ 26 ], and for non-randomized studies by use of NewcastleOttawa's risk of bias tool [ 27 ]. For preclinical studies, we used SYRCLE Risk of Bias tool [ 28 ]. Two authors independently assessed the risk of bias of the included studies. A third author was consulted to resolve discrepancies related to risk of bias.

Besides, to overcome the fact that there were too many items classified as “unclear” because of the poor description of details on experimental design and methods, we included three items as other bias: (a) inappropriate influence of funders, (b) mention of randomization at any level, and (c) mention of blinding at any level. For inappropriate influence of funders, “Yes” indicated non-industry source of funding, no funding, or no conflict of interest, “No” indicated the study was funded by industry- or author-mentioned conflict of interests, “unclear” indicated funding source or conflict of interest was not mentioned. For mention of randomization or blinding, “Yes” indicated reported and “No” indicated unreported.

An overall score was calculated by adding all the items scores as yes equals one, while no and not applicable equal zero. A score was given for every paper to classify them as poor, fair, or good conducted studies, where a score from 0 to 5 was considered poor, 6–9 as fair, and 10–14 as good.

Data extraction

For clinical studies, details about the study design, cell type, primary outcome assessment, follow-up time and results were extracted.

Data on animal model characteristics (animal species, total sample size, total groups, number of animals in control group, number of animals in intervention group), lymphedema model (tail, hindlimb, etc.), cell administration characteristics (cell type, source, as well as administration route, dose, timing and anatomical site of intervention), and primary outcome measures (evaluation of the lymphatic flow, quantification of edema, density of lymphatic capillaries and tissue fibrosis) were extracted.

For included articles, all independent comparisons were identified. Replications were also collected separately. Information on primary outcome was extracted from both text and graphs, when raw data or mean/median/incidence, SD/SE were reported or recalculated. In several studies, the results were adapted to be able to be analyzed with the rest of the studies. Gsys 2.4.6. software (Hokkaido University Nuclear Reaction Data Centre) was used to obtain values from graphs. When the number of animals was reported as a range, the lowest group size was collected. When no clear data could be extracted, the report was excluded from further meta-analysis.

Statistical analyses

Quantitative analysis was conducted using Review Manager (RevMan) version 5.3 software (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark). Treatment effects were first calculated separately for each study outcome. For all analyses, a random effect, inverse variance model was used to calculate standardized mean differences (SMD) and 95% confidence intervals (CI). Because most animal experiments use fewer than ten animals per group, we used Hedge's G effect sizes (which is based on Cohen’s D but includes a correction factor for small sample size bias) for SMD analyses. The effect of heterogeneity (I 2 ) was used to measure the degree of inconsistency across pooled studies due to variability rather than chance, with larger values indicative of high heterogeneity (0–25% is considered to reflect very low heterogeneity; 25–50% reflects low heterogeneity; 50–75% reflects moderate heterogeneity; > 75% reflects high heterogeneity). Considering the anticipated heterogeneity, random effects models were used to conducted meta-analysis. Mean effect size, 95% confidence intervals (95% CI), significance, weight and forest plots were analyzed by the inverse variance method and the standard mean differences. The possibility of publication bias was assessed by analyzing funnel plot asymmetry (with trim-and-fill). The trim-and-fill method provides an estimate of the number of missing studies, and also provides an estimated intervention effect ‘adjusted’ for the publication bias (based on the filled studies). Finally, to explore sources of heterogeneity, stratified meta-analysis and meta-regression were performed.

A total of 20 articles were selected for analysis. Six of these were clinical studies [ 29 , 30 , 31 , 32 , 33 , 34 ], including a randomized clinical trial, three nonrandomized clinical trials and two prospective controlled studies (Table 1 ). A case report and an observational study were excluded from the analysis. Five of them studied the effect of cell therapy on the upper limb, while the other studied lower limb edema. Mesenchymal stromal cells (MSCs) of different origins were used: three studies used bone marrow-derived MSCs (BM-MSCs) and the remaining three used adipose-derived MSCs (ADSCs). The follow‐up period ranged from 3 to 12 months.

Fourteen animal studies [ 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ] were included in the analysis (Table 2 ). These studies included three different animal models (mouse, rat and rabbit). In murine models, tail, hind limb, back skin flap, or lymph node transplantation was used. In rabbit models, hind limb was used. The cell types used included stem or progenitor cells (BM-MSCs, ADSCs, muscle‐derived stem cells and multipotent progenitor cells) and differentiated cells (lymphatic endothelial cells and T reg cells), and the number of cells used ranged from 10 4 to 10 7 . The follow‐up period ranged from 14 days to 6 months.

Assessment of study quality and risk of bias

The study design, including details of the method of randomization of subjects to treatment groups, criteria for eligibility in the study, blinding, method of assessing the outcome, and handling of protocol deviations are important features defining study quality. Due to the high risk of bias (data not shown) and the fact that only one of the human studies included was a properly blinded randomized controlled trial, a meta-analysis was not performed for clinical studies.

None of the pre-clinical studies had published protocols nor were registered with CAMARADES (University of Edinburgh, Scotland). Therefore, the selective outcome reporting item on the SYRCLE tool was scored as “unclear.” There was insufficient information reported for many of the remaining nine questions which were scored as “unclear.” Several studies reported any randomization, although details were not given. 50% reported any blinding, either of investigators, animal handlers or outcome assessors. Overall, all studies had significant risks of bias according to the SYRCLE tool (Fig. 3 ), but these were not sufficiently remarkable as to be excluded from any analyses. Only two studies (Conrad et al. and Zhou et al.) did not report sample size for control and intervention groups, and thus those studies were not included in the meta-analysis.

Assessment of bias in 14 animal studies using the SYRCLE risk of bias tool

Meta-analysis and effect evaluation

Meta-analysis was performed for outcomes that had data in at least three studies. The outcomes analyzed were: quantification of edema, density of lymphatic capillaries, evaluation of the lymphatic flow, and tissue fibrosis.

Quantification of edema

Eleven studies were included to investigate the effect of cell therapy treatment on edema reduction in secondary lymphedema. The pooled estimate showed a significant decrease in edema (SMD 3.18; 95% CI 1.798, 4.567 ( p < 0.001); however, between-study heterogeneity was very high ( I 2 = 92%; Fig. 4 ). Subgroup analysis as a function of the animal model used did not reduce heterogeneity. Subgrouping as a function of cell type indicated a similar reduction in edema with stem or progenitor cell treatment than differentiated cell treatment, with no evidence of heterogeneity in this subgroup (Table 3 ). Random effect meta-regression analysis was applied to estimate functional relationship of effect size on follow-up time. The regression coefficient was -0.02, and it was statistically insignificant ( p > 0.05). These results indicated that the effect of follow-up time on the effect size was insignificant. Consistently, a linear relationship was not found (Fig. 5 ).

Density of lymphatic capillaries

Forest plot of the effects of cell therapy on the edema reduction

Meta-regression analysis of follow-up time on effect of the cell therapy on the edema reduction

Ten studies were included to investigate the effect of the cell therapy treatment on the lymphatic regeneration in secondary lymphedema. The overall pooled analysis showed a significant increase in lymphatic vessel density in experimental group versus control group (SMD 6.35; 95% CI 4.115, 8.581; p = 0.00). However, the test for heterogeneity was significant ( I 2 = 93%; Fig. 6 ). Subgroup analysis as a function of animal model did not show differences between groups and did not reduce heterogeneity. Analysis as a function of cell type could not be carried out due to the small number of studies (Table 3 ). Random effect meta-regression analysis was applied and a regression coefficient of 0.03 was found, which was statistically insignificant ( p > 0.05). These results indicated that follow-up time does not explain the heterogeneity found between the studies (Fig. 7 ).

Evaluation of the lymphatic flow

Forest plot of the effects of cell therapy on the lymphatic regeneration

Meta-regression analysis of follow-up time on effect of the cell therapy on the lymphatic regeneration

Four studies were included to investigate the effect of the cell therapy treatment on the lymphatic perfusion restoration in secondary lymphedema. The pooled estimate suggested a significant improvement of lymphatic perfusion (SMD 2.49; 95% CI 0.583, 4.394 ( p = 0.01); I 2 = 88%, Fig. 8 ). Due to the limited availability of data, it was not possible to conduct subgroup analyses. Using random effects meta-regression analysis, the regression coefficient was -0.04, which was not statistically significant ( p > 0.05). The results indicated that follow-up time does not explain the heterogeneity between studies (Fig. 9 ).

Tissue fibrosis

Forest plot of the effects of cell therapy on the lymphatic perfusion restoration

Meta-regression analysis of follow-up time on effect of the cell therapy on lymphatic perfusion restoration

Only three studies were included to investigate the effect of cell therapy treatments on the fibrosis reduction in secondary lymphedema. The analysis of the effect size showed a significant reduction in the fibrosis (SMD 4.39; 95% CI 1.439, 7.352 ( p < 0.01); I 2 = 82%, Fig. 10 ). Subgroup analysis was not carried out due to the small number of studies included. The regression coefficient was found to be -0.19 and statistically insignificant ( p > 0.05) using random effect meta-regression analysis. The study's heterogeneity was not explained by the follow-up period, according to the findings (Fig. 11 ).

Forest plot of the effects of cell therapy on the fibrosis reduction

Meta-regression analysis of follow-up time on effect of the cell therapy on the fibrosis reduction

Publication Bias

The publication bias evaluation (Funnel plots) for the meta-analysis of lymphatic regeneration (ten studies) is shown in Fig. 12 . After adjusting for missing studies, we found that the point estimate of the overall effect size continued to show a positive effect in favor of cell therapy (SMD 5.65 [CI 95% 2.48–8.83]). No significant publication bias was observed for edema reduction, lymphatic perfusion restoration and fibrosis reduction. This confirms that if there were a publication bias, the effect of cell therapy on secondary lymphedema would not be modified.

Funnel plot (with trim-and-fill) analysis of the cell therapy on the lymphatic regeneration

In the present study, we performed a systematic review and meta-analysis to evaluate the safety and efficacy of stem cell therapy for the treatment of secondary lymphedema, both in preclinical and clinical studies. We found that cell therapy proved to generate a robust beneficial effect in animal models of secondary lymphedema. Although several in vitro and in vivo studies have reported beneficial effects of cell therapy against secondary lymphedema [ 21 , 49 , 50 ], a formal meta-analysis that assesses the regenerative activity of cell therapy in animal models of secondary lymphedema had not been performed.

Animal studies are critical for understanding disease processes and assessing the safety and effectiveness of treatments. Animal trials, however, are inherently heterogeneous, even more than clinical trials. Understanding sources of heterogeneity and their influence on effect size is critical to successfully translating preclinical findings to human diseases [ 51 ].

No animal model mimics perfectly the pathophysiology of human lymphedema [ 52 ], mainly because animals present higher regenerative capacity and it is difficult to classify the severity of edema [ 49 ]. There are also significant differences between models [ 52 ]. Although the tail model yields more consistent results than the hindlimb model, lymphedema resolves naturally over time, thus confounding results of additional interventions [ 53 ]. Of note, the current lack of standardization in study design and outcome measures make it hard to compare preclinical results. Despite the experimental heterogeneity of available studies, insight from animal models has shed light on the molecular mechanisms underlying lymphedema, e.g., lymphangiogenesis [ 54 ], fibrosis [ 55 ] and inflammation [ 56 , 57 ].

Regarding the human studies, only six studies were identified and included for the analysis, and since only one of them is a randomized clinical trial, it was not possible to perform the meta-analysis. Furthermore, the difference in the follow-up period between the studies did not allow us to confirm the observed effect of cell therapy on secondary lymphedema. However, it should be noted that the current human studies showed promising results of BM-MSCs [ 29 , 30 , 33 ] and ADSCs [ 31 , 32 , 34 ] in terms of reduction in edema, relief of symptoms, and an improved quality-of-life. Although no adverse effects related to cancer have been observed, the potential risk of cancer recurrence of using stem cells in the treatment of secondary lymphedema should be studied. A recently published Phase I study has found no evidence of breast cancer recurrence at 4-year follow up [ 58 ]. However, to further substantiate this relevant safety concern, a greater number of patients must be followed up longer-term in randomized clinical studies to formally rule out any contribution of stem cell transplants to cancer recurrence.

In the preclinical studies included in the review, different cell types have been tested for secondary lymphedema. In all cases, stem/progenitor cells have shown promise in halting lymphedema progression, sometimes even reverse the pathological process. However, the underlying mechanisms are not clear. It is speculated that stem cells may differentiate into lymphatic endothelial progenitor cells that in turn generate new lymphatics, or secrete cytokines to induce lymphangiogenesis [ 59 ]. Several studies have combined cell therapy with growth factors, such as VEGF‐C [ 36 ] and PRP [ 41 ] which are thought to costimulate lymphangiogenesis. Co-transplantation with lymphatic endothelial cells (LECs) [ 40 ] may guide differentiation of stem cells to LEPCs. Combination of cell therapy with lymph node transfer [ 44 ] improved both lymphangiogenesis and lymphatic flow. Of course, immune modulation could be another cell-based approach to tackle this disease. Gousopoulos et al. have shown that treatment with T reg cells reversed major hallmarks of lymphedema, such as edema, inflammation, and fibrosis [ 43 ]. Cell-based therapies seem thus to improve lymphedema's outcomes (edema reduction, lymphatic regeneration, lymphatic perfusion restoration, and fibrosis reduction), and the effect is seen across multiple species (mouse, rat, and rabbit), so that translation of these novel therapies to humans seems to be warranted.

The main limitations of this study are (i) the significant methodological differences between studies, especially the animal model used, the number of infused cells and timing of follow-up; (ii) small sample sizes and small study dataset for the meta-analysis, with most studies having no pre-published protocols or sample size estimations; (iii) the included studies had moderate or unknown bias risks, mainly due to poor reporting detail, and (iv) lack of operator blindness and randomization. These limitations emphasize the importance of applying more rigor to reporting standards and publishing in vivo experimental protocols [ 60 ].

Conclusions

Cell-based therapies have the potential to improve secondary lymphedema through their effects on the edema, lymphangiogenesis and fibrosis. The underlying mechanisms remain unclear. Due to relevant heterogeneity between studies, further randomized controlled and blinded studies are required to substantiate the use of these novel therapies in clinical practice.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

Adipose-derived stem cells

Bone marrow-derived mesenchymal stem cells

Embryonic stem cells

Induced pluripotent stem cells

Effect of heterogeneity

Lymphatic endothelial cells

Lymphatic endothelial progenitor cells

Mesenchymal stromal cells

Standardized mean differences

95% Confidence intervals

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This work was supported by grants from the Department of Health of the Basque Government (2020111004, 2020333021, 2019222008, 2018222032 and 2017222004), Diputación Foral de Gipuzkoa, Instituto de Salud Carlos III (PI19/01621), cofunded by the European Union (European Regional Development Fund/ European Science Foundation, Investing in your future) and the Department of Economic Development of the Basque Government (Elkartek program).

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Hector Lafuente and Ibon Jaunarena have contributed equally to this work

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Tissue Engineering Group, Biodonostia Health Research Institute, 20014, San Sebastián, Spain

Hector Lafuente & Ander Izeta

Gynecology Oncology Unit, Donostia University Hospital, 20014, San Sebastián, Spain

Ibon Jaunarena & Arantza Lekuona

Obstetrics and Gynaecology Group, Biodonostia Health Research Institute, 20014, San Sebastián, Spain

Clinical Epidemiology Group, Biodonostia Health Research Institute, 20014, San Sebastián, Spain

Eukene Ansuategui

School of Engineering, Tecnun-University of Navarra, 20009, San Sebastián, Spain

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EA and AL developed a search strategy for each database and collected the citations; HL and IJ performed the assessment of study quality and risk of bias, the data extraction and statistical analysis; HL and AI were major contributors in writing the manuscript. All authors read and approved the final manuscript.

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Lafuente, H., Jaunarena, I., Ansuategui, E. et al. Cell therapy as a treatment of secondary lymphedema: a systematic review and meta-analysis. Stem Cell Res Ther 12 , 578 (2021). https://doi.org/10.1186/s13287-021-02632-y

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Koya’s NPCD device proves more effective than APCDs in lymphedema

Patients using the Dayspring system saw a greater reduction in limb volume and experienced improved quality of life compared to APCDs.

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Koya Medical has shared data highlighting that its non-pneumatic compression device (NPCD) demonstrated better efficacy and improved quality of life in patients with lower extremity lymphedema.

The NPCD device, dubbed Dayspring, is a non-pneumatic treatment that provides continuous, static compression to manage lymphedema. The system comes with a mesh garment made from Koya’s patented Flexframe technology, a rechargeable controller, and a mobile app.

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Data from the TEAYS study (NCT05507346), published in the Journal of Vascular Surgery , found that Dayspring outperformed advanced pneumatic compression device (APCD) – the standard of care for treating lymphedema – in several areas. Patients using Dayspring saw a significantly greater reduction in limb volume (369.9mL versus 83.1mL) and experienced improved quality of life, with a mean lymphedema quality of life questionnaire (LYMQOL) score increase of 1.01 compared to 0.17 for APCD.

According to US-based company Koya, TEAYS is the eighth study investigating Dayspring since its Food and Drug Administration (FDA) clearance in May 2021. The study enrolled 71 patients with confirmed lower extremity lymphedema, comparing Dayspring with APCDs.

The gold standard for lymphedema treatment, APCDs use air-filled chambers to deliver intermittent pneumatic pressure in cycles, compared to the continuous, static compression provided by NPCDs. This mechanism actively pumps fluid away from the limb. However, NPCDs may be more comfortable and easier to use compared to APCDs, promoting better long-term adherence in some patients. Data from this study demonstrated that Dayspring showed superior adherence of 81%, compared to 56% with APCD.

The TEAYS study’s lead investigator and associate professor of surgery at the University of Tennessee Health Science Center Michael Barfield said: “The introduction of Dayspring represents a clinically differentiated and therapeutically distinct advancement in the treatment of lower extremity lymphedema.

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“Patients participating in the TEAYS study expressed a strong preference for the Dayspring treatment over advanced pneumatic compression devices. The ability for patients to remain mobile while receiving effective treatment is a game-changer in improving adherence and overall quality of life.”

In November 2023, Koya secured $30m in financing led by healthcare investment company OrbiMed, to support the expansion and strategic growth of Dayspring. This followed on from a February 2022 Series B funding round where Koya secured $26m, led by 3×5 Partners.

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Current diagnostic and quantitative techniques in the field of lymphedema management: a critical review

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Published: 05 September 2024
Volume 41 , article number 241 , ( 2024 )

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Mary Vargo ORCID: orcid.org/0000-0002-6286-6876 1 ,
Melissa Aldrich ORCID: orcid.org/0000-0002-8114-7607 2 ,
Paula Donahue ORCID: orcid.org/0000-0003-4656-6539 3 ,
Emily Iker ORCID: orcid.org/0000-0002-6882-1089 4 ,
Louise Koelmeyer ORCID: orcid.org/0000-0002-2736-2330 5 ,
Rachelle Crescenzi ORCID: orcid.org/0000-0003-1008-4570 6 &
Andrea Cheville ORCID: orcid.org/0000-0001-7668-6115 7

Lymphedema evaluation entails multifaceted considerations for which options continue to evolve and emerge. This paper provides a critical review of the current status of diagnostic and quantitative measures for lymphedema, from traditional and novel bedside assessment tools for volumetric and fluid assessment, to advanced imaging modalities. Modalities are contrasted with regard to empirical support and feasibility of clinical implementation. The manuscript proposes a grid framework for comparing the ability of each modality to quantify specific lymphedema characteristics, including distribution, dysmorphism, tissue composition and fluid content, lymphatic anatomy and function, metaplasia, clinical symptoms, and quality of life and function. This review additionally applies a similar framework approach to consider how well assessment tools support important clinical needs, including: (1) screening, (2) diagnosis and differential diagnosis, (3) individualization of treatment, and (4) monitoring treatment response. The framework highlights which clinical needs are served by an abundance of assessment tools and identifies others that have problematically few. The framework clarifies which tools have greater or lesser empirical support. The framework is designed to assist stakeholders in selecting appropriate diagnostic and surveillance modalities, gauging levels of confidence when applying tools to specific clinical needs, elucidating overarching patterns of diagnostic and quantitative strengths and weaknesses, and informing future investigation.

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Introduction

Lymphedema diagnostic methods comprise an area of vigorous current research, with multifaceted priorities including early detection, establishing diagnosis and pathophysiology, localization, guiding intervention, and surveillance of severity and response to therapy [ 1 ]. Clinical use requires weighing empirical standards including favorable reliability, validity, diagnostic accuracy, precision, and sensitivity, as well as meeting feasibility demands related to cost, time, space, level of training, level of personnel, least possible risk, and patient acceptance. In the setting of cancer-related lymphedema, increasing rigor continues to be applied to a prospective surveillance and early intervention model of care. Additionally, in patients with cancer diagnoses, differential diagnostic distinctions may arise between benign versus malignant lymphedema, between lymphedema and neuromusculoskeletal or soft tissue conditions producing confounding locoregional symptoms, and between lymphedema and other etiologies of limb swelling or enlargement, especially venous disorders, lipedema, and systemic comorbidities.

Most of the existing diagnostic literature for lymphedema emphasizes breast cancer-related and upper quadrant lymphedema, especially regarding traditional or common measures such as tape measurement, water displacement and bioimpedance spectroscopy [ 2 ]. Lower extremity lymphovenous insufficiency is also extremely common, yet not as well studied [ 3 ]. Given the importance of lymphedema in the vascular space, three American vascular societies collectively published an expert opinion consensus on lymphedema diagnosis and treatment which suggests agreement from the experts with diagnostic work-up and risk factors for lymphedema, though highlights the high degree of variability regarding lymphedema treatment and practice patterns necessitating further investigation [ 4 ]. Furthermore, the International Society of Lymphology 2020 guidelines highlight the complexity and vast array of lymphedema clinical contexts, which “impact individualized patient care” [ 5 ]. Additionally, lymphedema has a striking 90% incidence in the survivors of head and neck cancer, however is still drastically under-diagnosed and treated from a recent publication utilizing a large US healthcare claims repository database [ 6 ]. Thus, there is a critical need for understanding and incorporating diagnostic and quantitative techniques into routine clinical practice which spans a significant and diverse population of individuals living with lymphedema.

Regarding detection protocols, overriding themes which have emerged in the literature include the importance of obtaining a baseline preoperative or pretreatment measurement whenever possible [ 4 , 7 , 8 , 9 ], and also to employ a consistent measurement modality in surveillance over time, rather than using different methodologies interchangeably [ 2 , 10 ]. None of the diagnostic methods have perfect accuracy and therefore there can be value in clustering observations from different available perspectives [ 2 ]. A 2020 systematic review of guidelines for detection of lymphedema noted overall limited evidence quality and could not make definitive conclusions, but found common themes including importance of clinical evaluation, use of duplex ultrasound to assess tissue thickness and fibrosis, computed tomography (CT) or magnetic resonance imaging (MRI) to rule out neoplasm, lymphoscintigraphy when needed to establish diagnosis, and measurement strategies including circumferences, perometry, and bioimpedance [ 3 ]. There is increasing advocacy for universal guidelines, especially for breast cancer-related lymphedema [ 11 ], incorporating symptoms, clinical examination and objective measurement, and also that all at-risk patients receive regular screening and education [ 12 ].

This paper explores the spectrum of traditional through emerging modalities, with the goal of evaluating practicable strategies by type of clinical scenario. The emphasis is on peripheral lymphedema, especially cancer-related lymphedema. Aims include (1) facilitation of best decision-making for modality choice in clinical and research applications, and (2) allowing overarching patterns to be identified, including strengths and gaps in current literature with regard to identified lymphedema assessment priorities.

A critical review was conducted by an experienced group of clinicians and researchers in the field of lymphedema and cancer rehabilitation, who identified modalities utilized for lymphedema diagnosis and analysis, and also identified core dimensions or purposes of lymphedema evaluation. The group was comprised of three physiatrists (AC, EI, MV), one physical therapist (PD), one occupational therapist (LK), one immunologist (MA), and one biochemist/molecular biophysicist (RC). The work of the group was conducted over a one-year period including independent efforts, six virtual meetings, and interspersed electronic communications. Preliminary content was presented at the Lymphedema Summit, sponsored by the Lymphology Association of North America (LANA) and the American Cancer Society (ACS), on October 7, 2023. Virtual meetings focused on the format and focus of this work, and, especially, on consensus with regard to the modalities themselves and on the integrative frameworks for core dimensions of lymphedema evaluation.

Via standard literature review, each of the modalities was briefly summarized with regard to their major capabilities and limitations, empirical and feasibility characteristics, as well as clinical versus research applicability. Primary authorship of each modality section was accorded with consideration of the diverse expertise of the authors, for content areas including history and physical examination (MV), tape measurement (MV), water displacement (MV), perometry (PD), bioimpedance (LK), tissue dielectric constant (PD), tonometry (PD), three-dimensional imaging (LK), patient reported outcomes (AC), lymphoscintigraphy (EI), ultrasound (EI), CT (EI), near-infrared fluorescence (MA), and MRI (RC). These summaries incorporated literature search as well as the expertise and experience of the authors. The literature search was broad and included primary studies as well as existing summative materials such as reviews and practice guidelines. An electronic mailbox was kept to which all authors had access, which included these documents, and other resources such as images and presentation materials. Each of the summaries was reviewed by all of the other authors and areas of controversy resolved via group communication.

Subsequently, via expert consensus process, five separate grids were generated with regards to the utility of each modality for assessing lymphedema characteristics, as well as for clinical dimensions of screening, diagnosis, individualizing treatment, and monitoring treatment response. Within each of these five categories, critical subcategories were identified through group consensus, and the utility of each modality for each subcategory was assigned a score of strong (S), indeterminate (I), unknown (U) and not useful or not applicable (N). A strong (S) rating was applied when the modality has an excellent favorable evidence basis as pertains to the specific subdomain, or, alternatively, a “Strong” rating could also be applied when at least 3 of 4 of the following four criteria were met:

Clinical practice-based acceptance, track record.

Some published evidence to support use.

Expert consensus.

Compelling theoretical basis.

If less than three of the above criteria were met but there remained a compelling rationale for use, an “intermediate” (I) rating would be assigned, such that at least 2 criteria were met or one criterion was strongly met. Feasibility was not used as a separate criterion, as this can vary with availability and accessibility of diagnostic modalities in individual treatment settings. However, feasibility considerations are generally implied within the clinical practice-based acceptance criterion. In situations of contextual variability, interpretation leaned towards the contemporary application of the modality (e.g., bioimpedance for early detection of breast cancer-related lymphedema). Furthermore, areas were highlighted that are especially relevant for research applications or a particularly active focus of current investigation.

The noninvasive office-based measures, including history and physical (H&P), patient reported outcome measures (PROMs), tape measure, perometry, water displacement, bioimpedance, tissue dielectric constant (TDC), tonometry, and three-dimensional (3D) camera, were placed on the left side of the charts and the more advanced imaging measures, including lymphoscintigraphy, ultrasound (US), indocyanine green lymphography (ICG), CT, and MRI, on the right side of the charts. It is recognized that ICG and ultrasound may also be performed in office, however they were considered advanced for the purpose of this review given their current less-frequent application by direct-treating lymphedema clinicians.

Lymphedema Assessment Modalities at Bedside or Office

History and physical examination.

Clinical H&P encompasses numerous domains including symptoms, time course, underlying risk factors, such as infectious history and other medical comorbidities, mobility, positioning, family and social history, cutaneous and soft tissue effects, motor-sensory and musculoskeletal abnormalities, and body weight. A varied taxonomy of descriptive terms may apply to skin and soft tissue characteristics, including basic characteristics as pitting, firmness, fibrosis, thickening, or erythema, to more elaborate descriptors including, but not limited to hyperkeratosis, lipodermatosclerosis, papillomatosis, nodular fibrosis, lymphedema rubra, phlebolymphedema, lymphangiomas (blisters containing lymph fluid), sausage digits, and elephantiasis verrucosa nostra [ 13 , 14 , 15 , 16 ]. Associated observations may include evidence of cellulitis, lymphorrhea, or wounds [ 5 ]. Palpation is employed to assess fibrosis, including skin and deeper tissue mobility, and extent of pitting, but reliable grading criteria for fibrosis are needed [ 17 ]. In the lower extremities, Stemmer’s sign (inability to pinch a skinfold at the dorsum of the second toe) is a classic observation [ 13 , 18 ], and individuals with history of axillary lymph node dissection may exhibit axillary cording especially early in the posttreatment course.

Various staging or grading paradigms exist, most notably the International society of lymphology (ISL) system ranging from subclinical lymphedema to lymphostatic elephantiasis, and which contains morphologic as well as size criteria [ 5 , 19 ]. The ISL stages include subclinical (0 or Ia), early accumulation with pitting (I), increased fat and fibrosis infiltration (II) and lymphostatic elephantiasis (III). Other paradigms have also been employed. The Campisi scale delineates 5 stages including, in order of severity, initial/irregular edema, persistent lymphedema, persistent lymphedema with lymphangitis, fibrolymphedema, and elephantiasis [ 13 , 20 ]. The National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) 5.0 (Grades 1–3), emphasizes soft tissue and skin characteristics, and in the severe category this scale incorporates limitation of self care as a criterion [ 21 ]. An earlier version, NCI-CTCAE 3.0 incorporates multiple lymphedema-related contexts including limb, head and neck, trunk/genital, lymphocele, cording and lymphedema-related fibrosis [ 22 ]. While not specific to lymphedema, the Pitting Edema Scale (1–4) has also been applied to lymphedema evaluation though reliability is likely limited [ 23 ].

Despite its ubiquity and importance to clinical care, studies are lacking with regard to accuracy and intra/interrater reliability of the physical examination for either clinical or research settings [ 4 ]. Lymphedema staging has value as a conceptual shorthand, and high feasibility to be incorporated into office visits. Limitations of clinical staging include imprecision regarding severity, that features of more than one stage may be present in the same individual, and that mixed etiologies of swelling may be present.

Bedside and office measures: general statement

An understanding of how to use and interpret the results of the bedside or office-based tools for surveillance and monitoring can greatly enhance the earliest diagnosis and treatment of lymphedema as well as give objective measures of change related to therapeutic intervention. A word of caution: no one device to-date can adequately measure all elements of therapeutic change given the heterogeneity of lymphedema. Furthermore, utility may break down in the absence of a reliable benchmark for comparison, such as a baseline measurement or unaffected contralateral limb. This requires a clinician to contextualize clinical interpretation.

Volume measurement

Volume measurement is an extension of the physical examination that can be undertaken with varying levels of technological sophistication. While parameters for detection exist, none are universally agreed upon, but volumetric thresholds of 3%, 5% or 10% change from baseline or in comparison to a normal contralateral side have been employed [ 5 , 24 ], as well as absolute value of 150-200 ml difference in volume [ 25 ]. ISL 2020 guidelines define severity as minimal (> 5 < 20% increase in limb volume), moderate (20–40% increase), or severe (> 40% increase), with some clinics preferring to use > 5–10% as minimal and > 10– < 20% as mild. The variability in limb volumes between different individuals limits utility of using absolute volume change as a severity parameter for breast cancer-related lymphedema [ 24 , 26 ]. Good reliability and validity have been found with numerous techniques including the traditional objective measures of water volumetry and tape measurement, as well as with more advanced approaches including perometry and (the nonvolumetric technique of) bioimpedance spectroscopy [ 27 ]. While most research has been conducted for breast cancer-related lymphedema, these principles apply to all types of lymphedema, including patients at risk for secondary lymphedema of the lower limbs who have had central operations with nodal sampling or resection.

Tape measurement

Tape measure-derived circumferential and volumetric measurements remain the most common clinical method [ 5 , 10 , 13 , 28 , 29 ] as well as the most extensively researched with regard to its reliability, validity and diagnostic accuracy [ 2 , 27 , 30 , 31 ]. Tape measurement has been employed in multiple trials, but there is potential for interrater variability, and likely low sensitivity for subclinical disease [ 24 ].

A difference or change of 2 cm or more at any one measurement site has been described as significant, (though of questionable reliability, especially in the setting of higher limb girths)[ 19 ] versus a combined difference of 5 cm or more summed over 5 sites along the limb [ 17 ]. Volumetric conversions may be performed by fulstrum or truncated cone calculations, with the former considered more accurate and less likely to overestimate volumes [ 31 ]. Formulaic adjustments also exist which account for dynamic factors such as body weight [ 32 ].

There is not universal agreement on measurement paradigms between fixed intervals or landmark-based. Taylor et al., examining the arms of breast cancer survivors with lymphedema, found volumes calculated from anatomic landmarks to be reliable, valid, and more accurate than those obtained from circumferential measurements based on distance from fingertips [ 30 ]. Sun et al. concurred with these findings, in a volumetric study of breast cancer patients assessed serially postoperatively, comparing landmark versus fixed-interval derived tape measurements to perometry as the gold standard. In the Sun study, the landmark-based measurements had better sensitivity and specificity than the fixed interval measures (93.1%/63.1% overall for landmark-based and 81.9%/16% for 4 cm intervals) though the landmark technique underestimated upper arm volumes and had only 63.2–66.7% sensitivity for the lower (5–10%) relative volume change subcategory [ 33 ].

Tape measurement and water displacement are highly correlated but can yield different values, with between 5% and 15–19% variation reported, so these techniques cannot be used interchangeably [ 30 , 31 ]. While reported diagnostic thresholds for treatment initiation vary, a clinical practice guideline on upper quadrant lymphedema yielded Grade B recommendations for tape measure use including volume ratio of 1.04 from the unaffected limb, volume differential > / = 200 ml between sides, and 5% or greater increase from baseline, but recommended against using a single site 2 cm difference as a diagnostic criterion [ 2 ].

Tape measurement has excellent feasibility regarding expense and accessibility. Concerns include the need for standardized protocols, training, and time to complete and compute measurements. Tape measurement is most applicable for limb rather than axial lymphedema, and like most volumetric measures it does not capture tissue composition.

Water displacement

Water displacement tanks for volumetric assessment have a limited role in most clinical settings due to feasibility barriers, though can be advantageous in research settings due to high degree of precision, with upper limb standard error of measurement of 3.6% compared to 6.6% for tape measurement [ 27 ]. However, error may be introduced if the limb is not submerged to a consistent level [ 30 ].

While water displacement is valid, accurate and reliable, disadvantages include being cumbersome, non-portable, requiring space, time and with risk of cross contamination [ 10 , 30 , 34 ]. Additionally, water displacement indicates the totality of volume but does not provide geometric detail on focal areas of enlargement. Measurement of lymphedema involvement near the root of the limb may be limited [ 5 ]. The Clinical Practice Guideline developed by the Oncology Section of the American Physical Therapy Association gave water displacement a Grade B recommendation, with criteria of > 200 ml or > 10% interlimb difference [ 2 ].

Perometry provides a quick measure of limb circumference measures and calculated summed volume using an infrared scanner frame that slides over the body region in seconds. The device measures arms, legs, torso, hands and feet depending on the perometer model. The advantages of using perometry are reliability of repeat measurements, rapid measurements with ease of repeating measurements and ability to evaluate limb circumference at 0.5 cm increments. Additionally, measures can be used for compression garment fitting, though some additional measurements may be necessary with custom garment fitting. In breast cancer-related lymphedema, perometry has good correlation with circumferential measures and good correction with bioimpedance spectroscopy [ 35 , 36 ]. Disadvantages include potential awkward patient positioning, expense of device, not easily transported requiring designated space, and limited centers with access to the equipment mostly found in research centers [ 35 , 37 ]. Additionally, there is difficulty with hand and foot measurements and positioning can be problematic for some patients to get accurate reproducible arm and leg volume results where consistency in measurement technique needs to be maintained for repeated measures over time [ 35 , 38 ]. Although considered a reliable measure of limb size and offers potential earlier detection of swelling compared to tape measure and palpation, as with other volume and circumference measurements, perometry is unable to discern extracellular fluid accumulation directly, rather volume changes could be related to muscle and fat changes as well within the area of interest. Therefore, similar to other devices of water displacement and tape measurements, perometry is not recommended as the sole method to measure and monitor lymphedema.

Bioimpedance

Bioimpedance technology is a method that measures biological impedance at different frequencies permitting clinicians to assess fluid compartments and body composition. This potentially provides clinicians a variety of information to help with making a clinical diagnosis of lymphedema and tailoring patient care treatment. Multiple frequency bioelectrical impedance analysis (MFBIA) and bioimpedance spectroscopy (BIS) provide a more comprehensive analysis compared with single frequency bioelectrical impedance analysis (SFBIA) by obtaining bioimpedance data at several different frequencies (MFBIA at different points from 1 to 1000 kHz and BIS continually from 0 to 1000 kHz) where BIS includes the crucial 0 kHz frequency [ 39 ] as part of its assessment. Impedance comprises resistance and reactance, indicating opposition from body fluids and cell membranes, respectively [ 40 ]. The inverse relationship between impedance and tissue fluid volume is a key principle [ 41 ]. The frequency of the current determines what is being measured, with zero frequency current unable to penetrate cell membranes [ 42 ]. Additionally, bioimpedance measures provide body composition data and phase angle data where a growing body of research is promising to inform oncology clinicians on changes to lean body mass and a prognostic factor in the advanced cancer setting, respectively [ 43 , 44 ].

Bioimpedance devices gage resistance to electrical current flow, especially in the extracellular fluid compartment at low frequencies. More specifically for bioimpedance spectroscopy (BIS) devices, an “impedance ratio” methodology is utilized for assessing unilateral arm or leglymphedema. This involves comparing the resistance at 0 kHz in the affected/at-risk limb to that in the unaffected limb, expressed as a ratio [ 45 ]. Alternatively, this ratio can be linearized into an L-Dex score, where abnormal values indicate deviations from the normal range (− 10 to + 10 L-Dex units) and a change exceeding 6.5 L-Dex units from baseline signifies subclinical lymphedema [ 46 ]. While this is currently a manufacturer-specific paradigm, similar scoring systems exist for other available bioimpedance devices. BIS is recognized for its non invasive effectiveness in measuring extracellular fluid and detecting subclinical changes indicative of lymphedema onset [ 42 , 47 ]. It offers high sensitivity, standardized cut-off measurements, and excellent inter-observer variability [ 48 , 49 ]. Moreover, BIS can assess intra and extracellular fluid as well as total body water [ 50 ], and is now eligible for insurance reimbursement in the United States.

Stand-on devices are available for BIS and MFBIA which incorporate stainless steel contact electrodes within hand and foot plates, with values graphically displayed over time. At this time, BIS has a larger body of research, as well as greater clinical penetration, however the extent to which BIS or MFBIA may be more advantageous than the other is unknown. Although BIS and MFBIA offer fluid and body composition measurements and are relatively quick to use, there is an expense to obtaining the technology which may also be on a subscription basis, and the information obtained in the severely obese population remains questionable [ 51 ].

Tissue dielectric constant—percent water content

Tissue dielectric constant (TDC) are focal measures of skin-to-fat water providing a quantified measure of tissue water within the skin and subcutis to aid a clinician’s assessment of local edema detection [ 52 ]. Advantages to TDC is its portable and focal assessment of superficial tissue water content for suspicious tissue allowing for comparison to contralateral focal body region. Focal measurements can be obtained on any skin region where newer devices provide user feedback on force and have the option of calculating the percent water ratio to “spot” scan for impairment. This portable tool provides rapid localized information on superficial water content on any skin region including torso, breast, top of hand and foot, and head and neck. TDC readings can be converted to percentage water content (PWC) for ease with comparing involved or at-risk with contralateral body regions [ 53 ]. Growing evidence reveals its use in early detection of breast lymphedema and the use of percent water content [ 52 , 53 , 54 , 55 , 56 , 57 ]. Disadvantages include the analysis of fluid is superficial to the skin and subdermis, depth assessment varies with the probe used typically ranging from 0.5 to 5.0 mm, focal measurement does not allow for efficient whole limb surveillance for edema, normative values appear to vary across body regions and are sparsely reported to-date, and evidence is lacking in how measures may change with advancing stages of lymphedema. Though this device also cannot be used without clinical examination, it offers promising use for focal swelling and comparison of contralateral sites on the trunk, breast, head, neck, feet and hands to provide clinicians an objective noninvasive measure of superficial fluid levels.

Tissue tonometry evaluates the resistance to pressure exerted on the skin providing an output of tissue induration in Newtons (N). Measurements assess local tissue areas and newer devices provide user feedback on speed and pressure for measurement accuracy. Some models require repeat measures and automatically compute the measurement average. The local skin measurement takes less than one minute to assess for an experienced clinician using the tool. Advantages to tonometry device are its ability to provide a measurement of tissue firmness and its portability and inter reliability [ 58 ]. Disadvantages are that measures may be influenced by ambient fluctuations, there are challenges with repeat measurement, device expense, limited literature on normative and impaired values, and uncertainty as to how the measures will vary across the stages of lymphedema [ 35 , 58 ], as fibrotic areas may soften with treatment while overly soft and edematous regions may harden with treatment. Research suggests potential for tonometry to inform on tissue fibrosis and treatment efficacy [ 59 , 60 , 61 , 62 ]. Further research is essential for a more in-depth understanding of this technology’s utility toward clinical assessment and treatment allocation in lymphedema.

Three-dimensional (3D) imaging

In the setting of lymphedema, 3D imaging technology advancements offer fast, noninvasive anthropometric body measurements of volume and circumference for baseline and longitudinal uses. The technology may involve scanners or a camera sensor attachment to a device with software subscription to obtain the images, in which currently limb and torso measurements are the most commonly measured. There is also the option for measurements of the hands, feet along with potential for the head and neck, necessitating further research to optimize the options across all body regions for clinical use. The 3D imaging outputs typically involve a silhouette of the body image captured providing total volume and circumferential measurements currently up to every 4 mm along the torso and limbs (arms and legs). The speed of obtaining circumferential and volumetric measures through 3D imaging offer a fast and portable opportunity for clinics to obtain a substantial amount of anthropometric data illustrating the change of volume and circumference over time [ 63 , 64 ]. Though this technology is efficient and reliable for certain body regions to use for the trained user, ongoing research is necessary to optimize model fitting and measurement extraction for entire body regions. Compared to the tape measure, the technology offers more promise with speed and interrater accuracy, yet this technology is more costly potentially involving a software subscription. Similar to perometry, 3D imaging currently cannot provide proficient data for “tight” circumferential measurements needed in particular regions when fitting for custom compression garments.

Patient reported outcome measures

Patient reported outcome measures (PROMs) assess latent constructs such as symptoms, quality of life (QoL), and self-efficacy that could not be otherwise quantified. PROMs typically measure defining, yet subjective, dimensions of a patient’s experience, and may be condition-specific or generic. In the case of lymphedema-specific PROMs, tools have been developed and validated to evaluate the impact of lymphedema on the physical, psychoemotional, functional, and social aspects of a patient’s life [ 65 , 66 , 67 , 68 , 69 , 70 ]. Most lymphedema-specific PROMs have been characterized with respect to both their psychometric (e.g., Cronbach’s alpha, intraclass correlation coefficients, etc.) and general measurement properties (e.g., reliability, responsiveness, validity, etc.) [ 71 , 72 ]. Access to performance information becomes critical when selecting contextually appropriate PROMs for clinical and investigative applications, since instruments may perform inconsistently across subgroups defined by lymphedema location, severity, and etiology, as well as in the presence of comorbid conditions like obesity and organ failure [ 73 ].

A subset of lymphedema-specific PROMs has been evaluated as screening tools to detect lymphedema. Separate instruments are used to screen for upper and lower extremity lymphedema. Upper extremity instruments include the Lymphedema Breast Cancer Questionnaire (area under the curve, or AUC, not reported) [ 74 , 75 ], and a telephone screening questionnaire developed by Norman et al. [ 76 ](sensitivity 0.96 and specificity 0.75). Lower extremity instruments include the Lower Extremity Lymphedema (LEL) Screening Questionnaire (AUC of 0.92) [ 73 ] and the Gynecological Cancer Lymphedema Questionnaire (GCLQ) (AUC of 0.95) [ 77 ].

Generic, or condition agnostic, PROMs have been shown to have acceptable to excellent measurement properties in the assessment of function and QoL among patients with lymphedema [ 78 , 79 ] . Use of generic PROMs allows for cross population comparisons and use of PROM data collected by other clinical disciplines. Additionally, generic PROMs have been developed and validated for administration via computerized adaptive testing (CAT) to increase precision and efficiency. At present, only two lymphedema-specific PROMs are available for CAT administration [ 80 , 81 ].

As lymphedema assessment tools PROMs offer salient benefits including low cost, ease of repeated longitudinal assessment, simple scoring and interpretation, availability in diverse languages, remote administration, and non-necessity of specialized training or personnel for high fidelity assessment. PROMs offer the only standardized means of quantifying the impact of lymphedema most pertinent to the patient, its treatment, and sequelae on a patient’s lived experience. However, PROMs are also subject to important limitations including respondent burden, inconsistent correlation with objective measures of lymphedema severity [ 82 ], and biases such as social acceptability, central tendency, end aversion, among others. Additionally, they may perform inconsistently across patient subgroups defined by sociodemographic and clinical characteristics.

Advanced imaging measures

Lymphoscintigraphy.

Lymphoscintigraphy has been considered the primary investigation to confirm the diagnosis of lymphedema, visualizing the functional status of the lymphatic system and guiding the management of lymphedema patients [ 83 ]. Lymphoscintigraphy is accurate and does not risk allergic reactions to contrast dye [ 84 , 85 ]. Lymphoscintigraphy has a sensitivity of 97% and a specificity of 100% [ 86 ]. The test requires injecting technetium Tc99m labeled antimony sulfur or albumin into the affected extremity’s second interdigital web space. Sequential images of bilateral extremities are performed in 20 min, and 3 h [ 87 ]. Lymphatic dysfunction is diagnosed if lymphoscintigraphy exhibits delayed transit time of the radiolabeled colloid to the regional lymph nodes, dermal backflow, asymmetric node uptake, and/or formation of collateral lymphatic channels [ 88 , 89 ] (Fig. 1 ). Lymphoscintigraphic study of breast cancer-related lymphedema has found excellent intra-rater reliability (ICC = 0.946) and interrater reliability (ICC = 0.846) [ 90 ]. Limitations include expense, planar images with limited spatial resolution (unless combined with CT), fuzzy or grainy images, radioactivity exposure and disposal issues, and time required for testing.

A combined scintigraphic and CT technique, SPECT-CT, allows functional visualization of altered lymphatic flow in three dimensions as opposed to lymphoscintigraphy which is planar, and SPECT-CT simultaneously demonstrates lymphatic stigmatae per CT imaging as above. While found to have some advantages in accuracy of lymphoscintigraphic staging of lymphedema compared to lymphoscintigraphy alone [ 91 ], it is costly and not routinely used.

Lymphoscintigraphy for assessment of lymphatic function. a Lower extremity lymphedema showing pooling of lymphatic fluid in left calf and decreased left pelvic lymph node activity. b Postmastectomy lymphedema with pooling in distal left upper limb and markedly reduced axillary lymph node activity

Because the physical examination is primarily subjective and does not represent subcutaneous tissue distribution and lymphedema tissue alteration, use of ultrasound has been advocated to enhance lymphedema staging [ 92 ]. (Fig. 2 ) A noninvasive tool, ultrasound offers visualization of the skin and subcutaneous tissue changes in extremities with chronic lymphedema, caused by changes in the extracellular matrix, such as connective tissue hypertrophy, fat accumulation resulting from both fat hypertrophy and an increased number of adipocytes, and interstitial protein-rich fluid accumulation [ 93 ]. The observation of these changes in various parts of the extremity may further elucidate the severity and extent of the disease.

Skin thickness, subcutaneous tissue thickness, and subcutaneous echogenicity all show a significant positive correlation with the ISL stage [ 94 ]. Ultrasound studies report interrater reliability, accuracy, and variability with some bias in small sample size groups.

In a study of ultrahigh frequency ultrasound of upper and lower limbs affected by secondary lymphedema, Bianchi et al. found a high correlation between the ultrasound and histological findings when used prospectively for preoperative and intraoperative analysis for lymphovenous anastomosis [ 95 , 96 , 97 ].

Unlike most forms of imaging, ultrasound can be administered at point of care, though user expertise is required, along with investment in the device.

Ultrasound to distinguish normal, lymphedema and lipedema. Lymphedema is associated with increased dermal thickness and with subcutaneous tissue hyperechogenicity, whereas lipedema is associated with increased thickness and hypoechogenicity of the subcutaneous fat (dermis marked in upper arrows, subcutaneous tissues in lower arrows)

Computed tomography

CT scans are essential in the evaluation of the causes of limb swelling. CT imaging can provide objective volume measurements and information about the structural characteristics of subcutaneous tissue in lymphedema [ 98 ]. CT scans demonstrate the alterations in epidermal and subcutaneous tissue, but can also detect neoplasms obstructing the lymphatics causing secondary lymphedema [ 99 ]. MRI and CT are useful tools for measuring both the volume of subcutaneous tissue and structural changes. CT imaging has been shown to have high sensitivity (93%) and specificity (100%) in confirming the diagnosis of lymphedema. CT imaging is not routinely applied to evaluate lymphedema because of the associated high cost and radiation exposure.

The subcutaneous tissue of lymphedema exhibits a pathognomonic honeycomb distribution of edema due to fibrotic tissue and fluid surrounding the accumulation of fatty tissue; the skin is thickened [ 99 , 100 , 101 ]. CT also can display the size and the number of lymph nodes, which helps define the type of primary lymphedema.

Lymphatic imaging with near-infrared (NIR) fluorescence

Two very similar methods for imaging shallow lymphatics use near-infrared fluorescence: Indocyanine Green Lymphography (ICG-L) and Near-InfraRed Fluorescence Lymphatic Imaging (NIRF-LI). Both ICG-L and NIRF-LI use intradermally injected ICG as a contrast dye to allow visualization of dermal lymphatics and lymph nodes to depths of 1 cm (ICG-L) or 3–4 cm (NIRF-LI) [ 102 , 103 ]. Slightly different optics technology also allows NIRF-LI to image lymphatic pumping in near-real time for extended periods of time [ 104 ]. Both technologies take advantage of the fact that light in the near-infrared (NIR) portion of the light spectrum (wavelength 600–800 nm) is not readily absorbed by melanin, water, hemoglobin, or other components of human tissue. For example, if you shine a flashlight at the base of a finger, most light wavelengths will be absorbed, but NIR wavelengths will penetrate the skin between your fingers and appear red. When injected intradermally, ICG binds to intracellular albumin and other large proteins that are selectively taken up by lymphatic, but not arterial or venular, capillaries. Dim NIR laser light shining on skin excites ICG, so that shallow lymphatic vessel anatomy (and pumping, with NIRF-LI) are visible.

NIR tools can provide information as to which collector vessels are used, as well as identify anatomical areas where lymph is stagnant, appearing as “dermal backflow (Fig. 3 ) Dermal backflow never appears in healthy limbs, but is almost always present with subclinical and clinical lymphedema [ 105 ]. In healthy lymphatics, ICG bound to large proteins is readily transported from interstitial spaces through primary capillaries directly into lymphatic collectors. Dermal backflow in patients with lymphedema, readily detected by ICG-L, appears as cloudiness, tiny tortuous vessels clusters, or punctate bright spots within cloudy areas. Such images represent lymph that is stagnating in interstitial spaces, primary capillaries, or small pre-collector vessels.

Breast Cancer-Related Lymphedema seen by Near-Infrared Fluorescence Lymphatic Imaging (NIRF-LI). Example images of (left) healthy lymphatics with well defined, linear lymphatic structure and contractile function, and (right) diseased lymphatics with fluorescent network of tortuous lymphatic vessels and dermal backflow

These imaging modalities can be used as tools for (1) early diagnosis of lymphedema, (2) objective assessment of lymphedema conservative and surgical treatments, and (3) discernment of lymphedema in a variety of clinical contexts, not limited to post-surgical lymphedema. ICG-L and NIRF-LI can detect failing lymphatic function well before clinically recognized lymphedema can be diagnosed. Of note, lymphatic dysfunction can be missed using clinical swelling as a criterion, thus delaying treatment. For example, Fig. 4 shows NIRF-LI images of breast cancer patients clearly displaying dermal backflow, yet arm swelling is below 5% (and even negative) [ 106 ]. Such patients are assumed to not have lymphedema, and are not treated when the lymphatics may be most amenable to favorable outcomes, before irreversible tissue changes, such as skin fibrosis and subdermal adipose accumulation, are established [ 107 ]. Importantly, a recent prospective longitudinal study of breast cancer patients showed that NIRF-LI detected dermal backflow 8–23 months before clinical lymphedema was diagnosed by arm swelling [ 108 ]. NIRF-LI has shown that manual lymphatic drainage and pneumatic compression therapy directly improve lymph movement, and a study of reparative lymphatic microsurgeries is underway [ 109 , 110 , 111 , 112 ]. Such studies demonstrating physiologic benefits of these treatment methods have provided evidence to medical insurers in support of their reimbursement. NIRF-LI has detected dermal backflow in breast cancer patients who have yet to receive mastectomy or lumpectomy with axillary lymph node dissection, suggesting effects of the cancer itself, [ 108 ] of neoadjuvant chemotherapy [ 113 ] and/or effects of inflammation (which has been shown to systemically halt lymph pumping) [ 114 ], as risk factors for lymphedema. Breast cancer patients who receive immediate lymphatic repair at the time of axillary lymph node dissection (the lymphatic microsurgical preventative healing approach, or LYMPHA technique) are reported to have lower incidence of lymphedema [ 115 ]. Longitudinal NIR imaging could track efficacy of LYMPHA, to determine if lymphatic pumping is always restored with lymphatic-vein anastomosis.

Breast Cancer-Related Lymphedema seen by Near-Infrared Fluorescence Lymphatic Imaging (NIRF-LI) in the setting of normal arm volumes. Dermal backflow (top images) is evident in three different breast cancer patients’ affected arms. White-light (bottom) images were also collected with a white-light camera mounted on the imager arm. Relative volume changes (RVC) for all three patients were negative, well below 5-10% used to clinically diagnose breast cancer-related lymphedema

A major limitation of ICG-L and NIRF-LI is the inability to show deep lymphatic vessels, such as the cisterna chyli/thoracic duct, although NIRF-LI can detect pulsing in collector vessels that are 3–4 cm deep, if there is no dermal backflow overlaid [ 103 ]. Nonetheless, in several cases, NIRF-LI has detected dermal backflow in patients with normal lymphoscintigraphy results, allowing early treatment for extremity lymphedema [ 102 ].

Magnetic resonance imaging (MRI) is a biomedical imaging modality with versatile image contrast that can be used to visualize anatomy at high spatial resolution, quantify tissue molecular composition, and probe vascular morphology and function in the lymphatic network comprised of vessels, nodes, and organs. MRI methods are clinically feasible to perform anatomical imaging at 3D high spatial resolution (typically 0.5–1 mm 2 in-plane) by standard T 1 - and T 2 -weighted MRI. Anatomical imaging in lymphedema can be used to measure the limb’s volume and soft tissue remodeling such as skin or subcutaneous adipose tissue thickening, for instance (Fig. 5 ). MRI contrast can also be sensitized to tissue molecular content in lymphedema. Dixon MRI separately visualizes water- and fat-dominant tissue composition in a single acquisition, and can quantify tissue water and fat-fraction asymmetries to inform disease severity and location [ 116 , 117 ]. MR lymphangiography with or without exogenous contrast agents is also clinically feasible with standard pulse sequences available on most hospital scanners, although further standardization of protocols and tracers is needed [ 118 ]. Non-tracer MR lymphangiography hyper-intense signal patterns in subcutaneous edema and tissue sodium content by sodium MRI are being investigated to inform individualized physical therapy strategies for edema mobilization [ 119 , 120 ]. While current cost and accessibility limit the widespread use of MRI in clinical lymphedema management, its high spatial resolution, noninvasive molecular specificity, and adaptability to functional lymphatic imaging offer particular advantages and clinical use scenarios [ 121 ].

Noninvasive MRI methods for structural and physiologic lymphedema assessment. Noninvasive MRI methods provide structural and physiologic imaging measures for upper-extremity lymphedema (top row) and lower-extremity lymphedema (bottom row). A Optimized image contrast at 3T MRI provided lymph node anatomical imaging sensitive to the afferent and efferent vessel and lymph node substructures. Structural MRI of soft tissue anatomy demonstrates tissue remodeling in disease such as skin and adipose tissue thickening, and fibrosis deposition. B MR lymphangiography visualizes deep lymphatic vessel morphology, such as in the thoracic duct anterior to the spinal cord. Edema is also visualized as hyper-intense signal on non-tracer MR lymphangiography to localize dependent edema and response to manual therapies. C Tissue composition in lymphedema can be quantified with 3T MR relaxometry (e.g. T 2 relaxation time map in upper-extremity unilateral lymphedema), and Dixon fat-fraction mapping. These measures indicate edematous and heterogeneous tissue in lymphedema, which responds to manual lymphatic drainage therapy. D Molecular imaging methods relevant for lymphedema include CEST-MRI of proteins (e.g. magnetization transfer ratio, MTR of amide proteins) and sodium MRI of endogenous tissue sodium content (mmol/L). Molecular imaging is being investigated for early biomarkers of edema formation and objective, localized measures of lymphatic disease severity. Together, MRI is a versatile modality to investigate lymphatic physiology and disease with high potential for clinical translation.

MRI offers exciting possibilities as a research tool to advance lymphedema care. Examples of advancements in lymphatic MRI include MR relaxometry of lymphatic fluid, lymph nodes, and soft tissue in lymphedema that is fundamental to optimizing anatomical image contrast across the lymphatic system [ 122 , 123 , 124 ]. MR lymphangiography has advanced in specificity for lymphatics by combining T 1 and T 2 shortening agents with techniques like DARC-MRL and contrast-enhanced MRL [ 125 ]. Dynamic lymphangiography analysis tools will be needed to translate these techniques into a clinical setting. Physiologic imaging is exploring MRI quantification of tissue protein, sodium, and fat composition in lymphedematous tissue to investigate the impact of lymphatic dysfunction on limb physiology and potentially image-based personalized risk factors for developing lymphedema or lipedema [ 126 , 127 , 128 ]. As novel therapeutics are developed for lymphedema, MRI modalities could likely play a significant role as objective, sensitive outcome measures of therapeutic mechanism and response to therapy. MRI research opportunities remain at all translational research levels to improve the specificity and objectivity of lymphatic disease assessment.

Dysmorphism: Shape and contour deviations. Metaplasia: Altered tissue integrity that is not on malignant trajectory.

Lymphedema evaluation: tables and summaries.

No individual method is effective for the entire range of lymphedema subdomains Domains Assessed by Specific Modalities (Table 1 ), with the fewest options available for dysmorphism and metaplasia. H&P, PROM’s, MRI and CT show the strongest multidimensional capabilities, with ultrasound and ICG also promising. The various methods available to assess volume are largely unidimensional, however some measures (perometry, 3D camera, and to some extent tape measure) do give detail about contour. Technologies such as bioimpedance and TDC, which assess fluid content, are becoming increasingly available, but these are limited in their ability to delineate other tissue composition factors such as fibrosis or fat, which require use of advanced measures including ultrasound, CT and MRI. Measures which are both clinically feasible and have good discrimination for soft tissue factors beyond extracellular fluid assessment are a priority for future work. Clinically feasible measures of lymphatic function are also a gap area.

(Table 2 ) This category relates mainly to clinical situations of individuals at risk for lymphedema, most commonly following cancer treatment. Screening constitutes an especially active focus of current lymphedema research. Furthermore, from a clinical viewpoint, mechanisms for early detection of cancer-related lymphedema are increasingly prioritized for integration into routine care [ 129 ]. The need to reconcile the dual priorities of optimizing both quality and feasibility, which are pertinent to all dimensions of lymphedema measurement, reaches primacy with screening, due to population health-level need for repeated measurements over time in a large number of patients.

Studies suggest that the sensitivity of bioimpedance is in the 70–76% range for cancer-related lymphedema when advanced measures including lymphoscintigraphy [ 48 ], or ICG [ 130 , 131 ] are used as reference standards. Bioimpedance has also exhibited favorable specificity in some studies. [ 132 , 134 ]. The international multicenter PREVENT randomized controlled trial data has found fewer patients progressing to clinically evident lymphedema when bioimpedance has been integrated into screening processes for breast cancer-related lymphedema [ 132 ]. Studies comparing bioimpedance to perometry have shown anywhere from modest [ 133 ] to good [ 134 , 135 , 136 ] correlation between the two modalities. Dylke et al. [ 48 ] found slightly better sensitivity and specificity with perometry (81%/96%) compared to bioimpedance spectroscopy (76%/93%), using lymphoscintigraphy as the reference standard, in the context of mild to moderate upper limb lymphedema. On the other hand, Czerniec et al. [ 136 ], while finding high concordance between bioimpedance spectroscopy and perometry, found significantly higher interlimb ratios with bioimpedance spectroscopy than perometry in individuals with clinically identified mild to severe lymphedema, and this pattern held true with both whole-arm and segmental analyses.

Overall, fluid-detection measures are becoming increasingly utilized for screening, based on favorable accuracy characteristics found in the breast cancer population, as well as feasibility, especially for Individualizing Treatment (Table 3 ). bioimpedance. However, this issue is not an entirely decided matter. Volumetric measurement techniques continue to be employed in screening research trials, and they also remain relevant based on common use. On the favorable side, volumetric measures exhibit value as complementary information, but on the challenging side, they can be difficult to upscale for frequent repeated measurements. Tape measurement prevails in most lymphedema practices and is particularly advantageous in stressed resource settings. Tape measurement can also be adapted for self-monitoring. Perometry has particularly good sensitivity to small volume change. 3D imaging via phone or tablet shows strong future potential given its promising convenience. PROM’s also show some favorable characteristics and, while not a stand-alone assessment, offer complementary information. In summary the use of a comprehensive multi-modal assessment is recommended with clinical evaluation and symptom reporting also important.

Despite favorable aspects of bioimpedance, current technology has limits, especially with regards to detecting axial (i.e., head and neck, trunk, breast, chest wall, genitalia) lymphedema, and for evaluation of other focality (such as dorsum feet or hands). Measures that are useful for axial lymphedema, such as ultrasound and TDC, are not yet in wide use for this purpose, and have their own feasibility considerations. While bioimpedance utilization has expanded, implementation challenges remain due to cost, as, despite its FDA approval for BIS in the United States, gaps remain in insurance coverage.

Diagnosis (Table 4 ) pertains to a range of clinical situations not limited to cancer-related lymphedema and may entail distinguishing lymphedema from other causes of swelling or soft tissue changes, and/or establishing the underlying disease causing lymphedema. Regarding lymphedema diagnosis, a noteworthy observation is that despite multiple available methodologies, no individual modality outperforms H&P, especially among the measurement tools available in office and at the bedside. H&P provides advantages of myriad components as well as overall pattern recognition. However, H&P can have limits diagnostically, especially in medically complex patients or those with mixed etiologies. Depending on context, distinguishing exact contributors may or may not make a difference in management, and H&P, including the crucial history portion, helps to identify when more testing is needed. ICG, MRI and lymphoscintigraphy do have areas of strength and can be considered when H&P alone provides insufficient objective and diagnostic confidence in distinguishing lymphedema from other etiologies, identifying earliest potential onset of lymphedema, and determining affected versus unaffected areas. Longitudinal assessment and/or utilizing more than one type of modality can also be helpful in verifying diagnosis in difficult or elusive cases.

The individualizing treatment (Table 4 ) category shows some areas of strength, especially with regard to distinguishing degree of involvement in affected territories, and informing treatment, with H&P, ultrasound, ICG, MRI and lymphoscintigraphy showing strongest characteristics, and some advantages also seen for tape measure, perometry, bioimpedance, and TDC. Limitations remain, especially in guiding follow up logistical needs, as well as in stratifying risk for adverse outcomes, especially as risks may be affected by changes in treatments. Therefore, while useful tools exist, optimizing their integration into clinical care paradigms is a priority.

The majority of modalities are highly limited, except for Monitoring Treatment Response (Table 5 ). the domain of detecting volumetric changes, which shows several effective options. Of these, perometry and water displacement have the highest precision to capture change over time, though tape measure is commonly used based on feasibility. Bioimpedance has defined criteria for intervention, and favorable utility for surveillance, though the emphasis of the bioimpedance literature to-date has been towards lymphedema identification and screening rather than on its reliability in chronic situations and clinically relevant improvements during rehabilitation. Other subdomains show a lack of abundant options, especially for tissue composition and metaplasia.

Several concurrent approaches are layered within this work. First, a comprehensive framework has been generated of assessment dimensions and subcategories of lymphedema diagnosis and quantification, which assists with a practical understanding of the wide-ranging considerations pertinent to this diverse topic. Second the S/I/U/N ratings are assigned, employing defined criteria with emphasis on the evidence basis. Third, the grid format allows identification of overarching patterns, such as (1) the strength and weakness of particular modalities versus others within-dimensions of lymphedema evaluation (diagnosis, screening, individualizing treatment, monitoring treatment response), (2) the lymphedema characteristics which can be most confidently assessed (i.e., volume, tissue composition, symptoms, etc.), and (3) the lymphedema evaluation dimensions which overall have the strongest or weakest evidence foundation.

The overriding purpose of the above process is to produce a point-in-time snapshot of lymphedema diagnostic methods to update clinicians in their selection process of situationally appropriate modalities, to apply to their patient care as well as program development. Accomplishing this goal requires the dual priorities of highlighting traditional methods of continuing relevance, as well as areas of exciting progress. The substantial remaining gaps are also accentuated.

While specific clinical context ultimately guides decision-making, patterns seen among the various forms of lymphedema evaluation are noteworthy. Of the lymphedema domains assessed by specific modalities (as seen in Table 1 ), the overall highest performing modalities across the spectrum of domains, with the greatest number of strong ratings, are MRI, H&P, CT, and PROMs; the lymphedema domains most likely to have strongly rated assessment methods are volume and fluid content. Of the various dimensions of lymphedema assessment (Tables 2 – 5 ), individualization of treatment attains the highest frequency of strong ratings (45%), followed by screening (24%), diagnosis (20%), and monitoring treatment response (15%). Across the 20 subcategories within these four tables of lymphedema dimensions, H&P demonstrates the highest number of strong ratings (11), followed by ICG (10), MRI (8), lymphoscintigraphy (7), bioimpedance (6), PROMs (5), ultrasound (5), tape measure (5), perometry (3), TDC (3), CT (3), 3D camera (2), water displacement (1), and tonometry (0). When modalities receiving either strong or intermediate ratings are considered, across these 20 subcategories, the values become, in order of frequency, H&P (15), MRI (14), ultrasound (12), ICG (11), tape measure (10), perometry (9), bioimpedance (9), TDC (9), lymphoscintigraphy (8),CT (8), PROMs (7), 3D camera (7), water displacement (5), and tonometry (3).

Dysmorphism: Shape and contour deviations.

Metaplasia: Altered tissue integrity that is not on malignant trajectory.

Of note, in considering diagnostic modalities, we elected not to include simple lymphography, which has become less favored due risks of lymphatic vessel cannulation and to potential for lymphatic damage with radioopaque contrast; however, lymphography may be especially useful, for deep/central lymphatic system imaging (thoracic duct, cisterna chyli), and is considered when other advanced imaging approaches are not available [ 137 , 138 ]. In the United States, ultrasound, ICG-L, MRI/MRL, CT or lymphoscintigraphy are more commonly used. But even the use of lymphoscintigraphy, considered the gold standard to diagnose lymphedema, is only used for ~ 6.7–9.5% of cancer-related lymphedema patients [ 139 ].

Clinical vs research considerations

No single type of measure is applicable to all aspects of clinical and research integration. For routine clinical use, modalities which are feasibly integrated into office or bedside settings will be favored, with radiologic imaging measures applied more selectively. Water displacement, while cumbersome for routine clinical use, has been advocated for research given its high precision, as has perometry. PROMs show favorable characteristics for use in clinical settings, including that they capture factors such as symptoms and function which are missed by other tools and provide clinicians with patient-specific impairments to tailor personalized care. But patient burden must be considered with PROMs, as well as clinic workflow and ability to clinically incorporate the information, therefore PROM tools need to be chosen very intentionally to assess target domains as efficiently as possible. In the research setting, use of more expanded PROM item banks may be appropriate. Bedside or clinic options which constitute a particularly strong focus of current research include bioimpedance, TDC, and 3D camera. Tools such as US and ICG have not yet enjoyed widespread clinical application in diagnosis, but ultrasound is one of the stronger noninvasive, portable modalities for evaluating soft tissues, and has potential for expanded role at the bedside. Additionally, ICG is beginning to show application beyond surgical planning, such as prognostication and possible role in guiding tailored lymphedema therapy [ 137 ] MRI is a multifaceted and evolving topic in current lymphedema research that will likely have a range of future applications albeit an inherent limitation for patients not compatible for MRI use. More specific qualities can also drive selection, for example the utility of MRI and CT in characterizing lymphedema involvement at the level of deep structures.

In clinical care, cost effectiveness remains a crucial component of feasibility. However, from another vantage point, lymphedema as a diagnostic entity has been widely considered as underrecognized and undertreated. Furthermore, the role of the full range of diagnostic options should be weighed for appropriate best practice. Challenging circumstances may require the incremental precision obtainable with overlapping or hierarchical approaches. The cost benefit of additional testing will likely vary based on context. Lipedema is an example of a clinical situation where additional testing may promote cost effectiveness, sparing costly lymphedema treatment.

An imaging toolbox that utilizes several different modalities could allow optimal understanding of lymphatic dysfunction but may be costly and present accessibility difficulties. For example, to present figures at the time of this writing, ICG-L imagers are commercially available, but they can cost hundreds of thousands of US dollars, and ICG costs $110 per vial in the United States. The billing code used by reparative microsurgeons for ICG-L prior to lymphovenous bypass and/or vascularized lymph node transplant reimburses at ~ $700. ICG-L is used in Europe for assessing lymphedema treatment efficacy, but there may currently be patent issues for such use in the US. NIRF-LI is only available for research use at present. Comparatively, lymphoscintigraphy averages $1500, and MRL may cost $900. Cost effectiveness studies are needed, with an imaging protocol streamlined to maximize the cost/benefit ratio.

Current and emerging themes

Simultaneous with judicious use of emerging technologies, traditional evaluation methods including clinical history and physical examination and other office-based measures remain highly relevant mainstays of comprehensive assessment for theexperienced clinician, who can order and interpret correctly the various modalities described.

Specific practice settings, especially whether high, medium or low in resources will influence feasibility in translation of available techniques.

Need exists for improved bedside measures of soft tissue characteristics, including tissue composition (moving beyond fluid content), dysmorphism and metaplasia.

Bioimpedance and PROMs may be particularly valuable for early detection and surveillance of lymphedema.

TDC is showing strong potential for detecting and assessing focal lymphedema.

3D camera is another emerging tool, for which more research is needed, with potential advantages including speed (compared to tape measurement) and feasibility factors (compared to perometry). 3D camera is also showing favorable spatial resolution (4 mm).

Use of ultrasound holds promise for more widespread use in evaluating tissue characteristics, especially for focal lymphedema, and has potential to serve as a bridge between bedside availability and traditional diagnostic imaging.

ICG and MRI to-date have been employed mainly in specialized situations such as presurgical evaluations and research, however potential clinical applicability has far-reaching implications, including guaging the effectiveness of therapy approaches on a physiological level.

Additional research studies focusing on correlation between advanced modalities (such as MRI, ICG or lymphoscintigraphy), and bedside tools such as bioimpedance, TDC, and perometry are encouraged to better inform clinical practice.

Imaging techniques such as MRI have a role in development of new therapies such as mechanistic or functional based treatment, even if not easily translatable into routine clinical care.

Application of artificial intelligence (AI) has potential to assist with interpretability of lymphedema diagnostic testing. However, a need exists for more standardized acquisitions with techniques to allow AI systems to be more reliable.

Limitations

In formulating the above charts and assigning specific ratings, the authors acknowledge inherent interpretative limitations due to (1) heterogeneous clinical contexts, including patient mix, physical, financial and workforce resources of various care environments, and models of care, and (2) varying technologies within some of the modality categories. Because of this contextual variance, our expert panel employed “current usual circumstances” as a best-fit guiding principle in gauging a particular modality, and also assumed that end-user clinicians or researchers were appropriately trained and experienced in use of the particular modality. However, even with these assumptions, the authors emphasize that the focus for the reader is most appropriately placed on patterns of observations, rather than considering any one particular rating as definitive for all situations.

Additionally, there have been some limitations in focus, most notably that this work has emphasized peripheral lymphedema, rather than the central lymphatic system. The lymphatic system is highly heterogeneous with peripheral and central aspects. Internally, the lymphatic networks will vary according to whether the topic is hepatic, intestinal, cardiac, and so forth. [ 137 ] Central lymphedema evaluation may center around evaluating for structural disruptions such as fistula or leakage [ 140 ], whereas peripheral etiologies are more likely to relate to lymphatic congestion [ 137 ], with the latter being implicit in this paper. Head and neck lymphedema may include external or internal components, or both. [ 141 ] In the brain, a combination of glyphatic system (parenchymal) and lymphatic (meningeal) function has been found [ 142 ].

Various other limitations are present. Much of the literature examining office-based modalities is problematic with regard to reference standards, obscuring the ability to interpret sensitivity, specificity and other aspects of empirical data. The literature overall is skewed towards breast cancer-related lymphedema; while this emphasis is understandable given its prevalence and the potential to intervene early, other clinical contexts, including lower limb etiologies, merit more attention. Some important related aspects are beyond the scope of this paper, including surgical planning, surveillance time-course models, and clinical aspects of risk factor evaluation. Laboratory medicine aspects of lymphedema such as genetic, biomarker, or inflammatory aspects of lymphedema are not explored. While cost factors are given consideration in our discussions of the modalities, detailed cost effectiveness analyses are beyond the current scope of available evidence Lastly, while we attempted to highlight areas particularly relevant to research, we acknowledge and even emphasize that virtually all of the domains and modalities assessed in this paper are relevant to lymphedema research.

Conclusions

Lymphedema diagnostic and quantitative methods encompass an increasing array of modalities, which are pertinent to various lymphedema characteristics, and applicable to clinical and research aims, including dimensions of diagnosis, screening, individualization of patient care, and monitoring treatment response. This paper provides guidance to clinicians in (1) affirming the role of traditional measures when appropriate, and (2) identifying instances when integrating emerging technologies and imaging modalities can enhance patient care.

Data availability

No datasets were generated or analysed during the current study.

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Acknowledgements

This research article was prepared for the 2023 Lymphedema Summit: Forward Momentum; Future Steps in Lymphedema Management. This Summit was sponsored by the American Cancer Society, the Lymphology Association of North America, Washington University School of Medicine in St. Louis, and the Stryker Corporation.

Open Access funding enabled and organized by CAUL and its Member Institutions. Lymphology Association of North America,Washington University in St. Louis,Stryker Corporation,American Cancer Society

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Department of Physical Medicine and Rehabilitation, MetroHealth Rehabilitation Institute, Case Western Reserve University, Cleveland, OH, USA

Center for Molecular Imaging, UTHealth, Houston, TX, USA

Melissa Aldrich

Department of Physical Medicine and Rehabilitation, Vanderbilt University Medical Center, Nashville, TN, USA

Paula Donahue

Lymphedema Center, Santa Monica, CA, USA

Australian Lymphoedema Education, Research & Treatment (ALERT) Program, Macquarie University, Sydney, Australia

Louise Koelmeyer

Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, USA

Rachelle Crescenzi

Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN, USA

Andrea Cheville

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All authors made substantial contributions to the conception, methodology, literature search, analysis, synthesis and consensus of information, and manuscript writing. PD assisted in identifying multiple members in the formation of this group. AC provided the concept and initial content for the clinical integration tables, and all authors substantially contributed successive iterations of these tables. EI prepared Figs. 1 , 2 , MA prepared Figs. 3 , 4 , and RC prepared Fig. 5 . PD and LK provided depth of expertise on emerging office-based tools, and EI, MA and RC on the imaging modalities. MV provided administrative oversight and overall synthesis of the manuscript. All authors read and approved the final manuscript.

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Vargo, M., Aldrich, M., Donahue, P. et al. Current diagnostic and quantitative techniques in the field of lymphedema management: a critical review. Med Oncol 41 , 241 (2024). https://doi.org/10.1007/s12032-024-02472-9

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Turk J Surg
v.33(2); 2017

Lymphedema: From diagnosis to treatment

Oğuz kayıran.

1 Division of Breast Surgery and Lymphedema Program, Magee-Womens Hospital of University of Pittsburgh Medical Center, Pittsburgh, USA

2 Department of Plastic and Reconstructive Surgery, Baltalimani Hospital, İstanbul, Turkey

Carolyn De La Cruz

3 Department of Plastic and Reconstructive Surgery, University of Pittsburgh Medical Center, Pittsburgh, USA

Atilla Soran

Lymphedema is a chronic and progressive disorder resulting from impaired lymphatic system function. In developed countries, upper extremity lymphedema is mainly the consequence of breast cancer surgery in which axillary lymph node dissection and radiation alter upper extremity lymphatic flow.

Diagnosis of lymphedema is made clinically. Nevertheless, there are numerous diagnostic tools available for disease staging. Recently, a new technology namely magnetic resonance lymphangiography has emerged in the medical field to assist in both diagnosis and management.

There are non-surgical and surgical treatment options available. Non-surgical methods are always the first-line treatment; however, surgical options can be explored in appropriate patients. Recent studies focus on the prevention of lymphedema using surgical techniques utilizing axillary reverse mapping to delineate arm lymphatics from axillary lymphatics.

Finding the most suitable technique for each type of lymphedema with variable stages is one of the most complicated decisions for practitioners. More studies are needed to reveal the exact biology of lymphedema to ensure complete understanding of the disease and improve outcomes.

INTRODUCTION

Lymphedema (LE) is the accumulation of protein-rich fluid in tissues. The impaired function of lymph vessels interrupts the drainage of lymphatic system that is a part of the circulatory system just like the arterial and venous structures. Lymph vessels remove excess fluid from tissues and transport it back to the circulation. In addition, the maturation of immune cells takes place in the lymphatic system; thus, it constitutes one of the most critical defense mechanisms throughout the body. Lymph capillaries are located in the dermis, woven like a cobweb, then drain to lymphatic vessels in the subcutaneous plane and ultimately to the deeper system and the thoracic duct.

Lymphedema can either be primary or secondary. Regardless of the etiology, it is clinically characterized with chronic swelling, localized pain, atrophic skin changes and secondary infections ( 1 ). However, the main devastating aspect of LE is the appearance of the affected limb that causes psychological morbidity. Primary LE is related to developmental abnormalities of the lymphatic system whereas secondary LE is attributed to the impairment of lymphatic vessels due to an acquired condition such as trauma, tumor, surgery or infection ( Table 1 ). In developing countries, secondary LE is mainly due to infections-infestations influencing lymphatic channels. On the other hand, in developed countries, secondary LE occurs most commonly after surgical removal of lymph nodes for cancer treatment ( 2 ). Breast cancer is the most common cancer among women in the world and Breast Cancer Related Lymphedema (BCRL) occurs more often than any other type of LE ( 3 ). This review will focus on BCRL.

The etiology of lymphedema

Primary	Secondary
Congenital	Trauma
Milroy disease	Tumor
Lymphedema praecox	Surgery
Lymphedema tarda	Infection-infestation
	Post-venous thrombosis

Breast Cancer Related Lymphedema is detected in 7–77% of patients who undergo axillary lymph node dissection (ALND) due to transection of lymph vessels as depicted in selected studies ( 4 ). Sentinel lymph node biopsy (SLNB) significantly reduces this risk to 3–7% ( 5 , 6 ). This incidence is based on multiple factors such as extent of disease, treatment modality (i.e. radiotherapy), and duration of follow-up ( 6 , 7 ). In addition to these, a study revealed that patients with occupations that require extra upper extremity activity had the worst stage and grade LE clinically ( 3 ). In another study, factors associated with the development of BCRL included occupation, infection, and increased BMI. Immediate reconstruction of the breast was not found as a risk factor for BCRL ( 8 ). A recent study reported a risk assessment tool using these BCRL predictors (RATE-L), which included significant predictors such as post-mastectomy radiation, age above 65 years, and axillary dissection ( 9 ).

Although there is no unique sign or criteria for defining LE, the diagnosis is usually made clinically by thorough evaluation and physical examination ( 2 , 3 , 10 ). Family history is important in the diagnosis of primary LE. The main symptoms are chronic swelling, progressive atrophic skin changes, and recurrent infections. It is important to identify whether the swelling is transient or persistent. In one study, it was reported that one-third of initial swelling attacks were transient ( 10 ). Since effective treatment of LE can be established in early stages, accurate and timely diagnosis is crucial ( 11 ). History of trauma or surgery must be addressed clearly. Physical examination consists of volume and shape discrepancies, and skin changes among the extremities. Figure 1 outlines the alternatives in the diagnosis of LE.

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A scheme for the available options in the diagnosis of lymphedema

BIS: bioimpedence spectroscopy; MRI: magnetic resonance imaging; NIRF: near infra-red fluorescence imaging; PDE: photo dynamic eye (PDE; Hamamatsu Photonics K.K., Hamamatsu, Japan); USG: ultrasonography; CT: computed tomography

Circumferential (>2 cm) and/or volume (>200 mL) differences between the affected and non-affected extremity can be performed to confirm the diagnosis ( 2 ). Volume can be measured by tape, water displacement or perometry (Perometer; Perosystems, Wuppertal, Germany) ( 12 ). Tape measurements require formula calculations; therefore, it is recommended that the measurements should be performed by the same person at defined intervals ( 12 ). It is mainly preferred on head and neck lymphedema follow-ups. Water displacement is an accurate method that is the gold-standard for volume assessment, especially on extremities ( 12 ); however, it is not used in daily practice because it doesn’t delineate the affected area. If there is an open wound, it is not feasible to use this technique. Perometry is a computer-based study that calculates the volume of the affected limb via infra-red optical electronic scanner and can demonstrate small changes, but is expensive ( 2 ).

Non-invasive measurements (tonometry, bioimpedence spectroscopy) and imaging techniques (lymphoscintigraphy, ultrasonography, computed tomography, and magnetic resonance imaging) may aid in the detection of LE. The principal mechanism of a tissue tonometer is to evaluate tissue resistance by applying compression. Skin pliability and fibrosis can be measured with a tonometer. It gives a good idea about how changes occur during LE treatment. Tissue dielectric constant and tonometry can measure skin texture and resistance ( 12 – 14 ). Ultrasonography, computed tomography and magnetic resonance imaging can show the presence of extra fluid within tissues ( 12 ).

Bioimpedence spectroscopy (BIS) is a new diagnostic tool to diagnose LE. It is a technique that assesses the extracellular fluid compartment before visible changes have settled ( 15 ). BIS mainly focuses on changes in electrical conductance of extracellular fluid. Since it depends on water content of the study area, advanced and fibrotic edema detected in late-stage LE may not be diagnosed properly by BIS ( 12 ). In other words, BIS is reliable in early-stage BCRL. A prospective observational study demonstrated the impact of L-Dex® (L-Dex; Impedimed, Brisbane, Australia) measurements in identification of subclinical BCRL and its use in routine clinical practice ( 16 ). L-Dex® is the score representing extracellular fluid ratio of the affected limb to the unaffected limb, and is sensitive in predicting the onset of LE up to 10 months prior to clinical diagnosis ( 15 ).

Lymphoscintigraphy is a nuclear medicine study and demonstrates slow or absent lymph flow usually in later stages of LE ( 12 ). Technetium 99m sulfur colloid is injected intradermally and the transit time to lymph node basins can be measured; however, subdermal lymphatics cannot be assessed. A new technique for imaging lymph vessels is Near Infra-Red Fluorescence Imaging (NIRF) by using indocyanine green. This dynamic test allows visualization of superficial lymphatic flow and functioning lymphatic vessels; thus, finds abnormalities at early stages. It can be used to stage the severity of disease and for preoperative-intraoperative planning ( 17 , 18 ) ( Figure 2 ). Lymphography is another entity where radio-opaque material is directly injected into peripheral lymph vessels. This technique is rarely done due to the risk of damaging lymph vessels.

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Near Infra-Red Fluorescence imaging (NIRF) for preoperative-intraoperative planning

Magnetic resonance lymphangiography is a new entity that involves the injection of Gadolinium into the hand or foot to clarify the course of lymphatics. Gadolinium can also get into the venous system making the interpretation of lymphatic channels difficult ( 19 ). Magnetic resonance venogram and ferumoxytole (Feraheme; Advanced Magnetics, Cambridge, MA, USA) are used to help to differentiate lymphatics from veins ( 19 , 20 ). With the advent of magnetic resonance lymphangiography, the severity of LE can be delineated while the anatomy of the lymphatic channels and the status of the soft tissues can also be depicted ( 20 ) ( Figure 3 ). We suggested an algorithm for the management of patients with LE, by using Magnetic resonance lymphangiography and LE stage in this review ( Figure 4 ).

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a, b. (a) Magnetic resonance lymphangiography. Three irregular tubular structures extending from the dorsal aspect of the wrist to the lateral/dorsal aspect of the right forearm are compatible with enlarged lymphatics. These vessels are subcutaneous and measure up to 3–4 mm in caliber. In the lateral and ventral aspect of the mid-portion of the forearm (in proximity to the expected location of two lymphovenuler anastomosis), there seems to be communication between these lymphatics and small venules, branches of the basilic and ventral branches of the cephalic vein. There is minimal dermal backflow in the lateral aspect of the mid-portion of the right forearm. (b) Lymphoscintigraphy. Abnormally delayed lymphatic transit and dermal backflow are identified in the left forearm

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An algorithm for the treatment of lymphedema according to magnetic resonance lymphangiography

LVA: lymphaticovenular bypass; VLNT: vascularized lymph node transfer

The International Society of Lymphology classified LE into 4 stages to overcome multiple classification schemes and obtain a consensus ( 3 ) ( Table 2 ). In addition, Campisi et al. ( 21 ) proposed a staging system consisting of 3 stages, especially for elders.

Staging of lymphedema adapted from The International Society of Lymphology

Stage	Description	Characteristics
0	Latent	Some damage to lymphatics; No visible edema yet
1	Spontaneously reversible, acute phase	Pitting edema; reversible with elevation of the arm. Usually, upon waking in the morning, the limb(s) or affected area is normal or almost normal size
2	Spontaneously irreversible, chronic phase	Spongy consistency and is “non-pitting,” Fibrosis found in Stage 2 lymphedema marks the beginning of the hardening of the limbs and increasing size
3	Elephantiasis; irreversible, end-stage	Irreversible and usually the limb(s) is/are very large. The tissue is hard (fibrotic) and unresponsive; consider debulking surgey at this stage

The management of LE consists of accurate diagnosis, successful classification and patient education. Unfortunately, there is no absolute cure for LE. On the other hand, effective treatment is available. Two main modalities include non-surgical and surgical options ( Table 3 ). The mainstays of non-surgical LE treatment modalities are complete decongestive therapy (CDT), compression therapy, advanced pneumatic compression pumps and exercise. These treatments are effective mainly in early-stage LE ( 2 ). There is a global trend for surgical intervention and surgical techniques including physiological and reductive methods.

Treatment options in lymphedema

Non-surgical treatments	Surgical treatments
Complete decongestive therapy	Reductive techniques
Manual lymph drainage	Direct excision
Compression therapy	Liposuction
Exercise	Physiological techniques
Skin care	Lymphatico-lymphatic by-pass
Compression garments	Lymphatico-venous by-pass
Advanced pneumatic compression therapy	Lymph node transfer

Laser therapy

Non-Surgical Treatments

Patient education is both crucial and mandatory ( 22 ). Self-care and risk-reductive practices, self-lymph drainage, skin care, proper alignment of bandages and garments, good nutrition, exercise and weight control are the basics prior to LE treatment ( 12 ).

Complete Decongestive Therapy

Complete Decongestive Therapy (CDT) is considered the gold-standard treatment method in the management of LE and includes two phases: reductive (phase 1) and maintenance (phase 2) ( 23 ). CDT is a good option in decreasing LE volume and includes manual lymph drainage, compression therapy, physical exercise, skin care as self-management, followed by wearing compression garments ( 23 , 24 ). Although it is safe and effective in most patients, it is expensive, time-consuming and needs certified therapists. In addition, patient compliance to long-term CDT is challenging. Nevertheless, CDT can be individualized with modifications until the lymphedematous volume reduction has been maximized.

Manual lymph drainage (MLD)

MLD is a hands-on technique and differs from standard massage by orienting the lymphedematous fluid to proper functioning lymphatics ( 24 ).

Compression Therapy

Compression therapy includes effective gradient compression with tubular bandaging on the affected limb ( 25 ). Short-stretch bandages provide low “resting pressure” when the patient is at rest and “working pressure” which allows muscle contractions to direct interstitial fluid flow ( 23 , 25 ). These bandages also reduce fibrosis in the skin ( 25 ). Compression garments are different from compression bandages and are preferred in long-term treatment.

Specific exercise is beneficial for LE patients ( 12 ). It is recommended that compression bandages or garments should be worn during activity ( 12 ). Patients with LE or people at-risk for LE are encouraged to exercise. A meta-analysis showed that active exercising reduces edema volume in BCRL ( 26 ). A recent pilot study demonstrated that yoga has beneficial effects on an individuals’ posture and strength ( 27 ).

Establishing proper hygiene is important for patients with LE. Low pH moisturizers are recommended to overcome skin cracking and drying, in order to prevent entrance of microorganisms ( 12 ).

Compression Garments

Initial control of LE can be achieved with the use of compression bandages. Long term control is obtained with compression garments ( 12 ). The type of the garment depends on the body part. Patients should have several garments to alternate and ensure the proper pressure and hygienic control. Accurate fitted garments are essential. Some patients require additional coverage night-or-day to control or reduce LE ( 12 ).

Advanced New Generation Pneumatic Compression Therapy

Advanced Pneumatic Compression (APC) therapy can be used as an adjunct to CDT either in early or late phases ( 12 , 28 ). It mimics the pump effect of muscular contraction on lymphatic system ( 2 ). Ranging between 35 and 180 mm-Hg, pump pressures are adjusted to mostly 20–60 mm-Hg ( 2 , 12 ). The pressure must be individualized in order to prevent skin damage during application. APC therapy was found beneficial in reducing LE, whereas compression sleeves prevented additional swelling without influencing volume reduction ( 2 ).

Laser Therapy

A number of randomized trials have reported that Low-Level Laser Therapy (LLLT) improved measurable physical parameters as well as subjective pain scores ( 29 ). LLLT increases lymphatic drainage by stimulating the formation of new lymph vessels, by improving lymphatic motricity, and by preventing formation of fibrotic tissue ( 30 ). Usually, LLLT is used in combination with CDT. Most studies did not report any adverse events to participants, although one study stated development of cellulitis in LLLT patients as an adverse event ( 31 ). Its causal relationship to LLLT was unknown.

SURGICAL TREATMENTS

Reductive techniques, direct excision.

These techniques include removal of lymphedematous tissue. Previously described methods such as the Charles procedure include complete removal of all subcutaneous tissue and skin grafting ( 32 ). This method, although effective at volume reduction, can be quite disfiguring. It also can require blood transfusions and lengthy wound healing. Another technique used in the past involved buried dermal flaps with variable success ( 33 ). Direct excision techniques may involve full-thickness skin grafting (FTSG) or vacuum-assisted closure therapy ( 2 ). In extreme cases, these techniques allow for improvement in quality of life.

Liposuction

Surgical debulking of the affected extremity using liposuction has been shown to be very effective at reducing the volume to near normal ( 34 ). This technique has been used in both congenital and acquired LE. It has also been used in cases of lipedema. It has been reported that liposuction technique provides long standing reduction in extremity size as compared to the normal side ( 35 ). This technique requires patient compliance with compression therapy to prevent regression. Patients considering this technique should undergo pre-operative conservative management with no pitting edema ( 34 ). It has been shown to be effective both in the upper and lower extremity, although it is more effective in the upper extremity. It is known that adipose tissue functions as a crucial organ and a cytokine-activated cell in LE ( 36 ). The removal of adipose tissue using liposuction does not affect the already decreased lymph transport system in LE ( 34 ). Moreover, a significant improvement was detected in skin blood flow and quality of life after liposuction ( 37 , 38 ). Its complications include infection, skin necrosis and recurrence.

PHYSIOLOGIC TECHNIQUES

Lymphatic venous anastomosis, lymphatico-lymphatic by-pass, and lymph node transfer can be listed as physiologic methods. Many of these methods use recent developments in technology to assist in identifying lymphatic channels and lymph nodes ( 2 , 39 ).

Lymphatic Venous Anastomosis (LVA) or Bypass

LVA was first described in an animal model with several human studies to follow ( 40 , 35 ). This technique involves the creation of connections between the lymphatic system and the venous system in the distal or proximal extremity. Superficial or deep lymphatics are anastomosed with neighboring veins. Fluorescence is used to help identify the lymphatic system and an operating microscope is used to assist in microsurgery ( 41 ). Single or multiple LVA’s have been reported by different authors using differing surgical sites ( 39 , 42 – 44 ). Supermicrosurgery (anastomosis less than 0.8 mm vessels) is used in this technique, in which lymphatic vessels and adjacent venules are anastomosed, mostly in an end-to-end fashion ( 39 , 43 ) ( Figure 5 ). Variations on the configuration of anastomosis type were described in several studies with variable success rates ( 45 , 46 ). Studies have reported improvement in patients both subjectively and objectively. In general, LVA’s have been shown to be a safe technique for the management of LE ( 39 , 43 ).

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Lymphovenous anastomosis. Please note supermicrosurgery is used to establish such an anastomosis

Vascularized Lymph Node Transfer

Vascularized lymph node transfer was first introduced in animal models ( 47 ). It has recently been applied to humans with gaining popularity. There are different options for lymph node transfer, namely the location of the donor and the recipient sites. Options for lymph node harvest include the lateral thoracic region, groin, submental region, supraclavicular region and intraabdominal lymph nodes ( 44 , 48 , 49 ). Each donor site has its particular anatomic advantages and disadvantages, and contains varying number of lymph nodes ranging from 1–10. The lymph nodes can be harvested together with a portion of the skin if necessary. These operations require microsurgical skills to perform an arterial and venous anastomosis to provide blood supply to the transferred tissue. The results of lymph node transfer are quite promising and have been shown to provide both objective and subjective improvements ( 35 ).

One consideration for lymph node transfer is the concern for possible LE at the donor site ( 50 ). Reverse lymph node mapping, originally described as a technique to refine axillary dissection, can be used to minimize lymph node harvest related morbidity ( 51 ). It allows differential identification of nodes which drain the neighboring extremity in addition to the ones that are included in the tissue to be removed. Reverse lymph node mapping involves the use of the photodynamic eye, Technetium and ICG dye. Using this technique, the surgeon can be reassured that no lymph nodes are removed that drain the extremity ( 51 ). Clinically, the benefit of lymph node transfer is to restore immunologic function to the extremity and improve fluid drainage. However, the action mechanism of lymph node transfers is poorly understood. The transferred nodes have been shown to be active in a number of studies. One proposed mechanism suggests that the new lymph nodes act as “pumps” which filter the surrounding fluid ( 52 ). The best site for lymph node implantation is currently unknown. In some cases, the nodes have been placed distally whereas in others they were implanted proximally ( 52 ). Well-designed controlled prospective studies are needed to clarify if the suggested functional surgical methods are beneficial in the long-term.

A variety of lymph node transfers includes a tissue portion to be transferred with lymph nodes. Such examples include transferring the lower abdominal tissue in case of total breast anatomical reconstruction (TBAR) and latissimus dorsi flaps with lymph nodes. In such cases, both the breast and the lymph nodes are reconstructed ( 44 , 50 , 53 ). Other types of flaps such as those harvested intraabdominally carry lymphatic tissue from the omentum ( 49 ). These can be harvested either by open surgery or laparoscopically.

Intraoperative Considerations

The nodal status defines one of the most important prognostic factors in breast cancer. However, although necessary, axillary dissection may compromise the lymphatic system thus contributing to the development of LE.

Recently, the lymphatic drainage of the arm and breast tissue were studied and it was found that preserving arm lymphatics during SLNB and/or ALND via a new concept called axillary reverse mapping (ARM) may reduce the risk of BCRL ( 4 , 54 , 55 ). ARM is based on the hypothesis that drainage of arm lymphatics differs from that of breast lymphatics ( 4 , 54 ). However, it was shown that lymphatic interconnections exist in the axilla between arm and breast lymphatics ( 56 ). The technique of mapping the arm and breast lymphatics is comprised of radioisotope injection to the breast and blue dye injection to the upper arm ( Figure 6 ). The lymphatic pathways and interconnections are determined. When a crossover is identified, blue nodes should be removed ( 55 ). ARM reduced BCRL when compared with conventional breast cancer surgeries, nevertheless, randomized controlled studies are needed ( 55 ).

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Object name is tjs-33-2-51-g06.jpg

The mapping of axillary lymphatics. A radioisotope is injected into the breast, whereas blue-dye is administered subcutaneously to the upper arm. The lymphatic flow of the breast and arm is separately revealed

Breast Cancer Related Lymphedema is a devastating disease affecting millions of women. Its treatment is aimed at curing the disease and reducing recurrence rate. However, treatment methods create both physical and psychological morbidity to the patients. BCRL influences daily activities and affects patient self-esteem in various ways. Modern surgical and non-surgical techniques offer numerous methods for the patients to overcome BCRL. In the future, we hope to ensure 100% success in the control or elimination of BCRL. Until then, the exact biology, pathogenesis of lymphatic system diseases and the treatment options require further research to be able to understand this devastating disease.

Peer-review: Externally peer-reviewed.

Author Contributions: Concept - O.K., C.D.L.A., K.T., A.T.; Design - O.K., C.D.L.A., K.T., A.T.; Supervision - O.K., C.D.L.A., K.T., A.T.; Resource - O.K., C.D.L.A.,, K.T., A.T.; Materials - O.K., C.D.L.A., K.T., A.T.; Data Collection and/or Processing - O.K., C.D.L.A., K.T., A.T.; Analysis and/or Interpretation - O.K., C.D.L.A., K.T., A.T.; Literature Search - O.K., C.D.L.A., K.T., A.T.; Writing Manuscript - O.K., C.D.L.A., K.T., A.T.; Critical Reviews - O.K., C.D.L.A., K.T., A.T.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study has received no financial support.

Health | New treatment could be “game-changing tool” in…

Health | New treatment could be “game-changing tool” in fight against Alzheimer’s, CSU research finds

Combination of drugs targets two brain proteins critical in neuroinflammation involved in brain aging and alzheimer’s.

Elizabeth Hernandez - Staff portraits in The Denver Post studio on October 5, 2022. (Photo by Eric Lutzens/The Denver Post)

The combination of drugs targets two brain proteins critical in neuroinflammation, which is involved in brain aging and Alzheimer’s, according to a study published in July in the Journal of Neuroinflammation featuring CSU researchers.

Results from the study show this medicine could become “a game-changing tool” against Alzheimer’s, researchers said.

“There are no effective treatments right now,” said Devin Wahl, a CSU postdoctoral fellow, who co-authored the study. “We have treatments that can manage symptoms, but we don’t have any that can stop the disease. We want to try to identify novel treatments that may be effective to slow, or even reduce, the effects of Alzheimer’s disease.”

This cocktail of medicines could also improve memory in aging adults, the study found, and, potentially, reverse cognitive decline.

The research came out of a partnership between CSU faculty member Tom LaRocca’s Healthspan Biology Lab and Colorado-based biotech company Sachi Bio.

“This is a novel and effective treatment to improve memory in mice,” said Prashant Nagpal, who co-founded Sachi Bio with his wife, Anushree Chatterjee. “A very important finding that we saw in this study is that you can reverse some cognitive decline. We are hoping to take this to human clinical trials next year.”

The mice behavioral tests measured memory and grip strength because grip strength and muscle function are closely linked to brain function, researchers said.

“If we can target what comes before Alzheimer’s disease, which is what this drug is meant to do, that will give people more treatment options, especially earlier in life,” Wahl said.

By next year or 2026, Nagpal hopes there will be a more conclusive data set including human trials.

“We’ve all been touched by seeing older parents and family members just being a shadow of themselves,” Nagpal said. “It’s just heartbreaking. It may seem like just a glimmer of hope, but can you latch onto it and just, you know, go for it?”

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Research Vessel Resilience Charts Course to the Future of Marine Research

Dedication of the new hybrid-electric vessel was celebrated by laboratory, state, tribal and federal officials

The RV Resilience vessel drives by PNNL Sequim campus.

RV Resilience, the Department of Energy’s new hybrid electric marine research vessel.

(Photo by Eric Francavilla | Pacific Northwest National Laboratory)

SEQUIM, Wash.—Officials gathered at the Sequim campus of the Department of Energy’s Pacific Northwest National Laboratory today to dedicate DOE’s first hybrid-electric research vessel, RV Resilience.

The event marks the start of a new era of marine energy research at PNNL-Sequim , part of DOE’s Office of Science national laboratory system and Resilience’s new home port. Speakers at the dedication included U.S. Sen. Maria Cantwell, U.S. Rep. Derek Kilmer, Washington State Rep. Steve Tharinger and representatives from DOE and PNNL.

“DOE is focused on clean energy solutions. The RV Resilience enables us to accelerate the development and deployment of novel marine energy technologies from testing at the bench scale to early demonstration under real ocean operating conditions,” said Geri Richmond, DOE’s undersecretary for science and innovation. “Demand for these technologies is likely to increase in the coming years, unlocking opportunities for ocean science and maritime industries equipped to explore new applications for marine energy research that will help power the blue economy.”

Richmond’s chief of staff, Ariel Marshall, spoke on her behalf at the dedication ceremony.

PNNL Director Steve Ashby speaks at podium to dedicate the RV Resilience.

The 50-foot research vessel will allow researchers to transport and install large equipment in Sequim Bay, such as demonstration-scale marine energy devices. These devices will help accelerate marine energy testing and support new partnerships with industry developers. In addition to reducing carbon emissions, the hybrid-electric vessel is nearly silent when operated in fully electric mode. This minimizes noise pollution for marine wildlife and enables more sensitive acoustic measurements during research operations.

“RV Resilience represents DOE’s and PNNL’s commitment to demonstrating how innovative approaches, like the design and construction of this unique hybrid vessel, can advance the nation’s quest for clean energy,” said Laboratory Director Steve Ashby.

The RV Resilience can operate on diesel engines or in a completely electric mode using onboard battery banks. These batteries can be charged with the diesel engines, at any marina or through a rapid charging station at the PNNL-Sequim dock.

The RV Resilience was made possible with support from DOE’s Office of Energy Efficiency and Renewable Energy and its Water Power Technologies Office. It will be managed and operated by researchers at PNNL-Sequim—a regional hub for marine energy research, development and testing—and enables research operations in nearby Sequim Bay.

“We’re exploring the potential of marine energy by conducting world-leading coastal and oceanographic science and research,” said Alejandro Moreno, associate principal deputy assistant secretary for EERE. “This new hybrid research vessel enables that work with fewer emissions and less impact on the ocean’s wildlife."

The RV Resilience is the latest in a series of investments that will grow PNNL’s capabilities in marine technology research to continue advancing renewable energy, climate resilience and national security. These planned investments include a pre-permitted marine testing site, an underwater cabled array connecting at-sea devices to shore facilities and an onshore microgrid and battery storage system.

Combined with the RV Resilience and a host of new onshore laboratory facilities, these capabilities will enable PNNL-Sequim to support DOE’s marine energy mission, including supporting the development of offshore wind and tidal energy, as well as marine carbon dioxide removal.

RV Resilience was built by Snow & Company in Seattle, Wash. To learn more about vessel specifications, visit PNNL’s website .

Pacific Northwest National Laboratory draws on its distinguishing strengths in chemistry , Earth sciences , biology and data science to advance scientific knowledge and address challenges in sustainable energy and national security . Founded in 1965, PNNL is operated by Battelle for the Department of Energy’s Office of Science, which is the single largest supporter of basic research in the physical sciences in the United States. DOE’s Office of Science is working to address some of the most pressing challenges of our time. For more information, visit https://www.energy.gov/science/ . For more information on PNNL, visit PNNL's News Center . Follow us on Twitter , Facebook , LinkedIn and Instagram .

Published: September 5, 2024

Research topics

Wellesley team’s new research on anesthesia unlocks important clues about the nature of consciousness

From left: Professor Mike Wiest and Wellesley College students Jess Lopes, Emeline Gaunce, and Derin Timuçin.

Research and innovation
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For decades, one of the most fundamental and vexing questions in neuroscience has been: what is the physical basis of consciousness in the brain? Most researchers favor classical models, based on classical physics, while a minority have argued that consciousness must be quantum in nature, and that its brain basis is a collective quantum vibration of “microtubule” proteins inside neurons.

New research by Wellesley College professor Mike Wiest and a group of Wellesley College undergraduate students has yielded important experimental results relevant to this debate, by examining how anesthesia affects the brain. Wiest and his research team found that when they gave rats a drug that binds to microtubules, it took the rats significantly longer to fall unconscious under an anesthetic gas. The research team’s microtubule-binding drug interfered with the anesthetic action, thus supporting the idea that the anesthetic acts on microtubules to cause unconsciousness.

“Since we don’t know of another (i.e,. classical) way that anesthetic binding to microtubules would generally reduce brain activity and cause unconsciousness,” Wiest says, “this finding supports the quantum model of consciousness.”

It’s hard to overstate the significance of the classical/quantum debate about consciousness, says Wiest, an associate professor of neuroscience at Wellesley. “When it becomes accepted that the mind is a quantum phenomenon, we will have entered a new era in our understanding of what we are,” he says. The new approach “would lead to improved understanding of how anesthesia works, and it would shape our thinking about a wide variety of related questions, such as whether coma patients or non-human animals are conscious, how mysterious drugs like lithium modulate conscious experience to stabilize mood, how diseases like Alzheimer’s or schizophrenia affect perception and memory, and so on.”

More broadly, a quantum understanding of consciousness “gives us a world picture in which we can be connected to the universe in a more natural and holistic way,” Wiest says. Wiest plans to pursue future research in this field, and hopes to explain and explore the quantum consciousness theory in a book for a general audience.

Wellesley students who co-authored the paper with Wiest are Sana Khan ’25, Yixiang Huang ’25, Derin Timucin ’27, Shantelle Bailey ’24, Sophia Lee ’23, Jessica Lopes ’26, Emeline Gaunce ’26, Jasmine Mosberger ’25, Michelle Zhan ’24, Bothina Abdelrahman ’26 and Xiran Zeng ’27. Published September 1 in eNeuro , the Wellesley study demonstrates that anesthesia works by binding to microtubules inside neurons, thus providing important evidence for a quantum theory of consciousness while reviving a focus on microtubules in anesthesia.

eNeuro is the Society for Neuroscience's open-access journal.

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Ongoing Research Aims to Develop Standards for Lymphedema Therapy
Before & After Results
Understanding Lymphedema
Lymphedema Treatment Act
About Lymphedema
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Nanotechnology could treat lymphedema. When lymphatic vessels fail, typically their ability to pump out the fluid is compromised. Researchers have now developed a new treatment using nanoparticles ...
Primary lymphoedema
Taija Mäkinen. Nature Cardiovascular Research (2023) Lymphoedema is the swelling of one or several parts of the body owing to lymph accumulation in the extracellular space. It is often chronic ...
Avoiding the Swell: Advances in Lymphedema Prevention, Detection, and
Lymphedema is a feared complication of cancer treatments that negatively affects survivors' quality of life. The true incidence of lymphedema is difficult to determine given its long latency period. As the number of survivors of cancer is increasing in the United States, lymphedema is poised to be a major health concern. The most noteworthy risk factor for lymphedema is comprehensive lymph ...
Cell therapy as a treatment of secondary lymphedema: a systematic
Ten studies were included to investigate the effect of the cell therapy treatment on the lymphatic regeneration in secondary lymphedema. The overall pooled analysis showed a significant increase in lymphatic vessel density in experimental group versus control group (SMD 6.35; 95% CI 4.115, 8.581; p = 0.00).
Study finds first possible drug treatment for lymphedema
Based on the research, bestatin (also known as ubenimex), is being tested in a clinical trial that started in May 2016 — known as ULTRA — as a treatment for secondary lymphedema, which occurs because of damage to the lymphatic system from surgery, radiation therapy, trauma or infection. Primary lymphedema, on the other hand, is hereditary.
Cell therapy as a treatment of secondary lymphedema: a systematic
Lymphedema, the accumulation of interstitial fluid caused by poor lymphatic drainage, is a progressive and permanent disease with no curative treatment. Several studies have evaluated cell-based therapies in secondary lymphedema, but no meta-analysis has been performed to assess their efficacy. We conducted a systematic review and meta-analysis of all available preclinical and clinical studies ...
The Future of Lymphedema: Potential Therapeutic Targets for ...
Purpose of Review This review aims to summarize the current knowledge regarding the pharmacological interventions studied in both experimental and clinical trials for secondary lymphedema. Recent Findings Lymphedema is a progressive disease that results in tissue swelling, pain, and functional disability. The most common cause of secondary lymphedema in developed countries is an iatrogenic ...
Koya's NPCD device proves more effective than APCDs in lymphedema
Data from the TEAYS study (NCT05507346), published in the Journal of Vascular Surgery, found that Dayspring outperformed advanced pneumatic compression device (APCD) - the standard of care for treating lymphedema - in several areas.Patients using Dayspring saw a significantly greater reduction in limb volume (369.9mL versus 83.1mL) and experienced improved quality of life, with a mean ...
Anti-inflammatory drug effective for treating lymphedema symptoms
This new treatment doesn't cure lymphedema, but our studies show it has the capacity to make the illness more livable, more workable." ... Further research in mice showed that using ketoprofen to target LTB4 induced lymphatic repair and reversed the disease processes. This indicated that perhaps other therapies could reverse the negative ...
Overview of Lymphedema for Physicians and Other Clinicians: A Review of
Lymphedema has historically been underrated in clinical practice, education, and scholarship to the detriment of many patients with this chronic, debilitating condition. The mechanical insufficiency of the lymphatic system causes the abnormal accumulation of protein-rich fluid in the interstitium, which triggers a cascade of adverse consequences such as fat deposition and fibrosis. As the ...
Mayo Clinic study suggests lower extremity lymphedema is a risk factor
ROCHESTER, Minn. — New research from Mayo Clinic finds that patients with lymphedema —swelling of the limbs caused by the accumulation of protein-rich fluids of the immune system — had twice the risk of developing skin cancer than patients without lymphedema.. Patients with lymphedema had a significantly higher frequency of developing basal cell carcinomas and squamous cell carcinomas on ...
Lymphedema: New Concepts in Diagnosis and Treatment
Purpose of Review This review's aim is to coalesce current evidence regarding the lymphatic system and lymphedema, bridge the gap from traditional approaches to emerging concepts, and present simple strategies that can be immediately implemented into everyday clinical practice. Recent Findings New evidence of the microcirculation redefines all edema as lymphedema and having the potential to ...
Current diagnostic and quantitative techniques in the field of
Lymphedema evaluation entails multifaceted considerations for which options continue to evolve and emerge. This paper provides a critical review of the current status of diagnostic and quantitative measures for lymphedema, from traditional and novel bedside assessment tools for volumetric and fluid assessment, to advanced imaging modalities. Modalities are contrasted with regard to empirical ...
Biomarker for lipedema, other lymphatic diseases discovered
November 23, 2020 - By Tracie White. Stanley Rockson co-authored a paper that identified a biomarker for lipedema, a little understood fat disorder that is often confused with obesity. Steve Fisch. Throughout her life, Kristy has been told she was obese and needed to lose weight. She was teased and tormented for looking fat.
Lymphedema: From diagnosis to treatment
Abstract. Lymphedema is a chronic and progressive disorder resulting from impaired lymphatic system function. In developed countries, upper extremity lymphedema is mainly the consequence of breast cancer surgery in which axillary lymph node dissection and radiation alter upper extremity lymphatic flow. Diagnosis of lymphedema is made clinically.
Living with Lymphedema and Lymphatic Disease
154 West 14th Street, 2nd Floor, New York, NY 10011 The Lymphatic Education & Research Network is a tax-exempt 501(c)3 nonprofit organization. Our Identification ...
Lymphedema after Breast Cancer Treatment
Breast cancer-related lymphedema is the most common form of lymphedema in the United States and other developed nations. •. Axillary lymph-node dissection and adjuvant radiation therapy are ...
Alzheimer's: New CSU treatment could be "game-changing tool"
New treatment could be "game-changing tool" in fight against Alzheimer's, CSU research finds Combination of drugs targets two brain proteins critical in neuroinflammation involved in brain ...
Research Vessel Resilience Charts Course to the Future of Marine
"This new hybrid research vessel enables that work with fewer emissions and less impact on the ocean's wildlife." The RV Resilience is the latest in a series of investments that will grow PNNL's capabilities in marine technology research to continue advancing renewable energy, climate resilience and national security. ...
Funding awarded for research on bagworms, bubonic plague, ancient
Bloch, Porto and their colleagues will develop and use new artificial intelligence software to analyze these fossils and search for hidden patterns. They'll use these data to determine how functional diversity — which measures the range of ways organisms use resources in their environment — was altered in mammal communities during the ...
Wellesley
New research by Wellesley College professor Mike Wiest and a group of Wellesley College undergraduate students has yielded important experimental results relevant to this debate, by examining how anesthesia affects the brain. Wiest and his research team found that when they gave rats a drug that binds to microtubules, it took the rats ...

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