Emerging Lymphedema Technologies & Treatment

This section of our website is dedicated to exploring some of the latest developing technologies and emerging treatment approaches underway worldwide to address the issue of lymphedema and lymphatic related conditions. Although these approaches are not widely available we believe it is worthwhile to stay informed concerning emerging technologies and treatments.

Emerging Technologies


Emerging Treaments

Emerging Technologies:

Bio-impedance Spectroscopy (BIS):

Until recently lymphedema was assessed based on water displacement measures and/or sum of arm circumference measures both of which were generally performed after signs and symptoms of lymphedema were observed. With recent technological developments in Bio-impedance Spectrometry (BIS) researchers and clinicians are now able to assess the incidence of lymphedema much more readily at a sub-clinical stage before any signs or symptoms of the condition are evident.

Bio-impedance spectrometry has been shown to be accurate relative to the common ‘gold standard’ of water displacement and sum of arm circumferences. In addition, there is a published study documenting inter-observer and intra-observer reliability (i.e. reproducibility) of BIS measurements using the U400 device by Impedimed. For further detail scientific journal references are listed below.

Bio-impedance Spectroscopy is a refinement and further development of the use of electrical impedance devices originally designed to measure body composition. BIS devices utilize frequency dependent electrical current flow characteristics to quantify changes in extracellular fluid levels in an individual limb. The existence of increased extracellular fluid, which constitutes lymphedema, can be determined by comparing impedance measures between the affected and unaffected limbs even prior to signs or symptoms of lymphedema being present.

Further refinements of BIS devices are currently underway to allow assessment of bi-lateral lymphedema. These new devices will calculate the difference in extracellular and intracellular fluid levels to assess lymphedema. Very recent studies show that there is no change in intracellular fluid levels in lymphedemic tissue hence increases in extracellular fluid levels relative to intracellular levels will constitute lymphedema.

BIS devices can be also be used to establish pre-operative and post-operative extracellular fluids levels of patients thereby improving efforts at early detection and early intervention. Changes in the impedance measures can assist medical personnel in assessing early signs of lymphedema and as a result enabling early treatment of the condition before the individual becomes symptomatic.

These devices are also useful in tracking clinical progress in the treatment of an existing lymphedema and assessing the benefits of one treatment method relative to alternative treatment approach. BIS measurements are unaffected by changes in the patient’s weight as a result of changes in fat or muscle mass. As well the portability of the BIS devices now allow for gathering lymphedema prevalence information in many more clinical settings.

References:

Czerniec, S., et al., Segmental measurement of breast cancer-related arm lymphoedema using perometry and bioimpedance spectroscopy. Support Care Cancer, 2010.

Ward, L.C., S. Czerniec, and S.L. Kilbreath, Operational equivalence of bioimpedance indices and perometry for the assessment of unilateral arm lymphedema. Lymphat Res Biol, 2009. 7(2): p. 81-5.

Moseley, A. and N. Piller, Reliability of bioimpedance spectroscopy and tonometry after breast conserving cancer treatment. Lymphat Res Biol, 2008. 6(2): p. 85-7.

Ward, L.C., S. Czerniec, and S.L. Kilbreath, Quantitative bioimpedance spectroscopy for the assessment of lymphoedema. Breast Cancer Res Treat, 2009. 117(3): p. 541-7.Smoot, B.J., J.F.

Wong, and M.J. Dodd, Comparison of diagnostic accuracy of clinical measures of breast cancer-related lymphedema: area under the curve. Arch Phys Med Rehabil, 2011. 92(4): p. 603-10.

Ward, L., Is BIS ready for prime time as the gold standard measure? Journal of Lymphoedema, 2009. 4(2): p. 52-56.

Jain, M.S., J.V. Danoff, and S.M. Paul, Correlation between bioelectrical spectroscopy and perometry in assessment of upper extremity swelling. Lymphology, 2010. 43: p. 85-94.

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Lymphoscintigraphy:

Lymphoscintigraphy is a specialized nuclear medicine imaging technique that provides pictures or scintigrams of the lymphatic system. As the lymphatic system is a delicate network of small vessels similar to blood vessels it can be mapped using radioactive tracer materials.

Unlike blood vessels the lymphatic system circulates lymph fluid, antigens, dead cell particles, large lipids, proteins and immunological agents in only one direction into the venous blood system of the body. The lymphatic system flows through the lymph nodes into major lymphatic ducts and terminates in the sub-clavian veins.

Due to the fact that the lymphatic fluid only flows one direction radioactive tracers can be injected distally into a limb or region of the body then radioactive emissions from the radiotracer can be detected by a special camera or imaging device that produces pictures and detailed molecular information concerning the integrity of the lymphatic system. Images from this technology show the location of where the lymphatic system is blocked or disrupted and whether any alternative lymphatic pathways are available to move lymph from an affected limb or region.

Lymphedema develops when the lymphatic system is unable to carry large proteins and lymph fluid away from a region of the body. This can occur from either primary or secondary causes such as congenital malformations of the lymphatic system as it develops or through accident, injury, radiation, surgery or inflammation.

Visual information provided by lymphoscintigraphy allows a more informed diagnosis of lymphedema by a physician as well as identifying those individuals who are ‘at risk’ for developing lymphedema. This information can inform clinical practice by enabling early interventions for ‘at risk’ individuals.

Scintigrams of the lymphatic system also allow Combined Decongestive Therapists to stimulate lymphatic flow into available pathways and away from disrupted or blocked regions.

Lymphoscintigraphy also has the potential to inform surgeons and radiologists with respect to whether the treatment protocol for a particular individual puts them at risk for lymphedema.

The following video provides a general overview of lymphoscintigraphy.

 

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Emerging Treatments:

Surgical Interventions

The following information provides a general overview of a number of emerging surgical procedures that are being investigated and in some cases practiced in isolated situations around the world in an attempt to improve lymphatic system function following the diagnosis of lymphedema. Currently these procedures are not widely available and have generally been undertaken in Europe, Japan and the United States.

Lymphatic Vessel Transplants

This procedure involves transplanting lymphatic collector vessels from a functioning region of the body into the lymphedemic limb in order to bypass a disrupted or underdeveloped lymphatic region. The intent of the transplant is to allow lymph flow from the limb into a properly functioning portion of the lymphatic system. To-date only two Canadians have received this procedure one in 2003 in Innsbruck, Austria by Prof. Dr. Pisa at the University of Innsbruck and the second in 2010 by Dr. R.G. Baumeister in Munich, Germany. Both these individuals had a diagnosis of primary lymphedema however surgeries are being performed for secondary lymphedemas as well.

At this point in time Dr. C. Campesi in Genoa, Italy now performs the majority of lymphatic transplant surgeries.   For more detailed information please reference the following studies:

Campisi, C, D Davini, C Bellini, et al:
Lymphatic microsurgery for the treatment of lymphedema. Microsurgery 26 (2006), 65-69.

Weiss, M, RG Baumeister, K Hahn: Dynamic lymph flow imaging in patients with oedema of the lower limb for the evaluation of the functional outcome after autologous lymph vessel transplantation: An 8-year follow-up study. Eur. J. Nucl. Med. Mol. Imaging 30 (2003), 202-206

Mawgawa, J, T Mikami, Y Yamamoto, et al: Types of lymphoscintigraphy and indications for lymphaticovenous anastomosis. Microsurgery 30 (2010), 437-442.

Campisi, C, F Boccardo: Microsurgical techniques for lymphedema treatment: derivative lymphatic-venous microsurgery. World J Surg. 28 (2004), 609-13.

Campisi, C, F Boccardo: Microsurgery for Lymphedema: A Real Possibility for a Cure. Department of Surgery, Unit of Lymphatic Surgery, S.Martino Hospital, University of Genoa, Italy

Click here to visit the European Lymphology Society's website partially dedicated to Lymphatic Vessel Transplant

Lymph Node Transplants

Surgical lymph node transplants are also being undertaken to correct a disrupted lymphatic system. This procedure involves transplanting functioning lymph nodes from unaffected areas and connecting the node to lymphatic collectors from the affected area. Some research has been done on this approach at Sunnybrook Hospital in Toronto however the practice is not widespread in Canada. Considerable debate and experimentation is currently ongoing throughout the world with respect to this surgical technique. Please consider the following research studies for further details concerning this approach.

Lin, CH, R Ali, SC Chen, et al: Vascularized groin lymph node tramsfer using the wrist as a recipient site for management of postmastectony upper extremity lymphedema. Plast. Reconstr. Surg. 123 (2009), 202-206

Lymphaticovenous Anastamosis Surgery

In general terms this surgery involves connecting functioning lymphatic vessels in an edemic region or limb to the venous side of the circulatory system upstream of the lymphatic disruption. This involves bypassing regional lymph nodes and streaming the lymph fluid directly into the venous blood system. Often there are a number of surgical anastamosis sites outside the vicinity of the disruption and located such that they will not cause future limitations to any aspect of the lymphatic system that currently drains the area.

Lymphoscintigraphy is being used in conjunction with this surgical approach to identify the most appropriate anastamosis sites as well as the type of lymphedema patients most suited for anastamosis surgery.

For more detailed information concerning this procedure please reference the following studies:

T. Mikami, M. Hosono, T. Tabuki, Y. Yamamoto, K. Yasumura, H. Sawada, K. Shizukuishi, J.Mawgawa: Classification of lymphoscintigraphy and relevance to surgical indication for lymphaticovenous anastomosis in upper limb lymphedema. Lymphology Journal Vol. 44 Num. 4 (2011) 155-166

Demirtas, Y, N Ozturk, O Yapici, et al: Supermicrosurgiacal lymphaticovenular anastomosis and lymphaticovenous implantation for treatment of unilateral lower extremity lymphdedema. Microsurgery 29 (2009), 609-618

Mawgawa, J, T Mikami, Y Yamamoto, et al: Types of lymphoscintigraphy and indications for lymphaticovenous anastomosis. Microsurgery 30 (2010), 437-442.

Pharmacological Solutions

The following Press Release is the first indication of any promising pharmacological-based therapy for addressing lymphedema.

PRESS RELEASE March 6, 2012, 2:30 p.m. EST

Research Team Discovers Four-Fold Improvement in Ability to Restore Lymphatic Function With Adenovirally-Delivered VEGF-C Gene Therapy After Lymph Node Transplant Surgery Compared to the Surgery Alone On Lymphedema Awareness Day, Researchers Present Pre-Clinical Data Offering Cautious Hope for Breast Cancer Patients Suffering From Secondary Lymphedema

VENTURA, CA, Mar 06, 2012 (MARKETWIRE via COMTEX) --  Lymphedema Awareness Day was established to support the needs of patients with lymphedema and to raise awareness for the need to develop new treatment options.

Today, researchers have presented investigational pre-clinical data on the first potential pharmacologic agent used in combination with surgery for the treatment of breast cancer associated lymphedema at the Gordon Research Conference for Molecular Mechanisms in Lymphatic Function & Disease.

Currently there is no advanced pharmacologically-based therapeutic for lymphedema," said Stanley G. Rockson, MD, Director, Center for Lymphatic and Venous Disorders, Stanford University School of Medicine, and Principal Investigator of the upcoming "first in human" trial for Lymfactin.

"Although the research is still early, the preliminary data show a remarkable improvement in the ability to successfully conduct lymph node transplant surgery with the benefit of Lymfactin."

Lymphedema occurs in about 20 percent of the three million patients with breast cancer. The condition occurs from trauma to the lymph nodes, and blockages in the lymphatic system as a result of breast cancer treatment. The symptoms include painful swelling and inflammation of the limbs. Turku, Finland-based Laurantis Pharma Oy is developing Lymfactin(TM), a vascular endothelial growth factor C (VEGF-C) in an adenoviral vector, for the treatment of secondary lymphedema associated with breast cancer. The therapy with Lymfactin involves a surgical operation where a lymph node flap is harvested from the patient's lower abdominal wall and injected with Lymfactin, which leads to the transient presence of the adenovirus containing the VEGF-C gene. The lymph node is then transferred to the axillary region.

"This new treatment is very promising," said Wendy Chaite, Founder, Lymphatic Research Foundation, a national organization devoted to advancing lymphatic research and to finding improved treatments and cures for lymphedema and lymphatic diseases.

"Lymphedema is one of those seldom discussed but far too common conditions that biotech and pharmaceutical companies have yet to explore. Although this research is at an early stage, the lack of any advanced treatments makes this research all the more important for those who suffer from this condition."

Professor Kari Alitalo of the University of Helsinki, who made the discovery that the growth factor VEGF-C regulates the growth and development of the lymphatic system in humans and other mammals, presented the findings. From this discovery and in association with his co-workers Dr. Tuomas Tammela and Dr. Anne Saaristo, they identified that if VEGF-C is injected into tissues in mice and subsequently in pigs, growth of new lymphatic vessels and the restoration of the lymphatic architecture is catalyzed. Previous studies have shown that transferring lymph nodes from the inguinal region to the axillary region in patients with secondary lymphedema following their treatment for breast cancer was found to offer a slight improvement in their condition. Removal of old scar tissue from the axilla is considered an important step of this procedure. The team in Finland then went a step further and showed that by combining VEGF-C injections with lymph node transfer in animal models using mice and then pigs, the response seen was even better than lymph node transfer alone. The results in mice indicated that lymphedema treated with lymph node transfer alone resulted in about 20% improvement. However, when combined with the administration of VEGF-C, the overall response was increased to around 80%. In collaboration with Dr. Rockson, Dr. Anne Saaristo, MD and Prof. Kari Alitalo, Laurantis researchers, are developing a treatment to potentially enable much higher transfer success. The Company plans to start a phase I/II study in patients with breast cancer associated lymphedema in early 2013. Lymfactin is an investigational therapy and has not been approved by the U.S. Food and Drug Administration. Target Indication: Breast Cancer Associated Lymphedema

The impairment of lymphatic drainage caused by dysfunction of the lymphatic vasculature leads to an accumulation of proteins and associated fluid, and finally to lymphedema -- a chronic progressive swelling of the affected tissues. Lymphedema can either be hereditary -- in which case it is diagnosed as "primary lymphedema" -- or it can occur as a consequence of a disease, trauma, surgery, or radiotherapy and thereby diagnosed as secondary lymphedema. Current treatment of lymphedema focuses on minimizing swelling, controlling pain, preventing infection, and improving the patient's overall quality of life. Treatments include exercise, wrappings, massage, pneumatic compression and compression garments. In severe cases of lymphedema, a surgery may be considered to remove excess tissue in the limb. While this reduces severe swelling, surgery cannot cure lymphedema. Scientific Rationale Vascular endothelial growth factors (VEGFs) are involved naturally in all types of vascular growth and are capable of directly inducing the growth of blood or lymphatic vessels in vivo. Vascular endothelial growth factor receptor 3 (VEGFR-3) is a major signaling pathway for lymphangiogenesis (growth of new lymphatic vessels) and is a high-affinity receptor for VEGF-C and VEGF-D.VEGF-C and VEGF-D induce the growth of lymphatic vessels through VEGFR-3 and are the primary growth factors associated with lymphatic vessel growth. VEGFR-3 signaling is required for the survival and maintenance of lymphatic vessels during embryonic development and inactivating mutations in VEGFR-3 lead to lymphedema and incomplete development of lymphatic vasculature in both mice and humans. VEGF-C is currently the only known growth factor that is both potent and specific enough to potentially be used in a lymphedema therapy.

Preclinical Data Laurantis has shown in the preclinical studies that adenovirally-delivered VEGF-C is the optimal growth factor for a lymphedema therapy. In a series of experiments, the effects of adenovirally-delivered VEGF-C were compared to controls in which seroma formation, lymphatic vessel function, lymph node morphology and histology were studied. Two months after transfer, VEGF-C-treated lymph nodes were larger than the treated controls and more lymph vessels had been formed. Adenovirally-delivered VEGF-C in support of lymph node transfer is a viable option for the treatment of lymphedema. About Laurantis Pharma Laurantis Pharma is a clinical-stage specialty pharmaceutical development company with a broad portfolio of first-in-class products based on two proprietary technologies. The Company's lead products target the treatment of a variety of inflammatory diseases and conditions including lymphatic disorders, atopic dermatitis, dry eye syndrome, and interstitial cystitis, as well as the treatment of bladder cancer. The Company's pipeline includes proprietary and patent-protected formulations and applications of cis-urocanic acid (cis-UCA), a locally acting anti-inflammatory and anti-proliferative agent. Laurantis Pharma is also developing Lymfactin(TM), a vascular endothelial growth factor C (VEGF-C) in an adenoviral vector, for the treatment of secondary lymphedema. Laurantis Pharma is located in Turku, Finland.

More information can be found at www.laurantis.com.             

CONTACT: David Sheon       

1 202 422-6999

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Genetic Investigations

To-date little is known about the genetic factors underlying lymphedema although recent investigations have identified five genes (VEGFR3, FOXC2, SOX18, HGF, MET) responsible for causing Primary Lymphedema. Clinical genetic testing is currently available for three of these genes (VEGFR3, SOX18 & HGF). Although it is known that mutations of these genes can have multiple effects considerable work remains to be done to track the outcomes of the mutations. Recent work published by the University of Pittsburgh has linked some genetic mutations to dysfunctions in the lymphatic system. 

Research is also underway at the University of Missouri under the direction of Dr. Jane Armer investigating the role that genetic predisposition may play in acquiring secondary lymphedema. Genetic research into lymphedema also continues at numerous universities across the United States and Europe.

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