Latest Research

• Featured Articles: Lymphatic Research and Biology

  Lymphatic Research and Biology provides original, peer-reviewed research from a variety of investigative disciplines, including genetics, biochemistry and biophysics, cellular and molecular biology, physiology and pharmacology, anatomy, developmental biology, and pathology. Stay informed with these new articles available on Fast Track.

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• Top-Read Articles on Lymphedema from Lymphatic Research and Biology

  Lymphatic Research and Biology, the official journal of the Lymphatic Education & Research Foundation, provides original, peer-reviewed research from a variety of investigative disciplines, including genetics, biochemistry and biophysics, cellular and molecular biology, physiology and pharmacology, anatomy, developmental biology, and pathology. Stay informed with complimentary, two-week access, beginning today, to these top-read articles on lymphedema.

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• Cytokine Candidate Genes Predict the Development of Secondary Lymphedema Following Breast Cancer….

  Cytokine Candidate Genes Predict the Development of Secondary Lymphedema Following Breast Cancer Surgery
  Lymphedema (LE) is a frequent complication of breast cancer treatment. LE is caused by a disruption in the lymphatic system that results in the accumulation of fluid in the interstitial space.1 LE manifests as swelling of the affected limb and is associated with chronic pain, disfigurement, reduced mobility, functional impairment, predisposition to infections, and increased health care costs.2–5

  The true incidence of breast cancer-related LE is unknown, though estimates range from 6% to 83%.6 This wide variation is due to differences in diagnostic criteria, measurement techniques, timing of measurements, duration of follow-up, and sample characteristics.7,8 In a recent review of 11 prospective cohort studies,9 the median incidence rate for LE within 3 years of breast cancer treatment was 20%. In the United States, this rate would mean that more than 500,000 breast cancer survivors are affected by this incurable condition.10

  Research is often directed at identifying risk factors for LE with the hope of developing interventions to reduce its incidence.11 In our previous study,12 we identified both phenotypic and genotypic differences between women who did and did not develop LE following breast cancer treatment. The phenotypic characteristics associated with LE were increased body mass index (BMI), increased number of lymph nodes removed, higher stage of disease, and having had a sentinel lymph node biopsy (SLNB). In addition, a number of candidate genes in the lymphatic and angiogenesis pathways were identified as being associated with LE (i.e., lymphocyte cytosolic protein 2 (LCP2), neuropilin-2 (NRP2), protein tyrosine kinase (SYK), Forkhead box protein C2 (FOXC2), vascular cell adhesion molecule 1 (VCAM1), and vascular endothelial growth factor C (VEGFC)). While this study was novel in uncovering associations between LE and lymphatic and angiogenic candidate genes, further investigation is warranted to identify additional molecular pathways.

  Several studies have suggested that cytokines may be involved in the pathophysiology of LE.13,14 Cytokines play a key role in modulating inflammatory responses, which may subsequently lead to lymphatic dysfunction and LE.13 In a study that used a specific bioassay and performed transcriptional microarray analysis on human skin,15 a number of cytokine genes (i.e., interleukin (IL) 4, IL6, IL10, IL13) were upregulated in LE specimens. In another study that investigated the role of inflammation in the regulation of fibrosis and lymphatic dysfunction,14 the blockade of T-helper 2 cytokines, including IL-4 and IL-13, prevented T-cell differentiation and its subsequent inflammatory response in a mouse-tail model of LE. This blockade resulted in less fibrosis and improved lymphatic function. Findings from these studies suggest that variations in cytokine genes may account for some of the differences in the development of LE. Therefore, the purpose of this study was to determine if variations in pro-and anti-inflammatory cytokine genes were associated with the development of LE following breast cancer treatment.

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• Mast Cell-Directed Recruitment of MHC Class II Positive Cells and Eosinophils Towards Mesenteric….

  Mast Cell-Directed Recruitment of MHC Class II Positive Cells and Eosinophils Towards Mesenteric Lymphatic Vessels in Adulthood and Elderly
  
  Abstract
  Background: Aging impairs mesenteric lymph flow, which is crucial for fluid and macromolecule homeostasis, fat absorption, and immune function. Previously, we demonstrated that mast cells (MCs) line mesenteric lymphatic vessels (MLVs) with a greater degree of basal activation of MCs in aged mesentery. The number of intact MCs available to react acutely to inflammatory stimuli was decreased with age. However, the role of mast cells in recruiting other immune cells towards MLVs and its aging-associated alterations has not been explored before in great detail.

  Methods and Results: In this study we treated live mesenteric tissue isolated from Sprague Dawley (SD) rats, as well as adult 9-mo and aged 24-mo Fischer-344 (F-344) rats for 2 hours with MC activators (48/80 and Substance P) and performed whole mount IHC and vital dye staining of the mesenteric segments containing MLVs to identify immune cell recruitment towards MLVs after mast cell (MC) activation. Number of major histocompatibility complex (MHC) class II positive APCs and eosinophils near MLVs was counted and compared between treatments and ages.

  Conclusions: With greater density of MCs near MLVs, we for the first time demonstrated that mesenteric MC activation by compound 48/80 and Substance P resulted in recruitment of MHC class II positive cells and eosinophils towards MLVs. This effect was reduced in cromolyn-injected rats, thus confirming that MCs are necessary for such recruitment. The immune cell presence near MLVs after MC activation was reduced in aged tissues. We link these findings to our previous report of lesser number of intact MCs available for initiating an acute immune response in aged mesentery. Cumulatively, these findings serve as the first step in study of the aging-associated mechanisms that link MCs, lymphatic vessels, and disordered immune function in the elderly.

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• Pressures and Timing of Intermittent Pneumatic Compression Devices for Efficient Tissue Fluid and Ly

  Abstract

  
  Pneumatic compression of tissues with lymph stasis is, aside from the manual massage, a commonly used therapeutic modality in limb lymphedema. A number of pneumatic devices have been constructed. There is lack of reports of comparative studies determining inflation pressure levels, inflation/deflation cycle times, and total pumping times.

  Aim: We tried to answer the question how high compression pressure and how long compression timing should be applied to the limb soft tissues to reach tissue fluid (TF) head pressure above 30 mmHg, necessary to initiate proximal flow.

  Methods: TF pressures were measured subcutaneously during intermittent pneumatic compression in the lymphedematous limbs stage II to IV. Pressures of 50, 80, and 120 mmHg and timing 5, 20, and 50 sec were applied.

  Results: a) the TF head pressures were lower than those in inflated chambers, b) inflation time of 5 and 20 sec was not long enough to generate TF head pressures above 30 mmHg, even if the compression pressures were as high as 120 mmHg, c) the 50 sec timing allowed to reach head pressures above 30 mmHg; however, they remained always lower than in the compression chamber, d) TF head pressures differed at various levels of the limb depending on the soft tissue mass, e) deflation of the inflated whole sleeve for 5 and 20 sec was followed by high end pressures, whereas that of 50 sec brought about pressure drop to 0, facilitating refilling with TF of the distal parts of the massaged limb.

  Conclusions: Our observations point to the necessity of applying high pressures and compression times over 50 sec, to generate effective TF pressures and provide enough time for creating TF flow. Short inflation times generate TF pressures as in one-chamber devices that preclude its effectiveness compared to the multi-chamber devices.

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• A New Soft Tissue Volume Measurement Strategy Using Ultrasonography

  Various techniques are available for measuring the status of lymphedema. A modified imaging technique using ultrasonography was developed to measure the structure of soft tissue area in a cost-effective manner. The purpose of this study was to measure the reliability and the accuracy of this new method. Ultrasonography was performed on both arms of twenty healthy female participants. At 10 cm above (AE) and below (BE) the elbow crease, soft tissue thickness at medial, lateral, inferior, and superior locations were measured by two examiners with minimal unnecessary pressure. After measuring twice on 16 sites for each participant, the amount of soft tissue in the cross-sectional area (ΔCSA) was acquired by a designed formulation. The ΔCSA was also compared with volumetry data (Perometer®). Cronbach’s alpha coefficient test was used for statistics. The intra-class and inter-class reliability measurements for all soft tissue areas were very strong (α=0.980 and 0.960, respectively; p<0.01). All AE and BE reliabilities showed very strong correlation and strong correlation of inter-BE measurement. All reliabilities of ΔCSA were very strong (≥0.950). All CCs (correlation coefficients) between ΔCSA, circumference, and volumetry were strong for AE and BE measurements, except for ΔCSA and circumference at BE. The strongest CC was between volumetry and circumference measurements. This study suggests that measuring the ΔCSA by ultrasonography could be an alternative way to measure the status of soft tissue indirectly with structural consideration.

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• Diagnosis and Treatment of Primary Lymphedema
  Consensus Document of the International Union of Phlebology (IUP)-2013
  
  Abstract
  Primary lymphedema can be managed effectively as a form of chronic lymphedema by a sequenced and targeted treatment and management program based around a combination of Decongestive Lymphatic Therapy (DLT) with compression therapy, when the latter is desired as an adjunct to DLT. Treatment in the maintenance phase should include compression garments, self-management, including self-massage, meticulous personal hygiene and skin care, in addition to lymphtransport-promoting excercises and activities, and, if desired, pneumatic compression therapy applied in the home. When conservative treatment fails, or gives sub-optimal outcomes, the management of primary lymphedema can be improved, where appropriate, with the proper addition of surgical interventions, either reconstructive or ablative. These two surgical therapies can be more effective when fully integrated with manual lymphatic drainage (MLD)-based DLT postoperatively. Compliance with a long-term commitment to MLD/DLT and particularly compression postoperatively is a critical factor in determining the success of any new treatment strategy involving either reconstructive or palliative surgery. The future of management of primary lymphedema has never been brighter with the new prospect of gene-and perhaps stem-cell oriented management. Learn More >
• Diagnosis and Treatment of Primary Lymphedema.
  Consensus Document of the International Union of Phlebology (IUP)-2013.
  
  Abstract
  Primary lymphedema can be managed effectively as a form of chronic lymphedema by a sequenced and targeted treatment and management program based around a combination of Decongestive Lymphatic Therapy (DLT) with compression therapy, when the latter is desired as an adjunct to DLT. Treatment in the maintenance phase should include compression garments, self-management, including self-massage, meticulous personal hygiene and skin care, in addition to lymphtransport-promoting excercises and activities, and, if desired, pneumatic compression therapy applied in the home. When conservative treatment fails, or gives sub-optimal outcomes, the management of primary lymphedema can be improved, where appropriate, with the proper addition of surgical interventions, either reconstructive or ablative. These two surgical therapies can be more effective when fully integrated with manual lymphatic drainage (MLD)-based DLT postoperatively. Compliance with a long-term commitment to MLD/DLT and particularly compression postoperatively is a critical factor in determining the success of any new treatment strategy involving either reconstructive or palliative surgery. The future of management of primary lymphedema has never been brighter with the new prospect of gene-and perhaps stem-cell oriented management. Learn More >
• Adiponectin-mediated modulation of lymphatic vessel formation and lymphedema
  Abstract
  Obesity is linked with an increased risk of lymphedema, which is a serious clinical problem. Adiponectin is a circulating adipokine that is down-regulated in obese states. We investigated the effects of adiponectin on lymphatic vessel formation in a model of lymphedema and dissected its mechanisms. Learn More >
• The Lymphatics and the Inflammatory Response: Lessons Learned from Human Lymphedema
  In lymphedema, there is a profound predisposition to infection with bacterial pathogens. It therefore seems appropriate to reconsider our unique functional definition of the lymphatic structures within a circulatory construct. While the lymphatics unquestionably fulfill a vital circulatory function, it seems more appropriate to view this complex network, comprised both of endothelial-lined vessels and of lymphoid tissue, as the nexus between the circulatory and immune systems. Viewed in this fashion, it becomes evident that the complex biology of regional lymphatic disruption is a manifestation of the interplay between these two vital bodily functions. Experimental lymph stasis in murine model has been utilized to effectively demonstrate the pathological attributes of human lymphedema, namely, inflammation, fat deposition, and fibrosis. Large-scale transcriptional corroborates the role of inflammatory mechanisms. The murine studies have set the stage for subsequent translational investigation of human lymphedema. Many of the gene expression pathways invoked by lymphedema are relevant to the inflammatory response and have provided a pragmatic approach to the successful identification of potentially relevant circulating biomarkers for human lymphedema. Learn More >
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