• Korean Journal of Radiology
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• v.24 no.2
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• pp.109-132
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• 2023

Lymphatic disorders encompass a broad spectrum of diseases involving the lymphatic system, ranging from traumatic lymphatic leaks to lymphatic malformations. Lymphatic disorders can be categorized into traumatic and non-traumatic disorders according to their etiology. These two categories may be further divided into subgroups depending on the anatomical location of the lymphatic pathology and their association with clinical syndromes. Thoracic duct embolization was a milestone in the field of lymphatic intervention that encouraged the application of percutaneous embolization techniques to treat leaks and reflux disorders in the lymphatic system. Additional access routes for embolization, including retrograde thoracic duct and transhepatic lymphatic access, have also been developed. This article comprehensively reviews a variety of options for the treatment of lymphatic disorders, from conservative management to the most recent embolization techniques.

• Korean Journal of Radiology
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• v.24 no.2
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• pp.95-108
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• 2023

Recent advances in lymphatic imaging have provided novel insights into the lymphatic system. Interventional radiology has played a significant role in the development of lymphatic imaging techniques and modalities. Radiologists should be familiar with the basic physiology and anatomy of the lymphatic system to understand the imaging features of lymphatic disorders, which reflect their pathophysiology. This study comprehensively reviews the physiological and anatomical aspects of the human lymphatic system as well as the latest lymphatic imaging techniques.

• Molecules and Cells
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• v.37 no.7
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• pp.503-510
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• 2014

Lymphatic vessels provide essential roles in maintaining fluid homeostasis and lipid absorption. Dysfunctions of the lymphatic vessels lead to debilitating pathological conditions, collectively known as lymphedema. In addition, lymphatic vessels are a critical moderator for the onset and progression of diverse human diseases including metastatic cancer and obesity. Despite their clinical importance, there is no currently effective pharmacological therapy to regulate functions of lymphatic vessels. Recent efforts to manipulate the Vascular Endothelial Growth Factor-C (VEGFC) pathway, which is arguably the most important signaling pathway regulating lymphatic endothelial cells, to alleviate lymphedema yielded largely mixed results, necessitating identification of new targetable signaling pathways for therapeutic intervention for lymphedema. Zebrafish, a relatively new model system to investigate lymphatic biology, appears to be an ideal model to identify novel therapeutic targets for lymphatic biology. In this review, we will provide an overview of our current understanding of the lymphatic vessels in vertebrates, and discuss zebrafish as a promising in vivo model to study lymphatic vessels.

• Journal of Pharmaceutical Investigation
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• v.40 no.spc
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• pp.75-82
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• 2010

Specific diseases like cancer and acquired immune deficiency syndrome (AIDS) occur at various organs including lymphatics and spread through lymphatic system. Thus, if therapeutic agents for such diseases are more distributed or targeted to lymphatic system, we can obtain several advantages like reduction of systemic side effect and increase of efficacy. For these reasons, much interest has been focused on the nature of lymphatics and a lot of studies for lymphatic delivery of drugs have been carried out. Because lymphatics consist of single layer endothelium and have high permeability compared with blood capillaries, especially, the studies using nano-sized carriers have been performed. Polymeric nano-particle, liposome, and lipid-based vehicle have been adopted for lymphatic delivery as carriers. According to the administration route and the kind of carrier, the extent of lymphatic delivery efficiency of nano-sized carriers has been changed and influenced by several factors such as size, charge, hydrophobicity and surface feature of carrier. In this review, we summarized the key factors which affect lymphatic uptake and the major features of carriers for achieving the lymphatic delivery. Lymphatic delivery of drug using nano-sized carriers has many fold improved ability of lymphatic delivery compared with that of conventional dosage forms, but it has not shown whole lymph selectivity yet. Even though nano-sized carriers still have the potential and worth to study as lymphatic drug delivery technology as before, full understanding of delivery mechanism and influencing factors, and setting of pharmacokinetic model are required for more ideal lymphatic delivery of drug.

• Molecules and Cells
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• v.37 no.3
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• pp.270-274
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• 2014

Lymphatic vessels are essential to regulate interstitial fluid homeostasis and diverse immune responses. A number of crucial factors, such as VEGFC, SOX18, PROX1, FOX2C, and GJC2, have been implicated in differentiation and/or maintenance of lymphatic endothelial cells (LECs). In humans, dysregulation of these genes is known to cause lymphedema, a debilitating condition which adversely impacts the quality of life of affected individuals. However, there are no currently available pharmacological treatments for lymphedema, necessitating identification of additional factors modulating lymphatic development and function which can be targeted for therapy. In this report, we investigate the function of genes associated with Bone Morphogenetic Protein (BMP) signaling in lymphatic development using zebrafish embryos. The knock-down of BMP type II receptors, Bmpr2a and Bmpr2b, and type I receptors, Alk3 and Alk3b, as well as SMAD5, an essential cellular mediator of BMP signaling, led to distinct lymphatic defects in developing zebrafish. Therefore, it appears that each constituent of the BMP signaling pathway may have a unique function during lymphatic development. Taken together, our data demonstrate that BMP signaling is essential for normal lymphatic vessel development in zebrafish.

• BMB Reports
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• v.54 no.6
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• pp.285-294
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• 2021

The lymphatic vasculature plays important role in regulating fluid homeostasis, intestinal lipid absorption, and immune surveillance in humans. Malfunction of lymphatic vasculature leads to several human diseases. Understanding the fundamental mechanism in lymphatic vascular development not only expand our knowledge, but also provide a new therapeutic insight. Recently, Hippo-YAP/TAZ signaling pathway, a key mechanism of organ size and tissue homeostasis, has emerged as a critical player that regulate lymphatic specification, sprouting, and maturation. In this review, we discuss the mechanistic regulation and pathophysiological significant of Hippo pathway in lymphatic vascular development.

• Maxillofacial Plastic and Reconstructive Surgery
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• v.36 no.3
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• pp.85-93
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• 2014

Purpose: Nodal metastasis is the main prognostic factor in the patients with oral squamous cell carcinoma (OSCC). We investigated the association between tumor-associated lymphatics and OSCC characteristics. Methods: Thirty-four specimens were used for the immunohistochemical staining with the antibody for vascular endothelial growth factor (VEGF)-C, VEGF-D, VEGF receptor (VEGFR)-3, phosphorylated VEGFR-3, D2-40, and matrix metallproteinases (MMPs). We observed the distribution of the lymphangiogenic factors and quantified the degree of expression. We determined lymphatic vessel density (LVD) and lymphatic vessel dilatation with D2-40 immunostaining. We assessed the association of LVD or lymphatic vessel dilatation with tumor progression or tumor differentiation. Results: OSCC cells expressed lymphangiogenic ligands. Lymphangiogenic receptor, VEGFR-3, was expressed and activated in some tumor cells as well as in tumor-associated endothelial cells. LVD was not associated with tumor size or nodal status, but lymphatic vessel dilatation was higher in tumors with nodal metastasis, and also higher in poorly differentiated tumors. In stromal area of OSCC, MMP-1 and MMP-10 were up-regulated and the basement membrane of tumor-associated endothelial cells was destroyed by these collagenases. Conclusion: In the primary tumors with nodal metastasis, especially in poorly differentiated OSCC, tumor cells invaded the dilated lymphatic vessels via ruptured sites. MMP-1 and MMP-10 are important in the lysis of the glycocalyx inside the tumor-associated lymphatic endothelial cells.

• Journal of Gastric Cancer
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• v.10 no.2
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• pp.55-62
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• 2010

Purpose: We evaluated the clinicopathological charicterics and prognostic impacts of lymphatic vessel invasion in gastric cancer without lymph node involvement. Materials and Methods: Among 1,795 patients who underwent gastric surgery with gastric cancer at the department of surgery, Hanyang university college of medicine from June 1992 to March 2009, we retrospectively evaluated 890 patients with lymph node negative gastric cancer. Results: The lymphatic vessel invasion correlated significantly with tumor stage, age, tumor size, perineural invasion and operation method. The survival rates were only significantly different between the patients with and without lymphatic vessel invasion in patients with stage Ia (P=0.036). Univariate and multivariate analysis demonstrated that blood vessel invasion and preoperative serum CEA level were significant factor influencing the survival rate in lymph node negative gastric cancer patients with lymphatic invasion. Conclusions: In patients with lymph node negative gastric cancer, the survival rate is significantly lower in those with lymphatic vessel invasion than in those without. Especially, in patients with stage Ia gastric cancer, the survival rates is significantly different between those with and those without lymphatic vessel invasion. Blood vessel invasion and preoperative serum CEA level is an adverse prognostic indicator in patients with stage Ia gastric cancer with lymphatic invasion. Thus we should consider further adjuvant therapies in case of need and need to show more concern to identify gastric cancer patients early at risk for recurrence.

• Archives of Plastic Surgery
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• v.49 no.1
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• pp.99-107
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• 2022

Background Dermal backflow (DBF), which refers to lymphatic reflux due to lymphatic valve insufficiency, is a diagnostic finding in lymphedema. However, the three-dimensional structure of DBF remains unknown. Photoacoustic lymphangiography (PAL) is a new technique that enables the visualization of the distribution of light-absorbing molecules, such as hemoglobin or indocyanine green (ICG), and can provide three-dimensional images of superficial lymphatic vessels and the venous system. This study reports the use of PAL to visualize DBF structures in the extremities of patients with lymphedema after cancer surgery. Methods Patients with a clinical or lymphographic diagnosis of lymphedema who previously underwent surgery for cancer at one of two participating hospitals were included in this study. PAL was performed using the PAI-05 system. ICG was administered subcutaneously in the affected hand or foot, and ICG fluorescence lymphography was performed using a near-infrared camera system prior to PAL. Results Between April 2018 and January 2019, 21 patients were enrolled and examined using PAL. The DBF was composed of dense, interconnecting, three-dimensional lymphatic vessels. It was classified into three patterns according to the composition of the lymphatic vessels: a linear structure of lymphatic collectors (pattern 1), a network of lymphatic capillaries and lymphatic collectors in an underlying layer (pattern 2), and lymphatic capillaries and precollectors with no lymphatic collectors (pattern 3). Conclusions PAL showed the structure of DBF more precisely than ICG fluorescence lymphography. The use of PAL to visualize DBF assists in understanding the pathophysiology and assessing the severity of cancer-related lymphedema.

• IMMUNE NETWORK
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• v.14 no.4
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• pp.182-186
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• 2014

Lymphatic vessels are routes for leukocyte migration and fluid drainage. In addition to their passive roles in migration of leukocytes, increasing evidence indicates their active roles in immune regulation. Tissue inflammation rapidly induces lymphatic endothelial cell proliferation and chemokine production, thereby resulting in lymphangiogenesis. Furthermore, lymphatic endothelial cells induce T cell tolerance through various mechanisms. In this review, we focus on the current knowledge on how inflammatory cytokines affect lymphangiogenesis and the roles of lymphatic vessels in modulating immune responses.