• 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.

• 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.

• 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.

• Archives of Plastic Surgery
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• v.45 no.2
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• pp.152-157
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• 2018

Background Intraoperative indocyanine green (ICG) lymphography can effectively detect functioning lymph vessels in edematous limbs. However, it is sometimes difficult to clearly identify their course in later-stage edematous limbs. For this reason, many surgeons rely on experience when they decide where to make the skin incision to locate the lymphatic vessels. The purpose of this study was to elucidate lymphatic vessel flow patterns in healthy upper extremities in a Korean population and to use these findings as a reference for lymphedema treatment. Methods ICG fluorescence lymphography was performed by injecting 1 mL of ICG into the second web space of the hand. After 4 hours, fluorescence images of lymphatic vessels were obtained with a near-infrared camera, and the lymphatic vessels were marked. Three landmarks were designated: the radial styloid process, the mid-portion of the cubital fossa, and the lower border of the deltopectoral groove. A straight line connecting the points was drawn, and the distance between the connected lines and the marked lymphatic vessels was measured at 8 points. Results There were 30 healthy upper extremities (15 right and 15 left). The average course of the main lymph vessels passed $26.0{\pm}11.6mm$ dorsal to the styloid process, $5.7{\pm}40.7mm$ medial to the mid-cubital fossa, and $31.3{\pm}26.1mm$ medial to the three-quarters point of the upper landmark line. Conclusions The main functioning lymphatic vessel follows the course of the cephalic vein at the forearm level, crosses the mid-cubital point, and travels medially toward the mid-axilla.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.1
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• pp.583-587
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• 2013

This study aimed to investigate tumor microvessel density (MVD) and lymphatic vessel density (LVD) using the Chalkley method as predictive markers for the risk of axillary lymph node metastasis and their relationship to other clinicopathological parameters in primary breast cancer cases. Forty two node-positive and eighty node-negative breast cancers were immunostained for CD34 and D2-40. MVD and LVD were counted by the Chalkley method at x400 magnification. There was a positive significant correlation of the MVD with the tumor size, coexisting ductal carcinoma in situ (DCIS) and lymph node metastases (P<0.05). In multivariate analysis, the MVD (2.86-4: OR 5.87 95%CI 1.05-32; >4: OR 20.03 95%CI 3.47-115.55), lymphovascular invasion (OR 3.46, 95% CI 1.13-10.58), and associated DCIS (OR 3.1, 95%CI 1.04-9.23) independently predicted axillary lymph node metastasis. There was no significant relationship between LVD and axillary lymph node metastasis. However, D2-40 was a good lymphatic vessel marker to enhance the detection of lymphatic invasion compared to H and E staining. In conclusion, MVD by the Chalkley method, lymphovascular invasion and associated DCIS can be additional predictive factors for axillary lymph node metastases in breast cancer. No relationship was identified between LVD and clinicopathological variables, including axillary lymph node metastasis.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.3
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• pp.1363-1367
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• 2014

This research was conducted to compare differences in colon cancer lymphatic vessel invasion (LVI) with D2-40 antibody labeling and regular HE staining, blood vessel invasion (BVI) with CD34 antibody labeling and HE staining and to assess the possibility of using D2-40-LVI/CD34-BVI in combination for predicting stage II colon cancer prognosis and guiding adjuvant chemotherapy.Anti-D2-40 and anti-CD34 antibodies were applied to tissue samples of 220 cases of stage II colon cancer to label lymphatic vessels and small blood vessels, respectively. LVI and BVI were assessed and multivariate COX regression analysis was performed for associations with colon cancer prognosis. Regular HE staining proved unable to differentiate lymphatic vessels from blood vessels, while D2-40 selectively labeled lymphatic endothelial cell cytosol and CD34 was widely expressed in large and small blood vessels of tumors as well as normal tissues. Compared to regular HE staining, D2-40-labeling for LVI and CD34-labeling for BVI significantly increased positive rate (22.3% vs 10.0% for LVI, and 19.1% vs 9.1% for BVI). Multivariate analysis indicated that TNM stage, pathology tissue type, post-surgery adjuvant chemotherapy, D2-40-LVI, and CD34-BVI were independent factors affecting whole group colon cancer prognosis, while HE staining-BVI, HE staining-LVI were not significantly related. When CD34-BVI/D2-40-LVI were used in combination for detection, the risk of death for patients with two or one positive results was 5.003 times that in the LVI(-)&BVI(-) group (95% CI 2.365 - 9.679). D2-40 antibody LVI labeling and CD34 antibody BVI labeling have higher specificity and accuracy than regular HE staining and can be used as molecular biological indicators for prognosis prediction and guidance of adjuvant chemotherapy for stage II colon cancer.

• Archives of Plastic Surgery
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• v.46 no.1
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• pp.46-56
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• 2019

Background When performing lymphovenous anastomosis, it is sometimes difficult to find venules in the proximity of an ideal lymphatic vessel that have a similar diameter to that of the lymphatic vessel. In this situation, larger venules can be used. Methods The authors evaluated the efficacy of and patient satisfaction with lymphovenous bypass with sleeve-in anastomosis. Between January 2014 and December 2016, we performed this procedure in 18 patients (eight upper extremities and 10 lower extremities) with secondary lymphedema. Lymphovenous bypass with sleeve-in anastomosis was performed under microscopy after injecting indocyanine green dye. The circumferential diameter was measured before lymphovenous bypass and at 1, 2, and 6 months after the procedure. An outcomes survey that included patients' qualitative satisfaction with lymphovenous bypass was conducted at 6 months postoperatively. Results Almost all patients showed quantitative improvements after surgery. The circumferential reduction rate in patients with stage II lymphedema of both the upper and lower extremities was significantly greater than in their counterparts with stage III/IV lymphedema. The circumferential reduction rate was lower in lower-extremity patients than in upper-extremity patients. Conclusions Lymphovenous bypass surgery with sleeve-in anastomosis in lymphedema patients is beneficial, and appears to be effective, when adequately-sized venules cannot be found in the proximity of an ideal lymphatic vessel.

• Maxillofacial Plastic and Reconstructive Surgery
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• v.32 no.1
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• pp.1-8
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• 2010

Background and Purpose: Vascular endothelial growth factor (VEGF)-C and VEGF receptor (VEGFR)-3 are involved in tumor lymphangiogenesis. Oral mucosal squamous cell carcinoma (OMSCC) preferentially metastasizes to cervical lymph nodes, so we investigated the expression and distribution of VEGFR-3 signaling proteins in OMSCC. Materials and Methods: Tissue samples of 18 OMSCC, 10 oral mucosal leukoplakia, and 3 normal oral mucosa were evaluated for expression of VEGF-C, VEGF-D, and VEGFR-3 by immunohistochemical staining. The presence of lymphatic vessels was determined using D2-40 staining, by which we also measured lymphatic vessel density (LVD). Results: 72% (13/18) and 56% (10/18) of tissue samples showed VEGF-C and VEGF-D immunopositivity in tumor cells and tumor-associated endothelial cells. VEGFR-3 was also expressed in most of OMSCC, which was up-regulated when compared with normal mucosa or with leukoplakia. Furthermore, LVD was higher in OMSCC than in leukoplakia. Conclusion: Taken together, our results suggest that autocrine activation of lymphatic endothelial cell via VEGFR-3 by VEGF-C and/or VEGF-D could be involved in progression of OMSCC. Therefore, VEGF-C/VEGFR-3 signaling pathway can be a molecular target for anti-metastatic therapy in OMSCC.

• Archives of Plastic Surgery
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• v.46 no.4
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• pp.344-349
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• 2019

Background Lymphaticovenous anastomosis is an important surgical treatment for lymphedema, with lymphaticovenous side-to-end anastomosis (LVSEA) and lymphaticovenous end-to-end anastomosis being the most frequently performed procedures. However, LVSEA can cause lymphatic flow obstruction because of regurgitation and tension in the anastomosis. In this study, we introduce a novel and simple procedure to overcome this problem. Methods Thirty-five female patients with lower extremity lymphedema who underwent lymphaticovenous anastomosis at our hospital were included in this study. Eighty-five LVSEA procedures were performed, of which 12 resulted in insufficient venous blood flow. For these 12 anastomoses, the proximal lymphatic vessel underwent clipping after the anastomotic procedure and the venous inflow was monitored. Subsequently, the proximal ligation after side-to-end anastomosis recovery (PLASTER) technique, which involves ligating the proximal side of the lymphatic vessel, was applied. A postoperative evaluation was performed using indocyanine green 6 months after surgery. Results Despite the clipping procedure, three of the 12 anastomoses still showed poor venous inflow. Therefore, it was not possible to apply the PLASTER technique in those cases. Among the nine remaining anastomoses in which the PLASTER technique was applied, three (33%) were patent. Conclusions Our findings show that achieving patent anastomosis is challenging when postoperative venous inflow is poor. We achieved good results by performing proximal ligation after LVSEA. Thus, the PLASTER technique is a particularly useful recovery technique when LVSEA does not result in good run-off.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.5
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• pp.3079-3083
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• 2013

Objective: To investigate the effects of endostar, a recombined humanized endostatin, plus cisplatin on the growth, lymphangiogenesis and lymphatic metastasis of the Lewis lung carcinoma (LLC) in mice. Methods: A tumor model were established in C57BL/6 mice by intravenious transplantation of LLC cells. Then the mice were randomized to receive administration with NS, endostar, cisplatin, or endostar plus cisplatin. After the mice were sacrificed, tumor multiplicity, tumor size and lymph node metastasis were assessed. Then the expression of vascular endothelial growth factor-c (VEGF-C) and podoplanin were determined by immunohistochemical staining. Results: Endostar plus cisplatin significantly suppressed tumor growth. lymphatic metastasis and prolonged survival time of the mice without obvious toxicity. The inhibition of lymphatic metastasis was associated with decreased microlymphatic vessel density (MLVD) and expression of VEGF-C. Conclusions: Endostar combined with cisplatin was more effective to suppress tumor growth and lymphatic metastasis than either agent alone. Thus this may provide a rational alternative for lung carcinoma treatment.