Abstract
Basic Science
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Connell, F., K. Kalidas, et al. (2012). “CCBE1 mutations can cause a mild, atypical form of generalized lymphatic dysplasia but are not a common cause of non-immune hydrops fetalis.” Clin Genet 81(2): 191–197.
Datar, S. A., E. G. Johnson, et al. (2011). “Altered Lymphatics in an Ovine Model of Congenital Heart Disease with Increased Pulmonary Blood Flow.” Am J Physiol Lung Cell Mol Physiol. 2011 Dec 29. [Epub ahead of print]
Delgado-Martin, C., C. Escribano, et al. (2011). “CXCL12 uses CXCR4 and a signaling core formed by bifunctional Akt, Erk1/2 and mTORC1 to control simultaneously chemotaxis and survival in mature dendritic cells.” J Biol Chem. 2011 Oct 28;286(43):37222–36.
Eidsmo, L., A. T. Stock, et al. (2011). “Reactive murine lymph nodes uniquely permit parenchymal access for T cells that enter via the afferent lymphatics.” J Pathol. 2011 Dec 13. doi: 10.1002/path.3975. [Epub ahead of print]
Facucho-Oliveira, J., M. Bento, et al. (2011). “Ccbe1 expression marks the cardiac and lymphatic progenitor lineages during early stages of mouse development.” Int J Dev Biol 55(10–12): 1007–1014.
Fevurly, R. D., S. Hasso, et al. (2012). “Novel zebrafish model reveals a critical role for MAPK in lymphangiogenesis.” J Pediatr Surg 47(1): 177–182.
PURPOSE: Lymphatic disorders are poorly understood with few animal models. We designed a novel assay to measure lymphatic development using transgenic zebrafish with fluorescently labeled endothelial cells. Two major branches of the vascular endothelial growth factor receptor (VEGFR) signaling pathway were examined: the MAPK and PI3K pathways. METHODS: Direct visualization of lymphatic development was performed in control embryos or under chemical inhibition. Treatment involved a 6-hour pulse of inhibitor at 3 days postfertilization. Fish were analyzed for the presence of the thoracic duct (TD) at 4 days postfertilization (n>100 specimens). RESULTS: Thoracic duct formation was prevented using selective inhibitors against kinases (MAPK, PI3K/TOR, or VEGFR). These kinases were important for TD formation because the lymphatic vessel failed to form in most of treated animals. Remarkably, MAPK pathway inhibition most robustly reduced lymphangiogenesis, demonstrated by a lack of lymphatic endothelial cells. CONCLUSION: We conclude that MAPK pathway function downstream of the VEGFRs is crucial at the early stages of TD development. This study provides a novel animal model and a potential target pathway for further investigation. We suggest further examination of MAPK pathway deregulation as a potential mechanism underlying lymphatic disease in humans.
Finley, S. D., M. O. Engel-Stefanini, et al. (2011). “Pharmacokinetics and pharmacodynamics of VEGF-neutralizing antibodies.” BMC Syst Biol 5(1): 193.
Finney, B. A., E. Schweighoffer, et al. (2011). “CLEC-2 and Syk in the megakaryocytic/platelet lineage are essential for development.” Blood. 2011 Dec 20. [Epub ahead of print]
Francois, M., N. L. Harvey, et al. (2011). “The transcriptional control of lymphatic vascular development.” Physiology (Bethesda) 26(3): 146–155.
Francois, M., K. Short, et al. (2011). “Segmental territories along the cardinal veins generate lymph sacs via a ballooning mechanism during embryonic lymphangiogenesis in mice.” Dev Biol. 2011 Dec 29. [Epub ahead of print]
Goyal, S., S. K. Chauhan, et al. (2012). “Blockade of prolymphangiogenic vascular endothelial growth factor C in dry eye disease.” Arch Ophthalmol 130(1): 84–89.
Hagerling, R., C. Pollmann, et al. (2011). “Intravital two-photon microscopy of lymphatic vessel development and function using a transgenic Prox1 promoter-directed mOrange2 reporter mouse.” Biochem Soc Trans 39(6): 1674–1681.
Hajrasouliha, A. R., T. Funaki, et al. (2012). “Vascular Endothelial Growth Factor-C Promotes Alloimmunity by Amplifying Antigen Presenting Cell Maturation and Lymphangiogenesis.” Invest Ophthalmol Vis Sci. 2012 Jan 26. [Epub ahead of print]
Higashi-Kuwata, N., T. Makino, et al. (2011). “Expression pattern of VEGFR-1, −2, −3 and D2–40 protein in the skin of patients with systemic sclerosis.” Eur J Dermatol 21(4): 490–494.
Hirai, S., M. Naito, et al. (2011). “The Origin of Lymphatic Capillaries in Murine Testes.” Journal of andrology. 2011 Nov 3. [Epub ahead of print]
Honma, M., M. Minami-Hori, et al. (2011). “Podoplanin expression in wound and hyperproliferative psoriatic epidermis: Regulation by TGF-beta and STAT-3 activating cytokines, IFN-gamma, IL-6, and IL-22.” J Dermatol Sci. 2011 Dec 8. [Epub ahead of print]
Inoue, Y., Y. Masutani, et al. (2011). “Integrated lymphography using fluorescence imaging and magnetic resonance imaging in intact mice.” Molecular imaging 10(5): 317–326.
Ji, R. C. (2011). “Macrophages are important mediators of either tumor- or inflammation-induced lymphangiogenesis.” Cell Mol Life Sci. 2011 Oct 8. [Epub ahead of print]
Jones, D., Y. Li, et al. (2012). “Mirtron MicroRNA-1236 Inhibits VEGFR-3 Signaling During Inflammatory Lymphangiogenesis.” Arterioscler Thromb Vasc Biol. 2012 Jan 5. [Epub ahead of print]
Kajiya, K., H. Kidoya, et al. (2011). “Promotion of Lymphatic Integrity by Angiopoietin-1/Tie2 Signaling during Inflammation.” Am J Pathol. 2011 Dec 24. [Epub ahead of print]
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Kazenwadel, J., G. A. Secker, et al. (2011). “Loss-of-function germline GATA2 mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature.” Blood. 2011 Dec 6. [Epub ahead of print]
Kinet, V., K. Castermans, et al. (2011). “The angiostatic protein 16K human prolactin significantly prevents tumor-induced lymphangiogenesis by affecting lymphatic endothelial cells.” Endocrinology 152(11): 4062–4071.
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Lapinski, P. E., S. Kwon, et al. (2012). “RASA1 maintains the lymphatic vasculature in a quiescent functional state in mice.” J Clin Invest. 122(2):733–47.
RASA1 (also known as p120 RasGAP) is a Ras GTPase-activating protein that functions as a regulator of blood vessel growth in adult mice and humans. In humans, RASA1 mutations cause capillary malformation-arteriovenous malformation (CM-AVM); whether it also functions as a regulator of the lymphatic vasculature is unknown. We investigated this issue using mice in which Rasa1 could be inducibly deleted by administration of tamoxifen. Systemic loss of RASA1 resulted in a lymphatic vessel disorder characterized by extensive lymphatic vessel hyperplasia and leakage and early lethality caused by chylothorax (lymphatic fluid accumulation in the pleural cavity). Lymphatic vessel hyperplasia was a consequence of increased proliferation of lymphatic endothelial cells (LECs) and was also observed in mice in which induced deletion of Rasa1 was restricted to LECs. RASA1-deficient LECs showed evidence of constitutive activation of Ras in situ. Furthermore, in isolated RASA1-deficient LECs, activation of the Ras signaling pathway was prolonged and cellular proliferation was enhanced after ligand binding to different growth factor receptors, including VEGFR-3. Blockade of VEGFR-3 was sufficient to inhibit the development of lymphatic vessel hyperplasia after loss of RASA1 in vivo. These findings reveal a role for RASA1 as a physiological negative regulator of LEC growth that maintains the lymphatic vasculature in a quiescent functional state through its ability to inhibit Ras signal transduction initiated through LEC-expressed growth factor receptors such as VEGFR-3.
Lee, H. S., S. K. Chauhan, et al. (2011). “Therapeutic Efficacy of Topical Epigallocatechin Gallate in Murine Dry Eye.” Cornea. 30(12):1465–72.
Lee, K. M., C. S. McKimmie, et al. (2011). “D6 facilitates cellular migration, and fluid flow, to lymph nodes by suppressing lymphatic congestion.” Blood. 118(23):6220–9.
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Li, Y., J. G. Wang, et al. (2011). “A modified rat model for cannulation and collection of thoracic duct lymph.” Lymphology 44(2): 82–88.
Liao, S., G. Cheng, et al. (2011). “Impaired lymphatic contraction associated with immunosuppression.” Proc Natl Acad Sci U S A. 2011 108(46):18784–9.
Lin, W., L. Jiang, et al. (2011). “Vascular endothelial growth factor-D promotes growth, lymphangiogenesis and lymphatic metastasis in gallbladder cancer.” Cancer letters. 314(2):127–36.
Luo, Y., W. Chen, et al. (2011). “Cryptotanshinone inhibits lymphatic endothelial cell tube formation by suppressing VEGFR-3/ERK and small GTPase pathways.” Cancer prevention research. 4(12):2083–91.
Miettinen, M. and Z. F. Wang (2011). “Prox1 Transcription Factor as a Marker for Vascular Tumors-Evaluation of 314 Vascular Endothelial and 1086 Nonvascular Tumors.” The American journal of surgical pathology. 2011 Nov 3. [Epub ahead of print]
Mkonyi, L. E., V. Bakken, et al. (2011). “Lymphangiogenesis Is Induced during Development of Periodontal Disease.” J Dent Res.. 91(1):71–7.
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Olivier, M., B. Foret, et al. (2012). “Capacities of Migrating CD1b Lymph Dendritic Cells to Present Salmonella Antigens to Naive T Cells.” PLoS One 7(1): e30430.
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Souza-Smith, F. M., K. M. Kurtz, et al. (2011). “Measurement of Cytosolic Ca2+ in Isolated Contractile Lymphatics.” J Vis Exp 2011 Dec 8;(58). pii: 3438. doi: 10.3791/3438.
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Sultan, A., S. S. Dadras, et al. (2011). “Prox-1, Podoplanin and HPV staining assists in identification of lymphangioma circumscriptum of the vulva and discrimination from vulvar warts.” Histopathology. 59(6):1274–7.
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Tao, S., M. Witte, et al. (2011). “Zebrafish prox1b Mutants Develop a Lymphatic Vasculature, and prox1b Does Not Specifically Mark Lymphatic Endothelial Cells.” PLoS One. 2011;6(12):e28934. Epub 2011 Dec 28.
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Torzicky, M., P. Viznerova, et al. (2011). “Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1/CD31) and CD99 Are Critical in Lymphatic Transmigration of Human Dendritic Cells.” J Invest Dermatol. 2011 Dec 22. doi: 10.1038/jid.2011.420. [Epub ahead of print]
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Wang, P. and Y. Cheng (2011). “Gene expression profile of lymphatic endothelial cells.” Cell Biol Int. 35(12): 1177–1187.
Yan, A., T. Avraham, et al. (2011). “Adipose-derived stem cells promote lymphangiogenesis in response to VEGF-C stimulation or TGF-beta1 inhibition.” Future Oncol 7(12): 1457–1473.
Yan, Z. X., Z. H. Jiang, et al. (2012). “Angiopoietin-2 promotes inflammatory lymphangiogenesis and its effect can be blocked by the specific inhibitor L1–10.” Am J Physiol Heart Circ Physiol 302(1): H215–223.
Yin, N., N. Zhang, et al. (2011). “Lymphangiogenesis is required for pancreatic islet inflammation and diabetes.” PLoS One 6(11): e28023.
Yoshimatsu, Y., T. Yamazaki, et al. (2011). “Ets family members induce lymphangiogenesis through physical and functional interaction with Prox1.” J Cell Sci 124(Pt 16): 2753–2762.
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Zampell, J., S. Elhadad, et al. (2011). “Toll-Like Receptor Deficiency Worsens Inflammation and Lymphedema after Lymphatic Injury.” Am J Physiol Cell Physiol. 2011 Nov 2. [Epub ahead of print]
Zampell, J. C., A. Yan, et al. (2011). “HIF-1alpha coordinates lymphangiogenesis during wound healing and in response to inflammation.” FASEB J. 2011 Nov 8. [Epub ahead of print]
Zhuo, W., Y. Chen, et al. (2011). “Endostatin specifically targets both tumor blood vessels and lymphatic vessels.” Front Med 5(4): 336–340.
Oncology
Ahmed, R. L., K. H. Schmitz, et al. (2011). “Risk factors for lymphedema in breast cancer survivors, the Iowa Women's Health Study.” Breast Cancer Res Treat 130(3): 981–991.
Albrecht, I. and G. Christofori (2011). “Molecular mechanisms of lymphangiogenesis in development and cancer.” Int J Dev Biol 55(4–5): 483–494.
Alitalo, A. and M. Detmar (2011). “Interaction of tumor cells and lymphatic vessels in cancer progression.” Oncogene. Dec 19. doi: 10.1038/onc.2011.602. [Epub ahead of print]
Bianchi, P. P., W. Petz, et al. (2011). “Laparoscopic lymphatic roadmapping with blue dye and radioisotope in colon cancer.” Colorectal Dis 13 Suppl 7: 67–69.
Cahill, R. A., M. Anderson, et al. (2012). “Near-infrared (NIR) laparoscopy for intraoperative lymphatic road-mapping and sentinel node identification during definitive surgical resection of early-stage colorectal neoplasia.” Surg Endosc 26(1): 197–204.
Grotz, T. E., A. S. Mansfield, et al. (2012). “Regional lymphatic immunity in melanoma.” Melanoma Res. 22(1):9–18.
Ito, Y., M. A. Shibata, et al. (2011). “Lymphangiogenesis and Axillary Lymph Node Metastases Correlated with VEGF-C Expression in Two Immunocompetent Mouse Mammary Carcinoma Models.” Int J Breast Cancer 2011: 867152.
Komatsu, S., D. Ichikawa, et al. (2012). “Differences of the Lymphatic Distribution and Surgical Outcomes Between Remnant Gastric Cancers and Primary Proximal Gastric Cancers.” J Gastrointest Surg. 2012 Jan 4. [Epub ahead of print]
Miettinen, M., M. Sarlomo-Rikala, et al. (2011). “Claudin-5 as an immunohistochemical marker for angiosarcoma and hemangioendotheliomas.” Am J Surg Pathol. 35(12):1848–56.
Nagahashi, M., S. Ramachandran, et al. (2012). “Sphingosine-1-phosphate produced by sphingosine kinase 1 promotes breast cancer progression by stimulating angiogenesis and lymphangiogenesis.” Cancer Res 72(3): 726–735.
Pan, D., X. Cai, et al. (2012). “Photoacoustic Sentinel Lymph Node Imaging with Self-Assembled Copper Neodecanoate Nanoparticles.” ACS Nano. 2012 Jan 20. [Epub ahead of print]
Rasmussen, J. C., S. Kwon, et al. (2011). “The Role of Lymphatics in Cancer as Assessed by Near-Infrared Fluorescence Imaging.” Ann Biomed Eng. 2011 Dec 3. [Epub ahead of print]
Rezende, L. F., F. V. Pedras, et al. (2011). “Preoperative upper limb lymphatic function in breast cancer surgery.” Rev Assoc Med Bras 57(5): 540–544.
Saaristo, A. M., T. S. Niemi, et al. (2012). “Microvascular Breast Reconstruction and Lymph Node Transfer for Postmastectomy Lymphedema Patients.” Ann Surg. 2012 Jan 9. [Epub ahead of print]
Schoppmann, A., D. Tamandl, et al. (2011). “Comparison of Lymphangiogenesis between Primary Colorectal Cancer and Corresponding Liver Metastases.” Anticancer Res 31(12): 4605–4611.
Yan, Z., C. Zhan, et al. (2011). “LyP-1-conjugated doxorubicin-loaded liposomes suppress lymphatic metastasis by inhibiting lymph node metastases and destroying tumor lymphatics.” Nanotechnology 22(41): 415103.
Clinical
Belczak, C. E., J. M. Godoy, et al. (2011). “Lymphoscintigraphic changes after harvesting of the saphenous vein for coronary artery bypass graft.” Rev Bras Cir Cardiovasc 26(3): 488–489.
Bellini, C., M. Rutigliani, et al. (2011). “Perinatal deaths and lymphatic system involvement: a diagnostic flow-chart applying immunohistochemical methods.” Lymphology 44(3): 131–133.
Burnand, K. M., D. M. Glass, et al. (2011). “Popliteal node visualization during standard pedal lymphoscintigraphy for a swollen limb indicates impaired lymph drainage.” AJR Am J Roentgenol 197(6): 1443–1448.
Cahill, R. A., F. Ris, et al. (2011). “Near-infrared laparoscopy for real-time intra-operative arterial and lymphatic perfusion imaging.” Colorectal Dis 13 Suppl 7: 12–17.
Campisi, C., M. H. Witte, et al. (2011). “General surgery, translational lymphology and lymphatic surgery.” Int Angiol 30(6): 504–521.
**Choi, I., S. Lee, et al. (2012). “9-Cis Retinoic Acid Promotes Lymphangiogenesis and Enhances Lymphatic Vessel Regeneration: Therapeutic Implications of 9-Cis Retinoic Acid for Secondary Lymphedema.” Circulation. 2012 Jan 24. [Epub ahead of print]
BACKGROUND: The lymphatic system plays a key role in tissue fluid homeostasis and lymphatic dysfunction due to genetic defects or lymphatic vessel obstruction can cause lymphedema, disfiguring tissue swellings often associated with fibrosis and recurrent infections without available cures to date. In this study, retinoic acids (RAs) were determined to be a potent therapeutic agent that is immediately applicable to reduce secondary lymphedema. METHODS AND RESULTS: We report that RAs promote proliferation, migration and tube formation of cultured lymphatic endothelial cells (LECs) by activating FGF-receptor signaling. Moreover, RAs control the expression of cell-cycle checkpoint regulators such as p27(Kip1), p57(Kip2) and the aurora kinases through both an Akt-mediated non-genomic action and a transcription-dependent genomic action that is mediated by Prox1, a master regulator of lymphatic development. Moreover, 9-cisRA was found to activate in vivo lymphangiogenesis in animals based on mouse trachea, matrigel plug and cornea pocket assays. Finally, we demonstrate that 9-cisRA can provide a strong therapeutic efficacy in ameliorating the experimental mouse tail lymphedema by enhancing lymphatic vessel regeneration. CONCLUSIONS: These in vitro and animal studies demonstrate that 9-cisRA potently activates lymphangiogenesis and promotes lymphatic regeneration in an experimental lymphedema model, presenting it as a promising novel therapeutic agent to treat human lymphedema patients.
Cormier, J. N., L. Rourke, et al. (2011). “The Surgical Treatment of Lymphedema: A Systematic Review of the Contemporary Literature (2004–2010).” Ann Surg Oncol. 19(2):642–51.
de Bruyn, G., A. Casaer, et al. (2011). “Hydrops fetalis and pulmonary lymphangiectasia due to FOXC2 mutation: an autosomal dominant hereditary lymphedema syndrome with variable expression.” Eur J Pediatr. 2011 Sep 15. [Epub ahead of print]
Feely, M. A., K. D. Olsen, et al. (2012). “Cutaneous lymphatics and chronic lymphedema of the head and neck.” Clin Anat 25(1): 72–85.
Felmerer, G., T. Sattler, et al. (2011). “Treatment of various secondary lymphedemas by microsurgical lymph vessel transplantation.” Microsurgery. 2011 Nov 24. doi: 10.1002/micr.20968. [Epub ahead of print]
Fukushima, K., S. Morokuma, et al. (2011). “Short-term and long-term outcomes of 214 cases of non-immune hydrops fetalis.” Early Hum Dev 87(8): 571–575.
Goyal, S., S. K. Chauhan, et al. (2011). “Blockade of Prolymphangiogenic Vascular Endothelial Growth Factor C in Dry Eye Disease.” Arch Ophthalmol. 130(1):84–9.
Hamilton, B. E., G. M. Nesbit, et al. (2011). “Characteristic imaging findings in lymphoceles of the head and neck.” AJR Am J Roentgenol 197(6): 1431–1435.
Hardavella, G., E. G. Tzortzaki, et al. (2011). “Lymphangiogenesis in COPD: Another link in the pathogenesis of the disease.” Respir Med. 2011 Dec 6. [Epub ahead of print]
Hodge, L. M. and H. F. Downey (2011). “Lymphatic pump treatment enhances the lymphatic and immune systems.” Exp Biol Med (Maywood) 236(10): 1109–1115.
Jesinger, R. A., G. E. Lattin, Jr., et al. (2011). “Vascular abnormalities of the breast: arterial and venous disorders, vascular masses, and mimic lesions with radiologic-pathologic correlation.” Radiographics 31(7): E117–136.
Kelley, P. M., M. M. Steele, et al. (2011). “Regressed lymphatic vessels develop during corneal repair.” Lab Invest 91(11): 1643–1651.
Kim, J. H., E. H. Han, et al. (2012). “Fetal topographical anatomy of the upper abdominal lymphatics: its specific features in comparison with other abdominopelvic regions.” Anat Rec (Hoboken) 295(1): 91–104.
Lim, C. Y., H. G. Seo, et al. (2011). “Measurement of lymphedema using ultrasonography with the compression method.” Lymphology 44(2): 72–81.
Lu, Q., D. Bui, et al. (2011). “Magnetic Resonance Lymphography at 3T: A Promising Noninvasive Approach to Characterise Inguinal Lymphatic Vessel Leakage.” Eur J Vasc Endovasc Surg. 43(1):106–11.
Murdaca, G., P. Cagnati, et al. (2012). “Current views on diagnostic approach and treatment of lymphedema.” Am J Med 125(2): 134–140.
Oh, T. G., J. W. Chung, et al. (2011). “Primary intestinal lymphangiectasia diagnosed by capsule endoscopy and double balloon enteroscopy.” World J Gastrointest Endosc 3(11): 235–240.
Olszewski, W. L. (2011). “The lymphovenous microsurgical shunts for treatment of lymphedema of lower limbs: indications in 2011.” Int Angiol 30(6): 499–503.
Olszewski, W. L., J. Cwikla, et al. (2011). “Pathways of lymph and tissue fluid flow during intermittent pneumatic massage of lower limbs with obstructive lymphedema.” Lymphology 44(2): 54–64.
Perros, F., P. Dorfmuller, et al. (2012). “Pulmonary Lymphoid Neogenesis in Idiopathic Pulmonary Arterial Hypertension.” Am J Respir Crit Care Med. 185(3):311–21.
Reinglas, J., R. Ramphal, et al. (2011). “The successful management of diffuse lymphangiomatosis using sirolimus: a case report.” Laryngoscope 121(9): 1851–1854.
Schander, A., H. F. Downey, et al. (2011). “Lymphatic pump manipulation mobilizes inflammatory mediators into lymphatic circulation.” Exp Biol Med (Maywood) 237(1):58–63.
Springer, S., M. Koller, et al. (2011). “Changes in quality of life of patients with lymphedema after lymphatic vessel transplantation.” Lymphology 44(2): 65–71.
Szuba, A., Z. Chachaj, et al. (2011). “Axillary lymph nodes and arm lymphatic drainage pathways are spared during routine complete axillary clearance in majority of women undergoing breast cancer surgery.” Lymphology 44(3): 103–112.
Unno, N., H. Tanaka, et al. (2011). “Influence of age and gender on human lymphatic pumping pressure in the leg.” Lymphology 44(3): 113–120.
Welch, J., S. Srinivasan, et al. (2011). “Conjunctival Lymphangiectasia: A Report of 11 Cases and Review of Literature.” Surv Ophthalmol. 2011 Oct 21. [Epub ahead of print]
Wu, X., Z. Yu, et al. (2011). “Comparison of approaches for microscopic imaging of skin lymphatic vessels.” Scanning. 2011 Sep 6. doi: 10.1002/sca.20285. [Epub ahead of print]
Zvonik, M., E. Foldi, et al. (2011). “The effects of reduction operation with genital lymphedema on the frequency of erysipelas and the quality of life.” Lymphology 44(3): 121–130.
Reviews
Foubert, P. and J. A. Varner (2012). “Integrins in tumor angiogenesis and lymphangiogenesis.” Methods in molecular biology 757: 471–486.
Hirakawa, S. (2012). “New insights into the molecular mechanisms of lymphangiogenesis and pathophysiology.” Yakugaku Zasshi 132(2): 211–214.
Jones, D. and W. Min (2011). “An overview of lymphatic vessels and their emerging role in cardiovascular disease.” J Cardiovasc Dis Res 2(3): 141–152.
Kanady, J. D. and A. M. Simon (2011). “Lymphatic communication: connexin junction, what's your function?” Lymphology 44(3): 95–102.
Margaris, K. N. and R. A. Black (2012). “Modelling the lymphatic system: challenges and opportunities.” J R Soc Interface. 2012 Jan 11. [Epub ahead of print]
Vascular Anomalies
Alkonyi, B., Y. Miao, et al. (2011). “A perfusion-metabolic mismatch in Sturge-Weber syndrome: A multimodality imaging study.” Brain Dev. 2011 Nov 8. [Epub ahead of print]
Arora, S. S., B. M. Plato, et al. (2011). “Adult presentation of PHACES syndrome.” Interv Neuroradiol. 17(2):137–46.
Ballah, D., A. M. Cahill, et al. (2011). “Vascular anomalies: what they are, how to diagnose them, and how to treat them.” Curr Probl Diagn Radiol 40(6): 233–247.
Bauland, C. G., T. H. Luning, et al. (2011). “Untreated hemangiomas: growth pattern and residual lesions.” Plast Reconstr Surg 127(4): 1643–1648.
Bauland, C. G., J. M. Smit, et al. (2012). “Similar risk for hemangiomas after amniocentesis and transabdominal chorionic villus sampling.” J Obstet Gynaecol Res. 38(2):371–5.
Bell, D., H. P. Kozakewich, et al. (2011). “Liver hemangiomas and elevated serum alpha-fetoprotein: unsolved questions.” Hum Pathol 42(9): 1369–1371; author reply 1371–1362.
Boscolo, E., J. B. Mulliken, et al. (2011). “VEGFR-1 Mediates Endothelial Differentiation and Formation of Blood Vessels in a Murine Model of Infantile Hemangioma.” Am J Pathol. 2011 Nov;179(5):2266–77.
Vascular endothelial growth factor receptor-1 (VEGFR-1) is a member of the VEGFR family, and binds to VEGF-A, VEGF-B, and placental growth factor. VEGFR-1 contributes to tumor growth and metastasis, but its role in the pathological formation of blood vessels is still poorly understood. Herein, we used infantile hemangioma (IH), the most common tumor of infancy, as a means to study VEGFR-1 activation in pathological vasculogenesis. IH arises from stem cells (HemSCs) that can form the three most prominent cell types in the tumor: endothelial cells, pericytes, and adipocytes. HemSCs can recapitulate the IH life cycle when injected in immuncompromised mice, and are targeted by corticosteroids, the traditional treatment for IH. We report here that VEGF-A or VEGF-B induces VEGFR-1-mediated ERK1/2 phosphorylation in HemSCs and promotes differentiation of HemSCs to endothelial cells. Studies of VEGFR-2 phosphorylation status and down-regulation of neuropilin-1 in the HemSCs demonstrate that VEGFR-2 and NRP1 are not needed for VEGF-A- or VEGF-B-induced ERK1/2 activation. U0216-mediated blockade of ERK1/2 phosphorylation or shRNA-mediated suppression of VEGFR-1 prevents HemSC-to-EC differentiation. Furthermore, the down-regulation of VEGFR-1 in the HemSCs results in decreased formation of blood vessels in vivo and reduced ERK1/2 activation. Thus, our study reveals a critical role for VEGFR-1 in the HemSC-to-EC differentiation that underpins pathological vasculogenesis in IH.
Cahill, A. M. and E. L. Nijs (2011). “Pediatric vascular malformations: pathophysiology, diagnosis, and the role of interventional radiology.” Cardiovasc Intervent Radiol 34(4): 691–704.
Cante, V., A. Pham-Ledard, et al. (2011). “First report of topical timolol treatment in primarily ulcerated perineal haemangioma.” Arch Dis Child Fetal Neonatal Ed.
Chakkittakandiyil, A., R. Phillips, et al. (2012). “Timolol Maleate 0.5% or 0.1% Gel-Forming Solution for Infantile Hemangiomas: A Retrospective, Multicenter, Cohort Study.” Pediatr Dermatol. 29(1):28–31.
Dai, Y., F. Hou, et al. (2011). “Preliminary investigation of human lymphatic malformations in vitro.” Laryngoscope 121(11): 2435–2442.
Francis, C. S., D. Kim, et al. (2011). “Nasofrontal heterotopic ossification following lymphangioma resection.” J Craniofac Surg 22(6): 2381–2384.
Greenberger, S. and J. Bischoff (2011). “Infantile Hemangioma-Mechanism(s) of Drug Action on a Vascular Tumor.” Cold Spring Harb Perspect Med 1(1): a006460.
Hammill, A. M., M. Wentzel, et al. (2011). “Sirolimus for the treatment of complicated vascular anomalies in children.” Pediatr Blood Cancer 57(6): 1018–1024.
BACKGROUND: Vascular anomalies comprise a diverse group of diagnoses. While infantile hemangiomas are common, the majority of these conditions are quite rare and have not been widely studied. Some of these lesions, though benign, can impair vital structures, be deforming, or even become life-threatening. Vascular tumors such as kaposiform hemangioendotheliomas (KHE) and complicated vascular malformations have proven particularly difficult to treat. PROCEDURE: Here we retrospectively evaluate a series of six patients with complicated, life-threatening vascular anomalies who were treated with the mTOR inhibitor sirolimus for compassionate use at two centers after failing multiple other therapies. RESULTS: These patients showed significant improvement in clinical status with tolerable side effects. CONCLUSIONS: Sirolimus appears to be effective and safe in patients with life-threatening vascular anomalies and represents an important tool in treating these diseases. These findings are currently being further evaluated in a Phase II safety and efficacy trial.
Hernandez-Martin, S., J. C. Lopez-Gutierrez, et al. (2011). “Brain Perfusion SPECT in Patients with PHACES Syndrome Under Propranolol Treatment.” Eur J Pediatr Surg. 2011 Nov 3. [Epub ahead of print]
Children with PHACES syndrome (PS) and visual impairment or stridor show a dramatic and immediate response to propranolol. However, this beta-blocking drug could be responsible for an eventually increased risk of ischemic stroke due to the underlying cerebral vascular disease. To more accurately understand the effects of propranolol on brain vascularization, we examined PS patients treated with this drug for airway or visual complications using brain perfusion SPECT (Single Photon Emission Computed Tomography). In the past, this examination has been shown to be useful in the management of patients with different neurovascular disorders. Clinical records and imaging studies were reviewed in 7 patients with a diagnosis of PS. All patients underwent magnetic resonance angiography (MRA), echocardiography, chest X-ray and ophthalmologic, neurological, and cardiologic assessments. They received 2–3 mg/kg/day propranolol in an attempt to treat stridor or avoid ophthalmologic occlusion. We performed SPECT after 3–6 months of treatment. SPECT showed a normal uptake in the frontal and temporal regions despite vascular abnormalities found with MRA imaging. Significant improvements of symptoms and in the volume of the hemangioma were noted in all cases without signs of a reduction of brain blood perfusion. Propranolol treatment was safe in our patients who did not show signs of perfusion changes. The high sensitivity for detecting functional impairment makes brain perfusion SPECT useful in the diagnosis and follow-up of patients with PS considered at risk of neurovascular impairment. Accurate knowledge of its pathophysiological basis, together with the appropriate technique and careful interpretation of reporting, will enhance the clinical use of brain SPECT in those patients.
Hochman, M., D. M. Adams, et al. (2011). “Current Knowledge and Management of Vascular Anomalies, II: Malformations.” Arch Facial Plast Surg 13(6): 425–433.
Hochman, M., D. M. Adams, et al. (2011). “Current knowledge and management of vascular anomalies: I. Hemangiomas.” Arch Facial Plast Surg 13(3): 145–151.
Hou, F., Y. Dai, et al. (2011). “A pilot in vivo model of human microcystic lymphatic malformations.” Arch Otolaryngol Head Neck Surg 137(12): 1280–1285.
Kim, S. W., K. Kauvanough, et al. (2011). “Long-term Outcome of Radiofrequency Ablation for Intraoral Microcystic Lymphatic Malformation.” Arch Otolaryngol Head Neck Surg 137(12): 1247–1250.
Kleber, C. J., A. Spiess, et al. (2011). “Urinary matrix metalloproteinases-2/9 in healthy infants and haemangioma patients prior to and during propranolol therapy.” Eur J Pediatr. 2011 Dec 28. [Epub ahead of print]
Kuroda, T., M. Kumagai, et al. (2011). “Critical infantile hepatic hemangioma: results of a nationwide survey by the Japanese Infantile Hepatic Hemangioma Study Group.” J Pediatr Surg 46(12): 2239–2243.
Lo, W., D. A. Marchuk, et al. (2011). “Updates and future horizons on the understanding, diagnosis, and treatment of Sturge-Weber syndrome brain involvement.” Dev Med Child Neurol. 2011 Dec 23. doi: 10.1111/j.1469–8749.2011.04169.x. [Epub ahead of print]
Love, Z. and D. P. Hsu (2011). “Low-flow vascular malformations of the head and neck: clinicopathology and image guided therapy.” J Neurointerv Surg. 2011 Oct 3. [Epub ahead of print]
Mabeta, P. and M. S. Pepper (2011). “Hemangiomas - current therapeutic strategies.” Int J Dev Biol 55(4–5): 431–437.
Mabeta, P. and M. S. Pepper (2011). “Inhibition of hemangioma development in a syngeneic mouse model correlates with bcl-2 suppression and the inhibition of Akt kinase activity.” Angiogenesis. 2011 Dec 25. [Epub ahead of print]
BACKGROUND: Hemangiomas are benign vascular tumors that are characterised by excessive angiogenesis. While there is no definitive treatment for these tumors, several angiogenesis inhibitors, including bleomycin, have been employed. To better understand the mechanism of bleomycin in accelerating haemangioma regression, we investigated the effects of the drug on hemangiomagenesis using a previously described mouse hemangioma model. bleomycin were tested in mice injected with endothelioma cells to induce hemangioma development. At termination, tissue samples from bleomycin-treated and control mice were stained with hematoxylin and eosin for histological examination. Bcl-2, flk-1 and vWF expression were studied by immunofluorescence microscopy. Hematological analysis was undertaken using a hemocounter. Akt activity was analyzed in tissue homogenates and endothelioma cells using ELISA. Also, caspase activity was analysed in endothelioma cells by ELISA. RESULTS: Bleomycin inhibited tumor growth in vivo in a dose-dependant manner. Our findings also revealed that bleomycin inhibited Akt activation and suppressed bcl-2. In vitro bleomycin increased caspase activation. CONCLUSION: Our observations reveal possible mechanisms for the inhibitory effects of bleomycin on hemangiomagenesis, and raise the possibility that bcl-2 might be an important therapeutic target in the treatment of hemangiomas.
Oiso, N. and A. Kawada (2011). “The dermoscopic features in infantile hemangioma.” Pediatr Dermatol 28(5): 591–593.
Ooi, C. Y., D. Brody, et al. (2011). “Liver transplantation for massive hepatic lymphangiomatosis in a child.” J Pediatr Gastroenterol Nutr 52(3): 366–369.
Pansuriya, T. C., R. van Eijk, et al. (2011). “Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome.” Nat Genet 43(12): 1256–1261.
Ollier disease and Maffucci syndrome are non-hereditary skeletal disorders characterized by multiple enchondromas (Ollier disease) combined with spindle cell hemangiomas (Maffucci syndrome). We report somatic heterozygous mutations in IDH1 (c.394C>T encoding an R132C substitution and c.395G>A encoding an R132H substitution) or IDH2 (c.516G>C encoding R172S) in 87% of enchondromas (benign cartilage tumors) and in 70% of spindle cell hemangiomas (benign vascular lesions). In total, 35 of 43 (81%) subjects with Ollier disease and 10 of 13 (77%) with Maffucci syndrome carried IDH1 (98%) or IDH2 (2%) mutations in their tumors. Fourteen of 16 subjects had identical mutations in separate lesions. Immunohistochemistry to detect mutant IDH1 R132H protein suggested intraneoplastic and somatic mosaicism. IDH1 mutations in cartilage tumors were associated with hypermethylation and downregulated expression of several genes. Mutations were also found in 40% of solitary central cartilaginous tumors and in four chondrosarcoma cell lines, which will enable functional studies to assess the role of IDH1 and IDH2 mutations in tumor formation.
Pan, W., Y. Gao, et al. (2011). “Novel sequences of subgroup J avian leukosis viruses associated with hemangioma in Chinese layer hens.” Virol J 8(1): 552.
ABSTRACT: BACKGROUND: Avian leukosis virus subgroup J (ALV-J) preferentially induces myeloid leukosis (ML) in meat-type birds. Since 2008, many clinical cases of hemangioma rather than ML have frequently been reported in association with ALV-J infection in Chinese layer flocks. RESULTS: Three ALV-J strains associated with hemangioma were isolated and their proviral genomic sequences were determined. The three isolates, JL093-1, SD09DP03 and HLJ09MDJ-1, were 7670, 7670, and 7633 nt in length. Their gag and pol genes were well conserved, with identities of 94.5–98.6% and 97.1–99.5%, respectively, with other ALV-J strains at the amino acid level (aa), while the env genes of the three isolates shared a higher aa identity with the env genes of other hemangioma strains than with those of ML strains. Interestingly, two novel 19-bp insertions in the U3 region in the LTR and 5'UTR, most likely derived from other retroviruses, were found in all the three isolates, thereby separately introducing one E2BP binding site in the U3 region in the LTR and RNA polymerase II transcription factorB and core promoter motif ten elements in the 5'UTR. Meanwhile, two binding sites in the U3 LTRs of the three isolates for NFAP-1 and AIB REP1 were lost, and a 1-base deletion in the E element of the 3'UTR of JL093-1 and SD09DP03 introduced a binding site for c-Ets-1. In addition to the changes listed above, the rTM of the 3'UTR was deleted in each of the three isolates. CONCLUSION: Our study is the first to discovery the coexistence of two novel insertions in the U3 region in the LTR and the 5'UTR of ALV-J associated with hemangioma symptoms, and the transcriptional regulatory elements introduced should be taken into consideration in the occurrence of hemangioma.
Piram, M., G. Lorette, et al. (2011). “Sturge-Weber Syndrome in Patients with Facial Port-Wine Stain.” Pediatr Dermatol. 29(1):32–7.
Price, C. J., C. Lattouf, et al. (2011). “Propranolol vs Corticosteroids for Infantile Hemangiomas: A Multicenter Retrospective Analysis.” Arch Dermatol 147(12): 1371–1376.
Redondo, P., L. Aguado, et al. (2011). “Diagnosis and management of extensive vascular malformations of the lower limb: part II. Systemic repercusion, diagnosis, and treatment.” J Am Acad Dermatol 65(5): 909–923; quiz 924.
Redondo, P., L. Aguado, et al. (2011). “Diagnosis and management of extensive vascular malformations of the lower limb: part I. Clinical diagnosis.” J Am Acad Dermatol 65(5): 893–906; quiz 907–898.
Restrepo, R., R. Palani, et al. (2011). “Hemangiomas revisited: the useful, the unusual and the new. Part 1: overview and clinical and imaging characteristics.” Pediatric radiology 41(7): 895–904.
Restrepo, R., R. Palani, et al. (2011). “Hemangiomas revisited: the useful, the unusual and the new. Part 2: endangering hemangiomas and treatment.” Pediatr Radiol 41(7): 905–915.
Rossler, J., T. Schill, et al. (2011). “Propranolol for proliferating infantile haemangioma is superior to corticosteroid therapy - a retrospective, single centre study.” J Eur Acad Dermatol Venereol. 2011 Oct 31. [Epub ahead of print]
Rozman, Z., R. Thambidorai, et al. (2011). “Lymphangioma: Is intralesional bleomycin sclerotherapy effective?” Biomed Imaging Interv J 7(3): e18.
Sakamoto, S., M. Kasahara, et al. (2011). “Living donor liver transplantation for multiple intrahepatic portosystemic shunts after involution of infantile hepatic hemangiomas.” J Pediatr Surg 46(6): 1288–1291.
Schumacher, W. E., B. A. Drolet, et al. (2011). “Spinal dysraphism associated with the cutaneous lumbosacral infantile hemangioma: a neuroradiological review.” Pediatr Radiol. 2011 Dec 4. [Epub ahead of print]
Schupp, C. J., J. B. Kleber, et al. (2011). “Propranolol therapy in 55 infants with infantile hemangioma: dosage, duration, adverse effects, and outcome.” Pediatr Dermatol 28(6): 640–644.
Swetman, G. L., D. R. Berk, et al. (2012). “Sildenafil for severe lymphatic malformations.” N Engl J Med 366(4): 384–386.
Vishvanath, A., T. Itinteang, et al. (2011). “Infantile haemangioma expresses tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), TRAIL receptors, osteoprotegerin and receptor activator for nuclear factor small ka, CyrillicB ligand (RANKL)(dagger).” Histopathology 59(3): 397–406.
Infantile haemangioma expresses tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), TRAIL receptors, osteoprotegerin and receptor activator for nuclear factor small ka, CyrillicB ligand (RANKL) Aims: To investigate the expression of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors and decoy receptors, including osteoprotegerin (OPG) in infantile haemangioma (IH). Methods and results: Immunostaining, Western blotting and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) were used on IH biopsies and haemangioma explant-derived cells (HaemEDCs). TRAIL and its receptors and decoy receptors, including OPG, are expressed in proliferating IH tissues and in HaemEDCs. Cells forming the endothelium of immature capillaries of proliferating IHs express abundant OPG and show punctate von Willebrand Factor (vWF) staining. As the cells mature and assume the characteristic of endothelial cells they increase expression of vWF, but lose expression of OPG. The endothelium of IH shows minimal expression of receptor activator for nuclear factor small ka, CyrillicB ligand (RANKL) compared with a small population of RANKL-positive cells located within the interstitium between microvessels. Proliferating HaemEDCs express significantly higher levels of OPG and decoy receptor 2 than the matched tissue samples. Increased OPG expression is detected in the extracellular matrix and in the conditioned medium of HaemEDCs. Conclusions: Our data suggest that OPG through the TRAIL pathway, but not the RANKL pathway, plays a role in regulating anti-apoptosis during the development of IH.
Walcott, B. P., E. R. Smith, et al. (2012). “Pial arteriovenous fistulae in pediatric patients: associated syndromes and treatment outcome.” J Neurointerv Surg. 2012 Jan 2. [Epub ahead of print]
Walcott, B. P., E. R. Smith, et al. (2012). “Dural arteriovenous fistulae in pediatric patients: associated conditions and treatment outcomes.” J Neurointerv Surg. 2012 Jan 2. [Epub ahead of print]
Weiss, I., T. M. O, et al. (2011). “Current treatment of parotid hemangiomas.” Laryngoscope 121(8): 1642–1650.
Wooderchak-Donahue, W., D. A. Stevenson, et al. (2011). “RASA1 analysis: Clinical and molecular findings in a series of consecutive cases.” Eur J Med Genet. 2011 Dec 8. [Epub ahead of print]
RASA1 mutations have been reported to be associated with hereditary capillary malformations (CM) with or without arteriovenous malformations (AVM), arteriovenous fistulas (AVF), or Parkes Weber syndrome. But the number of cases with RASA1 mutations reported to date is relatively small and the spectrum of phenotypes caused by mutations in this gene is not well defined. Mutation results and clinical findings in thirty-five unrelated consecutive cases sent for RASA1 molecular sequencing testing at ARUP Laboratories within the last two years were evaluated. Eight individuals had a pathogenic RASA1 mutation of which six were novel. These eight individuals all had CMs (seven had multifocal CMs; one had multiple CMs), and six also had a brain or facial AVM. Two individuals with multifocal CMs including one with a fast flow lesion had a variant of uncertain significance. All other individuals, including sixteen with CMs and one with a vein of Galen aneurysm, tested negative for a RASA1 mutation. Our data suggest that multifocal CM is the key clinical finding to suggest a RASA1 mutation. The clinical diagnostic mutation detection rate among all samples sent for RASA1 testing was 29% (10/35) which increases to approximately 39% (10/26) if patients without CMs are excluded.
Wu, J., B. Tarabishy, et al. (2011). “Cortical calcification in Sturge-Weber Syndrome on MRI-SWI: relation to brain perfusion status and seizure severity.” J Magn Reson Imaging 34(4): 791–798.
Xu, D., T. M. O, et al. (2011). “Isolation, characterization, and in vitro propagation of infantile hemangioma stem cells and an in vivo mouse model.” J Hematol Oncol 4(1): 54.
BACKGROUND: Infantile hemangiomas (IH) are the most common benign tumors of infancy. The typical clinical course consists of rapid growth during the first year of life, followed by natural and gradual involution over a multi-year time span through unknown cellular mechanisms. Some tumors respond to medical treatment with corticosteroids or beta-blockers, however, when this therapy fails or is incomplete, surgical extirpation may be necessary. Noninvasive therapies to debulk or eliminate these tumors would be an important advance. The development of an in vitro cell culture system and an animal model would allow new insights into the biological processes involved in the development and pathogenesis of IH. RESULTS: We observed that proliferative stage IH specimens contain significantly more SALL4+ and CD133+ cells than involuting tumors, suggesting a possible stem cell origin. A tumor sphere formation assay was adapted to culture IH cells in vitro. Cells in IH tumor spheres express GLUT1, indicative of an IH cell of origin, elevated levels of VEGF, and various stem/progenitor cell markers such as SALL4, KDR, Oct4, Nanog and CD133. These cells were able to self-renew and differentiate to endothelial lineages, both hallmarks of tumor stem cells. Treatment with Rapamycin, a potent mTOR/VEGF inhibitor, dramatically suppressed IH cell growth in vitro. Subcutaneous injection of cells from IH tumor spheres into immunodeficient NOD-SCID mice produced GLUT1 and CD31 positive tumors with the same cellular proliferation, differentiation and involution patterns as human hemangiomas. CONCLUSIONS: The ability to propagate large numbers of IH stem cells in vitro and the generation of an in vivo mouse model provides novel avenues for testing IH therapeutic agents in the future.
Ye, C., L. Pan, et al. (2011). “Somatic mutations in exon 17 of the TEK gene in vascular tumors and vascular malformations.” J Vasc Surg. 54(6):1760–8.
OBJECTIVE: As a common disease, the molecular etiology of noninherited vascular anomalies is still poorly understood. Recently, somatic mutations in exon 17 of the endothelial cell tyrosine kinase receptor Tie-2 (encoded by TEK) were identified in 49.1% of patients with common sporadic venous malformation, a subtype of vascular anomalies. We assessed whether such a mutational region also had a role in the Chinese population or in other subtypes of noninherited vascular anomalies (vascular tumors and vascular malformations). METHODS: Direct sequencing of polymerase chain reaction (PCR)-amplified DNA, extracted from 139 lesions in 129 individuals with noninherited vascular anomalies (vascular tumors or vascular malformations) and 60 control samples, was used for detecting the mutations in exon 17 of the TEK gene. Mutations were confirmed by allele-specific PCR. Clone sequences were then used for the mutations identified for the first time. We also explored the associations between these mutations and clinical characteristics (gender, onset age, number of lesions, severity, category, and recurrence of the disease) in both vascular tumors and vascular malformations. RESULTS: Two somatic TEK mutations (Y897C, R915C) were identified in vascular tumors, and seven somatic TEK mutations (Y897H, Y897C, L914F, R915C, S917I, R918C, R918H) were identified in vascular malformations. Among these mutations, R918C (2,752 C>T) and R918H (2,753 G>A) were first identified in noninherited vascular anomalies. Somatic TEK mutations were detected in lesions from 4 of 23 (17.4%) vascular tumors and 35 of 106 (33.0%) vascular malformations, where most mutations were single substitutions in vascular tumors (100%) and vascular malformations (88.6%), while the remainders were double substitutions. In addition to the reported venous malformation, such mutations were identified in some other subtypes of vascular anomalies, including vascular tumors (infantile hemangioma, pyogenic granuloma, and epithelioid hemangioma) and vascular malformations (capillary malformation, arteriovenous malformation, capillary lymphatic malformation, and capillary arteriovenous malformation). By contrast, these mutations were absent from the control tissues or blood. However, mutations showed no association (P>.05) with clinical characteristics in vascular anomalies or either of its two types (vascular tumors or vascular malformations). CONCLUSIONS: Our study revealed that somatic mutations in exon 17 of the TEK gene were more common in noninherited vascular anomalies than previously reported. Furthermore, such substitutions may shed new light on the molecular etiology, diagnosis, and potential therapeutic targets of vascular anomalies.