Abstract
Featured Article
OBJECTIVE: One of the hallmarks of inflammation is lymphangiogesis that drains the interstitial fluids. During chronic inflammation, angiogenesis is induced by a variety of inflammatory mediators, such as prostaglandins (PGs). However, it remains unknown whether they enhance lymphangiogenesis. We examined the roles of cyclooxygenase-2 (COX-2) and PGE(2) receptor signaling in enhancement of lymphangiogenesis during proliferative inflammation. METHODS AND RESULTS: Lymphangiogenesis estimated by podoplanin/vascular endothelial growth factor (VEGF) receptor-3/LYVE-1 expression was upregulated during proliferative inflammation seen around and into subcutaneous Matrigel plugs containing fibroblast growth factor-2 (125 ng/site). A COX-2 inhibitor (celecoxib) significantly reduced lymphangiogenesis in a dose-dependent manner, whereas topical PGE(2) enhanced lymphangiogenesis. Topical injection of fluorescein isothiocyanate-dextran into the Matrigel revealed that lymphatic flow from the Matrigels was COX-2 dependent. Lymphangiogenesis was suppressed in the granulation tissues of mice lacking either EP3 or EP4, suggesting that these molecules are receptors in response to endogenous PGE(2). An EP3-selective agonist (ONO-AE-248) increased the expression of VEGF-C and VEGF-D in cultured macrophages, whereas an EP4-selective agonist (ONO-AE1-329) increased VEGF-C expression in cultured macrophages and increased VEGF-D expression in cultured fibroblasts. CONCLUSIONS: Our findings suggest that COX-2 and EP3/EP4 signaling contributes to lymphangiogenesis in proliferative inflammation, possibly via induction of VEGF-C and VEGF-D, and may become a therapeutic target for controlling lymphangiogenesis.
In this manuscript, Hosono and colleagues attempt to study the interrelationship between inflammation and lymphangiogenesis. Based on previous work, they examine the role of prostaglandins and their inhibition on an animal model of inflammation using subcutaneous Matrigel plugs implanted in mice. Matrigel plugs stimulated with FGF-2 showed increased VEGFR-3 expression, lymphatic tube formation, and presence of macrophages , which were repressed by Prostaglandin inhibitors (COX-2 inhibitor Celecoxib) in a dose dependent fashion. They conclude that COX-2 stimulates lymphangiogenesis. They expand the studies to assess the direct effect of Prostaglandin PGE2 on inflammation-associated lymphangiogenesis. This was also associated with increased VEGFR-3 expression as well as VEGF-c and D. Mice lacking PGE receptors (EP1, EP2, EP3, and EP4) were exposed to FGF-2 and only EP3 -/- and EP4 -/- knockout mice were found to have reduced VEGFR-3 expression and decreased lymphatic vessel density. Lastly, they studied the effect of selective EP agonists on fibroblasts and macrophages, the major cell types involved in granulation tissue. They found that EP3-treated fibroblasts showed increased VEGF-D expression whereas EP3 and EP4-treated macrophages expressed VEGF-C or VEGF-D depending on the origin of the macrophage, concluding that Prostaglandin upregulation of lymphangiogenesis is cell-type dependent. These studies suggest that lymphangiogenesis inhibition may be achieved by selective targeting of Prostaglandin COX-2 and specifically the EP3 and EP4 receptors. Conversely, stimulation of these pathways may enhance lymphangiogenesis.
Basic Science
Avraham, T., S. Daluvoy, et al. (2010). “Blockade of Transforming Growth Factor-{beta}1 Accelerates Lymphatic Regeneration during Wound Repair.” Am J Pathol. 177(6):3202–3214. Epub 2010 Nov 5.
Lymphedema is a complication of cancer treatment occurring in approximately 50% of patients who undergo lymph node resection. Despite its prevalence, the etiology of this disorder remains unknown. In this study, we determined the effect of soft tissue fibrosis on lymphatic function and the role of transforming growth factor (TGF)-beta1 in the regulation of this response. We determined TGF-beta expression patterns in matched biopsy specimens collected from lymphedematous and normal limbs of patients with secondary lymphedema. To determine the role of TGF-beta in regulating tissue fibrosis, we used a mouse model of lymphedema and inhibited TGF-beta function either systemically with a monoclonal antibody or locally by using a soluble, defective TGF-beta receptor. Lymphedematous tissue demonstrated a nearly threefold increase in the number of cells that stained for TGF-beta1. TGF-beta inhibition markedly decreased tissue fibrosis, increased lymphangiogenesis, and improved lymphatic function compared with controls. In addition, inhibition of TGF-beta not only decreased TGF-beta expression in lymphedematous tissues, but also diminished inflammation, migration of T-helper type 2 (Th2) cells, and expression of profibrotic Th2 cytokines. Similarly, systemic depletion of T-cells markedly decreased TGF-beta expression in tail tissues. Inhibition of TGF-beta function promoted lymphatic regeneration, decreased tissue fibrosis, decreased chronic inflammation and Th2 cell migration, and improved lymphatic function. The use of these strategies may represent a novel means of preventing lymphedema after lymph node resection.
Baxter, S. A., D. Y. Cheung, et al. (2010). “Regulation of the lymphatic endothelial cell cycle by the PROX1 homeodomain protein.” Biochim Biophys Acta. 1813(1):201–12. Epub 2010 Oct 30.
The homeobox transcription factor PROX1 is essential for the development and maintenance of lymphatic vasculature. How PROX1 regulates lymphatic endothelial cell fate remains undefined. PROX1 has been shown to upregulate the expression of Cyclin E, which mediates the G(1) to S transition of the cell cycle. Here we demonstrate that PROX1 activates the mouse Cyclin E1 (Ccne1) promoter via two proximal E2F binding sites. We have determined that the N-terminal region of PROX1 is sufficient to activate a 1kb Ccne1 promoter whereas the homeodomain is dispensable for activation. We have identified that the Prospero domain 1 (PD1) is required for the nuclear localization of PROX1. Our comparison of two DNA binding deficient constructs of PROX1 showed a cell-type specific difference between these two proteins in both their localization and function. We demonstrated that siRNA mediated knockdown of PROX1 in lymphatic endothelial cells decreases progression from G(1) to S phase of the cell cycle. We conclude that PROX1 activates the Ccne1 promoter independent of DNA binding and our results illustrate a novel role for PROX1 in the regulation of lymphatic endothelial cell proliferation.
Bertram, C. D., C. Macaskill, et al. (2011). “Simulation of a chain of collapsible contracting lymphangions with progressive valve closure.” J Biomech Eng 133(1): 011008.
Bouta, E. M., C. W. McCarthy, et al. (2011). “Biomaterial Guides for Lymphatic Endothelial Cell Alignment and Migration.” Acta Biomater. 7(3):1104–13. Epub 2010 Oct 23.
Brown, H. M., R. L. Robker, et al. (2010). “Development and Hormonal Regulation of the Ovarian Lymphatic Vasculature.” Endocrinology. 151(11):5446–55. Epub 2010 Sep 15.
The lymphatic vasculature plays a number of essential physiological roles including maintaining fluid homeostasis, providing a network for the transport of immune cells, and facilitating the uptake of fat-soluble nutrients from the gastrointestinal tract. Although the critical importance and remodeling capacity of the blood vasculature has been well described within the ovary, just a few reports describe the lymphatic vasculature. Using histological and molecular techniques, we report the kinetics of ovarian lymphangiogenesis and the hormonal regulation of lymphangiogenic growth factors associated with key stages of ovarian follicle growth. We exploited the Adamts1-null mouse model, a model with a previously characterized lymphatic defect to further interrogate the mechanisms controlling ovarian lymphangiogenesis. The establishment and development of the ovarian lymphatic vascular network in postnatal developing ovaries was associated with the presence and hormonal regulation of the lymphangiogenic growth factors and their receptors, including Vegfc, Vegfd, and Vegfr3. We characterized the hormonally regulated remodeling of the ovarian lymphatic vasculature in response to FSH and estradiol. The lymphatic network was defective in the Adamts1-null ovary, clearly demonstrating both the involvement of FSH/estradiol and the Adamts1 (a disintegrin and metalloproteinase with thrombospondin motifs 1) protease in ovarian lymphangiogenesis. This study provides the first evidence of a malleable lymphatic system responsive to hormonal changes of the female reproductive cycle, at least in the mouse ovary, suggesting a role for lymphatic vessel functions in normal folliculogenesis.
Choi, I., H. K. Chung, et al. (2011). “Visualization of lymphatic vessels by Prox1-promoter directed GFP reporter in a bacterial artificial chromosome-based transgenic mouse.” Blood. 6;117(1):362–5. Epub 2010 Oct 20.
While the blood vessel-specific fluorescent transgenic mouse has been an excellent tool to study vasculogenesis and angiogenesis, a lymphatic-specific fluorescent mouse model has not been established to date. Here, we report a transgenic animal model that expresses the green fluorescent protein (GFP) under the promoter of Prox1, a master control gene in lymphatic development. Generated by using a ∼200-kb long bacterial artificial chromosome (BAC) harboring the entire Prox1 gene, this Prox1-GFP mouse was found to faithfully recapitulate the expression pattern of the Prox1 gene in lymphatic endothelial cells and other Prox1-expressing organs, and enabled us to conveniently visualize detailed structure and morphology of lymphatic vessels and networks throughout development. Our data demonstrate that this novel transgenic mouse can be extremely useful for detection, imaging and isolation of lymphatic vessels and monitoring wound-associated lymphangiogenesis. Together, this Prox1-GFP transgenic mouse will be a great tool for the lymphatic research.
Cooley, L. S., M. M. Handsley, et al. (2010). “Reversible transdifferentiation of blood vascular endothelial cells to a lymphatic-like phenotype in vitro.” J Cell Sci. 123(Pt 21):3808–16. Epub 2010 Oct 12.
Blood vascular cells and lymphatic endothelial cells (BECs and LECs, respectively) form two separate vascular systems and are functionally distinct cell types or lineages with characteristic gene expression profiles. Interconversion between these cell types has not been reported. Here, we show that in conventional in vitro angiogenesis assays, human BECs of fetal or adult origin show altered gene expression that is indicative of transition to a lymphatic-like phenotype. This change occurs in BECs undergoing tubulogenesis in fibrin, collagen or Matrigel assays, but is independent of tube formation per se, because it is not inhibited by a metalloproteinase inhibitor that blocks tubulogenesis. It is also reversible, since cells removed from 3D tubules revert to a BEC expression profile upon monolayer culture. Induction of the lymphatic-like phenotype is partially inhibited by co-culture of HUVECs with perivascular cells. These data reveal an unexpected plasticity in endothelial phenotype, which is regulated by contact with the ECM environment and/or cues from supporting cells.
Dashkevich, A., W. Bloch, et al. (2010). “Immunohistochemical study of remodeling of myocardial lymphatic and blood microvascular structures in terminal heart failure: differences between ischemic and dilated cardiomyopathy.” Lymphology 43(3):110–117.
Del Giacco, L., A. Pistocchi, et al. (2010). “Prox1b Activity is essential in zebrafish lymphangiogenesis.” PLoS One 5(10): e13170.
Dixon, J. B. (2010). “Mechanisms of chylomicron uptake into lacteals.” Ann N Y Acad Sci 1207 Suppl 1: E52–57.
Right from birth, the lymphatics play a crucial role in dietary functions. A majority of the lipid absorbed from the newborn's lipid-rich diet enters the blood circulation through the lymphatic system, which transports triglyceride-loaded particles known as chylomicrons from the villi of the small intestine to the venous circulation near the heart. In light of the significance of this role, as well as the fact that lipid transport from the gut was one of the earliest discovered functions of the lymphatic vasculature, it is surprising that so little is known about how chylomicrons initially gain access to the lymphatic vessel. This review will focus on the current mechanisms thought to be important in this process and highlight important questions that need to be answered in the future.
Du, Y., Y. Liu, et al. (2011). “LYVE-1 enhances the adhesion of HS-578T cells to COS-7 cells via hyaluronan.” Clin Invest Med 34(1): E45.
Dzieciatkowska, M., M. V. Wohlauer, et al. (2010). “Proteomic Analysis of Human Mesenteric Lymph.” Shock. Dec 9. [Epub ahead of print]
Flister, M. J., L. D. Volk, et al. (2011). “Characterization of Prox1 and VEGFR-3 expression and lymphatic phenotype in normal organs of mice lacking p50 subunit of NF-kappaB.” Microcirculation. 18(2):85–101.
Furuya, M., S. B. Kirschbaum, et al. (2010). “Lymphatic Endothelial Murine Chloride Channel Calcium-Activated 1 Is a Ligand for Leukocyte LFA-1 and Mac-1.” J Immunol. 185(10):5769–77. Epub 2010 Oct 11.
Gehlert, S., C. Theis, et al. (2010). “Exercise-induced decline in the density of LYVE-1-positive lymphatic vessels in human skeletal muscle.” Lymphat Res Biol 8(3):165–173.
Geudens, I., R. Herpers, et al. (2010). “Role of delta-like-4/Notch in the formation and wiring of the lymphatic network in zebrafish.” Arterioscler Thromb Vasc Biol 30(9):1695–1702.
OBJECTIVE: To study whether Notch signaling, which regulates cell fate decisions and vessel morphogenesis, controls lymphatic development. METHODS AND RESULTS: In zebrafish embryos, sprouts from the axial vein have lymphangiogenic potential because they give rise to the first lymphatics. Knockdown of delta-like-4 (Dll4) or its receptors Notch-1b or Notch-6 in zebrafish impaired lymphangiogenesis. Dll4/Notch silencing reduced the number of sprouts producing the string of parchordal lymphangioblasts; instead, sprouts connecting to the intersomitic vessels were formed. At a later phase, Notch silencing impaired navigation of lymphatic intersomitic vessels along their arterial templates. CONCLUSIONS: These studies imply critical roles for Notch signaling in the formation and wiring of the lymphatic network.
Gordon, E. J., S. Rao, et al. (2010). “Macrophages define dermal lymphatic vessel calibre during development by regulating lymphatic endothelial cell proliferation.” Development 137(22): 3899–3910.
Macrophages have been suggested to stimulate neo-lymphangiogenesis in settings of inflammation via two potential mechanisms: (1) acting as a source of lymphatic endothelial progenitor cells via the ability to transdifferentiate into lymphatic endothelial cells and be incorporated into growing lymphatic vessels; and (2) providing a crucial source of pro-lymphangiogenic growth factors and proteases. We set out to establish whether cells of the myeloid lineage are important for development of the lymphatic vasculature through either of these mechanisms. Here, we provide lineage tracing evidence to demonstrate that lymphatic endothelial cells arise independently of the myeloid lineage during both embryogenesis and tumour-stimulated lymphangiogenesis in the mouse, thus excluding macrophages as a source of lymphatic endothelial progenitor cells in these settings. In addition, we demonstrate that the dermal lymphatic vasculature of PU.1(-/-) and Csf1r(-/-) macrophage-deficient mouse embryos is hyperplastic owing to elevated lymphatic endothelial cell proliferation, suggesting that cells of the myeloid lineage provide signals that act to restrain lymphatic vessel calibre in the skin during development. In contrast to what has been demonstrated in settings of inflammation, macrophages do not comprise the principal source of pro-lymphangiogenic growth factors, including VEGFC and VEGFD, in the embryonic dermal microenvironment, illustrating that the sources of patterning and proliferative signals driving embryonic and disease-stimulated lymphangiogenesis are likely to be distinct.
Grimaldo, S., M. Garcia, et al. (2010). “Specific role of lymphatic marker podoplanin in retinal pigment epithelial cells.” Lymphology 43(3):128–134.
Hermans, K., F. Claes, et al. (2010). “Role of synectin in lymphatic development in zebrafish and frogs.” Blood 116(17): 3356–3366.
Huggenberger, R., S. Ullmann, et al. (2010). “Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation.” J Exp Med. 207(10):2255–69. Epub 2010 Sep 13.
The role of lymphangiogenesis in inflammation has remained unclear. To investigate the role of lymphatic versus blood vasculature in chronic skin inflammation, we inhibited vascular endothelial growth factor (VEGF) receptor (VEGFR) signaling by function-blocking antibodies in the established keratin 14 (K14)-VEGF-A transgenic (Tg) mouse model of chronic cutaneous inflammation. Although treatment with an anti-VEGFR-2 antibody inhibited skin inflammation, epidermal hyperplasia, inflammatory infiltration, and angiogenesis, systemic inhibition of VEGFR-3, surprisingly, increased inflammatory edema formation and inflammatory cell accumulation despite inhibition of lymphangiogenesis. Importantly, chronic Tg delivery of the lymphangiogenic factor VEGF-C to the skin of K14-VEGF-A mice completely inhibited development of chronic skin inflammation, epidermal hyperplasia and abnormal differentiation, and accumulation of CD8 T cells. Similar results were found after Tg delivery of mouse VEGF-D that only activates VEGFR-3 but not VEGFR-2. Moreover, intracutaneous injection of recombinant VEGF-C156S, which only activates VEGFR-3, significantly reduced inflammation. Although lymphatic drainage was inhibited in chronic skin inflammation, it was enhanced by Tg VEGF-C delivery. Together, these results reveal an unanticipated active role of lymphatic vessels in controlling chronic inflammation. Stimulation of functional lymphangiogenesis via VEGFR-3, in addition to antiangiogenic therapy, might therefore serve as a novel strategy to treat chronic inflammatory disorders of the skin and possibly also other organs.
Ishii, E., A. Shimizu, et al. (2010). “Lymphangiogenesis associated with acute cellular rejection in rat liver transplantation.” Transplant Proc 42(10):4282–4285.
Kholova, I., G. Dragneva, et al. (2010). “Lymphatic vasculature is increased in heart valves, ischaemic and inflamed hearts and in cholesterol-rich and calcified atherosclerotic lesions.” Eur J Clin Invest. Dec 3. [Epub ahead of print]
Laco, F., M. H. Grant, et al. (2011). “Cellular trans/-differentiation and morphogenesis towards the lymphatic lineage in regenerative medicine.” Stem Cells Dev. 20(2):181–95. Epub 2010 Oct 29.
Lee, J. Y., C. Park, et al. (2010). “Podoplanin-Expressing Cells Derived From Bone Marrow Play a Crucial Role in Postnatal Lymphatic Neovascularization.” Circulation. 122(14):1413–25. Epub 2010 Sep 20.
Lee, S. J., W. He, et al. (2010). “Evaluation of clearance mechanisms with transscleral drug delivery.” Invest Ophthalmol Vis Sci 51(10):5205–5212.
PURPOSE: The goal of this study was to examine elimination pathways when delivering subconjunctivally administered hydrophilic agents to the retinas of rat eyes. METHODS: The distribution of sodium fluorescein released from an episcleral implant was compared in live and postmortem eyes. Elimination of the subconjunctivally administered hydrophilic agent IgG through blood and lymphatic vessels was investigated by immunohistochemistry. Additionally, lymphatic elimination of subconjunctivally injected sodium fluorescein was quantitatively evaluated. RESULTS: NaFl released from an episcleral implant was successfully delivered to the subretinal space in the postmortem eye but failed to do so in the live eye. Immunohistochemical visualization of the conjunctival tissue demonstrated dense distribution of blood and lymphatic vessels while also confirming the elimination of subconjunctivally administered IgG through these same vessels. The lymphatic elimination rate after injection of 75.6 mug of a hydrophilic agent, sodium fluorescein, into the subconjunctival space was determined to be 105 ng/min between 30 and 60 minutes. CONCLUSIONS: Conjunctival blood and lymphatic vessel elimination considerably limit transscleral hydrophilic drug delivery to the retina.
Martin, A., H. Gasse, et al. (2010). “Absence of lymphatic vessels in the dog dental pulp: an immunohistochemical study.” J Anat. 217(5):609–15.
Navarro, A., R. E. Perez, et al. (2011). “Polarized Migration of Lymphatic Endothelial Cells is Critically Dependent on Podoplanin Regulation of Cdc42.” Am J Physiol Lung Cell Mol Physiol. 300(1):L32–42. Epub 2010 Oct 29.
Nishimukai, M., M. Yamashita, et al. (2010). “Lymphatic absorption of choline plasmalogen is much higher than that of ethanolamine plasmalogen in rats.” Eur J Nutr. Dec 9. [Epub ahead of print]
Ostergaard, P., M. A. Simpson, et al. (2011). “Rapid identification of mutations in GJC2 in primary lymphoedema using whole exome sequencing combined with linkage analysis with delineation of the phenotype.” J Med Genet. Jan 25. [Epub ahead of print]
Pan, W. R., C. M. Le Roux, et al. (2011). “Variations in the lymphatic drainage pattern of the head and neck: further anatomic studies and clinical implications.” Plast Reconstr Surg 127(2):611–620.
Pavlakovic, H., J. Becker, et al. (2010). “Soluble VEGFR-2: an antilymphangiogenic variant of VEGF receptors.” Ann N Y Acad Sci 1207 Suppl 1:E7–15.
Qin, J., X. Chen, et al. (2010). “Nuclear Receptor COUP-TFII Controls Pancreatic Islet Tumor Angiogenesis by Regulating Vascular Endothelial Growth Factor/Vascular Endothelial Growth Factor Receptor-2 Signaling.” Cancer Res. 70(21):8812–21. Epub 2010 Oct 26.
Rossi, A., E. Gabbrielli, et al. (2010). “Human microvascular lymphatic and blood endothelial cells produce fibrillin: deposition patterns and quantitative analysis.” J Anat. 217(6):705–14. doi: 10.1111/j.1469-7580.2010.01306.x. Epub 2010 Oct 11.
Rouzaut, A., S. Garasa, et al. (2010). “Dendritic cells adhere to and transmigrate across lymphatic endothelium in response to IFN-alpha.” Eur J Immunol. 40(11):3054-63. Epub 2010 Oct 27.
Saban, M. R., T. J. Sferra, et al. (2010). “Neuropilin-VEGF signaling pathway acts as a key modulator of vascular, lymphatic and inflammatory cell responses of the bladder to intravesical BCG treatment.” Am J Physiol Renal Physiol. 299(6):F1245–56. Epub 2010 Sep 22.
Sena, L. M., S. J. Fishman, et al. (2010). “Magnetic resonance lymphangiography with a nano-sized gadolinium-labeled dendrimer in small and large animal models.” Nanomedicine (Lond) 5(8):1183–1191.
Souza-Smith, F. M., K. M. Kurtz, et al. (2010). “Adaptation of mesenteric collecting lymphatic pump function following acute alcohol intoxication.” Microcirculation 17(7):514–524.
Sun, B. L., F. M. Xie, et al. (2011). “Blocking cerebral lymphatic drainage deteriorates cerebral oxidative injury in rats with subarachnoid hemorrhage.” Acta Neurochir Suppl 110(2):49–53.
Sun, Z. J., Y. Cai, et al. (2010). “LMO2 promotes angiogenesis probably by up-regulation of bFGF in endothelial cells: an implication of its pathophysiological role in infantile haemangioma.” Histopathology 57(4):622–632.
Tang, X. L., J. F. Sun, et al. (2010). “Blocking neuropilin-2 enhances corneal allograft survival by selectively inhibiting lymphangiogenesis on vascularized beds.” Mol Vis 16:2354–2361.
Thiemann, S. and L. G. Baum (2010). “The Road Less Traveled: Regulation of Leukocyte Migration Across Vascular and Lymphatic Endothelium by Galectins.” J Clin Immunol. Sep 22. [Epub ahead of print]
Tomanek, R. J., L. P. Christensen, et al. (2010). “Embryonic coronary vasculogenesis and angiogenesis are regulated by interactions between multiple FGFs and VEGF and are influenced by mesenchymal stem cells.” Dev Dyn. 239(12):3182–91.
Trevaskis, N. L., W. N. Charman, et al. (2010). “Targeted drug delivery to lymphocytes: a route to site specific immunomodulation?” Mol Pharm. 7(6):2297–309. Epub 2010 Nov 12.
Lymphocytes are central to the progression of autoimmune disease, transplant rejection, leukaemia, lymphoma and lymphocyte-resident viral diseases such as HIV/AIDs. Strategies to target drug treatments to lymphocytes, therefore, represent an opportunity to enhance therapeutic outcomes in disease states where many current treatment regimes are incompletely effective and promote significant toxicities. Here we demonstrate that highly lipophilic drug candidates that preferentially access the intestinal lymphatics after oral administration, show significantly enhanced access to lymphocytes leading to improved immunomodulatory activity. When co-administered with such drugs, lipids enhance lymphocyte targeting via a three tiered action: promotion of drug absorption from the gastrointestinal tract, enhancement of lymphatic drug transport and stimulation of lymphocyte recruitment into the lymphatics. This strategy has been exemplified using a highly lipophilic immunosuppressant (JWH015) where co-administration with selected lipids led to significant increases in lymphatic transport, lymphocyte targeting and IL-4 and IL-10 expression in CD4 + and CD8 + lymphocytes after ex vivo mitogen stimulation. In contrast, administration of a 2.5-fold higher dose of JWH015 in a formulation that did not stimulate lymph transport had no effect on antiinflammatory cytokine levels, in spite of equivalent drug exposure in the blood. The current data suggest that complimentary drug design and delivery strategies that combine highly lipophilic, lymphotropic drug candidates with lymph-directing formulations provide enhanced selectivity, potency and therapeutic potential for drug candidates with lymphocyte associated targets.
Vickerman, M. B., P. A. Keith, et al. (2009). “VESGEN 2D: automated, user-interactive software for quantification and mapping of angiogenic and lymphangiogenic trees and networks.” Anat Rec (Hoboken) 292(3):320–332.
Von Der Weid, P. Y. and S. Rehal (2010). “Lymphatic pump function in the inflamed gut.” Ann N Y Acad Sci 1207 Suppl 1: E69–74.
Wardrop, K. E. and J. A. Dominov (2010). “Proinflammatory Signals and the Loss of Lymphatic Vessel Hyaluronan Receptor-1 (LYVE-1) in the Early Pathogenesis of Laminin {alpha}2-Deficient Skeletal Muscle.” J Histochem Cytochem. Sep 27. [Epub ahead of print]
Clinical
Adams, K. E., J. C. Rasmussen, et al. (2010). “Direct evidence of lymphatic function improvement after advanced pneumatic compression device treatment of lymphedema.” Biomed Opt Express 1(1):114–125.
Barresi, L., I. Tarantino, et al. (2011). “Pancreatic cystic lymphangioma in a 6-year-old girl, diagnosed by endoscopic ultrasound (EUS) fine needle aspiration.” Endoscopy 43(S 02): E61–E62.
Castro, E., W. Tony Parks, et al. (2011). “Neither normal nor diseased placentas contain lymphatic vessels.” Placenta. Feb 10. [Epub ahead of print]
BACKGROUND: Scant data on placental lymphatic vessels have pointed to the absence of lymphatic circulation. A recent study on mesenchymal dysplasia (MD), however, has identified pathologic lymphangiogenesis using the D2-40 lymphatic marker. These conflicting data have prompted us to investigate whether lymphatic vessels are present in normal developing placentas and in placental disorders characterized by cistern formation. DESIGN: Seventeen human placentas without significant pathological abnormality ranging from 12 to 39 weeks of gestational age were studied. Cisternal placental disorders were represented by mesenchymal dysplasia (n = 1), partial hydatitiform mole (n = 2), spontaneous abortion (n = 3) and complete hydatiform mole (n = 2). To identify lymphatic vessels, we used lymphatic endothelial markers Prox-1 and D2-40. The pan-endothelial marker CD31 was used to highlight overall placental vasculature and to determine if the lining cells of cisterns were of endothelial origin. Lymphatic marker positivity was assessed in maternal (decidual) as well as in fetal (chorionic villous) vasculature. RESULTS: No staining with Prox-1 or D2-40 was identified in fetal vessels in developing or term placentas, or in selected cisternal placental disorders, although both markers highlighted a number of thin-walled decidual vessels. Cistern lining cells were negative for Prox-1, D2-40 and CD31. D2-40 consistently marked stromal cells in chorionic villi and highlighted perivascular/pericellular extracellular matrix. CONCLUSION: We established that no lymphatic vasculature is present in the chorionic villi during development, at term or in selected edematous placental disorders. The cisternal lining cells are not endothelial cells; most likely they are of stromal cell origin. Lymphangiogenesis is a part of decidual vascular remodeling during gestation.
de Mooij, Y. M., N. M. van den Akker, et al. (2011). “Aberrant lymphatic development in euploid fetuses with increased nuchal translucency including Noonan syndrome.” Prenat Diagn 31(2):159–166.
Greenberger, S., H. Reznik-Wolf, et al. (2010). “Severe Congenital Lymphedema Not Caused by Mutations in Known Lymphedema Genes.” Br J Dermatol.
Grunewald, T. G., L. Damke, et al. (2010). “First report of effective and feasible treatment of multifocal lymphangiomatosis (Gorham-Stout) with bevacizumab in a child.” Ann Oncol 21(8):1733–1734.
Kim, T. H., J. Y. Lee, et al. (2010). “Remodelling of nasal mucosa in mild and severe persistent allergic rhinitis with special reference to the distribution of collagen, proteoglycans, and lymphatic vessels.” Clin Exp Allergy. 40(12):1742–54. Epub 2010 Sep 23.
Maegawa, J., T. Mikami, et al. (2010). “Lymphaticovenous shunt for the treatment of chylous reflux by subcutaneous vein grafts with valves between megalymphatics and the great saphenous vein: A case report.” Microsurgery. 30(7):553–6.
Maegawa, J., T. Mikami, et al. (2010). “Types of lymphoscintigraphy and indications for lymphaticovenous anastomosis.” Microsurgery 30(6):437–442.
Mukenge, S. M., M. Catena, et al. (2010). “Assessment and Follow-Up of Patency After Lymphovenous Microsurgery for Treatment of Secondary Lymphedema in External Male Genital Organs.” Eur Urol. Nov 24. [Epub ahead of print]
Schook, C. C., J. B. Mulliken, et al. (2010). “Differential Diagnosis of Lower Extremity Enlargement in Pediatric Patients Referred with a Diagnosis of ”Lymphedema“.” Plast Reconstr Surg. Dec 23. [Epub ahead of print]
Suarez-Farinas, M., J. Fuentes-Duculan, et al. (2011). “Resolved Psoriasis Lesions Retain Expression of a Subset of Disease-Related Genes.” J Invest Dermatol. 131(2):391–400. Epub 2010 Sep 23.
Psoriasis is a complex inflammatory disease that usually heals without visible scarring. Histological evaluation often suggests complete resolution, but reversal of genomic disease-associated alterations has not yet been defined. Gene expression profiling was used to determine the extent to which the psoriasis genes were reversed after 3 months of etanercept treatment in patients who responded to treatment. We reviewed the histology, leukocyte counts, and PCR data for inflammatory genes, to compare recovery of these parameters and the genomic studies. Many cellular markers do return close to nonlesional levels, although five inflammatory genes did not improve by > 75% (IL-12p35, MX1, IL-22, IL-17, and IFNgamma). Psoriasis-related genes with < 75% improvement were defined as comprising a “residual disease genomic profile,” composed of 248 probe sets. Genes of interest in psoriasis tissue that did not return to baseline included LYVE-1, WNT5A, RAB31, and AQP9. It appears that even when the epidermal reaction in psoriasis is fully resolved, inflammation, as defined by expression of key cytokines and chemokines, is not completely resolved in treated lesions. We also found that structural cells of the skin continued to express molecular alterations, and that some subtle features of skin structure, for example, lymphatics, were not fully normalized with treatment.
Sutkowska, E., A. Bator, et al. (2010). “Different lymphscintigraphic patterns in patients with lymphedema distichiasis.” Lymphology 43(2):73–77.
Tang, Q. Y., J. Wen, et al. (2011). “Clinical outcome of nutrition-oriented intervention for primary intestinal lymphangiectasia.” World J Pediatr 7(1):79–82.
Vasileiou, A. M., R. Bull, et al. (2011). “Oedema in obesity; role of structural lymphatic abnormalities.” Int J Obes (Lond). Jan 25. [Epub ahead of print]
Venkatramani, R., N. S. Ma, et al. (2011). “Gorham's disease and diffuse lymphangiomatosis in children and adolescents.” Pediatr Blood Cancer. 56(4):667–70. Epub 2010 Dec 22.
Zampell, J. C., A. Yan, et al. (2011). “Temporal and spatial patterns of endogenous danger signal expression after wound healing and in response to lymphedema.” Am J Physiol Cell Physiol. Jan 19. [Epub ahead of print]
Zhang, F., G. Niu, et al. (2010). “Preclinical Lymphatic Imaging.” Mol Imaging Biol. Sep 23. [Epub ahead of print]
Oncology
Anagnostou, V. K., D. G. Tiniakos, et al. (2010). “Multiplexed analysis of angiogenesis and lymphangiogenesis factors predicts outcome for non-small cell lung cancer patients.” Virchows Arch. Dec 14. [Epub ahead of print]
Crane, L. M., G. Themelis, et al. (2010). “Intraoperative near-infrared fluorescence imaging for sentinel lymph node detection in vulvar cancer: First clinical results.” Gynecol Oncol. 120(2):291–5. Epub 2010 Nov 6.
Cuong, N. V. and M. F. Hsieh (2010). “Molecular Targeting of Liposomal Nano-particles to Lymphatic System.” Curr Cancer Drug Targets. 11(2):147–55.
Emmett, M. S., S. Lanati, et al. (2010). “CCR7 mediates directed growth of melanomas towards lymphatics.” Microcirculation. Nov 24. [Epub ahead of print]
Hadj, A. K., C. Malcontenti-Wilson, et al. (2010). “Lymphatic Patterns of Colorectal Liver Metastases.” J Surg Res. Oct 8. [Epub ahead of print]
Karpova, M. B., K. Fujii, et al. (2011). “Evaluation of lymphangiogenic markers in Sezary syndrome.” Leuk Lymphoma. 52(3):491–501. Epub 2010 Sep 17.
Kim, M., Y. J. Koh, et al. (2010). “CXCR4 signaling regulates metastasis of chemoresistant melanoma cells by a lymphatic metastatic niche.” Cancer Res. 70(24):10411–21. Epub 2010 Nov 5.
Kluger, M. S. and O. R. Colegio (2011). “Lymphangiogenesis Linked to VEGF-C from Tumor-Associated Macrophages: Accomplices to Metastasis by Cutaneous Squamous Cell Carcinoma?” J Invest Dermatol 131(1):17–19.
Le Fourn, E., E. Duhard, et al. (2010). “Changes in the nail unit in patients with secondary lymphoedema identified using clinical, dermoscopic and ultrasound examination.” Br J Dermatol. Dec 14. [Epub ahead of print]
Lund, A. W. and M. A. Swartz (2010). “Role of Lymphatic Vessels in Tumor Immunity: Passive Conduits or Active Participants?” J Mammary Gland Biol Neoplasia. 15(3):341–52. Epub 2010 Sep 11.
McDonald, D. M. (2010). “New antibody to stop tumor angiogenesis and lymphatic spread by blocking receptor partnering.” Cancer Cell 18(6):541–543.
Mumprecht, V., M. Honer, et al. (2010). “In vivo Imaging of Inflammation- and Tumor-Induced Lymph Node Lymphangiogenesis by Immuno-Positron Emission Tomography.” Cancer Res. 70(21):8842–51. Epub 2010 Oct 26.
Qiuhang, Z., W. Zhenlin, et al. (2010). “Lymphatic drainage of the skull base: comparative anatomic and advanced imaging studies in the rabbit and human with implications for spread of nasopharyngeal carcinoma.” Lymphology 43(3):98–109.
Shibata, M. A., J. Ambati, et al. (2010). “The endogenous soluble VEGF Receptor-2 isoform suppresses lymph node metastasis in a mouse immunocompetent mammary cancer model.” BMC Med 8(1):69.
Tammela, T., A. Saaristo, et al. (2011). “Photodynamic ablation of lymphatic vessels and intralymphatic cancer cells prevents metastasis.” Sci Transl Med 3(69):69ra11.
Wang, J., B. Wang, et al. (2010). “Cytoplasmic HuR expression correlates with angiogenesis, lymphangiogenesis, and poor outcome in lung cancer.” Med Oncol. Nov 3. [Epub ahead of print]
Yin, X., J. Truty, et al. (2010). “A critical role for lymphatic endothelial heparan sulfate in lymph node metastasis.” Mol Cancer 9(1):316.
Reviews
Al-Rawi, M. A. and W. G. Jiang (2011). “Lymphangiogenesis and cancer metastasis.” Front Biosci 16:723–739.
Alexander, J. S., G. V. Chaitanya, et al. (2010). “Emerging roles of lymphatics in inflammatory bowel disease.” Ann N Y Acad Sci 1207 Suppl 1:E75–85.
Antonopoulos, R., G. Charalampopoulos, et al. (2010). “Familial renal retroperitoneal lymphangiomatosis: personal experience and review of literature.” JBR-BTR 93(5):258–261.
Chakraborty, S., S. Zawieja, et al. (2010). “Lymphatic system: a vital link between metabolic syndrome and inflammation.” Ann N Y Acad Sci 1207 Suppl 1:E94–102.
Hiratsuka, S. (2011). “Vasculogenensis, angiogenesis and special features of tumor blood vessels.” Front Biosci 16:1413–1427.
Kohan, A., S. Yoder, et al. (2010). “Lymphatics in intestinal transport of nutrients and gastrointestinal hormones.” Ann N Y Acad Sci 1207 Suppl 1: E44–51.
Linares, P. M. and J. P. Gisbert (2010). “Role of growth factors in the development of lymphangiogenesis driven by inflammatory bowel disease: A review.” Inflamm Bowel Dis. Dec 3. [Epub ahead of print]
Miller, A. J. (2011). “The grossly invisible and generally ignored lymphatics of the mammalian heart.” Med Hypotheses. Jan 31. [Epub ahead of print]
Onimaru, M. and Y. Yonemitsu (2011). “Angiogenic and lymphangiogenic cascades in the tumor microenvironment.” Front Biosci (Schol Ed) 3:216–225.
Renton, J. P. and R. J. Smith (2011). “Current treatment paradigms in the management of lymphatic malformations.” Laryngoscope. 121(1):56–9.
Rockson, S. G. (2010). “Causes and consequences of lymphatic disease.” Ann N Y Acad Sci 1207 Suppl 1:E2–6.
Vascular Anomalies
Adams, D. M. (2011). “Special considerations in vascular anomalies: hematologic management.” Clin Plast Surg 38(1): 153–160.
Al Dhaybi, R., J. Powell, et al. (2010). “Differentiation of vascular tumors from vascular malformations by expression of Wilms tumor 1 gene: evaluation of 126 cases.” J Am Acad Dermatol 63(6):1052–1057.
Altas, M., O. F. Bayrak, et al. (2010). “Angiotensin-converting enzyme insertion/deletion gene polymorphism in patients with familial multiple cerebral cavernous malformations.” J Clin Neurosci 17(8):1034–1037.
Avery, G., C. Davis, et al. (2011). “Hemangioma causing deformational plagiocephaly.” J Craniofac Surg 22(1):223–225.
Bard, S., M. I. Shiman, et al. (2010). “Severe respiratory syncytial virus infection complicating treatment for infantile hemangioma.” J Am Acad Dermatol 63(6):1109–1110.
Bianca, S., G. Bartoloni, et al. (2010). “Familial nuchal cystic hygroma without fetal effects: Genetic counselling and further evidence for an autosomal recessive subtype.” Congenit Anom (Kyoto) 50(2):139–140.
Blaise, S., H. Riom, et al. (2010). “Blue Rubber Bleb Nevus Syndrome Treated with Polidocanol Foam Sclerotherapy.” Dermatol Surg. 36(12):2067–8. Epub 2010 Oct 11.
Bonanno, C., M. Paccanaro, et al. (2011). “Propranolol for severe hemangioma of infancy.” J Cardiovasc Med (Hagerstown) 12(1):73.
Bonet-Coloma, C., I. Minguez-Martinez, et al. (2011). “Clinical Characteristics, Treatment, and Evolution in 14 Cases of Pediatric Orofacial Lymphangioma.” J Oral Maxillofac Surg. Jan 20. [Epub ahead of print]
Boutarbouch, M., D. Ben Salem, et al. (2010). “Multiple cerebral and spinal cord cavernomas in Klippel-Trenaunay-Weber syndrome.” J Clin Neurosci 17(8):1073–1075.
Buckmiller, L. M., G. T. Richter, et al. (2010). “Diagnosis and management of hemangiomas and vascular malformations of the head and neck.” Oral Dis 16(5):405–418.
Chim, H., B. Drolet, et al. (2010). “Vascular anomalies and lymphedema.” Plast Reconstr Surg 126(2):55e–69e.
Cuccaro, P., A. Rapacciuolo, et al. (2011). “Propranolol for severe hemangioma of infancy.” J Cardiovasc Med (Hagerstown) 12(1):5.
Dompmartin, A., M. Vikkula, et al. (2010). “Venous malformation: update on aetiopathogenesis, diagnosis and management.” Phlebology 25(5):224–235.
Dong, S. Z., M. Zhu, et al. (2010). “Use of foetal MRI in diagnosing hepatic hemangioendotheliomas: a report of four cases.” Eur J Radiol 75(3):301–305.
Drolet, B. A., S. L. Chamlin, et al. (2010). “Prospective Study of Spinal Anomalies in Children with Infantile Hemangiomas of the Lumbosacral Skin.” J Pediatr. 157(5):789–94. Epub 2010 Sep 9.
Drolet, B. A. and I. J. Frieden (2010). “Characteristics of infantile hemangiomas as clues to pathogenesis: does hypoxia connect the dots?” Arch Dermatol 146(11):1295–1299.
Eidemuller, M., E. Holmberg, et al. (2011). “Breast Cancer Risk after Radiation Treatment at Infancy: Potential Consequences of Radiation-Induced Genomic Instability.” Radiat Prot Dosimetry. Feb 4. [Epub ahead of print]
Eivazi, B., A. J. Fasunla, et al. (2011). “Low flow vascular malformations of the head and neck: a study on brightness mode, color coded duplex and spectral Doppler sonography.” Eur Arch Otorhinolaryngol. Feb 16. [Epub ahead of print]
Fabian, I. D., I. Ben-Zion, et al. (2011). “Reduction in astigmatism using propranolol as first-line therapy for periocular capillary hemangioma.” Am J Ophthalmol 151(1):53–58.
Fay, A., J. Nguyen, et al. (2010). “Conceptual approach to the management of infantile hemangiomas.” J Pediatr 157(6):881–888 e881–885.
Fernandez-Pineda, I., J. C. Lopez-Gutierrez, et al. (2010). “Vincristine-ticlopidine-aspirin: an effective therapy in children with Kasabach-Merritt phenomenon associated with vascular tumors.” Pediatr Hematol Oncol
Ferrandiz-Pulido, C., J. Mollet, et al. (2010). “Tufted angioma associated with Kasabach-Merritt phenomenon: a therapeutic challenge.” Acta Derm Venereol 90(5):535–537.
Funayama, E., S. Sasaki, et al. (2011). “How do the type and location of a vascular malformation influence growth in klippel-trenaunay syndrome?” Plast Reconstr Surg 127(1):340–346.
Gao, W., X. Qiao, et al. (2011). “Contribution of skin trauma to infantile skin hemangioma.” Med Hypotheses. Jan 8. [Epub ahead of print]
Greene, A. K. (2011). “Management of hemangiomas and other vascular tumors.” Clin Plast Surg 38(1):45–63.
Greene, A. K., C. A. Perlyn, et al. (2011). “Management of lymphatic malformations.” Clin Plast Surg 38(1):75–82.
Gupta, A. and H. Kozakewich (2011). “Histopathology of vascular anomalies.” Clin Plast Surg 38(1):31–44.
Guye, E., M. Chollet-Rivier, et al. (2011). “Propranolol treatment for subglottic haemangioma.” Arch Dis Child Fetal Neonatal Ed.
Hamdoon, Z., W. Jerjes, et al. (2010). “Cystic hygroma treated with ultrasound guided interstitial photodynamic therapy: case study.” Photodiagnosis Photodyn Ther 7(3):179–182.
Hassanein, A. H., J. B. Mulliken, et al. (2011). “Evaluation of terminology for vascular anomalies in current literature.” Plast Reconstr Surg 127(1):347–351.
Herbert, A., H. Ng, et al. (2011). “Hypoxia regulates the production and activity of glucose transporter-1 and indoleamine 2,3 dioxygenase in monocyte-derived endothelial-like cells: possible relevance to infantile haemangioma pathogenesis.” Br J Dermatol. 164(2):308–15.
Hoeger, P. H. (2011). “Infantile haemangioma: New aspects on the pathogenesis of the most common skin tumour in children.” Br J Dermatol 164(2):234–235.
Huisman, T. A., S. Singhi, et al. (2010). “Non-invasive imaging of intracranial pediatric vascular lesions.” Childs Nerv Syst 26(10):1275–1295.
Impellizzeri, P., C. Romeo, et al. (2010). “Sclerotherapy for cervical cystic lymphatic malformations in children. Our experience with computed tomography-guided 98% sterile ethanol insertion and a review of the literature.” J Pediatr Surg 45(12):2473–2478.
Irving, N. D., J. H. Lim, et al. (2010). “Sturge-Weber syndrome: ear, nose, and throat issues and neurologic status.” Pediatr Neurol 43(4):241–244.
Itinteang, T., A. Vishvanath, et al. (2011). “Mesenchymal stem cells in infantile haemangioma.” J Clin Pathol. 64(3):232–236. Epub 2011 Jan 17.
Jacobs, I. N. and A. M. Cahill (2011). “Special considerations in vascular anomalies: airway management.” Clin Plast Surg 38(1):121–131.
Jia, J. and Y. F. Zhao (2010). “Biomarkers: important clues to the pathogenesis of infantile haemangioma and their clinical significance.” Chin J Dent Res 13(2):105–108.
Jinnin, M., T. Ishihara, et al. (2010). “Recent progress in studies of infantile hemangioma.” J Dermatol 37(11):939–955.
Kelly, M. (2010). “Kasabach-Merritt phenomenon.” Pediatr Clin North Am 57(5):1085-1089. 57(5):1085–9. Epub 2010 Aug 21.
Kelly, M. E., A. M. Juern, et al. (2010). “Immunosuppressive effects in infants treated with corticosteroids for infantile hemangiomas.” Arch Dermatol 146(7):767–774.
Khunger, N. and M. Pahwa (2010). “Dramatic response of a large hemifacial infantile hemangioma associated with PHACE syndrome to topical timolol lotion.” Br J Dermatol. Dec 15. [Epub ahead of print]
Laury, A. R., M. Bongiovanni, et al. (2010). “Thyroid Pathology in PTEN-Hamartoma Tumor Syndrome: Characteristic Findings of a Distinct Entity.” Thyroid. 21(2):135–44. Epub 2010 Dec 29.
Le Huu, A. R., C. H. Jokinen, et al. (2010). “Expression of prox1, lymphatic endothelial nuclear transcription factor, in kaposiform hemangioendothelioma and tufted angioma.” Am J Surg Pathol 34(11):1563–1573.
Lee, T. S., G. M. Schwartz, et al. (2010). “Rhinoplasty for cleft and hemangioma-related nasal deformities.” Curr Opin Otolaryngol Head Neck Surg. Oct 19. [Epub ahead of print]
Li, X., R. Zhang, et al. (2010). “Crystal structure of CCM3, a cerebral cavernous malformation protein critical for vascular integrity.” J Biol Chem 285(31):24099–24107.
Lopez Gutierrez, J. C. (2011). “PHACES syndrome and ectopia cordis.” Interact Cardiovasc Thorac Surg. Jan 19. [Epub ahead of print]
Maisnam, I., T. Das, et al. (2010). “Blue rubber bleb nevus syndrome causing refractory anaemia.” J Assoc Physicians India 58: 246–249.
Marin-Manzano, E., A. Utrilla Lopez, et al. (2010). “Cervical cystic lymphangioma in a patient with blue rubber bleb nevus syndrome: clinical case report and review of the literature.” Ann Vasc Surg 24(8):1136 e1131–1135.
Martin, J. R., S. G. Pels, et al. (2010). “Assisted reproduction in a patient with Klippel-Trenaunay syndrome: management of thrombophilia and consumptive coagulopathy.” J Assist Reprod Genet. Dec 29. [Epub ahead of print]
Minato, H., S. Kaji, et al. (2010). “Solitary intrapulmonary cystic lymphangioma in an infant: A case report with literature review.” Pathol Res Pract. 206(12):851–6. Epub 2010 Oct 16.
Mishra, A., W. J. Holmes, et al. (2010). “Role of propranolol in the management of periocular hemangiomas.” Plast Reconstr Surg 126(2):671.
Mogler, C., C. Beck, et al. (2010). “Elevated expression of c-kit in small venous malformations of blue rubber bleb nevus syndrome.” Rare Tumors 2(2):e36.
Muscarella, L. A., V. Guarnieri, et al. (2010). “Small deletion at the 7q21.2 locus in a CCM family detected by real-time quantitative PCR.” J Biomed Biotechnol 2010. Epub 2010 Jul 27.
Ni, N., R. S. Wagner, et al. (2010). “New Developments in the Management of Periocular Capillary Hemangioma in Children.” J Pediatr Ophthalmol Strabismus: 1–8.
Niclauss, L., D. Delay, et al. (2010). “Therapy of acute massive pulmonary embolism associated with Klippel-Trenaunay syndrome.” Ann Vasc Surg 24(8):1138 e1135–1137.
Niramis, R., S. Watanatittan, et al. (2010). “Treatment of cystic hygroma by intralesional bleomycin injection: experience in 70 patients.” Eur J Pediatr Surg 20(3):178–182.
Niti, K. and P. Manish (2010). “Microcystic lymphatic malformation (lymphangioma circumscriptum) treated using a minimally invasive technique of radiofrequency ablation and sclerotherapy.” Dermatol Surg 36(11):1711–1717.
Ohta, N., S. Fukase, et al. (2010). “Treatments of various otolaryngological cystic diseases by OK-4321: its Indications and Limitations.” Laryngoscope. 120(11):2193–6.
Ohta, N., S. Fukase, et al. (2010). “Effects and mechanism of OK-432 therapy in various neck cystic lesions.” Acta Otolaryngol 130(11):1287–1292.
Oishi, S. N. and M. Ezaki (2010). “Venous thrombosis and pulmonary embolus in pediatric patients with large upper extremity venous malformations.” J Hand Surg Am 35(8):1330–1333.
Oiso, N., M. Kimura, et al. (2011). “Clinical, Dermoscopic, and Histopathologic Features in a Case of Infantile Hemangioma without Proliferation.” Pediatr Dermatol 28(1):66–68.
Ono, S., N. Iwai, et al. (2010). “OK-432 therapy for chylous pleural effusion or ascites associated with lymphatic malformations.” J Pediatr Surg 45(9):e7–e10.
Ozdemir, H., I. Marakoglu, et al. (2010). “Klippel-Trenaunay syndrome manifesting as gingival overgrowth and teeth agenesis.” J Clin Pediatr Dent 34(4):351–354.
Pandey, A., A. N. Gangopadhyay, et al. (2010). “Evaluation of topical steroids in the treatment of superficial hemangioma.” Skinmed 8(1):9–11.
Pereira de Godoy, J. M. and A. C. Fett-Conte (2010). “Dominant inheritance and intra-familial variations in the association of Sturge-Weber and Klippel-Trenaunay-Weber syndromes.” Indian J Hum Genet 16(1):26–27.
Prasetyono, T. O. and I. Djoenaedi (2011). “Efficacy of intralesional steroid injection in head and neck hemangioma: a systematic review.” Ann Plast Surg 66(1):98–106.
Przewratil, P., A. Sitkiewicz, et al. (2010). “Soluble receptors for vascular endothelial growth factor (sVEGFR1/sVEGFR2) in infantile hemangioma.” Growth Factors. 28(6):417–25. Epub 2010 Sep 21.
Rodriguez-Manero, M., L. Aguado, et al. (2010). “Pulmonary arterial hypertension in patients with slow-flow vascular malformations.” Arch Dermatol 146(12):1347–1352.
Sarialioglu, F., A. Erbay, et al. (2010). “Response of infantile hepatic hemangioma to propranolol resistant to high-dose methylprednisolone and interferon-alpha therapy.” Pediatr Blood Cancer 55(7):1433–1434.
Solari, V., D. Mullassery, et al. (2011). “Laparoscopic excision of a retroperitoneal lymphatic malformation in a newborn.” J Pediatr Surg 46(2):e15–17.
Stephens, D., S. Pillai, et al. (2010). “Serous borderline tumor of the fallopian tube in a patient with Klippel-Trenaunay syndrome.” J Pediatr Surg 45(11):2244–2246.
Suh, K. Y. and I. J. Frieden (2010). “Infantile hemangiomas with minimal or arrested growth: a retrospective case series.” Arch Dermatol 146(9):971–976.
Sun, Z. J., Y. Cai, et al. (2010). “LMO2 promotes angiogenesis probably by up-regulation of bFGF in endothelial cells: an implication of its pathophysiological role in infantile haemangioma.” Histopathology 57(4):622–632.
Tomelleri, G., M. Cappellari, et al. (2010). “Blue rubber bleb nevus syndrome with late onset of central nervous system symptomatic involvement.” Neurol Sci 31(4):501–504.
Trautmann, K., A. Bethke, et al. (2011). “Bevacizumab for recurrent hemangioendothelioma.” Acta Oncol 50(1):153–154.
Turin, E., M. A. Grados, et al. (2010). “Behavioral and psychiatric features of Sturge-Weber syndrome.” J Nerv Ment Dis 198(12):905–913.
Venkatramani, R., N. S. Ma, et al. (2011). “Gorham's disease and diffuse lymphangiomatosis in children and adolescents.” Pediatr Blood Cancer 56(4):667–670.
Yang, Y., M. Sun, et al. (2011). “Bleomycin A5 sclerotherapy for cervicofacial lymphatic malformations.” J Vasc Surg. 53(1):150–5. Epub 2010 Sep 16.
Zabel, T. A., J. Reesman, et al. (2010). “Neuropsychological features and risk factors in children with Sturge-Weber syndrome: four case reports.” Clin Neuropsychol 24(5):841–859.