Abstract
Featured Manuscript
Chronic venous disease and venous hypertension are common consequences of valve insufficiency, yet the molecular mechanisms regulating the formation and maintenance of venous valves have not been studied. Here, we provide what we believe to be the first description of venous valve morphogenesis and identify signaling pathways required for the process. The initial stages of valve development were found to involve induction of ephrin-B2, a key marker of arterial identity, by venous endothelial cells. Intriguingly, developing and mature venous valves also expressed a repertoire of proteins, including prospero-related homeobox 1 (Prox1), Vegfr3, and integrin-alpha9, previously characterized as specific and critical regulators of lymphangiogenesis. Using global and venous valve-selective knockout mice, we further demonstrate the requirement of ephrin-B2 and integrin-alpha9 signaling for the development and maintenance of venous valves. Our findings therefore identified molecular regulators of venous valve development and maintenance and highlighted the involvement of common morphogenetic processes and signaling pathways in controlling valve formation in veins and lymphatic vessels. Unexpectedly, we found that venous valve endothelial cells closely resemble lymphatic (valve) endothelia at the molecular level, suggesting plasticity in the ability of a terminally differentiated endothelial cell to take on a different phenotypic identity.
Bazigou et al, in studying venous valve development, identify parallel signaling mechanisms in venous and lymphatic valve morphogenesis, both involving Prox-1, integrin alpha9, VEGFR-3. They studied valve morphogenesis in a mouse model, demonstrating analogous molecular mechanisms, suggesting “that valve endothelial cell possess a unique identity independent of the type of vessel in which it develops, but is likely attributed to the function of the luminal valve”.
They show that mouse and human valves are morphologically similar, then study venous valve development, demonstrating expression of markers for arterial as well as lymphatic endothelium (ephrin-B2, integrin alpha9, its ligand Fibronectin-EIIIA, Prox-1. VEGFR-3,) during varying stages of maturation. Knock-out mouse models lacking ephrin-B2, intrgrin-alpha9, Fibronectin-EIIIA resulted in defective venous valves. Both venous and lymphatic valves required sustained integrin alpha-9 and ephrin-B2 signaling for valve “maintenance”, with some differences, possibly attributed by harsher requirements for venous valves in vivo. Nonetheless, the common processes identified in venous and lymphatic valve morphogenesis is fascinating.
Basic Science
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Davis, M. J., E. Rahbar, et al. (2011). Determinants of valve gating in collecting lymphatic vessels from rat mesentery. Am J Physiol Heart Circ Physiol. 301(1):H48–60. Epub 2011 Apr 1.
Secondary lymphatic valves are essential for minimizing backflow of lymph and are presumed to gate passively according to the instantaneous trans-valve pressure gradient. We hypothesized that valve gating is also modulated by vessel distention, which could alter leaflet stiffness and coaptation. To test this hypothesis, we devised protocols to measure the small pressure gradients required to open or close lymphatic valves and determine if the gradients varied as a function of vessel diameter. Lymphatic vessels were isolated from rat mesentery, cannulated and pressurized using a servo-control system. Detection of valve leaflet position simultaneously with diameter and intraluminal pressure changes in 2-valve segments revealed the detailed temporal relationships between these parameters during the lymphatic contraction cycle. The timing of valve movements was similar to that of cardiac valves but only when lymphatic afterload was elevated. The pressure gradients required to open or close a valve were determined in 1-valve segments during slow, ramp-wise pressure elevation, either from the input or output side of the valve. Tests were conducted over a wide range of baseline pressures (and thus diameters) in passive vessels as well as in vessels with two levels of imposed tone. Surprisingly, the pressure gradient required for valve closure varied more than 20-fold (0.1 to 2.2 cmH(2)O) as a passive vessel progressively distended. Similarly, the pressure gradient required for valve for valve opening varied 6-fold with vessel distention. Finally, our functional evidence supports the concept that lymphatic muscle tone exerts an indirect effect on valve gating.
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Lymphedema is a manifestation of lymphatic system insufficiency. It arises from primary lymphatic dysplasia or secondary obliteration after lymph node dissection or irradiation. Although improvement of swelling can be achieved by comprehensive non-operative therapy, treatment of this condition requires lifelong care and good compliance. Recently molecular-based treatments using VEGF-C have been investigated by several researchers. We designed the present study to determine whether the therapeutic efficacy of implanted human adipose-derived stem cells (hADSCs) could be improved by applying a gelatin hydrogel containing VEGF-C (VEGF-C hydrogel) to the site of tissue injury in a lymphedema mouse model. Four weeks after the operation, we evaluated edema and determined lymphatic vessel density at various post-operative time points. Mice treated with hADSCs and VEGF-C hydrogel showed a significantly decreased dermal edema depth compared to the groups of mice that received hADSCs only or VEGF-C hydrogel only. Immunohistochemical analysis also revealed that the hADSC/VEGF-C hydrogel group showed significantly greater lymphatic vessel regeneration than all the other groups. hADSCs were detected in the implantation sites of all mice in the hADSC/VEGF-C group, and exhibited a lymphatic endothelial differentiation phenotype as determined by co-staining PKH-labeled hADSCs for the lymphatic marker LYVE-1. Our results suggest that co-administration of hADSCs and VEGF-C hydrogel has a substantial positive effect on lymphangiogenesis.
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Intraluminal valves are required for the proper function of lymphatic collecting vessels and large lymphatic trunks like the thoracic duct. Despite recent progress in the study of lymphvasculogenesis and lymphangiogenesis, the molecular mechanisms controlling the morphogenesis of lymphatic valves remain poorly understood. Here, we report that gap junction proteins, or connexins (Cxs), are required for lymphatic valvulogenesis. Cx37 and Cx43 are expressed early in mouse lymphatic development in the jugular lymph sacs, and later in development these Cxs become enriched and differentially expressed by lymphatic endothelial cells on the upstream and downstream sides of the valves. Specific deficiencies of Cx37 and Cx43 alone or in combination result in defective valve formation in lymphatic collecting vessels, lymphedema, and chylothorax. We also show that Cx37 regulates jugular lymph sac size and that both Cx37 and Cx43 are required for normal thoracic duct development, including valve formation. Another Cx family member, Cx47, whose human analog is mutated in some families with lymphedema, is also highly enriched in a subset of endothelial cells in lymphatic valves. Mechanistically, we present data from Foxc2-/- embryos suggesting that Cx37 may be a target of regulation by Foxc2, a transcription factor that is mutated in human lymphedema-distichiasis syndrome. These results show that at least three Cxs are expressed in the developing lymphatic vasculature and, when defective, are associated with clinically manifest lymphatic disorders in mice and man.
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We studied the effects of PDGF-BB on changes in the diameters of murine lymph vessels with or without intact endothelia. PDGF-BB induced dilation of the lymph vessels with endothelia. Pretreatment with L-NAME or removal of the endothelium caused a significant attenuation in the PDGF-BB-induced dilation. PDGF-BB also produced dose-related reduction of the diameters of the lymph vessels without endothelia. To evaluate intracellular signal transduction and Ca(2+) -dependence of the PDGF-BB-induced tonic contraction, we investigated the effects of imatinib, GW5074 (an inhibitor of Raf-1 kinase), U-73122 (an inhibitor of phospholipase C), and xestopongin C on the PDGF-BB-induced reduction responses. All of these inhibitors caused a significant attenuation in the PDGF-BB-induced reduction response. The PDGF-BB-induced reduction response was significantly decreased by treatment with Ca(2+) -free Krebs-bicarbonate solution or nifedipine. Higher concentrations of PDGF-BB produced a marked reduction of lymph vessel diameter within both high K(+) Krebs-bicarbonate solution and Ca(2+) -free high K(+) Krebs solution containing 1mM EGTA. These findings suggest that PDGF-BB induced endothelium-dependent NO-mediated relaxation of lymphatic smooth muscles in murine lymph vessels. PDGF-BB also induced PDGF receptor beta-mediated tonic contraction of the muscles through increased Ca(2+) influx through the membrane and the release of membrane-bound and intracellular Ca(2+).
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Oncology
Ahmed Omar, M. T., A. Abd-El-Gayed Ebid, et al. (2011). “Treatment of post-mastectomy lymphedema with laser therapy: double blind placebo control randomized study.” J Surg Res 165(1): 82–90.
Akkilic-Materna, M., C. Massone, et al. (2011). “Imiquimod and Lymphatic Field Clearance: A New Hypothesis Based on a Remote Immune Action on Skin Cancer.” Acta Derm Venereol Jun;91(4):432–5.
Ammar, A., R. A. Mohammed, et al. (2011). “Lymphatic expression of CLEVER-1 in breast cancer and its relationship with lymph node metastasis.” Anal Cell Pathol (Amst). 34(1):67–78.
BACKGROUND: Mechanisms regulating breast cancer lymph node metastasis are unclear. Staining of CLEVER-1 (common lymphatic endothelial and vascular endothelial receptor-1) in human breast tumors was used, along with in vitro techniques, to assess involvement in the metastatic process. Methods: 148 sections of primary invasive breast cancers, with 10 yr follow-up, were stained with anti-CLEVER-1. Leukocyte infiltration was assessed, along with involvement of specific subpopulations by staining with CD83 (mature dendritic cells, mDC), CD209 (immature DC, iDC) and CD68 (macrophage, Mvarphi). In vitro expression of CLEVER-1 on lymphatic (LEC) and blood endothelial cells (BEC) was examined by flow cytometry. Results: In vitro results showed that although both endothelial cell types express CLEVER-1, surface expression was only evident on LEC. In tumour sections CLEVER-1 was expressed in blood vessels (BV, 61.4% of samples), lymphatic vessels (LV, 18.2% of samples) and in Mvarphi/DCs (82.4% of samples). However, only CLEVER-1 expression in LV was associated with LN metastasis (p=0.027) and with Mvarphi indices (p=0.021). Although LV CLEVER-1 was associated with LN positivity there was no significant correlation with recurrence or overall survival, BV CLEVER-1 expression was, however, associated with increased risk of recurrence (p=0.049). The density of inflammatory infiltrate correlated with CLEVER-1 expression in BV (p<0.001) and LV (p=0.004). Conclusions: The associations between CLEVER-1 expression on endothelial vessels and macrophage/leukocyte infiltration is suggestive of its regulation by inflammatory conditions in breast cancer, most likely by macrophage-associated cytokines. Its upregulation on LV, related surface expression, and association with LN metastasis suggest that it may be an important mediator of tumor cell metastasis to LN.
Blumgart, E. I., R. F. Uren, et al. (2011). “Predicting lymphatic drainage patterns and primary tumour location in patients with breast cancer.” Breast cancer research and treatment.
Detailed knowledge of the lymphatic drainage of the breast is limited. Lymphoscintigraphy is a technique used during breast cancer treatment to accurately map patterns of lymphatic drainage from the primary tumour to the draining lymph nodes. This study aimed to create a statistical model to analyse the spread of breast cancer and primary tumour location using a large lymphoscintigraphy database, and visualise the results with a novel computational model. This study was based on lymphoscintigraphy data from 2,304 breast cancer patients treated at the Royal Prince Alfred Hospital Medical Centre in Sydney, Australia. Bayesian inferential techniques were implemented to estimate the probabilities of lymphatic drainage from each region of the breast to each draining node field, to multiple node fields, and to determine probabilities of tumour prevalence in each breast region. A finite element model of the torso and discrete model of the draining node fields were created to visualise these data and a software tool was developed to display the results (www.abi.auckland.ac.nz/breast-cancer). Results confirmed that lymphatic drainage is most likely to occur to the axillary node field, and that there is significant likelihood of drainage to the internal mammary node field. The likelihood of lymphatic drainage from the whole breast to the axillary, internal mammary, infraclavicular, supraclavicular and interpectoral node fields were 98.2, 35.3, 1.7, 3.1, and 0.7%, respectively; whilst the probability of lymphatic drainage to multiple node fields was estimated to be 36.4%. Additionally, primary tumours are most likely to develop in the upper regions of the breast. The models developed provide quantitative estimates of lymphatic drainage of the breast, giving important insights into understanding breast cancer metastasis and have the potential to benefit both clinicians and patients during breast cancer diagnosis and treatment.
Dirican, A., O. Andacoglu, et al. (2011). “The short-term effects of low-level laser therapy in the management of breast-cancer-related lymphedema.” Support Care Cancer 19(5): 685–690.
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Lee, A. S., D. H. Kim, et al. (2011). “Erythropoietin induces lymph node lymphangiogenesis and lymph node tumor metastasis.” Cancer Res. 71(13):4506–17. Epub 2011 May 17.
Cancer therapy often produces anemia in patients that is treated with erthropoietin (EPO) to stimulate red blood cell production. However, concerns have recently arisen that EPO treatment may promote later tumor metastasis and mortality. The mechanisms underlying such effects are unknown but it is clear that EPO has pleiotropic effects in cell types other than hematopoietic cells. In this study, we investigated how EPO affects lymphangiogenesis and lymph node tumor metastasis in mouse models of breast cancer and melanoma. In these models, EPO increased lymph node lymphangiogenesis and lymph node tumor metastasis in a manner associated with increased migration, capillary-like tube formation and dose- and time-dependent proliferation of human lymphatic endothelial cells. EPO increased sprouting of these cells in a thoracic duct lymphatic ring assay. These effects were abrogated by co-treatment with specific inhibitors of PI3K or MAP kinase, under conditions where EPO increased Akt and ERK1/2 phosphorylation. Intraperitoneal administration of EPO stimulated peritoneal lymphangiogenesis and systemic treatment of EPO increased infiltration of CD11b+ macrophages in tumor draining lymph nodes. Lastly, EPO increased VEGF-C expression in lymph node-derived CD11b+ macrophages as well as in bone marrow-derived macrophages in a dose- and time-dependent manner. Our results establish that EPO exerts a powerful lymphangiogenic function and can drive both lymph node lymphangiogenesis and nodal metastasis in tumor-bearing animals.
Lu, S. M., L. Yu, et al. (2011). “Twist modulates lymphangiogenesis and correlates with lymph node metastasis in supraglottic carcinoma.” Chinese Medical Journal 124(10): 1483–1487.
McNeely, M. L., C. J. Peddle, et al. (2011). “Conservative and dietary interventions for cancer-related lymphedema: a systematic review and meta-analysis.” Cancer 117(6): 1136–1148.
Mihara, M., G. Uchida, et al. (2011). “Lymphaticovenous anastomosis for facial lymphoedema after multiple courses of therapy for head-and-neck cancer.” J Plast Reconstr Aesthet Surg. 64(9):1221–5. Epub 2011 Mar 5.
Ou, J., J. Li, et al. (2011). “Endostatin suppresses colorectal tumor-induced lymphangiogenesis by inhibiting expression of fibronectin extra domain A and integrin alpha9.” J Cell Biochem. 112(8):2106–14.
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Pereira de Godoy, J. M., L. M. Azoubel, et al. (2011). “Evaluation of a clinical model of breast cancer-related lymphedema.” Breast J 17(1): 117–118.
Ridner, S. H., M. S. Dietrich, et al. (2011). “Body mass index and breast cancer treatment-related lymphedema.” Support Care Cancer. 19(6):853–7. Epub 2011 Jan 16.
Ruddell, A., M. I. Harrell, et al. (2011). “B lymphocytes promote lymphogenous metastasis of lymphoma and melanoma.” Neoplasia 13(8): 748–757.
Stanczyk, M., W. L. Olszewski, et al. (2010). “Lack of functioning lymphatics and accumulation of tissue fluid/lymph in interstitial “lakes” in colon cancer tissue.” Lymphology 43(4): 158–167.
Tassenoy, A., J. De Mey, et al. (2011). “Postmastectomy lymphoedema: different patterns of fluid distribution visualised by ultrasound imaging compared with magnetic resonance imaging.” Physiotherapy 97(3): 234–243.
Xu, J., C. Zhang, et al. (2011). “Lymphatic endothelial cell-secreted CXCL1 stimulates lymphangiogenesis and metastasis of gastric cancer.” Int J Cancer. Mar 8. [Epub ahead of print]
Yang, H., C. Kim, et al. (2011). “Soluble Vascular Endothelial Growth Factor Receptor-3 Suppresses Lymphangiogenesis and Lymphatic Metastasis in Bladder Cancer.” Mol Cancer 10(1): 36.
Zhang, F., G. Niu, et al. (2011). “Imaging tumor-induced sentinel lymph node lymphangiogenesis with LyP-1 peptide.” Amino acids. Jul 19. [Epub ahead of print]
Zhang, J., A. Gill, et al. (2011). “Upregulation of the signal transducers and activators of transcription 3 (STAT3) pathway in lymphatic metastases of papillary thyroid cancer.” Int J Clin Exp Pathol 4(4): 356–362.
Zhao, D., S. H. Wang, et al. (2011). “Intratumoral c-Met expression is associated with vascular endothelial growth factor C expression, lymphangiogenesis, and lymph node metastasis in oral squamous cell carcinoma: implications for use as a prognostic marker.” Hum Pathol. Apr 28. [Epub ahead of print]
Reviews
Cohen, M. S. and M. L. Forrest (2011). “Lymphatic drug delivery: therapy, imaging and nanotechnology.” Advanced Drug Delivery Reviews. Jun 6. [Epub ahead of print]
Detry, B., F. Bruyere, et al. (2011). “Digging deeper into lymphatic vessel formation in vitro and in vivo.” BMC Cell Biology 12(1): 29.
Drummond, G. B. (2011). “To the interstitial space - and beyond!” J Physiol. 589(Pt 12):2925. Epub 2011 May 3.
Francois, M., N. L. Harvey, et al. (2011). “The transcriptional control of lymphatic vascular development.” Physiology 26(3): 146–155.
Huxley, V. H. and J. P. Scallan (2011). “Lymphatic Fluid: Exchange Mechanisms and Regulation.” J Physiol. 589(Pt 12):2935–43. Epub 2011 Apr 26.
Khunger, N. (2010). “Lymphatic malformations: current status.” J Cutan Aesthet Surg 3(3): 137–138.
Leong, S. P. (2011). “The role of the lymphovascular system in cancer metastasis.” Lymphology 44(1): 42–44.
Linares, P. M. and J. P. Gisbert (2011). “Role of growth factors in the development of lymphangiogenesis driven by inflammatory bowel disease: A review.” Inflammatory Bowel Diseases 17(8): 1814–1821.
Loukas, M., S. S. Bellary, et al. (2011). “The lymphatic system: A historical perspective.” Clin Anat. May 4. [Epub ahead of print]
Michael, S., S. Charikleia, et al. (2011). “Lymphedema and breast cancer: a review of the literature.” Breast Cancer. 18(3):174–80. Epub 2011 Feb 18. Erratum: 18(3):181.
Millikan, L. E. (2011). “Lymphatics and blood vessels.” Clin Dermatol 29(2): 226–230.
Mirza, B., L. Ijaz, et al. (2010). “Cystic hygroma: an overview.” J Cutan Aesthet Surg 3(3): 139–144.
Negrini, D. and A. Moriondo (2011). “Lymphatic Anatomy and Biomechanics.” J Physiol. 589(Pt 12):2927–34. Epub 2011 Apr 11.
Schulte-Merker, S., A. Sabine, et al. (2011). “Lymphatic vascular morphogenesis in development, physiology, and disease.” J Cell Biol 193(4): 607–618.
The lymphatic vasculature constitutes a highly specialized part of the vascular system that is essential for the maintenance of interstitial fluid balance, uptake of dietary fat, and immune response. Recently, there has been an increased awareness of the importance of lymphatic vessels in many common pathological conditions, such as tumor cell dissemination and chronic inflammation. Studies of embryonic development and genetically engineered animal models coupled with the discovery of mutations underlying human lymphedema syndromes have contributed to our understanding of mechanisms regulating normal and pathological lymphatic morphogenesis. It is now crucial to use this knowledge for the development of novel therapies for human diseases.
Wu, X. and N. F. Liu (2011). “FOXC2 transcription factor: a novel regulator of lymphangiogenesis.” Lymphology 44(1): 35–41.
Yanez, J. A., S. W. Wang, et al. (2011). “Intestinal lymphatic transport for drug delivery.” Advanced Drug Delivery Reviews. Jun 13. [Epub ahead of print]
Clinical
Altit, G., H. Patel, et al. (2011). “Octreotide Management Of Intestinal Lymphangiectasia In A Teenage Heart Transplant Patient.” Journal of Pediatric Gastroenterology and Nutrition. Jul 28. [Epub ahead of print]
Avila, N. A., A. J. Dwyer, et al. (2011). “Imaging features of lymphangioleiomyomatosis: diagnostic pitfalls.” AJR Am J Roentgenol 196(4): 982–986.
Bongi, S. M., A. Del Rosso, et al. (2011). “Manual lymph drainage improves upper limb oedema and hand function in patients with systemic sclerosis (SSC) in oedematous phase.” Arthritis Care Res (Hoboken). 63(8):1134–41.
Brewer, M. B. and D. P. Singh (2011). “Massive Localized Lymphedema: Review of an Emerging Problem and Report of a Complex Case in the Mons Pubis.” Ann Plast Surg. May 27. [Epub ahead of print]
Chang, L., M. F. Cheng, et al. (2011). “The role of lymphoscintigraphy in diagnosis and monitor the response of physiotherapeutic technique in congenital lymphedema.” Clin Nucl Med 36(4): e11–12.
Davies, D. M., P. J. de Vries, et al. (2011). “Sirolimus Therapy for Angiomyolipoma in Tuberous Sclerosis and Sporadic Lymphangioleiomyomatosis: A Phase 2 trial.” Clin Cancer Res. 17(12):4071–81. Epub 2011 Apr 27.
Daya, S. M. and R. Papdopoulos (2011). “Ocular Coherence Tomography in Lymphangiectasia.” Cornea. Jul 25. [Epub ahead of print]
Ebata, R., J. Abe, et al. (2011). “Increased Production of Vascular Endothelial Growth Factor-D and Lymphangiogenesis in Acute Kawasaki Disease.” Circ J. 75(6):1455–62. Epub 2011 Apr 12.
Garcia, A. M. and B. E. Dicianno (2011). “The frequency of lymphedema in an adult spina bifida population.” Am J Phys Med Rehabil 90(2): 89–96.
Ghatak, S., S. Ray, et al. (2011). “An unusual cause of acute abdomen in adults: giant cystic lymphangioma of the pancreatic head. A clinical case and literature review.” JOP 12(3): 266–270.
Huang, P. M. and Y. C. Lee (2011). “A New Technique of Continuous Pleural Irrigation with Minocycline Administration for Refractory Chylothorax.” Thorac Cardiovasc Surg. Mar 22. [Epub ahead of print]
Kamble, R. B., R. Shetty, et al. (2011). “Technical note: MRI lymphangiography of the lower limb in secondary lymphedema.” Indian J Radiol Imaging 21(1): 15–17.
Kapoor, S., V. Ghosh, et al. (2011). “Cystic hygroma and hirsutism in a child with Catel-Manzke syndrome.” Clin Dysmorphol 20(2): 117–120.
Keichel, S., M. L. Barcena de Arellano, et al. (2011). “Lymphangiogenesis in deep infiltrating endometriosis.” Human reproduction. Jul 25. [Epub ahead of print]
Kocak, G., E. Kocak, et al. (2011). “A rare cause of severe hypoalbuminemia in a patient with primary hypoparathyroidism: intestinal lymphangiectasia.” Acta clinica Belgica 66(3): 246–247.
Lahteenvuo, M., K. Honkonen, et al. (2011). “Growth factor therapy and autologous lymph node transfer in lymphedema.” Circulation 123(6): 613–620.
BACKGROUND: Lymphedema after surgery, infection, or radiation therapy is a common and often incurable problem. Application of lymphangiogenic growth factors has been shown to induce lymphangiogenesis and to reduce tissue edema. The therapeutic effect of autologous lymph node transfer combined with adenoviral growth factor expression was evaluated in a newly established porcine model of limb lymphedema. METHODS AND RESULTS: The lymphatic vasculature was destroyed within a 3-cm radius around an inguinal lymph node. Lymph node grafts and adenovirally (Ad) delivered vascular endothelial growth factor (VEGF)-C (n=5) or VEGF-D (n=9) were used to reconstruct the lymphatic network in the inguinal area; AdLacZ (beta-galactosidase; n=5) served as a control. Both growth factors induced robust growth of new lymphatic vessels in the defect area, and postoperative lymphatic drainage was significantly improved in the VEGF-C/D-treated pigs compared with controls. The structure of the transferred lymph nodes was best preserved in the VEGF-C-treated pigs. Interestingly, VEGF-D transiently increased accumulation of seroma fluid in the operated inguinal region postoperatively, whereas VEGF-C did not have this side effect. CONCLUSIONS: These results show that growth factor gene therapy coupled with lymph node transfer can be used to repair damaged lymphatic networks in a large animal model and provide a basis for future clinical trials of the treatment of lymphedema.
Lanjouw, E., D. E. R. KP, et al. (2011). “Acquired Scrotal Lymphangioma Successfully Treated Using Carbon Dioxide Laser Ablation.” Dermatol Surg. 37(4):539–42. Epub 2011 Mar 9.
Leduc, O., V. Crasset, et al. (2011). “Impact of manual lymphatic drainage on hemodynamic parameters in patients with heart failure and lower limb edema.” Lymphology 44(1): 13–20.
Lucas, M. and Y. Andrade (2011). “Congenital lymphedema with tuberous sclerosis and clinical hirschsprung disease.” Pediatr Dermatol 28(2): 194–195.
McCormack, F. X., Y. Inoue, et al. (2011). “Efficacy and safety of sirolimus in lymphangioleiomyomatosis.” N Engl J Med 364(17): 1595–1606.
BACKGROUND: Lymphangioleiomyomatosis (LAM) is a progressive, cystic lung disease in women; it is associated with inappropriate activation of mammalian target of rapamycin (mTOR) signaling, which regulates cellular growth and lymphangiogenesis. Sirolimus (also called rapamycin) inhibits mTOR and has shown promise in phase 1-2 trials involving patients with LAM. METHODS: We conducted a two-stage trial of sirolimus involving 89 patients with LAM who had moderate lung impairment–a 12-month randomized, double-blind comparison of sirolimus with placebo, followed by a 12-month observation period. The primary end point was the difference between the groups in the rate of change (slope) in forced expiratory volume in 1 second (FEV(1)). RESULTS: During the treatment period, the FEV(1) slope was −12+/−2 ml per month in the placebo group (43 patients) and 1+/−2 ml per month in the sirolimus group (46 patients) (P<0.001). The absolute between-group difference in the mean change in FEV(1) during the treatment period was 153 ml, or approximately 11% of the mean FEV(1) at enrollment. As compared with the placebo group, the sirolimus group had improvement from baseline to 12 months in measures of forced vital capacity, functional residual capacity, serum vascular endothelial growth factor D (VEGF-D), and quality of life and functional performance. There was no significant between-group difference in this interval in the change in 6-minute walk distance or diffusing capacity of the lung for carbon monoxide. After discontinuation of sirolimus, the decline in lung function resumed in the sirolimus group and paralleled that in the placebo group. Adverse events were more common with sirolimus, but the frequency of serious adverse events did not differ significantly between the groups. CONCLUSIONS: In patients with LAM, sirolimus stabilized lung function, reduced serum VEGF-D levels, and was associated with a reduction in symptoms and improvement in quality of life. Therapy with sirolimus may be useful in selected patients with LAM. (Funded by the National Institutes of Health and others; MILES ClinicalTrials.gov number, NCT00414648.).
Morcaldi, G., F. Boccardo, et al. (2010). “Congenital lymphatic dysplasia in Kabuki syndrome: first report of an unusual association.” Lymphology 43(4): 188–191.
Narang, T., D. Dipankar, et al. (2011). “Lymphangioma circumscriptum and Whimster's hypothesis revisited.” Skinmed 9(2): 123–124.
North, J., K. White, et al. (2011). “Acquired, verrucous, gluteal lymphangioma in the setting of Crohn's disease.” J Am Acad Dermatol 64(5): e90–91.
Oexle, K., M. Hempel, et al. (2011). “3.7 Mb tandem microduplication in chromosome 5p13.1-p13.2 associated with developmental delay, macrocephaly, obesity, and lymphedema. Further characterization of the dup(5p13) syndrome.” Eur J Med Genet.
Rasalkar, D. D. and W. C. Chu (2010). “Generalized cystic lymphangiomatosis.” Pediatr Radiol 40 Suppl 1: S47.
Rajebi, M. R., G. Chaudry, et al. (2011). “Intranodal Lymphangiography: Feasibility and Preliminary Experience in Children.” Journal Of Vascular and Interventional Radiology : JVIR. 22(9):1300–5. Epub 2011 Jun 29.
Ruan, Z., Y. Zhou, et al. (2011). “Clinical Use of Lymphangiography for Intractable Spontaneous Chylothorax.” Thorac Cardiovasc Surg. May 9. [Epub ahead of print]
Schook, C. C., J. B. Mulliken, et al. (2011). “Differential diagnosis of lower extremity enlargement in pediatric patients referred with a diagnosis of lymphedema.” Plast Reconstr Surg 127(4): 1571–1581.
Shegokar, R. and K. K. Singh (2011). “Stavudine entrapped lipid nanoparticles for targeting lymphatic HIV reservoirs.” Pharmazie 66(4): 264–271.
Shon, W., C. M. Ida, et al. (2011). “Cutaneous angiosarcoma arising in massive localized lymphedema of the morbidly obese: a report of five cases and review of the literature.” J Cutan Pathol. 38(7):560–4. Epub 2011 Apr 26.
Suarez-Vilela, D., F. M. Izquierdo, et al. (2011). “Diffuse lymphangiomatous hyperplasia of the spleen with hyaline bodies. A pseudotumoral proliferation arising from the lymphatic vessels of the periarteriolar lymphatic sheath.” Virchows Arch 458(4): 505–509.
Tan, I. C., E. A. Maus, et al. (2011). “Assessment of lymphatic contractile function after manual lymphatic drainage using near-infrared fluorescence imaging.” Arch Phys Med Rehabil 92(5): 756–764 e751.
Turrentine, J. E., A. J. Brown, et al. (2011). “Leg swelling, erythema, and bullae in a 6-year-old girl with chronic lymphatic insufficiency.” Pediatr Dermatol 28(2): 189–190.
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]
von der Weid, P. Y., S. Rehal, et al. (2011). “Role of the lymphatic system in the pathogenesis of Crohn's disease.” Curr Opin Gastroenterol. 27(4):335–41.
Ward, L., A. Winall, et al. (2011). “Assessment of bilateral limb lymphedema by bioelectrical impedance spectroscopy.” Int J Gynecol Cancer 21(2): 409–418.
Ward, L. C., E. Dylke, et al. (2011). “Reference ranges for assessment of unilateral lymphedema in legs by bioelectrical impedance spectroscopy.” Lymphat Res Biol 9(1): 43–46.
Watson, T., E. Martinez, et al. (2011). “Renal lymphangiomatosis, interrupted IVC with persistent primitive hepatic venous plexus and multiple anomalous venous channels: parts of an overlap syndrome?” Pediatric Radiology. Jul 20. [Epub ahead of print]
Yamamoto, T., N. Matsuda, et al. (2011). “Lower Extremity Lymphedema Index: A Simple Method for Severity Evaluation of Lower Extremity Lymphedema.” Ann Plast Surg. Jul 5. [Epub ahead of print]
Yamamoto, T., M. Narushima, et al. (2011). “Characteristic indocyanine green lymphography findings in lower extremity lymphedema: the generation of a novel lymphedema severity staging system using dermal backflow patterns.” Plast Reconstr Surg 127(5): 1979–1986.
Yang, Y. S., G. C. Ma, et al. (2011). “Experimental treatment of bilateral fetal chylothorax using in utero pleurodesis.” Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology. May 16. [Epub ahead of print]
Zabeck, H., T. Muley, et al. (2011). “Management of Chylothorax in Adults: When is Surgery Indicated?” Thorac Cardiovasc Surg. 59(4):243-6. Epub 2011 Mar 21.
Vascular Anomalies
Adepoju, O., A. Wong, et al. (2011). “Expression of HES and HEY genes in infantile hemangiomas.” Vascular cell 3(1): 19.
Baer, A. H., H. A. Parmar, et al. (2011). “Hemangiomas and vascular malformations of the head and neck: a simplified approach.” Neuroimaging clinics of North America 21(3): 641–658.
Bagazgoitia, L., A. Torrelo, et al. (2011). “Propranolol for Infantile Hemangiomas.” Pediatr Dermatol. 28(2):108–14. Epub 2011 Mar 8.
Barbara, D. W. and J. L. Wilson (2011). “Anesthesia for Surgery Related to Klippel-Trenaunay Syndrome: A Review of 136 Anesthetics.” Anesth Analg. 113(1):98–102. Epub 2011 Apr 5.
Bauland, C. G., T. H. Luning, et al. (2011). “Untreated hemangiomas: growth pattern and residual lesions.” Plast Reconstr Surg 127(4): 1643–1648.
Bhavsar, T., D. Saeed-Vafa, et al. (2010). “Retroperitoneal cystic lymphangioma in an adult: A case report and review of the literature.” World J Gastrointest Pathophysiol 1(5): 171–176.
Boscolo, E., C. L. Stewart, et al. (2011). “JAGGED1 Signaling Regulates Hemangioma Stem Cell-to-Pericyte/Vascular Smooth Muscle Cell Differentiation.” Arteriosclerosis, thrombosis, and Vascular Biology. Jul 14. [Epub ahead of print]
Brandon, K., P. Burrows, et al. (2011). “Arteriovenous Malformation: A Rare Manifestation of PHACE Syndrome.” Pediatr Dermatol 28(2): 180–184.
Carr, C. W., H. H. Zimmerman, et al. (2011). “5q14.3 neurocutaneous syndrome: A novel continguous gene syndrome caused by simultaneous deletion of RASA1 and MEF2C.” Am J Med Genet A. 155A(7):1640–5. Epub 2011 May 27.
Ceyhan, A. M., G. Aynali, et al. (2011). “Congenital giant juvenile xanthogranuloma initially masquerading as hemangioma.” Eur J Dermatol. 21(3):431–3.
Chai, Q., W. L. Chen, et al. (2011). “Preliminary Experiences in Treating Infantile Hemangioma With Propranolol.” Ann Plast Surg.
The aim of this study was to evaluate the outcome of treating infantile hemangioma with the use of oral propranolol. A total of 27 patients with hemangiomas were treated with oral propranolol therapy. The subjects included 21 females and 6 males whose age ranged between 3 weeks and 7 months. Locations of lesions were as follows: 22 on the face and neck, 3 on the trunk, and 2 on the limbs. The dose of 0.5 mg/kg/d of propranolol was administered; and was gradually doubled to a maximum of 2 mg/kg/d. The treatment lasted for a period of 2.75 to 5.75 months without major complications. Two days later, a change in color was observed in 100% of patients, and 2 weeks later >75% reduction in diameter of the original lesion was found in 25.9% of patients. Treating infantile hemangioma with the use of oral propranolol is effective and reliable.
Chaudry, G., P. E. Burrows, et al. (2011). “Sclerotherapy of Abdominal Lymphatic Malformations with Doxycycline.” Journal of vascular and interventional radiology : JVIR.
Chee, D., R. Phillips, et al. (2010). “The potential of capillary birthmarks as a significant marker for capillary malformation-arteriovenous malformation syndrome in children who had nontraumatic cerebral hemorrhage.” J Pediatr Surg 45(12): 2419–2422.
Corti, P., S. Young, et al. (2011). “Interaction between alk1 and blood flow in the development of arteriovenous malformations.” Development. 138(8):1573–82. Epub 2011 Mar 9.
Cushing, S. L., R. J. Boucek, et al. (2011). “Initial experience with a multidisciplinary strategy for initiation of propranolol therapy for infantile hemangiomas.” Otolaryngol Head Neck Surg 144(1): 78–84.
de Graaf, M., M. P. J. B. J, et al. (2011). “Adverse effects of propranolol when used in the treatment of hemangiomas: A case series of 28 infants.” J Am Acad Dermatol. 65(2):320–7. Epub 2011 May 20.
Deepinder, F. (2011). “GI bleeding, colon varicosities and visceral enlargement as a manifestation of Klippel-Trenaunay Syndrome.” Clinical Gastroenterology and Hepatology : The Official Clinical Practice Journal of the American Gastroenterological Association. Jun 30. [Epub ahead of print]
Doege, C., M. Pritsch, et al. (2011). “An association between infantile haemangiomas and erythropoietin treatment in preterm infants.” Arch Dis Child Fetal Neonatal Ed. May 5. [Epub ahead of print]
Erbay, A., F. Sanrialioglu, et al. (2010). “Propranolol for infantile hemangiomas: a preliminary report on efficacy and safety in very low birth weight infants.” Turk J Pediatr 52(5): 450–456.
Hammill, A. M., M. Wentzel, et al. (2011). “Sirolimus for the treatment of complicated vascular anomalies in children.” Pediatr Blood Cancer. Mar 28. [Epub ahead of print]
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.
Handra-Luca, A. and E. Montgomery (2011). “Vascular malformations and hemangiolymphangiomas of the gastrointestinal tract: morphological features and clinical impact.” International Journal of Clinical and Experimental Pathology 4(5): 430–443.
Hassanein, A. H., A. I. Alomari, et al. (2011). “Pilomatrixoma imitating infantile hemangioma.” J Craniofac Surg 22(2): 734–736.
Hermans, D. J., I. M. van Beynum, et al. (2011). “Kaposiform hemangioendothelioma with kasabach-merritt syndrome: a new indication for propranolol treatment.” J Pediatr Hematol Oncol 33(4): e171–173.
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.
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.
Itinteang, T., A. H. Withers, et al. (2011). “Pharmacologic therapies for infantile hemangioma: is there a rational basis?” Plastic and Reconstructive Surgery 128(2): 499–507.
Jiang, C., X. Hu, et al. (2011). “A Prospective Self-Controlled Phase II Study of Imiquimod 5% Cream in the Treatment of Infantile Hemangioma.” Pediatr Dermatol 28(3): 259–266.
Juca, N. B., M. G. Crisostomo, et al. (2011). “Acral microcystic lymphangioma: differential diagnosis in verrucous lesions of the extremities.” An Bras Dermatol 86(2): 343–346.
Kadota, Y., T. Utsumi, et al. (2011). “Lymphatic and venous malformation or “lymphangiohemangioma” of the anterior mediastinum: case report and literature review.” General Thoracic and Cardiovascular Surgery 59(8): 575–578.
Kahana, A., B. L. Bohnsack, et al. (2011). “Subtotal excision with adjunctive sclerosing therapy for the treatment of severe symptomatic orbital lymphangiomas.” Archives of ophthalmology 129(8): 1073–1076.
Kim, L. H., M. Hogeling, et al. (2011). “Propranolol: useful therapeutic agent for the treatment of ulcerated infantile hemangiomas.” J Pediatr Surg 46(4): 759–763.
Kramer, U., U. Ernemann, et al. (2011). “Pretreatment evaluation of peripheral vascular malformations using low-dose contrast-enhanced time-resolved 3D MR angiography: initial results in 22 patients.” AJR Am J Roentgenol 196(3): 702–711.
Leaute-Labreze, C., S. Prey, et al. (2011). “Infantile haemangioma: Part II. Risks, complications and treatment.” J Eur Acad Dermatol Venereol. May 14. [Epub ahead of print]
Leboulanger, N., C. Garel, et al. (2011). “Propranolol Therapy for Hemorrhagic Lymphangioma of the Tongue.” Arch Otolaryngol Head Neck Surg. 137(8):813–5. Epub 2011 May 16.
Lee, J. Y., J. Y. Choi, et al. (2010). “Characterization of congenital lymphatic and blood vascular malformations in the head and neck using blood pool scintigraphy and spect.” Lymphology 43(4): 149–157.
Legiehn, G. M. and M. K. Heran (2010). “A Step–by-Step Practical Approach to Imaging Diagnosis and Interventional Radiologic Therapy in Vascular Malformations.” Semin Intervent Radiol 27(2): 209–231.
Leonardi-Bee, J., K. Batta, et al. (2011). “Interventions for infantile haemangiomas (strawberry birthmarks) of the skin.” Cochrane Database Syst Rev 5: CD006545.
Li, J., X. Chen, et al. (2011). “Demographic and Clinical Characteristics and Risk Factors for Infantile Hemangioma: A Chinese Case-Control Study.” Arch Dermatol. May 16. [Epub ahead of print]
Li, Q., P. Mitchell, et al. (2011). “A case of cerebral and retinal vascular anomaly in a patient with Klippel-Trenaunay-Weber syndrome.” Journal of Neurology, Neurosurgery, and Psychiatry. 82(9):1049–50. Epub 2011 Jul 11.
Luzzatto, C. M. (2011). “OK–432 is not Suitable for Abdominal Lymphatic Malformations.” Eur J Pediatr Surg 21(3): 211.
Mishra, A., W. Holmes, et al. (2011). “Management of complicated facial hemangiomas with Beta-blocker (propranolol) therapy.” Plast Reconstr Surg 127(4): 1742–1743; author reply 1743.
Morkane, C., J. W. Gregory, et al. (2011). “Adrenal suppression following intralesional corticosteroids for periocular haemangiomas.” Archives of Disease in Childhood 96(6): 587–589.
Nabatian, A. S., S. S. Milgraum, et al. (2011). “PHACE without Face? Infantile Hemangiomas of the Upper Body Region with Minimal or Absent Facial Hemangiomas and Associated Structural Malformations.” Pediatr Dermatol. 28(3):235–41. Epub 2011 Mar 31.
Ni, N., S. Guo, et al. (2011). “Current concepts in the management of periocular infantile (capillary) hemangioma.” Current Opinion in Ophthalmology. 22(5):419–25.
Ozeki, M., T. Fukao, et al. (2011). “Propranolol for intractable diffuse lymphangiomatosis.” N Engl J Med 364(14): 1380–1382.
Petteruti, F., G. De Luca, et al. (2011). “Capillary hemangioma mimicking a dumbbell–shaped mediastinal neurinoma.” Ann Thorac Surg 91(6): 1993.
Rekhi, B., S. Sethi, et al. (2011). “Kaposiform hemangioendothelioma in tonsil of a child associated with cervical lymphangioma: a rare case report.” World J Surg Oncol 9(1): 57.
Sainsbury, D. C., G. Kessell, et al. (2011). “Intralesional bleomycin injection treatment for vascular birthmarks: a 5-year experience at a single United kingdom unit.” Plast Reconstr Surg 127(5): 2031–2044.
Schiestl, C., K. Neuhaus, et al. (2011). “Efficacy and safety of propranolol as first-line treatment for infantile hemangiomas.” European Journal of Pediatrics 170(4): 493–501.
Schupp, C. J., S. Holland-Cunz, et al. (2010). “Multiple hemangiomas and hemangiomatosis–risk factors and outcome over an eight year period.” Eur J Pediatr Surg 20(6): 379–381.
Sherer, D. M., M. Dalloul, et al. (2011). “First-trimester septated cystic hygroma and cavum velum interpositum cyst.” J Clin Ultrasound. 39(6):356–8. Epub 2011 May 2.
Tan, S. T., T. Itinteang, et al. (2011). “Low-dose propranolol for multiple hepatic and cutaneous hemangiomas with deranged liver function.” Pediatrics 127(3): e772–776.
Tejedor, M., A. Martin-Santiago, et al. (2010). “Congenital plaque-type glomuvenous malformation associated with chylous ascites.” Pediatr Dermatol 27(6): 673–675.
Thoumazet, F., C. Leaute-Labreze, et al. (2011). “Efficacy of systemic propanolol for severe infantile haemangioma of the orbit and eyelid: a case study of eight patients.” The British Journal of Ophthalmology. Jun 14. [Epub ahead of print]
Trindade, F., H. Kutzner, et al. (2011). “Hobnail hemangioma reclassified as superficial lymphatic malformation: A study of 52 cases.” Journal of the American Academy of Dermatology. Aug 5. [Epub ahead of print]
Yildirim, O., A. Bicer, et al. (2010). “Expression of platelet-derived growth factor ligand and receptor in cerebral arteriovenous and cavernous malformations.” J Clin Neurosci 17(12): 1557–1562.
Zhu, Y., G. Qiu, et al. (2011). “Kaposiform hemangioendothelioma with adolescent thoracic scoliosis: a case report and review of literature.” Eur Spine J. 20 Suppl 2:S309–13. Epub 2011 Mar 9.