Abstract
Featured Article
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.
Gordon and colleagues investigate the role of macrophages on embryonic dermal lymphangiogenesis. Whereas macrophages contribute to lymphangiogenesis in the setting of inflammation and malignancy, these authors demonstrate 1) an independent origin of macrophages and lymphatic endothelial cells, and 2) different roles for macrophages during lymphatic development. Lineage tracing experiments showed that cells derived from myeloid cells adjacent to dermal lymphatic vessels were PROX-1-negative. Likewise, in a tumor lymphangiogenesis model, cells of myeloid lineage did not evolve into lymphatic endothelial progenitors. Lymphatic vessels were hyperplastic in PU.1 −/− mouse embryos (which lack macrophages and other white blood cells and die in the perinatal period), suggesting a role for myeloid/macrophage cells (embryos of Rag2 −/− mice lacking lymphocytes had normal lymphatics, supporting the role of macrophages in defining lymphatic caliber). Further investigations demonstrated this effect was 1) not related to apoptosis. 2) tissue-specific, and 3) not related to macrophage-derived pro-lymphangiogenic factors.
Basic Science
Algars, A., M. Karikoski, et al. (2011). “Different role of CD73 in leukocyte trafficking via blood and lymph vessels.” Blood. Feb 23. [Epub ahead of print]
CD73 is involved in the extracellular ATP metabolism by dephosphorylating extracellular AMP to adenosine and thus regulating permeability of the blood vessels and leukocyte traffic into the tissues. It is also present on lymphatic vessels, where its distribution and function have not been characterized. We found that CD73 is expressed on a subpopulation of afferent lymph vessels but is absent on efferent lymphatics, unlike LYVE-1 and podoplanin, which are expressed on both types of lymphatics. The extracellular nucleotide metabolism on lymphatic endothelium differs from that on blood vessel endothelium as lymphatic endothelium has lower NTPDase and higher ecto-5′-nucleotidase/CD73 activity than blood vascular endothelium. In knockout mice the lack of CD73 on lymphocytes decreases migration of lymphocytes to the draining lymph nodes more than 50% while CD73 deficient lymph vessels mediate lymphocyte trafficking as efficiently as the wild type lymphatics. Thus, although endothelial CD73 is important for permeability and leukocyte extravasation in blood vessels it does not have a role in these functions on lymphatics. Instead, lymphocyte CD73 is intimately involved in lymphocyte migration via afferent lymphatic vessels.
Golubovskaya VM, Cance WG. FAK AND P53 Protein Interactions. Anticancer Agents Med Chem. 2011.
Focal Adhesion Kinase plays a major role in cell adhesion, motility, survival, proliferation, metastasis, angiogenesis and lymphangiogenesis. In 2004, we have cloned the promoter sequence of FAK and found that p53 inhibits its activity (BBA, 1678, 2004). In 2005, we were the first group to show that FAK and p53 proteins directly interact in the cells (JBC, 280, 2005). We have shown that FAK and p53 proteins interact in the cytoplasm and in the nucleus by immunoprecipitation, pull-down and confocal microscopy assays. We have shown that FAK inhibited activity of p53 with the transcriptional targets: p21, Bax and Mdm-2 through protein-protein interactions. We identified the 7 amino-acid site in p53 that is involved in interaction with FAK protein. The present review will discuss the interaction of FAK and p53 proteins and discuss the mechanism of FAK-p53 loop regulation: inhibition of FAK promoter activity by p53 protein and also inhibition of p53 transcriptional activity by FAK protein.
Grimaldo S, Yuen D, Ecoiffier T, Chen L. Very Late Antigen-1 Mediates Corneal Lymphangiogenesis. Invest Ophthalmol Vis Sci. 2011.
Purpose. To investigate the specific role of VLA-1 (Very late antigen-1; also known as integrin alpha1beta1) in corneal inflammatory lymphangiogenesis in vivo and lymphatic endothelial cell functions in vitro. Methods. Standard suture-induced corneal inflammatory lymphangiogenesis model was used in normal adult BALB/c mice to test the effect of systemic administration of VLA-1 neutralizing antibody on lymphatic formation and macrophage infiltration in vivo. Additionally, human lymphatic endothelial cell culture system was used to examine the effect of VLA-1 gene depletion on lymphatic endothelial cell functions in vitro using small interfering RNAs. Results. Our data demonstrated, for the first time, that VLA-1 blockade significantly suppressed corneal lymphangiogenesis and macrophage infiltration during inflammation. Moreover, VLA-1 gene depletion led to a marked inhibition of lymphatic endothelial cell processes of adhesion, proliferation, and capillary tube formation. Conclusions. These novel findings together indicate that VLA-1 is critically involved in processes of lymphangiogenesis. Further investigation on this factor may provide novel therapies for corneal inflammation, transplant rejection, and other lymphatic-related disorders in the1 body.
Millward, I. R., R. M. Kirberger, et al. (2011). “Comparative Popliteal and Mesenteric Computed Tomography Lymphangiography of the Canine Thoracic Duct.” Vet Radiol Ultrasound. Feb 22 [Epub ahead of print]
Thoracic duct computed tomography (CT) lymphangiograms were performed on seven clinically normal dogs. The appearance of the thoracic duct system was compared following administration of contrast medium through a mesenteric lymphatic vessel vs. ultrasound guided percutaneous injection into a popliteal lymph node using helical and sequential CT acquisition modes. The number of visible thoracic duct branches and the largest thoracic duct branch cross-sectional area and mean Hounsfield units (HU) were determined from thoracic vertebra 9 to lumbar vertebra 1. Procedural time and patient discomfort were also assessed. Popliteal administration produced a successful thoracic duct lymphangiogram in eight of 11 dogs (73%) after two attempts, while mesenteric administration was successful in eight of 10 dogs (80%) after a single attempt. Popliteal lymphography required 46% of the time and was associated with less patient discomfort than mesenteric lymphangiography. The number of thoracic duct branches seen was not significantly different for either administration technique (P = 0.256) or CT acquisition mode (P = 0.417). However, the cross-sectional area and mean HU of the largest thoracic duct branch were greater with mesenteric administration (P < 0.001), and helical image acquisition (P < 0.001). The thoracic duct branch number, size, and location were highly variable between dogs. Percutaneous popliteal lymphography appears to be an acceptable alternative to mesenteric lymphangiography for the detection of thoracic duct branches in the dog when using either helical or sequential CT acquisition modes.
Nassar, T., S. A. Qadri, et al. (2011). “High plasma levels and effective lymphatic uptake of docetaxel in an orally available nanotransporter formulation.” Cancer Res. Mar 1. [Epub ahead of print]
Docetaxel, an efficient chemotherapeutic drug, exhibits low and variable oral bioavailability due to the active efflux by P-gp and more so to CYP3A4 gut metabolism. Using a spray-drying technique, docetaxel was incorporated in PLGA nanocapsules (NCs) which were embedded in entero-coated microparticles. An oral administration of the NC formulation elicited a higher absolute bioavailability than both a docetaxel solution (276%) and a free docetaxel NC formulation (400%) injected intravenously, a 5mg/kg dose. The BI and BII NC formulations elicited Cmax values that were 1735 and 2254% respectively; higher than the Cmax value of the oral docetaxel solution combined with blank microparticles, a 10mg/kg dose. No significant difference in AUC was observed between the batches. These unexpected results can be explained only if the pharmacokinetics of docetaxel had been modified. It was shown that NCs released from the microparticles penetrated the enterocytes, bypassing P-gp; apparently circumventing gut metabolism and accumulating within the lymphatic system from where both intact or biodegraded NCs and free docetaxel were progressively released into the circulation as plausibly supported by the fluorescent imaging results. Furthermore, the circulating docetaxel in plasma was unencapsulated and circulated either in free form or bound to albumin. Both free docetaxel NCs and microparticles exhibited in vitro efficacy on WRC 256 cells suggesting that the activity of docetaxel was not altered. This delivery concept has potential for clinical translation, perhaps allowing docetaxel chemotherapy to be switched from intravenous to oral delivery.
Shetty, S., C. J. Weston, et al. (2011). “Common Lymphatic Endothelial and Vascular Endothelial Receptor-1 Mediates the Transmigration of Regulatory T Cells across Human Hepatic Sinusoidal Endothelium.” J Immunol. Mar 2. [Epub ahead of print]
The common lymphatic endothelial and vascular endothelial receptor (CLEVER-1; also known as FEEL-1 and stabilin-1) is a recycling and intracellular trafficking receptor with multifunctional properties. In this study, we demonstrate increased endothelial expression of CLEVER-1/stabilin-1 at sites of leukocyte recruitment to the inflamed human liver including sinusoids, septal vessels, and lymphoid follicles in inflammatory liver disease and tumor-associated vessels in hepatocellular carcinoma. We used primary cultures of human hepatic sinusoidal endothelial cells (HSEC) to demonstrate that CLEVER-1/stabilin-1 expression is enhanced by hepatocyte growth factor but not by classical proinflammatory cytokines. We then showed that CLEVER-1/stabilin-1 supports T cell transendothelial migration across HSEC under conditions of flow with strong preferential activity for CD4 FoxP3(+) regulatory T cells (Tregs). CLEVER-1/stabilin-1 inhibition reduced Treg transendothelial migration by 40% and when combined with blockade of ICAM-1 and vascular adhesion protein-1 (VAP-1) reduced it by >80%. Confocal microscopy demonstrated that 60% of transmigrating Tregs underwent transcellular migration through HSEC via ICAM-1- and VAP-1-rich transcellular pores in close association with CLEVER-1/stabilin-1. Thus, CLEVER-1/stabilin-1 and VAP-1 may provide an organ-specific signal for Treg recruitment to the inflamed liver and to hepatocellular carcinoma.
Wang, Y. L., X. H. Wang, et al. (2011). “Plasma nitric oxide and left ventricular function in rabbits after cardiac lymphatic obstruction.” Bosn J Basic Med Sci 11:17–19.
This study was designed to investigate the effect of cardiac lymphatic obstruction on plasma nitric oxide (NO) and left ventricular function. The plasma NO was measured in study group (n = 21) and control group rabbits (n = 12) before, and 3, 7, 14, 30 and 90 days after the obstruction of cardiac lymphatic vessels. Left ventricular ejection fraction was measured with echocardiography. There was a significant reduction in the left ventricular ejection fraction following the lymphatic obstruction (0.72+/−0.02 vs. 0.61+/−0.02, p < 0.01). Plasma NO in the control group remained unchanged during the observation period (54.2+/−4.4 vs. 52.0+/−4.2 mumol/L, p > 0.05). In the study group, there was a small but significant increase in the plasma NO on day 3, 7 and 14 following the lymphatic obstruction (52.3+/−4.1 vs. 73.4+/−5.9 mumol/L, p < 0.01). The plasma NO returned to the baseline levels on day 30 but reduced to 44.9+/−3.6 mumol/L on 90 days after the lymphatic obstruction (p < 0.05). In conclusion, cardiac lymphatic obstruction was associated with a significant reduction in left ventricular function. It was also associated with an increase in the plasma NO in the first 2 weeks but there was a significant reduction in the NO levels three months after the lymphatic obstruction.
Yaghmaei, M., F. Mashhadiabbas, et al. (2011). “Histologic evaluation of inferior alveolar lymphatics: an anatomic study.” Oral Surg Oral Med Oral Pathol Oral Radiol Endod. Feb 16. [Epub ahead of print]
The purpose of this study was to investigate the presence of a lymphatic system within the inferior alveolar canal, using specific immunohistochemical staining. Lymphatic capillaries are characterized by a thin wall with an irregular profile. They are superficial to organs and collect the lymph. Currently, the lymphatic system of the mandible and the floor of the mouth are attributed to the periosteum. The inferior alveolar canal within the mandible houses the inferior alveolar nerve, artery, and vein. Owing to the surgical vulnerability of the canal, several recent studies have focused on defining the exact contents and arrangements within the canal as well as precise measurements of the diameter of its components. No study has been performed on the existence of a lymphatic system within the inferior alveolar canal, the presence of which has significant importance for surgical management of malignant lesions. Presence of lymph channels would make the inferior alveolar nerve a potential route for spreading malignant cells. In this study, podoplanin-positive thin-walled vessels, considered to be lymphatic vessels, were traced within the inferior alveolar canal.
Yin, X., S. C. Johns, et al. (2011). “Lymphatic endothelial heparan sulfate deficiency results in altered growth responses to VEGF-C.” J Biol Chem. Feb 22. [Epub ahead of print]
Growth and remodeling of lymphatic vasculature occurs during development and during various pathologic states. A major stimulus for this process is the unique lymphatic vascular endothelial growth factor VEGF-C. Other endothelial growth factors, such as fibroblast growth factor-2 (FGF-2) or VEGF-A may also contribute. Heparan sulfate is a linear sulfated polysaccharide that facilitates binding and action of some vascular growth factors such as FGF-2 and VEGF-A. However, a direct role for heparan sulfate in lymphatic endothelial growth and sprouting responses, including those mediated by VEGF-C, remains to be examined. We demonstrate that VEGF-C binds to heparan sulfate purified from primary lymphatic endothelia; and activation of lymphatic endothelial Erk1/2 in response to VEGF-C is reduced by interference with heparin or pre-treatment of cells with heparinase, which destroys heparan sulfate. Such treatment also inhibited phosphorylation of the major VEGF-C receptor VEGFR-3 upon VEGF-C stimulation. Silencing lymphatic heparan sulfate chain biosynthesis inhibited VEGF-C mediated Erk1/2 activation, and abrogated VEGFR-3 receptor-dependent binding of VEGF-C to the lymphatic endothelial surface. These findings prompted targeting of lymphatic N-deacetylase/N-sulfotransferase-1 (Ndst1), a major sulfate-modifying heparan sulfate biosynthetic enzyme. VEGF-C mediated Erk1/2 phosphorylation was inhibited in Ndst1-silenced lymphatic endothelia; and scratch-assay responses to VEGF-C and FGF-2 were reduced in Ndst1 deficient cells. In addition, lymphatic Ndst1 deficiency abrogated cell-based growth and proliferation responses to VEGF-C. In other studies, lymphatic endothelia cultured ex-vivo from Ndst1 gene-targeted mice demonstrated reduced VEGF-C and FGF-2 mediated sprouting in collagen matrix. Lymphatic heparan sulfate may represent a novel molecular target for therapeutic intervention.
Oncology
Boccardo, F. M., F. Casabona, et al. (2011). “Surgical Prevention of Arm Lymphedema After Breast Cancer Treatment.” Ann Surg Oncol. Mar 3. [Epub ahead of print]
PURPOSE: To prospectively assess the efficacy of the lymphatic microsurgical preventive healing approach (LYMPHA) to prevent lymphedema after axillary dissection (AD) for breast cancer treatment. METHODS: Among 49 consecutive women referred from March 2008 to September 2009 to undergo complete AD, 46 were randomly divided in 2 groups. Twenty-three underwent the LYMPHA technique for the prevention of arm lymphedema. The other 23 patients had no preventive surgical approach (control group). The LYMPHA procedure consisted of performing lymphatic-venous anastomoses (LVA) at the time of AD. All patients underwent preoperative lymphoscintigraphy (LS). Patients were followed up clinically at 1, 3, 6, 12, and 18 months by volumetry. Postoperatively, LS was performed after 18 months in 41 patients (21 treatment group and 20 control group). Arm volume and LS alterations were assessed. RESULTS: Lymphedema appeared in 1 patient in the treatment group 6 months after surgery (4.34%). In the control group, lymphedema occurred in 7 patients (30.43%). No statistically significant differences in the arm volume were observed in the treatment group during follow-up, while the arm volume in the control group showed a significant increase after 1, 3, and 6 months from operation. There was significant difference between the 2 groups in the volume changes with respect to baseline after 1, 3, 6, 12, and 18 months after surgery (every timing P value < 0.01). CONCLUSIONS: LYMPHA represents a valid technique for primary prevention of secondary arm lymphedema with no risk of leaving undetected malignant disease in the axilla.
Cai, S., Y. Xie, et al. (2010). “Carrier-based intralymphatic cisplatin chemotherapy for the treatment of metastatic squamous cell carcinoma of the head & neck.” Ther Deliv 1:237–245.
BACKGROUND: Since head and neck squamous cell carcinoma (HNSCC) preferentially metastasizes to the locoregional lymphatics, treatment of the tumor-draining cervical lymph nodes is paramount. RESULTS: We developed a hyaluronan-cisplatin (HA-Pt) nanoconjugate with prolonged lymphatic retention and greatly improved tumor tissue deposition for the treatment of metastatic HNSCC. We also developed an orthotopic metastatic xenograft model of HNSCC to examine the efficacy of the nanoconjugate. HNSCC (1/week × 3 weeks) were completely cured for 57% of the female mice in the HA-Pt treatment group, which demonstrated greatly hindered HNSCC progression compared with the standard cisplatin therapy (p < 0.05). CONCLUSION: With this insight, we will be able to optimize the carriers for better uptake, penetration and retention within cancer cells.
Cidon, E. U., C. Perea, et al. (2011). “Life after breast cancer: dealing with lymphoedema.” Clin Med Insights Oncol 5:9–14.
BACKGROUND: In recent years, breast cancer (BC) mortality rates have declined, reflecting advances in early detection. Prevention and management of treatment sequelae that could impair function or quality of life have increased in relevance. Lymphoedema after BC treatment is one of these sequelae. It is caused by an acquired interruption or damage to the axillary lymphatic system and it is characterized by an abnormal accumulation of fluids and other substances in the tissue. PURPOSE: We observed a group of patients with incidents of BC aiming to estimate the lymphoedema incidence, degree, time course, symptoms and treatment they received. METHODS AND RESULTS: We evaluated 127 women. Median age was 58 years. 66% were postmenopausal. The median number of axillary nodes was 9. Over the first five years of follow-up we were informed about hand/arm swelling, thickness or tiredness by 37% of this group. The median of axillary nodes affected by metastatic cells in our patients with lymphoedema was 6. The symptoms they referred to us as the most relevant were heaviness (33%), tiredness (27%), jewelry or clothing too tight (25%), swelling and indentations (9%) and difficulty writing (6%). Several of them had psychological problems. CONCLUSION: We know of the relevance of lymphoedema in BC patients but its natural history and most effective therapies are poorly understood. Self-reported symptoms are relevant to promptly start therapy.
Yin XD, Huang WB, Lu CY, Zhang L, Wang LW, Xie GH. A preliminary study on correlations of triple-phase multi-slice CT scan with histological differentiation and intratumoral microvascular/lymphatic invasion in gastric cancer. Chin Med J (Engl). 2011;124:347–351.
BACKGROUND: Many studies have shown that cancer cell differentiation and microvascular invasion play a principle role in cancer progression and metastasis, and non-invasive imaging techniques such as CT, MRI and US assessing the differentiation and the surgical resectibility and the prognosis of cancers are now of great importance. This study aimed to explore the correlation of triple-phase multi-slice CT scan with the histological differentiation and intratumor microvascular/lymphatic invasion of progressive gastric cancer. METHODS: The present study included 64 patients with gastric cancer, all of whom underwent routinal and dual-phase contrast enhancement multi-slice CT examinations of the upper abdomen before surgery. The post-operative specimens were used for determination of histological differentiation, cancer cell invasion of intratumoral microvascular/lymphatic vessel identified by CD34 and D2-40 expression. Correlations between contrast enhancement ratio (CER) of triple-phase multi-slice CT scan in gastric cancer and histological differentiation as well as intratumoral microvascular/lymphatic invasion were compared and analyzed. RESULTS: There was a significant correlation between CER of triple-phase CT scan in gastric cancer and tumor histological differentiation (P < 0.05). CER of the arterial phase in gastric cancer with intratumoral microvascular invasion was significantly higher than that without invasion (0.61 +/− 0.28 vs. 0.46 +/− 0.14, P < 0.05); CER of the arterial-parenchymal phase was significantly lower in gastric cancer with intratumoral microvascular invasion than that without invasion (1.81 +/− 0.39 vs. 2.28 +/− 0.80, P < 0.05). However, CER of the parenchymal phase in gastric cancer with intratumoral lymphatic invasion was significantly higher than that without invasion (1.25 +/− 0.57 vs. 1.00 +/− 0.35, P < 0.05). CONCLUSIONS: CER of triple-phase multi-slice CT scan in gastric cancer is closely correlated with intratumoral microvascular and lymphatic invasion, and also could be used as a marker for histological differentiation.
Zhang, W., X. J. He, et al. (2011). “Inducible nitric oxide synthase expression correlates with angiogenesis, lymphangiogenesis, and poor prognosis in gastric cancer patients.” Hum Pathol. Feb 16. [Epub ahead of print]
Increased nitric oxide synthase expression plays a key role in tumor progression. To examine inducible nitric oxide synthase expression and its correlation with clinical variables, such as tumor progression, angiogenesis, lymphangiogenesis, and prognosis in gastric cancer, we studied inducible nitric oxide synthase expression in gastric cancer samples from 211 patients with 5-year follow-up. CD105 and D2-40 were adopted as biomarkers for tumor angiogenesis and lymphangiogenesis, respectively. Inducible nitric oxide synthase staining was mainly found in the cytoplasm of gastric cancer tumor cells. Positive inducible nitric oxide synthase immunoreactivity was seen in 54.03% of gastric cancer specimens, which was correlated with lymph node metastasis, vascular invasion, distant metastasis, and TNM stage. Compared with inducible nitric oxide synthase negative patients, inducible nitric oxide synthase-positive patients had significantly shorter survival times and higher microvessel density and lymphatic vessel density. Intratumor and peritumor blood microvessel density and lymphatic vessel density correlated with inducible nitric oxide synthase expression (Spearman rho test, P < .05). We conclude that inducible nitric oxide synthase expression correlates with lymph node metastasis, vascular invasion, distant metastasis, TNM stage, and poor survival rate in gastric cancer. We propose that synthesized inducible nitric oxide synthase increases angiogenesis, and lymphangiogenesis thus promotes tumor progression. Inducible nitric oxide synthase expression may be a good biomarker for poor prognosis in gastric cancer.
Zhang Y, Tang H, Cai J, Zhang T, Guo J, Feng D, et al. Ovarian cancer-associated fibroblasts contribute to epithelial ovarian carcinoma metastasis by promoting angiogenesis, lymphangiogenesis and tumor cell invasion. Cancer Lett. 2011;303:47–55.
Cancer-associated fibroblasts (CAFs) are thought to play an essential role in cancer initiation and development. However, little research has been done to evaluate the role of CAFs in epithelial ovarian cancer (EOC) development. To address this issue, ninety-one specimens were immunostained with alpha-smooth muscle actin (alpha-SMA) and fibroblast activation protein (FAP) antibodies to quantify CAFs, and antibodies D2-40 and CD34 to evaluate the lymphatic vessel density (LVD) and microvessel density (MVD) of the lesions. We found there were no alpha-SMA or FAP positive fibroblasts in normal ovary tissues. More CAFs were found in EOC than in borderline tumors and benign tumors (P < 0.01). Abundant CAFs in EOC were associated with advanced-stage disease (P = 0.002), the occurrence of lymph node metastases (P = 0.02) and omentum metastases (P < 0.0001), and increased LVD (P = 0.002) and MVD (P = 0.0004). CAFs isolated from EOC tissues induced more cancer cells to invade (P = 0.003) and migrate (P = 0.005) compared with normal fibroblasts (NFs) isolated from normal ovary tissues in vitro. Our data indicate that CAFs play a vital role in ovarian cancer progression and metastasis. Targeting CAFs as a therapeutic strategy against ovarian cancer is an intriguing concept that needs further study.
Clinical
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: e11–12.
We describe the case of a 4-month-old girl who was admitted for bilateral legs swelling for several weeks. Lymphoscintigraphy revealed the absence of the radiotracer proximal to the ilioinguinal nodes up to 6 hours postinjection. In light of the clinical and image findings, a diagnosis of congenital lymphedema was compatible. Systemic corticosteroid was given, and physical massage was applied at the lower extremities for 3 weeks. Repeat lymphoscintigraphy revealed faster lymphatic flow and liver visualization, demonstrating improvement in lymphatic function. This case illustrates the usefulness of lymphoscintigraphy in diagnosis and evaluating therapy response of lymphedema in children.
Freeman, H. J. and M. Nimmo (2011). “Intestinal lymphangiectasia in adults.” World J Gastrointest Oncol 3:19–23.
Intestinal lymphangiectasia in the adult may be characterized as a disorder with dilated intestinal lacteals causing loss of lymph into the lumen of the small intestine and resultant hypoproteinemia, hypogammaglobulinemia, hypoalbuminemia and reduced number of circulating lymphocytes or lymphopenia. Most often, intestinal lymphangiectasia has been recorded in children, often in neonates, usually with other congenital abnormalities but initial definition in adults including the elderly has become increasingly more common. Shared clinical features with the pediatric population such as bilateral lower limb edema, sometimes with lymphedema, pleural effusion and chylous ascites may occur but these reflect the severe end of the clinical spectrum. In some, diarrhea occurs with steatorrhea along with increased fecal loss of protein, reflected in increased fecal alpha-1-antitrypsin levels, while others may present with iron deficiency anemia, sometimes associated with occult small intestinal bleeding. Most lymphangiectasia in adults detected in recent years, however, appears to have few or no clinical features of malabsorption. Diagnosis remains dependent on endoscopic changes confirmed by small bowel biopsy showing histological evidence of intestinal lymphangiectasia. In some, video capsule endoscopy and enteroscopy have revealed more extensive changes along the length of the small intestine. A critical diagnostic element in adults with lymphangiectasia is the exclusion of entities (e.g. malignancies including lymphoma) that might lead to obstruction of the lymphatic system and “secondary” changes in the small bowel biopsy. In addition, occult infectious (e.g. Whipple's disease from Tropheryma whipplei) or inflammatory disorders (e.g. Crohn's disease) may also present with profound changes in intestinal permeability and protein-losing enteropathy that also require exclusion. Conversely, rare B-cell type lymphomas have also been described even decades following initial diagnosis of intestinal lymphangiectasia. Treatment has been historically defined to include a low fat diet with medium-chain triglyceride supplementation that leads to portal venous rather than lacteal uptake. A number of other pharmacological measures have been reported or proposed but these are largely anecdotal. Finally, rare reports of localized surgical resection of involved areas of small intestine have been described but follow-up in these cases is often limited.
Harada K, Yamahara K, Ohnishi S, Otani K, Kanoh H, Ishibashi-Ueda H, et al. Sustained-release adrenomedullin ointment accelerates wound healing of pressure ulcers. Regul Pept. 2011.
Pressure ulcers are one of the most common complications in elderly, incontinent or paralyzed patients. For the healing of pressure ulcers, the development of granulation tissue and reepithelialization are required. Adrenomedullin (AM), an endogenous vasodilator peptide, is reported to stimulate the proliferation and migration of various cells including endothelial cells, fibroblasts and keratinocytes. Therefore, we hypothesized that AM might accelerate the healing process of pressure ulcers in which these cells were involved. We developed a sustained-release ointment containing human recombinant AM, and applied it in a mouse model of pressure ulcer twice a day for 14days. Human AM was efficiently absorbed in wound area, but its blood concentration was negligible. AM ointment significantly reduced the wound area on day 5 to 7 after injury. In addition, AM ointment accelerated the formation of granulation tissue and angiogenesis as well as lymphangiogenesis after 7days of treatment. Immunological analysis revealed that Ki-67-positive proliferating cells in granulation tissue expressed AM receptors. In summary, sustained-released AM significantly improved wound healing of pressure ulcers through acceleration of granulation and induction of angiogenesis and lymphangiogenesis. Therefore, sustained-release AM ointment may be a novel therapeutic agent for pressure ulcers.
Huggenberger, R., S. S. Siddiqui, et al. (2011). “An important role of lymphatic vessel activation in limiting acute inflammation.” Blood. Mar 1. [Epub ahead of print]
In contrast to the established role of blood vessel remodeling in inflammation, the biological function of an activated lymphatic vasculature in acute inflammation has remained less explored. We studied two established models of acute cutaneous inflammation, namely oxazolone-induced delayed-type hypersensitivity reactions and UVB irradiation, in K14-VEGF-C and K14-VEGF-D transgenic mice. These mice have an expanded network of cutaneous lymphatic vessels. Transgenic delivery of the lymphangiogenic factors VEGF-C and of the VEGFR-3 specific ligand mouse VEGF-D significantly limited acute skin inflammation in both experimental models, with a strong reduction of dermal edema. Interestingly, expression of VEGFR-3 by lymphatic endothelium was strongly downregulated at the mRNA and protein level, in acutely inflamed skin, and there was no VEGFR-3 expression detectable on inflamed blood vessels and dermal macrophages. There was no major reduction of the inflammatory cell infiltrate or in the composition of the inflammatory cytokine milieu in the inflamed skin of VEGF-C or VEGF-D transgenic mice. However, the increased network of lymphatic vessels in these mice significantly enhanced lymphatic drainage from the ear skin. Together, these results provide evidence that specific lymphatic vessel activation limits acute skin inflammation via promotion of lymph flow from the skin and reduction of edema formation.
Kashima, T. G., A. Dongre, et al. (2011). “Lymphatic Involvement in Vertebral and Disc Pathology.” Spine (Phila Pa 1976). Feb 18. [Epub ahead of print]
STRUCTURED ABSTRACT: STUDY DESIGN: Analysis of lymphatic vessels in childhood and adult normal and pathological vertebral bone and intervertebral disc tissue. OBJECTIVE: To determine whether lymphatic vessels are present in spinal vertebrae and intervertebral discs in normal children and adults (4–30 years) as well as in pathological lesions of the spine. SUMMARY OF BACKGROUND DATA: There is uncertainty regarding the presence or absence of lymphatic vessels in normal intervertebral discs and the role of lymphatics in the pathobiology of disc degeneration and infective, neoplastic and other spinal pathology. METHODS: The presence of the specific lymphatic endothelial cell markers, podoplanin and LYVE-1 was determined immunohistochemically in normal cervical, thoracic and lumbar disc and vertebral tissues of adults and children, as well as in a wide range of spinal disorders. RESULTS: Lymphatics were not found in intact normal intervertebral discs or within spinal vertebrae of children or adults. Lymphatics were present in the outer periosteum and paraspinal ligaments and surrounding connective tissue. Lymphatic vessels were seen in infected and displaced degenerate disc tissue. Lymphatic vessels in vertebral bone were only seen when neoplastic and non-neoplastic lesions of the spine were associated with vertebral destruction and the lesion extending through the bone cortex into surrounding connective tissue. CONCLUSION: Lymphatics are not found in intact normal spinal vertebrae or the intervertebral discs of children or adults. Lymphatics in vertebral bone are found in pathological lesions of the spine when these have extended beyond the normal anatomical confines of the vertebra or intervertebral disc; this most likely occurs by ingrowth of lymphatics from surrounding connective tissues. These findings strongly suggest that metastatic tumor spread to the spine does not occur by lymphatics and that lymph node involvement of primary malignant spinal tumors only occurs following extra-osseous spread.
Marco-Lattur, M. D., A. Payeras, et al. (2011). “Intestinal lymphangiectasia: an undescribed cause of malabsorption and incomplete immunological recovery in HIV-infected patients.” Enferm Infecc Microbiol Clin. Feb 24. [Epub ahead of print]
BACKGROUND: Although paradoxical virological and immunological response after HAART has been well studied, intestinal lymphangiectasia (IL) in HIV-1 infected patients has not previously described. METHODS: To describe HIV patients who developed IL. DESIGN: Clinical Case series. PATIENTS: 4 patients with HIV and IL diagnosis based on clinical, endoscopic and pathological findings. RESULTS: All four cases had prior mycobacterial infections with abdominal lymph node involvement and a very low CD4 cell count nadir. They developed intestinal lymphangiectasia despite appropriate virological suppression with HAART and repeatedly negative mycobacterial cultures. Two patients were clinically symptomatic with oedemas, ascites, diarrhoea, asthenia, weight loss; but the other two were diagnosed with malabsorption as a result of laboratory findings, with hypoproteinemia and hypoalbuminemia. Three of them were diagnosed by video capsule endoscopy. CONCLUSIONS: IL should be considered in HIV-1 infected patients who present with clinical or biochemical malabsorption parameters when there is no immunological recovery while on HAART.
Suami, H., D. W. Chang, et al. (2011). “Use of indocyanine green fluorescent lymphography for evaluating dynamic lymphatic status.” Plast Reconstr Surg 127(3): 74e–76e.
Sura, R., J. F. Colombel, et al. (2011). “Lymphatics, tertiary lymphoid organs and the granulomas of Crohn's disease: an immunohistochemical study.” Aliment Pharmacol Ther. Mar 2 [Epub ahead of print]
Background Case studies in the past repeatedly suggested that the fundamental alteration in Crohn's disease occurs in the regional lymphatics of the intestine. Aim To evaluate the lymphatic inflammation in Crohn's disease, and to characterise lymphoid aggregates and granulomas in and surrounding lymphatics and blood vasculature. Methods Forty-eight tissue blocks from 24 Crohn's disease patients and 23 tissue blocks from 23 control patients were selected. Tissue sections were immunostained with a lymphatic endothelial cell marker (D2-40), a marker for blood vasculature (FVIII), and markers for T cells (CD3), B cells (CD20) and macrophages (CD68). Results Lymphangiectasia and lymphocytic perilymphangitis were demonstrated in all 24 patients, lymphocyte-obstructed lymphatics in seven patients, granuloma-obstructed lymphatics in nine patients and inflammatory lymphoid follicles in all 24 patients. Free-standing granulomas occurred in 19 patients, and in three further patients granulomas were in or attached to blood vascular units. Conclusions This study, employing immunohistochemistry, revealed, better than standard microscopy, the association of inflammation, granulomas and tertiary lymphoid follicles or organs with the lymphatic vasculature in Crohn's disease. Disease in some patients was characterised by perilymphangitis and lymphoid follicular inflammation and in others by granulomas, some of which totally obstructed lymphatics. These findings have aetiological, therapeutic and prognostic implications.
Vascular Anomalies
Chen, W. L., Z. Q. Huang, et al. (2011). “Percutaneous sclerotherapy of massive macrocystic lymphatic malformations of the face and neck using fibrin glue with OK-432 and bleomycin.” Int J Oral Maxillofac Surg. Feb 28. [Epub ahead of print]
Fadell, M. F., 2nd, B. V. Jones, et al. (2011). “Prenatal diagnosis and postnatal follow-up of rapidly involuting congenital hemangioma (RICH).” Pediatr Radiol. Feb 22. [Epub ahead of print]
Morais, P., S. Magina, et al. (2011). “Efficacy and safety of propranolol in the treatment of parotid hemangioma.” Cutan Ocul Toxicol. Feb 21. [Epub ahead of print]
Oztunc, F., B. Koca, et al. (2011). “Generalised lymphangiomatosis in an 8-year-old girl who presented with cardiomegaly.” Cardiol Young: 1–3.
Generalised lymphangiomatosis is a rare disease that is characterized by widespread bony and soft tissue involvement of lymphangioma. Radiological evaluation is crucial because the site and extent of the lymphangioma are important prognostic factors. The computed tomography, ultrasonography and magnetic resonance images showed sharply defined, non-enhanced cystic lesions involving the mediastinum, bones, spleen, lung, and lower neck. We report here a case that was referred to us for investigation of marked cardiomegaly.
Peridis, S., G. Pilgrim, et al. (2011). “A meta-analysis on the effectiveness of propranolol for the treatment of infantile airway haemangiomas.” Int J Pediatr Otorhinolaryngol. Feb 16. [Epub ahead of print]
Tubbs, R. S., N. Bradley, et al. (2011). “Involvement of the brachial plexus and its branches by cystic hygromas.” J Neurosurg Pediatr 7:282–285.
Lymphatic malformations that involve the nervous system are uncommon. The authors review their experience with involvement of the brachial plexus and its branches by cystic hygromas. A retrospective review of the authors' experience with pathology of the pediatric brachial plexus revealed 4 cases involving patients with compression of this structure and its branches due to cystic hygroma. Although such cases are apparently rare, the neurosurgeon should consider malformations of the lymphatic system in the differential diagnosis of masses involving the brachial plexus and its branches.