Serum Vascular Endothelial Growth factor-C Levels Research Articles

Correlation of serum VEGF-C, ANGPTL4, and activin A levels with frailty

BackgroundSecretory factors linked to lymphogenesis, such as vascular endothelial growth factor C (VEGF-C), angiopoietin like protein 4 (ANGPTL4), and activin A (ACV-A), have been recognized as potential markers of chronic inflammatory status and age-related diseases. Furthermore, these factors may also be linked to frailty. The primary objective of this study was to examine the serum VEGF-C, ANGPTL4, and ACV-A levels in young individuals, healthy older individuals, and older individuals with pre-frailty and frailty, and to determine their association with pro-inflammatory factor levels. MethodsWe conducted an observational study, enrolling a total of 210 older individuals and 20 young healthy volunteers. Participants were divided into four groups based on the Freid frailty phenotype: healthy young group, older patients without frailty group, pre-frail older group, and frail older group. Plasma and peripheral blood mononuclear cells (PBMCs) were collected from all four groups. ELISA was used to measure the serum levels of VEGF-C, ANGPTL4, ACV-A, and pro-inflammatory cytokines, while RT-qPCR was used to measure the transcription level of VEGF-C, ANGPTL4 and ACV-A in PBMCs. ResultsIn comparison to healthy young individuals and older participants without frailty, older participants with frailty exhibited lower renal function, higher serum levels and transcription levels of VEGF-C, ANGPTL4, ACV-A, and elevated levels of pro-inflammatory cytokines (CRP, IL-1β, and TNF-α). Multiple linear regression analysis revealed that serum levels of VEGF-C, ANGPTL4, and ACV-A were positively correlated with the frailty index, independent of age, eGFR, and comorbidities. Furthermore, the receiver operating characteristic (ROC) curve analysis demonstrated that serum levels of VEGF-C, ANGPTL4, and ACV-A have great accuracy in predicting frailty. ConclusionElevated serum levels of VEGF-C, ANGPTL4, and ACV-A are associated with frailty status.

Relationship of Vascular Endothelial Growth Factor C, a Lymphangiogenesis Modulator, With Edema Formation, Congestion and Outcomes in Acute Heart Failure

Although vascular endothelial growth factor C (VEGF-C) is a known lymphangiogenesis modulator, its relationship with congestion formation and outcomes in acute heart failure (AHF) is unknown. Serum VEGF-C levels were measured in 237 patients hospitalized for AHF. The population was stratified by VEGF-C levels and linked with clinical signs of congestion and outcomes. The study's population was divided in VEGF-C tertiles: low (median [Q25-Q75]: 33 [15-175]), medium (606 [468-741]) and high (1141 [968-1442] pg/mL). The group with low VEGF-C on admission presented with the highest prevalence of severe lower-extremity edema (low VEGF-C vs medium VEGF-C vs high VEGF-C): 30% vs 13% vs 20%; P = 0.02); the highest percentage of patients with ascites: 22% vs 9% vs 6%; P = 0.006; and the lowest proportion of patients with pulmonary congestion: 22% vs 30% vs 46%; P = 0.004. The 1-year mortality rate was the highest in the low VEGF-C tertile: 35% vs 28% vs 18%, respectively; P = 0.049. The same pattern was observed for the composite endpoint (death and AHF rehospitalization): 45% vs 43% vs 26%; P = 0.029. The risks of death at 1-year follow-up and composite endpoint were significantly lower in the high VEGF-C group. Low VEGF-C was associated with more severe signs of congestion (signs of fluid accumulation) and adverse clinical outcomes.

Vascular endothelial growth factor C gene expression and its serum level as potential biomarkers for obesity in Egyptian children

Background and objectivesObesity is a serious health issue among children, and it's linked to a higher risk of chronic illness. Increased adipose tissue, which is highly vascularized due to angiogenesis, causes adverse health problems. Angiogenesis and lymphangiogenesis are regulated by vascular endothelial growth factor C (VEGF-C), and poor lymphatic vessel function is linked to increased adipocyte accumulation. Therefore, our study analyzes VEGF-C gene expression and its serum level in children with obesity in Egypt and correlates them with metabolic, clinical, and biochemical parameters. Subjects & methodsWe compared VEGF-C gene expression in blood and its serum level from 50 unrelated children with obesity and 50 normal healthy controls chosen randomly of matched age and gender recruited from Pediatric Clinics, both inpatient and outpatient, Menoufia University, Egypt, from March to June 2021, in a case-control study. The expression levels of VEGF-C mRNA were evaluated using a real-time quantitative reverse transcription-polymerase chain reaction and the serum VEGF-C level was measured using an enzyme-linked immunosorbent assay (ELISA). ResultsFasting plasma glucose, fasting insulin, homeostatic model assessment for insulin resistance (HOMA-IR), triacylglycerol (TAG), total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDLC), serum VEGF-C, and VEGF-C expression levels were significantly higher in obese children group compared with the control (P < 0.001). In addition, serum VEGF-C levels were significantly inversely correlated with FT4 (P = 0.009) and significantly directly correlated with total cholesterol (P = 0.005) and LDL-C levels (P = 0.006) in the obese children group. Moreover, VEGF-C expression levels were also significantly inversely correlated with HDL-C levels (P = 0.001) and significantly directly correlated with fasting insulin (P = 0.002) and HOMA-IR (P = 0.001) in the obese children group. ConclusionVEGF-C gene expression and its serum levels could be used for follow-up of obese children with metabolic abnormalities.

Serum VEGF-C as an evaluation marker of disease activity in adult-onset Still's disease.

In view of the possible involvement of vascular endothelial growth factor-C (VEGF-C) in pathogenesis of adult-onset Still's disease (AOSD) based on our previous genome-wide association study (GWAS) results, the primary objective of this study, therefore, was to investigate the correlations between the content of VEGF-C in serum and clinical and biochemical markers of AOSD. Blood samples were collected from 80 patients with AOSD, 26 with rheumatoid arthritis (RA), 30 with systemic lupus erythematosus (SLE) and 31 healthy control subjects. The serum VEGF-C levels were determined using an enzyme-linked immunosorbent assay (ELISA). Statistical analysis and comparisons were conducted. A significantly higher serum VEGF-C level was observed in patients with AOSD than in HC. Serum VEGF-C levels had high AUC value of 0.8145 for distinguishing AOSD group from healthy group with sensitivity of 0.7097 and specificity of 0.8250. It also showed good diagnostic value to differentiate AOSD from other autoinflammatory diseases with sensitivity of 0.7500 and specificity of 0.5500. AOSD patients with fever, arthralgia, skin rash, sore throat, lymphadenopathy, splenomegaly hepatomegaly and pleuritis, had a higher level than those who did not have these symptoms (p = 0.0012, p = 0.0092, p = 0.0056, p = 0.0123, p = 0.0068, p = 0.0030, p = 0.0020, and p = 0.0018, respectively). The serum VEGF-C levels were also positively correlated with laboratory features and several cytokines related to AOSD disease activity. In conclusion, our study unveiled a close association between serum VEGF-C levels and AOSD including disease activity and clinical hematological manifestations, suggesting the potential utility of VEGF-C as a candidate biomarker to assess disease activity in AOSD.

Association of Lymphangiogenic Factors With Pulmonary Arterial Hypertension in Systemic Sclerosis.

Pulmonary arterial hypertension (PAH) is a major complication in systemic sclerosis (SSc), a disease marked by vascular and lymphatic vessel abnormalities. This study was undertaken to assess the role of the lymphangiogenic factors vascular endothelial growth factor C (VEGF-C) and angiopoietin 2 (Ang-2) and the soluble forms of their respective cognate receptors, soluble VEGF receptor 3 (sVEGFR-3) and soluble TIE-2, in patients with SSc, and to evaluate their predictive ability as markers for PAH development in SSc. In this cohort study, we used multiplex bead assays to assess serum levels of lymphangiogenic factors in 2 well-characterized SSc cohorts: an unselected identification cohort of SSc patients from Oslo University Hospital (n = 371), and a PAH-enriched validation cohort of SSc patients from Zurich University Hospital and Oslo University Hospital (n = 149). As controls for the identification and validation cohorts, we obtained serum samples from 100 healthy individuals and 68 healthy individuals, respectively. Patients in whom SSc-related PAH was identified by right-sided heart catheterization (RHC) in both cohorts were studied in prediction analyses. PAH was defined according to the European Society of Cardiology/European Respiratory Society 2015 guidelines for the diagnosis and treatment of PAH. Associations of serum levels of lymphangiogenic factors with the risk of PAH development were assessed in logistic regression and Cox regression analyses. Associations in Cox regression analyses were expressed as the hazard ratio (HR) with 95% confidence interval (95% CI). In the identification cohort, SSc patients had lower mean serum levels of VEGF-C and higher mean serum levels of Ang-2 compared to healthy controls (for VEGF-C, mean ± SD 2.1 ± 0.5 ng/ml in patients versus 2.5 ± 0.4 ng/ml in controls; for Ang-2, mean ± SD 6.1 ± 7.6 ng/ml in patients versus 2.8 ± 1.8 ng/ml in controls; each P < 0.001); these same trends were observed in SSc patients with PAH compared to those without PAH. The association of serum VEGF-C levels with SSc-PAH was confirmed in the PAH-enriched RHC validation cohort. For prediction analyses, we assembled all 251 cases of SSc-PAH identified by RHC from the identification and validation cohorts. In multivariable Cox regression analyses adjusted for age and sex, the mean serum levels of VEGF-C and sVEGFR-3 were predictive of PAH development in patients with SSc (for VEGF-C, HR 0.53 [95% CI 0.29-0.97], P = 0.04; for sVEGFR-3, HR 1.21 [95% CI 1.01-1.45], P = 0.042). These findings support the notion that lymphangiogenesis is deregulated during PAH development in SSc, and indicate that VEGF-C could be a promising marker for early PAH detection in patients with SSc.

Qingjie Fuzheng Granule suppresses lymphangiogenesis in colorectal cancer via the VEGF-C/VEGFR-3 dependent PI3K/AKT pathway

ScopeTo investigate the effect of Qingjie Fuzheng Granule (QFG) on lymphangiogenesis and lymphatic metastasis in colorectal cancer. MethodsThe effects of QFG on the expression and secretion of vascular endothelial growth factor-C (VEGF-C) in HCT-116 cells were investigated both in vitro and in vivo. HCT-116 cells were treated with different concentrations (0.2, 0.5, and 1.0 mg/mL) of QFG. The VEGF-C expression level was determined using RT-qPCR and western blotting, and the VEGF-C concentration in supernatant was measured by ELISA. Tumor xenograft models of HCT-116 cells were generated using BALB/c nude mice, and the mice were randomly divided into a control group (gavaged with normal saline) and QFG group (gavaged with 2 g/kg QFG). The effect of QFG on tumor growth was evaluated by comparing the volume and weight of tumors between two groups. Immunohistochemistry (IHC) and RT-qPCR were performed to detect the expression levels of VEGF-C, vascular endothelial growth factor receptor 3 (VEGFR-3), and LYVE-1 (lymphatic vessel endothelial hyaluronan receptor 1). ELISA was performed to measure the concentration of serum VEGF-C. TMT proteomics technology and Reactome pathway analysis were used to explore the mechanism of QFG inhibiting lymphangiogenesis in tumor. The VEGF-C (5 ng/mL)-stimulated human lymphatic endothelial cell (HLEC) model was conducted to evaluate the effect of QFG on lymphangiogenesis in vitro. The model cells were treated with different concentrations (0.2, 0.5, and 1.0 mg/mL) of QFG. Cell viability was then determined using an MTT assay. The cell migration, invasion, and tube-formation ability were analyzed using transwell migration, matrigel invasion and tube formation assays, respectively. The underlying mechanism was uncovered, the levels of VEGFR-3, matrix metalloproteinase 2 (MMP-2), matrix metalloproteinase 9 (MMP-9), p-PI3K/PI3K, p-AKT/AKT and p-mTOR/ mTOR were detected using western blotting. ResultsQFG significantly reduced VEGF-C expression and secretion in HCT-116 cells. QFG evidently suppressed in vivo tumor growth and the expression of VEGF-C, VEGFR-3, and LYVE-1. The serum VEGF-C level was also reduced by QFG. Moreover, TMT proteomics technology and Reactome pathway analysis identified 95 differentially expressed protein and multiple enriched pathway about matrix metalloproteinase and extracellular matrix, which is direct associate with lymphangiogenesis. In vitro experiment, QFG inhibited the viability, migration, invasion and tube formation of HLECs. Additionally, QFG reduced the VEGFR-3, MMP-2, MMP-9 expression levels, and the p-PI3K/PI3K, p-AKT/AKT, p-mTOR/ mTOR ratios. ConclusionQFG can exert its effect on both tumor cells and HLECs, exhibiting ani- lymphangiogenesis in colorectal cancer via the VEGF-C/VEGFR-3 dependent PI3K/AKT pathway pathway.

Relación entre los niveles séricos del factor de crecimiento endotelial-vascular C, la afectación ganglionar axilar y la sobrevida libre de enfermedad en pacientes con cáncer de mama operable sometidas a biopsia selectiva del ganglio centinela

ObjectivesTo investigate the association between serum levels of vascular-endothelial growth factor-C (VEGF-C) and axillary node involvement. Material and methodsWe performed a prospective study and subsequent analysis of 174 patients with early-stage breast cancer who had undergone sentinel node biopsy (SNB). ResultsThe mean VEGF-C plasma concentration was 6561.5 pg/ml. No association was found between VEGF-C plasma concentration and axillary node involvement in SNB (p=0.626). On multivariate logistic regression analysis, serum VEGF-C levels were not predictive of node involvement. The median interval to recurrence or last follow-up was 51 months (mean, 49 months), with a maximum of 80 months (25th percentile: 42 months, 75th percentile, 62 months). A reduction of 1000 points in serum VEGF-C levels (1k) increased instant risk, with HR 1.357 (95%CI: 1.004-1.838). This increased risk was 35% for each 1000-point decrease in serum levels, demonstrated in the Kaplan-Meier analysis. ConclusionsSerum VEGF-C levels are not related to risk of node involvement in early-stage breast cancer and, therefore, cannot be used to predict the presence of node involvement in SNB. Patients with serum VEGF-C levels above the mean have a lower risk of recurrence in the first 4 years of follow-up than those with levels below the mean. This difference was statistically significant in the multivariate analysis and consequently deserves confirmation in future studies designed specifically for this aim.

Increased circulating levels of vascular endothelial growth factor C can predict outcome in resectable gastric cancer patients.

Neoangiogenesis has proven to be a relevant pathogenetic mechanism in gastric cancer (GC) and lymphatic spread represents an important well-known prognostic factor. Vascular endothelial growth factor C (VEGF-C) plays a key role in lymphangiogenesis and its blood levels in GC patients are easily measurable. This analysis aimed to investigate the prognostic role of preoperative VEGF-C blood levels. VEGF-C serum levels were determined by enzyme-linked immunoadsorbent assay (ELISA) in 186 patients observed at our institution from January 2004 until December 2009 and 82 healthy subjects. Statistical analyses were performed using SPSS 21.0. VEGF-C levels were significantly higher in GC patients (median: 287.4 pg/mL; range, 76.2-865.2 pg/mL) than in the control group (median VEGF-C: 31 pg/mL; range, 12-97 pg/mL). A significant correlation between VEGF-C levels, T, N and tumor stage has been described. The median overall survival (OS) was statistically significantly higher in pts with low serum VEGF-C levels [median: not reached (NR) vs. 26 months; P<0.0001]. Higher preoperative VEGF-C levels correlated also with earlier disease relapse and poor disease-free survival (DFS) (median NR in each subgroup, P=0.005). Furthermore, high VEGF-C levels [hazard ratio (HR) =2.7; P=0.018] and tumor grading (HR =0.44; P=0.007) were independent prognostic factors for OS at multivariate analysis. Our study showed that increased VEGF-C levels are significantly associated with advanced regional lymph node involvement and poor OS and DFS in pts with resected GC paving the way to a possible application as prognostic factor in the clinical practice.

Abstract 16719: Vascular Endothelial Growth Factor-C and Mortality in Patients With Stable Coronary Artery Disease and Cancer: A Subanalysis of the ANOX Study

Background: Recent basic studies suggest the importance of lymphatic vasculature as a therapeutic target in cardiovascular diseases, whereas clinical investigations of vascular endothelial growth factor-C (VEGF-C), a central player in lymphangiogenesis, have focused on its diagnostic possibilities for various malignancies. The expression levels in tumors and/or circulating levels of VEGF-C correlates with lymph node and distant metastasis, and poor prognosis. However, the relationship between VEGF-C and mortality in patients with stable coronary artery disease (CAD) and cancer is unknown. Methods: Serum VEGF-C levels were measured in 133 patients with stable CAD and cancer, enrolled in the development of novel biomarkers related to angiogenesis or oxidative stress to predict cardiovascular events (ANOX) study, and followed up for 3 years. The outcome was all-cause death. Results: During the follow-up, 43 patients (32%) died from any cause (10 patients from cardiovascular cause, and 25 patients from cancer). In Kaplan-Meier analysis, lowest quartile of VEGF-C was significantly associated with all-cause death (hazard ratio [HR], 2.6; 95% confidence interval [CI], 1.4-4.8, but not with cancer-related death (HR, 1.8; 95% CI, 0.8-4.2). After adjustment for established risk factors, low VEGF-C levels and the lowest quartile of VEGF-C were both significantly associated with all-cause death (HR for 1-SD increase, 0.67; 95% CI, 0.47-0.95; HR for values below the 25th percentile, 3.3; 95% CI, 1.7-6.3; respectively). Even after additional adjustment of N-terminal pro-brain natriuretic peptide, contemporary sensitive cardiac troponin-I, and high-sensitivity C-reactive protein, low VEGF-C levels and the lowest quartile of VEGF-C were both significantly associated with all-cause death (HR for 1-SD increase, 0.69; 95% CI, 0.48-0.99; HR for values below the 25th percentile, 2,7; 95% CI, 1.4-5.5; respectively). Conclusions: In patients with stable CAD and cancer, a low VEGF-C value was independently associated with all-cause mortality beyond established risk factors and standard cardiovascular biomarkers. These findings may indicate the difficulty to use elevated VEGF-C as a prognostic marker in patients with cancer.

Serum vascular endothelial growth factor‑C levels predict lymph node metastasis and prognosis of patients with gallbladder cancer

Lymph node metastasis is the primary site of metastasis for patients with gallbladder cancer (GBC). Vascular endothelial growth factor-C (VEGF-C) has been implicated in the control of lymphangiogenesis and lymph node metastasis in various malignant tumors. However, the function of circulating VEGF-C is unclear and it is often difficult to evaluate lymph node metastasis and provide a prognosis for GBC. In the present study, ELISA was used to measure the preoperative serum VEGF-C (sVEGF-C) levels of 51 patients with GBC, 15 patients with chronic cholecystitis and 10 healthy volunteers. The results revealed a significantly increased sVEGF-C level in patients with GBC compared with the healthy donors, however no statistically significant difference was identified between patients with GBC and chronic cholecystitis. sVEGF-C levels were associated with lymph node metastasis in GBC and presented a positive correlation with VEGF-C expression and lymphatic vessel density (LVD) in patients with GBC. The mean survival time with high sVEGF-C was significantly reduced compared with low sVEGF-C. A similar result was also observed for VEGF-C expression and LVD. In summary, sVEGF-C levels may predict lymph node metastasis and the prognosis of patients with GBC.

High serum vascular endothelial growth factor C predicts better relapse-free survival in early clinically node-negative breast cancer.

A recent meta-analysis indicated that higher tumoral expression of vascular endothelial growth factor C (VEGF-C) was related to poorer relapse-free and overall survival in breast cancer patients. However, a retrospective study found that higher circulating VEGF-C levels were associated with better survival in breast cancer patients. In 2009, we initiated a prospective study to determine the utility of preoperative serum VEGF-C levels for predicting the risk of sentinel lymph node involvement in early breast cancer and to assess serum VEGF-C levels as a prognostic factor for relapse-free and overall survival. We analyzed serum samples from 174 patients with early breast cancer who underwent sentinel lymph node biopsies. VEGF-C levels were determined using an ELISA. Serum VEGF-C levels were normally distributed, with a median value of 6561.5 pg/mL, and did not correlate with any other clinical or pathological variables. During a median follow-up period of 58 months, the five-year relapse-free survival rate was higher in patients with VEGF-C levels above the median than in patients with lower levels (95.3% vs. 85.9%, p < 0.04). No association was found between VEGF-C levels and overall survival. Our study demonstrates that the prognosis was better for early breast cancer patients with high serum VEGF-C levels.

Serum VEGF-C levels as a candidate biomarker of hypervolemia in chronic kidney disease.

Attaining and maintaining optimal “dry weight” is one of the principal goals during maintenance hemodialysis (MHD). Recent studies have shown a close relationship between Na+ load and serum vascular endothelial growth factor-C (VEGF-C) levels; thus, we aimed to investigate the role of VEGF-C as a candidate biomarker of hypervolemia. Physical examination, basic laboratory tests, N-terminal pro b-type natriuretic peptide (NT-ProBNP), echocardiography, and bioimpedance spectroscopy data of 3 groups of study subjects (euvolemic MHD patients, healthy controls, and hypervolemic chronic kidney disease [CKD] patients) were analyzed. Research data for MHD patients were obtained both before the first and after the last hemodialysis (HD) sessions of the week. Data of 10 subjects from each study groups were included in the analysis. Serum VEGF-C levels were significantly higher in hypervolemic CKD versus in MHD patients both before the first and after the last HD sessions (P = .004 and P = .000, respectively). Healthy controls had serum VEGF-C levels similar to and higher than MHD patients before the first and after the last HD sessions of the week (P = .327 and P = .021, respectively). VEGF-C levels were correlated with bioimpedance spectroscopy results (r2 0.659, P = .000) and edema (r2 0.494, P =0.006), but not with ejection fraction (EF) (r2 −0.251, P = .134), blood pressures (systolic r2 0.037, P = 0.824, diastolic r2 −0.067, P = .691), and NT-ProBNP (r2 −0.047, P = .773). These findings suggest that serum VEGF-C levels could be a potential new biomarker of hypervolemia. The lack of correlation between VEGF-C and EF may hold a promise to eliminate this common confounder. Further studies are needed to define the clinical utility of VEGF-C in volume management.

Role of vascular endothelial growth factor C in classical Hodgkin lymphoma

We performed three different studies to obtain additional data on the biological and prognostic role of vascular endothelial growth factor C (VEGFC) in classical Hodgkin lymphoma (cHL): (1) serum VEGFC levels were measured by enzyme-linked immunosorbent assay in 80 patients; (2) immunohistochemical VEGFC expression in tumor tissue was evaluated using a case–control study in 62 patients; (3) gene expression of VEGFC was investigated in vitro in six cHL cell lines, and was compared with expression in inflammatory lymph nodes. Higher serum VEGFC levels were found in patients with cHL than in healthy volunteers (median, 7675 vs. 1358 pg/mL, p < 0.001) and high VEGFC expression in tissue predicted worse progression-free survival at 7 years (41% vs. 91%, p < 0.0001). VEGFC expression in all Hodgkin lymphoma cell lines was higher than the mean expression level in inflammatory lymph nodes. Our data suggest that Hodgkin and Reed–Sternberg cells produce VEGFC, and VEGFC expression could be a novel prognostic factor in cHL.

Abstract 12898: Serum Vascular Endothelial Growth Factor-C Levels are Inversely Associated With Major Adverse Cardiovascular Events in Patients With Arteriosclerotic Obliterans

Background: Vascular endothelial growth factor-C (VEGF-C), a homologue of VEGF family, plays a key role in lymphangiogenesis. Recently, we demonstrated that VEGF-C is closely associated with dyslipidemia and atherosclerosis. However, the relationship between serum VEGF-C levels and cardiovascular events in patients with atherosclerotic disease is unknown. Methods and Results: We performed a prospective cohort study involving a total of 209 patients with arteriosclerotic obliterans (ASO) (age, 73±8 y [SD]; male, 75%; hypertension, 88%; diabetes, 69%; dyslipidemia, 72%; history of smoking, 76%; Fontaine class, 2.1±0.8). Serum levels of VEGF-C, VEGF-A and high-sensitivity C-reactive protein (hsCRP) were determined employing specific enzyme-linked immunosorbent assays. The primary outcome was major adverse cardiac events (MACEs) defined as all-cause mortality, hospitalization due to acute coronary syndrome, stroke, congestive heart failure, aortic disease, and coronary/peripheral revascularization. Patients were followed up over a 4 year period. The median follow-up was 484 (IQR, 220-955) days. During the follow-up period, MACEs developed in a total of 86 patients (41.1 %). Patients were divided into two groups based on the median of each biomarker. In Kaplan-Meier analyses, low-VEGF-C (P=0.014, by log-rank test), but not high-hsCRP or high-VEGF-A, was significantly associated with MACEs. Multivariate Cox proportional hazard analyses revealed that serum levels of VEGF-C (hazard ratio [HR], 0.79 [per 1-SD increase]; 95% confidence interval [CI], 0.63-0.99; P=0.04), but not hsCRP or VEGF-A, were inversely and significantly associated with MACEs after adjustment for age, gender, and established risk factors. Finally, we performed stepwise Cox proportional hazard analysis including data on age, gender, established risk factors, Fontaine class and serum levels of hsCRP, VEGF-A and VEGF-C. Notably, Fontaine class (HR, 1.4; 95% CI, 1.1-1.8; P=0.002) and the VEGF-C level (HR [per 1-SD increase], 0.80; 95% CI, 0.64-0.99; P=0.045), but not other parameters, were independent predictors of MACEs. Conclusions: A low VEGF-C value may serve as a predictive marker of cardiovascular events in patients with ASO.

Effect of thoracic epidural anaesthesia on serum vascular endothelial growth factor C and cytokines in patients undergoing anaesthesia and surgery for colon cancer

Serum vascular endothelial growth factor-C (VEGF-C), transforming growth factor-β (TGF-β), and interleukin (IL)-6 promote angiogenesis and metastases in colon cancer. We hypothesized that patients who received propofol-epidural anaesthesia (PEA) would exhibit decreases in VEGF-C, TGF-β, and IL-6 and an increase in IL-10 compared with patients who received general anaesthesia (GA). Colon cancer surgery patients were randomly assigned to the PEA (n=20) or GA (n=20) group. Serum VEGF-C, TGF-β, IL-6, and IL-10 levels before surgery and 24 h after surgery were measured. Patients who received PEA showed decreases in VEGF-C [526 (261) vs 834 (304) pg ml(-1), P=0.001], TGF-β (P=0.027), and IL-6 (P=0.007) and an increase in IL-10 (P=0.001) 24 h after surgery compared with patients subjected to GA. The visual analogue scale scores at rest and during coughing at 2 and 24 h after operation were significantly lower in PEA patients (P<0.05). PEA reduces serum concentrations of factors associated with angiogenesis during colon cancer surgery. ChiCTR-TRC-13003146 (www.chictr.org).

Decreased serum level and increased urinary excretion of vascular endothelial growth factor-C in patients with chronic kidney disease

BackgroundInterstitial tonicity increases vascular endothelial growth factor-C (VEGF-C), a lymphangiogenic factor in salt-induced hypertension. Therefore, it can be assumed that changes of serum VEGF-C level may be associated with increasing blood pressure. However, there is no report about the changes of serum VEGF-C levels in patients with chronic kidney disease (CKD). The aims of this study were to investigate the changes of serum and urine VEGF-C levels in patients with CKD stage 3–4 and to evaluate the relationship between blood pressure and serum VEGF-C levels in the patients with CKD stage 5 and hemodialysis. MethodsGlomerular filtration rate (GFR) was assessed by the Modification of Diet in Renal Disease equation. Blood pressure and VEGF-C levels (serum and urine) were measured by enzyme-linked immunosorbent assay (ELISA) in nine patients with stage 3–4 CKD, 41 hemodialysis patients, and eight healthy individuals. ResultsThe median serum level of VEGF-C in patients with stage 3–4 CKD and stage 5 hemodialysis significantly decreased in comparison with healthy individuals. Urinary VEGF-C excretion increased in patients with stage 3–4 CKD compared with healthy control patients. For 41 hemodialysis patients, the serum level of VEGF-C in patients with stage 1 or stage 2 hypertension with hemodialysis did not significantly increase when compared with prehypertension hemodialysis patients. ConclusionWe demonstrated that circulating levels of VEGF-C were decreased in patients with CKD, and the decrease of VEGF-C in patients with stage 3–4 CKD coincided with an increase in the urinary excretion of VEGF-C.

Serum spleen tyrosine kinase and vascular endothelial growth factor-C levels predict lymph node metastasis of oesophageal squamous cell carcinoma

Lymph node involvement is a key feature and an independent prognostic factor of oesophageal squamous cell carcinoma. However, an accurate and robust assay to predict the lymphatic spread of oesophageal squamous cell carcinoma is unavailable. The purpose of this study was to determine whether serum vascular endothelial growth factor-C (VEGF-C) and spleen tyrosine kinase levels are potential markers of lymph node metastasis in patients with oesophageal squamous cell carcinoma. In the study, 108 patients with oesophageal squamous cell carcinoma and 24 healthy subjects participated. Serum spleen tyrosine kinase and VEGF-C concentrations were examined by enzyme-linked immunosorbent assays. Patients with oesophageal squamous cell carcinoma had significantly elevated VEGF-C and decreased spleen tyrosine kinase in serum when compared with normal controls (P < 0.05). Pearson's correlation analysis revealed that serum spleen tyrosine kinase was negatively correlated with the serum VEGF-C level in oesophageal squamous cell carcinoma patients (r = -0.453, P = 0.000). In addition, surgical resections of the oesophageal tumour profoundly brought both serum spleen tyrosine kinase and VEGF-C closer to the normal range at 2 weeks after operation (P < 0.05). Statistical analysis showed that enhanced serum VEGF-C and reduced spleen tyrosine kinase significantly correlated with the stage of regional lymph node metastasis, tumour size and the status of primary tumour extension, but not with other clinicopathological features of the patients (P < 0.05). Our data suggest that both serum spleen tyrosine kinase and VEGF-C levels are valuable in the preoperative evaluation of lymph node metastasis in patients with oesophageal squamous cell carcinoma.

Serum vascular endothelial growth factor‐C combined with multi‐detector CT in the preoperative diagnosis of lymph node metastasis of gastric cancer

To investigate whether serum vascular endothelial growth factor-C (SVEGF-C) and multi-detector computed tomography (MDCT) can predict lymph node metastasis (LNM) in gastric cancer (GC). The SVEGF-C level of 80 patients with GC was examined by enzyme linked immunosorbent assay. An MDCT scan of the abdomen was performed. Kaplan - Meier survival analysis was used to analyse survival. In patients with GC, a higher level of SVEGF-C was found in the LNM group (650.9 ± 198.6 vs 451.0 ± 115.5 pg/mL, P = 0.000) and in patients with distant metastases (834.3 ± 80.0 pg/mL vs 557.9 ± 187.0 pg/mL, P = 0.000). With a cut-off value of 542.5 pg/mL, the sensitivity, specificity, accuracy, positive predictive value and negative predictive value of SVEGF-C for predicating LNM were 82.8, 81.8, 82.5, 92.3 and 64.3%, respectively. MDCT could not be employed to detect the LNM. When SVEGF-C associated with MDCT was employed to determine LNM in GC, the sensitivity, specificity, accuracy, positive predictive value and negative predictive value were 91.4, 86.4, 90.0, 94.6 and 79.2%, respectively. No difference of SVEGF-C level was found among N1, N2 and N3 groups (P > 0.05). The 5-year overall survival was 47.5%. A shorter mean survival time were found in patients with SVEGF-C >834.3 pg/ml (43.3 ± 2.8 months vs 67.4 ± 2.5 months, P = 0.000) and in patients who were MDCT-positive (42.7 ± 3.8 months vs 60.8 ± 2.2 months, P = 0.0034). SVEGF-C may be a biomarker for a preoperative diagnosis of LNM. In conjunction with MDCT, SVEGF-C can improve the accuracy of a diagnosis of LNM in GC. A higher SVEGF-C level and an MDCT-positive finding could predict the poorer prognosis of GC.

The role and significance of serum SYK and VEGF-C in metastasis of the lymph nodes of pulmonary adenocarcinoma.

Lung cancer has become one of the most dangerous malignant tumor in the world nowadays, whose pathogenesis is complex involving multi-genes and multi-elements. In this study, we try to explore the values of serum SYK and vascular endothelial growth factor-C (VEGF-C) in lymph node metastasis of lung adenocarcinoma. Serum SYK and VEGF were examined in 160 lung adenocarcinoma patients with various metastasis lesions and 40 healthy volunteers by ELISA. The serum SYK level of the lung adenocarcinoma patients were remarkably lower than those of normal persons (P <0.05); The SYK level decreased while the lymph nodes area increased along with their metastasis (P <0.05), and the serum VEGF-C level were remarkably higher than those of healthy objects (P <0.05). The VEGF-C level increased with the increase of lymph nodes metastasis (P <0.05). For the serum level of SYK and VEGF-C, there was no statistical difference in sex and age (P <0.05). Negative correlation was found between SYK and VEGF-C (r =0.650, P <0.05). The serum level of SYK and VEGF-C are closely related to the lymph nodes metastasis of lung adenocarcinoma. Combination detection of SYK and VEGF-C might be helpful for the predict of lymph nodes metastasis of lung adenocarcinoma.

Association of serum vascular endothelial growth factor-C (VEGF-C) with lymph node metastasis and prognosis in pancreatic adenocarcinoma

4620 Background: Accurate staging and prognostic information is essential for treatment planning in pancreatic adenocarcinoma (PA). Current methods include endoscopic ultrasound, CT scanning, and serum CA 19–9 levels. Despite these, many patients considered resectable experience early relapse and die from their disease and within this group nodal status correlates with overall survival. For patients metastatic at presentation the prognosis is often variable with limited treatment options. Vascular endothelial growth factor- C (VEGF-C) plays a crucial role in lymphangiogenesis and has been implicated in promoting lymph node metastasis in PA. Prior studies demonstrate diagnostic utility of serum levels of VEGF-C in determining nodal involvement and prognosis in lung, gastric, and cervical cancer. We investigated if serum VEGF-C levels would predict nodal involvement or prognosis in pancreatic cancer. Methods: Pretreatment serum VEGF-C levels were measured in 40 PA patients who were node-negative (N0 =12), node-positive (N1=14) or metastatic (M1=14) at diagnosis using ELISA. Diagnostic accuracy was compared to conventional methods. Kaplan-Meier survival analysis was done for all patients and longitudinal samples were evaluated in 15 patients who were without disease or with early or late relapse. Results: Serum VEGF-C levels were significantly higher in node positive versus node negative disease (p=0.03) or controls (p=0.03). Serum VEGF-C levels correlated with overall survival across all stages regardless of treatment (p=0.04) and there was a prognostic trend seen within stages and on longitudinal sampling. The positive predictive value for nodal involvement was higher for serum VEGF-C than conventional imaging (73% versus 60%) as was the negative predictive value (60% versus 35%). CA 19–9 levels were unrelated to nodal status or survival. Conclusions: Serum VEGF-C levels appear useful in nodal staging and prognosis in pancreatic cancer. The finding that serum VEGF-C was elevated in N1 and M1 subjects, but not in N0 subjects, is consistent with a mechanism in which VEGF-C contributes to disease progression through increased metastasis. Therapeutic agents blocking VEGF-C may have clinical benefit in pancreatic cancer. No significant financial relationships to disclose.