Higher Serum Vascular Endothelial Growth Factor Levels Research Articles

Rituximab, Bevacizumab (Avastin) and CHOP (RA-CHOP) for Patients with Diffuse Large B-Cell Lymphoma (DLBCL).

IntroductionBevacizumab is a humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF). Non-Hodgkin's lymphoma (NHL) patients with a high serum VEGF levels have an inferior overall survival compared to patients with low VEGF levels. Rituximab plus CHOP (R-CHOP) prolongs time to treatment failure and survival in patients with DLBCL. But further improvement is needed, particularly with patients with high-intermediate and high risk international index disease. This study was designed to assess the feasibility of the combination of bevacizumab plus R-CHOP (RA-CHOP).MethodBevacizumab was administered at 15 mg/kg IV on day 1 of each cycle over 30–90 minutes. R-CHOP was administered on day 2 of cycle 1 and on day 1 of subsequent cycles. Patients were monitored for cardiac function with echocardiogram and for proteinuria. Serum levels of bevacizumab and rituximab were measured to assess pharmacokinetics. Serum and urine samples were also analyzed for circulating VEGF. Tumor samples were stained for VEGF by immunohistochemistry.ResultsTwelve patients (10 males, and 2 females) with newly-diagnosed DLBCL were enrolled. The median age was 48 years (range 29–63). Three patients had stage II primary mediastinal, 2 stage III, and 7 stage IV disease. ECOG performance status ranged from 0–1. Nine patients had an elevated LDH with a median international index score of 2 (range 0–3). Nine patients had an international index score of 2–3. A total of 80 cycles (range 2–8; median 7) of RA-CHOP was administered. Bevacizumab was held in 5 cycles in 3 patients-due to 1) elevated liver enzymes in the setting of positive hepatitis C serology, 2) transient proteinuria, and 3) DVT associated with central line. The following grade 3 toxicities were observed: 4 febrile neutropenia with infection related to central line, 2 DVT (both central line associated), 1 elevated liver enzymes, and 2 transient hypertension. Grade 4 toxicities included 3 absolute neutropenia with 2 febrile neutropenia, and 1 HSV esophagitis. Two patients are too early to assess response. Best response included CR in 3, PR in 4 (2 with normal PET scans), SD in 1. One patient progressed and another achieved a PR after 4 cycles but further treatment was not given due to severe depression.ConclusionIn this patient population, treatment with RA-CHOP did not result in any grade 3 or 4 proteinuria, heart failure or bleeding. Hypertension was transient and thrombosis was associated with central line placement. Correlative studies and pharmacokinetics are being analyzed and will be available for presentation.

High serum levels of vascular endothelial growth factor predict poor response to transarterial chemoembolization in hepatocellular carcinoma: A prospective study

Vascular endothelial growth factor (VEGF) is an important mediator of tumor angiogenesis. A high serum VEGF level has been shown to predict poor response to chemotherapy and poor survival in several cancers, but its prognostic value in hepatocellular carcinoma (HCC) remains unknown. We conducted a prospective study to evaluate the prognostic significance of pretreatment serum VEGF levels on tumor response to treatment and survival of patients with HCC undergoing transarterial chemoembolization (TACE). Pretreatment serum VEGF levels were measured by an enzyme-linked immunosorbent assay in 80 patients with inoperable HCC undergoing TACE. Serum VEGF levels were correlated with clinical data, tumor response to TACE and survival results. The median serum VEGF level was 240 pg/ml (range 9-1730). Serum VEGF levels were positively correlated with the presence of venous tumor thrombus (P=0.011). Pretreatment serum VEGF levels were significantly higher in patients with progressive disease (median 434 pg/ml) than those with stable (median 176 pg/ml, P=0.010) or responsive disease (median 142 pg/ml, P<0.001) after TACE. Patients with serum VEGF >240 pg/ml had significantly worse survival than those with serum VEGF <240 pg/ml (median survival 6.8 vs. 19.2 months, P=0.007). In a Cox multivariate analysis, serum VEGF >240 pg/ml was an independent prognostic factor of survival. In conclusion, the results of this study suggest that serum VEGF level may be useful as a novel prognostic predictor of tumor response and survival of patients with inoperable HCC undergoing TACE treatment.

Poems syndrome: role of two angiogenic factors, VEGF and EPO.

POEMS syndrome is a rare disorder characterized by the combination of polyneuropathy, organomegaly, endocrinopathy, M‐protein and skin changes. The pathogenesis of this multisystemic disease is not known. Recently, an association with high levels of serum VEGF (vascular endothelial growth factor), a multifunctional cytokine that induces angiogenesis and microvascular hyperpermeability, has been reported. Both VEGF and erythropoietin (EPO), an acidic glycoprotein hormone that also promotes endothelial proliferation, are under the control of a transcription factor called hypoxia‐inducible factor (HIF). To determine whether these angiogenic factors may have a pathogenic role in POEMS, we longitudinally evaluated VEGF and EPO serum concentrations by ELISA in ten patients during the clinical course and in relation to the therapy response. All patients had initially high levels of VEGF and low EPO concentration and there was an inverse correlation between VEGF and EPO levels during the disease progression. We have also analyzed sural nerve biopsies of seven POEMS patients. The presence of VEGF/VEGF‐R and EPO/EPO‐R immunostaining in the endoneurial and perineurial vessels has been shown, as well as in some of the non‐myelin forming Schwann cells identified as glial fibrillary acidic protein (GFAP) positive cells.

Evaluation of the impact of laparoscopic ovarian drilling on Doppler indices of ovarian stromal blood flow, serum vascular endothelial growth factor, and insulin-like growth factor-1 in women with polycystic ovary syndrome

Objective To study the serum levels and correlation of vascular endothelial growth factor (VEGF), insulin-like growth factor 1 (IGF-1), hormonal profile, and Doppler blood flow changes within the ovarian stroma before and after laparoscopic ovarian drilling (LOD) in women with clomiphene-resistant polycystic ovary syndrome (PCOS). Design Prospective controlled study. Setting University teaching hospital. Patient(s) Twenty-five women with clomiphene-resistant PCOS (group 1) and 20 women with regular menstrual cycles as a comparison group (group 2). Intervention(s) Laparoscopic ovarian drilling. Main outcome measure(s) Serum levels of VEGF, IGF-1, and Doppler indices of ovarian stromal blood flow. Result(s) The serum levels of VEGF, IGF-1, T, and LH were significantly higher in group 1 before LOD than in group 2. The Doppler indices (pulsatility index and resistance index) of ovarian stromal blood flow were also significantly lower in group 1 before LOD than in group 2. The serum levels of VEGF, T, and LH were significantly reduced in group 1 after LOD compared with in group 1 before LOD. Doppler indices (pulsatility index and resistance index) of ovarian stromal blood flow were significantly increased after LOD. The VEGF levels before LOD were positively correlated with IGF-1, LH, and T. After LOD, the VEGF levels were positively correlated with LH and T. Conclusion(s) Higher serum levels of VEGF and IGF-1 may explain the increased vascularity that was demonstrated by Doppler blood flow measurements in PCOS. Laparoscopic ovarian drilling reduced serum VEGF, IGF-1, T, and LH and reduced ovarian blood flow velocities, which may explain the reduction of ovarian hyperstimulation syndrome in women with PCOS after LOD.

Simultaneous elevation of the serum concentrations of vascular endothelial growth factor and interleukin-6 as independent predictors of prognosis in aggressive non-Hodgkin's lymphoma.

Therapeutic approaches for non-Hodgkin's lymphoma (NHL) are currently based on the International Prognostic Index (IPI). Research on biological prognostic factors has been actively pursued in recent years, with serum vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) being identified as prognostic factors for NHL. Here, we determined that serum VEGF and IL-6 levels are independent prognostic factors for aggressive lymphoma. Compared with normal controls, serum VEGF and IL-6 levels were significantly higher in patients with aggressive lymphoma or adult T-cell leukemia/lymphoma. Furthermore, overall and disease-free survival rates for patients with high levels of VEGF or IL-6 were significantly poorer than for patients with low levels. In addition, the prognosis for patients with high levels of both serum VEGF and IL-6 was significantly poorer than that for patients with high levels of either VEGF or IL-6 or with low levels of both VEGF and IL-6. Multivariate analyses of a variety of prognostic factors, including the five IPI factors, revealed that serum VEGF and IL-6 were both independent prognostic factors for overall survival of aggressive lymphoma. Therefore, a combination of VEGF and IL-6 represents a useful prognostic factor for aggressive lymphoma.

Serum vascular endothelial growth factor predicts venous invasion in hepatocellular carcinoma: a prospective study.

To evaluate the correlation between serum vascular endothelial growth factor (VEGF) level and the clinicopathologic features in patients with hepatocellular carcinoma (HCC). VEGF is an important angiogenic factor regulating tumor angiogenesis. A high serum VEGF level has been shown to be associated with tumor progression and metastasis in several human cancers, but its significance in HCC is unclear. The correlation between serum VEGF level and tumor pathologic features in patients with HCC has not been studied before. Preoperative serum samples and tumor specimens were prospectively collected in 100 patients undergoing resection of HCC. Serum VEGF level was measured by enzyme-linked immunosorbent assay, and tumor VEGF expression was assessed by immunohistochemical study. Histopathologic examination was performed by a pathologist without prior knowledge of the serum VEGF level or tumor VEGF expression. Preoperative serum VEGF levels ranged from 15 to 1,789 pg/mL (median 269). When serum VEGF levels were compared between groups categorized by different clinicopathologic variables, significant correlation was found between a high serum VEGF level and absence of tumor capsule, presence of intrahepatic metastasis, presence of microscopic venous invasion, and advanced stage. There was a positive correlation between the serum VEGF level and tumor expression of VEGF as well as platelet count. When the 75th percentile serum VEGF level (500 pg/mL) was used as a cutoff level, the frequency of venous invasion in patients with a high serum VEGF level was significantly greater compared with patients with a low serum VEGF level. By multivariate analysis, a serum VEGF level of more than 500 pg/mL and tumor size more than 5 cm were independent preoperative factors predictive of microscopic venous invasion. During a median follow-up of 11.6 months, 48% of patients with a serum VEGF level of more than 500 pg/mL and 27% of those with a serum VEGF level of 500 pg/mL or less developed postoperative recurrence. These results show that a high preoperative serum VEGF level is a predictor of microscopic venous invasion in HCC, suggesting that the serum VEGF level may be useful as a biologic marker of tumor invasiveness and a prognostic factor in HCC.

This month in J Lab Clin Med: Issue highlights for April 2000

This month in J Lab Clin Med: Issue highlights for April 2000

Levels of vascular endothelial growth factor are elevated in patients with ectopic pregnancy: is this a novel marker?

Objective: To determine serum levels of vascular endothelial growth factor (VEGF) and evaluate their capacity to serve as a marker for the diagnosis of ectopic pregnancy (EP). Design: Prospective, case-controlled study. Setting: A tertiary care center. Patient(s): Twenty women with EP, 10 women with normal intrauterine pregnancy, and 10 women with abnormal intrauterine pregnancy, all at comparable stages of gestation. Intervention(s): Serum samples were obtained from all women. Main Outcome Measure(s): All samples were analyzed for VEGF, progesterone, and β-hCG by specific methods. Result(s): Women with EP had higher serum levels of VEGF than women with normal intrauterine pregnancy and women with abnormal intrauterine pregnancy (median levels, 226.8 pg/mL, 24.4 pg/mL, and 59.4 pg/mL, respectively). With a cutoff level of 200 pg/mL, serum VEGF could distinguish intrauterine from extrauterine pregnancy with a sensitivity of 60%, specificity of 90%, and positive predictive value of 86%. Conclusion(s): The increased serum VEGF levels in women with EP may facilitate this challenging diagnosis and reduce maternal morbidity and mortality.

Serum Vascular Endothelial Growth Factor in Epithelial Ovarian Neoplasms: Correlation with Patient Survival

Objective. To investigate the relationship between serum vascular endothelial growth factor (VEGF) and clinicopathological factors and to determine whether VEGF is an independent prognostic factor of ovarian cancer patients.Methods. Fifty-six women with International Federation of Gynecology and Obstetrics stages I to IV epithelial ovarian cancer undergoing surgery were enrolled. Clinical and pathologic items were recorded. Pretreatment VEGF serum samples of the 56 women were measured by an enzyme-linked immunosorbent assay. The results were correlated to clinical data. The histopathologic items and serum VEGF influencing clinical outcome were evaluated comparatively.Results. The median VEGF serum level in ovarian cancer patients was 458.7 pg/mL. The 75% quatile was defined as the cutoff level. Elevated vascular endothelial growth factor serum levels before therapy correlated significantly with poorer disease-free survival (DFS) (log rank test, P = 0.001) and overall survival (OS) (log rank test, P < 0.001) on all of the 56 patients. Besides, significantly reduced DFS (log rank test, P = 0.001) and OR (log rank test, P = 0.006) were also observed on 40 patients with residual disease less than 2 cm. High histologic grade (RR = 2.24 for DFS; RR = 2.38 for OS) and elevated serum VEGF levels (RR = 3.34 for DFS; RR = 4.47 for OS) are the prognostic factors on the 56 ovarian carcinoma patients by multivariate analyses. The advanced surgical staging (RR = 3.28 for DFS; RR = 3.84 for OS), high histologic grade (RR = 2.55 for DFS; RR = 2.44 for OS), and elevated serum VEGF levels (RR = 5.62 for DFS; RR = 5.37 for OS) are the prognostic factors for 40 ovarian carcinoma patients with residual disease less than 2 cm by multivariate analyses.Conclusions. Pretreatment VEGF serum levels might be regarded as an additional factor in predicting the outcome of ovarian cancer patients. It also could provide prognostic information in clinically relevant subsets, such as those of residual disease less than 2 cm. Anti-angiogenic therapy, if is available, might be a new treatment modality for ovarian cancer patients with poor prognosis predicted by VEGF and other clinical parameters.

Circulating vascular endothelial growth factor in patients with colorectal cancer.

The expression of vascular endothelial growth factor (VEGF), a glycoprotein that selectively promotes proliferation of endothelial cells, has been associated with cancer development. The aim of the present study was to determine whether serum levels of VEGF correlate with disease progression in patients with colorectal cancer. VEGF levels were measured by a highly sensitive enzyme-linked immunosorbent assay in sera from 67 patients with colorectal cancer, 14 patients with colorectal adenomas, and 72 healthy volunteers, and in tissue homogenates from 10 patients with colorectal cancer. Serum VEGF levels were significantly higher in patients with colorectal cancer than in patients with colorectal adenomas or in normal controls (p < 0.01). In patients with colorectal cancer, serum VEGF levels were significantly associated with Dukes stage (p < 0.01) and with carcinoembryonic antigen levels (r = 0.725, p < 0.001). Patients with hepatic and/or lymph node metastasis had higher serum VEGF levels than those without. Surgical resection of the colorectal tumor led to a decrease in serum VEGF levels whether or not metastasis was present (p < 0.05). The tumor-bearing tissue contained significantly more VEGF than normal-appearing mucosa (p < 0.05). VEGF is involved in the development of colorectal cancer. Measurement of VEGF in the serum may be a useful noninvasive clinical marker for evaluating the disease status.

Evaluation of tissue and serum VEGF in patients with head and neck carcinoma.

Serum vascular endothelial growth factor (VEGF) was measured in 54 cancer patients with head and neck carcinoma. In addition, tumor VEGF was examined by immunohistochemistry in sections of biopsies obtained within 4 weeks to serum sampling in 37 of these patients. Serum VEGF levels were higher in the sera of the tumor patients than in the sera of healthy control subjects (P < 0.005). Patients with stage II-IV tumors showed increased levels of serum VEGF, whereas patients with stage I tumors did not. The receiver operating characteristics (ROC) of serum VEGF were similar to those observed with TPS (tissue protein specific antigen). Immunohistochemistry of tissue sections showed that 24/37 tumors were VEGF positive. No connection was observed between strong VEGF staining of tumor tissue sections and high levels of serum VEGF. We conclude that serum VEGF could be a useful marker for monitoring head and neck carcinoma patients, but that serum and tissue VEGF levels do not appear to correlate with each other.

Increased Serum Levels of Vascular Endothelial Growth Factor in Patients with Inflammatory Bowel Disease

Background: Vascular endothelial growth factor (VEGF) is a potent angiogenic, vascular permeability-enhancing, and calcium-dependent enzyme-modulating cytokine with overexpression in various pathologic disorders, including granulomatous inflammation, tissue repair, delayed hypersensitivity reactions, rheumatoid arthritis, and tissue ischemia. The present study investigates the role of VEGF in chronic inflammatory bowel disease. Methods: Thirty-one patients with Crohn's disease, 15 patients with ulcerative colitis, and 9 healthy volunteers were studied. VEGF serum levels were measured with a solid-phase enzyme-linked immunosorbent assay. Results: Significantly increased VEGF serum levels were observed in both active Crohn's disease and active ulcerative colitis when compared with healthy controls. Patients with active Crohn's disease and active ulcerative colitis showed significantly higher VEGF serum levels than patients with quiescent disease. No difference was observed between inactive disease and healthy controls. In addition, strongly increased VEGF serum levels were found in patients with Crohn's disease with fistulas in the absence of clinical, endoscopic, histologic, and laboratory findings of disease activity. Conclusions: Significantly increased VEGF serum levels were observed in patients with active Crohn's disease and ulcerative colitis, which suggests that VEGF has an important role in chronic inflammatory bowel disease. Its possible association with fistulas has yet to be determined.

ELEVATED SERUM VASCULAR ENDOTHELIAL GROWTH FACTOR IN CHILDREN WITH CROHN'S DISEASE

INTRODUCTION: Vascular endothelial growth factor (VEGF) is a cytokine produced by macrophages which targets endothelial cells, resulting in increased vascular permeability and angiogenesis. We hypothesized that VEGF would be released in increased amounts by gut tissues of patients with inflammatory bowel disease (IBD). Therefore, we suspected children with active Crohn's disease (CD) or ulcerative colitis (UC) would have elevated levels of VEGF in serum. METHODS: Sera were obtained from 80 children with CD, 50 children with UC, and 36 children without IBD. For children with IBD, clinical and laboratory data were gathered prospectively at the time of blood sampling. Disease activity for children with CD was assessed by the Pediatric Crohn's Disease Activity Index, and for children with UC by the clinical score of Kozarek. Serum VEGF levels were measured by ELISA. Statistical analysis was performed by analysis of variance followed by post-hoc Student's t tests. RESULTS: Mean VEGF was significantly elevated (p<0.005) in patients with CD (449±34.7 pg/ml) compared to UC patients (299±38.9 pg/ml) and controls (247±45.1 pg/ml). Children with moderate/severe CD (PCDAI > 30) had higher serum levels of VEGF than either children with inactive CD or controls. Table CONCLUSION: Serum VEGF is increased in children with Crohn's disease, especially those with active disease. This suggests that activated macrophages of CD patients manufacture this cytokine, and that VEFG might mediate new blood vessel formation and wound healing seen in Crohn's disease.

Vascular endothelial growth factor levels in serum and follicular fluid of patients undergoing in vitro fertilization

Objective: To define the relationship between serum and follicular fluid (FF) levels of vascular endothelial growth factor (VEGF), E 2, and P in patients undergoing IVF; to quantify the effects of hCG on serum levels of VEGF during early pregnancy; and to report serial measurements of serum and ascites fluid levels of VEGF in a patient with severe ovarian hyperstimulation syndrome (OHSS). Design: Prospective observational study. Setting: University IVF program. Patient(s): Women undergoing conventional IVF, receiving donated oocytes or spontaneously conceiving. One patient hospitalized with severe OHSS. Main Outcome Measure(s): Concentrations of VEGF, E 2, and P in serum, FF, or peritoneal fluid. Result(s): At the time of egg retrieval, FF VEGF concentrations were positively correlated with serum and FF P concentrations and with patient age. At 11 to 14 days after ET, pregnant recipients of autologous fresh embryos had higher serum VEGF levels than both nonpregnant recipients of autologous fresh embryos and pregnant recipients of donor eggs. Elevated serum VEGF levels in a patient with severe OHSS coincided with the clinical onset and recurrence of symptoms. Conclusion(s): In patients undergoing IVF, FF VEGF levels at the time of egg retrieval correlated with the degree of follicular luteinization. There is a significant ovarian contribution to circulating VEGF levels during early gestation. Elevated serum VEGF levels may be a factor in the etiology of OHSS symptoms.