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Purpose: To investigate serum levels of VEGF, IGF-1 and FGF-2, and relationships with several clinical characteristics in children and adolescents with autism spectrum disorder (ASD) with and without bipolar disorder (BD)., Method: 40 subjects with ASD + BD as study group, and 40 subjects with ASD as control group were included. Serum levels of VEGF, IGF-1, and FGF-2 were measured using commercial enzyme-linked immunosorbent assay kits., Results: The study group was significantly higher than the control group in terms of ASD severity, self-harming behavior and sleep disturbance. Serum VEGF and FGF-2 levels were significantly higher in the ASD + BD group than in the control group. There was no significant difference in serum IGF-1 levels between the two groups. There was no correlation between VEGF, IGF-1 and FGF-2 serum levels and ASD severity in the study group. However there was a negative correlation between VEGF levels and age at first diagnosis of BD, and a positive correlation between IGF-1 levels and the number of bipolar episodes in the study group., Conclusion: Growth factors like VEGF and FGF-2 may be potential biomarkers of bipolar disorder in young subjects with ASD. Given the difficulty of clinical management of BD in young subjects with ASD, potential biomarkers would help clinicians in the diagnosis and follow up of BD in this special population. Further research is needed whether VEGF and FGF-2 can be potential biomarkers in the clinical management of young subjects with ASD and BD., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Certain mediators, such as soluble growth factors and cytokines, among others, are implicated in the immunopathogenesis of systemic sclerosis (SSc)., Objectives: This study aimed to examine the association between serum levels of vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), interferon alpha (IFN-α), and basic fibroblast growth factor (bFGF) and the clinical presentation and course of SSc., Material and Methods: This longitudinal, observational study included 43 patients with SSc and 24 healthy subjects. Serum concentrations of VEGF, IL-8, IFN-α, and bFGF were measured at baseline in patients previously treated for SSc. Medical history of patients was analyzed retrospectively at the time of cytokine measurement to infer clinical correlations, and during follow-up for a median of 5 years, assessing the incidence of death or cancer., Results: The bFGF and IFN-α concentrations differed between SSc patients and controls (p < 0.01). In turn, organ involvement and SSc phenotypes did not impact studied cytokine concentrations, similar to systemic steroid and/or immunosuppressant use at enrollment. However, we have documented a positive correlation between the current oral steroid dose and serum levels of IL-8 and bFGF. Furthermore, patients with a VEGF level ≥95.7 pg/mL and IFN-α level ≥3.6 pg/mL required cyclophosphamide therapy more often, currently or in the past (approx. 3-fold and 4-fold, respectively). Substantially elevated VEGF and IFN-α concentrations at baseline were associated with higher cancer occurrence (n = 4) during follow-up, while elevated circulating IL-8 level was associated with an increased risk of death (n = 9)., Conclusions: The SSc group was characterized by higher serum concentrations of bFGF and IFN-α compared to healthy controls. Patients treated with cyclophosphamide or receiving higher systemic steroid doses, thus suffering from a more severe disease type, had increased cytokine levels. Elevated circulating IFN-α and VEGF levels might be correlated with cancer, whereas raised IL-8 levels may be associated with an increased risk of death. However, further research is needed to verify our findings.

Background: Sarcoidosis is a systemic inflammatory granulomatous disease, frequently affecting the lung. If left untreated, it may end in lung fibrosis. Proangiogenic and profibrotic vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β1, fibroblast growth factor (FGF)-2 and platelet-derived growth factor (PDGF)-AB are a known therapeutical target in pulmonary fibrosing diseases, e.g. IPF, but there is no targeted therapy option for pulmonary fibrosis in sarcoidosis., Objectives: The aim of our study was to determine the association of these markers' serum levels on lung function and the patients' quality of life in a long-term follow-up of sarcoidosis patients, to provide further information for finding targeted therapy options for pulmonary sarcoidosis., Methods: 54 patients with sarcoidosis underwent blood sampling, pulmonary function testing and answered the King's Brief Interstitial Lung Disease (K-BILD) questionnaire at baseline and at three-years follow-up. Serum levels of profibrotic and angiogenic markers were assessed at baseline by enzyme-linked immunosorbent assay., Results: Between 2015 and 2018, 54 patients with biopsy proven sarcoidosis were enrolled. Throughout the observation period, there was a significant decrease in the diffusion capacity for carbon monoxide (DLCO) [%] (-6.5504 ± 13,39, p = 0.001) and forced expiratory volume in one second predicted (FEV1) [%] (-6.07 ± 12.09, p = 0.001). Patients with greater impairment of forced vital capacity (FVC) did have significantly higher serum levels of VEGF (p = 0.03) and PDGF-AB (p<0.001). The K-BILD questionnaire did not change significantly during follow-up. However, patients with worsening K-BILD scores did have significantly higher serum-levels of PDGF-AB (2.67 pg/ml ± 0.93 vs. 1.88 pg/ml ± 0.60, p = 0.004) at baseline, compared to those with unchanged or increasing K-BILD scores., Conclusions: Among patients with pulmonary sarcoidosis, baseline serum levels of VEGF and PDGF-AB were associated with pulmonary function impairment. Furthermore, PDGF-AB was associated with worsening K-BILD scores. No such association was observed for FGF-2 and TGF-ß1. VEGF and PDGF-AB may be possible prognostic and therapeutic targets in sarcoidosis as a fibrosing ILD beyond IPF., Competing Interests: The authors have declared that no competing interests exist.

Background: Oral propranolol has become first-line treatment for infantile hemangiomas (IHs). This study focused on identifying cytokines related to the biology of IH and early regression indicators of IH after propranolol treatment., Methods: For inclusion, the patients had to be aged less than 1 year and have an IH with a largest diameter ≥2 cm. Patients were scheduled to receive 1 year of propranolol treatment. Serum cytokines involved in angiogenesis, vasculogenesis, and/or chronic inflammation were analyzed at 0, 1, and/or 12 months after treatment using Multiplex Luminex assays., Results: Among the 49 evaluable patients, 33 completed the 1-year treatment: 16 showed excellent response and 12 had good response to propranolol. Significant decreases in serum MMP-2, bFGF, VEGF-α, and MCP-1 levels were observed after 1 year of treatment compared to pretreatment values. The maximal diameters of the lesions significantly correlated with pretreatment serum VEGF-α, bFGF, and MMP-9. Patients with higher bFGF and VEGF levels showed better response to propranolol at 1 year., Conclusion: MMP-2, VEGF-α, bFGF, and MCP-1 may involve in the biology of IH and their downregulation may be associated with involution processes of IH. Pretreatment bFGF and VEGF could be novel biomarkers for predicting response to propranolol., Impact: We found that decreases in the concentrations of MMP-2, bFGF, VEGF, and MCP-1 were associated with regression of the hemangioma, which indicates that one of the mechanisms of propranolol in the treatment of proliferative hemangiomas may involve downregulation of those cytokines. Patients with higher bFGF and VEGF levels showed better response to propranolol at 1 year. Importantly, serum bFGF higher than 37.07 pg/mL may predict an excellent response to propranolol. Therefore, along with the patient's age and the size and visual characteristics of the lesion, bFGF levels could help determine the viability of propranolol use in the treatment of IHs. Our study represented extensive serum profiling in IH, reporting the indicators and molecules clearly related to IH regression with propranolol treatment. The authors believe that monitoring serum cytokines, including MMP-2, bFGF, VEGF, and MCP-1, in IH patients could be important, in addition to clinical follow-up, for determining when to start and end propranolol treatment.

Background and aim: Recent evidence suggests that growth factors might be involved in the pathophysiology of attention deficit hyperactivity disorder (ADHD). The aim of this study was to determine whether serum levels of brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3), nerve growth factor (NGF), fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor (VEGF) were altered in children with ADHD. Methods: Serum levels of BDNF, GDNF, NT-3, NGF, VEGF and FGF-2 were analyzed in 49 treatment- naive children with ADHD and age, gender matched 36 healthy controls using enzyme-linked immunosorbent assay. ADHD symptoms were scored by Du Paul ADHD Rating Scale and Strengths and Difficulties Questionnaire. Results: We found that serum VEGF levels were significantly lower ( p  < 0.001) and GDNF levels were significantly higher in ADHD group compared to control group ( p  = 0.003). However, we found no correlations between ADHD symptoms and serum VEGF or GDNF levels. Furthermore, we observed no significant alterations in serum BDNF, NT-3, NGF, FGF-2 levels in children with ADHD. Conclusion: To our knowledge, the present study is the first to examine serum VEGF and FGF-2 levels in children with ADHD. Our results indicate that VEGF and GDNF might be involved in the etiology of ADHD. Further studies are required to determine the role of growth factors in the etiology and consequently in the treatment of ADHD.

Background: Several new drugs are approved for treatment of patients with multiple myeloma (MM), but no validated biomarkers are available for the prediction of a clinical outcome. We aimed to establish whether pretreatment blood and bone marrow plasma concentrations of major cytokines and angiogenic factors (CAFs) of patients from a phase 3 trial of a MM treatment could have a prognostic and predictive value in terms of response to therapy and progression-free and overall survival and whether these patients could be stratified for their prognosis., Methods: Blood and bone marrow plasma levels of Ang-2, FGF-2, HGF, VEGF, PDGF-β, IL-8, TNF-α, TIMP-1, and TIMP-2 were determined at diagnosis in MM patients enrolled in the GIMEMA MM0305 randomized controlled trial by an enzyme-linked immunosorbent assay (ELISA). These levels were correlated both reciprocally and with the type of therapy and patients' characteristics and with a group of non-MM patients as controls., Results: No significant differences were detected between the blood and bone marrow plasma levels of angiogenic cytokines. A cutoff for each CAF was established. The therapeutic response of patients with blood plasma levels of CAFs lower than the cutoff was better than the response of those with higher levels in terms of percentage of responding patients and quality of response., Conclusion: FGF-2, HGF, VEGF, and PDGF-β plasma levels at diagnosis have predictive significance for response to treatment. The stratification of patients based on the levels of CAFs at diagnosis and their variations after therapy is useful to characterize different risk groups concerning outcome and response to therapy., Trial Registration: Clinical trial information can be found at the following link: NCT01063179.

Background: Propranolol has become the treatment of choice for infantile hemangiomas (IH). Neither the pathogenesis of IH nor the mechanism of action of propranolol on them are well understood. Possible explanations include the inhibition of angiogenesis by decreasing vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), induction of vascular endothelial cell apoptosis and vasoconstriction., Objectives: The aim of the study was to assess serum concentrations of VEGF and bFGF in the course of propranolol therapy of IH in children, and to assess their clinical implications., Material and Methods: The study included 51 children with IH treated with propranolol. The participants were assessed before, during and after the therapy with Hemangioma Activity Score (HAS), Doppler ultrasound (US) of the lesions, as well as VEGF and bFGF serum concentrations., Results: All children showed clinical improvement measured in the HAS. A complete involution of the IH was reported in 32 (63%) children at the time of decision of the gradual withdrawing of propranolol, and in 28 (61%) patients at the end of the treatment (out of 46 patients present at the follow up after 1.5 months). Doppler US at the follow-up showed a complete disappearance of the blood flow in the lesion in 24 (52%) children and its reduction in 12 (26%) children. There was a significant decrease in VEGF and bFGF during and after treatment compared to pretreatment values. There was a correlation between the outcome of the Doppler US and changes in bFGF during and after treatment. Changes in VEGF during treatment did not correlate with changes in the Doppler US., Conclusions: Serum concentrations of VEGF and bFGF decreased during the propranolol treatment of IH, which may indicate the effect of propranolol on both. However, the statistical analysis showed their low prognostic value as biochemical markers of propranolol treatment. Clinical evaluation combined with Doppler US is the most valuable method of monitoring the therapy.

Few preliminary reports studied the utility of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) for differentiation between infantile hemangiomas (IHs) and vascular malformations. The aim of this study was to investigate the role of serum VEGF and bFGF levels in differentiating IHs from vascular malformations and identifying the stage and clinical course of IHs. Serum levels of VEGF and bFGF were assessed in 60 infants and children with various cutaneous vascular anomalies defined in 3 groups: proliferating IHs (n = 25), involuting IHs (n = 23), and vascular malformations (n = 12), in comparison with their levels in 40 healthy matched control. Serum levels of VEGF and bFGF were significantly elevated in all groups as compared to control ( P < .001, respectively). Both proliferating and involuting IHs had comparable levels of both markers ( P > .05, respectively) that were significantly higher in comparison with vascular malformations ( P < .05, respectively). Significantly lower VEGF levels were found in IHs that had regressed spontaneously (n = 11) compared to those regressed by treatment (n = 37), ( P < .05); meanwhile, bFGF showed no significant difference between both groups ( P > .05). Using receiver operating characteristic curves, a combined use of VGEF and bFGF yielded a sensitivity of 85.42% and a specificity of 100% for differentiating IHs from vascular malformations. Serum VEGF and/or bFGF levels are increased in cutaneous vascular anomalies and can differentiate IHs from vascular malformations. None of these markers could help in identifying the stage of IHs. Low VEGF is associated with spontaneous regression of IHs.

Background: Angiogenesis is the process of new vessel formation originating from the existing vascular network. It plays an important role in the growth and spread of malignancies, including brain tumors. The process of angiogenesis is characterized by increased expression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), and by the release of their soluble forms into circulation., Objectives: The aim of the study was to evaluate serum levels of VEGF and bFGF in children with malignant and benign brain tumors., Material and Methods: The study group (group N) included 106 children diagnosed with brain tumors. The children in group N were classified according to tumor pathology into 3 subgroups: N1 (n = 63): patients with malignant tumors, excluding anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM); N2 (n = 25): patients with benign tumors; and N3 (n = 18): patients with high grade gliomas (AA and GBM). VEGF and bFGF were determined by ELISA in blood samples before the initiation of chemotherapy. VEGF and bFGF levels were compared within the subgroups in relation to tumor grading and the extent of surgery., Results: The median VEGF in patients with brain tumors was significantly higher than in the control group. The median levels of VEGF and bFGF in subgroup N1 were significantly higher than in the control group. The differences in VEGF and bFGF concentrations between the subgroups in relation to the extent of tumor resection were not significant., Conclusions: Significantly higher plasma VEGF levels in children with brain neoplasms may reflect enhanced angiogenesis in the tumors.

Aim of the Study: To investigate whether serum levels of VEGF, bFGF and endoglin correlate with tumor VEGF and bFGF expression or microvessel density (MVD) in ovarian cancer., Patients and Methods: Forty five patients with epithelial ovarian cancers (EOCs) and 38 patients with benign ovarian tumors (BOTs) were included into the study. Serum levels of VEGF, bFGF and endoglin were assessed using ELISA. The expression of VEGF and bFGF in tumor samples were evaluated using ELISA of supernatants obtained from tumor homogenization. MVD was analyzed using immunohistochemistry with antibodies against CD31, CD34 and CD105., Results: Serum VEGF levels were significantly higher in EOCs than in BOTs (436.6pg/ml [19.67-2860] vs 295.5pg/ml [123-539], P=0.025). Serum endoglin levels were lowered in the group EOCs when compared to BOTs (33,720g/ml [12,220-73,940] vs 42,390pg/ml [19,380-56,910], P=0.015). There were no differences in bFGF levels between studied groups. EOCs have significantly higher CD105 MVD (25 vessels/mm2 [0-57] vs 6 vessels/mm2 [0-70], P<0.001) and tumor VEGF (405.9pg/mg protein [0-3000] vs 2.225 [0-634.7], P<0.001) expression than BOTs, while, bFGF expression was higher in BOTs than in EOCs (2076pg/mg protein [668.1-8718] vs 847.3pg/mg protein [188.9-8333], P=0.003). In patients with EOCs we have observed negative correlation between serum VEGF concentration and its tissue expression (r Spearman=-0.571, P=0.0261), and serum VEGF concentration correlated positively with CD34-MVD (r Spearman=0.545, P=0.0289). In a multiple regression analysis we have observed only the negative correlation between serum VEGF and CD105-MVD (r=-0.5288, P=0.0427)., Conclusions: Serum VEGF is a useful marker for prediction of ovarian cancer MVD and tumor VEGF expression., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Regorafenib is an oral multi-kinase inhibitor used as salvage therapy for metastatic colorectal cancer (mCRC). We tested whether serum cytokine levels are associated with clinical outcome in the mCRC patients receiving regorafenib. Serum samples were collected before treatment start, day 21, and progressive disease, and eleven angiogenic and inflammatory cytokine serum levels were examined. Fifty-four patients of a total of 62 enrolled patients were eligible for the analyses. The chemokine ligand 5 (CCL5) levels ≤ cut-off value (59959 pg/ml) at baseline was associated with relative tumor shrinkage (P = 0.021), better progression-free survival (PFS) (P = 0.036) and overall survival (OS) (P = 0.019). Vascular endothelial growth factor A (VEGF-A) levels showing a decrease on day 21 were significantly associated with a better PFS (P = 0.021). CCL5 levels ≤ cut-off was associated with any grade hand-foot skin reaction (HFSR) (P = 0.025) and thrombocytopenia (P = 0.013). Low chemokine ligand 2 levels at baseline were associated with grade 2 ≤ HFSR. High angiopoietin-2 and basic fibroblast growth factor (bFGF) levels at baseline were associated with grade 3 ≤ total bilirubin increase and transaminases increase, respectively. Low bFGF levels at baseline were associated with grade 3 ≤ hypertension. No correlation with severe events was observed. Baseline serum CCL5 levels and decrease of the serum VEGF-A levels may serve as potential predictive markers for survival or treatment-specific toxicities in mCRC patients receiving regorafenib., Competing Interests: HS and NM received commercial research grant from Takeda Pharmaceutical Co. The authors have no conflicts of interest in this work.

Objective: To investigate the effect of topical propranolol gel on the levels of plasma vascular endothelial growth factor (VEGF), basic fibroblastic growth factor (bFGF) and matrix metalloproteinases-9 (MMP-9) in proliferating infantile hemangiomas (IHs) of superficial type., Methods: 33 consecutive children with superficial IHs were observed pre-treatment, 1 and 3 months after application of topical propranolol gel for the levels of plasma VEGF, MMP-9 and bFGF by enzyme-linked immunosorbent assay (ELISA) in Department of General Surgery of Dongfang Hospital from February 2013 to February 2014. The plasma results of IHs were compared with those of 30 healthy infants. The clinical efficacy in IHs was evaluated by Achauer system. Differences of plasma results between the healthy group and the IHs group pre-treatment were analyzed using Mann-Whitney U-test. Paired sample comparisons of any two time points of pre-treatment, 1 month and 3 months after treatment in IHs were evaluated by Wilcoxon signed-rank test., Results: The clinical efficiency of topical propranolol gel at 1, 3 months after application were 45.45%, 81.82% respectively. The levels of plasma VEGF and MMP-9 in patients pre- treatment were higher than those in healthy infants [(362.16 ± 27.29) pg/ml vs (85.63 ± 8.14) pg/ml, (1376.41 ± 42.15) pg/ml vs (687.27 ± 44.1) pg/ml, P < 0.05], but the level of bFGF did not show significant difference [(176.03 ± 13.60 ) pg/ml vs (235.94 ± 35.43 ) pg/ml, P > 0. 05 ]. The concentrations of VEGF and bFGF at 1, 3 months after treatment decreased obviously [(271.51 ± 18.59) pg/ml vs (362.16 ± 27.29 ) pg/ml, (135.85 ± 12.66) pg/ml vs (176.03 ± 13.60) pg/ml], 1 month after treatment vs pre-treatment, P < 0.05; (240.80 ± 19.89) pg/ml vs (362.16 ± 27.29) pg/ml, (107.31 ± 5.82) pg/ml vs (176.03 ± 13.60) pg/ml, 3 month after treatment vs pre-treatment, P < 0.05, whereas the levels of plasma MMP-9 declined slightly [(1321.18 ± 48.74) pg/ml vs (1376.41 ± 42.15 ) pg/ml, (1468.68 ± 32.78) pg/ml vs (1376.41 ± 42 2.15 ) pg/ml, P > 0.05 ]., Conclusions: Propranolol gel may suppress the proliferation of superficial infantile bemangiomas by reducing VEGF and bFGF.

Introduction: Data about angiogenic factors in diabetic foot syndrome (DFS) are insufficient. Therefore, in the present study we focus on circulating endothelial progenitor cells (EPCs) and two major angiogenic factors: vascular endothelial growth factor (VEGF-A) and fibroblast growth factor (FGF-2) in patients with DFS., Materials and Methods: We included 75 subjects: 45 patients with type 2 diabetes and 30 controls. The study group was divided into 2 subgroups: 23 patients with diabetic foot and 22 patients without diabetic complications. The concentration of VEGF-A, soluble VEGF receptor 2 (sVEGF-R2) and FGF-2 were measured in plasma samples. The number of circulating EPCs was determined in peripheral venous blood. The number of endothelial progenitor cells was measured with FACSCalibur flow cytometer using monoclonal antibodies directed against antigens specific for EPCs., Results: In our study we observed significant higher levels of VEGF-A and FGF-2 and lower sVEGF-R2 concentration in patients with T2DM compared to healthy subjects. The conducted analysis showed decreased levels of VEGF-A and elevated levels of FGF-2 in patients with DM complicated DFS compared to diabetic patients without DFS. Increased circulating EPCs number was reported in patients with DFS, and the difference was almost statistically significant., Conclusions: The high concentration of VEGF-A and FGF-2, and a positive correlation between them indicate their participation in the process of angiogenesis in T2DM. Decreased sVEGF-R2 may result from inactivation of VEGF-A during complexes formation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Graves' ophthalmopathy (GO) is thought to be an inflammatory disorder of autoimmune background. The aim of this study is to investigate the involvement of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b-FGF) in patients with Graves' ophthalmopathy (GO)., Methods: Serum concentrations of VEGF and b-FGF of 48 GO patients, 30 Graves' hyperthyroid disease (GD) patients without ophthalmopathy, and 30 healthy controls were measured by Enzyme-Linked Immunosorbent Assay (ELISA). Patients with GO were subdivided into two groups according to clinical activity scores (CAS): a score of 3 or less is considered as inactive (CAS ≤ 3, inactive GO, n = 14), and 4 or more is considered active eye disease (CAS ≥ 4, active GO; n = 34). All of the patients with active GO underwent corticosteroid therapy., Results: The concentrations of serum VEGF and b-FGF were significantly higher in patients with GO and in those with GD than in controls. The serum levels of VEGF and b-FGF in patients with active GO were higher than those in patients with inactive GO and those in GD patients (P < 0.05). Moreover, serum VEGF and b-FGF concentratison were significantly correlated with CAS in GO patients (p < 0.01). Mean VEGF and b-FGF levels in corticosteroid-responsive patients (CAS decreases ≥3 after treatment) decreased significantly after corticosteroid treatment (P < 0.05), and these changes were accompanied by a decrease of CAS (P < 0.05)., Conclusion: The results suggest that serum VEGF and b-FGF levels were increased in patients with active GO and could reflect the degree of ocular inflammatory activity.

Aim: The role of angiogenesis in inflammatory bowel diseases (IBD) remains controversial. We investigated the role of serum concentration levels of VEGF and bFGF in IBD patients and assessed their potential association to disease activity., Patients and Methods: Blood samples were obtained from 40 IBD patients with moderate to severe attack of the disease and 40 healthy controls. VEGF and bFGF serum levels were assessed. C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were measured as markers of disease activity and correlated to VEGF and bFGF., Results: The demographic characteristics of both patients and controls were homogenous, in regard of age, sex, smoke and concomitant diseases. VEGF serum levels were significantly higher in IBD patients compared to controls (1158.5±845.4 pg/ml vs 464.6±283.1 pg/ml, p<0.001). Serum concentration levels of bFGF did not differ between groups. Linear regression analysis showed no direct association between VEGF or bFGF and CRP or ESR., Conclusion: VEGF, but not bFGF, may have a prominent role in patients with IBD, without though direct association to disease activity., Key Words: bFGF, Inflammatory bowel disease, VEGF.

Background: Circulating factors in patients with gastric/gastroesophageal junction (GEJ) cancers may promote tumor progression and metastasis and may be targeted for therapy., Methods: Serum levels of ligands-vascular endothelial growth factor A (VEGF-A), fibroblast growth factor 2 (FGF2), epidermal growth factor (EGF), hepatocyte growth factor (HGF)-from four targetable pathways were measured before surgery, and levels were correlated to clinicopathologic characteristics and overall survival (OS)., Results: In 147 patients who underwent potentially curative resection for gastric/GEJ adenocarcinoma, VEGF-A levels were higher in patients with R1 versus R0 resection (p = 0.037). High EGF levels were associated with poorly differentiated tumors (p = 0.02). Elevated FGF2 levels were found in Lauren diffuse-type tumors (p = 0.017) and tumors with seven or more metastatic nodes (N3) (p < 0.042). Patients with advanced-staged tumors had higher HGF levels (p = 0.012). At a median follow-up of 35 months, 46 patients (31 %) had died. Increased VEGF and HGF levels were correlated with decreased OS (p = 0.009 and 0.005). An adjusted total value (ATV) of all factors was better than any single factor in stratifying patients into good and poor prognosis groups (5-year OS 84.1 vs. 53.9 %, p = 0.005). By multivariate analysis, serum VEGF-A and ATV were significant independent prognostic factors (along with T and N category) for OS (p = 0.028 and 0.013, respectively)., Conclusions: In patients undergoing resection for gastric and GEJ cancer, high levels of angiogenic and growth factors are associated with unfavorable tumor characteristics and poorer overall survival. Thus levels of these factors can help delineate tumor biology and stratify prognosis.

Background/aims: Recent experimental research revealed that statins at low doses induce angiogenesis, which in turn may be related to the course of atherosclerosis. There are no clinical studies evaluating the effect of 'low-dose' statins on serum levels of angiogenesis regulators in diabetic subjects. We aimed to explain how low doses of statins modify the serum concentrations of two potent proangiogenic factors, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), in patients with type 2 diabetes., Methods: Measurements of fasting glucose level, HbA1c, 1,5-anhydro-D-glucitol and lipid profile were taken from 47 patients with type 2 diabetes treated with low doses of atorvastatin (10 mg daily) or simvastatin (10-20 mg daily), from 45 statin-free patients with type 2 diabetes and from 23 nondiabetic subjects. Measurements of VEGF and bFGF in serum were taken using the BD™ Cytometric Bead Array., Results and Conclusion: Statins used in low doses in patients with type 2 diabetes reduce the serum concentration of VEGF and bFGF which suggests antiangiogenic potential of these doses. Nevertheless, this effect could be neutralized by postprandial hyperglycemia., (© 2014 S. Karger AG, Basel.)

Background: Several anticancer agents including paclitaxel have an inhibitory effect on angiogenesis., Aims: To compare the overall response rate and time to progression with changes in circulating angiogenic factors during palliative treatment with weekly paclitaxel., Material and Methods: Patients with metastatic BC, ECOG 0-2, received weekly paclitaxel, concomitant with trastuzumab if HER2+ BC (n = 7). Circulating vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were determined at base-line and before start of new course., Results: Fifty-five of 63 included patients were evaluable. The overall response rate including stable disease ≥24 weeks (CR + PD + SD) was obtained in 25 of the evaluable patients (45%). The median time to progression (TTP) was 5.3 months and overall survival (OS) 16.7 months. Patients with triple negative breast cancer (TNBC) showed a trend towards higher base-line VEGF compared with hormone receptor positive or HER2+ tumours and had shorter TTP. Significant differences in VEGF and bFGF levels at 12 weeks were found between patients with longer versus shorter TTP (VEGF: p = 0.046, bFGF: p = 0.005) and between patients gaining versus lacking clinical benefit (VEGF: p = 0.05, bFGF: p = 0.02)., Conclusions: The clinical utility of circulating VEGF may be a useful tool for monitoring treatment efficacy., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Mesenchymal stem cells (MSCs) are the leading cellular constituents used in regenerative medicine. MSCs repair and reconstruct wounds of acute traumata and radiation-induced burns through proliferation, differentiation, and trophic activity. However, repair effect of MSCs on severe burn wounds remain to be clarified because severe burns are much more complex traumata than radiation-induced burns. Survival and proliferation of MSCs in microenvironments affected by severe burns are very important for improving wound repair/regeneration. This study aimed to elucidate the survival and proliferation effects and the potential proliferation mechanism of serum from severe burn patients (BPS) on human umbilical cord MSCs (hUCMSCs) in vitro., Methods: The hUCMSCs were isolated, cultured, and identified. Next, we evaluated the effects of BPS on cell numbers, cell cycle progression, cyclin D expression, and key proteins and genes of the Notch signaling pathway. Putative mechanisms underlying the proliferation of hUCMSCs were investigated., Results: BPS markedly increased the number of hUCMSCs, and the results of the cell cycle studies indicated that BPS induced cell cycle progression into the M phase. Cyclin D expression was higher with BPS than in the control group. Moreover, Notch-1, a key determinant of hUCMSC activation and proliferation, and its target gene Hes-1 were overexpressed after BPS treatment. Proliferation numbers of hUCMSC, rate of proliferation period (G2/M+S), and the expression of cyclin D, Notch-1, and Hes-1 were markedly decreased by Notch signaling inhibitors (DAPT/GSI). In the case of BPS, basic fibroblast growth factor and vascular endothelial growth factor were the key factors that promoted hUCMSC proliferation., Conclusion: This study provides novel evidence for the role of BPS in the survival and rapid proliferation of hUCMSCs and suggests that these cells could be used for cell therapy-based clinical applications for treating severe burns. Furthermore, hUCMSC proliferation was induced by basic fibroblast growth factor/vascular endothelial growth factor in BPS through activation of Notch signal.

Background: Debate about the potential effects that surgery might have on cancer cells dormancy and angiogenesis prompted us to investigate the impact of breast surgery on circulating angiogenesis modulating gene transcripts and proteins., Methods: Blood samples from 10 female patients diagnosed with breast cancer and 6 with fibroadenoma were collected before surgery and post-operatively on days 3 and 7 (breast cancer patients only). A set of 84 angiogenesis-associated transcripts were assessed using quantitative PCR arrays, and circulating protein levels (vascular endothelial growth factor A (VEGFA), IL8 and fibroblast growth factor 2 (FGF2) were measured using ELISA in the same samples. The results were investigated against clinicopathological data and patient outcome., Results: Plasma levels of VEGFA and IL8 after surgery were significantly elevated in the breast cancer group compared to the control group (P = 0.038 and P = 0.021, respectively). In the cohort of breast cancer patients, VEGFA increased on day 3 (P = 0.038) and declined on day 7 (P= 0.017), while IL8 did not change on day 3 but showed a significant decline on day 7 (P = 0.02). FGF2 levels did not change significantly over time. Regarding gene transcripts, we detected upregulation of a significant number of angiogenesis-specific genes in patients with breast cancer versus controls: sphingosine kinase 1(SPHK1), epidermal growth factor (EGF), vascular endothelial growth factor C (VEGFC), neuropilin 1 (NRP1), fibroblast growth factor (FGF1), laminin alpha 5 (LAMA5), collagen type IV alpha 3 (COL4A3), IL8, ephrin B2 (EFNB2), ephrin A3 (EFNA3), tyrosine endothelial kinase (TEK), integrin beta 3 (ITGB3), AKT1, thrombospondin 1 (THBS1), chemokine (C-C motif) ligand 11 (CCL11) and TIMP metallopeptidase inhibitor 3 (TIMP3). Surgery induced an altered expression in several keygenes in breast cancer patients. We identified an upregulation of COL4A3 and downregulation of chemokine (C-X-C motif) ligand 9 (CXCL9), EGF, FGF1, Kinase insert domain receptor (KDR), Placental growth factor (PGF), TIMP3 and VEGFC., Conclusion: Breast cancer patients have a different expression profile of circulating angiogenesis biomarkers compared to patients with fibroadenoma. Moreover, mastectomy promotes a transient increase of VEGFA and a shift in the expression patterns of a broad panel of angiogenesis-related circulating gene transcripts.

Objectives: The aim of this study was to investigate the possible role of angiogenin, vascular endothelial growth factor, (VEGF) and basic fibroblast growth factor (bFGF) in the pathogenesis of BD., Design and Methods: Sixty-five patients with BD and 21 healthy control subjects were included in the study, and serum angiogenin, bFGF, and VEGF concentrations were measured by using in-vitro enzyme immunoassay (ELISA) kits according to the manufacturer's instructions., Results: The median serum angiogenin level was significantly higher in patients with BD (391.8; range:151.6-594.8 pg/ml) than controls (298.8; range:241.9-449.6 pg/ml) (p = 0.001). The levels were similar in both ocular and non-ocular BD patients (p = 0.537). The mean serum bFGF level was higher in patients with BD (38.8 ± 12.3 pg/ml) than controls (33.2 ± 11.3 pg/ml); the median serum VEGF level was also higher in BD patients (239.7; range:53-991.3 pg/ml) than controls (189.4; range:53.6-357.9 pg/ml). But these differences were not statistically significant. Serum bFGF and VEGF levels were also not different statistically in ocular and non-ocular Behçet's patients. There was no statistically significant relationship between serum angiogenin, bFGF, and VEGF levels and the presence of active eye disease or anatomic location of uveitis. While there was a correlation of borderline significance in angiogenin levels between the patients with anterior uveitis and panuveitis (p = 0.053), we did not obtain any correlation between serum angiogenin, bFGF, and VEGF levels and the duration of BD., Conclusions: This study suggests that angiogenin may be associated with pathophysiology of BD, and highlights the need of further investigation of the role of angiogenin, bFGF, and VEGF serum levels in BD susceptibility and its clinical manifestations.

Objective: In this study, we examined the frequency of serum elevation as well as the prognostic significance of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in endometrial cancer (EC) type I and a biologically aggressive variant of EC type II., Materials and Methods: Pretreatment serum levels of bFGF and VEGF were evaluated by commercially available enzyme-linked immunosorbent assay (ELISA) for cancer patient samples with type I EC (n=70) and type II EC (n=64) and compared to a cohort of normal individuals (n=64). Values were correlated with clinicopathological characteristics and outcome., Results: Median pretreatment VEGF values were 470.4pg/ml (range, 164.3-598.4pg/ml) for type I EC, 608.8pg/ml (range, 354.2-783.6pg/ml) for type II of EC patients and 215.6pg/ml (range, 128.3-332.9pg/ml) for normal healthy subjects (p<0.001). Elevated serum VEGF concentration correlated significantly with advanced FIGO stage in type II EC (p=0.011). Median values of bFGF were 10.7pg/ml (range, 0.5-22.5pg/ml) for type I EC, 21.2 (range, 0.5-62.4pg/ml) for type II EC and 1.1 (range, 0-7.2pg/ml) in controls (p<0.0001). The pretreatment bFGF levels correlated with advancing tumor stages in types I and II EC (p <0.05). Multivariate analysis with Cox proportional hazard regression models revealed that high bFGF serum level correlated with shorter overall survival (OS) in type I EC (HR, 0.39, p<0.001) and in type II EC (HR, 0.47, p=0.01) and disease-free survival (DFS) (HR, 0.53, p=0.03 and HR, 0.51, p=0.02, respectively)., Conclusion: High preoperative bFGF levels predict a poor prognosis in patients with EC, and the prognostic value is independent of established prognostic parameters. These data suggest that bFGF might potentially serve as a marker in prognosis and offer a possibility to individualize treatment regimen., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Introduction: Angiogenesis is involved in the pathogenesis of arthritis., Objectives: The aim of the study was to assess the serum levels of selected angiogenic cytokines and their association with clinical presentation in patients with psoriatic arthritis (PsA) and SAPHO syndrome., Patients and Methods: We studied 98 patients: 80 with PsA and 18 with SAPHO syndrome. The following data were recorded: age, sex, disease duration, joint involvement, type of psoriasis, nail involvement, and treatment. The following indices used to assess the activity of PsA and SAPHO were measured: PASI, BASDAI, BASFI, BASMI, BASG, and VAS pain. We determined erythrocyte sedimentation rate, C‑reactive protein (CRP), and platelet count. The serum levels of vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), basic and acidic fibroblast growth factors (FGFb and FGFa) were determined using an enzyme‑linked immunosorbent assay., Results: In patients with PsA, VEGF levels were positively correlated with CRP (P = 0.04), BASFI (P = 0.03), and disease duration (P = 0.007). No differences were found between patients with and without nail psoriasis in the VEGF or EGF levels (P = 0.32 and P = 0.85, respectively). There were no differences between patients with the peripheral and axial forms of arthritis in VEGF or EGF levels (P = 0.56 and P = 0.28, respectively). No significant correlations were observed between EGF and FGF levels and clinical presentation in patients with PsA. In patients with SAPHO, no significant correlations were found between angiogenic cytokine levels and clinical presentation., Conclusions: Our data suggest a role of VEGF in the pathogenesis of PsA. Further studies are required to better understand the role of angiogenic cytokines in PsA.

Platelets sequester angiogenesis regulatory proteins which suggests an avenue for developing biomarkers to monitor disease. We describe a comparison of angiogenesis regulatory proteins found in platelets of colorectal cancer patients and normal controls. Platelet and plasma content of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet derived growth factor (PDGF), platelet factor 4 (PF4), thrombospondin-1 (TSP-1) and endostatin in 35 patients with colon cancer were compared with 84 age-matched healthy controls using ELISAs. We standardized the platelet preparation procedure, introduced process controls and normalized the respective protein levels to platelet numbers using an actin ELISA. Statistically significant differences were found in the median levels of VEGF, PF4 and PDGF in platelets of patients with cancer compared to healthy individuals. Platelet concentrations in cancer patients versus controls were: VEGF 1.3 versus 0.6 pg/10(6), PF4 18.5 versus 9.4 ng/10(6), and PDGF 34.1 versus 21.0 pg/10(6). Multivariable logistic regression analysis indicated that PDGF, PF4 and VEGF were independent predictors of colorectal carcinoma and as a set provided statistically significant discrimination (area under the curve = 0.893, P < .0001). No significant differences were detected for bFGF, endostatin, or TSP-1. Reference Change Value analysis determined that the differences seen were not clinically significant. Plasma levels yielded no correlations.

This study was aimed to assess the clinical significances of the serum VEGF and bFGF in Thai patients with de novo NHL. Serum VEGF and bFGF concentrations were measured from 79 adult patients with newly diagnosed stage 2-4 non-Hodgkin lymphomas by quantitative sandwich enzyme immunoassay. At the time of diagnosis, the serum VEGF concentrations from 79 patients ranged from 72.0 to 2919.4 pg/mL, with a mean of 668.0 pg/dL. The serum bFGF concentrations ranged from undetectable to 2919.4 pg/mL, with a mean of 12.15 pg/dL. Multivariate analysis identified higher than the mean of serum VEGF, B symptoms, bulky diseases, anemia, and treatment with CHOP or R-CHOP as independent variables influencing the complete remission rate. From a Cox proportional hazards model, variables independently associated with overall survival were bone marrow involvement, more extranodal involvement, poor performance status, anemia, and higher than the mean of serum bFGF.

Aim: To investigate the correlation between the level of serum VEGF and bFGF with metastasis and re- currence of osteosarcoma., Methods: 52 patients with osteosarcoma and 60 healthy people as control group were selected. The serum contents of VEGF and bFGF were determined with ELISA before and after operation., Results: The serum contents of VEGF and bFGF before operation were significantly higher than that in control group ( P < 0.01). The serum contents of VEGF and bFGF after operation descreased significantly but were significantly higher than that in control group(P<0. 01). The serum contents of VEGF and bFGF before operation were positively related to the size of primarily tumor, Enneking type and tumor differentiation(P<0.05). The serum contents of VEGF and bFGF before and after operation were different significantly between recurrence and metastasis positive group with recurrence and metastasis negative group ( P < 0. 01). The Cox proportional hazards model showed that the serum contents of VEGF and bFGF before and after operation were an independent factor of the recurrence and metastasis for osteosar- coma patients after operative ( P <0. 01)., Conclusion: The serum contents of VEGF and bFGF before and after operation can offer valuable assessments in evaluation of progression and metastasis prognosis.

Aim: To study the expression and clinical significance of serum vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in children with acute leukemia (AL)., Methods: The serum VEGF and bFGF level before chemotherapy from 40 cases of children with newly diagnosed AL, after 1 course of treatment from from 37 cases of children with complete remission (CR) and no- remission(NR) , and 40 cases of healthy children (control group) were detected by ELISA technology., Results: Before treatment, the serum VEGF and bF-GF level of the AL group and different types of AL were significantly higher than the control group(P<0.05), while the serum VEGF and bFGF level were no significant difference between the different types of AL ( P > 0.05). Before treatment, the serum VEGF and bFGF level were no significant difference between the AL CR and NR children; After treatment, the serum VEGF and bFGF level of CR children decreased significantly, compared with the prior-treatment and NR children the different was significant ( P < 0. 05); While the serum VEGF and bFGF level of NR children were no significant difference between prior-treatment and post-treatment., Conclusion: The serum VEGF and bFGF level have high expression in children with AL, the serum VEGF and bFGF level can be used as indicators of AL efficacy, and are correlation with the prognosis of children with AL.

Objective: Vascular disease is common in mixed connective tissue disease (MCTD). The aim of the present study was to investigate, whether dysbalance of angiogenic and angiostatic factors occurs in MCTD., Methods: In all, 38 patients with MCTD, and 40 patients with systemic sclerosis (SSc) for comparison, were included. Four centres contributed to this cross-sectional analysis. A total of 66 healthy volunteers were used as controls. The serum levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and endostatin were determined by ELISA. For comparisons between controls and patients with MCTD and detection of associations of serum levels with dichotomous clinical parameters in patients with MCTD the Mann-Whitney test was used., Results: Serum levels of the angiogenic factor VEGF were significantly elevated in patients with MCTD and SSc. Significantly increased levels of the angiostatic factor endostatin were also detected in MCTD, but not in SSc. No differences were observed for bFGF. Levels of VEGF were higher in patients with MCTD with pulmonary arterial hypertension (PAH), acrosclerosis and myositis. In multivariate linear regression analysis, an additive model of PAH, myositis and lymphadenopathy accounted for 79% of the variability of the VEGF levels (r=0.889)., Conclusions: Molecular factors modulating angiogenic responses are dysregulated in patients with MCTD and SSc with increases of VEGF in MCTD and SSc and selective upregulation of endostatin in MCTD. Furthermore, high serum levels of VEGF might characterise patients with MCTD with a more severe course of the disease with increased prevalence of PAH and myositis.

Background: Hyperbaric oxygen (HBO) therapy is an effective adjunct treatment for ischemic disorders such as chronic infection or chronic wounds. It combines hyperoxic effects with the stimulating potential of post-therapeutic reactive hypoxia. As its crucial effects, stimulation of fibroblast growth, induction of collagen synthesis and the initiation of angiogenesis are discussed. Angiogenesis is a multistage process resulting in the growth of blood vessels. It includes degradation of extracellular matrix, proliferation and migration of different cell populations and finally formation of new vessel structures. This complex chain of procedures is orchestrated by different cytokines and growth factors. Crucial mediators of angiogenesis are basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF); their in-vivo function is still not fully understood., Methods: Forty-three patients suffering from sudden sensorineural hearing loss or tinnitus were treated with HBO. The therapy included 10 sessions of 90 minutes each, one session a day. Serological levels of bFGF and VEGF were assessed by enzyme-linked immunosorbent assays performed according to the manufacturer's instructions on day 1, 2, 5 and 10 of HBO therapy and were compared to mean values of the control group, related to the patient's age and sex, and their development observed over the ten days of HBO., Results: There was no sex- or age dependency of bFGF observed in the present study, whereas under HBO our results showed a significant mitigation of the bFGF concentration. In the present data, there was no connection between the VEGF concentration and the patients' ages. Women showed significantly higher levels of VEGF. There was no significant change of VEGF concentration or the VEGF/bFGF ratio during HBO. All scored results varied within the range of standard values as described in the current literature., Conclusions: A significant effect of HBO on serum concentrations of bFGF and VEGF was not verified in the present study. Additional application of exogenous growth factors in conjunction with HBO was not obviously linked by a coherent cause-and-effect chain as far as wound healing is concerned.

We investigated the plasma levels of VEGF and FGF-2, important factors for regulation of neuroplasticity such as neurogenesis, in patients in remission from major depressive disorders (MDD). The plasma VEGF levels were significantly higher in the MDD patients than in the matched control subjects, while no significant difference in plasma FGF-2 levels was found. In particular, the MDD patients with family history of psychiatric disorders, but not patients without such a family history, showed significantly higher values of plasma VEGF than the controls. Although this is a preliminary study, altered VEGF levels might be involved in the pathophysiology of MDD.

Hypoxia frequently complicates the course of chronic obstructive pulmonary disease (COPD). Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are the two most potent angiogenic factors and may play a role in adaptation to hypoxia. The aims of the study were to assess the serum levels of VEGF and bFGF and to evaluate their mutual relationship in hypoxic patients with exacerbated COPD. The study group consisted of 50 hypoxic (PaO(2) 53 mmHg) patients with exacerbated COPD. Control groups were 30 stable COPD patients with PaO(2) 70 mmHg, and 30 healthy blood donors. The serum concentrations of VEGF and bFGF were measured using commercial enzyme-linked immunoassay kits. Patients with exacerbated COPD had significantly higher serum VEGF levels (1,089.16 +/- 1,128.03 pg/mL) compared to those with stable COPD (197.68 +/- 178.06 pg/mL) (p < 0.0001) and healthy blood donor group (257.69 +/- 170.4 pg/mL) (p < 0.0001). Serum bFGF levels were significantly higher in the exacerbated COPD group (6.15 +/- 2.56 pg/mL) compared to control groups (p = 0.0001). Basic FGF was undetectable in the stable COPD and blood donor groups. Since VEGF and bFGF correlated significantly with the majority of factors investigated in COPD patients, multivariate analysis was performed. According to the step-wise regression analysis, VEGF was best determined by PaO(2), WBC and IL-6. Basic FGF was best determined by PaO(2) and pH. The highly significant, simple correlation between VEGF and bFGF was lost in multivariate analysis. This suggests that their correlation is not independent, but due to factors that remain in the model after step-wise regression. These are essentially linked to the level of hypoxia. Results of our study suggest that VEGF and bFGF production is stimulated in hypoxic patients with exacerbated COPD. Elevated levels of VEGF and bFGF may activate the process of neoangiogenesis, which may lead to increased perfusion and an improvement in tissue oxygenation in this group of patients.

Objective: To document the expression patterns of various matrixins, cytokines and angiogenic factors in plasma to assess their involvement in the pathogenesis of moyamoya disease (MMD)., Methods: This study included plasma samples from 20 MMD patients and nine healthy individuals. The plasma concentration of five matrix metalloproteinases (MMP-1, MMP-2, MMP-3, MMP-9, MMP-12), monocyte chemoattractant protein-1 (MCP-1), resistin, three interleukins (IL-1beta, IL-6, IL-8), tumour necrosis factor-alpha, vascular endothelial growth factor (VEGF), platelet-derived growth factor BB (PDGF-BB) and basic fibroblast growth factor was determined using multianalyte profiling systems. The concentration of the tissue inhibitors of metalloproteinase (TIMP-1 and TIMP-2) was measured using ELISA. Gelatin zymography for MMP-2 and MMP-9 was also performed., Results: MMD patients exhibited significantly higher plasma concentrations of MMP-9, MCP-1, IL-1beta, VEGF and PDGF-BB, and lower plasma concentrations of MMP-3, TIMP-1 and TIMP-2 compared with healthy controls. Significant correlations were found among MMP-9, MCP-1, VEGF, PDGF-BB and TIMP-2 in MMD patients., Conclusion: There were distinctive expression patterns of matrixins, cytokines and angiogenic factors in MMD patients, which seemed to correlate with disease pathogenesis. The balance between MMPs and TIMPs was disrupted in MMD and correlated with disease pathogenesis. Increased plasma levels of MCP-1 and VEGF in MMD patients may play a role in the recruitment of vascular progenitor cells and in the formation of collateral vessels.

Background: Angiogenesis and proangiogenic cytokines are involved in neoplastic development. The role of these processes in lymphoma formation has not been established. The aim of the study was to assess angiogenesis on the basis of serum levels of vascular-endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in childhood lymphomas. The prognostic value of these parameters was determined in the examined children., Procedure: Forty-two children with lymphomas (Hodgkin and non-Hodgkin Lymphomas) were studied (group A). Group A was divided into two subgroups: A(CR)-30 children with complete remission (CR) and A(PR+P+ER)-12 children with partial remission (PR), progressive disease (P), and early relapse (ER). The control group (group C) consisted of healthy 20 children. Using enzyme-linked immunosorbent assays we quantified VEGF and bFGF in serum of the healthy children and of the children with lymphomas., Results: The serum VEGF concentration in group A was 633.4 pg/ml (24.0-1,210.5) and was significantly higher (P = 0.0001) in comparison with group C (144.6 pg/ml; 32.3-734.8). In subgroup A(PR+P+ER), the baseline serum VEGF concentration was 865.0 pg/ml (205.8-1,209.2) and was significantly higher (P = 0.02) than in subgroup A(CR) (564.0 pg/ml; 24.0-1,210.5). The high serum VEGF concentration in children with lymphomas was the only independent risk factor for treatment failure (OR = 8.64; 95 CI: 1.51-49.34; P = 0.01). The cutoff point for the serum VEGF level >or=633.4 pg/ml as a parameter predicting treatment failure was established (P = 0.01)., Conclusion: Baseline serum VEGF concentration constitutes a prognostic marker for the progression of Hodgkin and non-Hodgkin Lymphomas in children., ((c) 2009 Wiley-Liss, Inc.)

Aim: The clinical manifestation of chronic mountain sickness (CMS) is polycythemia, pulmonary hypertension and mionectic blood. However, the pathogenesis of it is not identified now. So it is necessary to investigate the effects of the angiogenic growth factors on the pathophysiologic development of CMS., Methods: The serum levels of basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) in 13 healthy Tibetan natives (Native), 17 healthy people in Xining (control group) and 35 CMS patients were determined by quantitative sandwich enzyme immunoassay. Meanwhile, the levels of Hb, Hct and SaO2 were determined., Results: The serum levels of bFGF (107.26 +/- 7.86) ng/L, PDGF (630.18 +/- 9.89) ng/L and VEGF (543.74 +/- 6.76) ng/L in CMS were significantly higher than those in Natives (37.01 +/- 9.16; 292.16 +/- 6.88; 125.51 +/- 7.26) ng/L, and in control group (40.58 +/- 5.34; 287.68 +/- 8.33; 76.26 +/- 4.60) ng/L, respectively (P < 0.01). There was no difference between the natives and the control group in bFGF and PDGF (P > 0.05), while there was predominant difference between the Natives and the control group in VEGF (P < 0.01). There was a predominant positive correlation between the serum levels of bFGF, PDGF or VEGF and hemoglobin concentrations in CMS respectively (P < 0.01). And there were positive relations between angiogenic growth factors each other., Conclusion: The serum levels of bFGF, PDGF and VEGF in patients with CMS significantly increase, these angiogenic growth factors may play important role on the pathophysiologic development of CMS; the VEGF level likely contributes to the adaptation to plateau hypoxia in healthy Tibetan natives; the elevated bFGF, PDGF and VEGF levels are likely associated with excessive erythropoiesis in CMS.

Impaired balance between proangiogenic and antiangiogenic factors has been implicated in the development of hemangiomas. Elevated vascular endothelial growth factor serum levels and basic fibroblastic growth factor urine levels in patients with proliferating hemangiomas were reported. However, whether these growth factors can be used for the differential diagnosis of vascular anomalies or assessment of the clinical course of hemangiomas has yet to be determined. We report here our preliminary results of serum vascular endothelial growth factor and basic fibroblastic growth factor levels as an aid in the diagnosis of hemangiomas and in the follow up of patients with this lesion. Twenty two children with infantile hemangioma (13 with proliferating hemangiomas, nine with involuting lesions), five children with vascular malformations, and 25 healthy children study group. Vascular endothelial growth factor and basic fibroblastic growth factor serum levels were analyzed by an ELISA assay. The serum vascular endothelial growth factor concentrations in children with proliferating hemangiomas were significantly higher than in patients with involuting hemangiomas, vascular malformations and healthy patients. The serum basic fibroblastic growth factor concentrations were low and similar in all patients with no statistical correlation between study groups. We concluded that (i) ELISA can easily determine vascular endothelial growth factor concentrations in different phases of hemangioma growth and help distinguishing them from vascular malformations. (ii) A potential role for vascular endothelial growth factor in the pathophysiology of hemangiomas is probable.

Background: Serum levels of IGF-I in patients affected with multiple myeloma (MM) have been scarcely studied. The present study is aimed to explore this point comparing 55 healthy subjects, 71 monoclonal gammopaties of uncertain significance (MGUS) and 77 overt MM patients. In the same subjects, basic FGF and VEGF, have been detected. All three mediators were analyzed in function of K-ras mutation and melphalan response. Concerning IGF-I, two representative monitoring examples have also been added., Methods: Cytokine determinations were performed by commercially available ELISA kits, while K12-ras mutation was investigated on genomic DNA isolated from bone marrow cell specimens by RFLP-PCR assay., Results: Significant reductions of IGF-I levels were observed in MGUS and MM as compared with healthy controls. In addition, MM subjects showed significantly decreased serum IGF-I levels than MGUS. Conversely, increasing levels were observed for bFGF and VEGF, molecules significantly correlated. A multivariate analysis corrected for age and gender confirmed the significant difference only for IGF-I values (P = 0.01). K12-ras mutation was significantly associated with malignancy, response to therapy and with significantly increased serum bFGF levels., Conclusion: IGF-I reduction in the transition: Controls-->MGUS-->MM and changes observed over time suggest that IGF-I should be furtherly studied in future clinical trials as a possible monitoring marker for MM.

Background: Clinical observations are suggesting accelerated granulation tissue formation in traumatic wounds treated with vacuum-assisted closure (VAC). Aim of this study was to determine the impact of VAC therapy versus alternative Epigard application on local inflammation and neovascularization in traumatic soft tissue wounds., Methods: Thirty-two patients with traumatic wounds requiring temporary coverage (VAC n = 16; Epigard n = 16) were included. At each change of dressing, samples of wound fluid and serum were collected (n = 80). The cytokines interleukin (IL)-6, IL-8, vascular endothelial growth factor (VEGF), and fibroblast growth factor-2 were measured by ELISA. Wound biopsies were examined histologically for inflammatory cells and degree of neovascularization present., Results: All cytokines were found to be elevated in wound fluids during both VAC and Epigard treatment, whereas serum concentrations were negligible or not detectable. In wound fluids, significantly higher IL-8 (p < 0.001) and VEGF (p < 0.05) levels were detected during VAC therapy. Furthermore, histologic examination revealed increased neovascularization (p < 0.05) illustrated by CD31 and von Willebrand factor immunohistochemistry in wound biopsies of VAC treatment. In addition, there was an accumulation of neutrophils as well as an augmented expression of VEGF (p < 0.005) in VAC wound biopsies., Conclusion: This study suggests that VAC therapy of traumatic wounds leads to increased local IL-8 and VEGF concentrations, which may trigger accumulation of neutrophils and angiogenesis and thus, accelerate neovascularization.

Background: The role of angiogenesis in the pathogenesis of pleural effusion (PE) has not been determined. The expression of angiogenic factors may represent useful markers for the diagnosis and prediction of disease outcome. To measure the pleural fluid (PF) and serum levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and Tie receptor tyrosine kinase (Tie-2) in order to investigate their role in the pathogenesis of PEs., Methods: Sixty-seven, 17 with transudative PEs due to heart failure and 50 with exudative PEs (malignant, 22; inflammatory, 15; undiagnosed, 13) were included in the study. PF and serum levels of the growth factors (VEGF, bFGF and Tie-2) were measured using enzyme-linked immunosorbent assays., Results: PF and serum VEGF levels but not bFGF and Tie-2 levels were higher (p<0.005) in exudates than in transudates. PF VEGF levels were significantly higher in malignant than inflammatory and undiagnosed PEs (p=0.03). In addition, PF Tie-2 levels were not found different in malignant or in parapneumonic PEs., Conclusion: Our results showed that VEGF is one of the main mediators in exudative PEs, but this effect is not mediated through the angiogenetic pathway Ang-1/Tie-2. However, the role of angiogenesis and its pathways in the pathogenesis of exudative PEs needs further exploration.

Background: Vascular endothelial growth factor (VEGF), interleukin-8 (IL-8) and basic fibroblast growth factor (basic FGF) are angiogenic growth factors which may be useful as biomarkers in drug development, where they could give early information on the antiangiogenic activity of novel anticancer compounds., Methods: We compared two commercially available assays, enzyme linked immunosorbent assay (ELISA) and a multiplexed bead-based immunoassay (xMAP), for the quantification of these factors in plasma samples from more than 100 cancer patients and healthy individuals., Results: For VEGF and IL-8, but not for basic FGF, xMAP was more sensitive than the respective ELISA. This was true for healthy subjects as well as for cancer patients. Intraassay precision was comparable between both assay formats. Linear regression analysis of VEGF concentrations demonstrated a good correlation between ELISA and xMAP. Bland-Altman analysis showed a systematic difference between both assays, with ELISA giving higher concentration values. VEGF levels were higher in female volunteers, and both assays were able to detect this difference., Conclusions: Multiplexed microsphere-based immunoassays have the potential to substitute ELISA for the detection of proangiogenic growth factors in clinical studies. Their shorter assay times and their ability to quantify multiple analytes in a small sample volume are advantageous.

In this study we have investigated changes in circulating angiogenic factors after a single zoledronic acid intravenous infusion. Thirty consecutive patients who had histologically confirmed breast (n=20) and lung cancer (n=10) associated with confirmation of bone metastases were included in the study. Serum was also available from 10 healthy volunteers. Four mg of Zoledronic acid (Zometa, Novartis) was administered as a 15-min infusion in 100-ml normal saline on an outpatient basis. Venous blood for assessment of serum parameters was drawn just before the beginning of drug infusion and again at 7 and 28 days after the zoledronic acid infusion. Serum levels of VEGF and bFGF were assayed with ELISA kits. Serum VEGF and bFGF levels were not significantly different from healthy control groups (P>0.05). However, we found that serum VEGF levels in lung cancer patients were significantly higher than in patients with breast cancer and controls (P=0.009, and P=0.022, respectively). We found no significant correlation between serum VEGF and bFGF levels. No statistically significant changes were seen following infusion of zoledronic acid in patients with bone metastases for both serum VEGF and bFGF levels (P>0.05). Unlike previous studies, zoledronic acid did not appear to exert an angiogenic activity as there was no reduction of VEGF and bFGF circulating levels after zoledronic acid infusion.

Background: We aimed to compare the effect of unfractionated heparin (UFH) and enoxaparin used as anticoagulants during hemodialysis (HD) on circulating levels of heparin-binding, endothelial-derived, proangiogenic factors-vascular endothelial (VEGF(165)) and basic fibroblast (bFGF) growth factor., Methods: We enrolled 22 chronic HD patients, who were randomly assigned to either enoxaparin (n=11) or UFH (n=11) anticoagulation, and followed prospectively for 12 weeks before crossing over to the alternate therapy for further 12 weeks. The cytokines were measured by immunoassay at the start, at 10 and 180min of HD., Results: The baseline VEGF(165) and bFGF levels were comparable during enoxaparin and UFH treatment. VEGF(165) significantly decreased during both enoxaparin (chi(2) ANOVA=33.0, P<10(-6)) and UFH (chi(2) ANOVA=27.2, P<10(-6)) anticoagulated HD, while over-HD bFGF remained stable regardless of the type of heparin. The switch from enoxaparin to UFH treatment was connected with 34% VEGF(165) decrease after 180min of HD and had no impact on bFGF. During UFH-anticoagulated HD 75% VEGF(165) decrease after 10min was negatively associated with heparin dosage and was more profound in patients with ischemic heart disease., Conclusion: The traditional UFH regimen, in contrast to enoxaparin treatment, is connected with dose-depended VEGF(165) decrease during HD procedure. The biological and possible clinical relevance of this observation requires further investigations.

Chronic lymphocytic leukemia (CLL) is characterized by extraordinary heterogeneity in terms of clinical course with overall survival ranging from several months to dozens of years. It is currently not possible to accurately predict the future clinical course in an individual patient. Angiogenesis has been recently reported as a potential prognostic factor in various hematological malignancies including CLL. The objective of the present study was to quantify plasma levels of key angiogenic activators vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in patients with CLL and determine their potential change after intensive fludarabine-based treatment. Peripheral blood EDTA plasma concentrations of bFGF and VEGF were measured using comercially available enzyme-linked immunosorbent assay in 73 patients with untreated CLL (43 males, 30 females, median age, 65 years, range 31-88) and 80 healthy donors serving as control group. We found statistically significant increase in concentrations in patients with chronic lymphocytic leukemia compared to the control group (p < 0.0001 for both cytokines). No differences in angiogenic factors were noted between subgroups with low vs. intermediate vs. high-risk stage according to modified Rai staging or males vs. females. In twelve patients who achieved at least partial response after intensive fludarabine-based treatment, levels of bFGF as well as VEGF decreased significantly (bFGF, p = 0.0005; VEGF, p = 0.0068); in addition, they were no more significantly different from controls (bFGF, p = 0.524; VEGF, p = 0.728). Our data showed that key angiogenic activators bFGF and VEGF were elevated in plasma ofCLL patients. Furthemore, treatment with intensive fludarabine-containing regimens resulted in significant decrease of both cytokines. These data suggest that angiogenic cytokines may indeed play a significant role in CLL biology and that treatment with combination of fludarabine, cyclophosphamide +/- rituximab may exhibit antiangiogenic properties. Further studies with longer follow-up are necessary for evaluation of a possible association between angiogenic markers and progression-free survival or overall survival.

Background: High expression of vascular endothelial growth factor (VEGF) induces subepithelial fibrosis associated with angiogenesis in patients with asthma. Thrombin is recognized as a new candidate mediating airway remodeling. Therefore, this study was designed to determine the role of up-regulated thrombin activity induced by VEGF on airway remodeling in patients with asthma., Methods: Levels of biochemical parameters in induced sputum were examined in 21 asthmatic patients and 11 normal control subjects., Results: Thrombin activity in induced sputum was significantly higher in asthmatic patients than in normal control subjects: median, 3.67 U/mL; range, 1.15 to 10.2 U/mL; vs median, 1.26 U/mL; range, 0.93 to 2.42 U/mL (p < 0.0001). In contrast, protein C activity in induced sputum was lower in asthmatic patients than in normal control subjects: median, 20%; range, 5 to 30%; vs 41%; range, 30 to 59% (p < 0.0001). VEGF level in induced sputum was positively correlated with thrombin activity in asthmatic patients (r = 0.55, p = 0.02), while inversely correlated with protein C activity (r = - 0.57, p = 0.01). Levels of basic fibroblast growth factor (bFGF), a major profibrotic factor, were also significantly higher in asthmatic patients than in normal control subjects. Moreover, thrombin activity was significantly correlated with bFGF level in asthmatic patients (r = 0.67, p = 0.003)., Conclusions: Increase in VEGF level leads to up-regulation of thrombin activity in asthmatic airways, and this elevated thrombin activity induces elevation of bFGF level. It will become to be a new strategy of asthma therapy to attenuate thrombin activity for the regulation of airway remodeling.

To study the serum levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in patients with myelodysplastic syndrome (MDS), serum from 43 MDS patients was examined by enzyme linked immunosorbent assay (ELISA). The results showed that serum levels of VEGF, bFGF in MDS patients were significantly elevated compared with normal control. Serum levels of VEGF and bFGF in RAEB patients and RAEBT patients were higher than that in RA patients and RAS patients (P < 0.05). No significant difference of serum levels of VEGF and bFGF was found between RAEBT patients and acute myeloid leukemia (AML) patients. The serum levels of VEGF and bFGF were correlated with the affected peripheral blood cells and the proportion of blast cells in bone marrow. There was positive correlation between serum VEGF and bFGF levels. It is concluded that the secretion of VEGF and bFGF in MDS patients is elevated and the serum levels of VEGF and bFGF are related to the classification and prognosis in MDS.

Background: Increased serum levels of angiogenesis-related factors such as endostatin, vascular endothelial cell growth factor (VEGF) or basic fibroblast growth factor (bFGF) have been demonstrated for a variety of solid and nonsolid tumours. Therefore, these factors have been suggested as diagnostic and in some studies as prognostic tumour markers., Objectives: The purpose of the present study was to investigate a possible correlation of endostatin, VEGF or bFGF serum levels with disease progression in melanoma. Especially, we compared these factors to the established melanoma marker S-100 B, which increases in advanced disease but often fails to indicate early metastatic spread to regional lymph nodes., Patients and Methods: Sera from 197 melanoma patients and 35 healthy controls were measured by enzyme-linked immunosorbent assay; 72 patients had primary tumours (American Joint Committee on Cancer stages I and II), 55 had regional lymph node metastasis (stage III) and 70 patients had distant organ metastasis (stage IV)., Results: Endostatin, VEGF and bFGF serum levels were significantly elevated in stage IV disease, compared with the control group. In stage III, endostatin and bFGF, but not VEGF or S-100 B, were significantly increased. However, follow-up of this patient group did not show a correlation with the future clinical course including time until progression or overall survival, arguing against a role of endostatin, VEGF or bFGF as prognostic markers., Conclusions: These data indicate that endostatin or bFGF might be useful as diagnostic markers for the early detection of locoregional metastasis.

Objective: To investigate the relationship between VEGF, bFGF and IGF-1 serum concentration and progression of pancreatic carcinoma., Methods: Fifty-six patients with pancreatic carcinoma were divided into resectable group (n = 32) and unresectable group (n = 24). Another group was normal group (n = 20). The expression and significance of these proangiogenic factors were respectively analyzed in different groups., Results: For pancreatic carcinoma group, concentrations of VEGF and bFGF were significantly higher than these of normal group (P < 0.01). Serum VEGF was significantly correlated with the resection of pancreatic carcinoma (P < 0.05) while bFGF and IGF were not. According to univariate analysis, serum VEGF was correlated with tumor grade, nodal disease, vascular invasion, distant metastases and tumor stage. Serum bFGF was associated with tumor size and grade. Serum IGF-1 was correlated with vascular invasion., Conclusions: Angiogenic factors play important roles in growth, invasion and metastasis. Detection of serum proangiogenic factors may have potential value in diagnosis and prognosis of pancreatic carcinoma.

Background: Angiogenesis has been extensively studied in acute myeloid leukemia (AML). Lactate dehydrogenase (LDH), a common biochemical marker for tumor burden and anaerobic glycolysis, is a poor prognostic factor for AML. Regulated by hypoxia-induced factor, both vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are responsive to cancer-related angiogenesis. To study the roles of serum LDH, VEGF and bFGF in AML angiogenesis, we investigated bone marrow vascularity in untreated AML patients, and analyzed its relationship to serum LDH, VEGF and bFGF levels., Methods: Eighteen (11 males, 7 females; mean age, 57.7 years) de novo, untreated AML patients were enrolled. Bone marrow vascularity was evaluated by staining bone marrow core biopsy tissue with endothelial cell marker CD31 or CD34. Serum LDH was determined with the Wroblewski-La Due method. Serum VEGF and bFGF were determined with enzyme-linked immunoassay. The relationship of LDH, VEGF and bFGF level to bone marrow vessel numbers was examined by linear regression., Results: Log LDH significantly correlated to AML bone marrow vascularity (r = 0.61; p = 0.007). VEGF and bFGF concentrations did not correlate with AML angiogenesis., Conclusion: These results suggest that serum LDH, but not VEGF and bFGF concentrations, can be used as a simple parameter for predicting vessel formation in AML bone marrow.

Objective: To determine if IGF-I, VEGF and bFGF, present in the serum of premature infants, are independent risk factors of the development of ROP. It was also our objective to design a multivariate model that included these three cytokines as indicator parameters in the ROP screening, in addition to the other parameters already in existence., Methods: 74 patients were recruited with a birth weight below 1500g or gestational age below 32 weeks. These were classified into those who developed ROP (N = 37) and those without ROP (N = 37). We obtained serum from each infant at the time of the first examination at 4-6 postnatal weeks. These samples were frozen until the time of analysis. The roles of gestational age and birth weight were also evaluated., Results: There were significant differences in the amount of the cytokines IGF-I and VEGF between the groups with or without ROP, but there were no significant differences for bFGF. The differences enabled us to establish a multivariate model including IGF-I and VEGF for the prediction of risk of ROP., Conclusions: Cytokine serum levels in premature infants can be useful as an indicator in ROP screening, as well as being used to predict the probability of suffering the illness.

Background: The main objective of this study was to determine whether there was a correlation in the levels of various angiogenesis-related factors between the tumor drainage and peripheral venous blood and whether appraisal of angiogenic factor levels in the tumor drainage venous blood could provide better prognostic information for patients with colorectal cancer than assessment of the peripheral venous blood., Methods: Plasma levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor, and endostatin were measured and compared in both tumor drainage and peripheral venous blood from 52 patients with colorectal cancer. Plasma levels of angiogenesis-related factors were also correlated with tumor stage and clinical outcomes., Results: The plasma endostatin level was significantly higher in peripheral blood than in tumor drainage venous blood (P < .001). The plasma VEGF level was significantly correlated with plasma endostatin levels (P = .028 in tumor drainage venous blood and P = .002 in peripheral venous blood). In both tumor drainage and peripheral venous blood, the VEGF level (but not the basic fibroblast growth factor or endostatin level) was significantly correlated with tumor stage and disease recurrence. However, in multivariate analysis, only plasma VEGF level in tumor drainage venous blood remained an independent predictor of disease recurrence., Conclusions: The plasma VEGF level in tumor drainage venous blood provided better prognostic information than that in peripheral venous blood. The plasma endostatin level was paradoxically significantly higher in peripheral than in tumor drainage blood, and this strongly suggests additional sources of endostatin in peripheral blood.