Changes in Serum Concentrations of Vascular Endothelial Growth Factors-A and B after Intravitreal Injection of Ranibizumab and Conbercept for Retinopathy of Prematurity.

INTRODUCTION: The aim of this study was to compare the changes in serum concentrations of vascular endothelial growth factor (VEGF)-A and B after intravitreal injection of ranibizumab (IVR) or conbercept (IVC) for retinopathy of prematurity (ROP). METHODS: In this prospective study, infants with type 1 ROP in both eyes were recruited in our hospital from September 2021 to February 2022, randomly assigned to the ranibizumab and conbercept groups and administered IVR or IVC (0.25 mg/0.025 mL). Blood samples were collected before the operation and 1 and 4 weeks after the operation to measure the concentrations of serum VEGF-A and B. RESULTS: A total of 20 ROP infants were randomly assigned to the ranibizumab (n = 10) and conbercept groups (n = 10). In the ranibizumab group, the serum VEGF-A concentrations before operation and 1 and 4 weeks after the operation were 73.55 ± 40.78, 11.47 ± 7.00, and 75.36 ± 30.87 pg/mL, respectively (p < 0.01). Least Significant Difference (LSD) pairwise comparison did not show any significant difference in the groups between 4 weeks postoperatively and preoperatively (p > 0.05). In the conbercept group, the serum VEGF-A concentrations before operation and 1 and 4 weeks after the operation were 86.69 ± 55.06, 14.68 ± 10.11, and 43.55 ± 57.92 pg/mL, respectively (p < 0.01). LSD comparison showed significant differences between 1 week and 4 weeks postoperatively and preoperatively (p < 0.05), but no significant differences were observed between 1 and 4 weeks postoperatively (p > 0.05). Regarding serum VEGF-B concentrations before the operation and 1 and 4 weeks after the operation, no significant differences were detected in the ranibizumab group (p > 0.05), but significant differences were observed in the conbercept group (7.26 ± 2.34, 3.09 ± 2.41, and 4.55 ± 3.37 ng/mL, respectively; p < 0.01). LSD showed significant differences between 1 or 4 weeks postoperatively and preoperatively (p < 0.05), but no significant difference was detected between 1 and 4 weeks postoperatively (p > 0.05). CONCLUSIONS: Serum VEGF-A levels in infants with ROP were suppressed after IVR or IVC but returned to preoperative levels at 4 weeks after IVR and remained lower than the preoperative levels at 4 weeks after IVC. Serum VEGF-B was not affected by IVR but was suppressed by IVC for 4 weeks.

Increased Serum VEGF-B Level Is Associated With Renal Function Impairment in Patients With Type 2 Diabetes.

Aims/Introduction: Renal function impairment related to type 2 diabetes (T2DM) presents serious threat to public health. Previous studies suggest that vascular endothelial growth factor-B (VEGF-B) might contribute to renal injury. Therefore, this study investigated the association of serum VEGF-B level with the risk of renal function impairment in T2DM patients. Materials and Methods: Serum VEGF-B levels were measured in 213 patients with type 2 diabetes and 31 healthy participants. Participants with type 2 diabetes were further divided into a group of 112 participants with eGFR<90 mL/min/1.73m2 and 101 participants with eGFR≥ 90 mL/min/1.73m2. Clinical data were collected, and a binary logistic regression model was employed to test the association between potential predictors and eGFR. Results: Serum VEGF-B levels evaluated in type 2 diabetes patients compared with healthy controls. In patients with type 2 diabetes, serum VEGF-B level was positively correlated with triglyceride, serum creatinine and cystatin C while negatively correlated with HDL-C and eGFR. Binary logistic regression showed that serum VEGF-B level was an independent risk factor of eGFR<90 mL/min/1.73m2. Conclusions: Serum VEGF-B level is associated with renal function impairment in patients with type 2 diabetes and may be a potential drug target for diabetic kidney disease.

The Aryl Hydrocarbon Receptor-Dependent TGF-α/VEGF-B Ratio Correlates With Disease Subtype and Prognosis in Multiple Sclerosis.

OBJECTIVE: To evaluate the aryl hydrocarbon receptor (AHR)-dependent transforming growth factor alpha (TGF-α)/vascular endothelial growth factor B (VEGF-B) ratio, which regulates the effects of metabolic, dietary, and microbial factors on acute and chronic CNS inflammation, as a potential marker in multiple sclerosis (MS). METHODS: TGF-α, VEGF-B, and AHR agonistic activity were determined in serum of 252 patients with relapsing-remitting (RR) MS, primary and secondary progressive MS, as well as during active disease (clinically isolated syndrome [CIS] and RRMS relapse). RESULTS: The TGF-α/VEGF-B ratio and AHR agonistic activity were decreased in all MS subgroups with a stable disease course as compared to controls. During active CNS inflammation in CIS and RRMS relapse, the TGF-α/VEGF-B ratio and AHR agonistic activity were increased. Conversely, in patients with minimal clinical impairment despite long-standing disease, the TGF-α/VEGF-B ratio and AHR agonistic activity were unaltered. Finally, the TGF-α/VEGF-B ratio and AHR agonistic activity correlated with neurologic impairment and time to conversion from CIS to MS. CONCLUSIONS: The AHR-dependent TGF-α/VEGF-B ratio is altered in a subtype, severity, and disease activity-specific manner and correlates with time to conversion from CIS to MS. It may thus represent a novel marker and serve as additive guideline for immunomodulatory strategies in MS. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that serum levels of AHR, TGF-α, and VEGF-B distinguish subtypes of MS and predict the severity and disease activity of MS.

Rapid decrease in serum VEGF-A levels may be a worse prognostic biomarker for patients with platinum-resistant recurrent ovarian cancer treated with bevacizumab and gemcitabine.

PURPOSE: The aim of this study was to investigate the association between changes in the levels of vascular endothelial growth factors (VEGFs) after treatment with bevacizumab and gemcitabine (Bev-Gem) and the clinical outcome. METHODS: Platinum-resistant ovarian cancer patients treated with Bev-Gem therapy at our hospital between 2014 and 2018 were identified. Serum VEGF levels at the first and second treatment cycle were measured by ELISA. All patients were categorized into two groups-patients with > 50% decrease in serum VEGF-A levels (Group A) and patients with < 50% decrease serum VEGF-A levels (Group B). The association between clinical outcome and serum VEGF levels was investigated between the two groups. RESULTS: Among 18 patients, 10 were in Group A and 8 in Group B. Group A exhibited a lower response rate (0% vs.75% p < 0.01) and clinical benefit rate (60% vs.100% p = 0.02) than Group B. The median serum VEGF-A level of Group A before the first cycle of Bev-Gem therapy was higher than that in Group B (61.2 vs. 3.7 pg/mL, p < 0.01). Group A exhibited worse PFS (7 vs., 10 months, p < 0.01) and OS (17 vs. 26 months, p = 0.04) than Group B. There were more patients with > 10% increase in serum VEGF-B levels in Group A than in Group B (p < 0.01). CONCLUSION: The rapid decrease in VEGF-A levels and the resultant increase in serum VEGF-B levels might be associated with an unfavorable clinical outcome. Large-scale studies are needed to further examine these results.

Diastolic dysfunction in men with severe obstructive sleep apnea syndrome but without cardiovascular or oxidative stress-related comorbidities.

BACKGROUND: We aimed to evaluate whether the severity of obstructive sleep apnea syndrome (OSAS) per se affects the prevalence of left ventricular (LV) diastolic dysfunction in patients without comorbidities. METHODS: A total of 42 patients with first-diagnosed severe OSAS [apnea-hypopnea index (AHI) > 30] and 25 controls (AHI < 5), having been referred for snoring to the Sleep Laboratory Department of our tertiary Hospital, were enrolled in the study. Inclusion criteria were absence of any cardiovascular or oxidative stress-related comorbidities, and age between 20 and 70 years. Clinical, laboratory, echocardiographic, and polysomnographic data were recorded prospectively. Diastolic dysfunction diagnosis and grading was based on 2016 ASE/EACVI recommendations. RESULTS: Severe OSAS was associated with significantly increased prevalence and degree of diastolic dysfunction (26/42; 61.9%) compared with controls (7/25; 28%) (p = 0.007). AHI ⩾ 55 (dichotomous value of severe OSAS subset) was also characterized by greater prevalence and degree of diastolic dysfunction compared with 30 < AHI < 55 patients (p = 0.015). In the severe OSAS subset, age >45 years-old, height <1.745 m, body-mass index (BMI) >27.76 kg m-2, OSAS severity (AHI > 57.35), oxidative stress (overnight reduction of reduced to oxidized glutathione ratio < 18.44%), and BMI/height ratio > 16.155 kg m-3 (an index describing 'dense', short-heavy patients) presented significant diagnostic utility in identifying diastolic dysfunction in ROC-curve analysis (0.697 ⩾ AUC ⩾ 0.855, 0.001 ⩽ p ⩽ 0.018). In binary logistic regression model, advanced age (OR 1.23, 95% CI 1.025-1.477; p = 0.026) and AHI (OR 1.123, 95% CI 1.007-1.253; p = 0.036) showed independent association with diastolic dysfunction in severe OSAS. CONCLUSIONS: The present prospective study may suggest that severe OSAS is significantly associated with LV diastolic dysfunction; OSAS clinical severity exerts a positive influence on (and possibly constitutes an independent risk factor of) LV diastolic dysfunction. The reviews of this paper are available via the supplementary material section.

Plasma levels of VEGF-A, VEGF B, and VEGFR-1 and applicability of these parameters as tumor markers in diagnosis of breast cancer.

The VEGF family members are important factors in promoting angiogenesis and lymphangiogenesis in malignant processes. The aim of this study was to investigate plasma concentrations of VEGF-A, VEGF-B and their soluble VEGFR-1 receptor and their diagnostic utility and potency as compared to CA 15-3 in breast cancer patients and in relation to the control group. The study included 120 breast cancer patients and 60 control patients. Plasma levels of tested parameters were determined with ELISA and CA 15-3 levels were determined with CMIA. Concentrations of all tested parameters in breast cancer patients showed statistically significant difference when compared to the control groups (benign breast tumor patients and/or healthy women). VEGF-B showed the highest values of sensitivity (Sn) and predictive value of a negative test result (NPV) in total BC group (90% and 66.7%, respectively) and, more importantly, in stages I-II of BC (SE: 86.8%; 92.7%, NPV: 82.8%; 88.9%, respectively). Among all parameters tested, VEGF-A showed the highest specificity (Sf) (76.7%) and predictive value of a positive test result (PPV) (84.8%), yet they were lower than for CA 15-3. VEGF-A was also the best parameter that had statistically significant Area Under Curve (AUC) in stages I (0.678) and II (0.768). In the whole group of BC patients all parameters tested showed statistically significant AUC, but the maximum range was obtained for the combination of VEGF-A and CA 15-3 (0.817). The combined analysis of the studied parameters and CA 15-3 resulted in an increase in sensitivity and AUC values, which provides hope for developing a new panel of biomarkers that may be used in BC diagnosis in the future.

The Evaluation of the Relationship between sTREM-1, VEGF-B, and VEGF Gene Expression Levels with Disease Activity of Behçet's Patients.

BACKGROUND: There is no specific marker that shows the disease activity in Behçet's disease. AIM: In this study, we aimed to investigate VEGF-B and VEGF gene expressions and sTREM-1 levels in association with the activation of Behçet's disease. STUDY DESIGN: Case-control study. METHODS: Clinical features of patients who applied in the rheumatology clinic and were diagnosed with BD according to the international working group's criteria were investigated. 30 healthy volunteers and 30 patients in the active period according to the EBDCAF scoring were studied. VEGF-B and VEGF gene expressions and sTREM-1 levels were studied in the serum samples of the patients and the control subjects. RESULTS: The VEGF-B expressions and sTREM-1 levels were higher in the BD than those in the healthy group, but this difference did not reach statistical significance. VEGF gene expression was statistically significant (p = 0.008). Behçet's disease patients with oral aphthae, genital ulcer, eye, joint, vascular, skin, and neurological involvement were analyzed separately as subgroups. We find that VEGF gene expression level of Behçet's disease patients with joint involvement (arthritis/arthralgia) and also VEGF-B and VEGF gene expression of Behçet's disease with vascular involvement (DVT/thrombophlebitis) were significantly higher (p = 0.035, p = 0.021). Each subgroup was analyzed with the control group. We determined that VEGF gene expression in all subgroups was significantly higher than that in the control group. At the same time, VEGF-B levels of patients with genital ulcer and vascular involvement (DVT/thrombophlebitis) were significantly higher than those in the control group. CONCLUSION: VEGF-B and VEGF gene expressions can be activity indicators for BD. In addition, this study shows that new treatment options should be explored for Behçet's disease patients with joint and vascular involvement. In the following years, new treatment methods are needed to investigate for revealing the role of the etiopathogenesis of BD and the activation and prognosis of VEGF by examining this study and providing much more participation. In our study group, the sTREM-1 levels were high but the results did not reach statistical significance. More studies are needed with larger groups in order the highlight the exact role of STREM-1 in Behçet's disease.

Evaluation of the growth factors VEGF-a and VEGF-B in the vitreous and serum of patients with macular and retinal vascular diseases.

VEGF-A and VEGF-B are proangiogenic and key regulating factors for blood vessel growth. This study aims to compare VEGF-A and VEGF-B levels in the serum and vitreous of patients with neovascular pathology versus non-neovascular pathology. Our findings showed vitreous VEGF-A and VEGF-B levels increased in patients with neovascular disease, with higher levels of VEGF-A compared to VEGF-B (p ≤ .05). In the diabetic retinopathy (DR) group, higher vitreous VEGF-A or VEGF-B were found in proliferative diabetic retinopathy (PDR) than in non-PDR. The strong correlation between VEGF-A and VEGF-B demonstrates a simultaneous pathological increase of cytokines (p < .001), suggesting besides VEGF-A, VEGF-B is another contributor to ocular pathologies involving angiogenesis. There was no correlation between vitreous and serum VEGF-A or VEGF-B; however, a correlation between vitreous (VEGF-A or VEGF-B) and macular volume (p < .05) in DR patients was found. Targeting VEGF-A and VEGF-B in macular and retinal vascular diseases, involving neovascularization, may improve treatment outcomes.

Plasma vascular endothelial growth factor B levels are increased in patients with newly diagnosed type 2 diabetes mellitus and associated with the first phase of glucose-stimulated insulin secretion function of ß-cell.

PURPOSE: To detect plasma vascular endothelial growth factor B (VEGF-B) in individuals with different glucose tolerance and investigate the relationship between plasma VEGF-B levels and the first phase of glucose-stimulated insulin secretion. METHODS: A cross-sectional study was conducted involving 45 patients with newly diagnosed type 2 diabetes mellitus (T2DM), 37 patients with impaired glucose regulation (IGR), and 39 Normal glucose tolerance (NGT) subjects, all of whom underwent intravenous glucose tolerance test. Plasma VEGF-B levels were assayed by ELISA. The first phase of insulin secretion was evaluated by acute insulin response (AIR), the area under the curve of the first-phase (0-10 min) insulin secretion (AUC) and glucose disposition index (GDI). RESULTS: The T2DM and IGR groups had higher plasma VEGF-B levels than the NGT group (P < 0.01). Plasma VEGF-B levels were negatively correlated with AIR, AUC, GDI, HOMA-ß (P < 0.01), and positively correlated with plasma glucose, HbA1c, triglyceride, free fatty acid (FFA), fasting insulin, and HOMA-IR (P < 0.01). Logistic regression analysis revealed that higher VEGF-B levels [145.59-180.07 pg/ml, OR 3.55 (95% CI 1.05-12.02) and >180.07 pg/ml, OR 3.64 (95% CI 1.16-11.42)] were related to a greater probability of ß-cell hypofunction, compared with low VEGF-B levels (<145.59 pg/ml). After adjusting for triglyceride or FFA, the association between VEGF-B levels and ß-cell hypofunction disappeared (P > 0.05). CONCLUSIONS: Our study provides evidence that plasma VEGF-B levels were higher in patients with newly diagnosed T2DM, and were strongly associated with glucose and lipid metabolism and the first-phase insulin secretion function of ß-cells. VEGF-B may be involved in the mechanism of ß-cell dysfunction in T2DM.

VEGF-B gene therapy inhibits doxorubicin-induced cardiotoxicity by endothelial protection.

Congestive heart failure is one of the leading causes of disability in long-term survivors of cancer. The anthracycline antibiotic doxorubicin (DOX) is used to treat a variety of cancers, but its utility is limited by its cumulative cardiotoxicity. As advances in cancer treatment have decreased cancer mortality, DOX-induced cardiomyopathy has become an increasing problem. However, the current means to alleviate the cardiotoxicity of DOX are limited. We considered that vascular endothelial growth factor-B (VEGF-B), which promotes coronary arteriogenesis, physiological cardiac hypertrophy, and ischemia resistance, could be an interesting candidate for prevention of DOX-induced cardiotoxicity and congestive heart failure. To study this, we administered an adeno-associated viral vector expressing VEGF-B or control vector to normal and tumor-bearing mice 1 wk before DOX treatment, using doses mimicking the concentrations used in the clinics. VEGF-B treatment completely inhibited the DOX-induced cardiac atrophy and whole-body wasting. VEGF-B also prevented capillary rarefaction in the heart and improved endothelial function in DOX-treated mice. VEGF-B also protected cultured endothelial cells from apoptosis and restored their tube formation. VEGF-B increased left ventricular volume without compromising cardiac function, reduced the expression of genes associated with pathological remodeling, and improved cardiac mitochondrial respiration. Importantly, VEGF-B did not affect serum or tissue concentrations of DOX or augment tumor growth. By inhibiting DOX-induced endothelial damage, VEGF-B could provide a novel therapeutic possibility for the prevention of chemotherapy-associated cardiotoxicity in cancer patients.

Serum vascular endothelial growth factor B is elevated in women with polycystic ovary syndrome and can be decreased with metformin treatment.

OBJECTIVE: To determine serum vascular endothelial growth factor B (VEGF-B) levels in polycystic ovary syndrome, their association with insulin resistance and ß-cell dysfunction, and the effect of metformin on serum VEGF-B levels. DESIGN: A cross-sectional, interventional study. PATIENTS: We recruited 103 women with polycystic ovary syndrome and 96 age-matched healthy controls. Serum VEGF-B levels were determined in all participants, and 44 polycystic ovary syndrome patients randomly received metformin. MEASUREMENTS: We measured VEGF-B levels in healthy controls and women with polycystic ovary syndrome before and after metformin treatment. RESULTS: Women with polycystic ovary syndrome had higher serum VEGF-B levels, which decreased with metformin treatment. In the lean and overweight/obese groups, patients with polycystic ovary syndrome had higher plasma VEGF-B levels than did healthy controls (P < 0·05). VEGF-B levels were correlated with body mass index, body fat percentage, M values, homeostasis model assessment of insulin resistance and ß-cell function indices. A multiple linear regression analysis showed that VEGF-B level was associated with M values after adjusting for age, body mass index, serum sex hormones and serum lipids in women with polycystic ovary syndrome. CONCLUSIONS: Serum VEGF-B is significantly higher in women with polycystic ovary syndrome and is closely and positively related to insulin resistance. Metformin treatment reduces VEGF-B levels and ameliorates insulin resistance.

Levels of angiogenesis-related vascular endothelial growth factor family in neovascular glaucoma eyes.

PURPOSE: This study aimed to evaluate the angiogenesis-related factors of the vascular endothelial growth factor (VEGF) family in the aqueous humour of patients with neovascular glaucoma (NVG). METHODS: This study involved 22 eyes of 22 patients with advanced NVG requiring antiglaucomatous surgery and 20 control subjects with cataracts. The NVG eyes received an intravitreal injection of ranibizumab (IVR) treatment before antiglaucomatous surgery. Aqueous humour and blood were collected at the time of IVR and cataract surgery. Protein concentration of VEGF-A, VEGF-B and placenta growth factor (PlGF) in aqueous humour and plasma was determined by ELISA tests. RESULTS: The mean concentration (standard deviation) of VEGF-A and PlGF in the aqueous humour of patients with NVG were 3037 (2387) pg/ml and 1078 (712) pg/ml, respectively; both were significantly higher than the control group (both p < 0.001). However, levels of VEGF-A and PlGF in the serum of NVG and control subjects remained low. High concentrations of VEGF-A were closely correlated with high levels of PlGF in patients with NVG (r = 0.593, p = 0.004). Concentrations of VEGF-B in aqueous humour and serum remained unchanged (p > 0.05). CONCLUSION: There were high concentrations of angiogenesis factors of the VEGF family, with the exception of VEGF-B, in the aqueous humour of patients with NVG, and there was a positive correlation between VEGF-A and PlGF. High PlGF levels in patients with NVG may provide another potential target for treatment of NVG.

Clinical association of circulating VEGF-B levels with hyperlipidemia and target organ damage in type 2 diabetic patients.

Vascular endothelial growth factor-B (VEGF-B is an important member of the VEGF protein family. Recent animal studies indicated that VEGF-B signaling had determinant roles in insulin resistance, lipid distribution and metabolism in type 2 diabetes. The clinical significance of VEGF-B in type 2 diabetes is still not clear. This study aimed to correlate VEGF-B levels with biochemistry characteristics and target organ damage in type 2 diabetic patients. Serum VEGF-B levels were measured using ELISA. A crosssectional control study, which included 180 type 2 diabetic patients and 62 healthy subjects, was carried out. Diabetic patients who were undergoing insulin therapy were not included. This results showed that serum VEGF-B levels did not differ between the type 2 diabetic patients and the healthy controls (169.2∓118.8 vs 163.5∓115.2 pg/mL; P=0.734). VEGF-B levels in type 2 diabetic patients were significantly associated with the levels of c-peptide, total cholesterol and triglyceride. T-test analysis showed that the associations of serum VEGF-B levels with insulin resistance, pancreatic reserve, HDL and LDL were not significant. Regression analysis showed that VEGF-B levels were significantly correlated with diabetic retinopathy and nephropathy. No significant association between VEGF-B and macro-vasculopathy was found. In conclusion, our study findings suggested that VEGF-B levels did not differ between the type 2 diabetic patients and the normal controls. High VEGF-B levels might correlate with the presence of hyperlipidemia and target organ damage in type 2 diabetic patients.

Branched-chain amino acids suppress the cumulative recurrence of hepatocellular carcinoma under conditions of insulin-resistance.

Branched-chain amino acids (BCAAs) reportedly inhibit the incidence of hepatocellular carcinoma (HCC) in patients with liver cirrhosis and obesity that is frequently associated with insulin resistance (IR). We previously reported that BCAAs exert a chemopreventive effect against HCC under IR conditions in rats. The aim of the present study was to examine the effect of BCAAs on the cumulative recurrence of HCC under IR conditions in the clinical practice. BCAA granules (Livact®, 12 g/day) were administered for 60 months following the local curative therapy for HCC, and several indices were determined. Treatment with BCAAs markedly inhibited the cumulative recurrence of HCC in patients with a high IR index [homeostasis model assessment (HOMA)-IR >2.5], but not in patients with HOMA-IR of ≤2.5. BCAA also improved the HOMA-IR, and the inhibitory effect was observed regardless of the serum albumin (Alb) levels. Similarly, BCAA treatment revealed a marked suppressive effect in patients with high fasting insulin [immune reactive insulin (IRI)>15 U/ml], but not with IRI of ≤15. BCAA treatment did not result in differences in HCC recurrence in patients with high and low glucose levels [fasting blood sugar (FBS)>110 and ≤110, respectively]. Furthermore, serum levels of the soluble form of vascular endothelial growth factor receptor 2 (sVEGFR2) were significantly inhibited along with these clinical effects. Our findings indicate that the inhibitory effect of BCAAs was achieved, at least partly, by coordinated effects of anti-angiogenesis and IR improvement. Since BCAAs are widely and safely used in clinical practice to treat patients with chronic liver diseases, BCAAs may represent a new strategy for secondary chemoprevention for HCC patients with IR. Moreover, our findings suggest that sVEGFR2 may be a useful clinical predictive marker for BCAA treatment under IR conditions.

Relationship of smoking and fibrosis in patients with chronic hepatitis C.

BACKGROUND & AIMS: Preliminary studies have suggested that in patients with chronic hepatitis C (CHC), cigarette smoking increases the risk for developing liver fibrosis. Hypoxia caused by smoking may induce expression of the cytokines' vascular endothelial growth factor (VEGF) and VEGF-D and their corresponding soluble tyrosine kinase receptors fms-like tyrosine kinase receptor (s-Flt) and kinase insert domain receptor (s-KDR). These cytokine levels are increased in animals with cirrhosis and in human beings with CHC. We studied whether the concentrations of VEGF, VEGF-D, s-Flt, and s-KDR were increased in CHC smokers with and without hepatic fibrosis. METHODS: A total of 170 CHC patients were identified retrospectively from a single center's database. In 59 patients, serum levels of VEGF, VEGF-D, s-Flt, and s-KDR were measured using an enzyme-linked immunosorbent assay. RESULTS: All 170 patients were hepatitis C virus RNA positive, 117 (69%) were men, 43 (25%) were smokers, and their mean (+/-SD) age was 47 (+/-6) years. Overall, 21% of smokers had Metavir fibrosis scores of 3 and 4 compared with 14% of nonsmokers (P < .01). In an age-weighted multivariate model using step-wise logistic regression, smoking, infection with hepatitis C virus genotype 1, male sex, and increased VEGF-D concentration all were significant independent predictors of more severe liver fibrosis (P < .05 for all observations). CONCLUSIONS: These data suggest that CHC patients who smoke may have more hepatic fibrosis. The data also suggest that increased VEGF and VEGF-D concentrations are associated with smoking and may be involved in the molecular mechanisms of fibrogenesis.

Serum vascular endothelial growth factor C (VEGF-C) as a specific biomarker for advanced cervical cancer: Relationship to insulin-like growth factor II (IGF-II), IGF binding protein 3 (IGF-BP3) and VEGF-A [corrected].

OBJECTIVES: An early non-invasive diagnosis of cervical cancer and its metastasis can save lives. We have shown that serum IGF-II levels can be effectively used for a specific early diagnosis of cervical cancer. Here, we shall determine if serum levels of vascular endothelial growth factors B and C (VEGF-A [corrected] VEGF-C) associated with vasculogenic and lymphogenic metastasis may be used for an early diagnosis of advanced metastatic cervical cancer and compare these levels with those of the serum IGF-II and IGF-binding protein 3 (IGF-BP3). MATERIAL AND METHODS: (a) Serum levels of IGF-II, IGF-BP3, VEGF-A [corrected] (VEGF(165)) and VEGF-C (ELISA kits) were determined in: 82 controls with normal Pap smears; 29 women with atypical squamous cells of undetermined significance (ASCUS) and normal cervical biopsy; 46 ASCUS and cervical intraepithelial neoplasia (CIN) on biopsy; 8 pre-therapy CIN-I; 23 successfully treated CIN-I; 75 persistent CIN-I; 14 CIN-II/III pre-therapy; 14 successfully treated CIN-II/III; 70 persistent CIN-II/III; 86 pre-therapy cervical cancer; 26 in early grades of cervical cancer; 21 in late grades of cervical cancer; 22 cervical cancer patients in remission; 50 persistent cervical cancer; 18 with ovarian cancer; and 57 with endometrial cancer. (b) Serial serum samples collected over 5 years in 5 women with progressing cervical cancer were also tested. (c) Serum and tissue VEGF-C were enumerated in 20 matched serum (ELISA) and tissue (semi-quantitative immunofluorescent antibody assay) samples from controls, early cervical cancer, late cervical cancer, ovarian cancer and endometrial cancer patients. Student's t test, chi-square analysis and linear regression analysis were used. RESULTS: (a) As anticipated, serum IGF-II levels were elevated as early as ASCUS with CIN on biopsy and continued to be elevated in CIN (all grades; pre-therapy and persistent) and cervical cancer (pre-therapy, early, late and persistent). Serum IGF-II levels were normal in ASCUS with normal biopsy, successfully treated CIN-I, II/III, cervical cancer as well as pre-therapy ovarian and endometrial cancers (therapy efficacy: P < 0.0001 by chi-square analysis). Serum IGF-BP3 showed a significant decrease with advancing disease. Serum VEGF-A [corrected] levels were the highest in pre-therapy, early, advanced and persistent cervical cancer, as well as in ovarian and endometrial cancers. Serum VEGF-C levels, on the other hand, were the highest in late and persistent cervical cancers, but not in ovarian or endometrial cancers. (b) In the 5 women with serial samples, the serum levels of the growth factors showed similar trends. (c) VEGF-C levels in serum and tissue were elevated in cervical cancers especially in advanced grades, while they were normal in serum and tissue from the controls and women with ovarian and endometrial cancers. There was a highly significant positive correlation between VEGF-C and IGF-II and a negative correlation between IGF-BP3 and VEGF-C (P < 0.0001). CONCLUSION: Serum IGF-II up-regulation is specific to cervical cancer and helps in the early diagnosis of malignant proliferation, while serum VEGF-C up-regulation appears to be a unique marker for an early diagnosis of cervical cancer metastasis. VEGF-C and IGF-II systems appear to be interrelated in cervical cancer, contributing to the early malignant cell proliferation and lympho-vascular metastasis. Serum IGF-BP3 and VEGF-A [corrected] appear to be common markers for all gynecological cancers.