Strong Vascular Endothelial Growth Factor Research Articles

Histopathological Evaluation of Angiogenic Markers in Non-Hodgkin's Lymphoma.

Background Angiogenesis plays a key role in the development, maintenance, and progression of tumor. The incidence of non-Hodgkin's lymphoma (NHL) is increasing from the past three decades. Materials and Methods The aim of the study is to evaluate microvessel density (MVD) using CD34 monoclonal antibody and vascular endothelial growth factor (VEGF) using monoclonal antibody that were studied in pretreatment paraffin-embedded tissue samples of 60 cases. Results MVD was found to be increased in parallel with increasing grade of tumor. B-NHL had a mean MVD of 79.5 ± 8.8 (no./mm 2 ), while T-NHL had a mean MVD of 183 ± 37.6 (no./mm 2 ). VEGF expression was seen in 42 cases (70%), 20 cases (33.3%) showed strong VEGF expression, and the remainder showed either weak (36.6%) or no (30%) staining. Strong VEGF expression is seen in 100% cases of T-NHL and 77.7% cases of B-NHL. Mean MVD and VEGF expression was found to be correlated significantly with the histological grade of NHL ( p = 0.001 and p = 0.000, respectively). Average microvessel counts were 53, 82.9, and 130.8 vessels (no./mm 2 ) for negative, weak, and strong VEGF staining, respectively. These differences were statistically significant ( p = 0.005 for strong vs. negative and p = 0.091 for strong vs. weak VEGF staining individually). Conclusion As the grade of tumor progresses, the angiogenic potential also advances which seems to depend on VEGF. The presence of higher MVD in high-grade lymphomas can be utilized for antiangiogenic drugs.

Expression of Vascular Endothelial Growth Factor in the Placenta of Iraqi Women Complicated with Hypertensive Disorder

During pregnancy, high blood pressure disorder is the most common medical complication in pregnancy. It is the foremost cause of maternal mortality and perinatal diseases. Vascular endothelial growth factor (VEGF) affects the growth of vascular endothelial cells, existence, and multiplying, which are known to be expressed in the human placenta. This study aimed to identify the expression VEGF in the placenta of hypertension and normotensive women. In this study, a cross-sectional study from november 2019 to February 2020. A total of 100 placentae involved 50 hypertensive cases and 50 normotensive groups were assessed. VEGF-A expression in two placentas groups was evaluated by immunohistochemistry techniques. Strong and moderate VEGF expression was seen in syncytiotrophoblasts, stromal and endothelial cells of hypertensive cases, while not seen in hypertensive cases. There were statistically significant differences in VEGF-A expression between hypertensive cases and normotensive group. In conclusion, VEGF-A expression was significantly increased in each of syncytiotrophoblasts, stroma and endothelial cells in the placenta of hypertensive cases, and it could be used to predict the development of hypertension.

The role of hesperidin on healing an incised wound in an experimentally induced diabetic adult male albino rats. Histological and Immunohistochemical Study

Background: Skin ulcers and poor healing are serious problems in diabetic patients. Products of citrus herbal are promising in new studies. Many benefits of hesperidin especially for cutaneous functions including skin healing have been demonstrated.Aim of the Study: The aim of this work was to evaluate the possible healing effect of hesperidin on diabetic skin injury in adult male albino rats.Materials and Methods: Forty adult male albino rats were randomly divided into four equal groups (10 rats, each). Group I: the control; group II: hesperidin; group III: untreated diabetic rats; and group IV, diabetic rats treated with hesperidin. Skin specimens were obtained and processed for histological study using Hematoxylin and Eosin (H & E), Mallory trichrome (M.T) and immunohistochemical study using vascular endothelial growth factor (VEGF) Electron microscopic examination was done. Morphometric measurements of epidermal thickness and area percentage of collagen fibers were carried out followed by statistical analysis.Results: The untreated diabetic group showed incomplete closure and scab covering proliferating epidermis. Another area of self- healed malformed skin revealed reepithelization with increased thickness of epidermis significantly. Epidermal cells showed loss of polarity and in between hyaline material. The underlying dermis revealed a significantly increased disorganized collagen fibers and massive inflammatory cells infiltration. Also, moderate VEGF immunoexpression was observed. Diabetic skin treated with hesperidin revealed complete closure of the wounds with thin apparently normal epidermis. The underlying dermis revealed normal amount of well-organized collagen fibers with few inflammatory cells infiltration and spaces between collagen fibers. Strong positive VEGF immunoexpression was observed reflecting enhanced angiogenesis.Conclusion: Diabetic skin injuries are healing badly in relatively prolonged time. Hesperidin can be used as an adjunctive or alternative agent in diabetic wound giving good cosmetic results.

Evaluation of Angiogenesis in Multiple Myeloma by VEGF Immunoexpression and Microvessel Density.

Background Multiple myeloma (MM) is a plasma cell disorder characterized by monoclonal proliferation of plasma cells in bone marrow. Plasmablastic MM is a morphologic subset of MM, containing ≥2% plasmablasts of all plasma cells. Methods The study included 30 consecutively diagnosed patients of MM (6 plasmablastic, 24 nonplasmablastic) over a span of 2 years. Angiogenesis in MM was assessed by analysis of vascular endothelial growth factor (VEGF) immunoexpression by plasma cells and microvessel density (MVD) using anti-CD34 antibody. CD34 and VEGF immunohistochemical staining was performed in all the 30 cases. Angiogenesis was studied in relation to plasmablastic morphology and clinical profile to determine if any correlation exists between these. Results The mean VEGF expression of 80.83 ± 7.36 in plasmablastic myeloma cases was significantly higher compared with a mean VEGF of 53.54 ±17.09 in nonplasmablastic cases. Most of the cases (66.6%) of plasmablastic myeloma exhibited strong (3+) VEGF expression. The difference in mean VEGF expression between plasmablastic and nonplasmablastic cases was found to be statistically significant ( p = 0.001). The mean MVD in plasmablastic cases was 44.8 ± 3.69, while in the nonplasmablastic category, the mean MVD was 23.7 ± 5.14, difference being statistically significant ( p < 0.05). Also, a positive correlation was found between VEGF expression and MVD. Conclusion A moderate/strong VEGF intensity and higher MVD were found in cases of plasmablastic MM, suggesting that a more aggressive histological disease may be associated with increased production of VEGF. This finding might be helpful to identify a subset of patients with adverse prognosis and to provide antiangiogenic therapy to improve their survival. However, studies comprising larger number of patients are required to bring out a statistical significance to further substantiate these findings.

Diabetes-Induced Inflammation and Vascular Alterations in the Goto–Kakizaki Rat Retina

ABSTRACT Purpose Diabetic retinopathy is characterized by multiple microcirculatory dysfunctions and angiogenesis resulting from hyperglycemia, oxidative stress, and inflammation. In this study, the retina and retinal pigmented epithelium of non-insulin-dependent diabetic Goto–Kakizaki (GK) rats were examined to detect microvascular alterations, gliosis, macrophage infiltration, lipid deposits, and fibrosis. Emphasis was given to the distribution of kinin B1 receptor (B1R) and vascular endothelial growth factor (VEGF), two major factors in inflammation and angiogenesis. Materials and methods 30-week-old male GK rats and age-matched Wistar rats were used. The retinal vascular bed was examined using ADPase staining. The level of lipid accumulation was graded using triglyceride staining with Oil red O. Macrophage and retinal microglia activation, as well as other markers, were revealed by immunohistochemistry and studied with confocal laser scanning microscopy. Results Abundant lipid deposits were observed in the Bruch’s membrane of GK rats. Immunohistochemistry and quantitative analysis showed significantly higher B1R, VEGF, Iba1 (microglia), CD11 (macrophages), fibronectin, and collagen I labeling in the diabetic retina. B1R immunolabeling was detected in the vascular layers of the GK retina. A strong VEGF staining within different retinal cell processes was detected and a pattern of GFAP staining suggested strong Müller cells/astrocytes reactivity. Microgliosis was apparent in the GK retina. A greater tortuosity of the retinal microvessels (an index of endothelial dysfunction) and their increased number were also observed in GK retinas. Conclusions Data suggest retinal vascular bed alterations in spontaneous type 2 diabetic retinas at 30 weeks. Lipid and collagen accumulation in the retina and choroid, in addition to retinal upregulation of VEGF and B1R, microgliosis, and Müller cell reactivity, may contribute to vascular alterations and inflammatory processes.

Impact of vascular endothelial growth factor (VEGF) and hypoxia-inductible factor-1 alpha (HIF-1) expression on the prognosis of locally advanced cervical carcinoma (LACC) treated with radiochemotherapy.

e17023 Background: Combination of radiotherapy plus platinum-based chemotherapy (RT-CT) is considered the standard treatment in LACC. The risk of recurrence after local treatment is around 50-70%. The role of angiogenesis in tumor progression has been shown in large series. The aim of this study was to determinate the impact of the expression of VEGF and HIF-1 on disease-free survival (DFS) and overall survival (OS) in patients with LACC receiving RT-CT. Methods: Expression of VEGF and HIF–1 was assessed by an immunohistochemistry (IHC) assay in 115 cases. Inmunostainning was considered negative (&lt; 10% of cells), slightly positive (&lt; 25%), moderate (26%-50%) and strongly positive (&gt; 50%). A univariate analysis was carried out for each variable using the log-rank test. Subsequently, a multivariate analysis was performed employing Cox’s proportional hazards model. Results: 115 patients (p) with LACC were included and received RT-CT between January/2003 and December/2012. IHC revealed absence of expression of VEGF in 12 (10,4%) cases, slightly positive in 34 (29,6%), moderate in 30 (26,1%) and strongly positive in 39 (33,9%). The expression of HIF-1 was negative in 63 (54,8%) cases and positive (weak or moderate) in 52 (45,2%). 76p (66,1%) showed a complete clinical response (CR), 26p (22,6%) partial response and 13p (11,3%) stable disease or progression. The median follow–up was 35 months (1-140). 56p (48,7%) relapsed. Univariate analysis indicate that ECOG &gt; 1, tumor size ≥ 4,5 cm, FIGO stage III-IVA, lymph nodes positive, non CR, CA125 post-treatment ≥ 35 U/mL, hemoglobin levels &lt;11 mg/dl (basal, nadir and post-treatment), strong expression VEGF and positive expression of HIF – 1 were all associated with a significant lower OS and DFS. In multivariate analysis strong expression of VEGF remained statistically significant, as tumor size, non CR and hemoglobin level post-treatment &lt; 11g/dL. Conclusions: IHC-assessed strong expression of VEGF was independent prognostic factor of shorter OS and DFS in patients with LACC treated with RT-CT. IHC determination of VEGF could be useful in clinical practice.

Chronic Subdural Hematoma: Role of Vascular Endothelial Growth Factor and Craniotomy in Pathophysiology and Prevention of Recurrence

AbstractCurrent body of evidence suggests that the maintenance or enlargement of chronic subdural hematoma (cSDH) is caused by multiple factors. Inflammatory and vascular endothelial growth factor (VEGF)–induced accumulation of hematoma plays an important role in pathophysiology of cSDH. If neomembrane is implicated in the propagation of inflammatory mediators, excision of the culprit membrane becomes essential to treat and prevent recurrence of cSDH. This retrospective study was conducted in a service hospital where 48 cases of cSDH were operated in 2 years. Patients were evaluated clinically and radiologically. Surgical procedure offered included burr hole craniotomy (BHC), twist drill craniotomy (TDC), or craniotomy (Cr) with excision of neomembrane. Cr was offered whenever there was suspicion or evidence of reaccumulation, solid or calcified hematoma formation, nonobliteration of the subdural space, or numerous thick membranes as were demonstrated in imaging. In Cr maximum part of outer neomembrane was excised and margins were coagulated. The excised outer neomembrane was sent for immunohistochemical examination to assess the VEGF expression. Depending on the VEGF expression as seen on the microscope, these expressions were grouped into weak, moderate, or strong VEGF expression. The study showed that cSDH patients with neomembrane formation benefit from Cr. The strong VEGF expression from the excised neomembrane further strengthens the proinflammatory VEGF theory propagation of cSDH. It further proves that excision of the culprit membrane is essential to prevent recurrences.

Biomarkers of angiogenesis as prognostic factors in myelodysplastic syndrome patients treated with hypomethylating agents

Angiogenesis occurs in response to tissue ischemia and wound healing, and contributes to the pathogenesis of a variety of diseases, such as benign and malignant neoplasia. Several studies have measured bone marrow microvessel density (MVD) in MDS patients and acute myeloid leukemia (AML) patients transformed from MDS, and MVD was higher in MDS patients than controls, but was lower than in AML patients. Vascular endothelial growth factor (VEGF) is expressed in bone marrow blast cells, and an autocrine VEGF signaling mechanism has been established in MDS. Increased bone marrow angiogenesis and VEGF concentrations are adverse prognostic features in all of these patients. In this study, 69 patients were treated in two groups: hypomethylating agents or supportive care with oxymetholone±pyridoxine. We evaluated the MVD and VEGF expression of paraffin-embedded bone marrow samples from patients. We also investigated the relationship between angiogenesis-related biomarkers including MVD, VEGF expression, and clinical factors.The patient median age was 65 years, and the median follow-up duration was 28 months. MVD assessment among subtypes of WHO MDS classification showed that the MVD of RCUD was significantly lower than in other types (p=0.02). However, there was no significant difference in VEGF expression according to the subtype of MDS. Although MVD and VEGF expression did not differ between risk groups based on the IPSS, the low risk group tended to have lower expression of angiogenesis-related biomarkers. MDS patients receiving hypomethylating agents had significantly lower MVD expression in responders than in non-responders (6.13±3.38 vs. 9.89±2.10, respectively, p=0.039). In a consecutive evaluation at the time of diagnosis and 3 months after the initial treatment, the group with a decrease or no change of MVD had a higher response rate compared to that in the group with an increase of MVD (92.9% vs. 58.8%, respectively, p=0.045). Adverse prognostic factors included older age, MDS type other than RCUD, a higher IPSS risk group, and abnormal cytogenetics. Although angiogenesis-related markers did not demonstrate any significant prognostic association with survival, MVD (≥10n/mm2) and a strong expression of VEGF seemed to be associated with lower survival rate.These data suggested that the MVD value might be helpful in predicting responsiveness to treatment, especially in MDS patients treated with hypomethylating agents. Although angiogenesis-related markers including VEGF did not demonstrate a significant association with survival outcomes, we observed that high MVD and strong VEGF expression seemed to be associated with lower survival rate. Therefore, biologic markers related to angiogenesis might have a potential as prognostic factors for MDS patients.

Gastric cancer-associated enhancement of von Willebrand factor is regulated by vascular endothelial growth factor and related to disease severity.

Backgroundvon Willebrand factor (vWF) is a potent regulator of angiogenesis, tumor growth, and metastasis. Yet, the expression pattern of vWF in human gastric cancer (GC) tissues and its relation to clinicopathological features of these cases remains unknown.MethodsTumor and 5-cm adjacent non-tumoral parenchyma specimens were collected from 99 patients with GC (early stages I/II and late stages III/IV), and normal specimens were collected from 32 healthy controls (reference group). Plasma vWF antigen (vWF:Ag) and vWF activity were assessed by ELISA. The role of vascular endothelial growth factor (VEGF) in differential vWF expression was investigated using cultured human umbilical vein endothelial cells (HUVECs). vWF and VEGF protein and mRNA expression levels were investigated by qRT-PCR, western blotting and immunohistochemistry (IHC) respectively. The correlation of IHC-detected vWF expression with patient clinicopathological characteristics was analyzed.ResultsCompared to the reference group, the patients with late GC showed significantly higher levels of vWF:Ag (72% (21-115) vs. 101% (40-136)) and vWF activity (62% (20-112) vs. 117% (33-169)) (both P < 0.001). The GC tumor tissues also showed higher vWF mRNA and protein levels than the adjacent non-tumoral parenchyma. Patients at late GC stage had significantly higher median number of vWF-positive cells than patients at early GC stage (P < 0.05). VEGF induced vWF mRNA and protein expression in HUVECs in dose- and time-dependent manners. Patients with late GC stage also had significantly higher serum VEGF than patients at early GC stage (23 ± 26 vs. 10 ± 12 pg/mL, P < 0.01). Most of the undifferentiated GC tumor tissues at late disease stage exhibited strong VEGF and VEGFR2 protein staining, which co-localized with the vWF protein staining pattern.ConclusionsGC-related plasma vWF:Ag and vWF activity levels become substantially elevated in the late stage of disease. The higher mRNA and protein expression of vWF in GC tumor stroma may be regulated by the VEGF-VEGFR2 signaling pathway in vitro and may contribute to GC progression in vivo.

Human ciliary epithelium as a source of synthesis and secretion of vascular endothelial growth factor in neovascular glaucoma.

Retinal ischemia-induced upregulation of vascular endothelial growth factor (VEGF) leads to endothelial proliferation of the anterior segment, resulting in neovascular glaucoma. To investigate the ciliary epithelium as a possible source of VEGF in human eyes enucleated for intractable neovascular glaucoma. In this proof-of-concept, laboratory-based study, 16 human enucleated eyes (8 with neovascular glaucoma and 8 as controls) were investigated. Presence of VEGF by immunohistochemical analysis (VEGF protein) and in situ hybridization (VEGF messenger RNA). In eyes with neovascular glaucoma, strong VEGF immunoreaction in the nonpigmented epithelial cells of the ciliary processes and in the retina was noted. In situ hybridization for VEGF messenger RNA revealed a similar pattern, with positive stain results only in eyes with neovascular glaucoma. A minimal amount of VEGF immunostaining was seen in control eyes. The nonpigmented ciliary epithelium is an important site of VEGF synthesis in patients with neovascular glaucoma. The ciliary epithelium may represent an additional focus of treatment in the management of neovascular glaucoma, especially in eyes that are nonresponsive to panretinal photocoagulation.

Correlation between ¹⁸F-fluoromisonidazole PET and expression of HIF-1α and VEGF in newly diagnosed and recurrent malignant gliomas.

Hypoxia and its consequences at the molecular level promote tumour progression and affect patient prognosis. One of the main early cellular events evoked by hypoxia is induction of hypoxia-inducible factor 1 (HIF-1) and subsequent upregulation of vascular endothelial growth factor (VEGF). In this study we sought to determine whether hypoxia detected by (18)F-fluoromisonidazole (FMISO) PET accurately reflects the expression of HIF-1α and VEGF in the tumour and can be used as a biomarker of antiangiogenic treatment and as a prognostic factor in newly diagnosed and recurrent malignant gliomas. Enrolled in this study were 32 patients with newly diagnosed glioma and 16 with recurrent glioma of grade III or grade IV. All the patients had undergone FMISO PET preoperatively. The maximum tumour-to-blood FMISO activity ratio (T/Bmax) was used to evaluate the degree of tumour hypoxia and the hypoxic volume (HV) was calculated using a tumour-to-blood FMISO uptake ratio of ≥1.2. Immunohistochemical expressions of HIF-1α and VEGF were evaluated semiquantitatively using the immunoreactivity score (IRS, scores 0 to 12) and the correlation was examined between IRS of HIF-1α or VEGF and FMISO uptake of the tumour (SUVtumour) using navigation-based sampling. Survival was estimated using the Kaplan-Meier method in relation to the T/Bmax and the HV. The T/Bmax and the HV in grade IV gliomas were significantly higher than in grade III gliomas (P < 0.01 and P < 0.01, respectively). Moderate to strong HIF-1α and VEGF expression was observed in the majority of malignant gliomas. The IRS of HIF-1α and VEGF in the tumour were not significantly different between grade III and grade IV gliomas. The IRS of HIF-1α in the tumour did not correlate with the SUVtumour of FMISO in either newly diagnosed or recurrent glioma. There was a significant but weak correlation between the IRS of VEGF and the SUVtumour of FMISO in newly diagnosed glioma, but not in recurrent glioma. The overall survival time in patients with a small HV and a low FMISO T/Bmax was significantly longer than in those with a large HV and a high FMISO T/Bmax (P < 0.01 and P < 0.05, respectively). Preoperative FMISO uptake is significantly correlated with the expression of VEGF in the tumour and might be used as a biomarker of antiangiogenic treatment in newly diagnosed malignant gliomas. However, caution is required because the correlation was weak and there was a large overlap of FMISO uptake between glioma with high and low VEGF expression. In addition, hypoxia determined by FMISO PET appears to be a suitable biomarker for predicting a highly malignant tumour and a poor prognosis in patients with malignant glioma.

Role of vascular endothelial growth factor, survivin, and inducible nitric oxide synthase expression in psoriasis: an immunohistochemical study

Background Psoriasis (PS) is a common chronic, relapsing, immune-mediated disease involving the skin and joints of genetically predisposing individuals. Despite numerous studies, the pathogenesis of PS has not been fully elucidated. However, many pathogenic theories have been suggested. There is much evidence that PS is a polygenic disease modified to expression by triggering factors. PS is characterized by hyperproliferation and abnormal differentiation of epidermal keratinocytes, lymphocyte infiltration consisting mostly of T lymphocytes, and various endothelial vascular changes in the dermal layer, such as angiogenesis, dilation, and high endothelial venule formation. Vascular endothelial growth factor (VEGF) is a major regulator of physiological and pathological angiogenesis, causing aberrant angiogenesis and vascular leakage in the upper dermis; it may also contribute to keratinocyte proliferation and epidermal barrier homeostasis in PS. Inducible nitric oxide synthase (iNOS) was found to be expressed in the keratinocytes of psoriatic lesions; in addition, there is increased expression of iNOS-specific mRNA transcripts. Survivin upregulation in psoriatic lesion in comparison with normal skin was evident, suggesting its role in the pathogenesis of PS. The aim of this study was to investigate the immunohistochemical expression of VEGF, survivin, and iNOS in psoriatic skin and to detect their role in the pathogenesis of PS. Patients and methods This study was carried out on 20 patients with PS vulgaris. Immunohistochemical reactions were carried out using the streptavidin-biotin immunoperoxidase system in this study to detect the extent of expression of VEGF, survivin, and iNOS in each specimen of the skin biopsy. Results A strong VEGF expression through the epidermis (mean 46.4 ΁ 19.7) was observed. VEGF was significantly upregulated in psoriatic skin in comparison with normal healthy skin ( P P P Conclusion VEGF, survivin, and iNOS appeared to be important factors in the pathogenesis of PS.

Vascular endothelial growth factor expression in hepatitis C virus (HCV)-related advanced hepatocellular carcinoma (HCC) compared with hepatitis B virus (HBV)-related advanced HCC.

4115 Background: HCC with different etiologic factors may result in activation of different signaling pathways. This study aimed to clarify if HBV-related HCC (HBV-HCC) and HCV-related HCC (HCV-HCC) may have difference in the expression of key molecules that are relevant to contemporary molecular targeted therapy. Methods: We enrolled patients diagnosed with advanced HCC from 2001 to 2011 who had tumor tissues obtained upon the diagnosis of advanced HCC at our center. Tumor slides were immunohistochemically stained for phosphorylated extracellular signal-regulated kinases (p-ERK), Raf kinase inhibitory protein (RKIP), and vascular endothelial growth factor (VEGF). The expressions of p-ERK and RKIP were evaluated according to percentages of positive-staining cells and graded as: 0: 0; 1+: 1-10%; 2+: 11-50%; 3+: &gt; 50%. Grades 0 and 1 were considered negative, and grades 2 and 3 positive. VEGF staining was evaluated as strong or weak according to staining intensity. The staining results of VEGF were further recorded as H scores, defined as intensity (0, 1, 2, or 3) × percentages of positive staining. Results: In total, 131 patients were enrolled in this study; 94 (72%) patients had HBV-HCC, and 37 (28%) patients had HCV-HCC. HBV-HCC and HCV-HCC had similar expression of p-ERK (positive: 45% vs. 51%, p = 0.491) and RKIP (positive: 83% vs. 84%, p = 0.912). HCV-HCC was more likely to have strong VEGF staining than HBV-HCC (95% vs. 72%, p = 0.005) and higher H scores for VEGF staining (289.5 vs. 248.8, p&lt; 0.001). In multivariate analysis adjusting for age, sex, macrovascular invasion, extrahepatic metastasis, and α-fetoprotein level, HCV-HCC remained an independent factor associated with strong VEGF staining. VEGF staining intensity was not associated with age, sex, macrovascular invasion, extrahepatic metastasis, and α-fetoprotein level. Conclusions: HCV-HCC has stronger VEGF expression than HBV-HCC. (This study was supported by the grant of NSC101-2314-B-002-141, 100CAP1020-2, and NTUH.101-N1965.)

Predictive significance of VEGF and HIF-1α expression in metastatic colorectal cancer patients receiving chemotherapy combined with bevacizumab.

e14672 Background: There is no suggested molecular indicator in identifying which patients will benefit from anti-angiogenic treatment in metastatic colorectal cancer. Over expression of vascular endothelial growth factor (VEGF) and Hypoxia Inducible Factor 1-alpha (HIF-1α) are associated with bad prognosis. In this study, VEGF and HIF-1α expression and their clinical significance are studied in tumor tissues of patients with colorectal cancer receiving treatment with bevacizumab. Methods: VEGF and HIF-1α were observed immunohistochemically in primary tumors of 53 patients. The expressions were separated by evaluating low and high of VEGF and HIF-1α expression. We evaluated whether expression of VEGF and HIF-1α can help to predict treatment response, progression free survival (PFS), and overall survival (OS). Results: Fifty-three patients were enrolled in the study. Median age was 55. VEGF was strongly expressed in 30 patients (57%) whilst low expression was observed in 23 of them (43%). When VEGF expression was evaluated in association with therapy response rates; the clinical benefit rate was 38% in the low expression group whereas it was 62% in high expression group. This difference was statistically significant (p=0.01). In the group with strong VEGF expression PFS was 10 months whereas it was 8 months in the low expression group (p=0.009). When evaluated for OS, 26 months versus 15 months was in favor of highly expressed VEGF group (p=0.03). Highly expressed HIF-1α was found in 29 patients (55%), on the other hand low expressed HIF-1α was detected in 24 (%45) patients. For clinical benefit rates, PFS and OS there was no difference between high and low expressed HIF-1α groups. Conclusions: It has been demonstrated that VEGF and HIF-1α expressions are associated with poor prognosis in several tumors, mainly colorectal carcinomas. With the better understanding of carciogenesis and angiogenesis at molecular level, especially VEGF and HIF-1α became target molecules of the therapy. According to results of our study, VEGF expression is a predictive factor in designating the metastatic colorectal cancer treatment.

Vascular endothelial growth factor expression and angiogenesis in various grades and subtypes of meningioma

Vascular endothelial growth factor (VEGF) expression has been extensively studied in astrocytoma, whereas relatively less literature exists on VEGF expression in meningioma. Patients operated for meningioma from 2006 to 2011 (n = 46) were included. Tumor was subtyped and graded as per WHO grading. Immunohistochemistry was performed for MIB labeling index, VEGF, and CD 34 staining. The patterns of VEGF expression in various histological subtypes and grades and its correlation with microvascular density were analyzed. This series consisted of 40 Grade I meningioma, 4 Grade II tumors, and 2 Grade III tumors. While 14 (30.4%) tumors showed no staining with VEGF antibody, 32 (69.6%) were positive for VEGF. Sixty five percent of Grade I tumors showed VEGF positivity, while 100% of Grade II and Grade III tumors were VEGF positive (P = 0.157). The mean microvascular density in VEGF-negative tumors was 9.00, while that of VEGF-positive tumors was 17.81(P = 0.013). There was a gradual increase in microvascular density from tumors which are negative for VEGF to tumors which expressed moderate to strong VEGF, the difference being statistically significant (P = 0.009). VEGF expression correlated with the microvascular density in meningioma irrespective of tumor grade, with a gradual increase in microvascular density in relation to the VEGF score.

Increased Angiogenesis-associated Poor Outcome in Acute Lymphoblastic Leukemia

Angiogenesis in solid tumors is important for tumor growth, invasion, and metastasis. However, angiogenesis plays also an important role in hematological malignancies. We have analyzed the expression of vascular endothelial growth factor (VEGF) in the leukemic blast cells and microvessel density (MVD) in the bone marrow biopsy samples of the patients with acute lymphoblastic leukemia (ALL). Bone marrow MVD of the patients with ALL was significantly higher compared with normal controls and complete remission (P<0.001), but slightly lower than in patients with relapsed ALL (P>0.05). The bone marrow blast VEGF expression was significantly higher in newly diagnosed ALL patients, with predominant strong VEGF expression as compared with complete remission patients (who had negative or weak VEGF expression) (P<0.05), whereas initial values were slightly lower than in relapsed patients. There was a strong positive correlation between VEGF expression and MVD at presentation of ALL. Stronger expression of VEGF on blast cells indicates shorter overall survival in ALL. Furthermore, initial values of MVD had positive correlation with overall survival and leukemia-free survival (P=0.024 and P=0.017, respectively). Our data suggest that increased angiogenesis (confirmed by immunohistochemical expression of VEGF in leukemic blasts), and MVD may play an important role in the pathophysiology of ALL with prognostic implications. Thus, targeting VEGF pathway may bring the new approach for ALL treatment-using antiangiogenic drugs and tyrosine kinase inhibitors in combination with standard chemotherapy regimens.

Difference in Pre- and Postchemotherapy Vascular Endothelial Growth Factor Levels as a Prognostic Indicator in Osteosarcoma

This retrospective analysis examined the difference in pre- and postchemotherapy levels of vascular endothelial growth factor (VEGF) as an indicator of osteosarcoma prognosis. VEGF protein levels were assessed immunohistochemically in primary tumour samples from 61 osteosarcoma patients diagnosed between February 2001 and July 2005. The difference in pre- and postchemotherapy VEGF protein reduction levels was categorized into weak (23 patients) and strong (38 patients). The 5-year survival rate was significantly lower in the weak VEGF reduction group (34.8%) than in the strong VEGF reduction group (73.7%). The weak VEGF reduction group had significantly higher rates of metastasis and recurrence. Multivariate analysis confirmed that the change in VEGF was an independent and significant factor for predicting a good prognosis. The analysis of VEGF will enable clinicians to tailor surgery and chemotherapy regimens more appropriately, earlier in the disease process.

Effect of Intravitreal Bevacizumab on Vascular Endothelial Growth Factor Expression in Patients with Proliferative Diabetic Retinopathy

PurposeTo investigate the effect of bevacizumab (Avastin; Genentech, San Francisco, CA, USA) on vascular endothelial growth factor (VEGF) expression and inflammation in fibrovascular membranes in patients with proliferative diabetic retinopathy (PDR).Materials and MethodsFibrovascular membranes from 19 eyes of 18 patients with PDR were studied using immunohistochemistry and analyzed in the following 3 groups; group 1: 4 inactive PDR eyes, group 2: 10 active PDR eyes treated preoperatively with adjunctive intravitreal bevacizumab, group 3: five active PDR eyes not treated preoperatively with bevacizumab. Immunohistochemical staining for VEGF, CD31 and CD68 were done.ResultsThe immunoreactivity to VEGF and CD 31-positive blood vessels was significantly higher in membranes from group 3 than group 1 (p = 0.007 for VEGF, 0.013 for CD 31-positive vessels). Intravitreal bevacizumab caused a reduction in VEGF expression and vascular densities in 4 out of 10 (40%) excised membranes from eyes with PDR. However, six membranes (60%) in group 2 still demonstrated relatively strong VEGF expression and high vascular density. Infiltration of macrophages was observed in 16 out of the 19 membranes, and the density of macrophages was increased in group 2 compared with group 1 (p = 0.043).ConclusionIntravitreal bevacizumab injections caused some reduction in VEGF expression and vascular densities in a limited number of active PDR patients. A single intravitreal bevacizumab injection may not be enough to induce complete blockage of VEGF and pathologic neovascularization in active PDR patients. Repeated injections, panretinal photocoagulation and/or PPV may be necessary following intravitreal bevacizumab to reinforce the anti-VEGF effect of the drug.

INTRAOCULAR AND SERUM LEVELS OF VASCULAR ENDOTHELIAL GROWTH FACTOR IN ACUTE RETINAL NECROSIS AND OCULAR TOXOPLASMOSIS

To determine the intraocular and serum vascular endothelial growth factor (VEGF) levels in patients with acute retinal necrosis (ARN) and compare those with VEGF levels found in patients with ocular toxoplasmosis (OT). Paired intraocular fluid and serum samples of 17 patients with ARN and of 16 patients with OT were analyzed by ELISA for VEGF levels, and the clinical records were reviewed. The mean intraocular VEGF levels in patients with ARN were higher than in patients with OT (P = 0.005), whereas the serum levels did not differ. Intraocular VEGF levels exceeded the serum levels in 8 of 17 patients (47%) with ARN compared with 1 of 16 patients (6%) with OT (P = 0.009). The group with high intraocular VEGF was associated with a more extensive retinitis and lower visual acuity at 3-month follow-up (P < 0.001 and P = 0.031, respectively). Intraocular VEGF levels were elevated in patients with ARN compared with OT patients. Our results suggest strong intraocular VEGF production in ARN, which might be of importance for the treatment of these patients.

HIF-1's Role in Estrogen-induced VEGF Expression: Implications for both Normal and Pathological Cell Proliferation.

Vascular endothelial growth factor (VEGF) is a potent inducer of vascular hyperpermeability and the key mediator of angiogenesis, both of which are involved in normal development and reproduction, as well as cancer and other diseases. VEGF is rapidly and strongly induced in endometrial epithelial cells by 17beta-estradiol (E2). We have proposed that this "immediate-early" response is the key to E2-induced cell proliferation. Recently, we linked E2-induced VEGF expression in the endometrium to the transcription factor hypoxia-inducible factor 1alpha (HIF-1alpha), which regulates over 100 genes essential for cellular adaptations to low oxygen and other stresses. E2, via the PI3K/Akt pathway, induces the rapid recruitment of both HIF-1alpha and ERalpha to the VEGF gene promoter. In contrast to the endometrium, however, E2 has little or no effect on VEGF expression in breast and endometrial cancer cells in vitro. We recently resolved this inconsistency by showing that the lack of E2 induction in vitro is due to a deficiency of HIF-1alpha caused by the high oxygen level to which cultured cells are exposed. Restoration of HIF-1alpha in endometrial and breast cancer cells restores rapid and strong VEGF expression by E2. Thus, VEGF-induced vascular hyperpermeability, which floods tissues with plasma proteins, should now be considered a potential mediator of E2-induced cell proliferation in both normal target tissues and E2-dependent tumors. In summary, we have for the first time linked E2 action to HIF-1alpha activation and VEGF expression, thereby providing new insight into E2's effects in target tissues, and into possible treatments for E2-associated cancers. (platform)