High Vascular Endothelial Growth Factor Research Articles

High Tumor Vascular Endothelial Growth Factor Expression Is Associated With Poorer Clinical Outcomes in Resected T3 Gastric Adenocarcinoma.

To investigate the clinical and prognostic significance of high vascular endothelial growth factor (VEGF) expression in resected T3 gastric adenocarcinoma (GA). Data of VEGF expression on 453 patients with resected T3 GA were collected from a single institute in Fuzhou, China. VEGF expression in the resected tumor tissues was evaluated by immunohistochemistry (IHC). Associations between VEGF expression outcomes and prognosis were investigated using by the χ(2) test, Kaplan-Meier plus log-rank test, and univariate and multivariate Cox models. In total, 48.6% (220/453) patients had low VEGF expression (IHC score ≤2+). Patients with high VEGF expression (IHC>2+; 233/453, 51.4%) had significantly poorer median recurrence-free survival time (20 vs 55 months, P < 001) and median overall survival time (28 vs 58 months; P < 001) than patients with low VEGF. High VEGF was associated with higher overall recurrence (68.2% vs 51.4%, P = 2.675 × 10(-4)), poorer overall survival (27.5% vs 47.3%, P = 1.719 × 10(-5)), and increased risk of recurrence (hazard ratio [HR], 1.71; 95% confidence interval [CI], 1.33-2.19; P = 2.43 × 10(-5)) and death (HR, 1.80; 95% CI, 1.41-2.3; P = 2.19 × 10(-6)). High VEGF expression is associated with a higher risk of recurrence and shorter survival in resected T3 GA. These findings may provide a foundation for evaluating VEGF-targeted molecular therapies in T3 GA.

Evaluation of vascular endothelial growth factor gene and protein expression in canine metastatic mammary carcinomas.

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that could be associated with the induction of endothelial cell proliferation and metastasis. In this study, we evaluated VEGF gene and protein expression in canine mammary tumors (CMT), including metastatic carcinomas, to determine if there is an influence of this marker in the malignant processes and aggressiveness of CMT. We also compared VEGF protein levels with clinicopathological features. The VEGF gene and protein expression levels were evaluated by reverse transcription-quantitative polymerase chain reaction and immunohistochemistry, respectively, in normal mammary gland samples, benign mammary tumors, nonmetastatic mammary carcinomas, and metastatic mammary carcinomas. High VEGF gene and protein levels were associated with malignant tumors compared with normal mammary glands (p = 0.0089 and p < 0.0001, respectively). Benign tumors showed an increased VEGF protein expression compared with normal samples (p = 0.0467). No significant differences in VEGF gene or protein levels were detected between benign and malignant tumors or between nonmetastatic and metastatic carcinomas, suggesting an absence in the correlation of VEGF with malignant processes and aggressiveness of CMT. No correlation of VEGF expression with clinical and histopathological parameters was observed, suggesting that VEGF could be important in the beginning of the mammary gland carcinogenic process and could be related to survival time.

Monoclonal gammopathy of cutaneous significance: review of a relevant concept.

Some dermatologic entities are strongly associated with the presence of a monoclonal gammopathy. They should be referred to as monoclonal gammopathy of cutaneous significance (MGCS). A short review of the main entities that fit into the spectrum of MGCS is provided. Amyloidosis, macroglobulinoderma and follicular hyperkeratotic spicules result from extravascular immunoglobulin or immunoglobulin-related protein deposition. Skin findings include papules and plaques, follicular spicules, purpura, haemorrhagic bullae, macroglossia and nail changes. The skin findings in cryoglobulinemia (CG) result from vascular immunoglobulin deposition, either as immune complexes within the vessel walls in mixed CG or within the lumina of small vessels in monoclonal CG. Mixed CG manifests as palpable purpura of leukocytoclastic vasculitis, and monoclonal CG as stellar and/or retiform purpura that can evolve into extensive skin necrosis. In some rare instances, immunoglobulins have a specific biological activity. This is, for example, the case when they bind lipoproteins that precipitate and induce hypocomplementemic xanthomas. Xanthoderma related to antiflavin activity of the monoclonal component or acquired angioedema related to anti-C1INH activity is other example. Abnormal cytokine secretion is the hallmark of some entities. High vascular endothelial growth factor levels correlate with some of the skin manifestations of the Polyneuropathy organomegaly endocrinopathy monoclonal component skin changes syndrome, such as hypertrichosis or the adenopathy and extensive skin patch overlying plasmacytoma syndrome. All the clinical manifestations of the Schnitzler syndrome are IL-1 mediated. In other MGCS, such as scleromyxedema, Clarkson syndrome, TEMPI syndrome, cutis laxa and the neutrophilic dermatoses, the link between the monoclocal component and the entity is clearly established, but not understood so far.

Serum levels of Dkk-1, sclerostin and VEGF in patients with ankylosing spondylitis and their association with smoking, and clinical, inflammatory and radiographic parameters

ObjectiveTo evaluate serum Dickkopf-1 (Dkk-1), sclerostin and vascular endothelial growth factor (VEGF) levels in patients with ankylosing spondylitis (AS) compared to healthy controls as well as their association with smoking, and clinical, inflammatory and radiographic parameters. MethodsSerum samples for total Dkk-1, sclerostin and VEGF were obtained from 57 tumour necrosis factor (TNF) inhibitor naïve patients with AS and 34 sex-, age- and body mass index (BMI)-matched controls. The erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Bath AS Disease Activity Index (BASDAI), Bath AS Functional Index (BASFI), modified Stroke AS Spine Score (mSASSS) and smoking status were assessed for each patient. ResultsThere was no significant difference in serum bone metabolism markers between AS patients and controls. Dkk-1 levels were significantly (P<0.05) higher in AS patients with elevated ESR and CRP and no syndesmophytes, and were significantly (P<0.001) correlated with sclerostin levels (r=0.592). VEGF levels were significantly (P<0.05) higher in AS patients with current and ever smoking, elevated ESR and CRP, and high BASDAI and BASFI, and were significantly (P<0.05) correlated with ESR (r=0.284), CRP (r=0.285), BASDAI (r=0.349) and BASFI (r=0.275). In multivariate regression analyses, high Dkk-1 levels were significantly (P≤0.001) associated with elevated ESR and CRP, no syndesmophytes and high sclerostin levels, and high VEGF levels significantly (P<0.05) with ever smoking, and elevated ESR and CRP. ConclusionIn AS, serum Dkk-1 concentrations appear to be related not only to syndesmophyte formation but also to systemic inflammation. Furthermore, high VEGF levels may be associated with smoking exposure.

The effects of ethanol on angiogenesis after myocardial infarction, and preservation of angiogenesis with rosuvastatin after heavy drinking.

The cardioprotective effects of moderate alcohol consumption and statins have been known for years. However, heavy or binge drinking confers a high risk of cardiovascular disease. This study aimed to investigate the effects of different levels of alcohol consumption on acute myocardial infarction that was induced experimentally in rats, with a focus on the potential mechanism of angiogenesis and the effects of statins on heavy drinking. The experimental rats were fed low-dose ethanol (0.5g/kg/day), high-dose ethanol (5g/kg/day), and high-dose ethanol with rosuvastatin (10mg/kg/day) during the entire experiment. Acute myocardial infarctions were induced 4 weeks after the beginning of the experiment. We assessed the capillary density in the myocardium via immunohistochemistry and quantified the expression of vascular endothelial growth factor (VEGF) and endostatin via enzyme-linked immunosorbent assay kits on the 4th day after myocardial infarction. The results revealed that low ethanol consumption promoted angiogenesis in association with higher VEGF and lower endostatin. High ethanol intake suppressed angiogenesis with unchanged VEGF and elevated endostatin. Treatment with rosuvastatin preserved angiogenesis following high ethanol intake, with an upregulation of VEGF. This study highlights that low ethanol consumption obviously promotes angiogenesis in myocardial-infarction rats while increasing the expression of VEGF, whereas high ethanol consumption inhibits ischemia-induced angiogenesis. This study also provides evidence that rosuvastatin alleviates the inhibitory effects of heavy drinking on angiogenesis.

Vascular endothelial growth factor levels in patients with obstructive sleep apnea: a meta-analysis.

Published articles regarding the blood levels of vascular endothelial growth factor (VEGF) in obstructive sleep apnea (OSA) patients are contradictory. The objective of this study was to explore whether VEGF levels is high or not in OSA subjects via quantitatively statistical analysis. The electronic databases of Pubmed, Web of Science, EMBASE were systematic searched. The VEGF levels and clinical characteristics of participants between OSA group and control group were extracted for analysis. Weighted mean difference (WMD) or standard mean difference (SMD) with 95% confidence interval (CI) was calculated by fixed effects or random effects model. Appropriate statistical software was employed for data synthesis. Totaling 15 articles with 697 participants were included in this study. Pooled meta-analysis showed that blood VEGF concentrations were significantly higher in OSA patients than in control subjects (SMD 1.89, 95% CI 0.92-2.87, p=0.000). Subgroup analysis demonstrated that when compared with control group, OSA patients with age ≥50years (SMD 2.54, 95% CI 1.28-3.80, p=0.000), apnea hypopnea index ≥30 events/h (SMD 2.47, 95% CI 1.20-3.73, p=0.000) had higher VEGF levels. Compared with control subjects, OSA patients had an elevated VEGF in serum (SMD 3.55, 95% CI 1.82-5.28, p=0.000) rather than in plasma. High blood VEGF concentrations were observed in OSA patients, particularly in the older and more serious patients.

High Ki-67 and Vascular Endothelial Growth Factor (VEGF) Protein Expression as Negative Predictive Factor for Combined Neoadjuvant Chemotherapy in Young Age Stage III Breast Cancer

Background: Breast cancer was, in general, a heterogeneous disease with diverse biological characteristics, types, subtypes and clinical behavior. Its treatment and management need to be personalized and individualized. Breast cancer in young ages, although rare, is usually a unique and more aggressive cancer associated with poorer prognosis. The combination of young age and advanced stages of breast cancer would make this particular breast cancer harder to treat and cure. Unfortunately, majority of Breast Cancer Patients in Bali were in younger ages, and at advanced stages, that the mainstay of treatment was neo adjuvant chemotherapy followed by other treatment modalities. Improve prognosis only, those patients who had had a complete pathological response involving primary tumor and regional lymph nodes in the axilla. Several factors had been studied and contributed to breast cancer response to combined neo-adjuvant chemotherapy. Usually, younger patients, was associated with high proliferation rate represented by Ki-67 and early distant metastasis represented by VEGF, which also had role as prognostic markers. The purpose of this study was to determine whether high Ki-67 and VEGF expression correlate with response to NAC and hence, they would be important predictive factors for response to NAC. Method: This study was a cross-sectional and a nested case-control study of stage III breast cancers affecting patients 40 years of age or less, at Sanglah General Hospital and Prima Medika Hospital, conducted from September 1st, 2012 until March 31st, 2014. Clinical and pathology reports were traced and recorded from both hospitals; routine Immunohistochemistry (IHC) examinations were performed by both pathology labs. Statistical analysis was performed using Chi-Square test, Odds Ratio (OR), and logistic regression analysis with p<0.05. Results: There were 66 Stage III young breast cancer patients, where 35 (53%) showed no or negative response and 31 (47%) showed a positive response. Cross-sectional analysis showed that there was a significant correlation between positive Ki-67 protein expression and response to NAC (p<0.05; OR 5.538; 1.856 – 16.524; 95% C.I.) and between positive VEGF protein expression and response to NAC (p<0.05; OR. 3.455; 1.251-9.539; 95% C.I.). In Case-Control study, bivariate analysis from 62 samples had shown that higher Ki-67 expression in the study group compared to control group (p=0.004; OR. 4.747; 1.575-14.312; 95% C.I.). Bivariate analysis also showed that VEGF expression was also higher in the study group compared to control group (p=0.042; OR.2.879; 1.026-8.074; 95% CI.). Multivariate analysis had shown that an adjusted OR. 4.747 (1.575-14.312; 95% C.I.; p=0.006) for Ki-67, and an adjusted OR. 2.553 (0.860-7.582; 95% C.I.; p=0.091) for VEGF. Conclusion: We concluded that high Ki-67 and VEGF protein expression was associated with less response to combined neo-adjuvant chemotherapy/NAC and that high Ki-67 protein expression was an independent risk factor for poorer response to NAC in Stage III young age breast cancer. The possible role of high VEGF expression as a risk factor for less responsive breast cancer in younger patients had to be considered.

Expression of vascular endothelial growth factor and microvessel density in gerbil model with inoculated hepatic alveolar echinococcsis

Objective To study the expression of vascular endothelial growth factor (VEGF) and microvessel density (MVD, CD34) in inoculated hepatic alveolar echinococcsis gerbil model and explore the clinical significance. Methods Sixty healthy gerbils were randomly divided into model group, control group and sham operation group. Each gerbil in both model and control groups had liver vaccination with 0.1 ml immature alveolar echinococcus protoscolex suspension or 0.1 ml phosphate buffered saline by open abdominal surgery, respectively, and the sham operation group only had abdominal surgical procedures. Gerbils were put to death on the 120th day post operation, extracted the eyeball and drawn the blood. The alveolar hydatid tissue, surrounding and distal liver tissue were removed from the model group, and normal liver tissue was collected from the other two groups. The VEGF and MVD-CD34 expression was detected by immunohistochemistry staining, Western Blot, and enzyme-linked immunosorbent assay (Elisa). Results Liver alveolar echinococcsis tissue was only observed in model group. The VEGF expression was observed as yellow or brown yellow granules located in the cytoplasma. The VEGF score and VEGF/β-actin ratio in the different parts were 5.13±1.81 and 1.12±0.05, 4.20±1.52 and 0.91±0.02, 2.46±1.06 and 0.28±0.02, 2.20±0.77 and 0.30±0.02, 2.13±1.72 and 0.25±0.01, respectively. The VEGF expression in different histological sites showed a gradient change, and bubble hydatid tissues had the highest VEGF expression (P<0.05). CD34 was expressed in alveolar hydatid tissue and surrounding liver tissue in model group and the CD34 positive cells was stained brown, while CD34 was mainly located in the cell membrane of endothelial cells. The CD34 scores and the CD34/β-actin ratio in the different parts were 5.06±2.46 and 0.66±0.01, 2.43±1.26 and 0.58±0.02, and the other tissues did not have CD34 expression. The alveolar hydatid tissue had higher CD34 expression than any other tissues (P<0.05). The respective serum VEGF and CD34 level in each group was (106.17±14.17)pg/ml, (38.13±21.36)pg/ml, (42.88±17.25)pg/ml, and (1.47±0.28)ng/ml; (0.82±0.12)ng/ml, (0.72±0.16)ng/ml, both are higher in model group than those in the other groups with statistical significance (P<0.05). Conclusion Angiogenesis is detected in gerbil alveolar hydatid tissues, which might be involved in the infiltrating growth of alveococcus. Key words: Alveolar echincoccosis, hepatic; Vascular endothelial growth factor; Microvessel density; Angiogenesis

Correlation between vascular endothelial growth factor and long-term prognosis in patients with acute myocardial infarction.

The aim of the present study was to investigate the correlation between plasma the levels of vascular endothelial growth factor (VEGF) and major adverse cardiovascular events (MACE) in patients with acute myocardial infarction (AMI). A total of 124 patients with AMI undergoing emergency percutaneous coronary intervention (PCI) were selected, and plasma VEGF levels were measured 7 days after the onset of AMI using an enzyme-linked immunosorbent assay. The patients were divided into the L (≤190 pg/ml VEGF) and H (>190 pg/ml VEGF) groups, and were followed up every 2 months for an average of 12 months. MACE were recorded during follow-up. On the basis of these results, the patients were further divided into the MACE and non-MACE (N-MACE) groups, and the serum VEGF concentration was compared between the two groups. At the 6-month follow-up, the incidence of MACE in the H group was found to be significantly reduced compared with the L group. The serum VEGF concentration in the N-MACE group was significantly higher compared with the MACE group. Multinomial logistic regression revealed that reduced VEGF levels (β=1.243; 95% CI, 1.018-1.326; P=0.026) were independent risk factors for MACE. In conclusion, high plasma VEGF levels at 7 days after AMI onset facilitate the long-term prognosis in the same infarct zone in patients with AMI, while low plasma VEGF levels are independent risk factors for MACE.

Relaxin deficiency results in increased expression of angiogenesis- and remodelling-related genes in the uterus of early pregnant mice but does not affect endometrial angiogenesis prior to implantation.

BackgroundExtensive uterine adaptations, including angiogenesis, occur prior to implantation in early pregnancy and are potentially regulated by the peptide hormone relaxin. This was investigated in two studies. First, we took a microarray approach using human endometrial stromal (HES) cells treated with relaxin in vitro to screen for target genes. Then we aimed to investigate whether or not relaxin deficiency in mice affected uterine expression of representative genes associated with angiogenesis and uterine remodeling, and also blood vessel proliferation in the pre-implantation mouse endometrium.MethodsNormal HES cells were isolated and treated with recombinant human relaxin (10 ng/ml) for 24 h before microarray analysis. Reverse transcriptase PCR was used to analyze gene expression of relaxin and its receptor (Rxfp1) in ovaries and uteri; quantitative PCR was used to analyze steroid receptor, angiogenesis and extracellular matrix remodeling genes in the uteri of wild type (Rln+/+) and Rln-/- mice on days 1-4 of pregnancy. Immunohistochemistry localized endometrial endothelial cell proliferation and mass spectrometry measured steroid hormones in the plasma.ResultsMicroarray analysis identified 63 well-characterized genes that were differentially regulated in HES cells after relaxin treatment. Expression of some of these genes was increased in the uterus of Rln+/+ mice by day 4 of pregnancy. There was significantly higher vascular endothelial growth factor A (VegfA), estrogen receptor 1 (Esr1), progesterone receptor (Pgr), Rxfp1, egl-9 family hypoxia-inducible factor 1 (Egln1), hypoxia inducible factor 1 alpha (Hif1α), matrix metalloproteinase 14 (Mmp14) and ankryn repeat domain 37 (Ankrd37) in Rln-/- compared to Rln+/+ mice on day 1. Progesterone receptor expression and plasma progesterone levels were higher in Rln-/- mice compared to Rln+/+ mice. However, endometrial angiogenesis was not advanced as pre-implantation endothelial cell proliferation did not differ between genotypes.ConclusionsRelaxin treatment modulates expression of a variety of angiogenesis-related genes in HES cells. However, despite accelerated uterine gene expression of steroid receptor, progesterone and angiogenesis and extracellular matrix remodeling genes in Rln-/- mice, there was no impact on angiogenesis. We conclude that although relaxin deficiency results in phenotypic changes in the pre-implantation uterus, endogenous relaxin does not play a major role in pre-implantation angiogenesis in the mouse uterus.Electronic supplementary materialThe online version of this article (doi:10.1186/s12958-016-0148-y) contains supplementary material, which is available to authorized users.

Locally advanced rectal cancers with simultaneous occurrence of KRAS mutation and high VEGF expression show invasive characteristics

In this study, we investigated the mutation status of KRAS gene in pretherapeutic and preoperative biopsies in 63 specimens of locally advanced rectal cancers in order to evaluate its potential predictive and/or prognostic role. Regions of interest of KRAS exon 2 were amplified and visualized on 2% agarose gel. Obtained PCR products were subjected to direct sequencing. KRAS mutations were detected in 35% of patients, 91% of which were located in codon 12 and 9% in codon 13. In general, KRAS mutation status did not affect the response to neoadjuvant chemoradiotherapy (CRT). However, patients harboring mutated KRAS gene, simultaneously with high vascular endothelial growth factor (VEGF) expression, exhibited a worse response to CRT (p=0.030), a more frequent appearance of local recurrences and distant metastasis (p=0.003), and shorter overall survival (p=0.001) compared to all others. On the contrary, patients with GGT>GCT KRAS mutation exhibited a significantly better response to CRT than those with any other type of KRAS mutation (p=0.017). Moreover, the presence of GGT>GCT mutation was associated with low VEGF and Ki67 expression (p=0.012 in both cases), parameters related to less aggressiveness of the disease. Our results suggest that KRAS mutation status could have some predictive and prognostic importance in rectal cancer when analyzed together with other parameters, such as VEGF and Ki67 expression. In addition, it seems that not only the presence but the type of KRAS mutation is important for examining its impact on CRT response.

Apatinib: A novel receptor tyrosine kinase inhibitor for the treatment of gastric cancer

Metastatic gastric cancer is a lethal disease characterized by a very short overall survival, underlining a critical need of new therapeutic options. Unfortunately, although several molecular targets have been investigated, only very few recently approved agents, such as trastuzumab in the HER2-positive setting and ramucirumab, led to a clinical improvement in the outcome of metastatic gastric cancer patients. VEGF (vascular endothelial growth factor) is one of the most potent angiogenic factors and is a signalling molecule secreted by many solid tumours. Since high VEGF expression is one of the characteristic features of gastric carcinomas, targeting VEGF is therefore considered as a promising therapeutic strategy for gastric cancer. In the scenario of possible new target therapies with particular regard to angiogenesis, apatinib is a novel receptor tyrosine kinase inhibitor selectively targeting VEGFR-2. It is an orally-bioavailable agent currently being studied in several solid tumour types showing a promising activity in gastric cancer. Due to the recent positive results as a third line of treatment for metastatic gastric cancer patients, apatinib may be an interesting and novel type of targeted treatment for metastatic gastric cancer in several lines of therapy. In this review, we summarize the available data of apatinib, mainly focused on the clinical aspect, in advanced/metastatic gastric cancer.

Neurogenic potential of engineered mesenchymal stem cells overexpressing VEGF.

Numerous signaling molecules are altered following nerve injury, serving as a blueprint for drug delivery approaches that promote nerve repair. However, challenges with achieving the appropriate temporal duration of recombinant protein delivery have limited the therapeutic success of this approach. Genetic engineering of mesenchymal stem cells (MSCs) to enhance the secretion of proangiogenic molecules such as vascular endothelial growth factor (VEGF) may provide an alternative. We hypothesized that the administration of VEGF-expressing human MSCs would stimulate neurite outgrowth and proliferation of cell-types involved in neural repair. When cultured with dorsal root ganglion (DRG) explants in vitro, control and VEGF-expressing MSCs (VEGF-MSCs) increased neurite extension and proliferation of Schwann cells (SCs) and endothelial cells, while VEGF-MSCs stimulated significantly greater proliferation of endothelial cells. When embedded within a 3D fibrin matrix, VEGF-MSCs maintained overexpression and expressed detectable levels over 21 days. After transplantation into a murine sciatic nerve injury model, VEGF-MSCs maintained high VEGF levels for 2 weeks. This study provides new insight into the role of VEGF on peripheral nerve injury and the viability of transplanted genetically engineered MSCs. The study aims to provide a framework for future studies with the ultimate goal of developing an improved therapy for nerve repair.

Aqueous Angiopoietin-Like 4 Levels Correlate With Nonperfusion Area and Macular Edema in Branch Retinal Vein Occlusion.

To investigate whether macular edema (ME) due to branch retinal vein occlusion (BRVO) associates with retinal overexpression of angiopoietin-like 4 (ANGPTL4). The aqueous ANGPTL4 and vascular endothelial growth factor (VEGF) levels in patients with ME due to BRVO were measured, and the relationships between ANGPTL4 levels and the degree of retinal ischemia and edema were determined. The study and control groups consisted of all consecutive patients who were scheduled to undergo intravitreal bevacizumab injection for treatment-naïve BRVO with ME and senile cataract surgery, respectively. The study group was divided into the major BRVO and macular BRVO subgroups on the basis of the involved retinal area. The aqueous ANGPTL4 and VEGF levels were measured by enzyme-linked immunosorbent assay. In the patients with BRVO, capillary nonperfusion area by fluorescein angiography and central subfield macular thickness (CSMT) and total macular volume (TMV) by spectral-domain optical coherence tomography were determined. Patients with ME due to BRVO (50 eyes) had higher aqueous ANGPTL4 and VEGF levels than the controls (61 eyes) (both P < 0.001). The major BRVO had higher ANGPTL4 and VEGF levels than the macular BRVO (both P < 0.001). The aqueous ANGPTL4 levels of all BRVO patients correlated positively with nonperfusion area (r = 0.901, P < 0.001), CSMT (r = 0.574, P < 0.001), and TMV (r = 0.453, P = 0.001), even after adjustment for VEGF levels. The aqueous ANGPTL4 levels correlated significantly with phenotypes of BRVO with ME. This suggests that ANGPTL4 may be a candidate biomarker and treatment target in ischemia-induced retinopathies, including BRVO.

Acquired Unilateral Nevoid Telangiectasia Accompanied by Liver Metastasis of Colon Cancer.

Dear Editor: Unilateral nevoid telangiectasia (UNT) syndrome is a rare vascular dermatosis, characterized by areas of superficial telangiectases distributed in a dermatomal, unilateral pattern usually on the upper trunk and extremities. The etiopathogenesis is not completely understood, but the most widely accepted theory is its association with hyperestrogenic condition1. Herein, we report a rare case of UNT accompanied by liver metastasis of colon cancer. A 26-year-old male presented with progressive asymptomatic erythematous telangiectactic patches localized to the left chest and abdomen of 5-month duration. Three months after from when he had noticed skin lesions, he was diagnosed with colon cancer with multiple metastases at lumbar spine, lung, intra-abdominal lymph nodes including the liver and started chemotherapy following the FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen. He had no history of hepatitis or alcoholism. No family members were known to have any similar condition. On physical examination, there were no palmar erythema, ascites, or hepatosplenomegaly suggestive of chronic liver disease. On examination of the skin, erythematous telangiectactic patches on the left chest and abdomen involving dermatomes C3-4 and T4-10 were observed (Fig. 1). Biopsy specimen of the skin revealed intact epidermis with thin-walled capillaries in the superficial dermis (Fig. 2). Immunohistochemical staining was negative for estrogen, progesterone, and vascular endothelial growth factor (VEGF) receptors. Laboratory investigations were within normal range including liver function test. However, circulating estrogen level (155.55 pg/ml; normal range, 40~115 pg/ml) and serum carcinoembryonic antigen level (329.50 ng/ml; normal range, 0~4.7 ng/ml), which may be due to colon cancer and multiple metastases. Based on clinical and histopathologic findings, a diagnosis of UNT syndrome accompanied by liver metastasis of colon cancer was made. Reported cases of UNT syndrome mostly occur in women during pregnancy or puberty and in men with alcoholic cirrhosis2. Rarely, it has also been described in patients with carcinoid tumor of stomach with liver metastasis3. Several cases reported in recent years have cast doubt on the view that estrogen is the causal agent of telangiectasia development because of normal estrogen levels or negative estrogen and progesterone receptors1,4. Turan et al.4 suggested that VEGF may play a role in the pathogenesis of UNT syndrome in patients with underlying hepatic disease. On the other hand, Smith et al.5 reported a case of UNT syndrome accompanied by chronic hepatitis C virus infection, with a normal serum estrogen profile and VEGF level but strong positive immunohistochemical staining of lesional skin with VEGF. They suggested this result supports the hypothesis that angiogenic factors play a role in the pathogenesis of UNT syndrome. VEGF is already known to be a commonly expressed angiogenic factor in human colorectal cancer metastases and high serum VEGF level is correlated with colon cancer liver metastasis. Despite being unable to check serum VEGF level, elevated estrogen and VEGF levels could be related to the pathogenesis of UNT syndrome in our patient who had colon cancer with multiple metastases including the liver. To our knowledge, this is the first report of UNT syndrome accompanied by liver metastasis of colon cancer. Fig. 1 (A) Multiple erythematous telangiectactic patches localized to left chest (12×8 cm sized). (B) abdomen (27×21 cm sized). Fig. 2 Normal epidermis with dilated thin-walled capillaries in the superficial dermis (H&E, ×100).

Free light chains and heavy/light chains in monitoring POEMS patients.

POEMS syndrome is defined by Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy and Skin changes. The vascular endothelial growth factor (VEGF) appears to play a key role in the pathogenesis of the syndrome, and its concentrations are deemed to correlate to disease activity. The aim of the present study was to verify whether other biochemical markers including serum free light chains (FLC) and heavy/light chains (HLC) would be of value in monitoring POEMS patients. Fifty-three serum samples were collected from seven POEMS patients at diagnosis and during a follow-up period (range 14-56 months). VEGF was measured using an ELISA method, while FLC and HLC concentrations were measured using Binding Site reagents on a BNII (Siemens) nephelometer. At diagnosis all patients presented high VEGF concentrations, while the κ/λFLC ratio (FLCr) was within the reference range. Four patients had abnormal HLC, HLCκ/HLCλ (HLCr) and FLC values. The relationship between the trend of VEGF and both HLC and FLC during the follow-up was analysed by means of Cohen's κ coefficient. VEGF and HLC values displayed a significant κ-Cohen (0.537, p=0.002) in all chemotherapy-responder patients while in non-responders it did not. Conversely, in both responders and non-responders, VEGF and FLC values did not attain a significance on κ-Cohen analysis. In three out of four responders HLCr values increased, thus reflecting an improved clinical condition. The findings made in the present study indicate that HLC, either as intact immunoglobulin or as HLCr, may provide useful information, particularly in identifying responders and confirm that the role of FLC is unreliable in monitoring patients with POEMS syndrome.

Serum levels of vascular endothelial growth factor in non-alcoholic fatty liver disease.

BackgroundThis study aimed to assess the significance of serum levels of vascular endothelial growth factor (VEGF) in non-alcoholic fatty liver disease (NAFLD).MethodsSixty-seven consecutive NAFLD patients and 47 healthy controls who visited our liver clinics between May 2008 and December 2010 were included. The NAFLD diagnosis required elevated alanine aminotransferase and/or gamma-glutamyl transpeptidase levels, evidence of hepatic steatosis on ultrasound and/or liver histology, and exclusion of other causes of liver injury. Serum VEGF levels were determined by an enzyme immunoassay. Liver biopsy was obtained in 34 NAFLD patients. Histological lesions were scored by a liver histopathologist.ResultsSerum VEGF levels tended to be lower in matched NAFLD patients than in healthy controls (296±146 vs. 365±186 pg/mL, P=0.092); levels in patients with non-alcoholic steatohepatitis (NASH) also tended to be lower than in those with simple fatty liver (FL) (279±149 vs. 359±190 pg/mL, P=0.095); while VEGF levels were significantly lower in NASH patients than in healthy controls (279±149 vs. 365±186 pg/mL, P=0.041). VEGF levels offered poor predictability for the differentiation between NAFLD patients and controls or between NASH and FL patients. However, patients with high VEGF levels (≥300 pg/mL) were significantly more likely to have FL, either in the total NAFLD population (67% vs. 35%, P=0.019) or in the 34 NAFLD patients with liver biopsy (57% vs. 15%, P=0.023), while those with high VEGF levels also had a significantly lower mean fibrosis score (0.7±0.9 vs. 1.6±1.0, P=0.017).ConclusionOur data suggest that serum VEGF levels are equally high in healthy controls and in patients with simple fatty liver, but tend to decrease when NASH develops.

Clinicopathological significance of vascular endothelial growth factor, thymidine phosphorylase and microvessel density in colorectal cancer.

Colorectal cancer is a common malignant disease, the incidence of which is increasing worldwide, therefore, identifying novel prognostic factors to improve adjuvant therapeutic strategies or postoperative monitoring is required. Angiogenesis, which is assessed by microvessel density (MVD), is significant in tumor growth and metastasis. However, the association between angiogenesis and clinical outcome remains controversial. In the present study, 84 surgically resected cases of colorectal cancer were examined to clarify the clinicopathological significance of vascular endothelial growth factor (VEGF), thymidine phosphorylase (TP) and cluster of differentiation (CD)34 expression levels. VEGF expression was identified to be significantly correlated with TP expression (r=0.45; P<0.0001) and MVD in the high VEGF expression group was observed to be significantly greater than that in the low VEGF expression group (P=0.0194). In the Dukes' stage D group, the MVD in the high TP expression group was significantly greater than that in the low TP expression group (P=0.0149). High VEGF expression was subsequently correlated with a short overall survival rate for patients exhibiting lymph node metastasis (P=0.0128); however, there was no significant difference in overall survival rate regarding the expression levels of TP and CD34. The results of the present study indicate that VEGF expression may serve as a prognostic factor for colorectal cancer patients exhibiting lymph node metastasis. Furthermore, angiogenesis, as assessed by MVD, is an important prognostic factor for tumor growth at the primary site.

A Novel Three–Dimensional Human Peritubular Microvascular System

Human kidney peritubular capillaries are particularly susceptible to injury, resulting in dysregulated angiogenesis, capillary rarefaction and regression, and progressive loss of kidney function. However, little is known about the structure and function of human kidney microvasculature. Here, we isolated, purified, and characterized human kidney peritubular microvascular endothelial cells (HKMECs) and reconstituted a three-dimensional human kidney microvasculature in a flow-directed microphysiologic system. By combining epithelial cell depletion and cell culture in media with high concentrations of vascular endothelial growth factor, we obtained HKMECs of high purity in large quantity. Unlike other endothelial cells, isolated HKMECs depended on high vascular endothelial growth factor concentration for survival and growth and exhibited high tubulogenic but low angiogenic potential. Furthermore, HKMECs had a different transcriptional profile. Under flow, HKMECs formed a thin fenestrated endothelium with a functional permeability barrier. In conclusion, this three-dimensional HKMEC-specific microphysiologic system recapitulates human kidney microvascular structure and function and shows phenotypic characteristics different from those of other microvascular endothelial cells.

Radiologic Features and Expression of Vascular Endothelial Growth Factor Stratify Survival Outcomes in Patients with Glioblastoma.

Vascular endothelial growth factor is a well-known tumor-specific biomarker that mediates angiogenesis in glioblastoma via hypoxia-dependent mechanisms. Our aim was to investigate the correlation of clinical characteristics, radiologic features, and vascular endothelial growth factor expression with survival outcomes in patients with glioblastoma. Clinical and radiologic data of 185 patients with glioblastoma were retrospectively reviewed. Vascular endothelial growth factor expression was examined in all cases via immunohistochemical analysis. Univariate and multivariate analyses were performed to identify the prognostic factors of progression-free survival and overall survival. Vascular endothelial growth factor expression levels were associated with the presence of ringlike tumor contrast enhancement. Age, preoperative Karnofsky Performance Scale score, gross total resection, and adjuvant therapy were identified as prognostic factors. Among patients undergoing gross total resection, high vascular endothelial growth factor expression was associated with longer progression-free survival (P = .011) and overall survival (P = .039). For tumors with high vascular endothelial growth factor expression, both the non-contrast-enhancing tumor component and peritumoral edema could stratify overall survival (P = .039 and .018, respectively), while only the presence of the non-contrast-enhancing tumor component predicted a longer progression-free survival (P = .024). Vascular endothelial growth factor expression level was not an independent prognostic factor in glioblastoma. However, high vascular endothelial growth factor expression might predict longer survival in patients in whom gross total resection was achieved. Furthermore, peritumoral edema and the non-contrast-enhancing tumor component could stratify survival outcomes in patients with high vascular endothelial growth factor tumors.