Elevated levels of the angiogenic cytokines basic fibroblast growth factor and vascular endothelial growth factor in sera of cancer patients.

The concentration of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) was determined in the serum of 90 untreated and 42 treated metastatic cancer patients, including patients with colorectal, breast, ovarian and renal carcinomas, with an enzyme-linked immunosorbent assay (ELISA). Levels higher than the 95th percentile of the concentrations of a control group, i.e. 7.5 pg ml(-1) for bFGF and 500 pg ml(-1) for VEGF, were identified as ''elevated''. One measurement during follow-up was included into the analysis per patient. For 19 treated patients, consecutive serum samples were analysed. Fifty-seven per cent of all untreated patients had elevated serum levels of one or both angiogenic factors. The fraction of patients with elevated serum levels of bFGF and/or VEGF was similar in the different tumour types. Agreement of bFGF levels and VEGF levels, classified in relation to their respective cut-off values, was present in 67% of all patients. Fifty-eight per cent of the patients with progressive disease during treatment compared with 15% of the patients showing response to treatment (chi-squared test P < 0.05) had elevated bFGF and/or VEGF serum levels. When consecutive serum samples were analysed, two-thirds of the patients showing progressive disease had increasing serum levels of the angiogenic factors compared with less than one-tenth of the patients showing response (chi-squared test P < 0.05). The lack of association between the serum bFGF and VEGF levels and the tumour type may suggest an aspecific host reaction responsible for solid tumour-related angiogenesis. The main determinants of the serum bFGF and VEGF concentration are the progression kinetics of the metastatic carcinomas.     

Quantitative analysis of basic fibroblast growth factor and vascular endothelial growth factor in human colorectal cancer.

Tumour growth is angiogenesis dependent. Some authors suggest a prognostic role of microvessel count in colorectal cancer. We tested the role of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) in the switch to the angiogenic phenotype in 35 patients with colorectal cancer at different stages of disease. We evaluated the two angiogenic factors, by enzyme-linked immunosorbent assay (ELISA), in tumour, peritumoral mucosa, pathological mesenteric and peripheral blood. We used ten endoscopic intestinal biopsies and ten peripheral blood samples from healthy subjects as control. bFGF was significantly lower in tumour tissues and in peritumoral mucosas than in healthy mucosas, whereas VEGF was up-regulated in tumours but not in peritumoral mucosa. Both angiogenic factors were greatly increased in mesenteric blood. VEGF tumour and serum levels were significantly correlated with the stage of disease. bFGF tumour and serum concentration were not correlated with the stage of disease. The high levels of bFGF in mesenteric blood suggest that this growth factor might be abnormally released from tumour tissue and peritumoral mucosa and could function as an early effector in the switch to the angiogenic phenotype. In contrast, VEGF, whose levels show a significant correlation with the stage of disease, could act in a following step, supporting tumour progression.     

Do serum angiogenic growth factors provide additional information to that of conventional markers in monitoring the course of metastatic breast cancer?

OBJECTIVE: Our work evaluated the potential role of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) serum levels with respect to that of conventional serum tumour markers, CEA and CA 15-3, in monitoring the course of metastatic breast cancer in 56 female patients treated with cytotoxic chemotherapy. METHODS: VEGF and bFGF concentrations were determined using a quantitative sandwich enzyme immunoassay technique. The positive predictive value (PPV) of each marker and of marker combinations for different types of clinical response was calculated. RESULTS: The highest PPV for overall disease control was shown by bFGF (70%), which also showed the highest PPV for both partial response (36.4%) and stable disease (63.2%). CEA showed the highest predictive value for progression (69.2%). A combined increase in CEA and bFGF or VEGF was associated with disease progression in all patients. CONCLUSIONS: Information provided by angiogenic factor levels seems to be independent of and is possibly complementary to that provided by conventional serum markers. bFGF showed the maximum predictive value for disease control and provided additional information to that obtained from CEA or CA 15-3 evaluation. It could therefore be a promising candidate for monitoring response to chemotherapy in advanced breast cancer.     

Vascular endothelial growth factor (VEGF) mRNA expression in human tumor models of different histologies

Background: Vascular endothelial growth factor (VEGF) is a polypeptidewith specific effects on endothelial cell growth and blood vesselpermeability. Recent studies demonstrated a key role for VEGFin tumor neovascularization, which is a prerequisite for tumorproliferation and metastasis Patients and methods: We studied the expression of VEGF mRNAin a panel of 65 different human tumor xeno-grafts of varioushistologies using Northern and slot blot analyses. Analysisof vessel density was performed morphologically and after immunohistochemicalstaining of endothelial cells Results: High expression levels were observed in 22/65 tumors.In melanoma, colorectal, gastric, breast and lung cancers onlysingle tumors showed strong expression signals, whereas 7/10renal cell carcinoma (RCC) xenografts demonstrated high levelsof VEGF mRNA. Vessel density analysis revealed a clear correlationof VEGF mRNA expression with vascularization in RCC (p - 0.0048).Patient survival time was compared for tumors showing high versuslow expression values. The overall 5-year survival rate wassignificantly lower for patients with high expression of VEGFmRNA (p - 0.0306) Conclusions: These data support the hypothesis that tumor cellsof various histologies secrete VEGF, which acts as a paracrinefactor to induce endothelial cell proliferation and vessel formationand mediates tumor progression VEGF, VPF, angiogenesis, vascularization, renal cell carcinoma, human tumor xenografts     

Vascular endothelial growth factor (VEGF)--a valuable serum tumour marker in patients with colorectal cancer?

INTRODUCTION: Neo-angiogenesis, of great importance for tumour growth and nutrition, is preferentially mediated by the cytokine vascular endothelial growth factor (VEGF), which has a direct effect on vascular endothelial cell proliferation and migration. This study was designed to clarify whether VEGF is a suitable tumour marker in sera of patients with a colorectal cancer, and whether VEGF concentrations in sera and tumour tissues are correlated with tumour extension (pTNM) and especially with tumour volume or size. Furthermore, the influence of VEGF levels on patients > prognosis was examined. METHODS: VEGF serum concentrations of 122 patients with colorectal cancer and 65 controls were determined with an ELISA kit. Additionally, VEGF concentrations of tumour and normal tissue were measured in 38 patients using the same ELISA. RESULTS: Our results demonstrate that VEGF is not a suitable diagnostic tumour marker in patients with colorectal cancer due to its low sensitivity (36%). However, a combination of the serum tumour markers CEA and VEGF can significantly increase the pre-operative diagnostic sensitivity to 62%. VEGF serum levels differed significantly between patients (mean 438 pg/ml) and controls (mean 203 pg/ml), and also between tumour and normal tissue (984 vs 89 pg/mg protein). Serum concentration showed a significant correlation to tumour volume and size. Patients with VEGF serum levels greater than cut-off had a poorer prognosis than those less than or equal to cut-off. For this reason VEGF could be used as a predictor of patients > outcome. Copyright Harcourt Publishers Limited.     

Plasma vascular endothelial but not fibroblast growth factor levels correlate with colorectal liver mestastasis vascularity and volume

The extent to which plasma levels of angiogenic factors in healthy individuals and tumour volume-related variations in colorectal cancer affect the accuracy of circulating angiogenic factors as predictors of colorectal cancer vascularity is unknown. We used enzyme-linked immunosorbant assay to measure plasma vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) levels in colorectal liver metastasis (CLM) patients, and 'no cancer' controls. CLM volume was determined from computerized tomography scans, and tumour vessel count and vessel volume from anti-endothelial antibody-stained biopsies. There was a significant (P= 0.03) increase in plasma VEGF level in 29 CLM patients (median 180.3 pg/ml(-1), iqr 132.5-284.8 pg/ml(-1) compared with 19 controls (median 125.8 pg/ml(-1), iqr 58.2-235.9 pg/ml(-1). There were significant correlations between plasma VEGF and tumour vessel count (r = 0.66, P = 0.03), tumour vessel volume (r= 0.59, P = 0.03), and CLM volume (r= 0.53, P = 0.03). A VEGF level in the upper quartile of the plasma VEGF distribution had a 70% sensitivity and 75% specificity in predicting an upper quartile liver metastasis tumour vessel count. No relation was identified between CLM and plasma bFGF levels. Plasma VEGF level predicted CLM vascularity, despite an overlap with normal levels and tumour volume-related variations.     

Impact of serum basic fibroblast growth factor on prognosis in human renal cell carcinoma

Renal cell carcinoma is often characterised by extensive vascularity and angiogenic factors may be of importance for disease progression. Using a sandwich enzyme immunoassay, basic fibroblast growth factor (bFGF) was analysed in the sera from 206 patients with renal cell carcinoma before the initiation of therapy. The median bFGF level was 3.0 pg/ml (range <1.0–70.9 pg/ml). The serum levels were significantly correlated to tumour stage and nuclear grade. Patients with tumour thrombus to the renal or the inferior caval vein had significantly higher serum bFGF levels compared with those with non-invading tumours (P=0.007). Patients with serum bFGF levels above 3.0 pg/ml had a worse prognosis, compared with those with lower levels (P=0.001). Furthermore, patients with tumours with vein invasion had a worse prognosis compared with those without invasion. After multivariate analysis, only tumour stage and grade remained as independent prognostic factors.     

Vascular endothelial growth factor and basic fibroblast growth factor urine levels as predictors of outcome in hormone-refractory prostate cancer patients: a cancer and leukemia group B study

Better prognostic markers are needed for hormone-refractory prostate cancer (HRPC) patients. No single biochemical or clinical parameter can reliably predict patient response to therapy or rapidity of disease progression. Peptide factors involved in major cancer growth pathways, such as tumor angiogenesis, are attractive candidates as markers of low- and high-risk HRPC patients. We analyzed prospectively collected urine specimens from 100 of 390 HRPC patients undergoing therapy with the growth factor antagonist suramin as part of CALGB 9480. Levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were assessed from day 1 of therapy (D1) and day 29 (D29) urine samples from this subset of 100 randomly selected patients. Growth factor levels were determined by standardized ELISA microtiter plate assays from a commercial (bFGF) or proprietary (VEGF) source. Pretreatment urine VEGF levels were predictive of survival. In univariate analysis, patients whose baseline urine VEGF level was < or =28 pg/ml (the median level) had an average survival of 17 months; those with baseline VEGF >28 pg/ml had a significantly shorter survival of 10 months (P = 0.024). This difference corresponded to a 60% increased risk of dying for the higher urine VEGF patients (hazard ratio, 1.62; P = 0.03) and remained significant in multivariate analysis (hazard ratio, 1.72, P = 0.02). No significant correlations between urine bFGF level or change in bFGF levels and survival were found. These results support the notion that certain peptide growth factor-mediated, mitogenic pathways are important in HRPC and that their levels can predict outcome.     

血清VEGF、bFGF与胃癌生物学行为的关系

目的:探讨VEGF、bFGF与胃癌的生物学行为的关系,复发转移患者血清VEGF、bFGF的表达水平与化疗疗效的关系。方法:应用ABC-ELISA方法检测胃癌患者血清VEGF、bFGF的表达情况。结果:(1)术前未作放化疗的胃癌组患者术前血清VEGF、bFGF表达水平明显高于健康体检者(P<0.05),也明显高于同组患者术后血清VEGF、bFGF表达水平(P<0.05)。(2)术前未作放化疗的胃癌组患者术前血清VEGF、bFGF的表达水平与原发肿瘤的浸润深度、TNM分期、淋巴结转移、远处转移有关。(3)术前未作放化疗的胃癌组患者术前血清VEGF与bFGF的表达水平呈正相关(r=0.439,P<0.01)。(4)胃癌患者复发转移组化疗前血清VEGF、bFGF的表达水平比健康体检者及无病生存组明显增高(P<0.05)。(5)胃癌患者复发转移组化疗后CR PR组血清VEGF、bFGF表达水平比化疗前明显减低(P<0.05),胃癌患者复发转移组化疗后NC PD组血清VEGF、bFGF表达水平比化疗前略高,但没有显著性差异(P>0.05),胃癌患者复发转移组化疗后CR PR组血清VEGF、bFGF表达水平比NC PD组明显低(P<0.05)。结论:胃癌患者血清VEGF、bFGF与胃癌生物学行为有关,而且与胃癌化疗疗效有关。血清VEGF、bFGF可能成为胃癌的诊断、术后随访、复发转移监测新的肿瘤标志物。     

Predictive value of vascular endothelial growth factor (VEGF) in metastasis and prognosis of human colorectal cancer.

Vascular endothelial growth factor (VEGF) may affect the phenotype of cancer cells, such as growth velocity and metastatic potential, due to its probable multifunctional property including a mitogenic activity for vascular endothelial cells. The present study was designed to investigate the association of VEGF mRNA expression with progression and metastasis of human colorectal cancer. The level of VEGF mRNA expression was quantified by Northern blot hybridization in tumorous and non-tumorous tissues obtained from 60 primary colorectal cancer patients. The ratio of the former to the latter was defined as the VEGF T/N ratio, and the prognostic significance of this ratio, following surgery, in addition to the relationship to progression and metastatic potential, was evaluated. The value of the VEGF T/N ratio was significantly correlated with the depth of tumour infiltration (P=0.046), the incidence of liver metastasis (P < 0.0001) and lymph node metastasis (P=0.036). Patient prognosis was estimated by the Kaplan-Meier method and the log-rank test. When the VEGF T/N ratio was higher than 4.8 for which the chi2 value of the log-rank test was maximal, the tumour was defined as showing overexpression of VEGF mRNA. Patients with overexpression of VEGF mRNA demonstrated poorer survival than patients without overexpression of VEGF mRNA (P < 0.001). The overall estimated hazard ratio for death in patients with overexpression of VEGF mRNA was 1.94 according to a multivariate analysis (P=0.005). Thus, VEGF is associated with the progression, invasion and metastasis of colorectal cancer, and overexpression of VEGF mRNA in the primary tumour is assumed to be closely correlated with poor prognosis in colorectal cancer patients. Moreover, the VEGF T/N ratio may be used as an independent prognostic marker in colorectal cancer patients.     

Increased serum concentration of angiogenic factors in malignant melanoma patients correlates with tumor progression and survival.

PURPOSE: To determine the predictive value of the angiogenic serum factors angiogenin, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and interleukin-8 (IL-8) for the prognosis of patients with malignant melanoma. PATIENTS AND METHODS: Angiogenin, VEGF, bFGF, and IL-8 were measured in sera of 125 melanoma patients with different stages of disease and with or without current therapy including interferon alfa and different cytostatics in comparison with 30 healthy controls using enzyme-linked immunosorbent assay. RESULTS: Serum levels of angiogenin, VEGF, bFGF, and IL-8 were significantly increased in melanoma patients compared with healthy controls. Elevated serum concentrations of VEGF, bFGF, and IL-8 were associated with advanced disease stages and tumor burden. Cytostatic therapy of patients was accompanied by increased serum levels of angiogenin, bFGF, and IL-8. As shown by univariate analysis, elevated serum levels of VEGF (P = .0001 and .0036), bFGF (P < .00005 and < .00005), and IL-8 (P < .00005 and < .00005) were strongly correlated with a poor overall and progression-free survival, respectively. Multivariate analysis revealed stage of disease (P = .0238), tumor burden (P = .0347), VEGF (P = .0036), bFGF (P = .0252), and IL-8 (P = .0447) as independent predictive factors of overall survival. Tumor burden (P = .0081), VEGF (P = .0245), and IL-8 (P = .0089) were found as independent predictive factors of progression-free survival. CONCLUSION: Our data suggest that the angiogenic serum factors VEGF, bFGF, and IL-8 are useful predictive markers for overall and progression-free survival in melanoma patients.     

Role of the VEGF ligand to receptor ratio in the progression of mismatch repair-proficient colorectal cancer

Background  

The VEGF family of ligands and receptors are intimately involved in tumor angiogenesis, lymphangiogenesis and metastasis. The evaluation of VEGF ligand/receptor ratios may provide a more profound understanding of the involvement of these proteins in colorectal tumour progression. The aim of this study was to elucidate the role of the VEGF ligand/receptor ratios on tumour progression and metastasis in patients with mismatch repair-proficient colorectal cancer.     

Elevated preoperative serum levels of angiogenic cytokines correlate to larger primary tumours and poorer survival in non-small cell lung cancer patients

We have analysed the predictive and prognostic information in preoperatively collected serum levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in patients clinically evaluated as operable non-small cell lung cancer (NSCLC). Fifty-eight patients with operable NSCLC were included. VEGF and bFGF levels in serum were analysed using enzyme linked immunosorbent assays (Quantikine human VEGF and Quantikine HS human FGF basic, R&D Systems). Univariate analysis demonstrated that tumour volume, platelet counts, VEGF and bFGF were significant prognostic factors. However, only bFGF remained significant in the multivariate analysis (P=0.014). Significant correlation's were demonstrated between VEGF levels and tumour volume (r=0.33; P=0.012) and platelet count (r=0.43; P=0.001). bFGF levels correlated significant with recurrent disease (r=0.34; P=0.01), platelet count (r=0.53, P<0.001) and performance status (r=0.29; P=0.029). Furthermore, bFGF levels and VEGF levels correlated significantly (r=0.44; P<0.001). We conclude that elevated circulating angiogenic cytokines correlate with tumour volume, higher relapse risk and poorer survival in patients with operable non-small cell lung cancer.     

Plasma vascular endothelial growth factor levels have prognostic significance in patients with acute myeloid leukemia but not in patients with myelodysplastic syndromes

BACKGROUND: Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are positive regulators of angiogenesis. Increased levels in urine, serum, plasma, or malignant tissue have been associated with an adverse prognosis in patients with solid tumors. METHODS: The authors used an enzyme-linked immunosorbent assay to measure VEGF and bFGF levels in plasma samples from 99 patients with previously untreated myelodysplastic syndromes (MDS) (n = 41 patients; 42%) or acute myeloid leukemia (AML) (n = 58 patients; 58%) and compared the results with the results from a group of normal control participants. RESULTS: Increased expression levels of VEGF and bFGF were found in the plasma from patients with AML and MDS (P < 0.01) compared with the levels found in the control group. Plasma levels of VEGF in patients with AML or MDS were similar (median, 30.63 pg/mL and 34.41 pg/mL, respectively). There was no significant difference in bFGF levels between patients with AML and patients with MDS (median, 6.38 pg/mL and 6.98 pg/mL, respectively). Elevated levels of VEGF were associated with reduced survival (P = 0.02) in patients with AML as well as lower complete remission (CR) rates (P = 0.004). Elevated VEGF levels were not associated with reduced remission duration (CRD) in patients with AML. There was no correlation between VEGF levels and survival, CRD, or CR rates in patients with MDS. There was no correlation between bFGF levels and CR rates or survival in patients with either AML or MDS. CONCLUSIONS: Plasma VEGF levels have prognostic significance in patients with AML. The lack of clinical relevance of VEGF levels in patients with MDS suggests some biologic difference between AML and MDS.     

Levels of vascular endothelial growth factor,hepatocyte growth factor/scatter factor and basic fibroblast growth factor in human gliomas and their relation to angiogenesis

Angiogenesis is a possible target in the treatment of human gliomas. To evaluate the role of 3 growth factors, vascular endothelial growth factor (VEGF), hepatocyte growth factor/scatter factor (HGF/SF) and basic fibroblast growth factor (bFGF), in the angiogenic cascade, we determined their levels in extracts of 71 gliomas by enzyme‐linked immunosorbent assay (ELISA). The levels of bFGF were only marginally different between gliomas of World Health Organization (WHO) grade II (low grade) and grades III and IV (high grade). In contrast, the mean concentrations of VEGF were 11‐fold higher in high‐grade tumors and those of HGF/SF 7‐fold, respectively. Both were highly significantly correlated with microvessel density (p < 0.001) as determined by immunostaining for factor VIII‐related antigen. In addition, VEGF and HGF/SF appeared to be independent predictive parameters for glioma microvessel density as determined by multiple regression analysis. We measured the capacity of all 3 factors to induce endothelial tube formation in a collagen gel. In this assay, bFGF was found to be an essential cofactor with which VEGF as well as HGF/SF were able to synergize independently. According to the concentrations of angiogenic factors, extracts from high‐grade tumors were significantly more potent in the tube formation assay than the low‐grade extracts (p = 0.02). Adding neutralizing antibodies to bFGF, VEGF and HGF/SF together with the extracts, tube formation was inhibited by up to 98%, 62% and 54%, respectively. Our findings suggest that bFGF is an essential cofactor for angiogenesis in gliomas, but in itself is insufficient as it is present already in the sparsely vascularized low‐grade tumors. Upon induction of angiogenesis in high‐grade tumors, bFGF may synergize with rising levels of not only VEGF but possibly also with HGF/SF, which appears here to be an independent angiogenic factor. Int. J. Cancer (Pred. Oncol.) 84:10–18, 1999. © 1999 Wiley‐Liss, Inc.     

Clinical significance of plasma vascular endothelial growth factor in gastrointestinal cancer

Circulating vascular endothelial growth factor (VEGF) was measured in gastric and colorectal cancer patients using an enzyme-linked immunosorbent assay (ELISA). Firstly, serum and plasma samples were collected from 20 normal controls to compare the values of VEGF and to determine which specimen type was most suitable for detecting circulating VEGF. Seventeen of 20 normal controls had plasma VEGF levels under the limit of detection (15 pg/ml) and the levels of the remaining three controls were 21, 22 and 38 pg/ml. In contrast, all serum samples indicated high levels of VEGF (mean 238 pg/ml), ranging from 44 to 450 pg/ml. In a time-course test of two normal controls serum VEGF values increased markedly between 30 and 60 min and remained high, whilst plasma VEGF values were low up to 480 min. Thus, plasma samples are more suitable for the measurement of circulating VEGF. Next, plasma VEGF levels were examined in 44 patients with gastric cancer (8 early, 7 advanced without remote metastasis and 29 metastatic), 13 with colorectal adenoma (2 with focal cancer) and 26 with colorectal carcinoma (8 advanced without metastasis and 18 metastatic) before treatment. An extremely high plasma concentration of VEGF was seen in some cancer patients with metastasis. To discriminate these patients, a cut-off level was determined, considering both the distribution of the sample concentration and the upper limit of 95% confidence area of VEGF in the cancer patients without metastasis. The cut-off value was 108 pg/ml and most cancer patients without metastases had VEGF levels below the cut-off value. In 11 of 29 metastatic gastric cancer patients (38%) and 9 of 18 metastatic colorectal cancer patients (50%), plasma VEGF levels were higher than the cut-off value. Survival was also analysed in the patients with metastasis. It was significantly longer in the patients with low VEGF levels (below the cut-off) than in those with high VEGF levels (logrank test, P = 0.042). 34 patients with metastasis (19 gastric cancer and 15 colorectal cancer) were treated with systemic chemotherapy, and their pretreatment levels of plasma VEGF and conventional tumour markers (CEA and CA19-9) were evaluated in relation to response. The response to chemotherapy was significantly higher in patients with low VEGF levels (< or = 108 pg/ml) than in those with high VEGF levels (P = 0.047). Such a difference was not observed with CEA/CA19-9. In conclusion, plasma VEGF is a useful marker for tumour metastasis and patient survival, and a possible predictive factor for the response of patients with gastrointestinal cancer to chemotherapy.     

Soluble vascular endothelial growth factor levels in patients with primary colorectal carcinoma. The Danish RANX05 Colorectal Cancer Study Group.

INTRODUCTION: Angiogenesis is decisive in tumour progression and metastasis. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor, and increased VEGF levels in patients with carcinomas may facilitate growth of both primary and secondary tumours. METHODS: Soluble (s) VEGF levels were determined in serum from 91 volunteer healthy blood donors and from 614 patients scheduled to undergo resection for primary colorectal cancer. None of the patients received pre- and/or post-operative chemo- and/or radiotherapy. The results of sVEGF were analysed with respect to Dukes> stage, gender, age and topographical tumour localization. RESULTS: Patients with colorectal cancer had significantly (P<0.0001) higher levels of sVEGF, compared to healthy blood donors. Patients with Dukes> stage D disease had significantly (P=0.01) higher values than patients with Dukes> stage A, B and C disease, who had comparable values. Patients with the primary tumour localized in the colon had significantly (P<0.0001) higher levels of sVEGF than patients with the primary tumour localized in the rectum. By classifying the patients into two groups, based on the upper limit of the 95(th)percentile of sVEGF of healthy individuals (sVEGF=465 pg/ml), we found a significantly (P<0.0001) reduced overall survival in patients with sVEGF >465 pg/ml compared to patients with sVEGF values below this level. Moreover, in the subgroup of patients with the carcinoma localized in the colon and sVEGF levels above 465 pg/ml, we found a significantly (P<0.0001) reduced overall survival compared to colon cancer patients with lower sVEGF values. In conclusion, data from the present study suggest a biological significance of VEGF in patients with colorectal cancer, and indicate that a high pre-operative sVEGF value is associated with poor outcome, but further research is needed to validate sVEGF as a cancer marker.     

Associations between hepatocyte growth factor, c-Met, and basic fibroblast growth factor and survival in endometrial cancer patients

Background:

Hepatocyte growth factor (HGF), c-Met, and basic fibroblast growth factor (bFGF) are molecular markers that contribute to angiogenesis and proliferation in numerous cancers. We assessed the prognostic significance of these factors in tumour and stroma of endometrial cancer (EC) patients (n=211).

Methods:

Immunohistochemistry (IHC) was used to detect tumour and stromal protein expression of the biomarkers. Associations between expression and clinicopathological factors were assessed using Chi-square tests. Kaplan–Meier curves, log-rank tests, and Cox regression were used to summarise associations between biomarker expression and overall survival (OS) and recurrence-free survival (RFS).

Results:

Tumour bFGF was significantly associated with high-grade endometrioid and clear cell histology (P<0.001), advanced stage (P=0.008), positive lymph-node involvement (P=0.002), poor OS (log-rank test, P=0.009), and poor RFS (P<0.001). In multivariable analyses, cases with HGF-positive, stromal bFGF-positive tumours had a lower risk of death compared with cases with HGF-positive, stromal bFGF-negative tumours (hazard ratio (HR): 0.14, 95% CI: 0.03, 0.60). Cases with HGF-positive, bFGF-positive tumours had a higher risk of recurrence compared with cases with negative expression of both markers (HR: 9.88, 95% CI: 2.63, 37.16).

Conclusion:

These IHC data show that tumour and stromal bFGF expression have opposite associations with survival outcomes in EC patients. If confirmed in larger studies, tumour-derived bFGF could be an attractive target in EC therapy.     

Pre-operative serum vascular endothelial growth factor can select patients for adjuvant treatment after curative resection in colorectal cancer

We aim to determine the clinical usefulness of pre-operative serum vascular endothelial growth factor (VEGF) as a predictor of outcome in patients undergoing curative resection for colorectal cancer. Serum VEGF was assayed by quantitative ELISA in 81 patients prior to curative resection for node-negative (n = 53) and node-positive (n = 28) disease. Median follow-up for patients without cancer death was 27 months (range 21-37). Pre-operative serum VEGF was significantly higher in patients who went on to develop metastases than those who did not (median, 713 pg ml-1 vs. 314 pg ml-1, P < 0.0001). Using multivariate Cox regression analysis, pre-operative serum VEGF was the most important prognostic factor independent of nodal status and adjuvant chemotherapy, and was superior to nodal status in predicting outcome (P < 0.00001). At 575 pg ml-1, pre-operative serum VEGF was 64% sensitive and 89% specific in predicting the development of metastases in curative resections, with a positive predictive value of 73% and a negative predictive value of 85%. Pre-operative serum VEGF is a powerful predictor of outcome following curative surgery for colorectal cancer. These data support the measurement of pre-operative serum VEGF as a method for selecting patients who require adjuvant therapy.