Serum endostatin levels are elevated in patients with soft tissue sarcoma

BACKGROUND: Solid tumors are angiogenesis dependent, and elevated levels of proangiogenic cytokines have been reported in a variety of histologies. Endostatin is an antiangiogenic fragment of the basement membrane protein, collagen XVIII. Because antiangiogenic protein fragments may be generated by tumor-derived proteases, the authors sought to determine whether circulating levels of endostatin were elevated in patients with localized soft tissue sarcoma. METHODS: The authors analyzed preoperative serum levels of endostatin, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) in 25 patients (14 males and 11 females; mean age, 44 years) with soft tissue sarcoma. For each serum sample, two aliquots were assayed in duplicate using a competitive enzyme immunoassay. Serum levels were compared with levels from 34 age-matched and gender-matched volunteer blood donors. RESULTS: Endostatin levels were significantly higher in sera from sarcoma patients than in sera from healthy controls (43.0 ng/mL vs. 25.8 ng/mL, respectively; P = 0.0002; Mann-Whitney U test). Significant elevations also were noted in VEGF and bFGF levels (P = 0.0002 and P = 0.0001, respectively). Furthermore, endostatin levels > 2 standard deviations above the control mean (55 ng/mL) were associated with an increased risk of tumor recurrence after resection (P = 0.047; log-rank test). CONCLUSIONS: Serum endostatin, VEGF, and bFGF levels are elevated in patients with soft tissue sarcoma. Elevated endostatin levels appear to be associated with tumor aggressiveness. The role of these cytokines in sarcoma angiogenesis and as potential targets for therapy warrants further study.     

Prospective analysis of circulating endostatin levels in patients with renal cell carcinoma

BACKGROUND: The aim of the current study was to assess circulating levels of endogenous endostatin in patients with renal carcinoma and to determine the relationship of these levels to circulating levels of vascular endothelial growth factor (VEGF) and prognosis. METHODS: The authors prospectively studied 66 patients (48 male, 18 female; mean age, 50 years) undergoing nephrectomy for renal carcinoma on clinical trials at the National Cancer Institute. Metastases were present in 51 of 66 patients (77%) at the time of nephrectomy. Preoperative and followup serum endostatin and VEGF levels were determined using competitive enzyme immunoassays and compared to a group of 32 age- and gender-matched healthy controls. Associations between circulating endostatin levels and clinicopathologic variables, including survival, were determined. RESULTS: Preoperative endostatin levels were higher in renal carcinoma patients than in healthy controls (P = 0.05). There was a weak to moderate correlation between pretreatment serum endostatin levels and serum VEGF levels (r = 0.47; P = 0.001), and levels of both proteins increased significantly following nephrectomy (P < 0.0001 and P < 0.0001, respectively; n = 41). In addition, patients whose endostatin levels increased more than twofold after nephrectomy had significantly poorer prognoses than patients without such an increase (P = 0.018). This association was more pronounced when patients without metastases were excluded (P = 0.0037). CONCLUSIONS: Circulating endostatin levels are elevated in patients with renal carcinoma and correlate with circulating VEGF levels. Endostatin levels increase after nephrectomy, and patients with the greatest increases experience shortened survival times. These findings suggest an association between tumor aggressiveness and the production of endogenous endostatin in patients with renal carcinoma.     

Pet birds and risk of lung cancer in North-Western Germany

The relationship between non-small cell lung cancer and platelet counts, serum levels of vascular endothelial growth factor (VEGF) and endostatin, is unclear. Platelet counts and serum VEGF and endostatin levels were measured preoperatively in 99 patients with non-small cell lung cancer, and the relationship between these factors and clinicopathological features, including prognosis, was examined. Mean serum VEGF level was slightly higher in patients than in healthy subjects (P=0.23). Mean serum endostatin level was 42.4+/-40.4 ng/ml in patients compared to 16.3+/-10.3 ng/ml in healthy subjects (P=0.0003). Serum endostatin levels were significantly higher in patients with involvement greater than T2 or stage IB, compared to other patients. Platelet count and serum endostatin level greater than the median were associated with poor prognosis. Our results suggested that platelet count and serum endostatin level may be useful markers for non-small cell lung cancer.     

Pretreatment serum endostatin as a prognostic indicator in metastatic gastric carcinoma

Endostatin is the C-terminal antiangiogenic fragment of the extracellular matrix protein collagen XVIII, and is generated by tumor-derived proteases. The presence of serum endostatin in patients with gastric cancer has not been reported. The authors assessed the serum levels of endostatin in patients with gastric carcinoma and evaluated their association with the levels of vascular endothelial growth factor (VEGF) and the clinical outcome. A total of 107 patients with gastric cancer were included in the study. Pretherapeutic serum levels of endostatin and VEGF were measured using an ELISA, and compared with those in 23 healthy controls. The serum levels of endostatin and VEGF were higher in gastric cancer patients than in healthy controls (endostatin, 70.1 +/- 16.6 vs. 52.2 +/- 6.2 ng/mL [p < 0.001]; VEGF, 55.1 +/- 7.6 vs. 32.1 +/- 2.4 ng/mL [p < 0.001]; mean +/- SD). Serum endostatin levels were significantly associated with the presence of distant metastases (r = 0.556, p < 0.001) and VEGF levels (r = 0.335, p < 0.001), but not with the depth of tumor invasion, differentiation, or regional lymph node status. A serum endostatin level above the 75th percentile of the distribution for the patients (79.2 ng/mL) was associated with a poor outcome (last follow-up at 42 months; median survival time, 9 vs. 20 months [log-rank, p = 0.017]; median time to progression, 5 vs. 10 months [log-rank, p = 0.022]) in the patients with metastatic gastric cancer. The results suggest for the first time that an elevated serum level of endostatin at the diagnosis of metastatic gastric cancer could be predictive of a poor outcome.     

化疗对乳腺癌患者血清血管生成调节因子水平的影响

目的探讨乳腺癌患者化疗期间血清血管内皮生长因子(VEGF)和内皮细胞抑制素(ES)水平的变化及其与疗效的关系。方法收集40例转移性乳腺癌患者化疗前、化疗1个周期和5—6个周期后的系列血清标本120份,采用酶联免疫吸附试验(EUSA)检测VEGF和ES水平;同时采用该方法检测血清可溶性血管细胞黏附因子-1(VCAM-1)水平。结果(1)化疗前,乳腺癌患者血清VEGF中位水平为496.6 pg/ml,是健康对照组的4.7倍(P<0.001);ES中位水平为95.5 ng/ml,比健康对照组低18.3%(P=0.183);VCAM-1中位水平为1077.1 ng/ml,较健康对照组明显增高(P< 0.001)。化疗前VEGF与血清VCAM-1水平、疾病分期和转移部位相关(P<0.05)。(2)化疗1个周期后,乳腺癌患者血清VEGF中位水平为524.8 pg/ml,较化疗前增高(P=0.047);ES中位水平为110.5 ng/ml,与化疗前差异无统计学意义(P=0.055);VCAM-1中位水平为975.6 ng/ml,与化疗前差异亦无统计学意义(P=0.27)。(3)化疗5—6个周期后,乳腺癌患者血清VEGF中位水平为306.5 pg/ml,较化疗前、化疗1个周期后明显下降(P值分别为0.009和0.005);ES中位水平为113.3 ng/ml,比化疗前明显增高(P=0.042),但与化疗1个周期差异无统计学意义(P>0.05)。血清VEGF水平的变化与疗效相关。病情稳定或缓解的27例乳腺癌患者,VEGF均出现不同程度下降, 13例病情进展者无VEGF下降;VCAM-1水平也出现了与VEGF类似的治疗相关反应;而ES水平与疗效无关(P>0.05),提示化疗对ES水平影响可能较小。结论乳腺癌全身化疗明显影响血清VEGF水平,VEGF下降可能是疾病得到控制的一个指标;随着治疗后病情的稳定或缓解,肿瘤血管生成具有向着抗血管生成活性状态发展的趋势。     

Serum endostatin and bFGF as predictive factors in advanced breast cancer patients treated with letrozole

Introduction To investigate the value of baseline serum levels of VEGF, bFGF, endostatin and their ratio as predictive factors of response to endocrine therapy in patients with metastatic breast cancer (MBC) and positive ER treated with letrozole after tamoxifen failure. Materials and method The serum levels of endostatin, VEGF and bFGF were determined in post-menopausal patients with progressing MBC from serum samples obtained before initiation of letrozole. The relation between serum angiogenic factor levels and TTP was investigated. Results Seventy-six patients (45.2%) presented a high endostatin level (>24.6 ng/ml), 40% low bFGF levels (0 pg/ml) and 50.4% low VEGF (≤187 ng/ml). With a median follow-up of 22 months, the median TTP was 12.3 months. Median TTP was worse in patients with high endostatin concentration as well as in the low bFGF group, but was not affected when VEGF was considered. When the two factors were combined, the median TTP of patients with endostatin >24.6 ng/ml and bFGF equal 0 pg/ml was 9.5 months versus 19.5 months in patients with endostatin ≤24.6 ng/ml and bFGF>0 pg/ml. Conclusions The baseline levels of bFGF and endostatin are predictive factors of efficacy in patients with MBC treated with letrozole and can select groups with different TTP.     

内皮抑素在肺癌患者外周血清及支气管肺泡灌洗液中的表达研究

 目的 探讨内皮抑素（Endostatin）在肺癌患者外周血清及支气管肺泡灌洗液（Bronchoalveolar lavage fluid，BALF）中的表达以及与肺癌临床病理生理特征的关系。方法 采用酶联免疫吸附法（Enzyme-linked immunosorbent assay，ELISA）检测初诊肺癌47例及肺良性病变18例患者外周血清及BALF中Endostatin的表达水平。结果 肺癌患者外周血清及BALF中Endostatin分别为（131．71±50．32）ng／ml和（502．56±302．00）ng／ml，显著高于肺良性病变者（P〈0．01）；肺癌晚期、有淋巴结及远处转移、肺腺癌患者外周血清及BALF中Endostatin高表达；肺癌患者Endostatin在外周血清及灌洗液中的表达呈线性正相关（P=0．000）。结论 检测外周血清及支气管肺泡灌洗液中Endostatin均有助于肺癌的诊断及较好提示其生物学行为。     

Elevated serum endostatin is associated with poor outcome in patients with non-Hodgkin lymphoma

BACKGROUND: Endostatin is a cleaved fragment of collagen Type XVIII and has antiangiogenic activity. The clinical significance of circulating, soluble endostatin (S-endostatin) is not known. METHODS: Pretreatment S-endostatin and serum vascular endothelial growth factor (S-VEGF) levels were measured in 143 patients with non-Hodgkin lymphoma (NHL) using competitive enzyme immunoassays and were compared with the levels from a control group (n = 24 participants). RESULTS: S-endostatin levels varied widely from 4.5 ng/mL to 116 ng/mL (median, 29.6 ng/mL), and the median level was higher in patients with NHL compared with patients in the control group (16.4 ng/mL; P = 0.05). High S-endostatin levels were associated with advanced disease stage (P < 0.0001) and high serum VEGF levels at diagnosis (P = 0.017). The median 5-year survival rate for patients who had S-endostatin concentrations within the highest tertile (> 36.0 ng/mL) was only 34% compared with 57% in patients who had lower S-endostatin levels (P = 0.019). A high S-endostatin level also was associated with a poor outcome in patients with large cell diffuse and immunoblastic lymphoma, which was the largest subgroup within the series (n = 60 patients). Patients who had high pretreatment levels of both S-VEGF and S-endostatin had particularly poor outcomes. High S-endostatin levels had an independent, adverse influence on survival it was entered as a factor into a multivariate analysis together with the factors included in the International Prognostic Index (relative risk, 1.80; 95% confidence interval, 1.08-2.98; P = 0.0024). CONCLUSIONS: High pretreatment levels of S-endostatin are associated with high serum VEGF levels and poor survival in patients with NHL. Prospective studies are warranted to establish the clinical value of longitudinal S-endostatin measurements.     

Elevated vascular endothelial growth factor (VEGF) serum levels in idiopathic myelofibrosis.

An increase of angiogenesis has been shown in idiopathic myelofibrosis with myeloid metaplasia (MMM) by microvessel density count method but evaluation of circulating angiogenic factors is still incomplete. In 31 patients affected by MMM and in 12 healthy subjects we evaluated the serum levels of VEGF (vascular endothelial growth factor) and correlated VEGF with clinical and laboratory features of disease. We found that MMM patients had circulating VEGF concentrations much higher than controls (Median 1208 ng/ml vs 138 ng/ml, P < 0.0001). No correlation was found between VEGF and Hb, WBC, PLT, LDH, creatinine, bone marrow cellularity, fibrosis, splenomegaly, hepatomegaly, and therapy. However, in the subgroup of patients with a normal or low VEGF concentration, a direct correlation between VEGF and platelet count (r = 0.90, P = 0.002) was detected. Moreover, patients with a platelet count < 300 x 10(9)/l had VEGF serum levels lower than patients with a higher PLT count (median VEGF 864 vs 1557 pg/ml, P = 0.001). In six patients and in eight controls we also had the opportunity to measure VEGF in the plasma and we calculated that VEGF concentration was much higher in platelet-rich than in platelet-poor plasma and that platetets of MMM patients contained four times more VEGF than those of healthy controls. These results indicate that VEGF is overproduced in MMM, thus confirming an increased angiogenic activity. Platelets are probably a major source of VEGF in MMM but not the only one.     

Overexpression of collagen XVIII is associated with poor outcome and elevated levels of circulating serum endostatin in non-small cell lung cancer.

PURPOSE: The aim of this study was to determine whether collagen XVIII expression is correlated with circulating serum endostatin and whether this has any prognostic value in patients with non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Serum endostatin levels were measured quantitatively by a competitive enzyme immunoassay, and collagen XVIII expression in tumor tissue was investigated with an immunohistochemical method in a series of 94 patients who underwent surgery for NSCLC. RESULTS: Sixty cases (63.8%) had positive immunohistochemical staining with anticollagen XVIII polyclonal antibodies, including strongly positive staining in 11 (11.7%) cases. The mean (+/- SD) serum endostatin level was 41.6 +/- 34.4 ng/ml in the patient group and 16.3 +/- 10.3 ng/ml in the control group (P < 0.0001). The 11 cases who were strongly collagen XVIII-positive had significantly higher serum endostatin levels than the cases who were negative or weakly positive (P = 0.0297). The 5-year survival rates of negative, weakly positive, and strongly positive patients were 77.8%, 56.9%, and 43.8%, respectively. The cases with strongly positive collagen XVIII expression had a significantly poorer outcome than cases with negative expression (P = 0.0027). A multivariate analysis with Cox proportional hazards model for disease-specific survival revealed that expression of collagen XVIII (strongly positive versus negative; weakly positive versus negative), tumor classification, and regional lymph node classification were independent prognostic factors. CONCLUSIONS: Our results suggest that expression of collagen XVIII in tumor tissue is strongly associated with a poorer outcome in NSCLC and correlates with elevated levels of circulating serum endostatin.     

Tamoxifen and aromatase inhibitors differentially affect vascular endothelial growth factor and endostatin levels in women with breast cancer.

PURPOSE: Circulating and cellular proangiogenic and antiangiogenic proteins such as vascular endothelial growth factor (VEGF) and endostatin contribute to the local angiogenic balance. We explored the effects of tamoxifen and aromatase inhibitors on concentrations of VEGF and endostatin in plasma, serum, and platelet releasate (induced by platelet activation). EXPERIMENTAL DESIGN: VEGF and endostatin concentrations were measured with a quantitative immunoassay before and after 1 to 5 weeks of treatment in 30 women with breast cancer treated with either tamoxifen (n = 14) or aromatase inhibitors (n = 16). Platelet activation was induced by a thrombin receptor agonist. RESULTS: Tamoxifen therapy resulted in an increase in platelet releasate concentrations of VEGF (P = 0.01) but no change in plasma VEGF. In contrast, aromatase inhibitor therapy did not affect serum, plasma, or platelet releasate VEGF. In univariate analysis, aspirin use attenuated the tamoxifen-associated increase in VEGF in the platelet releasate and decreased serum levels of VEGF (P = 0.03). Aromatase inhibitor therapy resulted in a decrease in serum endostatin concentrations (P = 0.04), whereas plasma concentrations of endostatin tended to be higher during treatment with aromatase inhibitors (P = 0.06). Tamoxifen therapy resulted in no change in serum or plasma endostatin concentrations. Platelet releasate concentrations of endostatin did not change with either treatment. Interindividual variability was noted among both aromatase inhibitor--and tamoxifen-treated patients. CONCLUSIONS: Tamoxifen and aromatase inhibitor therapy affect VEGF and endostatin levels and likely contribute to the angiogenic balance in breast cancer patients. Aspirin decreased the proangiogenic effects of tamoxifen, suggesting that antiplatelet and/or antiangiogenic therapy might improve the effectiveness of tamoxifen in women with breast cancer.     

Elevated perioperative serum vascular endothelial growth factor levels in patients with colon carcinoma

BACKGROUND: To the authors' knowledge, little is known to date regarding the prognostic relevance of measuring serum levels of vascular endothelial growth factor (VEGF), a potent stimulator of angiogenesis, in patients with colon carcinoma who undergo surgery. METHODS: Preoperative and postoperative VEGF serum levels were determined by enzyme-linked immunoadsorbent assay in 81 patients with colon carcinoma who were undergoing surgery. Fifty healthy individuals served to define normal VEGF serum levels. RESULTS: Preoperative VEGF serum levels were significantly higher in the group of patients with colon carcinoma (mean, 504.1 pg/mL +/- 223 pg/mL; range, 285-1390 pg/mL; 95% confidence interval [95%CI], 49 pg/mL) compared with the control group (mean, 78.1 pg/mL +/- 22 pg/mL; range, 40-110 pg/mL; 95%CI, 4.3 pg/mL; P < 0.001). Multiple regression analysis demonstrated a significant correlation (r) between preoperative VEGF serum levels and age (r = - 0.275; P = 0.013), Dukes stage (r = 0.488; P < 0.001), and carcinoembryonic antigen (CEA) levels (r = 0.285; P < 0.018). No significant correlation was found between preoperative VEGF serum levels and disease site, patient gender, tumor size, tumor grade, or performance status. Moreover, preoperative VEGF serum levels were significantly lower in patients who underwent curative surgery compared with patients who underwent noncurative surgery (443 pg/mL +/- 117 pg/mL vs. 821 +/- 353 pg/mL, respectively; P < 0.0001). Logistic regression analysis selected preoperative VEGF and CEA serum levels as the only good prognostic indicators of curative and noncurative surgery (P < 0.001; relative risk, 2.98 and 2.03, respectively). Furthermore, VEGF serum levels dropped significantly after surgery, with a further downward trend until the 30th postoperative day (P < 0.001). Stepwise regression analysis selected preoperative VEGF serum level as the only variable associated significantly with the prediction of both disease-specific survival and disease-free survival (P = 0.001). CONCLUSIONS: Preoperative serum VEGF levels may be useful for predicting outcome in patients with colon carcinoma who undergo surgery.     

Vascular endothelial growth factor levels in ovarian cyst fluid correlate with malignancy.

Ovarian cancer is a richly vascularized neoplasm with solid and cystic components. The purpose of this study was to determine whether cyst fluid could be used to quantitatively evaluate production of angiogenic factors in ovarian lesions. ELISA was used to measure vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in the cyst fluid of patients with ovarian cancer (n = 13), benign cysts and cystadenomas (n = 23), borderline tumors (n = 5), and functional cysts (n = 8). VEGF levels were markedly elevated in the fluid of malignant cysts (38.5+/-8.2 ng/ml) as compared with benign (1.6+/-0.4 ng/ml; P < 0.001), borderline (5.7+/-1.5 ng/ml; P < 0.001), or functional cysts (3.8+/-2.0 ng/ml; P < 0.001). The presence of VEGF in cancer cells was confirmed by immunohistochemistry. Follow-up of patients with malignant and borderline lesions demonstrated a correlation between VEGF levels in cyst fluid and tumor recurrence (P = 0.03). bFGF in malignant cysts was either undetectable or very low (0.3+/-0.2 ng/ml), and no significant differences were found in bFGF levels among malignant, benign, borderline, and functional cysts. This study demonstrates that ovarian malignancy is associated with dramatic elevation of VEGF levels in ovarian cyst fluid. Conversely, there is no correlation between cyst fluid bFGF levels and malignant transformation. The high levels of VEGF in malignant cysts are consistent with the hypothesis that this growth factor plays an important role in ovarian cancer related-angiogenesis and tumor progression and represents a potentially important target of antiangiogenic therapy.     

Serum endostatin levels correlate with enhanced extracellular matrix degradation and poor patients' prognosis in bladder cancer

Endostatin, the proteolytic fragment of collagen XVIII, is an inhibitor of angiogenesis and tumor growth. Interestingly, elevated circulating endostatin levels have been found to correlate with poor patients' prognosis in several cancers. The aim of this study was to assess the prognostic value of endostatin in bladder cancer (BC) and to gain insight into the mechanisms involved in its production. This retrospective study included a total of 337 patients with BC and 103 controls. Collagen XVIII gene expression was analyzed using real-time PCR (n = 82). Endostatin tissue localization was assessed by immunohistochemistry (n = 27). Endostatin serum (n = 87) and urine (n = 153) levels were determined by ELISA. In 12 cases, both serum and paraffinized tissue samples from the same patients were available. We found decreased collagen XVIII tissue expression and increased endostatin urine and serum concentration in samples of patients with BC compared to controls. High serum endostatin levels correlated with the presence of lymph node metastases and MMP-7 concentrations and were independently associated with poor metastasis-free and disease-specific survival. Immunohistochemical analysis revealed a strong endostatin staining in the wall of tumor associated blood vessels in superficial but not in muscle-invasive BCs. Based on these, we concluded that elevated endostatin levels in patients with BC are the consequence of enhanced extracellular matrix degradation and are independent from collagen XVIII expression. Furthermore, serum endostatin levels may provide prognostic information independent from histopathological parameters and may therefore help to optimize therapy decisions. Loss of endostatin expression in tumor associated blood vessels might represent an important step supporting tumor-induced angiogenesis.     

Serum endostatin predicts tumor vascularity in hepatocellular carcinoma

BACKGROUND: Tumor angiogenesis is a strong prognostic factor in patients with hepatocellular carcinoma (HCC). However, to the authors' knowledge, details regarding the serum levels of proangiogenic and antiangiogenic growth factors controlling this process are not yet known. METHODS: Serum endostatin, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) levels were measured by the enzyme immunoassay method in prospectively collected samples from 33 HCC patients who had received no preoperative therapy. The angiogenic score (AS) and endostatin localization were evaluated using immunohistochemistry. RESULTS: Significant decreases in serum endostatin (P = 0.0007) and bFGF (P = 0.0004) were observed in postoperative samples compared with the preoperative values. A very strong direct correlation was noted between VEGF and endostatin (P < 0.0001). Only the preoperative serum endostatin was found to have a significant (P = 0.0025) inverse correlation with the AS. Furthermore, the combined positivity for bFGF and VEGF and negativity for endostatin was found to have a significantly (P = 0.0069) positive correlation with AS. Significantly high levels of endostatin were noted in patients with trabecular-type tumors (P = 0.0446) and in patients with hepatitis B infection (P = 0.0183). The serum endostatin level was found to be significantly (P = 0.0166) higher in living patients and patients with high serum endostatin levels had a tendency (P = 0.0871) toward long survival. Tissue endostatin expression was found to have a direct correlation with the serum endostatin level (P = 0.0117). CONCLUSIONS: The measurement of serum endostatin can predict tumor vascularity and may serve as a promising tool in the antiangiogenic therapy for patients with HCC.     

肝细胞癌介入栓塞前后血管内皮生长因子和内皮抑素的变化与预后的关系

目的 探讨肝细胞癌患者肝动脉化疗栓塞术(TACE)前后血管内皮生长因子(VEGF)和内皮抑素(ES)变化规律与预后的关系.方法 酶联免疫吸附试验(ELISA)法检测患者TACE术前及术后1周血清VEGF和ES水平.结果 肿瘤直径≥5 cm的患者,ES在治疗前后分别为(43.35±9.80)ng/ml、(48.35±10.89)ng/ml;VEGF分别为(310.23±64.31)ng/ml、(369.10±60.11)ng/ml.肿瘤伴有门静脉癌栓的患者ES在治疗前后分别为(54.28±8.78)ng/ml、(50.28±7.51)ng/ml;VEGF分别为(331.26±63.38)ng/ml、(400.29±60.98)ng/ml.VEGF和ES水平与肿瘤大小、门静脉癌栓以及临床分期密切相关(P＜0.05).肝细胞癌患者临床分期越晚,TACE前、后VEGF和ES水平均越高.晚期肝癌患者VEGF/ES比值明显高于早期患者.VEGF/ES比值越低生存时间越长.结论 VEGF、ES、VEGF/ES比值可作为预测肝细胞癌治疗效果的指标.     

High serum levels of vascular endothelial growth factor predict poor response to transarterial chemoembolization in hepatocellular carcinoma: a prospective study

Vascular endothelial growth factor (VEGF) is an important mediator of tumor angiogenesis. A high serum VEGF level has been shown to predict poor response to chemotherapy and poor survival in several cancers, but its prognostic value in hepatocellular carcinoma (HCC) remains unknown. We conducted a prospective study to evaluate the prognostic significance of pretreatment serum VEGF levels on tumor response to treatment and survival of patients with HCC undergoing transarterial chemoembolization (TACE). Pretreatment serum VEGF levels were measured by an enzyme-linked immunosorbent assay in 80 patients with inoperable HCC undergoing TACE. Serum VEGF levels were correlated with clinical data, tumor response to TACE and survival results. The median serum VEGF level was 240 pg/ml (range 9-1730). Serum VEGF levels were positively correlated with the presence of venous tumor thrombus (P=0.011). Pretreatment serum VEGF levels were significantly higher in patients with progressive disease (median 434 pg/ml) than those with stable (median 176 pg/ml, P=0.010) or responsive disease (median 142 pg/ml, P<0.001) after TACE. Patients with serum VEGF >240 pg/ml had significantly worse survival than those with serum VEGF <240 pg/ml (median survival 6.8 vs. 19.2 months, P=0.007). In a Cox multivariate analysis, serum VEGF >240 pg/ml was an independent prognostic factor of survival. In conclusion, the results of this study suggest that serum VEGF level may be useful as a novel prognostic predictor of tumor response and survival of patients with inoperable HCC undergoing TACE treatment.     

NSCLC微波消融前后血清VEGF、Arg-1、iNOS水平变化及其相关性

目的 探讨微波消融治疗非小细胞肺癌(NSCLC)的疗效,分析微波消融前后NSCLC患者血清血管内皮生长因子(VEGF)、精氨酸酶-1(Arg-1)、诱导型一氧化氮合酶(iNOS)浓度的变化及三者之间的关系.方法 选取30例健康体检者作为对照组,30例晚期NSCLC患者为试验组,用酶联免疫吸附试验(ELISA)法检测健康体检者、晚期NSCLC患者微波消融术前及术后第1天、第3天、1个月血清VEGF、Arg-1、iNOS浓度.结果 微波消融治疗晚期NSCLC的有效率为33.3％ (10/30),疾病控制率为70.0％(21/30).微波消融术前NSCLC患者血清VEGF、Arg-1、iNOS浓度分别为(816.56±13.26)pg/ml、(5.17±0.20) ng/ml、(544.18±13.93) pg/ml,明显高于对照组的(93.43±9.93) pg/ml、(1.08±0.05) ng/ml、(8.08-±0.33) pg/ml,差异均有统计学意义(t=239.093,P＜0.001;t=110.359,P＜0.001;t=210.792,P＜0.001).晚期NSCLC患者微波消融术后第1天、第3天、1个月血清VEGF浓度分别为(708.41±10.49)pg/ml、(592.63±7.25) pg/ml、(521.91±8.32) pg/ml,均较治疗前明显降低(均P ＜0.05);Arg-1浓度分别为(5.95±0.10) ng/ml、(7.02±0.13) ng/ml、(7.67±0.92) ng/ml,均较治疗前明显升高(均P ＜0.05);iNOS浓度分别为(453.01±9.48)pg/ml、(393.21±9.42) pg/ml、(352.60±8.31)pg/ml,均较治疗前明显降低(均P＜0.05).NSCLC患者治疗前血清iNOS与VEGF表达呈正相关(r =0.379,P=0.039),Arg-1与VEGF表达呈负相关(r=-0.556,P=0.001),iNOS与Arg-1表达无关(r=-0.238,P=0.205).结论 微波消融是一种有效的NSCLC局部治疗手段,除可直接杀灭癌细胞外,亦可影响VEGF、Arg-1、iNOS表达水平,VEGF与iNOS和Arg-1有一定相关性,而iNOS与Arg-1无关.微波消融可在一定程度上改变肿瘤微环境,刺激机体产生抗肿瘤免疫.     

Increased serum VEGF in 13 children with Wilms' tumour falls after surgery but rising levels predict poor prognosis

Vascular endothelial cell growth factor (VEGF, a potent endothelial cell mitogen in vitro) may be important in tumour development and its spread in vivo. In this preliminary study, we tested the hypotheses that (i) raised serum levels in Wilms' tumour fall after surgery, and (ii) rising levels predict adverse outcome. Serum VEGF was measured (ELISA) in 13 children about to undergo surgery, and serially on the following day, a week later, and finally 3-6 months after surgery. A simple follow-up at 6 months was also performed. The control group was 60 healthy adults. Before surgery, the median (inter-quartile range) VEGF in the children was 20 ng/ml (10.4-70.5) and was 1 ng/ml (0.5-4.0) in the adults. This difference is statistically highly significant (P=0.0001). After surgery, levels in the children fell significantly to 1.3 ng/ml (0.5-7.95) the following day and to 1.9 ng/ml (0.5-5.0) the following week (P<0.001, ANOVA). Six months after surgery, three of the children had died. A level of >10 ng/ml measured 3 months after surgery correctly identified all three deaths: levels were 1.3 ng/ml (0.5-1.9) in the survivors and were 20.0 ng/ml (15-104) in those who died. These data indicate a rapid reduction in raised VEGF following surgery for Wilms' tumour, but that rising levels predict poor prognosis.     

VEGF, TNF-alpha and 8-isoprostane levels in exhaled breath condensate and serum of patients with lung cancer

The aim of the present study was to evaluate the levels of VEGF, 8-isoprostane and TNF-alpha in EBC and serum of patients with primary lung cancer prior to the initiation of any treatment, in order to evaluate their possible diagnostic role. Furthermore, associations between VEGF, 8-isoprostane and TNF-alpha levels in EBC and serum with clinicopathologic factors were investigated. We enrolled 30 patients with lung cancer (mean age 65.2+/-10.5 years) and 15 age and gender-matched healthy smokers as controls. Serum and EBC were collected before any treatment. TNF-alpha, VEGF and 8-isoprostane levels in EBC and serum were analyzed by an immunoenzymatic method (ELISA). A statistically significant difference was observed between lung cancer patients and the control group regarding the values of TNF-alpha, both in EBC (52.9+/-5.0 pg/ml vs. 19.4+/-3.9 pg/ml, p<0.0001) and serum (44.5+/-6.3 pg/ml vs. 22.2+/-4.3 pg/ml, p=0.035). Moreover, EBC VEGF levels were higher in patients with T3-T4 tumor stage compared to T1-T2 (9.3+/-2.8 pg/ml vs. 2.3+/-0.7pg/ml, p=0.047). A statistically significant correlation was also observed between serum and EBC values of VEGF (r=0.52, p=0.019). In addition, serum levels of VEGF were higher in lung cancer patients than in controls (369.3+/-55.1 pg/ml vs. 180.5+/-14.7 pg/ml, p=0.046). VEGF serum levels were also found higher in patients with advanced stage of disease (IIIB-IV) and distant nodal metastasis (N2-N3). No differences were observed in 8-isoprostane in EBC between lung cancer patients and controls. In contrast, serum 8-isoprostane levels were higher in lung cancer patients compared to controls (24.9+/-3.6 pg/ml vs. 12.9+/-1.6 pg/ml, p=0.027) and were higher in patients with advanced disease. All three biomarkers presented acceptable reproducibility in the EBC on two consecutive days. In conclusion, we have shown that TNF-alpha, VEGF and 8-isoprostane are elevated in the serum of lung cancer patients and increased serum VEGF and 8-isoprostane levels are related to advanced disease. In EBC, increased TNF-alpha levels were observed in lung cancer patients, whereas increased VEGF levels were observed in advanced T-stage. Further longitudinal studies are warranted for the evaluation of the prognostic role of these biomarkers in lung cancer.