Vascular endothelial growth factor levels and induction of permeability in malignant pleural effusions.

Vascular endothelial growth factor (VEGF) is an important mediator of angiogenesis and vascular permeability. We hypothesized that malignant pleural effusions may contain high levels of VEGF protein as well as other cytokines implicated in these processes. Pleural effusions cytologically proven to be malignant were collected from 39 patients with various types of cancer, and VEGF, interleukin-8, and angiogenin levels in the effusions were determined by immunoassay. Negative controls were nonmalignant ascites and serum samples from healthy individuals. VEGF levels were significantly higher than those of control samples in pleural effusions secondary to breast, mesothelioma, and non-small cell lung cancer and when all malignant pleural effusion samples were pooled. Neither interleukin-8 nor angiogenin levels were elevated in malignant pleural effusions relative to the control samples. Vascular permeability, which was measured by using the Miles assay in nude mice, was increased proportionately with VEGF levels in the malignant pleural effusions; this increase in permeability induced by injection of recombinant VEGF or the malignant effusions was reduced by pretreating the mice with a VEGF receptor antibody.     

晚期恶性肿瘤血清VEGF含量测定的临床意义

目的：探讨血清血管内皮生长因子（VEGF）浓度在晚期恶性肿瘤中的临床意义。方法：应用酶联免疫吸附试验（ELISA）测定40例晚期恶性肿瘤（非小细胞肺癌、鼻咽癌、食管癌）患者血清的VEGF浓度,10名健康成人作为对照。结果：40例晚期恶性肿瘤患者血清VEGF浓度为（477．07±374．10）pg／ml,显著高于健康成人（139．09±133．41）pg／ml,差异有统计学意义（P=0．016）,其中治疗前血清VEGF浓度在非小细胞肺癌为（518．53±378．99）pg／ml,食管癌为（399．21±393．69）pg／ml,鼻咽癌为（500．68±348．48）pg／ml,与健康成人比较差异有统计学意义（P值分别为0．011、0．044和0．019）。化疗有效患者的血清VEGF浓度（400．41±332．84）pg／ml显著低于化疗前浓度（777．10±666．01）pg／ml,差异有统计学意义（P=0．034）。结论：血清VEGF可作为晚期恶性肿瘤监测病情、判断放疗和预后一个有用的指标。     

晚期恶性肿瘤血清VEGF含量测定的临床意义

Objective: To elucidate the clinical significance of serum vascular endothelial growth factor (VEGF) level in patients with advanced cancer. Methods: Enzyme linked immunosorbent assay (ELISA) was used to determine the serum VEGF concentration in 40 patients with advanced cancer [non-small cell lung cancer (NSCLC), esophageal cancer (EC) and nasopharyngeal carcinoma (NPC)] before and after chemotherapy and 10 healthy volunteers as control group. Results: The serum VEGF concentrations in 40 cases of advanced cancer patients were significantly higher than those of 10 healthy control cases [(477.07 ± 374.10 ) pg/mL vs (139.09 ± 133.41 ) pg/mL; P = 0.016]. The serum VEGF concentrations in patients with NSCLC, EC and NPC were (518.53 ± 378.99) pg/mL, (399.21 ± 393.69) pg/mL and (500.68 ± 348.48) pg/mL, respectively. The differences were all statistically significant as compared with healthy control group (P values were 0.011,0.044 and 0.019, respectively). The serum VEGF concentrations of the patients in response to chemotherapy was significantly lower than those of the same patients before they undergoing chemotherapy [(400.41 332.84) pg/mL vs (777.10 ± 666.01) pg/mL; P = 0.034]. Conclusion: The serum VEGF level might be a novel and promising tumor marker of advanced malignancies and a predictor of disease progression, prognosis and therapeutic efficacy.     

血管内皮生长因子在恶性肿瘤患者表达的临床研究

目的通过测定血管内皮生长因子(VEGF)在肿瘤患者血清及恶性渗出液中的含量,以明确VEGF能否作为肿瘤标志物。方法通过酶联免疫吸附法测定VEGF在健康人、肿瘤患者血清及恶性渗出液中的含量。结果恶性肿瘤患者血清中VEGF含量较健康组高,且有显著差异(P<0．01),但多数肿瘤转移与非转移组比较无差异(肝癌患者除外),非转移性胃肠道肿瘤患者血清中VEGF与CEA、CA19-9有相关性,其他恶性肿瘤血清中VEGF与CEA、CA19-9均无相关性。22例肺癌患者渗出液中VEGF中位数229．2pg/ml,比其血清中VEGF中位数高(62．2pg/ml)。有恶性渗出液患者血清中VEGF与其渗出液中VEGF无相关性,渗出液中VEGF与其CEA、CA19- 9及LDH亦无相关性。肺癌患者经治疗血清中VEGF随病情好转而下降,也可随病情进展而升高。结论①恶性肿瘤患者血清中VEGF水平比健康人高。②VEGF可作为一个非特异性的肿瘤标志物,且与治疗疗效呈正相关。     

血管内皮生长因子在恶性肿瘤患者表达的临床研究

目的 通过测定血管内皮生长因子（VEGF）在肿瘤患者血清及恶性渗出液中的含量，以明确VEGF能否作为肿瘤标志物。方法 通过酶联免疫吸附法测定VEGF在健康人、肿瘤患者血清及恶性渗出液中的含量。结果 恶性肿瘤患者血清中VEGF含量较健康组高，且有显著差异（P〈0．01），但多数肿瘤转移与非转移组比较无差异（肝癌患者除外），非转移性胃肠道肿瘤患者血清中VEGF与CEA、CA19-9有相关性，其他恶性肿瘤血清中VEGF与CEA、CAl9．9均无相关性。22例肺癌患者渗出液中VEGF中位数229．2pg／ml，比其血清中VEGF中位数高（62．2pg/ml）。有恶性渗出液患者血清中VEGF与其渗出液中VEGF无相关性。渗出液中VEGF与其CEA、CA19-9及LDH亦无相关性。肺癌患者经治疗血清中VEGF随病情好转而下降，也可随病情进展而升高。结论 ①恶性肿瘤患者血清中VEGF水平比健康人高。②VEGF可作为一个非特异性的肿瘤标志物，且与治疗疗效呈正相关。     

妇科恶性肿瘤患者血清中血管内皮生长因子测定的临床意义

背景与目的:实验和临床证明恶性肿瘤的生长、浸润和转移与肿瘤血管生成有关,这过程由多种血管生长因子调控,如血管内皮生长因子(vascularendothelialgrowthfactor,VEGF)。目前在妇科恶性肿瘤患者中测定血清VEGF水平的研究报道不多。本研究测定妇科恶性肿瘤患者血清中VEGF的水平,并探讨其能否成为一种新的肿瘤标记物。材料与方法:采用R&DSystemsIncminneapolisMNUSA生产的QuantikineHumamVEGF试剂盒,用ELISA方法测定50例宫颈癌、39例子宫内膜癌和89例卵巢癌患者的术前血清,以及其中3例卵巢癌术后3、6、9个月及复发时血清的VEGF水平;另用80例健康妇女血清的VEGF水平作为对照。用SPSS9.0统计软件包进行统计分析。用5th和95th位数的区间描述变异程度。结果:80例健康妇女的血清VEGF中位水平为218.5ng/L(42.06-671.70ng/L)。50例宫颈癌、39例子宫内膜癌和89例卵巢癌患者术前血VEGF中位水平分别为272.00ng/L(91.94-745.53ng/L)、383.50ng/L(105.67-776.50ng/L)和479.85ng/L(99.47-1326.88ng/L),子宫内膜癌和卵巢癌患者术前血清VEGF水平显著高于健康妇女(P<0.0001),宫颈癌患者术前血清VEGF与健康妇女相比无显著性差异(P>0.05)。3例卵巢癌患者术后3、6、9个月无复发时测定的血清VEGF水平较术前明显下降,其中2例术     

High level of vascular endothelial growth factor in hemorrhagic pleural effusion of cancer

Angiogenic cytokines, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and angiogenin, are candidates for the induction of pleural effusions because they have been implicated in the induction of neovascularization, vascular permeability, and hemorrhage both in the inflammatory process and in tumor progression. Thus, we hypothesized that these angiogenic factors in effusion might be involved in the clinical manifestation of malignant pleural disease. We measured the levels of VEGF, bFGF, and angiogenin in pleural effusions and sera from 40 patients. Pleural effusions due to malignancy (1,350 pg/ml) contained significantly higher levels of VEGF than effusions due to inflammatory diseases (102 pg/ml; p = 0.034). Furthermore, hemorrhagic effusions showed significantly higher VEGF levels (1,942 pg/ml) than non-hemorrhagic effusions (202 pg/ml; p = 0.016) in malignant patients. In contrast, neither bFGF nor angiogenin were correlated with any clinical manifestation of pleural effusion. Immunohistochemical study revealed that malignant cells in the pleura were stained with anti-VEGF antibody. Our data suggest that VEGF secreted from tumor cells may be involved in the accumulation of pleural effusion in malignancy, and that increased levels of VEGF may induce hemorrhagic effusion.     

血管内皮生长因子在常见恶性肿瘤诊治中的临床价值

目的:探讨血管内皮生长因子(VEGF)在常见恶性肿瘤诊断、治疗和预后中的临床意义。方法:应用酶联免疫吸附法(ELISA)检测544例恶性肿瘤患者及87例对照者血清中VEGF浓度和CEA、CA50等6种肿瘤标记物的水平。计算VEGF的灵敏度、特异度、阳性预测值和阴性预测值,分析患者治疗前血清VEGF水平对其近期疗效的影响以及VEGF和其他肿瘤标记物联合检测结果与患者疗效的关系。结果:①各种肿瘤患者血清VEGF平均水平均高于对照组,其中以胃癌、肝癌和肺癌患者较高;②VEGF以200.6(ng/L)为医学参考值上限,其灵敏度为54.2%,特异度为95.4%;有负荷组患者灵敏度可达到74.9%,而无负荷者仅为20.4%,其差别有统计学意义(P<0.01);③肿瘤患者随着血清VEGF平均水平的升高,其疗效逐渐降低(P<0.05)。五种肿瘤标记物联合分析显示,随着患者血清肿瘤标记物阳性数目的增多,无效患者的比例呈上升趋势,当患者血清肿瘤标记物阳性数目达到3种或以上时,约89%的患者显示无效。结论:血清VEGF是一种广谱的肿瘤标记物,对多种肿瘤的辅助诊断均有重要的临床价值,且对初诊肿瘤患者,VEGF是一个良好的检测指标,其鉴别诊断价值优于其他6种肿瘤标记物。VEGF与其他肿瘤标记物联合检测有助于临床疗效评价、预后评估和病情随访监测。     

Optimal therapy of malignant pleural effusions

A randomized phase III trial of bleomycin, tetracycline and talc following chest tube drainage and a meta-analysis of relative benefit of bleomycin and tetracycline as sclerosing agents were performed to determine the optimal approach to malignant pleural effusion (MPE). Fifty patients were randomized to receive bleomycin (n=16), tetracycline (n=19) or talc (n=16) following chest tube drainage. Treatment groups were balanced for pretreatment characteristics. The study was ended prematurely because of the removal of parenteral tetracycline from the market. Overall, 52% of randomized patients had successful control of effusion 30 days after sclerosis. There were no differences between any of the three treatment groups in terms of 30 day control of effusion, overall survival (6 months), resclerosis rate, pain with sclerosis, fever, or duration of hospitalization (6 days). A meta-analysis was performed using the four previously reported trials of tetracycline vs. bleomycin and revealed a 20.6% advantage to the use of bleomycin (95% C.I. 7.9%-33.3%) (p=0.002). This phase III failed to demonstrate a significant difference between the three agents in terms of control of MPE at 30 days, side effects or survival. However, because of small sample size, this study lacks sufficient power to observe potentially clinically important differences between treatment groups. Inclusion of data from four previous trials in a meta-analysis showed that bleomycin may be superior. The median duration of hospitalization and the overall success rate of all three sclerosing agents in this study argue convincingly that new approaches to palliate MPE are needed.     

良恶性胸腔积液的鉴别诊断

胸腔积液是一个常见的临床表现,其良恶性的判断治疗和与预后密切相关.许多方法和指标都曾尝试用于恶性胸腔积液的诊断,各有利弊.随着分子生物学和实验技术的迅速发展,新的诊断指标和检测方法不断涌现.本文综述了近年来相关的临床研究结果,对各种诊断方法进行了客观评价.     

恶性心包积液中血管内皮生长因子分泌水平的研究

目的：通过检测良、恶性心包积液中血管内皮生长因子（VEGF）的水平,探讨VEGF在恶性心包积液生成中的作用。方法：用EIA法检测22例恶性心包积液与16例非恶性心包积液及血清中VEGF水平,比较良、恶性心包积液中VEGF水平差异;并观察丝裂霉素心包腔内化疗后VEGF水平改变。结果：恶性心包积液中VEGF水平明显高于非恶性心包积液;肺癌与乳腺癌导致心包积液VEGF水平无明显差异;心包腔内化疗只可暂时降低VEGF水平。结论：恶性心包积液的VEGF明显增高,VEGF与恶性心包积液的发生、发展相关。     

ZD6474, an inhibitor of vascular endothelial growth factor receptor tyrosine kinase, inhibits growth of experimental lung metastasis and production of malignant pleural effusions in a non-small cell lung cancer model

ZD6474 is a novel, orally active inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase, with some additional activity against epidermal growth factor receptor (EGFR) tyrosine kinase. The purpose of this study was to determine the potential of ZD6474 in the control of established experimental lung metastasis and pleural effusions produced by human non-small cell lung cancer (NSCLC) cells. PC14PE6 (adenocarcinoma) and H226 (squamous cell carcinoma) cells express high levels of EGFR and only PC14PE6 cells overexpress VEGF. Neither ZD6474 nor the EGFR tyrosine kinase inhibitor gefitinib inhibit proliferation of PC14PE6 or H226 cells in vitro. Both PC14PE6 and H226 cells inoculated intravenously into nude mice induced multiple lung nodules after 5-7 weeks. In addition, PC14PE6 cells produced bloody pleural effusions. Daily oral treatment with ZD6474 did not reduce the number of lung nodules produced by PC14PE6 or H226 cells, but did reduce the lung weight and the size of lung nodules. ZD6474 also inhibited the production of pleural effusions by PC14PE6 cells. Histological analyses of lung lesions revealed that ZD6474 treatment inhibited activation of VEGFR-2 and reduced tumor vascularization and tumor cell proliferation. Therapeutic effects of ZD6474 were considered likely to be due to inhibition of VEGFR-2 tyrosine kinase because gefitinib was inactive in this model. These results indicate that ZD6474, an inhibitor of VEGFR-2, may be useful in controlling the growth of established lung metastasis and pleural effusions by NSCLC.     

Pleuroperitoneal shunting for malignant pleural effusions

Traditional therapy for malignant pleural effusions includes thoracentesis or tube drainage with instillation of irritants to achieve pleurodesis. This can require a lengthy hospitalization, causes pain and discomfort, and has an appreciable failure rate. Because of these drawbacks, the authors used a shunting device to transfer fluid to the peritoneal cavity in 17 patients with malignant pleural effusions. Eleven patients had undergone previous therapeutic thoracenteses and three had chest tube placement with failed sclerosis. The shunt was a subcutaneous valved pump chamber with attached pleural and peritoneal catheters, which used manual compression to transfer fluid against the normal abdominal/pleural pressure gradient. Operative placement under local or general anesthesia was performed without complication. Five patients achieved minimal benefit, either because of moribund status or their inability to compress the pump effectively. In the other 12 patients, there was radiographic evidence of diminished or stabilized pleural effusion; respiratory symptoms were effectively palliated, and no further treatment for their effusion was required. Peritoneal dissemination of malignant cells has not been clinically detected. We feel that pleuroperitoneal shunting is a valid new method for treatment of malignant pleural effusions which can effectively palliate respiratory symptoms with low morbidity. Advantages include the absence of external tubing and the possibility for only a short hospitalization or even outpatient placement. Shunting is applicable for patients who are able to perform the requisite pumping and is particularly suitable for those with trapped lungs or who have failed attempted pleural sclerosis.     

Interferon instillation for malignant pleural effusions

BACKGROUND: Malignant pleural effusions can be managed in various ways includinginstillation of antineoplastic agents. Instillations of alfainterferon-2b (IFN-     

Pleuroperitoneal shunt for malignant pleural effusions

The malignant pleural effusion was introduced into the abdominal cavity by the manual compression of a pleuroperitoneal shunt tube, which was indwelt in the subcutaneous tissue of the lateral chest under local anesthesia. Seven patients having malignant pleural effusion, due to lung cancer in 4 and breast cancer in 3, were used as subjects. This technique caused no serious complications. Retention of pleural effusion was markedly reduced in all of the 7 patients. Three patients, whose performance status (P.S.) was preoperatively determined to be 3 or 2, could be discharged during early periods. This technique seemed to be highly feasible in these patients, but not in those having P.S. of 4. Since peritoneal dissemination of the tumor was seen in 1 of 3 patients examined by autopsy, there is a possibility that this technique might have contributed to spread and scattering of tumor cells in the peritoneal cavity. These results suggested that this technique is useful therapeutic means for the treatment of patients in whom hospitalization is necessary due to the presence of malignant pleural effusion, while this technique involves the risk of artificial induction of peritoneal dissemination of tumor cells. Therefore, the application of this technique should be decided based on the prognosis of each patient.     

粘质沙雷菌菌苗治疗恶性胸腔积液的临床观察

目的：评价粘质沙雷菌菌苗（Ｓ－３１１抗癌菌苗）治疗恶性胸腔积液的作用和毒性。方法：３５例恶性胸腔积液患应用Ｓ－３１１抗癌菌苗胸腔内给药治疗。结果：有效率８８．６％（３１／３５），完全缓解率４８．６％（１７／３７）。不良反应有发热、寒颤和胸痛。结论：Ｓ－３１１抗癌菌菌苗治疗恶性胸腔积液疗效肯定。     

血管内皮生长因子及其受体与骨肉瘤关系的研究进展

血管内皮生长因子（ＶＥＧＦ）是一种序列高度保守、高度特异性的促血管内皮细胞生长因子,广泛分布于人和动物体内的大脑、肾脏、肝脏、脾脏、胰腺和骨骼等组织中,对内皮细胞具有强烈的促有丝分裂作用,刺激血管内皮细胞增殖和血管通透性增加,促进新生血管形成。ＶＥＧＦ通过与血管内皮细胞表面受体（ＶＥＧＦＲ）特异性结合发挥生物学效应。抑制ＶＥＧＦ及ＶＥＧＦＲ的活性可以减缓或阻滞骨肉瘤侵袭和转移。研究表明,ＶＥＧＦ及ＶＥＧＦＲ对肿瘤血管及淋巴管的生成及肿瘤侵袭和转移起重要作用。本文对ＶＥＧＦ及ＶＥＧＦＲ与骨肉瘤血管与淋巴管生成及其侵袭与转移的关系作一综述。     

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.     

Clinical significance of vascular endothelial growth factor C and vascular endothelial growth factor receptor 3 in patients with nonsmall cell lung carcinoma

BACKGROUND: Vascular endothelial growth factor C (VEGF-C) plays an important role in lymphangiogenesis and activates VEGF receptor 3 (VEGFR-3). By contrast, lymphatic spread is an important prognostic factor in patients with nonsmall cell lung carcinoma (NSCLC). The objective of the current study was to determine whether the expression of VEGF-C and VEGFR-3 correlates with clinicopathologic factors and prognosis in patients with primary NSCLC. METHODS: The authors conducted a retrospective review of 180 consecutive patients who underwent complete resection for NSCLC and who did not receive any chemotherapy or radiotherapy prior to surgery. Immunohistochemical staining for VEGF-C and VEGFR-3 was performed. The clinicopathologic implications of VEGF-C and VEGFR-3 expression were analyzed statistically. RESULTS: Of 180 patients with NSCLC, 137 patients (76.1%) were positive for VEGF-C, and 40 patients (22.2%) were positive for VEGFR-3. VEGF-C expression was observed frequently in patients with adenocarcinoma (P = 0.026). For VEGFR-3 expression, significant correlations were demonstrated with age (P = 0.02), gender (P = 0.008), and histologic differentiation in patients with squamous cell carcinoma (P = 0.03). Patients who had positive staining for VEGF-C showed significantly less favorable survival rates compared with patients who had negative staining for VEGF-C (P = 0.003). The survival rates of patients who had positive staining for VEGFR-3 also were significantly lower compared with patients who had negative staining for VEGFR-3 (P < 0.001). Patients who had positive staining for both VEGF-C and VEGFR-3 exhibited the most unfavorable prognoses. Univariate analysis revealed the following prognostic factors: gender (P = 0.03), tumor status (T1,T2 vs. T3; P < 0.01), lymph node status (negative vs. positive; P < 0.01), tumor size (< or = 35 mm vs. > 35 mm; P < 0.01), disease stage (Stage I vs. Stages II and III; P < 0.01), VEGF-C expression (negative vs. positive; P < 0.01), VEGFR-3 expression (negative vs. positive; P < 0.01) and combined VEGF-C and/or VEGFR-3 expression (both positive vs. VEGF-C or VEGFR-3 positive; P < 0.01). Multivariate analysis demonstrated that VEGFR-3 expression was the only independent negative prognostic factor (P < 0.01). CONCLUSIONS: VEGF-C and VEGFR-3 expression may be indicative of survival rates for patients with NSCLC.