Autocrine IL-6-induced Stat3 activation contributes to the pathogenesis of lung adenocarcinoma and malignant pleural effusion

Malignant pleural effusion (MPE) is a poor prognostic sign for patients with non-small-cell lung cancer (NSCLC). The generation of MPE is largely regulated by vascular endothelial growth factor (VEGF), and upregulation of VEGF by Stat3 has been observed in several types of tumor cells. In this study, we demonstrate constitutively activated Stat3 in several human lung cancer cell lines and in tumor cells infiltrated in the pleurae of patients with adenocarcinoma cell lung cancer (ADCLC) and MPE. The observations suggest that activated Stat3 plays a role in the pathogenesis of ADCLC. In PC14PE6/AS2 cells, a Stat3-positive human ADCLC cell line, autocrine IL-6 activated Stat3 via JAKs, not via Src kinase. PC14PE6/AS2 cells express higher VEGF mRNA and protein than do Stat3-negative PC14PE6/AS2/dnStat3 cells. In an animal model, PC14P6/AS2/dnStat3 cells produced no MPE and less lung metastasis than did PC14P6/AS2 cells. PC14PE6/AS2 cells also expressed higher VEGF protein, microvessel density, and vascular permeability in tumors than did PC14P6/AS2/dnStat3 cells. Therefore, we hypothesize that autocrine IL-6 activation of Stat3 in ADCLC may be involved in the formation of malignant pleural effusion by upregulating VEGF. Higher levels of IL-6 and VEGF were also found in the pleural fluids of patients with ADCLC than in patients with congestive heart failure. The autocrine IL-6/Stat3/VEGF signaling pathway may also be activated in patients with ADCLC and MPE. These findings provide novel targets for the management of MPE.     

肺腺癌合并恶性胸腔积液患者血管生成素-2与胸腔积液局部控制及预后的关系

目的 探讨胸腔积液及血清中血管生成素-2（Ang-2）与肺腺癌合并恶性胸腔积液（MPE）患者胸腔积液局部控制及预后的关系。方法 收集肺腺癌合并MPE患者的胸腔积液及血液标本,采用ELISA法测定胸腔积液和血清中Ang-2水平,分析其与临床病理特征、胸腔积液局部控制情况及预后的关系。结果 胸腔积液和血清Ang-2水平分别为（26.67±8.82）pg／ml和（361.18±97.58） pg／ml。采用ROC曲线分析,当截断值为25.57 pg／ml时,胸腔积液Ang-2水平预测胸腔积液局部控制情况效能为最佳。Logistic回归分析显示胸腔积液Ang-2水平是胸腔积液局部控制情况的独立因素（OR=5.65,95%CI：2.40～16.78,P<0.001）。Cox多因素分析表明胸腔积液Ang-2水平（HR=1.15, 95%CI：1.01～1.32） 及胸腔积液局部控制情况（HR=0.42,95%CI：0.19～0.89）是影响肺癌合并MPE患者生存预后的独立因素。血清Ang-2水平与胸腔积液局部控制情况及预后无关（P＞0.05）。结论 胸腔积液Ang-2水平可作为肺腺癌合并MPE患者预测胸腔积液局部控制及判断预后的分子标志物,具有重要的临床应用价值。     

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.     

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.     

Endostatin variations in childhood acute lymphoblastic leukaemia--comparison with basic fibroblast growth factor and vascular endothelial growth factor

Angiogenic factors such as basic fibroblast growth factor (bFGF) or vascular endothelial growth factor (VEGF) were previously studied in childhood acute lymphoblastic leukaemia (ALL) but little is known concerning the anti-angiogenic response in ALL. At diagnosis, the plasma levels of the anti-angiogenic factor endostatin were significantly higher in 33 children with ALL than in controls (median values 17.7 and 7.6 ng/ml, respectively, p=0.0192) but no relationship was observed with plasma bFGF or VEGF levels. The highest levels were observed in patients with an hyperdiplo?d karyotype. Expression of mRNA for collagen XVIII/endostatin in lymphoblasts was detected in 19/24 cases but protein secretion was found only in 14/28 supernatants of cultured lymphoblasts. No direct relationship appeared between secretion of endostatin by lymphoblasts and plasma levels. In addition, endostatin levels remained elevated in remission, suggesting that endostatin could have a stromal origin as well. No prognostic value of plasma endostatin could be assessed. In conclusion, the present data indicate that an anti-angiogenic response is observed in some ALL children, but its physiopathological importance remains to be established.     

胸腔热灌注化疗治疗肺癌胸腔积液的临床观察

目的 观察胸腔热灌注化疗对比胸腔置管化疗治疗肺癌所致恶性胸腔积液的临床疗效及不良反应.方法 纳入103例肺癌胸腔积液患者,胸腔热灌注化疗组65例,胸腔置管化疗组38例.观察胸腔积液控制率、胸腔积液进展时间、胸腔积液中血管内皮生长因子(VEGF)浓度与疗效的关系以及不良反应发生情况.结果 热灌注化疗组和置管化疗组的胸腔积液控制率分别为81.5％和52.6％,差异有统计学意义(x2=9.834,P=0.002).两组患者的中位胸腔积液进展时间分别为3.10个月和2.15个月,差异有统计学意义(x2=10.512,P=0.001).胸腔积液中VEGF低浓度患者接受胸腔热灌注化疗和腔内置管化疗后的中位胸腔积液进展时间分别为3.34个月和2.20个月,差异有统计学意义(x2=9.409,P=0.002),但VEGF高浓度亚组,两种治疗方法的中位胸腔积液进展时间分别为2.85个月和2.10个月,差异无统计学意义(x2=2.429,P=0.119).两组患者的不良反应主要为消化道不良反应、乏力及血液毒性,热灌注化疗组患者乏力较置管化疗组常见(67.7％∶13.2％;x2 =28.595,P＜0.001).结论 胸腔热灌注化疗治疗肺癌所致恶性胸腔积液较常规腔内置管化疗提高了胸腔积液控制率,且可延长胸腔积液进展时间,不良反应易于耐受,胸腔积液进展时间延长在胸腔积液VEGF低浓度亚组中尤为明显,VEGF可作为胸腔热灌注化疗的疗效预测因素.     

CD8~＋CD25~＋FOXP3~＋调节性T淋巴细胞在恶性胸腔积液中的表达及其临床意义

目的通过检测恶性胸腔积液中CD8＋CD25＋Foxp3＋调节性T淋巴细胞（T8reg）的表达,探讨其与恶性胸腔积液患者临床预后的关系。方法同步采集30例肺癌合并胸腔积液患者的胸腔积液和外周血,20例良性胸腔积液患者的胸腔积液和外周血,另采集20例健康对照者外周血,用流式细胞术检测上述标本中CD8＋CD25＋Foxp3＋T淋巴细胞的表型、百分比,分析其与恶性胸腔积液患者生存时间的关系。结果恶性胸腔积液组中T8reg占总CD8＋T细胞的比例显著高于良性胸腔积液组[（2.20±0.25）%vs（0.38±0.05）%,P=0.018],亦高于自身外周血组[（0.52±0.06）%,P=0.000],恶性胸腔积液患者外周血中T8reg的比例高于正常健康者外周血中的比例[（0.52±0.06）%vs（0.31±0.04）%,P=0.005]。而良性胸腔积液组胸腔积液、外周血（0.34±0.04）%与健康对照组外周血三组中T8reg细胞的数量占总CD8＋T细胞比例没有明显升高,差别没有统计学意义（P〉0.05）。T8reg高、低表达水平组患者的中位生存时间分别为105、195d,两者差异有统计学意义（P=0.004）。Cox回归模型多因素分析显示MPE中T8reg的表达水平、肿瘤大小是影响MPE患者预后的独立因素（P值分别为0.018、0.006）。结论肺癌伴胸膜转移患者的MPE及其外周血T8reg细胞的比例明显增高;MPE中T8reg细胞表达下降预示MPE患者生存率会明显改善,提示CD8＋CD25＋Foxp3＋T细胞在肺癌发生、发展的免疫病理过程中具有显著意义。     

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.     

Osteopontin is involved in the formation of malignant pleural effusion in lung cancer

Malignant pleural effusion (MPE) is associated with advanced-stage lung cancer and is a poor prognostic sign for these patients. Osteopontin (OPN) is a multifunctional cytokine that is involved in the tumor progression and angiogenesis of lung cancer cells. The purpose of this study is to investigate and provide evidence for the role of OPN in the formation of MPE associated with lung cancer. In this study, we established an OPN knockdown murine lung cancer cell line, 3LL cells, utilizing the small interfering RNA (siRNA) technique. To reveal the effect of OPN on the formation of MPE associated with lung cancer, we directly injected OPN knockdown 3LL cells, 3LL/OPN siRNA, or control cells, 3LL/control siRNA, into the pleural space of C57BL/6 mice. OPN knockdown significantly reduced the formation of MPE, but did not inhibit in vivo tumor growth of 3LL cells in mice. Vascular endothelial growth factor (VEGF) concentration in MPE was markedly decreased in the 3LL/OPN siRNA in comparison with that of the 3LL/control siRNA. In vitro, recombinant OPN protein enhanced VEGF secretion from human umbilical vein endothelial cell (HUVEC) or human mesothelial cell line, Met5A cells, in a concentration-dependent manner. These results suggest that OPN is positively involved in the formation of MPE of lung cancer presumably by promoting VEGF secretion from vascular endothelial cells or mesothelial cells. OPN could be an effective target molecule for reducing MPE in lung cancer patients.     

抗血管生成治疗在恶性胸腔积液中的应用进展CSCD

恶性胸腔积液(malignant pleural effusions,MPE)是晚期肿瘤的常见并发症,肺癌和恶性胸膜间皮瘤(malignant pleural mesothelioma,MPM)是MPE最常见的病因。MPE的治疗原则是在针对病因的全身治疗的基础上对胸腔进行局部治疗。血管内皮生长因子(vascular endothelial growth factor,VEGF)在MPE形成中的多个环节起着关键作用。贝伐珠单抗能抑制VEGF的活性,减少MPE的形成,改善患者预后。本综述系统回顾了贝伐珠单抗及其他抗血管生成药物在非小细胞肺癌(non-small cell lung cancer,NSCLC)和MPM相关MPE中的研究进展,阐述了不同抗血管生成药物对MPE的临床疗效和安全性。     

Basic fibroblast growth factor in mesothelioma pleural effusions: correlation with patient survival and angiogenesis

The expression of angiogenic factors may represent useful markers for diagnosis and prediction of disease outcome. Basic fibroblast growth factor (b-FGF) is a potent angiogenic factor which promotes in vitro growth of endothelial cells and in vivo vessel formation. We investigated the expression of b-FGF in patients affected with malignant and non-malignant pleural diseases and presenting clinically with non-specific signs and symptoms. We also studied the relationships between the expression of b-FGF in patients with malignant pleural mesothelioma (MM) and tumour aggressiveness, assessed as tumour vessel density (TVD), or patient survival. Basic-FGF was measured by immunoassay in the serum and pleural effusions (PE) of 37 patients. Of these, MM was diagnosed in 15/37 patients while the remaining patients had either peripheral lung adenocarcinoma (PLA) or benign inflammatory pleural disease (BPD). The mean b-FGF level measured 8.5+/-6.1 pg/ml in the PE of the malignant group (MM + PLA) and 23.9+/-19.8 in the PE of the non-malignant group (BPD) (p=0.001). The mean b-FGF level was significantly lower in the PE of MM patients (6.9+/-5.2 pg/ml) compared to BPD patients (p=0.004). Linear regression analysis showed a significant inverse correlation (r=-0.59; p=0.041) between b-FGF levels found in MM PE and patient survival. A noteworthy relationship between high serum b-FGF levels and reduced survival was also observed (r=-0.57; p=0.052). Interestingly, both serum (r=0.48; p=0.114) and PE (r=0.26; p=0.413) b-FGF levels in MM patients correlated poorly with TVD. Our data indicate that b-FGF is significantly more expressed in non-malignant compared to malignant PE, this difference being particularly evident between MM and BPD. Our results also suggest that high b-FGF levels correlate with poor MM patient survival through mechanisms which may be independent of b-FGF angiogenic potential.     

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.     

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.     

Serum endostatin levels are elevated and correlate with serum vascular endothelial growth factor levels in patients with stage IV clear cell renal cancer.

Clear cell renal carcinoma (CCRC) is a highly angiogenic tumor known to secrete vascular endothelial cell growth factor (VEGF). Endostatin is an endogenous antiangiogenic agent with antitumor activity in mice. The purpose of this study was to evaluate serum levels of endostatin in normal subjects and in patients with CCRC and to examine the relationship of these levels to circulating VEGF levels. Fifteen patients (mean age, 48 years) on a clinical protocol for stage IV CCRC at the National Cancer Institute were included in the study. Archived prenephrectomy serum samples were analyzed for endostatin and VEGF concentrations. Endostatin and VEGF levels were compared with those of an age-matched group of volunteer blood donors (n = 18) using a competitive enzyme immunoassay. Data were analyzed using the Mann-Whitney U test and the Spearman rank correlation. Median serum endostatin levels were 24.6 ng/ml (range, 15.1-54.0 ng/ml) in CCRC patients versus 14.1 ng/ml (range, 1.0-19.3 ng/ml) in healthy controls (P < 0.0001). Median VEGF levels were 3.4 ng/ml (range, 0.1-11.2 ng/ml) and 2.5 ng/ml (range, 0.1-4.2 ng/ml), respectively (P = 0.065). A highly significant correlation was observed between endostatin and VEGF levels among the CCRC patients (r = 0.81, P = 0.0003) but not among controls (r = -0.22, P = 0.37). Endostatin levels are detectable in serum from healthy subjects as well as from CCRC patients. Levels are significantly elevated and correlate with VEGF levels in CCRC patients. Elucidating the nature of this correlation may lend insight into the regulation of tumor angiogenesis in patients with renal cancer.     

Clinical utility of vascular endothelial growth factor in diagnosing malignant pleural effusions

While the early diagnosis of cancer has been fully respected, it is still however often difficult for clinicians to confirm malignant pleural effusions (PE), which essentially indicate the end-stage cancer. It has now been demonstrated that vascular endothelial growth factor (VEGF) is a pivotal angiogenesis factor and associated with tumor growth and metastasis. The aim of this study was then to assess the diagnostic performance of VEGF in malignant PE. In this controlled and blinded prospective study, 113 consecutive patients with PE were recruited. For each eligible case, the VEGF levels of pleural fluid (PF) and serum were examined simultaneously using enzyme immunoassay. The reference standard for malignant PE was clinical evaluation and PF cytology with pleural biopsy, other examination and follow-up added as needed. According to the final diagnoses, 81 qualified cases were grouped as malignant (n=32) and benign (n=49) PE. For PF VEGF level, the mean in malignant group was higher than that in benign group (1358+/-1493 pg/mL vs. 422+/-317 pg/mL, p=0.001). As did for serum VEGF level (650+/-533 pg/mL vs. 137+/-189 pg/mL, p<0.001). Using receiver operating characteristic analysis, the determined diagnostic cut-off points of VEGF levels of PF and serum for malignant PE were 959.25 pg/mL and 212.36 pg/mL, with sensitivities of 47%, 69% and specificities of 96%, 88%, respectively. For cascade connection and parallel operation of PF VEGF and serum VEGF, the sensitivities were 34%, 81% at specificities of 98%, 86%, respectively. These findings suggest that VEGF could be used in diagnosing malignant PE as a useful adjunct of conventional algorithm. Different VEGF test strategies, including test on PF, serum and both, may be selected according to practical needs.     

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.     

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.     

康莱特联合奥沙利铂胸腔灌注治疗恶性胸腔积液及对RCAS1、VEGF表 达的影响

目的:探讨康莱特联合奥沙利铂胸腔灌注治疗恶性胸腔积液的临床价值以及灌注治疗对恶性胸腔积液中SiSo细胞上的受体结合肿瘤抗原(RCAS1)、血管内皮生长因子(VEGF)表达的影响。方法:选取110例非小细胞肺癌并胸腔积液患者,分为康莱特组35例,奥沙利铂组35例及联合用药组40例,分别收集胸腔注药前及每次注药48h后的胸水标本,采用酶联免疫吸附测定（ELISA）方法检测胸水标本中的RCAS1、VEGF水平。结果:三组疗效比较,联合组优于康莱特组（P<0.01）。生活质量改善方面,联合组优于康莱特组与奥沙利铂组（P<0.05）。三组治疗后的毒副反应比较,康莱特组低于联合组及奥沙利铂组（P<0.05）。三组治疗前、第1周期治疗后、第2周期治疗后胸水RCAS1及VEGF表达水平均有逐渐下降趋势（P<0.05）,联合用药组较其它两组下降更明显（P<0.001）。结论:康莱特联合奥沙利铂胸腔灌注对控制恶性胸腔积液具有一定的临床价值,检测胸水RCAS1、VEGF表达水平可评估康莱特联合奥沙利铂灌注治疗效果。     

Serum vascular endothelial growth factor (VEGF) and bcl-2 levels in advanced stage non-small cell lung cancer

The characteristic changes in cancer process are assumed to be genetic alterations about the imbalance of cell proliferation and apoptotic cell death. This study was conducted to determine the value of the circulating vascular endothelial growth factor (VEGF) and Bcl-2 in patients with advanced stage non-small cell lung cancer (NSCLC). These serum factors were measured of 52 NSCLC patients pathologically verified on before and after chemotherapy in comparison with 16 healthy controls by using ELISA method. Both of the serum levels of VEGF (p = 0.015) and Bcl-2 (p < 0.001) were increased significantly in NSCLC patients compared with the healthy controls. No statistically significant relationships between investigated elevated serum parameters and various characteristics of patients and disease such as stage and tumor burden were determined. Likewise, we also found no correlation between serum VEGF and Bcl-2. Cytotoxic therapy of patients was accompanied by unchanged serum levels of serum factors. The median survival of all patients was 27 weeks and one-year survival rate was 22.4 percent. With the median serum levels as the cut-off value, patients were divided into high- and low-serum parameter groups. While we found that patients' performance status (p < 0.0001), serum LDH level (p = 0.0002), response to chemotherapy (p = 0.0023), and stage of the disease (p = 0.0085) were prognostic factors for survival, serum VEGF (p = 0.48) and Bcl-2 (p = 0.91) levels were determined as ineffective on survival in patients with advanced NSCLC. In conclusion, our data suggest that these serum factors, VEGF and Bcl-2, are useful diagnostic factors, not predictive and prognostic markers for overall survival in advanced NSCLC patients.     

Imbalance between vascular endothelial growth factor and endostatin correlates with the prognosis of operable non-small cell lung cancer

Background

Angiogenesis is regulated by a balance of pro-angiogenic and anti-angiogenic factors. Vascular endothelial growth factor (VEGF) and endostatin respectively represents a frequent component of inducers and inhibitors in the process of angiogenesis. The ratio of VEGF/endostatin may reflect the balance of angiogenic switch. This study aimed to determine whether an imbalance between VEGF/endostatin exists in operable non-small cell lung cancer (NSCLC) patients and to assess the correlation, if any, between the imbalance and the prognosis.

Methods

Preoperative serum levels of VEGF and endostatin were simultaneously determined by quantitiative enzyme-linked immunosorbent assay (ELISA) and the ratio of them was calculated among 98 NSCLC patients and 51 healthy controls. The relationship between these factors and clinicopathological features, including prognosis, was examined.

Results

The ratio of VEGF/endostatin levels was significantly higher in operable NSCLC patients [median, 10.4; interquartile range (IQR), 5.9–19.8] than in normal controls [median, 5.1; IQR, 3.3–9.7] (P = 0.002). While the ratio in patients who were still alive for more than 60 months was 8.3 (IQR, 4.3–17.9), the ratio in those who died was 12.9 (IQR, 8.0–22.1) (p = 0.017). In subgroup analysis of patients with pathological stage N0, there was a statistically significant increase of the survival time in the group with a lower ratio than in the group with a higher ratio (p = 0.032). Multivariate analysis confirmed that the VEGF/endostatin ratio was an independent prognostic factor (p = 0.018).

Conclusion

There was an imbalance between VEGF and endostatin in serum of operable NSCLC patients. The imbalance correlated with the prognosis of operable NSCLC.