Elevated Serum Vascular Endothelial Growth Factor and Basic Fibroblast Growth Factor Levels in Patients with Thymic Epithelial Neoplasms

Neovascularization, an essential event for the growth of solid tumors, is regulated by a number of angiogenic factors, among which vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), are considered to exert potent angiogenic activity. In this study, we investigated whether serum VEGF and bFGF levels could be predictors of the development and extension of thymic epithelial neoplasms. The subjects of this study were 37 patients with thymoma, 6 with thymic carcinoma, and 23 healthy volunteers. Serum samples were collected before clinical treatment. Serum VEGF levels were significantly (P < 0.05) elevated in the patients with thymic carcinoma (1 080 ± 1 185 pg/ml) compared with those in the healthy volunteers (407 ± 589 pg/ml). Serum bFGF levels were also significantly (P < 0.05) elevated in the patients with thymic carcinoma (2 740 ± 631 pg/ml) compared with those in the healthy volunteers (1 728 ± 1 192 pg/ml). However, the serum VEGF and bFGF levels did not significantly differ between the patients with thymoma and the healthy volunteers. Serum VEGF and bFGF levels did not significantly differ according to the stage and pathological subtype of thymoma. Moreover, there was no correlation between the serum levels of VEGF and those of bFGF. Thus, while serum VEGF and bFGF levels may serve as markers for thymic epithelial tumors, it is unlikely that circulating VEGF and bFGF could be used as markers for assessing the progression of thymoma tumors. Received: November 10, 2000 / Accepted: May 15, 2001     

High Serum Vascular Endothelial Growth Factor Levels Predict Poor Prognosis after Radiofrequency Ablation of Hepatocellular Carcinoma: Importance of Tumor Biomarker in Ablative Therapies

Background Radiofrequency ablation (RFA) is a recently developed treatment for hepatocellular carcinoma (HCC). Thus far, the prognostic impact of tumor biomarkers has not been evaluated in this treatment. High serum level of vascular endothelial growth factor (VEGF) has been shown to predict microscopic vascular invasion and metastasis in HCC. This study investigated the prognostic significance of pre-treatment serum VEGF level in patients with HCC undergoing RFA treatment. Methods Serum VEGF levels were measured using enzyme-linked immunosorbent assay in 120 patients with HCC undergoing RFA, and in 15 healthy controls. Serum VEGF levels were correlated with clinicopathological features of the HCC patients. The prognostic significance of serum VEGF levels was assessed by univariate and multivariate analyses. Results The median serum VEGF level in the HCC patients was 240 pg/mL (range 17–1162), significantly higher than that of healthy controls (p = .024). The serum VEGF levels were significantly correlated with platelet counts (r = .487, p < .001) but not other clinicopathological features. Patients with serum VEGF level > 240 pg/mL had worse overall and recurrence-free survival compared with those with serum VEGF level > 240 pg/mL (p = .005 and .002, respectively). By multivariate analysis, serum VEGF level was a significant prognostic factor of both overall and recurrence-free survival. Conclusions High pre-treatment serum VEGF levels predict poor prognosis after RFA of HCC. This study highlights the importance of tumor biomarker as a prognostic predictor in ablative therapy for HCC, which has an intrinsic problem of unavailability of histopathological prognostic features.     

肝细胞癌介入栓塞术后促血管生成因子表达的变化

目的探讨经导管肝动脉化疗栓塞术(TACE)后肝癌组织血管内皮生长因子(VEGF)和碱性成纤维细胞生长因子(bFGF)蛋白表达的变化。方法手术切除的肝癌标本共48例,其中单纯手术25例(单纯手术组),TACE后二期手术23例(TACE组)。采用免疫组化及图像分析的方法检测各标本中VEGF和bFGF的阳性表达。结果TACE组VEGF平均吸光度(A)值显著高于单纯手术组,分别为0.152±0.021和0.131±0.012(P<0.01)。TACE组bFGF平均A值为0.127±0.023,高于单纯手术组(0.111±0.016,P<0.05)。结论TACE治疗后残留肝癌组织VEGF和bF-GF的表达上调,可能在TACE后肝癌的复发和转移中发挥重要作用。     

血管内皮生长因子受体-3与胃癌临床病理因素的关系

目的　探讨血管内皮生长因子受体 3(VEGFR 3)与胃癌临床病理因素的关系。方法　应用免疫组织化学SP法测定胃癌及胃良性病变中VEGFR 3的表达 ,并以此来计数淋巴管密度。结果　淋巴管密度胃癌组为( 5 .80 0 0± 2 .3189)个 /× 2 0 0 ,胃良性病变组为 ( 2 .380 0± 0 .4 6 2 9)个 /× 2 0 0 (P =0 .0 0 0 ) ;有淋巴结转移者为 ( 6 .94 83± 1.5 831)个 /× 2 0 0 ,无淋巴结转移者为 ( 2 .772 7± 0 .4 2 89)个 /× 2 0 0 (P =0 .0 0 0 ) ;低分化组为( 7.6 818± 0 .982 9)个 /× 2 0 0 ,高 中分化组为 ( 3.5 0 0 0± 1.0 2 82 )个 /× 2 0 0 (P =0 .0 0 0 ) ;pTNM分期Ⅰ Ⅱ期为( 4 .2 917± 1.6 880 )个 /× 2 0 0 ,Ⅲ Ⅳ期组为 ( 8.0 6 2 5± 0 .75 94 )个 /× 2 0 0 (P =0 .0 0 0 )。结论　胃癌淋巴管密度与其 pTNM分期、分化程度及有无淋巴结转移相关     

碱性成纤维细胞生长因子和血管生成与胃癌发展的关系

目的:探讨碱性成纤维细胞生长因子(basic fibroblast growth factor,bFGF)和血管生成与胃癌发展的关系.方法:应用免疫组织化学方法检测56例人胃癌组织碱性成纤维细胞生长因子表达和微血管密度(microvasculardensity,MVD),分析bFGF和MVD及其与胃癌组织学分型、浸润深度、生长方式、淋巴结转移、远处转移和预后的关系.结果:bFGF阳性者MVD值显著高于bFGF阴性者(P<0.01),MVD值和bFGF表达与胃癌浸润深度(P<0.05)、淋巴结转移(P<0.01)和远处转移(P<0.05)密切相关;MVD≥43或bFGF表达阳性的胃癌患者5年生存率较低.结论:血管生成在胃癌发展中具有重要作用,bFGF不仅与胃癌的血管生成有关,而且与胃癌的生长和浸润转移也有关,MVD或bFGF可作为判断胃癌患者预后的指标.     

血管内皮细胞生长因子在食管癌中的表达及意义

目的 探讨食管癌血管内皮细胞生长因子（VEGF）表达及其与肿瘤血管新生和病理学特点的关系。方法 对40例手术切除的原发性食管癌标本进行免疫组织化学染色,确定其VEGF的表达及微血管密度。结果 40例食管癌患者中27例VEGF蛋白表达阳性,阳性率为67．5％,微血管密度在食管癌VEGF表达阴性、弱阳性和强阳性者间比较差别具有显著性意义（P＜0．05）,有淋巴结转移者VEGF表达阳性率较无淋巴结转移者明显增高（P＜0．01）。结论 食管癌VEGF表达水平与肿瘤血管新生强度、淋巴结转移有密切关系。     

Prognostic Impact of Surgical Complications and Preoperative Serum Hepatocyte Growth Factor in Hepatocellular Carcinoma Patients After Initial Hepatectomy

Introduction  The relationship between postoperative complications and survival after hepatectomy is not completely understood. The purpose of this study was to determine if surgical complications would have a prognostic impact and to identify any difference of the prognostic factors between a complication group and complication-free group for hepatocellular carcinoma (HCC) patients after initial hepatectomy. Patients and Methods  One hundred consecutive HCC patients were analyzed in this study. Operative variables and liver functional markers were compared between the complication group and complication-free group. The diagnostic accuracy for predicting complications was evaluated by the receiver operating characteristic (ROC) curve. The Kaplan–Meier method with log-rank test was employed for survival analysis. Univariate and multivariate analyses were performed to identify the prognostic factors in each group. Results and discussion  A total of 45 complications in 32 patients were observed according to the modified Clavien classification. The albumin, γ-glutamyl transferase, choline esterase, indocyanine green retention rate at 15 min (ICGR₁₅), hyaluronic acid, prealbumin, hepatocyte growth factor (HGF), HH15, and LHL15 levels before hepatectomy, operative time, and blood loss were significantly different between the two groups. Multivariate analysis revealed that γ-glutamyl transferase, ICGR₁₅, and HGF were independent risk factors for postoperative complications. The values of the areas under the ROC curve for predicting complications proved the significance of the predictions. Although the recurrence-free survival rates were not significantly different, the overall survival rates were significantly different between the two groups. Univariate and multivariate analyses for the overall survival rate showed that the stage of the HCC and HGF for the complication group and tumor size for the complication-free group were independent prognostic factors for overall survival. Conclusion  Postoperative surgical complications could have a prognostic impact on overall survival in HCC patients after initial hepatectomy. Serum HGF could be a factor connected to complications and survival in this group.     

胆管癌组织中VEGF和c-myc的表达及其意义

目的　探讨VEGF和c myc在胆管癌组织中的表达和二者之间的相关性及其在胆管癌发生、发展和转移中的作用。方法　应用免疫组化ABC法对 38例胆管癌组织和 2 0例正常胆管组织中VEGF和c myc的表达进行检测。结果　VEGF和c myc在胆管癌组织中的表达阳性率分别为 84 .2 % (32 /38)和 6 5 .8% (2 5 /38) ,明显高于正常胆管组织中的表达阳性率〔5 0 .0 % (10 /2 0 )和 2 0 .0 % (4/2 0 )〕 ,差异有统计学意义 (P<0 .0 5 ) ;VEGF与c myc的表达呈正相关 (r=0 .99,P<0 .0 1) ,二者的协同表达与胆管癌的淋巴结转移有关 ,而与肿瘤的分级无关。结论　VEGF可能在胆管癌形成、发展和转移中与c myc基因有协同作用 ,且与胆管癌的淋巴结转移有关。     

胃癌组织中核因子-κBp65 的表达及其与血管内皮生长因子的关系

目的　研究胃癌组织中核因子 κBp6 5 (NF κBp6 5 )的表达及其与血管内皮生长因子 (VEGF)的关系。方法　应用免疫组化SP法 ,对 5 6例胃癌组织检测NF κBp6 5和VEGF的表达 ,并与良性组织作对照研究。 结果　胃癌组织中NF κBp6 5和VEGF的表达阳性率分别为 6 2 .5 %和 76 .8% ,显著高于胃粘膜不典型增生表达阳性率的 33.3%和 4 4 .4 % (P<0 .0 5 )及正常胃粘膜表达阳性率的 0和 8.3% (P<0 .0 1)。NF κBp6 5的表达与胃癌临床分期、浸润深度和淋巴结转移有关 (P<0 .0 5 ) ,与病理类型无关 (P>0 .0 5 )。NF κBp6 5表达与VEGF呈正相关 (r =0 .36 ,P<0 .0 1)。结论　NF κBp6 5可能通过上调VEGF的表达 ,在胃癌的发生、发展中发挥重要作用。     

先兆子痫肾病患者肾组织中血管内皮细胞生长因子表达的临床意义

目的：了解血管内皮细胞生长因子（VEGF）在先兆子痫肾病患者肾组织中表达的意义及其与先兆子痫肾病临床和病理表现之间的关系.方法：以正常肾组织为对照,采用特异性抗体和免疫组织化学染色方法对19例先兆子痫肾病患者肾组织中VEGF分布及其强度变化进行观察,分析其与内皮细胞增生、蛋白尿之间的关系.结果：先兆子痫肾病患者肾组织中VEGF表达在妊娠终止后早期阶段无论在强度变化上,还是在分布上与正常人相比均有明显差异,随着妊娠终止后时间的延长,VEGF的表达逐渐减弱并恢复至正常表达水平（P＜0.01）.先兆子痫肾病患者肾组织VEGF的表达还与肾小球内皮细胞增生程度关系密切,VEGF表达增强组患者肾小球内皮细胞增生程度明显高于VEGF正常表达组（P＜0.05）.此外,还发现VEGF表达增强组患者蛋白尿程度明显高于VEGF正常表达组（P＜0.05）.结论：先兆子痫肾病肾组织中VEGF的表达与内皮细胞损伤所致的形态学改变、蛋白尿之间关系密切,且肾组织VEGF的表达随着妊娠终止后时间的延长逐渐减弱并恢复至正常表达水平.     

Prognostic Value of Vascular Endothelial Growth Factor and its Receptors Flt-1 and Flk-1 in Astrocytic Tumours

Summary  Background. Vascular endothelial growth factor (VEGF)/vascular permeability factor (VPF) is an important regulator of angiogenesis and vascular permeability.  Method. We examined immunohistochemically expressions of VEGF and its corresponding receptors Flt-1 and Flk-1 in a series of 50 astrocytic tumours, and correlated their expressions with the degree of angiogenesis, brain edema and prognosis.  Findings. There were significant relationships between VEGF, Flk-1 expressions and glioma malignancy grading, intratumoural vascularity and peritumoural brain edema, respectively. Patients with VEGF positive low grade astrocytoma and glioblastoma multiforme had a significantly shorter mean overall survival time than those with negative tumours (P=0.0010 and 0.0180, respectively). Flk-1 is also a significant prognostic factor within each tumour grade, which has a negative impact on overall survival. Additionally, overexpression of VEGF and Flk-1 were significantly associated with earlier recurrence in patients with low grade astrocytomas (P=0.0018 and 0.0240, respectively).  Interpretation. It is possible to subcategorize each grade of astrocytic tumours based on their VEGF and Flk-1 staining pattern, which may be crucial in predicting the biological behavior of tumours and thus provide useful information with regard to adequate treatment.     

bFGF对体外关节软骨细胞创伤愈合与增殖的影响

目的：探讨碱性成纤维细胞生长因子（ｂａｓｉｃ ｆｉｂｒｏｂｌａｓｔ ｇｒｏｗｔｈ ｆａｃｔｏｒ,ｂＦＧＦ）对关节软骨细胞创伤愈合与增殖行为的影响。方法;采用体外创伤愈合模型及ＭＴＴ比色方法,对软骨细胞创伤愈合与增殖行为进行分析。结果：ｂＦＧＦ浓度为５ｎｇ／ｍｌ时,即可显著促进软骨细胞创伤愈合,浓度为５０ｎｇ／ｍｌ时,其促进作用达到最大值。     

碱性成纤维细胞生长因子对急性坏死性胰腺炎犬肠道细菌移位的影响

目的 探讨基因重组碱性成纤维细胞生长因子(bFCF)对急性坏死性胰腺炎犬(ANP)肠道细菌移位的影响。方法 杂种犬23只,分对照组(n=7)、ANP组(n=8)和bFCF组(n=8)。bFCF组犬复制ANP模型后,每日静脉注射bFCF(5μg/kg)。结果 bFCF治疗ANP后,肠粘膜损伤明显减轻,脏器细菌培养阳性率下降50％,细菌移位数量减少15～30倍,肠粘膜蛋白质、DNA含量显著增加(P<0.05),丙二醛含量明显减少(P<0.05)。结论 bFCF可显著减少ANP时肠道细菌移位,其机制可能是通过增加肠粘膜蛋白质合成,促进肠粘膜损伤修复有关。     

Development and Validation of Small-diameter Vascular Tissue From a Decellularized Scaffold Coated With Heparin and Vascular Endothelial Growth Factor

To overcome shortcomings of current small‐diameter vascular prostheses, we developed a novel allogenic vascular graft from a decellularized scaffold modified through heparin immobilization and vascular endothelial growth factor (VEGF) coating. The VEGF coating and release profiles were assayed by enzyme‐linked immunosorbent assay, the biological activity of modified surface was validated by human umbilical vein endothelial cells seeding and proliferation for 10 days in vitro. In vivo, we implanted either a modified or a nonmodified scaffold as bilateral carotid allogenic graft in canines (n = 15). The morphological examination of decellularized scaffolds showed complete removal of cellular components while the extracellular matrix structure remained intact. After modification, the scaffolds possessed local sustained release of VEGF up to 20 days, on which the cells cultured showed significantly higher proliferation rate throughout the time after incubation compared with the cells cultured on nonmodified scaffolds (P < 0.0001). After 6 months of implantation, the luminal surfaces of modified scaffolds exhibited complete endothelium regeneration, however, only a few disorderly cells and thrombosis overlay the luminal surfaces of nonmodified scaffolds. Specifically, the modified scaffolds exhibited significantly smaller hyperplastic neointima area compared with the nonmodified, not only at midportion (0.56 ± 0.07 vs. 2.04 ± 0.12 mm², P < 0.0001), but also at anastomotic sites (1.76 ± 0.12 vs. 3.67 ± 0.20 mm², P < 0.0001). Moreover, modified scaffolds had a significantly higher patency rate than the nonmodified after 6 months of implantation (14/15 vs. 7/15, P = 0.005). Overall, this modified decellularized scaffold provides a promising direction for fabrication of small‐diameter vascular grafts.     

Immunohistochemical Analysis of Vascular Endothelial Growth Factor and Hepatocyte Growth Factor,and Their Receptors,in Transplanted Islets in Rats

Purpose. Our previous studies showed that transplanted islets increasingly express a marker of neovascularization, platelet endothelial cell adhesion molecule-1 (PECAM-1), as well as vascular endothelial growth factor (VEGF). Hepatocyte growth factor (HGF) is another stimulator of neovascularization. In this study, we examined the expression of these growth factors and their receptors; fetal liver kinase-1 (Flk-1) for VEGF and c-Met for HGF, to acertain whether VEGF and HGF play a role in the neovascularization of transplanted islets. Methods. Islets were isolated from male Lewis rats by collagenase digestion and the discontinuous dextran gradient method, then transplanted into the bilateral subnephrocapsular space. The kidneys were excised 1–28 days after transplantation, then fixed in formaldehyde and embedded in paraffin. Serial slices were immunostained for VEGF, HGF, Flk-1, or c-Met, respectively. Results. Islets in the normal pancreas were positively stained for VEGF, HGF, and c-Met; however, Flk-1 was only stained at the periphery of the islets. In the transplanted islets, staining for VEGF, HGF, and c-Met was positive, but Flk-1 was not stained. Moreover, staining for HGF and c-Met became stronger in the transplanted islets with time. Conclusion. These results suggest that HGF, rather than VEGF, may play a role in the neovascularization of transplanted islets.     

乳腺癌患者血清和肿瘤组织VEGF表达与临床预后的关系

目的探讨乳腺癌患者血清和肿瘤组织中血管内皮细胞生长因子（VEGF）的表达以及与临床预后的关系。方法以44例乳腺癌患者、13例乳腺良性疾病患者和40例正常人为研究对象，分别采用酶联免疫吸附法（ELISA）检测其血清VEGF水平，采用免疫组化LSAB法检测其组织中VEGF、雌激素受体（ER）和原癌基因C-erbB-2蛋白的表达，并分析其与临床预后因素如淋巴结转移情况及临床分期的关系。结果乳腺癌组血清和组织中VEGF表达水平（113．88pg／ml，20723．99）均明显高于乳腺良性疾病组（55．79pg／ml，3594．74），P〈0．001，而乳腺良性疾病组与正常对照组（41．30pg／ml，-）比较差异无统计学意义（P〉0．05）；且血清和组织中VEGF的表达呈正相关（r=0．48，P〈0．01）。有淋巴结转移者血清和组织中VEGF的表达水平（129．60pg／ml，28506．82）明显高于无淋巴结转移者（80．80pg／ml，14656．73），P〈0．01；血清和组织中VEGF的表达与肿瘤的临床分期有关（P〈0．01），但与患者年龄和肿瘤大小无关（P〉0．05）。乳腺癌患者血清和组织中VEGF表达水平与组织中ER表达呈负相关（r=-0．45，P〈0．05），与C-erbB-2表达呈正相关（r=0．48，P〈0．01）。结论乳腺癌患者血清和肿瘤组织中VEGF表达呈正相关，且与其临床预后有关，可作为乳腺癌患者预后判断的重要参考指标之一。     

组织因子 mRNA在肝癌患者组织中表达升高的意义

目的 检测组织因子(TF)在肝癌组织中的表达并探讨其临床意义.方法 采用RT-PCR方法检测肝癌、癌旁及对照组肝组织(各27例)中TF mRNA的表达,并结合临床病理资料进行分析.结果 TF在肝癌组织中的表达阳性率及相对表达强度分别为62.96%(17/27)和0.567±0.268,均较癌旁组织的33.33%(9/27)和0.469±0.184及对照组肝组织的29.63%(8/27)和0.353±0.121高(P＜0.05),其相对表达强度与肿瘤大小、肝内和肝外转移及门静脉癌栓有关(P＜0.05),而与患者性别、AFP、HBsAg、是否合并肝硬变、肿瘤分化程度、癌灶数目、包膜浸润及淋巴转移均无关(P＞0.05).结论 TF在肝癌组织中的表达升高与部分侵袭转移指标有关,提示其可能参与了肝细胞癌的发生及侵袭、转移.     

血管内皮细胞生长因子与增殖细胞核抗原联合检测用于大肠癌临床预后判定

目的　探讨大肠癌血管内皮细胞生长因子 (VEGF)及增殖细胞核抗原 (PCNA)与大肠癌术后有无潜在性转移及复发的关系。方法　对 5 9例已获确诊的大肠癌石蜡标本作免疫组化SP法染色 ,检测其VEGF及PCNA的表达 ,并与 12例正常大肠组织和 16例大肠腺瘤进行比较。结果　大肠癌VEGF的表达明显高于大肠腺瘤 (P<0 .0 5 ) ;DukesA +B期大肠癌VEGF的表达与DukesC +D期比较 ,差异有显著性 (P<0 .0 5 ) ;术后复发组VEGF的表达明显高于无复发组 (P<0 .0 5 )。增殖活性表达提示 ,大肠癌分化程度越低 ,有淋巴结或肝转移时 ,其PCNA指数增高 ;术后有、无复发者之间 ,其PCNA指数差异有显著性 (P<0 .0 5 )。结论　大肠癌VEGF与PCNA的表达与肿瘤的浸润、转移密切相关。手术时虽然无明显转移灶 ,VEGF阳性及PCNA活性增强时仍可能有潜在的转移存在。     

Expression of Vascular Endothelial Growth Factor (VEGF) and Epidermal Growth Factor Receptor (EGFR) is an Independent Prognostic Indicator of Worse Outcome in Gastric Cancer Patients

BACKGROUND: Unlike other human tumors, gastric cancer remains a great therapeutic challenge since no standardized postoperative treatment exists. Knowledge of molecular pathways determining the behavior of individual gastric tumors seems to be crucial for therapeutic decisions, and evaluation of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) expression might be critical for prognosis, assessment, and identification of patients that could be treated with tailored therapies. METHODS: VEGF and EGFR determination was performed in 88 gastric cancer samples as well as 25 normal gastric mucosa specimens from non-cancer patients using a commercially available immunohistochemistry kit. In all samples, the correlation of VEGF and EGFR expression was investigated with each other, and with other prognostic indicators in all samples, and, finally, with survival rates in 69 patients undergoing potentially curative surgery. RESULTS: Forty-eight per cent (42 cases) of gastric cancers expressed VEGF, and 44% (39 cases) stained for EGFR. In curatively treated patients, VEGF and EGFR expression was demonstrated to correlate with worse survival in both univariate and multivariate analyses. Molecular profiling was shown to more accurately estimate the risk of cancer-related death than TNM stage, and, of most interest, to allow sorting out high-risk patients within the same stage. CONCLUSIONS: These findings provide evidence that contemporary evaluation of VEGF and EGFR expression may be crucial to select gastric cancer patients with poor prognosis who may benefit of tailored treatments.