Cytosol vascular endothelial growth factor in endometrial carcinoma: correlation with disease-free survival

OBJECTIVE: The aim of this study was to evaluate whether vascular endothelial growth factor (VEGF) could be a marker for disease-free survival in endometrial carcinoma patients. METHODS: Fifty-three patients with endometrial carcinoma undergoing surgery were enrolled. Clinical and pathologic items were recorded. Cytosol VEGF was quantified by enzyme immunoassay. The microvessel density (MVD) of the excised tumors was immunohistochemically assessed. The relationship among MVD, cytosol VEGF concentration of the tumor tissues, and clinicopathologic parameters was analyzed. The risk factors influencing clinical outcome were tested. RESULTS: Higher cytosol VEGF concentrations and MVD values were noted in tumors with advanced stage (more than stage I) (917 versus 125 pg/mg, P = 0.03; 94.1 +/- 37.8 versus 60.8 +/- 38.9, P = 0.008), lymphovascular emboli (917 versus 102 pg/mg, P = 0.001; 94.4 +/- 33.2 versus 62.4 +/- 40.7, P = 0.009), and lymph node metastasis (1032 versus 95 pg/mg, P < 0.001; 116.5 +/- 30.8 versus 56.7 +/- 33.3, P < 0.001). The cytosol VEGF and MVD showed a positive linear correlation (VEGF versus MVD, r = 0.41, P = 0.003). Grade 3 tumor and overexpressed cytosol VEGF (> 800 pg/mg) are independent risk factors for recurrence. There was a trend that patients with grade 1 or 2 tumors and normal-expressed VEGF had the highest probability of disease-free survival, and patients with grade 3 tumors and overexpressed cytosol VEGF had the poorest probability of disease-free survival. CONCLUSIONS: Cytosol VEGF had a good correlation with the disease progression and metastasis in endometrial carcinoma, and it might also be an independent prognostic factor for disease-free survival of endometrial carcinoma patients.     

Secretion of vascular endothelial growth factor in adenocarcinoma and squamous cell carcinoma of the uterine cervix.

OBJECTIVE: To determine whether major differences in vascular endothelial growth factor secretion exist between adenocarcinomas of the uterine cervix compared with squamous cell carcinomas. METHODS: The secretion of vascular endothelial growth factor by eight fresh cervical cancer cell preparations (four adenocarcinomas and four squamous cell carcinomas) and four established squamous cell lines was evaluated using a sensitive enzyme-linked immunosorbent assay in vitro. RESULTS: All cervical tumors secreted significant amounts of vascular endothelial growth factor, and no significant differences between fresh and established squamous cell lines were detectable. In contrast, a highly significant difference in vascular endothelial growth factor secretion was noted between fresh adenocarcinomas (mean = 2712, range between 1700 to 3500 pg/mL/10(5) cells/48 hours) when compared with fresh squamous (mean = 575, range between 200 to 950 pg/mL/10(5) cells/48 hours) or established squamous cervical carcinoma cell lines (mean = 712, range between 400 to 1000 pg/mL/10(5) cells/48 hours) (F-test, P< or =.001). CONCLUSION: These data strongly suggest that major differences in the secretion of vascular endothelial growth factor exist between squamous cell carcinoma and adenocarcinomas of the uterine cervix. Therefore, at least some of the differences in the natural biologic behavior of these two histologic types of cervical cancer, including the propensity for earlier lymphatic and hematogenous metastasis as well as the lower response to radiation treatment, could be related to major differences in the secretion of this powerful angiogenic and immunosuppressive cytokine.     

Expression of cyclooxygenase-2 in advanced stage ovarian serous carcinoma: correlation with tumor cell proliferation, apoptosis, angiogenesis, and survival

OBJECTIVE: Cyclo-oxygenase-2 seems to be involved at various steps in the processes of tumor progression. The objective of this study was to examine the relationship between cyclo-oxygenase-2 expression and tumor proliferation, apoptosis and angiogenesis in patients with advanced stage high-grade ovarian carcinoma. STUDY DESIGN: Specimens from 118 patients with high-grade and advanced stage (III, IV) serous ovarian carcinoma were evaluated by immunohistochemistry for cyclo-oxygenase-2, Ki-67, vascular endothelial growth factor, and bcl-2 expression. Tumor microvessel density was assessed with CD34 immunostaining. We investigated the relationships between cyclo-oxygenase-2 expression and clinicopathologic characteristics, tumor angiogenesis (tumor microvessel density and vascular endothelial growth factor expression), and tumor proliferation and apoptosis. The effect of cyclooxygenase-2 expression on patient survival was determined. RESULTS: There was a significant positive correlation between cyclo-oxygenase-2 expression in tumor cells and markers of tumor proliferation and angiogenesis. In univariate survival analysis, high cyclo-oxygenase-2 and high Ki-67 expression showed a significant impact of on patient survival (P < .001). In multivariate regression analysis, only Ki-67 expression retained its significance as an independent poor prognostic factor (death hazard ratio, 2.0; 95% CI, 1.2-3.3; P < .001). CONCLUSION: Expression of cyclo-oxygenase-2 correlates with tumor proliferation and tumor angiogenesis but not with apoptotic markers (bcl-2 expression) in high-grade, advanced-stage serous ovarian carcinoma.     

Effect of vascular endothelial growth factor inhibition on endometrial implant development in a murine model of endometriosis

The main factor involved in neovascularization of ectopic endometrial tissue in endometriosis is the vascular endothelial growth factor (VEGF), which is produced both by the endometrial implant and by peritoneal macrophages. On the other hand, bevacizumab is an antiangiogenic agent used in the treatment of different tumors, like colorectal, pulmonary, and recently mammary. We evaluated the effect of the inhibition of VEGF activity with bevacizumab (Avastin) on ectopic endometrial growth in a murine model of endometriosis. Two months old female BALB/c mice had surgery performed to induce endometriotic-like lesions. Treatment with bevacizumab started on post-surgery day 15 and continued during 2 weeks. Then, animals were sacrificed, peritoneal fluid was collected, and endometriotic-like lesions were counted, measured, and removed. Cell proliferation, vascular density, and apoptosis were assessed by immunohistochemistry for proliferating cell nuclear antigen (PCNA), immunohistochemistry for CD34, and Terminal Deoxynucleotidil Transferase-Mediated dUTP Nick End Labeling (TUNEL), respectively. Vascular endothelial growth factor levels were evaluated in the peritoneal fluid by enzyme-linked immunoassay (ELISA). Treatment with bevacizumab significantly inhibited endometriotic lesion development (P < .05). Consistently, bevacizumab significantly inhibited cell proliferation in lesions (P < .01), reduced vascular density (P < .001), as well as increased the apoptotic cell percentage (P < .001). In addition, bevacizumab reduced VEGF levels in peritoneal fluid of endometriosis-induced animals (P < .05). In conclusion, this study suggests a direct effect of bevacizumab on the reduction of endometrial implant growth and supports further research on VEGF inhibition as a novel therapeutic modality in endometriosis.     

Angiogenesis in endometrial carcinoma

Increasing microvessel density correlates with adverse prognosis in many tumors. The aim of this study was to quantify angiogenesis in a range of endometrial carcinomas, by measuring microvessel density in the stroma, and to explore any relationship with known prognostic features. Sections from 60 hysterectomy specimens were stained with Factor VIII related antigen, and the microvessel count per mm² of stroma was determined for each case. Carcinomas arising in an atrophic or inactive endometrium had a significantly higher stromal vascular density than those arising in a hyperplastic or proliferative endometrium. There was no significant association between stromal vascular density, and age, histologic grade, tumor type, presence of lymphovascular space permeation, or depth of myometrial invasion. We conclude that higher stromal vascularity is a feature of the more aggressive subtype of endometrial carcinomas arising in an atrophic endometrium but does not correlate with any other prognostic features.     

Association of elevated C-reactive protein levels with an impaired prognosis in patients with surgically treated endometrial cancer

OBJECTIVE: To evaluate whether C-reactive protein (CRP) serum levels are associated with prognosis in surgically treated endometrial cancer. METHODS: In the present multicenter study, CRP serum levels were measured preoperatively in 403 surgically staged patients with endometrioid endometrial cancer. Results were correlated to clinical data. RESULTS: The mean (standard deviation) serum CRP level in patients with endometrial cancer was 1.0 (1.8) mg/dL. Serum CRP levels were associated with tumor stage (P=.01), but not with tumor grade (P=.8), lymph node involvement (P=.8), and age at diagnosis (P=.9). In a univariable survival analysis, serum CRP levels, tumor stage, tumor grade, and age at diagnosis were associated with disease-free and overall survival (all P <.001). In a multivariable Cox regression model, serum CRP levels (P=.001, P=.004), tumor stage (P <.001, P <.001), tumor grade (P=.02, P=.009), and age at diagnosis (P=.002, P=.001) were independent prognostic factors for disease-free and overall survival. CONCLUSION: Our results suggest that elevated serum CRP levels are associated with a less favorable prognosis in patients with surgically treated endometrial cancer. LEVEL OF EVIDENCE: II.     

Expression of aquaporin-1 in normal, hyperplasic, and carcinomatous endometria

OBJECTIVE: To explore the relationship between aquaporin-1 (AQP1) and endometrial adenocarcinoma. METHOD: Intratumoral microvessel density (IMD) was assessed as well as AQP1 and vascular endothelial growth factor expression in samples from 117 women, 75 with endometrioid adenocarcinoma, 17 with endometrial hyperplasia, and 25 with normal proliferative endometria. RESULTS: AQP1 was located in the epithelial cells of microvessels and small vessels in all samples. The AQP1/IMD ratio was highest in samples from the first, less in samples from the second, and least in samples from the third group. In samples from endometrioid adenocarcinoma, the AQP1/IMD ratio was significantly correlated with histologic grade, surgical stage, myometrial invasion, and extrauterine metastasis. There was a positive correlation between AQP1 expression and IMD and between AQP1/IMD ratio and VEGF expression. CONCLUSION: AQP1 may be involved in the tumorigenesis and progression of endometrioid adenocarcinoma by promoting angiogenesis, and AQP1 level may be both a tumor indicator and a new therapeutic target.     

Microvessel density index as a prognostic factor in a low histological differentiation stage of endometrial carcinoma

OBJECTIVE: Angiogenesis in malignant tumors is a prognostic factor associated with tumor growth and metastasis. Studies of angiogenesis in breast, prostate and lung cancer showed that neovascularisation correlates with likelihood of metastasis and recurrence. Our study was to evaluate microvessel density as a prognostic factor in endometrial cancer. METHODS: Between 1995-1999, 58 women were treated for endometrial carcinoma. The primary treatment consisted of total abdominal hysterectomy, bilateral salpingoophorectomy and pelvic lymphadenectomy. The microscopic examination of paraffin blocks showed the areas of the deepest myometrial invasion. The microvessels within the invasive cancer were highlighted by means of immuno-cytochemical staining to detect CD-31 antigen. RESULTS: Microvessel count was related to likelihood of recurrence. We found statistically significant differences between patients who died after operation and patients with nonrecurrence process. All patients were in the same stage and grade of endometrial carcinoma. CONCLUSION: Microvessel density index seems to be an important factor for planing postoperation treatment in endometrial carcinoma.     

Expression of vascular endothelial growth factor in adenocarcinomas of the uterine cervix and its relation to angiogenesis and p53 and c-erbB-2 protein expression

OBJECTIVE: The purpose of this study was to evaluate vascular endothelial growth factor (VEGF) expression in adenocarcinomas of the uterine cervix and its correlation with clinicopathologic features, angiogenesis, and expression of p53 and c-erbB-2 proteins. METHODS: Thirty-seven cases of FIGO clinical stage I and II adenocarcinoma of the uterine cervix were examined by immunohistochemical studies with anti-VEGF, anti-CD34, anti-p53, and anti-c-erbB-2 antibodies. Computerized image analysis was used to evaluate microvessel density (MVD). RESULTS: Thirty-one tumors (83.8%) were classified as VEGF positive. Six tumors (16.2%) showed p53 protein expression while 11 tumors (29.7%) expressed the c-erbB-2 protein. MVD ranged from 13.3 to 44.8, with a median value of 25.5 (26.9 +/- 7.5). Tumors expressing VEGF had a significantly higher MVD than those that did not express VEGF (P < 0.05). VEGF expression was significantly associated with c-erbB-2 protein expression (P < 0.05). The spatial distributions of both VEGF expression and c-erbB-2 expression were similar in tumor tissues. In univariate log-rank analysis, stage (P = 0.0250), lymphovascular space invasion (P = 0.0156), and MVD (P = 0.0360) were associated with shortened survival. CONCLUSION: VEGF expression plays a role in promoting angiogenesis in cervical adenocarcinomas and c-erbB-2 is likely to be involved in the up-regulation of VEGF expression.     

Maternal plasma vascular endothelial growth factor concentrations in normal and hypertensive pregnancies and their relationship to peripheral vascular resistance

OBJECTIVE: The aim of this study was to measure maternal plasma vascular endothelial growth factor concentrations during normal and hypertensive pregnancies and examine their relationship with maternal total peripheral resistance values. STUDY DESIGN: Plasma concentrations of total immunoreactive vascular endothelial growth factor and total peripheral resistances were measured serially throughout pregnancy in 20 women with preeclampsia, 24 women with gestational hypertension, and 26 normotensive control women. One-way analysis of variance and a regression model were used to analyze the vascular endothelial growth factor levels in the groups and the relationship between vascular endothelial growth factor concentration and total peripheral resistance. RESULTS: At 10 to 14 weeks' gestation plasma vascular endothelial growth factor concentrations in all subjects were 4 to 5 times greater than the levels measured post partum (P <.0001). Mean vascular endothelial growth factor concentrations were similar in the control and gestational hypertension groups; in both groups levels remained stable until 34 to 36 weeks' gestation, when levels increased a further 1.3-fold (P <.01). In comparison, vascular endothelial growth factor concentrations in subjects in the preeclampsia group were greater at 28 to 32 weeks' gestation (P =.002) and at 34 to 36 weeks' gestation (P <.001). Vascular endothelial growth factor concentrations were also increased during the 4 weeks that preceded the diagnosis of preeclampsia (P <.05). Vascular endothelial growth factor concentrations were associated with the elevated total peripheral resistance observed during the clinical disorder in the preeclampsia group but not in the other groups. CONCLUSION: Maternal plasma vascular endothelial growth factor concentrations increased before the clinical onset of preeclampsia and were further elevated during the vasoconstricted state observed in this disorder. We speculate that the hyperdynamic circulation that characterizes the latent phase of preeclampsia causes vascular shear stress, which in turn increases the levels of circulating vascular endothelial growth factor. Because vascular endothelial growth factor normally acts as a vasodilator, its increase may represent an unsuccessful vascular rescue response.     

Longitudinal serum concentrations of placental growth factor: evidence for abnormal placental angiogenesis in pathologic pregnancies

OBJECTIVE: Complicated pregnancies demonstrate abnormal decidual and placental villous vasculature. We examined maternal concentrations of vascular endothelial growth factor and placental growth factor in normal pregnancies and in pregnancies that were complicated by isolated idiopathic small-for-gestational-age (SGA) newborn infants, preeclampsia alone, or preeclampsia with SGA newborn infants at the time of clinical disease and before the onset of clinical signs. STUDY DESIGN: Serum vascular endothelial growth factor and placental growth factor were measured by enzyme-linked immunosorbent assay in cross-sectional and longitudinal cohorts of pregnant nulliparous women. The results were compared by Wilcoxon tests or a mixed-models method, respectively. RESULTS: In the cross-sectional study, serum placental growth factor was reduced in abnormal pregnancy relative to control subjects (SGA newborn infants, 18 [P =.04]; preeclampsia, 20; or preeclampsia with small- for-gestational-age newborn infants, 11 [P =.0001]) as early as 15 to 19 weeks of gestation in preeclampsia with SGA newborn infants. Vascular endothelial growth factor was <30 pg/mL in all serum specimens from pregnant women. CONCLUSION: We postulate that decreased placental growth factor production results in abnormalities of placental angiogenesis through direct and indirect effects on other vasculotropic growth factors.     

The association of interleukin 6 with clinical and laboratory parameters of acute pelvic inflammatory disease.

OBJECTIVE: We sought (1) to determine whether interleukin 6 levels are increased in plasma and cervical secretions and endometrial tissue obtained from women with a clinical diagnosis of pelvic inflammatory disease, (2) to determine whether interleukin 6 levels in these sample sites reflected the clinical severity of acute infection, and (3) to determine whether interleukin 6 levels in endometrial tissue obtained from these women were higher in the presence of histologic endometritis. STUDY DESIGN: We performed a prospective pilot study on 20 women with a clinical diagnosis of pelvic inflammatory disease (patients) and then compared them with 20 women presenting to the gynecology clinic without pelvic complaints (control subjects). Interleukin 6 levels were measured by enzyme-linked immunologic testing in plasma, cervical secretions, and endometrial biopsy specimens. RESULTS: Cervical interleukin 6 levels were higher in patients than control subjects (median, 317 vs 111 pg/mL; P =.003). Among women with pelvic inflammatory disease, statistically significant positive correlations were noted between the clinical severity score and the erythrocyte sedimentation rate (r = 0.45; P =.04), the clinical severity score and the white blood cell count (r = 0.49; P =.03), the plasma interleukin 6 levels and the erythrocyte sedimentation rate (r = 0.55; P =.02), and the plasma interleukin 6 levels and the white blood cell count (r = 0.54, P =.01). Endometrial tissue interleukin 6 levels were also higher in patients with versus those without histologic endometritis (median, 427 vs 17 pg/mL; P =.004). CONCLUSION: In this pilot study interleukin 6 levels in cervical secretions were significantly higher in women with pelvic inflammatory disease versus those without pelvic inflammatory disease. In women with pelvic inflammatory disease, endometrial tissue samples with histologic evidence of endometritis were observed to have higher levels of interleukin 6. Interleukin 6 may be a useful adjunct to the clinical diagnosis of pelvic inflammatory disease.     

Prognostic significance of vascular endothelial growth factor expression in ovarian cancer patients: a long-term follow-up

Abstract.   Rudlowski C, Pickart A-K, Fuhljahn C, Friepoertner T, Schlehe B, Biesterfeld S, Schroeder W. Prognostic significance of vascular endothelial growth factor VEGF expression in ovarian cancer patients: a long-term follow-up. Int J Gynecol Cancer 2006; 16(Suppl. 1): 183–189.
The purpose of the study was to determine vascular endothelial growth factor (VEGF) concentrations in ascites from ovarian cancer and to correlate these data with VEGF expression in ovarian tumors, serum VEGF concentrations, and clinicopathologic characteristics. Ascites, serum, and tumor tissue from 65 ovarian carcinomas and eight borderline tumors were collected. VEGF concentration in peritoneal fluids and sera was determined using enzyme immunoassay. VEGF tumor expression was evaluated immunohistochemically. Significantly higher VEGF concentrations were found in ascites from malignant tumors (median, 2575 pg mL⁻¹) compared with borderline tumors (median 181.9 pg mL⁻¹) and benign peritoneal fluid (184.5 pg mL⁻¹). Both VEGF ascites concentration and tumor expression correlated with advanced tumor stages and ascites volume. Elevated VEGF ascites levels were negatively correlated to patient survival. No differences between VEGF serum levels could be observed between ovarian cancer patients and patients with benign cysts. This study showed for the first time the clinical significance of elevated VEGF ascites level in ovarian carcinomas. VEGF is expressed by ovarian tumor cells and locally released in the malignant peritoneal fluid but is not increased in the serum of preoperative ovarian cancer patients. The enhanced VEGF level support novel therapeutic perspectives by VEGF inhibition.     

Clinicopathologic study of vascular endothelial growth factor, thrombospondin-1, and microvessel density assessed by CD34 in patients with stage III ovarian carcinoma

Abstract.   Karavasilis V, Malamou-Mitsi V, Briasoulis E, Tsanou E, Kitsou E, Pavlidis N. Clinicopathologic study of vascular endothelial growth factor, thrombospondin-1, and microvessel density assessed by CD34 in patients with stage III ovarian carcinoma. Int J Gynecol Cancer 2006; 16(Suppl. 1): 241–246.
The aim of the study was to investigate angiogenesis in patients with advanced-stage ovarian carcinoma. We used paraffin-embedded tumor tissues from 33 patients diagnosed with FIGO III ovarian cancer who had optimal surgery and received platinum-based chemotherapy. The tissue expression of CD34, vascular endothelial growth factor (VEGF), and thrombospondin-1 (TSP-1) was assessed immunohistochemically. CD34 stained hot spot areas were used to evaluate tumor microvessel density (MVD). VEGF and TSP-1 were assessed by semiquantitative methods. The studied molecules were investigated for relationship with standard clinicopathologic parameters. MVD count was high: median value of 39, range 12–143 microvessels/mm². VEGF was present in all cases and stained strong in 91%. Stroma staining for TSP-1 was weak in 79% of the cases, strong in 6%, and absent in five (15%). We did not find correlations between the three studied markers and histologic type or tumor grade. MVD score did not relate to VEGF or TSP-1. We only observed a trend toward a longer survival in patients with tumors expressing high TSP-1 (60 vs. 36 months, P = 0.1). Proangiogenetic factor VEGF is highly expressed in advanced-stage ovarian carcinomas. The findings of this study may offer support for considering VEGF-targeted therapeutics in ovarian cancer treatment research.     

Expression of GLUT-1 in epithelial ovarian carcinoma: correlation with tumor cell proliferation, angiogenesis, survival and ability to predict optimal cytoreduction

Objective

GLUT-1 is involved at various steps in the processes of tumor progression. The objective of this study was to examine the relationship between GLUT-1 expression and tumor proliferation and angiogenesis in epithelial ovarian carcinoma.

Materials and methods

Specimens from 213 patients with epithelial ovarian carcinoma were evaluated by immunohistochemistry for GLUT-1, Ki-67, and vascular endothelial growth factor. Tumor microvessel density was assessed with CD34 immunostaining. We investigated the relationships between GLUT-1 expression and clinicopathologic characteristics, tumor angiogenesis (tumor MVD and vascular endothelial growth factor expression), and tumor proliferation (Ki-67). The effect of GLUT-1 expression on patient survival and on the volume of residual disease after cytoreduction was determined.

Results

There was a significant positive correlation between expression of GLUT-1, Ki-67, and microvessel density. In univariate survival analysis, high GLUT-1 expression, high Ki-67 expression and high tumor microvessel density showed a significant impact on patient survival (p = 0.0001). In multivariate analysis including patients with all tumor stages, after controlling for age, race, stage, grade, MVD, and the 3 markers (GLUT-1, Ki-67 and VEGF), only age (HR 1.5; 95% CI 1-2.3), stage (HR 3.6; 95% CI 1.8-7.5) and grade (HR 2.3; 95% CI 1.2-4.5) retained their significance as independent poor prognostic factors. Tumors simultaneously overexpressing GLUT-1 and Ki-67 were less likely to be optimally cytoreduced as compared to tumors overexpressing only one or neither of those two markers (OR: 3.8, p = 0.01).

Conclusion

Expression of GLUT-1 correlates with tumor proliferation and microvessel density in epithelial ovarian carcinoma. In addition, patients with rapidly proliferating advanced stage tumors overexpressing GLUT-1 have a lesser chance for optimal cytoreduction.     

VEGF、MMP2、MVD与卵巢癌临床病理关系的研究

目的 :研究卵巢癌中VEGF、MMP2的表达和MVD与临床病理参数和预后的关系并探讨其临床价值。方法 :采用免疫组化技术检测 5 3例卵巢癌和 10例卵巢交界性肿瘤中VEGF、MMP2的表达水平 ,用CD34标记新生血管内皮细胞 ,在显微镜下观察血管密度。结果 :卵巢癌中MVD与年龄呈正相关 (P =0 .0 16 ) ,粘液性囊腺癌中MVD高于其它组织学类型 (P <0 .0 1)。卵巢癌中VEGF的表达与FIGO手术分期呈正相关 (P =0 .0 0 1) ,VEGF表达还与腹水量呈正相关 (P =0 .0 0 2 )。MVD与VEGF、MMP2表达呈正相关 (P值分别为 0 .0 2 1和 0 .0 31) ,VEGF表达与MMP2表达呈正相关 (P =0 .0 0 2 )。VEGF、MMP2强阳性表达和MVD较高 (≥ 10 /HP)的患者预后差 (P值分别为 0 .0 2 6 ,0 .0 36和 0 .0 38)。结论 :VEGF是重要的血管生成因子 ,MMP2不仅在肿瘤的浸润和转移中意义重大 ,而且在肿瘤的血管生成中发挥作用。卵巢癌的FIGO手术分期、MVD及VEGF、MMP2表达与预后相关 ,特别是MMP2在肿瘤的浸润、转移和血管生成中有双重作用 ,既有助于判断患者对传统治疗的敏感性 ,而且对开发针对肿瘤的生物特异性治疗具有启发作用。     

Intratumoral blood flow analysis in endometrial carcinoma: correlation with tumor characteristics and risk for recurrence.

OBJECTIVE: The aim of this study was to correlate intratumoral blood flow as assessed by transvaginal color Doppler ultrasound with tumor histopathologic characteristics, tumoral stage, and risk for recurrence in endometrial carcinoma. METHODS: Forty-five patients (mean age: 58.2 years, range: 30 to 83 years) with surgically treated endometrial carcinoma preoperatively evaluated with transvaginal color Doppler ultrasound were included in this retrospective study. The lowest arterial resistance index (RI) and highest peak systolic velocity (PSV) were used for intratumoral blood flow analysis. Individual tumor characteristics evaluated were tumor growth pattern, tumor size, histologic type, tumor grade, myometrial infiltration depth, cervical involvement, lymph node metastasis, and lymph-vascular space invasion (LVSI). Tumoral stage and risk for recurrence were also evaluated. RESULTS: Significantly lower RI was found in tumors with the following characteristics: infiltrative growth pattern (P = 0,013), grade 3 (P = 0.001), infiltrating >or=50% of the myometrium (P = 0.006), cervical involvement (P = 0.009), LVSI (P = 0.008), lymph-node metastasis (P = 0.049), stage >or=Ic (P = 0.004), and high risk for recurrence (P = 0.001). Significantly higher PSV was found in tumors that were grade 3 (P = 0.034), infiltrating >or=50% of the myometrium (P = 0.029), stage >or=Ic (P = 0.015), and with a high risk for recurrence (P = 0.002). CONCLUSIONS: Our data indicate that a correlation between intratumoral blood flow features and histopathological characteristics, tumor stage, and risk for recurrence exists in endometrial cancer. Further prospective studies are needed to determine the clinical usefulness of preoperative assessment of tumor vascularization in these carcinomas.     

Overexpression of estrogen receptor-alpha in the endometrial carcinoma cell line Ishikawa: inhibition of growth and angiogenic factors

BACKGROUND: A high level of estrogen receptor-alpha (ER-alpha) is believed to be favorable in the prognosis and treatment of endometrial, ovarian, and breast cancer. High levels of ER-alpha have been shown to inhibit the growth and invasive, metastatic potential of breast cancer cell lines. To bring about these inhibitory effects, ER-alpha probably acts through other cellular factors involved in the regulation of cell growth. OBJECTIVE: To investigate the role of high levels ER-alpha in growth inhibition of endometrial cancer cells. METHODS: A human ER-alpha cDNA was stably overexpressed in an endometrial cancer cell line, namely, Ishikawa. ER-alpha-overexpressing, parent, and control Ishikawa cells were grown in vitro and their growth rates were compared by cell count. ER-alpha-overexpressing and parent Ishikawa cells were also grown in vitro as tumors in a chicken chorioallantoic membrane (CAM) model, and tumor growth and angiogenesis was measured. Finally, levels of angiogenesis-modulating factors, nitric oxide synthase (NOS), and vascular endothelial growth factor (VEGF) were examined in relation to ER overexpression. RESULTS: The growth of Ishikawa cells was found inhibited in culture as well as in the CAM model. Angiogenesis of CAM tumors was also found inhibited in ER-overexpressing cells. Angiogenic factor VEGF was inhibited whereas the activity of NOS was found elevated following ER overexpression. CONCLUSION: Our work on the Ishikawa cell line indicates that high levels of ER-alpha in endometrial cancer may inhibit cancer growth by modulating angiogenic factors, thereby limiting the blood supply to the growing tumor. Our results support the earlier data from other groups that have shown a positive correlation between high ER content and better prognosis of endometrial cancers.     

Fractional excretion of angiogenic factors in women with severe preeclampsia

OBJECTIVE: We estimated the fractional excretions of soluble fms-like tyrosine kinase 1 (sFlt-1), vascular endothelial growth factor, and placental growth factor of severely preeclamptic women at the time of disease clinical manifestation. METHODS: Levels of free sFlt-1, vascular endothelial growth factor, and placental growth factor were measured by immunoassay from time-matched serum-urine samples from 64 women in the following groups: nonpregnant reproductive aged (n = 9), healthy pregnant controls (n = 13), mildly preeclamptic women (n = 15), and women with severe preeclampsia (n = 27). Urinary concentrations of angiogenic factors were normalized to creatinine and fractional excretions calculated. Correlations were estimated between fractional excretions of angiogenic factors, albuminuria, nonspecific proteinuria and urine protein-to-creatinine ratio. RESULTS: Severely preeclamptic women had more than double urinary vascular endothelial growth factor (P = .01) and fractional excretion of vascular endothelial growth factor compared with mildly preeclamptic women (P = .007) or pregnant controls (P < .001). Serum, urine and fractional excretion levels of sFlt-1 were much higher among severely preeclamptic women compared with all the other pregnant groups (P < .001). Conversely, severely preeclamptic women had lower serum placental growth factor levels compared with healthy pregnant women (P < .05) and mildly preeclamptic groups (P < .05). Severely preeclamptic women had increased fractional excretions of placental growth factor, albumin, proteinuria, and random urine total protein/creatinine ratio. Among severely preeclamptic women there was no correlation between proteinuria and fractional excretion of vascular endothelial growth factor (r = 0.30, P = .127) or sFlt-1 (r = 0.35, P = .07). There was a significant correlation between fractional excretion for placental growth factor, random urine total protein/creatinine ratio (r = 0.60, P = .002), and nonspecific proteinuria (r = 0.50, P = .01). CONCLUSION: Severe preeclampsia is characterized by increased fractional excretion of angiogenic factors and especially of vascular endothelial growth factor, likely reflecting 2 separate phenomena that may have additive effects: "endogenous" renal production and glomerular "leakage."