卵巢肿瘤组织中HABP-1、VEGF的表达及其临床病理意义

目的 研究HABP-1、VEGF在卵巢肿瘤组织中的表达及其临床意义。方法 通过应用免疫组化SP法来检测20例卵巢良性肿瘤、30例卵巢交界性肿瘤、102例卵巢恶性肿瘤中HABP-1和VEGF的表达情况。结果 HABP-1和VEGF在卵巢癌和卵巢交界性肿瘤中的阳性表达率显著高于卵巢良性肿瘤。HABP-1在卵巢癌组织中的阳性表达率与患者的年龄和病理类型无统计学意义(P＞0.05),而与病理分级、临床分期、淋巴结和腹膜转移等有显著统计学意义(P＜0.05)。结论 HABP-1和VEGF在卵巢癌的发生、发展中起到了至关重要的作用,可作为判断卵巢癌恶性程度、病情进展的重要指标,联合检测用于指导临床诊断。     

mRNA EXPRESSION OF PTEN AND VEGF GENES IN EPITHELIAL OVARIAN CANCER

VEGF gene, also known as vascular permeability factor, has been mapped to chromosome 6p21.3[11]. Biochemically, it is a heparin binding glycoprotein that has in at least four molecular isoforms, among which, VEGF165 occurs most common. VEGF can act as a specific mitogen for a variety of endothelial cells in vitro and as an angiogenic molecule in vivo [11,12]. VEGF is a potent multifunctional cytokine that exerts several potentially independent actions on the vascular endothelium, includin…     

CTGF、VEGF在卵巢癌中的表达及临床意义

目的 研究结缔组织生长因子(CTGF)、血管内皮生长因子(VEGF)的表达在卵巢癌发生、发展中的作用及临床意义.方法 采用免疫组化法检测92例卵巢癌组织和11例正常卵巢组织中CTGF和VEGF的表达,比较CTGF、VEGF在卵巢癌中表达的关系,并分析其在卵巢癌发生、发展中的临床意义及对预后的影响.结果CTGF在卵巢癌组织中的阳性表达率为19.6%,明显低于正常卵巢组织的81.8%(P﹤0.001);VEGF在卵巢癌组织中的表达率为89.1%,明显高于正常卵巢组织的27.3%(P﹤0.001).CTGF的阴性表达与卵巢癌患者的FIGO分期及淋巴结转移有关(P﹤0.05),但与患者的年龄及病理分级无关(P﹥0.05);VEGF的阳性表达与卵巢癌患者的淋巴结转移有关(P﹤0.05),但与患者的年龄、病理分级及FIGO分期无关(P﹥0.05).CTGF与VEGF在卵巢癌组织中的表达呈负相关(r=-0.444,P﹤0.05).结论 CTGF和VEGF的表达可能与卵巢癌的发生、发展及预后密切相关.     

Platinum/paclitaxel-based chemotherapy in advanced ovarian carcinoma: glutathione S-transferase genetic polymorphisms as predictive biomarkers of disease outcome

Background. The glutathione S-transferases (GSTs) are a group of multifunctional enzymes that catalyze the conjugation of glutathione with a variety of electrophilic compounds, including cytotoxic agents. A significant percentage of normal individuals exhibit genetic polymorphism with a homozygous deletion (null genotype) of the genes, leading to absence of the enzyme.Methods. In the present study we analyzed GSTM1 and GSTT1 polymorphisms in the genomic DNA isolated from peripheral blood of patients with ovarian cancer treated with chemotherapy (paclitaxel and cisplatinum) after cytoreductive surgery and assessed its correlation with the clinical outcome of these patients. The median follow-up for the patients was 30 months.Results. The estimated 3-year survival rate was 59.8% for all patients and 20.8% for carriers of GSTM1-wt/GSTT1-wt (wt indicates wild type) genotype combination (37.7% for GSTM1-wt alone) compared with 83.1% for non-GSTM1-wt/GSTT1-wt genotype carriers (100% for GSTM1-null). The mean survival time was significantly better in patients who are carriers of the GSTM1-null genotype (40.5 vs. 33.5; P = 0.006) or carriers of non-GSTM1-wt/GSTT1-wt genotypes (55.4 vs. 30.7; P = 0.009). The progression-free interval was more favorable for GSTM1-null carriers (41.9 vs. 27.4; P = 0.024).Conclusion. The study suggests that characterization of the drug-metabolizing genetic individual profile can be of great interest in clinical oncology. It can define the optimal chemotherapy for each patient, improve the efficiency, and reduce the incidence of drug toxicity and poor drug responses.     

ING4与VEGF在卵巢肿瘤中的表达及其临床意义

目的:研究ING4与VEGF在卵巢癌中的表达及其与卵巢癌发生发展的关系。方法:采用免疫组化SP法检测104例卵巢组织中ING4与VEGF的表达情况,并用CD43标记血管内皮计数MVD。结果:ING4蛋白在正常卵巢组织、卵巢交界性肿瘤组织和卵巢癌组织中表达呈阶梯性降低,三组间差异有统计学意义(P＜0.01),VEGF蛋白在正常卵巢组织、卵巢交界性肿瘤组织和卵巢癌组织中表达呈阶梯形增高,三组间差异有统计学意义(P＜0.01)。ING4的表达随着FIGO分期升高和病理分级的降低表达减弱,各组间有显著差异(P＜0.01)。VEGF的表达随着FIGO分期升高和病理分级的降低表达增强,各组间有显著差异(P＜0.05）。ING4和VEGF在卵巢癌组织中的表达呈负相关（r=-0.29,P＜0.05）。ING4表达阴性者MVD高于ING4阳性者(P＜0.01),VEGF表达阳性者MVD高于VEGF阴性者(P＜0.05)。联合分析表明ING4阴性VEGF阳性组预后比其它蛋白表达组明显较差(P＜0.05)。结论:ING4和VEGF表达与卵巢癌的发生发展和血管生成、转移、预后密切相关。     

卵巢癌组织中APE1、VEGF的表达和MVD检测的临床意义

目的:研究脱嘌呤脱嘧啶核酸内切酶1(apurinic/apyrimidinic endonuclease 1,APE1)、血管内皮生长因子(vascular endothelial growth factor,VEGF)和微血管密度(microvessel density,MVD)在上皮性卵巢癌组织中的表达情况及其临床意义.方法:采用免疫组织化学SP法检测80例上皮性卵巢癌组织中APE1、VEGF表达和MVD计数情况,统计分析APE1和VEGF、MVD在上皮性卵巢癌组织中的相关性.结果:APE1在卵巢癌组织中表达阳性率为81.3％,VEGF在卵巢癌组织中表达阳性率为72.5％.APE1、VEGF表达均与卵巢癌FI-GO分期、细胞分化程度、淋巴结转移有关(P＜0.05).MVD计数在中晚期(Ⅲ期+Ⅳ期)、低分化、淋巴结转移阳性的卵巢癌组织中显著高于早期(Ⅰ期+Ⅱ期)、高/中分化、淋巴结转移阴性的卵巢癌组织(P＜0.05).卵巢癌组织中APE1和VEGF表达、MVD计数之间均为正相关(P=0.000).和APE1表达阴性的卵巢癌组织相比,APE1表达阳性的卵巢癌组织中MVD计数显著升高,具有统计学意义(37.2±12.4vs 14.3±5.5,t =5.682,P=0.000).结论:APE1可能通过促进卵巢癌组织中新生血管形成在卵巢癌发生发展中发挥重要作用.     

Small interfering RNA targeting MDR1 inhibits ovarian cancer growth and increases efficacy of chemotherapy in vivo

Objective  

To further validate a knockdown approach for circumventing the multidrug resistance gene (MDR1), we used small interfering RNA(siRNA) targeting MDR1 gene to inhibit the expression of MDR1 gene and P-glycoprotein(P-gp) in vivo.     

Effect of paclitaxel on vascular endothelial growth factor (VEGF) and interleukin (IL)-8 in serum of patients with recurrent ovarian cancer: a comparison of weekly vs triweekly regimens

Antiangiogenic scheduling of cancer chemotherapeutics has been increasingly recognized to be a potential application of the paclitaxel in cancer therapy. The purpose of this study is to confirm antiangiogenic effects of weekly low-dose paclitaxel in recurrent ovarian carcinoma. Measurements of serum vascular endothelial cell growth factor (VEGF) and interleukin (IL)-8 were performed using enzyme-linked immunosorbent assay (ELISA) kits. Serum was collected with written informed consents. Serum levels of VEGF and IL-8 were measured in patients with benign ovarian tumors, low malignant potential ovarian tumors (LMP), and ovarian carcinomas. Among 20 patients with pretreated recurrent ovarian carcinoma, 10 patients receiving treatment with paclitaxel (180 mg/m2) given once every 3 weeks (triweekly paclitaxel) and the other 10 patients receiving treatment with weekly paclitaxel (80 mg/m2) were randomly allocated. Sera from these patients were collected before treatment and 3 weeks after initiation of treatment to determine changes of VEGF and IL-8 levels. Although VEGF levels were highest in patients with ovarian carcinoma, there was no significant difference among benign, LMP, and carcinoma. Among patients with detectable levels of IL-8, ovarian carcinoma showed significantly higher IL-8 levels than benign tumors followed by LMP. VEGF levels in patients with treatment by triweekly paclitaxel did not show any significant change before and after treatment, while those in patients with treatment by weekly paclitaxel decreased significantly after treatment. Similarly, in patients with detectable IL-8 levels, weekly paclitaxel resulted in a significant decrease of IL-8 levels after treatment, while triweekly paclitaxel did not result in any significant change of IL-8 levels. The present study demonstrated that weekly but not triweekly paclitaxel had significant antiangiogenic effects.     

卵巢癌患者血浆miR-205、miR-212及miR-429的水平分析及意义

目的 探讨卵巢癌患者血浆miR-205、miR-212及miR-429水平,分析3者与卵巢癌临床病理学特征的关系。方法 收集本院收治的71例上皮性卵巢癌患者未经治疗前的血浆标本（上皮性卵巢癌组）,采用实时定量RT-PCR（qRT-PCR）法检测以上标本的miR-205、miR-212及miR-429水平,收集卵巢癌患者的临床病理学参数（年龄、临床分期、分化程度、组织类型及淋巴结转移情况）,比较不同miR-205、miR-212及miR-429水平的临床病理参数分布差异,采用受试者工作特征曲线（ROC）评价血浆miR-205、miR-212及miR-429水平在卵巢癌诊断中的临床价值。同时选取同期的68例女性健康体检者（健康对照组）及66例良性卵巢肿瘤患者（良性卵巢肿瘤组）的血浆标本作对照。结果 上皮性卵巢癌组的血浆miR-205水平高于良性卵巢肿瘤组和健康对照组,但miR-212和miR-429水平低于良性卵巢肿瘤组和健康对照组,差异均有统计学意义（P<0.05）;上皮性卵巢癌组中的miR-205水平与年龄、临床分期、分化程度及淋巴结转移有关,miR-212水平与临床分期、分化程度有关,miR-429水平与临床分期、淋巴结转移有关,以上差异均有统计学意义（P<0.05）;卵巢癌患者血浆miR-205水平与miR-212及miR-429均呈负相关（r=-0.572、-0.325）,miR-212与miR-429呈正相关（r=0.473）,差异均有统计学意义（P<0.05）;血浆miR-205、miR-212及miR-429诊断卵巢癌的AUC、灵敏度和特异度分别为0.915、92.1%和86.2%,0.944,87.3%和91.0%,0.905、88.5%和83.6%。结论 卵巢癌患者血浆中miR-205呈高表达,miR-212和miR-429呈低表达,与临床病理学参数有关,且在卵巢癌诊断中有一定的价值,可用于卵巢癌的辅助诊断和病情评估。     

Current status and future prospects of hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) clinical trials in ovarian cancer

Abstract

The natural history of advanced-stage epithelial ovarian cancer is one of clinical remission after surgery and platinum/taxane-based intravenous (IV) and/or intraperitoneal (IP) chemotherapy followed by early or late recurrence in the majority of patients. Prevention of progression and recurrence remains a major hurdle in the management of ovarian cancer. Recently, many investigators have evaluated the use of normothermic and hyperthermic intraoperative IP drug delivery as a management strategy. This is a narrative review of the current status of clinical trials of hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) in ovarian cancer and the future directions for this treatment strategy. The existing studies on HIPEC in patients with epithelial ovarian cancer are mostly retrospective in nature, are heterogeneous with regards to combined inclusion of primary and recurrent disease and lack unbiased data. Until data are available from evidence-based trials, it is reasonable to conclude that surgical cytoreduction and HIPEC is a rational and interesting, though still investigative, approach in the management of epithelial ovarian cancer, whose use should be employed within prospective clinical trials.     

Expression of DNA repair genes in ovarian cancer samples: biological and clinical considerations

The purpose of this study was to investigate retrospectively the mRNA expression of genes involved in different DNA repair pathways implicated in processing platinum-induced damage in 171 chemotherapy-naïve ovarian tumours and correlate the expression of the different genes with clinical parameters. The expression of genes involved in DNA repair pathways (PARP1, ERCC1, XPA, XPF, XPG, BRCA1, FANCA, FANCC, FANCD2, FANCF and PolEta), and in DNA damage transduction (Chk1 and Claspin) was measured by RT-PCR in 13 stage I borderline and 77 stage I and 88 III ovarian carcinomas. ERCC1, XPA, XPF and XPG genes were significantly less expressed in stage III than in stage I carcinoma; BRCA1, FANCA, FANCC, FANCD2 gene expressions were low in borderline tumours, higher in stage I carcinomas and lower in stage III samples. High levels of ERCC1, XPA, FANCC, XPG and PolEta correlated with an increase in Overall Survival (OS) and Progression Free Survival (PFS), whilst high BRCA1 levels were associated with PFS on univariate analysis. With multivariate analyses no genes retained an association when adjusted by stage, grade and residual tumour. A tendency towards a better PFS was observed in patients with the highest level of ERCC1 and BRCA1 after platinum-based therapy than those given both platinum and taxol. The expression of DNA repair genes differed in borderline stage I, stage I and stage III ovarian carcinomas. The role of DNA repair genes in predicting the response in ovarian cancer patients seems far from being established.     

Evolving concepts in the management of drug resistant ovarian cancer: Dose dense chemotherapy and the reversal of clinical platinum resistance

Despite the initially high response rate to standard front-line debulking surgery followed by platinum-based chemotherapy, the relapse rate in ovarian cancer is high and many patients will recur within 6 months of completing platinum based treatment. These patients may still require further chemotherapy despite being considered “platinum resistant”. In this setting, response rates to conventionally scheduled second line platinum and non-platinum agents is low, ranging between 5% and 15%. There is an emerging body of evidence that in this scenario, chemotherapeutic activity can be enhanced using unconventionally scheduled “dose-dense” platinum and non-platinum based regimens with improved response rates of up to 65%. Randomised studies to evaluate the impact of this approach on survival in recurrent, platinum resistant disease are urgently required to confirm the promising phase II findings if there is to be a change in the standard of care of patients with platinum resistant disease. In this review we discuss the evolving strategies to overcome resistance in patients with platinum resistant ovarian cancer with a particular focus on alterations in dose schedule as a means of reversing platinum resistance.     

Evaluation of azacitidine and entinostat as sensitization agents to cytotoxic chemotherapy in preclinical models of non-small cell lung cancer

Recent clinical data in lung cancer suggests that epigenetically targeted therapy may selectively enhance chemotherapeutic sensitivity. There have been few if any studies rigorously evaluating this hypothesized priming effect. Here we describe a series of investigations testing whether epigenetic priming with azacitidine and entinostat increases sensitivity of NSCLC to cytotoxic agents.We noted no differences in chemosensitivity following treatment with epigenetic therapy in in vitro assays of viability and colony growth. Using cell line and patient-derived xenograft (PDX) models, we also observed no change in responsiveness to cisplatin in vivo. In select models, we noted differential responses to irinotecan treatment in vivo. In vitro epigenetic therapy prior to tumor implantation abrogated response of H460 xenografts to irinotecan. Conversely, in vitro epigenetic therapy appeared to sensitize A549 xenografts (tumor growth inhibition 51%, vs. 22% in mock-pretreated control). In vivo epigenetic therapy enhanced the response of adenocarcinoma PDX to irinotecan.Taken together, these data do not support broadly applicable epigenetic priming in NSCLC. Priming effects may be context-specific, dependent on both tumor and host factors. Further preclinical study is necessary to determine whether, and in which contexts, priming with epigenetic therapy has potential to enhance chemotherapeutic efficacy in NSCLC patients.     

Proteomic biomarkers in combination with CA 125 for detection of epithelial ovarian cancer using prediagnostic serum samples from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial

BACKGROUND:

When epithelial ovarian cancer is detected at an early stage (I‐II), the 5‐year survival rate is between 70% and 90%; whereas, when it is detected in late stages (III‐IV), the 5‐year survival rate slips to <30%. In a previous report, the authors observed that proteomic biomarkers and cancer antigen 125 (CA 125) exhibited a sensitivity of 84% at a specificity of 98% for identifying sera from patients who had stage I disease at the time of surgery, significantly improving the sensitivity of CA 125 alone. The challenge, however, is to detect ovarian cancer before clinical diagnosis. The current study was part of a large effort to compare different multimarker biomarker panels for the early detection of ovarian cancer. Several biomarkers were evaluated alone and in combination with CA 125 in prediagnostically collected sera from women in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.

METHODS:

Proximal prediagnostic sera from 118 women with ovarian cancer (cases) and from 951 age‐matched women (controls) (8 controls per case, including 4 randomly selected from the general population, 2 with CA 125 levels ≥35 U/mL, and 2 with a positive family history of breast/ovarian cancer) were analyzed using the CA 125 immunoassay and surface‐enhanced laser desorption and ionization time‐of‐flight mass spectrometry to measure 7 proteins (apolipoprotein A1, truncated transthyretin, transferrin, hepcidin, β‐2 microglobulin, connective tissue activating protein III), and interalpha‐trypsin inhibitor heavy‐chain 4). Data were analyzed by 2 statistical strategies that combined the 7 markers and CA 125 into 1 predictive score for disease classification.

RESULTS:

CA 125 levels were elevated (≥35 U/mL) in 61.5% of 65 patients who had CA 125 data available from samples that were collected <12 months before cancer diagnosis; however, levels of the additional 7 biomarkers were not different between cases and the 3 control groups individually or combined. Two panels that combined CA 125 and the 7 biomarkers failed to improve the sensitivity of CA 125 alone.

CONCLUSIONS:

In contrast to earlier findings from analyzes of postdiagnostically collected sera, the addition of 7 biomarkers to CA 125 did not improve sensitivity for preclinical diagnosis beyond CA 125 alone. Cancer 2012;. © 2011 American Cancer Society.