Protein expression levels of carcinoembryonic antigen (CEA) in Danish ovarian cancer patients: from the Danish 'MALOVA'ovarian cancer study

AIMS: To determine the variation in expression of carcinoembryonic antigen (CEA) in 760 epithelial ovarian tumours from Denmark, and to correlate expression with clinicopathological parameters and prognosis for the disease. METHODS: Using tissue arrays (TA), we analysed CEA expression in tissues from 189 women diagnosed with low malignant potential ovarian tumours (LMP, borderline ovarian tumours) and 571 women diagnosed with ovarian cancer (OC). RESULTS: Using 30% as the cut-off level for CEA over-expression, 18% of LMPs and 4% of OCs were positive. A higher proportion of mucinous tumours were positive compared with other histological subtypes (p<0.00001). A univariate survival analysis suggested a shorter disease specific survival for patients with 30% or higher CEA expression in the tumour tissue (p = 0.004). In a Cox survival analysis, which included 569 OC cases subgrouped by stage (I to IV), the highest CEA expression compared with no expression was found to be a prognostic factor (level 3 versus negative: HR = 2.12, 95%CI 1.11-4.05). FIGO stage, residual tumour after primary surgery, age at diagnosis, other histological types versus serous adenocarcinoma and low versus high histological grade tumours were also prognostic factors. CONCLUSION: These data suggest that CEA expression is an independent prognostic factor for mucinous OC in Danish patients.     

Expression of EphA2 and EphrinA-1 in vulvar carcinomas and its relation to prognosis

AIMS: To examine the expression of EphA2 and EphrinA-1 in vulvar squamous cell carcinomas and investigate their prognostic relevance. METHODS: Tumours from 224 patients with vulvar squamous cell carcinomas were investigated for expression of EphA2 and EphrinA-1 using single and double immunostaining methods. RESULTS: High expression (strong/moderate staining intensity) of EphA2 and EphrinA-1 was observed in 114 (51%) and 126 (56%) vulvar carcinomas, respectively. In the three cases tested using the double immunostaining method, colocalisation of EphA2 and EphrinA-1 proteins was identified in the same neoplastic cells. High EphA2 expression was significantly correlated to high expression of EphrinA-1 (p<0.01) and cyclin A (p<0.01), large tumour size (p = 0.03), deep invasion (p<0.01) and higher FIGO stage (p = 0.05). A correlation between high EphrinA-1 expression and high levels of cyclin A (p<0.01) and p21 (p<0.01), deep invasion (p<0.01) and higher FIGO stage (p = 0.01) was also seen. In univariate analysis, high expression of EphrinA-1 was associated with poor survival (p = 0.03). However, in the multivariate analysis neither EphrinA-1 nor EphA2 were significantly correlated to survival. CONCLUSIONS: EphA2 and EphrinA-1 were overexpressed in 51% and 56% of the vulvar squamous cell carcinomas, respectively, and high levels of EphA2 and EphrinA-1 proteins were associated with deep tumour invasion and high FIGO stage. However, EphA2 and EphrinA-1 were not independently associated with clinical outcome in vulvar carcinomas.     

High GOLPH3 expression is associated with a more aggressive behavior of epithelial ovarian carcinoma

Overexpression of GOLPH3 (Golgi phosphoprotein 3, 34 kDa) is associated with the progression of many solid tumor types leading to an unfavorable clinical outcome. The present study examined the association between GOLPH3 expression and tumor development, clinicopathological factors, and prognosis of epithelial ovarian carcinoma. GOLPH3 expression was examined by immunohistochemistry in 18 normal ovarian samples, 28 benign tumors, 55 serous borderline ovarian tumors, and 135 epithelial ovarian carcinomas. The association of GOLPH3 expression with clinical characteristics, response to chemotherapy, and overall survival of epithelial ovarian carcinoma patients was analyzed on fresh tissue samples. GOLPH3 mRNA and protein expression in ovarian cancer and normal ovarian tissues were detected by real-time quantitative RT-PCR and Western blotting, respectively. The results are the following: (1) GOLPH3 immunostaining localized to the cytoplasm in two patterns, condensed into large granules with perinuclear distribution, and dispersed in the cytoplasm as fine granules. (2) GOLPH3 expression was higher in epithelial ovarian carcinoma than in normal ovarian tissues at the mRNA and protein level. The frequency of high-level expression of GOLPH3 increased progressively from benign (cystadenoma) to borderline neoplasms to malignant lesions. (3) Dispersed cytoplasmic GOLPH3 expression in epithelial ovarian carcinoma patients was highly correlated with FIGO stage (p?<?0.001), tumor histological grade (p?=?0.003), lymph node involvement (p?=?0.001), and chemotherapy response (p?=?0.034). (4) A dispersed pattern of GOLPH3 expression was an independent prognostic factor for poor overall survival. Patients with low dispersed cytoplasmic GOLPH3 expression had significantly longer overall survival than patients with high dispersed cytoplasmic expression. In contrast, GOLPH3 condensed expression was not correlated with clinicopathological features, chemotherapy response, or prognosis. GOLPH3 gene expression might play a role in tumorigenesis in epithelial ovarian carcinoma as upregulation of GOLPH3 expression is associated with a more aggressive tumor phenotype. GOLPH3 immunohistochemistry may be of value to predict the outcome of ovarian carcinoma patients.     

Distribution of p53 expression in tissue from 774 Danish ovarian tumour patients and its prognostic significance in ovarian carcinomas

The clinical roles played by normal and altered p53 in cancer are under intensive investigation, but larger studies describing the pattern as well as the prognostic value are still needed. The aim of this study was, using tissue array (TA), to examine the overexpression of p53 protein in 774 epithelial ovarian tumour tissues from Danish women and to evaluate whether p53 tissue expression levels correlate with clinicopathological parameters and prognosis. The distribution of p53 expression levels at different stages of disease, in different histological subtypes, and the prognostic value of p53 tissue expression were examined. Overall, p53 was expressed in 24/189 (13%) low malignant potential ovarian tumours (LMP) and in 278/585 (48%) ovarian cancers (OC). No significant difference in frequency of p53 tissue expression in LMP tissue was noted with increasing tumour stage (p=0.98). By contrast, there was a significant increase in the frequency of p53 tissue expression in OC with increasing FIGO stage (p<0.00001). Multivariate Cox regression analysis found that less than 20% tissue expression of p53 was associated with longer OC disease-specific survival. Tissue p53 expression may be of prognostic value in women with OC.     

Numerical abnormalities of chromosomes 1, 11, 17, and X are associated with stromal invasion in serous and mucinous epithelial ovarian tumours

The clinical behaviour of ovarian tumours of low malignant potential (LMP) is unpredictable and it has been suggested that the majority of these lesions have no invasive potential. This study has analysed 92 epithelial ovarian tumours [11 mucinous cystadenomas, 18 mucinous LMP tumours, 15 mucinous carcinomas (9 FIGO stage I), 16 serous cystadenomas, 15 serous LMP tumours, and 17 serous carcinomas (11 FIGO stage I)] for numerical abnormalities of chromosomes 1, 11, 17, and X by interphase cytogenetics. Overall, numerical aberrations were identified in none of the cystadenomas, 15 per cent of serous LMP tumours, 17 per cent of mucinous LMP tumours, 67 per cent of mucinous carcinomas, and 82 per cent of invasive serous carcinomas. In mucinous LMP tumours, chromosome gains were associated with spindled nuclear morphology. Chromosome abnormalities were significantly more frequent in invasive mucinous (overall p< 0·01; stage I p< 0·05) and serous (overall p< 0·001; stage I p< 0·01) carcinomas than in the corresponding LMP tumours. No significant relationship between either stromal invasion or tumour type and the pattern of chromosome loss or gain was identified, although monosomy X was identified almost exclusively in invasive serous carcinomas. These observations are consistent with the concept that LMP tumours are unlikely to be precursors of ovarian carcinoma, but suggest that chromosome instability is important in the development of the invasive phenotype. Copyright © 1999 John Wiley & Sons, Ltd.     

The proliferation markers Ki-67/MIB-1, phosphohistone H3, and survivin may contribute in the identification of aggressive ovarian carcinomas

The identification of new proliferation markers could have clinical implications in ovarian carcinoma by stratifying patients for treatment and follow-up. The aim of this study was to evaluate the diagnostic and prognostic value of the proliferation markers Ki-67/MIB-1, phosphorylated histone H3 (PHH3), and survivin in epithelial ovarian tumors. Ninety women with a pelvic mass who underwent surgery at the Department of Gynecological Oncology were included: 68 ovarian carcinomas, 11 borderline tumors, and 11 ovarian cystadenomas. We performed mitotic count and immunohistochemical analyses of Ki-67/MIB-1, PHH3, and survivin, related to clinicopathological parameters. Uni- and multivariate analyses of five-year overall survival were performed. We found statistically significant correlations between mitotic count, Ki-67/MIB-1, PHH3, and survivin. The expression of all proliferation markers was significantly higher in the carcinomas than in the borderline and benign tumors (p<0.05). There was, however an overlap of indices between the different malignancy groups. Women with advanced stage cancers (FIGO stage III and IV) had significantly higher tumor expression of all markers compared to patients with early stage cancers (FIGO stage I and II). Women with advanced disease and complete chemotherapy response had higher Ki67/MIB-1 expression than women without complete chemotherapy response. All markers had an impact on survival in the univariate analyses. In the multivariate analysis, however, only age and stage of disease reached statistical significance as prognostic factors. In conclusion, the proliferation markers Ki-67/MIB-1, PHH3, and survivin are positively correlated with each other and with tumor grade, and may contribute in the identification of aggressive ovarian carcinomas.     

Limited prognostic value of tissue protein expression levels of cyclin E in Danish ovarian cancer patients: from the Danish 'MALOVA' ovarian cancer study

The primary objective of this study was to assess the expression of cyclin E in tumour tissues from 661 patients with epithelial ovarian tumours. The second was to evaluate whether cyclin E tissue expression levels correlate with clinico-pathological parameters and prognosis of the disease. Using tissue arrays (TA), we analysed the cyclin E expression levels in tissues from 168 women with borderline ovarian tumours (BOT) (147 stage I, 4 stage II, 17 stage III) and 493 Ovarian cancer (OC) patients (127 stage I, 45 stage II, 276 stage III, 45 stage IV). Using a 10% cut-off level for cyclin E overexpression, 20% of the BOTs were positive with a higher proportion of serous than mucinous tumours. Sixty-two per cent of the OCs were positive for cyclin E expression with the highest percentage found in clear cell carcinomas. Results based on univariate and multivariate survival analyses with a 10% cut-off value showed that cyclin E had no independent prognostic value. In conclusion, we found cyclin E expression in tumour tissue to be of limited prognostic value to Danish OC patients.     

Expression of c-erbB-2, c-myc, and c-ras oncoproteins, insulin-like growth factor receptor I, and epidermal growth factor receptor in ovarian carcinoma.

AIMS--To assess whether the overexpression of five dominant oncogene encoded proteins is crucial to the pathogenesis of ovarian carcinoma and whether this provides any useful prognostic information. METHODS--The expression of the insulin-like growth factor 1 receptor (ILGFR 1), epidermal growth factor receptor (EGFR), and the c-erbB-2, c-ras, and c-myc products was studied by multiparameter flow cytometry in 80 patients with epithelial ovarian cancer for whom long term follow up was available. RESULTS--Overexpression of ILGFR 1, EGFR, c-erbB-2, c-ras and c-myc was found in, respectively, nine of 80 (11%), 10 of 80 (12%), 19 of 80 (24%), 16 of 80 (20%) and 28 of 80 (35%) ovarian carcinomas. The levels of expression of ILGFR 1, EGFR, c-erbB-2 and c-ras were significantly higher in the tumours of patients with recurrent or persistent disease after chemotherapy than in the tumours of patients at initial presentation (p < 0.02). Multivariate analysis showed that residual tumour (p < 0.001), FIGO stage (p = 0.002), EGFR overexpression (p = 0.030) and previous chemotherapy (p = 0.034) were independent variables for predicting survival. CONCLUSIONS--Overexpression of these oncoproteins only occurs in a small proportion of ovarian carcinomas but may have an important role in the progression of the disease.     

Detection of the Soluble Heat Shock Protein 27 (hsp27) in Human Serum by an ELISA

Abstract

Increased levels of autoantibodies against heat shock protein 27 (hsp27) in patients with breast, ovarian, or endometrial cancer strongly suggest the presence and increased levels of hsp27 in their circulation. Therefore, we have developed a sensitive and reproducible ELISA for quantification of soluble hsp27 levels in biological fluid such as serum. The assay is highly specific for hsp27. The limit of detection of the ELISA is about 0.5 ng/mL. The mean intra‐ and inter‐coefficients of variation were 7.45 and 8.18, respectively. The recovery of the recombinant protein was nearly 100%. The assay could detect soluble hsp27 levels in normal human serum when the level was >0.5 ng/mL. Out of 28 serum samples we tested, 10 samples were not detected for any hsp27 level in our ELISA. However, hsp27 levels could be detected in the other 18 samples. The median serum hsp27 level was 3.27 ng/mL when all the 28 normal control samples were included. Low levels of hsp27 in normal human serum may be useful to distinguish the hsp27 levels in breast or other cancer patients during the progression of the disease. Therefore, the use of hsp27 ELISA could be extremely useful in evaluating the role of soluble hsp27 in breast or other cancers.     

Correlation of serum CA125 with stage, grade and survival of patients with epithelial ovarian cancer at a single centre

To evaluate the relationship between serum CA125 tumour marker level before and after surgery of epithelial ovarian carcinoma and assess its potential role as a prognostic factor. A retrospective review of 87 patients with epithelial ovarian carcinoma at a single centre between January 2001 and December 2005 was performed. Serum CA125 levels were assessed for their relationship to pathological stage, tumour grade, tumour volume and age as well as overall survival. A total of 75 patients, mean age 58.94 years and median follow-up of 24 months were included in the analysis. While the preoperative CA125 level did not correlate significantly with stage, tumour grade or survival, the postoperative CA125 correlated to FIGO stage (p<0.0001), tumour grade (p<0.0001) and overall survival (p=0.01). Reduced survival was noted with increasing age at the time of surgery (p=0.009) and bulk of the residual disease postoperatively (p=0.011).     

Loss of ARID1A expression is related to shorter progression-free survival and chemoresistance in ovarian clear cell carcinoma

Recently, the ARID1A gene has been identified as a novel tumor suppressor in ovarian clear cell carcinoma. The prognostic significance of the loss of ARID1A expression is not known. The current study was designed to evaluate whether ARID1A was a prognostic factor for progression, survival, and chemoresistance in ovarian clear cell carcinoma. A total of 60 patients, who were surgically treated for primary ovarian clear cell adenocarcinoma, were enrolled. Surgical specimens were examined for ARID1A protein expression by immunohistochemistry. The correlations between the loss of ARID1A expression and clinicopathological characteristics, prognosis, and chemosensitivity were investigated. Loss of ARID1A expression was identified in 9 (15.0%) of 60 ovarian clear cell carcinoma samples. Loss of ARID1A staining intensity (0+) was more frequently found in cells of clear cell carcinomas than in high-grade serous carcinomas (P<0.01). Loss of ARID1A expression was significantly correlated with advanced FIGO stage and high CA125 levels (P=0.02, 0.01). There were no significant correlations between loss of ARID1A expression and patient age, status of residual tumor, Ki-67 labeling index, or the status of endometriosis. Loss of ARID1A correlated with shorter progression-free survival of patients with clear cell carcinomas treated with platinum-based chemotherapy (P<0.01). Loss of ARID1A expression tended to correlate with shorter overall survival in patients with ovarian clear cell carcinomas treated with platinum-based chemotherapy. When data were stratified for the multivariate analysis, only the loss of ARID1A expression remained a significant (P=0.03) predictor of reduced progression-free survival. Of the 60 patients with ovarian clear cell carcinomas, 14 patients had measurable residual tumor after primary cytoreductive surgery. Tumors with loss of ARID1A expression were more likely to be chemoresistant than tumors with positive ARID1A expression (100.0 vs 40.0%, P=0.04). This study demonstrates that loss of ARID1A in ovarian clear cell carcinoma is a negative prognostic factor in patients treated with platinum-based chemotherapy. Measurement of ARID1A expression may be a method to predict resistance to platinum-based chemotherapy in patients with ovarian clear cell carcinoma.     

Overexpression of β-catenin and cyclinD1 predicts a poor prognosis in ovarian serous carcinomas

Ovarian serous cancer is the most common subtype of epithelial ovarian cancer, and is the leading cause of death from gynecologic cancer. There is an important need for exploration of diagnostic and prognostic markers for this disease. β-catenin and cyclinD1 play central roles in the tumorigenesis for certain cancers. The role of β-catenin and cyclinD1 in diagnosis and prognosis of ovarian serous carcinoma is uncertain. In the present study, the expression of β-catenin and cyclinD1 was examined in 60 ovarian serous carcinomas patients with immunohistochemical staining. The relationship between expression of β-catenin and cyclinD1 and FIGO stage, pathological grade was analyzed. Kaplan-Meier survival function was used to analyze the prognosis. Overexpression of β-catenin is more often detected in patients with FIGO stage III and IV than in those with stage I, and II (P=0.003). No significant relationship was found between expression of β-catenin and pathological grade (P=0.817). Positive expression of β-catenin related to lower survival rate (P=0.034). The expression of cyclinD1 had no relationship with FIGO stage (P=0.829). Overexpression of cyclinD1 was positively to pathological grade (P=0.017) and survival rate (P=0.009). There is a significantly positive relationship between expression of β-catenin and cyclinD1 (P=0.014). No statistical significance was found between expression of β-catenin and cyclinD1 and other pathological parameters. Conclusions: Expression of β-catenin and cyclinD1 may be used as predict markers for poor prognosis.     

Decreased CD44 standard form expression correlates with prognostic variables in ovarian carcinomas.

Expression of CD44 standard form (CD44s) was evaluated by automated immunohistochemical analysis using the anti-CD44 A3D8 clone in 101 ovarian epithelial neoplasms including 82 primary tumors (64 carcinomas and 18 tumors of low malignant potential [LMP]), 9 lymph node metastases, 8 malignant ascites, and 2 peritoneal implants. Immunostaining was scored semiquantitatively. Tumors were graded according to the FIGO (International Federation of Gynecology and Obstetrics) classification system. Tumor stage and patient survival were determined from the patient records. While 9 of 18 LMP tumors expressed CD44s, only 15 of 64 carcinomas expressed it. In the carcinomas, univariate analysis revealed that decreased CD44s expression correlated with high tumor grade, advanced stage, and shortened survival. Loss of CD44s expression also was noted in the tumor cells in 8 of 9 lymph node metastases, 7 of 8 malignant ascites, and 1 of 2 implants. Multivariate analysis revealed that only tumor stage independently correlated with patient survival. Loss of CD44s expression determined by immunohistochemical analysis is more common in ovarian carcinomas than in LMP tumors; correlates with prognostic variables including tumor grade, stage, and survival; and may have an important role in the dissemination of ovarian cancer.     

Expression of survivin is associated with malignant potential in epithelial ovarian carcinoma

Survivin is a new member of the inhibitor of apoptosis family of anti-apoptotic proteins. It has been reported that survivin is expressed during fetal development and in cancer tissues. Because suppression of apoptosis is important for carcinogenesis and tumor growth, we investigated the expression of survivin in human endometrial carcinomas. We analyzed serial frozen sections for survivin protein expression in 26 patients with ovarian epithelial carcinoma and 10 patients with benign cystadenoma of the ovary by fluorescent immunohistochemistry. We analyzed the relationship between the percentages of survivin-stained cells and the characteristics of the patient including histological classification, clinical stage, histological grade, and clinical outcome. Survivin was weakly detected in some benign ovarian cystadenomas (0-12.1%). There was, however, abundant survivin immunoreactivity in the nucleus and/or cytoplasm of the epithelial ovarian carcinoma cells. Scoring on the basis of the percentage of positive cells indicated that survivin expression was significantly associated with PCNA-labeling index, clinical stage, histological grade, clinical outcome, and survival rate (p<0.01, respectively). We conclude that the survivin protein is a defining diagnostic marker for epithelial ovarian carcinomas that may also yield prognostic information.     

Alpha-methylacyl-CoA racemase (AMACR) expression in epithelial ovarian cancer

Alpha-methylacyl-CoA racemase (AMACR) is involved in the cellular metabolism of fatty acids. It is a prognostic factor in prostate and colorectal cancer. So far, little is known about its expression and prognostic role in ovarian cancer. We investigated the expression of AMACR in a total of 420 ovarian tumors (388 carcinomas, 32 borderline tumors) by immunohistochemistry on tissue microarrays of two independent patient cohorts. In both cohorts, cytoplasmic AMACR expression was identified in 11.8% (16/136) and 5.4% (13/239), respectively, of the ovarian carcinomas. In contrast, borderline tumors did not show any AMACR expression. AMACR expression was significantly associated with histological subtype, FIGO stage, and grade in one cohort and low estrogen receptor levels in the other cohort. In univariate analysis, AMACR expression was significantly associated with poor overall survival (log rank, p = 0.006) and an independent prognostic factor in a multivariate analysis (HR 3.3; CI 1.3–7.9; p = 0.008) but could not be verified in the second cohort. Unlike in other tumor entities, AMACR expression does not seem to have an unequivocal prognostic impact in ovarian cancer. The prevalence may limit the value of AMACR for the differential diagnosis between metastatic colorectal carcinomas and primary ovarian carcinomas, whereas the association with estrogen receptor expression deserves further studies.     

Foxp3,TGF-β1,VEGF,CD3-ζ和IL-10在卵巢上皮性癌中的表达与预后相关分析

 目的 研究叉头蛋白 3（Foxp3）、转化生长因子 β1（TGF- β1）、血管内皮生长因子（VEGF）、CD3-ζ、IL-10 等免疫抑制因子的表达强度与卵巢上皮性癌预后的相关性。 方法 采用免疫组织化学 SP 法，检测 5 种因子分别在79 例卵巢上皮性癌、16 例卵巢交界性肿瘤、30 例卵巢良性肿瘤和 20 例正常卵巢组织中的表达情况，应用计算机图像分析系统和人工半定量评分方法分别对 Foxp3、TGF-β1 和 VEGF、CD3-ζ、IL-10 的表达结果进行评判，并分析 5 种因子在卵巢上皮性癌中表达强度相互之间的相关性，及其表达强度与卵巢上皮性癌预后的相关性。 结果 TGF-β1 在正常卵巢组织中的表达强度明显低于卵巢上皮性癌、卵巢交界性肿瘤和卵巢良性肿瘤组织（P = 0.009），而其他 4 种因子在卵巢上皮性癌组织中的表达强度均明显高于卵巢交界性肿瘤、卵巢良性肿瘤和正常卵巢组织（均 P < 0.001）。TGF-β1 的表达强度只与 CD3-ζ 有关（P = 0.001），CD3-ζ 的表达强度与其他 4 种因子均有关（P < 0.01），Foxp3、VEGF、IL-10 的表达强度相互之间均具有明显的相关性（均 P < 0.01）。Foxp3 和 TGF-β1 的表达强度均与卵巢上皮性癌的总生存期有关（P 值分别为 0.010、0.013），而 VEGF、CD3-ζ、IL-10 的表达强度均与卵巢上皮性癌的总生存期无相关性；Logistic 回归分析显示，TGF-β1、术后残余和化疗规范性为卵巢上皮癌的 3 个重要预后因素（P < 0.05）；在卵巢上皮性癌中，TGF-β1 的表达强度与患者年龄、FIGO 分期、病理分级、术后残余、淋巴结转移以及化疗规范性等病理特征均无相关性。 结论 5 种免疫抑制因子在卵巢上皮性癌组织中均呈高表达，Foxp3 和 TGF-β1 的表达强度与卵巢上皮性癌的预后有关。     

Prognostic and predictive values of Nrf2, Keap1, p16 and E-cadherin expression in ovarian epithelial carcinoma

Objectives: Despite considerable interest in the Nuclear factor-erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein-1 (Keap1), p16 and epithelial cadherin (E-cadherin) activation in carcinoma progression, contradictory results regarding association of Nrf2/Keap1/E-cadherin and p16 expression with clinico-pathological features and prognosis have been reported. The predictive value of these markers in ovarian carcinoma is unknown. Methods/Materials: In this retrospective study, 108 cases were evaluated immunohistochemically with antibodies to Nrf2, Keap1, estrogen receptor (ER), p16 and E-cadherin. The results were compared with histological and clinical data, disease-free survival (DFS) and overall survival (OS). Results: A cohort of 108 ovarian carcinomas (47 serous, 23 mucinous, 13 endometrioid and 25 clear cell), including 68 FIGO stage I-II cases and 40 FIGO stage III-IV cases was studied. The age of patients (P=0.005), FIGO stage (P<0.001), immunohistochemical expression of Keap1 (P<0.000), E-cadherin (P=0.045), p53 (P=0.003), p16 (P<0.001) and ER (P=0.004) were significant factors between different histological subtypes. Patients with serous carcinoma were older in age, presented with more advanced stage disease, worst prognosis, highest Keap1 expression and least percentage of E-cadherin immunoreactivity. In univariate analysis, FIGO staging (P=0.000 for DFS; P=0.000 for OS), Nrf2 (P=0.010 for DFS; P=0.001 for OS), and p16 (P=0.004 for DFS; P=0.019 for OS) were associated with worse prognosis. After multivariate analysis, FIGO staging and Nrf2 remained significance prognostic factors. Conclusions: There were differences in the expression of Nrf2, Keap1, p16 and E-cadherin between different ovarian carcinoma subtypes. In multivariate analysis, FIGO stage and Nrf2 expression were associated with poorer DFS and OS.     

Increased expression of microRNA-196a predicts poor prognosis in human ovarian carcinoma

Objective: Overexpression of MicroRNA-196a (miR-196a) has recently been reported in different types of human cancers. However, the prognostic value of miR-196a in ovarian carcinoma remains unknown. In this study, we investigated the expression of miR-196a in ovarian carcinoma and its relationship with tumor progression and clinical prognosis. Methods: The expression level of miR-196a was examined by quantitative Real-time PCR (qRT-PCR) in surgically removed ovarian cancer tissues and ovarian cancer cell lines. The correlation between miR-196a expression and clinical features and prognosis were statistically analyzed. Results: The results showed that the miR-196a expression was significantly upregulated in tumor tissues and ovarian cancer cell lines compared with that in normal ovarian surface tissues and normal ovarian epithelial cells. Moreover, miR-196a expression was positively correlated with FIGO stage (P <0.001), tumor size (P =0.020), and lymph nodes metastasis (P =0.019). Kaplan-Meier analysis demonstrated that high levels of miR-196a expression was associated with poorer overall survival (P <0.001) and recurrent-free survival (P =0.003), especially in patients with advanced disease (P =0.002). Multivariate analysis suggested that miR-196a expression was an independent prognostic factor for overall survival of patients with ovarian carcinoma. Conclusions: In conclusion, miR-196a may play an important role in the progression of ovarian carcinoma, and could be used as an independent prognostic biomarker for patients with ovarian carcinoma.     

Prognostic value of tissue protein expression levels of MIB‐1 (Ki‐67) in Danish ovarian cancer patients. From the ‘MALOVA’ ovarian cancer study

The primary objective of this study was to assess the expression of MIB‐1 (Ki‐67) in tumour tissues from 808 patients with epithelial ovarian tumours. The second was to evaluate, whether MIB‐1 (Ki‐67) tissue expression levels correlate with clinicopathological parameters and prognosis of the disease. Using tissue arrays (TA), we analysed the MIB‐1 (Ki‐67) expression levels in tissues from 202 women with borderline ovarian tumours (BOT) (177 stage I, 5 stage II, 19 stage III, 1 stage IV) and 606 ovarian cancer (OC) patients (177 stage I, 64 stage II, 311 stage III, 54 stage IV). Using a 10% cut‐off level for MIB‐1 (Ki‐67) overexpression, 12% of the BOTs and 51% of the OCs were positive for MIB‐1 (Ki‐67) expression. The frequency of MIB‐1 (Ki‐67) expression‐positive OC increased with increasing FIGO stage (p = 0.003), increasing histological grade (p ≤ 0.0001), and a significantly different distribution of MIB‐1 (Ki‐67) positive and negative tumours were found in adenocarcinoma NOS, serous adenocarcinomas, mucinous adenocarcinomas, endometrioid adenocarcinomas, non‐epithelial and clear‐cell carcinomas (p = 0.016). Univariate Kaplan–Meier survival analysis performed on all OC cases showed a significant shorter disease specific survival in patients with positive MIB‐1 (Ki‐67) expression in the tumour tissue (p ≤ 0.0001). In a Cox survival analysis including 606 FIGO stages I to IV OC cases, FIGO stage (II vs I: HR = 3.00, 95% CI: 1.81–4.99, III–I: HR = 6.41, 95% CI: 3.90–10.50, IV vs I: HR = 12.69, 95% CI: 7.21–22); age at diagnosis pr.10 years (HR = 1.27, 95% CI: 1.15–1.40), residual tumour after surgery (HR = 1.95, 95% CI: 1.40–2.73) and MIB‐1 (Ki‐67) expression (HR = 1.31, 95% CI: 1.08–1.60) had a significant independent impact on survival. Histological grade (p = 0.14) and histological tumour type (p = 0.35) had no significant independent impact on survival. In conclusion, our results predict that an increased level of MIB‐1 (Ki‐67) expression in tumour tissue, points to a less favourable outcome for OC patients.     

c-kit蛋白和血小板源生长因子受体α在卵巢上皮性肿瘤中的表达

目的探讨c-kit蛋白、血小板源生长因子受体α(PDGFRα)在卵巢上皮性肿瘤中的表达及其与卵巢癌临床病理的关系.方法采用免疫组织化学法(SP法)检测c-kit蛋白、PDGFRα,分析c-kit蛋白、PDGFRα在卵巢上皮性肿瘤中的表达与肿瘤分型、分化程度及国际妇产科联盟(FIGO)分期的关系.结果(1)c-kit蛋白在卵巢上皮性癌中表达的阳性率为50.70%,明显高于正常卵巢组织(10.00%)及良性卵巢肿瘤(20.00%)(P均<0.01).PDGFRα在卵巢上皮性癌中表达的阳性率为63.38%,明显高于正常卵巢组织(15.00%)及良性卵巢肿瘤(25.00%)(P均<0.01).(2)c-kit蛋白在浆液性卵巢癌中表达的阳性率高于黏液性卵巢癌(57.63%比16.67%,P<0.05),而PDGFRα在浆液性及黏液性卵巢癌中表达阳性率筹异无统计学意义(P>0.05).低分化卵巢癌组c-kit蛋白及PDGFRa表达的阳性率明显高于高中分化卵巢癌组(69.23%比40.00%,80.77%比53.33%,P<0.05).在Ⅲ～Ⅳ期与Ⅰ～Ⅱ期卵巢癌中c-kit蛋白及PDGFRα表达的阳性率差异无统计学意义(P>0.05).(3)卵巢上皮性癌的c-kit蛋白和PDGFRα表达无相关性(P>0.05).结论 c-kit蛋白与PDGFRα的表达与卵巢上皮性癌细胞的分化程度相关联.对c-kit蛋白与PDGFRα的检测可用于判断卵巢上皮性肿瘤的恶性程度及其预后.