Heparanase expression correlates with poor survival in metastatic ovarian carcinoma

OBJECTIVE: To analyze the expression of Heparanase, an enzyme involved in cancer metastasis and angiogenesis, in ovarian and breast carcinoma cells in effusions. METHODS: Heparanase protein expression was analyzed in malignant effusions from ovarian (=200) and breast (=41) carcinoma patients using immunocytochemistry. The levels of secreted heparanase were analyzed in 45 effusion supernatants using a newly established ELISA test. Heparanase expression levels were analyzed for clinical significance. RESULTS: Heparanase was expressed at the cell membrane in 106/200 (53%) ovarian and 22/41 (54%) breast carcinomas. Cytoplasmic expression was found in 180/200 (90%) ovarian and 26/41 (63%) breast carcinomas. Reactive mesothelial cells showed frequent cytoplasmic, but not membrane expression. ELISA showed secreted heparanase in all 45 analyzed effusions. Higher levels were detected in peritoneal compared to pleural effusions (p=0.031). In univariate survival analysis of ovarian carcinoma patients with post-chemotherapy effusions, membrane expression in >5% of tumor cells correlated with shorter overall survival (OS, p=0.013). FIGO stage (p=0.03 for all patients, p=0.045 for those with post-chemotherapy specimens) and response to first-line chemotherapy (p<0.0001 for all patients, p=0.049 for those with post-chemotherapy specimens) were the clinical parameters related to OS. In Cox analysis of this subset of patients, heparanase expression (p=0.02) and response to chemotherapy (p=0.049) were independent predictors of poor OS. Heparanase expression did not correlate with survival in breast carcinoma. CONCLUSIONS: Our data show that heparanase is frequently expressed in metastatic gynecologic adenocarcinomas, and that it is secreted into the effusion fluid in body cavities. The correlation between heparanase expression and poor survival in ovarian carcinoma suggests a role for this molecule in ovarian cancer metastasis and supports its role as a marker of aggressive clinical behavior at disease recurrence.     

Multidrug resistance-related phenotype and apoptosis-related protein expression in ovarian serous carcinomas

OBJECTIVE: Multidrug resistance (MDR) to chemotherapy is a major obstacle in attempts to improve the clinical outcome of ovarian carcinoma patients. The MDR-related phenotype is associated with over-expression of certain drug transporters, such as P-glycoprotein (P-gp), multidrug resistance protein 1 (MRP1), and lung resistance protein (LRP). The aim of this study was to evaluate the extent and prognostic significance of MDR-related protein expression in ovarian serous carcinomas. In addition, we correlated expression of these proteins with the apoptosis-related proteins p53, bcl-2, and bax. METHODS: Consecutive sections from 60 cases of ovarian serous carcinoma were assessed immunohistochemically for expression of P-gp, MRP1, LRP, p53, bcl-2, and bax. The level of protein expression was scored based on staining intensity and extent. RESULTS: Strong P-gp expression was observed in 12 (20%), MRP1 in 39 (65%), LRP in 27 (45%), p53 in 45 (75%), bcl-2 in 25 (41.7%), and bax in 30 (50%) of the 60 tumors. MRP1 expression was associated with both p53 and bcl-2 expressions (P = 0.01 and P = 0.03, respectively). Univariate analysis of survival revealed a significant inverse correlation between P-gp expression and patient survival (P = 0.015). Moreover, P-gp expression was significantly increased in tumors of patients unresponsive to chemotherapy (P = 0.009). Multivariate analysis revealed that only FIGO stage and P-gp expression were useful negative independent predictors of survival (P = 0.035 and P = 0.045, respectively). CONCLUSIONS: Our pilot study demonstrates that P-gp expression may be a reliable independent prognostic factor of survival in patients with ovarian serous carcinoma. Moreover, P-gp immunostaining may be useful for dividing ovarian carcinoma patients into chemoresponsive and chemoresistant groups.     

The PAC-1 dual specificity phosphatase predicts poor outcome in serous ovarian carcinoma

OBJECTIVE: Data regarding signal transduction pathways in human tumors are largely confined to cell line studies to date. We have recently reported on the activation and prognostic role of mitogen-activated protein kinases (MAPK) in ovarian carcinoma in effusions. The objective of the present study was to investigate the expression and clinical role of dual-specificity phosphatases (DUSP), inhibitors of MAPK signaling, in ovarian cancer cells at this site. METHODS: Thirty-nine fresh frozen malignant effusions from patients diagnosed with serous ovarian carcinoma were studied for mRNA expression of the DUSP MKP-1, MKP-4, MKP-5, and PAC-1 using RT-PCR. DUSP expression was analyzed for possible correlation with patient age, disease stage, tumor grade, histological grade, chemotherapy status, and survival. RESULTS: MKP-1 and PAC-1 mRNA were found in 36 and 37 effusions, respectively, with expression levels showing considerable variation. MKP-4 and MKP-5 were uniformly absent. MKP-1 showed no association with clinicopathologic parameters. However, PAC-1 expression was significantly higher in effusions obtained before the institution of treatment with both platinum compounds (P = 0.029) and paclitaxel (P = 0.036). In univariate survival analysis, high level of expression of PAC-1 mRNA predicted significantly worse overall survival compared to low expression (mean = 30 vs. 52 months, median = 25 vs. 46 months) (P = 0.007). CONCLUSIONS: Despite the limited size of this cohort, our results present the first evidence supporting a clinical role for PAC-1 in ovarian carcinoma. In view of the improved outcome associated with activation of all three MAPK families, as well as their elevated expression and activation in post-chemotherapy specimens presented in our previous work, they also suggest that PAC-1 is a true negative regulator of MAPK in ovarian carcinoma cells in effusions.     

E-Cadherin complex protein expression and survival in ovarian carcinoma

OBJECTIVE:The aim of this study was to analyze the correlation between expression of E-cadherin complex proteins, epidermal growth factor receptor (EGFR), and c-erbB-2 and disease outcome in advanced-stage ovarian carcinomas. METHODS: Sections from 75 primary ovarian carcinomas (=37) and metastatic lesions (=38) from 45 patients diagnosed with advanced-stage ovarian carcinoma (FIGO stage III-IV) were immunostained and evaluated for staining pattern, extent, and intensity. Patients were divided in two groups based on disease outcome. Long-term survivors (21 patients) and short-term survivors (24 patients) were defined using a double cutoff of 36 months for disease-free survival (DFS) and 60 months for overall survival (OS). Mean follow-up period was 70 months. The mean values for DFS and OS were 109 and 125 months for long-term survivors, as compared to 3 and 21 months for short-term survivors, respectively. RESULTS: Comparison of all primary and metastatic lesions showed upregulation of gamma-catenin protein expression in the latter (P = 0.05). When segregated according to disease outcome, the expression of all studied proteins, with the exception of EGFR, was more diffuse in tumors of short-term survivors. The presence of cytoplasmic staining for c-erbB-2 was associated with poor survival in the entire cohort (P = 0.007), as well as in primary tumors alone (P = 0.003), in survival analysis. Similar results were seen in the evaluation of primary tumors for gamma-catenin (P = 0.002). CONCLUSIONS: gamma-Catenin, and possibly c-erbB-2, are valid markers of poor survival in advanced-stage ovarian carcinoma.     

HLA-G expression in effusions is a possible marker of tumor susceptibility to chemotherapy in ovarian carcinoma

OBJECTIVE: We recently showed that the levels of secreted human leukocyte antigen-G (HLA-G), a nonclassical MHC class I antigen, are significantly elevated in malignant effusions in ovarian carcinoma compared to benign ones. The objective of this study was to evaluate the expression and clinical role of HLA-G in effusions and corresponding solid tumors from patients diagnosed with advanced-stage ovarian carcinoma. METHODS: Effusions (= 148), corresponding primary tumors (= 66), and metastatic lesions (= 122) were analyzed using immunohistochemistry with an anti-HLA-G monoclonal antibody. RESULTS: HLA-G was detected in cancer cells in 49/148 (33%) effusions, 33/66 (50%) primary tumors, and 59/122 (48%) solid metastases. These differences did not reach statistical significance. Expression in effusions and solid metastases significantly correlated (P = 0.029). HLA-G expression in tumor cells was significantly lower in effusions obtained during or following chemotherapy (P = 0.038). The presence of HLA-G-positive tumor cells in effusions obtained prior to the institution of chemotherapy correlated with better overall survival (P = 0.042). HLA-G expression in primary tumors and solid metastases did not correlate with any of the clinicopathologic parameters studied. CONCLUSIONS: HLA-G is expressed in a significant number of ovarian carcinomas at all anatomic sites. The reduced expression of HLA-G in post-chemotherapy effusions and its correlation with improved survival may be related to preferential susceptibility of HLA-G-expressing cells at this site. Our findings suggest a new role for HLA-G as a prognostic indicator in advanced-stage ovarian cancer in effusions.     

膜联蛋白A8在卵巢上皮性浆液性肿瘤中的表达及临床意义

目的:检测膜联蛋白A8(Annexin A8,ANXA8)在卵巢组织中的表达,探讨其表达与卵巢上皮性浆液性恶性肿瘤患者临床病理参数及预后的相关性。方法:采用免疫组织化学法检测75例卵巢组织(正常卵巢组织组11例、卵巢浆液性良性肿瘤组13例、卵巢浆液性交界性肿瘤组17例、卵巢浆液性恶性肿瘤组34例)中ANXA8的表达,分析其与卵巢癌患者临床病理参数及疾病预后的关系。结果:ANXA8主要定位于细胞膜及细胞质,ANXA8在卵巢浆液性恶性肿瘤组中的高表达率(23/34,67.65%)明显高于正常卵巢组织组(1/11,9.09%)、卵巢浆液性良性肿瘤组(3/13,23.08%)及卵巢浆液性交界性肿瘤组(5/17,29.41%),差异有统计学意义(P分别为0.001、0.006、0.010)。在34例卵巢浆液性恶性肿瘤患者中,FIGOⅢ~Ⅳ期患者的ANXA8的高表达率(21/24,87.5%)明显高于FIGOⅠ~Ⅱ期患者(2/10,20.0%),差异具有统计学意义(P<0.001);盆腹腔残余病灶直径>1 cm患者的ANXA8高表达率(15/17,88.2%)明显高于残余病灶≤1 cm患者(8/17,41.2%),差异有统计学意义(P=0.010)。Kaplan-Meier生存分析表明,FIGO分期、淋巴转移、残余病灶、ANXA8的表达都是影响总生存期(OS)的重要因素(均P<0.05)。Cox多元回归分析表明ANXA8的高表达是影响卵巢浆液性恶性肿瘤患者预后的独立危险因素(P=0.019,HR=11.465,95%CI:1.498~87.757)。结论:ANXA8在卵巢上皮性浆液性恶性肿瘤组织中表达升高,且与卵巢癌不良预后有关,可用于临床监测卵巢上皮性浆液性恶性肿瘤患者病情变化。     

Immunohistochemical staining of the mismatch repair gene, hMSH2, and survival in patients with ovarian carcinoma

OBJECTIVE: hMSH2 is a mismatch repair gene. The protein of this gene can be demonstrated by immunohistochemical methods. The authors wanted to analyze whether the percent of positive nuclear area staining of the hMSH2 protein correlated with survival in patients with ovarian carcinoma. METHODS: One hundred and two patients with epithelial ovarian carcinoma were studied. Slides were prepared from snap frozen tissue. Quantification of staining and DNA index were performed using image analysis. In addition to hMSH2, FIGO stage, grade, histology, and level of cytoreduction were analyzed as prognostic factors. RESULTS: Mean follow-up was 64 months and median was 59 months. Nineteen patients had stage I cancers, 4 stage II, 59 stage III, and 20 stage IV. Optimal cytoreduction was accomplished in 71% of patients. hMSH2 staining was significantly higher in better differentiated tumors (p=0.006), but there was no difference in staining among the FIGO stages (p=0.43). Cox regression analysis revealed FIGO stage (p=0.0005), level of cytoreduction (p=0.006) and hMSH2 staining (p=0.016) to be independent predictors of survival in patients with ovarian carcinoma. CONCLUSION: The hMSH2 protein can be demonstrated by immunohistochemical methods and quantified by image analysis. hMSH2 staining was shown to be an independent prognostic indicator of survival in patients with ovarian carcinoma.     

Expression of cell cycle proteins in ovarian carcinoma cells in serous effusions-biological and prognostic implications

OBJECTIVE: The aim of this study was to investigate the expression of cell cycle proteins in ovarian carcinoma cells in serous effusions and respective solid tumors. METHODS: Fifty-five malignant effusions and 38 tumors (20 primary, 18 metastatic) were immunohistochemically stained for cyclin A, p27(kip1), and Ki-67. Staining extent (0-100% cells) and intensity (0-3 scale) were scored. Cyclin A and p27(kip1) expression was additionally studied in 29 malignant effusions using immunoblotting. Immunohistochemistry results in effusions were evaluated for possible association with clinicopathologic parameters. RESULTS: Nuclear immunoreactivity for all markers was detected on carcinoma cells in the majority of effusions using immunohistochemistry. Similarly, immunoblotting showed the presence of cyclin A and p27(kip1) in 29/29 and 25/29 specimens, respectively. Intense (3) immunoreactivity for Ki-67 was detected more often in peritoneal effusions, compared with those of pleural location (P = 0.036). Staining in primary and metastatic lesions was generally comparable to that of tumor cells in effusions. Staining for p27(kip1) was more diffuse in effusion specimens obtained prior to the institution of chemotherapy (P = 0.042). In an analysis of all effusions, an association was observed between the number of cells that were immunoreactive for Ki-67, cyclin A, and p27(kip1) (cyclin A-Ki-67: P = 0.008; p27(kip1)-Ki-67: P = 0.019; cyclin A-p27(kip1): P = 0.032). In survival analysis, the presence of more diffuse (P = 0.042) and intense (P = 0.019) staining for cyclin A correlated with prolonged overall survival. CONCLUSIONS: The expression of the studied cell cycle markers does not differ markedly between ovarian carcinoma cells in the pleural and peritoneal cavity, supporting our previous studies of several metastasis-associated molecules. The presence of cyclin-A-positive cell populations is associated with a more favorable disease outcome, possibly due to the targeting of proliferating cells by chemotherapeutic agents. However, the decline in the fraction of p27(kip1)-positive cells in posttreatment specimens may point to additional mechanisms involved in this selection.     

p53 Expression as a Prognostic Indicator of 5-Year Survival in Endometrial Cancer

BACKGROUND: One of the most common genetic alterations to occur in human cancers is an alteration of the p53 tumor suppressor gene. The purpose of this article was to build upon the authors' previous work with p53 and determine whether p53 was a prognostic indicator of 5-year survival. METHODS: One hundred thirty-seven consecutively surgically treated patients with endometrial cancer had their p53 expression studied by immunoperoxidase staining and quantified by image analysis. All patients were evaluable for 5-year survival. RESULTS: One hundred three patients had endometrioid adenocarcinoma; 6, adenosquamous carcinoma; 14, papillary serous carcinoma; 10, clear cell carcinoma; and 4, undifferentiated carcinoma. p53 expression ranged from 0.0 to 58.2% positive nuclear area with a mean of 11.5% (median 2.6%) for the cohort. For the patients with endometrioid carcinoma, the mean p53 expression was 7.1% while for the nonendometrioid tumors it was 24.6% (P<0.001). Fifty-nine of the 103 endometrioid tumors (57.3%) stained positive for p53 while 32 of the 34 nonendometrioid (94.1%) tumors stained positive (P<0.001). Increasing histologic grade correlated with an increasing p53 expression (P = 0.003). The percentage of tumors expressing p53 was found to be higher in FIGO stage II, III, and IV than in FIGO stage I cancer (P = 0.003). However, mean p53 expression did not differ between early (stage I) and advanced (stage II, III, and IV) cancers (P = 0.088). Utilizing 5-year survival as the endpoint for multivariate analysis, FIGO stage (P = 0.0028) and p53 expression (P<0.001) were the only independent prognostic indicators found. CONCLUSION: p53 expression is more commonly found in nonendometrioid than in endometrioid adenocarcinoma of the endometrium. It, along with FIGO stage, is an independent prognostic indicator of 5-year survival.     

MIB-1: a predictor of survival in patients with ovarian carcinoma

Geisler JP, Geisler HE, Wiemann MC, Zhou Z, Miller GA, Crabtree W. MIB-1: A predictor of survival in patients with ovarian carcinoma. Int J Gynecol Cancer 1998; 8 : 392–396.
Objective: MIB-1, a monoclonal antibody, reacts with the Ki-67 antigen, functioning as a marker of proliferation index. This study was carried out to determine whether MIB-1 staining, using image analysis, was a prognostic indicator in patients with ovarian carcinoma.
Methods: The tumors from 93 consecutive patients receiving primary surgical therapy for ovarian cancer were evaluated with MIB-1. Staining was quantified by image analysis. The patients were followed for a mean of 41 months (median, 37 months; minimum, 27 months; maximum, 68 months). Their charts were reviewed to determine survival, histologic type, grade, stage, and level of cytoreduction.
Results: Seventy-three patients had serous carcinomas, eight clear cell carcinomas, four endometrioid carcinomas, four mucinous carcinomas, two transitional carcinomas, and two undifferentiated carcinomas. Sixteen patients had stage I disease, four patients had stage II disease, 53 patients had stage III disease, and 20 patients had stage IV disease. Thirty-nine patients died within the observation period of the study. The MIB-1 staining of those patients alive at the conclusion of the study (28.3%) was significantly less than the MIB-1 staining of those who died (42.6%) ( P < 0.001). No patient whose tumor had MIB-1 staining of less than 22.0% died during the observation period of the study. MIB-1 staining less than 22.0% ( P = 0.020), FIGO stage ( P = 0.025), and the level of cytoreduction ( P = 0.0006) were independent predictors of survival.
Conclusion: In this series of 93 patients with ovarian carcinoma, MIB-1 monoclonal antibody staining was shown to be an independent prognostic indicator of survival. No patient whose tumor stained less than 22% positive nuclear area for MIB-1 died of her ovarian carcinoma.     

Wee1 is a novel independent prognostic marker of poor survival in post-chemotherapy ovarian carcinoma effusions

Objective

Wee1-like kinase (Wee1) is a tyrosine kinase which negatively regulates entry into mitosis at the G2 to M-phase transition and has a role in inhibition of unscheduled DNA replication in S-phase. The present study investigated the clinical role of Wee1 in advanced-stage (FIGO III–IV) ovarian serous carcinoma.

Methods

Wee1 protein expression was analyzed in 287 effusions using immunohistochemistry. Expression was analyzed for association with clinicopathologic parameters, including survival. Forty-five effusions were additionally studied using Western blotting. Wee1 was further silenced in SKOV3 and OVCAR8 cells by siRNA knockdown and proliferation was assessed.

Results

Nuclear expression of Wee1 in tumor cells was observed in 265/287 (92%) and 45/45 (100%) effusions by immunohistochemistry and Western blotting, respectively. Wee1 expression by immunohistochemistry was significantly higher in post-chemotherapy disease recurrence compared to pre-chemotherapy effusions obtained at diagnosis (p = 0.002). Wee1 silencing in SKOV3 and OVCAR8 cells reduced proliferation. In univariate survival analysis of the entire cohort, a trend was observed between high (> 25% of cells) Wee1 expression and poor overall survival (p = 0.083). Survival analysis for 109 patients with post-chemotherapy effusions showed significant association between Wee1 expression and poor overall survival (p = 0.004), a finding which retained its independent prognostic role in Cox multivariate analysis (p = 0.003).

Conclusions

Wee1 is frequently expressed in ovarian serous carcinoma effusions, and its expression is significantly higher following exposure to chemotherapy. The present study is the first to report that Wee1 is an independent prognostic marker in serous ovarian carcinoma.     

p53 and bcl-2 in epithelial ovarian carcinoma: their value as prognostic indicators at a median follow-up of 60 months

OBJECTIVE: p53 is the most common tumor suppressor gene involved with human malignancies. Mutations in p53 are present in approximately 50% of human malignancies. bcl-2 is a protooncogene. Expression of its protein product is related to better prognosis in several malignancies. METHODS: One hundred and three patients with epithelial ovarian carcinoma were studied. Immunohistochemical staining using the pAb1801 monoclonal antibody to p53 and the anti-bcl-2 124 monoclonal antibody to bcl-2 was performed. Image analysis was used to measure percentage positive nuclear area staining of mutant p53. In addition to bcl-2 and p53, FIGO stage, grade, histology, and level of cytoreduction were analyzed as prognostic factors. Univariate as well as Cox regression analysis was performed. RESULTS: One hundred and three patients were followed for a mean of 60 months. Twenty patients had FIGO stage I disease, 4 stage II, 59 stage III, and 20 stage IV. Immunohistochemical staining for mutant p53 was not significantly related to DNA index (P = 0.99) but was related to increasing FIGO stage (P < 0.001) and increasing histologic grade (P = 0.039). Using Cox regression analysis, increased mutant p53 staining was an independent predictor of survival in these patients (P = 0.0032), along with stage (P < 0. 0001) and level of cytoreduction (P < 0.0001). Although by itself bcl-2 was not an independent prognostic indicator (P = 0.18), the combination of p53 and bcl-2 was independently predictive of survival (P = 0.038). CONCLUSION: This study confirms the authors' earlier report on the importance of p53 as a prognostic indicator of survival in ovarian carcinoma. Cox regression analysis reveals mutant p53 staining to be a better independent indicator of prognosis and survival in patients with ovarian carcinoma than the combination of bcl-2 and p53.     

SREBP1、ACLY在卵巢上皮性癌中的表达及临床意义

目的:研究胆固醇调节元件结合蛋白1(SREBP1)、ATP柠檬酸裂解酶(ACLY)在卵巢上皮性肿瘤组织中的表达,探讨其与患者临床病理参数和预后的相关性。方法:采用免疫组织化学法检测SREBP1、ACLY在卵巢良性肿瘤、卵巢交界性肿瘤和卵巢上皮性癌中的表达。结果:SREBP1、ACLY蛋白在卵巢上皮性癌组织中的阳性表达率(67.71%,70.83)显著高于卵巢良性肿瘤(31.25%,37.5%)、卵巢交界性肿瘤(13.33%,13.33%)(P<0.05)。卵巢上皮性癌组织中SREBP1、ACLY蛋白阳性表达率与FIGO分期、组织学分级明显相关(P<0.05);卵巢上皮性癌中SFEBP1蛋白表达与ACLY蛋白的表达呈正相关(r=0.83,P<0.001)。卵巢上皮性癌组织学分级、FIGO分期、SREBP1和ACLY表达水平均与患者预后有关(P<0.05),FIGO分期是影响卵巢癌患者预后的独立因素(P<0.05)。结论:SREBP1、ACLY蛋白与卵巢上皮性癌的发生、发展和预后有关。SREBP1、ACLY可能成为治疗卵巢癌的新靶点。     

葡萄糖转运蛋白1在卵巢上皮性癌组织中的表达及其与碱性成纤维生长因子、增殖细胞核抗原表达的关系

目的探讨卵巢上皮性癌组织中葡萄糖转运蛋白1(GLUT1 )的表达及其与碱性成纤维生长因子(bFGF)、增殖细胞核抗原(PCNA)表达的关系。方法采用免疫组化链霉菌抗生物素蛋白过氧化物酶连接法(SP法)检测6例正常卵巢、20例卵巢良性肿瘤、7例卵巢交界性肿瘤和44例卵巢上皮性癌组织中GLUT1、bFGF、PCNA的表达,并对GLUT1 与bFGF、PCNA表达的关系进行了相关性分析。结果GLUT1 在正常卵巢、卵巢良性肿瘤组织中不表达,而在卵巢交界性肿瘤及卵巢上皮性癌组织中阳性表达率分别为6 /7、91% (40 /44),卵巢上皮性癌组织中GLUT1 的阳性表达率明显高于卵巢交界性肿瘤组织(P<0 05)。卵巢上皮性癌组织中GLUT1 的阳性表达率与病理分级、手术病理分期、远处转移、淋巴结转移均呈明显正相关(P<0 01),而与病理类型无关(P=0 513)。在卵巢上皮性癌组织中,bFGF阳性表达25例,其中3例GLUT1 染色强度为( ++)、22例( +++);阴性表达19例,其中4例GLUT1 染色强度为( -)、4例( +)、8例( ++)、3例( +++),bFGF阳性表达者GLUT1 染色强度高于bFGF阴性表达者,差异有统计学意义(P<0 01)。GLUT1 染色强度与PCNA标记指数相关,GLUT1 染色强度为( +)、( ++)、( +++)的卵巢上皮性癌组织的PCNA标记指数分别为0 40、0 43、0 69,GLUT1 染色强度为( +++)的卵巢     

Prognostic value of matrix metalloproteinase-9 (gelatinase-B) expression in epithelial ovarian tumors

PURPOSE OF INVESTIGATION: To determine the expression of matrix metalloproteinase-9 (MMP-9) expression in malignant and borderline ovarian tumors and its correlation to prognosis. METHODS: Forty-five patients with primary epithelial ovarian tumors were enrolled in this retrospective study from 1988 to 2002. Only malignant (n = 30) and borderline (n = 15) ovarian tumors constituted the study group. All cases were surgically staged according to FIGO criteria. Patient characteristics and clinico-pathological findings were obtained from hospital records. Paraffin-embedded tissue blocks were treated with MMP-9 immunohistochemical stain. The percentage of the total number of tumors staining positively was categorised and awarded a score of 0 to 4: < 5% as 0, < or = 6-25% as 1, 26-50% as 2, 51-75% as 3 and 76-100% as 4. The intensity of immunostaining was scored on a 3-point scale: 1, weak; 2, moderate and 3, intense. A weighed score for each tumor specimen was produced by multiplying the percentage score with the intensity score and was defined as the 'epithelial MMP-9 score'. Stromal staining was also assessed as weak, moderate and intense. Cases with final epithelial MMP-9 scores < or = 6 and > 6 were then recategorised into two groups, accordingly. Based on degree of stromal staining, cases were recategorised into two final groups as mildly stained and intense or moderately stained. Tumor stages were regrouped as early (Stage I-II) and late (Stage III-IV), respectively. RESULTS: Mean ages of cases with malignant and borderline ovarian tumors were 57.2 +/- 3.1 and 49.7 +/- 2.1 years, respectively. Epithelial MMP-9 scores were higher in malignant tumors compared to borderline tumors (p = 0.014). However, with regard to stromal MMP-9 staining, no significant difference was observed among malignant and borderline tumors (p = 0.113). Among malignant ovarian tumors, epithelial MMP-9 scores did not differ between early versus late-staged and well versus poorly differentiated tumors. Median survival time of cases with epithelial MMP-9 scores < or = 6 and > 6 were 24 months and 32 months, respectively (log-rank: 0.93, p = 0.335). Cases with weak stromal MMP-9 staining had a longer median survival (48 months) compared to cases with moderate or intense stromal MMP-9 staining (24 months, log-rank: 4.46, p = 0.03). CONCLUSION: Epithelial MMP-9 expression generally appears in the malignant form of ovarian tumors compared to borderline tumors. MMP-9 expression in the stroma but not in the epithelium contributes to poor survival in ovarian cancers.     

A study of heat shock protein 27 in endometrial carcinoma

OBJECTIVE: Heat shock protein 27 (HSP27) is a relatively small protein produced in response to pathophysiologic stress. The purpose of this study was to determine prospectively whether HSP27 was associated with known prognostic factors in patients with endometrial carcinoma. METHODS: One hundred fifty-three consecutive patients with endometrial carcinoma were studied. Slides were prepared from fresh tissue. HSP27 was analyzed using a semiquantitative measurement. Patient records were examined for FIGO stage, grade, depth of myometrial invasion, histology, lymphovascular space invasion, time to recurrence, and survival. RESULTS: The mean follow-up was 53 months (median 56 months, range 30-68 months). Endometrioid tumors showed significantly higher HSP27 staining than nonendometrioid tumors (P = 0.005). Patients alive at the conclusion of this study had significantly higher mean HSP27 staining than patients who were deceased (P < 0.001). Logistic regression revealed HSP27 staining (P = 0.02), FIGO stage (P = 0. 014), and lymphovascular space invasion (P = 0.046) to be independently predictive of survival. CONCLUSION: HSP27 staining is significantly higher in endometrioid than nonendometrioid tumors. HSP27 staining is an independent prognostic indicator in patients with endometrial carcinoma, the most common gynecologic malignancy in the United States.     

HSP27 in patients with ovarian carcinoma: still an independent prognostic indicator at 60 months follow-up

OBJECTIVE: Heat shock protein 27 (HSP27) is produced in response to pathophysiologic stress in animal cells. The authors have previously shown that HSP27 is an independent prognostic indicator in patients with ovarian carcinoma. The present study was performed to see whether HSP27 remained an independent prognostic indicator with longer follow-up. METHODS: One hundred and three consecutive patients with epithelial ovarian carcinoma were studied. Slides were prepared from fresh tissue. HPS27 staining was performed as previously described. Patient records were examined for FIGO stage, grade, histology, level of cytoreduction and survival. RESULTS: One hundred and three patients were followed for a mean of 60 months. Twenty patients had FIGO Stage I disease, four Stage II, 59 Stage III, and 20 Stage IV. Immunohistochemical (IHC) staining for HSP27 was not related to histologic grade, level of cytoreduction or histologic subtype. A statistically significant decrease in HSP27 staining was found to correlate with increased FIGO stage (p = 0.008). Using cox-regression analysis, HSP27 staining (p = 0.025), stage (p = 0.0012), and level of cytoreduction (p < 0.0001) were independent predictors of survival in these patients. CONCLUSION: Cox-regression analysis found HSP27 to be an independent indicator of prognosis and survival in patients with ovarian carcinoma who had longer follow-up. Decreased HSP27 staining was related to decreased survival. This study confirms the authors' earlier report on the importance of HSP27 as a prognostic indicator in ovarian carcinoma.