Prognostic role of E-cadherin in patients with advanced serous ovarian cancer

Purpose

To analyse correlation between expression of E-cadherin and clinical and pathological features and overall survival in advanced-stage serous ovarian carcinoma.

Methods

The expression of E-cadherin was analysed immunohistochemically in formalin-fixed, paraffin-embedded samples from 54 patients with advanced-stage serous ovarian cancer and related to clinicopathological characteristics and patients survival. The clinicopathological characteristics included the stage according to the International Federation of Gynecology and Obstetrics (FIGO), tumour differentiation, number of mitoses per 10 high-power fields (HPF), residual tumour size, and vascular invasion. Only patients with serous ovarian cancer FIGO stages III–IV were included. Overall survival (OS) was defined as time from surgery to the last follow-up date on 01.10.2010. OS was evaluated using Kaplan–Meier method, and log-rank test was used to asses the differences between the positive and E-cadherin negative group. Multivariate analysis was completed using the Cox proportional hazard regression model.

Results

E-cadherin immunoreactivity was not associated with FIGO stage, tumour grade, number of mitotic figures per 10 HPF, residual tumour volume or vascular invasion. Negative E-cadherin expression significantly predicted shorter OS (p < 0.001). The multivariate analyses showed that negative E-cadherin (p < 0.001), FIGO stage (p = 0.012) and residual tumour size >1 cm after the initial cytoreductive surgery (p < 0.001) were predictors of shorter OS.

Conclusion

Negative E-cadherin expression like presence of residual tumour after primary cytoreductive surgery and higher FIGO stage seem to predict unfavourable clinical outcome in patients with advanced-stage serous ovarian cancer. Negative expression of E-cadherin was shown to be a significant independent predictor of poorer OS. E-cadherin as marker has prognostic value.     

Prognostic role of immunosuppressive acidic protein in advanced ovarian cancer

OBJECTIVE: Our purpose was to investigate immunosuppressive acidic protein in the prognostic characterization of advanced ovarian cancer. STUDY DESIGN: Serum levels of immunosuppressive protein were prospectively measured in 80 patients with untreated ovarian carcinoma. To evaluate the prognostic significance of immunosuppressive acidic protein levels, cutoff points were studied every 50 μg/ml between 450 and 1350 μg/ml. RESULTS: Pretreatment immunosuppressive acidic protein levels were not significantly associated with stage, histotype, grade of differentiation, postoperative residual tumor, and response to chemotherapy. The most significant association with survival was observed at a cutoff value of 1100 μg/ml (p = 0.0089). In the univariate analysis for overall survival, International Federation of Gynecology and Obstetrics stage and immunosuppressive acidic protein status were found to have a role in predicting ovarian cancer prognosis. In the multivariate analysis only immunosuppressive acidic protein status was significantly associated with survival. A statistical correlation was found between serum levels and overall survival (p = 0.0104, χ² 6.56), including immunosuppressive acidic protein as a continuous variable. CONCLUSION: Our data suggest that immunosuppressive acidic protein assay is a potentially useful tool in the prognostic characterization of advanced ovarian cancer. (Am J Obstet Gynecol 1996;175:1606-10.)     

Prognostic factors in patients with ovarian cancer]

350 patients with ovarian cancer were operated and irradiated postoperatively in the Center of Oncology in Kraków. 5-year survival with no recurrence was 41.7% (I.--77.3%, II.--44.1%, III.--7.7%). Stage, histological grade and residual volume tumor appears to be an important prognostic factors.     

Prognostic significance of Sphase fraction in ovarian cancer patients

INTRODUCTION: The established of prognostics factors in ovarian cancer patients can be used to predict the outcome of the disease, and gives possibilities to identified the group of patients who must be treated more aggressive. Some authors believe that (SPF) is prognostic factor in ovarian cancer. AIM OF THE STUDY: Evaluation of prognostic significance of S phase fraction in ovarian cancer patients determined by flow cytometric (FC) analysis. MATERIAL AND METHODS: Percent of S phase fraction by FC was investigated in group of 102 ovarian cancer patients from freshfrozen samples. FIGO: I--18 (17.65%), II--10 (9.8%), III--66 (64.7%), IV--8 (7.85%). Histopathologic grades (G): G1--u 30 (29.5%), (G2)--43 (42.16%), G3--26 (25.5%), Gx--2.94%). Serous tumours--66 (64.7%), endometrioid--5 (14.7%), undifferentiated--10 (9.8%), mucinous--7 (6.9%), clear cell tumours--4 (3.9%). The oldest patient was 82 and the youngest 24 mean 54 years. After primary citoreductive surgery patients was treated with intravenous chemotherapy 6 cycles. Tissue was fixed in liquid nitrogen (-195 degrees C), and after different period of time prepared according Vidlov method. SPF was measured with FACScan flow cytometr (FACS-Calibur Becton-Dickinson). In statistical analysis established confidential level was 95% (p < 0.05). RESULTS: We excluded 7 patients from the study. Average SPF in whole group--13.0637% (0.58-57.62), average SPF in aneuploidy group--13.536% standard deviation (SD)--10.71, in diploidy group--12.365%, SD 10.63. No differentiation between groups was found p = 0.66. We did not find, in whole group a ny influence of SPF on survival p = 0.992. CONCLUSION: S-phase fraction has no prognostic significance in ovarian cancer.     

Elevated RON protein expression in endometriosis and disease-associated ovarian cancers

Background

Recepteur d’origine nantais (RON) protein expression has been demonstrated to correlate with tumor progression, metastasis, and prognosis, and its mRNA expression increases in deeply infiltrating endometriotic lesions. However, it remains unclear whether RON protein expression also increases in endometriotic lesions, and may be a risk factor of malignant transformation in endometriotic lesions.

Methods

The protein expression of RON in control (n = 19), eutopic (n = 16), and ectopic (n = 51) endometria, as well as in endometriosis-associated ovarian cancers (EAOC, n = 16) was determined by immunohistochemical (IHC) staining.

Results

Endometriotic lesions expressed low levels of RON protein, but no RON protein expression appeared in matched eutopic or control endometrium. EAOC exhibited high levels of RON protein. The frequency and IHC score of RON protein expression were both significantly higher in EAOC [100.0% (14/14), 5.37 ± 0.74] than those in endometriotic lesions [51.0% (26/51), 2.15 ± 1.12; P = 0.002, 0.001]. Multivariate analysis of covariance only revealed a correlation of RON protein expression and EAOC (P = 0.006), but no correlations of RON protein expression and clinical parameters (P > 0.05).

Conclusions

These obtained results suggest that increased RON expression might be involved in the pathogenesis of endometriosis and disease-associated ovarian cancers.

     

Prognostic factors in ovarian cancer

The improvement in the treatment of ovarian cancer is based on the recognition of the prognostic factors. The 5-year survival rate of 174 patients with epithelial ovarian malignancies after primary operation at the University Department of Obstetrics and Gynecology in Ljubljana and treated with adjuvant therapy at the Institute of Oncology in Ljubljana in the period 1970-1980 was 29.3% (56% for stage I, 36% for stage II, 23% for stage III and 4.5% for stage IV). The amount of residual tumor after the primary operation was prognostically very important (5-year survival in stage III in cases of residual tumor less than 2 cm is 46.6%, in tumor greater than 2 cm only 18.6%). The histological type of tumor, considering the stage, was not important prognostically. On the contrary the grade of differentiation was prognostically very important even in advanced cases: 5 year survival for stage III in cases of well differentiated serous tumors was 61%, in moderately and poorly differentiated cases it was only 7%. Younger patients have better prognosis than older ones, because the tumors are better differentiated, too. Since ovarian cancers are diagnosed too late in 65% of cases in advanced stages, today all efforts should be focussed on early diagnosis, which is probably the only factors that can lead to the dramatic fall of the mortality rate.     

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.     

Prognostic factors in patients with stage I epithelial ovarian cancer

We analyzed factors predictive of relapse risk in patients with stage I invasive epithelial ovarian cancer: 252 patients from the Princess Margaret Hospital provided a data base for hypothesis generation, and data on 267 patients from the Norwegian Radium Hospital were used for hypothesis testing. The outcomes in most analyses in the two series were very similar, validating the following conclusions. Differentiation (grade) was the most powerful predictor of relapse, followed by dense adherence (which resulted in outcomes equivalent to those in stage II) and, finally, large-volume ascites. When the effects of these three factors were accounted for, then none of the following were prognostic: bilaterality (stage Ib), cyst rupture (stage Ic), capsular penetration (stage Ic), tumor size, histologic subtype, patient age, year of diagnosis, and postoperative therapy. These results allow simplification of stage I substaging, as only differentiation, dense adherence, and large-volume ascites (? peritoneal cytology) need be considered. The 5-year relapse-free rate was 98% in patients with grade 1 tumors in whom both dense adherence and large-volume ascites were absent. These patients are adequately treated by operation alone. Although the relapse risk was high enough in the remaining patients to warrant postoperative treatment, a significant benefit could be shown only for a small subset of patients, namely those with densely adherent tumors treated with abdominopelvic radiotherapy. In grades 2 and 3, none of the therapies used in either series was superior to pelvic radiotherapy or operation alone.     

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.     

Prognostic factors in advanced ovarian cancer

In this review, different factors with suspected effect on survival of patients with advanced ovarian cancer are analysed. The volume of residual disease after surgical debulking is one of the most important factors predicting outcome. However, the extent of cytoreduction may not be the only 'responsible' factor indicating a better prognosis; the underlying biology of those debulkable tumors may also play a role in defining the more favorable outcome. Seven reports have studied different prognostic factors by multivariate analysis: performance status, stage, age, grade, histology, tumor size, residual tumor, type of chemotherapy given, and ploidy status are the most common analysed parameters. A meta-analysis indicated that treatment with cisplatin and disease stage are the only independent prognostic variables. Some investigators have developed prognostic indexes with good predictive power, incorporating objective prognostic variables. This approach may be more useful than applying individual factors to each patient. The absolute titer of carbohydrate antigen 125, its decline after several courses of chemotherapy, or its half-life have been correlated with prognosis in some instances, but low sensitivity may be a problem. Other biologic factors with some prognostic potential in ovarian cancer are the expression of lung-resistance protein and the over-expression of c-erbB-2, both perhaps related to resistance to chemotherapy, the product of the metastasis suppressor gene nm23, the epidermal growth factor receptor, heat shock proteins (HSP-60), and plasma or ascites levels of macrophage colony-stimulating factor. Most of these predictors were explored in selected and often small series of patients, and their roles should be confirmed in well-designed confirmatory trials.     

Prognostic analysis of invasive circulating tumor cells (iCTCs) in epithelial ovarian cancer

Goals

Circulating tumor cells (CTCs) have been introduced as a biomarker in detecting advanced epithelial ovarian cancer (EOC). The goals are to examine the prevalence of the invasive subpopulation of CTCs (iCTCs) in patients at high risk of EOC and to compare this biomarker to serum CA125.

Methods

We used a unique cell adhesion matrix (CAM)-based, functional cell enrichment and identification platform to isolate iCTCs from 129 preoperative patients. We confirmed the identity of iCTCs using positive epithelial (Epi +) markers and negative hematopoietic lineage (HL −) markers. Sensitivity and specificity of the assays were examined and iCTCs/CA125 were correlated with overall survival (OS), progression-free survival (PFS) and clinical parameters.

Results

We found a 41.2% sensitivity, 95.1% specificity and 77.8% positive predictive value (PPV) of the iCTC assay in detecting patients with stage I and II EOC malignancy, and a 83% sensitivity and 97.3% PPV in detecting all stages of EOC malignancy. However, a positive CA125 test provided weak evidence to detect stage I and II malignancy (61.6% PPV) and all EOC (92.1% PPV), because of its 76.2% specificity. A significantly stronger concordance in OS and PFS of clinical factors (tumor stage, debulking and platinum sensitivity) was noted for elevated iCTCs than for serum CA125.

Conclusion

The CAM-initiated CTC enrichment/identification method enabled the detection of early stage EOC. iCTCs were better correlated with worse OS and PFS, more specific and better PPV than CA125 in detecting EOC malignancy in patients at high risk of EOC.     

Prognostic value of various subtypes of extracellular DNA in ovarian cancer patients

Background

Patients with ovarian cancer represent a heterogeneous population with a variable prognosis and response to chemotherapy. Plasma DNA has been shown to have a prognostic value in different types of cancer including ovarian carcinoma. Whether total circulating DNA, which can be assessed much easier without knowing the tumor-specific mutations, has similar informative value is currently unknown. The aim of this study was to evaluate the prognostic value of extracellular DNA in advanced ovarian cancer.

Methods

This prospective study included 67 patients (pts) with ovarian cancer treated with 1st line paclitaxel and carboplatin (25 pts) and paclitaxel, carboplatin and bevacizumab (42 pts). Thirty-five patients had optimal surgical debulking before chemotherapy. Extracellular DNA was quantified using real time PCR before administration of chemotherapy (67 pts) and after 6 cycles of chemotherapy (44 pts).

Results

Total extracellular DNA (ecDNA), as well as extracellular DNA of nuclear (nDNA) and mitochondrial origin (mtDNA) significantly (p?<?0.05) decreased after 6 cycles of chemotherapy (by 54%, 63% and 52%, respectively. Patients with stage I disease had significantly lower mtDNA compared to patients with stage II-IV (8604 vs. 16, 984 ge/mL, p?=?0.03). Patients with lower baseline nDNA had superior progression-free (HR?=?0.35 (0.14–0.86)) and overall survival (HR?=?0.18 (0.04–0.77). The prognostic value of nDNA was confirmed independent of tumor stage and confirmed in multivariate analysis.

Conclusions

Our data suggest that ecDNA of both, nuclear and mitochondrial origin could be added to prognostic markers in ovarian cancer. Analysis of ecDNA does not require the knowledge of tumor-specific mutations in contrast to the quantification of tumor-derived ecDNA. Study of the dynamics and cell type-specific source of the ecDNA could shed light on its biology in cancer and might help to direct the treatment of ovarian cancer.

     

Prognostic value of lymph node ratio in patients with advanced epithelial ovarian cancer

ObjectiveLymph node status is an established prognostic factor in epithelial ovarian cancer (EOC). Lymph node ratio (number of positive LN/number of resected LN) reflects both qualitative and quantitative lymph node spread as well as surgical effort and extent of disease. We evaluated whether LNR is a more precise prognostic factor than conventional lymph node status in patients with EOC.MethodsThe present retrospective study includes 809 patients with EOC, who underwent primary cytoreductive surgery between 2000–2013. Clinico-pathological parameters and survival data were extracted from a prospectively maintained tumor registry database. The optimal cut-off point for LNR was calculated by using Martingale residuals. Survival analyses were calculated using Kaplan–Meier method and Cox regression models.ResultsLymphadenectomy was performed in 693 (85.7%) out of 809 patients. Median number of removed LN was 64 (IQR 25–75%: 39–84). LNR of 0.25 was identified as the optimal prognostic cut-off value. The estimated 5-year-OS rates were 69.3% for patients with node-negative EOC compared to 33.1% for patients with any lymph node metastasis (p < 0.001). The estimated 5-year-OS rates were 42.5% for patients with LNR ≤ 0.25, and 18.0% for patients with LNR > 0.25 (p < 0.001). Additionally in multivariate analysis LNR > 0.25 was approved to be an independent prognostic factor for overall survival (adjusted HR 1.44, 95% CI 1.04–2.00; p = 0.028).ConclusionLNR more precisely predicts overall survival than conventional lymph node status in EOC patients undergoing primary debulking surgery.     

Prognostic significance of iNOS in epithelial ovarian cancer

OBJECTIVE: To study the association of inducible nitric oxide synthase (iNOS) expression with clinicopathological factors and prognosis in epithelial ovarian cancer. METHODS: The study included 301 patients with primary epithelial ovarian cancer. iNOS expression was evaluated by immunohistochemistry using a mouse monoclonal antibody. RESULTS: iNOS positivity was observed as granular deposits in the cancer cell cytoplasm. The mean percentage of iNOS-positive cells was 50% in primary tumors (n=301), and 62% in metastatic lesions (n=43). iNOS expression correlated significantly with histological subtype of the tumor, as high (> 70%) iNOS expression was observed in mucinous tumors (p=0.009). Poorly differentiated tumors showed a tendency to low (< or = 70%) iNOS expression but without statistical significance. Low iNOS expression associated also significantly with large primary residual tumor (p=0.007) and tumor recurrence (p=0.04). The 10-year prognosis of the patients with high iNOS expression was better in disease-related survival (DRS) (p=0.009). However, in multivariate analysis only FIGO stage, primary residual tumor, and grade of the tumor were independent prognostic factors for DRS, but not the iNOS expression. CONCLUSIONS: A major proportion of human epithelial ovarian cancers expressed iNOS. The positive expression was an indicator of better disease-related survival. However, iNOS positivity could not overcome the importance of clinicopathological factors in prediction of prognosis.     

术前血清CRP测定对评估卵巢上皮癌预后的价值

目的:探讨血清C反应蛋白(C-reactive protein,CRP)与上皮性卵巢癌(epithelial ovarian cancer,EOC)临床病理参数、CA125的相关性及评估EOC预后的价值。方法:测定61例EOC患者术前血清CRP及CA125,分析CRP与临床病理参数及CA125的相关性。结果:术前EOC患者血清CRP的中位数为13.06mg/L,CRP阳性者38例(38/61),明显高于对照组(P<0.001)。术前血清CRP水平与EOC的FIGO分期、淋巴结转移、腹水形成关系密切。FIGOⅢ~Ⅳ期、淋巴结转移阳性、腹水形成者CRP中位数显著增高。多因素Logistic回归分析也提示肿瘤FIGO分期、腹水形成和淋巴结转移与CRP阳性表达相关(P<0.05)。研究还表明,CRP水平与手术方式满意度及残余灶大小关系非常密切,CRP值越高,预示手术满意度越差、残余灶越大;血清CRP、CA125的秩和相关分析显示CRP与CA125之间存在正相关(P=0.000)。结论:术前血清CRP可作为判断EOC预后的有价值指标。