Prognostic Factor In Epithelial Ovarian Cancer Research Articles

Prognostic value of monocyte to lymphocyte ratio (MLR) in epithelial ovarian cancer (EOC).

e17066 Background: Identifying high-risk early-stage EOC patients (p) is a major issue. Also, controversy about the role of neoadjuvant chemotherapy prior to surgery in advanced EOC is still ongoing. A high MLR is related to poorer outcomes in several cancers, and also in ovarian cancer according to limited retrospective series. We explored the clinical value of MLR in a cohort of EOC p. Methods: We included all EOC p diagnosed in our center, from January 2008 to April 2017, who had undergone radical treatment. Overall survival (OS) was assessed by Kaplan Meyer. Maximally selected rank statistics was used to determine the MLR cut-off value for the greatest OS discrimination. The hazard ratio (HR) of death of MLR was explored by multivariate Cox regression models, adjusted by age at diagnosis, stage I/II versus (vs) III/IV, high grade serous carcinomas (HGSC) vs other, primary surgery vs interval surgery after neoadjuvant chemotherapy (PS, IS), residual disease < 1 vs > 1cm, year of diagnosis, and hemoglobin, neutrophils, platelets and MLR at diagnosis. Results: 124 p were included. Median age at diagnosis was 58.7 years; 55.6% were HGSC;67.7% stage III/IV; 69.3% received PS; 14.3% had residual disease > 1cm. Median OS was 75 months. MLR was the laboratory parameter that more significantly impacted on OS in our model (p = 0.02). Optimal MLR cut-off was 0.38. The MLR > 0.38 group (MLR-hi) had a higher-risk of death (HR = 2.9; 95% IC: 1.3–6.5) with respect to those with MLR < = 0.38 (MLR-lo). Median OS were 100 and 35 months, respectively. In the MLR-lo group, median age at diagnosis was 56.9 years (vs 61.9 in the MLR-hi, p 0.047), 44.8% were HGSC (vs 61.2%, p 0.134), and 49.97% were stages I/II (vs 14.2%, p 0.001). MLR-hi p who had undergone PS or IS had similar OS (p = 0.63). In contrast, among MLR-lo p, PS showed significantly higher OS than IS (p < 0.0001). Conclusions: In our cohort, MLR was an independent prognostic factor in EOC. Its potential role to identify high-risk early-stage p and to predict worse outcomes after PS among advanced-stage p need to be explored in larger cohorts.

Visceral adiposity as a predictor of survival in patients with epithelial ovarian cancer receiving platinum and taxane-based chemotherapy.

e17031 Background: Obesity has been linked to worse outcomes in epithelial ovarian cancer (EOC), due to underlying metabolic dysfunction. Visceral fat (i.e. central obesity) compared to subcutaneous fat is more metabolically active and has been linked to higher rates of obesity-related comorbidities such as hypertension and diabetes, but less is known of the impact of increased visceral adiposity on EOC outcomes. Thus, our goal was to evaluate if visceral adiposity, as determined by computed tomography (CT) morphometric measurements, was associated with worse outcomes in EOC patients undergoing platinum and taxane-based chemotherapy. Methods: EOC patients diagnosed between 12/2004 and 5/2016 who received neoadjuvant or adjuvant treatment with platinum and taxane-based chemotherapy were included. Data on age, stage, grade, histology, BMI, comorbidities, treatment approaches and outcomes were collected. CT images closest to the time of diagnosis were retrospectively evaluated for mid-waist visceral fat volume (VFV), mid-waist subcutaneous fat volume (SFV) and the ratio of mid-waist VFV/SFV. Visceral adiposity is commonly defined as a VFV/SFV ≥ 0.4. Cox regression models were used to analyze time-to-event outcomes. Results: Two hundred fifty-eight EOC patients were evaluated. Seventy-five percent of patients were diagnosed with Stage III or IV disease, with high grade serous as the most common histology (72%). Median age at diagnosis was 62.4 years. Approximately 65% were obese; the median BMI was 26.8 (IQR 23.1 – 32.6). The median VFV/SFV ratio was 0.46 (IQR 0.32 – 0.70). Patients were categorized into those with a VFV/SFV ratio greater than 0.4 or a ratio less than 0.4. When comparing these two groups, there was no difference in progression free survival (PFS) for women with a VFV/SFV ratio greater or less than 0.4 (p = 0.22). However, a VFV/SFV ratio of greater than 0.4 was associated with worse overall survival (OS) (p = 0.01). Conclusions: We found that visceral adiposity, defined as a VFV/SFV ratio greater than 0.4, appeared to be associated with decreased OS, but not PFS. These findings suggest that body fat distribution may be an important prognostic factor for EOC and should be further explored as we expect the obesity epidemic to continue and influence EOC oncologic outcomes.

Optimal cutoff age for predicting prognosis associated with serous epithelial ovarian cancer: what is the best age cutoff?

ObjectiveElderly age is one of the poor prognostic factors in epithelial ovarian cancer (EOC), but the optimal age cut-off is not known. The present study sought to identify the ideal age cutoff that represents a negative prognostic factor in EOC, considering the geriatric assessment.MethodsHazard ratios (HRs) with p-values were calculated using all possible age cutoffs with stage, histology, grade, optimality and comorbidities as covariates in multivariate Cox regression model. The trends of p-value and HR by age cutoff were further evaluated in a subgroup of histology and in The Cancer Genome Atlas (TCGA) dataset. In addition, propensity score-matching analysis using the identified age cutoff was performed.ResultsAn age of 66 years was shown to be the most significant cutoff for defining old age with independent prognostic power (HR=1.45; 95% confidence interval=1.04–2.03; p=0.027). This result was also observed with the analyses of serous histology subgroup and with the analysis of a TCGA dataset with serous EOC. In survival analysis, patients aged ≥66 years had significantly worse overall survival compared with younger individuals (56 months vs. 87 months; p=0.006), even following propensity score matching (57 vs. 78 months; p=0.038).ConclusionAn age of 66 years is the best cutoff to define elderly age in serous EOC patients considering the geriatric assessment, and this information can be used in the administration of individualized therapies in elderly EOC patients.

Increased expression of long noncoding RNA HMMR-AS1 in epithelial ovarian cancer: an independent prognostic factor.

Evidence has indicated that long noncoding RNA (lncRNAs) may have significant roles in cancer. In this study, we aimed to investigate the expression pattern and prognostic value of a noncoding RNA named as HMMR antisense RNA 1 (HMMR-AS1) in epithelial ovarian cancer (EOC). Differences in the expression of HMMR-AS1 between EOC and matched normal tissues were analyzed using RT-PCR. The correlation between HMMR-AS1 levels and the clinicopathological factors of the EOC patients was analyzed by x2-test. Kaplan-Meier analysis and Cox proportional hazards regression models were explored to reveal the correlations of HMMR-AS1 expression with survival of patients. HMMR-AS1 was significantly upregulated in human EOC tissues compared with adjacent normal tissues (p < 0.01). Clinicopathologic analysis revealed that high expression of HMMR-AS1 was associated with advanced FIGO stage (p = 0.013) and positive lymphatic metastasis (p = 0.010). Moreover, patients with higher HMMR-AS1 expression displayed shorter overall survival time (p = 0.0075) and progression-free survival time (p = 0.0013) than those with lower HMMR-AS1 expression. More importantly, multivariate analysis suggested that high expression of HMMR-AS1 was an independent prognostic indicator for EOC patients. Our data suggested that HMMR-AS1 may be considered a novel prognostic factor in EOC and a specific diagnostic indicator for patients with EOC.

Expression of orphan GPR56 correlates with tumor progression in human epithelial ovarian cancer.

G protein-coupled receptor 56 (GPR56) has been demonstrated to be a significant prognostic predictor in several types of malignances, including melanoma, glioblastoma, breast cancer, colon cancer, and pancreatic cancer. GPR56 has a putative mucin-like extracellular domain, indicating functions for this receptor in the cell-cell interactions and triggering different downstream signaling pathways responsible for regulating cell survival, proliferation, adhesion, and migration. But the expression and clinical significance of GPR56 has not been elucidated in epithelial ovarian cancer (EOC). We detected GPR56 expression by immunohistochemistry in 110 samples of ovarian serous carcinoma to explore the correlation between its expression and clinicopathologic characteristics and overall survival. As the result, we found that GPR56 expression is significantly associated with advanced FIGO stage (P = 0.01) and positive lymph node invasion (P = 0.016), and it serves as an independent unfavorable prognostic factor through univariate and multivariate analysis. GPR56 knockdown could dramatically decrease the proliferation and invasion of epithelial ovarian cancer cells through down-regulating the RhoA-GTP level and up-regulating the E-cadherin level, which indicates GPR56 could promote the progression and invasion of EOC. In conclusion, GPR56 expression was demonstrated as an independent prognostic factor in EOC, suggesting that GPR56 may play an oncogenic role through the Rho and E-cadherin pathway and GPR56 could be a novel potential drug target in EOC.

VEGF gene polymorphisms and outcome of epithelial ovarian cancer patients.

Since VEGF polymorphisms were associated with variable protein production, we analyzed herein their roles in outcome of epithelial ovarian cancer (EOC) patients. Genotypes of 85 patients with primary EOC were identified in DNA by real-time PCR. Progression-free survival and overall survival were analyzed using Kaplan-Meier method, univariate Cox model and bootstrap resampling study. At 60 months of follow-up, progression-free survival was shorter in patients with VEGF c.-2578 CC genotype compared with others (52.7 vs 82.2%; p = 0.04). Those patients had 2.15 more chance of presenting disease progression than others (p = 0.04); bootstrap study validated the result (p = 0.03). Our data suggest that VEGF c.-2578C>A polymorphism acts as a prognostic factor in EOC.

TGF-β1 and IL-10 expression in epithelial ovarian cancer cell line A2780

Purpose: Ovarian cancer is a leading cause of death among gynaecological malignancies. Transforming growth factor-beta 1 (TGF β1) and interleukin-10 (IL-10) are cytokines in the tumour microenvironment and may play critical roles in immune suppression. This study highlights these roles and immunosuppressive functions in epithelial ovarian cancer (EOC).Methods: TGF-β1 and IL-10 expression was compared in malignant, benign, and borderline cancerous tissues and tumour-free tissue by immunohistochemistry. Relationships among the levels of these cytokines, correlation of expression level with EOC prognosis, and cytokine involvement in immunosuppression were investigated.Results: Immunohistochemical analysis of TGF-β1 and IL-10 in epithelial cells showed the presence of epithelial, borderline, and benign ovarian tumour growth, and normal ovarian growth. TGF-β1 (P = 0.121), residual tumour after surgery (P = 0.231) and standard chemotherapy (P = 0.121) were prognostic factors for EOC. There were no significant differences in clinicopathologic factors between specimens expressing TGF-β1 at low and high levels, indicating that TGF-β1 is an independent factor in EOC diagnosis. Higher concentrations of TGF-β1 (1754.690 ± 3416.487 pg/ml) and IL 10 (2731.7101 ± 6.1613 pg/ml) were observed in A2780-conditioned than in control medium.Conclusion: TGF-β1 and IL-10 play pivotal roles in EOC and can lead to immune evasion. Targeting these cytokines for tumour treatment, specifically at early stages, may prevent tumour progression.Keywords: Epithelial ovarian cancer, TGF-β1, IL-10, histopathology

Abstract POSTER-BIOL-1301: The receptor tyrosine kinase AXL modulates oncogenic signaling and epithelial mesenchymal transition in epithelial ovarian cancer

Abstract Metastasis in epithelial ovarian cancer (EOC) is lethal, and results into a 5-year-survival rate lower than 30%. In EOC, tumor cells undergo Epithelial-Mesenchymal Transition (EMT) to attain the invasive and migratory potential crucial for metastasis. The analysis of molecular heterogeneity in EOC also demonstrated the important role of EMT. Our group has previously classified EOC tumors and cell lines into 5 distinct molecular subtypes based on their global gene expression patterns. Among these subtypes, the Mesenchymal subtype is believed to be driven by EMT. Receptor Tyrosine Kinases (RTKs), which play a pivotal role in proliferation and survival pathways, have been strongly indicated to mediate signals in EMT. Upon interrogating the kinome expression patterns by determining the top 10 ranked kinases in each molecular subtype, the RTK AXL was revealed to have a significantly high ranking in the Mesenchymal subtype. The purpose of this study is to elucidate the role of AXL in oncogenic signaling and EMT in EOC. Western Blotting of total Axl protein in a panel of 40 EOC cell lines revealed a distinctive pattern among the 5 molecular subtypes. Upon ligand activation by Gas6 in Axl-expressing cell lines, pERK and pAkt, two signaling molecules downstream of Axl, displayed a unique temporal signaling pattern specific to the Mesenchymal subtype. This resulted into an implication of the preferential sensitivity to Axl-specific inhibitors in the Mesenchymal subtype. The IC-50 of R428, one small molecule inhibitor specific to Axl, was significantly lower in the Mesenchymal cell lines compared to the other subtypes (Average of 2.91 μM versus 9.38 μM; p-value=0.01) Stable clones were generated by using shRNAs to knockdown AXL in Mesenchymal EOC lines. shAXL SKOV3 cells demonstrated a reversal of EMT evident by restoration of Ecadherin. siRNA mediated transient silencing of AXL showed a reduction in cell motility with decreased total displacement and velocity measured over 12 hours (31.98 μm compared to 44.59 μm, p-value=0.01; and 17.35 μm/second compared to 23.15 μm/second, pvalue= 0.03) measured by using single cell tracking. Survival analysis showed that AXL over expression correlated positively with poor overall survival of EOC in both univariate (HR=2.2 p-value=6.46e−11), and multivariate analysis (HR=1.513 p-value=0.0012). In conclusion, AXL is significantly over-expressed and displays a unique signaling pattern in the Mesenchymal subtype of EOC. Knocking down AXL in the Mesenchymal cell lines affects their EMT phenotype and migratory properties. AXL is an independent prognostic factor for EOC and is a clinically relevant target that is potentially involved in cross talks between RTK oncogenic signaling and EMT. Citation Format: Jane Antony, Tuan Zea Tan, Andrew Paterson, Chiara Recchi, Hani Gabra, Jean Paul Thiery, Ruby Yun-Ju Huang. The receptor tyrosine kinase AXL modulates oncogenic signaling and epithelial mesenchymal transition in epithelial ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1301.

Prognostic values of 5-hmC, 5-mC and TET2 in epithelial ovarian cancer.

DNA methylation is an important epigenetic modification that is frequently altered in cancer. Recent reports showed that the level of 5-hydroxymethylcytosine (5-hmC) was altered in various types of cancers. The influence of DNA methylation in epithelial ovarian cancer (EOC) is not fully understood. Therefore, the aim of the present study was to investigate factors involved in DNA demethylation in EOC compared with normal ovarian tissues. We examined the expression of 5-hmC, 5-mC, and TET2 by immunohistochemistry in 130 cases of EOC and 40 cases of normal ovarian tissues. We assessed the prognostic values of 5-hmC, 5-mC, and TET2 in clinical outcome of EOC. We discovered a significant decrease in 5-hmC and TET2 expression in EOC compared with normal ovarian tissues. In contrast, there was a significant increase in 5-mC expression in EOC compared with normal ovarian tissues. The expression of 5-hmC, 5-mC, and TET2 correlated with pathologic stage, tumor grading, lymph node metastasis, and vascular thrombosis. Furthermore, decreased level of 5-hmC predicts poor prognosis of EOC patients. The expression of 5-hmC was an independent prognostic factor for overall survival of EOC patients. The data suggest that loss of 5-hmC is an epigenetic event of EOC, and the expression of 5-hmC could serve as a prognostic factor for EOC.

The level of RECQL1 expression is a prognostic factor for epithelial ovarian cancer.

BackgroundThe human RECQ DNA helicase family is involved in genomic stability. Gene mutations of RECQL2, RECQL3, and RECQL4 are associated with genetic disorders and induce early aging and carcinogenesis. Although previous studies have reported that the level of RECQL1 expression is correlated with the prognosis of some of malignancies, the function of RECQL1 is not yet clarified. The present study aimed to examine the relationship between prognosis and the level of RECQL1 expression in epithelial ovarian cancer (EOC), and to identify the role of RECQL1 in EOC cells.MethodsThe level of RECQL1 expression was determined immunohistochemically in 111 patients with EOC who received initial treatment at Hirosaki University hospital between 2006 and 2011. Effects of RECQL1 on cell growth or apoptosis were examined in vitro using wild-type and OVCAR-3 cells (RECQL1(+) cells) and similar cells transfected with RECQL1 siRNA transfected (RECQL1(−) cells).ResultsThe level of RECQL1 expression was not related to histological type, clinical stage, or retroperitoneal lymph node metastasis, but the expression level was significantly higher (P = 0.002) in patients with recurrence than those without recurrence, and progression-free survival and complete response rate to chemotherapy were also improved in patients with RECQL1-low expression (n = 39) stage III/IV EOC (P = 0.02 and P <0.05 vs RECQL1-high expression patients (n = ), respectively). A cell proliferation and colony formation assays revealed significantly less growth of RECQL1(−) cells compared to RECQL1(+) cells. A flow cytometry using annexin V -FITC and propidium iodide (PI) staining revealed a significant increase in apoptotic RECQL1(−) cells. Cell cycle analysis showed a significantly greater distribution in subG1 phase indicating apoptotic cells in RECQL1(−) cells than in RECQL1(+) cells.ConclusionsThese results suggest that RECQL1 is a prognostic factor for EOC and that RECQL1 contributes to potential malignancy by inhibiting apoptosis.

The level of RECQL1 expression is a prognostic factor for epithelial ovarian cancer

The human RECQ DNA helicase family is involved in genomic stability. Gene mutations of RECQL2, RECQL3, and RECQL4 are associated with genetic disorders and induce early aging and carcinogenesis. Although previous studies have reported that the level of RECQL1 expression is correlated with the prognosis of some of malignancies, the function of RECQL1 is not yet clarified. The present study aimed to examine the relationship between prognosis and the level of RECQL1 expression in epithelial ovarian cancer (EOC), and to identify the role of RECQL1 in EOC cells. The level of RECQL1 expression was determined immunohistochemically in 111 patients with EOC who received initial treatment at Hirosaki University hospital between 2006 and 2011. Effects of RECQL1 on cell growth or apoptosis were examined in vitro using wild-type and OVCAR-3 cells (RECQL1(+) cells) and similar cells transfected with RECQL1 siRNA transfected (RECQL1(−) cells). The level of RECQL1 expression was not related to histological type, clinical stage, or retroperitoneal lymph node metastasis, but the expression level was significantly higher (P = 0.002) in patients with recurrence than those without recurrence, and progression-free survival and complete response rate to chemotherapy were also improved in patients with RECQL1-low expression (n = 39) stage III/IV EOC (P = 0.02 and P <0.05 vs RECQL1-high expression patients (n = ), respectively). A cell proliferation and colony formation assays revealed significantly less growth of RECQL1(−) cells compared to RECQL1(+) cells. A flow cytometry using annexin V -FITC and propidium iodide (PI) staining revealed a significant increase in apoptotic RECQL1(−) cells. Cell cycle analysis showed a significantly greater distribution in subG1 phase indicating apoptotic cells in RECQL1(−) cells than in RECQL1(+) cells. These results suggest that RECQL1 is a prognostic factor for EOC and that RECQL1 contributes to potential malignancy by inhibiting apoptosis.

Prognostic importance of survivin, Ki-67, and topoisomerase IIα in ovarian carcinoma

Stage, tumor grade and histological subtype determine the clinical behavior in ovarian tumors. Some additional factors are related to tumor cell biology and are the useful predictors for identifying the patients with poor prognosis. The aim of this study is to evaluate the prognostic significance of survivin, Ki-67 and Topoisomerase IIα (TOPO IIα) in epithelial ovarian cancer (EOC). Seventy-three patients with EOC were included in this study. Survivin, Ki-67 and TOPO IIα expressions were studied by immunohistochemistry on formalin-fixed, paraffin-embedded tissue sections. Nuclear staining for all antibodies was scored on a three-tiered system and more than 10 % staining was accepted as expression. The relationship between the expressions of survivin, Ki-67, TOPO IIα and clinicopathological parameters including age, stage, grade, platinum resistance and survival was evaluated. Survivin, Ki-67 and TOPO IIα expressions were found in 20, 82 and 86 % of the tumors, respectively. Ki-67 and TOPO IIα expressions were found to be related to poor overall survival (p = 0.005, 0.004, respectively), while survivin expression was not associated with overall survival. There was no association between TOPO IIα and Ki-67 expressions and histological subtype, stage or grade. However, we found an important relationship between TOPO IIα expression and platinum resistance (p = 0.044). Platinum resistance was found to be an independent prognostic factor in EOC. Ki-67 and TOPO IIα expressions were found to be related to poor overall survival, and TOPO IIα expression was found to be associated with platinum resistance.

Prognostic significance of serum microRNA-221 expression in human epithelial ovarian cancer

To evaluate the feasibility of using serum microRNA (miR)-221 as a noninvasive diagnostic and prognostic biomarker in epithelial ovarian cancer (EOC). In this retrospective study, real-time reverse transcription-polymerase chain reaction was used to measure miR-221 expression in serum samples from patients with EOC and healthy age-matched controls. Correlations between serum miR-221 levels and clinicopathological factors and prognosis were explored. Serum miR-221 was upregulated in patients with EOC (n = 96) compared with healthy controls (n = 35). The level of serum miR-221 expression was significantly associated with International Federation of Gynecology and Obstetrics stage, and tumour grade. Furthermore, multivariate analysis of overall survival showed that high serum miR-221 expression was an independent unfavourable prognostic factor in EOC. These findings indicate that serum miR-221 may have a role as a novel diagnostic and prognostic marker, and may have potential as a therapeutic target in EOC.

Overexpression of PRMT5 Promotes Tumor Cell Growth and Is Associated with Poor Disease Prognosis in Epithelial Ovarian Cancer

PRMT5 has been reported to be involved in the processes of tumor progression at various steps. The aim of this study was to examine the role of PRMT5 in epithelial ovarian cancer (EOC). In this study, PRMT5 and Ki-67 expression were examined by immunohistochemistry (IHC) in cohorts of normal, benign, and cancerous ovarian tissues. PRMT5 overexpression was observed in 83.1% (98/118) of EOCs, and it was significantly associated with serous type, poor differentiation, advanced tumor stage, lymph node invasion, presence of residual tumor, and high expression of Ki-67 (p<0.05, respectively). Moreover, overexpression of PRMT5 was an independent prognostic marker for decreased overall survival and progression-free survival in univariate survival analysis and multivariate Cox regression analysis. In ovarian cancer cell lines A2780 and SKOV3, PRMT5 knockdown by siRNA inhibited cell growth/proliferation and induced apoptosis via upregulation of E2F-1. These results suggest that overexpression of PRMT5 correlates with an aggressive malignant phenotype and may constitute a novel prognostic factor for EOC. Thus, PRMT5 may represent a clinically effective new target for therapy of ovarian cancer.

Validating the impact of a molecular subtype in ovarian cancer on outcomes: A study of theOVCADConsortium

Most patients with epithelial ovarian cancer (EOC) are diagnosed at advanced stage and have a poor prognosis. However, a small proportion of these patients will survive, whereas others will die very quickly. Clinicopathological factors do not allow precise identification of these subgroups. Thus, we have validated a molecular subclassification as new prognostic factor in EOC. One hundred and ninety-four patients with Stage II-IV EOC were characterized by whole-genome expression profiling of tumor tissues and were classified using a published 112 gene set, derived from an International Federation of Gynecology and Obstetrics (FIGO) stage-directed supervised classification approach. The 194 tumor samples were classified into two subclasses comprising 95 (Subclass 1) and 99 (Subclass 2) tumors. All nine FIGO II tumors were grouped in Subclass 1 (P = 0.001). Subclass 2 (54% of advanced-stage tumors) was significantly correlated with peritoneal carcinomatosis and non-optimal debulking. Patients with Subclass 2 tumors had a worse overall survival for both serous and non-serous histological subtypes, as revealed by univariate analysis (hazard ratios [HR] of 3.17 and 17.11, respectively; P ≤ 0.001) and in models corrected for relevant clinicopathologic parameters (HR 2.87 and 12.42, respectively; P ≤ 0.023). Significance analysis of microarrays revealed 2082 genes that were differentially expressed in advanced-grade serous tumors of both subclasses and the focal adhesion pathway as the most deregulated pathway. In the present validation study, we have shown that, in advanced-stage serous ovarian cancer, two approximately equally large molecular subtypes exist, independent of classical clinocopathological parameters and presenting with highly different whole-genome expression profiles and a markedly different overall survival. Similar results were obtained in a small cohort of patients with non-serous tumors.

EGRI and FOSB gene expressions in cancer stroma are independent prognostic indicators for epithelial ovarian cancer receiving standard therapy

Stromal components interact with cancer cells to promote growth and metastasis. The purpose of this study was to identify genes expressed in stroma, which could provide prognostic information in epithelial ovarian cancer (EOC). Seventy-four patients were included. We performed gene expression profiling and confirmed array data using RT-PCR and immunohistochemistry. By microarray analysis, 52 candidate genes associated with progression free survival (PFS) were identified (P < 0.005). Expression of the early growth response 1 (EGR1) and FBJ murine osteosarcoma viral oncogene homolog B (FOSB) genes was further analyzed. Array data were confirmed by RT-PCR and multivariate analysis demonstrated that both EGR1 and FOSB expression in cancer stroma, and EGR1 expression in cancer are independent prognostic factors in EOC. Immunohistochemically, EGR1 protein is localized in cancer cells and α-smooth muscle actin positive stromal fibroblasts. The EGR1 and FOSB expression in stromal cells and EGR1 expression in cancer cells are prognostic indicators in EOC.

Trop-2 overexpression as an independent marker for poor overall survival in ovarian carcinoma patients

Background Prognostic factors currently available are insufficient to predict the clinical course of epithelial ovarian cancer (EOC). In a previous microarray study we identified the human trophoblast cell surface antigen Trop-2 as one of the top differentially expressed genes in serous papillary EOCs compared to normal human ovarian surface epithelial (HOSE) short-term cultures. The aim of the present investigation was to analyse Trop-2 expression at mRNA and protein level and to assess its prognostic significance in EOC. Methods Using quantitative real-time PCR we tested a total of 104 fresh-frozen EOC tissues and 24 HOSE for Trop-2 mRNA expression. Trop-2 protein expression was then examined by immunohistochemistry in matched formalin-fixed paraffin-embedded EOC samples and in 13 normal ovaries. Finally, we correlated Trop-2 expression to EOC conventional clinicopathological features and patient outcomes. Results We found a significant Trop-2 mRNA and protein upregulation in EOCs compared to normal controls ( p < 0.001). Trop-2 protein overexpression was significantly associated with the presence of ascites ( p = 0.04) and lymph node metastases ( p = 0.04). By univariate survival analysis, Trop-2 protein overexpression was significantly associated with decreased progression-free ( p = 0.02) and overall survival ( p = 0.01). Importantly, Trop-2 protein overexpression was an independent prognostic marker for shortened survival time in multivariate Cox regression analysis ( p = 0.04, HR = 2.35, CI 95% = 1.03–5.34). Conclusions Our results indicate, for the first time, that Trop-2 protein overexpression correlates with an aggressive malignant phenotype and may constitute a novel prognostic factor for EOC. The targeting of Trop-2 overexpression by immunotherapeutic strategies may represent an attractive and potentially effective approach in patients harbouring EOC.

Prognostic significance of CD3+ tumor-infiltrating lymphocytes in ovarian carcinoma

Objective. Epithelial ovarian cancer (EOC) is the most common cause of death among gynecological malignancies in Europe and North America. Although the presence of tumor-infiltrating mononuclear cells has been documented in EOC, the association of tumor-infiltrating mononuclear cells with clinical outcome remains controversial. The aim of the present study was to investigate the prognostic significance of CD3+ tumor-infiltrating T lymphocytes (TIL) on overall survival of EOC patients. Methods. We evaluated retrospectively by immunohistochemistry the distribution of CD3+ TIL in tumor specimens of 116 EOC patients. The expression of estrogen and progesterone receptors, Ki-67, DNA topoisomerase IIα, p21, p53, HER-2/neu, bax and bcl-2 was also evaluated by immunohistochemistry. The prognostic significance of CD3+ TIL and other immunohistochemical and clinical parameters was evaluated with log-rank test. Multivariate analysis was performed using the Cox regression. Results. CD3+ TIL were observed in all tumor samples, both in cancer stroma and within cancer epithelium (intraepithelial TIL). The median counts of stromal TIL and intraepithelial TIL were 338 lymphocytes/mm 2 (range 81–2094 lymphocytes/mm 2) and 125 lymphocytes/mm 2 (range 7–481 lymphocytes/mm 2), respectively. In univariate analysis, age, stage, grade, presence of residual tumor, expression of progesterone receptors, Ki-67, DNA topoisomerase IIα and intraepithelial CD3+ TIL count were significant predictors of overall survival. On multivariate analysis, only the presence of residual tumor, stage, expression of progesterone receptors and intraepithelial CD3+ TIL count were found to be significant independent predictors of overall survival. Conclusion. Present data indicate that the intraepithelial CD3+ TIL count is a significant prognostic factor in EOC.

Grado de expresión y valor pronóstico de las proteínas p53 y HER2/neu en el tejido ovárico benigno y en el cáncer de ovario

To investigate the prognostic value of p53 and HER2/neu overexpression in epithelial ovarian cancer (EOC). p53 and HER2/neu immunostaining were performed in 198 tissue samples, 124 EOC, 44 benign ovarian tumors and 30 normal ovaries. Nuclear p53 and membranous HER2/neu immunostaining were evaluated. Neither p53 nor HER2/neu overexpression was seen in the benign ovarian tumors. HER2/neu immunostaining was observed in one normal ovary. P53 overexpression was found in 25% EOC and was related with advanced stage, endometrioid, clear cell and undifferentiated types, grade G3, and sub-optimal surgery. HER2/neu immunostaining was observed in 24.2% and it was associated with advanced stage, clear cell and undifferentiated types, and suboptimal surgery. Both, p53 and HER2/neu overexpression decreased overall and progression-free survival, but in the multivariant analysis, only HER2/neu overexpression was an independent prognostic factor of overall survival (RR = 2.8; 95% confidence interval [CI], 1.2-5.6) and recurrence (RR = 2.8; 95% CI, 1.1-7.1). Simultaneous p53 and HER2/neu overexpression made the prognosis worse (p < 0.01). HER2/neu overexpression (but not p53 overexpression) is a major prognostic factor in EOC.

Prognostic significance of tumor angiogenesis in epithelial ovarian cancer: in association with transforming growth factor β and vascular endothelial growth factor

We aimed to evaluate the prognostic significance of microvessel density (MVD), vascular endothelial growth factor (VEGF), and transforming growth factor β (TGFβ), as well as to find out the relationship between MVD, and VEGF and TGFβ in epithelial ovarian cancer (EOC). Surgical specimens of 47 patients with stage I–IV primary EOC, who underwent extended surgical staging according to FIGO, were investigated. Five-μm thick tissue sections were immunostained with antibody to factor VIII-related antigen, and MVD was assessed at three separate areas of ×200 magnification. Expressions for VEGF and TGFβ were evaluated by immunohistochemical staining using related monoclonal antibodies. Results were correlated with clinicopathologic factors and survival. We did not find any correlation between MVD and clinicopathologic factors, or patient survival. Similarly, there was no association between the degree of VEGF staining and survival or clinicopathologic factors, except preoperative ascites volume, which was higher in patients showing moderate and intense VEGF staining than those with weak VEGF staining (P = 0.052). The expression of TGFβ was inversely correlated with preoperative CA-125 levels (P &lt; 0.05). Furthermore, there was no correlation between MVD and the staining intensity of VEGF or TGFβ. In conclusion, angiogenesis does not appear as a prognostic factor in EOC. We suggest that VEGF is an important mediator of ascites formation, and that TGFβ, which is supposed to have tissue-specific actions in tumorigenesis, may have growth-inhibitory functions in EOC.