Stage Epithelial Ovarian Cancer Research Articles

COX-1 Inhibitors: Beyond Structure Toward Therapy.

Biosynthesis of prostaglandins from arachidonic acid (AA) is catalyzed by cyclooxygenase (COX), which exists as COX-1 and COX-2. AA is in turn released from the cell membrane upon neopathological stimuli. COX inhibitors interfere in this catalytic and disease onset process. The recent prominent discovery involvements of COX-1 are mainly in cancer and inflammation. Five classes of COX-1 inhibitors are known up to now and this classification is based on chemical features of both synthetic compounds and substances from natural sources. Physicochemical interactions identification between such molecules and COX-1 active site was achieved through X-ray, mutagenesis experiments, specific assays and docking investigations, as well as through a pharmacometric predictive model building. All these insights allowed the design of new highly selective COX-1 inhibitors to be tested into those disease models in which COX-1 is involved. Particularly, COX-1 is expressed at high levels in the early to advanced stages of human epithelial ovarian cancer, and it also seems to play a pivotal role in cancer progression. The refinement of COX-1 selective inhibitor structure has progressed to the stage that some of the inhibitors described in this review could be considered as promising active principle ingredients of drugs and hence part of specific therapeutic protocols. This review aims to outline achievements, in the last 5 years, dealing with the identification of highly selective synthetic and from plant extracts COX-1 inhibitors and their theranostic use in neuroinflammation and ovarian cancer. Their gastrotoxic effect is also discussed.

Laparoscopic surgical staging in women with early stage epithelial ovarian cancer performed by recently certified gynecologic oncologists

ObjectiveTo compare the surgical and oncological outcomes of laparoscopic versus open surgical staging in patients with early stage ovarian cancer performed by recently certified gynecologic oncologists. Study designA retrospective comparative observational study was performed, which included women who had undergone laparoscopic comprehensive surgical staging for early stage epithelial ovarian cancer between June, 2008 and January, 2014. Patients were compared with women who had undergone laparotomic staging between June, 2006 and January, 2014. ResultsA total of 50 and 58 patients underwent, laparoscopic and laparotomy surgical staging, respectively. The patients’ baseline characteristics were similar in both groups. Women in the laparoscopy group had a significantly lower preoperative CA-125 value (p=0.01). The operative time was similar between groups. The patients in the laparotomy group had significantly higher estimated blood loss (p≤0.001) and larger ovarian masses (p=0.001). Estimated blood loss was significantly higher in laparotomy versus laparoscopy; median (IQ range) 200 (200–225) ml and 500 (300–1000) ml (p≤0.0001). Intraoperative complications and postoperative complication rate was similar in both groups regardless of the type of surgical procedure; and laparoscopy was associated with a significantly shorter length of the hospital stay (p≤0.001). The number of lymph node retrieved and upstaging rate, as well as progression free survival and overall survival rates, were similar in both groups. ConclusionsLaparoscopic surgical staging of apparent early stage ovarian cancer has similar surgical and oncological outcomes to laparotomy when recently certified gynecologic oncologists perform the procedures.

Glasgow prognostic score is an independent marker for poor prognosis with all cases of epithelial ovarian cancer

Inflammatory markers are important prognostic factors in various cancers. This study investigated whether inflammatory markers of the Glasgow prognostic score (GPS) predicted progression‐free survival (PFS) and overall survival (OS) for patients with all cases of epithelial ovarian cancer (OC). Pretreatment GPS was examined for the correlations with PFS and OS in 216 patients in all stages of epithelial OC. Statistical analyses were performed using the Mann–Whitney U‐test. PFS and OS were analyzed using the Kaplan–Meier method. Cox's proportional hazard regression was used for univariate and multivariate analyses. For all patients, the median PFS was 35.1 months, and median OS was 46.7 months; follow‐up range was 1–162 months. Kaplan–Meier analysis revealed that patients with high GPS (GPS 2) at pretreatment had a shorter PFS and OS than did patients with lower GPS (GPS 0 + 1) in for early, advanced, and all‐stages of OC (PFS: P < 0.001 for early‐, advanced‐ and all‐stages; OS; P < 0.001 for early‐ and all‐stage, P = 0.015 for advanced‐stage). GPS (GPS 2) was also found to be an independent predictor of both recurrence (P = 0.002) and survival (P = 0.001) of all cases of epithelial OC by a multivariate analysis. GPS can serve as an indicator of poor prognosis in patients with all stages of epithelial OC, including early‐stage disease and regardless of histology.

Abstract B27: Investigation of small GTPase genes in epithelial ovarian cancer.

Abstract Background: Epithelial Ovarian Cancer (EOC) is a lethal gynecologic malignancy and the fifth cause of cancer mortality in women in the US. Normal ovarian physiology is intricately connected to tightly regulated small GTP binding proteins of the Ras superfamily (Ras, Rac, Rho, Rab, Arf, and Ran) which regulate key cellular processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. These proteins function in a highly coordinated manner through signaling cascades and feedback loops within and among the small GTPase subfamilies. We hypothesized that single nucleotide polymorphisms (SNPs) in small GTPase genes are associated with epithelial ovarian cancer (EOC) risk and aberrant expression of these genes correlates with tumor characteristics including overall survival (OS). Methods: In a discovery set of 7931 EOC cases and 9206 controls we investigated 9,356 SNPs from 112 genes, 657 of which showed associations up to the significance level of p&amp;lt;0.05. We genotyped 407 of the most significant SNPs from 112 genes in a combined dataset (discovery and replication) which consisted of 18,736 EOC cases and 23,448 controls (of European ancestry) from 43 studies in the Ovarian Cancer Association Consortium (OCAC), using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). Odds ratios and 95% confidence intervals were calculated using unconditional logistic regression under log-additive models. A False Discovery Rate (FDR) q&amp;lt;0.2 was applied. Pearson's correlation tests were performed on the expression of genes with tumor characteristics and OS in 561 ovarian tumors: serous (n=464); endometrioid (n=52); clear cell carcinoma (n=28) and mucinous (n=17) subtypes. Results: The most significantly associated SNP associations with EOC were: AKAP6 rs1955513, (OR=0.9, p=3.3x10-4) in all invasive; ARGHEF10L rs10788679, (OR=1.05, p=2.6x10-4) in serous; RAB31 rs1166373, (OR=1.25, p=4.0x10-3) in endometrioid; KRAS rs4963872, (OR=1.35, P=4.5x10-4) in mucinous EOC and TNIK rs6780532, (OR=0.88, p=7.7x10-3) in clear cell carcinoma. Increased expression of AKAP6 and TNIK was marginally correlated with advanced EOC stage (p&amp;lt;0.05) while high KRAS expression was correlated with OS (HR=1.18, p=0.038). Conclusions: Genetic variation in the small GTPase genes appears to be associated with ovarian cancer risk and aberrant expression of these genes correlates with tumor characteristics and OS. Citation Format: Hui-Yi Lin, Yin Xiong, Jonathan Tyrer, Douglas C. Marchion, Alvaro NA Monteiro, Andrew Berchuck, Joellen M. Schildkraut, Ellen L. Goode, Susan J. Ramus, Simon A. Gayther, Paul DP Pharoah, Steven A. Narod, Thomas A. Sellers, Catherine M. Phelan. Investigation of small GTPase genes in epithelial ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B27.

Use of Plasma Metabolomics to Identify Diagnostic Biomarkers for Early Stage Epithelial Ovarian Cancer.

The early detection of ovarian carcinoma is difficult due to the absence of recognizable physical symptoms and a lack of sensitive screening methods. The currently available biomarkers (such as CA125 and HE4) are insufficiently reliable to distinguish early stage (I/II) epithelial ovarian cancer (EOC) patients from normal individuals because they possess a relatively poor sensitivity and specificity. To evaluate the application of metabolomics to biomarker discovery in the early stages of epithelial ovarian cancer (EOC), plasma samples from 21 early stage EOC patients and 31 healthy controls were analyzed with ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC/Q-Tof/MS) in conjunction with multivariate statistical analysis. Eighteen metabolites, including lysophospholipids, 2-piperidone and MG (18:2), were found to be disturbed in early stage EOC with satisfactory diagnostic accuracy (AUC=0.920). These biomarkers were specifically validated in the EOC nude mouse model, and five of the biomarkers (lysophospholipids, adrenoyl ethanolamide et al.) were highly suspected of being associated with EOC because they were differentially expressed with the same tendency in the EOC nude mice versus normal controls. In conclusion, the selected metabolic biomarkers have considerable utility and significant potential for diagnosing early ovarian cancer and investigating its underlying mechanisms.

Expression of Gab1 Is Associated with Poor Prognosis of Patients with Epithelial Ovarian Cancer.

Growth factor receptor-bound protein-2 (Grb2) can act as the scaffold protein recruiting other molecules to the stimulated receptors. Grb2-associated binding protein 1 (Gab1) is involved in cell proliferation, and its expression may enhance the carcinogenesis and cancer progression. However, the function of Gab1 remains to be investigated. Epithelial ovarian cancer (EOC) is the most lethal malignancy in the female reproductive system with increasing incidence and unsatisfied overall survival (OS). We investigated the expression of Gab1 in EOC tissues and the correlations between Gab1 expression and the clinicopathological characteristics of patients with EOC using Spearman rank test. The staining results were evaluated based on both the percentage of Gab1-positive tumor cells and the staining intensity for Gab1 expression. Kaplan-Meier survival analysis and Cox proportional hazards analysis were used to compare the postoperative OS between EOC patients with high Gab1 expression and those with low Gab1 expression. The high expression of Gab1 was positively correlated with advanced FIGO stage and lymph node metastasis of EOC. Univariate analysis showed that advanced FIGO stage, pathological grade, lymph node metastasis or Gab1 expression were associated with poor OS. Moreover, multivariate analysis revealed that Gab1 expression could be an independent prognostic factor for the poor OS of EOC patients (P = 0.042). We propose that Gab1 expression is correlated with poor prognosis of EOC patients and may act as an independent prognostic indicator.

Clinical implication of the serum galectin-1 expression in epithelial ovarian cancer patients.

Backgroundgalectin-1 has been implicated in tumor invasion and metastasis and is frequently over-expressed in epithelial ovarian cancer (EOC), but its potential as a biomarker remains unclear. In this novel study, we have explored the possible use of galectin-1 as a biomarker for EOC.Methodsgalectin-1 in sera was evaluated by ELISA in a pilot panel of EOC patients, healthy volunteers, patients with benign gynecologic tumors or other gynecologic malignancies. We examined galectin-1 expression in EOC tumor samples by Western Blot, qRT-PCR and immunohistochemistry. In vitro experiments were conducted to elucidate the biologic role of galectin-1 in EOC progression using over-expression of galectin-1 in OVCAR-3 cells. We also looked for the association of galectin-1 expression with clinic pathological variables and survival outcomes in EOC.ResultsA significant difference was detected in serum galectin-1 between EOC patients with non-metastatic and those with metastatic disease, but not between EOC patients and healthy volunteers. It increased in recurrent cases and decreased after debulking surgery. Both of galectin-1 mRNA and protein levels were increased in 90 % of the examined EOC tissue samples, compared with a wedge resection of a normal ovary. High galectin-1 in peritumor stroma was primarily detected in advanced stages of EOC. Over expression of galectin-1 significantly increased the ability of OVCAR-3 cells’ migration and invasion.ConclusionsOur results suggest that galectin-1 might play a role in tumor progression and be associated with poor outcome in EOC. It could be a novel prognostic and progression biomarker in EOC patients.

Macrophage Blockade Using CSF1R Inhibitors Reverses the Vascular Leakage Underlying Malignant Ascites in Late-Stage Epithelial Ovarian Cancer

Malignant ascites is a common complication in the late stages of epithelial ovarian cancer (EOC) that greatly diminishes the quality of life of patients. Malignant ascites is a known consequence of vascular dysfunction, but current approved treatments are not effective in preventing fluid accumulation. In this study, we investigated an alternative strategy of targeting macrophage functions to reverse the vascular pathology of malignant ascites using fluid from human patients and an immunocompetent murine model (ID8) of EOC that mirrors human disease by developing progressive vascular disorganization and leakiness culminating in massive ascites. We demonstrate that the macrophage content in ascites fluid from human patients and the ID8 model directly correlates with vascular permeability. To further substantiate macrophages' role in the pathogenesis of malignant ascites, we blocked macrophage function in ID8 mice using a colony-stimulating factor 1 receptor kinase inhibitor (GW2580). Administration of GW2580 in the late stages of disease resulted in reduced infiltration of protumorigenic (M2) macrophages and dramatically decreased ascites volume. Moreover, the disorganized peritoneal vasculature became normalized and sera from GW2580-treated ascites protected against endothelial permeability. Therefore, our findings suggest that macrophage-targeted treatment may be a promising strategy toward a safe and effective means to control malignant ascites of EOC.

Upregulated CDK16 Expression in Serous Epithelial Ovarian Cancer Cells.

BackgroundAs CDK-16 has been shown to be upregulated in several transformed cancer lines, we hypothesized that the cyclin-dependent kinase 16 (CDK-16) may be upregulated in serous epithelial ovarian cancer (EOC) cells. Therefore, we comparatively examined the mRNA and protein expression of CDK-16 in samples resected from serous EOC patients and normal controls.Material/MethodsTissue samples were collected from 70 serous EOC patients and 40 normal controls. Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) was conducted to assess mRNA expression. CDK-16 protein expression was assessed by semi-quantitative immunohistochemical staining. Differences in mRNA and protein expression between serous EOC cells and normal tissue cells were tested with the Kruskal-Wallis test and analysis of variance (ANOVA).ResultsBoth CDK-16 mRNA and protein expression were significantly higher in serous EOC tumor cells as compared to normal control ovarian cells (p<0.01). Although there was no significant correlation between CDK-16 mRNA expression and serous EOC stage (p=0.0794), there was a significant correlation between CDK-16 mRNA expression and serous EOC grade (p<0.0001). Moreover, there were significant correlations between CDK-16 protein expression and serous EOC stage (p<0.0001) and grade (p<0.0001).ConclusionsCDK-16 upregulation in serous EOC cells may represent a negative feedback loop to promote ovarian cell differentiation in malignantly-transformed serous EOC cells. Further in-depth investigation on CDK-16’s role in serous EOC is needed.

Medical treatment of early stage and rare histological variants of epithelial ovarian cancer.

Epithelial ovarian cancer is often considered a single pathological entity, but increasing evidence suggests that it is rather a group of different neoplasms, each with unique pathological characteristics, molecular features, and clinical behaviours. This heterogeneity accounts for the different sensitivity to antineoplastic drugs and makes the treatment of ovarian tumours a challenge.For early-stage disease, as well as for heavily pre-treated patients with recurrent ovarian cancer, the benefit of chemotherapy remains uncertain.Clear-cell, mucinous, low-grade serous, and endometrioid carcinomas show different molecular characteristics, which require different therapeutic approaches. In the era of personalised cancer medicine, understanding the pathogenesis and the genetic background of each subtype of epithelial ovarian tumour may lead to a tailored therapy, maximising the benefits of specific treatments and possibly reducing the side effects. Furthermore, personal factors, such as the patient’s performance status, should be taken into account in the management of ovarian cancer, with the aim of safeguarding the patients’ quality of life.

Overexpression of tumor necrosis factor receptor-associated protein 1 (TRAP1) are associated with poor prognosis of epithelial ovarian cancer.

Tumor necrosis factor receptor-associated protein 1 (TRAP1 or Hsp75) is a member of the mitochondrial heat shock proteins. TRAP1 expression is associated with drug and apoptosis resistance in various human cancers. This study assessed TRAP1 expression in tissue specimens of epithelial ovarian cancer (EOC) and its association with clinicopathological features and survival of EOC patients. Tissue samples from 356 patients were collected for immunohistochemical analysis of TRAP1 expression. TRAP1 levels in EOC tissues were significantly higher than that in noncancerous tissues. TRAP1 expression was associated with poor EOC differentiation, advanced pT stages, lymph node and distant metastasis, and advanced FIGO stages (p < 0.05). Kaplan-Meier survival analysis showed that TRAP1 expression was associated with poor prognosis of EOC patients and multivariate analysis revealed that TRAP1 expression (relative risk 6.720, CI 4.100-11.015, p < 0.001), tumor grade (p = 0.001), pathology stages (p = 0.001), and FIGO stage (p = 0.017) were all independent predictors of patients' overall survival. These data demonstrate for the first time that increased TRAP1 expression was significantly associated with EOC stages and poor prognosis. Future studies are needed to confirm the role of TRAP1 as a prognostic tumor marker in EOC.

Abstract POSTER-BIOL-1335: Threonyl-tRNA synthetase overexpression correlates with angiogenesis and progression of human ovarian cancer

Abstract Ovarian tumors create a dynamic microenvironment that promotes angiogenesis and reduces immune responses. There is growing evidence that tRNA synthetases have a role in cell signaling separate from their function in protein synthesis. Our research has revealed that threonyl-tRNA synthetase (TARS) has an extracellular angiogenic activity. Exploration of protein and mRNA databases further showed a connection between TARS expression and ovarian cancer. The objective of this study was to test the hypothesis that TARS is secreted by ovarian cancer cells and that its expression in clinical samples correlates with angiogenic markers and ovarian cancer progression. TARS secretion by SKOV3 human ovarian cancer cells was induced by hypoxia or tumor necrosis factor-α (TNF-α) as detected by ELISA and Western blot of culture media (p&amp;lt;0.001). For the clinical study, TARS, vascular endothelial growth factor (VEGF) and PECAM were assessed by immunohistochemistry in serial sections of paraffin embedded ovarian tissues from 70 patients diagnosed with epithelial ovarian cancer and 12 control patients. Serum samples from 31 tissue-matched patients were analyzed by ELISA for TARS, CA125, and tumor necrosis factor-α (TNF-α). There was a strong association between the tumor expression of TARS and advancing stage of epithelial ovarian cancer (p&amp;lt;0.001). TARS expression and localization were also correlated with VEGF (p&amp;lt;0.001). A significant proportion of samples included heavy TARS staining of infiltrating leukocytes which also correlated with stage (p=0.017). Patient serum TARS was related to tumor TARS and angiogenic markers, but did not achieve significance with respect to stage. Multivariate Cox proportional hazard models revealed a surprising inverse relationship between TARS expression and mortality risk in late stage disease (p=0.062). Together these results show that TARS is secreted in response to cell stress and that its expression is increased in epithelial ovarian cancer according to stage and angiogenic progression. These findings and the association of TARS with disease survival provide clinical validation that TARS is associated with angiogenesis in ovarian cancer. These results encourage further study of TARS as a regulator of the tumor microenvironment and possible target for diagnosis and/or treatment in ovarian cancer. Citation Format: Theresa L. Wellman, Midori Eckenstein, Cheung Wong, Mercedes Rincon, Takamaru Ashikaga, Sharon L. Mount, Christopher S. Francklyn, Karen M. Lounsbury. Threonyl-tRNA synthetase overexpression correlates with angiogenesis and progression of human 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-1335.

Abstract 1579: Circulating cell-free DNA as a diagnostic marker for epithelial ovarian cancer and an association with epithelial-mesenchymal transition

Abstract Objectives: Although technologies continue to develop, there are still many limitations on detecting circulating tumor cells in blood. In addition, the great genetic heterogeneity in ovarian cancer is one of the major concerns. Therefore, we aimed to investigate the cell-free DNA (cfDNA) as a diagnostic marker for epithelial ovarian cancer (EOC) and evaluate the cfDNA level of epithelial-mesenchymal transition markers. Methods: Blood was preoperatively collected from women who were assigned to surgery for pelvic mass. DNA was extracted using Qiagen DNA Mini kit and quantification of total cfDNA was performed using real-time PCR with TaqMan Assay with primers directed to the following genes: GAPDH, β-globin, β-actin, E-cadherin, and fibronectin. Results: A total of 32 patients with EOC and 17 patients of benign ovarian disease (controls) were included. The median cfDNA level of β-globin was 0 (range, 0-0.35)GE/ml in EOC and 0.41 (range, 0-33.5)GE/ml in control (p = 0.04). The sensitivity of β-globin cfDNA (&amp;gt;0.4 GE/ml) was 51.9%, which was lower than that of CA-125 (96.3%, if CA-125 &amp;gt;35IU/ml). cfDNA was significantly higher in advanced stage of EOC than early stage EOC (p = 0.02). Plasma E-cadherin level was significantly related with β-globin cfDNA (coefficient 0.886, p&amp;lt;0.001). However, there was no significant association with cfDNA amount and survival outcomes. Conclusions: Circulating cfDNA can be a promising target for early detection of EOC. The levels of epithelial-mesenchymal transition markers showed a different pattern in plasma and were associated with other cfDNA amounts. Citation Format: Yu-Jin Koo, Kyung-Jin Min, Jin-Hwa Hong, Jae-Kwan Lee. Circulating cell-free DNA as a diagnostic marker for epithelial ovarian cancer and an association with epithelial-mesenchymal transition. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1579. doi:10.1158/1538-7445.AM2015-1579

Does omentectomy in epithelial ovarian cancer affect survival? An analysis of the Surveillance, Epidemiology, and End Results database.

Although omentectomy is part of the staging and treatment of epithelial ovarian cancer (EOC), its performance in a patient with a grossly normal omentum—acknowledging its role in debulking gross tumor deposits—has never been definitively shown to improve survival. Using Surveillance, Epidemiology, and End Results data from 1998 to 2010, we identified patients with EOC and assessed their age, race, year of diagnosis, tumor grade, histologic subtype, International Federation of Gynecology and Obstetrics stage, lymph node dissection, nodal findings, and performance of omentectomy. We compared disease-specific survival (DSS) based on the presence or absence of omentectomy using log-rank univariate analysis, Cox multivariate analysis, and Kaplan-Meier survival curves. A total of 20,975 patients with invasive EOC underwent surgical treatment. Initial univariate analysis indicated a lower mean DSS with performance of omentectomy. However, multivariate analysis demonstrated no significant association between DSS and performance of omentectomy (hazard ratio, 0.978; P = 0.506). The DSS was improved if lymphadenectomy was performed (hazard ratio, 0.60; P < 0.001). In recent years, there was a trend toward decreased performance of omentectomy.To look specifically at patients without bulky omental disease, a subset analysis was done looking at patients with stage I-IIIA disease who had had lymphadenectomy performed. There were 5454 patients in the group who underwent an omentectomy and 2404 patients in the group who did not. No difference in DSS was seen between the groups based on performance of omentectomy (P = 0.89). However, the analysis was limited by the lack of Surveillance, Epidemiology, and End Results data on the extent of omentectomy, amount of residual disease, and adjuvant chemotherapy. In this analysis, performance of omentectomy in patients with EOC without bulky disease (≤stage IIIA) did not seem to confer improvement in survival. A randomized control trial would be needed to fully address this question.

High Pretreatment Plasma D-dimer Levels Are Associated With Poor Prognosis in Patients With Ovarian Cancer Independently of Venous Thromboembolism and Tumor Extension.

ObjectiveElevated plasma D-dimer (DD) is associated with decreased survival among patients with breast, lung, and colon cancers. The present study clarifies the prognostic significance of pretreatment plasma DD levels in patients with epithelial ovarian cancer (EOC).MethodsWe investigated pretreatment DD levels and other variables for overall survival using univariate and multivariate analyses in 134 consecutive patients with EOC stages II to IV who were initially treated between November 2004 and December 2010.ResultsThe median follow-up period was 53 (7–106) months. Univariate analysis significantly associated elevated pretreatment DD (≥2.0 μg/mL) levels to poor 5-year overall survival rates irrespective of previously treated venous thromboembolism (72.2% vs 52.6%, P = 0.039). Cancer antigen 125 levels of 200 U/mL or higher (P = 0.011), distant metastases (P = 0.0004), residual tumors (P < 0.0001), and International Federation of Gynecology and Obstetrics stage III/IV (P = 0.0033) were also poor prognostic factors. Multivariate analysis independently associated DD levels of 2.0 μg/mL or higher (P = 0.041), distant metastases (P = 0.013), and residual tumors (P < 0.0001) with poor overall survival.ConclusionsHigh pretreatment DD levels are associated with poor overall survival in patients with EOC independently of venous thromboembolism and tumor extension and might comprise a promising prognostic biomarker for patients with EOC.

Plasma immune analytes in patients with epithelial ovarian cancer

ObjectivesInflammation is a common feature of epithelial ovarian cancer (EOC), and measurement of plasma markers of inflammation might identify candidate markers for use in screening or presurgical evaluation of patients with adnexal masses. MethodsPlasma specimens from cohorts of 100 patients with advanced EOC (AJCC Stage III and IV), 50 patients with early stage EOC (Stage I and II), and 50 patients with benign surgical conditions were assayed for concentrations of multiple cytokines, toll-like receptor agonists, and vascular growth factors via ELISA and electrochemiluminescence. Immune proteins were then analyzed for association with EOC. Differences in plasma protein levels between benign, early, and advanced EOC patient groups were assessed with and without adjustment for plasma cancer antigen 125 (CA-125) levels. ResultsOut of 23 proteins tested, six—including interferon gamma (IFNγ), interleukin 6 (IL-6), IL-8, IL-10, tumor necrosis factor alpha (TNFα), and placental growth factor (PlGF)—were univariately associated with EOC (all p<0.005), and one—IL-6—was associated with early stage EOC (p<0.0001). Heat shock protein 90kDa beta member 1 (HSP90B1, gp96) was associated with EOC and early stage EOC with borderline statistical significance (p=0.039 and p=0.026, respectively). However, when adjusted for (CA-125), only HSP90B1 independently predicted EOC (p=0.008), as well as early stage EOC (p=0.014). ConclusionsMultiple plasma cytokines, including IFNγ, IL-6, IL-8, IL-10, TNFα, PlGF, and HSP90B1 are associated with EOC. Of these, HSP90B1 is associated with EOC independent from the biomarker CA-125.

May the platelet to lymphocyte ratio be a prognostic factor for epithelial ovarian cancer?

The study aimed to evaluate changes in hematologic parameters, including white blood cell, platelet count, platelet indices, the platelet to lymphocyte and neutrophil to lymphocyte ratios in patients with early and advanced stages of epithelial ovarian cancers. The study included 100 patients with epithelial ovarian cancer who underwent primary staging exploratory laparotomy. Preoperative hematologic parameters, tumor histopathologic type, grade, stage and serum CA-125 levels were retrospectively analyzed. These parameters were compared between the patients with early (stage I-II) and advanced (stage III-IV) ovarian cancer. White blood cell count and platelet indices, including mean platelet volume, platelet distribution width and platelet crit did not show a statistically significant difference between groups with early and advanced ovarian cancer. However, the neutrophil to lymphocyte ratio, platelet count, the platelet to lymphocyte ratio and CA-125 level showed a statistically significant difference between the two groups (p<0.05, p<0.01, p<0.001, p<0.01 respectively). It was found that the neutrophil to lymphocyte ratio, platelet count and the platelet to lymphocyte ratio increased with the increasing stage of ovarian cancer. Furthermore, it was seen that the platelet to lymphocyte ratio is an independent prognostic factor related to the stage of epithelial ovarian cancer.

Threonyl-tRNA synthetase overexpression correlates with angiogenic markers and progression of human ovarian cancer.

BackgroundOvarian tumors create a dynamic microenvironment that promotes angiogenesis and reduces immune responses. Our research has revealed that threonyl-tRNA synthetase (TARS) has an extracellular angiogenic activity separate from its function in protein synthesis. The objective of this study was to test the hypothesis that TARS expression in clinical samples correlates with angiogenic markers and ovarian cancer progression.MethodsProtein and mRNA databases were explored to correlate TARS expression with ovarian cancer. Serial sections of paraffin embedded ovarian tissues from 70 patients diagnosed with epithelial ovarian cancer and 12 control patients were assessed for expression of TARS, vascular endothelial growth factor (VEGF) and PECAM using immunohistochemistry. TARS secretion from SK-OV-3 human ovarian cancer cells was measured. Serum samples from 31 tissue-matched patients were analyzed by ELISA for TARS, CA-125, and tumor necrosis factor-α (TNF-α).ResultsThere was a strong association between the tumor expression of TARS and advancing stage of epithelial ovarian cancer (p < 0.001). TARS expression and localization were also correlated with VEGF (p < 0.001). A significant proportion of samples included heavy TARS staining of infiltrating leukocytes which also correlated with stage (p = 0.017). TARS was secreted by ovarian cancer cells, and patient serum TARS was related to tumor TARS and angiogenic markers, but did not achieve significance with respect to stage. Multivariate Cox proportional hazard models revealed a surprising inverse relationship between TARS expression and mortality risk in late stage disease (p = 0.062).ConclusionsTARS expression is increased in epithelial ovarian cancer and correlates with markers of angiogenic progression. These findings and the association of TARS with disease survival provide clinical validation that TARS is associated with angiogenesis in ovarian cancer. These results encourage further study of TARS as a regulator of the tumor microenvironment and possible target for diagnosis and/or treatment in ovarian cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-620) contains supplementary material, which is available to authorized users.

High expression of UCH37 is significantly associated with poor prognosis in human epithelial ovarian cancer.

Ubiquitin carboxyl-terminal hydrolase 37 (UCH37) is a member of deubiquitinating enzymes. It can suppress protein degradation through disassembling polyubiquitin from the distal subunit of the chain. The aim of this study was to assess the value of UCH37 in predicting tumor recurrence after curative resection in epithelial ovarian cancer (EOC) patients. In this study, the expression level of UCH37 in 5 paired EOC and normal tissue was tested by Western blot. And the association of UCH37 expression and prognostic value was analyzed in 100 tumor specimens from EOC patients, who underwent curative resection between 2003 and 2011. We found that UCH37 was up-regulated in most of the tumor tissue and high expression of UCH37 was an independent significant predictor associated with the poor outcome and recurrence of EOC (p=0.0037 and p=0.0042 in overall and disease-free survival, respectively), especially in the advanced stage of EOC (p=0.0106 and p=0.0115 in overall and disease-free survival, respectively), and may become a novel predictor for prognosis of EOC patients after curative resection. Our data suggest for the first time that UCH37 overexpression is associated with advanced tumor progression and poor clinical outcome of EOC patients and may help physicians make informed decisions regarding adjuvant treatment following curative resection.

PET radiotracer [18F]-P6 selectively targeting COX-1 as a novel biomarker in ovarian cancer: Preliminary investigation

Cyclooxygenase-1 (COX-1), but not COX-2, is expressed at high levels in the early stages of human epithelial ovarian cancer where it seems to play a key role in cancer onset and progression. As a consequence, COX-1 is an ideal biomarker for early ovarian cancer detection. A series of novel fluorinated COX-1-targeted imaging agents derived from P6 was developed by using a highly selective COX-1 inhibitor as a lead compound. Among these new compounds, designed by structural modification of P6, 3-(5-chlorofuran-2-yl)-5-(fluoromethyl)-4-phenylisoxazole ([18/19F]-P6) is the most promising derivative [IC50 = 2.0 μM (purified oCOX-1) and 1.37 μM (hOVCAR-3 cell COX-1)]. Its tosylate precursor was also prepared and, a method for radio[18F]chemistry was developed and optimized. The radiochemistry was carried out using a carrier-free K18F/Kryptofix 2.2.2 complex, that afforded [18F]-P6 in good radiochemical yield (18%) and high purity (>95%). In vivo PET/CT imaging data showed that the radiotracer [18F]-P6 was selectively taken up by COX-1-expressing ovarian carcinoma (OVCAR 3) tumor xenografts as compared with the normal leg muscle. Our results suggest that [18F]-P6 might be an useful radiotracer in preclinical and clinical settings for in vivo PET-CT imaging of tissues that express elevated levels of COX-1.