Primary Epithelial Ovarian Cancer Research Articles

PO-236 Human ligase profiling to predict platinum sensitivity and clinical outcome in primary epithelial ovarian cancers

IntroductionOvarian cancer (OC) is the third most common gynaecological cancer among women worldwide. In Europe, OC is the main cause of death among all the gynaecological tumours. DNA ligases play an essential role in maintaining genomic integrity by joining DNA breaks generated during replication and recombination. The human ligases, LIG I, LIG III and LIG IV are ATP-dependent DNA ligases. Our objective was to evaluate if ligases expressions could predict platinum sensitivity and clinical outcome in epithelial ovarian cancers.Material and methodsInvestigation of LIG I, LIG III and LIG IV expression in ovarian epithelial cancer was carried out in 525 consecutive ovarian epithelial cancer cases treated at Nottingham University Hospitals (NUH) between 1997 and 2010. Ligase expression was correlated to clinicopathological features, recurrence free survival (RFS) and ovarian cancer specific survival (OCSS).Results and discussionsHigh expression of LIG I was significantly associated with serous carcinoma (p<0.0001), higher FIGO stage at presentation (p<0.0001), higher tumour grade (p<0.0001), non-optimal surgical tumour de-bulking (p=0.004). High cytoplasmic ligase III expression was significantly associated with higher FIGO stage (p=0.002), higher histology grade (p=0.028), residual tumour following surgery (p=0.001), measurable disease before chemotherapy (p=0.006) and platinum resistance (p=0.025). High LIG IV expression was significantly associated with less residual tumour following surgical excision (p=0.006) and better response to platinum based chemotherapy (p=0.049). High LIG I and LIG III protein expressions were correlated with poor survival outcome. However, LIG IV was correlated with favourable outcome. LIG I expression was independently associated with poor outcome in cox multivariate model.ConclusionHuman Ligases are promising predictive biomarkers of platinum response and clinical outcome in epithelial ovarian cancer.

Trends and outcomes of women with synchronous endometrial and ovarian cancer.

This retrospective observational study examined trends, characteristics, and survival of women with synchronous endometrial and ovarian cancer (SEOC) in the Surveillance, Epidemiology, and End Results Program between 1973 and 2013. Among 235,454 women with primary endometrial cancer, synchronous ovarian cancer was seen in 4,082 (1.7%) women with the proportion being decreased from 2.0% to 1.6% between 1983 and 2013 (P=0.049); and the proportion of concurrent endometrioid tumors in the two cancer sites has increased from 24.2% to 49.9% among SEOC women (P<0.001). When compared to endometrial cancer without synchronous ovarian cancer, endometrioid histology in the two cancer sites was associated with improved cause-specific survival while non-endometrioid histology in the ovarian cancer was associated with decreased cause-specific survival (adjusted-P<0.01). Among 110,063 women with primary epithelial ovarian cancer, synchronous endometrial cancer was seen in 3,940 (3.6%) women with the proportion being increased from 2.2% to 4.4% between 1973 and 2013 (P<0.001); and the proportion of concurrent endometrioid tumors in the two cancer sites had increased from 24.3% to 50.2% among SEOC women (P<0.001). When compared to primary epithelial ovarian cancer without synchronous endometrial cancer, SEOC was associated with better cause-specific survival if ovarian cancer is endometrioid type or if endometrial cancer is endometrioid type (adjusted-P<0.001). Across the two cohorts, the proportion of SEOC reached to the peak in the late-40 years of age and then decreased significantly (P<0.001). In conclusion, our study suggests that synchronous ovarian cancer has decreased among endometrial cancer whereas synchronous endometrial cancer has increased among epithelial ovarian cancer.

Prevalence and molecular characteristics of defective mismatch repair epithelial ovarian cancer in a Japanese hospital-based population

The prevalence and molecular characteristics of defective mismatch repair epithelial ovarian cancers in the Japanese population have scarcely been investigated. Immunohistochemistry for mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2) was performed in formalin-fixed paraffin-embedded sections prepared from resected primary epithelial ovarian cancers in patients who underwent oophorectomy at our institution between April 2005 and September 2014. Genetic and/or epigenetic alterations of the mismatch repair genes were investigated in patients with loss of any mismatch repair proteins in the tumor. There were 305 patients with a median age of 54 years (range, 18-83 years). Loss of expression in the ovarian tumor of one or more mismatch repair proteins was observed in 3 of the 305 patients (0.98%): 2 patients MLH1/PMS2 loss and 1 patient showed MSH2/MSH6 loss. Genetic testing of these three patients failed to reveal any pathogenic germline mutations of MLH1 or MSH2. One patient with MLH1/PMS2 loss showed hypermethylation of the promoter region of MLH1. Somatic mutations were found in each of the alleles of MLH1 (c.545dupG and deletion of exons 2-19) in the other patient with MLH1/PMS2 loss. In the patient with MSH2/MSH6 loss, two somatic mutations were detected in MSH2 (c.229_230delAG and c.1861C>T), although we could not determine whether these mutations were biallelic or not. The prevalence of defective mismatch repair epithelial ovarian cancer in the Japanese hospital-based population was extremely low. Molecular mechanism involved in such defective mismatch repair ovarian cancers seems to be epigenetic events through MLH1 promotor hypermethylation or somatically mutated mismatch repair genes without germline mismatch repair mutation.

Ovarian Cancer Surgery in Australia and New Zealand: A Survey to Determine Changes in Surgical Practice Over 10 Years.

This study aimed to survey all practicing certified gynecological oncologists (CGOs) in Australia and New Zealand to determine their current surgical practice for primary advanced epithelial ovarian cancer (EOC) and compare the findings with an identical survey conducted 10 years previously. A questionnaire was e-mailed to all 53 practicing CGOs in Australia and New Zealand in July 2017 assessing their definition of optimal debulking for EOC, their use of neoadjuvant chemotherapy, and the surgical procedures they use to achieve cytoreduction. Results were compared with an identical study performed in 2007 using χ and logistic regression analysis. Response rate was 89% (47/53). A higher percentage of patients received neoadjuvant chemotherapy before surgery in 2017 than in 2007 (43% vs 16%, respectively). In 2017, CGOs were more likely to define optimal debulking as zero residual disease (R0; 21/44 [48%] vs 6/34 [18%], P < 0.001). To achieve this, CGOs were significantly more likely to independently perform stripping/resection of the diaphragm (44/47 [94%] vs 15/34 [44%], P < 0.001) and, with assistance from surgical colleagues, perform resection of upper para-aortic lymph nodes (39/46 [85%] vs 21/34 [62%], P = 0.02) and parenchymal liver metastases (30/46 [65%] vs 13/34 [38%], P = 0.02). They were now less likely to resect/reimplant the ureter without assistance (23% vs 53%, P = 0.01). A surgeon's definition of optimal debulking as R0 was significantly associated with a high use of neoadjuvant chemotherapy (in ≥50% of patients). Certified gynecological oncologists' definition of optimal debulking for primary EOC is more likely to be R0 in 2017 than in 2007. Radical abdominal surgery was performed more often in 2017, requiring assistance by a surgical colleague in many cases. An increased use of neoadjuvant chemotherapy was the only factor significantly associated with CGOs' definition of optimal debulking as R0.

The Role of PAR1 Autoantibodies in Patients with Primary Epithelial Ovarian Cancer.

This study aimed to analyze the predictive, prognostic and diagnostic value of autoantibodies to coagulation factor II thrombin receptor (F2R; protease-activated receptor 1, PAR1) (PAR1-AB) in patients with primary epithelial ovarian cancer (EOC). A total of 197 patients with primary EOC and 200 healthy female blood donors were included in the study. Enzyme-linked immunosorbent assay was applied to determine PAR1-AB levels in blood sera taken preoperatively. Correlation of PAR1-AB with clinicopathological outcome, progression-free (PFS) and overall (OS) survival was analyzed and patients were compared with controls. PAR1-AB was significantly negatively correlated with histological grading (p=0.008) and was significantly lower in the patient group compared to healthy controls (p<0.001). There was no significant correlation of PAR1-AB level with PFS or OS. This study showed PAR1-AB to significantly decrease in patients with primary EOC and with histological high-grade carcinoma. The relevance of PAR1-AB in early detection of ovarian cancer and follow-up for EOC should be further investigated.

Immunobiochemical pathways of neopterin formation and tryptophan breakdown via indoleamine 2,3-dioxygenase correlate with circulating tumor cells in ovarian cancer patients– A study of the OVCAD consortium

ObjectiveCirculating tumor cells (CTCs) may represent a chronic stimulus for the immune system. In the present study we investigated the potential association of CTCs, the immune activation marker neopterin, and the ratio of kynurenine to tryptophan (Kyn/Trp) as a measure for tryptophan breakdown. MethodsNeopterin, tryptophan and kynurenine levels were measured in plasma samples from patients with benign gynecological diseases (n=65) and with primary advanced epithelial ovarian cancer (EOC) at diagnosis (n=216) and six months after adjuvant platinum-based chemotherapy (n=45) by an enzyme-linked immunosorbent assay and high performance liquid chromatography. The presence of CTCs had been assessed in a previous study by qPCR-based analysis of CTC-related transcripts in the blood. The respective plasma levels in EOC and benign samples were compared using a two-tailed Chi2 or Fisher's exact test. The associations of the analytes and Kyn/Trp with clinicopathological parameters, platinum-sensitivity, and the presence of CTC-related transcripts were assessed using a two-sided t-test. Associations with patient outcome were evaluated using Cox regression analysis. ResultsIn EOC, elevated Kyn/Trp and neopterin levels were associated with advanced disease, peritoneal carcinomatosis, ascites, sub-optimal debulking, poor response to therapy and worse outcome. Likewise, neopterin and Kyn/Trp were elevated in CTC-positive patients, both at diagnosis and at follow-up in platinum-sensitive disease. ConclusionsWe observed concomitant alterations of CTCs and immune system related biomarkers suggesting that immune responses along with increase of neopterin and Kyn/Trp concentrations are not necessarily only located at the site of the tumor, but may also go on in the circulation.

70P - mTORC1 and its downstream effectors predict poor outcome in primary epithelial ovarian cancer

Background: Ovarian cancer is associated with the highest mortality rate among gynaecologic malignancies. There is a need to refine classification of ovarian cancer and identify novel targets. The mammalian target of rapamycin (mTOR) pathway has a crucial role in the regulation of translation of specific proteins associated with ovarian cancer progression. The major downstream effectors of mTOR are eukaryotic initiation factor 4E-binding protein 1 (4EBP1) and ribosomal protein S6 kinase (p70S6K). We aimed to investigate the biological significance of this pathway in ovarian cancer. Methods: Investigation of mTORC1, 4EBP1 and p70S6K protein expression, was carried out on tissue microarrays of 195 consecutive ovarian epithelial cancers treated at Nottingham University Hospitals (NUH) between 2000 and 2007. Clinicopathological and outcome data were collected. Results: High cytoplasmic expression of both 4EBP1 and p70S6K was associated with serous type carcinoma (p = 0.005 and p = 0.02 respectively). High expression of 4EBP1 was seen more frequently in cases treated with early debulking (p = 0.005). Univariate outcome analysis showed an inverse association between 4EBP1 expression and overall survival (p = 0.005) and development of local recurrence (p = 0.005). P70S6K showed inverse association with local recurrence (p = 0.002). High cytoplasmic expression of mTORC1 was inversely associated local recurrence (p = 0.032) and borderline significance with poor overall survival (p = 0.079). Conclusions: mTORC1 and its downstream effectors, 4EBP1 and p70S6K positive expression predicts local recurrence and poor survival in ovarian cancer patients. Therefore, this could be targeted as a potential pathway that could improve patients’ survival and reduce tumour recurrence. Legal entity responsible for the study: N/A Funding: Has not received any funding Disclosure: All authors have declared no conflicts of interest.

Increased HE4 mRNA Expression Correlates with High Level Of eIF3a mRNA And Better Survival in Women with Epithelial Ovarian Cancer.

Human epididymis protein 4 (HE4) is one of the most promising biomarkers for epithelial ovarian cancer (EOC). The majority of previous studies utilized the serum level or tissue protein expression of HE4 based upon immunohistochemistry (IHC) to evaluate the role of HE4 in the diagnosis, prognosis, and surveillance of EOC, but very little is known about HE4 mRNA expression. Eukaryotic translation initiation factor 3a (eIF3a) is implicated in oncogenesis and has been investigated extensively as a potential biomarker for malignancy. We previously reported a positive correlation between IHC expressions of eIF3a and HE4 in EOC. In the present study, we performed RT-PCR to determine mRNA expressions of HE4 and eIF3a in 30 normal ovarian tissues, 45 benign, 20 borderline and 94 malignant ovarian tumors. The association of HE4 and eIF3a mRNA expressions with clinicopathological characteristics and patient survivals was investigated. IHC was also performed in the same participants to investigate the correlation between mRNA and protein levels of HE4. HE4 mRNA level was found to be 48.42 ± 74.55 (mean ± SD, range: 0.01-343.99), significantly higher in primary EOC than in the borderline tumor, benign tumor, and normal ovarian tissue (P<0.001). The cutoff value was 13.99 for HE4 to discriminate malignant from benign tumors at 68.1% sensitivity and 93.0% specificity. By Spearman's correlation test, HE4 mRNA expression was indicated to positively correlate with serum CA125 level (r=0.530, P<0.001). Higher HE4 mRNA expression was associated with decreased frequency of lymph node metastasis (P=0.038) and better overall survival (OS) (P=0.007) in primary EOC. Multivariable analysis showed an independent prognostic value of the relative mRNA level of HE4 greater than one for OS (Hazard Ratio, 0.069, 95%CI, 0.009-0.530, P=0.010). eIF3a mRNA expression in women with primary EOC was 0.95 ± 1.19 (mean ± SD, range: 0.06-7.46), which was in a positive linear correlation with HE4 mRNA expression (r=0.310, P=0.002). In the present study, the HE4 mRNA level was unparalleled with IHC expression of HE4 (P>0.05). Collectively, our study revealed that increased HE4 mRNA expression correlates with high level of eIF3a mRNA and better survival in women with EOC, which calls for further investigations.

Effect of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy on relapse pattern in primary epithelial ovarian cancer: a propensity score based case-control study.

ObjectiveHyperthermic intraperitoneal chemotherapy (HIPEC) has been proposed as a treatment in ovarian cancer. A recently published RCT demonstrated that HIPEC prolongs disease-free survival (DFS) and overall survival (OS) in ovarian cancer. The aim of the study was to investigate oncologic results of cytoreductive surgery+HIPEC compared with cytoreductive surgery alone in advanced primary ovarian cancer with a particular attention to the pattern of recurrence.MethodsThis is a retrospective case control study with a propensity score (PS) matching of the patients. All the patients treated for primary advanced ovarian cancer who underwent interval surgery with or without HIPEC were collected; a PS was calculated in order to match cases to controls.ResultsAmong 77 eligible patients 56 patients were included in the study. Preoperative patients' characteristics were homogeneous. No difference in morbidity and mortality after surgery were recorded. DFS was not different among the 2 groups (13.2 vs. 13.9 months, p=0.454) but OS was better in patients treated with HIPEC with no median reached vs. 35.5 months (p=0.048). Patients treated with cytoreductive surgery alone were more likely to have a peritoneal recurrence (43% vs. 14%).ConclusionHIPEC seems to affect the relapse pattern with lesser peritoneal recurrence. This difference in relapse pattern seems to affect the OS with better results in patients treated with HIPEC. Further studies are needed to confirm these findings.

Peritoneal cancer index as a predictor of survival in advanced stage serous epithelial ovarian cancer: a prospective study.

ObjectiveA numerical score, the peritoneal cancer index (PCI), was developed to reflect the extent of tumor growth in gastric and colorectal cancers and to tailor treatment. This study aimed to examine the value of the PCI score in advanced epithelial ovarian cancer (EOC) regarding completeness of surgical cytoreduction and survival.MethodsThis was a prospective observational cohort study. Patients with primary serous EOC at International Federation of Gynecology and Obstetrics (FIGO) stages IIIB or higher were included. Patients with FIGO stage IVB as well as those assigned to receive neoadjuvant treatment were excluded from the study. The PCI was obtained and registered intraoperatively.ResultsIn the study period we recruited 96 patients with serous EOC stage IIIB–IVA. A PCI score cut-off value of 13 was calculated using a receiver operator characteristic (ROC) curve, above which worse survival is expected (area under the curve [AUC]=0.641; 95% confidence interval [CI]=0.517–0.765; sensitivity and specificity 80.6%, 45.0%, respectively; p=0.050). A multivariate analysis determined that suboptimal surgical cytoreduction was the only independent predictive factor for recurrence (odds ratio [OR]=7.548; 95% CI=1.473–38.675; p=0.015). A multivariate analysis determined that only suboptimal surgical cytoreduction (hazard ratio [HR]=2.33; 95% CI=0.616–8.795; p=0.005), but not PCI score >13 (HR=1.289; 95% CI=0.329–5.046; p=0.716), was an independent predictive factor for death.ConclusionWe conclude from this study that the PCI score is a reliable tool helping to assess the extent of disease in advanced serous EOC patients and may help predicting complete surgical cytoreduction but cannot qualify as a predictor of survival.

Tumor-associated macrophages and the tumor immune microenvironment of primary and recurrent epithelial ovarian cancer

Tumor-infiltrating lymphocytes (TILs) are associated with better prognosis in newly diagnosed epithelial ovarian cancer (EOC), but clinical trials of immunotherapies in patients with heavily treated disease reveal limited activity. Understanding the tumor microenvironment (TME) of primary and recurrent EOC should guide future trials. Here, we evaluated the TME of paired primary and recurrent tumors (n = 17), and non-paired primary (n = 20) and recurrent (n = 15) tumors, for CD8+ T cells, FOXP3+ regulatory T cells (Tregs), CD68+ tumor-associated macrophages (TAMs), programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1). CD8+ T cells were similar in primary and recurrent tumors, but Tregs were higher in recurrent tumors (P = .0210). Higher TAM density (≥5%) associated with higher Tregs (P = .001) and CD8+ T cells (P < .001) in recurrent tumors, but only with higher Tregs in primary tumors (P = .02). TAM-dense recurrent tumors expressed PD-L1 on tumor and immune cells, whereas TAM-dense primary tumors expressed PD-L1 predominantly on immune cells. In survival analyses, higher Tregs in primary tumors correlated with decreased time to first recurrence (17.0 versus 28.5 months, P = .022). Conversely, higher Tregs in recurrent tumors correlated with longer overall survival (OS) from recurrence (median not met versus 20.0 months, P = .022). TAM density did not affect patient survival. However, patients with increased TAMs at recurrence (n = 5) had longer OS from recurrence compared to patients without increased TAMs (n = 12) (56.0 versus 20.0 months); with the small sample size, this did not reach statistical significance (P = .074). Further characterization of the evolution of the TME is warranted.

The PAX8 cistrome in epithelial ovarian cancer.

PAX8 is a lineage-restricted transcription factor that is expressed in epithelial ovarian cancer (EOC) precursor tissues, and in the major EOC histotypes. Frequent overexpression of PAX8 in primary EOCs suggests this factor functions as an oncogene during tumorigenesis, however, the biological role of PAX8 in EOC development is poorly understood. We found that stable knockdown of PAX8 in EOC models significantly reduced cell proliferation and anchorage dependent growth in vitro, and attenuated tumorigenicity in vivo. Chromatin immunoprecipitation followed by next generation sequencing (ChIP-seq) and transcriptional profiling were used to create genome-wide maps of PAX8 binding and putative target genes. PAX8 binding sites were significantly enriched in promoter regions (p < 0.05) and superenhancers (p < 0.05). MEME-ChIP analysis revealed that PAX8 binding sites overlapping superenhancers or enhancers, but not promoters, were enriched for JUND/B and ARNT/AHR motifs. Integrating PAX8 ChIP-seq and gene expression data identified PAX8 target genes through their associations within shared topological association domains. Across two EOC models we identified 62 direct regulatory targets based on PAX8 binding in promoters and 1,330 putative enhancer regulatory targets. SEPW1, which is involved in oxidation-reduction, was identified as a PAX8 target gene in both cell line models. While the PAX8 cistrome exhibits a high degree of cell-type specificity, analyses of PAX8 target genes and putative cofactors identified common molecular targets and partners as candidate therapeutic targets for EOC.

Ovarian Cancer in Elderly Patients: Patterns of Care and Treatment Outcomes According to Age and Modified Frailty Index.

The present study assessed the predictive value of age and Modified Frailty Index (mFI) on the management of primary epithelial ovarian cancer (EOC) patients aged 70 years or older (elderly). A retrospective multicenter study selected elderly EOC patients treated between 2006 and 2014. Treatments were analyzed according to the following age group categories: (1) 70 to 75 years versus (2) older than 75 years, and mFI of less than 4 (low frailty) versus greater than or equal to 4 (high frailty). Seventy-eight patients were identified (40 in age group 1 and 38 in age group 2). The mFI was greater than or equal to 4 in 23 women. Median age of low frailty and high frailty was not significantly different (75.6 vs 75.3). Comorbidities were equally distributed according to age, whereas diabetes, hypertension, obesity, and chronic renal failure were more frequent in the high-frailty group. Performance status was different only according to mFI. Twenty percent of age group 1 versus 55.3% of age group 2 underwent none or only explorative surgical approach (P = 0.003), whereas surgical approaches were similar in the 2 frailty groups. The rate of postoperative complications was higher in high-frailty patients compared with low-frailty patients (23.5% vs 4.3%; P = 0.03). Chemotherapy was administered to all the patients, a monotherapy regimen to 50% of them. No differences in toxicity were registered, except more hospital recovery in the high-frailty cohort. Median survival time was in favor of younger patients (98 versus 30 months) and less-frailty patients (56 vs 27 months). Elderly EOC patients can receive an adequate treatment, but patients who are older than 75 years can be undertreated, if not adequately selected. The pretreatment assessment of frailty through mFI could be suggested in the surgical and medical management.

Concomitant venous thromboembolism at the time of primary EOC diagnosis: Perioperative outcomes and survival analyses.

To compare outcomes among women with epithelial ovarian cancer (EOC) undergoing primary surgery who present without venous thromboembolism (VTE) versus with VTE and placement of inferior vena cava (IVC) filter. Women who underwent primary surgery for EOC between 1/2/2003 and 12/30/2011 were identified. Patient characteristics were retrospectively abstracted, including diagnosis of VTE within 30days prior to surgery and placement of IVC filter. Associations with overall survival (OS) were evaluated using Cox proportional hazards models. A total of 843 patients met inclusion criteria; 817 patients (Group 1) did not have VTE at the time of EOC diagnosis and 26 patients (Group 2) had a VTE and IVC placement within 30days prior to surgery. Group 2 had worse performance status, lower albumin, and more likely to have clear cell histology. Groups 1 and 2 were similar in terms of perioperative outcomes. Mortality within 90days of surgery was 6.4% in Group 1 versus 11.5% in Group 2 (p=0.24). Although median OS for group 1 was much higher than group 2, 56.6m versus 25.7m, in this cohort this difference did not reach statistical significance (adjusted HR 1.39, 95% CI 0.85-2.29, p=0.19). Patients with VTE diagnosed at the time of EOC diagnosis have poor outcomes. This may reflect more aggressive tumor biology, worse overall health of the patient following VTE, or may reflect worse survival secondary to the VTE. Patients must be carefully selected for surgery in the setting of VTE.

PAX8 is a potential marker for the diagnosis of primary epithelial ovarian cancer.

The present study aimed to investigate the clinical significance of paired-box 8 (PAX8) in primary epithelial ovarian cancer (PEOC). Using immunohistochemical (IHC) staining, the expression of PAX8 in 60 patients with PEOC, 20 patients with ovarian benign lesions and 10 patients with metastatic ovarian cancer (MOC), was examined based on the clinicopathological profiles of the patients. The correlation between PAX8 expression and the clinicopathological parameters or prognosis of patients was statistically analyzed. PAX8 was revealed to be highly expressed in PEOC, but not in MOC, as indicated by IHC staining. The rate of positivity of PAX8 in PEOC was 92% (57/60) with no significant difference of PAX8 expression found between the various pathological types of PEOC (P=0.871). The rate of positivity of PAX8 in ovarian benign tumors was 85%, demonstrating no significant difference in comparison with that of PEOC (P=0.761). PAX8 staining and statistical analysis revealed that the higher the grade of PEOC, the less the cancer cell had differentiated (P=0.033) and the more the cancer had advanced according to International Federation of Gynaecological Oncologists (FIGO) staging (P=0.003). Survival rate statistics showed that PEOC patients with higher PAX8 expression exhibited a shorter postoperative survival rate (P=0.009). PAX8 was specifically expressed in PEOC, and its expression level was associated with the degree of cancer cell differentiation, FIGO stage, and survival rate, indicating that PAX8 is a potential marker for the diagnosis of PEOC.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for the treatment of advanced epithelial and recurrent ovarian carcinoma: a single center experience

Background: With standard treatment of epithelial ovarian cancer (EOC), prognosis is very poor. The aim of this study is to show early and late results in patients who underwent cytoreductive surgery and intraperitoneal chemotherapy.Patients and methods: This was a retrospective single centre study. All patients with advanced and recurrent ovarian cancer treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) or modified early postoperative intraperitoneal chemotherapy (EPIC) were included in the study.Results: In the period 1995–2014, 116 patients were treated, 55 with primary EOC and 61 with recurrent EOC. The mean age was 59 years (26–74). Statistically, median survival time was significantly longer in the group with primary advanced cancer of the ovary (41.3 months) compared to relapsed ovarian cancer (27.3 months). Survival for the primary EOC was 65 and 24% at 3 and 5 years, respectively. Survival for recurrent EOC was 33 and 16% at 3 and 5 years, respectively. Mortality was 1/116 (0.8%). Morbidity was 11/116 (9.5%). Peritoneal cancer index (PCI) was ≤20 in 59 (51%) patients and statistically, their average survival was significantly longer than in the group of 57 (49%) patients with PCI >20 (p = 0.014).Conclusions: In advanced or recurrent EOC, a curative therapeutic approach was pursued that combined optimal cytoreductive surgery and intraperitoneal chemotherapy. PCI and timing of the intervention (primary or recurrent) were the strongest independent prognostic factors.

Prognostic Value of the Age-Adjusted Charlson Comorbidity Index (ACCI) on Short- and Long-Term Outcome in Patients with Advanced Primary Epithelial Ovarian Cancer.

We evaluated the prognostic impact of the age-adjusted Charlson Comorbidity Index (ACCI) on both postoperative morbidity and overall survival (OS) in patients with advanced epithelial ovarian cancer (EOC) treated at a tertiary gynecologic cancer center. Exploratory analysis of our prospectively documented tumor registry was performed. Data of all consecutive patients with stage IIIB-IV ovarian cancer who underwent primary cytoreductive surgery (PDS) from January 2000 to June 2016 were analyzed. Patients were divided into three groups, based on their ACCI: low (0-1), intermediate (2-3), and high (≥4), and postoperative surgical complications were graded according to the Clavien-Dindo classification (CDC). The Fisher's exact test, log-rank test, and Cox regression models were used to investigate the predictive value of the ACCI on postoperative complications and OS. Overall, 793 consecutive patients were identified; 328 (41.4%) patients were categorized as low ACCI, 342 (43.1%) as intermediate ACCI, and 123 (15.5%) as high ACCI. A high ACCI was significantly associated with severe postoperative complications (CDC 3-5; odds ratio 3.27, 95% confidence interval 1.97-5.43, p<0.001). Median OS for patients with a low, intermediate, or high ACCI was 50, 40, and 23months, respectively (p<0.001), and the ACCI remained a significant prognostic factor for OS in multivariate analysis (p=0.001). The same impact was observed in a sensitivity analysis including only those patients with complete tumor resection. The ACCI is associated with perioperative morbidity in patients undergoing PDS for EOC, and also has a prognostic impact on OS. The potential role of the ACCI as a selection criteria for different therapy strategies is currently under investigation in the ongoing, prospective, multicenter AGO-OVAR 19 trial.

Emerging Role of Nestin as an Angiogenesis and Cancer Stem Cell Marker in Epithelial Ovarian Cancer: Immunohistochemical Study.

Ovarian cancer is the most fatal gynecologic malignancy and the existing second-line treatments have not been confirmed to be effective. Cancer stem cells research has a leading role to explore promising therapeutic applications. Nestin was postulated to reflect cancer stem cell properties in various tumors, correlating with poor prognosis. Furthermore, nestin is proposed as a reliable neovascularization marker. This study aimed to elucidate the status of nestin expression in various epithelial ovarian cancers (EOCs), its neoangiogenic properties, and investigate its potential association with clinicopathologic parameters. A total of 80 primary EOCs (37 serous, 20 Mucinous, 13 endometrioid, and 10 clear cell carcinomas) were immunohistochemically stained with nestin. Staining intensity and automated microvascular density (MVD) were assessed. Positive nestin expression was defined in ≈47.5% of all EOC; more commonly in ≈60% of the serous tumors. It was noticeably expressed in tumor spheroids. Nestin expression significantly correlated with overall tumor grade, lymph node, distant metastasis, and stage. Nestin neoangiogenesis was detectable in all cases (average=60.1). The nestin expression in tumor cells significantly correlated with Nestin/MVD. The average Nestin/MVD was significantly an independent predictor of high tumor stage. As a stem cell marker, nestin is expressed in cells of EOC including those growing as spherules and correlated with poor prognosis. Thus, nestin may be a novel therapeutic target for tumor angiogenesis and a combination therapy that includes nestin-targeting agents may be an effective therapeutic approach. In addition, detection of Nestin/stem cells and Nestin/MVD can be used as predictors of disease.

DACT1 Overexpression in type I ovarian cancer inhibits malignant expansion and cis-platinum resistance by modulating canonical Wnt signalling and autophagy

Type I epithelial ovarian cancer (EOC) is primarily resistant to platinum-based chemotherapies and needs novel therapeutics. Given the aberrant Wnt activation in type I EOC and the involvement of Dapper1 Antagonist of Catenin-1 (DACT1) in Wnt signalling, the role of DACT1 in tumourigenesis of type I EOC was evaluated. Firstly, all tested EOC cell lines and primary EOC tissues, especially type I EOC, were observed to have significantly lower DACT1 expression than normal controls. Next, 3AO cells, which arise from a patient with primary mucinous EOC and express low endogenous levels of DACT1, were transfected with a lentivirus carrying full-length DACT1 (3AO-DACT1), grew slower and formed smaller tumours in nude mice compared to 3AO-NC. Furthermore, 3AO-DACT1 had lower levels of key mediators of canonical Wnt signalling, Dvl2 and β-catenin, GSK-3β with phosphorylated Ser9, and the Wnt/β-catenin target genes, with significantly lower nuclear β-catenin levels. Additionally, 3AO-DACT which contained higher levels of lipidated LC3 (LC3-II) and Beclin1, but lower levels of p62/SQSTM1, were more sensitive to cis-platinum. And chloroquine partially rescued its cis-platinum resistance. We identified DACT1 as a negative regulator in type I EOC, protecting against malignant expansion by inhibiting canonical Wnt signalling and cis-platinum resistance by regulating autophagy.

CDK6 protects epithelial ovarian cancer from platinum‐induced death via FOXO3 regulation

Epithelial ovarian cancer (EOC) is an infrequent but highly lethal disease, almost invariably treated with platinum‐based therapies. Improving the response to platinum represents a great challenge, since it could significantly impact on patient survival. Here, we report that silencing or pharmacological inhibition of CDK6 increases EOC cell sensitivity to platinum. We observed that, upon platinum treatment, CDK6 phosphorylated and stabilized the transcription factor FOXO3, eventually inducing ATR transcription. Blockage of this pathway resulted in EOC cell death, due to altered DNA damage response accompanied by increased apoptosis. These observations were recapitulated in EOC cell lines in vitro, in xenografts in vivo, and in primary tumor cells derived from platinum‐treated patients. Consistently, high CDK6 and FOXO3 expression levels in primary EOC predict poor patient survival. Our data suggest that CDK6 represents an actionable target that can be exploited to improve platinum efficacy in EOC patients. As CDK4/6 inhibitors are successfully used in cancer patients, our findings can be immediately transferred to the clinic to improve the outcome of EOC patients.