Primary Ovarian Carcinoma Research Articles

Differentiation between ovarian metastasis from colorectal carcinoma and primary ovarian carcinoma: Evaluation of tumour markers and “mille-feuille sign” on computed tomography/magnetic resonance imaging

PurposeThe purpose of this retrospective study was to evaluate the usefulness of serum tumour markers and morphological characteristics in CT/MRI to differentiate between ovarian metastases from colorectal carcinomas (OMCRC) and primary ovarian carcinomas (POC). MethodPreoperative radiological images of 41 OMCRCs from 27 patients (mean age ± SD: 52.2 ± 10.7 years) and 46 POCs from 36 patients (52.1 ± 12.7 years) were included. Three blinded gynecological radiologists classified tumour morphology into ‘mille-feuille sign', ‘solid and cystic’, ‘multicystic without nodules’, and ‘multicystic with nodules’ groups and analysed using Fisher’s exact test. Serum carcinoembryonic antigen (CEA), cancer antigen 125 (CA125), and carbohydrate antigen 19-9 levels were compared by Wilcoxon rank-sum test. Results‘Mille-feuille sign’ indicated OMCRC (OMCRC: 8/41, POC: 1/46, specificity = 0.98, p = 0.011) and had excellent interobserver agreement (Fleiss’s kappa value = 0.96). ‘Solid and cystic’ indicated POC (18/41 vs 41/45, p < 0.001) and ‘multicystic without nodules’ indicated OMCRC (8/41 vs 2/46, p = 0.041). There was no significant difference in ‘multicystic with nodules’. CA125 levels were higher in POCs (292.5 U/mL vs. 41.0 U/mL, p = 0.003). CEA levels were higher in OMCRCs (24.5 ng/mL vs 2 ng/mL, p < 0.001). CEA (< 6.3 ng/mL) AND (CA125 (≥87.0 U/mL) OR ‘solid and cystic’) indicated POC with high accuracy (3/41 vs 44/46, accuracy = 0.94, p < 0.001). ConclusionsOur new method with morphological classification and tumour markers were useful for differentiating the two tumours. In particular, the ‘mille-feuille sign’ frequently indicated OMCRC with high specificity and excellent interobserver agreement.

Prevalence and impact of hepatitis B virus infection in ovarian cancer patients in an endemic area-A retrospective cohort study.

Hepatitis B virus (HBV) infection is associated with many extrahepatic malignancies, but its association with and impact on ovarian cancer has not been examined. We therefore examined the prevalence of HBV infection among women with primary ovarian carcinoma in an endemic area, and whether this impacts the presentation and survival of these patients. In a retrospective study, we reviewed 523 patients presenting with primary ovarian cancer and known HBV status between 1 January 2006 and 31 December 2017. Patients were divided into HBV-positive and negative groups for the comparison of the patient characteristics and presentation, including staging and histological types, and short term (2years) mortality from ovarian cancer. Among the 10.1% (53/523) patients screened positive for HBV, more of them presented with advanced staging at FIGO stage 3 or above (OR 1.378, 95% CI 1.063-1.787), although there were no significant differences in patient characteristics. Within 24months from presentation, there were more deaths due to malignancy in the HBV-positive group (73.3% vs 44.2%, OR 1.659, 95% CI 1.135-2.425). On multivariate analysis after adjusting for nulliparity status, previous use of oestrogens, presence of metastases, histological type (epithelial or others) and grading (high grade or not), whether optimal debulking was performed, and chemotherapy, HBV infection was independently associated with increased death within 24months of presentation (aOR 2.683, 95% CI 1.015-7.091). In conclusion, the findings of this study suggested an adverse effect of chronic HBV infection on survival within two years of presentation in patients with primary ovarian cancer.

Primary papillary serous carcinoma presenting as acute ovarian torsion in postmenopausal woman: a case report

A 51-year-old postmenopausal woman, with an uneventful past gynecologic history, was admitted to the present hospital with a diagnosis of severe pelvic pain due to a suspected ovarian torsion treated with different drugs intravenously without any improvement of symptoms. As a consequence of the increasing pelvic pain, a laparoscopic surgical treatment was decided: a left necrotic ovarian mass and pelvic peritoneal carcinomatosis were visualized and the procedure was converted from laparoscopy to laparotomy that confirmed a diagnosis of primary ovarian papillary serous carcinoma and permitted an adequate treatment. This is a rare case in literature of severe pelvic pain due to an acute ovarian torsion that permitted a prompt diagnosis and treatment of malignancy.

Colorectal Carcinoma Presenting as Ovarian Metastasis: A Case Report

There is a common occurrence of colorectal adenocarcinoma metastasis to the ovary and in rare circumstances, these cases may present clinically as primary ovarian cancer and histologically as primary endometrioid carcinoma of the ovary. Approximately 3.6% to 7.4% of patients with colon cancer have ovarian metastasis at the time of initial presentation, of which, 45% are mistaken for primary ovarian tumors. The author reports the case of a 60-year-old female presenting with fatigue and pelvic pain secondary to a pelvic mass. Computed tomography (CT) revealed a lobulated, heterogeneous pelvic mass measuring 11.1 × 10.5 × 9.8 cm, and ultrasound (US) showed complex 13.8 × 8.2 × 12.3 cm mass posterior to the uterus. Upon examination of the specimen following debulking procedure, endometrioid carcinoma of the ovaries was initially considered. However, immunohistochemical stains were performed and showed malignant cells positive for cytokeratin (CK) 20, caudal type homeobox (CDX) 2, and specific AT-rich sequence binding (SATB) protein 2, consistent with metastatic colorectal carcinoma. This report highlights the diagnostic challenges arising with differentiation between primary endometrioid ovarian carcinoma and metastatic colorectal adenocarcinoma to the ovary and the potential clinical consequences of misdiagnosis.

A Case Report of Primary Ovarian Squamous Cell Carcinoma: Pathways (And Pitfalls) To A Difficult Diagnosis

A Case Report of Primary Ovarian Squamous Cell Carcinoma: Pathways (And Pitfalls) To A Difficult Diagnosis

Clinicopathological Study of 117 Body Fluids: Comparison of Conventional Smear and Cell Block Technique.

Background. Cell block method (CB) has emerged as an invaluable tool for diagnosis of effusions. It can help overcome the problems faced by conventional smear (CS) by differentiating between reactive, inflammatory and malignant cells. The aim of the study is to compare and correlate the CB diagnosis with the CS findings of various pathological conditions including malignancy. Materials and Methods. Two years prospective cross-sectional study of 117 fluids received for routine examination and/or for cytology was conducted. CS as well as CB was simultaneously prepared from the fluid and the results were correlated and tabulated for statistical analysis. Results. Mean age of presentation was 43±21.1 years and male: female ratio was 1.3:1. Ascitic fluid (46.2%) was the most common followed by pleural (40.2%). Among malignancies, primary ovarian and lung carcinoma were the most common to present with malignant ascites (33.3%) and pleural effusion (66.7%) respectively. Six suspicious for malignancy on CS were provided a definitive diagnosis of malignancy on CB. Overall, CB increased the yield of malignancy by 8.3%. The agreement between CB and CS for malignant effusions and suspicious for malignancy were 41.7% and 14.3% respectively. Sensitivity of CS method when compared to CB, for malignant peritoneal and pleural effusions was 90% and 75% respectively while the specificity was 68% and 79% respectively. Conclusion. CB has a better diagnostic yield of malignancy and helps in providing a definitive diagnosis for cases that are suspicious for malignancy on CS. Hence, CB should be routinely employed along with CS for all effusions.

High density of CD66b in primary high-grade ovarian cancer independently predicts response to chemotherapy.

Ovarian carcinoma (OC) is the most lethal female genital cancer. After a primary curative surgical approach followed by chemotherapy, a fraction of the patients recur with chemoresistant disease. Data indicate a favorable therapeutic effect of tumor-infiltrating neutrophils (TIN) in OC. Our aim was to investigate the prognostic role of CD66b expression, corresponding to neutrophilic infiltration for recurrence-free survival (RFS) and overall survival (OS) in patients with OC. A collective of 47 primary serous ovarian carcinoma and their matching recurrences were processed and stained with CD66b using immunohistochemistry. Tumors from patients with RFS of more than 6months were defined as chemosensitive. Statistical analysis of CD66b expression was performed to assess the clinical endpoints. High density of CD66b expressing neutrophils in primary carcinoma was associated with chemosensitivity (p = 0.014) and longer RFS (p = 0.001). Univariate analysis identified high density of CD66b expressing neutrophils as a predictor for favorable RFS (HR 0.41, 95% CI 0.22-0.76, p < 0.005). Residual disease > 2cm (HR 3.67, 95% CI 1.62-8.31, p < 0.002) and higher number of chemotherapy cycles (HR 1.28, 95% CI 1.05-1.55, p < 0.013) were associated with worse RFS. Multivariate analysis showed that high density of CD66b expressing neutrophils (HR 0.22, 95% CI 0.10-0.48, p < 0.001) and residual disease > 2cm (HR 3.69, 95% CI 1.43-9.53, p < 0.007) were independent predictors of RFS but had no impact on OS. High CD66b neutrophil density in primary high-grade OC predicts good response to initial chemotherapy and longer recurrence-free survival independent of known risk factors.

Comparative\xa0transcriptome analysis of matched primary and distant metastatic ovarian carcinoma

BackgroundHigh grade serous ovarian carcinoma (HGSOC) is the most common subtype of epithelial ovarian cancers (EOC) with poor prognosis. In most cases EOC is widely disseminated at the time of diagnosis. Despite the optimal cytoreductive surgery and chemotherapy most patients develop chemoresistance, and the 5-year overall survival being only 25–35%.MethodsHere we analyzed the gene expression profiles of 10 primary HGSOC tumors and 10 related omental metastases using RNA sequencing and identified 100 differentially expressed genes.ResultsThe differentially expressed genes were associated with decreased embryogenesis and vasculogenesis and increased cellular proliferation and organismal death. Top upstream regulators responsible for this gene signature were NR5A1, GATA4, FOXL2, TP53 and BMP7. A subset of these genes were highly expressed in the ovarian cancer among the cancer transcriptomes of The Cancer Genome Atlas. Importantly, the metastatic gene signature was suggestive of poor survival in TCGA data based on gene enrichment analysis.ConclusionBy comparing the gene expression profiles of primary HGSOC tumors and their matched metastasis, we provide evidence that a signature of 100 genes is able to separate these two sample types and potentially predict patient survival. Our study identifies functional categories of genes and transcription factors that could play important roles in promoting metastases and serve as markers for cancer prognosis.

Abstract GMM-027: DYNLL1 INHIBITS DNA END RESECTION IN BRCA1-DEFICIENT CELLS AND REGULATES PARP INHIBITOR SENSITIVITY

Abstract High-grade serous ovarian carcinoma (HGSOC) patients with germline mutations in BRCA1/2 exhibit high sensitivity and improved outcome to double strand DNA break (DSB)-inducing agents [i.e. platinum and Poly(ADP-ribose) polymerase inhibitors (PARPi)] due to underlying defects in DNA repair via homologous recombination (HR). Due to their effectiveness, three PARP inhibitors (olaparib, rucaparib, niraparib) have recently gained FDA approval for the treatment of HGSOCs. However, de novo and acquired resistance to these agents is common even in the BRCA mutation carriers, and pose a significant, and unsolved, clinical challenge. Therefore, we adopted a systematic approach to comprehensibly identify unexplored factors/pathways that could be responsible for PARPi/platinum resistance in BRCA-defective HGSOC patients. Here we identify DYNLL1 as a negative regulator of DNA end resection through a loss-of-function CRISPR screen in BRCA1-mutant ovarian carcinoma cells. DNA end resection is a vital process that initiates homologous recombination (HR)-mediated repair of double-stranded DNA breaks (DSBs), and consequently influences genome stability. In BRCA-defective HGSOC patients, DNA end resection is greatly compromised and contribute to the loss of HR and PARP inhibitor sensitivity. Loss of DYNLL1 allows DNA end resection and restores HR in BRCA1-mutant cells, thereby inducing resistance to platinum drugs and PARP inhibitors. In primary ovarian carcinomas low BRCA1 expression correlates with increased chromosomal aberrations, and the junction sequences of somatic structural variants indicate the loss of HR. Concurrent decrease in DYNLL1 expression in BRCA1 low ovarian cancers ‘rescued' this phenotype with reduced genomic alterations and increased homology at putative lesions. DYNLL1 limits nucleolytic degradation of DNA ends by interacting with the DNA end resection machinery (MRN complex, BLM helicase and DNA2) in cells. The impact of DYNLL1 on end resection can be re-capitulated in vitro and this is dependent on direct interaction with MRE11. In the absence of exogenous stress, depletion of DYNLL1 slows DNA replication fork progression due to ectopic activity of MRE11. Therefore, we infer that DYNLL1 is an important anti-resection factor that significantly influences genomic stability and response to DNA damaging chemotherapy. Citation Format: Yizhou Joseph He, Khyati Meghani, Marie-Christine Caron, Chunyu Yang, Daryl A. Ronato, Jie Bian, Anchal Sharma, Jessica Miller, Niraj Joshi, Alexandre Detappe, John G. Doench, Gaelle Legube, David E. Root, Alan D. D'Andrea, Pascal Drané, Subhojyoti De, Panagiotis Konstantinopoulos, Jean-Yves Masson, and Dipanjan Chowdhury. DYNLL1 INHIBITS DNA END RESECTION IN BRCA1-DEFICIENT CELLS AND REGULATES PARP INHIBITOR SENSITIVITY [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-027.

Prognostic impact of pelvic and para-aortic lymphadenectomy on clinically-apparent stage I primary mucinous epithelial ovarian carcinoma: a multi-institutional study with propensity score-weighted analysis.

The exact impact of full-staging lymphadenectomy on patients with primary mucinous epithelial ovarian carcinoma confined to the ovary is still unclear. In this study, we investigated the prognostic impact of lymphadenectomy covering both pelvic and para-aortic lymph nodes in patients with clinically-apparent stage I mucinous epithelial ovarian carcinoma, using data from multi-institutions under a central pathological review system and analyses with a propensity score-based method. We conducted a regional multi-institutional retrospective study between 1986 and 2017. Among 4730 patients with malignant ovarian tumors, a total of 186 women with mucinous epithelial ovarian carcinoma were eligible. We evaluated differences in survival outcomes between patients with both pelvic and para-aortic lymphadenectomy and those with only pelvic lymphadenectomy and/or clinical lymph node evaluation. To analyze the therapeutic effects, the baseline imbalance between patients with both pelvic and para-aortic lymphadenectomy and others was adjusted with an inverse probability of treatment weighting using propensity score involving independent clinical variables. Fifty-five patients received both pelvic and para-aortic lymphadenectomy. With PS-based adjustment, both pelvic and para-aortic lymphadenectomy did not have additive effects regarding overall survival (P=0.696) and recurrence-free survival (P=0.978). Multivariate analysis similarly showed no significant impact of both pelvic and para-aortic lymphadenectomy on their prognosis. The effect of pelvic and para-aortic lymphadenectomy is limited for clinically-apparent stage I primary mucinous epithelial ovarian carcinoma as long as full peritoneal and clinical lymph node evaluations are conducted. The results of this study should be used as the basis for additional studies, including prospective trials.

Chromosomal Instability and mTORC1 Activation through PTEN Loss Contribute to Proteotoxic Stress in Ovarian Carcinoma.

High-grade serous ovarian carcinoma commonly arises from fallopian tube secretory epithelium and is characterized by a high level of chromosomal instability. To model the acquisition of aneuploidy during early carcinogenesis, chromosome missegregation was induced in immortalized tubal epithelial cells, which proved acutely detrimental to cellular fitness. The phenotype was characterized by accumulation of misfolded proteins, activation of the unfolded protein response (UPR), decreased protein synthesis, and enhanced vulnerability to proteasome inhibition. However, chromosome missegregation also resulted in heightened transformation potential, assessed by colony formation in soft agar. Ovarian cancer cells retained intrinsic sensitivity to proteasome inhibitors under adherent culture conditions, but acquired resistance as spheroids (recapitulating their native configuration in ascites) by downregulating protein synthesis via mTORC1 suppression. Loss of PTEN drove constitutive mTORC1 activity, enhanced proteotoxic stress, as evidenced by UPR induction, and resensitized tumor spheroids to proteasome inhibition both in vitro and in vivo. In cohorts of primary ovarian carcinomas, mTORC1 and UPR signaling pathways were closely associated. These results implicate attenuation of protein synthesis as a protective mechanism in tumor spheroids, which may explain the overall poor response to bortezomib in clinical trials of patients with advanced ovarian cancer. However, patients with PTEN-deficient tumors may represent a subpopulation potentially amenable to treatment with proteasome inhibitors or other therapeutic agents that disrupt protein homeostasis. SIGNIFICANCE: Chromosome instability and protein synthesis are important factors that determine the efficacy of proteotoxic stress-inducing agents, such as proteasome inhibitors, in the treatment of ovarian cancer.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/21/5536/F1.large.jpg.

CircPLEKHM3 acts as a tumor suppressor through regulation of the miR-9/BRCA1/DNAJB6/KLF4/AKT1 axis in ovarian cancer

BackgroundEmerging evidence has shown that circular RNAs (circRNAs) play essential roles in cancer biology and are potential biomarkers and targets for cancer therapy. However, the expression and function of circRNAs in ovarian carcinogenesis and its progression remain elusive.MethodsRNA sequencing was performed to reveal circRNA expression profiles in ovarian cancerous and normal tissues. Single-molecule RNA in-situ hybridization was used to quantify circPLEKHM3 expression in tumor tissues. Cell-based in-vitro and in-vivo assays were subsequently conducted to support the clinical findings.ResultsCircPLEKHM3 was identified as one of the most significantly down-regulated circRNAs in ovarian cancer tissues compared with normal tissues. Its expression was further decreased in peritoneal metastatic ovarian carcinomas compared to primary ovarian carcinomas. Patients with lower circPLEKHM3 tend to have a worse prognosis. Functionally, circPLEKHM3 overexpression inhibited cell growth, migration and epithelial–mesenchymal transition, whereas its knockdown exerted an opposite role. Further analyses showed that circPLEKHM3 sponged miR-9 to regulate the endogenous expression of BRCA1, DNAJB6 and KLF4, and consequently inactivate AKT1 signaling. In addition, AKT inhibitor MK-2206 could block the tumor-promoting effect of circPLEKHM3 depletion, and potentiate Taxol-induced growth inhibition of ovarian cancer cells.ConclusionsOur findings demonstrated that circPLEKHM3 functions as a tumor suppressor in ovarian cancer cells by targeting the miR-9/BRCA1/DNAJB6/KLF4/AKT1 axis and may be used as a prognostic indicator and therapeutic target in ovarian cancer patients. The new strategy for treating ovarian cancer by a combination therapy of Taxol with MK-2206 is worth further investigation, especially in ovarian cancer patients with loss of circPLEKHM3 expression.

1879PD - Primary ovarian carcinomas arising in BRCA1 mutation carriers contain a small fraction of BRCA1-proficient cells, which rapidly repopulate tumor mass during neoadjuvant chemotherapy but become outgrown by BRCA1-deficient clones during platinum-free intervals

BackgroundSomatic loss of the wild-type allele is a key event in the pathogenesis of BRCA1-driven carcinomas. BRCA1 deficiency renders pronounced sensitivity of these tumors to platinum compounds and PARP inhibitors. MethodsWe analyzed BRCA1 loss of heterozygosity (LOH) in serial ovarian cancer (OC) samples, which were obtained from BRCA1 germ-line mutation carriers before neoadjuvant chemotherapy (NACT), at surgery and at disease relapse. Results26/36 (72%) OC had BRCA1 LOH before NACT. 15 (58%) of these 26 tumors showed retention of the normal BRCA1 allele after NACT. The analysis of linked SNPs and FISH assay strongly indicated, that the restoration of BRCA1 function is caused not by the second mutation, but by the selection of pre-existing BRCA1-proficient cells. Tumor relapses were available in 7 patients with BRCA1 LOH in the chemonaive tumor and/or BRCA-proficiency in the residual post-NACT neoplasm; 6 (86%) of these relapses had BRCA1 LOH thus resembling the primary tumor. Secondary open reading frame (ORF) restoring BRCA1 mutation was detected in 1 recurrent OC. Serial samples retained same TP53 mutation during the treatment course. Whole exome sequencing revealed that chemonaive, post-NACT and relapsed tumors had both shared and individual mutations. Conclusions1) BRCA1 LOH is not the first event in the pathogenesis of BRCA1-driven cancer: gain of TP53 mutation probably precedes BRCA1 inactivation in order to prevent apoptosis; 2) Chemonaïve BRCA1-driven tumors contain a small fraction of BRCA1-proficient cells, which rapidly repopulate the tumor lump during the first weeks of therapy; 3) Change of BRCA1 status during NACT may call to reconsider the existing approaches to adjuvant therapy, as the residual post-NACT tumor masses are likely to be platinum-resistant; 4) The balance between BRCA1-deficient and BRCA1-proficient cells is a subject of fluctuations, depending whether therapy is applied or not; 5) Clinical trials on BRCA1-driven OCs need to address the issue of intratumoral heterogeneity of BRCA1 status. Legal entity responsible for the studyThe authors. FundingRussian Science Foundation (grant 19-15-00168). DisclosureAll authors have declared no conflicts of interest.

Analysis of Differentially Expressed MicroRNAs and Circulating Tumor Cells as Predictive Biomarkers of Platinum Chemoresistance in Primary Ovarian Carcinomas: A Prospective Study

Lesson Learned.Circulating tumor cells, microRNA markers, or other biomarkers merit examination as part of correlative scientific analyses in prospective clinical trials.Background.Platinum chemotherapy resistance occurs in approximately 25% of patients with ovarian carcinoma; however, no biomarkers of ovarian carcinoma chemoresistance have been validated. We performed a prospective trial designed to identify tumor‐based predictive biomarkers of platinum resistance.Methods.Tumor specimens were collected from 29 women with newly diagnosed histopathologically proven primary ovarian carcinoma. Of these, 23 women had specimens accessible for assessment and outcome data available regarding chemosensitive versus chemoresistance status via review of the medical record. Tumor slices were stained with antibodies against two microRNAs (miRNAs 29b and 199a) differentially expressed in chemoresistant ovarian cancer cell lines. Additionally, blood samples obtained at the time of diagnosis were analyzed for the presence of circulating tumor cells (CTCs).Results.The average age of the patients was 64 years, and 82.6% had high‐grade epithelial carcinomas. The baseline median CA‐125 was 464 (range 32–2,782). No statistically significant differences were observed in miR29b or 199a expression in platinum‐resistant/refractory versus platinum‐sensitive tumors. Furthermore, the presence of CTCs was not found to be statistically significantly predictive of eventual platinum resistance.Conclusion.Our analysis showed no differences in miR29b and 199a expression, and differences in baseline CTCs in women with newly diagnosed ovarian tumors were not statistically significant.

Ultrasound features and clinical outcome of patients with malignant ovarian masses diagnosed during pregnancy: experience of a gynecological oncology ultrasound center

ObjectiveThe number of women diagnosed with ovarian masses during pregnancy has increased in recent years and the management of these women can be controversial. We aim to describe ultrasound characteristics...

Fallopian Tube Carcinoma

Primary fallopian tube carcinoma is a rare and difficult to cure disease. It is often grouped under the epithelial ovarian cancer umbrella, together with primary ovarian and peritoneal carcinomas. More recent evidence has suggested that epithelial ovarian cancers originate from a fallopian tube precursor. The mainstay of treatment is surgical cytoreduction and platinum-based chemotherapy. There is much debate over the best timing for surgery and the best approach to delivering the chemotherapy: traditional intravenous once every 3 weeks regimen, versus intraperitoneal, versus dose-dense intravenous regimens. Although these debates continue, novel targeted therapies, including bevacizumab and poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors, have emerged. PARP inhibitors are particularly efficacious in patients with BRCA1/2 gene mutations, and their use has been shown to prolong patient survival. This article reviews the pathologic etiology; describes the heredity, treatment challenges, and controversies; and summarizes novel therapies in primary fallopian tube carcinoma.

Tumor stroma proportion to predict platinum chemoresistance in primary ovarian carcinomas: A prospective study.

5581 Background: Platinum chemotherapy resistance occurs in approximately 25% of patients with ovarian carcinoma and represents a major barrier to effective care of this patient population. To date there are no effective nor validate predictive biomarkers of chemoresistance of ovarian carcinomas. We performed a prospective trial designed to enroll patients with ovarian masses suspicious for ovarian cancer, with the goal of identifying tumor-based predictive biomarkers of platinum resistance. Methods: 60 women were enrolled on the study. Tumor specimens were collected from 49 of these women with newly diagnosed pelvic masses, of which 29 were found to have histopathologically proven primary ovarian carcinoma. Of these primary malignant cases, 24 had specimens accessible for assessment of tumor-stroma proportion and data available regarding chemosensitive vs chemoresistance status via review of the medical record using a UMN IRB-approved protocol. Tumor slices were stained with H&amp;E and also for antibodies against two microRNAs (29b and 199a) differentially expressed in ovarian cancer cell lines. Tumor-stroma proportions were assessed by two experienced pathologists blinded to chemoresistance status, with &lt;50% stroma scored as low proportion, &gt;50% scored as high proportion. Results: The average age of assessed patients with malignant tumors was 62. 87.5% had high-grade epithelial carcinomas. Baseline median CA-125 was 416 (range 32-2782). 80% of ovarian cancer patients with chemoresistance had tumor stroma proportions &gt;50%; 73.7% of cancer patients with chemosensitive tumors had proportions &lt;50% (p-value: 0.047). Expression of miR29b or 199a did not significantly correlate with chemoresistance. Conclusions: Tumor-stroma proportion is a useful predictive biomarker of platinum chemoresistance. If validated in larger datasets, it would be a relatively inexpensive and helpful tool for tailoring treatment strategies and clinical decision-making in women with ovarian cancer.

Delay in time to adjuvant chemotherapy and its impact on outcome in completely resected advanced ovarian malignancies treated with CRS, CRS+IP and CRS +HIPEC.

e17051 Background: The relationship between initiation time of adjuvant chemotherapy in ovarian cancer and prognosis has remained controversial. This study was done to determine whether time from optimal cytoreductive surgery (CRS) to initiation of adjuvant chemotherapy impacts disease free &amp; overall survival in advanced ovarian carcinoma. Methods: Total of 185 patients with primary advanced epithelial ovarian carcinoma (Stage IIIc or selected Stage IV), underwent optimal cytoreduction (either as upfront or interval) &amp; adjuvant chemotherapy. The analysis of interval between day of surgery and start of adjuvant chemotherapy and its impact on outcome was done. Results: CRS with intraperitoneal (IP) chemotherapy either in the form of IP port or hyperthermic intraperitoneal chemotherapy (HIPEC) was done in 135patients (60+ 75) and CRS alone in 50 patients. The median delay in starting adjuvant chemotherapy was 35 days for the whole cohort (32 days in the CRS group, 34 days in CRS+ IP group and 41 days in CRS+ HIPEC group). Delay in chemotherapy, as defined by more than 42 days had significant impact on DFS in CRS alone group (36 months vs 17 months: p = 0.02) had some impact in patients receiving intraperitoneal chemotherapy (38 versus 28 months; p = 0.78) &amp; no impact on CRS+HIPEC group (35 vs 32 months; p = 0.17). In comparison to HIPEC vs non HIPEC group (CRS &amp; CRS+IP), there was a meaningful impact on DFS with reference to delay in non HIPEC group ( 38 vs 22 months p = .08 whereas in the HIPEC group delay didn’t have any impact(35vs 32 months p = 017). There was trend towards better OS (88 vs 71 months p = 0.49). Conclusions: Delay in starting adjuvant chemotherapy certainly had impact on outcome with respect to CRS &amp; CRS + IP arm (non HIPEC group) whereas the delay didn’t have an impact in the HIPEC group owing to the fact that single dose of chemotherapy during surgery in heated environment may substitute for the delay. However well designed clinical studies needs to be designed to evaluate the impact of single dose of intraperitoneal heated therapy &amp; its interplay in delay on starting adjuvant chemotherapy.

Expression of Syk and MAP4 proteins in ovarian cancer

PurposeWe have previously reported on the prognostic importance of the calpain family of proteins in ovarian cancer, especially calpain-2. Spleen tyrosine kinase (Syk) phosphorylates a variety of cytoskeletal proteins with studies suggesting potential interactions between Syk and conventional calpains. Microtubule-associated protein 4 (MAP4) has been reported to be regulated by Syk.MethodsThe current study assessed Syk and MAP4 protein expression, by immunohistochemistry on a tissue microarray comprised of cores from primary ovarian carcinomas (n = 575), to evaluate associations with patient clinical outcomes and other clinicopathological factors and sought to determine whether there were any correlations between the expression of Syk, MAP4 and the calpain system.ResultsMAP4 expression was significantly associated with ovarian cancer histological subtype (P < 0.001), stage (P = 0.001), grade (P < 0.001) and residual tumour (P = 0.005). Despite this finding, we found no significant association existing between MAP4 expression and overall survival. Syk expression was also found significantly associated with histological subtype (P < 0.001). Syk seems to play a contradictory role with respect to tumour progression: low cytoplasmic Syk expression was significantly associated with low stage (P = 0.013), and low nuclear Syk expression with chemo-resistance in patients treated with taxane-containing therapy (P = 0.006). Interestingly, despite the lack of association in the whole cohort, high nuclear Syk expression was significantly associated with better overall survival in certain subgroups (P = 0.001).ConclusionsThe current study indicates a lack of correlation between calpain-2 expression and Syk and MAP4. Syk, MAP4 and calpain-1 appeared to significantly correlate with each other in the whole cohort, with calpain-1 being more highly associated with MAP4 and Syk in mucinous carcinomas. Overall, the current results suggest that Syk, MAP4, and calpain-1 expression are correlated with each other and these proteins may be involved in early stages of tumour spread.

Human Ovarian Cancer Tumor Formation in Severe Combined Immunodeficient (SCID) Pigs.

Ovarian cancer (OvCa) is the most lethal gynecologic malignancy, with two-thirds of patients having late-stage disease (II-IV) at diagnosis. Improved diagnosis and therapies are needed, yet preclinical animal models for ovarian cancer research have primarily been restricted to rodents, for data on which can fail to translate to the clinic. Thus, there is currently a need for a large animal OvCa model. Therefore, we sought to determine if pigs, being more similar to humans in terms of anatomy and physiology, would be a viable preclinical animal model for OvCa. We injected human OSPC-ARK1 cells, a chemotherapy-resistant primary ovarian serous papillary carcinoma cell line, into the neck muscle and ear tissue of four severe combined immune deficient (SCID) and two non-SCID pigs housed in novel biocontainment facilities to study the ability of human OvCa cells to form tumors in a xenotransplantation model. Tumors developed in ear tissue of three SCID pigs, while two SCID pigs developed tumors in neck tissue; no tumors were detected in non-SCID control pigs. All tumor masses were confirmed microscopically as ovarian carcinomas. The carcinomas in SCID pigs were morphologically similar to the original ovarian carcinoma and had the same immunohistochemical phenotype based on expression of Claudin 3, Claudin 4, Cytokeratin 7, p16, and EMA. Confirmation that OSPC-ARK1 cells form carcinomas in SCID pigs substantiates further development of orthotopic models of OvCa in pigs.