Metabolomic Characterization of Ovarian Epithelial Carcinomas by HRMAS-NMR Spectroscopy

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D. Ben Sellem

2011-01-01

Full Text Available Objectives. The objectives of the present study are to determine if a metabolomic study by HRMAS-NMR can (i discriminate between different histological types of epithelial ovarian carcinomas and healthy ovarian tissue, (ii generate statistical models capable of classifying borderline tumors and (iii establish a potential relationship with patient's survival or response to chemotherapy. Methods. 36 human epithelial ovarian tumor biopsies and 3 healthy ovarian tissues were studied using 1H HRMAS NMR spectroscopy and multivariate statistical analysis. Results. The results presented in this study demonstrate that the three histological types of epithelial ovarian carcinomas present an effective metabolic pattern difference. Furthermore, a metabolic signature specific of serous (N-acetyl-aspartate and mucinous (N-acetyl-lysine carcinomas was found. The statistical models generated in this study are able to predict borderline tumors characterized by an intermediate metabolic pattern similar to the normal ovarian tissue. Finally and importantly, the statistical model of serous carcinomas provided good predictions of both patient's survival rates and the patient's response to chemotherapy. Conclusions. Despite the small number of samples used in this study, the results indicate that metabolomic analysis of intact tissues by HRMAS-NMR is a promising technique which might be applicable to the therapeutic management of patients.

Recent alcohol consumption and risk of incident ovarian carcinoma

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Kelemen, Linda E; Bandera, Elisa V; Terry, Kathryn L

2013-01-01

Studies evaluating the association between alcohol intake and ovarian carcinoma (OC) are inconsistent. Because OC and ovarian borderline tumor histologic types differ genetically, molecularly and clinically, large numbers are needed to estimate risk associations.......Studies evaluating the association between alcohol intake and ovarian carcinoma (OC) are inconsistent. Because OC and ovarian borderline tumor histologic types differ genetically, molecularly and clinically, large numbers are needed to estimate risk associations....

A multi-stage process including transient polyploidization and EMT precedes the emergence of chemoresistent ovarian carcinoma cells with a dedifferentiated and pro-inflammatory secretory phenotype.

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Rohnalter, Verena; Roth, Katrin; Finkernagel, Florian; Adhikary, Till; Obert, Julia; Dorzweiler, Kristina; Bensberg, Maike; Müller-Brüsselbach, Sabine; Müller, Rolf

2015-11-24

DNA-damaging drugs induce a plethora of molecular and cellular alterations in tumor cells, but their interrelationship is largely obscure. Here, we show that carboplatin treatment of human ovarian carcinoma SKOV3 cells triggers an ordered sequence of events, which precedes the emergence of mitotic chemoresistant cells. The initial phase of cell death after initiation of carboplatin treatment is followed around day 14 by the emergence of a mixed cell population consisting of cycling, cell cycle-arrested and senescent cells. At this stage, giant cells make up >80% of the cell population, p21 (CDKN1A) in strongly induced, and cell numbers remain nearly static. Subsequently, cell death decreases, p21 expression drops to a low level and cell divisions increase, including regular mitoses of giant cells and depolyploidization by multi-daughter divisions. These events are accompanied by the upregulation of stemness markers and a pro-inflammatory secretory phenotype, peaking after approximately 14 days of treatment. At the same time the cells initiate epithelial to mesenchymal transition, which over the subsequent weeks continuously increases, concomitantly with the emergence of highly proliferative, migratory, dedifferentiated, pro-inflammatory and chemoresistant cells (SKOV3-R). These cells are anchorage-independent and grow in a 3D collagen matrix, while cells on day 14 do not survive under these conditions, indicating that SKOV3-R cells were generated thereafter by the multi-stage process described above. This process was essentially recapitulated with the ovarian carcinoma cell line IGROV-1. Our observations suggest that transitory cells characterized by polyploidy, features of stemness and a pro-inflammatory secretory phenotype contribute to the acquisition of chemoresistance.

[Preneoplasias of ovarian carcinoma: biological and clinical aspects of different pathways of tumorigenesis].

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Staebler, A

2011-11-01

Ovarian carcinomas consist of a heterogeneous group of malignant epithelial neoplasms with specific pathogenic mechanisms. This review provides a brief introduction to the different pathways of tumor progression and the associated molecular changes. However, the main focus will be on two areas with major paradigm shifting developments in recent years. Mutational analysis of ovarian clear cell carcinomas, endometrioid carcinomas and endometriotic lesions identified mutations in the ARID1A gene as common and early genetic changes in carcinomas with associated endometriosis and in atypical endometriosis itself. Extensive pathological work-up of the fallopian tubes of BRCA1/2 mutation carriers have demonstrated the existence of serous tubal intraepithelial carcinomas (STIC). Further studies showed that this lesion can also be found in 50-60% of patients with serous ovarian carcinomas without BRCA1/2 germline mutations. Pre-precursors which share the p53 mutations with STICs but proliferate very little are called p53-signatures and provide conclusive evidence that STICs develop in the fallopian tubes.

Normal-sized ovarian papillary serous carcinoma: a case report.

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Wu, W C; Lai, C I; Huang, L C; Chiu, T H; Hung, Y C; Chang, W C

2010-01-01

A normal-sized ovarian papillary serous carcinoma is rare. We present the case of a 46-year-old woman with progressive abdominal fullness of one week's duration. The medical evaluation revealed abdominal carcinomatosis with normal-sized ovaries and an elevated serum CA-125 level of 147,365.8 U/ml. Cytoreductive surgery (hysterectomy, bilateral salpingo-oophorectomy, omentectomy, lymphadenectomy, infracolic omentectomy, peritoneal biopsy, washing cytology, and appendectomy) was performed. The histologic examination revealed an ovarian serous papillary carcinoma. Adjuvant chemotherapy was administered. The serum CA-125 level decreased after completion of treatment. Normal-sized ovarian serous surface papillary carcinomas should be kept in mind as an origin of disease in patients who have peritoneal carcinomatosis, which sometimes is a diagnostic dilemma of the disease source. We report this case to emphasize the clinical symptoms and importance of the early and accurate diagnosis of a normal-sized ovarian papillary serous carcinoma.

Appendectomy with cytoreductive surgery for ovarian and type 2 endometrial carcinoma.

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Wong, L F A; Wahab, N A; Gleeson, N

2014-01-01

There is considerable variation within and between cancer centers in the practice of appendectomy as part of cytoreductive surgery for ovarian carcinoma and in the surgical staging of endometrial carcinoma. The purpose of this study was to determine the prevalence and the type of appendiceal pathology, the morbidity associated with appendectomy in gynaecologic cancer surgery. This is a retrospective review of all cytoreductive surgery for ovarian carcinoma and surgical staging for endometrial carcinoma with appendectomy over a four year period. Two hundred and fifty-one patients (38 patients for endometrial carcinoma surgery and 213 patients for ovarian cytoreduction) had an appendectomy performed. Metastases to the appendix was present in 46 (23.2%) of primary ovarian carcinoma and one (2.6%) primary endometrial carcinosarcoma. The appendix was more likely to be involved in advanced stage ovarian cancer with positive peritoneal washings, omental deposits, grade 3 differentiation, and papillary serous histology. Sixteen (6.4%) co-incidental primary appendiceal tumours were detected. No postoperative morbidity specific to appendectomy was identified. One case of ovarian carcinoma was upstaged from IC to IIIA by the appendiceal metastases. There was no upstaging of disease in the endometrial carcinoma group. Appendectomy is an integral part of ovarian cytoreductive surgery but the authors found it did not upstage the disease in a clinically significant manner. The incidence of co-incidental appendiceal primary tumours was high in this series and may add value to the procedure in preventing further surgeries. The absence of procedure related morbidity is reassuring. The authors recommend appendectomy for all ovarian staging surgery and its consideration in type 2 endometrial cancer.

WWOX protein expression varies among ovarian carcinoma histotypes and correlates with less favorable outcome

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Nunez, María I; Mills, Gordon B; Aldaz, C Marcelo; Rosen, Daniel G; Ludes-Meyers, John H; Abba, Martín C; Kil, Hyunsuk; Page, Robert; Klein-Szanto, Andres JP; Godwin, Andrew K; Liu, Jinsong

2005-01-01

The putative tumor suppressor WWOX gene spans the common chromosomal fragile site 16D (FRA16D) at chromosome area 16q23.3-24.1. This region is a frequent target for loss of heterozygosity and chromosomal rearrangement in ovarian, breast, hepatocellular, prostate carcinomas and other neoplasias. The goal of these studies was to evaluate WWOX protein expression levels in ovarian carcinomas to determine if they correlated with clinico-pathological parameters, thus providing additional support for WWOX functioning as a tumor suppressor. We performed WWOX protein expression analyses by means of immunobloting and immunohistochemistry on normal ovaries and specific human ovarian carcinoma Tissue Microarrays (n = 444). Univariate analysis of clinical-pathological parameters based on WWOX staining was determined by χ 2 test with Yates' correction. The basic significance level was fixed at p < 0.05. Immunoblotting analysis from normal ovarian samples demonstrated consistently strong WWOX expression while 37% ovarian carcinomas showed reduced or undetectable WWOX protein expression levels. The immunohistochemistry of normal human ovarian tissue sections confirmed strong WWOX expression in ovarian surface epithelial cells and in epithelial inclusion cysts within the cortex. Out of 444 ovarian carcinoma samples analyzed 30% of tumors showed lack of or barely detectable WWOX expression. The remaining ovarian carcinomas (70%) stained moderately to strongly positive for this protein. The two histotypes showing significant loss of WWOX expression were of the Mucinous (70%) and Clear Cell (42%) types. Reduced WWOX expression demonstrated a significant association with clinical Stage IV (FIGO) (p = 0.007), negative Progesterone Receptor (PR) status (p = 0.008) and shorter overall survival (p = 0.03). These data indicate that WWOX protein expression is highly variable among ovarian carcinoma histotypes. It was also observed that subsets of ovarian tumors demonstrated loss of

Estrogen receptor beta rs1271572 polymorphism and invasive ovarian carcinoma risk: pooled analysis within the Ovarian Cancer Association Consortium.

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Galina Lurie

Full Text Available The association of ovarian carcinoma risk with the polymorphism rs1271572 in the estrogen receptor beta (ESR2 gene was examined in 4946 women with primary invasive ovarian carcinoma and 6582 controls in a pooled analysis of ten case-control studies within the Ovarian Cancer Association Consortium (OCAC. All participants were non-Hispanic white women. Odds ratios (ORs and 95% confidence intervals (CIs were estimated using unconditional logistic regression adjusted for site and age. Women with the TT genotype were at increased risk of ovarian carcinoma compared to carriers of the G allele (OR = 1.10; 95%; CI: 1.01-1.21; p = 0.04; the OR was 1.09 (CI: 0.99-1.20; p = 0.07 after excluding data from the center (Hawaii that nominated this SNP for OCAC genotyping A stronger association of rs1271572 TT versus GT/GG with risk was observed among women aged ≤50 years versus older women (OR = 1.35; CI: 1.12-1.62; p = 0.002; p for interaction = 0.02 that remained statistically significant after excluding Hawaii data (OR = 1.34; CI: 1.11-1.61; p = 0.009. No heterogeneity of the association was observed by study, menopausal status, gravidity, parity, use of contraceptive or menopausal hormones, tumor histological type, or stage at diagnosis. This pooled analysis suggests that rs1271572 might influence the risk of ovarian cancer, in particular among younger women.

The utility of serum N-ERC/mesothelin as a biomarker of ovarian carcinoma.

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Saeki, Harumi; Hashizume, Akane; Izumi, Hiroshi; Suzuki, Fujihiko; Ishi, Kazuhisa; Nojima, Michio; Maeda, Masahiro; Hino, Okio

2012-10-01

Ovarian carcinoma has been difficult to diagnose at an early stage. Recently, it has been recognized that the measurement of blood N-ERC/mesothelin levels aids early detection in and postoperative therapeutic monitoring of patients with mesothelioma, who have been exposed to asbestos. ERC/mesothelin has also been reported to be expressed in ovarian carcinoma. We determined serum N-ERC/mesothelin levels in patients with ovarian carcinoma using an enzyme-linked immunosorbent assay (ELISA). In addition, we immunohistochemically evaluated surgically resected specimens for C-ERC/mesothelin expression. As a result, of the 32 patients with ovarian tumors (18 carcinoma, 2 borderline tumors), one patient with serous adenocarcinoma showed increased N-ERC/ mesothelin levels. Immunohistochemically, of the 20 ovarian tumor (carcinoma and borderline tumor) specimens evaluated for serum N-ERC/mesothelin, 9 (45.0%) were positive for C-ERC/mesothelin. The C-ERC/mesothelin-positive specimens were found to be serous and clear cell adenocarcinomas. If serum N-ERC/mesothelin, which is considered useful for early detection in and therapeutic monitoring of patients with mesothelioma, may also be used for ovarian carcinoma monitoring, it may be a valuable serum tumor marker for the early detection of ovarian carcinoma.

Fibrolamellar hepatocellular carcinoma with ovarian metastasis - an unusual presentation.

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Ciurea, Silviu Horia; Matei, Emil; Stănescu, CodruŢ Silvian; Lupescu, Ioana Gabriela; Boroş, Mirela; Herlea, Vlad; Luca, Niculina Ioana; DorobanŢu, Bogdan Mihail

2017-01-01

Fibrolamellar carcinoma (FLC) has been considered a distinct clinical entity vs. hepatocellular carcinoma, with respect to its epidemiology, etiology, and prognosis. We describe the unusual case of a 23-year-old female patient with FLC and ovarian (Krukenberg) and peritoneal metastases, clinically mimicking an ovarian carcinoma. Multiple recurrences occurred despite initial R0 resection and chemotherapy, requiring surgical treatment. The patient survived five years and died from generalized disease. The particularities of our case are discussed by comparison with the other two similar cases and other date from the literature. To our knowledge, the ovarian involvement encountered in our case is the third case published in literature, being explained by the superficial location of the liver tumor.

Genetic variation in TYMS in the one-carbon transfer pathway is associated with ovarian carcinoma types in the Ovarian Cancer Association Consortium

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Kelemen, Linda E; Goodman, Marc T; McGuire, Valerie

2010-01-01

We previously reported the risks of ovarian carcinoma for common polymorphisms in one-carbon transfer genes. We sought to replicate associations for DPYD rs1801265, DNMT3A rs13420827, MTHFD1 rs1950902, MTHFS rs17284990, and TYMS rs495139 with risk of ovarian carcinoma overall and to use the large...

Evidence for a time-dependent association between FOLR1 expression and survival from ovarian carcinoma

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Köbel, M; Madore, J; Ramus, S J

2014-01-01

BACKGROUND: Folate receptor 1 (FOLR1) is expressed in the majority of ovarian carcinomas (OvCa), making it an attractive target for therapy. However, clinical trials testing anti-FOLR1 therapies in OvCa show mixed results and require better understanding of the prognostic relevance of FOLR1...... stage I/II tumours, patients with FOLR1-positive HGSC showed increased OS during the first 2 years only (hazard ratio=0.44, 95% confidence interval=0.20-0.96) and patients with FOLR1-positive clear cell carcinomas (CCC) showed decreased PFS independent of follow-up time (HR=1.89, 95% CI=1.10-3.25, N=259...

Clinicopathologic significance of HLA-G and HLA-E molecules in Tunisian patients with ovarian carcinoma.

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Babay, Wafa; Ben Yahia, Hamza; Boujelbene, Nadia; Zidi, Nour; Laaribi, Ahmed Baligh; Kacem, Dhikra; Ben Ghorbel, Radhia; Boudabous, Abdellatif; Ouzari, Hadda-Imene; Rizzo, Roberta; Rebmann, Vera; Mrad, Karima; Zidi, Inès

2018-06-01

The human leukocyte antigen (HLA)-G and HLA-E, non classical HLA class I molecules, have been highly implicated in immune tolerance. HLA-G and HLA-E molecules were proposed as putative markers of several advanced cancers. As a step towards a better understanding of ovarian carcinoma, we evaluated the expression of both HLA-G and HLA-E molecules and explored their prognostic implication. HLA-G and HLA-E expression were studied by immunohistochemistry on ovarian carcinoma tissues. This expression was semi-quantitatively scored into four expression groups and correlated to clinicopathological parameters and patients' survival. HLA-G and HLA-E have been found to be highly expressed in ovarian carcinoma tissues (Respectively, 72.4% and 96.8%). They are frequently co-expressed. Univariate and multivariate analysis revealed that a positive HLA-G expression status in tumor tissue is a promising candidate parameter to predict disease recurrence in addition to the disease status in Tunisian patients with ovarian carcinoma. Moreover, the elevated HLA-E expression was associated with serous ovarian carcinoma subtype as well as with advanced stages of ovarian carcinoma. HLA-G and HLA-E are highly represented in ovarian carcinoma suggesting a potential association with progressive disease mechanism. HLA-G and HLA-E molecules might be new candidates' markers for ovarian carcinoma progression. Copyright © 2018 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

DNA methylation profiling of ovarian carcinomas and their in vitro models identifies HOXA9, HOXB5, SCGB3A1, and CRABP1 as novel targets

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Tropé Claes G

2007-07-01

Full Text Available Abstract Background The epigenetics of ovarian carcinogenesis remains poorly described. We have in the present study investigated the promoter methylation status of 13 genes in primary ovarian carcinomas (n = 52 and their in vitro models (n = 4; ES-2, OV-90, OVCAR-3, and SKOV-3 by methylation-specific polymerase chain reaction (MSP. Direct bisulphite sequencing analysis was used to confirm the methylation status of individual genes. The MSP results were compared with clinico- pathological features. Results Eight out of the 13 genes were hypermethylated among the ovarian carcinomas, and altogether 40 of 52 tumours were methylated in one or more genes. Promoter hypermethylation of HOXA9, RASSF1A, APC, CDH13, HOXB5, SCGB3A1 (HIN-1, CRABP1, and MLH1 was found in 51% (26/51, 49% (23/47, 24% (12/51, 20% (10/51, 12% (6/52, 10% (5/52, 4% (2/48, and 2% (1/51 of the carcinomas, respectively, whereas ADAMTS1, MGMT, NR3C1, p14ARF, and p16INK4a were unmethylated in all samples. The methylation frequencies of HOXA9 and SCGB3A1 were higher among relatively early-stage carcinomas (FIGO I-II than among carcinomas of later stages (FIGO III-IV; P = 0.002, P = 0.020, respectively. The majority of the early-stage carcinomas were of the endometrioid histotype. Additionally, HOXA9 hypermethylation was more common in tumours from patients older than 60 years of age (15/21 than among those of younger age (11/30; P = 0.023. Finally, there was a significant difference in HOXA9 methylation frequency among the histological types (P = 0.007. Conclusion DNA hypermethylation of tumour suppressor genes seems to play an important role in ovarian carcinogenesis and HOXA9, HOXB5, SCGB3A1, and CRABP1 are identified as novel hypermethylated target genes in this tumour type.

Antiangiogenic and Antitumor Effects of Src Inhibition in Ovarian Carcinoma

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Han, Liz Y.; Landen, Charles N.; Trevino, Jose G.; Halder, Jyotsnabaran; Lin, Yvonne G.; Kamat, Aparna A.; Kim, Tae-Jin; Merritt, William M.; Coleman, Robert L.; Gershenson, David M.; Shakespeare, William C.; Wang, Yihan; Sundaramoorth, Raji; Metcalf, Chester A.; Dalgarno, David C.; Sawyer, Tomi K.; Gallick, Gary E.; Sood, Anil K.

2011-01-01

Src, a nonreceptor tyrosine kinase, is a key mediator for multiple signaling pathways that regulate critical cellular functions and is often aberrantly activated in a number of solid tumors, including ovarian carcinoma. The purpose of this study was to determine the role of activated Src inhibition on tumor growth in an orthotopic murine model of ovarian carcinoma. In vitro studies on HeyA8 and SKOV3ip1 cell lines revealed that Src inhibition by the Src-selective inhibitor, AP23846, occurred within 1 hour and responded in a dose-dependent manner. Furthermore, Src inhibition enhanced the cytotoxicity of docetaxel in both chemosensitive and chemoresistant ovarian cancer cell lines, HeyA8 and HeyA8-MDR, respectively. In vivo, Src inhibition by AP23994, an orally bioavailable analogue of AP23846, significantly decreased tumor burden in HeyA8 (P = 0.02), SKOV3ip1 (P = 0.01), as well as HeyA8-MDR (P < 0.03) relative to the untreated controls. However, the greatest effect on tumor reduction was observed in combination therapy with docetaxel (P < 0.001, P = 0.002, and P = 0.01, for the above models, respectively). Proliferating cell nuclear antigen staining showed that Src inhibition alone (P = 0.02) and in combination with docetaxel (P = 0.007) significantly reduced tumor proliferation. In addition, Src inhibition alone and in combination with docetaxel significantly down-regulated tumoral production of vascular endothelial growth factor and interleukin 8, whereas combination therapy decreased the microvessel density (P = 0.02) and significantly affected vascular permeability (P < 0.05). In summary, Src inhibition with AP23994 has potent antiangiogenic effects and significantly reduces tumor burden in preclinical ovarian cancer models. Thus, Src inhibition may be an attractive therapeutic approach for patients with ovarian carcinoma. PMID:16951177

The expression of aldehyde dehydrogenase 1 (ALDH1) in ovarian carcinomas and its clinicopathological associations: a retrospective study

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Huang, Ruixia; Li, Xiaoran; Holm, Ruth; Trope, Claes G; Nesland, Jahn M; Suo, Zhenhe

2015-01-01

Background Aldehyde dehydrogenase 1 (ALDH1) is widely used as a specific cancer stem cell marker in a variety of cancers, and may become a promising target for cancer therapy. However, the role of its expression in tumor cells and the microenvironment in different cancers is still controversial. Methods To clarify the clinicopathological effect of ALDH1 expression in ovarian carcinoma, a series of 248...

Screening of the residual normal ovarian tissue adjacent to orthotopic epithelial ovarian carcinomas in nude mice.

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Zhu, G H; Wang, S T; Yao, M Z; Cai, J H; Chen, C Y; Yang, Z X; Hong, L; Yang, S Y

2014-04-16

The objective of this study was to explore the feasibility and methods of screening the residual normal ovarian tissue adjacent to orthotopic ovarian carcinomas in nude mice. Human epithelial ovarian cancer cells (OVCAR3) were subcutaneously implanted for a tumor source and ovarian orthotopic transplantation. The cancer tissue, proximal paraneoplastic tissue, middle paraneoplastic tissue, remote paraneoplastic tissue, and normal ovarian tissue were removed. CK-7, CA125, p53, survivin, MMP-2, and TIMP-2 expression was detected by reverse transcription polymerase chain reaction. We obtained 35 paraneoplastic residual ovarian tissues with normal biopsies from 40 cases of an orthotopic epithelial ovarian carcinoma model (87.5%). CK-7, CA125, p53, survivin, MMP-2, and TIMP-2 expression was lower in proximal paraneoplastic tissue than in cancer tissue (P tissue (P tissue as well as among residual normal ovarian tissues with different severity (P > 0.05). In ovarian tissues of 20 normal nude mice, the expression of CK- 7, CA125, p53, survivin, MMP-2, and TIMP-2 was negative. Overall, the expression levels of CK-7, CA125, p53, survivin, MMP-2, TIMP-2, and other molecular markers showed a decreasing trend in the non-cancer tissue direction. The expression levels can be used as standards to screen residual normal ovarian tissue. We can obtain relatively safe normal ovarian tissues adjacent to epithelial ovarian cancer.

Endonucleases induced TRAIL-insensitive apoptosis in ovarian carcinoma cells

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Geel, Tessa M. [Department of Pathology and Medical Biology, Groningen University Institute for Drug Exploration (GUIDE), University Medical Center Groningen (UMCG), Hanzeplein 1, 9713 GZ, Groningen (Netherlands); Meiss, Gregor [Institute of Biochemistry, Justus-Liebig-University Giessen, D-35392 Giessen (Germany); Gun, Bernardina T. van der; Kroesen, Bart Jan; Leij, Lou F. de [Department of Pathology and Medical Biology, Groningen University Institute for Drug Exploration (GUIDE), University Medical Center Groningen (UMCG), Hanzeplein 1, 9713 GZ, Groningen (Netherlands); Zaremba, Mindaugas; Silanskas, Arunas [Institute of Biotechnology, Vilnius LT-02241 (Lithuania); Kokkinidis, Michael [IMBB/FORTH and University of Crete/Department of Biology, GR-71409 Heraklion/Crete (Greece); Pingoud, Alfred [Institute of Biochemistry, Justus-Liebig-University Giessen, D-35392 Giessen (Germany); Ruiters, Marcel H. [Department of Pathology and Medical Biology, Groningen University Institute for Drug Exploration (GUIDE), University Medical Center Groningen (UMCG), Hanzeplein 1, 9713 GZ, Groningen (Netherlands); Synvolux therapeutics, Groningen (Netherlands); McLaughlin, Pamela M. [Department of Pathology and Medical Biology, Groningen University Institute for Drug Exploration (GUIDE), University Medical Center Groningen (UMCG), Hanzeplein 1, 9713 GZ, Groningen (Netherlands); Rots, Marianne G., E-mail: m.g.rots@med.umcg.nl [Department of Pathology and Medical Biology, Groningen University Institute for Drug Exploration (GUIDE), University Medical Center Groningen (UMCG), Hanzeplein 1, 9713 GZ, Groningen (Netherlands)

2009-09-10

TRAIL induced apoptosis of tumor cells is currently entering phase II clinical settings, despite the fact that not all tumor types are sensitive to TRAIL. TRAIL resistance in ovarian carcinomas can be caused by a blockade upstream of the caspase 3 signaling cascade. We explored the ability of restriction endonucleases to directly digest DNA in vivo, thereby circumventing the caspase cascade. For this purpose, we delivered enzymatically active endonucleases via the cationic amphiphilic lipid SAINT-18{sup Registered-Sign }:DOPE to both TRAIL-sensitive and insensitive ovarian carcinoma cells (OVCAR and SKOV-3, respectively). Functional nuclear localization after delivery of various endonucleases (BfiI, PvuII and NucA) was indicated by confocal microscopy and genomic cleavage analysis. For PvuII, analysis of mitochondrial damage demonstrated extensive apoptosis both in SKOV-3 and OVCAR. This study clearly demonstrates that cellular delivery of restriction endonucleases holds promise to serve as a novel therapeutic tool for the treatment of resistant ovarian carcinomas.

Ovarian Embryonal Carcinoma in a Dog.

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Banco, B; Ferrari, R; Stefanello, D; Groppetti, D; Pecile, A; Faverzani, S; Longo, M; Zani, D D; Ravasio, G; Caniatti, M; Grieco, V

2017-11-01

A 17-month-old female doberman pinscher was referred for an abdominal mass and ascites. Exploratory laparotomy revealed the presence of a large neoplastic mass replacing the right ovary and associated with multiple mesovarian, mesometrial and peritoneal nodules. An ovariohysterectomy was performed. Grossly, the tumour was soft and multilocular with large areas of haemorrhage and necrosis. Microscopically, it was infiltrative and composed of round and polygonal cells arranged respectively in solid sheets or forming distorted tubular structures separated by thick fibrovascular septae. Tubules contained necrotic debris, proteinaceous fluid or small endoluminal papillary structures. Marked cellular atypia, multiple neoplastic emboli and high mitotic count were observed. Immunohistochemically, the round cells uniformly expressed placental alkaline phosphatase, while the polygonal cells arranged in tubules and papillae expressed cytokeratin (CK) AE1/AE3 and CK7. A final diagnosis of metastasizing ovarian embryonal carcinoma (EC), a primitive germ cell tumour characterized by rudimentary epithelial differentiation was made. Canine ovarian EC should be considered as a differential diagnosis for undifferentiated aggressive ovarian tumours in young dogs. Copyright © 2017 Elsevier Ltd. All rights reserved.

THE ABERRANT PROMOTER HYPERMETHYLATION PATTERN OF THE ANTI - ANGIOGENIC TSP1 GENE IN EPITHELIAL OVARIAN CARCINOMA: AN INDIAN STUDY

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Ramesh

2015-06-01

Full Text Available PURPOSE: The promoter hypermethylation patterns of Thrombospodin - 1 gene in 50 EOC patients were studied and the methylation pattern was correlated with various clinic pathological parameters. METHODS: The promoter hypermethylation pattern of the TSP - 1 gene was assessed using nested PCR and Methylation specific PCR. STATISTICAL ANALYSIS: All the available data was statistically analyzed using the Chi square test or Fisher Exact Test on the SPSS software version 22.0 and a value <0.0 5 was considered statistically significant. RESULTS: Forty of the fifty ovarian carcinoma samples reported positive for methylation corresponding to a methylation frequency of 80%. A methylation frequency of 89.2%, 83.3% and 42.8% was observed in malignant , Low malignant potential (borderline and benign sample cohorts. CONCLUSION: From the results drawn from this study, it clearly shows that the anti angiogenic protein TSP - 1 is extensively hypermethylated in ovarian carcinoma and that it accumulates over t he progression of the disease from benign to malignant. As previous reports suggest that there is no evidence of mutation of this gene, promoter hypermethylation may be a crucial factor for the down regulation of the gene. Further by clubbing together the promoter hypermethylation pattern of TSP - 1 gene with hypermethylation patterns of other TSG may provide a better insight into the application of using methylation profiles of TSG as a biomarker in the detection of ovarian carcinoma.

Mevalonate Pathway Antagonist Suppresses Formation of Serous Tubal Intraepithelial Carcinoma and Ovarian Carcinoma in Mouse Models.

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Kobayashi, Yusuke; Kashima, Hiroyasu; Wu, Ren-Chin; Jung, Jin-Gyoung; Kuan, Jen-Chun; Gu, Jinghua; Xuan, Jianhua; Sokoll, Lori; Visvanathan, Kala; Shih, Ie-Ming; Wang, Tian-Li

2015-10-15

Statins are among the most frequently prescribed drugs because of their efficacy and low toxicity in treating hypercholesterolemia. Recently, statins have been reported to inhibit the proliferative activity of cancer cells, especially those with TP53 mutations. Because TP53 mutations occur in almost all ovarian high-grade serous carcinoma (HGSC), we determined whether statins suppressed tumor growth in animal models of ovarian cancer. Two ovarian cancer mouse models were used. The first one was a genetically engineered model, mogp-TAg, in which the promoter of oviduct glycoprotein-1 was used to drive the expression of SV40 T-antigen in gynecologic tissues. These mice spontaneously developed serous tubal intraepithelial carcinomas (STICs), which are known as ovarian cancer precursor lesions. The second model was a xenograft tumor model in which human ovarian cancer cells were inoculated into immunocompromised mice. Mice in both models were treated with lovastatin, and effects on tumor growth were monitored. The molecular mechanisms underlying the antitumor effects of lovastatin were also investigated. Lovastatin significantly reduced the development of STICs in mogp-TAg mice and inhibited ovarian tumor growth in the mouse xenograft model. Knockdown of prenylation enzymes in the mevalonate pathway recapitulated the lovastatin-induced antiproliferative phenotype. Transcriptome analysis indicated that lovastatin affected the expression of genes associated with DNA replication, Rho/PLC signaling, glycolysis, and cholesterol biosynthesis pathways, suggesting that statins have pleiotropic effects on tumor cells. The above results suggest that repurposing statin drugs for ovarian cancer may provide a promising strategy to prevent and manage this devastating disease. ©2015 American Association for Cancer Research.

Aurora-A overexpression and aneuploidy predict poor outcome in serous ovarian carcinoma.

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Lassus, Heini; Staff, Synnöve; Leminen, Arto; Isola, Jorma; Butzow, Ralf

2011-01-01

Aurora-A is a potential oncogene and therapeutic target in ovarian carcinoma. It is involved in mitotic events and overexpression leads to centrosome amplification and chromosomal instability. The objective of this study was to evaluate the clinical significance of Aurora-A and DNA ploidy in serous ovarian carcinoma. Serous ovarian carcinomas were analysed for Aurora-A protein by immunohistochemistry (n=592), Aurora-A copy number by CISH (n=169), Aurora-A mRNA by real-time PCR (n=158) and DNA ploidy by flowcytometry (n=440). Overexpression of Aurora-A was found in 27% of the tumors, cytoplasmic overexpression in 11% and nuclear in 17%. The cytoplasmic and nuclear overexpression were nearly mutually exclusive. Both cytoplasmic and nuclear overexpression were associated with shorter survival, high grade, high proliferation index and aberrant p53. Interestingly, only cytoplasmic expression was associated with aneuploidy and expression of phosphorylated Aurora-A. DNA ploidy was associated with poor patient outcome as well as aggressive clinicopathological parameters. In multivariate analysis, Aurora-A overexpression appeared as an independent prognostic factor for disease-free survival, together with grade, stage and ploidy. Aurora-A protein expression is strongly linked with poor patient outcome and aggressive disease characteristics, which makes Aurora-A a promising biomarker and a potential therapeutic target in ovarian carcinoma. Cytoplasmic and nuclear Aurora-A protein may have different functions. DNA aneuploidy is a strong predictor of poor prognosis in serous ovarian carcinoma. Copyright © 2010 Elsevier Inc. All rights reserved.

Primary pelvic hydatic cyst mimicking ovarian carcinoma

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Faruk Abike

2011-05-01

Full Text Available Hydatic cyst is an illness that appears in consequence of the cystic form of small strap-shaped worm Echinococcus granulosis. Frequently, cysts exist in the lungs and liver. Peritoneal involvement is rare, and generally occurs as a result of second inoculation from rupture of a liver-located hydatic cyst. Primary ovarian hydatic cyst is very rare. A 56-year-old female patient was admitted to Emergency Service with the complaint of stomachache and swollen abdomen. From ultrasonographic examination, a right ovarian 52 × 45-mm heterogeneous semi-solid cystic mass and right hydronephrosis were detected. As a result of the tomographic examination, the right ovarian growth was judged to be a 60 × 45-mm lobule contoured, septal, heterogeneously cystic mass (ovarian carcinoma. Depending on these indicators and with the diagnosis of ovarian carcinoma, laparotomy was planned. During the observation, a mass that compressed on the right ureter and dilatation in the right ureter were determined. The mass was approximately 6 cm long and smoothly contoured, including widespread adhesions, and also obliteration of the pouch of Douglas. The mass was excised and total abdominal hysterectomy and bilateral salpingo-oopherectomy performed. After a pathological examination, hydatid cyst was diagnosed. Although pointing at the issue of the distinctive diagnosis of pelvic and peritoneal mass, it should be realized that the existence of primary peritoneal and pelvic involvement of the hydatic cyst is generally a result of the second inoculation, and is also more common in regions in which Echinococcus granulosa is endemic and livestock production is prevalent.

Anti-L1CAM radioimmunotherapy is more effective with the radiolanthanide terbium-161 compared to lutetium-177 in an ovarian cancer model

International Nuclear Information System (INIS)

Gruenberg, Juergen; Lindenblatt, Dennis; Cohrs, Susan; Fischer, Eliane; Dorrer, Holger; Zhernosekov, Konstantin; Koester, Ulli; Tuerler, Andreas; Schibli, Roger

2014-01-01

The L1 cell adhesion molecule (L1CAM) is considered a valuable target for therapeutic intervention in different types of cancer. Recent studies have shown that anti-L1CAM radioimmunotherapy (RIT) with 67 Cu- and 177 Lu-labelled internalising monoclonal antibody (mAb) chCE7 was effective in the treatment of human ovarian cancer xenografts. In this study, we directly compared the therapeutic efficacy of anti-L1CAM RIT against human ovarian cancer under equitoxic conditions with the radiolanthanide 177 Lu and the potential alternative 161 Tb in an ovarian cancer therapy model. Tb was produced by neutron bombardment of enriched 160 Gd targets. 161 Tb and 177 Lu were used for radiolabelling of DOTA-conjugated antibodies. The in vivo behaviour of the radioimmunoconjugates (RICs) was assessed in IGROV1 tumour-bearing nude mice using biodistribution experiments and SPECT/CT imaging. After ascertaining the maximal tolerated doses (MTD) the therapeutic impact of 50 % MTD of 177 Lu- and 161 Tb-DOTA-chCE7 was evaluated in groups of ten mice by monitoring the tumour size of subcutaneous IGROV1 tumours. The average number of DOTA ligands per antibody was 2.5 and maximum specific activities of 600 MBq/mg were achieved under identical radiolabelling conditions. RICs were stable in human plasma for at least 48 h. 177 Lu- and 161 Tb-DOTA-chCE7 showed high tumour uptake (37.8-39.0 %IA/g, 144 h p.i.) with low levels in off-target organs. SPECT/CT images confirmed the biodistribution data. 161 Tb-labelled chCE7 revealed a higher radiotoxicity in nude mice (MTD: 10 MBq) than the 177 Lu-labelled counterpart (MTD: 12 MBq). In a comparative therapy study with equitoxic doses, tumour growth inhibition was better by 82.6 % for the 161 Tb-DOTA-chCE7 than the 177 Lu-DOTA-chCE7 RIT. Our study is the first to show that anti-L1CAM 161 Tb RIT is more effective compared to 177 Lu RIT in ovarian cancer xenografts. These results suggest that 161 Tb is a promising candidate for future clinical

Expression of CD44v6 and Its Association with Prognosis in Epithelial Ovarian Carcinomas

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Dang-xia Zhou

2012-01-01

Full Text Available The aim of this study was to evaluate CD44v6 protein expression and its prognostic value of CD44v6 in ovarian carcinoma. The expression of CD44v6 was analyzed in 62 patients with ovarian carcinoma by immunohistochemical method. The data obtained were analyzed by univariate and multivariate analyses. The present study clearly demonstrates that tumor tissues from 41 (66.1% patients showed positive expression with CD44v6. The expression of CD44v6 was significantly correlated with histological type, FIGO stage and histological grade of ovarian carcinomas. Concerning the prognosis, the survival period of patients with CD44v6 positive was shorter than that of patients with CD44v6 negative (36.6% versus 66.7%, 5-year survival, P<0.05. Univariate analysis showed that CD44v6 expression, histological type, FIGO stage and histological grade were associated with 5-year survival, and CD44v6 expression was associated with histological type, FIGO stage and histological grade and 5-year survival. In multivariate analysis, using the COX-regression model, CD44v6 expression was important prognostic factor. In conclusion, these results suggest that CD44v6 may be related to histological type, FIGO stage and histological grade of ovarian carcinomas, and CD44v6 may be an important molecular marker for poor prognosis in ovarian carcinomas.

Effect of radiation on cell-mediated cytotoxicity and lymphocyte subpopulations in patients with ovarian carcinoma

International Nuclear Information System (INIS)

Kohorn, E.I.; Mitchell, M.S.; Dwyer, J.M.; Knowlton, A.H.; Klein-Angerer, S.

1978-01-01

Lymphocyte subpopulations and cell-mediated cytotoxicity (CMI) were studied during radiation therapy in 16 patients with ovarian carcinoma. The total lymphocyte count became depressed in all patients. The depression was more marked among T cells, while the proportion of B cells remained unaffected. In patients with Stage I and II ovarian cancer, CMI was depressed significantly by radiotherapy after 7 days of treatment, remained low at 14 days but recovered despite continuation of radiation. This depression of CMI occurred at a delivered dose of 1,000 rads with subsequent recovery. Patients with Stage III ovarian cancer given pelvic and abdominal radiation were found to have no consistent depression of CMI, a finding similar to that in Stage III ovarian carcinoma patients given chemotherapy

Mevalonate Pathway Antagonist Inhibits Proliferation of Serous Tubal Intraepithelial Carcinoma and Ovarian Carcinoma in Mouse Models

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Kobayashi, Yusuke; Kashima, Hiroyasu; Wu, Ren-Chin; Jung, Jin- Gyoung; Kuan, Jen-Chun; Gu, Jinghua; Xuan, Jianhua; Sokoll, Lori; Visvanathan, Kala; Shih, Ie-Ming; Wang, Tian-Li

2015-01-01

Purpose Statins are among the most frequently prescribed drugs because of their efficacy and low toxicity in treating hypercholesterolemia. Recently, statins have been reported to inhibit the proliferative activity of cancer cells, especially those with TP53 mutations. Since TP53 mutations occur in almost all of the ovarian high-grade serous carcinoma, we determined if statins suppressed tumor growth in animal models of ovarian cancer. Experimental Design Two ovarian cancer mouse models were employed. The first one was a genetically engineered model, mogp-TAg, in which the promoter of oviduct glycoprotein-1 was used to drive the expression of SV40 T-antigen in gynecologic tissues. These mice spontaneously develop serous tubal intraepithelial carcinomas (STICs), which are known as ovarian cancer precursor lesions. The second model was a xenograft tumor model in which human ovarian cancer cells were inoculated into immunocompromised mice. Mice in both models were treated with lovastatin, and effects on tumor growth were monitored. The molecular mechanisms underlying the anti-tumor effects of lovastatin were also investigated. Results Lovastatin significantly reduced the development of STICs in mogp-TAg mice and inhibited ovarian tumor growth in the mouse xenograft model. Knockdown of prenylation enzymes in the mevalonate pathway recapitulated the lovastatin-induced anti-proliferative phenotype. Transcriptome analysis indicated that lovastatin affected the expression of genes associated with DNA replication, Rho/PLC signaling, glycolysis, and cholesterol biosynthesis pathways, suggesting that statins have pleiotropic effects on tumor cells. Conclusion The above results suggest that repurposing statin drugs for ovarian cancer may provide a promising strategy to prevent and manage this devastating disease. PMID:26109099

[Expression of Jagged1 mRNA in human epithelial ovarian carcinoma tissues and effect of RNA interference of Jagged1 on growth of xenograft in nude mice].

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Liu, G Y; Gao, Z H; Li, L; Song, T T; Sheng, X G

2016-06-25

To investigate the expression of Jagged1 in human epithelial ovarian carcinoma tissues and the effect of Jagged1 on growth of xenograft in nude mice. (1) Forty-eight cases of ovarian cancer and 30 cases of patients with benign epithelial ovarian tumor in the Henan Province Xinxiang Central Hospital during Feb. 2011 to Mar. 2014 were enrolled in this study. The mRNA expression of Jagged1, Notch1 and the downstream target genes Hes1, Hey1 were analyzed by using realtime PCR method. (2) The ovarian cancer xenograft models in nude mice were constructed by injecting SKOV3 cells in axillary subcutaneouswere. The nude mice were randomly divided into Jagged1 interference group, blank plasmid group and control group. Each group had 10 mice. They were transfected with pcDNA3.1(+)-siRNA-Jagged1, blank plasmid pDC3.1 and phosphate buffer, respectively. The tumor volumes and tumor masses were measured 14 days after transfection and the inhibition rate was calculated. The relative mRNA expression of Jagged1, Notch1, Hes1 and Hey1 in xenograft tissues after transfection in each group was detected by using realtime PCR technique and the relative protein expression of Jagged1, Notch1, Hes1 and Hey1 in xenograft tissues was detected by utilizing western blot method. (1) The relative mRNA expression of Jagged1, Notch1, Hes1 and Hey1 in ovarian cancer tissues were higher than benign ovarian tumor tissues, the differences were statistically significant (Ptissues of nude micein Jagged1 interference group were lower than that in the other two groups, the differences were statistically significant (Ptissues of nude mice among the three groups (P>0.05). Jagged1 is highly expressed in epithelial ovarian carcinoma. Jagged1 gene interference in xenograft tumor can inhibit ovarian cancer cell growth and improve tumor suppressor rate, which probably play roles by inhibiting Notch1 signaling pathway.

Cytotoxic effect of essential oil of thyme (Thymus broussonettii on the IGR-OV1 tumor cells resistant to chemotherapy

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L. Ait M'Barek

2007-11-01

Full Text Available The anti-tumor effect of the Moroccan endemic thyme (Thymus broussonettii essential oil (EOT was investigated in vitro using the human ovarian adenocarcinoma IGR-OV1 parental cell line OV1/P and its chemoresistant counterparts OV1/adriamycin (OV1/ADR, OV1/vincristine (OV1/VCR, and OV1/cisplatin (OV1/CDDP. All of these cell lines elicited various degrees of sensitivity to the cytotoxic effect of EOT. The IC50 values (mean ± SEM, v/v were 0.40 ± 0.02, 0.39 ± 0.02, 0.94 ± 0.05, and 0.65 ± 0.03% for OV1/P, OV1/ADR, OV1/VCR, and OV1/CDDP, respectively. Using the DBA-2/P815 (H2d mouse model, tumors were developed by subcutaneous grafting of tumor fragments of similar size obtained from P815 (murin mastocytoma cell line injected in donor mouse. Interestingly, intra-tumoral injection of EOT significantly reduced solid tumor development. Indeed, by the 30th day of repeated EOT treatment, the tumor volumes of the animals were 2.00 ± 0.27, 1.35 ± 0.20, and 0.85 ± 0.18 cm³ after injection with 10, 30, or 50 µL per 72 h (six times, respectively, as opposed to 3.88 ± 0.50 cm³ for the control animals. This tumoricidal effect was associated with a marked decrease of mouse mortality. In fact, in these groups of mice, the recorded mortality by the 30th day of treatment was 30 ± 4, 18 ± 4, and 8 ± 3%, respectively, while the control animals showed 75 ± 10% of mortality. These data indicate that the EOT which contains carvacrol as the major component has an important in vitro cytotoxic activity against tumor cells resistant to chemotherapy as well as a significant antitumor effect in mice. However, our data do not distinguish between carvacrol and the other components of EOT as the active factor.

Validation of in vitro cell models used in drug metabolism and transport studies; genotyping of cytochrome P450, phase II enzymes and drug transporter polymorphisms in the human hepatoma (HepG2), ovarian carcinoma (IGROV-1) and colon carcinoma (CaCo-2, LS180) cell lines

International Nuclear Information System (INIS)

Brandon, Esther F.A.; Bosch, Tessa M.; Deenen, Maarten J.; Levink, Rianne; Wal, Everdina van der; Meerveld, Joyce B.M. van; Bijl, Monique; Beijnen, Jos H.; Schellens, Jan H.M.; Meijerman, Irma

2006-01-01

Human cell lines are often used for in vitro biotransformation and transport studies of drugs. In vivo, genetic polymorphisms have been identified in drug-metabolizing enzymes and ABC-drug transporters leading to altered enzyme activity, or a change in the inducibility of these enzymes. These genetic polymorphisms could also influence the outcome of studies using human cell lines. Therefore, the aim of our study was to pharmacogenotype four cell lines frequently used in drug metabolism and transport studies, HepG2, IGROV-1, CaCo-2 and LS180, for genetic polymorphisms in biotransformation enzymes and drug transporters. The results indicate that, despite the presence of some genetic polymorphisms, no real effects influencing the activity of metabolizing enzymes or drug transporters in the investigated cell lines are expected. However, this characterization will be an aid in the interpretation of the results of biotransformation and transport studies using these in vitro cell models

Anti-CEA monoclonal antibody in the diagnosis of colorectal, lung and ovarian carcinoma

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Jiang, N.; Lu, B.; Lu, X.; Sha, X.; Yue, D.

2000-01-01

This study evaluated the diagnostic value of radioimmnoimaging (RII) with 99 Tc labeled monoclonal antibody C50, raised originally against carcinoembryonic antigen (anti-CEA) in various tumors. 152 pathologically confirmed patients with a tumor were imaged prior to surgery with an anti-CEA monoclonal antibody labeled with 99 Tc. There were 115 patients with ovarian carcinoma, 26 patients with colorectal carcinoma and 11 patients with lung carcinoma. Images were acquired at 3-6 h post injection and were analyzed by the double blind method. Images of patients with ovarian cancer were compared with B-ultrasound images. Immunohistochemical staining was performed on all cases of colorectal cancer. All RII images demonstrated excellent contrast, clear lesions, and no serious toxic or other side reactions occurred. Transient chills and fever were observed in 3 cases. This study showed a sensitivity=88.2%, specificity=83.2%, and an accuracy=4.0%. The smallest lesion size detected was 2 x 2 cm. The total combined lesion detection rate for primary, metastatic, and recurrence lesions was 84.4%. We conclude that 99 Tc labeled anti-CEA MoAb C50 can be used in the diagnosis of colorectal carcinoma, ovarian carcinoma, and lung carcinoma

Oxidatively Modified Proteins in the Serous Subtype of Ovarian Carcinoma

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Sharifeh Mehrabi

2014-01-01

Full Text Available Serous subtype of ovarian cancer is considered to originate from fallopian epithelium mucosa that has been exposed to physiological changes resulting from ovulation. Ovulation influences an increased in inflammation of epithelial ovarian cells as results of constant exposure of cells to ROS. The imbalance between ROS and antioxidant capacities, as well as a disruption of redox signaling, causes a wide range of damage to DNA, proteins, and lipids. This study applied spectrophotometric, dinitrophenylhydrazone (DNPH assay, two-dimensional gel electrophoresis, and Western blot analyses to assess the levels of oxidatively modified proteins in 100 primary serous epithelial ovarian carcinoma and normal/surrounding tissues. These samples were obtained from 56 Caucasian and 44 African-American patients within the age range of 61±10 years. Analyses showed that the levels of reactive protein carbonyl groups increased as stages progressed to malignancy. Additionally, the levels of protein carbonyls in serous ovarian carcinoma among African Americans are 40% (P<0.05 higher relative to Caucasian at similar advanced stages. Results suggest that oxidative stress is involved in the modification of carbonyl protein groups, leading to increased aggressiveness of epithelial ovarian tumors and may contribute to the disease's invasiveness among African Americans.

Anti-L1CAM radioimmunotherapy is more effective with the radiolanthanide terbium-161 compared to lutetium-177 in an ovarian cancer model

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Gruenberg, Juergen; Lindenblatt, Dennis; Cohrs, Susan; Fischer, Eliane [Paul Scherrer Institute, Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Villigen (Switzerland); Dorrer, Holger [Paul Scherrer Institute, Laboratory of Radiochemistry and Environmental Chemistry, Villigen (Switzerland); Zhernosekov, Konstantin [ITG Isotope Technologies Garching GmbH, Garching (Germany); Koester, Ulli [Institut Laue-Langevin, Grenoble (France); Tuerler, Andreas [Paul Scherrer Institute, Laboratory of Radiochemistry and Environmental Chemistry, Villigen (Switzerland); University of Bern, Department of Chemistry and Biochemistry, Berne (Switzerland); Schibli, Roger [Paul Scherrer Institute, Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Villigen (Switzerland); ETH Zurich, Department of Chemistry and Applied Biosciences, Zurich (Switzerland)

2014-10-15

The L1 cell adhesion molecule (L1CAM) is considered a valuable target for therapeutic intervention in different types of cancer. Recent studies have shown that anti-L1CAM radioimmunotherapy (RIT) with {sup 67}Cu- and {sup 177}Lu-labelled internalising monoclonal antibody (mAb) chCE7 was effective in the treatment of human ovarian cancer xenografts. In this study, we directly compared the therapeutic efficacy of anti-L1CAM RIT against human ovarian cancer under equitoxic conditions with the radiolanthanide {sup 177}Lu and the potential alternative {sup 161}Tb in an ovarian cancer therapy model. Tb was produced by neutron bombardment of enriched {sup 160}Gd targets. {sup 161}Tb and {sup 177}Lu were used for radiolabelling of DOTA-conjugated antibodies. The in vivo behaviour of the radioimmunoconjugates (RICs) was assessed in IGROV1 tumour-bearing nude mice using biodistribution experiments and SPECT/CT imaging. After ascertaining the maximal tolerated doses (MTD) the therapeutic impact of 50 % MTD of {sup 177}Lu- and {sup 161}Tb-DOTA-chCE7 was evaluated in groups of ten mice by monitoring the tumour size of subcutaneous IGROV1 tumours. The average number of DOTA ligands per antibody was 2.5 and maximum specific activities of 600 MBq/mg were achieved under identical radiolabelling conditions. RICs were stable in human plasma for at least 48 h. {sup 177}Lu- and {sup 161}Tb-DOTA-chCE7 showed high tumour uptake (37.8-39.0 %IA/g, 144 h p.i.) with low levels in off-target organs. SPECT/CT images confirmed the biodistribution data. {sup 161}Tb-labelled chCE7 revealed a higher radiotoxicity in nude mice (MTD: 10 MBq) than the {sup 177}Lu-labelled counterpart (MTD: 12 MBq). In a comparative therapy study with equitoxic doses, tumour growth inhibition was better by 82.6 % for the {sup 161}Tb-DOTA-chCE7 than the {sup 177}Lu-DOTA-chCE7 RIT. Our study is the first to show that anti-L1CAM {sup 161}Tb RIT is more effective compared to {sup 177}Lu RIT in ovarian cancer xenografts

Sex hormone-binding globulin (SHBG expression in ovarian carcinomas and its clinicopathological associations.

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Ruixia Huang

Full Text Available Sex hormone-binding globulin (SHBG is known as a carrier protein. It is classically thought to be mainly synthesized in the liver and then secreted into the circulating system, where it binds to sex steroids with a high affinity and modulates the bio-availability of the hormones. Other organs known to produce SHBG include brain, uterus, testis, prostate, breast and ovary, and the local expressed SHBG may play an important role in tumor development. However, SHBG expression status and its clinicopathological significance in ovarian cancer cells are not reported yet. In our present study, we examined and found the variable SHBG expression in four ovarian cancer cell lines (OV-90, OVCAR-3, SKOV-3 and ES-2 by immunocytochemistry and Western blotting. We then extended our study to 248 ovarian carcinoma samples, which were collected at The Norwegian Radium Hospital, Oslo University Hospital with complete clinical information, and discovered that SHBG was variably expressed in these ovarian carcinomas. Higher level of SHBG expression was significantly associated with more aggressive histological subtype (p = 0.022, higher FIGO stage (p = 0.018 and higher histological grade (grade of differentiation, p = 0.020, although association between SHBG expression and OS/PFS was not observed. Our results demonstrate that ovarian cancer cells produce SHBG and higher SHBG expression in ovarian carcinoma is associated with unfavorable clinicopathological features.

Ovarian Small Cell Carcinoma Hypercalcemic Type: A Case Report

LENUS (Irish Health Repository)

Rahma, M B.

2016-09-01

A 31-year-old female was diagnosed with small cell carcinoma of the ovary hypercalcaemic type (OSCCHT) post left oophorectomy. This is a rare aggressive ovarian tumour of which less than 300 cases were reported.

SIRT1 Regulates the Chemoresistance and Invasiveness of Ovarian Carcinoma Cells

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David Hamisi Mvunta

2017-08-01

Full Text Available BACKGROUND: SIRT1 is a longevity gene that forestalls aging and age-related diseases including cancer, and has recently attracted widespread attention due to its overexpression in some cancers. We previously identified the overexpression of SIRT1 in ovarian carcinoma (OvCa as a poor prognostic factor. However, mechanistic insights into the function of SIRT1 in OvCa have yet to be elucidated. METHODS: Quantitative real-time reverse PCR (qRT-PCR and Western blotting were employed to examine the expression of SIRT1 in a panel of human OvCa cell lines. si-RNA or sh-RNA and cDNA technologies were utilized to knockdown or overexpress SIRT1, respectively. The effects of SIRT1 on proliferation and chemoresistance were examined using a WST-1 assay, and the underlying mechanisms were confirmed using an apoptotic assay, and the quantification of glutathione (GSH, and reactive oxygen species (ROS. The aggressiveness of SIRT1 was analyzed using in vitro invasion and migration assays. RESULTS: SIRT1 was more strongly expressed in OvCa cell lines than in the immortalized ovarian epithelium at the gene and protein levels. Stress up-regulated the expression of SIRT1 in dose- and time-dependent manners. SIRT1 significantly enhanced the proliferation (P < .05, chemoresistance (P < .05, and aggressiveness of OvCa cells by up-regulating multiple antioxidant pathways to inhibit oxidative stress. Further study into the overexpression of SIRT1 demonstrated the up-regulation of several stemness-associated genes and enrichment of CD44v9 via an as-yet-unidentified pathway. CONCLUSIONS: Our results suggest that SIRT1 plays a role in the acquisition of aggressiveness and chemoresistance by OvCa, and has potential as a therapeutic target for OvCa.

Efficacy of neratinib in the treatment of HER2/neu-amplified epithelial ovarian carcinoma in vitro and in vivo.

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Menderes, Gulden; Bonazzoli, Elena; Bellone, Stefania; Black, Jonathan D; Lopez, Salvatore; Pettinella, Francesca; Masserdotti, Alice; Zammataro, Luca; Litkouhi, Babak; Ratner, Elena; Silasi, Dan-Arin; Azodi, Masoud; Schwartz, Peter E; Santin, Alessandro D

2017-05-01

Epithelial ovarian carcinoma is the most lethal of gynecologic malignancies. There is a need to optimize the currently available treatment strategies and to urgently develop novel therapeutic agents against chemotherapy-resistant disease. The objective of our study was to evaluate neratinib's preclinical efficacy in treating HER2-amplified ovarian cancer. Neratinib's efficacy in treating HER2-amplified ovarian cancer was studied in vitro utilizing six primary tumor cell lines with differential HER2/neu expression. Flow cytometry was utilized to assess IC 50 , cell signaling changes, and cell cycle distribution. Neratinib's in vivo efficacy was evaluated in HER2-amplified epithelial ovarian carcinoma xenografts. Three of six (50%) ovarian cancer cell lines were HER2/neu-amplified. Neratinib showed significantly higher efficacy in treating HER2/neu-amplified cell lines when compared to the non-HER2/neu-amplified tumor cell lines (mean ± SEM IC 50 :0.010 μM ± 0.0003 vs. 0.076 μM ± 0.005 p Neratinib treatment significantly decreased the phosphorylation of the transcription factor S6, leading to arrest of the cell cycle in G0/G1 phase. Neratinib prolonged survival in mice harboring HER2-amplified epithelial ovarian carcinoma xenografts (p = 0.003). Neratinib inhibits proliferation, signaling, cell cycle progression and tumor growth of HER2-amplified epithelial ovarian carcinoma in vitro. Neratinib inhibits xenograft growth and improves overall survival in HER2/neu-amplified ovarian cancer in vivo. Clinical trials are warranted.

Ovarian carcinoma in a 14-year-old with classical salt-wasting congenital adrenal hyperplasia and bilateral adrenalectomy.

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Pina, Christian; Khattab, Ahmed; Katzman, Philip; Bruckner, Lauren; Andolina, Jeffrey; New, Maria; Yau, Mabel

2015-05-01

A 14-year-old female with classical congenital adrenal hyperplasia because of 21-hydroxylase deficiency underwent bilateral adrenalectomy at 6 years of age as a result of poor hormonal control. Because the patient was adrenalectomized, extra adrenal androgen production was suspected. Imaging studies including pelvic ultrasound and pelvic magnetic resonance imaging (MRI) were obtained to evaluate for adrenal rest tumors of the ovaries. Abdominal MRI was obtained to evaluate for residual adrenal tissue. A cystic lesion arising from her right ovary suspicious for ovarian neoplasm was noted on pelvic MRI. Right salpingo-oophorectomy was performed and histopathological examination revealed ovarian serous adenocarcinoma, low-grade, and well-differentiated. Tumor marker CA-125 was elevated and additional ovarian cancer staging workup confirmed stage IIIC due to one lymph node positive for carcinoma. The patient then developed a large left ovarian cyst, which led to a complete total abdominal hysterectomy and removal of the left ovary and fallopian tube. Pathology confirmed ovarian serous adenocarcinoma with microscopic focus of carcinoma in the left ovary. After numerous complications, the patient responded well to chemotherapy, CA-125 levels fell and no evidence of carcinoma was observed on subsequent imaging. To our knowledge, this is the first reported case of an ovarian serous adenocarcinoma in a patient with CAH. Although rare, we propose that the ovaries were the origin of androgen production and not residual adrenal tissue. The relationship between CAH and ovarian carcinomas has yet to be established, but further evaluation is needed given the poor survival rate of high-grade serous ovarian carcinoma.

Cancer stem-like cells of ovarian clear cell carcinoma are enriched in the ALDH-high population associated with an accelerated scavenging system in reactive oxygen species.

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Mizuno, T; Suzuki, N; Makino, H; Furui, T; Morii, E; Aoki, H; Kunisada, T; Yano, M; Kuji, S; Hirashima, Y; Arakawa, A; Nishio, S; Ushijima, K; Ito, K; Itani, Y; Morishige, K

2015-05-01

In ovarian cancer cases, recurrence after chemotherapy is frequently observed, suggesting the involvement of ovarian cancer stem-like cells (CSCs). The chemoresistance of ovarian clear cell carcinomas is particularly strong in comparison to other epithelial ovarian cancer subtypes. We investigated the relationship between a CSC marker, aldehyde dehydrogenase 1 (ALDH1), and clinical prognosis using ovarian clear cell carcinoma tissue samples. Furthermore, we investigated the antioxidant mechanism by which CSCs maintain a lower reactive oxygen species (ROS) level, which provides protection from chemotherapeutic agents. Immunohistochemical staining was performed to examine the CSC markers (CD133, CD44, ALDH1) using ovarian clear cell carcinoma tissue samples (n=81). Clear cell carcinoma cell lines (KOC-7C, OVTOKO) are separated into the ALDH-high and ALDH-low populations by ALDEFLUOR assay and fluorescence-activated cell sorting (FACS). We compared the intracellular ROS level, mRNA level of the antioxidant enzymes and Nrf2 expression of the two populations. High ALDH1 expression levels are related to advanced stage in clear cell carcinoma cases. ALDH1 expression significantly reduced progression free survival. Other markers are not related to clinical stage and prognosis. ALDH-high cells contained a lower ROS level than ALDH-low cells. Antioxidant enzymes were upregulated in ALDH-high cells. ALDH-high cells showed increased expression of Nrf2, a key transcriptional factor of the antioxidant system. ALDH-positive CSCs might have increased Nrf2-induced antioxidant scavengers, which lower ROS level relevant to chemoresistance in ovarian clear cell carcinoma. Copyright © 2014 Elsevier Inc. All rights reserved.

Precursor lesions of high-grade serous ovarian carcinoma: morphological and molecular characteristics.

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Gross, Amy L; Kurman, Robert J; Vang, Russell; Shih, Ie-Ming; Visvanathan, Kala

2010-01-01

The lack of proven screening tools for early detection and the high mortality of ovarian serous carcinoma (OSC), particularly high grade, have focused attention on identifying putative precursor lesions with distinct morphological and molecular characteristics. The finding of occult invasive and intraepithelial fallopian tube carcinomas in prophylactically removed specimens from asymptomatic high-risk BRCA 1/2-mutation carriers supports the notion of an origin for OSC in the fallopian tube. The intraepithelial carcinomas have been referred to as serous intraepithelial carcinomas (STICs) but our own findings (unpublished data) and recent reports have drawn attention to a spectrum of changes that fall short of STICs that we have designated serous tubal intraepithelial lesions (STILs).

Precursor Lesions of High-Grade Serous Ovarian Carcinoma: Morphological and Molecular Characteristics

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Amy L. Gross

2010-01-01

Full Text Available The lack of proven screening tools for early detection and the high mortality of ovarian serous carcinoma (OSC, particularly high grade, have focused attention on identifying putative precursor lesions with distinct morphological and molecular characteristics. The finding of occult invasive and intraepithelial fallopian tube carcinomas in prophylactically removed specimens from asymptomatic high-risk BRCA 1/2-mutation carriers supports the notion of an origin for OSC in the fallopian tube. The intraepithelial carcinomas have been referred to as serous intraepithelial carcinomas (STICs but our own findings (unpublished data and recent reports have drawn attention to a spectrum of changes that fall short of STICs that we have designated serous tubal intraepithelial lesions (STILs.

Inhibition of IGF-1-Mediated Cellular Migration and Invasion by Migracin A in Ovarian Clear Cell Carcinoma Cells.

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Ukaji, Tamami; Lin, Yinzhi; Banno, Kouji; Okada, Shoshiro; Umezawa, Kazuo

2015-01-01

Previously we isolated migracin A from a Streptomyces culture filtrate as an inhibitor of cancer cell migration. In the present research, we found that migracin A inhibited migration and invasion of ovarian clear cell carcinoma ES-2 cells. In the course of our mechanistic study, migracin A was shown to enhance vasohibin-1 expression in an angiogenesis array. We also confirmed that it increased the mRNA expression of this protein. Moreover, overexpression of vasohibin-1 lowered the migration but not the invasion of ES-2 cells. Then, we looked for another target protein employing a motility array, and found that migracin A lowered the IGF-1 expression. Knockdown of IGF-1 by siRNA decreased the migration and invasion of ES-2 cells. Migracin A also decreased Akt phosphorylation involved in the downstream signaling. Crosstalk analysis indicated that overexpression of vasohibin-1 decreased the IGF-1 expression. On the other hand, it showed no direct anticancer activity in terms of the ES-2 growth in agar. Migracin A inhibited the migration and IGF-1 expression in not only ES-2 but also another ovarian clear cell carcinoma JHOC-5 cells. In addition, it also inhibited capillary tube formation of human umbilical vein endothelial cells. Since its cytotoxicity is very low, migracin A may be a candidate for an anti-metastasis agent not exhibiting prominent toxicity.

[Risk factors of endometriosis associated ovarian carcinoma in women aged 45 years and older].

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He, Z X; Wang, S; Li, Z F; Zhu, L; Leng, J H; Lang, J H

2017-05-25

Obiective: To explore the risk factors of endometriosis-associated ovarian cancer (EAOC) in women with ovarian endometriosis aged 45 years and older in China. Methods: The medical records of total 1 038 women aged 45 years and older with a surgicopathological diagnosis of ovarian endometriosis treated at Peking Union Medical College Hospital from December 1994 to December 2014 were reviewed. Histology evaluation determined ovarian endometriosis with ( n =30) or without ( n =1 008) ovarian cancer. Results: (1) There were 30 (2.9%, 30/1 018) cases confirmed as having EAOC. Clear cell carcinoma (63.3%, 17/30) and endometrioid adenocarcinoma (23.3%, 7/30) were commonly observed subtypes and 70.0% of EAOC patients were at stage Ⅰ. (2) Compared women with ovarian endometriosis in the same age group, patients with EAOC were older (50.8 vs 48.5 years, P =0.002). There were more in postmenopausal status at diagnosis of EAOC ( P 0.05). Conclusions: For women with ovarian endometriosis aged 45 years and older, the subgroup of patients characterized by postmenopausal status and ovarian endometrioma (≥8 cm) have a higher risk of EAOC. Active intervention or intensive follow-up should be considered for this population group, especially for those concurrent with endometrial disorders.

Experimental and clinical analysis of the characteristics of a chimeric monoclonal antibody, MOv18, reactive with an ovarian cancer-associated antigen

NARCIS (Netherlands)

Molthoff, C. F.; Buist, M. R.; Kenemans, P.; Pinedo, H. M.; Boven, E.

1992-01-01

Monoclonal antibody (Mab) MOv18 preferentially reacts with gynecological carcinomas. We have analyzed the characteristics of murine MOv18 (m-MOv18) and chimeric MOv18 (c-MOv18). We found no differences in affinity and binding to IGROV1 cells between c-MOv18 as IgG and F(ab')2 fragments and m-MOv18.

DNA methylation profiles of ovarian epithelial carcinoma tumors and cell lines.

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Sahar Houshdaran

2010-02-01

Full Text Available Epithelial ovarian carcinoma is a significant cause of cancer mortality in women worldwide and in the United States. Epithelial ovarian cancer comprises several histological subtypes, each with distinct clinical and molecular characteristics. The natural history of this heterogeneous disease, including the cell types of origin, is poorly understood. This study applied recently developed methods for high-throughput DNA methylation profiling to characterize ovarian cancer cell lines and tumors, including representatives of three major histologies.We obtained DNA methylation profiles of 1,505 CpG sites (808 genes in 27 primary epithelial ovarian tumors and 15 ovarian cancer cell lines. We found that the DNA methylation profiles of ovarian cancer cell lines were markedly different from those of primary ovarian tumors. Aggregate DNA methylation levels of the assayed CpG sites tended to be higher in ovarian cancer cell lines relative to ovarian tumors. Within the primary tumors, those of the same histological type were more alike in their methylation profiles than those of different subtypes. Supervised analyses identified 90 CpG sites (68 genes that exhibited 'subtype-specific' DNA methylation patterns (FDR<1% among the tumors. In ovarian cancer cell lines, we estimated that for at least 27% of analyzed autosomal CpG sites, increases in methylation were accompanied by decreases in transcription of the associated gene.The significant difference in DNA methylation profiles between ovarian cancer cell lines and tumors underscores the need to be cautious in using cell lines as tumor models for molecular studies of ovarian cancer and other cancers. Similarly, the distinct methylation profiles of the different histological types of ovarian tumors reinforces the need to treat the different histologies of ovarian cancer as different diseases, both clinically and in biomarker studies. These data provide a useful resource for future studies, including those of

Characterization of exosomes derived from ovarian cancer cells and normal ovarian epithelial cells by nanoparticle tracking analysis.

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Zhang, Wei; Peng, Peng; Kuang, Yun; Yang, Jiaxin; Cao, Dongyan; You, Yan; Shen, Keng

2016-03-01

Cellular exosomes are involved in many disease processes and have the potential to be used for diagnosis and treatment. In this study, we compared the characteristics of exosomes derived from human ovarian epithelial cells (HOSEPiC) and three epithelial ovarian cancer cell lines (OVCAR3, IGROV1, and ES-2) to investigate the differences between exosomes originating from normal and malignant cells. Two established colloid-chemical methodologies, electron microscopy (EM) and dynamic light scattering (DLS), and a relatively new method, nanoparticle tracking analysis (NTA), were used to measure the size and size distribution of exosomes. The concentration and epithelial cellular adhesion molecule (EpCAM) expression of exosomes were measured by NTA. Quantum dots were conjugated with anti-EpCAM to label exosomes, and the labeled exosomes were detected by NTA in fluorescent mode. The normal-cell-derived exosomes were significantly larger than those derived from malignant cells, and exosomes were successfully labeled using anti-EpCAM-conjugated quantum dots. Exosomes from different cell lines may vary in size, and exosomes might be considered as potential diagnosis biomarkers. NTA can be considered a useful, efficient, and objective method for the study of different exosomes and their unique properties in ovarian cancer.

Expression of Tissue Factor in Epithelial Ovarian Carcinoma Is Involved in the Development of Venous Thromboembolism.

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Sakurai, Manabu; Matsumoto, Koji; Gosho, Masahiko; Sakata, Akiko; Hosokawa, Yoshihiko; Tenjimbayashi, Yuri; Katoh, Takashi; Shikama, Ayumi; Komiya, Haruna; Michikami, Hiroo; Tasaka, Nobutaka; Akiyama-Abe, Azusa; Nakao, Sari; Ochi, Hiroyuki; Onuki, Mamiko; Minaguchi, Takeo; Yoshikawa, Hiroyuki; Satoh, Toyomi

2017-01-01

Our 2007 study of 32 patients with ovarian cancer reported the possible involvement of tissue factor (TF) in the development of venous thromboembolism (VTE) before treatment, especially in clear cell carcinoma (CCC). This follow-up study further investigated this possibility in a larger cohort. We investigated the intensity of TF expression (ITFE) and other variables for associations with VTE using univariate and multivariate analyses in 128 patients with epithelial ovarian cancer initially treated between November 2004 and December 2010, none of whom had received neoadjuvant chemotherapy. Before starting treatment, all patients were ultrasonographically screened for VTE. The ITFE was graded based on immunostaining of surgical specimens. Histological types were serous carcinoma (n = 42), CCC (n = 12), endometrioid carcinoma (n = 15), mucinous carcinoma (n = 53), and undifferentiated carcinoma (n = 6). The prevalence of VTE was significantly higher in CCC (34%) than in non-CCC (17%, P = 0.03). As ITFE increased, the frequencies of CCC and VTE increased significantly (P epithelial ovarian cancer may involve TF expression in cancer tissues.

HER2 overexpression and amplification is present in a subset of ovarian mucinous carcinomas and can be targeted with trastuzumab therapy

International Nuclear Information System (INIS)

McAlpine, Jessica N; Gilks, C Blake; Miller, Dianne M; Wiegand, Kimberly C; Vang, Russell; Ronnett, Bridgett M; Adamiak, Anna; Köbel, Martin; Kalloger, Steve E; Swenerton, Kenneth D; Huntsman, David G

2009-01-01

The response rate of ovarian mucinous carcinomas to paclitaxel/carboplatin is low, prompting interest in targeted molecular therapies. We investigated HER2 expression and amplification, and the potential for trastuzumab therapy in this histologic subtype of ovarian cancer. HER2 status was tested in 33 mucinous carcinomas and 16 mucinous borderline ovarian tumors (BOT)). Five cases with documented recurrence and with tissue from the recurrence available for testing were analyzed to determine whether HER2 amplification status changed over time. Three prospectively identified recurrent mucinous ovarian carcinomas were assessed for HER2 amplification and patients received trastuzumab therapy with conventional chemotherapy. Amplification of HER2 was observed in 6/33 (18.2%) mucinous carcinomas and 3/16 (18.8%) BOT. HER2 amplification in primary mucinous carcinomas was not associated with an increased likelihood of recurrence. The prospectively identified recurrent mucinous carcinomas showed overexpression and amplification of HER2; one patient's tumor responded dramatically to trastuzumab in combination with conventional chemotherapy, while another patient experienced an isolated central nervous system recurrence after trastuzumab therapy. HER2 amplification is relatively common in ovarian mucinous carcinomas (6/33, 18.2%), although not of prognostic significance. Trastuzumab therapy is a treatment option for patients with mucinous carcinoma when the tumor has HER2 amplification and overexpression

Akt2/ZEB2 may be a biomarker for exfoliant cells in ascitic fluid in advanced grades of serous ovarian carcinoma.

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Liu, Changmei; Yang, Fangmei

2015-09-01

Ovarian cancers present a mild clinical course when diagnosed early but an aggressive pathway when diagnosed in the peri- and postmenopausal periods. However, the predictability of tumor progression is stochastic and is difficult to predict. In the present study, we hypothesized to examine the key pathways that are dysregulated to promote epithelial-mesenchymal transition in serous ovarian carcinoma. Examination of these steps would help to identify ascitic fluid with cells poised for metastasis or otherwise. We focused on examining the Akt2 expression, mainly because of its report as being overamplified in the aggressive variants of ovarian cancer, as well as TGFbeta-sensitivity of Akt2 that forms the key basis for metastasis initiation of most kinds of carcinoma. We obtained primary ovarian carcinoma samples as well as ascitic fluid and distantly metastatic ovarian carcinoma to examine the expression of Akt2. The results of the study demonstrated that in malignant exfoliated ovarian cancer cells, Smad4 expression was tremendously increased in the nuclei, suggesting nuclear translocation of Smad, which thereafter may have activated ZEB2, and thereafter genomically affected the expression of E-cadherin, myosin II, and vimentin, key components for initiating and sustaining metastasis. All of these may have been stimulated by increased cellular expression of Akt2 in metastatic variants of the serous ovarian carcinoma. The reliance on Akt2 and TGF beta signaling may also potentiate the case for Akt inhibitors or small molecule inhibitors of TGFbeta signaling like doxycycline as adjunct chemotherapy in serous ovarian carcinoma, especially the metastatic variants.

Epidemiology in ovarian carcinoma: Lessons from autopsy.

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Güth, Uwe; Arndt, Volker; Stadlmann, Sylvia; Huang, Dorothy Jane; Singer, Gad

2015-08-01

We challenge epidemiologic knowledge regarding ovarian carcinoma (OC) by bridging the gap between clinical and autopsy data. Autopsy reports, histological slides and clinical files from 660 patients in whom OC was diagnosed from 1975-2005 were studied (autopsy cohort, n=233; Clinical Cancer Registry from the local gyneco-oncologic center, n=427). Out of the autopsy cohort, we identified four distinct subgroups of patients: 1) OC was diagnosed before autopsy, n=156 (67.0%). 2) OC was an incidental finding, n=16 (6.8%). 3) The ovarian tumors were not primary OC but rather metastases from other primary tumors; this revised diagnosis was first made by using current histopathological knowledge/techniques, n=24 (10.3%). 4) Death was directly due to OC in its final stage and OC was first diagnosed by autopsy, n=37 (15.9%); when these cases were added to the Clinical Cancer Registry to an adjusted OC incidence model, the autopsy cases comprised 8.8% of the adjusted cohort and almost doubled the percentage of oldest patients (≥80 years at diagnosis) from 4.9% to 9.3% (p=0.013). Epidemiological data from the 1970s-1990s may overestimate true incidence because up to 10% of carcinomas in the ovary were not properly classified. Patients who were first diagnosed with OC by autopsy comprise a distinct subgroup. These are patients who have not been seen by specialized oncologists and thus play no role in their perception of the disease. Nevertheless, these cases have impact on prevalence and incidence data of OC and in an era of reduced autopsy rates will probably be overlooked. Copyright © 2015 Elsevier Inc. All rights reserved.

Functional role and prognostic significance of CD157 in ovarian carcinoma.

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Ortolan, Erika; Arisio, Riccardo; Morone, Simona; Bovino, Paola; Lo-Buono, Nicola; Nacci, Giulia; Parrotta, Rossella; Katsaros, Dionyssios; Rapa, Ida; Migliaretti, Giuseppe; Ferrero, Enza; Volante, Marco; Funaro, Ada

2010-08-04

CD157, an ADP-ribosyl cyclase-related cell surface molecule, regulates leukocyte diapedesis during inflammation. Because CD157 is expressed in mesothelial cells and diapedesis resembles tumor cell migration, we investigated the role of CD157 in ovarian carcinoma. We assayed surgically obtained ovarian cancer and mesothelial cells and both native and engineered ovarian cancer cell lines for CD157 expression using flow cytometry and reverse transcription-polymerase chain reaction (RT-PCR), and for adhesion to extracellular matrices, migration, and invasion using cell-based assays. We investigated invasion of human peritoneal mesothelial cells by serous ovarian cancer cells with a three-dimensional coculture model. Experiments were performed with or without CD157-blocking antibodies. CD157 expression in tissue sections from ovarian cancer patients (n = 88) was examined by immunohistochemistry, quantified by histological score (H score), and categorized as at or above or below the median value of 60, and compared with clinical parameters. Statistical tests were two-sided. CD157 was expressed by ovarian cancer cells and mesothelium, and it potentiated the adhesion, migration, and invasion of serous ovarian cancer cells through different extracellular matrices. CD157-transfected ovarian cancer cells migrated twice as much as CD157-negative control cells (P = .001). Blockage of CD157 inhibited mesothelial invasion by serous ovarian cancer cells in a three-dimensional model. CD157 was expressed in 82 (93%) of the 88 epithelial ovarian cancer tissue specimens. In serous ovarian cancer, patients with CD157 H scores of 60 or greater had statistically significantly shorter disease-free survival and overall survival than patients with lower CD157 H scores (CD157 H score > or =60 vs or =60 vs <60: median overall survival = 45 months, 95% CI = 21.21 to 68.79 vs unreached, P = .024). Multivariable Cox regression showed that CD157 is an independent prognostic factor for recurrence

Primary peritoneal clear cell carcinoma versus ovarian carcinoma versus malignant transformation of endometriosis: a vexing issue.

Science.gov (United States)

Insabato, Luigi; Natella, Valentina; Somma, Anna; Persico, Marcello; Camera, Luigi; Losito, Nunzia Simona; Masone, Stefania

2015-05-01

Peritoneum is a site for both primary and secondary tumors. Primary peritoneal tumors are fairly rare. The most common primary tumors of the peritoneum are malignant mesothelioma and serous papillary adenocarcinoma. Clear cell carcinoma of the peritoneum is extremely rare and often misdiagnosed as mesothelioma, serous carcinoma, or metastatic adenocarcinoma, so it represents a diagnostic challenge for both clinicians and pathologists. Up to date, to the best of our knowledge, only 11 cases of primary peritoneal clear cell carcinoma have been reported in the English literature. Distinguishing this tumor of the peritoneum versus ovarian carcinoma can be problematic. Herein, we report a rare case of primary peritoneal clear cell carcinoma occurring in a 49-year-old woman, along with a review of the literature. © The Author(s) 2015.

Annexin A4 fucosylation enhances its interaction with the NF-kB p50 and promotes tumor progression of ovarian clear cell carcinoma.

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Wang, Huimin; Deng, Lu; Cai, Mingbo; Zhuang, Huiyu; Zhu, Liancheng; Hao, Yingying; Gao, Jian; Liu, Juanjuan; Li, Xiao; Lin, Bei

2017-12-08

To study the structural relationship between annexin A4 and the Lewis y antigen and compare their expression and significance in ovarian clear cell carcinoma, and to explore how annexin A4 fucose glycosylation effects the interaction between annexin A4 and NF-kB p50, and how it promotes tumour progression of ovarian clear cell carcinoma. Structural relationships between annexin A4 and Lewis y antigen were detected using immunoprecipitation. Annexin A4 and Lewis y antigen expression in various subtypes of ovarian cancer tissues was detected by immunohistochemistry, and the relation between their expression was examined. Any interactions between annexin A4 and NF-kB p50 in ovarian clear cell carcinoma were detected by co-immunoprecipitation. Then looked for changes in expression of Lewis y antigen, annexin A4, NF-kB p50 and a number of downstream related molecules before and after transfection annexin A4 or FUT1, and also analyzed changes in biological processes. Lewis y antigen is a part of annexin A4 structure. The expression rate of both annexin A4 and Lewis y antigen was significantly higher in ovarian clear cell carcinoma than in other subtypes of epithelial ovarian cancer, and are associated with the clinical stages, chemotherapy resistance and poor prognostic. The interaction between annexin A4 and NF-kB p50 promoted cell proliferation, adhesion, invasion, metastasis ability and autophagy, and inhibits apoptosis, Lewis y enhanced this interaction. Annexin A4 contains Lewis y structure, Lewis y antigen modification of annexin A4 enhances its interaction with NF-kB p50, which promotes ovarian clear cell carcinoma malignancy progression.

MAL2 and tumor protein D52 (TPD52 are frequently overexpressed in ovarian carcinoma, but differentially associated with histological subtype and patient outcome

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Fanayan Susan

2010-09-01

Full Text Available Abstract Background The four-transmembrane MAL2 protein is frequently overexpressed in breast carcinoma, and MAL2 overexpression is associated with gain of the corresponding locus at chromosome 8q24.12. Independent expression microarray studies predict MAL2 overexpression in ovarian carcinoma, but these had remained unconfirmed. MAL2 binds tumor protein D52 (TPD52, which is frequently overexpressed in ovarian carcinoma, but the clinical significance of MAL2 and TPD52 overexpression was unknown. Methods Immunohistochemical analyses of MAL2 and TPD52 expression were performed using tissue microarray sections including benign, borderline and malignant epithelial ovarian tumours. Inmmunohistochemical staining intensity and distribution was assessed both visually and digitally. Results MAL2 and TPD52 were significantly overexpressed in high-grade serous carcinomas compared with serous borderline tumours. MAL2 expression was highest in serous carcinomas relative to other histological subtypes, whereas TPD52 expression was highest in clear cell carcinomas. MAL2 expression was not related to patient survival, however high-level TPD52 staining was significantly associated with improved overall survival in patients with stage III serous ovarian carcinoma (log-rank test, p Conclusions MAL2 is frequently overexpressed in ovarian carcinoma, and TPD52 overexpression is a favourable independent prognostic marker of potential value in the management of ovarian carcinoma patients.

Struma ovarii mimicking ovarian carcinoma: a case report and review of the literature

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Landim, Fabio Machado [Hospital Geral Doutor Waldemar de Alcantara, Fortaleza, CE (Brazil)

2008-07-01

Struma Ovarii is a rare neoplasia. It is a monodermic mixed teratoma, with predominance of thyroid tissue and represents 3% of ovarian teratomas. This article reports a case of Struma Ovarii in a 66 years-old patient, with a progressive abdominal mass, ascites and high levels of CA-125. The findings were highly suggestive of ovarian carcinoma. The CT scan showed a complex ovarian lesion and the patient was submitted to an exploratory laparotomy. The pathology report showed a left ovary Struma Ovarii. (author)

Subtypes of Ovarian Cancer and Ovarian Cancer Screening

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Masafumi Koshiyama

2017-03-01

Full Text Available Ovarian cancer is the foremost cause of gynecological cancer death in the developed world, as it is usually diagnosed at an advanced stage. In this paper we discuss current issues, the efficacy and problems associated with ovarian cancer screening, and compare the characteristics of ovarian cancer subtypes. There are two types of ovarian cancer: Type I carcinomas, which are slow-growing, indolent neoplasms thought to arise from a precursor lesion, which are relatively common in Asia; and Type II carcinomas, which are clinically aggressive neoplasms that can develop de novo from serous tubal intraepithelial carcinomas (STIC and/or ovarian surface epithelium and are common in Europe and the USA. One of the most famous studies on the subject reported that annual screening using CA125/transvaginal sonography (TVS did not reduce the ovarian cancer mortality rate in the USA. In contrast, a recent study in the UK showed an overall average mortality reduction of 20% in the screening group. Another two studies further reported that the screening was associated with decreased stage at detection. Theoretically, annual screening using CA125/TVS could easily detect precursor lesions and could be more effective in Asia than in Europe and the USA. The detection of Type II ovarian carcinoma at an early stage remains an unresolved issue. The resolving power of CA125 or TVS screening alone is unlikely to be successful at resolving STICs. Biomarkers for the early detection of Type II carcinomas such as STICs need to be developed.

Subtypes of Ovarian Cancer and Ovarian Cancer Screening.

Science.gov (United States)

Koshiyama, Masafumi; Matsumura, Noriomi; Konishi, Ikuo

2017-03-02

Ovarian cancer is the foremost cause of gynecological cancer death in the developed world, as it is usually diagnosed at an advanced stage. In this paper we discuss current issues, the efficacy and problems associated with ovarian cancer screening, and compare the characteristics of ovarian cancer subtypes. There are two types of ovarian cancer: Type I carcinomas, which are slow-growing, indolent neoplasms thought to arise from a precursor lesion, which are relatively common in Asia; and Type II carcinomas, which are clinically aggressive neoplasms that can develop de novo from serous tubal intraepithelial carcinomas (STIC) and/or ovarian surface epithelium and are common in Europe and the USA. One of the most famous studies on the subject reported that annual screening using CA125/transvaginal sonography (TVS) did not reduce the ovarian cancer mortality rate in the USA. In contrast, a recent study in the UK showed an overall average mortality reduction of 20% in the screening group. Another two studies further reported that the screening was associated with decreased stage at detection. Theoretically, annual screening using CA125/TVS could easily detect precursor lesions and could be more effective in Asia than in Europe and the USA. The detection of Type II ovarian carcinoma at an early stage remains an unresolved issue. The resolving power of CA125 or TVS screening alone is unlikely to be successful at resolving STICs. Biomarkers for the early detection of Type II carcinomas such as STICs need to be developed.

Expression of Hyaluronan Synthases (HAS1–3) and Hyaluronidases (HYAL1–2) in Serous Ovarian Carcinomas: Inverse Correlation between HYAL1 and Hyaluronan Content

International Nuclear Information System (INIS)

Nykopp, Timo K; Anttila, Maarit; Rilla, Kirsi; Sironen, Reijo; Tammi, Markku I; Tammi, Raija H; Hämäläinen, Kirsi; Heikkinen, Anna-Mari; Komulainen, Marja; Kosma, Veli-Matti

2009-01-01

Hyaluronan, a tumor promoting extracellular matrix polysaccharide, is elevated in malignant epithelial ovarian tumors, and associates with an unfavorable prognosis. To explore possible contributors to the accumulation of hyaluronan, we examined the expression of hyaluronan synthases (HAS1, HAS2 and HAS3) and hyaluronidases (HYAL1 and HYAL2), correlated with hyaluronidase enzyme activity hyaluronan content and HAS1–3 immunoreactivity. Normal ovaries (n = 5) and 34 serous epithelial ovarian tumors, divided into 4 groups: malignant grades 1+2 (n = 10); malignant grade 3 (n = 10); borderline (n = 4) and benign epithelial tumors (n = 10), were analyzed for mRNA by real-time RT-PCR and compared to hyaluronidase activity, hyaluronan staining, and HAS1–3 immunoreactivity in tissue sections of the same specimens. The levels of HAS2 and HAS3 mRNA (HAS1 was low or absent), were not consistently increased in the carcinomas, and were not significantly correlated with HAS protein or hyaluronan accumulation in individual samples. Instead, the median of HYAL1 mRNA level was 69% lower in grade 3 serous ovarian cancers compared to normal ovaries (P = 0.01). The expression of HYAL1, but not HYAL2, significantly correlated with the enzymatic activity of tissue hyaluronidases (r = 0.5; P = 0.006). An inverse correlation was noted between HYAL1 mRNA and the intensity of hyaluronan staining of the corresponding tissue sections (r = -0.4; P = 0.025). The results indicate that in serous epithelial ovarian malignancies HAS expression is not consistently elevated but HYAL1 expression is significantly reduced and correlates with the accumulation of hyaluronan. (233 words)

Peritoneal Adhesion and Angiogenesis in Ovarian Carcinoma Are Inversely Regulated by Hyaluronan: The Role of Gonadotropins

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Yael Chagit Tzuman

2010-01-01

Full Text Available Ovarian carcinoma is the leading cause of death among gynecologic cancers. Although transformation of the outer ovarian epithelium was linked with ovulation, the disease is significantly more prevalent and severe in postmenopausal women. We postulated that menopause could augment ovarian cancer progression through the effects of gonadotropins on multifocal seeding to the mesothelial layer lining the peritoneum. This seeding is mediated by integrins as well as by CD44 interaction with hyaluronan (HA. Here, we report the effect of gonadotropins on HA synthesis and degradation and on peritoneal adhesion. A significant concentration- and time-dependent induction in expression levels of HA synthases (HASs and hyaluronidases (Hyals was observed in vitro on stimulation of human epithelial ovarian carcinoma cells by gonadotropins. Hormonal regulation of HA-mediated adhesion was manifested in vivo as well, by fluorescence microscopy of stained MLS multicellular tumor spheroids. The number of spheroids adhered to the mesothelium of ovariectomized CD-1 nude mice 9.5 hours after intraperitoneal insertion was significantly higher than in nonovariectomized mice. Inhibition of HA synthesis by 6-diazo-5-oxo-1-norleucine (DON both in spheroids and ovariectomized mice significantly reduced the number of adhered spheroids. Thus, the change in the hormonal environment during menopause assists in HA-dependent adherence of ovarian cancer spheroids onto the peritoneum. However, HA is antiangiogenic and it can significantly suppress tumor progression. Accordingly, angiogenesis of the adhered spheroids was significantly elevated in DON-treated tumors. These results can explain the selective pressure that can lead to simultaneously increased tumor expression of both HASs and Hyals.

MAL2 and tumor protein D52 (TPD52) are frequently overexpressed in ovarian carcinoma, but differentially associated with histological subtype and patient outcome

International Nuclear Information System (INIS)

Byrne, Jennifer A; Sutherland, Robert L; Fazio, Anna de; O'Brien, Philippa M; Maleki, Sanaz; Hardy, Jayne R; Gloss, Brian S; Murali, Rajmohan; Scurry, James P; Fanayan, Susan; Emmanuel, Catherine; Hacker, Neville F

2010-01-01

The four-transmembrane MAL2 protein is frequently overexpressed in breast carcinoma, and MAL2 overexpression is associated with gain of the corresponding locus at chromosome 8q24.12. Independent expression microarray studies predict MAL2 overexpression in ovarian carcinoma, but these had remained unconfirmed. MAL2 binds tumor protein D52 (TPD52), which is frequently overexpressed in ovarian carcinoma, but the clinical significance of MAL2 and TPD52 overexpression was unknown. Immunohistochemical analyses of MAL2 and TPD52 expression were performed using tissue microarray sections including benign, borderline and malignant epithelial ovarian tumours. Inmmunohistochemical staining intensity and distribution was assessed both visually and digitally. MAL2 and TPD52 were significantly overexpressed in high-grade serous carcinomas compared with serous borderline tumours. MAL2 expression was highest in serous carcinomas relative to other histological subtypes, whereas TPD52 expression was highest in clear cell carcinomas. MAL2 expression was not related to patient survival, however high-level TPD52 staining was significantly associated with improved overall survival in patients with stage III serous ovarian carcinoma (log-rank test, p < 0.001; n = 124) and was an independent predictor of survival in the overall carcinoma cohort (hazard ratio (HR), 0.498; 95% confidence interval (CI), 0.34-0.728; p < 0.001; n = 221), and in serous carcinomas (HR, 0.440; 95% CI, 0.294-0.658; p < 0.001; n = 182). MAL2 is frequently overexpressed in ovarian carcinoma, and TPD52 overexpression is a favourable independent prognostic marker of potential value in the management of ovarian carcinoma patients

Tumor infiltrating lymphocyte therapy for ovarian cancer and renal cell carcinoma

DEFF Research Database (Denmark)

Andersen, Rikke; Donia, Marco; Westergaard, Marie Christine Wulff

2015-01-01

stimulated the interest in developing this approach for other indications. Here, we summarize the early clinical data in the field of adoptive cell transfer therapy (ACT) using tumor-infiltrating lymphocytes for patients with renal cell carcinoma (RCC) and ovarian cancer (OC). In addition we describe...

In vitro determination of cytotoxic drug response in ovarian carcinoma using the fluorometric microculture cytotoxicity assay (FMCA).

Science.gov (United States)

Csóka, K; Tholander, B; Gerdin, E; de la Torre, M; Larsson, R; Nygren, P

1997-09-17

The fluorometric microculture cytotoxicity assay (FMCA), a short-term in vitro assay based on the concept of total tumor cell kill, was used for testing the cytotoxic drug sensitivity of tumor cells from patients with ovarian carcinoma. A total of 125 fresh specimens was obtained, 98 (78%) of which were analyzed successfully. Data from 45 patients were available for clinical correlations. The FMCA appeared to yield clinically relevant cytotoxic drug sensitivity data for ovarian carcinoma as indicated by a comparison with tumor samples obtained from patients with non-Hodgkin's lymphoma or kidney carcinoma. Considering the most active single agent in vitro actually given in vivo, and using the median drug activity among all ovarian carcinoma samples as a cut-off, the sensitivity of the assay and its specificity were 75 and 52%, respectively. Cross-resistance in vitro was frequently observed between standard drugs but not between standard drugs and Taxol. Ten percent of the specimens showed an extreme resistance for at least 4 of 6 of the drugs investigated.

Characterization of MicroRNA-200 pathway in ovarian cancer and serous intraepithelial carcinoma of fallopian tube.

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Yang, Junzheng; Zhou, Yilan; Ng, Shu-Kay; Huang, Kuan-Chun; Ni, Xiaoyan; Choi, Pui-Wah; Hasselblatt, Kathleen; Muto, Michael G; Welch, William R; Berkowitz, Ross S; Ng, Shu-Wing

2017-06-17

Ovarian cancer is the leading cause of death among gynecologic diseases in Western countries. We have previously identified a miR-200-E-cadherin axis that plays an important role in ovarian inclusion cyst formation and tumor invasion. The purpose of this study was to determine if the miR-200 pathway is involved in the early stages of ovarian cancer pathogenesis by studying the expression levels of the pathway components in a panel of clinical ovarian tissues, and fallopian tube tissues harboring serous tubal intraepithelial carcinomas (STICs), a suggested precursor lesion for high-grade serous tumors. RNA prepared from ovarian and fallopian tube epithelial and stromal fibroblasts was subjected to quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR) to determine the expression of miR-200 families, target and effector genes and analyzed for clinical association. The effects of exogenous miR-200 on marker expression in normal cells were determined by qRT-PCR and fluorescence imaging after transfection of miR-200 precursors. Ovarian epithelial tumor cells showed concurrent up-regulation of miR-200, down-regulation of the four target genes (ZEB1, ZEB2, TGFβ1 and TGFβ2), and up-regulation of effector genes that were negatively regulated by the target genes. STIC tumor cells showed a similar trend of expression patterns, although the effects did not reach significance because of small sample sizes. Transfection of synthetic miR-200 precursors into normal ovarian surface epithelial (OSE) and fallopian tube epithelial (FTE) cells confirmed reduced expression of the target genes and elevated levels of the effector genes CDH1, CRB3 and EpCAM in both normal OSE and FTE cells. However, only FTE cells had a specific induction of CA125 after miR-200 precursor transfection. The activation of the miR-200 pathway may be an early event that renders the OSE and FTE cells more susceptible to oncogenic mutations and histologic differentiation. As high

OVX1, macrophage-colony stimulating factor, and CA-125-II as tumor markers for epithelial ovarian carcinoma - A critical appraisal

NARCIS (Netherlands)

van Haaften-Day, C; Shen, Y; Xu, FJ; Yu, YH; Berchuck, A; Havrilesky, LJ; de Bruijn, HWA; van der Zee, AGJ; Bast, RC; Hacker, NF

2001-01-01

BACKGROUND. Ovarian carcinoma remains the leading cause of death from gynecologic malignancy in Australia, the Netherlands, and the United States. CA-125-II, the most widely used serum marker, has limited sensitivity and specificity for detecting small-volume, early-stage disease. Therefore, a panel

Characterization of chemically induced ovarian carcinomas in an ethanol-preferring rat model: influence of long-term melatonin treatment.

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Luiz Gustavo A Chuffa

Full Text Available Ovarian cancer is the fourth most common cause of cancer deaths among women, and chronic alcoholism may exert co-carcinogenic effects. Because melatonin (mel has oncostatic properties, we aimed to investigate and characterize the chemical induction of ovarian tumors in a model of ethanol-preferring rats and to verify the influence of mel treatment on the overall features of these tumors. After rats were selected to receive ethanol (EtOH, they were surgically injected with 100 µg of 7,12-dimethyl-benz[a]anthracene (DMBA plus sesame oil directly under the left ovarian bursa. At 260 days old, half of the animals received i.p. injections of 200 µg mel/100 g b.w. for 60 days. Four experimental groups were established: Group C, rats bearing ovarian carcinomas (OC; Group C+EtOH, rats voluntarily consuming 10% (v/v EtOH and bearing OC; Group C+M, rats bearing OC and receiving mel; and Group C+EtOH+M, rats with OC consuming EtOH and receiving mel. Estrous cycle and nutritional parameters were evaluated, and anatomopathological analyses of the ovarian tumors were conducted. The incidence of ovarian tumors was higher in EtOH drinking animals 120 days post-DMBA administration, and mel efficiently reduced the prevalence of some aggressive tumors. Although mel promoted high EtOH consumption, it was effective in synchronizing the estrous cycle and reducing ovarian tumor mass by 20%. While rats in the C group displayed cysts containing serous fluid, C+EtOH rats showed solid tumor masses. After mel treatment, the ovaries of these rats presented as soft and mobile tissues. EtOH consumption increased the incidence of serous papillary carcinomas and sarcomas but not clear cell carcinomas. In contrast, mel reduced the incidence of sarcomas, endometrioid carcinomas and cystic teratomas. Combination of DMBA with EtOH intake potentiated the incidence of OC with malignant histologic subtypes. We concluded that mel reduces ovarian masses and the incidence of

Plasminogen activator inhibitor-1 is an independent prognostic factor of ovarian cancer and IMD-4482, a novel plasminogen activator inhibitor-1 inhibitor, inhibits ovarian cancer peritoneal dissemination.

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Nakatsuka, Erika; Sawada, Kenjiro; Nakamura, Koji; Yoshimura, Akihito; Kinose, Yasuto; Kodama, Michiko; Hashimoto, Kae; Mabuchi, Seiji; Makino, Hiroshi; Morii, Eiichi; Yamaguchi, Yoichi; Yanase, Takeshi; Itai, Akiko; Morishige, Ken-Ichirou; Kimura, Tadashi

2017-10-27

In the present study, the therapeutic potential of targeting plasminogen activator inhibitor-1 (PAI-1) in ovarian cancer was tested. Tissues samples from 154 cases of ovarian carcinoma were immunostained with anti-PAI-1 antibody, and the prognostic value was analyzed. Among the samples, 67% (104/154) showed strong PAI-1 expression; this was significantly associated with poor prognosis (progression-free survival: 20 vs. 31 months, P = 0.0033). In particular, among patients with stage II-IV serous adenocarcinoma, PAI-1 expression was an independent prognostic factor. The effect of a novel PAI-1 inhibitor, IMD-4482, on ovarian cancer cell lines was assessed and its therapeutic potential was examined using a xenograft mouse model of ovarian cancer. IMD-4482 inhibited in vitro cell adhesion to vitronectin in PAI-1-positive ovarian cancer cells, followed by the inhibition of extracellular signal-regulated kinase and focal adhesion kinase phosphorylation through dissociation of the PAI-urokinase receptor complex from integrin αVβ3. IMD-4482 caused G0/G1 cell arrest and inhibited the proliferation of PAI-1-positive ovarian cancer cells. In the xenograft model, IMD-4482 significantly inhibited peritoneal dissemination with the reduction of PAI-1 expression and the inhibition of focal adhesion kinase phosphorylation. Collectively, the functional inhibition of PAI-1 significantly inhibited ovarian cancer progression, and targeting PAI-1 may be a potential therapeutic strategy in ovarian cancer.

Hypoxia-Activated Alkylating Agents in BRCA1-Mutant Ovarian Serous Carcinoma.

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Conroy, Michael; Borad, Mitesh J; Bryce, Alan H

2017-07-26

Breast cancer 1 antigen (BRCA 1) and breast cancer 2 antigen (BRCA2) genes play a significant role in deoxyribonucleic acid (DNA) repair by means of interstrand crosslink repair, and deleterious germline mutations of these are responsible for most hereditary breast and ovarian cancers. Therapeutic strategies which specifically target interstrand crosslink repair can therefore be helpful in patients with harmful mutations. We describe two patients with advanced ovarian cancer and deleterious BRCA1 mutations who were treated with TH-302, a hypoxia-activated alkylating agent.

Phosphorylated 4E binding protein 1: a hallmark of cell signaling that correlates with survival in ovarian cancer.

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Castellvi, Josep; Garcia, Angel; Rojo, Federico; Ruiz-Marcellan, Carmen; Gil, Antonio; Baselga, Jose; Ramon y Cajal, Santiago

2006-10-15

Growth factor receptors and cell signaling factors play a crucial role in human carcinomas and have been studied in ovarian tumors with varying results. Cell signaling involves multiple pathways and a myriad of factors that can be mutated or amplified. Cell signaling is driven through the mammalian target of rapamycin (mTOR) and extracellular regulated kinase (ERK) pathways and by some downstream molecules, such as 4E binding protein 1 (4EBP1), eukaryotic initiation factor 4E, and p70 ribosomal protein S6 kinase (p70S6K). The objectives of this study were to analyze the real role that these pathways play in ovarian cancer, to correlate them with clinicopathologic characteristics, and to identify the factors that transmit individual proliferation signals and are associated with pathologic grade and prognosis, regardless specific oncogenic alterations upstream. One hundred twenty-nine ovarian epithelial tumors were studied, including 20 serous cystadenomas, 7 mucinous cystadenomas, 11 serous borderline tumors, 16 mucinous borderline tumors, 29 serous carcinomas, 16 endometrioid carcinomas, 15 clear cell carcinomas, and 15 mucinous carcinomas. Tissue microarrays were constructed, and immunohistochemistry for the receptors epidermal growth factor receptor (EGFR) and c-erb-B2 was performed and with phosphorylated antibodies for protein kinase B (AKT), 4EBP1, p70S6K, S6, and ERK. Among 129 ovarian neoplasms, 17.8% were positive for c-erb-B2, 9.3% were positive for EGFR, 47.3% were positive for phosphorylated AKT (p-AKT), 58.9% were positive for p-ERK, 41.1% were positive for p-4EBP1, 26.4% were positive for p70S6K, and 15.5% were positive for p-S6. Although EGFR, p-AKT, and p-ERK expression did not differ between benign, borderline, or malignant tumors, c-erb-B2, p-4EBP1, p-p70S6K, and p-S6 were expressed significantly more often in malignant tumors. Only p-4EBP1 expression demonstrated prognostic significance (P = .005), and only surgical stage and p-4EBP1 expression

WNT7A/?-catenin signaling induces FGF1 and influences sensitivity to niclosamide in ovarian cancer

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King, Mandy L.; Lindberg, Mallory E.; Stodden, Genna R.; Okuda, Hiroshi; Ebers, Steven D.; Johnson, Alyssa; Montag, Anthony; Lengyel, Ernst; MacLean, James A.; Hayashi, Kanako

2014-01-01

We previously characterized the link between WNT7A and the progression of ovarian cancer. Other groups have identified FGF1 as a relevant risk factor in ovarian cancer. Here, we show a linkage between these two signaling pathways that may be exploited to improve treatment and prognosis of patients with ovarian cancer. High expression of WNT7A and FGF1 are correlated in ovarian carcinomas and poor overall patient survival. A chromatin immunoprecipitation assay demonstrated that WNT7A/?-catenin...

Compliance to consensus recommendations, surgeon's experience, and introduction of a quality assurance and management program: influence on therapy of early-stage ovarian carcinoma.

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Kommoss, Stefan; Harter, Philipp; Traut, Alexander; Strutas, Deivis; Riegler, Nina; Buhrmann, Christine; Gomez, Ruth; du Bois, Andreas

2009-05-01

State-of-the-art surgical staging and adjuvant chemotherapy in early-stage ovarian carcinoma have an impact on patient's outcome, but compliance to guidelines and consensus recommendations is still poor. This article reports on our results before and after introduction of a quality assurance and management program in our clinic in 2001. Patients with ovarian carcinoma limited to the pelvis who underwent primary surgery in our hospital from 1997 to October 2007 were eligible for this study. Univariate and multivariate logistic regression analyses were performed to evaluate the impact of compliance with our management program and physician's experience in ovarian carcinoma surgery on achieving both standards of surgery and chemotherapy. In a total of 117 women, a significant impact on adherence to guideline-defined comprehensive surgical staging was found for poor Eastern Cooperative Oncology Group performance status (odds ratio [OR], 22.16; confidence interval [CI] 3.2-152.0; P = 0.002) and year of surgery before 2001 (OR, 47.60; CI, 9.20-245.22; P grading less than G3 (OR, 4.14; CI, 1.20-14.22; P = 0.02) was a statistically significant predictor for receiving standard adjuvant chemotherapy. Survival analyses showed a trend toward improved survival for patients having received guideline-adopted therapy, but event numbers were too low for adequate analyses. The introduction of a quality assurance program for treatment of ovarian carcinoma represents a major improvement of patient care. It led to a higher compliance with consensus recommendations and showed already a trend toward improved outcome. Further outcome research should focus on methods for implementation of guidelines in daily practice in institutions caring for patients with ovarian carcinoma.

STUDY OF OVARIAN CHANGES IN RATS WITH MAMMARY CARCINOMAS

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Maja Zečević

2013-03-01

Full Text Available The aim of this study was to estimate ovarian changes in 7,12 dimethylbenz (α anthracene (DMBA induced rat mammary carcinomas. The study was carried out on female virgin albino Wistar rats (n=35, age=35-37days, body mass 120-140g, divided into control (n=10 and experimental group (n=25. Anesthetised animals of experimental group were inoculated with 2 mg mixture (1 mg of DMBA and 1 mg of cholesterol-buffer into the fifth left mammary gland. The animals were sacrificed 90 days after implantation, and ovaries and mammary glands were investigated. Mammary gland carcinomas (in situ and/or invasive were pathohistologically verified in 19 experimental animals. Histological, histochemical, and immunohistochemical (cytokeratin AE1/AE3 and PCNA studies of ovaries were performed.Besides non-neoplastic changes, such as decrease in ovary’s volume, reduction in the rate of follicular development and numerous corpora lutea formation were found in the vicinity of preneoplastic changes: papillomatous epithelial hyperplasia and inclusion cysts, microglandular formations with dysplasia and seromucinous microcystic formation. Intensive diffuse PCNA expression was present in the epithelium of glandlike structures, follicular and inclusion cysts.These morphological changes confirmed that DMBA is a pluripotent carcinogen capable to induce a wide spectrum of preneoplastic lesions in the ovaries. The present dilemma is whether the changes described are the consequence of the direct effects of DMBA or of hormonal activity of the induced breast carcinomas, or both.

MV-NIS or Investigator's Choice Chemotherapy in Treating Patients With Ovarian, Fallopian, or Peritoneal Cancer

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2018-04-27

Fallopian Tube Transitional Cell Carcinoma; Malignant Ovarian Clear Cell Tumor; Malignant Ovarian Endometrioid Tumor; Malignant Ovarian Serous Tumor; Ovarian Seromucinous Carcinoma; Ovarian Transitional Cell Carcinoma; Primary Peritoneal Serous Adenocarcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Undifferentiated Fallopian Tube Carcinoma; Undifferentiated Ovarian Carcinoma

High grade serous ovarian carcinoma with serous tubal intraepithelial carcinoma in a case presented with atypical glandular cell favor neoplasm cervical cytology and dermatomyositis

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Mun-Kun Hong

2015-04-01

Conclusion: The patient had serous carcinoma of the ovary with tubal STIC, which presented as dermatomyositis. The AGC-FN identified from a Pap smear hinted at a diagnosis of ovarian carcinoma. These presentations point to an occult malignancy in the genital tract and demand careful diagnostic workup.

Radioimmunoassay of the normal serum glycoprotein (CX1) in monitoring ovarian malignancy

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Wass, M.; Searle, F.; Bagshawe, K.D.

1981-01-01

A glycoprotein designated CX 1, of molecular weight 80,000, has been extracted from adenocarcinomas of the ovary and its measurement by radioimmunoassay established. CX 1 is present in the normal ovary and in normal serum. It is present in various non-ovarian carcinomas but in much greater amount in ovarian adenocarcinoma and in ascitic fluid associated with this cancer. Increased concentrations are found in the serum of patients with various cancers. In about 60% of patients with Stage III and IV ovarian adenocarcinoma, serum values are elevated and they correlate with the course of the disease, providing information which probably has clinical value. (author)

A genetically engineered ovarian cancer mouse model based on fallopian tube transformation mimics human high-grade serous carcinoma development.

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Sherman-Baust, Cheryl A; Kuhn, Elisabetta; Valle, Blanca L; Shih, Ie-Ming; Kurman, Robert J; Wang, Tian-Li; Amano, Tomokazu; Ko, Minoru S H; Miyoshi, Ichiro; Araki, Yoshihiko; Lehrmann, Elin; Zhang, Yongqing; Becker, Kevin G; Morin, Patrice J

2014-07-01

Recent evidence suggests that ovarian high-grade serous carcinoma (HGSC) originates from the epithelium of the fallopian tube. However, most mouse models are based on the previous prevailing view that ovarian cancer develops from the transformation of the ovarian surface epithelium. Here, we report the extensive histological and molecular characterization of the mogp-TAg transgenic mouse, which expresses the SV40 large T-antigen (TAg) under the control of the mouse müllerian-specific Ovgp-1 promoter. Histological analysis of the fallopian tubes of mogp-TAg mice identified a variety of neoplastic lesions analogous to those described as precursors to ovarian HGSC. We identified areas of normal-appearing p53-positive epithelium that are similar to 'p53 signatures' in the human fallopian tube. More advanced proliferative lesions with nuclear atypia and epithelial stratification were also identified that were morphologically and immunohistochemically reminiscent of human serous tubal intraepithelial carcinoma (STIC), a potential precursor of ovarian HGSC. Beside these non-invasive precursor lesions, we also identified invasive adenocarcinoma in the ovaries of 56% of the mice. Microarray analysis revealed several genes differentially expressed between the fallopian tube of mogp-TAg and wild-type (WT) C57BL/6. One of these genes, Top2a, which encodes topoisomerase IIα, was shown by immunohistochemistry to be concurrently expressed with elevated p53 and was specifically elevated in mouse STICs but not in the surrounding tissues. TOP2A protein was also found elevated in human STICs, low-grade and high-grade serous carcinoma. The mouse model reported here displays a progression from normal tubal epithelium to invasive HGSC in the ovary, and therefore closely simulates the current emerging model of human ovarian HGSC pathogenesis. This mouse therefore has the potential to be a very useful new model for elucidating the mechanisms of serous ovarian tumourigenesis, as well as

Consortium analysis of gene and gene–folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk

DEFF Research Database (Denmark)

Kelemen, Linda E; Terry, Kathryn L; Goodman, Marc T

2014-01-01

SCOPE: We reevaluated previously reported associations between variants in pathways of one-carbon (1-C) (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake. METHODS AND RESULTS: Odds rat...

Expression of the glioma-associated oncogene homolog 1 (gli1 in advanced serous ovarian cancer is associated with unfavorable overall survival.

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Alessandra Ciucci

Full Text Available Recent evidence links aberrant activation of Hedgehog (Hh signaling with the pathogenesis of several cancers including medulloblastoma, glioblastoma, melanoma as well as pancreas, colorectal, and prostate carcinomas. Here we investigated the role of the transcription factor Gli1 in ovarian cancer. To this end, the expression profile of Gli1 was examined in normal ovaries, ovarian tumors, and ovarian cancer cell lines, and the in vitro effects of a specific Hh-pathway blocker, KAAD-cyclopamine, or a specific Gli1 inhibitor (GANT58 on cell proliferation and on Hh target gene expression were also assessed. Results obtained showed that epithelial cells in ovarian cancer tissue express significantly higher levels of nuclear Gli1 than in normal ovarian tissue, where the protein was almost undetectable. In addition, multivariate analysis showed that nuclear Gli1 was independently associated to poor survival in advanced serous ovarian cancer patients (HR = 2.2, 95%CI 1.0-5.1, p = 0.04. In vitro experiments demonstrated Gli1 expression in the three ovarian carcinoma cell lines tested, A2780, SKOV-3 and OVCAR-3. Remarkably, although KAAD-cyclopamine led to decreased cell proliferation, this treatment did not inhibit hedgehog target gene expression in any of the three ovarian cancer cell lines, suggesting that the inhibition of cell proliferation was a nonspecific or toxic effect. In line with these data, no differences on cell proliferation were observed when cell lines were treated with GANT58. Overall, our clinical data support the role of Gli1 as a prognostic marker in advanced serous ovarian cancer and as a possible therapeutic target in this disease. However, our in vitro findings draw attention to the need for selection of appropriate experimental models that accurately represent human tumor for testing future therapies involving Hh pathway inhibitors.

Mismatch repair and treatment resistance in ovarian cancer

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Helleman, Jozien; Staveren, Iris L van; Dinjens, Winand NM; Kuijk, Patricia F van; Ritstier, Kirsten; Ewing, Patricia C; Burg, Maria EL van der; Stoter, Gerrit; Berns, Els MJJ

2006-01-01

The treatment of ovarian cancer is hindered by intrinsic or acquired resistance to platinum-based chemotherapy. The aim of this study is to determine the frequency of mismatch repair (MMR) inactivation in ovarian cancer and its association with resistance to platinum-based chemotherapy. We determined, microsatellite instability (MSI) as a marker for MMR inactivation (analysis of BAT25 and BAT26), MLH1 promoter methylation status (methylation specific PCR on bisulfite treated DNA) and mRNA expression of MLH1, MSH2, MSH3, MSH6 and PMS2 (quantitative RT-PCR) in 75 ovarian carcinomas and eight ovarian cancer cell lines MSI was detected in three of the eight cell lines i.e. A2780 (no MLH1 mRNA expression due to promoter methylation), SKOV3 (no MLH1 mRNA expression) and 2774 (no altered expression of MMR genes). Overall, there was no association between cisplatin response and MMR status in these eight cell lines. Seven of the 75 ovarian carcinomas showed MLH1 promoter methylation, however, none of these showed MSI. Forty-six of these patients received platinum-based chemotherapy (11 non-responders, 34 responders, one unknown response). The resistance seen in the eleven non-responders was not related to MSI and therefore also not to MMR inactivation. No MMR inactivation was detected in 75 ovarian carcinoma specimens and no association was seen between MMR inactivation and resistance in the ovarian cancer cell lines as well as the ovarian carcinomas. In the discussion, the results were compared to that of twenty similar studies in the literature including in total 1315 ovarian cancer patients. Although no association between response and MMR status was seen in the primary tumor the possible role of MMR inactivation in acquired resistance deserves further investigation

Mismatch repair and treatment resistance in ovarian cancer

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Helleman, Jozien; Staveren, Iris L van [Department of Medical Oncology, Erasmus MC/Daniel den Hoed Cancer Center, Rotterdam (Netherlands); Dinjens, Winand NM [Department of Pathology, Erasmus MC/Daniel den Hoed Cancer Center, Rotterdam (Netherlands); Kuijk, Patricia F van; Ritstier, Kirsten [Department of Medical Oncology, Erasmus MC/Daniel den Hoed Cancer Center, Rotterdam (Netherlands); Ewing, Patricia C [Department of Pathology, Erasmus MC/Daniel den Hoed Cancer Center, Rotterdam (Netherlands); Burg, Maria EL van der; Stoter, Gerrit [Department of Medical Oncology, Erasmus MC/Daniel den Hoed Cancer Center, Rotterdam (Netherlands); Berns, Els MJJ [Department of Medical Oncology, Erasmus MC/Daniel den Hoed Cancer Center, Rotterdam (Netherlands); Erasmus MC, Department of Medical Oncology, Josephine Nefkens Institute, Room Be424, P.O. Box 1738, 3000 DR (Netherlands)

2006-07-31

The treatment of ovarian cancer is hindered by intrinsic or acquired resistance to platinum-based chemotherapy. The aim of this study is to determine the frequency of mismatch repair (MMR) inactivation in ovarian cancer and its association with resistance to platinum-based chemotherapy. We determined, microsatellite instability (MSI) as a marker for MMR inactivation (analysis of BAT25 and BAT26), MLH1 promoter methylation status (methylation specific PCR on bisulfite treated DNA) and mRNA expression of MLH1, MSH2, MSH3, MSH6 and PMS2 (quantitative RT-PCR) in 75 ovarian carcinomas and eight ovarian cancer cell lines MSI was detected in three of the eight cell lines i.e. A2780 (no MLH1 mRNA expression due to promoter methylation), SKOV3 (no MLH1 mRNA expression) and 2774 (no altered expression of MMR genes). Overall, there was no association between cisplatin response and MMR status in these eight cell lines. Seven of the 75 ovarian carcinomas showed MLH1 promoter methylation, however, none of these showed MSI. Forty-six of these patients received platinum-based chemotherapy (11 non-responders, 34 responders, one unknown response). The resistance seen in the eleven non-responders was not related to MSI and therefore also not to MMR inactivation. No MMR inactivation was detected in 75 ovarian carcinoma specimens and no association was seen between MMR inactivation and resistance in the ovarian cancer cell lines as well as the ovarian carcinomas. In the discussion, the results were compared to that of twenty similar studies in the literature including in total 1315 ovarian cancer patients. Although no association between response and MMR status was seen in the primary tumor the possible role of MMR inactivation in acquired resistance deserves further investigation.

Mismatch repair and treatment resistance in ovarian cancer

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van der Burg Maria EL

2006-07-01

Full Text Available Abstract Background The treatment of ovarian cancer is hindered by intrinsic or acquired resistance to platinum-based chemotherapy. The aim of this study is to determine the frequency of mismatch repair (MMR inactivation in ovarian cancer and its association with resistance to platinum-based chemotherapy. Methods We determined, microsatellite instability (MSI as a marker for MMR inactivation (analysis of BAT25 and BAT26, MLH1 promoter methylation status (methylation specific PCR on bisulfite treated DNA and mRNA expression of MLH1, MSH2, MSH3, MSH6 and PMS2 (quantitative RT-PCR in 75 ovarian carcinomas and eight ovarian cancer cell lines Results MSI was detected in three of the eight cell lines i.e. A2780 (no MLH1 mRNA expression due to promoter methylation, SKOV3 (no MLH1 mRNA expression and 2774 (no altered expression of MMR genes. Overall, there was no association between cisplatin response and MMR status in these eight cell lines. Seven of the 75 ovarian carcinomas showed MLH1 promoter methylation, however, none of these showed MSI. Forty-six of these patients received platinum-based chemotherapy (11 non-responders, 34 responders, one unknown response. The resistance seen in the eleven non-responders was not related to MSI and therefore also not to MMR inactivation. Conclusion No MMR inactivation was detected in 75 ovarian carcinoma specimens and no association was seen between MMR inactivation and resistance in the ovarian cancer cell lines as well as the ovarian carcinomas. In the discussion, the results were compared to that of twenty similar studies in the literature including in total 1315 ovarian cancer patients. Although no association between response and MMR status was seen in the primary tumor the possible role of MMR inactivation in acquired resistance deserves further investigation.

CD117 expression in fibroblasts-like stromal cells indicates unfavorable clinical outcomes in ovarian carcinoma patients.

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Ruixia Huang

Full Text Available The stem cell factor (SCF receptor CD117 (c-kit, is widely used for identification of hematopoietic stem cells and cancer stem cells. Moreover, CD117 expression in carcinoma cells indicates a poor prognosis in a variety of cancers. However the potential expression in tumor microenvironment and the biological and clinical impact are currently not reported. The expression of CD117 was immunohistochemically evaluated in a serial of 242 epithelial ovarian cancer (EOC cases. Thirty-eight out of 242 cases were CD117 positive in fibroblast-like stromal cells and 22 cases were positive in EOC cells. Four cases were both positive in fibroblast-like stromal cells and EOC cells for CD117. CD117 expression in fibroblast-like stromal cells in ovarian carcinoma was closely linked to advanced FIGO stage, poor differentiation grade and histological subtype (p<0.05, and it was significantly associated with poor overall survival (OS and progression free survival (PFS (Kaplan-Meier analysis; p<0.05, log-rank test. CD117 expression in ovarian carcinoma cells was not associated with these clinicopathological variables. The CD117 positive fibroblast-like stromal cells were all positive for mesenchymal stem/stromal cell (MSC marker CD73 but negative for fibroblast markers fibroblast activation protein (FAP and α smooth muscle actin (α-SMA, indicating that the CD117+/CD73+ fibroblast-like stromal cells are a subtype of mesenchymal stem cells in tumor stroma, although further characterization of these cells are needed. It is concluded herewith that the presence of CD117+/CD73+ fibroblast-like stromal cells in ovarian carcinoma is an unfavorable clinical outcome indication.

Expression of IL-18, IL-18 Binding Protein, and IL-18 Receptor by Normal and Cancerous Human Ovarian Tissues: Possible Implication of IL-18 in the Pathogenesis of Ovarian Carcinoma

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Liat Medina

2014-01-01

Full Text Available Proinflammatory cytokine IL-18 has been shown to be elevated in the sera of ovarian carcinoma patients. The aim of the study was to examine the levels and cellular origin of IL-18, IL-18 binding protein, and IL-18 receptor in normal and cancerous ovarian tissues. Ovarian tissue samples were examined by immunohistochemical staining for IL-18, IL-18BP, and IL-18R and mRNA of these cytokines was analyzed with semiquantitative PT-PCR. IL-18 levels were significantly higher in cancerous ovarian tissues (P=0.0007, IL-18BP levels were significantly higher in normal ovarian tissues (P=0.04, and the ratio of IL-18/IL-18BP was significantly higher in cancerous ovarian tissues (P=0.036. Cancerous ovarian tissues expressed significantly higher IL-18 mRNA levels (P=0.025, while there was no difference in the expression of IL-18BP mRNA and IL-18R mRNA between cancerous and normal ovarian tissues. IL-18 and IL-18BP were expressed dominantly in the epithelial cells of both cancerous and normal ovarian tissues, while IL-18R was expressed dominantly in the epithelial cells of cancerous ovarian tissues but expressed similarly in the epithelial and stromal cells of normal cancerous tissues. This study indicates a possible role of IL-18, IL-18BP, and IL-18R in the pathogenesis of epithelial ovarian carcinoma.

Small cell ovarian carcinoma: genomic stability and responsiveness to therapeutics.

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Gamwell, Lisa F; Gambaro, Karen; Merziotis, Maria; Crane, Colleen; Arcand, Suzanna L; Bourada, Valerie; Davis, Christopher; Squire, Jeremy A; Huntsman, David G; Tonin, Patricia N; Vanderhyden, Barbara C

2013-02-21

The biology of small cell ovarian carcinoma of the hypercalcemic type (SCCOHT), which is a rare and aggressive form of ovarian cancer, is poorly understood. Tumourigenicity, in vitro growth characteristics, genetic and genomic anomalies, and sensitivity to standard and novel chemotherapeutic treatments were investigated in the unique SCCOHT cell line, BIN-67, to provide further insight in the biology of this rare type of ovarian cancer. The tumourigenic potential of BIN-67 cells was determined and the tumours formed in a xenograft model was compared to human SCCOHT. DNA sequencing, spectral karyotyping and high density SNP array analysis was performed. The sensitivity of the BIN-67 cells to standard chemotherapeutic agents and to vesicular stomatitis virus (VSV) and the JX-594 vaccinia virus was tested. BIN-67 cells were capable of forming spheroids in hanging drop cultures. When xenografted into immunodeficient mice, BIN-67 cells developed into tumours that reflected the hypercalcemia and histology of human SCCOHT, notably intense expression of WT-1 and vimentin, and lack of expression of inhibin. Somatic mutations in TP53 and the most common activating mutations in KRAS and BRAF were not found in BIN-67 cells by DNA sequencing. Spectral karyotyping revealed a largely normal diploid karyotype (in greater than 95% of cells) with a visibly shorter chromosome 20 contig. High density SNP array analysis also revealed few genomic anomalies in BIN-67 cells, which included loss of heterozygosity of an estimated 16.7 Mb interval on chromosome 20. SNP array analyses of four SCCOHT samples also indicated a low frequency of genomic anomalies in the majority of cases. Although resistant to platinum chemotherapeutic drugs, BIN-67 cell viability in vitro was reduced by > 75% after infection with oncolytic viruses. These results show that SCCOHT differs from high-grade serous carcinomas by exhibiting few chromosomal anomalies and lacking TP53 mutations. Although BIN-67 cells are

The in vitro antitumor activity of vitamins C and K3 against ovarian carcinoma.

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von Gruenigen, Vivian E; Jamison, James M; Gilloteaux, Jacques; Lorimer, Heather E; Summers, Marcia; Pollard, Robert R; Gwin, Carley A; Summers, Jack L

2003-01-01

The objective was to evaluate the cytotoxic effect and mechanism of action of vitamins C (VC) and K3 (VK3) on ovarian carcinoma. Cytotoxicity assays were performed on ovarian cancer cell lines with VC, VK3 or a VC/VK3 combination. FIC index was employed to evaluate synergism. Flow cytometry was accomplished at 90% cytotoxic doses. Light, transmission electron microscopy and DNA isolation were performed. Antitumor activity was exhibited by both VC, VK3 and VC/VK3. VC/VK3 demonstrated synergistic activity. VC/VK3 may induce a G1 block in the cell cycle. Combined vitamin treatment resulted in cells that maintain apparently intact nuclei while extruding pieces of organelle-free cytoplasm. Degradation of chromosomal DNA was observed. Cell death (autoschizis) displayed characteristics of both apoptosis and necrosis. The cytotoxic effects observed may enable vitamins C and K3 to play an adjuvant role in the treatment of ovarian cancer.

Ovarian Cancer Risk Factors by Histologic Subtype: An Analysis From the Ovarian Cancer Cohort Consortium.

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Wentzensen, Nicolas; Poole, Elizabeth M; Trabert, Britton; White, Emily; Arslan, Alan A; Patel, Alpa V; Setiawan, V Wendy; Visvanathan, Kala; Weiderpass, Elisabete; Adami, Hans-Olov; Black, Amanda; Bernstein, Leslie; Brinton, Louise A; Buring, Julie; Butler, Lesley M; Chamosa, Saioa; Clendenen, Tess V; Dossus, Laure; Fortner, Renee; Gapstur, Susan M; Gaudet, Mia M; Gram, Inger T; Hartge, Patricia; Hoffman-Bolton, Judith; Idahl, Annika; Jones, Michael; Kaaks, Rudolf; Kirsh, Victoria; Koh, Woon-Puay; Lacey, James V; Lee, I-Min; Lundin, Eva; Merritt, Melissa A; Onland-Moret, N Charlotte; Peters, Ulrike; Poynter, Jenny N; Rinaldi, Sabina; Robien, Kim; Rohan, Thomas; Sandler, Dale P; Schairer, Catherine; Schouten, Leo J; Sjöholm, Louise K; Sieri, Sabina; Swerdlow, Anthony; Tjonneland, Anna; Travis, Ruth; Trichopoulou, Antonia; van den Brandt, Piet A; Wilkens, Lynne; Wolk, Alicja; Yang, Hannah P; Zeleniuch-Jacquotte, Anne; Tworoger, Shelley S

2016-08-20

An understanding of the etiologic heterogeneity of ovarian cancer is important for improving prevention, early detection, and therapeutic approaches. We evaluated 14 hormonal, reproductive, and lifestyle factors by histologic subtype in the Ovarian Cancer Cohort Consortium (OC3). Among 1.3 million women from 21 studies, 5,584 invasive epithelial ovarian cancers were identified (3,378 serous, 606 endometrioid, 331 mucinous, 269 clear cell, 1,000 other). By using competing-risks Cox proportional hazards regression stratified by study and birth year and adjusted for age, parity, and oral contraceptive use, we assessed associations for all invasive cancers by histology. Heterogeneity was evaluated by likelihood ratio test. Most risk factors exhibited significant heterogeneity by histology. Higher parity was most strongly associated with endometrioid (relative risk [RR] per birth, 0.78; 95% CI, 0.74 to 0.83) and clear cell (RR, 0.68; 95% CI, 0.61 to 0.76) carcinomas (P value for heterogeneity [P-het] < .001). Similarly, age at menopause, endometriosis, and tubal ligation were only associated with endometrioid and clear cell tumors (P-het ≤ .01). Family history of breast cancer (P-het = .008) had modest heterogeneity. Smoking was associated with an increased risk of mucinous (RR per 20 pack-years, 1.26; 95% CI, 1.08 to 1.46) but a decreased risk of clear cell (RR, 0.72; 95% CI, 0.55 to 0.94) tumors (P-het = .004). Unsupervised clustering by risk factors separated endometrioid, clear cell, and low-grade serous carcinomas from high-grade serous and mucinous carcinomas. The heterogeneous associations of risk factors with ovarian cancer subtypes emphasize the importance of conducting etiologic studies by ovarian cancer subtypes. Most established risk factors were more strongly associated with nonserous carcinomas, which demonstrate challenges for risk prediction of serous cancers, the most fatal subtype. © 2016 by American Society of Clinical Oncology.

BAG3 upregulates Mcl-1 through downregulation of miR-29b to induce anticancer drug resistance in ovarian cancer.

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Sugio, Asuka; Iwasaki, Masahiro; Habata, Shutaro; Mariya, Tasuku; Suzuki, Miwa; Osogami, Hiroyuki; Tamate, Masato; Tanaka, Ryoichi; Saito, Tsuyoshi

2014-09-01

Ovarian cancer is the leading cause of death from gynecologic cancer, reflecting its often late diagnosis and its chemoresistance. We identified a set of microRNAs whose expression is altered upon BAG3 knockdown. Our primary objective was to examine the relationships between BAG3, miR-29b and Mcl-1, an antiapoptotic Bcl-2 family protein, in ovarian cancer cells. Ovarian cancer cells were cultured and their responsiveness to paclitaxel was tested. Microarray analysis was performed to identify microRNAs differentially expressed in ES2 BAG3 knockdown ovarian cancer cells and their control cells. Primary ovarian cancer tissues were obtained from 56 patients operated on for ovarian cancer. The patients' clinical and pathological data were obtained from their medical records. BAG3 knockdown increased the chemosensitivity to paclitaxel of ES2 ovarian clear cell carcinoma cells to a greater degree than AMOC2 serous adenocarcinoma cells. qRT-PCR analysis showed that miR-29b expression was significantly upregulated in primary cancer tissue expressing low levels of BAG3, as compared to tissue expressing high levels. Moreover, levels of miR-29b correlated significantly with progression-free survival. Upregulation of miR-29b also reduced levels of Mcl-1 and sensitized ES2 cells to low-dose paclitaxel. BAG3 knockdown appears to downregulate expression of Mcl-1 through upregulation of miR-29b, thereby increasing the chemosensitivity of ovarian clear cell carcinoma cells. This suggests that BAG3 is a key determinant of the responsiveness of ovarian cancer cells, especially clear cell carcinoma, to paclitaxel and that BAG3 may be a useful therapeutic target for the treatment of ovarian cancer. Copyright © 2014 Elsevier Inc. All rights reserved.

Prognostic implications of the nuclear localization of Y-box-binding protein-1 and CXCR4 expression in ovarian cancer: their correlation with activated Akt, LRP/MVP and P-glycoprotein expression.

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Oda, Yoshinao; Ohishi, Yoshihiro; Basaki, Yuji; Kobayashi, Hiroaki; Hirakawa, Toshio; Wake, Norio; Ono, Mayumi; Nishio, Kazuto; Kuwano, Michihiko; Tsuneyoshi, Masazumi

2007-07-01

The nuclear localization of Y-box-binding protein-1 (YB-1) is known to be a poor prognostic factor in several human malignancies, including ovarian carcinoma. Following on from our basic study dealing with microarray analyses of YB-1-associated gene expression in ovarian cancer cells, we examined whether nuclear localization of YB-1 is associated with the expression of CXCR4, a vault protein named lung resistance-related vault protein (LRP/MVP), phosphorylated Akt (p-Akt) or P-glycoprotein (P-gp) in human ovarian carcinoma. Fifty-three surgically resected ovarian carcinomas treated with paclitaxel and carboplatin were examined immunohistochemically for nuclear YB-1 expression and intrinsic expression of p-Akt, P-gp, LRP/MVP and CXCR4. Nuclear expression of YB-1 demonstrated significant correlation with p-Akt, P-gp and LRP expression, but no relationship with CXCR4 expression. By multivariate analysis, only YB-1 nuclear expression and CXCR4 expression were independent prognostic factors with regard to overall survival. These results indicate that YB-1 nuclear expression and CXCR4 expression are important prognostic factors in ovarian carcinoma.

Morphological and immunohistochemical pattern of tubo-ovarian dysplasia and serous tubal intraepithelial carcinoma.

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Chene, Gautier; Cayre, Anne; Raoelfils, Ines; Lagarde, Nicole; Dauplat, Jacques; Penault-Llorca, Frederique

2014-12-01

Histopathological examination of material from prophylactic salpingo-oophorectomies performed in patients at genetic risk of ovarian cancer can reveal abnormalities interpreted as possible pre-cancerous "ovarian dysplasia" and tubal precursors lesions. We sought to study the morphological features and immunohistochemical expression patterns of neoplasia-associated markers in prophylactically removed ovaries and fallopian tubes (pBSO) in comparison with a group of serous tubal intraepithelial carcinoma (STIC) and non-cancerous controls. Morphological features and immunohistochemical expression patterns of Ki-67 (for proliferation biomarker), p53 (key pathway of mullerian serous tumorogenesis), Bcl2 (anti-apoptotic), γH2AX (a double-strand breaks marker) and ALDH1 (a stem cell marker significantly associated with early-stage ovarian cancer) were blindly evaluated by two pathologists in 111 pBSO, 12 STICs and 116 non-cancerous salpingo-oophorectomies (control group) (nBSO). Morphological ovarian and tubal dysplasia scores were significantly higher in the pBSO than in controls (respectively, 8.8 vs 3.12, pSTICs compared with the controls whereas expression patterns of Ki67, p53 and bcl2 were low to moderate in the pBSO group. STICs overexpressed Ki67 and p53 while bcl2 expression was low; Interestingly, ALDH1 expression was low in non dysplastic epithelium, high in dysplasia and constantly low in STICs. The morphological and immunohistochemical profile of tubo-ovarian dysplasia and STICs might be consistent with progression toward neoplastic transformation in the Serous Carcinogenesis Sequence. These changes may be pre-malignant and could represent an important phase in early neoplasia. ALDH1 activation in pBSO samples and its extinction in STICs should be considered as a target for prevention. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Comparison of Clinical Characteristic and Prognosis between Ovarian Clear Cell Carcinoma and Serous Carcinoma: A 10-Year Cohort Study of Chinese Patients.

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Ye, Shuang; Yang, Jiaxin; You, Yan; Cao, Dongyan; Huang, Huifang; Wu, Ming; Chen, Jie; Lang, Jinghe; Shen, Keng

2015-01-01

To compare the clinicopathologic features and prognosis of Chinese patients with ovarian clear cell carcinoma (CCC) and serous carcinoma (SC). A retrospective cohort study was designed to investigate the clinicopathologic characteristic and prognosis of patients with CCC and SC who were diagnosed and treated in in a tertiary referral center (Peking Union Medical College Hospital) between 1999 and 2009. The Kaplan-Meier method and Cox regression were employed in the survival analysis. A total of 504 cases were included in the study, comprising 197 cases of CCC and 307 cases of SC. The mean age of the patients with SC was greater than of CCC patients (3.6±0.94, PPatients with CCC were more likely to be early-stage and optimally debulked (Ppatients with CCC had normal values, and the level was significantly lower than in patients with SC (Ppatients had platinum-resistant tumors compared with platinum-sensitive disease (45.7% in CCC vs. 61.0% in SC [P=0.008]). The 5-year survival rate was 51.2% in the CCC group vs. 49.8% in the SC group (P=0.428). Patients with advanced CCC had a statistically significant poorer overall survival (OS) compared with their SC counterparts (38.0 vs. 52.0 months; hazard ratio 1.584, 95% confidence interval [CI] 1.167-2.150, P=0.003). However, the advantage of improved progression-free survival (PFS) existed across all stages. Women with ovarian CCC presented at a younger age and early stage. Patients with ovarian CCC also had improved PFS, but they had similar OS compared to patients with SC. However, patients with advanced CCC had decreased survival.

Combination of radiotherapy and selective chemotherapy in the treatment of advanced ovarian carcinomas

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Dietz, R.; Brachetti, A.; Universitaet des Saarlandes, Homburg/Saar

1982-01-01

A report is given on 160 patients suffering from ovarian carcinomas the stages which were exactly determined by TNM classification. 32 patients had tumors of the stages T1-T3, 128 patients had tumors of the stage T4. All T3 subgroups showed favorable results after radical surgery and a postoperative combination of radiotherapy and selective cytostatic chemotherapy. The therapy plans including radiotherapy had more advantages than those without radiotherapy. Furthermore, the cytostatic treatment was more successful after a chemotherapy resistance test than after blind administration of cytostatic drugs. (orig.) [de

BRCA1 Expression Is Epigenetically Repressed in Sporadic Ovarian Cancer Cells by Overexpression of C-Terminal Binding Protein 2

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Taymaa May

2013-06-01

Full Text Available INTRODUCTION: Ovarian cancer is the leading cause of mortality from gynecological malignancy despite advancements in novel therapeutics. We have recently demonstrated that the transcriptional co-repressor C-terminal binding protein 2 (CtBP2 is overexpressed in epithelial ovarian carcinoma. MATERIALS AND METHODS: Reverse-transcribed cDNA from CtBP2 wild-type and knockdown ovarian cancer cell lines was hybridized to Affymetrix Gene 1.0 ST microarrays, and differentially expressed genes were studied. Immunohistochemical analysis of CtBP2 and BRCA1 staining of ovarian tissues was performed. Chromatin immunoprecipitation (ChIP and luciferase assays were carried out. The effect of the drugs 4-methylthio-2-oxobutyric acid (MTOB and poly(ADP-ribose polymerase (PARP inhibitor Olaparib on CtBP2 wild-type and knockdown cell lines was examined using methylthiazol tetrazolium assays and an xCELLigence System. RESULTS: Eighty-five genes involved in DNA repair, mitotic checkpoint, nucleosome assembly, and the BRCA1 network were differentially regulated by CtBP2 expression. ChIP and luciferase reporter assays using a BRCA1 promoter-regulated luciferase construct indicated that the CtBP2 complex binds the BRCA1 promoter and represses BRCA1 transcription. Immunohistochemistry illustrated a significant inverse CtBP2 and BRCA1 expression in a panel of malignant ovarian tumor tissues. The CtBP2 inhibitor MTOB suppressed ovarian cancer cell survival in a CtBP2-dependent manner. Ovarian cancer cells with CtBP2 knockdown did not display increased sensitivity to the PARP inhibitor Olaparib. CONCLUSION: CtBP2 is an ovarian cancer oncogene that may play a significant role in epigenetically silencing BRCA1 function in sporadic epithelial ovarian cancer. CtBP2-specific inhibitors, such as MTOB, may be effective adjunct therapies in the management of patients with CtBP2-positive ovarian carcinoma.

Outcomes of Incidental Fallopian Tube High-Grade Serous Carcinoma and Serous Tubal Intraepithelial Carcinoma in Women at Low Risk of Hereditary Breast and Ovarian Cancer.

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Chay, Wen Yee; McCluggage, W Glenn; Lee, Cheng-Han; Köbel, Martin; Irving, Julie; Millar, Joanne; Gilks, C Blake; Tinker, Anna V

2016-03-01

The natural history and optimal management of serous tubal intraepithelial carcinoma (STIC), regardless of BRCA status, is unknown. We report the follow-up findings of a series of incidental fallopian tube high-grade serous carcinomas (HGSCs) and STICs identified in women at low risk for hereditary breast and ovarian cancer (HBOC), undergoing surgery for other indications. Cases of incidental STIC and HGSC were identified from 2008. Patients with known BRCA1 or BRCA2 mutations, or a family history of ovarian or breast cancer before the diagnosis of STIC or HGSC were excluded. A retrospective chart review was conducted to obtain clinical data. Eighteen cases were identified with a median follow-up of 25 months (range, 4-88 months). Twelve of 18 patients had a diagnosis of STIC with no associated invasive HGSC and 6 had STIC associated with other invasive malignancies. Completion staging surgery was performed on 7 of the 18 patients, including 5 of 12 in which there was STIC only identified on primary surgery; 3 cases were upstaged from STIC only to HGSC based on the staging surgery. Recurrence of HGSC occurred in 2 of the 18 patients. BRCA testing was performed on 3 patients, 1 of whom tested positive for a pathogenic BRCA1 mutation. Our study suggests that completion staging surgery for incidental STICs in non-BRCA patients may be considered. These patients should be offered hereditary testing. The Pelvic-Ovarian cancer INTerception (POINT) Project is an international registry set up to add to our understanding of STICs.

Therapeutic potential of paclitaxel-radiation treatment of a murine ovarian carcinoma

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Milas, Luka; Saito, Yoshihiro; Hunter, Nancy; Milross, Christopher G.; Mason, Kathryn A.

1996-01-01

Background. Paclitaxel has been shown to radiosensitize tumor cells in culture by arresting them in the most radiosensitive G 2 and M cell cycle phases. In vivo preclinical studies are now necessary to obtain full insight into the radiopotentiating potential of this drug and its ability to increase the therapeutic gain of radiotherapy. We tested its ability to enhance the tumor radioresponse of an ovarian carcinoma and to influence the normal tissue radioresponse of recipient mice. Methods. Mice bearing 8-mm isotransplants of a syngeneic ovarian carcinoma, designated OCA-I, in their legs were treated with 40 mg/kg paclitaxel i.v., 14-60 Gy single-dose local tumor irradiation, or both; radiation was given under ambient conditions 1-96 h after paclitaxel. Tumor growth delay, tumor cure rate (TCD 50 assay), and delay in tumor recurrences were measured. Normal tissue radioresponse was determined using jejunal crypt cell survival at 3.5 days after exposure of mice to 9-14 Gy single dose of total body irradiation; the mice were untreated or treated with 40 mg/kg i.v. paclitaxel 4-96 h before irradiation. Results. Paclitaxel alone was effective against OCA-I, but its combination with irradiation produced supra-additive tumor growth delay. It also reduced TCD 50 values and delayed tumor recurrences. The enhancement of tumor radioresponse ranged from 1.33 to 1.96; the value increased as the time between paclitaxel administration and tumor irradiation increased up to 48 h, but then decreased again at 96 h. In contrast, paclitaxel protected jejunum against radiation damage by factors of 1.03 to 1.07 when given 24-96 h before irradiation. It showed some potentiation of damage (by a factor of 1.07), but only when given 4 h before irradiation. Conclusions. Paclitaxel potentiated tumor radioresponse if given within 4 days before irradiation, whereas it caused radioprotection of normal tissue (jejunum) at that time. Therefore, paclitaxel significantly increased therapeutic gain

Metastatic liver tumor from cystic ovarian carcinomas. CT and MRI appearance

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Tang, Yi; Yamashita, Yasuyuki; Ogata, Ichiro; Namimoto, Tomohiro; Abe, Yasuko; Urata, Joji; Takahashi, Mutsumasa [Kumamoto Univ. (Japan). School of Medicine

1999-08-01

The initial and follow-up CT and MRI images of ten patients with hepatic metastases from ovarian tumors were retrospectively analyzed to establish their features and sequential changes in appearance. Ten patients with hepatic metastasis from ovarian tumors received initial and follow-up CT and MRI examinations. Six patients were followed up every two to three weeks before surgical tumor resection. Both CT and MR images were analyzed by two radiologists. A total of fourteen lesions were detected by CT and MRI in 10 patients. All 14 lesions were demonstrated as areas of marked hyperintensity on T2-weighted MRI. Eleven cyst-like tumors were demonstrated as round or oval low density lesions on CT and as areas of hypointensity on T1-weighted imaging. Three lesions were shown as solid masses with slightly low attenuation at the initial CT examination and slightly low or iso-intensity areas on T1-weighted imaging, and these lesions showed early peripheral globular enhancement and delayed enhancement on contrast-enhanced CT and MR imaging. Cystic formation was observed two to three weeks later after initial study in all the 3 solid lesions. Rapid subcapsular effusion, which showed obvious enhancement on delayed Gd-DTPA enhanced MR imaging, was observed in two patients. The hepatic metastatic tumor from cystic ovarian carcinoma may manifest as a well-defined cystic lesion or as a solid mass, and the solid mass shows delayed enhancement on contrast-enhanced CT and MR imaging. Furthermore, rapid cystic formation and rapid subcapsular extension is frequently seen. (author)

KRAS/BRAF Analysis in Ovarian Low-Grade Serous Carcinoma Having Synchronous All Pathological Precursor Regions

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Kohei Nakamura

2016-04-01

Full Text Available Ovarian low-grade serous carcinoma is thought to begin as a serous cystadenoma or adenofibroma that progresses in a slow stepwise fashion. Among the low-grade serous carcinomas, there is a high frequency of activating mutations in the KRAS or BRAF genes; however, it remains unclear as to how these mutations contribute to tumor progression. This is the first report to track the histopathological progression of serous adenofibroma to low-grade serous carcinoma. Each stage was individually analyzed by pathological and molecular genetic methods to determine what differences occur between the distinct stages of progression.

[Effect and mechanism of endoplasmic reticulum stress on cisplatin resistance in ovarian carcinoma].

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Tian, Jing; Hu, Xiaoming; Qu, Quanxin

2014-05-01

The study intended to investigate the effect and mechanism of endoplasmic reticulum stress on cisplatin resistance in ovarian carcinoma. RT-PCR and Western blot were used to test the expression of mTOR and Beclin1 mRNA and protein in ovarian cancer SKOV3 cells after saquinavir induction. MTT assay was used to analyze the influence of saquinavir on cisplatin sensitivity in SKOV3 cells. The IC50 of SKOV3 cells was (5.490 ± 1.148) µg/ml. After induced by Saquinavair 10 µmol/L and 20 µmol/L, the IC50 of SKOV3 cells was increased to (11.199 ± 0.984) µg/ml and (14.906 ± 2.015) µg/ml, respectively. It suggested that the sensitivity of ovarian cancer cells to cisplatin was decreased significantly (P = 0.001). The expression of mTOR and Beclin1 mRNA and protein was significantly different among the five groups: the (Saquinavair+DDP) group of, Saquinavair group, LY294002 group, DDP group and control group (P cisplatin sensitivity in the SKOV3 cells after Saquinavir induced ER stress (P cisplatin in SKOV3 cells. The mechanism of the decrease of sensitivity to cisplatin in SKOV3 cells may be that ERS regulates cell autophagy through the mTOR and Beclin1 pathways. ERS of tumor cells and autophagy may become a new target to improve the therapeutic effect of chemotherapy and to reverse the drug resistance in tumor treatment.

ALDH1-high ovarian cancer stem-like cells can be isolated from serous and clear cell adenocarcinoma cells, and ALDH1 high expression is associated with poor prognosis.

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Takafumi Kuroda

Full Text Available Cancer stem-like cells (CSCs/cancer-initiating cells (CICs are defined as a small population of cancer cells that have high tumorigenicity. Furthermore, CSCs/CICs are resistant to several cancer therapies, and CSCs/CICs are therefore thought to be responsible for cancer recurrence after treatment and distant metastasis. In epithelial ovarian cancer (EOC cases, disease recurrence after chemotherapy is frequently observed, suggesting ovarian CSCs/CICs are involved. There are four major histological subtypes in EOC, and serous adenocarcinoma and clear cell adenocarcinoma are high-grade malignancies. We therefore analyzed ovarian CSCs/CICs from ovarian carcinoma cell lines (serous adenocarcinoma and clear cell adenocarcinoma and primary ovarian cancer cells in this study. We isolated ovarian CSCs/CICs as an aldehyde dehydrogenase 1 high (ALDH1(high population from 6 EOC cell lines (3 serous adenocarcinomas and 3 clear cell adenocarcinomas by the ALDEFLUOR assay. ALDH1(high cells showed greater sphere-forming ability, higher tumorigenicity and greater invasive capability, indicating that ovarian CSCs/CICs are enriched in ALDH1(high cells. ALDH1(high cells could also be isolated from 8 of 11 primary ovarian carcinoma samples. Immunohistochemical staining revealed that higher ALDH1 expression levels in ovary cancer cases are related to poorer prognosis in both serous adenocarcinoma cases and clear cell adenocarcinoma cases. Taken together, the results indicate that ALDH1 is a marker for ovarian CSCs/CICs and that the expression level of ALDH1 might be a novel biomarker for prediction of poor prognosis.

Plexin-B1 silencing inhibits ovarian cancer cell migration and invasion

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Ye, Shuangmei; Chen, Yin; You, Lanying; Zhang, Yiqun; Xu, Gang; Zhou, Jianfeng; Ma, Ding; Wang, Shixuan; Hao, Xing; Zhou, Ting; Wu, Mingfu; Wei, Juncheng; Wang, Yongjun; Zhou, Li; Jiang, Xuefeng; Ji, Li

2010-01-01

Elevated Plexin-B1 expression has been found in diverse human cancers and in non-neoplastic tissues, and it mediates diverse biological and pathological activities. However, whether or not Plexin-B1 expression is involved in human ovarian tumors remains unclear. In the present study, Plexin-B1 expression was explored in benign and malignant human ovarian tumor tissues. In addition, the impact of Plexin-B1 expression on ovarian cancer cell proliferation, migration and invasion were investigated in vitro. Plexin-B1 expression was analyzed in normal and benign ovarian tissues and serous ovarian tumors (both borderline and malignant) by immunohistochemical staining, as well as in four human ovarian cancer cell lines (A2780, C13*, SKOV3, and OV2008) by RT-PCR and western blot analyses. Furthermore, endogenous Plexin-B1 expression was suppressed by Plexin-B1 siRNA in SKOV3 cells, which overexpress Plexin-B1. Protein levels of Plexin-B1, AKT and AKT Ser473 were examined by western blot analysis. Cell proliferation, migration and invasion were measured with MTT, wound healing and boyden chamber assays, respectively, and the cytoskeleton was monitored via F-actin staining. Expression levels of Plexin-B1 protein were significantly higher in serous ovarian carcinomas than in normal ovaries or benign ovarian neoplasms, and in the former, Plexin-B1 expression was positively correlated with lymphatic metastasis, and the membrane and cytoplasm of cancer cells stained positively. SKOV3 cells displayed the highest Plexin-B1 expression at both the mRNA and protein levels among the four tested human ovarian cancer cell lines and was selected as a cell model for further in vitro experiments. Plexin-B1 siRNA significantly suppressed phosphorylation of AKT at Ser473 in SKOV3 cells, but it did not alter total AKT expression. In addition, silencing of Plexin-B1 in SKOV3 cells inhibited cell migration and invasion and reorganized the cytoskeleton, whereas cell proliferation was not

TNF-α expression, risk factors, and inflammatory exposures in ovarian cancer: evidence for an inflammatory pathway of ovarian carcinogenesis?

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Gupta, Mamta; Babic, Ana; Beck, Andrew H.; Terry, Kathryn

2016-01-01

Inflammatory cytokines, like tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6), are elevated in ovarian cancer. Differences in cytokine expression by histologic subytpe or ovarian cancer risk factors can provide useful insight into ovarian cancer risk and etiology. We used ribonucleic acid (RNA) in-situ hybridization to assess TNF-α and IL-6 expression on tissue microarray slides from 78 epithelial ovarian carcinomas (51 serous, 12 endometrioid, 7 clear cell, 2 mucinous, 6 other) from a population-based case control study. Cytokine expression was scored semi-quantitatively and odds ratios (OR) and 95% confidence intervals (CI) were calculated using polytomous logistic regression. TNF-α was expressed in 46% of the tumors while sparse IL-6 expression was seen only 18% of the tumors. For both markers, expression was most common in high grade serous carcinomas followed by endometrioid carcinomas. Parity was associated with a reduced risk of TNF-α positive (OR=0.3, 95% CI: 0.1-0.7 for 3 or more children versus none) but not TNF-α negative tumors (p-heterogeneity=0.02). In contrast, current smoking was associated with a nearly three fold increase in risk of TNF-α negative (OR=2.8, 95% CI: 1.2, 6.6) but not TNF-α positive tumors (p-heterogeneity = 0.06). Our data suggests that TNF-α expression in ovarian carcinoma varies by histologic subtype and provides some support for the role of inflammation in ovarian carcinogenesis. The novel associations detected in our study need to be validated in a larger cohort of patients in future studies. PMID:27068525

Intraperitoneal P-32 for adjuvant and consolidative therapy in ovarian carcinoma

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Condra, Kellie S.; Mendenhall, William M.; Morgan, Linda S.; Freeman, Debra E.; Marcus, Robert B.; Hagan, Michael P.

1996-01-01

Purpose/Objective: To determine the role of intraperitoneal radioactive chromic phosphate (P-32) in the treatment of patients with ovarian carcinoma. Survival results, patterns of recurrence, and treatment morbidity are reported for patients treated adjuvantly after primary surgery and for patients treated with the intent of consolidation after second-look laparotomy. Materials and Methods: Between 1976 and 1993, 25 patients with ovarian carcinoma were treated with 15 mCi P-32 as adjuvant therapy and 43 patients received P-32 as consolidation after second-look laparotomy. The majority of patients (13 of 19) treated adjuvantly had high-risk early-stage disease (IAG 3, IBG 2-3, IC) or more advanced stages (6 patients). Thirty-nine patients received consolidative P-32 after negative second-look laparotomy (35 Stage II-IV and 4 Stage I) and 4 Stage III patients were treated after positive second-look laparotomy. All patients had 2-year minimum follow-up (median, 7.9 years). Results: Ten-year abdominal control and cause-specific survival rates for adjuvant P-32 were 83% and 82%, respectively. For patients treated with consolidative P-32, 5-year abdominal control and cause-specific survival rates were 65% and 78%, respectively. The 5-year cause-specific survival rate for 35 patients with Stage II-IV disease treated with consolidative P-32 after negative second-look laparotomy was 81%. A component of peritoneal failure was the primary mode of recurrence (15 of 22 failures). Four patients required surgical intervention for small-bowel obstruction. No patients died of treatment-related complications. Conclusion: P-32 is well tolerated with acceptable toxicity. In comparing our results to the literature, adjuvant P-32 appears to offer improved cause-specific survival compared with observation alone and equivalent cause-specific survival compared with adjuvant chemotherapy. Consolidative P-32 after negative second-look laparotomy resulted in improved 5-year cause

Peritoneal and mediastinal highly differentiated follicular carcinoma of ovarian origin

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Carey, Kathleen; Jain, Manoj; Krishna, Murli; Accurso, Joseph

2014-01-01

A 70-year-old female patient presented to her primary care doctor with persistent elevated alkaline phosphatase of suspected metastatic etiology. Computed tomography demonstrated epicardial and peritoneal nodules. Biopsy of one of the peritoneal nodules revealed thyroid tissue and extraovarian struma ovarii was considered. The patient had a history of remote total abdominal hysterectomy and bilateral salpingo-oophorectomy 31 years prior for endometriosis with no available pathology from that surgery. The patient recalls being told that she had a left ovarian cyst. A thyroid ultrasound was performed that demonstrated multiple nodules without concerning features; however, due to high clinical suspicion, a total thyroidectomy was performed. Upon full histological evaluation a 0.5 cm papillary microcarcinoma was found. Given the rarity of metastatic papillary cancer to the peritoneum and the small size and grade of the tumor, a diagnosis of highly differentiated follicular carcinoma of ovarian origin was favored. The patient was subsequently treated with radioiodine therapy

Nuclear expression of Snail1 in borderline and malignant epithelial ovarian tumours is associated with tumour progression

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Tuhkanen, Hanna; Soini, Ylermi; Kosma, Veli-Matti; Anttila, Maarit; Sironen, Reijo; Hämäläinen, Kirsi; Kukkonen, Laura; Virtanen, Ismo; Mannermaa, Arto

2009-01-01

Transcription factor Snail1 has a central role in induction of epithelial-mesenchymal transition (EMT). The aim of the present study was to elucidate the expression of Snail1 protein during epithelial ovarian tumourigenesis and to study the association of Snail1 expression with clinicopathological factors and prognosis. Epithelial and stromal fibroblast-like fusiform cells of 14 normal ovarian samples, 21 benign, 24 borderline and 74 malignant epithelial ovarian tumours were studied for Snail1 protein using immunohistochemistry. Nuclei of surface peritoneal cells of normal ovaries (n = 14) were regarded as negative for Snail1. Nuclear expression of Snail1 protein in epithelial ovarian tumours was increased during tumour progression from precursor lesions into carcinomas both in epithelial (p = 0.006) and stromal cells (p = 0.007). Nuclei of benign tumours (n = 21) were negative for Snail1. In borderline tumours (n = 24) occasional positive epithelial cells were found in 2 (8%) samples and in 3 (13%) samples stromal cells were focally positive for Snail1. In carcinomas (n = 74) focal Snail1 staining in epithelial cells was present in 17 (23%) tumours, and in stromal cells in 18 (24%) tumours. Nuclear expression of Snail1 in epithelial or stromal cells was not associated with clinicopathological factors or prognosis. Nuclear Snail1 expression seems to be related to tumour progression, and expression in borderline tumours indicates a role for Snail1 in early epithelial ovarian tumour development. Snail1 also appears to function more generally in tissue remodelling as positive staining was demonstrated in stromal cells

Molecular Alterations of TP53 are a Defining Feature of Ovarian High-Grade Serous Carcinoma: A Rereview of Cases Lacking TP53 Mutations in The Cancer Genome Atlas Ovarian Study.

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Vang, Russell; Levine, Douglas A; Soslow, Robert A; Zaloudek, Charles; Shih, Ie-Ming; Kurman, Robert J

2016-01-01

The Cancer Genome Atlas has reported that 96% of ovarian high-grade serous carcinomas (HGSCs) have TP53 somatic mutations suggesting that mutation of this gene is a defining feature of this neoplasm. In the current study, 5 gynecologic pathologists independently evaluated hematoxylin and eosin slides of 14 available cases from The Cancer Genome Atlas classified as HGSC that lacked a TP53 mutation. The histologic diagnoses rendered by these pathologists and the accompanying molecular genetic data are the subject of this report. Only 1 case (Case 5), which contained a homozygous deletion of TP53, had unanimous interobserver agreement for a diagnosis of pure HGSC. In 1 case (Case 3), all 5 observers (100%) rendered a diagnosis of HGSC; however, 3 observers (60%) noted that the histologic features were not classic for HGSC and suggested this case may have arisen from a low-grade serous carcinoma (arisen from an alternate pathway compared with the usual HGSC). In 2 cases (Cases 4 and 12), only 3 observers (60%) in each case, respectively, interpreted it as having a component of HGSC. In the remaining 10 (71%) of tumors (Cases 1, 2, 6-11, 13, and 14), the consensus diagnosis was not HGSC, with individual diagnoses including low-grade serous carcinoma, high-grade endometrioid carcinoma, HGSC, metastatic carcinoma, clear cell carcinoma, atypical proliferative (borderline) serous tumor, and adenocarcinoma, not otherwise specified. Therefore, 13 (93%) of the tumors (Cases 1-4 and 6-14) were either not a pure HGSC or represented a diagnosis other than HGSC, all with molecular results not characteristic of HGSC. Accordingly, our review of the TP53 wild-type HGSCs reported in The Cancer Genome Atlas suggests that 100% of de novo HGSCs contain TP53 somatic mutations or deletions, with the exception of the rare HGSCs that develop from a low-grade serous tumor precursor. We, therefore, propose that lack of molecular alterations of TP53 are essentially inconsistent with the

Being treated in higher volume hospitals leads to longer progression-free survival for epithelial ovarian carcinoma patients in the Rhone-Alpes region of France

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Huguet, Marius; Perrier, Lionel; Bally, Olivia; Benayoun, David; De Saint Hilaire, Pierre; Beal Ardisson, Dominique; Morelle, Magali; Havet, Nathalie; Joutard, Xavier; Meeus, Pierre; Gabelle, Philippe; Provençal, Jocelyne; Chauleur, Céline; Glehen, Olivier; Charreton, Amandine

2018-01-01

Background To investigate the relationship between hospital volume activities and the survival for Epithelial Ovarian Carcinoma (EOC) patients in France. Methods This retrospective study using prospectively implemented databases was conducted on an exhaustive cohort of 267 patients undergoing first-line therapy during 2012 in the Rhone-Alpes Region of France. We compared Progression-Free Survival for Epithelial Ovarian Carcinoma patients receiving first-line therapy in high- (i.e. ≥ 12 cases/...

Epigenetic alteration of p16 and retinoic acid receptor beta genes in the development of epithelial ovarian carcinoma.

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Bhagat, Rahul; Kumar, Sandeep Sriram; Vaderhobli, Shilpa; Premalata, Chennagiri S; Pallavi, Venkateshaiah Reddihalli; Ramesh, Gawari; Krishnamoorthy, Lakshmi

2014-09-01

Silencing of tumor suppressor and tumor-related genes by promoter hypermethylation is one of the major events in ovarian carcinogenesis. In this study, we analyzed aberrant promoter methylation of p16 and RAR-β genes in 134 epithelial ovarian carcinomas (EOCs), 23 low malignant potential (LMP) tumors, 26 benign cystadenomas, and 15 normal ovarian tissues. Methylation was investigated by methylation-specific PCR (MSP), and the results were confirmed by bisulfite DNA sequencing. Relative gene expression of p16 and RAR-β was done using quantitative reverse transcriptase PCR (qRT-PCR) on 51 EOC cases, 9 LMP tumors, and 7 benign cystadenomas with 5 normal ovarian tissues. Aberrant methylation for p16 and RAR-β was present in 43 % (58/134) and 31 % (41/134) in carcinoma cases, 22 % (05/23) and 52 % (12/23) in LMP tumors, and 42 % (11/26) and 69 % (18/26) in benign cystadenomas. No methylation was observed in any of the normal ovarian tissues. The mRNA expression level of p16 and RAR-β was significantly downregulated in EOC and LMP tumors than the corresponding normal tissues whereas the expression level was normal in benign cystadenomas for p16 and slightly reduced for RAR-β. A significant correlation of p16 promoter methylation was observed with reduced gene expression in EOC. For RAR-β, no significant correlation was observed between promoter methylation and gene expression. Our results suggest that epigenetic alterations of p16 and RAR-β have an important role in ovarian carcinogenesis and that mechanism along with methylation plays a significant role in downregulation of RAR-β gene in ovarian cancer.

[Immunotherapy in epithelial ovarian carcinoma: hope and reality].

Science.gov (United States)

Lavoué, V; Foucher, F; Henno, S; Bauville, E; Catros, V; Cabillic, F; Levêque, J

2014-03-01

Epithelial ovarian carcinoma (EOC) has a worst prognosis with little progress in terms of survival for the last two decades. Immunology received little interest in EOC in the past, but now appears very important in the natural history of this cancer. This review is an EOC immunology state of art and focuses on the place of immunotherapy in future. A systematic review of published studies was performed. Medline baseline interrogation was performed with the following keywords: "Ovarian carinoma, immunotherapy, T-lymphocyte, regulator T-lymphocyte, dendritic cells, macrophage, antigen, chemotherapy, surgery, clinical trials". Identified publications (English or French) were assessed for the understanding of EOC immunology and the place of conventional treatment and immunotherapy strategy. Intratumoral infiltration by immune cells is a strong prognotic factor in EOC. Surgery and chemotherapy in EOC decrease imunosuppression in patients. The antitumoral immunity is a part of the therapeutic action of surgery and chemotherapy. Until now, immunotherapy gave some disappointing results, but the new drugs that target the tolerogenic tumoral microenvironnement rise and give a new hope in the treatment of cancer. Immunology controls the EOC natural history. The modulation of immunosuppressive microenvironment associated with the stimulation of antitumoral immunity could be the next revolution in the treatment of cancer. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Assessment of a Chemotherapy Response Score (CRS) System for Tubo-Ovarian High-Grade Serous Carcinoma (HGSC)

DEFF Research Database (Denmark)

Ditzel, Helena M; Strickland, Kyle C; Meserve, Emily E

2018-01-01

A chemotherapy response score (CRS) system was recently described to assess the histopathologic response and prognosis of patients with tubo-ovarian high-grade serous carcinoma (HGSC) receiving neoadjuvant chemotherapy. The current study was performed as an independent assessment of this CRS syst...

High cytotoxicity of cisplatin nanocapsules in ovarian carcinoma cells depends on uptake by caveolae-mediated endocytosis

NARCIS (Netherlands)

Hamelers, I.H.L.; Staffhorst, R.W.H.M.; Voortman, J.; de Kruijff, B.; Reedijk, J.; van Bergen en Henegouwen, P.M.P.; de Kroon, A.I.P.M.

2009-01-01

Purpose: Cisplatin nanocapsules, nanoprecipitates of cisplatin encapsulated in phospholipid bilayers, exhibit increased in vitro toxicity compared with the free drug toward a panel of human ovarian carcinoma cell lines. To elucidate the mechanism of cell killing by nanocapsules and to understand the

Are all pelvic (nonuterine) serous carcinomas of tubal origin?

Science.gov (United States)

Przybycin, Christopher G; Kurman, Robert J; Ronnett, Brigitte M; Shih, Ie-Ming; Vang, Russell

2010-10-01

It has been proposed that the presence of tubal intraepithelial carcinoma (TIC), in association with one-third to nearly half of pelvic serous carcinomas, is evidence of fallopian tube origin for high-grade serous carcinomas that would have been otherwise classified as primary ovarian or peritoneal. To address this hypothesis, we evaluated a series of 114 consecutive pelvic (nonuterine) gynecologic carcinomas at our institution (2006 to 2008) to determine the frequency of TIC in 52 cases in which all the resected fallopian tube tissue was examined microscopically. These 52 cases were classified as ovarian (n=37), peritoneal (n=8), or fallopian tube (n=7) in origin as per conventional criteria based on disease distribution. The presence of TIC and its location and relationship to invasive carcinoma in the fallopian tubes and ovaries were assessed. Among the 45 cases of ovarian/peritoneal origin, carcinoma subtypes included 41 high-grade serous, 1 endometrioid, 1 mucinous, 1 high-grade, not otherwise specified, and 1 malignant mesodermal mixed tumor. TIC was identified in 24 cases (59%) of high-grade serous carcinoma but not among any of the other subtypes; therefore, the term serous TIC (STIC) is a more specific appellation. STICs were located in the fimbriated end of the tube in 22 cases (92%) and in the ampulla in 2 (8%); they were unilateral in 21 (88%) and bilateral in 3 (13%). STICs in the absence of an associated invasive carcinoma in the same tube were detected in 7 cases (30%) and with invasive carcinoma in the same tube in 17 (71%). Unilateral STICs were associated with bilateral ovarian involvement in 15 cases and unilateral (ipsilateral) ovarian involvement in 5 (the remaining case with a unilateral STIC had a primary peritoneal tumor with no ovarian involvement); the bilateral STICs were all associated with bilateral ovarian involvement. Six of the 7 primary tubal tumors were high-grade serous carcinomas, and 4 of these 6 (67%) had STICs. Based on

Clinical outcomes of fertility-sparing treatments in young patients with epithelial ovarian carcinoma.

Science.gov (United States)

Hu, Jun; Zhu, Li-rong; Liang, Zhi-qing; Meng, Yuan-guang; Guo, Hong-yan; Qu, Peng-peng; Ma, Cai-ling; Xu, Cong-jian; Yuan, Bi-bo

2011-10-01

To assess the clinical outcomes of fertility-sparing treatments in young patients with epithelial ovarian carcinoma (EOC). A retrospective study of young EOC inpatients (≤40 years old) was performed during January 1994 and December 2010 in eight institutions. Data were analyzed from 94 patients treated with fertility-sparing surgery with a median follow-up time of 58.7 months. As histologic grade increased, overall survival (OS) and disease-free survival (DFS) of patients receiving fertility-sparing surgery declined. Neither staging surgery nor laparoscopy of early stage EOC with conservative surgery had a significant effect on OS or DFS. Normal menstruation recommenced after chemotherapy in 89% of the fertility-sparing group. Seventeen pregnancies among twelve patients were achieved by the end of the follow-ups. Fertility-sparing treatment for patients with EOC Stage I Grade 1 could be cautiously considered for young patients. The surgical procedure and surgical route might not significantly influence the prognosis. Standard chemotherapy is not likely to have an evident impact on ovarian function or fertility in young patients.

Expression of Stem Cell Markers in Preinvasive Tubal Lesions of Ovarian Carcinoma.

Science.gov (United States)

Chene, G; Ouellet, V; Rahimi, K; Barres, V; Meunier, L; De Ladurantaye, M; Provencher, D; Mes-Masson, A M

2015-01-01

In order to better understand the ovarian serous carcinogenic process with tubal origin, we investigated the expression of stem cell markers in premalignant tubal lesions (serous tubal intraepithelial carcinoma or STIC). We found an increased stem cell marker density in the normal fallopian tube followed by a high CD117 and a low ALDH and CD44 expression in STICs raising the question of the role of the stem cell markers in the serous carcinogenic process.

Expression of Stem Cell Markers in Preinvasive Tubal Lesions of Ovarian Carcinoma

Directory of Open Access Journals (Sweden)

G. Chene

2015-01-01

Full Text Available In order to better understand the ovarian serous carcinogenic process with tubal origin, we investigated the expression of stem cell markers in premalignant tubal lesions (serous tubal intraepithelial carcinoma or STIC. We found an increased stem cell marker density in the normal fallopian tube followed by a high CD117 and a low ALDH and CD44 expression in STICs raising the question of the role of the stem cell markers in the serous carcinogenic process.

BRCA1 Expression is an Important Biomarker for Chemosensitivity: Suppression of BRCA1 Increases the Apoptosis via Up-regulation of p53 and p21 During Cisplatin Treatment in Ovarian Cancer Cells

Directory of Open Access Journals (Sweden)

Ikuo Konishi

2006-01-01

Full Text Available BRCA1 is a tumor suppressor which plays a crucial role in the repair of DNA double-strand breaks, and its abnormality is responsible for hereditary ovarian cancer syndrome. It has recently been reported that reduced expression of BRCA1 is also common in sporadic ovarian carcinoma via its promoter hypermethylation, and that ovarian carcinoma patients negative for BRCA1 expression showed favorable prognosis. To address if BRCA1 expression plays a role in the chemotherapeutic response, we analyzed the effect of BRCA1 suppression on the sensitivity to cisplatin and paclitaxel in ovarian cancer cells. Specific siRNA for BRCA1 gene was transfected into 3 ovarian cancer cell lines with various p53 status. Reduced expression of BRCA1 by transfection of BRCA1-siRNA resulted in a 5.3-fold increase in sensitivity to cisplatin in p53-wild A2780 cells, but not in p53-mutated A2780/CDDP and p53-deleted SKOV3 cells. Regarding the sensitivity to paclitaxel, BRCA1 suppression caused no significant changes in all the 3 cell lines. For ionizing radiation sensitivity, BRCA1 suppression also showed a significant higher sensitivity in A2780 cells. Growth curve and cell cycle analyses showed no signifi cant differences between BRCA1-siRNA-transfected A2780 cells and control cells. However, cisplatin treatment under suppression of BRCA1 showed a significantly increased apoptosis along with up-regulation of p53 and p21 in A2780 cells. Accordingly, reduced expression of BRCA1 enhances the cisplatin sensitivity and apoptosis via up-regulation of p53 and p21, but does not affect the paclitaxel sensitivity. Expression of BRCA1 might be an important biomarker for cisplatin resistance in ovarian carcinoma.

Intravital Microscopy in Evaluating Patients With Primary Peritoneal, Fallopian Tube, or Stage IA-IV Ovarian Cancer

Science.gov (United States)

2018-06-04

Fallopian Tube Carcinoma; Primary Peritoneal Carcinoma; Stage I Ovarian Cancer; Stage IA Ovarian Cancer; Stage IB Ovarian Cancer; Stage IC Ovarian Cancer; Stage II Ovarian Cancer; Stage IIA Ovarian Cancer; Stage IIB Ovarian Cancer; Stage IIC Ovarian Cancer; Stage III Ovarian Cancer; Stage IIIA Ovarian Cancer; Stage IIIB Ovarian Cancer; Stage IIIC Ovarian Cancer; Stage IV Ovarian Cancer

Kinetics and tissue distribution of the radiolabeled chimeric monoclonal antibody MOv18 IgG and F(ab')2 fragments in ovarian carcinoma patients

NARCIS (Netherlands)

Buist, M. R.; Kenemans, P.; den Hollander, W.; Vermorken, J. B.; Molthoff, C. J.; Burger, C. W.; Helmerhorst, T. J.; Baak, J. P.; Roos, J. C.

1993-01-01

Twenty-four patients suspected of having ovarian carcinoma received i.v. injection with a combination of radiolabeled intact IgG (1 mg) and F(ab')2 fragments (1 mg) of the chimeric monoclonal antibody MOv18, each form labeled with 1.85 MBq 131I or 125I. Laparotomy was performed either 2 or 6 days

Early telomere shortening and genomic instability in tubo-ovarian preneoplastic lesions.

Science.gov (United States)

Chene, Gautier; Tchirkov, Andrei; Pierre-Eymard, Eleonore; Dauplat, Jacques; Raoelfils, Ines; Cayre, Anne; Watkin, Emmanuel; Vago, Philippe; Penault-Llorca, Frederique

2013-06-01

Genetic instability plays an important role in ovarian carcinogenesis. We investigated the level of telomere shortening and genomic instability in early and preinvasive stages of ovarian cancer, serous tubal intraepithelial carcinoma (STIC), and tubo-ovarian dysplasia (TOD). Fifty-one TOD from prophylactic salpingo-oophorectomies with BRCA1 or 2 mutation, 12 STICs, 53 tubo-ovarian high-grade serous carcinoma, and 36 noncancerous controls were laser capture microdissected from formalin-fixed, paraffin-embedded sections, analyzed by comparative genomic hybridization (array CGH) and for telomere length (using quantitative real-time PCR based on the Cawthon's method). TOD and STICs were defined by morphologic scores and immunohistochemical expressions of p53, Ki67, and γH2AX. TOD showed marked telomere shortening compared with noncancerous controls (P STICs had even shorter telomeres than TOD (P = 0.0008). Ovarian carcinoma had shorter telomeres than controls but longer than STICs and dysplasia. In TOD, telomeres were significantly shorter in those with BRCA1 mutation than in those with BRCA2 mutation (P = 0.005). In addition, γH2AX expression in TOD and STIC groups with short telomeres was significantly increased (P STICs. The total number of genetic alterations was the highest in ovarian cancers. These findings suggest that genetic instability occurs in early stages of ovarian tumorigenesis. STICs and noninvasive dysplasia are likely an important step in early serous ovarian neoplasia. ©2013 AACR

The effect of adjuvant radiation on survival in early stage clear cell ovarian carcinoma.

Science.gov (United States)

Hogen, Liat; Thomas, Gillian; Bernardini, Marcus; Bassiouny, Dina; Brar, Harinder; Gien, Lilian T; Rosen, Barry; Le, Lisa; Vicus, Danielle

2016-11-01

To assess the impact of adjuvant radiotherapy (RT) on survival in patients with stage I and II ovarian clear cell carcinoma (OCCC). Data collection and analysis of stage I and II OCCC patients treated at two tertiary centers in Toronto, between 1995 and 2014, was performed. Descriptive statistics and Kaplan-Meier survival probability estimates were completed. The log-rank test was used to compare survival curves. 163 patients were eligible. 44 (27%) patients were treated with adjuvant RT: 37 of them received adjuvant chemotherapy (CT), and 7 had RT only. In the no-RT group, there were 119 patients: 83 patients received adjuvant CT and 36 had no adjuvant treatment. The 10year progression free survival (PFS) was 65% for patients treated with RT, and 59% no-RT patients. There were a total of 41 (25%) recurrences in the cohort: 12 (27.2%) patients in RT group and 29 (24.3%) in the no-RT group. On multivariable analysis, adjuvant RT was not significantly associated with an increased PFS (0.85 (0.44-1.63) p=0.63) or overall survival (OS) (0.84 (0.39-1.82) p=0.66). In the subset of 59 patients defined as high-risk: stage IC with positive cytology and/or surface involvement and stage II: RT was not found to be associated with a better PFS (HR 1.18 (95% CI: 0.55-2.54) or O S(HR 1.04 (95% CI: 0.40-2.69)). Adjuvant RT was not found to be associated with a survival benefit in patients with stage I and II ovarian clear cell carcinoma or in a high risk subset of patients including stage IC cytology positive/surface involvement and stage II patients. Copyright © 2016 Elsevier Inc. All rights reserved.

CYP1B1, Oxidative Stress, and Inflammation in the Etiology of Ovarian Epithelial Cancer Using an Avian Model of Ovarian Carcinoma

National Research Council Canada - National Science Library

Hales, Dale B

2007-01-01

.... Research in ovarian cancer has been hampered by a lack of suitable animal models. With the exception of the laying hen, no other animal gets ovarian epithelial cancer analogous to the human disease...

Pancreatic Metastasis of High-Grade Papillary Serous Ovarian Carcinoma Mimicking Primary Pancreas Cancer: A Case Report

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Yusuf Gunay

2012-01-01

Full Text Available Introduction. Reports of epithelial ovarian carcinomas metastatic to the pancreas are very rare. We herein present a metastasis of high grade papillary serous ovarian cancer to mid portion of pancreas. Case. A 42-year-old patient was admitted with a non-specified malignant cystic lesion in midportion of pancreas. She had a history of surgical treatment for papillary serous ovarian adenocarcinoma. A cystic lesion was revealed by an abdominal computerized tomography (CT performed in her follow up . It was considered as primary mid portion of pancreatic cancer and a distal pancreatectomy was performed. The final pathology showed high-grade papillary serous adenocarcinoma morphologically similar to the previously diagnosed ovarian cancer. Discussion. Metastatic pancreatic cancers should be considered in patients who present with a solitary pancreatic mass and had a previous non-pancreatic malignancy. Differential diagnosis of primary pancreatic neoplasm from metastatic malignancy may be very difficult. A biopsy for tissue confirmation is required to differentiate primary and secondary pancreatic tumors. Although, the value of surgical resection is poorly documented, resection may be considered in selected patients. Conclusion. Pancreatic metastasis of ovarian papillary serous adenocarcinoma has to be kept in mind when a patient with pancreatic mass has a history of ovarian malignancy.

Twenty-five year outcome of sequential abdominopelvic radiotherapy and alkylating agent chemotherapy for ovarian carcinoma

International Nuclear Information System (INIS)

Bellairs, Ellen E.; Twiggs, Leo B.; Potish, Roger A.

1997-01-01

Purpose: A prospective study of sequential surgery, abdominopelvic radiotherapy and single agent alkylating chemotherapy was conducted to evaluate survival and toxicity in the management of ovarian carcinoma. Methods: From 1970-1976, 95 women with stage I-III epithelial ovarian carcinoma were scheduled to receive postoperative radiotherapy consisting of 20.0 Gy to the whole abdomen (1.0 Gy/day), a 29.75 Gy pelvic boost (1.75 Gy/day) and 10 subsequent courses of Melphalan (1 mg/kg/course). Endpoints were overall survival, disease-free survival(DFS), and acute and chronic toxicity. Results: The evaluable 94 patients included 19 stage I, 25 stage II, and 50 stage III. Of the latter, 21 had no palpable disease postoperatively (IIIN) and 29 had postoperative palpable disease (IIIP). Overall survival at 5, 10, 15 and 20 years was 42%, 30%, 23% and 22%. DFS for the entire group was 54% at 5 years and remained 50% from 10 to 25 years. All but two recurrences were noted within the first 27 months. No recurrence or treatment-related deaths occurred after 8 years. After 10 years, the survival of the study group became parallel to the general population. Prognostic factors were only related to stage (p<.001) and the presence of postoperative palpable disease(p<.001). DFS at 25 years was 95 % for stage I, 71% at 5 years and 66% from 10 to 25 years for stage II, and 17% at 5 years and 11% thereafter for stage III patients(p<.001). Although no stage IIIP patients were cured, 25% lived beyond 2 years. Five year DFS was significantly better in IIIN (45%) vs. IIIP (0%) patients (p<.001). The 65 patients without postoperative palpable disease, (stage I-IIIN) achieved DFS at 5 and 25 years of 69%, and 61%, respectively. Of 31 patients undergoing a second-look surgery, 84% were found to be free of tumor. Two recurred at 3.5 and 7 years after surgery. Acute tolerance was acceptable. Chronic toxicity included an 11.7% rate of small bowel obstruction requiring surgery and a 3% rate of

Cytogenetic Evolution of Human Ovarian Cell Lines Associated with Chemoresistance and Loss of Tumorigenicity

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Stéphanie Struski

2003-01-01

Full Text Available In order to identify genomic changes associated with a resistant phenotype acquisition, we used comparative genomic hybridization (CGH to compare a human ovarian cell line, Igrov1, and four derived subcell lines, resistant to vincristine and presenting a reversion of malignant properties. Multicolor FISH (Multiplex‐FISH and Spectral Karyotype and conventional FISH are also used to elucidate the karyotype of parental cell line. The drug‐resistant subcell lines displayed many chromosomal abnormalities suggesting the implication of different pathways leading to a multidrug resistance phenotype. However, these cell lines shared two common rearrangements: an unbalanced translocation der(8t(8;13(p22;q? and a deletion of the 11p. These chromosomal imbalances could reflected the acquisition of the chemoresistance (der(8 or the loss of tumorigenicity properties (del(11p. Colour figure can be viewed on http://www.esacp.org/acp/2003/25‐3/struski.htm.

Increased cell survival by inhibition of BRCA1 using an antisense approach in an estrogen responsive ovarian carcinoma cell line

International Nuclear Information System (INIS)

Annab, Lois A; Hawkins, Rebecca E; Solomon, Greg; Barrett, J Carl; Afshari, Cynthia A

2000-01-01

-day period (Fig. 2a). The BRCA1 antisense population also exhibited a threefold to sixfold increase in cell growth compared with control cells in the presence of estrogen treatment. BG-1 BRCA1 antisense clones demonstrated a similar response to pooled population studies, enhanced growth with estrogen, and failure to die upon estrogen depletion (Fig. 2b). The BRCA1 antisense clones were further examined for other associated tumorigenic properties. All of the antisense clones were able to form colonies in soft agar (2-23 colonies per 10 4 cells plated; data not shown), whereas control clones were deficient in their ability to form colonies (0-0.8 colonies per 10 4 cells plated). Table 1 shows, in the presence of estrogen, the clone with the lowest levels of BRCA1 (AS-4) produced significantly more colonies (133 ± 17.9 colonies per 10 4 cells plated) than the control clone (NEO; 6 ± 3.1 colonies per 10 4 cells plated). Clones AS-4 and NEO were also injected with matrigel subcutaneously into ovariectomized athymic mice. Almost twice as many sites were positive for the AS-4 clone (14 out of 14) as for the NEO clone (eight out of 14) 42 days after injection. In addition, BRCA1 antisense tumors averaged twice the size of control tumors. The BRCA1 reduced cells also formed tumors with half the latency of control cells in the presence of implanted estrogen (11 days versus 21 days until tumor formation). The present studies show that reduction in BRCA1 levels, using an antisense retroviral vector in the estrogen dependent BG-1 ovarian carcinoma cell line, contributes to confirmation of the hypothesis that BRCA1 plays a pivotal role in the balance between cell death and cell proliferation. BRCA1 RNA and protein levels were successfully reduced in populations and isolated clones of antisense infected BG-1 cells. Decreased BRCA1 levels rescued the BG-1 cells from growth arrest or cell death in adverse growth conditions in monolayer or soft agar conditions. Furthermore, a BRCA1

Image-guided biopsy in patients with suspected ovarian carcinoma: a safe and effective technique?

International Nuclear Information System (INIS)

Griffin, Nyree; Grant, Lee A.; Freeman, Susan J.; Berman, Laurence H.; Sala, Evis; Jimenez-Linan, Mercedes; Earl, Helena; Ahmed, Ahmed Ashour; Crawford, Robin; Brenton, James

2009-01-01

In patients with suspected advanced ovarian carcinoma, a precise histological diagnosis is required before commencing neo-adjuvant chemotherapy. This study aims to determine the diagnostic accuracy and complication rate of percutaneous biopsies performed under ultrasound or computed tomography guidance. Between 2002 to 2007, 60 consecutive image-guided percutaneous biopsies were performed in patients with suspected ovarian cancer. The following variables were recorded: tissue biopsied, imaging technique, experience of operator, biopsy needle gauge, number of passes, complications, and final histology. Forty-seven patients had omental biopsies, 12 pelvic mass biopsies, and 1 para-aortic lymph node biopsy. Thirty-five biopsies were performed under ultrasound, 25 under computed tomography guidance. Biopsy needle gauges ranged from 14-20 swg with two to five passes for each patient. There were no complications. Histology was obtained in 52 (87%) patients. Percutaneous image-guided biopsy of peritoneal disease or pelvic mass is safe with high diagnostic accuracy. The large-gauge biopsy needle is as safe as the small gauge needle, but has the added value of obtaining tissue samples for immunohistochemistry and genomic studies. (orig.)

Primary Fallopian Tube Carcinoma

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Prasad K Shetty

2011-01-01

Full Text Available Primary Fallopian Tube Carcinoma (PFTC is rare and accounts for about 0.3% of all gynecologic cancers. Less than 1500 cases have been reported in the literature. It arises in postmenopausal women and typically presents with abdominal pelvic pain, vaginal bleeding and watery discharge. However, a correct diagnosis is rarely achieved preoperative, and in many cases, the diagnosis is made after incidental surgery for unrelated conditions commonly being ovarian carcinoma . Compared with ovarian carcinoma, PFTC more often presents at early stages, but it has a worse prognosis. PFTC is usually managed in the same manner as ovarian cancer. We report a case of Left PFTC that presented as Left ovarian mass, and we briefly review the literature.

Increase in Docetaxel-Resistance of Ovarian Carcinoma-Derived RMG-1 Cells with Enhanced Expression of Lewis Y Antigen

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Bei Lin

2011-10-01

Full Text Available Epithelial carcinomas of the ovary exhibit the highest mortality rate among gynecologic malignancies. Studies found that the metabolism of glycolipids or carbohydrates is associated with acquirement of anticancer drug-resistance by cancer cells. This study was to characterize possible involvement of Lewis Y (LeY antigen in the drug-resistance of cancer cells. We transfected the α1,2-fucosyltransferase gene into human ovarian carcinoma-derived RMG-1 cells and established RMG-1-hFUT cells with enhanced expression of LeY. We determined the effects of docetaxel on the survival of cells by MTT assaying and observed the apoptosis of cells in the presence of docetaxel by flow cytometric analysis and by transmission electron microscopy. Plasma membranes and intracellular granules in RMG-1-hFUT cells were stained with anti-LeY antibody, the intensity of the staining was higher than that in control cells. The RMG-1-hFUT cells exhibited higher resistance to docetaxel than the control cells with regard to the docetaxel concentration and time course. After treatment with 10 μg/mL docetaxel for 72 h, the control cells, but not RMG-1-hFUT, contained abundant positively stained cell debris due to disintegration of the cytoskeleton. On transmission electron microscopy, although the control cells treated with docetaxel as above showed the following morphology, i.e., absence of villi, cells shrunken in size, pyknosis, agglutinated chromatin and cell buds containing nuclei in the process of apoptosis, the RMG-1-hFUT cells showed only agglutinated chromatin and vacuoles in the cytoplasm. In summary, cells with enhanced expression of LeY were shown to acquire docetaxel-resistance, indicating the possible involvement of glycoconjugates in the drug-resistance.

Complete resection of locally advanced ovarian carcinoma fixed to the pelvic sidewall and involving external and internal iliac vessels.

Science.gov (United States)

Nishikimi, Kyoko; Tate, Shinichi; Matsuoka, Ayumu; Shozu, Makio

2017-08-01

Locally advanced ovarian carcinomas may be fixed to the pelvic sidewall, and although these often involve the internal iliac vessels, they rarely involve the external iliac vessels. Such tumors are mostly considered inoperable. We present a surgical technique for complete resection of locally advanced ovarian carcinoma fixed to the pelvic sidewall and involving external and internal iliac vessels. A 69-year-old woman presented with ovarian carcinoma fixed to the right pelvic sidewall, which involved the right external and internal iliac arteries and veins and the right lower ureter, rectum, and vagina. We cut the external iliac artery and vein at the bifurcation and at the inguinal ligament to resect the external artery and vein. Then, we reconstructed the arterial and venous supplies of the right external artery and vein with grafts. After creating a wide space immediately inside of the sacral plexus to allow the tumor fixed to pelvic sidewall with the internal iliac vessels to move medially, we performed total internal iliac vessel resection. We achieved complete en bloc tumor resection with the right external and internal artery and vein, right ureter, vagina, and rectum adhering to the tumor. There were no intra- or postoperative complications, such as bleeding, graft occlusion, infection, or limb edema. Exfoliation from the sacral plexus and total resection with external and internal iliac vessels enables complete resection of the tumor fixed to the pelvic sidewall. Copyright © 2017 Elsevier Inc. All rights reserved.

Genomic and sieroproteomic analysis for the identification of molecular tumor markers for diagnosis, therapy and follow-up of ovarian and endometrial carcinomas

International Nuclear Information System (INIS)

Pecorelli, S.

2009-01-01

The aim of the study is the identification, through the analysis of genomic and proteomic expression profiles, of novel molecular bio markers correlated with pathogenesis, progression, diagnosis or therapy of ovarian cancer. Patients referring to the Division of Gynecologic Oncology at the University of Brescia have been enrolled in the study starting from April 2007. 66 patients with ovarian carcinoma were included (49 with primary ovarian cancer and 17 with relapse/progression). Controls included 134 patients with histologically proven benign pelvic masses (64 uterine fibromas, 36 benign ovarian cysts, 34 endometriosis). All patients signed an informed consent according to institutional guidelines. Clinico pathological features of patients were collected

[Combination of adriamycin and cis-diammine-dichloro-platinum (II) in the treatment of advanced, therapy-resistant, ovarian carcinoma (author's transl)].

Science.gov (United States)

Cavalli, F; Stoller, U; Tschopp, L; Sonntag, R W; Brunner, K W

1978-06-02

Adriamycin (doxorubicin, Adriblastin) and cis-diammine-dichloro-platinum (II) (DDP, NSC 119 875) were used in the treatment of 18 patients with ovarian carcinoma, usually after intensive pre-treatment, both in a dosage of 50 mg/m2 once every 4 weeks. Forced diuresis was initiated at the same time. On average three such treatments were given. Six patients showed partial remission defined as decrease of tumour mass by more than 50% or as almost complete disappearance of ascites during more than two months without concomitant diuretic treatment. The remission time was 2+, 3, 3+, 3.5, 7+, and 9+ months. In all patients severe gastrointestinal toxicity occurred, however the myelosuppressive action was only moderate. Nephrotoxicity was negligible. Combined chemotherapy with Adriblastin and DDP thus seems effective even in intensively pretreated patients with ovarian carcinoma.

Molecular analysis of high-grade serous ovarian carcinoma with and without associated serous tubal intra-epithelial carcinoma.

Science.gov (United States)

Ducie, Jennifer; Dao, Fanny; Considine, Michael; Olvera, Narciso; Shaw, Patricia A; Kurman, Robert J; Shih, Ie-Ming; Soslow, Robert A; Cope, Leslie; Levine, Douglas A

2017-10-17

Many high-grade serous carcinomas (HGSCs) of the pelvis are thought to originate in the distal portion of the fallopian tube. Serous tubal intra-epithelial carcinoma (STIC) lesions are the putative precursor to HGSC and identifiable in ~ 50% of advanced stage cases. To better understand the molecular etiology of HGSCs, we report a multi-center integrated genomic analysis of advanced stage tumors with and without STIC lesions and normal tissues. The most significant focal DNA SCNAs were shared between cases with and without STIC lesions. The RNA sequence and the miRNA data did not identify any clear separation between cases with and without STIC lesions. HGSCs had molecular profiles more similar to normal fallopian tube epithelium than ovarian surface epithelium or peritoneum. The data suggest that the molecular features of HGSCs with and without associated STIC lesions are mostly shared, indicating a common biologic origin, likely to be the distal fallopian tube among all cases.High-grade serous carcinomas (HGSCs) are associated with precursor lesions (STICs) in the fallopian epithelium in only half of the cases. Here the authors report the molecular analysis of HGSCs with and without associated STICs and show similar profiles supporting a common origin for all HGSCs.

The eukaryotic translation elongation factor eEF1A2 induces neoplastic properties and mediates tumorigenic effects of ZNF217 in precursor cells of human ovarian carcinomas

Energy Technology Data Exchange (ETDEWEB)

Sun, Yu; Wong, Nicholas; Guan, Yinghui; Salamanca, Clara M.; Cheng, Jung Chien; Lee, Jonathan M.; Gray, Joe W.; Auersperg, Nelly

2008-04-25

Ovarian epithelial carcinomas (OEC) frequently exhibit amplifications at the 20q13 locus which is the site of several oncogenes, including the eukaryotic elongation factor EEF1A2 and the transcription factor ZNF217. We reported previously that overexpressed ZNF217 induces neoplastic characteristics in precursor cells of OEC. Unexpectedly, ZNF217, which is a transcriptional repressor, enhanced expression of eEF1A2. In this study, array comparative genomic hybridization, single nucleotide polymorphism and Affymetrix analysis of ZNF217-overexpressing cell lines confirmed consistently increased expression of eEF1A2 but not of other oncogenes, and revealed early changes in EEF1A2 gene copy numbers and increased expression at crisis during immortalization. We defined the influence of eEF1A2 overexpression on immortalized ovarian surface epithelial cells, and investigated interrelationships between effects of ZNF217 and eEF1A2 on cellular phenotypes. Lentivirally induced eEF1A2 overexpression caused delayed crisis, apoptosis resistance and increases in serum-independence, saturation densities, and anchorage independence. siRNA to eEF1A2 reversed apoptosis resistance and reduced anchorage independence in eEF1A2-overexpressing lines. Remarkably, siRNA to eEF1A2 was equally efficient in inhibiting both anchorage independence and resistance to apoptosis conferred by ZNF217 overexpression. Our data define neoplastic properties that are caused by eEF1A2 in nontumorigenic ovarian cancer precursor cells, and suggest that eEF1A2 plays a role in mediating ZNF217-induced neoplastic progression.

Monoclonal antibody DS6 detects a tumor-associated sialoglycotope expressed on human serous ovarian carcinomas.

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Kearse, K P; Smith, N L; Semer, D A; Eagles, L; Finley, J L; Kazmierczak, S; Kovacs, C J; Rodriguez, A A; Kellogg-Wennerberg, A E

2000-12-15

A newly developed murine monoclonal antibody, DS6, immunohistochemically reacts with an antigen, CA6, that is expressed by human serous ovarian carcinomas but not by normal ovarian surface epithelium or mesothelium. CA6 has a limited distribution in normal adult tissues and is most characteristically detected in fallopian tube epithelium, inner urothelium and type 2 pneumocytes. Pre-treatment of tissue sections with either periodic acid or neuraminidase from Vibrio cholerae abolishes immunoreactivity with DS6, indicating that CA6 is a neuraminidase-sensitive and periodic acid-sensitive sialic acid glycoconjugate ("sialoglycotope"). SDS-PAGE of OVCAR5 cell lysates has revealed that the CA6 epitope is expressed on an 80 kDa non-disulfide-linked glycoprotein containing N-linked oligosaccharides. Two-dimensional non-equilibrium pH gradient gel electrophoresis indicates an isoelectric point of approximately 6.2 to 6.5. Comparison of the immunohistochemical distribution of CA6 in human serous ovarian adenocarcinomas has revealed similarities to that of CA125; however, distinct differences and some complementarity of antigen expression were revealed by double-label, 2-color immunohistochemical studies. The DS6-detected CA6 antigen appears to be distinct from other well-characterized tumor-associated antigens, including MUC1, CA125 and the histo-blood group-related antigens sLea, sLex and sTn. Copyright 2000 Wiley-Liss, Inc.

Acetyl-L-Carnitine Hydrochloride in Preventing Peripheral Neuropathy in Patients With Recurrent Ovarian Epithelial Cancer, Primary Peritoneal Cavity Cancer, or Fallopian Tube Cancer Undergoing Chemotherapy

Science.gov (United States)

2014-12-29

Fatigue; Malignant Ovarian Mixed Epithelial Tumor; Neuropathy; Neurotoxicity Syndrome; Ovarian Brenner Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Pain; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma

Expression patterns of emmprin and monocarboxylate transporter-1 in ovarian epithelial tumors.

Science.gov (United States)

Fukuoka, Miyoko; Hamasaki, Makoto; Koga, Kaori; Hayashi, Hiroyuki; Aoki, Mikiko; Kawarabayashi, Tatsuhiko; Miyamoto, Shingo; Nabeshima, Kazuki

2012-10-01

Emmprin is a transmembrane glycoprotein known as a matrix metalloproteinase inducer and is highly up-regulated in malignant cancer cells. The monocarboxylate transporters (MCTs) are responsible for H(+)-linked transport of monocarboxylates across the cell membrane. It was recently demonstrated that proper plasma membrane localization and activity of MCTs require the presence of emmprin as a chaperone and that MCT-1 also acts as chaperone for emmprin. The objectives of this study were to clarify emmprin and MCT-1 expression patterns in ovarian epithelial tumors and to elucidate the clinicopathological significance of co-localization of the two molecules. Immunohistochemical analysis of 205 epithelial tumors indicated that emmprin is always localized in cell membranes but its distribution differs according to tumor type: in lateral membranes in 89 % of adenomas, in lateral and basal membranes in 76 % of borderline tumors, and in membranes surrounding the entire cell in 98 % of carcinomas. Most carcinomas in situ also showed a lateral and basal expression pattern. In only 21 % of the carcinomas, the cells expressing membranous MCT-1 showed co-localized emmprin expression. Poor co-localization of the two molecules was more frequently found in serous carcinomas. However, the overall survival was not significantly different for the good and poor co-localization carcinoma groups. These findings indicate that the emmprin expression pattern might discriminate between invasive carcinomas and borderline tumors including carcinoma in situ. Moreover, there may be an as yet unidentified regulatory mechanism(s), for localization of MCT-1 and emmprin in cell membranes in vivo.

DNA damage signaling and apoptosis in preinvasive tubal lesions of ovarian carcinoma.

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Chene, Gautier; Ouellet, Veronique; Rahimi, Kurosh; Barres, Veronique; Caceres, Katia; Meunier, Liliane; Cyr, Louis; De Ladurantaye, Manon; Provencher, Diane; Mes Masson, Anne Marie

2015-06-01

High-grade serous ovarian cancer (HGSC) is the most life-threatening gynecological malignancy despite surgery and chemotherapy. A better understanding of the molecular basis of the preinvasive stages might be helpful in early detection and diagnosis. Genetic instability is 1 of the characteristics shared by most human cancers, and its level is variable through precancerous lesions to advanced cancer. Because DNA damage response (DDR) has been described as 1 of the first phases in genomic instability, we investigated the level of DDR activation and the apoptosis pathway in serous tubal intraepithelial carcinoma (STIC), the potential precursor of HGSC. A tissue microarray including 21 benign fallopian tubes, 21 STICs, 17 HGSCs from patients with STICs (associated ovarian cancer [AOC]) from the same individuals, and 30 HGSCs without STICs (non-AOC) was used in this study.Immunohistochemistry was performed to evaluate the level of DDR proteins (pATM, pChk2, γH2AX, 53BP1, and TRF2), apoptosis proteins (Bcl2, BAX, and BIM), and cyclin E. The expression of all DDR proteins increased from benign fallopian tubes to STICs. The level of expression of pATM, pChk2, γH2AX, and TRF2 was also increased in STICs in comparison with AOC. BAX, BIM, and cyclin E expressions were high in STICs, whereas Bcl2 expression was low. Immunohistochemical profiles of AOC and non-AOC were also different. These results suggest an activation of the DDR and apoptosis pathways in STICs, indicating that genomic instability may occur early in the precancerous lesions of HGSC.

Gorlin syndrome and bilateral ovarian fibroma

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Pirschner, Fernanda; Bastos, Pollyana Marçal; Contarato, George Luiz; Bimbato, Anna Carolina Bon Lima; Filho, Antônio Chambô

2012-01-01

INTRODUCTION Gorlin syndrome (GS), also known as nevoid basal cell carcinoma syndrome (NBCCS), is a rare hereditary, autosomal dominant disease that affects various systems. Its prevalence is estimated at 1/57,000 to 1/256,000 of the population. It is characterized by basal cell carcinomas, multiple odontogenic keratocysts, skeletal abnormalities and ovarian fibroma, among other disorders. PRESENTATION OF CASE To report the case of a young patient with Gorlin syndrome and bilateral ovarian fibroma. DISCUSSION A 20-year old patient with Gorlin syndrome presented with facial asymmetry, broad nasal root, dental abnormalities, micrognathism, convergent strabismus, multiple pigmented lesions on the trunk and face, pectus excavatum, kyphoscoliosis and a palpable mass in the abdomen occupying the entire pelvic region. CONCLUSION Gorlin–Goltz syndrome is a hereditary pathology that includes numerous clinical manifestations. Diagnosis is clinical and genetic confirmation is unnecessary. PMID:22771908

Characterization of aldehyde dehydrogenase 1 high ovarian cancer cells: Towards targeted stem cell therapy.

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Sharrow, Allison C; Perkins, Brandy; Collector, Michael I; Yu, Wayne; Simons, Brian W; Jones, Richard J

2016-08-01

The cancer stem cell (CSC) paradigm hypothesizes that successful clinical eradication of CSCs may lead to durable remission for patients with ovarian cancer. Despite mounting evidence in support of ovarian CSCs, their phenotype and clinical relevance remain unclear. We and others have found high aldehyde dehydrogenase 1 (ALDH(high)) expression in a variety of normal and malignant stem cells, and sought to better characterize ALDH(high) cells in ovarian cancer. We compared ALDH(high) to ALDH(low) cells in two ovarian cancer models representing distinct subtypes: FNAR-C1 cells, derived from a spontaneous rat endometrioid carcinoma, and the human SKOV3 cell line (described as both serous and clear cell subtypes). We assessed these populations for stem cell features then analyzed expression by microarray and qPCR. ALDH(high) cells displayed CSC properties, including: smaller size, quiescence, regenerating the phenotypic diversity of the cell lines in vitro, lack of contact inhibition, nonadherent growth, multi-drug resistance, and in vivo tumorigenicity. Microarray and qPCR analysis of the expression of markers reported by others to enrich for ovarian CSCs revealed that ALDH(high) cells of both models showed downregulation of CD24, but inconsistent expression of CD44, KIT and CD133. However, the following druggable targets were consistently expressed in the ALDH(high) cells from both models: mTOR signaling, her-2/neu, CD47 and FGF18/FGFR3. Based on functional characterization, ALDH(high) ovarian cancer cells represent an ovarian CSC population. Differential gene expression identified druggable targets that have the potential for therapeutic efficacy against ovarian CSCs from multiple subtypes. Copyright © 2016 Elsevier Inc. All rights reserved.

Recent Concepts of Ovarian Carcinogenesis: Type I and Type II

Directory of Open Access Journals (Sweden)

Masafumi Koshiyama

2014-01-01

Full Text Available Type I ovarian tumors, where precursor lesions in the ovary have clearly been described, include endometrioid, clear cell, mucinous, low grade serous, and transitional cell carcinomas, while type II tumors, where such lesions have not been described clearly and tumors may develop de novo from the tubal and/or ovarian surface epithelium, comprise high grade serous carcinomas, undifferentiated carcinomas, and carcinosarcomas. The carcinogenesis of endometrioid and clear cell carcinoma (CCC arising from endometriotic cysts is significantly influenced by the free iron concentration, which is associated with cancer development through the induction of persistent oxidative stress. A subset of mucinous carcinomas develop in association with ovarian teratomas; however, the majority of these tumors do not harbor any teratomatous component. Other theories of their origin include mucinous metaplasia of surface epithelial inclusions, endometriosis, and Brenner tumors. Low grade serous carcinomas are thought to evolve in a stepwise fashion from benign serous cystadenoma to a serous borderline tumor (SBT. With regard to high grade serous carcinoma, the serous tubal intraepithelial carcinomas (STICs of the junction of the fallopian tube epithelium with the mesothelium of the tubal serosa, termed the “tubal peritoneal junction” (TPJ, undergo malignant transformation due to their location, and metastasize to the nearby ovary and surrounding pelvic peritoneum. Other theories of their origin include the ovarian hilum cells.

The role of the fallopian tube in ovarian cancer.

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Tone, Alicia A; Salvador, Shannon; Finlayson, Sarah J; Tinker, Anna V; Kwon, Janice S; Lee, Cheng-Han; Cohen, Trevor; Ehlen, Tom; Lee, Marette; Carey, Mark S; Heywood, Mark; Pike, Judith; Hoskins, Paul J; Stuart, Gavin C; Swenerton, Kenneth D; Huntsman, David G; Gilks, C Blake; Miller, Dianne M; McAlpine, Jessica N

2012-05-01

High-grade serous carcinoma (HGSC) is the most common and lethal subtype of ovarian cancer. Research over the past decade has strongly suggested that "ovarian" HGSC arises in the epithelium of the distal fallopian tube, with serous tubal intraepithelial carcinomas (STICs) being detected in 5-10% of BRCA1/2 mutation carriers undergoing risk-reducing surgery and up to 60% of unselected women with pelvic HGSC. The natural history, clinical significance, and prevalence of STICs in the general population (ie, women without cancer and not at an increased genetic risk) are incompletely understood, but anecdotal evidence suggests that these lesions have the ability to shed cells with metastatic potential into the peritoneal cavity very early on. Removal of the fallopian tube (salpingectomy) in both the average and high-risk populations could therefore prevent HGSC, by eliminating the site of initiation and interrupting spread of potentially cancerous cells to the ovarian/peritoneal surfaces. Salpingectomy may also reduce the incidence of the 2 next most common subtypes, endometrioid and clear cell carcinoma, by blocking the passageway linking the lower genital tract to the peritoneal cavity that enables ascension of endometrium and factors that induce local inflammation. The implementation of salpingectomy therefore promises to significantly impact ovarian cancer incidence and outcomes.

Paradigm Shift in the Management Strategy for Epithelial Ovarian Cancer.

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Fujiwara, Keiichi; McAlpine, Jessica N; Lheureux, Stephanie; Matsumura, Noriomi; Oza, Amit M

2016-01-01

The hypothesis on the pathogenesis of epithelial ovarian cancer continues to evolve. Although epithelial ovarian cancer had been assumed to arise from the coelomic epithelium of the ovarian surface, it is now becoming clearer that the majority of serous carcinomas arise from epithelium of the distal fallopian tube, whereas clear cell and endometrioid cancers arise from endometriosis. Molecular and genomic characteristics of epithelial ovarian cancer have been extensively investigated. Our understanding of pathogenesis of the various histologic types of ovarian cancer have begun to inform changes to the strategies for management of epithelial ovarian cancer, which represent a paradigm shift not only for treatment but also for prevention, which previously had not been considered achievable. In this article, we will discuss novel attempts at the prevention of high-grade serous ovarian cancer and treatment strategies for two distinct entities in epithelial ovarian cancer: low-grade serous and clear cell ovarian carcinomas, which are relatively rare and resistant to conventional chemotherapy.

Bithionol inhibits ovarian cancer cell growth In Vitro - studies on mechanism(s) of action

International Nuclear Information System (INIS)

Ayyagari, Vijayalakshmi N; Brard, Laurent

2014-01-01

Drug resistance is a cause of ovarian cancer recurrence and low overall survival rates. There is a need for more effective treatment approaches because the development of new drug is expensive and time consuming. Alternatively, the concept of ‘drug repurposing’ is promising. We focused on Bithionol (BT), a clinically approved anti-parasitic drug as an anti-ovarian cancer drug. BT has previously been shown to inhibit solid tumor growth in several preclinical cancer models. A better understanding of the anti-tumor effects and mechanism(s) of action of BT in ovarian cancer cells is essential for further exploring its therapeutic potential against ovarian cancer. The cytotoxic effects of BT against a panel of ovarian cancer cell lines were determined by Presto Blue cell viability assay. Markers of apoptosis such as caspases 3/7, cPARP induction, nuclear condensation and mitochondrial transmembrane depolarization were assessed using microscopic, FACS and immunoblotting methods. Mechanism(s) of action of BT such as cell cycle arrest, reactive oxygen species (ROS) generation, autotaxin (ATX) inhibition and effects on MAPK and NF-kB signalling were determined by FACS analysis, immunoblotting and colorimetric methods. BT caused dose dependent cytotoxicity against all ovarian cancer cell lines tested with IC 50 values ranging from 19 μM – 60 μM. Cisplatin-resistant variants of A2780 and IGROV-1 have shown almost similar IC 50 values compared to their sensitive counterparts. Apoptotic cell death was shown by expression of caspases 3/7, cPARP, loss of mitochondrial potential, nuclear condensation, and up-regulation of p38 and reduced expression of pAkt, pNF-κB, pIκBα, XIAP, bcl-2 and bcl-xl. BT treatment resulted in cell cycle arrest at G1/M phase and increased ROS generation. Treatment with ascorbic acid resulted in partial restoration of cell viability. In addition, dose and time dependent inhibition of ATX was observed. BT exhibits cytotoxic effects on various

[Expansion of secretory cells in the fallopian tubal epithelium in the early stages of the pathogenesis of ovarian serous carcinomas].

Science.gov (United States)

Asaturova, A V; Ezhova, L S; Faizullina, N M; Adamyan, L V; Khabas, G N; Sannikova, M V

to investigate the frequency of the types of fallopian tubal secretory cell expansion (SCE) in diseases of the reproductive organs and to determine the immunophenotype and biological role of the cells in the early stages of the pathogenesis of high-grade ovarian serous carcinomas (HGOSC). The investigation enrolled 287 patients with extraovarian diseases and ovarian serous tumors varying in grade, whose fallopian tubes were morphologically and immunohistochemically examined using p53, Ki-67, PAX2, Bcl-2, beta-catenin, and ALDH1 markers. The material was statistically processed applying the Mann-Whitney test and χ2 test. The rate of secretory cell proliferation (SCP) (more than 10 consecutive secretory cells) and that of secretory cell overgrowth (SCO) (more than 30 consecutive secretory cells) increase with age in all investigated reproductive system diseases. The rate of SCP in the corpus fimbriatum of the patients with HGOSC was 5.9 times higher than that in those with extraovarian disease (pepithelium (2.8), in SCP (1.3), in SCO (1.2), in serous tubal intraepithelial carcinoma (STIC) (1.0), and in HGOSC (0.9); Bcl-2 was in the intact epithelium (2.2), in SCP (2.1), STIC (0.9), and in HGOSC (0.6), β-catenin was in the intact epithelium (0.5), in SCP (2.85), in SCO (2.95), in STIC (0.6), and in HGOSC (0.5); ALDH1 was in the intact epithelium (0.5), in SCP (2.91), in SCO (2.92), in STIC (1.2), and in HGOSC (0.6). There were statistically significant differences with a 95% confidence interval (pepithelium and pathology (fallopian tube lesions and HGOSC); 2) Bcl-2 between the intact epithelium and SCE (SCP and SCO) and between SCE and HGOSC; 3) beta-catenin between the intact epithelium and SCE (SCP and SCO) and between SCE and HGOSC; 4) ALDH1 between the intact epithelium and SCE, between and SCE and STIC, and between STIC and HGOSC. SCE was shown to be an independent intraepithelial lesion. The incidence of this abnormality increased with age and significantly

A genomic and transcriptomic approach for a differential diagnosis between primary and secondary ovarian carcinomas in patients with a previous history of breast cancer

International Nuclear Information System (INIS)

Meyniel, Jean-Philippe; Alran, Séverine; Rapinat, Audrey; Gentien, David; Roman-Roman, Sergio; Mignot, Laurent; Sastre-Garau, Xavier; Cottu, Paul H; Decraene, Charles; Stern, Marc-Henri; Couturier, Jérôme; Lebigot, Ingrid; Nicolas, André; Weber, Nina; Fourchotte, Virginie

2010-01-01

The distinction between primary and secondary ovarian tumors may be challenging for pathologists. The purpose of the present work was to develop genomic and transcriptomic tools to further refine the pathological diagnosis of ovarian tumors after a previous history of breast cancer. Sixteen paired breast-ovary tumors from patients with a former diagnosis of breast cancer were collected. The genomic profiles of paired tumors were analyzed using the Affymetrix GeneChip ® Mapping 50 K Xba Array or Genome-Wide Human SNP Array 6.0 (for one pair), and the data were normalized with ITALICS (ITerative and Alternative normaLIzation and Copy number calling for affymetrix Snp arrays) algorithm or Partek Genomic Suite, respectively. The transcriptome of paired samples was analyzed using Affymetrix GeneChip ® Human Genome U133 Plus 2.0 Arrays, and the data were normalized with gc-Robust Multi-array Average (gcRMA) algorithm. A hierarchical clustering of these samples was performed, combined with a dataset of well-identified primary and secondary ovarian tumors. In 12 of the 16 paired tumors analyzed, the comparison of genomic profiles confirmed the pathological diagnosis of primary ovarian tumor (n = 5) or metastasis of breast cancer (n = 7). Among four cases with uncertain pathological diagnosis, genomic profiles were clearly distinct between the ovarian and breast tumors in two pairs, thus indicating primary ovarian carcinomas, and showed common patterns in the two others, indicating metastases from breast cancer. In all pairs, the result of the transcriptomic analysis was concordant with that of the genomic analysis. In patients with ovarian carcinoma and a previous history of breast cancer, SNP array analysis can be used to distinguish primary and secondary ovarian tumors. Transcriptomic analysis may be used when primary breast tissue specimen is not available

Expression of DNA repair genes in ovarian cancer samples: biological and clinical considerations.

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Ganzinelli, M; Mariani, P; Cattaneo, D; Fossati, R; Fruscio, R; Corso, S; Ricci, F; Broggini, M; Damia, G

2011-05-01

The purpose of this study was to investigate retrospectively the mRNA expression of genes involved in different DNA repair pathways implicated in processing platinum-induced damage in 171 chemotherapy-naïve ovarian tumours and correlate the expression of the different genes with clinical parameters. The expression of genes involved in DNA repair pathways (PARP1, ERCC1, XPA, XPF, XPG, BRCA1, FANCA, FANCC, FANCD2, FANCF and PolEta), and in DNA damage transduction (Chk1 and Claspin) was measured by RT-PCR in 13 stage I borderline and 77 stage I and 88 III ovarian carcinomas. ERCC1, XPA, XPF and XPG genes were significantly less expressed in stage III than in stage I carcinoma; BRCA1, FANCA, FANCC, FANCD2 gene expressions were low in borderline tumours, higher in stage I carcinomas and lower in stage III samples. High levels of ERCC1, XPA, FANCC, XPG and PolEta correlated with an increase in Overall Survival (OS) and Progression Free Survival (PFS), whilst high BRCA1 levels were associated with PFS on univariate analysis. With multivariate analyses no genes retained an association when adjusted by stage, grade and residual tumour. A tendency towards a better PFS was observed in patients with the highest level of ERCC1 and BRCA1 after platinum-based therapy than those given both platinum and taxol. The expression of DNA repair genes differed in borderline stage I, stage I and stage III ovarian carcinomas. The role of DNA repair genes in predicting the response in ovarian cancer patients seems far from being established. Copyright © 2010 Elsevier Ltd. All rights reserved.

Contribution of transcription factor, SP1, to the promotion of HB-EGF expression in defense mechanism against the treatment of irinotecan in ovarian clear cell carcinoma

International Nuclear Information System (INIS)

Miyata, Kohei; Yotsumoto, Fusanori; Nam, Sung Ouk; Odawara, Takashi; Manabe, Sadao; Ishikawa, Toyokazu; Itamochi, Hiroaki; Kigawa, Junzo; Takada, Shuji; Asahara, Hiroshi; Kuroki, Masahide; Miyamoto, Shingo

2014-01-01

Ovarian clear cell carcinoma (OCCC) is a worst histological subtype than other ovarian malignant tumor. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a promising target for ovarian cancer therapy. The aims of this study were to validate the efficacy of HB-EGF–targeted therapy for OCCC and to identify the transcription factor that contributed to the induction of HB-EGF by SN38 treatment in OCCC cells. HB-EGF was highly expressed in OCCC cells, and an increase of HB-EGF was induced by SN38 which had only antitumor effect among conventional anticancer agents on OCCC. A specific inhibitor of HB-EGF, a cross-reacting material 197 (CRM197), led to a synergistic increase in the number of apoptotic OCCC cells with the treatment of SN38. The luciferase assay with 5′-deletion promoter constructs identified a GC-rich element between −125 and −178 (the distal transcription start site was denoted +1) as a cis-regulatory region, and the treatment of SN38 induced luciferase activity in this region. An in silico and chromatin immunoprecipitation analysis estimated that SP1 bound to the cis-regulatory region of HB-EGF in OCCC cells. Real-time PCR and cell viability assays showed that the transfection of a small interfering RNA targeting SP1 suppressed the expression of HB-EGF induced by SN38, resulting in the enhanced sensitivity of SN38. Taken together, these results indicate that induction of HB-EGF expression contributed to defense mechanism against treatment of SN38 through the transcriptional activity of SP1 in OCCC cells

Sp1-CD147 positive feedback loop promotes the invasion ability of ovarian cancer.

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Zhao, Jing; Ye, Wei; Wu, Juan; Liu, Lijuan; Yang, Lina; Gao, Lu; Chen, Biliang; Zhang, Fanglin; Yang, Hong; Li, Yu

2015-07-01

CD147 is a novel cancer biomarker that has been confirmed to be overexpressed in ovarian carcinoma, which is significantly associated with poor prognosis. Although the Sp1 protein regulates the expression level of CD147, it remains unclear whether Sp1 phosphorylation plays a role in this regulation. A dual-luciferase assay revealed that T453 and T739 mutations decreased the activity of Sp1 binding to the promoter of CD147, followed by a decrease in CD147 mRNA and protein expression. Western blot analysis showed that CD147 promoted Sp1 phosphorylation at T453 and T739 through the PI3K/AKT and MAPK/ERK pathways. In addition, blocking the Sp1-CD147 positive feedback loop reduced the invasion ability of HO-8910pm cells. Immunohistochemical staining showed that the components of the feedback loop were overexpressed in ovarian cancer tissues. The correlation analysis revealed a significant correlation between phospho-Sp1 (T453), phospho-Sp1 (T739) and CD147 expression levels, with correlation coefficients of r=0.477 and r=0.461, respectively. Collectively, our results suggest that a Sp1-CD147 positive feedback loop plays a critical role in the invasion ability of ovarian cancer cells.

Apatone® induces endometrioid ovarian carcinoma (MDAH 2774 cells to undergo karyolysis and cell death by autoschizis: A potent and safe anticancer treatment

Directory of Open Access Journals (Sweden)

Jacques Gilloteaux

2015-12-01

Full Text Available Ovarian cancers are still the most lethal gynecologic malignancy. As a novel strategy against this poor outcome cytotoxic alterations induced by a pro-oxidant treatment on human ovarian endometrioid carcinoma (MDAH 2774 cells are revisited by using light, scanning and transmission electron microscopy. A series of sequential and concomitant cellular and organelle injuries induced by ascorbate: menadione combination (VC: VK3 or Apatone® is emphasized. This adjuvant or treatment is able to kill majority of these tumor cells through ‘autoschizic cell death’, a mode of cell death different than apoptosis. Autoschizic cell death is significant after a short period of treatment to decrease the ovarian tumor cell population through induced injuries that proceed from membranes to most organelles: karyolysis with nucleolar segregation and fragmentation, autophagy of mitochondria, lysosome and other organelles as well as cytoskeletal defects. The cytoskeletal damages are evidenced by morphology changes that included auto- or self-excised pieces of cytoplasm lacking organelles apparently facilitated by grouping of vacuolated endoplasm. These results obtained against this endometrioid ovary cell line are comforted by other studies using Apatone® against other carcinomas in vitro and in vivo. Altogether these reports support Apatone® as a new drug that can favorably be used as a novel potent, safe, and inexpensive clinical adjuvant or treatment against ovarian cancers. Keywords: Ascorbate, Menadione, Endometrioid ovarian cancer MDAH 2774, Autoschizis cell death, DNA

PAPP-A proteolytic activity enhances IGF bioactivity in ascites from women with ovarian carcinoma

Science.gov (United States)

Thomsen, Jacob; Hjortebjerg, Rikke; Espelund, Ulrick; Ørtoft, Gitte; Vestergaard, Poul; Magnusson, Nils E.; Conover, Cheryl A.; Tramm, Trine; Hager, Henrik; Høgdall, Claus; Høgdall, Estrid; Oxvig, Claus; Frystyk, Jan

2015-01-01

Pregnancy-associated plasma protein-A (PAPP-A) stimulates insulin-like growth factor (IGF) action through proteolysis of IGF-binding protein (IGFBP)-4. In experimental animals, PAPP-A accelerates ovarian tumor growth by this mechanism. To investigate the effect of PAPP-A in humans, we compared serum and ascites from 22 women with ovarian carcinoma. We found that ascites contained 46-fold higher PAPP-A levels as compared to serum (P IGF-I receptor (IGF-IR) in vitro (+31%, P IGF-I, and lower levels of IGF-II (P IGF-IR in all but one tumor, whereas all tumors expressed PAPP-A, IGFBP-4, IGF-I and IGF-II. Addition of recombinant PAPP-A to ascites increased the cleavage of IGFBP-4 and enhanced IGF-IR activation (P IGFs and these proteins are also present in ascites. We suggest that both soluble PAPP-A in ascites and tissue-associated PAPP-A serve to increase IGF bioactivity and, thereby, to stimulate IGF-IR-mediated tumor growth. PMID:26336825

Should CA-125 response criteria be preferred to response evaluation criteria in solid tumors (RECIST) for prognostication during second-line chemotherapy of ovarian carcinoma?

DEFF Research Database (Denmark)

Gronlund, Bo; Høgdall, Claus; Hilden, Jørgen

2004-01-01

-line chemotherapy. PATIENTS AND METHODS: From a single-institution registry of 527 consecutive patients with primary ovarian carcinoma, 131 records satisfied the inclusion criteria: ovarian carcinoma of International Federation of Gynecology and Obstetrics stage IC to IV, first-line chemotherapy with paclitaxel...... and a platinum compound, refractory or recurrent disease, and second-line chemotherapy consisting of topotecan or paclitaxel plus carboplatin. Univariate and multivariate analyses of survival were performed using the landmark method. RESULTS: In patients with measurable disease by RECIST and with assessable...... sites (solitary v multiple; hazard ratio, 0.47; P = .020) were identified as contributory prognostic factors for survival, whereas the parameters of RECIST (responders v nonresponders), as well as the remaining variables, had nonsignificant prognostic impact. CONCLUSION: The GCIG CA-125 response...

Evaluation of the antitumor effects of c-Myc-Max heterodimerization inhibitor 100258-F4 in ovarian cancer cells.

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Wang, Jiandong; Ma, Xiaoli; Jones, Hannah M; Chan, Leo Li-Ying; Song, Fang; Zhang, Weiyuan; Bae-Jump, Victoria L; Zhou, Chunxiao

2014-08-21

Epithelial ovarian carcinoma is the most lethal gynecological cancer due to its silent onset and recurrence with resistance to chemotherapy. Overexpression of oncogene c-Myc is one of the most frequently encountered events present in ovarian carcinoma. Disrupting the function of c-Myc and its downstream target genes is a promising strategy for cancer therapy. Our objective was to evaluate the potential effects of small-molecule c-Myc inhibitor, 10058-F4, on ovarian carcinoma cells and the underlying mechanisms by which 10058-F4 exerts its actions. Using MTT assay, colony formation, flow cytometry and Annexin V FITC assays, we found that 10058-F4 significantly inhibited cell proliferation of both SKOV3 and Hey ovarian cancer cells in a dose dependent manner through induction of apoptosis and cell cycle G1 arrest. Treatment with 10058-F4 reduced cellular ATP production and ROS levels in SKOV3 and Hey cells. Consistently, primary cultures of ovarian cancer treated with 10058-F4 showed induction of caspase-3 activity and inhibition of cell proliferation in 15 of 18 cases. The response to 10058-F4 was independent the level of c-Myc protein over-expression in primary cultures of ovarian carcinoma. These novel findings suggest that the growth of ovarian cancer cells is dependent upon c-MYC activity and that targeting c-Myc-Max heterodimerization could be a potential therapeutic strategy for ovarian cancer.

Diagnostic efficacy of the preoperative lymphoscintigraphy, Ga-67 scintigraphy and computed tomography for detection of lymph node metastasis in cases with ovarian or endometrial carcinoma

Energy Technology Data Exchange (ETDEWEB)

Ozalp, S.; Yalcin, O.T.; Polay, S. [Osmangazi Univ. School of Medicine, Dept. of Obstetrics and Gynecology, Eskisehir (Turkey); Aslan, N.; Vardareli, E. [Osmangazi Univ. School of Medicine, Dept. of Nuclear Medicine, Eskisehir (Turkey); Adapinar, B. [Osmangazi Univ. School of Medicine, Dept. of Radiology, Eskisehir (Turkey)

1999-02-01

Background: To investigate the diagnostic efficacy of preoperative lymphoscintigraphy (LS), Ga-67 scintigraphy (GS) and computed tomography (CT) for detection of lymph node metastasis in patients with endometrial or ovarian carcinoma. Methods: The results of preoperative LS, GS and CT used to detect lymph node metastasis were compared to the postoperative histopathological results of lymph node dissection materials of a total of 37 patients, including 16 patients with endometrial and 21 patients with ovarian carcinomas. The diagnostic efficacy of these methods for detecting lymph node metastasis were calculated. Results: When the results of all of the patients were taken into account, the preoperative LS, GS and CT were found to have sensitivities of 50%, 20% and 40% and specificities of 51.8%, 96.3%, and 92.6%, respectively, for detection of pelvic lymph node metastasis. The same methods had sensitivities of 27.3%, 27.3% and 72.7% and specificities of 88.5%, 88.5%, 84.6%, respectively, for detecting para-aortic lymph node metastasis in all patients. Conclusion: These data suggested that although LS, GS and CT had relatively high specificity, low sensitivity of these imaging methods precluded their routine preoperative use for diagnosis of lymph node metastasis of ovarian or endometrial carcinoma. (au) 22 refs.

Comparison of abdominopelvic CT results and findings at second-look laparotomy in ovarian carcinoma patients

International Nuclear Information System (INIS)

Reuter, K.L.; Griffin, T.; Hunter, R.E.

1987-01-01

Restaging in epithelial ovarian carcinoma after primary therapy has proven difficult by standard noninvasive methods and commonly requires second-look laparotomy. In the authors' study to date preoperative abdominopelvic CT (CBT) results and operative findings have been compared in 24 patients (25 studies) with ovarian adenocarcinoma currently clinically free of disease originally graded as FIGO stage III or IV, except for one patient with stage IC, undergoing second-look laparotomy to determine tumor status. There were ten true-negative, three false-negative, 12 true-positive, and no false-positive CBTs. Negative studies were associated with positive findings at laparotomy, including microscopic foci, in only 12% of all cases; thus, CBT in the series has shown a better correlation with surgery than in previous studies. Currently the authors are combining monoclonal antibody scanning with the CBT results with the goal of possibly avoiding second-look surgery in certain patients

MINOR HUMAN-ANTIBODY RESPONSE TO A MOUSE AND CHIMERIC MONOCLONAL-ANTIBODY AFTER A SINGLE IV INFUSION IN OVARIAN-CARCINOMA PATIENTS - A COMPARISON OF 5 ASSAYS

NARCIS (Netherlands)

BUIST, MR; KENEMANS, P; VANKAMP, GJ; Haisma, Hidde

The human anti-(mouse Ig) antibody (HAMA) response was measured in serum of 52 patients suspected of having ovarian carcinoma who had received an i.v. injection of either the murine monoclonal antibody (mAb) OV-TL 3 F(ab')(2) (n = 28, 1 mg) or the chimeric mouse/human mAb MOv18 (cMOv18; n = 24, 3

Cancer Associated Fibroblasts express pro-inflammatory factors in human breast and ovarian tumors

Energy Technology Data Exchange (ETDEWEB)

Erez, Neta, E-mail: netaerez@post.tau.ac.il [Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 69978 (Israel); Glanz, Sarah [Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 69978 (Israel); Raz, Yael [Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 69978 (Israel); Department of Obstetrics and Gynecology, LIS Maternity Hospital, Tel Aviv Sourasky Medical Center, affiliated with Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv (Israel); Avivi, Camilla [Department of Pathology, Sheba Medical Center, Tel Hashomer, affiliated with Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv (Israel); Barshack, Iris [Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 69978 (Israel); Department of Pathology, Sheba Medical Center, Tel Hashomer, affiliated with Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv (Israel)

2013-08-02

Highlights: •CAFs in human breast and ovarian tumors express pro-inflammatory factors. •Expression of pro-inflammatory factors correlates with tumor invasiveness. •Expression of pro-inflammatory factors is associated with NF-κb activation in CAFs. -- Abstract: Inflammation has been established in recent years as a hallmark of cancer. Cancer Associated Fibroblasts (CAFs) support tumorigenesis by stimulating angiogenesis, cancer cell proliferation and invasion. We previously demonstrated that CAFs also mediate tumor-enhancing inflammation in a mouse model of skin carcinoma. Breast and ovarian carcinomas are amongst the leading causes of cancer-related mortality in women and cancer-related inflammation is linked with both these tumor types. However, the role of CAFs in mediating inflammation in these malignancies remains obscure. Here we show that CAFs in human breast and ovarian tumors express high levels of the pro-inflammatory factors IL-6, COX-2 and CXCL1, previously identified to be part of a CAF pro-inflammatory gene signature. Moreover, we show that both pro-inflammatory signaling by CAFs and leukocyte infiltration of tumors are enhanced in invasive ductal carcinoma as compared with ductal carcinoma in situ. The pro-inflammatory genes expressed by CAFs are known NF-κB targets and we show that NF-κB is up-regulated in breast and ovarian CAFs. Our data imply that CAFs mediate tumor-promoting inflammation in human breast and ovarian tumors and thus may be an attractive target for stromal-directed therapeutics.

Cancer Associated Fibroblasts express pro-inflammatory factors in human breast and ovarian tumors

International Nuclear Information System (INIS)

Erez, Neta; Glanz, Sarah; Raz, Yael; Avivi, Camilla; Barshack, Iris

2013-01-01

Highlights: •CAFs in human breast and ovarian tumors express pro-inflammatory factors. •Expression of pro-inflammatory factors correlates with tumor invasiveness. •Expression of pro-inflammatory factors is associated with NF-κb activation in CAFs. -- Abstract: Inflammation has been established in recent years as a hallmark of cancer. Cancer Associated Fibroblasts (CAFs) support tumorigenesis by stimulating angiogenesis, cancer cell proliferation and invasion. We previously demonstrated that CAFs also mediate tumor-enhancing inflammation in a mouse model of skin carcinoma. Breast and ovarian carcinomas are amongst the leading causes of cancer-related mortality in women and cancer-related inflammation is linked with both these tumor types. However, the role of CAFs in mediating inflammation in these malignancies remains obscure. Here we show that CAFs in human breast and ovarian tumors express high levels of the pro-inflammatory factors IL-6, COX-2 and CXCL1, previously identified to be part of a CAF pro-inflammatory gene signature. Moreover, we show that both pro-inflammatory signaling by CAFs and leukocyte infiltration of tumors are enhanced in invasive ductal carcinoma as compared with ductal carcinoma in situ. The pro-inflammatory genes expressed by CAFs are known NF-κB targets and we show that NF-κB is up-regulated in breast and ovarian CAFs. Our data imply that CAFs mediate tumor-promoting inflammation in human breast and ovarian tumors and thus may be an attractive target for stromal-directed therapeutics

The Prognostic Value of BRCA1 and PARP Expression in Epithelial Ovarian Carcinoma

DEFF Research Database (Denmark)

Hjortkjær, Mette; Waldstrøm, Marianne; Jakobsen, Anders

2017-01-01

BRCA1/2 mutation status in epithelial ovarian cancer (EOC) presently relies on genetic testing which is resource consuming. Immunohistochemistry is cheap, fairly reproducible, and may identify gene product alterations due to both germline and somatic mutations and other defects along the BRCA gene...... tissue from 170 patients with EOC was stained immunohistochemically with BRCA1 and PARP antibodies. Semiquantitative analyses were performed to determine loss of, equivocal, and retained BRCA1 and high versus low PARP protein expression. These parameters were analyzed for relation with patient...

Ovarian metastases: Computed tomographic appearances

International Nuclear Information System (INIS)

Megibow, A.J.; Hulnick, D.H.; Bosniak, M.A.; Balthazar, E.J.

1985-01-01

Computed tomographic scans of 34 patients with ovarian metastases were reviewed to assess the radiographic appearances and to correlate these with the primary neoplasms. Primary neoplasms were located in the colon (20 patients), breast (six), stomach (five), small bowel (one), bladder (one), and Wilms tumor of the kidney (one). The radiographic appearance of the metastatic lesions could be described as predominantly cystic (14 lesions), mixed (12 lesions), or solid (seven lesions). The cystic and mixed lesions tended to be larger in overall diameter than the solid. The metastases from gastric carcinoma appeared solid in four of five cases. The metastases from the other neoplasms had variable appearances simulating primary ovarian carcinoma

Secretory cell outgrowths, p53 signatures, and serous tubal intraepithelial carcinoma in the fallopian tubes of patients with sporadic pelvic serous carcinoma.

Science.gov (United States)

Mittal, Neha; Srinivasan, Radhika; Gupta, Nalini; Rajwanshi, Arvind; Nijhawan, Raje; Gautam, Upasana; Sood, Swati; Dhaliwal, Lakhbir

2016-01-01

High-grade serous carcinomas of ovarian, tubal, and peritoneal origin are together referred as pelvic serous carcinoma. The fallopian tubes, ovarian surface epithelium, and the tuboperitoneal junctional epithelium are all implicated in pelvic serous carcinogenesis. The aim of this study is to identify putative precursor lesions of serous carcinoma including secretory cell outgrowths (SCOUTs), serous tubal intraepithelial carcinoma (STIC), and p53 signatures and assign its probable site of origin. Prospective case-control study of consecutive specimen comprising 32 serous carcinomas and 31 controls (10 normal adnexa, 10 benign and 6 atypically proliferative surface epithelial tumors, and 5 other carcinomas). Sectioning and extensive examination of the fimbrial end (SEE-FIM) protocol along with immunohistochemistry for Bcl-2, p53, and Ki-67 was employed for evaluating invasive carcinoma and precursor lesions in cases versus controls. SCOUT, p53 signatures, and STIC were most frequent in the serous carcinomas. p53 signatures and STIC were always seen in the fimbrial end. STICs were exclusively present in serous carcinomas, more common in ipsilateral tubes of cases with dominant ovarian mass. Multifocal p53 signatures with STIC were seen in 7 (21.9%) cases. STIC was present with or without an invasive carcinoma in 25% and in 6.25% of cases of pelvic serous carcinomas, respectively. The junctional epithelia did not show any lesion in any group. SEE-FIM protocol is recommended for evaluation of sporadicpelvic (ovarian/tubal/peritoneal) serous carcinoma. Based on the presence of STIC or invasive carcinoma, nearly 60% of all pelvic serous carcinomas are of fallopian tubal origin.

Overexpression of human sperm protein 17 increases migration and decreases the chemosensitivity of human epithelial ovarian cancer cells

International Nuclear Information System (INIS)

Li, Fang-qiu; Han, Yan-ling; Liu, Qun; Wu, Bo; Huang, Wen-bin; Zeng, Su-yun

2009-01-01

Most deaths from ovarian cancer are due to metastases that are resistant to conventional therapies. But the factors that regulate the metastatic process and chemoresistance of ovarian cancer are poorly understood. In the current study, we investigated the aberrant expression of human sperm protein 17 (HSp17) in human epithelial ovarian cancer cells and tried to analyze its influences on the cell behaviors like migration and chemoresistance. Immunohistochemistry and immunocytochemistry were used to identify HSp17 in paraffin embedded ovarian malignant tumor specimens and peritoneal metastatic malignant cells. Then we examined the effect of HSp17 overexpression on the proliferation, migration, and chemoresistance of ovarian cancer cells to carboplatin and cisplatin in a human ovarian carcinoma cell line, HO8910. We found that HSp17 was aberrantly expressed in 43% (30/70) of the patients with primary epithelial ovarian carcinomas, and in all of the metastatic cancer cells of ascites from 8 patients. The Sp17 expression was also detected in the metastatic lesions the same as in ovarian lesions. None of the 7 non-epithelial tumors primarily developed in the ovaries was immunopositive for HSp17. Overexpression of HSp17 increased the migration but decreased the chemosensitivity of ovarian carcinoma cells to carboplatin and cisplatin. HSp17 is aberrantly expressed in a significant proportion of epithelial ovarian carcinomas. Our results strongly suggest that HSp17 plays a role in metastatic disease and resistance of epithelial ovarian carcinoma to chemotherapy

Altered expression pattern of circular RNAs in primary and metastatic sites of epithelial ovarian carcinoma.

Science.gov (United States)

Ahmed, Ikhlak; Karedath, Thasni; Andrews, Simeon S; Al-Azwani, Iman K; Mohamoud, Yasmin Ali; Querleu, Denis; Rafii, Arash; Malek, Joel A

2016-06-14

Recently, a class of endogenous species of RNA called circular RNA (circRNA) has been shown to regulate gene expression in mammals and their role in cellular function is just beginning to be understood. To investigate the role of circRNAs in ovarian cancer, we performed paired-end RNA sequencing of primary sites, peritoneal and lymph node metastases from three patients with stage IIIC ovarian cancer. We developed an in-house computational pipeline to identify and characterize the circRNA expression from paired-end RNA-Seq libraries. This pipeline revealed thousands of circular isoforms in Epithelial Ovarian Carcinoma (EOC). These circRNAs are enriched for potentially effective miRNA seed matches. A significantly larger number of circRNAs are differentially expressed between tumor sites than mRNAs. Circular and linear expression exhibits an inverse trend for many cancer related pathways and signaling pathways like NFkB, PI3k/AKT and TGF-β typically activated for mRNA in metastases are inhibited for circRNA expression. Further, circRNAs show a more robust expression pattern across patients than mRNA forms indicating their suitability as biomarkers in highly heterogeneous cancer transcriptomes. The consistency of circular RNA expression may offer new candidates for cancer treatment and prognosis.

Minor human antibody response to a mouse and chimeric monoclonal antibody after a single i.v. infusion in ovarian carcinoma patients: a comparison of five assays

NARCIS (Netherlands)

Buist, M. R.; Kenemans, P.; van Kamp, G. J.; Haisma, H. J.

1995-01-01

The human anti-(mouse Ig) antibody (HAMA) response was measured in serum of 52 patients suspected of having ovarian carcinoma who had received an i.v. injection of either the murine monoclonal antibody (mAb) OV-TL 3 F(ab')2 (n = 28, 1 mg) or the chimeric mouse/human mAb MOv18 (cMOv18; n = 24, 3 mg).

Staging and treatment of ovarian carcinoma

International Nuclear Information System (INIS)

De Palo, G.; Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan

1989-01-01

The staging and treatment of ovarian cancer is reviewed with special attention to developments during the last decade. Pathways of spread, presurgical and surgical staging are described and discussed, as are the biologic characters of the different histologic subtypes. Principles of surgery, endoperitoneal and external radiotherapy, single-drug and multiple-drug systemic chemotherapy (therapeutic and adjuvant), intraperitoneal chemotherapy, second-line chemotherapy, hormone therapy and the use of biologic response modifiers are reported and discussed with background of recent clinical trials. It is concluded that considerable progress has been made concerning diagnosis, staging and treatment of ovarian cancer. The proportion of cases in advanced stages has thus decreased and the survival rate increased. However, it is also obvious that the long-term prognosis for patients with advanced disease has not significantly improved over the last 10 years, despite introduction of multiple-drug regimens with high initial response rates. Ovarian cancer remains the most important gynecologic cause of death in the Western countries. (orig.)

History of Comorbidities and Survival of Ovarian Cancer Patients, Results from the Ovarian Cancer Association Consortium

DEFF Research Database (Denmark)

Minlikeeva, Albina N; Freudenheim, Jo L; Eng, Kevin H

2017-01-01

carcinoma who participated in 23 studies included in the Ovarian Cancer Association Consortium, we explored associations between histories of endometriosis; asthma; depression; osteoporosis; and autoimmune, gallbladder, kidney, liver, and neurological diseases and overall and progression-free survival...... with ovarian cancer outcome in the overall sample nor in strata defined by histologic subtype, weight status, age at diagnosis, or stage of disease (local/regional vs. advanced).Conclusions: Histories of endometriosis; asthma; depression; osteoporosis; and autoimmune, gallbladder, kidney, liver, or neurologic......Background: Comorbidities can affect survival of ovarian cancer patients by influencing treatment efficacy. However, little evidence exists on the association between individual concurrent comorbidities and prognosis in ovarian cancer patients.Methods: Among patients diagnosed with invasive ovarian...

Assessment of the Na/I symporter as a reporter gene to visualize oncolytic adenovirus propagation in peritoneal tumours

Energy Technology Data Exchange (ETDEWEB)

Merron, Andrew; McNeish, Iain A. [Queen Mary' s School of Medicine and Dentistry, Centre for Molecular Oncology, Institute of Cancer, London (United Kingdom); Baril, Patrick; Tran, Lucile; Vassaux, Georges [CHU Hotel Dieu, INSERM, Nantes (France); CHU de Nantes, Institut des Maladies de l' Appareil Digestif, Nantes (France); Martin-Duque, Pilar [Instituto Aragones de Ciencias de la Salud, Zaragoza (Spain); Vieja, Antonio de la [Instituto de Investigaciones Biomedicas, Madrid (Spain); Briat, Arnaud [INSERM U877, Grenoble (France); Harrington, Kevin J. [Chester Beatty Laboratories, Institute of Cancer Research, London (United Kingdom)

2010-07-15

In vivo imaging of the spread of oncolytic viruses using the Na/I symporter (NIS) has been proposed. Here, we assessed whether the presence of NIS in the viral genome affects the therapeutic efficacy of the oncolytic adenovirus dl922-947 following intraperitoneal administration, in a mouse model of peritoneal ovarian carcinoma. We generated AdAM7, a dl922-947 oncolytic adenovirus encoding the NIS coding sequence. Iodide uptake, NIS expression, infectivity and cell-killing activity of AdAM7, as well as that of relevant controls, were determined in vitro. In vivo, the propagation of this virus in the peritoneal cavity of tumour-bearing mice was determined using SPECT/CT imaging and its therapeutic efficacy was evaluated. In vitro infection of ovarian carcinoma IGROV-1 cells with ADAM7 led to functional expression of NIS. However, the insertion of NIS into the viral genome resulted in a loss of efficacy of the virus in terms of replication and cytotoxicity. In vivo, on SPECT/CT imaging AdAM7 was only detectable in the peritoneal cavity of animals bearing peritoneal ovarian tumours for up to 5 days after intraperitoneal administration. Therapeutic experiments in vivo demonstrated that AdAM7 is as potent as its NIS-negative counterpart. This study demonstrated that despite the detrimental effect observed in vitro, insertion of the reporter gene NIS in an oncolytic adenovirus did not affect its therapeutic efficacy in vivo. We conclude that NIS is a highly relevant reporter gene to monitor the fate of oncolytic adenovectors in live subjects. (orig.)

Assessment of the Na/I symporter as a reporter gene to visualize oncolytic adenovirus propagation in peritoneal tumours

International Nuclear Information System (INIS)

Merron, Andrew; McNeish, Iain A.; Baril, Patrick; Tran, Lucile; Vassaux, Georges; Martin-Duque, Pilar; Vieja, Antonio de la; Briat, Arnaud; Harrington, Kevin J.

2010-01-01

In vivo imaging of the spread of oncolytic viruses using the Na/I symporter (NIS) has been proposed. Here, we assessed whether the presence of NIS in the viral genome affects the therapeutic efficacy of the oncolytic adenovirus dl922-947 following intraperitoneal administration, in a mouse model of peritoneal ovarian carcinoma. We generated AdAM7, a dl922-947 oncolytic adenovirus encoding the NIS coding sequence. Iodide uptake, NIS expression, infectivity and cell-killing activity of AdAM7, as well as that of relevant controls, were determined in vitro. In vivo, the propagation of this virus in the peritoneal cavity of tumour-bearing mice was determined using SPECT/CT imaging and its therapeutic efficacy was evaluated. In vitro infection of ovarian carcinoma IGROV-1 cells with ADAM7 led to functional expression of NIS. However, the insertion of NIS into the viral genome resulted in a loss of efficacy of the virus in terms of replication and cytotoxicity. In vivo, on SPECT/CT imaging AdAM7 was only detectable in the peritoneal cavity of animals bearing peritoneal ovarian tumours for up to 5 days after intraperitoneal administration. Therapeutic experiments in vivo demonstrated that AdAM7 is as potent as its NIS-negative counterpart. This study demonstrated that despite the detrimental effect observed in vitro, insertion of the reporter gene NIS in an oncolytic adenovirus did not affect its therapeutic efficacy in vivo. We conclude that NIS is a highly relevant reporter gene to monitor the fate of oncolytic adenovectors in live subjects. (orig.)

Twist-1 Up-Regulation in Carcinoma Correlates to Poor Survival

Directory of Open Access Journals (Sweden)

Alimujiang Wushou

2014-11-01

Full Text Available Epithelial-to-mesenchymal transition (EMT facilitates tumor metastasis. Twist is a basic helix-loop-helix protein that modulates many target genes through E-box-responsive elements. There are two twist-like proteins, Twist-1 and Twist-2, sharing high structural homology in mammals. Twist-1 was found to be a key factor in the promotion of metastasis of cancer cells, and is known to induce EMT. Twist-1 participation in carcinoma progression and metastasis has been reported in a variety of tumors. However, controversy exists concerning the correlation between Twist-1 and prognostic value with respect to carcinoma. A systematic review and meta-analysis were performed to determine whether the expression of Twist-1 was associated with the prognosis of carcinoma patients. This analysis included 17 studies: four studies evaluated lung cancer, three evaluated head and neck cancer, two evaluated breast cancer, two evaluated esophageal cancer, two evaluated liver cancer and one each evaluated osteosarcoma, bladder, cervical and ovarian cancer. A total of 2006 patients were enrolled in these studies, and the median trial sample size was 118 patients. Twist-1 expression was associated with worse overall survival (OS at both 3 years (hazard ratio “HR” for death = 2.13, 95% CI = 1.86 to 2.45, p < 0.001 and 5 years (HR for death = 2.01, 95% CI = 1.76 to 2.29, p < 0.001. Expression of Twist-1 is associated with worse survival in carcinoma.

Quality of Life and Care Needs of Patients With Persistent or Recurrent Ovarian Cancer, Fallopian Tube Cancer, or Peritoneal Cancer

Science.gov (United States)

2017-05-03

Anxiety; Fatigue; Nausea and Vomiting; Neurotoxicity Syndrome; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Stage I Ovarian Cancer; Stage IA Fallopian Tube Cancer; Stage IB Fallopian Tube Cancer; Stage IC Fallopian Tube Cancer; Stage II Ovarian Cancer; Stage IIA Fallopian Tube Cancer; Stage IIB Fallopian Tube Cancer; Stage IIC Fallopian Tube Cancer; Stage III Ovarian Cancer; Stage III Primary Peritoneal Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIC Fallopian Tube Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer

Mesothelin as a biomarker for ovarian carcinoma: a meta-analysis

Directory of Open Access Journals (Sweden)

KRISTIAN MADEIRA

2016-06-01

Full Text Available The objective of this work was to estimate the accuracy of mesothelin as a biomarker for ovarian cancer. A quantitative systematic review was performed. A comprehensive search of the Medline, LILACS, SCOPUS, Embase, Cochrane Central Register of Controlled Trials, Biomed Central, and ISI Web of Science databases was conducted from January 1990 to June 2015. For inclusion in this systematic review, the papers must have measured mesothelin levels in at least two histological diagnoses; ovarian cancer (borderline or ovarian tumor vs. benign or normal ovarian tissue. For each study, 2 x 2 contingency tables were constructed. We calculated the sensitivity, specificity and diagnostic odds ratio. The verification bias was performed according to QUADAS-2. Statistical analysis was performed with the software Stata 11, Meta-DiSc(r and RevMan 5.2. Twelve studies were analyzed, which included 1,561 women. The pooled sensitivity was 0.62 (CI 95% 0.58 - 0.66 and specificity was 0.94 (CI 95% 0.92 - 0.95. The DOR was 38.92 (CI 95% 17.82 - 84.99. Our systematic review shows that mesothelin cannot serve alone as a biomarker for the detection of ovarian cancer.

Serous tubal intraepithelial carcinomas associated with high-grade serous ovarian carcinomas: a systematic review.

Science.gov (United States)

Chen, F; Gaitskell, K; Garcia, M J; Albukhari, A; Tsaltas, J; Ahmed, A A

2017-05-01

Serous tubal intraepithelial carcinomas (STICs) have been documented in high-grade serous ovarian carcinomas (HGSOCs). However, the rate of association between STICs and HGSOCs and, therefore, the fraction of HGSOCs that are likely to have originated from the fallopian tube (FT), has remained unclear. To appraise the literature describing the association between STICs and established HGSOCs. Ovid MEDLINE and EMBASE were searched. Studies were included if they evaluated the frequency of STICs in HGSOCs, and were published in an English peer-reviewed journal. Appropriate studies were evaluated for their compliance with the 'Strengthening and Reporting of Observational Studies in Epidemiology (STROBE)' criteria. Ten articles met the study selection criteria. The reported coexistence between STICs and HGSOCs ranged from 11% to 61% (mean: 31%, 95% CI: 17-46%). STICs were rarely found in other gynaecological cancers. Small sample size, lack of objective criteria to identify STICs and the retrospective nature of the studies contributed to the variability in reporting the rate of the association. STICs were identified commonly in the FTs of women with HGSOC. Finding the true rate of association between STICs and HGSOCs will require further investigations. While there is evidence that a fraction of HGSOCs arise from the FTs, an accurate estimate of that fraction remains to be determined. The lack of an accurate estimate of the association makes it difficult to evaluate the potential magnitude of reduction of HGSOCs following prophylactic salpingectomy. A systematic review of the incidence of STICs in HGSOCs identifies significant methodological inconsistencies. © 2017 Royal College of Obstetricians and Gynaecologists.

Secretory cell outgrowths, p53 signatures, and serous tubal intraepithelial carcinoma in the fallopian tubes of patients with sporadic pelvic serous carcinoma

Directory of Open Access Journals (Sweden)

Neha Mittal

2016-01-01

Full Text Available Context: High-grade serous carcinomas of ovarian, tubal, and peritoneal origin are together referred as pelvic serous carcinoma. The fallopian tubes, ovarian surface epithelium, and the tuboperitoneal junctional epithelium are all implicated in pelvic serous carcinogenesis. Aims: The aim of this study is to identify putative precursor lesions of serous carcinoma including secretory cell outgrowths (SCOUTs, serous tubal intraepithelial carcinoma (STIC, and p53 signatures and assign its probable site of origin. Settings and Design: Prospective case-control study of consecutive specimen comprising 32 serous carcinomas and 31 controls (10 normal adnexa, 10 benign and 6 atypically proliferative surface epithelial tumors, and 5 other carcinomas. Subjects and Methods: Sectioning and extensive examination of the fimbrial end (SEE-FIM protocol along with immunohistochemistry for Bcl-2, p53, and Ki-67 was employed for evaluating invasive carcinoma and precursor lesions in cases versus controls. Results: SCOUT, p53 signatures, and STIC were most frequent in the serous carcinomas. p53 signatures and STIC were always seen in the fimbrial end. STICs were exclusively present in serous carcinomas, more common in ipsilateral tubes of cases with dominant ovarian mass. Multifocal p53 signatures with STIC were seen in 7 (21.9% cases. STIC was present with or without an invasive carcinoma in 25% and in 6.25% of cases of pelvic serous carcinomas, respectively. The junctional epithelia did not show any lesion in any group. Conclusions: SEE-FIM protocol is recommended for evaluation of sporadicpelvic (ovarian/tubal/peritoneal serous carcinoma. Based on the presence of STIC or invasive carcinoma, nearly 60% of all pelvic serous carcinomas are of fallopian tubal origin.

Serous tubal intraepithelial carcinoma localizes to the tubal-peritoneal junction: a pivotal clue to the site of origin of extrauterine high-grade serous carcinoma (ovarian cancer).

Science.gov (United States)

Seidman, Jeffrey D

2015-03-01

Recent data suggest that intraepithelial carcinoma of the fallopian tube [serous tubal intraepithelial carcinoma (STIC)] is the precursor of high-grade extrauterine serous carcinoma. A more specific location for the origin of this lesion is suggested by the recently described junction between the fallopian tubal epithelium and the peritoneum [tubal-peritoneal junction (TPJ)]. Fallopian tubes from 202 patients with advanced-stage high-grade extrauterine serous carcinoma or carcinosarcoma were evaluated histologically as were 124 prophylactic salpingo-oophorectomy specimens. These included 54 patients with BRCA or other high-risk mutation or a family history of BRCA mutation and 70 with a personal or family history of breast carcinoma. STIC was found in 81 of 202 patients with serous carcinoma (40.1%). STIC was present in 73 of 141 (52%) cases in which the fimbriae were present and in 62 of 100 (62%) cases in which the TPJ was present (P not significant). In comparison with these groups, when fimbriae and TPJ were absent, STIC was found in 8 of 61 (13%) cases (PSTIC. The mean size of STIC was 1.7 mm. In 32 cases (39.5%), the lesion was flat and in 49 (60.5%), papillary. The mean size of flat STICs was 0.8 mm as compared with 2.3 mm for papillary STICs (P=0.00005). STIC was identified in the same tissue fragment as the junction in 48 cases. The mean distance of STIC to the junction was 1.8 mm. In 11 cases, STIC was flanked by peritoneal mesothelium on one side and tubal epithelium on the opposite side. In 51 patients, the mean distance of invasive carcinoma from the TPJ was 1.8 mm. This distance was 1.9 mm when STIC was present (37 cases) in comparison with 1.5 mm when STIC was absent (14 cases) (P not significant). In 27 of 42 cases (64%), STIC was contiguous with invasive carcinoma. Lamina propria invasion was present in 71% of cases in which STIC was present as compared with 26% of cases in which STIC was absent (PSTIC was present as compared with 26% of cases in

Prognostic and clinicopathological significance of Cacna2d1 expression in epithelial ovarian cancers: a retrospective study

Science.gov (United States)

Yu, Dandan; Holm, Ruth; Goscinski, Mariusz Adam; Trope, Claes G; Nesland, Jahn M; Suo, Zhenhe

2016-01-01

Ovarian cancer is the most lethal gynecologic malignancy, in which cancer stem cells (CSC) have been reported to be the driving force of relapse and therapy-resistance. It is therefore important to explore CSC markers in ovarian cancer. This project aimed to explore the correlation between the expression of potential CSC maker Cacna2d1 and clinicopathological parameters in 238 epithelial ovarian cancer (EOC) samples. Immunohistochemically, positive Cacna2d1 expression was observed in 83.6% (199/238) of the EOC tumors, among which 107 tumors (44.9%) were highly positive and 92 (38.7%) tumors were weakly positive for the Cacna2d1 protein expression. Among the 158 serous carcinomas, the Cacna2d1 positivity was 148 (93.7%), in which 88 (55.7%) were highly positive, and 60 (38.0%) were weakly positive for the Cacna2d1 protein expression. Most strikingly, the Cacna2d1 was specifically expressed in the infiltration front areas of the EOC tumors. Statistical analyses showed that positive expression of Cacna2d1 was significantly associated with advanced FIGO stage (P<0.001), histological subtype (P=0.017) and tumor differentiation (P=0.015). Positive Cacna2d1 protein expression was significantly associated with poor overall survival (OS) and shorter progression free survival (PFS) in both total EOCs and serous carcinomas, although multivariate analyses did not reach statistical significance. In summary, our results suggest Cacna2d1 protein may play a crucial role in promoting aggressive EOC behavior and progression, and Cacna2d1 may serve as a novel predictive prognostic marker and a potential target for therapeutic intervention in EOCs. PMID:27725913

MicroRNA-194 promotes the growth, migration, and invasion of ovarian carcinoma cells by targeting protein tyrosine phosphatase nonreceptor type 12

Directory of Open Access Journals (Sweden)

Liang T

2016-07-01

Full Text Available Tian Liang, Liru Li, Yan Cheng, Chengcheng Ren, Guangmei Zhang Department of Gynecology and Obstetrics, The first Affiliated Hospital of Harbin Medical University, Nangang District, Harbin, Hei Longjiang, People’s Republic of China Abstract: Ovarian carcinoma is the most lethal gynecologic malignancy among women. Ovarian cancer metastasis is the main reason for poor prognosis. MicroRNAs (miRNAs have been shown to play an important role in tumorigenesis and metastasis in various cancers by affecting the expression of their targets. In this study, we explored the role of miR-194 in ovarian cancer. Real-time polymerase chain reaction assays showed that miR-194 was significantly upregulated in ovarian cancer tissues. Overexpression of miR-194 in ovarian cancer cells promotes cell proliferation, migration, and invasion; in contrast, inhibition of the expression of miR-194 has the opposite effects. Meanwhile, bioinformatics tools were used to identify protein tyrosine phosphatase nonreceptor type 12 (PTPN12 as a potential target of miR-194. The luciferase assay showed that miR-194 directly binds to the 3'-untranslated region of PTPN12. Western blot analysis and quantitative real-time polymerase chain reaction assay revealed that PTPN12 expression was negatively associated with miR-194 expression in both ovarian cancer tissues and cells. Thus, we conclude that miR-194 targets PTPN12 and functions as an oncogene in ovarian cancer cells. This novel pathway may provide a new insight to explain ovarian cancer development and metastasis. Keywords: miR-194, ovarian cancer, PTPN12, metastasis

Recent alcohol consumption and risk of incident ovarian carcinoma: a pooled analysis of 5,342 cases and 10,358 controls from the Ovarian Cancer Association Consortium

International Nuclear Information System (INIS)

Kelemen, Linda E; Köbel, Martin; Lurie, Galina; Thompson, Pamela J; Carney, Michael E; Moysich, Kirsten; Edwards, Robert; Bunker, Clare; Jensen, Allan; Høgdall, Estrid; Cramer, Daniel W; Bandera, Elisa V; Vitonis, Allison F; Olson, Sara H; King, Melony; Chandran, Urmila; Lissowska, Jolanta; Garcia-Closas, Montserrat; Yang, Hannah; Webb, Penelope M; Schildkraut, Joellen M; Goodman, Marc T; Terry, Kathryn L; Risch, Harvey A; Rossing, Mary Anne; Brinton, Louise A; Doherty, Jennifer A; Ness, Roberta B; Kjær, Susanne Krüger; Chang-Claude, Jenny

2013-01-01

Studies evaluating the association between alcohol intake and ovarian carcinoma (OC) are inconsistent. Because OC and ovarian borderline tumor histologic types differ genetically, molecularly and clinically, large numbers are needed to estimate risk associations. We pooled data from 12 case-control studies in the Ovarian Cancer Association Consortium comprising 5,342 OC cases, 1,455 borderline tumors and 10,358 controls with quantitative information on recent alcohol intake to estimate odds ratios (OR) and 95% confidence intervals (CI) according to frequencies of average daily intakes of beer, wine, liquor and total alcohol. Total alcohol intake was not associated with all OC: consumption of >3 drinks per day compared to none, OR=0.92, 95% CI=0.76-1.10, P trend=0.27. Among beverage types, a statistically non-significant decreased risk was observed among women who consumed >8 oz/d of wine compared to none (OR=0.83, 95% CI=0.68-1.01, P trend=0.08). This association was more apparent among women with clear cell OC (OR, 0.43; 95% CI, 0.22-0.83; P trend=0.02), although based on only 10 cases and not statistically different from the other histologic types (P value for statistical heterogeneity between histologic types = 0.09). Statistical heterogeneity of the alcohol- and wine-OC associations was seen among three European studies, but not among eight North American studies. No statistically significant associations were observed in separate analyses evaluating risk with borderline tumors of serous or mucinous histology. Smoking status did not significantly modify any of the associations. We found no evidence that recent moderate alcohol drinking is associated with increased risk for overall OC, or that variation in risk is associated strongly with specific histologic types. Understanding modifiable causes of these elusive and deadly cancers remains a priority for the research community

WNT7A/β-catenin signaling induces FGF1 and influences sensitivity to niclosamide in ovarian cancer.

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King, M L; Lindberg, M E; Stodden, G R; Okuda, H; Ebers, S D; Johnson, A; Montag, A; Lengyel, E; MacLean Ii, J A; Hayashi, K

2015-06-01

We previously characterized the link between WNT7A and the progression of ovarian cancer. Other groups have identified FGF1 as a relevant risk factor in ovarian cancer. Here, we show a linkage between these two signaling pathways that may be exploited to improve treatment and prognosis of patients with ovarian cancer. High expression of WNT7A and FGF1 are correlated in ovarian carcinomas and poor overall patient survival. A chromatin immunoprecipitation assay demonstrated that WNT7A/β-catenin signaling directly regulates FGF1 expression via TCF binding elements in the FGF1-1C promoter locus. In vitro gene manipulation studies revealed that FGF1 is sufficient to drive the tumor-promoting effects of WNT7A. In vivo xenograft studies confirmed that the stable overexpression of WNT7A or FGF1 induced a significant increase in tumor incidence, whereas FGF1 knockdown in WNT7A overexpressing cells caused a significant reduction in tumor size. Niclosamide most efficiently abrogated WNT7A/β-catenin signaling in our model, inhibited β-catenin transcriptional activity and cell viability, and increased cell death. Furthermore, niclosamide decreased cell migration following an increase in E-cadherin subsequent to decreased levels of SLUG. The effects of niclosamide on cell functions were more potent in WNT7A-overexpressing cells. Oral niclosamide inhibited tumor growth and progression in an intraperitoneal xenograft mouse model representative of human ovarian cancer. Collectively, these results indicate that FGF1 is a direct downstream target of WNT7A/β-catenin signaling and this pathway has potential as a therapeutic target in ovarian cancer. Moreover, niclosamide is a promising inhibitor of this pathway and may have clinical relevance.

Monitoring of chemotherapy successfulness of Platina/Taxol chemotherapy protocol by using determination of serum urokinase plasminogen activator (uPA and soluble urokinase plasminogen activator receptor (suPAR in patients with ovarian carcinoma FIGO II

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Dženita Ljuca

2007-05-01

Full Text Available In about 70% of cases, ovarian carcinoma has been diagnosed at an advanced stage. Invasion and metastasis of solid tumors request protease activity resulting in basal membrane destruction and surrounding matrix. In that process, urokinase plasminogen activator (uPA and its receptor, urokinase plasminogen activator receptor (suPAR play a key role, that via plasmin activation lead to basal membrane and matrix degradation in surrounding of the tumor, enable to its invasion and metastasis. Determination of serum concentration of those tumor markers can be useful in preoperative as well as in postoperative period. Their serum concentrations in ovarian cancer patients may help in good monitoring of remission or progression during chemotherapy treatment. In late 1950s and eariy 1960s, when it was found out that malignant ovarian tumors were chemosensitive, their chemotherapy treatment has begun. In the beginning it was used only mono-therapy, and by discovering new cytostatics it was replaced by poly-chemotherapy. Now days, in the therapy of advanced stages of ovarian carcinoma combination of cisplatine or carboplatine with paclitaxel is considering as standard treatment. Aim of this study was to determine serum uPA, suPAR and CEA in FIGO II and III patients with different histo-logical type (serous, mucinous, clear cell tumor before and after PT chemotherapy protocol during following three cycles. In this prospective study we have analyzed 17 patients with ovarian carcinoma, those have been after surgery treated by chemotherapy. Serum levels of uPA and suPAR have been determined by ELISA-test (Imubind uPA, Imubind uPAR, American Diagnostica, and CEA by OPUS Imunoassay method. Results of this study have shown that uPA, suPAR and CEA met criteria for prognostic markers for monitoring of successful-ness of platina/taxol chemotherapy protocol for serous, mucinous and clear cell tumor FIGO II and III stage of ovarian carcinoma. In case of PT chemotherapy

Distinct Patterns of Stromal and Tumor Expression of ROR1 and ROR2 in Histological Subtypes of Epithelial Ovarian Cancer

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C.E. Henry

2017-06-01

Full Text Available OBJECTIVE: The ROR1 and ROR2 receptor tyrosine kinases have both been implicated in ovarian cancer progression and have been shown to drive migration and invasion. There is an increasing importance of the role of stroma in ovarian cancer metastasis; however, neither ROR1 nor ROR2 expression in tumor or stromal cells has been analyzed in the same clinical cohort. AIM: To determine ROR1 and ROR2 expression in ovarian cancer and surrounding microenvironment and examine associations with clinicopathological characteristics. METHODS: Immunohistochemistry for ROR1 and ROR2 was used to assess receptor expression in a cohort of epithelial ovarian cancer patients (n = 178. Results were analyzed in relation to clinical and histopathological characteristics and survival. Matched patient sample case studies of normal, primary, and metastatic lesions were used to examine ROR expression in relation to ovarian cancer progression. RESULTS: ROR1 and ROR2 are abnormally expressed in malignant ovarian epithelium and stroma. Higher ROR2 tumor expression was found in early-stage, low-grade endometrioid carcinomas. ROR2 stromal expression was highest in the serous subtype. In matched patient case studies, metastatic samples had higher expression of ROR2 in the stroma, and a recurrent sample had the highest expression of ROR2 in both tumor and stroma. CONCLUSION: ROR1 and ROR2 are expressed in tumor-associated stroma in all histological subtypes of ovarian cancer and hold potential as therapeutic targets which may disrupt tumor and stroma interactions.

Immunological comparison of ovarian and colonic CEA

International Nuclear Information System (INIS)

Burtin, P.; Gendron, M.C.; Maunoury, M.T.; Lamerz, R.; Schnabel, G.

1982-01-01

Ovarian and colonic CEA were compared immunologically by means of antisera prepared against each of them. CEAs of both origins were found identical by immunodiffusion methods. In radioimmunological experiments, slight differences were observed between some but not all ovarian CEAs and colonic CEAs and also between different preparations of colonic CEA: no organ specificity of ovarian CEA could be demonstrated. Finally, CEA level was measured in 41 sera of patients with ovarian carcinoma by two radioimmunoassays, one using colonic CEA as tracer and standard and anti-colonic CEA serum, the other using ovarian CEA and anti-ovarian CEA serum: the values given by the two assays were highly correlated (rsub(s) = 0.8107), meaning that an organ specific assay for ovarian CEA is not needed. (Auth.)

Progesterone signaling mediated through progesterone receptor membrane component-1 in ovarian cells with special emphasis on ovarian cancer.

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Peluso, John J

2011-08-01

Various ovarian cell types including granulosa cells and ovarian surface epithelial cells express the progesterone (P4) binding protein, progesterone receptor membrane component-1 (PGRMC1). PGRMC1 is also expressed in ovarian tumors. PGRMC1 plays an essential role in promoting the survival of both normal and cancerous ovarian cell in vitro. Given the clinical significance of factors that regulate the viability of ovarian cancer, this review will focus on the role of PGRMC1 in ovarian cancer, while drawing insights into the mechanism of PGRMC1's action from cell lines derived from healthy ovaries as well as ovarian tumors. Studies using PGRMC1siRNA demonstrated that P4's ability to inhibit ovarian cells from undergoing apoptosis in vitro is dependent on PGRMC1. To confirm the importance of PGRMC1, the ability of PGRMC1-deplete ovarian cancer cell lines to form tumors in intact nude mice was assessed. Compared to PGRMC1-expressing ovarian cancer cells, PGRMC1-deplete ovarian cancer cells formed tumors in fewer mice (80% compared to 100% for controls). Moreover, the number of tumors derived from PGRMC1-deplete ovarian cancer cells was 50% of that observed in controls. Finally, the tumors that formed from PGRMC1-deplete ovarian cancer cells were about a fourth the size of tumors derived from ovarian cancer cells with normal levels of PGRMC1. One reason for PGRMC1-deplete tumors being smaller is that they had a poorly developed microvasculature system. How PGRMC1 regulates cell viability and in turn tumor growth is not known but part of the mechanism likely involves the regulation of genes that promote cell survival and inhibit apoptosis. Copyright © 2011 Elsevier Inc. All rights reserved.

A diagnostic dilemma following risk-reducing surgery for BRCA1 mutation – a case report of primary papillary serous carcinoma presenting as sigmoid cancer

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Nash Guy F

2007-09-01

Full Text Available Abstract Background Women that carry germ-line mutations for BRCA1 or BRCA2 genes are at an increased risk of developing breast, ovarian and peritoneal cancer. Primary peritoneal carcinoma is a rare tumour histologically identical to papillary serous ovarian carcinoma. Risk-reducing surgery in the form of mastectomy and oophorectomy in premenopausal women has been recommended to prevent breast and ovarian cancer occurrence and decrease the risk of developing primary peritoneal cancer. Case presentation We present a case report of a woman with a strong family history of breast cancer who underwent risk-reducing surgery in the form of bilateral salpingo-oophorectomy following a mastectomy for a right-sided breast tumour. Following the finding of a BRCA1 mutation, a prophylactic left-sided mastectomy was performed. After remaining well for twenty-seven years, she presented with rectal bleeding and altered bowel habit, and was found to have a secondary cancer of the sigmoid colon. She was finally diagnosed with primary papillary serous carcinoma of the peritoneum (PSCP. Conclusion PSCP can present many years after risk-reducing surgery and be difficult to detect. Surveillance remains the best course of management for patients with known BRCA mutations.

Randomized phase II trial of carboplatin versus paclitaxel and carboplatin in platinum-sensitive recurrent advanced ovarian carcinoma: a GEICO (Grupo Espanol de Investigacion en Cancer de Ovario) study.

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González-Martín, A J; Calvo, E; Bover, I; Rubio, M J; Arcusa, A; Casado, A; Ojeda, B; Balañá, C; Martínez, E; Herrero, A; Pardo, B; Adrover, E; Rifá, J; Godes, M J; Moyano, A; Cervantes, A

2005-05-01

The aim of this study was to determine whether the response rate for the paclitaxel-carboplatin combination is superior to carboplatin alone in the treatment of patients with platinum-sensitive recurrent ovarian carcinoma. Patients with recurrent ovarian carcinoma, 6 months after treatment with a platinum-based regimen and with no more than two previous chemotherapy lines, were randomized to receive carboplatin area under the curve (AUC) 5 (arm A) or paclitaxel 175 mg/m(2) + carboplatin AUC 5 (arm B). The primary end point was objective response, following a 'pick up the winner' design. Secondary end points included time to progression (TTP), overall survival, tolerability and quality of life (QoL). Eighty-one patients were randomized and included in the intention-to-treat analysis. The response rate in arm B was 75.6% [26.8% complete response (CR) + 48.8% partial response (PR)] [95% confidence interval (CI) 59.7% to 87.6%] and 50% in arm A (20% CR + 30% PR) (95% CI 33.8% to 66.2%). No significant differences were observed in grade 3-4 hematological toxicity. Conversely, mucositis, myalgia/arthralgia and peripheral neurophaty were more frequent in arm B. Median TTP was 49.1 weeks in arm B (95% CI 36.9-61.3) and 33.7 weeks in arm A (95% CI 25.8-41.5). No significant differences were found in the QoL analysis. Paclitaxel-carboplatin combination is a tolerable regimen with a higher response rate than carboplatin monotherapy in platinum-sensitive recurrent ovarian carcinoma.

Imaging features of ovarian metastases from colonic adenocarcinoma in adolescents

International Nuclear Information System (INIS)

Kauffman, W.M.; Jenkins, J.J. III; Helton, K.; Rao, B.N.; Winer-Muram, H.T.; Pratt, C.B.

1995-01-01

This paper describes the imaging features of ovarian metastases from adenocarcinoma of the colon in adolescent females. We reviewed retrospectively abdominal and pelvic computed tomographic and pelvic ultrasound examinations, histologic slices, and clinical charts of six adolescent females with ovarian metastases secondary to adenocarcinoma of the colon. One patient had ovarian metastasis at presentation and was presumed to have a primary ovarian tumor. The ovarian metastases were either solid (n = 3), complex with both solid and cystic components (n = 2), or multilocular cysts (n = 1). The ovarian lesions were large, ranging from 6 cm to 18 cm in diameter. Colorectal carcinoma in adolescent females is frequently associated with ovarian metastases. One imaging characteristic differs in adult and adolescent ovarian metastases, although they do have features in common: in adolescents, a smaller proportion of colorectal ovarian metastases are multicystic (17%) compared with the adult series (45%). These lesions are frequently large and may be complex, multicystic, or solid. Although it is a rare disease, the differential dignosis of adnexal masses in adolescent females should include ovarian metastases from adenocarcinoma of the colon. (orig.)

Connective tissue growth factor mediates TGF-β1-induced low-grade serous ovarian tumor cell apoptosis.

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Cheng, Jung-Chien; Chang, Hsun-Ming; Leung, Peter C K

2017-10-17

Ovarian low-grade serous carcinoma (LGSC) is a rare disease and is now considered to be a distinct entity from high-grade serous carcinoma (HGSC), which is the most common and malignant form of epithelial ovarian cancer. Connective tissue growth factor (CTGF) is a secreted matricellular protein that has been shown to modulate many biological functions by interacting with multiple molecules in the microenvironment. Increasing evidence indicates that aberrant expression of CTGF is associated with cancer development and progression. Transforming growth factor-β1 (TGF-β1) is a well-known molecule that can strongly up-regulate CTGF expression in different types of normal and cancer cells. Our previous study demonstrated that TGF-β1 induces apoptosis of LGSC cells. However, the effect of TGF-β1 on CTGF expression in LGSC needs to be defined. In addition, whether CTGF mediates TGF-β1-induced LGSC cell apoptosis remains unknown. In the present study, we show that TGF-β1 treatment up-regulates CTGF expression by activating SMAD3 signaling in two human LGSC cell lines. Additionally, siRNA-mediated CTGF knockdown attenuates TGF-β1-induced cell apoptosis. Moreover, our results show that the inhibitory effect of the CTGF knockdown on TGF-β1-induced cell apoptosis is mediated by down-regulating SMAD3 expression. This study demonstrates an important role for CTGF in mediating the pro-apoptotic effects of TGF-β1 on LGCS.

The glycosphingolipid P₁ is an ovarian cancer-associated carbohydrate antigen involved in migration.

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Jacob, F; Anugraham, M; Pochechueva, T; Tse, B W C; Alam, S; Guertler, R; Bovin, N V; Fedier, A; Hacker, N F; Huflejt, M E; Packer, N; Heinzelmann-Schwarz, V A

2014-10-14

The level of plasma-derived naturally circulating anti-glycan antibodies (AGA) to P1 trisaccharide has previously been shown to significantly discriminate between ovarian cancer patients and healthy women. Here we aim to identify the Ig class that causes this discrimination, to identify on cancer cells the corresponding P1 antigen recognised by circulating anti-P1 antibodies and to shed light into the possible function of this glycosphingolipid. An independent Australian cohort was assessed for the presence of anti-P1 IgG and IgM class antibodies using suspension array. Monoclonal and human derived anti-glycan antibodies were verified using three independent glycan-based immunoassays and flow cytometry-based inhibition assay. The P1 antigen was detected by LC-MS/MS and flow cytometry. FACS-sorted cell lines were studied on the cellular migration by colorimetric assay and real-time measurement using xCELLigence system. Here we show in a second independent cohort (n=155) that the discrimination of cancer patients is mediated by the IgM class of anti-P1 antibodies (P=0.0002). The presence of corresponding antigen P1 and structurally related epitopes in fresh tissue specimens and cultured cancer cells is demonstrated. We further link the antibody and antigen (P1) by showing that human naturally circulating and affinity-purified anti-P1 IgM isolated from patients ascites can bind to naturally expressed P1 on the cell surface of ovarian cancer cells. Cell-sorted IGROV1 was used to obtain two study subpopulations (P1-high, 66.1%; and P1-low, 33.3%) and observed that cells expressing high P1-levels migrate significantly faster than those with low P1-levels. This is the first report showing that P1 antigen, known to be expressed on erythrocytes only, is also present on ovarian cancer cells. This suggests that P1 is a novel tumour-associated carbohydrate antigen recognised by the immune system in patients and may have a role in cell migration. The clinical value of our data

Prognostic significance of CA 125 and TPS levels after 3 chemotherapy courses in ovarian cancer patients

NARCIS (Netherlands)

van Dalen, A; Favier, J; Burges, A; Hasholzner, U; de Bruijn, HWA; Dobler-Girdziunaite, D; Dombi, VH; Fink, D; Giai, M; McGing, P; Harlozinska, A; Kainz, C; Markowska, J; Molina, R; Sturgeon, C; Bowman, A; Einarsson, R

2000-01-01

Objective. To evaluate the prognostic significance of and predictive value for survival of CA 125 and TPS levels after three chemotherapy courses in ovarian cancer patients. Methods. We analyzed in a prospective multicenter study the 1- and 2-year overall survival (OS) in ovarian carcinoma patients.

Coexistence of borderline ovarian epithelial tumor, primary pelvic hydatid cyst, and lymphoepithelioma-like gastric carcinoma.

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Gungor, Tayfun; Altinkaya, Sunduz Ozlem; Sirvan, Levent; Lafuente, Roberto Alvarez; Ceylaner, Serdar

2011-06-01

Borderline ovarian tumors (BOTs) represent a heterogeneous group of ovarian epithelial neoplasms. Despite a favorable prognosis, 10-20% of BOTs exhibit progressively worsening clinic. Primary involvement of pelvic organs with echinococcus is very rare. Lymphoepithelioma-like gastric carcinoma is a rare neoplasm of the stomach. A 58-year-old woman referred with abdominal swelling and gastric complaints. Imaging studies revealed a huge cystic mass with multiple septations and solid component, another cystic mass with an appearance of cyst hydatid in the pelvis, and thickening of the small curvature of stomach. Gastroscopy revealed an ulcer with a suspicious malignant appearance, and histology of the endoscopic specimen showed severe chronic inflammation and lymphocytic infiltration. No other involvement of hydatid cyst was detected. In the exploration, there was a 25cm cystic lesion with solid components arising from right ovary, another 6cm cyst over the former, 7cm cystic lesion arising from left ovary, and 10cm mass near the small curvature of the stomach. Excision of the masses; total gastrectomy with esophagojejunal anastomosis; total abdominal hysterectomy; bilateral salpingo-oophorectomy; omentectomy; appendectomy; splenectomy; and pelvic, paraaortic, and coeliac lympadenectomy were performed. Final pathology revealed lymphoepithelioma-like gastric carcinoma, bilateral serous BOT, and hydatid cyst. Hydatid cyst should always be considered in the differential diagnosis of abdominopelvic masses in endemic regions of the world. Preoperative diagnosis of primary pelvic hydatid disease is difficult and awareness of its possibility is very important especially in patients residing in or coming from endemic areas. Copyright © 2011. Published by Elsevier B.V.

Granisetron, Aprepitant, and Dexamethasone in Preventing Nausea and Vomiting in Patients Receiving Chemotherapy for Stage II, III, or IV Ovarian Cancer

Science.gov (United States)

2018-04-24

Nausea and Vomiting; Ovarian Brenner Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Seromucinous Carcinoma; Ovarian Serous Cystadenocarcinoma; Stage II Ovarian Cancer; Stage IIA Fallopian Tube Cancer; Stage IIA Ovarian Cancer; Stage IIB Fallopian Tube Cancer; Stage IIB Ovarian Cancer; Stage IIC Fallopian Tube Cancer; Stage IIC Ovarian Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer; Undifferentiated Ovarian Carcinoma

A case of severe encephalitis while on PD-1 immunotherapy for recurrent clear cell ovarian cancer

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Morgan Burke

2018-05-01

Full Text Available Recurrent clear cell ovarian carcinoma is a difficult to treat condition and early trial data has suggested a possible role for immune checkpoint inhibitors. Nivolumab is an anti-PD-1 immunotherapy that has been used in this setting. While immune related toxicity of these agents has been well described, the occurrence of immune specific neurotoxicity is thought to be rare. We present a case of severe encephalitis while on PD-1 immunotherapy for a recurrent ovarian clear cell cancer and we believe this to be the first such reported case associated with the use of PD-1 inhibitor monotherapy. In this case, a 64-year-old woman with persistent clear cell ovarian cancer on Nivolumab presented with a severe fever of unknown origin and delirium; initial imaging and diagnostic work-up suggested a neurological etiology, but with no clear source. We concluded that this was a severe case of immune related encephalitis, thought to be brought about by the anti-PD-1 immunotherapy which responded well to systemic corticosteroids and plasmapheresis and the patient able to make a full recovery. We present a summary of the case and its management as well as a review of the literature on the previously reported neurotoxicity's of PD-1 inhibitors.

Clinicopathologic study of serous tubal intraepithelial carcinoma with invasive carcinoma: is serous tubal intraepithelial carcinoma a reliable feature for determining the organ of origin?

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Gao, Faye F; Bhargava, Rohit; Yang, Huaitao; Li, Zaibo; Zhao, Chengquan

2013-08-01

In the past several decades, the concept of serous ovarian carcinoma has been revised repeatedly. However, the exact pathogenesis remains controversial. The most popular current concept is origin from the epithelium of the fimbriated ends of the fallopian tubes. The objective of our study was to evaluate the characteristic clinical and morphologic features of serous tubal intraepithelial carcinoma (STIC) and associated invasive carcinomas. One hundred sixteen consecutive cases of STIC seen from 2007 to 2011 were included in this study. High-grade serous carcinoma (HGSC) with or without a mixed component was identified in 107 cases (92.2%), non-HGSC in 5 cases, and STICs without invasive carcinoma in 4 cases. Using conventional criteria, HGSCs were classified as fallopian tube in origin in 65 cases (60.7%), as ovarian in 30 (28.0%), as peritoneal in 9 (8.4%), and as endometrial in 3 (2.8%). Among the 107 cases with HGSCs, most STICs (86; 80%) were present unilaterally, whereas invasive tumors more commonly involved the ovaries bilaterally (79%; 84 cases). These findings support the hypothesis that STIC acts as a precursor lesion for most fallopian tube, ovarian, and peritoneal HGSCs, but not for endometrial HGSC. Copyright © 2013 Elsevier Inc. All rights reserved.

Serous tubal intraepithelial carcinoma upregulates markers associated with high-grade serous carcinomas including Rsf-1 (HBXAP), cyclin E and fatty acid synthase.

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Sehdev, Ann Smith; Kurman, Robert J; Kuhn, Elisabetta; Shih, Ie-Ming

2010-06-01

Serous tubal intraepithelial carcinoma (STIC) has been proposed as a precursor for many pelvic high-grade serous carcinomas. Our previous analysis of the ovarian cancer genome identified several genes with oncogenic potential that are amplified and/or overexpressed in the majority of high-grade serous carcinomas. Determining whether these genes are upregulated in STICs is important in further elucidating the relationship of STICs to high-grade serous carcinomas and is fundamental in understanding the molecular pathogenesis of high-grade serous carcinomas. In this study, 37 morphologically defined STICs were obtained from 23 patients with stage IIIC/IV high-grade serous carcinomas. Both STICs and the high-grade serous carcinomas were analyzed for expression of Rsf-1 (HBXAP), cyclin E, fatty acid synthase (FASN) and mucin-4. In addition, they were examined for expression of established markers including p53, Ki-67 and p16. We found that diffuse nuclear p53 and p16 immunoreactivity was observed in 27 (75%) of 36 and 18 (55%) of 33 STICs, respectively, whereas an elevated Ki-67 labeling index (>or=10%) was detected in 29 (78%) of 37 STICs. Cyclin E nuclear staining was seen in 24 (77%) of 35 STICs, whereas normal tubal epithelial cells were all negative. Increased Rsf-1 and FASN immunoreactivity occurred in 63%, and 62% of STICs, respectively, compared with adjacent normal-appearing tubal epithelium. Interestingly, only one STIC showed increased mucin-4 immunoreactivity. Carcinomas, when compared with STICs, overexpressed p16, Rsf-1, cyclin E and FASN in a higher proportion of cases. In conclusion, STICs express several markers including Rsf-1, cyclin E and FASN in high-grade serous carcinomas. In contrast, mucin-4 immunoreactivity either did not change or was reduced in most STICs. These results suggest that overexpression of Rsf-1, cyclin E and FASN occurs early in tumor progression.

Serous ovarian, fallopian tube and primary peritoneal cancers

DEFF Research Database (Denmark)

Sørensen, Rie D; Schnack, Tine H; Karlsen, Mona A

2015-01-01

OBJECTIVE: The aim of this systematic review is to analyze data on risk factors, epidemiology, clinicopathology and molecular biology from studies comparing primary peritoneal cancer, fallopian tube cancer and ovarian cancer of serous histology, in order to achieve a greater understanding...... of whether or not these disorders should be considered as separate entities. METHODS: A systematic literature search was conducted in PubMed and MEDLINE. Case-control studies comparing primary serous peritoneal or fallopian tube carcinomas with primary serous ovarian carcinomas or a control group were...... included. RESULTS: Twenty-eight studies were found eligible. Primary peritoneal cancer patients were older, had higher parity, were more often obese and had poorer survival compared to ovarian cancer patients. Differences in protein expression patterns of Her2/neu, estrogen and progestin receptors...

Histone Deacetylase Inhibitor Therapy in Epithelial Ovarian Cancer

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Noriyuki Takai

2010-01-01

Full Text Available Since epigenetic alterations are believed to be involved in the repression of tumor suppressor genes and promotion of tumorigenesis in ovarian cancers, novel compounds endowed with a histone deacetylase (HDAC inhibitory activity are an attractive therapeutic approach. In this review, we discuss the biologic and therapeutic effects of HDAC inhibitors (HDACIs in treating ovarian cancer. HDACIs were able to mediate inhibition of cell growth, cell cycle arrest, apoptosis, and expression of genes related to the malignant phenotype in a variety of ovarian cancer cell lines. Furthermore, HDACIs were able to induce the accumulation of acetylated histones in the chromatin of the p21WAF1 gene in human ovarian carcinoma cells. In xenograft models, some of HDACIs have demonstrated antitumor activity with only few side effects. Some clinical trials demonstrate that HDACI drugs provide an important class of new mechanism-based therapeutics for ovarian cancer. In this review, we discuss the biologic and therapeutic effects of HDACIs in treating ovarian cancer, especially focusing on preclinical studies and clinical trials.

Morphologic, Immunophenotypic, and Molecular Features of Epithelial Ovarian Cancer.

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Ramalingam, Preetha

2016-02-01

Epithelial ovarian cancer comprises a heterogeneous group of tumors. The four most common subtypes are serous, endometrioid, clear cell, and mucinous carcinoma. Less common are transitional cell tumors, including transitional cell carcinoma and malignant Brenner tumor. While in the past these subtypes were grouped together and designated as epithelial ovarian tumors, these tumor types are now known to be separate entities with distinct clinical and biologic behaviors. From a therapeutic standpoint, current regimens employ standard chemotherapy based on stage and grade rather than histotype. However, this landscape may change in the era of personalized therapy, given that most subtypes (with the exception of high-grade serous carcinoma) are relatively resistant to chemotherapy. It is now well-accepted that high-grade and low-grade serous carcinomas represent distinct entities rather than a spectrum of the same tumor type. While they are similar in that patients present with advanced-stage disease, their histologic and molecular features are entirely different. High-grade serous carcinoma is associated with TP53 mutations, whereas low-grade serous carcinomas are associated with BRAF and KRAS mutations. Endometrioid and clear cell carcinomas typically present as early-stage disease and are frequently associated with endometriosis. Mucinous carcinomas typically present as large unilateral masses and often show areas of mucinous cystadenoma and mucinous borderline tumor. It must be emphasized that primary mucinous carcinomas are uncommon tumors, and metastasis from other sites such as the appendix, colon, stomach, and pancreaticobiliary tract must always be considered in the differential diagnosis. Lastly, transitional cell tumors of the ovary, specifically malignant Brenner tumors, are quite uncommon. High-grade serous carcinoma often has a transitional cell pattern, and adequate sampling in most cases shows more typical areas of serous carcinoma. Immunohistochemical

Rapidly growing ovarian endometrioid adenocarcinoma involving the vagina: A case report

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Sunghun Na

2011-12-01

Conclusion: Epithelial ovarian cancer may grow very rapidly. The frequent measurement of tumor size by ultrasonography may provide important information on detection in a subset of ovarian carcinomas that develop from preexisting, detectable lesions.

Automatic classification of ovarian cancer types from cytological images using deep convolutional neural networks.

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Wu, Miao; Yan, Chuanbo; Liu, Huiqiang; Liu, Qian

2018-06-29

Ovarian cancer is one of the most common gynecologic malignancies. Accurate classification of ovarian cancer types (serous carcinoma, mucous carcinoma, endometrioid carcinoma, transparent cell carcinoma) is an essential part in the different diagnosis. Computer-aided diagnosis (CADx) can provide useful advice for pathologists to determine the diagnosis correctly. In our study, we employed a Deep Convolutional Neural Networks (DCNN) based on AlexNet to automatically classify the different types of ovarian cancers from cytological images. The DCNN consists of five convolutional layers, three max pooling layers, and two full reconnect layers. Then we trained the model by two group input data separately, one was original image data and the other one was augmented image data including image enhancement and image rotation. The testing results are obtained by the method of 10-fold cross-validation, showing that the accuracy of classification models has been improved from 72.76 to 78.20% by using augmented images as training data. The developed scheme was useful for classifying ovarian cancers from cytological images. © 2018 The Author(s).

BRCA Mutation Frequency and Patterns of Treatment Response in BRCA Mutation–Positive Women With Ovarian Cancer: A Report From the Australian Ovarian Cancer Study Group

Science.gov (United States)

Alsop, Kathryn; Fereday, Sian; Meldrum, Cliff; deFazio, Anna; Emmanuel, Catherine; George, Joshy; Dobrovic, Alexander; Birrer, Michael J.; Webb, Penelope M.; Stewart, Colin; Friedlander, Michael; Fox, Stephen; Bowtell, David; Mitchell, Gillian

2012-01-01

Purpose The frequency of BRCA1 and BRCA2 germ-line mutations in women with ovarian cancer is unclear; reports vary from 3% to 27%. The impact of germ-line mutation on response requires further investigation to understand its impact on treatment planning and clinical trial design. Patients and Methods Women with nonmucinous ovarian carcinoma (n = 1,001) enrolled onto a population-based, case-control study were screened for point mutations and large deletions in both genes. Survival outcomes and responses to multiple lines of chemotherapy were assessed. Results Germ-line mutations were found in 14.1% of patients overall, including 16.6% of serous cancer patients (high-grade serous, 22.6%); 44% had no reported family history of breast or ovarian cancer. Patients carrying germ-line mutations had improved rates of progression-free and overall survival. In the relapse setting, patients carrying mutations more frequently responded to both platin- and nonplatin-based regimens than mutation-negative patients, even in patients with early relapse after primary treatment. Mutation-negative patients who responded to multiple cycles of platin-based treatment were more likely to carry somatic BRCA1/2 mutations. Conclusion BRCA mutation status has a major influence on survival in ovarian cancer patients and should be an additional stratification factor in clinical trials. Treatment outcomes in BRCA1/2 carriers challenge conventional definitions of platin resistance, and mutation status may be able to contribute to decision making and systemic therapy selection in the relapse setting. Our data, together with the advent of poly(ADP-ribose) polymerase inhibitor trials, supports the recommendation that germ-line BRCA1/2 testing should be offered to all women diagnosed with nonmucinous, ovarian carcinoma, regardless of family history. PMID:22711857

Excluding Lynch syndrome in a female patient with metachronous DNA mismatch repair deficient colon- and ovarian cancer

NARCIS (Netherlands)

S. Crobach (Stijn); Jansen, A.M.L. (Anne M. L.); Ligtenberg, M.J.L. (Marjolein J. L.); Koopmans, M. (Marije); M. Nielsen (Maartje); F.J. Hes (Frederik); J.T. Wijnen (Juul); W.N.M. Dinjens (Winand); T. van Wezel (Tom); H. Morreau (Hans)

2017-01-01

textabstractPatients synchronously or metachronously presenting with ovarian and colon cancer can pose diagnostic challenges. A primary colon carcinoma can metastasize to one or both ovaries, two independent primary tumors can arise or an ovarian carcinoma can metastasize to the colon. Clinical and

Downregulation of Connective Tissue Growth Factor by Three-Dimensional Matrix Enhances Ovarian Carcinoma Cell Invasion

Science.gov (United States)

Barbolina, Maria V.; Adley, Brian P.; Kelly, David L.; Shepard, Jaclyn; Fought, Angela J.; Scholtens, Denise; Penzes, Peter; Shea, Lonnie D.; Sharon Stack, M

2010-01-01

Epithelial ovarian carcinoma (EOC) is a leading cause of death from gynecologic malignancy, due mainly to the prevalence of undetected metastatic disease. The process of cell invasion during intra-peritoneal anchoring of metastatic lesions requires concerted regulation of many processes, including modulation of adhesion to the extracellular matrix and localized invasion. Exploratory cDNA microarray analysis of early response genes (altered after 4 hours of 3-dimensional collagen culture) coupled with confirmatory real-time RT-PCR, multiple three-dimensional cell culture matrices, Western blot, immunostaining, adhesion, migration, and invasion assays were used to identify modulators of adhesion pertinent to EOC progression and metastasis. cDNA microarray analysis indicated a dramatic downregulation of connective tissue growth factor (CTGF) in EOC cells placed in invasion-mimicking conditions (3-dimensional type I collagen). Examination of human EOC specimens revealed that CTGF expression was absent in 46% of the tested samples (n=41), but was present in 100% of normal ovarian epithelium samples (n=7). Reduced CTGF expression occurs in many types of cells and may be a general phenomenon displayed by cells encountering a 3D environment. CTGF levels were inversely correlated with invasion such that downregulation of CTGF increased, while its upregulation reduced, collagen invasion. Cells adhered preferentially to a surface comprised of both collagen I and CTGF relative to either component alone using α6β1 and α3β1 integrins. Together these data suggest that downregulation of CTGF in EOC cells may be important for cell invasion through modulation of cell-matrix adhesion. PMID:19382180

Shortened telomeres in serous tubal intraepithelial carcinoma: an early event in ovarian high-grade serous carcinogenesis.

Science.gov (United States)

Kuhn, Elisabetta; Meeker, Alan; Wang, Tian-Li; Sehdev, Ann Smith; Kurman, Robert J; Shih, Ie-Ming

2010-06-01

Short telomeres are one of the main genetic manifestations in human cancer, as they have been shown to play an important role in inducing chromosomal instability and in contributing to tumor progression. The purpose of this study was to determine if changes in telomere length occur in serous tubal intraepithelial carcinoma (STIC), the putative precursor of "ovarian" high-grade serous carcinoma (HGSC). Twenty-two STICs from 15 patients with concurrent but discrete HGSCs were analyzed for telomere length on formalin-fixed, paraffin-embedded sections by conducting p53 immunofluorescence to assist in identifying STICs and telomere-specific FISH. Telomere length (short, long, or no change) in STICs was compared with HGSCs using normal fallopian tube epithelium and stromal cells as controls. We found that STICs had the shortest telomeres, as 18 (82%) of 22 STICs had short telomeres, whereas only 2 (9%) showed no change and 2 (9%) had long telomeres compared with the normal-looking tubal epithelium. In contrast, among 12 paired HGSCs and STICs, 6 HGSCs showed an increase in telomere length, one showed a decrease in length and 5 did not show any change when compared with their matched STICs, although, such as STICs, the majority of HGSCs had shorter telomeres than the associated normal tubal epithelial cells. These differences in telomere length between normal tubal epithelial cells and STICs, and between STICs and HGSCs were statisticaly significant (PSTICs provides further support to the proposal that STICs are precursors of HGSC and opens new areas of research in elucidating the early events of ovarian high-grade serous carcinogenesis.

miR-21-3p is a positive regulator of L1CAM in several human carcinomas.

Science.gov (United States)

Doberstein, Kai; Bretz, Niko P; Schirmer, Uwe; Fiegl, Heidi; Blaheta, Roman; Breunig, Christian; Müller-Holzner, Elisabeth; Reimer, Dan; Zeimet, Alain G; Altevogt, Peter

2014-11-28

Expression of L1 cell adhesion molecule (L1CAM) occurs frequently in human cancers and is associated with poor prognosis in cancers such as ovarian, endometrial, breast, renal cell carcinoma and pancreatic ductal adenocarcinoma. L1CAM promotes cell motility, invasion, chemoresistance and metastasis formation. Elucidating genetic processes involved in the expression of L1CAM in cancers is of considerable importance. Transcription factors such as SLUG, β-catenin/TCF-LEF, PAX8 and VHL have been implicated in the re-activation of L1CAM in various types of cancers. There is increasing evidence that micro-RNAs can also have strong effects on gene expression. Here we have identified miR-21-3p as a positive regulator of L1CAM expression. Over-expression of miR-21-3p (miR-21*) but not the complementary sequence miR-21-5p (miR-21) could strongly augment L1CAM expression in renal, endometrial and ovarian carcinoma derived cell lines by an unknown mechanism involving transcriptional activation of the L1CAM gene. In patient cohorts from renal, endometrial and ovarian cancers we observed a strong positive correlation of L1CAM and miR-21-3p expressions. Although L1CAM alone was a reliable marker for overall and disease free survival, the combination of L1CAM and miR-21-3p expressions strongly enhanced the predictive power. Our findings shed new light on the complex regulation of L1CAM in cancers and advocate the use of L1CAM/miR-21-3p for diagnostic application. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Is CA-125 an additional help to radiologic findings for differentiation borderline ovarian tumor from stage I carcinoma?

International Nuclear Information System (INIS)

Lee, Eun Joo; Kim, See Hyung; Kim, Young Hwan; Lee, Hee Jung

2011-01-01

Background Borderline ovarian tumors (BOTs) are difficult to differentiate from stage I carcinoma using radiological findings. Little is known about the correlation between CA-125 levels and radiological findings for predicting BOTs or carcinoma. Purpose To assess the role of CA-125, in addition to that of radiological findings, in differentiating BOTs from stage I carcinoma. Material and Methods The study received institutional review board approval, with waiver of informed consent. We evaluated 100 patients (two groups: BOT, 58 patients; stage I carcinoma, 42 patients) using radiological findings, including location and size of each tumor, number and size of septations, papillary projections and vegetations, peritoneal implants, ascites, and preoperative CA-125 levels. The differences in CA-125 levels according to bilateral location, solid components, and thickness of septations between the two groups were evaluated using the McNemar test. Correlations of CA-125 level to size and number of septations were evaluated by the independent sample t test. Results No statistical correlation was found between CA-125 level and location, size, and number of septations between the two groups. Solid components within the tumors were similar in the two groups, but the CA-125 level was significantly higher in stage I carcinoma than in BOTs. The number of septations per tumor was similar in the two groups; thick septations were more frequent in stage I carcinoma than in BOTs, and a significantly higher titer of CA-125 was found in stage I carcinoma. Discriminant analysis of solid components and thickness of septations resulted in accurate diagnosis of 70.6% of the tumors (80.6% of BOTs and 69.7% of stage I carcinomas). Conclusion CA-125 levels for solid components and thickness of septations are lower in BOTs. These may be helpful in predicting the risk of carcinoma, even if BOTs cannot be conclusively differentiated from stage I carcinoma

Recent alcohol consumption and risk of incident ovarian carcinoma: a pooled analysis of 5,342 cases and 10,358 controls from the Ovarian Cancer Association Consortium

Directory of Open Access Journals (Sweden)

Kelemen Linda E

2013-01-01

Full Text Available Abstract Background Studies evaluating the association between alcohol intake and ovarian carcinoma (OC are inconsistent. Because OC and ovarian borderline tumor histologic types differ genetically, molecularly and clinically, large numbers are needed to estimate risk associations. Methods We pooled data from 12 case-control studies in the Ovarian Cancer Association Consortium comprising 5,342 OC cases, 1,455 borderline tumors and 10,358 controls with quantitative information on recent alcohol intake to estimate odds ratios (OR and 95% confidence intervals (CI according to frequencies of average daily intakes of beer, wine, liquor and total alcohol. Results Total alcohol intake was not associated with all OC: consumption of >3 drinks per day compared to none, OR=0.92, 95% CI=0.76-1.10, P trend=0.27. Among beverage types, a statistically non-significant decreased risk was observed among women who consumed >8 oz/d of wine compared to none (OR=0.83, 95% CI=0.68-1.01, P trend=0.08. This association was more apparent among women with clear cell OC (OR, 0.43; 95% CI, 0.22-0.83; P trend=0.02, although based on only 10 cases and not statistically different from the other histologic types (P value for statistical heterogeneity between histologic types = 0.09. Statistical heterogeneity of the alcohol- and wine-OC associations was seen among three European studies, but not among eight North American studies. No statistically significant associations were observed in separate analyses evaluating risk with borderline tumors of serous or mucinous histology. Smoking status did not significantly modify any of the associations. Conclusions We found no evidence that recent moderate alcohol drinking is associated with increased risk for overall OC, or that variation in risk is associated strongly with specific histologic types. Understanding modifiable causes of these elusive and deadly cancers remains a priority for the research community.

IMP3 expression in human ovarian cancer is associated with improved survival

DEFF Research Database (Denmark)

Noske, Aurelia; Faggad, Areeg; Wirtz, Ralph

2009-01-01

The insulin-like growth factor-II mRNA-binding protein IMP3 plays an important role in embryogenesis and recent reports suggest an involvement in tumorigenesis. Although IMP3 expression has been well studied in mouse and human fetal and adult gonads, its role in ovarian cancer is unknown. We...... investigated the expression of IMP3 at protein and mRNA levels in a cohort of primary ovarian carcinomas and in 11 ovarian cancer cell lines. Western blot analysis revealed an expression of IMP3 in all ovarian cancer cell lines and immunohistochemistry demonstrated a positive cytoplasmic staining in 32 of 68...... carcinomas (47%). In contrast, epithelium of borderline tumors, as well as, benign ovarian lesions and normal ovaries exhibited only weak or no IMP3 expression. In univariate Kaplan-Meier analysis, IMP3 protein expression was significantly associated with better overall survival (P=0.048). To confirm...

Appendiceal pathology at the time of oophorectomy for ovarian neoplasms.

Science.gov (United States)

Timofeev, Julia; Galgano, Mary T; Stoler, Mark H; Lachance, Jason A; Modesitt, Susan C; Jazaeri, Amir A

2010-12-01

To investigate the prevalence of appendiceal pathology in women undergoing surgery for a suspected ovarian neoplasm and the predictive value of intraoperative findings to determine the need for appendectomy at the time of surgery. Retrospective analysis of patients who underwent oophorectomy and appendectomy during the same surgical procedures at the University of Virginia Health System from 1992 to 2007. Observations were stratified based on the nature (benign, borderline, or malignant) and histology (serous compared with mucinous) of the ovarian neoplasm, frozen compared with final pathological diagnosis, and the gross appearance of the appendix. Among the 191 patients identified, frozen section was consistent with seven mucinous and 35 serous carcinomas, 16 serous and 33 mucinous borderline tumors, 71 mucinous and serous cystadenomas, and 29 cases of suspected metastatic tumor from a gastrointestinal primary. The highest rates of coexisting appendiceal pathology were associated with serous ovarian cancers (94.4% of grossly abnormal and 35.3% of normal appendices) and ovarian tumors suspected to be of primary gastrointestinal origin (83.3% grossly abnormal and 60.0% normal appendices harbored coexisting mucinous neoplasms). Linear regression analysis revealed that appearance of the appendix and frozen section diagnosis of the ovarian pathology were statistically significant predictors of coexisting appendiceal pathology, but the latter was more important. The prevalence of coexisting, clinically significant appendiceal pathology is low with a frozen section diagnosis of serous or mucinous cystadenoma. Appendectomy is recommended when frozen section diagnosis is mucinous or serous ovarian carcinoma, borderline tumor or metastatic carcinoma of suspected gastrointestinal origin.

Molecular Imaging of Ovarian Carcinoma Angiogenesis

National Research Council Canada - National Science Library

Chen, Xiaoyuan

2007-01-01

.... Ovarian cancer is angiogenesis dependent. Integrin , a key player in tumor angiogenesis and metastasis, has been identified as a target for diagnostic and therapeutic interventions for several highly proliferative and metastatic tumor types...

Ovarian Cancer Susceptibility Alleles and Risk of Ovarian Cancer in BRCA1 and BRCA2 Mutation Carriers

Science.gov (United States)

Ramus, Susan J.; Antoniou, Antonis C; Kuchenbaecker, Karoline B.; Soucy, Penny; Beesley, Jonathan; Chen, Xiaoqing; McGuffog, Lesley; Sinilnikova, Olga M.; Healey, Sue; Barrowdale, Daniel; Lee, Andrew; Thomassen, Mads; Gerdes, Anne-Marie; Kruse, Torben A.; Jensen, Uffe Birk; Skytte, Anne-Bine; Caligo, Maria A.; Liljegren, Annelie; Lindblom, Annika; Olsson, Håkan; Kristoffersson, Ulf; Stenmark-Askmalm, Marie; Melin, Beatrice; Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Timothy R.; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Złowocka, Elżbieta; Gronwald, Jacek; Huzarski, Tomasz; Byrski, Tomasz; Cybulski, Cezary; Toloczko-Grabarek, Aleksandra; Osorio, Ana; Benitez, Javier; Duran, Mercedes; Tejada, Maria-Isabel; Hamann, Ute; Rookus, Matti; van Leeuwen, Flora E.; Aalfs, Cora M.; Meijers-Heijboer, Hanne E.J.; van Asperen, Christi J.; van Roozendaal, K.E.P.; Hoogerbrugge, Nicoline; Collée, J. Margriet; Kriege, Mieke; van der Luijt, Rob B.; Peock, Susan; Frost, Debra; Ellis, Steve D.; Platte, Radka; Fineberg, Elena; Evans, D. Gareth; Lalloo, Fiona; Jacobs, Chris; Eeles, Ros; Adlard, Julian; Davidson, Rosemarie; Eccles, Diana; Cole, Trevor; Cook, Jackie; Paterson, Joan; Douglas, Fiona; Brewer, Carole; Hodgson, Shirley; Morrison, Patrick J.; Walker, Lisa; Porteous, Mary E.; Kennedy, M. John; Pathak, Harsh; Godwin, Andrew K.; Stoppa-Lyonnet, Dominique; Caux-Moncoutier, Virginie; de Pauw, Antoine; Gauthier-Villars, Marion; Mazoyer, Sylvie; Léoné, Mélanie; Calender, Alain; Lasset, Christine; Bonadona, Valérie; Hardouin, Agnès; Berthet, Pascaline; Bignon, Yves-Jean; Uhrhammer, Nancy; Faivre, Laurence; Loustalot, Catherine; Buys, Saundra; Daly, Mary; Miron, Alex; Terry, Mary Beth; Chung, Wendy K.; John, Esther M; Southey, Melissa; Goldgar, David; Singer, Christian F; Tea, Muy-Kheng; Pfeiler, Georg; Fink-Retter, Anneliese; Hansen, Thomas v. O.; Ejlertsen, Bent; Johannsson, Oskar Th.; Offit, Kenneth; Kirchhoff, Tomas; Gaudet, Mia M.; Vijai, Joseph; Robson, Mark; Piedmonte, Marion; Phillips, Kelly-Anne; Van Le, Linda; Hoffman, James S; Toland, Amanda Ewart; Montagna, Marco; Tognazzo, Silvia; Imyanitov, Evgeny; Isaacs, Claudine; Janavicius, Ramunas; Lazaro, Conxi; Blanco, Ignacio; Tornero, Eva; Navarro, Matilde; Moysich, Kirsten B.; Karlan, Beth Y.; Gross, Jenny; Olah, Edith; Vaszko, Tibor; Teo, Soo-Hwang; Ganz, Patricia A.; Beattie, Mary S.; Dorfling, Cecelia M; van Rensburg, Elizabeth J; Diez, Orland; Kwong, Ava; Schmutzler, Rita K.; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Heidemann, Simone; Niederacher, Dieter; Preisler-Adams, Sabine; Gadzicki, Dorotehea; Varon-Mateeva, Raymonda; Deissler, Helmut; Gehrig, Andrea; Sutter, Christian; Kast, Karin; Fiebig, Britta; Schäfer, Dieter; Caldes, Trinidad; de la Hoya, Miguel; Nevanlinna, Heli; Aittomäki, Kristiina; Plante, Marie; Spurdle, Amanda B.; Neuhausen, Susan L.; Ding, Yuan Chun; Wang, Xianshu; Lindor, Noralane; Fredericksen, Zachary; Pankratz, V. Shane; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Bonanni, Bernardo; Bernard, Loris; Dolcetti, Riccardo; Papi, Laura; Ottini, Laura; Radice, Paolo; Greene, Mark H.; Mai, Phuong L.; Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; Pharoah, Paul D.P.; Gayther, Simon A.; Simard, Jacques; Easton, Douglas F.; Couch, Fergus J.; Chenevix-Trench, Georgia

2012-01-01

Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67–0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21–1.83) P-trend = 1.8 × 10−4, rs717852 HR = 1.25 (95% CI: 1.10–1.42) P-trend = 6.6 × 10−4, rs9303542 HR = 1.16 (95% CI: 1.02–1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81–0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10–1.42) P-trend = 6.1 × 10−4. The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer. PMID:22253144

Diet and Physical Activity Change or Usual Care in Improving Progression-Free Survival in Patients With Previously Treated Stage II, III, or IV Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Science.gov (United States)

2018-02-14

Fallopian Tube Clear Cell Adenocarcinoma; Fallopian Tube Endometrioid Adenocarcinoma; Fallopian Tube Mucinous Adenocarcinoma; Fallopian Tube Serous Adenocarcinoma; Fallopian Tube Transitional Cell Carcinoma; Malignant Ovarian Brenner Tumor; Ovarian Clear Cell Adenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Adenocarcinoma; Ovarian Seromucinous Carcinoma; Ovarian Serous Adenocarcinoma; Ovarian Transitional Cell Carcinoma; Primary Peritoneal Serous Adenocarcinoma; Stage IIA Fallopian Tube Cancer AJCC v6 and v7; Stage IIA Ovarian Cancer AJCC V6 and v7; Stage IIB Fallopian Tube Cancer AJCC v6 and v7; Stage IIB Ovarian Cancer AJCC v6 and v7; Stage IIC Fallopian Tube Cancer AJCC v6 and v7; Stage IIC Ovarian Cancer AJCC v6 and v7; Stage IIIA Fallopian Tube Cancer AJCC v7; Stage IIIA Ovarian Cancer AJCC v6 and v7; Stage IIIA Primary Peritoneal Cancer AJCC v7; Stage IIIB Fallopian Tube Cancer AJCC v7; Stage IIIB Ovarian Cancer AJCC v6 and v7; Stage IIIB Primary Peritoneal Cancer AJCC v7; Stage IIIC Fallopian Tube Cancer AJCC v7; Stage IIIC Ovarian Cancer AJCC v6 and v7; Stage IIIC Primary Peritoneal Cancer AJCC v7; Stage IV Fallopian Tube Cancer AJCC v6 and v7; Stage IV Ovarian Cancer AJCC v6 and v7; Stage IV Primary Peritoneal Cancer AJCC v7; Undifferentiated Fallopian Tube Carcinoma; Undifferentiated Ovarian Carcinoma

ESR1/SYNE1 polymorphism and invasive epithelial ovarian cancer risk: an Ovarian Cancer Association Consortium study

DEFF Research Database (Denmark)

Doherty, Jennifer A; Rossing, Mary Anne; Cushing-Haugen, Kara L

2010-01-01

, respectively. A SNP 19 kb downstream of ESR1 (rs2295190, G-to-T change) was associated with invasive ovarian cancer risk, with a per-T-allele odds ratio (OR) of 1.24 [95% confidence interval (CI), 1.06-1.44, P = 0.006]. rs2295190 is a nonsynonymous coding SNP in a neighboring gene called spectrin repeat...... through the Ovarian Cancer Association Consortium, with 5,279 invasive epithelial cases and 7,450 controls. The per-T-allele OR for this 12-study set was 1.09 (95% CI, 1.02-1.17; P = 0.017). Results for the serous subtype in the 15 combined studies were similar to those overall (n = 3,545; OR, 1.09; 95......% CI, 1.01-1.18; P = 0.025), and our findings were strongest for the mucinous subtype (n = 447; OR, 1.32; 95% CI, 1.11-1.58; P = 0.002). No association was observed for the endometrioid subtype. In an additional analysis of 1,459 borderline ovarian cancer cases and 7,370 controls, rs2295190...

Germline fumarate hydratase mutations in patients with ovarian mucinous cystadenoma

DEFF Research Database (Denmark)

Ylisaukko-oja, Sanna K.; Cybulski, Cezary; Lehtonen, Rainer

2006-01-01

Germline mutations in the fumarate hydratase (FH) gene were recently shown to predispose to the dominantly inherited syndrome, hereditary leiomyomatosis and renal cell cancer (HLRCC). HLRCC is characterized by benign leiomyomas of the skin and the uterus, renal cell carcinoma, and uterine...... leiomyosarcoma. The aim of this study was to identify new families with FH mutations, and to further examine the tumor spectrum associated with FH mutations. FH germline mutations were screened from 89 patients with RCC, skin leiomyomas or ovarian tumors. Subsequently, 13 ovarian and 48 bladder carcinomas were...

Intestinal Obstruction due to Bilateral Ovarian Cystic Teratoma in a ...

African Journals Online (AJOL)

Teratoma is the most common ovarian tumour associated with pregnancy. The complications in pregnancy include torsion, rupture and malignant transformation mimicking ovarian carcinoma. Its association with intestinal obstruction is uncommon. Case: A 35 year old gravida 5 para 4 woman with 18 week gestation was ...

TLR9 agonists oppositely modulate DNA repair genes in tumor versus immune cells and enhance chemotherapy effects.

Science.gov (United States)

Sommariva, Michele; De Cecco, Loris; De Cesare, Michelandrea; Sfondrini, Lucia; Ménard, Sylvie; Melani, Cecilia; Delia, Domenico; Zaffaroni, Nadia; Pratesi, Graziella; Uva, Valentina; Tagliabue, Elda; Balsari, Andrea

2011-10-15

Synthetic oligodeoxynucleotides expressing CpG motifs (CpG-ODN) are a Toll-like receptor 9 (TLR9) agonist that can enhance the antitumor activity of DNA-damaging chemotherapy and radiation therapy in preclinical mouse models. We hypothesized that the success of these combinations is related to the ability of CpG-ODN to modulate genes involved in DNA repair. We conducted an in silico analysis of genes implicated in DNA repair in data sets obtained from murine colon carcinoma cells in mice injected intratumorally with CpG-ODN and from splenocytes in mice treated intraperitoneally with CpG-ODN. CpG-ODN treatment caused downregulation of DNA repair genes in tumors. Microarray analyses of human IGROV-1 ovarian carcinoma xenografts in mice treated intraperitoneally with CpG-ODN confirmed in silico findings. When combined with the DNA-damaging drug cisplatin, CpG-ODN significantly increased the life span of mice compared with individual treatments. In contrast, CpG-ODN led to an upregulation of genes involved in DNA repair in immune cells. Cisplatin-treated patients with ovarian carcinoma as well as anthracycline-treated patients with breast cancer who are classified as "CpG-like" for the level of expression of CpG-ODN modulated DNA repair genes have a better outcome than patients classified as "CpG-untreated-like," indicating the relevance of these genes in the tumor cell response to DNA-damaging drugs. Taken together, the findings provide evidence that the tumor microenvironment can sensitize cancer cells to DNA-damaging chemotherapy, thereby expanding the benefits of CpG-ODN therapy beyond induction of a strong immune response.

Distinct DNA Methylation Profiles in Ovarian Tumors: Opportunities for Novel Biomarkers

Directory of Open Access Journals (Sweden)

Lorena Losi

2018-05-01

Full Text Available Aberrant methylation of multiple promoter CpG islands could be related to the biology of ovarian tumors and its determination could help to improve treatment strategies. DNA methylation profiling was performed using the Methylation Ligation-dependent Macroarray (MLM, an array-based analysis. Promoter regions of 41 genes were analyzed in 102 ovarian tumors and 17 normal ovarian samples. An average of 29% of hypermethylated promoter genes was observed in normal ovarian tissues. This percentage increased slightly in serous, endometrioid, and mucinous carcinomas (32%, 34%, and 45%, respectively, but decreased in germ cell tumors (20%. Ovarian tumors had methylation profiles that were more heterogeneous than other epithelial cancers. Unsupervised hierarchical clustering identified four groups that are very close to the histological subtypes of ovarian tumors. Aberrant methylation of three genes (BRCA1, MGMT, and MLH1, playing important roles in the different DNA repair mechanisms, were dependent on the tumor subtype and represent powerful biomarkers for precision therapy. Furthermore, a promising relationship between hypermethylation of MGMT, OSMR, ESR1, and FOXL2 and overall survival was observed. Our study of DNA methylation profiling indicates that the different histotypes of ovarian cancer should be treated as separate diseases both clinically and in research for the development of targeted therapies.

Cytotoxic drug sensitivity testing of tumor cells from patients with ovarian carcinoma using the fluorometric microculture cytotoxicity assay (FMCA).

Science.gov (United States)

Csoka, K; Larsson, R; Tholander, B; Gerdin, E; de la Torre, M; Nygren, P

1994-08-01

The automated fluorometric microculture cytotoxicity assay (FMCA) is based on the measurement of fluorescence generated from cellular hydrolysis of fluorescein diacetate (FDA) to fluorescein by viable cells after a 72-hr culture period in microtiter plates. The FMCA was adopted for chemosensitivity testing of tumor cells from patients with ovarian carcinoma. Thirty-seven samples of solid tumors and malignant effusions were obtained from 35 patients at diagnosis or relapse. Tumor cells from solid samples and effusions were prepared by enzymatic digestion and centrifugation, respectively, followed by Percoll or Ficoll purification. The fluorescence was proportional to the number of cells/well and considerably higher in tumor cells than in contaminating normal cells. The effect of up to 19 cytotoxic drugs was successfully assessed in 70% of the samples and there was a good correlation between drug sensitivity data reported by the FMCA and the DiSC assay performed in parallel. The overall drug sensitivity pattern in vitro corresponded well to the clinical experience. The effect of cisplatin varied considerably between patients and resistance was found also in cases not previously exposed to cytotoxic drugs. The FMCA is a rapid and simple method that seems to report clinically relevant cytotoxic drug sensitivity data in ovarian carcinomas. In the future, this method may contribute to optimizing chemotherapy by assisting in individualized drug selection and new drug development.

Glycerol-3-phosphate Acyltransferase 1 Promotes Tumor Cell Migration and Poor Survival in Ovarian Carcinoma.

Science.gov (United States)

Marchan, Rosemarie; Büttner, Bettina; Lambert, Jörg; Edlund, Karolina; Glaeser, Iris; Blaszkewicz, Meinolf; Leonhardt, Gregor; Marienhoff, Lisa; Kaszta, Darius; Anft, Moritz; Watzl, Carsten; Madjar, Katrin; Grinberg, Marianna; Rempel, Eugen; Hergenröder, Roland; Selinski, Silvia; Rahnenführer, Jörg; Lesjak, Michaela S; Stewart, Joanna D; Cadenas, Cristina; Hengstler, Jan G

2017-09-01

Glycerophosphodiesterase EDI3 (GPCPD1; GDE5; GDPD6) has been suggested to promote cell migration, adhesion, and spreading, but its mechanisms of action remain uncertain. In this study, we targeted the glycerol-3-phosphate acyltransferase GPAM along with choline kinase-α (CHKA), the enzymes that catabolize the products of EDI3 to determine which downstream pathway is relevant for migration. Our results clearly showed that GPAM influenced cell migration via the signaling lipid lysophosphatidic acid (LPA), linking it with GPAM to cell migration. Analysis of GPAM expression in different cancer types revealed a significant association between high GPAM expression and reduced overall survival in ovarian cancer. Silencing GPAM in ovarian cancer cells decreased cell migration and reduced the growth of tumor xenografts. In contrast to these observations, manipulating CHKA did not influence cell migration in the same set of cell lines. Overall, our findings show how GPAM influences intracellular LPA levels to promote cell migration and tumor growth. Cancer Res; 77(17); 4589-601. ©2017 AACR . ©2017 American Association for Cancer Research.

A CASE REPORT OF MULTIPLE PRIMARY SQUAMOUS CELL CARCINOMAS OF THE OVARY AND SIGMOID COLON

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A. B. Villert

2016-01-01

Full Text Available Squamous cell ovarian and sigmoid colon carcinomas are extremely rare malignancies. Because of their rarity, it is difficult to investigate the clinical characteristics and prognosis of patients with theses malignancies, and therefore, the increased interest in each clinical case report is highly relevant. Multiple primary squamous cell ovarian and sigmoid colon carcinomas are the subject of discussion and differential diagnosis of sigmoid colon cancer with secondary ovarian cancer. Histopathological and clinical characteristics of the tumors were present and evidences in favor of the multiple primary malignancies were given. The association of squamous cell ovarian and sigmoid colon carcinomas with human papilloma virus type 16 was shown.

Prognostic roles of neutrophil to lymphocyte ratio and platelet to lymphocyte ratio in ovarian cancer: a meta-analysis of retrospective studies.

Science.gov (United States)

Zhao, Zhe; Zhao, Xinrui; Lu, Jingjing; Xue, Jing; Liu, Peishu; Mao, Hongluan

2018-04-01

The systemic inflammatory response markers have been reported to be associated with the prognosis of various cancers. We conducted this meta-analysis of retrospective studies to evaluate and identify the prognostic impact of neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) on ovarian cancer. PubMed, EMBASE, and China National Knowledge Infrastructure databases were included to search for eligible studies. The following terms were used: "neutrophil to lymphocyte ratio", "NLR", "platelet to lymphocyte ratio", "PLR", "ovarian cancer", "ovary cancer", "ovarian carcinoma", "ovary carcinoma", "ovarian neoplasm", "ovary neoplasm", "ovarian tumor", and "ovary tumor". The random-effects model was chosen to estimate the pooled HR with 95% CI. Heterogeneity between studies was assessed by Higgins I 2 value. The stability and heterogeneity of studies were analyzed by sensitivity analysis. Publication bias was examined by Egger's test and Begg's test with the funnel plots. 13 studies consisting of 3467 patients were considered for meta-analysis. We found that the high NLR had a poor prognostic impact on OS and PFS in ovarian cancer, with a pooled HR 1.70, 95% CI 1.35-2.15 and HR 1.77, 95% CI 1.48-2.12, respectively. Similarly, the results showed the high PLR adversely affected OS and PFS in ovarian cancer, with a pooled HR 2.05, 95% CI 1.70-2.48 and HR 1.85, 95% CI 1.53-2.25, respectively. In conclusion, we found that both NLR and PLR had an unfavorable impact on PFS and OS of patients with ovarian cancer. Our meta-analysis supported that NLR/PLR could be effective prognostic predictors of ovarian cancer.

Termination of Pregnancy in a Patient with Advanced Ovarian Cancer

OpenAIRE

Suna Özdemir; Çetin Çelik; Kazım Gezginç; Hasan Esen

2010-01-01

Ovarian cancer during pregnancy is a rare entity and the management of the disease can be challenging for the patient and the clinician. In this case, we report a case of advanced ovarian carcinoma diagnosed during pregnancy, which was managed with termination of pregnancy and chemotheraphy. The patient was underwent exploratory laparatomy including the right ovarian cystectomy, omentectomy, appendectomy, pelvic and para-aortic lymphadenectomy after frozen section of borderline serous cystade...

Microenvironmental Regulation of Chemokine (C-X-C-motif) Receptor 4 in Ovarian Carcinoma

Science.gov (United States)

Barbolina, Maria V.; Kim, Mijung; Liu, Yueying; Shepard, Jaclyn; Belmadani, Abdelhak; Miller, Richard J.; Shea, Lonnie D.; Stack, M. Sharon

2010-01-01

The majority of women diagnosed with epithelial ovarian carcinoma (EOC) succumb due to complications of metastatic disease, suggesting that anti-metastatic therapies may improve patient survival. EOC metastasis involves intra-peritoneal shedding of cells from the primary tumor, followed by adhesion and localized penetration of the submesothelial matrix to anchor metastatic implants. Accumulation of malignant ascites is also common. Thus, a unique microenvironmental niche is established, which includes malignant cells and a plethora of soluble factors secreted by – or in response to – tumor cells. As cells penetrating the sub-mesothelial surface encounter an interstitial collagen-rich ECM, we have used 3-dimensional type I collagen (3DCI) gels to model early events resulting from intra-peritoneal anchoring. In this study we demonstrate a novel pathway of CXCR4 upregulation through β1-integrin- and NFκB- dependent signaling pathways in response to 3DCI. We also demonstrate the involvement of CXCR4-SDF1 axis in collagen invasion and proliferation, relevant to the metastatic EOC. Our data show that CXCR4 expression in human EOCs, as well as SDF1 presence in the ascites, is correlated with disease progression and metastasis. These data emphasize the importance of CXCR4 – SDF1 axis in EOC metastasis and suggest that this mechanism should be accounted for when targeting EOC metastasis. PMID:20460402

Endometriosis-Associated Ovarian Cancer: A Review of Pathogenesis

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Shu-Wing Ng

2013-03-01

Full Text Available Endometriosis is classically defined as the presence of endometrial glands and stroma outside of the endometrial lining and uterine musculature. With an estimated frequency of 5%–10% among women of reproductive age, endometriosis is a common gynecologic disorder. While in itself a benign lesion, endometriosis shares several characteristics with invasive cancer, has been shown to undergo malignant transformation, and has been associated with an increased risk of epithelial ovarian carcinoma (EOC. Numerous epidemiologic studies have shown an increased risk of EOC among women with endometriosis. This is particularly true for women with endometrioid and clear cell ovarian carcinoma. However, the carcinogenic pathways by which endometriosis associated ovarian carcinoma (EAOC develops remain poorly understood. Current molecular studies have sought to link endometriosis with EAOC through pathways related to oxidative stress, inflammation and hyperestrogenism. In addition, numerous studies have sought to identify an intermediary lesion between endometriosis and EAOC that may allow for the identification of endometriosis at greatest risk for malignant transformation or for the prevention of malignant transformation of this common gynecologic disorder. The objective of the current article is to review the current data regarding the molecular events associated with EAOC development from endometriosis, with a primary focus on malignancies of the endometrioid and clear cell histologic sub-types.

Serous tubal intraepithelial carcinoma, chronic fallopian tube injury, and serous carcinoma development.

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Malmberg, Karin; Klynning, Charlotta; Flöter-Rådestad, Angelique; Carlson, Joseph W

2016-06-01

Ovarian carcinoma is the deadliest gynecological malignancy. Previous studies have suggested that the fallopian tube may be the primary site for high-grade serous carcinoma. In prophylactic salpingo-oophorectomies from women with hereditary high risk for ovarian cancer, precursors can be assessed prior to onset and studied as a model for serous cancer precursor lesions. Epidemiologic studies indicate that carcinogenesis may be a result of chronic fallopian tube injury. The aims of this study were to (1) to examine the incidence of serous tubal intraepithelial carcinoma (STIC) in relation to other clinical parameters and (2) to evaluate whether chronic fallopian tube injury was related to cancer development. This study enrolled 101 women, comprising the following three groups: hereditary (n = 60), sporadic serous cancer (n = 18; endometrial cancers were excluded), and control (n = 23). The cases were histologically examined and clinical risk factors were collected. The histological changes were compared between different patients and correlated to clinical risk factors. STICs were identified primarily on the fallopian tube fimbria. The incidence of STIC was 3 % in the hereditary patients. In sporadic serous cancer cases, 61 % were associated with STIC and tubal carcinoma (p STIC and invasive cancer were seen more often in the older patients than in the younger patients (p = 0.528). This small study, no correlation with chronic tubal injury or inflammation was identified.

Magnetic Resonance Imaging Characteristics of Ovarian Clear Cell Carcinoma.

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Wei Wang

Full Text Available To probe the magnetic resonance imaging (MRI features of ovarian clear cell carcinoma (OCCC.This study retrospectively collected MRI data for 21 pathology-confirmed OCCCs from 19 female patients. The MRI findings were analyzed to determine the tumor size, shape/edge, shape and number of protrusions within the cyst, cystic or necrotic components, signal intensity (SI and enhancement features.The age of the 19 patients ranged from 28 to 63 years (mean age: 53 years. Unilateral tumors were found in 17 patients (17/19, 89%; the average size of all tumors was 10.8 cm. The tumors on MRI were classified into two categories: (a "cystic adnexal mass with solid protrusions" in 12 (57% and (b "solid adnexal mass with cystic areas or necrosis" in 9 (43%. For group a, high to very high SI was observed for most tumors (10/12, 83% on T1-weighted images (T1WIs, and very high SI was observed on T2-weighted images (T2WIs for all 12 tumors. Most solid protrusions were irregular and few in number and exhibited heterogeneous intermediate SI on T1WIs and T2WIs and prolonged enhanced SI in the contrast study. All 9 OCCCs in group b were predominantly solid masses with unequally sized necrotic or cystic areas in which some cysts were located at the periphery of the tumor (4/9, 44%. The solid components in all 9 tumors showed iso- or slightly high SI on T1WIs, heterogeneous iso-high SI on T2WIs and heterogeneous prolonged enhancement. According to FIGO classification, 14 tumors (14/19, 74% were stages I-II, and 5 (5/19, 26% were stages III-IV.On MRI, OCCCs present as large unilateral multilocular or unilocular cystic masses with irregular intermediate SI solid protrusions or predominantly solid masses with cysts or necrosis at an early FIGO stage.

Vaccine Therapy With or Without Sirolimus in Treating Patients With NY-ESO-1 Expressing Solid Tumors

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2016-10-03

Anaplastic Astrocytoma; Anaplastic Oligoastrocytoma; Anaplastic Oligodendroglioma; Estrogen Receptor Negative; Estrogen Receptor Positive; Glioblastoma; Hormone-Resistant Prostate Cancer; Metastatic Prostate Carcinoma; Metastatic Renal Cell Cancer; Recurrent Adult Brain Neoplasm; Recurrent Bladder Carcinoma; Recurrent Breast Carcinoma; Recurrent Colorectal Carcinoma; Recurrent Esophageal Carcinoma; Recurrent Gastric Carcinoma; Recurrent Hepatocellular Carcinoma; Recurrent Lung Carcinoma; Recurrent Melanoma; Recurrent Ovarian Carcinoma; Recurrent Prostate Carcinoma; Recurrent Renal Cell Carcinoma; Recurrent Uterine Corpus Carcinoma; Resectable Hepatocellular Carcinoma; Sarcoma; Stage IA Breast Cancer; Stage IA Ovarian Cancer; Stage IA Uterine Corpus Cancer; Stage IB Breast Cancer; Stage IB Ovarian Cancer; Stage IB Uterine Corpus Cancer; Stage IC Ovarian Cancer; Stage II Uterine Corpus Cancer; Stage IIA Breast Cancer; Stage IIA Lung Carcinoma; Stage IIA Ovarian Cancer; Stage IIB Breast Cancer; Stage IIB Esophageal Cancer; Stage IIB Lung Carcinoma; Stage IIB Ovarian Cancer; Stage IIB Skin Melanoma; Stage IIC Ovarian Cancer; Stage IIC Skin Melanoma; Stage IIIA Breast Cancer; Stage IIIA Esophageal Cancer; Stage IIIA Lung Carcinoma; Stage IIIA Ovarian Cancer; Stage IIIA Skin Melanoma; Stage IIIA Uterine Corpus Cancer; Stage IIIB Breast Cancer; Stage IIIB Esophageal Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Skin Melanoma; Stage IIIB Uterine Corpus Cancer; Stage IIIC Breast Cancer; Stage IIIC Esophageal Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Skin Melanoma; Stage IIIC Uterine Corpus Cancer; Stage IV Bladder Urothelial Carcinoma; Stage IV Esophageal Cancer; Stage IV Ovarian Cancer; Stage IV Prostate Cancer; Stage IV Skin Melanoma; Stage IVA Uterine Corpus Cancer; Stage IVB Uterine Corpus Cancer

Bilateral primary fallopian tube papillary serous carcinoma in postmenopausal woman: Report of two cases

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Dipanwita Nag

2016-01-01

Full Text Available Primary carcinoma of the fallopian tube is rare and accounts for about 0.14-1.8% of all gynecological malignancies. Correct diagnosis is rarely made preoperatively as clinically tubal carcinoma closely resembles ovarian carcinoma. Here, we report two cases of bilateral primary fallopian tube carcinomas. Case 1: A 54-year-old female presented with postmenopausal bleeding, abdominal pain, and pervaginal watery discharge for 10 days. Ultrasonography (USG of pelvis showed endometrial thickening and multiple tiny echogenic foci in omentum suggestive of omental cake. With a provisional diagnosis of endometrial carcinoma, total abdominal hysterectomy with bilateral salpingo-oophorectomy and omentectomy was done. On gross examination, small and rudimentary right ovary was adherent to the fimbrial end of the tube. Left-sided tubo-ovarian mass was present, cut section of which showed yellowish solid area in tubal wall and encroaching on ovarian surface. On histological examination, sections from the fimbrial end of both fallopian tubes showed features of papillary serous adenocarcinoma. Case 2: 70-year-old lady, 15 years postmenopausal presented with gradual onset pain and swelling of abdomen, urinary incontinence since 4 days. USG showed bulky uterus, 5 cm × 2 cm fibroid, bilateral tubes, and ovaries were not visualized. Serum cancer antigen-125 was raised (159.7 U/ml. Total hysterectomy and bilateral salpingo-oophorectomy with infracolic omentectomy was done. On gross examination, ovaries were firmly attached to tubes and no apparent solid area was noted. On microscopy, papillary serous adenocarcinoma arising from tubal wall was seen infiltrating focally into ovarian stroma; tubal epithelium showed dysplastic change. Sections from omentum showed numerous psammoma bodies.

Risk factors of epithelial ovarian carcinomas among women with endometriosis

DEFF Research Database (Denmark)

Thomsen, Line H.; Schnack, Tine H.; Buchardi, Kristina

2017-01-01

INTRODUCTION: To evaluate the published literature on epidemiologic risk factors for epithelial ovarian cancer among women with a diagnosis of endometriosis. MATERIAL AND METHODS: A systematic literature search was conducted in PubMed and Scopus. Studies comparing epidemiologic risk factors...... an elevated risk of epithelial ovarian cancer. However, due to the limited number and size of studies in this area we cannot draw definitive conclusions. Further research into a risk factor profile among women with endometriosis is needed before clear recommendations can be made....... of epithelial ovarian cancer among women with endometriosis were included. A quality assessment was conducted using the Newcastle-Ottawa Scale. RESULTS: Eight of 794 articles met the inclusion criteria. A lower risk of epithelial ovarian cancer was observed in women with documented complete surgical excision...

Pathogenesis of Ovarian Serous Carcinoma as the Basis for Immunologic Directed Diagnosis and Treatment

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2004-08-01

Co[ýVr/ lgbt t A eic , n Sc t 1t’.jar lni ttItrtii, I’alogy Review Ovarian Tumorigenesis A Proposed Model Based on Morphological and Molecular...surface epithelium. We tested muliplex detection of antibodies to candidate ovarian TAAs and statistical modeling for discrimination of sera of ovarian...cancer patients and controls. The best model generated an AUC of 0.86 (0.78-0.90) for discrimination of sera of EOC patients and healthy patients using

Sphingosine kinase 1/sphingosine-1-phosphate (S1P)/S1P receptor axis is involved in ovarian cancer angiogenesis.

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Dai, Lan; Liu, Yixuan; Xie, Lei; Wu, Xia; Qiu, Lihua; Di, Wen

2017-09-26

Sphingosine kinase (SphK)/sphingosine-1-phosphate (S1P)/S1P receptor (S1PR) signaling pathway has been implicated in a variety of pathological processes of ovarian cancer. However, the function of this axis in ovarian cancer angiogenesis remains incompletely defined. Here we provided the first evidence that SphK1/S1P/S1PR 1/3 pathway played key roles in ovarian cancer angiogenesis. The expression level of SphK1, but not SphK2, was closely correlated with the microvascular density (MVD) of ovarian cancer tissue. In vitro , the angiogenic potential and angiogenic factor secretion of ovarian cancer cells could be attenuated by SphK1, but not SphK2, blockage and were restored by the addition of S1P. Moreover, in these cells, we found S1P stimulation induced the angiogenic factor secretion via S1PR 1 and S1PR 3 , but not S1PR 2 . Furthermore, inhibition of S1PR 1/3 , but not S1PR 2 , attenuated the angiogenic potential and angiogenic factor secretion of the cells. in vivo , blockage of SphK or S1PR 1/3 could attenuate ovarian cancer angiogenesis and inhibit angiogenic factor expression in mouse models. Collectively, the current study showed a novel role of SphK1/S1P/S1PR 1/3 axis within the ovarian cancer, suggesting a new target to block ovarian cancer angiogenesis.

ULTRASOUND CRITERIA OF EARLY DIAGNOSTICS OF OVARIAN CARCINOMA

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L. A. Ashrafyan

2015-01-01

Full Text Available Introduction. Ovarian cancer (OC in Russia is ranked the seventh within the structure of general cancer diseases and the third within the gynecological tumors, due to such reasons the problem of early diagnostics is still actual. New technologies, such as color Doppler ultrasonography,3D power Doppler ultrasonography contribute to increasing of opportunities of ultrasound analysis to detect any malignancy signs.Materials and methods. The paper sets out the results of comprehensive ultrasound study of 68 patients with morphologically verified OC at stages IА–В, IIА–В. The control group was made of 100 female patients with morphologically verified ovarian tumors (serosal cystadenomas, thecomas, fibromas. A complex of the following ultrasound methods was used during the study: 2D and 3D ultrasonography in B mode, in color Doppler and power mapping mode, 3D angiography, spectrum Doppler imaging.Results. Maximum size of tumor varied within a range between 37 and 300 mm (108 ± 61.2 mm. It worth noting that no direct dependence between the size of neoplasm and process phase was established. When assessing the echostructure, all ovarian tumors were divided into 3 structure types: cystic type (57.8 % of cases, cystic and solid type (33.3 % of cases, solid type (8.9 % of cases. The conducted analysis of types of small pelvis neoplasm echostructures enabled to evolve the sonographic types of ovarian tumors, more or less associated with the malignant transformation. The most relevanl Doppler ultrasonography exponents characteristic for benignant and malignant processes: resistance index in benignant tumors was 0.56, at OC – 0.32 (р < 0.001; average arterial blood velocity in benignant tumors – 7.8 cm/s, at OC – 20.1 cm/s (р < 0.001; average maximum venous flow velocity in benignant tumors – 3.2 cm/s, at OC – 9.3 cm/s (р < 0.001.Conclusion. Therefore modern ultrasonography can detect and differentiate rather efficiently the localized

Whole abdominal irradiation in ovarian carcinoma

International Nuclear Information System (INIS)

Romestaing, P.; Gallo, C.; Gerard, J.F.; Ardiet, J.M.; Carrie, C.

1989-01-01

The prognosis of ovarian cancers, which are frequently diagnosed at a late stage, can probably be improved by whole abdominal radiotherapy. 45 patients in Lyon and 8 patients in Montelimar (7 stage I or C, 10 stage II and 36 stage III) were treated by whole abdominal radiotherapy, generally after 6 courses of chemotherapy (46 cases). The overall 5-year survival of this group of patients was 48% (Kaplan-Meier method). When the patients treated by complete resection at 1st look surgery (19 cases) are compared with those in whom 1st look surgery was incomplete (34 cases), the actuarial survival was 83% versus 27%. This study demonstrates that whole abdominal radiotherapy is feasible without any serious long-term complications after two operations and 6 courses of chemotherapy. These encouraging results need to be confirmed by randomized prospective studies [fr

The O-Linked Glycome and Blood Group Antigens ABO on Mucin-Type Glycoproteins in Mucinous and Serous Epithelial Ovarian Tumors.

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Varvara Vitiazeva

Full Text Available Mucins are heavily O-glycosylated proteins where the glycosylation has been shown to play an important role in cancer. Normal epithelial ovarian cells do not express secreted mucins, but their abnormal expression has previously been described in epithelial ovarian cancer and may relate to tumor formation and progression. The cyst fluids were shown to be a rich source for acidic glycoproteins. The study of these proteins can potentially lead to the identification of more effective biomarkers for ovarian cancer.In this study, we analyzed the expression of the MUC5AC and the O-glycosylation of acidic glycoproteins secreted into ovarian cyst fluids. The samples were obtained from patients with serous and mucinous ovarian tumors of different stages (benign, borderline, malignant and grades. The O-linked oligosaccharides were released and analyzed by negative-ion graphitized carbon Liquid Chromatography (LC coupled to Electrospray Ionization tandem Mass Spectrometry (ESI-MSn. The LC-ESI-MSn of the oligosaccharides from ovarian cyst fluids displayed differences in expression of fucose containing structures such as blood group ABO antigens and Lewis-type epitopes.The obtained data showed that serous and mucinous benign adenomas, mucinous low malignant potential carcinomas (LMPs, borderline and mucinous low-grade carcinomas have a high level of blood groups and Lewis type epitopes. In contrast, this type of fucosylated structures were low abundant in the high-grade mucinous carcinomas or in serous carcinomas. In addition, the ovarian tumors that showed a high level of expression of blood group antigens also revealed a strong reactivity towards the MUC5AC antibody. To visualize the differences between serous and mucinous ovarian tumors based on the O-glycosylation, a hierarchical cluster analysis was performed using mass spectrometry average compositions (MSAC.Mucinous benign and LMPs along with mucinous low-grade carcinomas appear to be different from

Preclinical therapeutic potential of a nitrosylating agent in the treatment of ovarian cancer.

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Shailendra Giri

Full Text Available This study examines the role of s-nitrosylation in the growth of ovarian cancer using cell culture based and in vivo approaches. Using the nitrosylating agent, S-nitrosoglutathione (GSNO, a physiological nitric oxide molecule, we show that GSNO treatment inhibited proliferation of chemoresponsive and chemoresistant ovarian cancer cell lines (A2780, C200, SKVO3, ID8, OVCAR3, OVCAR4, OVCAR5, OVCAR7, OVCAR8, OVCAR10, PE01 and PE04 in a dose dependent manner. GSNO treatment abrogated growth factor (HB-EGF induced signal transduction including phosphorylation of Akt, p42/44 and STAT3, which are known to play critical roles in ovarian cancer growth and progression. To examine the therapeutic potential of GSNO in vivo, nude mice bearing intra-peritoneal xenografts of human A2780 ovarian carcinoma cell line (2 × 10(6 were orally administered GSNO at the dose of 1 mg/kg body weight. Daily oral administration of GSNO significantly attenuated tumor mass (p<0.001 in the peritoneal cavity compared to vehicle (phosphate buffered saline treated group at 4 weeks. GSNO also potentiated cisplatin mediated tumor toxicity in an A2780 ovarian carcinoma nude mouse model. GSNO's nitrosylating ability was reflected in the induced nitrosylation of various known proteins including NFκB p65, Akt and EGFR. As a novel finding, we observed that GSNO also induced nitrosylation with inverse relationship at tyrosine 705 phosphorylation of STAT3, an established player in chemoresistance and cell proliferation in ovarian cancer and in cancer in general. Overall, our study underlines the significance of S-nitrosylation of key cancer promoting proteins in modulating ovarian cancer and proposes the therapeutic potential of nitrosylating agents (like GSNO for the treatment of ovarian cancer alone or in combination with chemotherapeutic drugs.

Female genital tract tuberculosis presenting as ovarian cancer

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Malihe Hasanzadeh

2014-01-01

Full Text Available Background: Tuberculosis (TB is still a major worldwide concern. There is no pathognomonic clinical feature or imaging findings for definite diagnosis of extra pulmonary TB. Therefore, TB involvement of Gastrointestinal or Genitourinary tract can be easily confused with peritoneal carcinomatosis and advanced ovarian carcinoma. Our aim is to emphasize the importance of considering the disease based upon the epidemiologic clues of the patients, while interpreting the positive results for a suspicious ovarian malignancy. Cases: This paper illustrates 8 cases of ovarian or peritoneal tuberculosis, whose initial diagnoses were malignant processes of the GU tract. Conclusion: Tuberculosis ( TB should be always being considered in the differential diagnosis of advanced ovarian cancer, especially in the regions that are endemic for the disease.

Prevention of Ovarian High-Grade Serous Carcinoma by Elucidating Its Early Changes

Science.gov (United States)

2014-10-01

serous ovarian cancer carcinogenesis. Sophia HL George, Ramlogan Sowamber, Anca Milea, Noor Salman and Patricia Shaw. September 2014. Masha Rivkin Ovarian...in mesenchymal-to-epithelial transition during high-grade serous carcinogenesis. Masha Rivkin Ovarian Cancer Symposium September 2014, Seattle WA

Incidental serous tubal intraepithelial carcinoma and early invasive serous carcinoma in the nonprophylactic setting: analysis of a case series.

Science.gov (United States)

Morrison, Jane C; Blanco, Luis Z; Vang, Russell; Ronnett, Brigitte M

2015-04-01

A precursor for invasive ovarian/pelvic high-grade serous carcinoma, termed serous tubal intraepithelial carcinoma (STIC), has been identified and characterized through careful analysis of the fallopian tubes in both prophylactic salpingo-oophorectomy specimens obtained from women with either a family history of breast and/or ovarian cancer or germline mutations of BRCA1 and BRCA2 and in cases of pelvic high-grade serous carcinoma. Data on incidental STICs and clinically occult microscopic invasive high-grade serous carcinomas are limited. We analyzed the clinicopathologic features of 22 cases, including 15 pure STICs and 7 STICs associated with microscopic invasive high-grade serous carcinomas, identified incidentally in fallopian tubes removed for nonprophylactic indications. Patient age ranged from 39 to 79 years (mean: 62.7; median: 61), with only 1 patient under the age of 50. No patients were known to carry BRCA1 or BRCA2 mutations. Of the 12 pure STICs for which the location in the fallopian tube could be established, 9 were in the fimbriated portion, 1 was at the junction of the fimbria and infundibulum, and 2 were in the nonfimbriated tube. Of the 7 STICs with associated invasive high-grade serous carcinoma, 3 were located in the fimbriated portion, 2 were at the junction of the fimbria and infundibulum, and 2 were in the nonfimbriated tube. The invasive components were in the fallopian tube in 6 cases, 4 in subepithelial stroma of tubal mucosa, and 2 as an intramucosal (exophytic) luminal lesion without invasion of underlying subepithelial stroma (size range: 1 to 4 mm). The remaining case had a microscopic focus of high-grade serous carcinoma within the ipsilateral ovary (1.3 mm cortical focus) identified only on deeper sections, without an associated invasive component in the fallopian tube. The preferential finding of atypical epithelium with the cytologic features of high-grade serous carcinoma, namely STIC, in the fallopian tubes rather than the

Modulators of Response to Tumor Necrosis-related Apoptosis Inducing Ligand (TRAIL) Therapy in Ovarian Cancer

Science.gov (United States)

2011-05-01

several human cancers including breast, ovarian, uterine cervical , rhabdomyosarcoma, and hepatocellular carcinoma(9, 18-21). When Six1 is expressed...during HPV-mediated carcinogenesis: a comparison between an in vitro cell model and cervical cancer. Int J Cancer 2008; 123:32-40. 22. Reichenberger KJ...to have recurrent carcinoma in the hernia sac during hernia repair. Of the 9 patients who were first diagnosed with recurrence based on positive

Genomic landscape of ovarian clear cell carcinoma via whole exome sequencing.

Science.gov (United States)

Kim, Se Ik; Lee, Ji Won; Lee, Maria; Kim, Hee Seung; Chung, Hyun Hoon; Kim, Jae-Weon; Park, Noh Hyun; Song, Yong-Sang; Seo, Jeong-Sun

2018-02-01

To analyze whole exome sequencing (WES) data on ovarian clear cell carcinoma (OCCC) in Korean patients via the technique of next generation sequencing (NGS). Genomic profiles were compared between endometriosis-associated OCCC (EMS-OCCC) and Non-EMS-OCCC. We used serum samples and cancer tissues, stored at the Seoul National University Hospital Human Biobank, that were initially collected from women diagnosed with OCCC between 2012 and 2016. In total, 15 patients were enrolled: 5 with pathologically confirmed EMS-OCCC and 10 with Non-EMS-OCCC. We performed NGS WES on 15 fresh frozen OCCC tissues and matched serum samples, enabling comprehensive genomic characterization of OCCC. OCCC was characterized by complex genomic alterations, with a median of 178 exonic mutations (range, 111-25,798) and a median of 343 somatic copy number variations (range, 43-1,820) per tumor sample. In all, 54 somatic mutations were discovered across 14 genes, including PIK3CA (40%), ARID1A (40%), and KRAS (20%) in the 15 Korean OCCCs. Copy number gains in NTRK1 (33%), MYC (40%), and GNAS (47%) and copy number losses in TET2 (73%), TSC1 (67%), BRCA2 (60%), and SMAD4 (47%) were frequent. The significantly altered pathways were associated with proliferation and survival (including the PI3K/AKT, TP53, and ERBB2 pathways) in 87% of OCCCs and with chromatin remodeling in 47% of OCCCs. No significant differences in frequencies of genetic alterations were detected between EMS-OCCC and Non-EMS-OCCC groups. We successfully characterized the genomic landscape of 15 Korean patients with OCCC. We identified potential therapeutic targets for the treatment of this malignancy. Copyright © 2017. Published by Elsevier Inc.

Metabolites from invasive pests inhibit mitochondrial complex II: A potential strategy for the treatment of human ovarian carcinoma?

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Ferramosca, Alessandra, E-mail: alessandra.ferramosca@unisalento.it [Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento, Lecce (Italy); Conte, Annalea; Guerra, Flora; Felline, Serena [Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento, Lecce (Italy); Rimoli, Maria Grazia [Dipartimento di Farmacia, Università di Napoli Federico II, Napoli (Italy); Mollo, Ernesto [Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Pozzuoli (Italy); Zara, Vincenzo [Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento, Lecce (Italy); Terlizzi, Antonio [Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento, Lecce (Italy); Stazione Zoologica Anton Dohrn, Napoli (Italy)

2016-05-13

The red pigment caulerpin, a secondary metabolite from the marine invasive green algae Caulerpa cylindracea can be accumulated and transferred along the trophic chain, with detrimental consequences on biodiversity and ecosystem functioning. Despite increasing research efforts to understand how caulerpin modifies fish physiology, little is known on the effects of algal metabolites on mammalian cells. Here we report for the first time the mitochondrial targeting activity of both caulerpin, and its closely related derivative caulerpinic acid, by using as experimental model rat liver mitochondria, a system in which bioenergetics mechanisms are not altered. Mitochondrial function was tested by polarographic and spectrophotometric methods. Both compounds were found to selectively inhibit respiratory complex II activity, while complexes I, III, and IV remained functional. These results led us to hypothesize that both algal metabolites could be used as antitumor agents in cell lines with defects in mitochondrial complex I. Ovarian cancer cisplatin-resistant cells are a good example of cell lines with a defective complex I function on which these molecules seem to have a toxic effect on proliferation. This provided novel insight toward the potential use of metabolites from invasive Caulerpa species for the treatment of human ovarian carcinoma cisplatin-resistant cells. -- Highlights: •Novel insight toward the potential use of the algal metabolites for the treatment of human diseases. •Caulerpin and caulerpinic acid inhibit respiratory complex II activity. •Both algal metabolites could be used as antitumor agents in ovarian cancer cisplatin-resistant cells.

Metabolites from invasive pests inhibit mitochondrial complex II: A potential strategy for the treatment of human ovarian carcinoma?

International Nuclear Information System (INIS)

Ferramosca, Alessandra; Conte, Annalea; Guerra, Flora; Felline, Serena; Rimoli, Maria Grazia; Mollo, Ernesto; Zara, Vincenzo; Terlizzi, Antonio

2016-01-01

The red pigment caulerpin, a secondary metabolite from the marine invasive green algae Caulerpa cylindracea can be accumulated and transferred along the trophic chain, with detrimental consequences on biodiversity and ecosystem functioning. Despite increasing research efforts to understand how caulerpin modifies fish physiology, little is known on the effects of algal metabolites on mammalian cells. Here we report for the first time the mitochondrial targeting activity of both caulerpin, and its closely related derivative caulerpinic acid, by using as experimental model rat liver mitochondria, a system in which bioenergetics mechanisms are not altered. Mitochondrial function was tested by polarographic and spectrophotometric methods. Both compounds were found to selectively inhibit respiratory complex II activity, while complexes I, III, and IV remained functional. These results led us to hypothesize that both algal metabolites could be used as antitumor agents in cell lines with defects in mitochondrial complex I. Ovarian cancer cisplatin-resistant cells are a good example of cell lines with a defective complex I function on which these molecules seem to have a toxic effect on proliferation. This provided novel insight toward the potential use of metabolites from invasive Caulerpa species for the treatment of human ovarian carcinoma cisplatin-resistant cells. -- Highlights: •Novel insight toward the potential use of the algal metabolites for the treatment of human diseases. •Caulerpin and caulerpinic acid inhibit respiratory complex II activity. •Both algal metabolites could be used as antitumor agents in ovarian cancer cisplatin-resistant cells.

Transcription factors and molecular epigenetic marks underlying EpCAM overexpression in ovarian cancer

NARCIS (Netherlands)

van der Gun, B. T. F.; de Groote, M. L.; Kazemier, H. G.; Arendzen, A. J.; Terpstra, P.; Ruiters, M. H. J.; McLaughlin, P. M. J.; Rots, M. G.

2011-01-01

BACKGROUND: The epithelial cell adhesion molecule (EpCAM) is overexpressed on carcinomas, and its downregulation inhibits the oncogenic potential of multiple tumour types. Here, we investigated underlying mechanisms of epcam overexpression in ovarian carcinoma. METHODS: Expression of EpCAM and DNA

Excluding Lynch syndrome in a female patient with metachronous DNA mismatch repair deficient colon- and ovarian cancer

OpenAIRE

Crobach, Stijn; Jansen, A.M.L. (Anne M. L.); Ligtenberg, M.J.L. (Marjolein J. L.); Koopmans, M. (Marije); Nielsen, Maartje; Hes, Frederik; Wijnen, Juul; Dinjens, Winand; Wezel, Tom; Morreau, Hans

2017-01-01

textabstractPatients synchronously or metachronously presenting with ovarian and colon cancer can pose diagnostic challenges. A primary colon carcinoma can metastasize to one or both ovaries, two independent primary tumors can arise or an ovarian carcinoma can metastasize to the colon. Clinical and immunohistochemical characterization can aid the diagnosis. Recently, we reported that in difficult cases finding pathogenic APC variants supports a colonic origin. In this case report we describe ...

Involvement of Chromatin Remodeling Genes and the Rho GTPases RhoB and CDC42 in Ovarian Clear Cell Carcinoma

Directory of Open Access Journals (Sweden)

Nicolai Skovbjerg Arildsen

2017-05-01

Full Text Available ObjectiveOvarian clear cell carcinomas (OCCCs constitute a rare ovarian cancer subtype with distinct clinical features, but may nonetheless be difficult to distinguish morphologically from other subtypes. There is limited knowledge of genetic events driving OCCC tumorigenesis beyond ARID1A, which is reportedly mutated in 30–50% of OCCCs. We aimed to further characterize OCCCs by combined global transcriptional profiling and targeted deep sequencing of a panel of well-established cancer genes. Increased knowledge of OCCC-specific genetic aberrations may help in guiding development of targeted treatments and ultimately improve patient outcome.MethodsGene expression profiling of formalin-fixed, paraffin-embedded (FFPE tissue from a cohort of the major ovarian cancer subtypes (cohort 1; n = 67 was performed using whole-genome cDNA-mediated Annealing, Selection, extension and Ligation (WG-DASL bead arrays, followed by pathway, gene module score, and gene ontology analyses, respectively. A second FFPE cohort of 10 primary OCCCs was analyzed by targeted DNA sequencing of a panel of 60 cancer-related genes (cohort 2. Non-synonymous and non-sense variants affecting single-nucleotide variations and insertions or deletions were further analyzed. A tissue microarray of 43 OCCCs (cohort 3 was used for validation by immunohistochemistry and chromogenic in situ hybridization.ResultsGene expression analyses revealed a distinct OCCC profile compared to other histological subtypes, with, e.g., ERBB2, TFAP2A, and genes related to cytoskeletal actin regulation being overexpressed in OCCC. ERBB2 was, however, not overexpressed on the protein level and ERBB2 amplification was rare in the validation cohort. Targeted deep sequencing revealed non-synonymous variants or insertions/deletions in 11/60 cancer-related genes. Genes involved in chromatin remodeling, including ARID1A, SPOP, and KMT2D were frequently mutated across OCCC tumors.ConclusionOCCCs appear

Comparison of glycoprotein expression between ovarian and colon adenocarcinomas

DEFF Research Database (Denmark)

Multhaupt, H A; Arenas-Elliott, C P; Warhol, M J

1999-01-01

, carcinoembryonic antigen, and cytokeratins 7 and 20 to detect tumor-associated glycoproteins and keratin proteins in ovarian and colonic carcinomas. RESULTS: CA125, carcinoembryonic antigen, and cytokeratins 7 and 20 can distinguish between colonic and serous or endometrioid adenocarcinomas of the ovary in both...... primary and metastatic lesions. Mucinous ovarian adenocarcinomas differed in that they express carcinoembryonic antigen and cytokeratins 7 and 20 and weakly express CA125. The other glycoprotein antigens were equally expressed by ovarian and colonic adenocarcinomas and therefore were of no use...... in distinguishing between these 2 entities. CONCLUSION: A panel of monoclonal antibodies against cytokeratins 7 and 20 antigens, CA125, and carcinoembryonic antigen is useful in differentiating serous and endometrioid adenocarcinomas of the ovary from colonic adenocarcinomas. Mucinous ovarian adenocarcinomas cannot...

Expression and clinical implication of Beclin1, HMGB1, p62, survivin, BRCA1 and ERCC1 in epithelial ovarian tumor tissues.

Science.gov (United States)

Ju, L-L; Zhao, C Y; Ye, K-F; Yang, H; Zhang, J

2016-05-01

The aim of the present study is to investigate the differential expression of Beclin1, HMGB1, p62, survivin, ERCC1 and BRCA1 protein in epithelial ovarian cancer (EOC) and to evaluate the relationship between autophagy and platinum resistance of EOC patients during platinum-based chemotherapy with the protein expression. Expression of Beclin1, HMGB1, p62, survivin, ERCC1 and BRCA1 were detected with immunohistochemistry in 60 patients, including 39 with epithelial ovarian cancer (EOC), 13 benign epithelial ovarian tumor tissue (BET) and 8 borderline ovarian tumor tissue. Beclin, p62 and ERCC1 expression was significantly higher in the EOC than the BET (p0.05). BRCA1 expression was lower in EOC than BET (pepithelial ovarian cancer.

[Methylation of selected tumor-supressor genes in benign and malignant ovarian tumors].

Science.gov (United States)

Cul'bová, M; Lasabová, Z; Stanclová, A; Tilandyová, P; Zúbor, P; Fiolka, R; Danko, J; Visnovský, J

2011-09-01

To evaluate the usefullness of examination of methylation status of selected tumor-supressor genes in early diagnosis of ovarian cancer. Prospective clinical study. Department of Gynecology and Obstetrics, Department of Molecular Biology, Jessenius Medical Faculty, Commenius University, Martin, Slovak Republic. In this study we analyzed hypermethylation of 5 genes RASSF1A, GSTP, E-cadherin, p16 and APC in ovarian tumor samples from 34 patients - 13 patients with epithelial ovarian cancer, 2 patients with border-line ovarian tumors, 12 patients with benign lesions of ovaries and 7 patients with healthy ovarian tissue. The methylation status of promoter region of tumor-supressor genes was determined by Methylation Specific Polymerase Chain Reaction (MSP) using a nested two-step approach with bisulfite modified DNA template and specific primers. Gene methylation analysis revealed hypermethylation of gene RASSF1A (46%) and GSTP (8%) only in malignant ovarian tissue samples. Ecad, p16 and APC genes were methylated both in maignant and benign tissue samples. Methylation positivity in observed genes was present independently to all clinical stages of ovarian cancer and to tumor grades. However, there was observed a trend of increased number and selective involvement of methylated genes with increasing disease stages. Furthermore, there was no association between positive methylation status and histological subtypes of ovarian carcinomas. RASSF1A and GSTP promoter methylation positivity is associated with ovarian cancer. The revealed gene-selective methylation positivity and the increased number of methylated genes with advancing disease stages could be considered as a useful molecular marker for early detection of ovarian cancer. However, there is need to find diagnostic approach of specifically and frequently methylated genes to determining a methylation phenotype for early detection of ovarian malignancies.

Identification of BRCA1-deficient ovarian cancers

DEFF Research Database (Denmark)

Skytte, Anne-Bine; Waldstrøm, Marianne; Rasmussen, Anders Aamann

2011-01-01

of offering genetic counseling and due to beneficial effects of PARP inhibitor treatment in this group. Since DNA sequencing is expensive and time-consuming efforts have been devoted to develop more indirect methods for BRCA screening that can improve the selection of patients for sequence-based BRCA testing....... Design. BRCA1-immunohistochemistry (IHC), fluorescence in-situ hybridization (FISH) and methylation analyses were performed on formalin-fixed, paraffin-embedded ovarian cancer tissue. Sample: 54 ovarian cancers; 15 BRCA1 cancers, 4 BRCA2 cancers, 10 cancers from patients with a family history...

Distribution volumes of macromolecules in human ovarian and endometrial cancers--effects of extracellular matrix structure.

Science.gov (United States)

Haslene-Hox, Hanne; Oveland, Eystein; Woie, Kathrine; Salvesen, Helga B; Tenstad, Olav; Wiig, Helge

2015-01-01

Elements of the extracellular matrix (ECM), notably collagen and glucosaminoglycans, will restrict part of the space available for soluble macromolecules simply because the molecules cannot occupy the same space. This phenomenon may influence macromolecular drug uptake. To study the influence of steric and charge effects of the ECM on the distribution volumes of macromolecules in human healthy and malignant gynecologic tissues we used as probes 15 abundant plasma proteins quantified by high-resolution mass spectrometry. The available distribution volume (VA) of albumin was increased in ovarian carcinoma compared with healthy ovarian tissue. Furthermore, VA of plasma proteins between 40 and 190 kDa decreased with size for endometrial carcinoma and healthy ovarian tissue, but was independent of molecular weight for the ovarian carcinomas. An effect of charge on distribution volume was only found in healthy ovaries, which had lower hydration and high collagen content, indicating that a condensed interstitium increases the influence of negative charges. A number of earlier suggested biomarker candidates were detected in increased amounts in malignant tissue, e.g., stathmin and spindlin-1, showing that interstitial fluid, even when unfractionated, can be a valuable source for tissue-specific proteins. We demonstrate that the distribution of abundant plasma proteins in the interstitium can be elucidated by mass spectrometry methods and depends markedly on hydration and ECM structure. Our data can be used in modeling of drug uptake, and give indications on ECM components to be targeted to increase the uptake of macromolecular substances. Copyright © 2015 the American Physiological Society.

Prognostic factors for ovarian epithelial cancer in the elderly: a case-control study.

Science.gov (United States)

Sabatier, Renaud; Calderon, Benoît; Lambaudie, Eric; Chereau, Elisabeth; Provansal, Magali; Cappiello, Maria-Antonietta; Viens, Patrice; Rousseau, Frederique

2015-06-01

Ovarian cancer is the leading cause of mortality by gynecologic cancers in Western countries. Many publications have suggested that age may be an independent prognostic factor in ovarian carcinoma. There are only few data concerning the impact of treatments and geriatric features within the elderly population. We collected data of older (≥ 70 years old) patients treated in our institution for an invasive ovarian carcinoma between 1995 and 2011. First we described usual clinical and pathological features for these patients, as well as their outcome. We compared these parameters with that of young (women (58% vs 41.7%), and older patients received less chemotherapy courses and less taxanes (38.4% vs 67.1%). Young patients had a longer overall survival (median, 65.2 vs 26.2 months, P = 8.5E-10, log-rank test). Multivariate analyses confirmed that age was an independent prognostic factor and that within the elderly set the International Federation of Gynecology and Obstetrics stage, surgery results, number of chemotherapy cycles administered and performance status had a significant prognostic value. No clear correlation could be observed between geriatric characteristics and treatments administration. Ovarian cancer prognosis is poorer for older women, but they are more frequently suboptimally treated. No correlation could be observed between geriatric factors and surgery or chemotherapy achievement. Treatment decision should be based on objective geriatric assessment in order to improve outcome in this population.

Microscopic Aspects of Autoschizic Cell Death in Human Ovarian Carcinoma (2774) Cells Following Vitamin C, Vitamin K3 or Vitamin C:K3 Treatment

Science.gov (United States)

Gilloteaux, Jacques; Jamison, James M.; Arnold, David; Taper, Henryk S.; von Gruenigen, Vivian E.; Summers, Jack L.

2003-08-01

Human ovarian carcinoma cells (MDAH 2774) were treated with sodium ascorbate (VC), menadione (VK3), or with a VC:VK3 combination for 1 h and then studied using light microscopy (LM) and scanning (SEM) and transmission electron (TEM) microscopy. Plasma membrane damage (blisters and blebs, hairy aspect) results from vitamin C (VC) treatment, while cytoskeletal damage and self-morsellation are caused by vitamin K3 (VK3) treatment. VC:VK3-treated cells exhibit exacerbated injuries characteristic of both VC and VK3 treatment as well as a significant decrease in cell diameters from 20 35 [mu]m for control cells to 7 12 [mu]m for VC:VK3 treatment. Moreover, after a 1-h exposure to the vitamin combination, autoschizis (43%), apoptosis (3%), and oncosis (1.9%) are observed at the percentages indicated. All cellular changes associated with autoschizis observed with SEM were confirmed by LM and TEM observations and are consistent with cell death by autoschizis: decrease in cell size, cytoplasmic self-excisions, degradation of the nucleus and nucleolus without formation of apoptotic bodies and, ultimately, karyorrhexis and karyolysis. These results also suggest that the vitamin combination may find clinical use in the treatment of ovarian cancer.

Synthetic Lethal Therapeutic Approaches for ARID1A-Mutated Ovarian Cancer

Science.gov (United States)

2017-10-01

Award Number: W81XWH-16-1-0496 TITLE: Synthetic lethal therapeutic approaches for ARID1A-mutated ovarian cancer PRINCIPAL INVESTIGATOR: Rugang...AND SUBTITLE Synthetic lethal therapeutic approaches for ARID1A-mutated ovarian cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-16-1-0496 5c...Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Epithelial ovarian cancer (EOC) is the leading cause of death among gynecological

[Ovarian carcinoma: new prognostic and therapeutic viewpoints].

Science.gov (United States)

Goldhirsch, A; Joss, R; Greiner, R; Brunner, K W

1980-11-01

Some recently developed concepts concerning the management of ovarian cancer are discussed. Cytoreductive surgery to debulk the tumor to a minimum, even in those cases which were considered inoperable in the past, improves the chances for cure. Adjuvant radiotherapy or combination chemotherapy with new drugs have proved highly effective in inducing complete remission and potential cures in these patients. The definition and better understanding of prognostic criteria play a primary role in the selection of treatment. In designing the strategy for adequate treatment, the following points are of major importance: (1) exact definition of tumor spread as determined by accurate surgical staging; (2) histologic and cytologic grading; and (3) evaluation of response.

Imaging of ovarian clear cell carcinoma

Energy Technology Data Exchange (ETDEWEB)

Hayashi, Toshihiko; Sawano, Seishi; Yamada, Keiko [Japanese Foundation for Cancer Research, Tokyo (Japan). Hospital] (and others)

1999-12-01

The aim of this study is to examine the appearance of ovarian clear cell adenocarcinoma (OCCA) on MR, CT, US. In 39 cases with OCCA, the imaging characteristics of OCCA were evaluated morphologically and classified into three groups, that was, monomural nodule type, multi-mural nodule type and predominantly solid type. Forty-three percent of the patients had endometriosis. Contrast material-enhanced MRI was the most useful method for diagnosis of OCCA. (author)

No significant role for beta tubulin mutations and mismatch repair defects in ovarian cancer resistance to paclitaxel/cisplatin

International Nuclear Information System (INIS)

Mesquita, Bárbara; Veiga, Isabel; Pereira, Deolinda; Tavares, Ana; Pinto, Isabel M; Pinto, Carla; Teixeira, Manuel R; Castedo, Sérgio

2005-01-01

The mechanisms of chemoresistance in ovarian cancer patients remain largely to be elucidated. Paclitaxel/cisplatin combination is the standard chemotherapeutic treatment for this disease, although some patients do not respond to therapy. Our goals were to investigate whether TUBB mutations and mismatch repair defects underlie paclitaxel and cisplatin resistance. Thirty-four patients with primary ovarian carcinomas (26 serous and eight clear cell carcinomas) treated with paclitaxel/cisplatin were analysed. TUBB exon 4 was analysed by nested PCR after a first round PCR using intronic primers. Microsatellite analysis was performed with the quasimonomorphic markers BAT 26 and BAT 34. Twenty-two of the 34 ovarian cancers (64.7%) presented residual tumour after surgery, seven of which (7/22; 31.8%) were shown to be chemoresistant (five serous and two clear cell tumours). Sequence analysis did not find any mutation in TUBB exon 4. Microsatellite instability was not detected in any of the ovarian carcinomas. We conclude that TUBB exon 4 mutations and mismatch repair defects do not play a significant role in paclitaxel/cisplatin resistance

Induction of PLSCR1 in a STING/IRF3-dependent manner upon vector transfection in ovarian epithelial cells.

Directory of Open Access Journals (Sweden)

Karthik M Kodigepalli

Full Text Available Toll-like receptors (TLRs are the primary sensors of the innate immune system that recognize pathogenic nucleic acids including double-stranded plasmid DNA (dsDNA. TLR signaling activates multiple pathways including IRF3 which is involved in transcriptional induction of inflammatory cytokines (i.e. interferons (IFNs. Phospholipid scramblase 1, PLSCR1, is a highly inducible IFN-regulated gene mediating anti-viral properties of IFNs. Herein, we report a novel finding that dsDNA transfection in T80 immortalized normal ovarian surface epithelial cell line leads to a marked increase in PLSCR1 mRNA and protein. We also noted a comparable response in primary mammary epithelial cells (HMECs. Similar to IFN-2α treated cells, de novo synthesized PLSCR1 was localized predominantly to the plasma membrane. dsDNA transfection, in T80 and HMEC cells, led to activation of MAPK and IRF3. Although inhibition of MAPK (using U0126 did not modulate PLSCR1 mRNA and protein, IRF3 knockdown (using siRNA significantly ablated the PLSCR1 induction. In prior studies, the activation of IRF3 was shown to be mediated by cGAS-STING pathway. To investigate the contribution of STING to PLSCR1 induction, we utilized siRNA to reduce STING expression and observed that PLSCR1 protein was markedly reduced. In contrast to normal T80/HMECs, the phosphorylation of IRF3 as well as induction of STING and PLSCR1 were absent in ovarian cancer cells (serous, clear cell, and endometrioid suggesting that the STING/IRF3 pathway may be dysregulated in these cancer cells. However, we also noted induction of different TLR and IFN mRNAs between the T80 and HEY (serous epithelial ovarian carcinoma cell lines upon dsDNA transfection. Collectively, these results indicate that the STING/IRF3 pathway, activated following dsDNA transfection, contributes to upregulation of PLSCR1 in ovarian epithelial cells.

Ovarian carcinoma: improved survival following abdominopelvic irradiation in patients with a completed pelvic operation

International Nuclear Information System (INIS)

Dembo, A.J.; Bush, R.S.; Beale, F.A.; Bean, H.A.; Pringle, J.F.; Sturgeon, J.; Reid, J.G.

1979-01-01

A prospective, stratified, randomized study of 190 postoperative ovarian carcinoma patients with Stages IB, II, and III (asymptomatic) presentations is reported. The median time of follow-up was 52 months. Patients in whom bilateral salpingo-oophorectomy and hysterectomy (BSOH) could not be completed because of extensive pelvic tumor had a poor prognosis which did not differ for any of the therapies tested. When BSOH was completed, pelvic plus abdominopelvic irradiation (P + AB) with no diaphragmatic shielding significantly improved patient survival rate and long-term control of occult upper abdominal disease in approximately 25% more patients than pelvic irradiation alone or followed by adjuvant daily chlorambucil therapy. The effectiveness of P + AB in BSOH-completed patients was independent of stage or tumor grade and was most clearly appreciated in patients with all gross tumor removed. Chlorambucil added to pelvic irradiation delayed the time to treatment failure without reducing the number of treatment failures

Ovarian preservation in locally advanced cervical cancer undergoing neoadjuvant chemotherapy and radical surgery: our experience and analysis of the literature.

Science.gov (United States)

Signorelli, Mauro; Bogani, Giorgio; Chiappa, Valentina; Ditto, Antonino; Scaffa, Cono; Martinelli, Fabio; Lorusso, Domenica; Raspagliesi, Francesco

2018-03-30

The aim of this study was to estimate the rate of ovarian metastases and recurrences among patients affected by locally advanced stage cancer patients (LACC), undergoing neoadjuvant chemotherapy (NACT) and radical surgery with conservation of ovaries. Retrospective evaluation of consecutive patients affected by LACC (stage IB2- IIB), treated by NACT followed by radical surgery at National Cancer Institute, Milan, Italy, between 1990-2015. Overall, 331 patients were included. Stage at presentation included stage IB2, IIA and IIB in 120 (36.3%), 63 (19%) and 148 (44.7%) patients, respectively. Main histotype was squamous cell carcinoma (n=265, 80.1%) followed by adenocarcinoma/adenosquamous (n=51, 15.4%), and more than half of patients had a grade 3 carcinoma . Overall, 102 (30.8%) women had at least one ovary preserved during surgery, while 229 (69.2%) had bilateral salpingo-oophorectomy. Comparing patients who had ovarian preservation with patients who had not, we observed that the two groups were comparable in terms of baseline characteristics. Survival outcomes were not influenced by ovarian preservation (disease-free (p=0.93) and overall (p=0.65) survivals). One (1%) woman had a localized ovarian recurrence. Our data suggest that ovarian preservation at the time of surgery is a safe option among women with LACC after NACT with no detrimental impact on oncologic outcome. Further prospective studies are warranted.

Origin of clear cell carcinoma: nature or nurture?

Science.gov (United States)

Kolin, David L; Dinulescu, Daniela M; Crum, Christopher P

2018-02-01

A rare but serious complication of endometriosis is the development of carcinoma, and clear cell and endometrioid carcinomas of the ovary are the two most common malignancies which arise from endometriosis. They are distinct diseases, characterized by unique morphologies, immunohistochemical profiles, and responses to treatment. However, both arise in endometriosis and can share common mutations. The overlapping mutational profiles of clear cell and endometrioid carcinomas suggest that their varied histologies may be due to a different cell of origin which gives rise to each type of cancer. Cochrane and colleagues address this question in a recent article in this journal. They show that a marker of ovarian clear cell carcinoma, cystathionine gamma lyase, is expressed in ciliated cells. Similarly, they show that markers of secretory cells (estrogen receptor and methylenetetrahydrofolate dehydrogenase 1) are expressed in ovarian endometrioid carcinoma. Taken together, they suggest that endometrioid and clear cell carcinomas arise from cells related to secretory and ciliated cells, respectively. We discuss Cochrane et al's work in the context of other efforts to determine the cell of origin of gynecological malignancies, with an emphasis on recent developments and challenges unique to the area. These limitations complicate our interpretation of tumor differentiation; does it reflect nature imposed by a specific cell of origin or nurture, by either mutation(s) or environment? Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

A novel serum microRNA panel to discriminate benign from malignant ovarian disease.

LENUS (Irish Health Repository)

Langhe, Ream

2015-01-28

Ovarian cancer is the seventh most common cancer in women and the most frequent cause of gynaecological malignancy-related mortality in women. Currently, no standardized reliable screening test exists. MicroRNA profiling has allowed the identification of signatures associated with diagnosis, prognosis and response to treatment of human tumours. The aim of this study was to determine if a microRNA signature could distinguish between malignant and benign ovarian disease. A training set of 5 serous ovarian carcinomas and 5 benign serous cystadenomas were selected for the initial experiments. The validation set included 20 serous ovarian carcinomas and 20 benign serous cystadenomas. The serum\\/plasma focus microRNA Exiqon panel was used for the training set. For the validation set a pick and mix Exiqon panel, which focuses on microRNAs of interest was used. A panel of 4 microRNAs (let-7i-5p, miR-122, miR-152-5p and miR-25-3p) was significantly down regulated in cancer patients. These microRNAs target WNT signalling, AKT\\/mTOR and TLR-4\\/MyD88, which have previously been found to play a role in ovarian carcinogenesis and chemoresistance. let-7i-5p, miR-122, miR-152-5p and miR-25-3p could act as diagnostic biomarkers in ovarian cancer.

Expression and function of androgen receptor coactivator p44/Mep50/WDR77 in ovarian cancer.

Directory of Open Access Journals (Sweden)

Martin Ligr

Full Text Available Hormones, including estrogen and progesterone, and their receptors play an important role in the development and progression of ovarian carcinoma. Androgen, its receptor and coactivators have also been implicated in these processes. p44/Mep50/WDR77 was identified as a subunit of the methylosome complex and lately characterized as a steroid receptor coactivator that enhances androgen receptor as well as estrogen receptor-mediated transcriptional activity in a ligand-dependent manner. We previously described distinct expression and function of p44 in prostate, testis, and breast cancers. In this report, we examined the expression and function of p44 in ovarian cancer. In contrast to findings in prostate and testicular cancer and similar to breast cancer, p44 shows strong cytoplasmic localization in morphologically normal ovarian surface and fallopian tube epithelia, while nuclear p44 is observed in invasive ovarian carcinoma. We observed that p44 can serve as a coactivator of both androgen receptor (AR and estrogen receptor (ER in ovarian cells. Further, overexpression of nuclear-localized p44 stimulates proliferation and invasion in ovarian cancer cells in the presence of estrogen or androgen. These findings strongly suggest that p44 plays a role in mediating the effects of hormones during ovarian tumorigenesis.

A non-synonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers

Science.gov (United States)

Ding, Yuan C.; McGuffog, Lesley; Healey, Sue; Friedman, Eitan; Laitman, Yael; Shani-Shimon–Paluch; Kaufman, Bella; Liljegren, Annelie; Lindblom, Annika; Olsson, Håkan; Kristoffersson, Ulf; Stenmark-Askmalm, Marie; Melin, Beatrice; Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Timothy R.; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Gronwald, Jacek; Huzarski, Tomasz; Cybulski, Cezary; Byrski, Tomasz; Osorio, Ana; Cajal, Teresa Ramóny; Stavropoulou, Alexandra V; Benítez, Javier; Hamann, Ute; Rookus, Matti; Aalfs, Cora M.; de Lange, Judith L.; Meijers-Heijboer, Hanne E.J.; Oosterwijk, Jan C.; van Asperen, Christi J.; García, Encarna B. Gómez; Hoogerbrugge, Nicoline; Jager, Agnes; van der Luijt, Rob B.; Easton, Douglas F.; Peock, Susan; Frost, Debra; Ellis, Steve D.; Platte, Radka; Fineberg, Elena; Evans, D. Gareth; Lalloo, Fiona; Izatt, Louise; Eeles, Ros; Adlard, Julian; Davidson, Rosemarie; Eccles, Diana; Cole, Trevor; Cook, Jackie; Brewer, Carole; Tischkowitz, Marc; Godwin, Andrew K.; Pathak, Harsh; Stoppa-Lyonnet, Dominique; Sinilnikova, Olga M.; Mazoyer, Sylvie; Barjhoux, Laure; Léoné, Mélanie; Gauthier-Villars, Marion; Caux-Moncoutier, Virginie; de Pauw, Antoine; Hardouin, Agnès; Berthet, Pascaline; Dreyfus, Hélène; Ferrer, Sandra Fert; Collonge-Rame, Marie-Agnès; Sokolowska, Johanna; Buys, Saundra; Daly, Mary; Miron, Alex; Terry, Mary Beth; Chung, Wendy; John, Esther M; Southey, Melissa; Goldgar, David; Singer, Christian F; Maria, Muy-Kheng Tea; Gschwantler-Kaulich, Daphne; Fink-Retter, Anneliese; Hansen, Thomas v. O.; Ejlertsen, Bent; Johannsson, Oskar Th.; Offit, Kenneth; Sarrel, Kara; Gaudet, Mia M.; Vijai, Joseph; Robson, Mark; Piedmonte, Marion R; Andrews, Lesley; Cohn, David; DeMars, Leslie R.; DiSilvestro, Paul; Rodriguez, Gustavo; Toland, Amanda Ewart; Montagna, Marco; Agata, Simona; Imyanitov, Evgeny; Isaacs, Claudine; Janavicius, Ramunas; Lazaro, Conxi; Blanco, Ignacio; Ramus, Susan J; Sucheston, Lara; Karlan, Beth Y.; Gross, Jenny; Ganz, Patricia A.; Beattie, Mary S.; Schmutzler, Rita K.; Wappenschmidt, Barbara; Meindl, Alfons; Arnold, Norbert; Niederacher, Dieter; Preisler-Adams, Sabine; Gadzicki, Dorotehea; Varon-Mateeva, Raymonda; Deissler, Helmut; Gehrig, Andrea; Sutter, Christian; Kast, Karin; Nevanlinna, Heli; Aittomäki, Kristiina; Simard, Jacques; Spurdle, Amanda B.; Beesley, Jonathan; Chen, Xiaoqing; Tomlinson, Gail E.; Weitzel, Jeffrey; Garber, Judy E.; Olopade, Olufunmilayo I.; Rubinstein, Wendy S.; Tung, Nadine; Blum, Joanne L.; Narod, Steven A.; Brummel, Sean; Gillen, Daniel L.; Lindor, Noralane; Fredericksen, Zachary; Pankratz, Vernon S.; Couch, Fergus J.; Radice, Paolo; Peterlongo, Paolo; Greene, Mark H.; Loud, Jennifer T.; Mai, Phuong L.; Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; Gerdes, Anne-Marie; Thomassen, Mads; Jensen, Uffe Birk; Skytte, Anne-Bine; Caligo, Maria A.; Lee, Andrew; Chenevix-Trench, Georgia; Antoniou, Antonis C; Neuhausen, Susan L.

2012-01-01

Background We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers. Methods IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers. Results Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 [Hazard ratio (HR) = 1.43; 95% CI: 1.06–1.92; p = 0.019] and BRCA2 mutation carriers (HR=2.21; 95% CI: 1.39–3.52, p=0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class 2 mutations than class 1 (mutations (class 2 HR=1.86, 95% CI: 1.28–2.70; class 1 HR=0.86, 95%CI:0.69–1.09; p-for difference=0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class 2 mutation carriers (HR = 2.42; p = 0.03). Conclusion The IRS1 Gly972Arg SNP, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class 2 mutation carriers. Impact These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers. PMID:22729394

Tumour detection and localization using 99Tcm-labelled OV-TL 3 Fab' in patients suspected of ovarian cancer

International Nuclear Information System (INIS)

Tibben, J.G.; Massuger, L.F.A.G.; Claessens, R.A.M.J.; Schijf, C.P.T.; Strijk, S.P.; Kenemans, P.; Corstens, F.H.M.; Pak, K.Y.

1992-01-01

Fab' fragments of the monoclonal antibody OV-TL 3, that recognizes an ovarian carcinoma-associated antigen (OA3), were labelled with 99 Tc m using D-glucarate as a ligand. Twenty patients suspected of having primary or recurrent ovarian cancer received intravenously 1 mg of the Fab' labelled with 740 MBq 99 Tc m . Both planar and single photon emission computed tomographic (SPECT) scintigraphy were performed up to 30 h after intravenous infusion. Imaging results were compared with X-ray computed tomography (CT), ultrasonography (US) and CA 125 serum level. Blood clearance was fast (t 1/2 of 9.5 h). Thirty-seven per cent of the injected dose (% ID) was excreted in the urine within the first 24 h, whereas 7% ID was excreted in the 24 h faeces. In one patient with an OA3 negative ovarian carcinoma, radioimmunoscintigraphy (RIS) did not visualize the tumour. In two other patients a benign ovarian cyst was found, also showing no elevated uptake. In 13 out of 17 patients ovarian cancer lesions were detected with RIS, whereas CT and US detected lesions in, respectively, 15 and 12 patients. Of 36 surgically defined tumour deposits larger than 1 cm in diameter, 53% were detected and localized with RIS, whereas CT and US detected 61 and 40%, respectively. Radioimmunoscintigraphy with 99 Tc m -OV-TL 3 Fab' is less distressing for the patients but the overall imaging performance is not improved when compared with 111 In-OV-TL 3 F(ab') 2 . (Author)

Whole abdominal irradiation following chemotherapy in advanced ovarian carcinoma

International Nuclear Information System (INIS)

Kuten, A.; Stein, M.; Steiner, M.; Rubinov, R.; Epelbaum, R.; Cohen, Y.

1988-01-01

One hundred and sixteen patients with advanced ovarian carcinoma, who underwent primary cytoreductive surgery, received 6-11 courses of chemotherapy by cis-platin (50 mg/m2) and adriamycin (50 mg/m2) every 21 days. This was followed by second look laparotomy in 66 patients with no clinical evidence of disease. Consolidation abdominal irradiation was administered to 43 patients. Two techniques of irradiation were employed: between 1980-1983 whole abdominal irradiation was used and patients were to receive 3000 cGy in 4 weeks (Schedule I). Due to myelosuppression only 13 of 26 patients (50%) completed the planned dose of radiation. Between 1983-1985 the target volume was divided into upper and lower parts. First, the lower abdomen received 3000 cGy in 3 weeks, and then the upper abdomen received the same dose (Schedule II). Sixteen of seventeen patients (94%) thus treated, completed the planned dose of radiation. The actuarial survival for all 116 patients was 28% of 5 years. Irradiated patients with negative second look laparotomy had a survival probability of 100% at 24 months. Irradiated patients with microscopic disease at second look operation had an actuarial 5-year survival of 66%. Patients with minimal residual disease at second look laparotomy, receiving consolidation abdominal irradiation, had an actuarial survival of 5% only at 36 months. It is concluded that consolidation radiotherapy is effective in patients with negative or microscopic residual disease at second-look laparotomy. In regard to bone marrow tolerance, split field technique of irradiation is preferred

Significance of the tumor markers CA 125 and CA 15-3 in postoperative diagnosis of ovarian and breast cancer

International Nuclear Information System (INIS)

Johannsen, B.; Bartel, U.; Elling, D.

1989-01-01

In 271 patients with ovarian carcinoma, benign ovarian tumors, breast cancer, and two control groups, serum levels of CA 125, CA 15-3, CEA and, partly, CA 19-9 were determined immunoradiometrically. According to the results of the determination of CA 125 in the follow-up of ovarian carcinoma, CA 125 represents a useful marker for early detection of recurrences, especially in cases of diffuse carcinoma dissemination. In incomplete tumor debulking, postoperative CA 125 serum levels did not prove to be helpful except that a positive level renders invasive diagnostic investigation no longer necessary. Postoperative follow-up in breast cancer early reveals distant metastases, with very high levels in patients with bone metastases. By simultaneous measurement of CA 15-3 and CEA the sensitivity could be increased from 86% (CA 15-3 only) to 93%. (author)

Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers

DEFF Research Database (Denmark)

Ramus, Susan J; Antoniou, Antonis C; Kuchenbaecker, Karoline B

2012-01-01

Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers ...

Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers

NARCIS (Netherlands)

Ramus, Susan J.; Antoniou, Antonis C.; Kuchenbaecker, Karoline B.; Soucy, Penny; Beesley, Jonathan; Chen, Xiaoqing; McGuffog, Lesley; Sinilnikova, Olga M.; Healey, Sue; Barrowdale, Daniel; Lee, Andrew; Thomassen, Mads; Gerdes, Anne-Marie; Kruse, Torben A.; Jensen, Uffe Birk; Skytte, Anne-Bine; Caligo, Maria A.; Liljegren, Annelie; Lindblom, Annika; Olsson, Håkan; Kristoffersson, Ulf; Stenmark-Askmalm, Marie; Melin, Beatrice; Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Timothy R.; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Złowocka, Elżbieta; Gronwald, Jacek; Huzarski, Tomasz; Byrski, Tomasz; Cybulski, Cezary; Toloczko-Grabarek, Aleksandra; Osorio, Ana; Benitez, Javier; Duran, Mercedes; Tejada, Maria-Isabel; Hamann, Ute; Rookus, Matti; van Leeuwen, Flora E.; Aalfs, Cora M.; Meijers-Heijboer, Hanne E. J.; van Asperen, Christi J.; van Roozendaal, K. E. P.; Hoogerbrugge, Nicoline; Collée, J. Margriet; Kriege, Mieke; van der Luijt, Rob B.; Peock, Susan; Frost, Debra; Ellis, Steve D.; Platte, Radka; Fineberg, Elena; Evans, D. Gareth; Lalloo, Fiona; Jacobs, Chris; Eeles, Ros; Adlard, Julian; Davidson, Rosemarie; Eccles, Diana; Cole, Trevor; Cook, Jackie; Paterson, Joan; Douglas, Fiona; Brewer, Carole; Hodgson, Shirley; Morrison, Patrick J.; Walker, Lisa; Porteous, Mary E.; Kennedy, M. John; Pathak, Harsh; Godwin, Andrew K.; Stoppa-Lyonnet, Dominique; Caux-Moncoutier, Virginie; de Pauw, Antoine; Gauthier-Villars, Marion; Mazoyer, Sylvie; Léoné, Mélanie; Calender, Alain; Lasset, Christine; Bonadona, Valérie; Hardouin, Agnès; Berthet, Pascaline; Bignon, Yves-Jean; Uhrhammer, Nancy; Faivre, Laurence; Loustalot, Catherine; Buys, Saundra; Daly, Mary; Miron, Alex; Terry, Mary Beth; Chung, Wendy K.; John, Esther M.; Southey, Melissa; Goldgar, David; Singer, Christian F.; tea, Muy-Kheng; Pfeiler, Georg; Fink-Retter, Anneliese; Hansen, Thomas v O.; Ejlertsen, Bent; Johannsson, Oskar Th; Offit, Kenneth; Kirchhoff, Tomas; Gaudet, Mia M.; Vijai, Joseph; Robson, Mark; Piedmonte, Marion; Phillips, Kelly-Anne; van Le, Linda; Hoffman, James S.; Ewart Toland, Amanda; Montagna, Marco; Tognazzo, Silvia; Imyanitov, Evgeny; Issacs, Claudine; Janavicius, Ramunas; Lazaro, Conxi; Blanco, Iganacio; Tornero, Eva; Navarro, Matilde; Moysich, Kirsten B.; Karlan, Beth Y.; Gross, Jenny; Olah, Edith; Vaszko, Tibor; teo, Soo-Hwang; Ganz, Patricia A.; Beattie, Mary S.; Dorfling, Cecelia M.; van Rensburg, Elizabeth J.; Diez, Orland; Kwong, Ava; Schmutzler, Rita K.; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Heidemann, Simone; Niederacher, Dieter; Preisler-Adams, Sabine; Gadzicki, Dorotehea; Varon-Mateeva, Raymonda; Deissler, Helmut; Gehrig, Andrea; Sutter, Christian; Kast, Karin; Fiebig, Britta; Schäfer, Dieter; Caldes, Trinidad; de la Hoya, Miguel; Nevanlinna, Heli; Aittomäki, Kristiina; Plante, Marie; Spurdle, Amanda B.; Neuhausen, Susan L.; Ding, Yuan Chun; Wang, Xianshu; Lindor, Noralane; Fredericksen, Zachary; Pankratz, V. Shane; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Bonanni, Bernardo; Bernard, Loris; Dolcetti, Riccardo; Papi, Laura; Ottini, Laura; Radice, Paolo; Greene, Mark H.; Mai, Phuong L.; Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; Pharoah, Paul D. P.; Gayther, Simon A.; Simard, Jacques; Easton, Douglas F.; Couch, Fergus J.; Chenevix-Trench, Georgia; Miedzybrodzka, Zosia; Gregory, Helen; Morrison, Patrick; Jeffers, Lisa; Ong, Kai-Ren; Hoffman, Jonathan; Donaldson, Alan; James, Margaret; Downing, Sarah; Taylor, Amy; Murray, Alexandra; Rogers, Mark T.; McCann, Emma; Barton, David; Porteous, Mary; Drummond, Sarah; Kivuva, Emma; Searle, Anne; Goodman, Selina; Hill, Kathryn; Murday, Victoria; Bradshaw, Nicola; Snadden, Lesley; Longmuir, Mark; Watt, Catherine; Gibson, Sarah; Haque, Eshika; Tobias, Ed; Duncan, Alexis; Izatt, Louise; Langman, Caroline; Whaite, Anna; Dorkins, Huw; Barwell, Julian; Serra-Feliu, Gemma; Ellis, Ian; Houghton, Catherine; Taylor, Jane; Side, Lucy; Male, Alison; Berlin, Cheryl; Eason, Jacqueline; Collier, Rebecca; Claber, Oonagh; Jobson, Irene; McLeod, Diane; Halliday, Dorothy; Durell, Sarah; Stayner, Barbara; Shanley, Susan; Rahman, Nazneen; Houlston, Richard; Bancroft, Elizabeth; D'Mello, Lucia; Page, Elizabeth; Ardern-Jones, Audrey; Kohut, Kelly; Wiggins, Jennifer; Castro, Elena; Mitra, Anita; Robertson, Lisa; Quarrell, Oliver; Bardsley, Cathryn; Goff, Sheila; Brice, Glen; Winchester, Lizzie; Eddy, Charlotte; Tripathi, Vishakha; Attard, Virginia; Lucassen, Anneke; Crawford, Gillian; McBride, Donna; Smalley, Sarah; Sinilnikova, Olga; Barjhoux, Laure; Verny-Pierre, Carole; Giraud, Sophie; Léone, Mélanie; Buecher, Bruno; Houdayer, Claude; Moncoutier, Virginie; Belotti, Muriel; Tirapo, Carole; Bressac-de-Paillerets, Brigitte; Remenieras, Audrey; Byrede, Véronique; Caron, Olivier; Lenoir, Gilbert; Urhammer, Nancy; Sobol, Hagay; Bourdon, Violaine; Noguchi, Tetsuro; Eisinger, François; Coulet, Florence; Colas, Chrystelle; Soubrier, Florent; Coupier, Isabelle; Pujol, Pascal; Peyrat, Jean-Philippe; Fournier, Joëlle; Révilliion, Françoise; Vennin, Philippe; Adenis, Claude; Rouleau, Etienne; Lidereau, Rosette; Demange, Liliane; Nogues, Catherine; Muller, Danièle; Fricker, Jean-Pierre; Barouk-Simonet, Emmanuelle; Bonnet, Françoise; Bubien, Virginie; Sevenet, Nicolas; Longy, Michel; Toulas, Christine; Guimbaud, Rosine; Gladieff, Laurence; Feillel, Viviane; Leroux, Dominique; Dreyfus, Hélène; Rebischung, Christine; Peysselon, Megalie; Coron, Fanny; Prieur, Fabienne; Lebrun, Marine; Kientz, Caroline; Frénay, Marc; Vénat-Bouvet, Laurence; Delnatte, Capucine; Mortemousque, Isabelle; Lynch, Henry T.; Snyder, Carrie L.; Hogervorst, F. B. L.; Verhoef, S.; Verheus, M.; van't Veer, L. J.; van Leeuwen, F. E.; Collée, M.; van den Ouweland, A. M. W.; Jager, A.; Hooning, M. J.; Tilanus-Linthorst, M. M. A.; Seynaeve, C.; van Asperen, C. J.; Wijnen, J. T.; Vreeswijk, M. P.; Tollenaar, R. A.; Devilee, P.; Ligtenberg, M. J.; Hoogerbrugge, N.; Ausems, M. G.; van der Luijt, R. B.; van Os, T. A.; Gille, J. J. P.; Waisfisz, Q.; Gomez-Garcia, E. B.; van Roozendaal, C. E.; Blok, Marinus J.; Caanen, B.; Oosterwijk, J. C.; van der Hout, A. H.; Mourits, M. J.; Vasen, H. F.; Thorne, Heather; Niedermayr, Eveline; Gill, Mona; Collins, Lucine; Gokgoz, Nalan; Selander, Teresa; Weerasooriya, Nayana; Karlsson, Per; Nordlilng, Margareta; Bergman, Annika; Einbeigi, Zakaria; Liedgren, Sigrun; Borg, Åke; Loman, Niklas; Soller, Maria; Jernström, Helena; Harbst, Katja; Henriksson, Karin; Arver, Brita; von Wachenfeldt, Anna; Barbany-Bustinza, Gisela; Rantala, Johanna; Grönberg, Henrik; Stattin, Eva-Lena; Emanuelsson, Monica; Ehrencrona, Hans; Rosenquist, Richard; Dahl, Niklas

2012-01-01

Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of

Myofibrillogenesis regulator 1 (MR-1 is a novel biomarker and potential therapeutic target for human ovarian cancer

Directory of Open Access Journals (Sweden)

Feng Jingjing

2011-06-01

Full Text Available Abstract Background Myofibrillogenesis regulator 1 (MR-1 is overexpressed in human cancer cells and plays an essential role in cancer cell growth. However, the significance of MR-1 in human ovarian cancer has not yet been explored. The aim of this study was to examine whether MR-1 is a predictor of ovarian cancer and its value as a therapeutic target in ovarian cancer patients. Methods Reverse-transcription polymerase chain reaction (PCR and quantitative real-time PCR were used to detect MR-1 mRNA levels in tissue samples from 26 ovarian cancer patients and 25 controls with benign ovarian disease. Anti-MR-1 polyclonal antibodies were prepared, tested by ELISA and western blotting, and then used for immunohistochemical analysis of the tissue samples. Adhesion and invasion of 292T cells was also examined after transfection of a pMX-MR-1 plasmid. Knockdown of MR-1 expression was achieved after stable transfection of SKOV3 cells with a short hairpin DNA pGPU6/GFP/Neo plasmid against the MR-1 gene. In addition, SKOV3 cells were treated with paclitaxel and carboplatin, and a potential role for MR-1 as a therapeutic target was evaluated. Results MR-1 was overexpressed in ovarian cancer tissues and SKOV3 cells. 293T cells overexpressed MR-1, and cellular spread and invasion were enhanced after transfection of the pMX-MR-1 plasmid, suggesting that MR-1 is critical for ovarian cancer cell growth. Knockdown of MR-1 expression inhibited cell adhesion and invasion, and treatment with anti-cancer drugs decreased its expression in cancer cells. Taken together, these results provide the first evidence of the cellular and molecular mechanisms by which MR-1 might serve as a novel biological marker and potential therapeutic target for ovarian cancer. Conclusions MR-1 may be a biomarker for diagnosis of ovarian cancer. It may also be useful for monitoring of the effects of anti-cancer therapies. Further studies are needed to clarify whether MR-1 is an early

Photodynamic action of LED-activated pyropheophorbide-α methyl ester in cisplatin-resistant human ovarian carcinoma cells

International Nuclear Information System (INIS)

Tan, Y; Xia, X S; Yu, H P; Bai, D Q; He, Y; Xu, C S; Leung, A W N

2009-01-01

Cisplatin-resistance is a major obstacle for the successful therapy to ovarian cancer, and exploring novel approach to deactivate cisplatin-resistant ovarian cells will improve the clinical outcomes. Our present study showed that there was no dark cytotoxicity of MPPa in the COC1/DDP cells at the dose of 0.25 – 4 μM, and LED-activated MPPa resulted in drug dose- and light-dependent cytotoxicity. Apoptotic rate 6 h after LED-activated MPPa (2 μM) increased to 16.71% under the light energy of 1 J/cm 2 . Confocal laser scanning microscopy showed that MPPa mainly localized in the intracellular membrane system, namely the endoplasmic reticulum, Golgi apparatus, lysosomes and mitochondria in the COC1/DDP cells. Mitochondrial membrane potential (ΔΨ m ) was collapsed when COC1/DDP cells were exposed to 2 μM MPPa for 20 h and then 1 J/cm 2 irradiation of LED source. These data demonstrated that LED-activated MPPa significantly deactivated cisplatin-resistant ovarian cell line COC1/DDP cells and enhanced apoptosis and decreased ΔΨ m , which suggests LED is an efficient light source for PDT and LED-activated MPPa can be developed as new modality for treating cisplatin-resistant ovarian

Increased oxidative stress mediates the antitumor effect of PARP inhibition in ovarian cancer

Directory of Open Access Journals (Sweden)

Dong Hou

2018-07-01

Full Text Available PARP inhibitors have been widely tested in clinical trials, especially for the treatment of breast cancer and ovarian cancer, and were shown to be highly successful. Because PARP primarily functions in sensing and repairing DNA strand breaks, the therapeutic effect of PARP inhibition is generally believed to be attributed to impaired DNA repair. We here report that oxidative stress is also increased by PARP inhibition and mediates the antitumor effect. We showed that PARP1 is highly expressed in specimens of high grade serous ovarian carcinoma and its activity is required for unperturbed proliferation of ovarian cancer cells. Inhibition or depletion of PARP leads to not only an increase in DNA damage, but also an elevation in the levels of reactive oxygen species (ROS. Importantly, antioxidant N-acetylcysteine (NAC significantly attenuated the induction of DNA damage and the perturbation of proliferation by PARP inhibition or depletion. We further showed that NADPH oxidases 1 and 4 were significantly upregulated by PARP inhibition and were partially responsible for the induction of oxidative stress. Depletion of NOX1 and NOX4 partially rescued the growth inhibition of PARP1-deficient tumor xenografts. Our findings suggest that in addition to compromising the repair of DNA damage, PARP inhibition or depletion may exert extra antitumor effect by elevating oxidative stress in ovarian cancer cells. Keywords: PARP1, Oxidative stress, NADPH oxidases, Ovarian cancer

Molecular changes preceding endometrial and ovarian cancer: a study of consecutive endometrial specimens from Lynch syndrome surveillance.

Science.gov (United States)

Niskakoski, Anni; Pasanen, Annukka; Lassus, Heini; Renkonen-Sinisalo, Laura; Kaur, Sippy; Mecklin, Jukka-Pekka; Bützow, Ralf; Peltomäki, Päivi

2018-03-27

Molecular alterations preceding endometrial and ovarian cancer and the sequence of events are unknown. Consecutive specimens from lifelong surveillance for Lynch syndrome provides a natural setting to address such questions. To molecularly define the multistep gynecological tumorigenesis, DNA mismatch repair gene mutation carriers with endometrial or ovarian carcinoma or endometrial hyperplasia were identified from a nation-wide registry and endometrial biopsy specimens taken from these individuals during 20 years of screening were collected. A total of 213 endometrial and ovarian specimens from Lynch syndrome individuals and 197 histology-matched (non-serous) samples from sporadic cases were available for this investigation. The specimens were profiled for markers linked to endometrial and ovarian tumorigenesis, including ARID1A protein expression, mismatch repair status, and tumor suppressor gene promoter methylation. In Lynch syndrome-associated endometrial and ovarian carcinomas, ARID1A protein was lost in 61-100% and mismatch repair was deficient in 97-100%, compared to 0-17% and 14-44% in sporadic cases (P = 0.000). ARID1A loss appeared in complex hyperplasia and deficient mismatch repair and tumor suppressor gene promoter methylation in histologically normal endometrium. Despite quantitative differences between Lynch syndrome and sporadic cases, ARID1A expression, mismatch repair, and tumor suppressor gene promoter methylation divided endometrial samples from both patient groups into three categories of increasing abnormality, comprising normal endometrium and simple hyperplasia (I), complex hyperplasia with or without atypia (II), and endometrial cancer (III). Complex hyperplasias without vs. with atypia were molecularly indistinguishable. In conclusion, surveillance specimens from Lynch syndrome identify mismatch repair deficiency, tumor suppressor gene promoter methylation, and ARID1A loss as early changes in tumor development. Our findings are

Biobehavioral modulation of the exosome transcriptome in ovarian carcinoma.

Science.gov (United States)

Lutgendorf, Susan K; Thaker, Premal H; Arevalo, Jesusa M; Goodheart, Michael J; Slavich, George M; Sood, Anil K; Cole, Steve W

2018-02-01

Social factors in the patient macroenvironment have been shown to influence molecular events in the tumor microenvironment and thereby influence cancer progression. However, biomarkers providing a window into the longitudinal effects of biobehavioral factors on tumor biology over time are lacking. Exosome analysis is a novel strategy for in vivo monitoring of dynamic changes in tumor cells. This study examined exosomal profiles from patients with low or high levels of social support for epithelial-mesenchymal transition (EMT) polarization and gene expression related to inflammation and β-adrenergic signaling. Exosomes were isolated from plasma sampled from a series of 40 women before primary surgical resection of advanced-stage, high-grade ovarian carcinoma. Samples were selected for analysis on the basis of extremes of low and high levels of social support. After exosomal isolation and RNA extraction, a microarray analysis of the transcriptome was performed. Primary analyses identified significant upregulation of 67 mesenchymal-characteristic gene transcripts and downregulation of 63 epithelial-characteristic transcripts in patients with low social support; this demonstrated increased EMT polarization (P = .0002). Secondary analyses using promoter sequence bioinformatics supported a priori hypotheses linking low social support to 1) increased activity of cyclic adenosine monophosphate response element binding protein (CREB)/activating transcription factor (ATF) family transcription factors that mediate the β-adrenergic response to catecholamines via the cyclic adenosine monophosphate/protein kinase A signaling pathway (mean fold change for CREB: 2.24 ± 0.65; P = .0019; mean fold change for ATF: 2.00 ± 0.55; P = .0049) and 2) increased activity of the proinflammatory nuclear factor κB/Rel family of transcription factors (mean fold change: 2.10 ± 0.70; P = .0109). These findings suggest the possibility of leveraging exosomes as a

A functional proteogenomic analysis of endometrioid and clear cell carcinomas using reverse phase protein array and mutation analysis: protein expression is histotype-specific and loss of ARID1A/BAF250a is associated with AKT phosphorylation

International Nuclear Information System (INIS)

Wiegand, Kimberly C; Lu, Yiling; Zhang, Fan; Anglesio, Michael S; Gilks, Blake; Mills, Gordon B; Huntsman, David G; Carey, Mark S; Hennessy, Bryan T; Leung, Samuel; Wang, Yemin; Ju, Zhenlin; McGahren, Mollianne; Kalloger, Steve E; Finlayson, Sarah; Stemke-Hale, Katherine

2014-01-01

Ovarian cancer is now recognized as a number of distinct diseases primarily defined by histological subtype. Both clear cell ovarian carcinomas (CCC) and ovarian endometrioid carcinomas (EC) may arise from endometriosis and frequently harbor mutations in the ARID1A tumor suppressor gene. We studied the influence of histological subtype on protein expression with reverse phase protein array (RPPA) and assessed proteomic changes associated with ARID1A mutation/BAF250a expression in EC and CCC. Immunohistochemistry (IHC) for BAF250a expression was performed on 127 chemotherapy-naive ovarian carcinomas (33 CCC, 29 EC, and 65 high-grade serous ovarian carcinomas (HGSC)). Whole tumor lysates were prepared from frozen banked tumor samples and profiled by RPPA using 116 antibodies. ARID1A mutations were identified by exome sequencing, and PIK3CA mutations were characterized by MALDI-TOF mass spectrometry. SAM (Significance Analysis of Microarrays) was performed to determine differential protein expression by histological subtype and ARID1A mutation status. Multivariate logistic regression was used to assess the impact of ARID1A mutation status/BAF250a expression on AKT phosphorylation (pAKT). PIK3CA mutation type and PTEN expression were included in the model. BAF250a knockdown was performed in 3 clear cell lines using siRNA to ARID1A. Marked differences in protein expression were observed that are driven by histotype. Compared to HGSC, SAM identified over 50 proteins that are differentially expressed in CCC and EC. These included PI3K/AKT pathway proteins, those regulating the cell cycle, apoptosis, transcription, and other signaling pathways including steroid hormone signaling. Multivariate models showed that tumors with loss of BAF250a expression showed significantly higher levels of AKT-Thr 308 and AKT-Ser 473 phosphorylation (p < 0.05). In 31 CCC cases, pAKT was similarly significantly increased in tumors with BAF250a loss on IHC. Knockdown of BAF250a by siRNA in

Serum level of tumor marker CA-125 in ovarian pathology

International Nuclear Information System (INIS)

Bagni, B.; Feggi, L.M.; Prandini, N.; Pasini, S.; Mollica, G.

1987-01-01

The tumor marker CA-125 is an embrional glycoprotein detectable in tissues derived from celomatic epitelium. Serum Ca-125 was determined by RIA in 66 patients with various ovarian pathologies (16 malignant at stage III-IV and 50 benign). Six patients with ovarian carcinoma were monitored during the first week after surgery and chemiotherapy for a total of 150 days of treatment. It has been observed that CA-125 serum level is consistently above the normal range (>35 U/ml) in all malignant diseases. In benign pathology, levels above the normal were found to be represented almost exclusively by ovarian endometriosis. Furthermore, the results demonstrate that chemiotherapy alone is capable of lowering CA-125 serum levels. This tumor marker may be of great advantage in diagnosis and follow-up of ovarian malignancy

Shared genetics underlying epidemiological association between endometriosis and ovarian cancer

DEFF Research Database (Denmark)

Lu, Yi; Cuellar-Partida, Gabriel; Painter, Jodie N

2015-01-01

Epidemiological studies have demonstrated associations between endometriosis and certain histotypes of ovarian cancer, including clear cell, low-grade serous and endometrioid carcinomas. We aimed to determine whether the observed associations might be due to shared genetic aetiology. To address...... this, we used two endometriosis datasets genotyped on common arrays with full-genome coverage (3194 cases and 7060 controls) and a large ovarian cancer dataset genotyped on the customized Illumina Infinium iSelect (iCOGS) arrays (10 065 cases and 21 663 controls). Previous work has suggested...... that a large number of genetic variants contribute to endometriosis and ovarian cancer (all histotypes combined) susceptibility. Here, using the iCOGS data, we confirmed polygenic architecture for most histotypes of ovarian cancer. This led us to evaluate if the polygenic effects are shared across diseases. We...

YY1 modulates taxane response in epithelial ovarian cancer

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Matsumura, Noriomi; Huang, Zhiqing; Baba, Tsukasa; Lee, Paula S.; Barnett, Jason C.; Mori, Seiichi; Chang, Jeffrey T.; Kuo, Wen-Lin; Gusberg, Alison H.; Whitaker, Regina S.; Gray, JoeW.; Fujii, Shingo; Berchuck, Andrew; Murphy, Susan K.

2008-10-10

The results of this study show that a high YY1 gene signature (characterized by coordinate elevated expression of transcription factor YY1 and putative YY1 target genes) within serous epithelial ovarian cancers is associated with enhanced response to taxane-based chemotherapy and improved survival. If confirmed in a prospective study, these results have important implications for the potential future use of individualized therapy in treating patients with ovarian cancer. Identification of the YY1 gene signature profile within a tumor prior to initiation of chemotherapy may provide valuable information about the anticipated response of these tumors to taxane-based drugs, leading to better informed decisions regarding chemotherapeutic choice. Survival of ovarian cancer patients is largely dictated by their response to chemotherapy, which depends on underlying molecular features of the malignancy. We previously identified YIN YANG 1 (YY1) as a gene whose expression is positively correlated with ovarian cancer survival. Herein we investigated the mechanistic basis of this association. Epigenetic and genetic characteristics of YY1 in serous epithelial ovarian cancer (SEOC) were analyzed along with YY1 mRNA and protein. Patterns of gene expression in primary SEOC and in the NCI60 database were investigated using computational methods. YY1 function and modulation of chemotherapeutic response in vitro was studied using siRNA knockdown. Microarray analysis showed strong positive correlation between expression of YY1 and genes with YY1 and transcription factor E2F binding motifs in SEOC and in the NCI60 cancer cell lines. Clustering of microarray data for these genes revealed that high YY1/E2F3 activity positively correlates with survival of patients treated with the microtubule stabilizing drug paclitaxel. Increased sensitivity to taxanes, but not to DNA crosslinking platinum agents, was also characteristic of NCI60 cancer cell lines with a high YY1/E2F signature. YY1

RNA-based ovarian cancer research from 'a gene to systems biomedicine' perspective.

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Gov, Esra; Kori, Medi; Arga, Kazim Yalcin

2017-08-01

Ovarian cancer remains the leading cause of death from a gynecologic malignancy, and treatment of this disease is harder than any other type of female reproductive cancer. Improvements in the diagnosis and development of novel and effective treatment strategies for complex pathophysiologies, such as ovarian cancer, require a better understanding of disease emergence and mechanisms of progression through systems medicine approaches. RNA-level analyses generate new information that can help in understanding the mechanisms behind disease pathogenesis, to identify new biomarkers and therapeutic targets and in new drug discovery. Whole RNA sequencing and coding and non-coding RNA expression array datasets have shed light on the mechanisms underlying disease progression and have identified mRNAs, miRNAs, and lncRNAs involved in ovarian cancer progression. In addition, the results from these analyses indicate that various signalling pathways and biological processes are associated with ovarian cancer. Here, we present a comprehensive literature review on RNA-based ovarian cancer research and highlight the benefits of integrative approaches within the systems biomedicine concept for future ovarian cancer research. We invite the ovarian cancer and systems biomedicine research fields to join forces to achieve the interdisciplinary caliber and rigor required to find real-life solutions to common, devastating, and complex diseases such as ovarian cancer. CAF: cancer-associated fibroblasts; COG: Cluster of Orthologous Groups; DEA: disease enrichment analysis; EOC: epithelial ovarian carcinoma; ESCC: oesophageal squamous cell carcinoma; GSI: gamma secretase inhibitor; GO: Gene Ontology; GSEA: gene set enrichment analyzes; HAS: Hungarian Academy of Sciences; lncRNAs: long non-coding RNAs; MAPK/ERK: mitogen-activated protein kinase/extracellular signal-regulated kinases; NGS: next-generation sequencing; ncRNAs: non-coding RNAs; OvC: ovarian cancer; PI3K

The immunohistochemical expression of endocrine gland-derived-VEGF (EG-VEGF) as a prognostic marker in ovarian cancer.

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Bălu, Sevilla; Pirtea, L; Gaje, Puşa; Cîmpean, Anca Maria; Raica, M

2012-01-01

Ovarian cancer-related angiogenesis is a complex process orchestrated by many positive and negative regulators. Many growth factors are involved in the development of the tumor-associated vasculature, and from these, endocrine gland-derived vascular endothelial growth factor (EG-VEGF) seems to play a crucial role. EG-VEGF is the first organ-specific angiogenic factor and its effects are restricted to the endothelial cells of the endocrine glands. Although EG-VEGF was detected in both normal and neoplastic ovaries, its clinical significance remains controversial. In the present study, we analyzed 30 patients with epithelial ovarian cancer, and the immunohistochemical expression of EG-VEGF was compared with the conventional clinico-pathological parameters of prognosis. Neoplastic cells of the ovarian carcinoma expressed EG-VEGF in 73.33% of the cases, as a cytoplasmic granular product of reaction. We found a strong correlation between the expression of EG-VEGF at protein level and tumor stage, grade, and microscopic type. The expression of EG-VEGF was found in patients with stage III and IV, but not in stage II. The majority of serous adenocarcinoma, half of the cases with clear cell carcinoma and two cases with endometrioid carcinoma showed definite expression in tumor cells. No positive reaction was found in the cases with mucinous carcinoma. Our results showed that EG-VEGF expression is an indicator not only of the advanced stage, but also of ovarian cancer progression. Based on these data, we concluded that EG-VEGF expression in tumor cells of the epithelial ovarian cancer is a good marker of unfavorable prognosis and could be an attractive therapeutic target in patients with advanced-stage tumors, refractory conventional chemotherapy.

[The morphological and immunohistochemical characteristics of changes in the fallopian tube mucosa in ovarian epithelial tumors].

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Asaturova, A V; Ezhova, L S; Faizullina, N M; Sannikova, M V; Khabas, G N

2016-01-01

to study the incidence of fallopian tube lesions (secretory cell proliferations (SCP), p53 signature, serous tubal intraepithelial lesions (STIL), and serous tubal intraepithelial carcinomas (STIC) in ovarian epithelial tumors and to propose their pathogenetic association with a certain histotype of the ovarian tumor. The investigation enrolled 136 patients with ovarian epithelial tumors, whose fallopian tubes were morphologically and immunohistochemically (IHC) examined using p53, Ki-67, and PAX2. Statistical analysis was carried out applying the Mann-Whitney test and χ(2) test. Lesions meeting the STIC criteria were found in 14.7% of cases (only in ovarian serous carcinoma (OSC)), those suspecting STICs were in 25.7%, and those without signs of STICs were in 59.6%. IFC examination diagnosed STIC in 10% of cases (only in OSC), STIL in 13.3%, p53 signature in 11.7% (only in serous tumors), and the normal/reactively changed tubal epithelium in 65%. The incidence of STILs correlated with the malignant potential of serous tumors significantly (pSTIC and high-grade OSC and revealed significant differences in the incidence of other fallopian tubal intraepithelial lesions in serous cystadenomas, borderline tumors, and OSC, in different ovarian carcinomas. The findings may suggest that the earliest stage in the pathogenesis of OSC is the development of SCP, followed by the formation of p53 signatures that may further give rise to STIL, and finally STC (due to the acquisition of additional mutations).

Risk of borderline ovarian tumors among women with benign ovarian tumors

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Guleria, Sonia; Jensen, Allan; Kjær, Susanne K

2018-01-01

tumors among women with a benign ovarian tumor. METHODS: This nationwide cohort study included all Danish women diagnosed with a benign ovarian tumor (n=139,466) during 1978-2012. The cohort was linked to the Danish Pathology Data Bank and standardized incidence ratios (SIR) with 95% confidence intervals...... (CI) were calculated. RESULTS: Women with benign ovarian tumors had increased risks for subsequent borderline ovarian tumors (SIR 1.62, 95% CI 1.43-1.82), and this applied to both serous (SIR 1.69, 95% CI 1.39-2.03) and mucinous (SIR 1.75, 95% CI 1.45-2.10) histotypes of borderline ovarian tumors....... The risk for borderline ovarian tumors was primarily increased for women diagnosed with a benign ovarian tumor before 40years of age. The risk remained increased up to 9years after a benign ovarian tumor diagnosis. Finally, the associations did not change markedly when analyzed for the different histotypes...

A comparison of CA125, HE4, risk ovarian malignancy algorithm (ROMA, and risk malignancy index (RMI for the classification of ovarian masses

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Cristina Anton

2012-01-01

Full Text Available OBJECTIVE: Differentiation between benign and malignant ovarian neoplasms is essential for creating a system for patient referrals. Therefore, the contributions of the tumor markers CA125 and human epididymis protein 4 (HE4 as well as the risk ovarian malignancy algorithm (ROMA and risk malignancy index (RMI values were considered individually and in combination to evaluate their utility for establishing this type of patient referral system. METHODS: Patients who had been diagnosed with ovarian masses through imaging analyses (n = 128 were assessed for their expression of the tumor markers CA125 and HE4. The ROMA and RMI values were also determined. The sensitivity and specificity of each parameter were calculated using receiver operating characteristic curves according to the area under the curve (AUC for each method. RESULTS: The sensitivities associated with the ability of CA125, HE4, ROMA, or RMI to distinguish between malignant versus benign ovarian masses were 70.4%, 79.6%, 74.1%, and 63%, respectively. Among carcinomas, the sensitivities of CA125, HE4, ROMA (pre-and post-menopausal, and RMI were 93.5%, 87.1%, 80%, 95.2%, and 87.1%, respectively. The most accurate numerical values were obtained with RMI, although the four parameters were shown to be statistically equivalent. CONCLUSION: There were no differences in accuracy between CA125, HE4, ROMA, and RMI for differentiating between types of ovarian masses. RMI had the lowest sensitivity but was the most numerically accurate method. HE4 demonstrated the best overall sensitivity for the evaluation of malignant ovarian tumors and the differential diagnosis of endometriosis. All of the parameters demonstrated increased sensitivity when tumors with low malignancy potential were considered low-risk, which may be used as an acceptable assessment method for referring patients to reference centers.

Overexpression of SnoN/SkiL, amplified at the 3q26.2 locus, in ovarian cancers: A role in ovarian pathogenesis

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Nanjundan, Meera; Cheng, Kwai Wa; Zhang, Fan; Lahad, John; Kuo, Wen-Lin; Schmandt, Rosemarie; Smith-McCune, Karen; Fishman, David; Gray, Joe W.; Mills, Gordon B.

2008-07-18

High-resolution array comparative genomic hybridization of 235 serous epithelial ovarian cancers demonstrated a regional increase at 3q26.2 encompassing SnoN/SkiL, a coregulator of SMAD/TGF{beta} signaling. SnoN RNA transcripts were elevated in {approx}80% of advanced stage serous epithelial ovarian cancers. In both immortalized normal (TIOSE) and ovarian carcinoma cell lines (OVCA), SnoN RNA levels were increased by TGF{beta} stimulation and altered by LY294002 and JNK II inhibitor treatment suggesting that the PI3K and JNK signaling pathways may regulate TGF{beta}-induced increases in SnoN RNA. In TIOSE, SnoN protein levels were reduced 15min post TGF{beta}-stimulation, likely by proteosome-mediated degradation. In contrast, in OVCA, SnoN levels were elevated 3h post-stimulation potentially as a result of inhibition of the proteosome. To elucidate the role of SnoN in ovarian tumorigenesis, we explored the effects of both increasing and decreasing SnoN levels. In both TIOSE and OVCA, SnoN siRNA decreased cell growth between 20 and 50% concurrent with increased p21 levels. In TIOSE, transient expression of SnoN repressed TGF{beta} induction of PAI-1 promoters with little effect on the p21 promoter or resultant cell growth. In contrast to the effects of transient expression, stable expression of SnoN in TIOSE led to growth arrest through induction of senescence. Collectively, these results implicate SnoN levels in multiple roles during ovarian carcinogenesis: promoting cellular proliferation in ovarian cancer cells and as a positive mediator of cell cycle arrest and senescence in non-transformed ovarian epithelial cells.

The diagnostic value of determination of serum GOLPH3 associated with CA125, CA19.9 in patients with ovarian cancer.

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Fan, H-Y; Duan, D-M; Liu, Y-F

2017-09-01

To evaluate the value of three tumor markers serum Golgi phosphoprotein-3 (GOLPH3), cancer antigen 125 (CA125) and cancer antigen 19-9 (CA19.9) in the diagnosis and postoperative evaluation of ovarian cancer by detecting these three markers. A total of 187 patients were studied and included in the ovarian cancer group, benign pelvic mass group, and the normal control group. The levels of serum Golgi phosphoprotein-3 (GOLPH3), cancer antigen 125 (CA125) and cancer antigen 199 (CA19.9) were detected, respectively, and their effects on the diagnosis, evaluation, pathology typing and staging of ovarian cancer were measured. The sensitivity of the detection of ovarian cancer by GOLPH3 combined with CA125 and CA19.9 was higher than that by a single marker (pserum GOLPH3 in patients with serous and endometrioid carcinoma was significantly higher than that in patients with mucinous carcinoma, clear-cell carcinoma and germ cell tumor (pserum GOLPH3 level between patients with ovarian malignancies at stage III-IV and those at stage I-II (p>0.05). The levels of serum GOLPH3, CA125 and CA19.9 in patients with ovarian malignancies after surgery were significantly lower than those before surgery (p<0.05). The combined detection by GOLPH3, CA125, and CA19.9 may improve the diagnosis rate of ovarian epithelial cancer. GOLPH3, as a new ovarian cancer tumor marker used in clinical diagnosis, is expected to become an important indicator for the early diagnosis of ovarian cancer and the determination of clinical surgery efficacy.

TP53 mutations in ovarian carcinomas from sporadic cases and carriers of two distinct BRCA1 founder mutations; relation to age at diagnosis and survival

International Nuclear Information System (INIS)

Kringen, Pedro; Wang, Yun; Dumeaux, Vanessa; Kristensen, Gunnar; Borresen-Dale, Anne-Lise; Dorum, Anne

2005-01-01

Ovarian carcinomas from 30 BRCA1 germ-line carriers of two distinct high penetrant founder mutations, 20 carrying the 1675delA and 10 the 1135insA, and 100 sporadic cases were characterized for somatic mutations in the TP53 gene. We analyzed differences in relation to BRCA1 germline status, TP53 status, survival and age at diagnosis, as previous studies have not been conclusive. DNA was extracted from paraffin embedded formalin fixed tissues for the familial cases, and from fresh frozen specimen from the sporadic cases. All cases were treated at our hospital according to protocol. Mutation analyses of exon 2 – 11 were performed using TTGE, followed by sequencing. Survival rates for BRCA1-familial cases with TP53 mutations were not significantly lower than for familial cases without TP53 mutations (p = 0.25, RR = 1.64, 95% CI [0.71–3.78]). Median age at diagnosis for sporadic (59 years) and familial (49 years) cases differed significantly (p < 0.001) with or without TP53 mutations. Age at diagnosis between the two types of familial carriers were not significantly different, with median age of 47 for 1675delA and 52.5 for 1135insA carriers (p = 0.245). For cases ≥50 years at diagnosis, a trend toward longer survival for sporadic over familial cases was observed (p = 0.08). The opposite trend was observed for cases <50 years at diagnosis. There do not seem to be a protective advantage for familial BRCA1 carriers without TP53 mutations over familial cases with TP53 mutations. However, there seem to be a trend towards initial advantage in survival for familial cases compared to sporadic cases diagnosed before the age of 50 both with and without TP53 mutations. However, this trend diminishes over time and for cases diagnosed ≥50 years the sporadic cases show a trend towards an advantage in survival over familial cases. Although this data set is small, if confirmed, this may be a link in the evidence that the differences in ovarian cancer survival reported, are

Cisplatin Resistant Spheroids Model Clinically Relevant Survival Mechanisms in Ovarian Tumors.

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Winyoo Chowanadisai

Full Text Available The majority of ovarian tumors eventually recur in a drug resistant form. Using cisplatin sensitive and resistant cell lines assembled into 3D spheroids we profiled gene expression and identified candidate mechanisms and biological pathways associated with cisplatin resistance. OVCAR-8 human ovarian carcinoma cells were exposed to sub-lethal concentrations of cisplatin to create a matched cisplatin-resistant cell line, OVCAR-8R. Genome-wide gene expression profiling of sensitive and resistant ovarian cancer spheroids identified 3,331 significantly differentially expressed probesets coding for 3,139 distinct protein-coding genes (Fc >2, FDR < 0.05 (S2 Table. Despite significant expression changes in some transporters including MDR1, cisplatin resistance was not associated with differences in intracellular cisplatin concentration. Cisplatin resistant cells were significantly enriched for a mesenchymal gene expression signature. OVCAR-8R resistance derived gene sets were significantly more biased to patients with shorter survival. From the most differentially expressed genes, we derived a 17-gene expression signature that identifies ovarian cancer patients with shorter overall survival in three independent datasets. We propose that the use of cisplatin resistant cell lines in 3D spheroid models is a viable approach to gain insight into resistance mechanisms relevant to ovarian tumors in patients. Our data support the emerging concept that ovarian cancers can acquire drug resistance through an epithelial-to-mesenchymal transition.

High Expression of SQSTM1/p62 Protein Is Associated with Poor Prognosis in Epithelial Ovarian Cancer

International Nuclear Information System (INIS)

Iwadate, Reiko; Inoue, Jun; Tsuda, Hitoshi; Takano, Masashi; Furuya, Kenichi; Hirasawa, Akira; Aoki, Daisuke; Inazawa, Johji

2014-01-01

High expression of SQSTM1/p62 (p62) protein, which functions as a hub for various cellular signaling pathways, has been detected in several human cancers. However, the clinicopathological impact of high p62 expression is largely unknown in epithelial ovarian cancer (EOC). Here, the expression level of p62 in primary EOCs (n=266) was assessed by immunohistochemistry, and its clinical significance was analyzed. Univariate and multivariate analyses were used to determine the impact of p62 expression on overall survival. p62 was expressed in the cytoplasm (Cyto) and/or nucleus (Nuc) in primary EOCs, and an expression subtype (Cyto High /Nuc Low ), showing high expression in the cytoplasm but low expression in the nucleus, was significantly correlated with serous carcinoma (P<0.001), advanced stage (P=0.005), presence of residual tumor (P<0.001), and low overall survival rate (P=0.013). Furthermore, in serous carcinomas (n=107), the p62 Cyto High /Nuc Low subtype was significantly correlated with low overall survival rate (P=0.019) as an independent factor (P=0.044). Thus, our findings suggest that high expression of cytoplasmic p62 may be a novel prognostic biomarker in EOC, particularly in serous carcinoma

Macrophage Capping Protein CapG Is a Putative Oncogene Involved in Migration and Invasiveness in Ovarian Carcinoma

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J. Glaser

2014-01-01

Full Text Available The actin binding protein CapG modulates cell motility by interacting with the cytoskeleton. CapG is associated with tumor progression in different nongynecologic tumor entities and overexpression in breast cancer cell lines correlates with a more invasive phenotype in vitro. Here, we report a significant CapG overexpression in 18/47 (38% of ovarian carcinomas (OC analyzed by qRealTime-PCR analyses. Functional analyses in OC cell lines through siRNA mediated CapG knockdown and CapG overexpression showed CapG-dependent cell migration and invasiveness. A single nucleotide polymorphism rs6886 inside the CapG gene was identified, affecting a CapG phosphorylation site and thus potentially modifying CapG function. The minor allele frequency (MAF of SNP rs6886 (c.1004A/G was higher and the homozygous (A/A, His335 genotype was significantly more prevalent in patients with fallopian tube carcinomas (50% as in controls (10%. With OC being one of the most lethal cancer diseases, the detection of novel biomarkers such as CapG could reveal new diagnostic and therapeutic targets. Moreover, in-depth analyses of SNP rs6886 related to FTC and OC will contribute to a better understanding of carcinogenesis and progression of OC.

Nuclear COMMD1 Is Associated with Cisplatin Sensitivity in Ovarian Cancer.

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Alina Fedoseienko

Full Text Available Copper metabolism MURR1 domain 1 (COMMD1 protein is a multifunctional protein, and its expression has been correlated with patients' survival in different types of cancer. In vitro studies revealed that COMMD1 plays a role in sensitizing cancer cell lines to cisplatin, however, the mechanism and its role in platinum sensitivity in cancer has yet to be established. We evaluated the role of COMMD1 in cisplatin sensitivity in A2780 ovarian cancer cells and the relation between COMMD1 expression and response to platinum-based therapy in advanced stage high-grade serous ovarian cancer (HGSOC patients. We found that elevation of nuclear COMMD1 expression sensitized A2780 ovarian cancer cells to cisplatin-mediated cytotoxicity. This was accompanied by a more effective G2/M checkpoint, and decreased protein expression of the DNA repair gene BRCA1, and the apoptosis inhibitor BCL2. Furthermore, COMMD1 expression was immunohistochemically analyzed in two tissue micro-arrays (TMAs, representing a historical cohort and a randomized clinical trial-based cohort of advanced stage HGSOC tumor specimens. Expression of COMMD1 was observed in all ovarian cancer samples, however, specifically nuclear expression of COMMD1 was only observed in a subset of ovarian cancers. In our historical cohort, nuclear COMMD1 expression was associated with an improved response to chemotherapy (OR = 0.167; P = 0.038, although this association could not be confirmed in the second cohort, likely due to sample size. Taken together, these results suggest that nuclear expression of COMMD1 sensitize ovarian cancer to cisplatin, possibly by modulating the G2/M checkpoint and through controlling expression of genes involved in DNA repair and apoptosis.

Termination of Pregnancy in a Patient with Advanced Ovarian Cancer

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Suna Özdemir

2010-04-01

Full Text Available Ovarian cancer during pregnancy is a rare entity and the management of the disease can be challenging for the patient and the clinician. In this case, we report a case of advanced ovarian carcinoma diagnosed during pregnancy, which was managed with termination of pregnancy and chemotheraphy. The patient was underwent exploratory laparatomy including the right ovarian cystectomy, omentectomy, appendectomy, pelvic and para-aortic lymphadenectomy after frozen section of borderline serous cystadenocarcinoma at the 14 week of gestation. After final histopathology, the patient was staged as having FIGO stage IIIC disease. The pregnancy was termineted with the decision of patient and her family. The patient was treated with chemotheraphy.

Clinicopathological and biological significance of aberrant activation of glycogen synthase kinase-3 in ovarian cancer

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Fu Y

2014-06-01

Full Text Available Yunfeng Fu,1 Xinyu Wang,1 Xiaodong Cheng,1 Feng Ye,2 Xing Xie,1,2 Weiguo Lu1,2 1Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, 2Women's Reproduction and Health Laboratory of Zhejiang Province, Hangzhou, People's Republic of China Background: Glycogen synthase kinase-3 (GSK-3 plays an important role in human cancer. The aim of this study is to evaluate the clinicopathological significance of expression of GSK-3α/β and pGSK-3α/βTyr279/216 in patients with epithelial ovarian cancer and to investigate whether GSK-3 inhibition can influence cell viability and tumor growth of ovarian cancer. Methods: Immunohistochemistry was used to examine expression of GSK-3α/β and pGSK-3α/βTyr279/216 in 71 human epithelial ovarian cancer tissues and correlations between protein expression, and clinicopathological factors were analyzed. Cell viability was determined by 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT assay following exposure of ovarian carcinoma cells to pharmacological inhibitors of GSK-3 or GSK-3 small interfering RNA. In vivo validation of tumor growth inhibition was performed with xenograft mice. Results: The expression levels of GSK-3α/β and pGSK-3α/βTyr279/216 in ovarian cancers were significantly higher than those in benign tumors. High expression of GSK-3α/β was more likely to be found in patients with advanced International Federation of Gynecology and Obstetrics (FIGO stages and high serum cancer antigen 125. Higher expression of pGSK-3α/βTyr279/216 was associated with advanced FIGO stages, residual tumor mass, high serum cancer antigen 125, and poor chemoresponse. Worse overall survival was revealed by Kaplan–Meier survival curves in patients with high expression of GSK-3α/β or pGSK-3α/βTyr279/216. Multivariate analysis indicated that FIGO stage, GSK-3α/β expression, and pGSK-3α/βTyr279/216 expression were independent prognostic factors for overall

Infrequent Expression of the Cancer-Testis Antigen, PASD1, in Ovarian Cancer

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Ghazala Khan

2015-01-01

Full Text Available Ovarian cancer is very treatable in the early stages of disease; however, it is usually detected in the later stages, at which time, treatment is no longer as effective. If discovered early (Stage I, there is a 90% chance of five-year survival. Therefore, it is imperative that early-stage biomarkers are identified to enhance the early detection of ovarian cancer. Cancer-testis antigens (CTAs, such as Per ARNT SIM (PAS domain containing 1 (PASD1, are unique in that their expression is restricted to immunologically restricted sites, such as the testis and placenta, which do not express MHC class I, and cancer, making them ideally positioned to act as targets for immunotherapy as well as potential biomarkers for cancer detection where expressed. We examined the expression of PASD1a and b in a number of cell lines, as well as eight healthy ovary samples, eight normal adjacent ovarian tissues, and 191 ovarian cancer tissues, which were predominantly stage I ( n = 164 and stage II ( n = 14 disease. We found that despite the positive staining of skin cancer, only one stage Ic ovarian cancer patient tissue expressed PASD1a and b at detectable levels. This may reflect the predominantly stage I ovarian cancer samples examined. To examine the restriction of PASD1 expression, we examined endometrial tissue arrays and found no expression in 30 malignant tumor tissues, 23 cases of hyperplasia, or 16 normal endometrial tissues. Our study suggests that the search for a single cancer-testes antigen/biomarker that can detect early ovarian cancer must continue.

Low or undetectable TPO receptor expression in malignant tissue and cell lines derived from breast, lung, and ovarian tumors

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Erickson-Miller Connie L

2012-09-01

Full Text Available Abstract Background Numerous efficacious chemotherapy regimens may cause thrombocytopenia. Thrombopoietin receptor (TPO-R agonists, such as eltrombopag, represent a novel approach for the treatment of chemotherapy-induced thrombocytopenia. The TPO-R MPL is expressed on megakaryocytes and megakaryocyte precursors, although little is known about its expression on other tissues. Methods Breast, lung, and ovarian tumor samples were analyzed for MPL expression by microarray and/or quantitative reverse transcription-polymerase chain reaction (qRT-PCR, and for TPO-R protein expression by immunohistochemistry (IHC. Cell line proliferation assays were used to analyze the in vitro effect of eltrombopag on breast, lung, and ovarian tumor cell proliferation. The lung carcinoma cell lines were also analyzed for TPO-R protein expression by Western blot. Results MPL mRNA was not detectable in 118 breast tumors and was detectable at only very low levels in 48% of 29 lung tumors studied by microarray analysis. By qRT-PCR, low but detectable levels of MPL mRNA were detectable in some normal (14-43% and malignant (3-17% breast, lung, and ovarian tissues. A comparison of MPL to EPOR, ERBB2, and IGF1R mRNA demonstrates that MPL mRNA levels were far lower than those of EPOR and ERBB2 mRNA in the same tissues. IHC analysis showed negligible TPO-R protein expression in tumor tissues, confirming mRNA analysis. Culture of breast, lung, and ovarian carcinoma cell lines showed no increase, and in fact, showed a decrease in proliferation following incubation with eltrombopag. Western blot analyses revealed no detectable TPO-R protein expression in the lung carcinoma cell lines. Conclusions Multiple analyses of breast, lung, and ovarian tumor samples and/or cell lines show no evidence of MPL mRNA or TPO-R protein expression. Eltrombopag does not stimulate growth of breast, lung, or ovarian tumor cell lines at doses likely to exert their actions on megakaryocytes and

Gorlin syndrome with an ovarian leiomyoma associated with a PTCH1 second hit.

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Akizawa, Yoshika; Miyashita, Toshiyuki; Sasaki, Ryo; Nagata, Reiko; Aoki, Ryoko; Ishitani, Ken; Nagashima, Yoji; Matsui, Hideo; Saito, Kayoko

2016-04-01

We describe a Gorlin syndrome (GS) case with two different second hit mutations of PTCH1, one in a keratocystic odontogenic tumor (KCOT) and the other in an ovarian leiomyoma. GS is a rare genetic condition manifesting as multiple basal cell nevi associated with other features such as medulloblastomas, skeletal abnormalities, and ovarian fibromas. A 21-year-old Japanese woman with a history of two KCOTs was diagnosed with GS according to clinical criteria. A PTCH1 mutation, c.1427del T, was detected in peripheral blood. A novel PTCH1 mutation, c.264_265insAATA, had been found in the maxillary KCOT as a second hit mutation. More recently, the ovarian tumor was detected during a gynecological examination. Laparoscopic adnexectomy was performed, and the pathological diagnosis of the ovarian tumor was leiomyoma. Interestingly, another novel mutation, loss of heterozygosity spanning from 9q22.32 to 9q31.2, including PTCH1 and 89 other genes, was detected in this ovarian tumor, providing evidence of a second hit mutation. This is the first report describing a GS-associated ovarian tumor carrying a second hit in the PTCH1 region. We anticipate that accumulation of more cases will clarify the importance of second hit mutations in ovarian tumor formation in GS. © 2016 Wiley Periodicals, Inc.

DC-CIK cells derived from ovarian cancer patient menstrual blood activate the TNFR1-ASK1-AIP1 pathway to kill autologous ovarian cancer stem cells.

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Qin, Wenxing; Xiong, Ying; Chen, Juan; Huang, Yongyi; Liu, Te

2018-03-22

Ovarian cancer stem cells (OCSCs) are highly carcinogenic and have very strong resistance to traditional chemotherapeutic drugs; therefore, they are an important factor in ovarian cancer metastasis and recurrence. It has been reported that dendritic cell (DC)-cytokine-induced killer (CIK) cells have significant killing effects on all cancer cells across many systems including the blood, digestive, respiratory, urinary and reproductive systems. However, whether DC-CIK cells can selectively kill OCSCs is currently unclear. In this study, we collected ovarian cancer patient menstrual blood (OCPMB) samples to acquire mononuclear cells and isolated DC-CIK cells in vitro. In addition, autologous CD44+/CD133+ OCSCs were isolated and used as target cells. The experimental results showed that when DC-CIK cells and OCSCs were mixed and cultured in vitro at ratios of 5:1, 10:1 and 50:1, the DC-CIK cells killed significant amounts of OCSCs, inhibited their invasion in vitro and promoted their apoptosis. The qPCR and Western blot results showed that DC-CIK cells stimulated high expression levels and phosphorylation of TNFR1, ASK1, AIP1 and JNK in OCSCs through the release of TNF-α. After the endogenous TNFR1 gene was knocked out in OCSCs using the CRISPR/Cas9 technology, the killing function of DC-CIK cells on target OCSCs was significantly attenuated. The results of the analyses of clinical samples suggested that the TNFR1 expression level was negatively correlated with ovarian cancer stage and prognosis. Therefore, we innovatively confirmed that DC-CIK cells derived from OCPMB could secret TNF-α to activate the expression of the TNFR1-ASK1-AIP1-JNK pathway in OCSCs and kill autologous OCSCs. © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

[The molecular biology of epithelial ovarian cancer].

Science.gov (United States)

Leary, Alexandra; Pautier, Patricia; Tazi, Youssef; Morice, Philippe; Duvillard, Pierre; Gouy, Sébastien; Uzan, Catherine; Gauthier, Hélène; Balleyguier, Corinne; Lhommé, Catherine

2012-12-01

Epithelial ovarian cancer frequently presents at an advanced stage where the cornerstone of management remains surgery and platinum-based chemotherapy. Unfortunately, despite sometimes dramatic initial responses, advanced ovarian cancer almost invariably relapses. Little progress has been made in the identification of effective targeted-therapies for ovarian cancer. The majority of clinical trials investigating novel agents have been negative and the only approved targeted-therapy is bevacizumab, for which reliable predictive biomarkers still elude us. Ovarian cancer is treated as a uniform disease. Yet, biological studies have highlighted the heterogeneity of this malignancy with marked differences in histology, oncogenesis, prognosis, chemo-responsiveness, and molecular profile. Recent high throughput molecular analyses have identified a huge number of genomic/phenotypic alterations. Broadly speaking, high grade serous carcinomas (type II) display significant genomic instability and numerous amplifications and losses; low grade (type I) tumors are genomically stable but display frequent mutations. Importantly, many of these genomic alterations relate to known oncogenes for which targeted-therapies are available or in development. There is today a real potential for personalized medicine in ovarian cancer. We will review the current literature regarding the molecular characterization of epithelial ovarian cancer and discuss the biological rationale for a number of targeted strategies. In order to translate these biological advances into meaningful clinical improvements for our patients, it is imperative to incorporate translational research in ovarian cancer trials, a number of strategies will be proposed such as the acquisition of quality tumor samples, including sequential pre- and post-treatment biopsies, the potential of liquid biopsies, and novel trial designs more adapted to the molecular era of ovarian cancer research.

CYP1B1, Oxidative Stress, and Inflammation in the Etiology of Ovarian Epithelial Cancer Using an Avian Model of Ovarian Carcinoma

Science.gov (United States)

2007-11-01

fibrovascular cores lined by atypical epithelial cells. Tumors 7 resembling human endometrioid carcinomas were generally characterized by a complex 8...presence of focal lesions, glandular structures, cells with pleomorphic nucleus with mitotic bodies and hyperplastic surface or stromal hyperplasia ...Non-tumor pathologies included increased atresia of developing stromal follicles, cystic structures, hyperplasia without any focal lesion or malignant

Conservative Management of Ovarian Fibroma in A Case of Gorlin-Goltz Syndrome Comorbid with Endometriosis.

Science.gov (United States)

Khodaverdi, Sepideh; Nazari, Leila; Mehdizadeh-Kashi, Abolfazl; Vahdat, Mansoureh; Rokhgireh, Samaneh; Farbod, Ali; Tajbakhsh, Banafsheh

2018-04-01

Ovarian fibromas are the most common benign solid ovarian tumors, which are often difficult to diagnose preoperatively. Ovarian fibromas, especially in bilateral cases, may be cases of Gorlin-Goltz syndrome (GGS), a rare autosomal dominant disorder with predisposition to basal cell carcinomas (BCCs) and other various benign and malignant tumors. This case report describes a 25 year-old female with GGS, bilateral ovarian fibroma, endometriosis and septated uterus, which was referred to the Gynecology Clinic of Rasoul-e-Akram Hospital in October 2016. This patient had facial asymmetry due to recurrent odontogenic keratocysts. In young cases of ovarian fibromas as reported here, conservative surgical management can preserve ovarian function and fertility. These patients must be followed up by a multidisciplinary team and submitted to periodic tests. Copyright© by Royan Institute. All rights reserved.

Conservative Management of Ovarian Fibroma in A Case of Gorlin-Goltz Syndrome Comorbid with Endometriosis

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Sepideh Khodaverdi

2018-01-01

Full Text Available Ovarian fibromas are the most common benign solid ovarian tumors, which are often difficult to diagnose preoperatively. Ovarian fibromas, especially in bilateral cases, may be cases of Gorlin-Goltz syndrome (GGS, a rare autosomal dominant disorder with predisposition to basal cell carcinomas (BCCs and other various benign and malignant tumors. This case report describes a 25 year-old female with GGS, bilateral ovarian fibroma, endometriosis and septated uterus, which was referred to the Gynecology Clinic of Rasoul-e-Akram Hospital in October 2016. This patient had facial asymmetry due to recurrent odontogenic keratocysts. In young cases of ovarian fibromas as reported here, conservative surgical management can preserve ovarian function and fertility. These patients must be followed up by a multidisciplinary team and submitted to periodic tests.

TRPM7 is required for ovarian cancer cell growth, migration and invasion

Energy Technology Data Exchange (ETDEWEB)

Wang, Jing; Liao, Qian-jin [The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013 (China); Zhang, Yi [Department of Obstetrics and Gynaecology, Xiangya Hospital, Central South University, Changsha 410078 (China); Zhou, Hui; Luo, Chen-hui; Tang, Jie; Wang, Ying; Tang, Yan; Zhao, Min; Zhao, Xue-heng [The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013 (China); Zhang, Qiong-yu [Department of Basic Medical Science, Yongzhou Vocational Technical College, Yong Zhou 425100 (China); Xiao, Ling, E-mail: lingxiaocsu@126.com [Department of Histology and Embryology, School of Basic Medical Sciences, Central South University, Changsha 410013 (China); Institute of Clinical Pharmacology, Central South University, Changsha 410018 (China)

2014-11-28

Highlights: • Silence of TRPM7 in ovarian cancer cells inhibits cell proliferation, migration and invasion. • Silence of TRPM7 decreases phosphorylation levels of Akt, Src and p38 in ovarian cancer cells. • Silence of TRPM7 increases expression of filamentous actin and number of focal adhesions in ovarian cancer cells. - Abstract: Our previous study demonstrated that the melastatin-related transient receptor potential channel 7 (TRPM7) was highly expressed in ovarian carcinomas and its overexpression was significantly associated with poor prognosis in ovarian cancer patients. However, the function of TRPM7 in ovarian cancer is mostly unknown. In this study, we examined the roles of TRPM7 in ovarian cancer cell proliferation, migration and invasion. We found that short hairpin RNA interference-mediated silence of TRPM7 significantly inhibited cell proliferation, colony formation, migration and invasion in multiple ovarian cancer cell lines. Mechanistic investigation revealed that silence of TRPM7 decreased phosphorylation levels of Akt, Src and p38 and increased filamentous actin and focal adhesion number in ovarian cancer cells. Thus, our results suggest that TRPM7 is required for proliferation, migration and invasion of ovarian cancer cells through regulating multiple signaling transduction pathways and the formation of focal adhesions.

Primary pelvic hydatic cyst mimicking ovarian carcinoma

OpenAIRE

Faruk Abike; Ilkkan Dunder; Omer Lutfi Tapisiz; Osman Temizkan; Banu Bingol; Ahmet Payasli; Lale Kutluay

2011-01-01

Hydatic cyst is an illness that appears in consequence of the cystic form of small strap-shaped worm Echinococcus granulosis. Frequently, cysts exist in the lungs and liver. Peritoneal involvement is rare, and generally occurs as a result of second inoculation from rupture of a liver-located hydatic cyst. Primary ovarian hydatic cyst is very rare. A 56-year-old female patient was admitted to Emergency Service with the complaint of stomachache and swollen abdomen. From ultrasonographic examina...

Surgical treatment of gastric carcinoma with ovarian metastases

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Olesinski Tomasz

2017-12-01

Full Text Available Ovarian metastases from extragenital neoplasms are rare. The prevalent sites of the primary tumors were the breast, colorectum and the stomach. The Krukenberg tumor (KT is defined as a gastrointestinal cancer which metastasized to the ovaries. Metastasis to the ovary may appear at the time of diagnosis of the primary tumor (synchronous or during observation (metachronous. Common clinical presentations are abdominal distention, pain, palpable mass, bloating, ascites or pain during sexual intercourse. Diagnosis can be made by ultrasound examinations, CT or EMR scans, laparotomy and/or a biopsy of the ovary. The current standard treatment for patients with metastatic gastric cancer is systemic chemotherapy, however, treatment strategy for KTs from gastric cancer has not been clearly established and surgical treatment is considered mainly for metachronous tumors. The prognosis of patients with ovarian metastasis of gastric cancer origin is poorer compared with that of other primary tumors. Although the results of cytoreductive surgery – especially in combination with modern chemotherapy – seems to be promising, the optimal therapeutic strategies for such patients requires further prospective studies.

Avelumab (anti-PD-L1) in platinum-resistant/refractory ovarian cancer: JAVELIN Ovarian 200 Phase III study design.

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Pujade-Lauraine, Eric; Fujiwara, Keiichi; Dychter, Samuel S; Devgan, Geeta; Monk, Bradley J

2018-03-27

Avelumab is a human anti-PD-L1 checkpoint inhibitor with clinical activity in multiple solid tumors. Here, we describe the rationale and design for JAVELIN Ovarian 200 (NCT02580058), the first randomized Phase III trial to evaluate the role of checkpoint inhibition in women with ovarian cancer. This three-arm trial is comparing avelumab administered alone or in combination with pegylated liposomal doxorubicin versus pegylated liposomal doxorubicin alone in patients with platinum-resistant/refractory recurrent ovarian, fallopian tube or peritoneal cancer. Eligible patients are not preselected based on PD-L1 expression and may have received up to three prior lines of chemotherapy for platinum-sensitive disease, but none for resistant disease. Overall survival and progression-free survival are primary end points, and secondary end points include biomarker evaluations and pharmacokinetics.

Ovarian cancer-related hypophosphatemic osteomalacia--a case report.

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Lin, Hung-An; Shih, Shyang-Rong; Tseng, Yu-Ting; Chen, Chi-Hau; Chiu, Wei-Yih; Hsu, Chih-Yao; Tsai, Keh-Sung

2014-12-01

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused primarily by benign mesenchymal tumors. It has been associated with malignancies in rare cases. High serum levels of fibroblast growth factor (FGF) 23 reported in a group of patients with ovarian cancer had normal serum phosphate levels. There had been no ovarian cancer-related hypophosphatemic osteomalacia in a search of the literature. We investigated a 57-year-old woman with progressive low back pain. Clinical, biochemical, and radiological assessments were performed. The patient's serum phosphate and FGF23 levels were evaluated at baseline and after treatment for ovarian cancer. The patient presented with progressive low back pain and weight loss during the previous 6 months. Imaging studies revealed low bone mineral density and multiple suspicious spinal metastatic lesions. Laboratory examination showed hypophosphatemia, hyperphosphaturia, normocalcemia, an elevated serum alkaline phosphatase level, and an elevated serum FGF23 level. Because TIO was suspected, a tumor survey was performed, and ovarian carcinoma with multiple metastasis was detected. After surgery and chemotherapy treatments for ovarian cancer, the serum phosphate and FGF23 levels returned to normal, and the low back pain improved. To our knowledge, this is the first case of ovarian cancer-related hypophosphatemic osteomalacia reported in the literature. TIO should be considered in patients with ovarian cancer presenting with weakness, bone pain, and fractures. Investigation of TIO is appropriate when these patients present hypophosphatemia.

Ovarian Cancer-Related Hypophosphatemic Osteomalacia—A Case Report

Science.gov (United States)

Lin, Hung-An; Shih, Shyang-Rong; Tseng, Yu-Ting; Chen, Chi-Hau; Chiu, Wei-Yih; Hsu, Chih-Yao

2014-01-01

Context: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused primarily by benign mesenchymal tumors. It has been associated with malignancies in rare cases. High serum levels of fibroblast growth factor (FGF) 23 reported in a group of patients with ovarian cancer had normal serum phosphate levels. There had been no ovarian cancer-related hypophosphatemic osteomalacia in a search of the literature. Objective: We investigated a 57-year-old woman with progressive low back pain. Design and Intervention: Clinical, biochemical, and radiological assessments were performed. The patient's serum phosphate and FGF23 levels were evaluated at baseline and after treatment for ovarian cancer. Results: The patient presented with progressive low back pain and weight loss during the previous 6 months. Imaging studies revealed low bone mineral density and multiple suspicious spinal metastatic lesions. Laboratory examination showed hypophosphatemia, hyperphosphaturia, normocalcemia, an elevated serum alkaline phosphatase level, and an elevated serum FGF23 level. Because TIO was suspected, a tumor survey was performed, and ovarian carcinoma with multiple metastasis was detected. After surgery and chemotherapy treatments for ovarian cancer, the serum phosphate and FGF23 levels returned to normal, and the low back pain improved. Conclusions: To our knowledge, this is the first case of ovarian cancer-related hypophosphatemic osteomalacia reported in the literature. TIO should be considered in patients with ovarian cancer presenting with weakness, bone pain, and fractures. Investigation of TIO is appropriate when these patients present hypophosphatemia. PMID:25181387

SERPINB3 in the chicken model of ovarian cancer: a prognostic factor for platinum resistance and survival in patients with epithelial ovarian cancer.

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Whasun Lim

Full Text Available Serine protease inhibitors (SERPINs appear to be ubiquitously expressed in a variety of species and play important roles in pivotal physiological processes such as angiogenesis, immune responses, blood coagulation and fibronolysis. Of these, squamous cell carcinoma antigen 1 (SCCA1, also known as a SERPINB3, was first identified in squamous cell carcinoma tissue from the cervix of women. However, there is little known about the SERPINB3 expression in human epithelial ovarian cancer (EOC. Therefore, in the present study, we investigated the functional role of SERPINB3 gene in human EOC using chickens, the most relevant animal model. In 136 chickens, EOC was found in 10 (7.4%. SERPINB3 mRNA was induced in cancerous, but not normal ovaries of chickens (P<0.01, and it was abundant only in the glandular epithelium of cancerous ovaries of chickens. Further, several microRNAs, specifically miR-101, miR-1668 and miR-1681 were discovered to influence SERPINB3 expression via its 3'-UTR which suggests that post-transcriptional regulation influences SERPINB3 expression in chickens. SERPINB3 protein was localized predominantly to the glandular epithelium in cancerous ovaries of chickens, and it was abundant in the nucleus of both chicken and human ovarian cancer cell lines. In 109 human patients with EOC, 15 (13.8%, 66 (60.6% and 28 (25.7% patients showed weak, moderate and strong expression of SERPINB3 protein, respectively. Strong expression of SERPINB3 protein was a prognostic factor for platinum resistance (adjusted OR; odds ratio, 5.94; 95% Confidence Limits, 1.21-29.15, and for poor progression-free survival (PFS; adjusted HR; hazard ratio, 2.07; 95% CI; confidence interval, 1.03-4.41. Therefore, SERPINB3 may play an important role in ovarian carcinogenesis and be a novel biomarker for predicting platinum resistance and a poor prognosis for survival in patients with EOC.

The MyD88+ phenotype is an adverse prognostic factor in epithelial ovarian cancer.

LENUS (Irish Health Repository)

d'Adhemar, Charles J

2014-01-01

The prognosis of epithelial ovarian cancer is poor in part due to the high frequency of chemoresistance. Recent evidence points to the Toll-like receptor-4 (TLR4), and particularly its adaptor protein MyD88, as one potential mediator of this resistance. This study aims to provide further evidence that MyD88 positive cancer cells are clinically significant, stem-like and reproducibly detectable for the purposes of prognostic stratification. Expression of TLR4 and MyD88 was assessed immunohistochemically in 198 paraffin-embedded ovarian tissues and in an embryonal carcinoma model of cancer stemness. In parallel, expression of TLR4 and MyD88 mRNA and regulatory microRNAs (miR-21 and miR-146a) was assessed, as well as in a series of chemosensitive and resistant cancer cells lines. Functional analysis of the pathway was assessed in chemoresistant SKOV-3 ovarian cancer cells. TLR4 and MyD88 expression can be reproducibly assessed via immunohistochemistry using a semi-quantitative scoring system. TLR4 expression was present in all ovarian epithelium (normal and neoplastic), whereas MyD88 was restricted to neoplastic cells, independent of tumour grade and associated with reduced progression-free and overall survival, in an immunohistological specific subset of serous carcinomas, p<0.05. MiR-21 and miR-146a expression was significantly increased in MyD88 negative cancers (p<0.05), indicating their participation in regulation. Significant alterations in MyD88 mRNA expression were observed between chemosensitive and chemoresistant cells and tissue. Knockdown of TLR4 in SKOV-3 ovarian cells recovered chemosensitivity. Knockdown of MyD88 alone did not. MyD88 expression was down-regulated in differentiated embryonal carcinoma (NTera2) cells, supporting the MyD88+ cancer stem cell hypothesis. Our findings demonstrate that expression of MyD88 is associated with significantly reduced patient survival and altered microRNA levels and suggest an intact\\/functioning TLR4\\/MyD88

The MyD88+ phenotype is an adverse prognostic factor in epithelial ovarian cancer.

Directory of Open Access Journals (Sweden)

Charles J d'Adhemar

Full Text Available The prognosis of epithelial ovarian cancer is poor in part due to the high frequency of chemoresistance. Recent evidence points to the Toll-like receptor-4 (TLR4, and particularly its adaptor protein MyD88, as one potential mediator of this resistance. This study aims to provide further evidence that MyD88 positive cancer cells are clinically significant, stem-like and reproducibly detectable for the purposes of prognostic stratification. Expression of TLR4 and MyD88 was assessed immunohistochemically in 198 paraffin-embedded ovarian tissues and in an embryonal carcinoma model of cancer stemness. In parallel, expression of TLR4 and MyD88 mRNA and regulatory microRNAs (miR-21 and miR-146a was assessed, as well as in a series of chemosensitive and resistant cancer cells lines. Functional analysis of the pathway was assessed in chemoresistant SKOV-3 ovarian cancer cells. TLR4 and MyD88 expression can be reproducibly assessed via immunohistochemistry using a semi-quantitative scoring system. TLR4 expression was present in all ovarian epithelium (normal and neoplastic, whereas MyD88 was restricted to neoplastic cells, independent of tumour grade and associated with reduced progression-free and overall survival, in an immunohistological specific subset of serous carcinomas, p<0.05. MiR-21 and miR-146a expression was significantly increased in MyD88 negative cancers (p<0.05, indicating their participation in regulation. Significant alterations in MyD88 mRNA expression were observed between chemosensitive and chemoresistant cells and tissue. Knockdown of TLR4 in SKOV-3 ovarian cells recovered chemosensitivity. Knockdown of MyD88 alone did not. MyD88 expression was down-regulated in differentiated embryonal carcinoma (NTera2 cells, supporting the MyD88+ cancer stem cell hypothesis. Our findings demonstrate that expression of MyD88 is associated with significantly reduced patient survival and altered microRNA levels and suggest an intact/functioning TLR4

Exosomal microRNA Signatures in the Diagnosis and Prognosis of Ovarian Cancer

Science.gov (United States)

2013-10-01

including CLL ,41 breast cancer,42 glioblastoma,43 thyroid papillary carcinoma,44 hepatocellular carcinoma,45 ovarian cancer,46 colon...modify cancer cell gene expression. Extracellular vesicles derived from cancer stem cells were shown to contain pro-angiogenic RNAs able to induce a pre...content differs. Extracellular vesicles from cancer stem cells contained miR29a, miR650, and miR151, all associated with tumor invasion and

Breast and ovarian cancers: a survey and possible roles for the cell surface heparan sulfate proteoglycans

DEFF Research Database (Denmark)

Yoneda, Atsuko; Lendorf, Maria E; Couchman, John R

2012-01-01

. Occurrence of breast and ovarian cancer is high in older women. Common known risk factors of developing these cancers in addition to age are not having children or having children at a later age, the use of hormone replacement therapy, and mutations in certain genes. In addition, women with a history......Tumor markers are widely used in pathology not only for diagnostic purposes but also to assess the prognosis and to predict the treatment of the tumor. Because tumor marker levels may change over time, it is important to get a better understanding of the molecular changes during tumor progression...... of breast cancer may also develop ovarian cancer. Here, the authors review the different tumor markers of breast and ovarian carcinoma and discuss the expression, mutations, and possible roles of cell surface heparan sulfate proteoglycans during tumorigenesis of these carcinomas. The focus is on two groups...

Prevalence of BRCA1 mutations in familial and sporadic greek ovarian cancer cases.

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Alexandra V Stavropoulou

Full Text Available Germline mutations in the BRCA1 and BRCA2 genes contribute to approximately 18% of hereditary ovarian cancers conferring an estimated lifetime risk from 15% to 50%. A variable incidence of mutations has been reported for these genes in ovarian cancer cases from different populations. In Greece, six mutations in BRCA1 account for 63% of all mutations detected in both BRCA1 and BRCA2 genes. This study aimed to determine the prevalence of BRCA1 mutations in a Greek cohort of 106 familial ovarian cancer patients that had strong family history or metachronous breast cancer and 592 sporadic ovarian cancer cases. All 698 patients were screened for the six recurrent Greek mutations (including founder mutations c.5266dupC, p.G1738R and the three large deletions of exon 20, exons 23-24 and exon 24. In familial cases, the BRCA1 gene was consequently screened for exons 5, 11, 12, 20, 21, 22, 23, 24. A deleterious BRCA1 mutation was found in 43/106 (40.6% of familial cancer cases and in 27/592 (4.6% of sporadic cases. The variant of unknown clinical significance p.V1833M was identified in 9/698 patients (1.3%. The majority of BRCA1 carriers (71.2% presented a high-grade serous phenotype. Identifying a mutation in the BRCA1 gene among breast and/or ovarian cancer families is important, as it enables carriers to take preventive measures. All ovarian cancer patients with a serous phenotype should be considered for genetic testing. Further studies are warranted to determine the prevalence of mutations in the rest of the BRCA1 gene, in the BRCA2 gene, and other novel predisposing genes for breast and ovarian cancer.

Relationship between promoter methylation & tissue expression of MGMT gene in ovarian cancer

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V Shilpa

2014-01-01

Full Text Available Background & objectives: Epigenetic alterations, in addition to multiple gene abnormalities, are involved in the genesis and progression of human cancers. Aberrant methylation of CpG islands within promoter regions is associated with transcriptional inactivation of various tumour suppressor genes. O 6 -methyguanine-DNA methyltransferase (MGMT is a DNA repair gene that removes mutagenic and cytotoxic adducts from the O 6 -position of guanine induced by alkylating agents. MGMT promoter hypermethylation and reduced expression has been found in some primary human carcinomas. We studied DNA methylation of CpG islands of the MGMT gene and its relation with MGMT protein expression in human epithelial ovarian carcinoma. Methods: A total of 88 epithelial ovarian cancer (EOC tissue samples, 14 low malignant potential (LMP tumours and 20 benign ovarian tissue samples were analysed for MGMT promoter methylation by nested methylation-specific polymerase chain reaction (MSP after bisulphite modification of DNA. A subset of 64 EOC samples, 10 LMP and benign tumours and five normal ovarian tissue samples were analysed for protein expression by immunohistochemistry. Results: The methylation frequencies of the MGMT gene promoter were found to be 29.5, 28.6 and 20 per cent for EOC samples, LMP tumours and benign cases, respectively. Positive protein expression was observed in 93.8 per cent of EOC and 100 per cent in LMP, benign tumours and normal ovarian tissue samples. Promoter hypermethylation with loss of protein expression was seen only in one case of EOC. Interpretation & conclusions: Our results suggest that MGMT promoter hypermethylation does not always reflect gene expression.

Bilateral ovarian fibroma associated with Gorlin syndrome

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Shahnaz Aram

2009-02-01

Full Text Available

• Gorlin syndrome (GS, also known as nevoid basal cell carcinoma syndrome (NBCCS, is a rare inherited multisystem disorder. This paper presents a 22-years-old Iranian woman with this syndrome whose past history was multiple keratocysts of maxillary bone. She was referred to gynecology clinic with the chief complaint of irregular menses and vaginal spotting. On examination, frontal bossing and hypertelorism were detected. Physical examination of genitalia disclosed bilateral adnexal masses. Pelvic ultrasound showed two solid, echogenous and calcified masses measuring 100*50*10 & 60*50*45 mm in the left and right ovaries, respectively. The patient underwent right oophorectomy and ovarian mass resection with preservation of intact ovarian tissue on the left side. On frozen and permanent histological sections, bilateral and calcified ovarian fibromas were diagnosed. Surprisingly, during the last follow-up one year after the surgery, we found that our patient was expecting a baby. It can be concluded that in the presence of bilateral and calcified ovarian fibromas, the possibility of GS should be considered. Accurate diagnosis is only possible with close attention to the familial and past medical history and physical examination. In these patients, careful follow up for detecting malignancies and other complications is highly recommended.
• KEY WORDS: Gorlin syndrome, ovarian fibroma, multiple keratocysts.

Risk factors of epithelial ovarian carcinomas among women with endometriosis: a systematic review.

Science.gov (United States)

Thomsen, Line H; Schnack, Tine H; Buchardi, Kristina; Hummelshoj, Lone; Missmer, Stacey A; Forman, Axel; Blaakaer, Jan

2017-06-01

The objective of this review was to evaluate the published literature on epidemiologic risk factors for epithelial ovarian cancer among women with a diagnosis of endometriosis. A systematic literature search was conducted in PubMed and Scopus. Studies comparing epidemiologic risk factors of epithelial ovarian cancer among women with endometriosis were included. A quality assessment was conducted using the Newcastle-Ottawa Scale. Eight of 794 articles met the inclusion criteria. A lower risk of epithelial ovarian cancer was observed in women with documented complete surgical excision of endometriotic tissue and suggested among women with unilateral oophorectomy. The use of oral contraceptives (≥10 years) may be associated with a lower risk of epithelial ovarian cancer among women with endometriosis, whereas older age at endometriosis diagnosis (≥45 years, pre- or postmenopausal), nulliparity, hyperestrogenism (endogenous or exogenous), premenopausal status at endometriosis diagnosis, solid compartments as well as larger size of endometrioma (≥9 cm in diameter at endometriosis diagnosis) were all associated with an increased risk of ovarian cancer. A subgroup of women with endometriosis characterized by endometriosis observed through surgery or imaging after the age of 45 years, nulliparity, postmenopausal status at endometriosis diagnosis, larger size of endometrioma (>9 cm) at endometriosis diagnosis, hyperestrogenism (endogenous or exogenous) and/or cysts with solid compartments may have an elevated risk of epithelial ovarian cancer. However, due to the limited number and size of studies in this area we cannot draw definitive conclusions. Further research into a risk factor profile among women with endometriosis is needed before clear recommendations can be made. © 2016 Nordic Federation of Societies of Obstetrics and Gynecology.

Germline mutations of BRCA1 gene exon 11 are not associated with platinum response neither with survival advantage in patients with primary ovarian cancer: understanding the clinical importance of one of the biggest human exons. A study of the Tumor Bank Ovarian Cancer (TOC) Consortium.

Science.gov (United States)

Dimitrova, Desislava; Ruscito, Ilary; Olek, Sven; Richter, Rolf; Hellwag, Alexander; Türbachova, Ivana; Woopen, Hannah; Baron, Udo; Braicu, Elena Ioana; Sehouli, Jalid

2016-09-01

Germline mutations in BRCA1 gene have been reported in up to 20 % of epithelial ovarian cancer (EOC) patients. Distinct clinical characteristics have been attributed to this special EOC population. We hypothesized that mutations in different BRCA1 gene exons may differently affect the clinical course of the disease. The aim of this study was to analyze, in a large cohort of primary EOCs, the clinical impact of mutations in BRCA1 gene exon 11, the largest exon of the gene sequence encoding the 60 % of BRCA1 protein. Two hundred sixty-three primary EOC patients, treated between 2000 and 2008 at Charité University Hospital of Berlin, were included. Patients' blood samples were obtained from the Tumor Ovarian Cancer (TOC) Network ( www.toc-network.de ). Direct sequencing of BRCA1 gene exon 11 was performed for each patient to detect mutations. Based on their BRCA1 exon 11 mutational status, patients were compared regarding clinico-pathological variables and survival. Mutations in BRCA1 exon 11 were found in 18 out of 263 patients (6.8 %). Further 10/263 (3.8 %) cases showed variants of uncertain significance (VUS). All exon 11 BRCA1-positive tumors (100 %) were Type 2 ovarian carcinomas (p = 0.05). Age at diagnosis was significantly younger in Type 2 exon 11 mutated patients (p = 0.01). On multivariate analysis, BRCA1 exon 11 mutational status was not found to be an independent predictive factor for optimal cytoreduction, platinum response, or survival. Mutations in BRCA1 gene exon 11 seem to predispose women to exclusively develop a Type 2 ovarian cancer at younger age. Exon 11 BRCA1-mutated EOC patients showed distinct clinico-pathological features but similar clinical outcome with respect to sporadic EOC patients.

Gene expression profiles as prognostic markers in women with ovarian cancer

DEFF Research Database (Denmark)

Jochumsen, Kirsten M; Tan, Qihua; Høgdall, Estrid V

2009-01-01

toward investigations for more individualized therapies and the use of gene expression profiles in the clinical practice. RNA from tumor tissue from 43 Danish patients with serous epithelial ovarian carcinoma (11 International Federation of Gynecology and Obstetrics [FIGO] stage I/II, 32 FIGO stage III...

Paracrine stimulation of P2X7 receptor by ATP activates a proliferative pathway in ovarian carcinoma cells.

Science.gov (United States)

Vázquez-Cuevas, Francisco G; Martínez-Ramírez, Angélica S; Robles-Martínez, Leticia; Garay, Edith; García-Carrancá, Alejandro; Pérez-Montiel, Delia; Castañeda-García, Carolina; Arellano, Rogelio O

2014-11-01

P2X7 is a purinergic receptor-channel; its activation by ATP elicits a broad set of cellular actions, from apoptosis to signals for survival. Here, P2X7 expression and function was studied in human ovarian carcinoma (OCA) cells, and biopsies from non-cancerous and cancer patients were analyzed by immunohistochemistry. Ovarian surface epithelium in healthy tissue expressed P2X7 at a high level that was maintained throughout the cancer. The cell lines SKOV-3 and CAOV-3 were used to investigate P2X7 functions in OCA. In SKOV-3 cells, selective stimulation of P2X7 by 2'(3')-O-(4-benzoylbenzoyl) adenosine-5'-triphosphate (BzATP) induced a dose-dependent increase of intracellular Ca(2+) concentration ([Ca(2+)](i)) but not cell death. Instead, BzATP increased the levels of phosphorylated ERK and AKT (pERK and pAKT), with an EC(50) of 44 ± 2 and 1.27 ± 0.5 μM, respectively; 10 μM BzATP evoked a maximum effect within 15 min that lasted for 120 min. Interestingly, basal levels of pERK and pAKT were decreased in the presence of apyrase in the medium, strongly suggesting an endogenous, ATP-mediated phenomenon. Accordingly: (i) mechanically stimulated cells generated a [Ca(2+)](i) increase that was abolished by apyrase; (ii) apyrase induced a decrease in culture viability, as measured by the MTS assay for mitochondrial activity; and (iii) incubation with 10 μM AZ10606120, a specific P2X7 antagonist and transfection with the dominant negative P2X7 mutant E496A, both reduced cell viability to 70.1 ± 8.9% and to 76.5 ± 5%, respectively, of control cultures. These observations suggested that P2X7 activity was auto-induced through ATP efflux; this increased pERK and pAKT levels that generated a positive feedback on cell viability. © 2014 Wiley Periodicals, Inc.

Long non-coding RNA TUG1 regulates ovarian cancer proliferation and metastasis via affecting epithelial-mesenchymal transition.

Science.gov (United States)

Kuang, Defeng; Zhang, Xiaoping; Hua, Shaofang; Dong, Wei; Li, Zhiguo

2016-10-01

Ovarian cancer is the fifth leading cause of cancer-related death in women worldwide, and recent studies have highlighted the role of long non-coding RNAs (lncRNAs) in cancer development. However, the role of lncRNAs in ovarian cancer is largely unclear. In this study, we focused on the taurine up-regulated gene 1 (TUG1) and examined its molecular mechanism in ovarian cancer. Here, we reported that TUG1 was up-regulated in ovarian cancer tissues and ovarian cancer cells, and TUG1 expression was positively correlated with tumor grade and FIGO stage. In vitro functional assays (CCK-8 assay, colony formation assay, and cell invasion assay) revealed that knock-down of TUG1 by small RNA inference significantly inhibited cell proliferation, colony formation and cell invasion in ovarian cancer cells. Further experiment showed that knock-down of TUG1 induced cell apoptosis and altered the protein expression levels of apoptosis-related mediators in ovarian cancer cells. More importantly, knock-down of TUG1 also reversed epithelial-mesenchymal transition in ovarian cancer. In summary, our results suggest that knock-down of TUG1 may represent a novel therapeutic strategy for the treatment of ovarian cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

Imaging Findings of Embryonal Cell Carcinoma in Ovary:A Case Report

International Nuclear Information System (INIS)

Kim, Hee Kyung; Park, Cheol Min; Choi, Jae Woong; Seol, Hae Young; Kim, Kyeong Ah

2004-01-01

Embryonal cell carcinoma is one of the malignant germ cell tumors. This tumor is commonly encountered in the testis, however, it rarely occurs in the ovary. To the best of our knowledge, no imaging findings of ovarian embryonal cell carcinoma have previously been reported. We describe the US and MRI findings of such a case

Polymorphism in the GALNT1 gene and epithelial ovarian cancer in non-Hispanic white women: the Ovarian Cancer Association Consortium

DEFF Research Database (Denmark)

Phelan, Catherine M; Tsai, Ya-Yu; Goode, Ellen L

2010-01-01

Aberrant glycosylation is a well-described hallmark of cancer. In a previous ovarian cancer case control study that examined polymorphisms in 26 glycosylation-associated genes, we found strong statistical evidence (P = 0.00017) that women who inherited two copies of a single-nucleotide polymorphism...... in the UDP-N-acetylgalactosamine:polypeptide N-acetylgalactosaminyltransferase, GALNT1, had decreased ovarian cancer risk. The current study attempted to replicate this observation. The GALNT1 single-nucleotide polymorphism rs17647532 was genotyped in 6,965 cases and 8,377 controls from 14 studies forming...... the Ovarian Cancer Association Consortium. The fixed effects estimate per rs17647532 allele was null (odds ratio, 0.99; 95% confidence interval, 0.92-1.07). When a recessive model was fit, the results were unchanged. Test for heterogeneity of the odds ratios revealed consistency across the 14 replication...

Anticancer immune reactivity and long-term survival after treatment of metastatic ovarian cancer with dendritic cells

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BERNAL, SAMUEL D.; ONA, ENRIQUE T.; RIEGO-JAVIER, AILEEN; DE VILLA, ROMULO; CRISTAL-LUNA, GLORIA R.; LAGUATAN, JOSEPHINE B.; BATAC, EUNICE R.; CANLAS, OSCAR Q.

2012-01-01

Hematopoietic stem cells collected by leukapheresis of a patient with metastatic ovarian carcinoma (OVCA) were induced into dendritic cell (DC) differentiation and fused with liposomal constructs of autologous and allogeneic ovarian carcinoma antigens (DC-OVCA). The proliferation of autologous T cells induced by DCs was determined by [3H]-thymidine uptake. Maximal T-cell proliferation was observed in co-cultures of DCs fused with liposomal OVCA constructs compared with intact autologous OVCA cells. The combination of autologous and allogeneic liposomal OVCA constructs induced greater T-cell proliferation than either alone. The cytotoxicity of DC-activated T cells against various target cells were analyzed by a 51Cr-release assay. The combination of autologous and allogeneic liposomal OVCA constructs showed the highest stimulation of T cell-mediated cytotoxicity against OVCA cells, but had minimal cytotoxicity against normal fibroblasts or leukemia cells. The liposomal preparations of DC-OVCA were injected monthly into a patient with metastatic ovarian carcinoma whose tumors progressed following multiple courses of chemotherapy. DCs analyzed from the patient post-immunization showed 2- to 3-fold greater OVCA cytotoxicity compared to pre-immunization DCs. Immunoblots using the patient's serum showed reactivity with a number of proteins from ovarian cancer extracts, but not in normal fibroblasts and breast cancer. Following the DC-OVCA treatment, the metastatic lesions progressively decreased in size to the point of being undetectable by serial CAT scans. Seven years following the initial diagnosis, the patient continues to be free of cancer. This report described the anticancer immune reactivity and anti-tumor response induced by DCs sensitized with liposomal constructs of OVCA antigens. Immune cell therapy may therefore be a useful adjunct to surgery and chemotherapy for the treatment of ovarian cancer. PMID:22740858

Unilateral follicular variant of papillary thyroid carcinoma with unique KRAS mutation in struma ovarii in bilateral ovarian teratoma: a rare case report

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Stanojevic Boban

2012-06-01

Full Text Available Abstract Background Struma ovarii (SO is a rare form of ovarian mature teratoma in which thyroid tissue is the predominant element. Because of its rarity, the differential diagnosis between benign and malignant SO has not been clearly defined. It is believed that malignant transformation of SO has similar molecular features with and its prognosis corresponds to that of malignant tumors originating in the thyroid. Case presentation We report 35-year-old woman with bilateral ovarian cysts incidentally detected by ultrasound during the first trimester of pregnancy. Four months after delivery of a healthy child without complication she was admitted to the hospital for acute abdominal pain. Laparoscopic left adnexectomy was performed initially in a regional hospital; right cystectomy was done later in a specialized clinic. Intraoperative frozen section and a final pathology revealed that the cyst from the left ovary was composed of mature teratomatous elements, normal thyroid tissue (>50% and a non-encapsulated focus of follicular variant of papillary thyroid carcinoma (PTC. Normal and cancerous thyroid tissues were tested for BRAF and RAS mutations by direct sequencing, and for RET/PTC rearrangements by RT-PCR/Southern blotting. A KRAS codon 12 mutation, the GGT → GTT transversion, corresponding to the Gly → Val amino acid change was identified in the absence of other genetic alterations commonly found in PTC. Conclusion To the best of our knowledge, this is the first time this mutation is described in a papillary thyroid carcinoma arising in struma in the ovarii. This finding provides further evidence that even rare mutations specific for PTC may occur in such tumors. Molecular testing may be a useful adjunct to common differential diagnostic methods of thyroid malignancy in SO.

LncRNA NEAT1 contributes to paclitaxel resistance of ovarian cancer cells by regulating ZEB1 expression via miR-194

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An J

2017-11-01

Full Text Available Jihong An,* Weiling Lv,* Yongzhou Zhang Department of Clinical Pharmacy, Huaihe Hospital of Henan University, Kaifeng, People’s Republic of China *These authors contributed equally to this work Background: Chemoresistance is one of the major obstacles for cancer therapy in the clinic. Nuclear paraspeckle assembly transcript 1 (NEAT1 has been reported as an oncogene in most malignancies such as lung cancer, esophageal cancer, and gastric cancer. This study is designed to investigate the function of NEAT1 in paclitaxel (PTX resistance of ovarian cancer and its potential molecular mechanism. Patients and methods: The expressions of NEAT1 and miR-194 in ovarian cancer tissues and cells were estimated by quantitative real-time polymerase chain reaction (qRT-PCR. MTT, flow cytometry, and Western blot assays were used to assess the effect of NEAT1 on PTX resistance in PTX-resistant ovarian cancer cells. Luciferase reporter assay was applied to examine the association between NEAT1, zinc finger E-box-binding homeobox 1 (ZEB1 and miR-194. Xenograft tumor model was established to confirm the biological role of NEAT1 in PTX resistance of ovarian cancer in vivo. Results: NEAT1 was upregulated, and miR-194 was downregulated in PTX-resistant ovarian cancer tissues and cells. Functionally, NEAT1 knockdown enhanced cell sensitivity to PTX via promoting PTX-induced apoptosis in vitro. NEAT1 was identified as a molecular sponge of miR-194 to upregulate ZEB1 expression. Mechanistically, NEAT1-knockdown-induced PTX sensitivity was mediated by miR-194/ZEB1 axis. Moreover, NEAT1 knockdown improved PTX sensitivity of ovarian cancer in vivo. Conclusion: NEAT1 contributed to PTX resistance of ovarian cancer cells at least partly through upregulating ZEB1 expression by sponging miR-194, elucidating a novel regulatory pathway of chemoresistance in PTX-resistant ovarian cancer cells and providing a possible long noncoding RNA (lncRNA-targeted therapy for ovarian cancer

Tumor angiogenesis in advanced stage ovarian carcinoma.

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Hollingsworth, H C; Kohn, E C; Steinberg, S M; Rothenberg, M L; Merino, M J

1995-07-01

Tumor angiogenesis has been found to have prognostic significance in many tumor types for predicting an increased risk of metastasis. We assessed tumor vascularity in 43 cases of advanced stage (International Federation of Gynecologists and Obstetricians stages III and IV) ovarian cancer by using the highly specific endothelial cell marker CD34. Microvessel counts and stage were associated with disease-free survival and with overall survival by Kaplan-Meier analysis. The plots show that higher stage, higher average vessel count at 200x (200x avg) and 400x (400x avg) magnification and highest vessel count at 400x (400x high) magnification confer a worse prognosis for disease-free survival. Average vessel count of less than 16 (400x avg, P2 = 0.01) and less than 45 (200x avg, P2 = 0.026) suggested a better survival. Similarly, a high vessel count of less than 20 (400x high, P2 = 0.019) conferred a better survival as well. The plots suggest that higher stage, higher average vessel count at 200x and 400x, and highest vessel count at 200x and 400x show a trend to worse overall survival as well. With the Cox proportional hazards model, stage was the best predictor of overall survival, however, the average microvessel count at 400x was found to be the best predictor of disease-free survival. These results suggest that analysis of neovascularization in advanced stage ovarian cancer may be a useful prognostic factor.

Hereditary Ovarian Cancer: Not Only BRCA 1 and 2 Genes

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Angela Toss

2015-01-01

Full Text Available More than one-fifth of ovarian tumors have hereditary susceptibility and, in about 65–85% of these cases, the genetic abnormality is a germline mutation in BRCA genes. Nevertheless, several other suppressor genes and oncogenes have been associated with hereditary ovarian cancers, including the mismatch repair (MMR genes in Lynch syndrome, the tumor suppressor gene, TP53, in the Li-Fraumeni syndrome, and several other genes involved in the double-strand breaks repair system, such as CHEK2, RAD51, BRIP1, and PALB2. The study of genetic discriminators and deregulated pathways involved in hereditary ovarian syndromes is relevant for the future development of molecular diagnostic strategies and targeted therapeutic approaches. The recent development and implementation of next-generation sequencing technologies have provided the opportunity to simultaneously analyze multiple cancer susceptibility genes, reduce the delay and costs, and optimize the molecular diagnosis of hereditary tumors. Particularly, the identification of mutations in ovarian cancer susceptibility genes in healthy women may result in a more personalized cancer risk management with tailored clinical and radiological surveillance, chemopreventive approaches, and/or prophylactic surgeries. On the other hand, for ovarian cancer patients, the identification of mutations may provide potential targets for biologic agents and guide treatment decision-making.

Hep par-1: a novel immunohistochemical marker for differentiating hepatocellular carcinoma from metastatic carcinoma

International Nuclear Information System (INIS)

Hanif, R.

2014-01-01

To evaluate the diagnostic utility of Hep par-1 in differentiating hepatocellular carcinoma from metastatic carcinoma taking histopathology as a gold standard. Study Design: Comparative cross-sectional study. Place and Duration of Study: Pathology Department, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, from April 2007 to February 2008. Methodology: Hep par-1 immunohistochemical stain was performed on 60 cases of liver carcinoma, 30 cases each of metastatic and hepatocellular carcinoma. Information regarding patient age, gender, sign and symptoms, radiographic findings, histological grade of tumour, and expression of Hep par-1 on hepatocellular and metastatic carcinoma were recorded on proforma sheet. Sensitivity, specificity, positive and negative predictive values, and accuracy of Hep par-1 were calculated using the formulas. Results: Hep par-1 expression was noted in 25 out of 30 cases of hepatocellular carcinoma (83%). Out of 30 cases of metastatic carcinoma, only one case expressed staining in < 5% tumour cells and remaining 29 cases showed no reactivity. The age of the patients with hepatocellular carcinoma ranged from 40 to 76 years with a median age of 60.5 years and 40 - 75 years for metastatic carcinomas with a median age of 57.5 years. Conclusion: Hep par-1 is a reliable immunohistochemical marker for cases of hepatocellular carcinoma (HCC). It can be used along with other markers in morphologically difficult cases when differential diagnosis lies between poorly differentiated HCC and metastatic carcinoma of liver. (author)

Exosomal DNMT1 mediates cisplatin resistance in ovarian cancer.

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Cao, Ya-Lei; Zhuang, Ting; Xing, Bao-Heng; Li, Na; Li, Qin

2017-08-01

Ovarian cancer is the most common malignancy in women. Owing to late syndromic presentation and lack of efficient early detection, most cases are diagnosed at advanced stages. Surgery and platinum-based chemotherapy are still the standard care currently. However, resistance invoked often compromises the clinical value of the latter. Expression of DNA methyltransferase 1 (DNMT1) was analysed by gene array. Protein was determined by immunoblotting. Exosome was isolated with commercial kit. Cell proliferation was measured by CCK8 method. Annexin V-PI double staining was performed for apoptosis evaluation. Xenograft model was established and administrated with exosome. Tumour growth and overall survival were monitored. We demonstrated the upregulation of DNMT1 in both tumour and derived cell line. DNMT1 transcripts were highly enriched in exosomes from conditioned medium of ovarian cells. Co-incubation with exosomes stimulated endogenous expression and rendered host cell the resistance to cytotoxicity of cisplatin. In vivo administration of DNMT1-containing exosomes exacerbated xenograft progression and reduced overall survival significantly. Moreover, treatment with exosome inhibitor GW4869 almost completely restored sensitivity in resistant cells. Our data elucidated an unappreciated mechanism of exosomal DNMT1 in cisplatin resistance in ovarian cancer, also indicating the potential of the combination of exosome inhibitor with cisplatin in resistant patients. Copyright © 2017 John Wiley & Sons, Ltd.

Hypermethylated APC in serous carcinoma based on a meta-analysis of ovarian cancer.

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Shen, Chunyan; Sheng, Qifang; Zhang, Xiaojie; Fu, Yuling; Zhu, Kemiao

2016-09-26

The reduced expression of the Adenomatous polyposis coli (APC) gene, a tumor suppressor gene, through promoter hypermethylation has been reported to play a key role in the carcinogenesis. However, the correlation between APC promoter hypermethylation and ovarian cancer (OC) remains to be clarified. A comprehensive literature search was carried out in related research databases. The overall odds ratio (OR) and corresponding 95 % confidence interval (CI) were used to evaluate the effects of APC promoter hypermethylation on OC and clinicopathological characteristics. Ultimately, 12 eligible studies were used in our study, including 806 OC samples, 429 normal controls, 109 benign lesions and 75 LMP samples. The pooled OR showed that APC promoter hypermethylation was significantly higher in OC than in normal and benign controls (OR = 6.18 and OR = 3.26, respectively). No significant correlation was observed between OC and low malignant potential (LMP) tumors (P = 0.436). In the comparison of OC and normal controls, subgroup analysis based on race showed that the overall OR of APC promoter hypermethylation was significant and similar in Asians and Caucasians (OR = 8.34 and OR = 5.39, respectively). A subgroup analysis based on sample type found that the pooled OR was significantly higher in blood than in tissue (OR = 18.71 and OR = 5.74, respectively). A significant association was not observed between APC promoter hypermethylation and tumor grade or tumor stage. The pooled OR indicated that APC promoter hypermethylation was significantly lower in serous carcinoma than in non-serous carcinoma (OR = 0.56, P = 0.02). No obvious publication bias was detected by Egger's test (all P > 0.05). APC promoter hypermethylation may be linked to the increased risk of OC. It was associated with histological type, but not with tumor grade or tumor stage. Moreover, hypermethylated APC may be a noninvasive biomarker using blood samples. Future

Squamous cell carcinoma of the rectum 21 years after radiotherapy for cervical carcinoma

International Nuclear Information System (INIS)

Leung, Kevin K; Madan, Anand; Heitzman, Joseph

2009-01-01

Squamous cell carcinoma (SCC) of the rectum is an extremely rare malignancy, accounting for 0.1-0.2% of rectal malignancies. It is associated with ulcerative colitis, prior radiation, schistosomiasis, ovarian cancer, endometrial cancer, human papilloma virus, colocutaneous fistulas and colonic duplication. Prior reported cases of SCC of the rectum have involved treatment with brachytherapy and external beam radiation. This case is particularly interesting because of the remote exposure of radiation (21 years previously) and the subsequent development of SCC of the rectum. Although extremely rare, SCC of the rectum can occur decades after radiation exposure. (author)

Pelvic inflammatory disease and risk of invasive ovarian cancer and ovarian borderline tumors

DEFF Research Database (Denmark)

Rasmussen, Christina B; Faber, Mette T; Jensen, Allan

2013-01-01

PURPOSE: The aim of the study was to examine the potential association between a history of pelvic inflammatory disease (PID) and risk of epithelial ovarian cancer or ovarian borderline tumors. METHODS: In a population-based case-control study in Denmark, we included 554 women with invasive ovarian...... cancer, 202 with ovarian borderline tumors, and 1,564 controls aged 35-79 years. The analyses were performed in multiple logistic regression models. RESULTS: We found a significantly increased risk of ovarian borderline tumors among women with a history of PID (OR = 1.50; 95% CI 1.......08-2.08) but no apparent association between PID and risk of invasive ovarian cancer (OR = 0.83; 95% CI 0.65-1.05). We found no effect of age at time of first PID or time since first PID on the risk for either condition. CONCLUSION: Our results suggest that a history of PID is associated with an increased risk of ovarian...

Outcomes of advanced epithelial ovarian cancer with integration of metronomic chemotherapy: An Indian rural cancer centre experience

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Avinash Pandey

2016-01-01

Full Text Available Background: Paclitaxel-platinum and optimal cytoreductive surgery are the standard of care for ovarian carcinoma. Poor socioeconomic profile and therapeutic constraints in rural India poses a therapeutic challenge. Aim: To evaluate outcomes of epithelial ovarian carcinoma. Objectives: To calculate disease-free survival (DFS, overall survival (OS, and factors affecting outcomes. Materials and Methods: Data of patients diagnosed as ovarian carcinoma registered between March 2009 and March 2014 were retrieved. Demographic profile, chemotherapy and response, surgery, and disease progression were collected. Patients who underwent surgery or completed three cycles of chemotherapy were selected. Kaplan-Meir survival was used to determine disease-free and OS. Log-rank test used to evaluate factors affecting outcome. Results: Median follow-up is 26 months. 93/102 patients (91% underwent cytoreductive surgery, of which 37 had primary cytoreduction (40% while 56 had interval cytoreduction. 21/93 (23%, 57/93 (61%, and 15/93 (16% patients were operated by local surgeons, surgeons of our hospital, and trained oncosurgeons, respectively. Induction paclitaxel-platinum was used in 35/63 (56% patients while 28/63 patients (44% received neoadjuvant metronomic chemotherapy. Median DFS and OS are 17 and 54 months respectively while 3 year OS of 66%. Median DFS of patients operated by oncosurgeons versus local surgeons were 22 months versus 15 months (P = 0.01, OS was 54 versus 26 months (P = 0.01.40/88 (45% patients received maintenance metronomic therapy after adjuvant chemotherapy with median of 6 months (range 2-18 months. Patients receiving metronomic maintenance had better DFS, 18 months versus 15 months (P = 0.69. Conclusion: Induction therapy in ovarian carcinoma helps in selecting patients for cytoreductive surgery. Outcomes are better if operated by trained oncosurgeons. Maintenance metronomic has potential to delay disease progression.

[Expressions of Ras and Sos1 in epithelial ovarian cancer tissues and their clinical significance].

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Xiao, Zheng-Hua; Linghu, Hua; Liu, Qian-Fen

2016-11-20

To detect the expressions of Ras and Sos1 proteins in human epithelial ovarian cancer (EOC) tissues and explore their correlation with the clinicopathological features of the patients. The expressions of Ras and Sos1 proteins were detected immunohistochemically in 62 EOC tissues, 5 borderline ovarian cancer tissues, 15 benign epithelial ovarian neoplasm tissues, and 18 normal ovarian tissues. The EOC tissues showed significantly higher expression levels of both Ras and Sos1 than the other tissues tested (Ptissues, Ras and Sos1 proteins were expressed mostly on the cell membrane and in the cytoplasm. The expression level of Ras was correlated with pathological types of the tumor (Ptissue-specific variation of Ras expression can lend support to a specific diagnosis of ovarian serous adenocarcinoma. The association of Ras and Sos1 protein expression with the tumor-free survival time of the patients awaits further investigation with a larger sample size.

Ovarian metastasis in a transposed ovary 10 years after primary cervical cancer: the importance of histologic examination and review of literature.