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Abstract Background Cell line models have proven to be effective tools to investigate a variety of ovarian cancer features. Due to the limited number of cell lines, particularly of the serous subtype, the heterogeneity of the disease, and the lack of cell lines that model disease progression, there is a need to further develop cell line resources available for research. This study describes nine cell lines derived from three ovarian cancer cases that were established at initial diagnosis and at subsequent relapse after chemotherapy. Methods The cell lines from three women diagnosed with high-grade serous ovarian cancer (1369, 2295 and 3133) were derived from solid tumor (TOV) and ascites (OV), at specific time points at diagnosis and relapse (R). Primary treatment was a combination of paclitaxel/carboplatin (1369, 3133), or cisplatin/topotecan (2295). Second line treatment included doxorubicin, gemcitabine and topotecan. In addition to molecular characterization (p53, HER2), the cell lines were characterized based on cell growth characteristics including spheroid growth, migration potential, and anchorage independence. The in vivo tumorigenicity potential of the cell lines was measured. Response to paclitaxel and carboplatin was assessed using a clonogenic assay. Results All cell lines had either a nonsense or missense TP53 mutations. The ability to form compact spheroids or aggregates was observed in six of nine cell lines. Limited ability for migration and anchorage independence was observed. The OV3133(R) cell line, formed tumors at subcutaneous sites in SCID mice. Based on IC50 values and dose response curves, there was clear evidence of acquired resistance to carboplatin for TOV2295(R) and OV2295(R2) cell lines. Conclusion The study identified nine new high-grade serous ovarian cancer cell lines, derived before and after chemotherapy that provides a unique resource for investigating the evolution of this common histopathological subtype of ovarian cancer.

PURPOSE: The ALLOCATE study was designed as a pilot to demonstrate the feasibility and clinical utility of real-time targeted molecular profiling of patients with recurrent or advanced ovarian cancer for identification of potential targeted therapies. PATIENTS AND METHODS: A total of 113 patients with ovarian cancer of varying histologies were recruited from two tertiary hospitals, with 99 patient cases suitable for prospective analysis. Targeted molecular and methylation profiling of fresh biopsy and archived tumor samples were performed by screening for mutations or copy-number variations in 44 genes and for promoter methylation of BRCA1 and RAD51C. RESULTS: Somatic genomic or methylation events were identified in 85% of all patient cases, with potentially actionable events with defined targeted therapies (including four resistance events) detected in 60% of all patient cases. On the basis of these findings, six patients received molecularly guided therapy, three patients had unsuspected germline cancer–associated BRCA1 / 2 mutations and were referred for genetic counseling, and two intermediate differentiated (grade 2) serous ovarian carcinomas were reclassified as low grade, leading to changes in clinical management. Additionally, secondary reversion mutations in BRCA1 / 2 were identified in fresh biopsy samples of two patients, consistent with clinical platinum/poly (ADP-ribose) polymerase inhibitor resistance. Timely reporting of results if molecular testing is done at disease recurrence, as well as early referral for patients with platinum-resistant cancers, were identified as factors that could improve the clinical utility of molecular profiling. CONCLUSION: ALLOCATE molecular profiling identified known genomic and methylation alterations of the different ovarian cancer subtypes and was deemed feasible and useful in routine clinical practice. Better patient selection and access to a wider range of targeted therapies or clinical trials will further enhance the clinical utility of molecular profiling. [ABSTRACT FROM AUTHOR]

Background: Coffee consumption has been shown to be associated with various health outcomes in observational studies. However, evidence for its association with epithelial ovarian cancer (EOC) is inconsistent and it is unclear whether these associations are causal.Methods: We used single nucleotide polymorphisms associated with (i) coffee and (ii) caffeine consumption to perform Mendelian randomization (MR) on EOC risk. We conducted a two-sample MR using genetic data on 44 062 individuals of European ancestry from the Ovarian Cancer Association Consortium (OCAC), and combined instrumental variable estimates using a Wald-type ratio estimator.Results: For all EOC cases, the causal odds ratio (COR) for genetically predicted consumption of one additional cup of coffee per day was 0.92 [95% confidence interval (CI): 0.79, 1.06]. The COR was 0.90 (95% CI: 0.73, 1.10) for high-grade serous EOC. The COR for genetically predicted consumption of an additional 80 mg caffeine was 1.01 (95% CI: 0.92, 1.11) for all EOC cases and 0.90 (95% CI: 0.73, 1.10) for high-grade serous cases.Conclusions: We found no evidence indicative of a strong association between EOC risk and genetically predicted coffee or caffeine levels. However, our estimates were not statistically inconsistent with earlier observational studies and we were unable to rule out small protective associations. [ABSTRACT FROM AUTHOR]

Background: High grade epithelial ovarian cancer (EOC) is commonly characterised by widespread peritoneal dissemination and ascites. Metastatic EOC tumour cells can attach directly to neighbouring organs or alternatively, maintain long term tumourigenicity and chemoresistance by forming cellular aggregates (spheroids). Cancer stem-like cells are proposed to facilitate this mechanism. This study aimed to investigate the role of Oct4A, an embryonic stem cell factor and known master regulator of pluripotency in EOC progression, metastasis and chemoresistance. Methods: To investigate the expression of Oct4A in primary EOC tumours, IHC and qRT-PCR analyses were used. The expression of Oct4A in chemonaive and recurrent EOC patient ascites-derived tumour cells samples was investigated by qRT-PCR. The functional role of Oct4A in EOC was evaluated by generating stable knockdown Oct4A clones in the established EOC cell line HEY using shRNA-mediated silencing technology. Cellular proliferation, spheroid forming ability, migration and chemosensitivty following loss of Oct4A in HEY cells was measured by in vitro functional assays. These observations were further validated in an in vivo mouse model using intraperitoneal (IP) injection of established Oct4A KD clones into Balb/c nu/nu mice. Results: We demonstrate that, compared to normal ovaries Oct4A expression significantly increases with tumour dedifferentiation. Oct4A expression was also significantly high in the ascites-derived tumour cells of recurrent EOC patients compared to chemonaive patients. Silencing of Oct4A in HEY cells resulted in decreased cellular proliferation, migration, spheroid formation and increased chemosensitivity to cisplatin in vitro. IP injection of Oct4A knockdown cells in vivo produced significantly reduced tumour burden, tumour size and invasiveness in mice, which overall resulted in significantly increased mouse survival rates compared to mice injected with control cells. Conclusions: This data highlights a crucial role for Oct4A in the progression and metastasis of EOC. Targeting Oct4A may prove to be an effective strategy in the treatment and management of epithelial ovarian tumours. [ABSTRACT FROM AUTHOR]

Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1. [ABSTRACT FROM AUTHOR]

Background Current treatment of ovarian cancer patients with chemotherapy leaves behind a residual tumor which results in recurrent ovarian cancer within a short time frame. We have previously demonstrated that a single short-term treatment of ovarian cancer cells with chemotherapy in vitro resulted in a cancer stem cell (CSC)-like enriched residual population which generated significantly greater tumor burden compared to the tumor burden generated by control untreated cells. In this report we looked at the mechanisms of the enrichment of CSC-like residual cells in response to paclitaxel treatment. Methods The mechanism of survival of paclitaxel-treated residual cells at a growth inhibitory concentration of 50% (GI50) was determined on isolated tumor cells from the ascites of recurrent ovarian cancer patients and HEY ovarian cancer cell line by in vitro assays and in a mouse xenograft model. Results Treatment of isolated tumor cells from the ascites of ovarian cancer patients and HEY ovarian cancer cell line with paclitaxel resulted in a CSC-like residual population which coincided with the activation of Janus activated kinase 2 (JAK2) and signal transducer and activation of transcription 3 (STAT3) pathway in paclitaxel surviving cells. Both paclitaxel-induced JAK2/STAT3 activation and CSC-like characteristics were inhibited by a low dose JAK2-specific small molecule inhibitor CYT387 (1 µM) in vitro. Subsequent, in vivo transplantation of paclitaxel and CYT387-treated HEY cells in mice resulted in a significantly reduced tumor burden compared to that seen with paclitaxel only-treated transplanted cells. In vitro analysis of tumor xenografts at protein and mRNA levels demonstrated a loss of CSC-like markers and CA125 expression in paclitaxel and CYT387treated cell-derived xenografts, compared to paclitaxel only-treated cell-derived xenografts. These results were consistent with significantly reduced activation of JAK2 and STAT3 in paclitaxel and CYT387-treated cell-derived xenografts compared to paclitaxel only-treated cell derived xenografts. Conclusions This proof of principle study demonstrates that inhibition of the JAK2/STAT3 pathway by the addition of CYT387 suppresses the 'stemness' profile in chemotherapy-treated residual cells in vitro, which is replicated in vivo, leading to a reduced tumor burden. These findings have important implications for ovarian cancer patients who are treated with taxane and/or platinum-based therapies. [ABSTRACT FROM AUTHOR]

High-grade ovarian serous carcinomas (HGSC) are characterized by TP53 mutations and non-random patterns of chromosomal anomalies, where the nature of the TP53 mutation may correlate with clinical outcome. However, the frequency of common somatic genomic events occurring in HGSCs from demographically defined populations has not been explored. Whole genome SNP array, and TP53 mutation, gene and protein expression analyses were assessed in 87 confirmed HGSC samples with clinical correlates from French Canadians, a population exhibiting strong founder effects, and results were compared with independent reports describing similar analyses from unselected populations. TP53 mutations were identified in 91% of HGSCs. Anomalies observed in more than 50% of TP53 mutation-positive HGSCs involved gains of 3q, 8q and 20q, and losses of 4q, 5q, 6q, 8p, 13q, 16q, 17p, 17q, 22q and Xp. Nearly 400 regions of non-overlapping amplification or deletion were identified, where 178 amplifications and 98 deletions involved known genes. The subgroup expressing mutant p53 protein exhibited significantly prolonged overall and disease-free survival as compared with the p53 protein null subgroup. Interestingly, a comparative analysis of genomic landscapes revealed a significant enrichment of gains involving 1q, 8q, and 12p intervals in the subgroup expressing mutant p53 protein as compared with the p53 protein null subgroup. Although the findings show that the frequency of TP53 mutations and the genomic landscapes observed in French Canadian samples were similar to those reported for samples from unselected populations, there were differences in the magnitude of global gains/losses of specific chromosomal arms and in the spectrum of amplifications and deletions involving focal regions in individual samples. The findings from our comparative genomic analyses also support the notion that there may be biological differences between HGSCs that could be related to the nature of the TP53 mutation. [ABSTRACT FROM AUTHOR]

Ovarian cancer is the leading cause of death from gynaecological malignancy. Despite improved detection and treatment options, relapse rates remain high. Combining immunotherapy with the current standard treatments may provide an improved prognosis, however, little is known about how standard chemotherapy affects immune potential (particularly T cells) over time, and hence, when to optimally combine it with immunotherapy (e.g., vaccines). Herein, we assess the frequency and ratio of CD8+ central memory and effector T cells as well as CD4+ effector and regulatory T cells (Tregs) during the first 18 weeks of standard chemotherapy for ovarian cancer patients. In this pilot study, we observed increased levels of recently activated Tregs with tumor migrating ability (CD4+CD25hi Foxp3+CD127-CCR4+CD38+ cells) in patients when compared to controls. Although frequency changes of Tregs as well as the ratio of effector T cells to Tregs were observed during treatment, the Tregs consistently returned to pre-chemotherapy levels at the end of treatment. These results indicate T cell subset distributions associated with recurrence may be largely resistant to being "re-set" to healthy control homeostatic levels following standard treatments. However, it may be possible to enhance T effector to Treg ratios transiently during chemotherapy. These results suggest personalized immune monitoring maybe beneficial when combining novel immuno-therapeutics with standard treatment for ovarian cancer patients. [ABSTRACT FROM AUTHOR]

Background: Cell line models have proven to be effective tools to investigate a variety of ovarian cancer features. Due to the limited number of cell lines, particularly of the serous subtype, the heterogeneity of the disease, and the lack of cell lines that model disease progression, there is a need to further develop cell line resources available for research. This study describes nine cell lines derived from three ovarian cancer cases that were established at initial diagnosis and at subsequent relapse after chemotherapy. Methods: The cell lines from three women diagnosed with high-grade serous ovarian cancer (1369, 2295 and 3133) were derived from solid tumor (TOV) and ascites (OV), at specific time points at diagnosis and relapse (R). Primary treatment was a combination of paclitaxel/carboplatin (1369, 3133), or cisplatin/topotecan (2295). Second line treatment included doxorubicin, gemcitabine and topotecan. In addition to molecular characterization (p53, HER2), the cell lines were characterized based on cell growth characteristics including spheroid growth, migration potential, and anchorage independence. The in vivo tumorigenicity potential of the cell lines was measured. Response to paclitaxel and carboplatin was assessed using a clonogenic assay. Results: All cell lines had either a nonsense or missense TP53 mutations. The ability to form compact spheroids or aggregates was observed in six of nine cell lines. Limited ability for migration and anchorage independence was observed. The OV3133(R) cell line, formed tumors at subcutaneous sites in SCID mice. Based on IC50 values and dose response curves, there was clear evidence of acquired resistance to carboplatin for TOV2295(R) and OV2295 (R2) cell lines. Conclusion: The study identified nine new high-grade serous ovarian cancer cell lines, derived before and after chemotherapy that provides a unique resource for investigating the evolution of this common histopathological subtype of ovarian cancer. [ABSTRACT FROM AUTHOR]

At the 4th Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup (GCIG) held in Vancouver, Canada, in June 2010, representatives of 23 cooperative research groups studying gynecologic cancers gathered to establish international consensus on issues critical to the conduct of large randomized trials. The process focused on 13 predetermined questions. Group A, 1 of the 3 discussion groups, addressed the first 5 questions, examining first-line therapies in newly diagnosed ovarian cancer patients.A1: What are the appropriate end points for different trials (maintenance, upfront chemotherapy trials including molecular drugs)?A2: Are there any subgroups defined by tumor biology who need specific treatment options/trials?A3: Is the 2004 GCIG-recommended standard comparator arm still valid?A4: What is the role of modifying dose, schedule, and delivery of chemotherapy?A5: What role does surgery play today? [ABSTRACT FROM AUTHOR]

The Gynecological Cancer Intergroup (GCIG) has previously reached consensus regarding the criteria that should be used in clinical trial protocols to define progression-free survival after first-line therapy as well as the criteria to define response to treatment in recurrent disease using the serum marker CA 125 and has specified the situations where these criteria should be used. However, the publications did not include detailed definitions, nor were they written to accommodate the new version of Response Evaluation Criteria In Solid Tumors (RECIST) criteria (version 1.1) now available. Thus, we recommend that the definitions described later in detail are incorporated into clinical trial protocols to maintain consistency. The criteria for defining progression are now acceptable in clinical trials of recurrent disease as they have since been validated (Pujade-Lauraine, personal communication, 2010). The GCIG requests that data from all clinical trials using these definitions are made available to GCIG trial centers so that continual validation and improvement can be accomplished. These definitions were developed from analyzing patients receiving cytotoxic chemotherapy and have not yet been validated in patients receiving molecular targeting agents. [ABSTRACT FROM AUTHOR]

To review the current status of large phase academic clinical trials for women with ovarian cancer, address cross-cutting issues, and identify promising areas for future collaboration.In May 2009, the Gynecologic Cancer Intergroup, which represents 19 Cooperative Groups conducting trials for women with gynecologic cancer, and the US National Cancer Institute convened a Clinical Trials Planning Meeting.The topics covered included the impact of new developments in cancer biology upon molecular targets and novel agents, pharmacogenomics, advances in imaging, the potential benefit of diet and exercise to reduce the risk of recurrence, academic partnership with industry, statistical considerations for phases 2 and 3 trials, trial end points, and symptom benefit and health-related quality-of-life issues. The clinical trials discussed spanned the spectrum of ovarian cancer from initial diagnosis, staging, and cytoreductive surgery to consolidation chemotherapy, and treatment of recurrent disease.Ongoing and effective collaboration with industry, government, and patients aims to ensure that the most important scientific questions can be answered rapidly. We encourage women with ovarian cancer and their oncologists to consider participation in the academic clinical trials conducted by the member groups of the Gynecologic Cancer Intergroup. [ABSTRACT FROM AUTHOR]

A correction is offered to the article "Whole–genome characterization of chemoresistant ovarian cancer," by several authors, including Ann-Marie Patch, Elizabeth L. Christie, Dariush Etemadmoghadam, in the 2015 volume 521.

Explains the Gynaecologic Cancer Intergroup's stand that definitions for response and progression of ovarian cancer according to serum CA 125 levels should be incorporated into ovarian cancer clinical trial protocols for relapse therapy. Definition of response; Rules for calculating CA 125 levels; Recommendation that CA 125 measurements be taken at specific time intervals.

A response by David D.L. Bowtell and his colleagues to a letter to the editor on their article "The genesis and evolution of highgrade serous ovarian cancer," published in a previous issue of the journal is presented.

Abstract: Objectives.: To evaluate the impact of PET/CT on the restaging and management of recurrent ovarian cancer. Methods. : From January 2002 to July 2003, all women undergoing either surveillance or investigation of possible recurrent ovarian cancer at the Centre for Molecular Imaging, The Peter MacCallum Cancer Centre, were invited to take part in a prospective evaluation of the clinical impact of PET/CT. Results.: Fifty-six women having 66 scans were available for analysis. All patients had at least 12months follow-up after the PET/CT unless they died before that time. Apart from one equivocal scan, all scans performed in women with a CA125 higher than 35IU/ml had a positive PET/CT. PET/CT altered the known disease distribution in 40 scans (64%). Overall, PET/CT showed less disease in six scans (9%) and more disease in 34 scans (52%). Regardless of the value of CA125, PET/CT identified a sub group of women with apparently localized disease or no definite evidence of disease. This group showed improved survival compared with women shown to have systemic disease. PET/CT resulted in a major change of management plan in 34 patients (58%). Conclusion. : PET/CT modifies the assessment of the distribution of recurrent ovarian cancer and alters patient management in a substantial proportion of patients. PET/CT appears to offer prognostic information. [Copyright &y& Elsevier]

High-grade serous cancer (HGSC), the most common subtype of ovarian cancer, often becomes resistant to chemotherapy, leading to poor patient outcomes. Intratumoral heterogeneity occurs in nearly all solid cancers, including ovarian cancer, contributing to the development of resistance mechanisms. In this study, we examined the spatial and temporal genomic variation in HGSC using high-resolution single-nucleotide polymorphism arrays. Multiple metastatic lesions from individual patients were analyzed along with 22 paired pretreatment and posttreatment samples. We documented regions of differential DNA copy number between multiple tumor biopsies that correlated with altered expression of genes involved in cell polarity and adhesion. In the paired primary and relapse cohort, we observed a greater degree of genomic change in tumors from patients that were initially sensitive to chemotherapy and had longer progression-free interval compared with tumors from patients that were resistant to primary chemotherapy. Notably, deletion or downregulation of the lipid transporter LRP1B emerged as a significant correlate of acquired resistance in our analysis. Functional studies showed that reducing LRP1B expression was sufficient to reduce the sensitivity of HGSC cell lines to liposomal doxorubicin, but not to doxorubicin, whereas LRP1B overexpression was sufficient to increase sensitivity to liposomal doxorubicin. Together, our findings underscore the large degree of variation in DNA copy number in spatially and temporally separated tumors in HGSC patients, and they define LRP1B as a potential contributor to the emergence of chemotherapy resistance in these patients. [ABSTRACT FROM AUTHOR]

Abstract: Ovarian cancer remains a leading cause of cancer death. A comparative proteomic study was performed on normal ovarian tissue (n =5) and grade 3 ovarian tumours (n =5) to search for differentially expressed proteins. In contrast to other studies, here we extracted proteins in soluble and insoluble protein fractions using commercial kits and also utilised three medium-range IPG strips that encompassed the broad pH range of 3–10 (pH 3–6, 5–8 and 7–10). Protein fractions were compared by 2D-PAGE and MALDI-TOF/TOF-MS. Nineteen differentially expressed proteins were identified: HSP60, Grp78, CK19, EF-Tu, MRLC2, prohibitin, Stress-70 protein, TPI and tubulin α6 were up-regulated in grade 3 tumours whereas annexin A2 and A5, antithrombin-III precursor, CBR1, GSTM2, GSTM3, RALDH1, serum albumin precursor, transthyretin precursor and vimentin were found to be down-regulated in grade 3 ovarian tumours. These proteins are associated with cytoskeleton rearrangement, cell metabolism, tumour suppression function, apoptosis and induction of host response. [Copyright &y& Elsevier]

Abstract: Background. : No consensus exists which patients with surgical stage 1 epithelial ovarian should receive postoperative chemotherapy. The purpose of this study was to evaluate the prognostic impact of preoperative CA-125 and to establish a prognostic index to identify patients in different risk categories. Methods. : Data of 600 surgically staged patients with FIGO stage 1 EOC treated in eleven gynecological cancer centers in Australia, the USA and Europe were analyzed. Eligible patients include those with invasive EOC where a preoperative CA-125 was obtained and standard surgical staging performed. Overall survival (OS) was chosen as study endpoint. Preoperative CA-125 values were compared with other prognostic factors, and univariate and multivariate Cox models were calculated. Results. : Two hundred and one patients (33.5%) had preoperative CA-125 ≤30 U/ml and CA-125 levels ≤30 U/ml were associated with lower grade, substage 1A and mucinous histologic cell type. Patients with elevated CA-125 levels were more likely to receive chemotherapy. OS probability was 95% and 85% for patients with pretreatment CA-125 ≤30 U/ml and >30 U/ml, respectively (p 0.003). Multivariate analysis confirmed preoperative serum CA-125 >30 U/ml (OR 2.7) and age at diagnosis >70 years (OR 2.6) as the only independent predictors for overall survival. Conclusion. : Pretreatment of CA-125 ≤30 U/ml dominates over histologic cell type, substage and grade to identify a subgroup of FIGO stage 1 patients with a genuinely good prognosis with extremely good survival and who could possibly be spared with adjuvant chemotherapy. [Copyright &y& Elsevier]

Objective. To determine the activity of capecitabine in women with platinum-resistant ovarian cancer.Methods. In this multi-centre phase II trial, 35 patients with platinum-resistant ovarian, primary peritoneal or fallopian tube carcinomas were treated with capecitabine 1250 mg/m2 twice daily for 14 days every 21 days. Platinum resistance was defined as progression within 4 months of completing the last platinum and all patients had previously received a taxane. Response was assessed by both RECIST criteria for patients with measurable disease and CA125 criteria. Responders were defined as patients with measurable disease who achieved a CR or PR according to RECIST criteria, patients without measurable disease who met the CA125 criteria for response and patients with stable measurable disease who met the CA125 criteria for response.Results. Patients had received a median of four prior chemotherapy regimens (range 1–9). The median number of cycles of capecitabine administered was 3 (range 1–10). The response rate using the combined RECIST and CA125 criteria was 9% (95% CI 2–25%). In patients evaluable using RECIST criteria, the response rate was 5% (95% CI 0–25%). In patients evaluable for CA125 response, the response rate was 7% (95% CI 1–22%). The median progression-free survival was 2.3 months, and the median survival was 7.1 months. Treatment was generally well tolerated with most frequent grade 3 toxicities being hand–foot syndrome (17%) and diarrhea (9%).Conclusion. Capecitabine is well tolerated but has limited activity in patients with heavily pre-treated platinum-resistant ovarian cancer. [Copyright &y& Elsevier]

Objective. Elevated levels of proteases are linked to the malignant phenotype in a wide variety of solid tumors. Therefore, the expression of plasminogen, matrix metalloproteinases (MMP-2 and MMP-9), and of the serine protease urokinase-type plasminogen activator (uPA) in serous epithelial carcinoma of the ovary were investigated.Methods. Plasminogen antigen was analyzed in tissue extracts and in the urine of patients with normal (n = 12), benign (n = 6), borderline (n = 9), and invasive serous tumors (n = 22) by Western immunoblotting using rabbit polyclonal plasminogen and murine monoclonal angiostatin antibodies. In the same tissue extracts, semiquantitative estimates of MMP-2, MMP-9, total MMP activity, and uPA activity were determined using semiquantitative gelatin zymography in the presence or absence of human plasminogen.Results. Bands corresponding to Glu-plasminogen (approximately 92 kDa) and Lys-plasminogen (approximately 86 kDa) were detected in all ovarian tissues and in corresponding urine samples. Densitometric analysis of combined Glu- or Lys-plasminogen levels showed significantly decreased levels in malignant compared to normal tissue. In Grade 3 cancers, there was no evidence of Glu-plasminogen or angiostatin. MMP activity was significantly elevated in both borderline and in Grade 3 ovarian cancer tissues. Increased tissue uPA activity on zymograms was detected only in Grade 3 ovarian cancer tissue.Conclusion. These data suggest that proteolytic activity of the plasminogen activation cascade increases in serous epithelial ovarian carcinoma. [Copyright &y& Elsevier]

Background: Inhibin is an ovarian hormone that inhibits the secretion of follicle-stimulating hormone (FSH) by the anterior pituitary gland. Women with granulosa-cell tumors of the ovary have elevated serum inhibin concentrations, but whether the concentrations are increased in women with other ovarian tumors is unknown. Methods: We measured serum inhibin and FSH concentrations before surgery in 212 postmenopausal women with suspected ovarian cancer and after surgery in 210 of them. Results: Eighteen of the 22 women (82 percent) with mucinous carcinomas (mucinous cystadenocarcinomas and mucinous borderline cystic tumors) of the ovary had elevated serum inhibin concentrations, whereas only 9 of the 53 women (17 percent) with serous carcinomas (serous cystadenocarcinomas and serous borderline cystic tumors) had elevated levels. Serum inhibin concentrations were also elevated in 2 of 12 women (17 percent) with clear-cell carcinomas, 4 of 26 women (15 percent) with undifferentiated carcinomas, 3 of 3 women (100 percent) with granulosa-cell tumors, and 5 of 27 women (19 percent) with other ovarian cancers. The serum concentrations of inhibin were increased in 2 of 28 women (7 percent) with nonovarian pelvic cancers and 11 of 41 women (27 percent) with benign ovarian diseases. All women but one with initially elevated serum inhibin concentrations had low values one week after surgery. Serum inhibin concentrations correlated negatively with serum FSH concentrations (P = 0.05) in women with granulosa-cell tumors but not in women with other tumors, suggesting that the inhibin secreted by tumors in the latter group has decreased biologic activity. Conclusions: Serum inhibin concentrations are elevated in most postmenopausal women with mucinous carcinomas of the ovary and in some women with other types of epithelial ovarian tumors. The concentrations fall after tumor removal. (N Engl J Med 1993;329:1539-42.) [ABSTRACT FROM AUTHOR]