Front-line chemo-immunotherapy with carboplatin-paclitaxel using oregovomab indirect immunization in advanced ovarian cancer: A randomized phase II study.

BACKGROUND: This randomized phase II study tested the hypothesis that schedule dependent chemo-immunotherapy with oregovomab improves progression free survival (PFS) and overall survival (OS) in optimally resected, Stage III/IV ovarian cancer. METHODS: Patients from both academic centers and private practice in the US and Italy with Stage III/IV optimally cytoreduced ovarian cancer were randomized to standard six cycle IV carboplatin-paclitaxel chemotherapy (CP) versus CP plus four immunizations with oregovomab (CPO). A translational assessment of a cellular immune response was the primary endpoint; PFS and OS were measured as secondary endpoints. FINDINGS: 97 patients at thirteen centers were accrued to the protocol, 47 to CPO and 50 to CP. Technical issues led to inconsistent performance of the primary CA125 ELISPOT leading to unevaluable results. At a median follow up of 42 months, PFS and OS outcomes revealed an unexpectedly large treatment effect for CPO relative to CP alone, with median PFS of 41.8 months (95% C.I.: 21.8 - N.E.) for CPO and 12.2 months (10.4-18.6) for CP (p = 0.0027, HR 0.46, CI 0.28-0.7). For OS, the median for CPO has not yet been reached (NE) (45.2-NE) and for CP was 43.2 months (31.8-NE) (p = 0.043, HR 0.35, CI 0.16-0.74). The oregovomab treatment resulted in no change in toxicity profile from CP. INTERPRETATION: The previously identified potential clinical benefit of IV CP when administered with oregovomab was further refined in this randomized phase II study. Increases of PFS and OS of statistically and clinically significant magnitude were evident in this study of a front line chemo-immunotherapy treatment of ovarian cancer.

In vitro and in vivo correlates of physiological and neoplastic human Fallopian tube stem cells.

High-grade serous cancer (HGSC) progresses to advanced stages without symptoms and the 5-year survival rate is a dismal 30%. Recent studies of ovaries and Fallopian tubes in patients with BRCA1 or BRCA2 mutations have documented a pre-metastatic intramucosal neoplasm that is found almost exclusively in the Fallopian tube, termed 'serous tubal intraepithelial carcinoma' or STIC. Moreover, other proliferations, termed p53 signatures, secretory cell outgrowths (SCOUTs), and lower-grade serous tubal intraepithelial neoplasms (STINs) fall short of STIC but share similar alterations in expression, in keeping with an underpinning of genomic disturbances involved in, or occurring in parallel with, serous carcinogenesis. To gain insight into the cellular origins of this unique tubal pathway to high-grade serous cancer, we cloned and both immortalized and transformed Fallopian tube stem cells (FTSCs). We demonstrated that pedigrees of FTSCs were capable of multipotent differentiation and that the tumours derived from transformed FTSCs shared the histological and molecular features of HGSC. We also demonstrated that altered expression of some biomarkers seen in transformed FTSCs and HGSCs (stathmin, EZH2, CXCR4, CXCL12, and FOXM1) could be seen as well in immortalized cells and their in vivo counterparts SCOUTs and STINs. Thus, a whole-genome transcriptome analysis comparing FTSCs, immortalized FTSCs, and transformed FTSCs showed a clear molecular progression sequence that is recapitulated by the spectrum of accumulated perturbations characterizing the range of proliferations seen in vivo. Biomarkers unique to STIC relative to normal tubal epithelium provide a basis for novel detection approaches to early HGSC, but must be viewed critically given their potential expression in lesser proliferations. Perturbations shared by both immortalized and transformed FTSCs may provide unique early targets for prevention strategies. Central to these efforts has been the ability to clone and perpetuate multipotent FTSCs.

Endometrial cancer: a review and current management strategies: part II.

Endometrial carcinoma is the most common gynecologic malignancy. A thorough understanding of the epidemiology, pathophysiology, and management strategies for this cancer allows the obstetrician-gynecologist to identify women at increased risk, contribute toward risk reduction, and facilitate early diagnosis. The Society of Gynecologic Oncology's Clinical Practice Committee has reviewed the literature through March of 2014 and created evidence-based practice recommendations for diagnosis and treatment. The level of recommendations used is based on the method used by the U.S. Preventive Services Task Force (A: There is good evidence to support the recommendation, B: There is fair evidence to support the recommendation, C: There is insufficient evidence to support the recommendation; however, the recommendation may be made on other grounds, D: There is fair evidence against the recommendation, E: There is good evidence against the recommendation.). It is not the purpose of this document to provide a complete review of the literature on all aspects of endometrial cancer. This article examines: • Adjuvant therapy, including radiation, vaginal brachytherapy, and chemotherapy • Therapy for advanced disease, including chemotherapy and radiation therapy alone and in combination as well as hormone therapy • Treatment for synchronous endometrial and ovarian cancer • Fertility-sparing treatment • Post-treatment patient surveillance • The role of hormone replacement therapy in the development of endometrial carcinoma • Novel targeted therapies.

Endometrial cancer: a review and current management strategies: part I.

Endometrial carcinoma is the most common gynecologic malignancy. A thorough understanding of the epidemiology, pathophysiology, and management strategies for this cancer allows the obstetrician-gynecologist to identify women at increased risk, contribute toward risk reduction, and facilitate early diagnosis. The Society of Gynecologic Oncology's Clinical Practice Committee has reviewed the literature and created evidence-based practice recommendations for diagnosis and treatment. This article examines: • Risk factors, including genetic predisposition • Diagnostic and metastatic evaluation • Surgical management of early and advanced cancer, including lymphadenectomy in early cancer.

Two-photon excited fluorescence imaging of endogenous contrast in a mouse model of ovarian cancer.

BACKGROUND AND OBJECTIVE: Ovarian cancer has an extremely high mortality rate resulting from poor understanding of the disease. In order to aid understanding of disease etiology and progression, we identify the endogenous fluorophores present in a mouse model of ovarian cancer and describe changes in fluorophore abundance and distribution with age and disease. STUDY DESIGN/MATERIALS AND METHODS: A mouse model of ovarian cancer was created by dosing with 4-vinylcyclohexene diepoxide, which induces follicular apoptosis (simulating menopause), and 7,12-dimethylbenz[a]anthracene, a known carcinogen. Imaging of ovarian tissue was completed ex vivo with a multiphoton microscope using excitation wavelength of 780 nm and emission collection from 405 to 505 nm. Two-photon excited fluorescence images and corresponding histologic sections with selective stains were used to identify endogenous fluorophores. RESULTS: The majority of collected fluorescence emission was attributed to NADH and lipofuscin, with additional contributions from collagen and elastin. Dim cellular fluorescence from NADH did not show observable changes with age. Changes in ovarian morphology with disease development frequently caused increased fluorescence contributions from collagen and adipose tissue-associated NADH. Lipofuscin fluorescence was much brighter than NADH fluorescence and increased as a function of both age and disease. CONCLUSIONS: Our finding of NADH fluorescence patterns similar to that seen previously in human ovary, combined with the observation of lipofuscin accumulation with age and disease also seen in human organs, suggests that the findings from this model may be relevant to human ovarian disease. Increased lipofuscin fluorescence might be used as an indicator of disease in the ovary and this finding warrants further study.

Parallel factor analysis of ovarian autofluorescence as a cancer diagnostic.

BACKGROUND AND OBJECTIVES: Endogenous fluorescence from certain amino acids, structural proteins, and enzymatic co-factors in tissue is altered by carcinogenesis. We evaluate the potential of these changes in fluorescence to predict a diagnosis of malignancy and to estimate the risk of developing ovarian cancer. STUDY DESIGN/MATERIALS AND METHODS: Ovarian biopsies were interrogated over 270-550 nm excitation and fluorescence was collected from 290 to 700 nm. Two hundred forty-nine measurements were performed on 49 IRB-consented patients undergoing oophorectomy. Data are analyzed using parallel factor analysis to determine excitation and emission spectra of the underlying fluorophores that contribute to the total detected fluorescence intensity. RESULTS: Using multivariate normal distribution fits and cross-validation techniques, sensitivity and specificity of 88% and 93%, respectively, are achieved when classifying malignant samples versus others, while 88% and 80%, respectively, are achieved when classifying normal post-menopausal patients as being either at high- or low-risk of developing ovarian cancer based on their personal and family history of cancer. Performance of classifying cancer increases when the normal group does not include benign neoplasm and endometriosis samples. Performance of high- versus low-risk classification decreases when normal samples include both pre- and post-menopausal women. Excitation over 270-400 and 380-560 nm, respectively, have the best diagnostic performance for cancer detection and risk-status assessment. CONCLUSIONS: Assessing the endogenous fluorescence could be useful in screening women at increased risk of developing ovarian cancer.

Complementary anti-cancer pathways triggered by inhibition of sideroflexin 4 in ovarian cancer.

DNA damaging agents are a mainstay of standard chemotherapy for ovarian cancer. Unfortunately, resistance to such DNA damaging agents frequently develops, often due to increased activity of DNA repair pathways. Sideroflexin 4 (SFXN4) is a little-studied inner mitochondrial membrane protein. Here we demonstrate that SFXN4 plays a role in synthesis of iron sulfur clusters (Fe-S) in ovarian cancer cells and ovarian cancer tumor-initiating cells, and that knockdown of SFXN4 inhibits Fe-S biogenesis in ovarian cancer cells. We demonstrate that this has two important consequences that may be useful in anti-cancer therapy. First, inhibition of Fe-S biogenesis triggers the accumulation of excess iron, leading to oxidative stress. Second, because enzymes critical to multiple DNA repair pathways require Fe-S clusters for their function, DNA repair enzymes and DNA repair itself are inhibited by reduction of SFXN4. Through this dual mechanism, SFXN4 inhibition heightens ovarian cancer cell sensitivity to DNA-damaging drugs and DNA repair inhibitors used in ovarian cancer therapy, such as cisplatin and PARP inhibitors. Sensitization is achieved even in drug resistant ovarian cancer cells. Further, knockout of SFXN4 decreases DNA repair and profoundly inhibits tumor growth in a mouse model of ovarian cancer metastasis. Collectively, these results suggest that SFXN4 may represent a new target in ovarian cancer therapy.

Chemotherapy in pregnancy.

One in 1000 pregnancies is complicated with cancer with the most common tumors being breast cancer, cervical cancer, thyroid, leukemia, lymphoma, and ovarian cancer. It is often assumed that cancer during pregnancy necessitates sacrificing the well-being of the fetus but in most cases appropriate treatment can be offered to the mother without placing the fetus at serious risk. The care of a pregnant woman with cancer involves evaluation of competing maternal and fetal risks and benefits. Although it is rare to administer chemotherapy during pregnancy, the risks depend on the drugs used and the gestational age of the fetus. During the period of organogenesis (4 to 13 wk), administration of cytotoxic drugs carries an increased risk of fetal malformations and fetal loss. Chemotherapy in the second or third trimester is associated with intrauterine growth retardation, prematurity, and low birth weight and bone marrow toxicity in many exposed infants.

Attitudes toward direct-to-consumer advertisements and online genetic testing among high-risk women participating in a hereditary cancer clinic.

Genetic testing for the breast cancer genes 1/2 (BRCA 1/2) has helped women determine their risk of developing breast and ovarian cancer. As interest in genetic testing has grown, companies have created strategies to disseminate information about testing, including direct-to-consumer advertising (DTCA) and online genetic testing. This study examined attitudes toward DTCA and online testing for BRCA among 84 women at a high-risk clinic as well as additional factors that may be associated with these attitudes, such as personal and familial cancer history, cancer worry and risk perception, and history with genetic testing/counseling. Results showed that the majority of the women held favorable attitudes toward DTCA for BRCA testing but did not support online testing. Factors such as familial ovarian cancer, cancer worry, and satisfaction with genetic counseling/testing were associated with positive attitudes toward DTCA, whereas personal breast cancer history was related to negative attitudes. The findings suggest that women may view DTCA as informational but rely on physicians for help in their decision to undergo testing, and also suggest that cancer history may affect women's acceptance of DTCA and genetic testing.

Metastatic serous endometrial carcinoma to the ureter.

Metastatic endometrial carcinoma involving the renal parenchyma has been reported. However, ureteral metastasis is exceedingly rare. Here we describe what we believe to be the first case report of metastatic endometrial serous carcinoma to the ureteral and renal pelvic urothelium. The patient is a 68 year old female diagnosed with endometrial serous carcinoma three years prior to presentation who was found to have metastatic disease within the right ureter and retroperitoneal lymph nodes. Following a complete response in the lymph nodes to chemotherapy, she was treated with robot-assisted right nephroureterectomy for residual, isolated PET-avid right ureteral metastasis.

Alterations of the extracellular matrix in ovarian cancer studied by Second Harmonic Generation imaging microscopy.

BACKGROUND: Remodeling of the extracellular matrix (ECM) has been implicated in ovarian cancer, and we hypothesize that these alterations may provide a better optical marker of early disease than currently available imaging/screening methods and that understanding their physical manifestations will provide insight into invasion. METHODS: For this investigation we use Second Harmonic Generation (SHG) imaging microcopy to study changes in the structure of the ovarian ECM in human normal and malignant ex vivo biopsies. This method directly visualizes the type I collagen in the ECM and provides quantitative metrics of the fibrillar assembly. To quantify these changes in collagen morphology we utilized an integrated approach combining 3D SHG imaging measurements and bulk optical parameter measurements in conjunction with Monte Carlo simulations of the experimental data to extract tissue structural properties. RESULTS: We find the SHG emission attributes (directionality and relative intensity) and bulk optical parameters, both of which are related to the tissue structure, are significantly different in the tumors in a manner that is consistent with the change in collagen assembly. The normal and malignant tissues have highly different collagen fiber assemblies, where collectively, our findings show that the malignant ovaries are characterized by lower cell density, denser collagen, as well as higher regularity at both the fibril and fiber levels. This further suggests that the assembly in cancer may be comprised of newly synthesized collagen as opposed to modification of existing collagen. CONCLUSIONS: Due to the large structural changes in tissue assembly and the SHG sensitivity to these collagen alterations, quantitative discrimination is achieved using small patient data sets. Ultimately these measurements may be developed as intrinsic biomarkers for use in clinical applications.

Correction: Proteogenomic Characterization of Ovarian HGSC Implicates Mitotic Kinases, Replication Stress in Observed Chromosomal Instability.

[This corrects the article PMC7289043.].

Proteogenomic Characterization of Ovarian HGSC Implicates Mitotic Kinases, Replication Stress in Observed Chromosomal Instability.

In the absence of a dominant driving mutation other than uniformly present TP53 mutations, deeper understanding of the biology driving ovarian high-grade serous cancer (HGSC) requires analysis at a functional level, including post-translational modifications. Comprehensive proteogenomic and phosphoproteomic characterization of 83 prospectively collected ovarian HGSC and appropriate normal precursor tissue samples (fallopian tube) under strict control of ischemia time reveals pathways that significantly differentiate between HGSC and relevant normal tissues in the context of homologous repair deficiency (HRD) status. In addition to confirming key features of HGSC from previous studies, including a potential survival-associated signature and histone acetylation as a marker of HRD, deep phosphoproteomics provides insights regarding the potential role of proliferation-induced replication stress in promoting the characteristic chromosomal instability of HGSC and suggests potential therapeutic targets for use in precision medicine trials.

A prototype hybrid intraoperative probe for ovarian cancer detection.

A novel prototype intraoperative system combining positron detection and optical coherence tomography (OCT) imaging has been developed for early ovarian cancer detection. The probe employs eight plastic scintillating fiber tips for preferential detection of local positron activity surrounding a central scanning OCT fiber providing volumetric imaging of tissue structure in regions of high radiotracer uptake. Characterization measurements of positron sensitivity, spatial response, and position mapping are presented for Tl(204)/Cs(137) sources as well as 18F-FDG. In conjunction with co-registered frequency domain OCT measurements the results demonstrate the potential for a miniaturized laparoscopic probe offering simultaneous functional localization and structural imaging for improved early cancer detection.

Laparoscopic optical coherence tomography imaging of human ovarian cancer.

OBJECTIVES: Ovarian cancer is the fourth leading cause of cancer-related death among women in the US largely due to late detection secondary to unreliable symptomology and screening tools without adequate resolution. Optical coherence tomography (OCT) is a recently emerging imaging modality with promise in ovarian cancer diagnostics, providing non-destructive subsurface imaging at imaging depths up to 2 mm with near-histological grade resolution (10-20 microm). In this study, we developed the first ever laparoscopic OCT (LOCT) device, evaluated the safety and feasibility of LOCT, and characterized the microstructural features of human ovaries in vivo. METHODS: A custom LOCT device was fabricated specifically for laparoscopic imaging of the ovaries in patients undergoing oophorectomy. OCT images were compared with histopathology to identify preliminary architectural imaging features of normal and pathologic ovarian tissue. RESULTS: Thirty ovaries in 17 primarily peri- or post-menopausal women were successfully imaged with LOCT: 16 normal, 5 endometriosis, 3 serous cystadenoma, and 4 adenocarcinoma. Preliminary imaging features developed for each category reveal qualitative differences in the homogeneous character of normal post-menopausal ovary, the ability to image small subsurface inclusion cysts, and distinguishable features for endometriosis, cystadenoma, and adenocarcinoma. CONCLUSIONS: We present the development and successful implementation of the first laparoscopic OCT probe. Comparison of OCT images and corresponding histopathology allowed for the description of preliminary microstructural features for normal ovary, endometriosis, and benign and malignant surface epithelial neoplasms. These results support the potential of OCT both as a diagnostic tool and an imaging modality for further evaluation of ovarian cancer pathogenesis.

Computer-aided identification of ovarian cancer in confocal microendoscope images.

The confocal microendoscope is an instrument for imaging the surface of the human ovary. Images taken with this instrument from normal and diseased tissue show significant differences in cellular distribution. A real-time computer-aided system to facilitate the identification of ovarian cancer is introduced. The cellular-level structure present in ex vivo confocal microendoscope images is modeled as texture. Features are extracted based on first-order statistics, spatial gray-level-dependence matrices, and spatial-frequency content. Selection of the features is performed using stepwise discriminant analysis, forward sequential search, a nonparametric method, principal component analysis, and a heuristic technique that combines the results of these other methods. The selected features are used for classification, and the performance of various machine classifiers is compared by analyzing areas under their receiver operating characteristic curves. The machine classifiers studied included linear discriminant analysis, quadratic discriminant analysis, and the k-nearest-neighbor algorithm. The results suggest it is possible to automatically identify pathology based on texture features extracted from confocal microendoscope images and that the machine performance is superior to that of a human observer.

Endogenous optical biomarkers of ovarian cancer evaluated with multiphoton microscopy.

PURPOSE: Among gynecologic cancers, ovarian cancer is the second most common and has the highest mortality. Currently, there is no accurate early diagnostic technique for ovarian cancer. Furthermore, little is understood regarding the early progression of this disease. We have imaged multiphoton interactions of endogenous tissue constituents from normal and abnormal ovarian biopsies that were kept viable during transport from the operating room and microscopy. EXPERIMENTAL DESIGN: The ovarian surface and underlying stroma were assessed with two-photon excited fluorescence (2PEF) and second harmonic generation (SHG). High-resolution, optically sectioned images were analyzed for epithelial morphology based on 2PEF and collagen density and structural integrity based on SHG. Additionally, multiwavelength 2PEF provided an estimation of the cellular redox ratio of epithelial cells. RESULTS: Normal tissue exhibited a uniform epithelial layer with highly structured collagen in the stroma, whereas abnormal tissue exhibited varied epithelium with large cells and substantial quantitative changes to the collagen structure. Samples from patients at high risk for developing ovarian cancer (based on their personal/family history of cancer) exhibited highly variable cellular redox ratios and changes in collagen structure that trended toward cancer samples. CONCLUSION: This study highlights differences in endogenous signals in viable ovarian biopsies based on quantitative collagen structural changes and redox ratio estimates that may lead to improved detection and further insights in ovarian cancer, particularly in the early stages of the disease.

Combination of 4-HPR and oral contraceptive in monkey model of chemoprevention of ovarian cancer.

4-(N-hydroxyphenyl) retinamide (4-HPR) and the oral contraceptives (OCP) are currently being used alone, and in combination, for the prevention of ovarian cancer. However, the mechanism of their effects has not been studied. Non-human primate models are ideal for studying the role of these and other drugs for cancer chemoprevention because of the genetic similarity between primates and humans in respect to hormone regulation and menstrual cycle. 4-HPR and OCP were administered to sixteen female adult Macacca mulatta (Rhesus macaques) for three months alone and in combination. Laparotomy was performed before and after treatment, and ovarian biopsies were obtained to evaluate the expression of retinoid and hormone receptors, and apoptosis. ER alpha was undetectable, but ER beta, PR, RXR alpha, and RXR gamma were constitutively expressed in the ovaries. 4-HPR induced RXR alpha and RXR gamma expression at a low level and, OCP induced expression of ER beta. However, the combination of 4-HPR with OCP had a larger effect on expression of retinoid receptors. Apoptosis was detected in the 4-HPR group (equivalent dose: 200 mg/day).

Antitumor activity of 4-(N-hydroxyphenyl)retinamide conjugated with poly(L-glutamic acid) against ovarian cancer xenografts.

OBJECTIVE: Natural and synthetic retinoids such as N-(4-hydroxyphenyl)retinamide (4HPR) have been used for prevention and treatment of a variety of cancers; however, relapse usually occurs after treatment is stopped. Furthermore, the retinoid analogues are insoluble in water, making it difficult for systemic administration. The purpose of this study was to develop and evaluate a water-soluble polymeric formulation of 4HPR that can release 4HPR over a period of a few days. METHODS: 4HPR was bound to a synthetic polyamino acid poly(L-glutamic acid) (PG). PG-4HPR was evaluated for its release kinetics and in vitro anti-proliferative and in vivo antitumor activities against ovarian cancer cell lines. RESULTS: The release profile of PG-4HPR in phosphate buffered saline at 37 degrees C followed a first order kinetic, with a rate constant of 8.8x10(-3) h(-1). Approximately 60% of 4HPR was released over a period of 100 h. In vitro, both 4HPR and PG-4HPR inhibited proliferation of three ovarian cancer cells lines (SKOV3, OVCA420, and OVCA433) and an immortalized human ovarian epithelium cell line (IOSE) in a time- and dose-dependent manner. Increasing the exposure time of SKOV3 cells to both agents from 1 to 5 days resulted in an increased apoptotic response. In vivo, PG-4HPR demonstrated significantly enhanced antitumor activities compared to 4HPR in both early treatment and later treatment protocols. Treatments with PG-4HPR suppressed the expression of VEGF and reduced blood flow into the tumor. CONCLUSIONS: PG-4HPR may have potential applications in the prevention and therapy of ovarian cancers.

Prevention and early detection of ovarian cancer: mission impossible?

Epithelial ovarian cancer is neither a common nor a rare disease. In the United States, the prevalence of ovarian cancer in postmenopausal women (1 in 2,500) significantly affects strategies for prevention and detection. If chemoprevention for ovarian cancer were provided to all women over the age of 50, side effects would have to be minimal in order to achieve an acceptable ratio of benefit to risk. This ratio might be improved by identifying subsets of individuals at increased risk or by bundling prevention of ovarian cancer with treatment for other more prevalent conditions. Approximately 10% of ovarian cancers are familial and relate to mutations of BRCA1, BRCA2, and mismatch repair genes. More subtle genetic factors are being sought in women with apparently sporadic disease. Use of oral contraceptive agents for as long as 5 years decreases the risk of ovarian cancer in later life by 50%. In one study, fenretinide (4-HPR) delayed development of ovarian cancer in women at increased risk of developing breast and ovarian cancer. Accrual to confirmatory studies has been prohibitively slow and prophylactic oophorectomy is recommended for women at increased genetic risk. Vaccines may have a role for prevention of several different cancers. Breast and ovarian cancers express mucins that could serve as targets for vaccines to prevent both cancers. Early detection of ovarian cancer requires a strategy with high sensitivity (> 75% for stage I disease) and very high specificity (> 99.6%) to achieve a positive predictive value of 10%. Transvaginal sonography (TVS) has achieved these values in some studies, but is limited by the cost of annual screening in a general population. Two-stage strategies that incorporate both serum markers and TVS promise to be more cost-effective. An algorithm has been developed that calculates risk of ovarian cancer based on serial CA125 values and refers patients at highest risks for TVS. Use of the algorithm is currently being evaluated in a trial with 200,000 women in the United Kingdom that will critically test the ability of a two-stage screening strategy to improve survival in ovarian cancer. Whatever the outcome, additional serum markers will be required to detect all patients in an initial phase of screening. More than 30 serum markers have been evaluated alone and in combination with CA125. Recent candidates include: HE4, mesothelin, M-CSF, osteopontin, kallikrein(s) and soluble EGF receptor. Proteomic approaches have been used to define a distinctive pattern of peaks on mass spectroscopy or to identify a limited number of critical markers that can be assayed by more conventional methods. Several groups are placing known markers on multiplex platforms to permit simultaneous assay of multiple markers with very small volumes of serum. Mathematical techniques are being developed to analyze combinations of marker levels to improve sensitivity and specificity. In the future, serum markers should improve the sensitivity of detecting recurrent disease as well as facilitate earlier detection of ovarian cancer.