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Introduction: High-grade serous ovarian cancer (HGSOC) is characterized by high mortality and prevalent recurrences. This study investigates the prognostic value of phosphoglycerate dehydrogenase (PHGDH) in HGSOC which has been linked to metabolic reprogramming and recurrences in other cancers., Methods: Data from 306 patients with advanced-stage HGSOC treated between 2008 and 2015 were analyzed. PHGDH expression levels were determined using immunohistochemistry and categorized as "low" or "high.", Results: PHGDH-high was associated with higher FIGO stage and increased use of neoadjuvant chemotherapy. Patients with PHGDH-high tumors had significantly worse survival than PHDH-low, even after adjusting for confounding factors., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers., Methods: Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data., Results: Genetic correlation analysis revealed significant genetic correlation between the two cancers ( r G = 0.43, P = 2.66 × 10 -5 ). We found seven loci associated with risk for both cancers ( P Bonferroni < 2.4 × 10 -9 ). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified ( P < 5 × 10 -7 ). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation., Conclusions: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis., Impact: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings., (©2020 American Association for Cancer Research.)

Background: Presence of residual disease after cytoreductive surgery is an important negative prognostic factor for patients with advanced stage epithelial ovarian cancer. Surgery is of limited benefit when the diameter of residual disease is >1 cm. Residual disease is difficult to predict before surgery. The multivariate model Cancer Ovarii Non-invasive Assessment of Treatment Strategy (CONATS) index, based on serum biomarker HE4, age, and World Health Organization performance status, predicted no visible residual disease in patients undergoing primary cytoreductive surgery with an area under the curve (AUC) of 0.85. The AUC of predicting residual disease >1 cm was not reported, although this can be of importance for pre-operative decision making, especially in fragile patients. We tested this model for predicting residual disease >1 cm in patients undergoing interval cytoreduction., Methods: We retrospectively included patients with advanced epithelial ovarian cancer who underwent interval cytoreduction between January 2010 and December 2017 in two tertiary centers in the Netherlands. HE4 was measured with electrochemiluminescence in pre-operative samples. The CONATS index was used to predict residual disease. AUCs were calculated to predict residual disease >1 cm., Results: A total of 273 patients were included. Mean (SD) age was 64 (11) years. Median number of cycles of neoadjuvant chemotherapy was 3 (range 3-6) and the most common regimen used consisted of carboplatin and paclitaxel. Before interval cytoreduction, 19 patients (7%) showed complete response to chemotherapy, 251 patients (92%) showed partial response, and 3 patients (1%) showed stable disease at imaging. Following surgery, 232 patients (85%) had residual disease ≤1 cm and 41 patients (15%) had residual disease >1 cm. The AUC was 0.80 for predicting residual disease >1 cm. In patients ≥70 years of age the AUC was 0.82., Conclusion: The CONATS index predicts surgical outcome after interval cytoreduction and is useful in counseling patients about the chance of whether an optimal interval cytoreduction can be achieved. This could be especially helpful in counseling elderly patients in whom surgery has a high risk of complications., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: A subset of patients with recurrent ovarian cancer (ROC) may benefit from antiestrogen therapy with higher response rates reported in tumors that are strongly estrogen receptor (ER)-positive (ER⁺). PARAGON is a basket trial that incorporates 7 phase 2 trials investigating the activity of anastrozole in patients with ER⁺ and/or progesterone receptor (PR)-positive (PR⁺) recurrent/metastatic gynecological cancers., Methods: Postmenopausal women with ER⁺ and/or PR⁺ ROC, who were asymptomatic and had cancer antigen 125 (CA125) progression after response to first line chemotherapy, where chemotherapy was not clinically indicated. Patients received anastrozole 1 mg daily until progression or unacceptable toxicity., Results: Fifty-four patients were enrolled (52 evaluable). Clinical benefit at three months (primary endpoint) was observed in 18 patients (34.6%; 95% confidence interval [CI]=23%-48%). Median progression-free survival (PFS) was 2.7 months (95% CI=2.1-3.1). The median duration of clinical benefit was 6.5 months (95% CI=2.8-11.7). Most patients progressed within 6 months of starting anastrozole but 12 (22%) continued treatment for longer than 6 months. Anastrozole was well tolerated. In the exploratory analysis, ER histoscores and the intensity of ER staining did not correlate with clinical benefit rate or PFS., Conclusion: A subset of asymptomatic patients with ER⁺ and/or PR⁺ ROC and CA125 progression had durable clinical benefit on anastrozole, with acceptable toxicity. Anastrozole may delay symptomatic progression and the time to subsequent chemotherapy. The future challenge is to identify the subset of patients most likely to benefit from an aromatase inhibitor and whether the clinical benefit could be increased by the addition of other agents., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2019. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology.)

Objective: Treatment options are limited for patients with recurrent/metastatic low-grade ovarian cancers (LGOCs) and serous borderline ovarian tumors (SBOTs) as response rates to chemotherapy are low. A subset of patients appears to derive clinical benefit from antiestrogens, but most studies have been retrospective and clinical benefit rates (CBR) remain uncertain. The primary aim of PARAGON was to prospectively investigate the CBR of anastrozole, an aromatase inhibitor, in patients with estrogen receptor (ER) and/or progesterone receptor (PR) positive LGOC and SBOT., Methods: Post-menopausal women with ER-positive and/or PR-positive recurrent/metastatic LGOCs and SBOTs and evaluable disease by RECIST v1.1 or GCIG CA125 criteria were treated with anastrozole 1 mg daily until progression or unacceptable toxicity., Results: Thirty-six patients were enrolled. Clinical benefit at 3 months (primary endpoint) was observed in 23 patients (64%, 95% CI 48%-78%) and was similar at 6 months (61%, 95% CI 43%-75%). The median duration of clinical benefit was 9.5 months (95% CI 8.3-25.8). Best study response was partial response by RECIST in 5 patients (14%), stable disease in 18 patients (50%) with progressive disease in 13 patients (36%). Median PFS was 11.1 months (95% CI 3.2-11.9). Anastrozole was well-tolerated. Patients with evidence of clinical benefit at 3 months reported less pain, fatigue, and improved physical and role functioning as early as 1 month of commencing treatment., Conclusions: Anastrozole was associated with a CBR of 61% of patients with recurrent ER-positive and/or PR-positive LGOC or SBOT for at least 6 months with acceptable toxicity., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Recent studies suggest that mucinous borderline ovarian tumors (MBOTs) belong to a high-risk group that is more likely to develop an invasive recurrence. The objective is to determine these risk factors., Methods: A monocentric retrospective review of all consecutive patients with intestinal-type MBOT diagnosed between 1993 and 2013. All tumors were evaluated by one pathologist without knowledge of clinical outcome. Extensive surgical staging and pathological tumor sampling (1 block/cm diameter in tumors <10 cm and 2 blocks/cm diameter in tumors >10 cm) were performed in all cases., Results: A total of 81 patients were included. Patients with micro-invasion were also included. None of the patients recurred. No bilateral tumors, nor tumors with International Federation of Gynecology and Obstetrics stage II or higher, were diagnosed. Median follow-up was 87 months., Conclusions: In our series of pure intestinal-type MBOT, including micro-invasion, no recurrences were observed. Given the heterogeneity of these tumors staging with at least unilateral salpingo-oophorectomy, extensive pathological sampling, and expert pathological review are of paramount importance to be able to diagnose a pure intestinal-type MBOT and excluding gastrointestinal mucinous tumors and more important, excluding an invasive focus, defining a mucinous ovarian carcinoma. When these conditions are fulfilled, the prognosis of pure intestinal-type MBOT is excellent., (© 2017 S. Karger AG, Basel.)

Although the occurrence of ovarian masses in pregnancy is relatively common, the majority of them is functional and resolve spontaneously; nevertheless, ovarian cancer is the fifth most common malignancy diagnosed in pregnancy. If malignancy is suspected, treatment should be decided on the basis of gestational age, stage of the disease and patient preferences. In early stage, ovarian cancer surgery may be planned preferably after 16 weeks of pregnancy, and chemotherapy can be administered from the second trimester if indicated as in non-pregnant patients. In advanced-stage disease, when complete cytoreduction is not achievable, neoadjuvant chemotherapy could be administered even in pregnancy. Chemotherapy should be a combination of carboplatin and paclitaxel in epithelial ovarian cancer patients and a combination of cisplatin, vinblastin and bleomycin in non-epithelial ovarian cancer. The outcome of patients with ovarian cancer diagnosed in pregnancy is similar to non-pregnant patients, and stage of the disease is the most important prognostic factor., (Copyright © 2016. Published by Elsevier Ltd.)

DNA replication errors that persist as mismatch mutations make up the molecular fingerprint of mismatch repair (MMR)-deficient tumors and convey them with resistance to standard therapy. Using whole-genome and whole-exome sequencing, we here confirm an MMR-deficient mutation signature that is distinct from other tumor genomes, but surprisingly similar to germ-line DNA, indicating that a substantial fraction of human genetic variation arises through mutations escaping MMR. Moreover, we identify a large set of recurrent indels that may serve to detect microsatellite instability (MSI). Indeed, using endometrial tumors with immunohistochemically proven MMR deficiency, we optimize a novel marker set capable of detecting MSI and show it to have greater specificity and selectivity than standard MSI tests. Additionally, we show that recurrent indels are enriched for the 'DNA double-strand break repair by homologous recombination' pathway. Consequently, DSB repair is reduced in MMR-deficient tumors, triggering a dose-dependent sensitivity of MMR-deficient tumor cultures to DSB inducers., (Copyright © 2014, Zhao et al.)

Objectives: To evaluate whole-body MRI with diffusion-weighted sequence (WB-DWI/MRI) for staging and assessing operability compared with CT and FDG-PET/CT in patients with suspected ovarian cancer., Methods: Thirty-two patients underwent 3-T WB-DWI/MRI, (18) F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) and CT before diagnostic open laparoscopy (DOL). Imaging findings for tumour characterisation, peritoneal and retroperitoneal staging were correlated with histopathology after DOL and/or open surgery. For distant metastases, FDG-PET/CT or image-guided biopsies were the reference standards. For tumour characterisation and peritoneal staging, WB-DWI/MRI was compared with CT and FDG-PET/CT. Interobserver agreement for WB-DWI/MRI was determined., Results: WB-DWI/MRI showed 94 % accuracy for primary tumour characterisation compared with 88 % for CT and 94 % for FDG-PET/CT. WB-DWI/MRI showed higher accuracy of 91 % for peritoneal staging compared with CT (75 %) and FDG-PET/CT (71 %). WB-DWI/MRI and FDG-PET/CT showed higher accuracy of 87 % for detecting retroperitoneal lymphadenopathies compared with CT (71 %). WB-DWI/MRI showed excellent correlation with FDG-PET/CT (κ = 1.00) for detecting distant metastases compared with CT (κ = 0.34). Interobserver agreement was moderate to almost perfect (κ = 0.58-0.91)., Conclusions: WB-DWI/MRI shows high accuracy for characterising primary tumours, peritoneal and distant staging compared with CT and FDG-PET/CT and may be valuable for assessing operability in ovarian cancer patients., Key Points: • Whole-body MRI with diffusion weighting (WB-DWI/MRI) helps to assess the operability of suspected ovarian cancer. • Interobserver agreement is good for primary tumour characterisation, peritoneal and distant staging. • WB-DWI/MRI improves mesenteric/serosal metastatic spread assessment compared with CT and FDG-PET/CT. • Retroperitoneal/cervical-thoracic nodal staging using qualitative DWI criteria was reasonably accurate. • WB-DWI/MRI and FDG-PET/CT showed the highest diagnostic impact for detecting thoracic metastases.

Objectives: This study aimed to compare the prognosis of patients with synchronous endometrial and ovarian cancer (SEOC) to matched controls with either endometrial cancer (EC) or ovarian cancer (OC)., Methods: A retrospective case-control study including all patients with SEOC who had been treated at 5 European tertiary gynecologic oncology centers between 1996 and 2011 and patients with either EC or OC matched for age, International Federation of Gynecology and Obstetrics (FIGO) stage, histology, year of diagnosis, and Eastern Cooperative Oncology Group performance score., Results: The study cohort comprised 77, 132, and 126 patients with SEOC, EC, and OC, respectively. The patient characteristics confirmed an equal distribution of matching factors, and the median follow-up did not differ (P = 0.44). 48.1% of the patients with SEOC showed early FIGO stage I for both EC and OC. The 5-year PFS rates differed between SEOC and EC (76.3% vs 86.3%; P = 0.047) but not the 5-year overall survival rates (71.6% vs 79.8%; P = 0.12) and did not differ between SEOC and OC (76.3% vs 63.8%; P = 0.19 and 71.6% vs 69.3%; P = 0.61, respectively). After the adjustment for the FIGO stage of the 2 components of SEOC, neither PFS nor overall survival rates were different., Conclusions: Prognosis of patients with SEOC tended to be the same in comparison with matched controls with either one EC or OC. Therefore, it could be considered that patients with SEOC may be eligible for clinical trials of the advanced tumor component if no additional therapy is indicated for the other component.

Purpose: Enzastaurin is an oral serine/threonine kinase inhibitor antitumor agent. Our phase II trial tested the efficacy and safety of enzastaurin added to a standard carboplatin/paclitaxel chemotherapy regimen in patients with newly diagnosed advanced ovarian cancer., Patients and Methods: This was a randomized, placebo-controlled study in patients with International Federation of Gynecology and Obstetrics stage IIB to IV ovarian, fallopian tube, or peritoneal epithelial carcinoma. Patients were randomly assigned to six cycles of chemotherapy (paclitaxel/carboplatin ± enzastaurin [PCE/PC]) followed by maintenance therapy (enzastaurin/placebo). Primary end point was progression-free survival (PFS). Secondary measures included response rate, safety assessment, and translational research., Results: A total of 142 patients were randomly assigned to PCE (n = 69) or PC (n = 73). Patients in the PCE group had a 3.7-month longer median PFS compared with patients in the PC group; this was not statistically significant (hazard ratio [HR], 0.80; 95% CI, 0.50 to 1.29; P = .37). Safety profiles of the treatment arms were comparable. Frequency of discontinuation because of adverse events was similar (PCE, 11.9%; PC, 9.7%). Multivariate analyses confirmed the importance of optimal debulking with regard to PFS (debulking optimal v suboptimal: HR, 0.51; 95% CI, 0.30 to 0.85; P = .009). HR for covariate stage (stage IIB to IIIB v IIIC to IV) was not statistically significant (0.75; 95% CI, 0.38 to 1.47; P = .40). Translational research of immunohistochemistry protein assays did not identify any markers significantly associated with treatment difference regarding PFS., Conclusion: The PCE combination increased PFS, but it was not significantly superior to PC in this phase II study.

Purpose: The combination of two tumour markers, CA125 and HE4, in the risk of ovarian malignancy assay (ROMA) has been shown to be successful in classifying patients into those who have a high or low risk of epithelial ovarian cancer. In the present study, the diagnostic accuracy of ROMA was assessed and compared to the diagnostic accuracy of the two most widely used ultrasound methods, namely the risk of malignancy index (RMI) and subjective assessment by ultrasound., Methods: From August, 2005 to March, 2009, 432 women with a pelvic mass who were scheduled to have surgery were enrolled in a single-centre prospective cohort study. A preoperative ultrasound was performed and preoperative CA125 and HE4 serum levels were measured. Once the final surgical pathology reports were obtained, the diagnostic accuracy and performance indices of ROMA, RMI and subjective assessment were calculated., Results: Of the 432 eligible patients, 374 could be analysed. Subjective assessment had the highest area under the receiver operator characteristic curve (AUC) (0.968, 95%CI:0.945-0.984), followed by the RMI (0.931, 95%CI:0.901-0.955). The subjective assessment and RMI both had significantly higher AUCs than the ROMA (0.893, 95%CI:0.857-0.922; P<0.0001 and P=0.0030, respectively). The pre- and postmenopausal populations generated similar results., Conclusion: Although new tumour markers models are promising, they do not contribute significantly to the diagnosis of ovarian cancer. Ultrasound, especially subjective assessment by ultrasound, remains superior in discriminating malignant from benign ovarian masses., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objective: The aim of this study is to evaluate the current opinion of the members of the European Society of Gynecological Oncology (ESGO) on the use of neoadjuvant chemotherapy (NACT) in stage IIIC and IV ovarian cancer., Methods: A link to a 21-item questionnaire, with questions about the management of patients with stage IIIC and IV ovarian cancer, was sent 3 times to the ESGO members (N = 1177)., Results: Of the 469 (40%) responding members, 70.2% believe there is sufficient evidence to use NACT followed by interval debulking for the treatment of stage IIIC and IV ovarian cancer. On the basis of a multivariable logistic regression analysis, no relationships between the belief in evidence for NACT and practice type (P = 0.15) or level of experience (P = 0.41) were observed. Only 5.3% of respondents never use NACT, and 30% uses NACT in less than 10% of their patients. Optimal debulking, defined as "no macroscopic residual tumor," is reported in more than 60% of the patients by 20% of the respondents at primary debulking, and by 34.6% of the respondents when interval debulking is performed. Whether a patient can be optimally primarily debulked is impossible to determine preoperatively according to 51.1% of the respondents. Computed tomographic scan (79.4%) and clinical examination (72.5%) are regarded as the most important modalities to predict operability. Diagnostic laparoscopy is used by 46.3% of the respondents. The most important reasons for choosing NACT are bulky disease in the upper abdomen (64.7%) and stage IV disease (58.7%)., Conclusions: Of the responding ESGO members, 70% believe there is sufficient evidence to treat patients with stage IIIC-IV ovarian cancer with NACT, and 30% uses NACT in less than 10% of their patients.

Background: Targeting of VEGF is a potential therapeutic option in patients with malignant ovarian ascites. We present the final results of a multicentre study of the efficacy and safety of aflibercept, a potent inhibitor of both VEGF and placental growth factor, in the treatment of malignant ascites., Methods: In this double-blind, placebo-controlled, parallel-group, phase 2 study, patients with advanced chemoresistant ovarian cancer and recurrent symptomatic malignant ascites were randomly assigned (1:1) via an interactive voice response system to either intravenous aflibercept (4 mg/kg every 2 weeks) or placebo, stratified by interval of time (≤ 2 weeks vs > 2 weeks) between the two most recent paracenteses before randomisation. Patients participated in the double-blind period (during which patients, investigators, and sponsor personnel were masked to treatment assignment) until they had a repeat paracentesis and for at least 60 days, and could also participate in an optional open-label period during which all patients received aflibercept. The primary efficacy endpoint was time to repeat paracentesis based on response during the double-blind period alone, and was analysed in the intention-to-treat population with censoring of patients who did not have a repeat paracentesis as of the last day of the double-blind period. Safety analyses included both double-blind and open-label periods. This study is registered at ClinicalTrials.gov, number NCT00327444., Findings: 55 patients with a median of four (range two to 11) previous lines of chemotherapy were randomly assigned to receive placebo (n=26) or aflibercept (n=29). Mean time to repeat paracentesis was significantly longer with aflibercept than with placebo (55·1 [SE 7·3] vs 23·3 [7·7] days; difference 31·8 days, 95% CI 10·6-53·1; p=0·0019). In the aflibercept group, two patients did not need a repeat paracentesis during 6 months of double-blind treatment. The most common grade 3 or 4 treatment-emergent adverse events were dyspnoea (six [20%] aflibercept vs two [8%] placebo), fatigue or asthenia (four [13%] vs 11 [44%]), and dehydration (three [10%] vs three [12%]). The frequency of fatal gastrointestinal events was higher with aflibercept (three intestinal perforations) than with placebo (one intestinal fistula leading to sepsis)., Interpretation: This study shows the effectiveness of VEGF blockade in the reduction of malignant ascites, but confirms the significant clinical risk of fatal bowel perforation in this population of patients with very advanced cancer. VEGF blockade should be used with caution in advanced ovarian cancer with abdominal carcinomatosis, and the benefit-risk balance should be thoroughly discussed for each patient., Funding: Sanofi Oncology., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Unlabelled: AIMS OF THE STUDY AND METHODS: Survival, complications and recurrences after diaphragmatic surgery at primary or interval debulking surgery were compared. One hundred and sixty three consecutive patients with stage III/IV ovarian cancer underwent diaphragmatic surgery between September 1993 and December 2007. Primary debulking was performed in group 1 (89) patients and interval debulking was performed in group 2 (74) patients. Cytoreductive outcome, overall survival (OS), disease-free survival (DFS) and post-operative complications were analysed., Results: Despite differences in baseline mean age (p=0.015), in FIGO stage III/IV (p=0.036) and in mean largest diameter of metastatic disease at the beginning of debulking surgery (p=0.037), the optimal debulking rates (residual tumour less than 1cm) were similar (p=0.065). Excision of diaphragmatic metastases was most frequently performed in group 1 (77.53%) and coagulation was most frequently performed in group 2 (58.10%). Similar overall survival and disease-free survival rates were found. After the propensity matching procedure, the largest diameter of metastatic disease at the time of debulking and no residual tumour (complete debulking) were demonstrated as independent prognostic factors for OS. Plaque-like lesions on the diaphragm metastases were significantly (p=0.015) more associated with diaphragm recurrence than papillary lesions. Minor and major complications related to diaphragmatic surgery as well as mean operating time, post-operative care in intensive care unit and length of hospitalisation were significantly higher in group 1 rather than in group 2 (p=0.043)., Conclusions: Diaphragmatic dissemination resulted in similar survival and cytoreductive rates after primary and interval debulking. However, the morbidity was less after interval debulking as fewer surgical procedures were performed., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Alterations in stromal tissue components can inhibit or promote epithelial tumorigenesis. Decorin (DCN) and lumican (LUM) show reduced stromal expression in serous epithelial ovarian cancer (sEOC). We hypothesized that common variants in these genes associate with risk. Associations with sEOC among Caucasians were estimated with odds ratios (OR) among 397 cases and 920 controls in two U.S.-based studies (discovery set), 436 cases and 1,098 controls in Australia (replication set 1) and a consortium of 15 studies comprising 1,668 cases and 4,249 controls (replication set 2). The discovery set and replication set 1 (833 cases and 2,013 controls) showed statistically homogeneous (P(heterogeneity)≥0.48) decreased risks of sEOC at four variants: DCN rs3138165, rs13312816 and rs516115, and LUM rs17018765 (OR = 0.6 to 0.9; P(trend) = 0.001 to 0.03). Results from replication set 2 were statistically homogeneous (P(heterogeneity)≥0.13) and associated with increased risks at DCN rs3138165 and rs13312816, and LUM rs17018765: all ORs = 1.2; P(trend)≤0.02. The ORs at the four variants were statistically heterogeneous across all 18 studies (P(heterogeneity)≤0.03), which precluded combining. In post-hoc analyses, interactions were observed between each variant and recruitment period (P(interaction)≤0.003), age at diagnosis (P(interaction) = 0.04), and year of diagnosis (P(interaction) = 0.05) in the five studies with available information (1,044 cases, 2,469 controls). We conclude that variants in DCN and LUM are not directly associated with sEOC, and that confirmation of possible effect modification of the variants by non-genetic factors is required.

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancy in the developed world, accounting for 4% of the deaths from cancer in women. We performed a three-phase genome-wide association study of EOC survival in 8,951 individuals with EOC (cases) with available survival time data and a parallel association analysis of EOC susceptibility. Two SNPs at 19p13.11, rs8170 and rs2363956, showed evidence of association with survival (overall P = 5 × 10⁻⁴ and P = 6 × 10⁻⁴, respectively), but they did not replicate in phase 3. However, the same two SNPs demonstrated genome-wide significance for risk of serous EOC (P = 3 × 10⁻⁹ and P = 4 × 10⁻¹¹, respectively). Expression analysis of candidate genes at this locus in ovarian tumors supported a role for the BRCA1-interacting gene C19orf62, also known as MERIT40, which contains rs8170, in EOC development.

Ovarian cancer accounts for more deaths than all other gynecological cancers combined. To identify common low-penetrance ovarian cancer susceptibility genes, we conducted a genome-wide association study of 507,094 SNPs in 1,768 individuals with ovarian cancer (cases) and 2,354 controls, with follow up of 21,955 SNPs in 4,162 cases and 4,810 controls, leading to the identification of a confirmed susceptibility locus at 9p22 (in BNC2). Here, we report on nine additional candidate loci (defined as having P ≤ 10⁻⁴) identified after stratifying cases by histology, which we genotyped in an additional 4,353 cases and 6,021 controls. We confirmed two new susceptibility loci with P ≤ 5 × 10⁻⁸ (8q24, P = 8.0 × 10⁻¹⁵ and 2q31, P = 3.8 × 10⁻¹⁴) and identified two additional loci that approached genome-wide significance (3q25, P = 7.1 × 10⁻⁸ and 17q21, P = 1.4 × 10⁻⁷). The associations of these loci with serous ovarian cancer were generally stronger than with other cancer subtypes. Analysis of HOXD1, MYC, TIPARP and SKAP1 at these loci and of BNC2 at 9p22 supports a functional role for these genes in ovarian cancer development.

Background: In this study the modulatory effect of the proteinase kinase C beta (PKC beta) selective inhibitor enzastaurin on CA125 expression and shedding in ovarian cancer cells (OVCAR-3 cells) was investigated. MATERIAL ANDMETHODS: OVCAR-3 cells were cultured in vitro and treated with increasing concentrations of carboplatin (2-1000 microM), paclitaxel (0.2-100 nM) or enzastaurin (1-100 microM) single agent. Growth inhibitory effects were evaluated by MTS and luminescence assay. CA 125 was determined in supernatans and in cell lysate using an electrochemo-iluminescence immunoassay., Results: Cell growth of OVCAR-3 cells was inhibited by single agent carboplatin, paclitaxel or enzastaurin in a dose dependent manner. Carboplatin caused a transient increase of CA125 in supernatans followed by a gradual decrease of CA125. Treatment with increasing doses of paclitaxel or enzastaurin caused an increase of CA125 shedding in culture medium but also the membrane bound fraction of CA125 was increased., Conclusion: These results suggest that enzastaurin, as paclitaxel, has a direct stimulatory effect on CA 125 synthesis and shedding in vitro., (Copyright 2010 Elsevier Inc. All rights reserved.)

Objectives: The purpose of this retrospective study was to evaluate diaphragmatic surgery in achieving optimal cytoreductive results and its associated complications during interval debulking surgery in patients with advanced ovarian cancer., Methods: After retrospective review of medical records, diaphragmatic surgery was performed in 74 of 128 consecutive patients with advanced epithelial ovarian cancer who underwent interval debulking, between September 1993 and December 2007. Four different approaches were performed: coagulation (group 1), stripping (group 2), combination of stripping with coagulation (group 3), and diaphragm full-thickness resection including muscle with pleura (group 4). Cytoreductive outcome, morbidity, overall survival, and disease-free survival were analyzed., Results: Two patients (2.7%) had International Federation of Gynecology and Obstetrics stage IIIB disease; 46 (62.16%), stage IIIC; and 26 (35.13%), stage IV. After 3 to 4 cycles of neoadjuvant platinum-based chemotherapy, the diaphragmatic disease was coagulated in 43 patients (58.10%) and was only stripped in 10 (13.51%); in 19 patients (25.67%), a combination of these techniques was applied; and in 2 (2.70%), the disease was resected, with the adjacent infiltrated part of the diaphragmatic muscle and the pleura above it. Debulking to no residual was achieved in 95%, 100%, 100%, and 50% for groups 1, 2, 3, and 4, respectively. The median disease-free survival was 15, 14, and 14 months, and the median overall survival was 34, 30, and 51 months for groups 1, 2, and 3, respectively, and were not reached for group 4. Minor and major complications were comparable among the groups. Pleural effusions were the most frequent associated complication, and chest tube placement (1.3%) or thoracocentesis (4%) were necessary for the relief of respiratory distress. The perioperative mortality rate was 0%., Conclusions: Diaphragmatic surgery during interval debulking enhances optimal cytoreduction rates and improves survival with acceptable and manageable morbidity. In patients with thick (>4 mm) or large (>1 cm) lesions, stripping the diaphragm or full-thickness resection of the diaphragmatic muscle is preferred.

Aim: To evaluate safety and fertility outcome after assisted conception in patients who were treated conservatively for a borderline ovarian tumor (BOT)., Methods: A systematic literature review using Medline was conducted. From all the relevant case series the following information was obtained for each reported patient: primary diagnosis; disease stage; surgical treatment; duration of follow-up; incidence of recurrence; current disease status; the number of controlled ovarian stimulation cycles and/or oocyte retrievals, and successful pregnancies., Results: Overall 588 articles were screened, of which finally 15 reports including 62 patients met the inclusion criteria. Within a median follow-up duration of 52 months in this small group of patients, overall 12 patients (19.4%) had recurrences, and those recurrences were again successfully treated by surgery in 11 patients. In terms of assisted reproductive outcome, in our series overall 152 ovarian stimulation cycles as well as 135 oocyte retrievals were performed with a baby-take-home rate of 28.3% per stimulated cycle., Conclusion: It is mandatory to counsel all patients with a history of BOT who are seeking treatment for infertility that, due to the limited data, it is unclear whether assisted reproductive techniques are associated with an increased risk of recurrence., (Copyright © 2010 S. Karger AG, Basel.)

Introduction: This safety lead-in study examined the pharmacokinetic and adverse event profile of combining enzastaurin with paclitaxel plus carboplatin as first-line therapy for the treatment of advanced-stage ovarian cancer and primary peritoneal carcinoma. The specific objectives of this study were to assess safety and tolerability after 2 cycles of treatment, to determine if enzastaurin alters paclitaxel and carboplatin pharmacokinetics, and to determine if enzastaurin pharmacokinetics is affected by paclitaxel and carboplatin., Methods: After debulking surgery, patients with previously untreated epithelial ovarian or primary peritoneal carcinoma received sequential paclitaxel (175 mg/m) and carboplatin (area under the curve, 5 mg x min/mL) on day 1 every 3 weeks for 6 cycles. Patients ingested an oral loading dose of 1125 mg enzastaurin on day 4 of cycle 1, followed by oral 500-mg enzastaurin daily until the end of therapy. Adverse events were graded according to the Common Terminology Criteria for Adverse Events v3.0., Results: There were 5 serious adverse events in 4 of 11 patients: soft tissue injury, wound infection, intestinal fistula, clostridial infection, and anemia. Coadministration with enzastaurin did not significantly alter paclitaxel and carboplatin pharmacokinetics (area under the curve ratio of treatment comparison asymptotically equal to 1.05 and 1.06, respectively). Enzastaurin exposures were unchanged (Cav,ss ratio of treatment comparison asymptotically equal to 0.95 for average steady-state total analyte concentrations of enzastaurin and its metabolite)., Conclusions: Adding enzastaurin to paclitaxel plus carboplatin chemotherapy is feasible for advanced ovarian cancer after radical cytoreduction. Enzastaurin did not alter paclitaxel or carboplatin pharmacokinetics, and enzastaurin exposures were not significantly changed by carboplatin and paclitaxel.

Objective: In the last decade several studies have been published using proteomics to unravel molecular pathways and to find biomarkers which can be used for diagnosis and/or prognostication in ovarian cancer. This review gives an overview of proteomic studies performed in ovarian cancer focusing on the nature of samples that have been used., Methods: Recent literature regarding the role of proteomic studies in ovarian cancer has been reviewed., Results: Most studies have focused on finding biomarkers for early diagnosis of ovarian cancer using blood samples though proteins identified until now are mainly acute phase reactants. Studies regarding platinum sensitivity have only been performed on cell culture models and need confirmation in tissue samples. Proteomic studies using ovarian cancer tissue are sparse and mostly contain a low number of samples., Conclusion: To date no biomarkers for early diagnosis or prognostication in ovarian cancer have been found using proteomics. We speculate that it would be interesting to investigate the tissue proteome in an attempt to overcome acute phase reactants and to facilitate the discovery of real tumor-specific biomarkers instead of the identification of secondary protein changes.

Background: There is a strong need for prognostic biomarkers in ovarian cancer patients due to the heterogeneous responses on current treatment modalities., Materials and Methods: This study investigates the feasibility of combining laser microdissection (LMD) and surface enhanced laser desorption ionization-time of flight mass spectrometry (SELDI-TOF MS) in ovarian cancer tissue to obtain protein profiles., Results: Ideal conditions for preparing a protein lysate were determined and subsequently analysed on SELDI-TOF MS. Applying these protocols on tissue of 9 ovarian cancer patients showed different protein profiles between platinum sensitive and resistant patients., Conclusion: This shows that combining optimised protocols for LMD with SELDI-TOF MS can be used to obtain discriminatory protein profiles. However, studies with large patient numbers and validation sets are essential to identify reliable biomarkers using this approach.

Study Objective: Port site metastases (PSM) after laparoscopic surgery for advanced-stage ovarian carcinoma are a cause of concern, but the pathophysiology is unknown. Because CO(2) pneumoperitoneum was recently demonstrated to be a cofactor in adhesion formation and tumor implantation in a laparoscopic mouse model, and because both could be prevented by the addition of 4% oxygen to the CO(2) pneumoperitoneum, we wanted to test the hypothesis that PSM could be related to tumor cell hypoxia during CO(2) pneumoperitoneum., Design: A randomized controlled pilot trial to compare the incidence of PSM in women undergoing laparoscopy with a pure CO(2) pneumoperitoneum in comparison with women with CO(2) pneumoperitoneum with the addition of 4% oxygen (Canadian Task Force classification C)., Setting: University Hospital Gasthuisberg, Leuven, Belgium., Patients: Since January 1, 2007, 22 consecutive women undergoing laparoscopy for suspected ovarian cancer with subsequent debulking laparotomy were included., Interventions: Diagnostic laparoscopy with 100% CO(2) versus laparoscopy with addition of 4% oxygen., Measurements and Main Results: In the control group, 9 (47%) PSM found in 19 port sites were excised. In the CO(2)+oxygen group, a similar incidence was found, that is, 8 (50%) PSM in 16 port sites. The incidence of PSM was higher in small women (p <.018) and in high-grade malignancies. The pathophysiology of PSM is unknown, but besides direct wound contamination, aerosolization of tumor cells and gas leaks have been suggested together with a causal relationship with the CO(2) pneumoperitoneum. Tumor cell hypoxia probably is not an important mechanism because PSM were not prevented by adding small amounts of oxygen to the CO(2) pneumoperitoneum., Conclusion: The hypothesis of tumor cell hypoxia by the CO(2) pneumoperitoneum as a mechanism for PSM could not be confirmed.

Objectives: In this paper we wish to present the reasons why i.p. chemotherapy cannot be accepted as standard of care for first-line systemic treatment of advanced ovarian carcinoma., Methods: The recent literature on i.p. chemotherapy is critically reviewed. All possible arguments against i.p. chemotherapy are reviewed., Conclusions: Intraperitoneal chemotherapy is associated with a higher toxicity rate than i.v. chemotherapy. For this reason, none of the regimens investigated in the three Gynecologic Oncology Group (GOG) studies can be used as standard treatment outside clinical protocols. The trials on i.p. chemotherapy have suggested a survival difference. However, in the two most recent trials, i.p. chemotherapy or not was not the only research question because different schedules and dosages were used. In addition, the significance of the most recent GOG 172 study was only weak (p = .03), and the result was nonsignificant for progression-free survival. Intraperitoneal chemotherapy should be used only in the context of properly designed clinical trials. These trials must either assess i.p. therapy in comparison with the standard treatment or address the issue of route of administration for equivalent dosages and schedules of the same drugs, and not a mosaic of these questions. In addition, these trials should investigate i.p. regimens that are less toxic than the regimens used in the three GOG trials, and which can be combined with molecular targeted therapies.

Background: In a previously published pilot study we explored the performance of microarrays in predicting clinical behaviour of ovarian tumours. For this purpose we performed microarray analysis on 20 patients and estimated that we could predict advanced stage disease with 100% accuracy and the response to platin-based chemotherapy with 76.92% accuracy using leave-one-out cross validation techniques in combination with Least Squares Support Vector Machines (LS-SVMs)., Methods: In the current study we evaluate whether tumour characteristics in an independent set of 49 patients can be predicted using the pilot data set with principal component analysis or LS-SVMs., Results: The results of the principal component analysis suggest that the gene expression data from stage I, platin-sensitive advanced stage and platin-resistant advanced stage tumours in the independent data set did not correspond to their respective classes in the pilot study. Additionally, LS-SVM models built using the data from the pilot study - although they only misclassified one of four stage I tumours and correctly classified all 45 advanced stage tumours - were not able to predict resistance to platin-based chemotherapy. Furthermore, models based on the pilot data and on previously published gene sets related to ovarian cancer outcomes, did not perform significantly better than our models., Conclusion: We discuss possible reasons for failure of the model for predicting response to platin-based chemotherapy and conclude that existing results based on gene expression patterns of ovarian tumours need to be thoroughly scrutinized before these results can be accepted to reflect the true performance of microarray technology.

Over the last decades, the management of borderline ovarian tumors (BOTs) has changed from radical surgery to more conservative therapy as a result of the need for fertility-sparing surgery and the increasing use of laparoscopy. The question is whether this is good clinical practice from an oncologic point of view. Here, recent literature regarding management of borderline ovarian neoplasms is reviewed, and oncologic concerns are discussed with emphasis on the mode of surgery and the possibility of fertility-sparing surgery and its consequences. Proper staging is defined as an exploration of the entire abdominal cavity with peritoneal washings, infracolic omentectomy, and multiple peritoneal biopsies as the cornerstone of a successful treatment, and this is only possible through a midline incision. For stage I disease, conservative surgery consisting of unilateral salpingo-oophorectomy or cystectomy in case of bilateral ovarian involvement or when the disease develops in the only remaining ovary is a valuable alternative in a number of young patients who want to preserve their fertility. Patients with advanced-stage disease or who are finished childbearing are treated with radical surgery consisting of peritoneal washings, total abdominal hysterectomy, bilateral salpingo-oophorectomy, infracolic omentectomy, complete peritoneal resection of macroscopic lesions, or multiple peritoneal biopsies; in case of mucinous BOTs, patients also are treated with an appendectomy.

Ovarian cancer accounts for 4% of all cancers in women and is the leading cause of death from gynaecologic malignancies. Because early-stage ovarian cancer is generally asymptomatic, approximately 75% of women present with advanced disease at diagnosis. Survival is highly dependent on stage of disease: 5-year survival in patients with early-stage is 80-90% compared to 25% for patients with advanced-stage disease. For all patients, a comprehensive surgical staging should be performed to obtain the histological confirmation of diagnosis and to evaluate the extent of disease. Patients with early-stage should both be optimally staged and be treated with adjuvant platinum-based chemotherapy if they have a medium or high-risk tumour. For advanced disease the currently recommended management is primary cytoreductive surgery followed by platinum-paclitaxel combination chemotherapy. Appropriate salvage therapy is based on the timing and nature of recurrence and the extent of prior chemotherapy. Surgical resection should be considered in patients with long-term remission, especially in those with isolated recurrences and good performance status. Platinum-based combination represents the standard second-line chemotherapy in patients with platinum-sensitive relapsed ovarian cancer. Salvage chemotherapy in platinum-refractory patients usually results in low response rates and short survival.

It has generally been accepted that pseudomyxoma peritonei/disseminated peritoneal adenomucinosis originates from appendiceal low-grade adenomatous mucinous tumors. A woman who underwent an appendectomy 42 years ago, presented with a unilateral ovarian tumor whose immunohistochemical phenotype and its association with a teratoma, strongly suggest that pseudomyxoma peritonei originated from a ruptured mucinous tumour arising from a mature cystic teratoma.

Purpose of Review: The treatment of borderline ovarian tumours has been similar to that for their invasive counterparts for a long time. However, in view of the good prognosis for borderline ovarian tumours, their occurrence in a younger age group and the development of less invasive techniques, the question can be asked as to whether a more conservative treatment is warranted., Recent Findings: Recent articles discuss the mode of surgery (laparotomy or laparoscopy), the possibility of fertility-sparing surgery, the need for restaging procedures and adjuvant therapy., Summary: The ultimate goal in treating patients with borderline ovarian cancer is defining those patients with bad prognostic factors and risk for recurrence and who consequently require more aggressive therapy. A proper staging procedure is crucial to estimate the risk. Translational research might help identify borderline tumours with poor prognosis. Fertility-sparing surgery is often a good option in young patients with Fédération International de Gynécologie et Obstétrie (FIGO) stage I disease or in selected cases with noninvasive implants, since long-term survival does not seem to be negatively influenced by conservative surgery.

Primary debulking surgery by a gynecologic oncologist remains the standard of care in advanced ovarian cancer. Optimal debulking surgery should be defined as no residual tumor load. In retrospective analyses, neoadjuvant chemotherapy followed by interval debulking surgery does not seem to worsen prognosis compared to primary debulking surgery followed by chemotherapy. However, we will have to wait for the results of future randomized trials to know whether neoadjuvant chemotherapy followed by interval debulking surgery is as good as primary debulking surgery in stage IIIC and IV patients. Interval debulking is defined as an operation performed after a short course of induction chemotherapy. Based on the randomized European Organization for Research and Treatment of Cancer-Gynecological Cancer Group (EORTC-GCG) trial, interval debulking by an experienced surgeon improves survival in some patients who did not undergo optimal primary debulking surgery. Based on Gynecologic Oncology Group (GOG) 152 data, interval debulking surgery does not seem to be indicated in patients who underwent primarily a maximal surgical effort by a gynecologic oncologist. Open laparoscopy is probably the most valuable tool for evaluating the operability primarily or at the time of interval debulking surgery.

Background: : The low incidence of ovarian adenosarcomas explains the paucity of available data regarding their biologic markers. Our aim was to investigate the presence of CD10, estrogen and progesterone receptors (ER and PR) in these tumors., Case: : Four cases of primary ovarian adenosarcoma were retrieved in our pathology databases. We assessed the immunohistochemical stainings for ER, PR and CD10 in 3 ovarian adenosarcomas without sarcomatous overgrowth (OAS), and 1 ovarian adenosarcoma with sarcomatous overgrowth (OAS-S). When considering the malignant stromal component, 2 OAS showed the presence of ER and PR, whereas the OAS-S was only ER positive. CD10 positivity was observed in the sarcomatous cells of all 3 OAS but was absent in the OAS-S., Conclusion: : The identification of a hormone sensitive disease is the main clinical implication of this study. Moreover, the current results add OAS to the list of CD10 positive ovarian tumors.

For several decades, endometriosis has been suspected of playing a role in the aetiology of ovarian cancer. The literature concerning a possible histogenesis of ovarian cancer from benign endometriosis is reviewed in this chapter. Epidemiological evidence from large-cohort studies confirms endometriosis as an independent risk factor for ovarian cancer. Further circumstantial evidence for this link was found in the common risk factors for ovarian cancer and endometriosis. These risk factors influence retrograde menstruation and endometriosis in the same positive or negative way. Based on data in the literature, the prevalence of endometriosis in epithelial ovarian cancer has been calculated to be 4.5, 1.4, 35.9, and 19.0% for serous, mucinous, clear-cell and endometrioid ovarian carcinoma, respectively. The risk of malignant transformation in ovarian endometriosis was calculated at 2.5% but this might be an underestimate. In addition, some authors described atypical endometriosis in a spatial and chronological association with ovarian cancer. Finally, molecular studies have detected common alterations in endometriosis and ovarian cancer. These data suggest that some tumours, especially endometrioid and clear-cell carcinomas, can arise from endometriosis. Moreover, endometriosis-associated ovarian cancer represents a distinct clinical entity, with a more favourable biological behaviour, given a lower stage distribution and better survival than non-endometriosis-associated ovarian cancer.

Background: It was the purpose of this study to test the monoclonal theory in ovarian carcinosarcoma., Methods: Twenty-six women with a diagnosis of ovarian carcinosarcoma were subjected to a clinicopathologic analysis. Biopsies from metastatic lesions obtained at primary surgery and surgery for recurrent disease were reviewed. Special attention was paid to the composition of metastatic lesions and to florid desmoplastic reaction as a potential pitfall for the detection of sarcomatous areas., Results: Biopsies derived from metastatic disease at primary surgery (n = 107) consisted of carcinoma cells only (n = 71, 66%), >50% carcinoma cells (n = 21, 20%), >50% sarcoma cells (n = 13, 12%), or sarcoma cells only (n = 2, 2%). The microscopic analysis demonstrated a preponderance of epithelial cells in the primary setting and suggested the epithelial component to drive the tumor, a finding consistent with the monoclonal theory. Biopsies derived from surgery for recurrent disease (n = 8) consisted of carcinoma cells only (0%), >50% carcinoma cells (n = 1, 13%), >50% sarcoma cells (n = 4, 50%), or sarcoma cells only (37%). Since sarcomatous cells dominated the tumorigenic cell population in the recurrent setting, this analysis revealed a change of the composition of metastatic lesions in time when compared to the data in the primary setting. This change was supported by the observation of a threefold higher incidence of sarcoma-dominated metastatic lesions at interval debulking when compared to primary debulking (24 vs 8%, respectively). The potential of a phenotypic change during ovarian cancer progression was further highlighted by the detection of two cases of carcinosarcoma that presented as a recurrence of epithelial ovarian carcinoma., Conclusion: Our results are consistent with the monoclonal theory of ovarian carcinosarcoma histogenesis, but suggest that there is a tendency toward a sarcomatous differentiation during disease progression. These data are important to understand the tumor biology and might have implications for a tailored treatment of ovarian carcinosarcoma.

Objective: To determine the activity and tolerability of gemcitabine in the palliative treatment of ovarian cancer., Methods: Patients affected by ovarian cancer, and with progressive disease after treatment with platinum/paclitaxel-based chemotherapy, were enrolled into this phase II study. Gemcitabine, 1000 mg/m(2), was administered on days 1, 8, and 15, by 30-min intravenous infusion. Cycles were repeated every 28 days., Results: Fifty patients were enrolled. All the patients were platinum and/or paclitaxel resistant (median number of previous regimens, 2; range, 1-5). Median platinum-free interval was 3 (range, 1-11) months and median paclitaxel-free interval was 6 (range, 1-36) months. A total of 210 courses were evaluable for toxicity, with a median number of four cycles administered per patient (range, 1-10). A grade 3 or 4 hematological toxicity was observed in 27 patients (54%) (anemia grade 3, 16%; grade 4, 2%; neutropenia grade 3, 24%; grade 4, 18%; thrombocytopenia grade 3, 8%; grade 4, 0%). A 20-50% dose reduction was required for 36 patients (72%, 55% of cycles). Blood transfusions were necessary for 15 patients (30%), while 2 (4%) were treated with erythropoetin. Granulocyte colony-stimulating factor was necessary in 4 patients (8%). Nonhematological toxicity was mild and manageable. Only 4 patients (8%) experienced a grade 3 hepatic toxicity (elevated liver enzymes). Forty-one patients (82%) are, so far, evaluable for response. Among them, 7 partial responses (17%; 95% confidence interval [CI], 6-29), 15 disease stabilizations (>16 weeks) (36.6%; 95% CI, 21.9-51.3), and 19 progressions (46.3%; 95% CI, 31.0-61.6) have been registered. An overall clinical benefit was observed in 53.7% of patients. Thirteen patients (31.7%) had a time-to-progression exceeding 24 weeks., Conclusions: This study confirms the activity and safety of gemcitabine in heavily pretreated patients with recurrent ovarian cancer.