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PURPOSE: Tubo-ovarian cancer (TOC) is a sentinel cancer for BRCA1 and BRCA2 pathogenic variants (PVs). Identification of a PV in the first member of a family at increased genetic risk (the proband) provides opportunities for cancer prevention in other at-risk family members. Although Australian testing rates are now high, PVs in patients with TOC whose diagnosis predated revised testing guidelines might have been missed. We assessed the feasibility of detecting PVs in this population to enable genetic risk reduction in relatives. PATIENTS AND METHODS: In this pilot study, deceased probands were ascertained from research cohort studies, identification by a relative, and gynecologic oncology clinics. DNA was extracted from archival tissue or stored blood for panel sequencing of 10 risk-associated genes. Testing of deceased probands ascertained through clinic records was performed with a consent waiver. RESULTS: We identified 85 PVs in 84 of 787 (11%) probands. Familial contacts of 39 of 60 (65%) deceased probands with an identified recipient (60 of 84; 71%) have received a written notification of results, with follow-up verbal contact made in 85% (33 of 39). A minority of families (n = 4) were already aware of the PV. For many (29 of 33; 88%), the genetic result provided new information and referral to a genetic service was accepted in most cases (66%; 19 of 29). Those who declined referral (4 of 29) were all male next of kin whose family member had died more than 10 years before. CONCLUSION: We overcame ethical and logistic challenges to demonstrate that retrospective genetic testing to identify PVs in previously untested deceased probands with TOC is feasible. Understanding reasons for a family member's decision to accept or decline a referral will be important for guiding future TRACEBACK projects.

Objectives Uterine carcinosarcoma (UCS) is a rare neoplasm with a poor prognosis and a paucity of evidence on treatment. The objective was to review the characteristics, treatment and outcomes of UCS cases across two gynaeoncology units and five private gynaeoncology practices in Melbourne. Methods UCS cases were identified from hysterectomy pathology records between 1994 and 2020 inclusive. Patient characteristics, histopathological stage, adjuvant therapy, recurrence and survival status were extracted from patient records. Results 208 cases of UCS were identified. The overall recurrence rate was 26.0% and the overall death rate was 60.1%. Increasing age at diagnosis was associated with an increased risk of death (adjusted OR 1.04, 95% CI 1.01-1.08, p=0.019). Risk of death was highest in Stage III disease (adjusted OR 4.37, 95% CI 1.67-11.40). Recurrence was a strong determinant of death, with an adjusted OR of 7.58 (p<0.001). Conclusions In this relatively large homogenous cohort of UCS cases, significant predictors for survival included age at diagnosis, stage of disease and recurrence.

TP53 mutations are implicated in the progression of mucinous borderline tumors (MBOT) to mucinous ovarian carcinomas (MOC). Optimized immunohistochemistry (IHC) for TP53 has been established as a proxy for the TP53 mutation status in other ovarian tumor types. We aimed to confirm the ability of TP53 IHC to predict TP53 mutation status in ovarian mucinous tumors and to evaluate the association of TP53 mutation status with survival among patients with MBOT and MOC. Tumor tissue from an initial cohort of 113 women with MBOT/MOC was stained with optimized IHC for TP53 using tissue microarrays (75.2%) or full sections (24.8%) and interpreted using established criteria as normal or abnormal (overexpression, complete absence, or cytoplasmic). Cases were considered concordant if abnormal IHC staining predicted deleterious TP53 mutations. Discordant tissue microarray cases were re-evaluated on full sections and interpretational criteria were refined. The initial cohort was expanded to a total of 165 MBOT and 424 MOC for the examination of the association of survival with TP53 mutation status, assessed either by TP53 IHC and/or sequencing. Initially, 82/113 (72.6%) cases were concordant using the established criteria. Refined criteria for overexpression to account for intratumoral heterogeneity and terminal differentiation improved concordance to 93.8% (106/113). In the expanded cohort, 19.4% (32/165) of MBOT showed evidence for TP53 mutation and this was associated with a higher risk of recurrence, disease-specific death, and all-cause mortality (overall survival: HR = 4.6, 95% CI 1.5-14.3, p = 0.0087). Within MOC, 61.1% (259/424) harbored a TP53 mutation, but this was not associated with survival (overall survival, p = 0.77). TP53 IHC is an accurate proxy for TP53 mutation status with refined interpretation criteria accounting for intratumoral heterogeneity and terminal differentiation in ovarian mucinous tumors. TP53 mutation status is an important biomarker to identify MB

With the recent introduction of the renewed National Cervical Screening Program (NCSP) in Australia, utilising primary human papillomavirus (HPV) nucleic acid testing (NAT) for known oncogenic HPV types rather than cervical cytology, we reflect on three asymptomatic women with negative oncogenic HPV test results and high-grade cervical abnormalities including cervical intraepithelial neoplasia (CIN) III and cervical squamous cell carcinoma (SCC). The two cases with CIN III had a 'probable' oncogenic subtype (HPV 53) identified on further testing, while the case of SCC had no HPV virus identified. These cases serve as a reminder of the need for ongoing diligence despite low-risk screening under the new program.Copyright © 2019 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists

Ovarian cancer is the most lethal gynecologic malignancy. Early detection would improve survival, but an effective diagnostic test does not exist. Novel biomarkers for early ovarian cancer diagnosis are therefore warranted. We performed intraoperative blood sampling from ovarian veins of stage I epithelial ovarian carcinomas and analyzed the serum proteome. Junction plakoglobin (JUP) was found to be elevated in venous blood from ovaries with malignancies when compared to those with benign disease. Peripheral plasma JUP levels were validated by ELISA in a multicenter international patient cohort. JUP was significantly increased in FIGO serous stage IA+B (1.97-fold increase; p < 0.001; n = 20), serous stage I (2.09-fold increase; p < 0.0001; n = 40), serous stage II (1.81-fold increase, p < 0.001, n = 23) and serous stage III ovarian carcinomas (1.98-fold increase; p < 0.0001; n = 34) vs. normal controls (n = 109). JUP plasma levels were not increased in early stage breast cancer (p = 0.122; n = 12). In serous ovarian cancer patients, JUP had a sensitivity of 85% in stage IA+B and 60% in stage IA-C, with specificities of 76 and 94%, respectively. A logistic regression model of JUP and Cancer Antigen 125 (CA125) revealed a sensitivity of 70% for stage IA+B and 75% for stage IA-C serous carcinomas at 100% specificity. Our novel ovarian blood sampling - proteomics approach identified JUP as a promising new biomarker for epithelial ovarian cancer, which in combination with CA125 might fulfill the test criteria for ovarian cancer screening.© Copyright © 2020 Weiland, Lokman, Klingler-Hoffmann, Jobling, Stephens, Sundfeldt, Hoffmann and Oehler.

Purpose Low-grade serous ovarian carcinoma (LGSC) responds poorly to chemotherapy and is characterized by activating mutations in the Ras sarcoma-mitogen-activated protein kinase (RAS-MAPK) pathway, including oncogenic BRAF. However, response to BRAF inhibitors is tumor-type specific. Significant improvement in survival is seen in patients with BRAF-mutant melanoma, but other cancer types, such as colorectal cancers, are generally less sensitive. We examined the frequency and characteristics of BRAF-mutated LGSC and described the response to treatment with BRAF inhibitors. Patients and Methods Mutations were assessed in LGSC (N = 65) by using targeted, exome, and whole-genome sequencing. Patient characteristics, treatment, and clinical outcome were assessed, and the median follow-up time was more than 5 years. BRAF inhibitors were trialed in two patients with a somatic BRAF V600E mutation: one patient received dabrafenib monotherapy and was monitored clinically, biochemically (cancer antigen [CA]-125 levels), and with positron emission tomography (PET) imaging. Expression of the BRAF V600E protein in this patient was assessed by immunohistochemistry. Results Among patients with LGSC, nine (13.8%) of 65 had a somatic BRAF mutation. Of the nine patients with BRAF mutation-positive LGSC, four experienced progressive disease that did not respond to conventional chemotherapy. Two of the patients experienced progression quickly and died as a result of disease progression, and two received targeted treatment. Two patients with BRAF V600E mutation received BRAF inhibitors at relapse and both achieved durable responses. Conclusion BRAF mutations are not uncommon in patients with LGSC and should be routinely tested, because BRAF inhibitors can be an effective treatment for these patients. The results highlight the need for targeted treatment in this rare tumor type, and a prospective study is needed to formally assess the response rate and clinical benefit.Copyright © 2019 Am

Introduction Uterine carcinosarcoma (UC), previously known as malignant mixed mullerian tumour (MMMT), is a rare uterine neoplasm containing both carcinomatous and sarcomatous components. It is an aggressive subtype of endometrial carcinoma associated with late diagnosis and poor prognosis, representing less than 5% of all uterine malignancies while accounting for more than 15% of uterine cancer related deaths. Due to the relatively low incidence of cases, the optimal management of these patients following primary surgical treatment remains uncertain. Objective To review the characteristics, treatment and outcomes of a cohort of cases of UC. Methods 92 cases of UC were identified from a retrospective observational study of patients whose primary operations were performed by four gynaeoncologists at Monash Health from 1994 to 2016 inclusive. Patient characteristics, histopathology reports, type(s) of adjuvant therapy, presence of recurrence and survival status were extracted from patient records. Staging was determined based on histopathology using the International Federation of Gynaecology and Obstetrics (FIGO) staging system. Results 33 (36%) patients were diagnosed with Stage I UC, 15 (16%) with Stage II, 27 (29%) with Stage III and 17 (18%) with Stage IV. The mean age at the time of primary surgery was 69.97 years, and the mean age at death was 73 years. There was an overall recurrence rate of 14% and death rate of 49%. The association between various patient, disease and treatment factors with survival was analysed. Age at diagnosis and stage of disease were both significant predictors of survival odds, with stage IV UC conferring the highest odds of death compared to stage I (OR 12.5, 95% CI 2-79.2), and increasing age at diagnosis demonstrating a small but significant increase in odds ratio for death (OR 1.06, 95% CI 1.005-1.12). However, there were no significant associations between type of adjuvant therapy and recurrence with death following both univariat

Accurately identifying patients with high-grade serous ovarian carcinoma (HGSOC) who respond to poly(ADP-ribose) polymerase inhibitor (PARPi) therapy is of great clinical importance. Here we show that quantitative BRCA1 methylation analysis provides new insight into PARPi response in preclinical models and ovarian cancer patients. The response of 12 HGSOC patient-derived xenografts (PDX) to the PARPi rucaparib was assessed, with variable dose-dependent responses observed in chemo-naive BRCA1/2-mutated PDX, and no responses in PDX lacking DNA repair pathway defects. Among BRCA1-methylated PDX, silencing of all BRCA1 copies predicts rucaparib response, whilst heterozygous methylation is associated with resistance. Analysis of 21 BRCA1-methylated platinum-sensitive recurrent HGSOC (ARIEL2 Part 1 trial) confirmed that homozygous or hemizygous BRCA1 methylation predicts rucaparib clinical response, and that methylation loss can occur after exposure to chemotherapy. Accordingly, quantitative BRCA1 methylation analysis in a pre-treatment biopsy could allow identification of patients most likely to benefit, and facilitate tailoring of PARPi therapy.Copyright © 2018, The Author(s).

Accurately identifying patients with high-grade serous ovarian carcinoma (HGSOC) who respond to poly(ADP-ribose) polymerase inhibitor (PARPi) therapy is of great clinical importance. Here we show that quantitative BRCA1 methylation analysis provides new insight into PARPi response in preclinical models and ovarian cancer patients. The response of 12 HGSOC patient-derived xenografts (PDX) to the PARPi rucaparib was assessed, with variable dose-dependent responses observed in chemo-naive BRCA1/2-mutated PDX, and no responses in PDX lacking DNA repair pathway defects. Among BRCA1-methylated PDX, silencing of all BRCA1 copies predicts rucaparib response, whilst heterozygous methylation is associated with resistance. Analysis of 21 BRCA1-methylated platinum-sensitive recurrent HGSOC (ARIEL2 Part 1 trial) confirmed that homozygous or hemizygous BRCA1 methylation predicts rucaparib clinical response, and that methylation loss can occur after exposure to chemotherapy. Accordingly, quantitative BRCA1 methylation analysis in a pre-treatment biopsy could allow identification of patients most likely to benefit, and facilitate tailoring of PARPi therapy.

Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11-1.19, P = 8.88 x 10-16) and among familial cases (OR: 1.24, 95% CI: 1.16-1.32, P = 6.19 x 10-11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.

Ovarian granulosa cell tumors (GCT) are hormonally-active neoplasms characterized, in the adult-subtype, by a mutation in the FOXL2 gene (C134W). They exhibit an indolent course with an unexplained propensity for late recurrence; ~80% of patients with aggressive, advanced stage tumors die from their disease; aside from surgery, therapeutic options are limited. To identify the molecular basis of advanced stage disease we have used whole transcriptome analysis of FOXL2 C134W mutation positive adult (a)GCT to identify genes that are differentially expressed between early (stage 1) and advanced (stage 3) aGCT. Transcriptome profiles for early (n=6) and stage 3 (n=6) aGCT, and for the aGCT-derived KGN, cell line identified 24 genes whose expression significantly differs between the early and stage 3 aGCT. Of these, 16 were more abundantly expressed in the stage 3 aGCT and 8 were higher in the stage 1 tumors. These changes were further examined for the genes which showed the greatest fold change: the cytokine CXCL14, microfibrillar-associated protein 5, insulin-like 3 and desmin. Gene Set Enrichment Analysis identified overexpression of genes on chromosome 7p15 which includes the homeobox A gene locus. The analysis therefore identifies a small number of genes with clearly discriminate patterns of expression arguing that the clinicopathological-derived distinction of the tumor stage is robust, whilst confirming the relative homogeneity of expression for many genes across the cohort and hence of aGCT. The expression profiles do however identify several overexpressed genes in both stage 1 and/or stage 3 aGCT which warrant further study as possible therapeutic targets.

Background and Aims: The Genomic Analysis of Mucinous Tumors (GAMuT) study is an international effort to understand molecular and genomic drivers of this rare tumor type. Grade 3 (G3) mucinous ovarian carcinoma is a deadly subgroup and genomically poorly understood. We had a unique opportunity to compare a primary borderline tumour with focal G3 carcinoma with later G3 metastatic sites collected at autopsy in order to understand drivers of metastatic spread. Method(s): The patient, aged 41 at diagnosis of Stage I ovarian mucinous carcinoma, had a 26-month progression-free interval, including normal serum markers at 21 months. Tumour cells were microdissected from snap-frozen tissue and DNA extracted. Whole-genome sequencing was performed on borderline and G3 areas of the primary tumour and four metastatic sites. Result(s): The primary tumour was mostly borderline in appearance with focal G3 carcinoma. At autopsy, G3 carcinoma was widespread in the body and was morphologically similar to the primary G3 area. Key drivers KRAS and TP53 mutations, chr7 and chr19 copy number events and p16 loss were shared at all sites. Surprisingly, the primary G3 cells were genetically highly similar to the borderline cells. The metastases were very concordant with each other, but extensive clonal diversification of metastases from the primary was seen including near doubling of copy number events and an increase in point mutations. Conclusion(s): This case demonstrates progression of a borderline to high-grade carcinoma with minimal genetic changes, however, progression to metastatic disease after a long dormancy period was associated with extensive copy number and point mutational events.

Purpose: To determine the relationship between obesity, diabetes, other major comorbidities and survival following a diagnosis of ovarian cancer. Method(s): We examined the association between obesity, as measured by body mass index (BMI), diabetes and other comorbidities and survival from ovarian cancer in a large (n=1404), population-based cohort of women diagnosed with epithelial ovarian cancer between 2002-2006. Information about pre-diagnostic BMI and medical history was obtained via a self-administered questionnaire. BMI at the commencement of primary chemotherapy and clinicopathologic data were abstracted from medical records and deaths were ascertained up to October 2011 via linkage with the Australian National Death Index. We also examined short- (>=5 years) and long-term (>5 years) survival, as well as survival differences by histological subtype. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were obtained using Cox regression. Result(s): After adjustment, a survival disadvantage was observed for women who were obese prior to diagnosis compared to women in the normal BMI range (BMI 30-34.9:HR 1.21, 95%CI 0.99-1.48; BMI>=35:HR 1.19, 95%CI 0.92-1.55). The association was similar for BMI at the commencement of primary chemotherapy. There was a suggestion that the adverse association between obesity and survival time was restricted to women with serous or endometrioid histological subtypes. Obesity conferred a survival disadvantage for both short- and long-term survival, with a stronger association in long-term survivors. Diabetes and other comorbidities did not appear to influence survival overall; however appeared to be important in the sub-group of women surviving longer than 5 years (HR1.44 and HR1.64, respectively). Conclusion(s): This is the first study to show that obesity is important in both short- and long-term survival following a diagnosis of ovarian cancer. More research examining diabetes, comorbidities and ovarian cancer surviv

Aims High-grade mucinous ovarian cancer (HG-MOC) represents less than 3% of all epithelial ovarian cancer (EOC); prognosis of advanced stage HG-MOC is extremely poor. Distinguishing primary high-grade mucinous cancers of presumed ovarian origin from extra-ovarian mucinous (EOM) cancer remains a clinical challenge. Improved therapeutic approaches are urgently needed as HG-MOC are largely resistant to standard platinum based treatment regimens. Methods National and international resources are being utilised to identify cases, including via CART-WHEEL.org, a web-based rare tumour database (BioGrid Australia), AOCS and existing tissue banks. Clinical parameters will be analysed in conjunction with expert pathology review and in-depth molecular characterization of advanced stage HG-MOC compared with early stage low-grade mucinous EOC and EOM tumours. Cytokeratin 7 and 20, and HER2 IHC and ISH testing will be performed. Results To date, 17/43 cases reviewed of potential HG-MOC have been identified as containing invasive HG-MOC in the frozen specimen available for research (39.5%). Twenty-two cases of EOM have been identified, including putative primary sites from the stomach (n=7), colon (n=4), and 'other' gastrointestinal sites (n=7); 23 cases of psuedomyxoma peritonei (15 with ovarian involvement) have been identified. Ongoing pathology review of cases with fresh and/or formalin fixed tissue (the latter, a cohort for validation purposes) is underway. Conclusion Addressing the molecular origins of rare aggressive HG-MOC may contribute to optimisation of systemic treatment approaches. Treatments that better target the regulatory pathways associated with HG-MOC may improve clinical outcomes in this aggressive disease.

Ovarian tissue cryopreservation and transplantation is a form of fertility preservation offered to young women at high risk of losing ovarian function after cancer treatment. While there have been successful births resulting from orthotopic site grafts, we report the first case of an ongoing pregnancy from a heterotopic graft in a patient who had previously undergone bilateral oopherectomy for a granulosa cell tumour. Frozen-thawed ovarian tissue was transplanted to the anterior abdominal wall. Subsequent ovarian stimulation and transabdominal ultrasound-guided oocyte retrieval from the grafts resulted in two oocytes. These were fertilized with ICSI and two embryos were transferred. Serial ultrasounds have confirmed an ongoing 26-week intrauterine twin pregnancy. Thus, this first demonstration of a pregnancy from a heterotopic graft site provides unequivocal evidence that cryopreservation preserves complete follicle development and that normal ovarian function can occur at a non-ovarian site. This provides optimism for further efforts to assist women who have had oophorectomy and pelvic surgery or radiotherapy, without an appropriate orthotopic site for grafting. © 2013 © The Author 2013. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Urine offers a number of attractive features as a sample type for biomarker discovery, including noninvasive sampling, quantity and availability, stability, and a narrow dynamic range. In this study we report the first application of isotope coded protein labeling (ICPL), coupled with in-solution isoelectric fractionation and LC-MALDI-TOF/TOF, to examine and prioritize urinary proteins from ovarian cancer patients. Following the definition of stringent exclusion criteria a total of 579 proteins were identified with 43% providing quantitation data. Protein abundance changes were validated for selected proteins by ESI-Qq-TOF MS, following which Western blot and immunohistochemical analysis by tissue microarray was used to explore the biological relevance of the proteins identified. Several established markers (e.g., HE4, osteopontin) were identified at increased levels in ovarian cancer patient urine, validating the approach used; we also identified a number of potential marker candidates (e.g., phosphatidylethanolamine binding protein 1, cell-adhesion molecule 1) previously unreported in the context of ovarian cancer. We conclude that the ICPL strategy for identification and relative quantitation of urine proteins is an appropriate tool for biomarker discovery studies, and can be applied for the selection of potential biomarker candidates for further characterization. © 2013 American Chemical Society.

Surgical staging in early-stage uterine cancer is controversial. Preoperative serum CA-125 may be of clinical value in predicting the presence of extra-uterine disease in patients with apparent early-stage endometrial cancer. Between October 6, 2005, and June 17, 2010, 760 patients were enrolled in an international, multicentre, prospective randomized trial (LACE) comparing laparotomy with laparoscopy in the management of endometrial cancer apparently confined to the uterus. Of these, 657 patients with endometrial adenocarcinoma had a preoperative serum CA-125 value recorded. Multiple cross-validation analysis was undertaken to correlate preoperative serum CA-125 with stage of disease (Stage I vs. Stage II+) after surgery. Patients' median preoperative serum CA-125 was 14 U/ml. A cutoff point of 30 U/ml was associated with the smallest misclassification error, and using this cutoff, 98 patients (14.9%) had elevated CA-125 levels. Of those, 36 (36.7%) had evidence of extra-uterine disease. Of the 116 patients (17.7%) with evidence of extra-uterine disease, 31.0% had an elevated CA-125 level. On univariate and multivariable logistic regression analysis, only preoperative CA-125 level, but no other preoperative clinical characteristics were found to be associated with extra-uterine spread of disease. Utilizing a cutoff point of 30 U/ml achieved a sensitivity, specificity, positive predictive value and negative predictive value of 31.0, 88.5, 36.7 and 85.7%, respectively. Elevated CA-125 above 30 U/ml in patients with apparent early-stage disease is a risk factor for the presence of extra-uterine disease and may assist clinicians in the management of patients with clinical Stage I endometrial cancer. Copyright © 2011 UICC.

Objective: The human DIMINUTO/DWARF1 homolog seladin-1/DHCR24 has been recently reported to be up-regulated in adrenocortical adenomas. Seladin-1 expression has been reported in the normal ovary. Granulosa cell tumours of the ovary (GCT) as with adrenocortical adenomas arise from a steroidogenic tissue, respond to pituitary hormone stimulation and synthesize steroid hormones. Design(s): To test the hypothesis that seladin-1 may also have a role in the pathogenesis of GCT, we determined the expression of seladin-1 in a cohort of GCT and in mucinous and serous cystadenocarcinomas and in normal ovary. Measurements: Expression was determined by RT-PCR using gene specific primers and probes combined with Southern blot analysis of the PCR products. Result(s): Seladin-1 expression was identified in the normal ovary, mucinous cystadenocarcinomas and serous cystadenocarcinomas of the ovary whereas no expression was observed in the GCT. Conclusion(s): Based on our results, seladin-1 is not expressed in the granulosa cells or at least not in those that give rise to GCT. © 2005 Blackwell Publishing Ltd.

Elevated preoperative serum inhibin concentrations have been reported in patients with granulosa cell tumor of the ovary. The aim of this study was to determine if elevations in serum inhibin predated clinical recurrence in patients with a diagnosis of granulosa cell tumor. Twenty-seven consecutive patients with granulosa cell tumor were followed prospectively to assess the relationship between serum inhibin concentrations and disease status. The serum inhibin concentrations in normal postmenopausal women were <77-130 U/liter. In patients with granulosa cell tumor at initial surgery, mean inhibin concentrations preoperatively were 2831 U/liter in 4 postmenopausal subjects (range 2130-3323 U/liter) and 3680 U/liter in each of 2 premenopausal women. In 5 postmenopausal subjects with a histological diagnosis of granulosa cell tumor who underwent secondary surgery because of a recurrent palpable mass, mean inhibin concentrations were 4216 U/liter (range 2672-7360). In 3 patients with known or suspected residual disease despite a secondary debulking operation the serum inhibin concentrations were 475, 1000, and 2541 U/liter. In 13 subjects who were clinically disease free with a previous diagnosis of granulosa cell tumor, serum inhibin concentrations remained within the normal range for reproductive status. We conclude: (1) Preoperative serum inhibin concentrations are typically elevated sevenfold above the normal premenopausal follicular phase levels in women with granulosa cell tumor; (2) after surgery, serum inhibin levels may become elevated up to 2 years before further surgery is undertaken; and (3) serum inhibin concentrations appear to be a valuable tumor marker for the diagnosis of primary or recurrent granulosa cell tumor.

Objective: We have previously reported on the point prevalence of ovarian lesions detected by transvaginal ultrasound (TVU) in 515 asymptomatic women at least 5 years postmenopause. The aims of this study were to report, in the same women, on the repeatability of visualization of the ovaries (TVU) and the natural history of ovarian lesions seen at baseline but not treated surgically and to assess whether any women developed new ovarian abnormalities 12 months later. Method(s): The study involved a cohort of 515 postmenopausal women recruited from the community, at least 5 years past their last period. They were assessed at baseline and again after 12 months with TVU and serum levels of inhibin and CA-125. Result(s): The right and left ovaries were seen on both occasions in 80% and 68% of women, respectively. Of the 49 women who had an ovarian lesion at baseline, did not undergo surgery at that time, and had a follow-up TVU, the lesion was unchanged 12 months later in 30 women. Four women developed a new ovarian lesion within the 12 months. None of the 14 women who underwent surgery on the basis of the ovarian appearance at baseline, or the 2 who had surgery on the basis of the ovarian appearance at follow-up, had an ovarian malignancy. Conclusion(s): The use of TVU in women at least 5 years after menopause is problematic because the ovaries cannot be visualized in all women and because TVU has the potential to identify many benign lesions that would otherwise remain undetected. These are important considerations in weighing up the risks and benefits of using TVU as a screening tool. © 2009 by The North American Menopause Society.

Objective(s). Granulosa cell tumors (GCT) and mucinous cystadenocarcinoma of the ovary are associated with elevated circulating levels of immunoreactive inhibin. Measurement of serum inhibin levels provides a useful tumor marker in the management of ovarian tumors. Inhibin is a dimeric ovarian glycoprotein hormone consisting of one alpha and one of two beta subunits. The beta subunits can dimerize to form activin. Activin is bound and its action modulated by another gonadal peptide, follistatin. In this study the patterns of expression of the three inhibin subunit genes, the follistatin gene, and the activin receptor type II gene have been determined. Methods. Gene expression was analyzed in RNA prepared from 16 primary ovarian tumors using reverse transcriptase-polymerase chain reaction (RT-PCR). Gene- specific primes were used for RT-PCR; the products were analyzed by Southern blot analysis with gene-specific riP-labeled probes. Results. Widespread expression of these genes was found in all of the tumor types examined. Abundant expression of the inhibin alpha subunit gene was observed in the GCT and to a lesser extent in the mucinous and serous tumors. beta subunit expression was also present in the GCT and to a lesser extent in the other tumors. Widespread expression of both the activin receptor type II and the follistatin genes was also observed. Conclusions. Expression of the inhibin subunit genes in GCT and some epithelial tumors confirms that these tumors are the source of the increased immunoreactive inhibin seen in the circulation of patients with ovarian tumors. Expression of the activin receptor type II and follistatin genes suggests a paracrine role for activin in these tumors which may be modulated by follistatin, particularly in the GCT.

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.

Background and objective. We have previously reported elevated serum immunoreactive inhibin (INH) levels in patients with ovarian malignancies, particularly granulosa cell and mucinous tumours. The present study was designed to compare INH measurements using a heterologous radioimmunoassay with cross-reactivity for inhibin alpha-subunit derived peptides with measurements obtained using a new ELISA specific for dimeric inhibin-A. It was hypothesized that granulosa cell tumours may secrete significant quantities of inhibin-A whereas mucinous tumours were unlikely to do so because of the lack of a relation between INH and FSH measurements in the latter group. Design. Serum samples obtained from women found to have ovarian cancer were assayed using the heterologous radioimmunoassay (the Monash assay) and using an ELISA specific for dimeric inhibin (the Groome assay) and the results were compared. Patients. Samples for assay were available from 69 normal post-menopausal control women, 12 patients with mucinous tumours of the ovary, 26 with serous tumours, 7 with granulosa cell tumours and 8 with various other ovarian tumours. Patients were post-menopausal or had been subjected to bilateral oophorectomy at the time these samples were collected. Measurements. The Monash and Groome assays were carried out as described previously. The upper limit of normal for post-menopausal women in the Monash assay was 122 U/l and for the Grooms assay was calculated to be 32 ng/l. Results. Among the 69 normal subjects, 4 were found to have elevated inhibin levels using the Monash RIA (133-190 U/l) and 4 were found to have elevated levels in the Groome ELISA (45.5-55.3 ng/l). Among 12 patients with mucinous tumours, 10 (83%) had elevated inhibin levels using the Monash assay but only 3 (25%) had elevated levels with the Groome assay (P < 0.005). Among 26 with serous tumours, 15 (58%) had elevated levels in the Monash assay but only 1 (4%) in the Groome assay (P < 0.001). Among 7 samples fr

BACKGROUND. The actions of the extracellular-matrix degrading enzymes, matrix metalloproteinases (MMPs), are implicated in tumorigenesis. The cellular localization of MMP-2, MMP-9, membrane type 1 (MT1)-MMP, tissue inhibitors of metalloproteinases (TIMPs) 1-3, and the presence of active gelatinases were investigated in endometrial carcinoma. METHODS. Endometrial carcinomas were grouped according to histologic grade (Grades 1-3), depth of myometrial invasion (0, < 50%, > 50%) and the presence of vascular/lymphatic invasion. Twenty-nine endometrial carcinoma biopsies were investigated immunohistochemically to determine the tissue localization of MMP-2 (gelatinase A), MMP-9 (gelatinase B), MT1-MMP, and TIMPs 1-3. In situ hybridization was performed to localize MMP-2 and MMP-9 mRNA. The presence of active gelatinases was assessed using in situ zymography. RESULTS. Epithelial tumor cells were the main site of MMP-2, MMP-9, and MT1-MMP protein. Variable stromal cell localization was also observed, particularly in areas adjacent to tumor nests. Semiquantitative analysis revealed increases in MMP-9 and MMP-2 but not MT1-MMP staining scores in tumor epithelial cells in the transition from histologic Grade 1 to Grades 2 and 3. Matrix metalloproteinase-9 and MT1-MMP staining scores in tumor cells were significantly associated with the presence of myometrial invasion and vascular/lymphatic invasion, while MMP-2 did not correlate with these factors. In addition, MT1-MMP was colocalized with MMP-2, supporting its role in the activation of proMMP-2. Tumor cells from all histologic grades stained intensely for TIMP-2 and TIMP-3 proteins, while variable stromal staining was observed. In Grade 1 carcinomas TIMP-1 was predominantly immunolocalized to the stromal compartment with variable tumor cell localization being observed in Grades 2 and 3 carcinomas. Matrix metalloproteinase-9 and MMP-2 mRNAs were predominantly observed in tumor epithelial cells as well as in the stroma to varyin

The inhibins are produced and secreted by several ovarian cancers. Monitoring serum levels by immunoassay may be a useful diagnostic aid in the initial assessment of this disease and in monitoring its potential recurrence following surgery. The assays are applicable to women after menopause when the majority of ovarian cancers are detected, and when the normal ovarian production of inhibin is low to negligible. A new inhibin immunoassay (total inhibin ELISA) has been developed with the intention of widespread clinical application. The assay readily detects granulosa cell and mucinous tumours. CA125, a widely used ovarian cancer marker, detects the other main ovarian cancer types (serous, endometrioid, undifferentiated) with high sensitivity. The combination of the two tests detects the majority of ovarian cancers with high specificity (95%) and sensitivity (95%). Studies have been undertaken to assess its application to women in the perimenopausal stage and to younger women during normal reproductive life. These studies are providing a platform for the introduction of the test into clinical practice. © 2004 Elsevier Ireland Ltd. All rights reserved.

Sarcomatous transformation of a granulosa cell tumor (GCT) is a rare event. We describe the development of a rapidly progressive sarcomatous change in a woman who had initially presented with a classical GCT. A first recurrence occurred 23 months after the initial diagnosis when she was treated with external beam radiotherapy to her pelvis. A second recurrence 76 months following her initial surgery was consistent with a GCT. At 92 months, she presented with a further recurrence, outside of the radiotherapy field. This last recurrence had a different histologic appearance with features of sarcomatous change. Molecular analysis, using both reverse transcription- polymerase chain reaction and complementary DNA microarrays, has been used to analyze tissue obtained before and after the observed change in the tumor. The data show that GCT-specific genes, such as inhibin alpha, estrogen receptor, and follicle-stimulating hormone receptor, have been downregulated in the sarcomatous change. Significant upregulation of genes associated with an inflammatory response was also noted in the sarcoma, and this was consistent with the presence of a marked inflammatory infiltrate seen on histopathology. This study represents the novel application of microarray technology and demonstrates the unexpected finding of expression of the fibroblast activation protein gene in normal ovary. Although tumors such as this may be targets for the novel fibroblast activating protein-directed chemotherapeutic monoclonal antibody sibrotuzumab, the finding of expression in the normal ovary suggests the need for caution. © 2007, IGCS and ESGO.

Quantitative polymerase chain reaction analysis of a panel of normal and malignant endometrial tissues revealed significant expression of both aromatase and estrogen receptor alpha in low-grade tumors, suggesting that local estrogen synthesis and action might contribute to the proliferation of these tumors. © 2006 American Society for Reproductive Medicine.

Elevated serum immunoreactive inhibin concentrations have been reported in patients with mucinous and granulosa cell tumors of the ovary. The present study aimed to determine whether the inhibins and/or the related peptides, the activins, were demonstrable within ovarian tumor tissue. Immunohistochemical analyses were performed on 11 ovarian tumors, 5 mucinous, 3 serous, 1 granulosa, 1 clear cell, and 1 metastatic colonic cancer. Both monoclonal and polyclonal antisera specific for inhibin-A, activin-A, and activin-B, and their alpha-, beta(B)-, and beta(B)-subunits were used. The mucinous cells of all five mucinous tumors showed positive staining for activin-A and activin-B, and their beta(A)- and beta(B)-subunits, and three stained positive for inhibin-A and the alpha-subunit. The granulosa cell tumor also showed positive staining for inhibin-A and the activins. The remaining tumors were negative. The findings are consistent with the hypersecretion of inhibin (and possibly activin) by some ovarian malignancies and suggest that immunohistochemistry for the inhibins and the activins should be explored further in the classification of ovarian malignancies.

Background: X chromosome inactivation, which silences gene expression from one of the two X chromosomes in females, is usually random. Skewed X inactivation has been implicated in both the expression and the suppression of X-linked disease phenotypes and has been reported to occur more frequently in breast and ovarian cancer patients, including BRCA1 or BRCA2 mutation carriers, than in control subjects. Method(s): We assessed the pattern of X chromosome inactivation using methylation-specific polymerase chain reaction amplification of the exon 1 microsatellite region of the X-linked androgen receptor (AR) gene in DNA from blood samples obtained from control subjects without a personal history of breast or ovarian cancer (n = 735), ovarian cancer patients (n = 313), familial breast cancer patients who did not carry mutations in BRCA1 or BRCA2 (n = 235), and affected and unaffected carriers of mutations in BRCA1 (n = 260) or BRCA2 (n = 63). We defined the pattern of X chromosome inactivation as skewed when the same X chromosome was active in at least 90% of cells. The association between skewed X inactivation and disease and/or BRCA mutation status was assessed by logistic regression analysis. The association between skewed X inactivation and age at cancer diagnosis was assessed by Cox proportional hazards regression analysis. All statistical tests were two-sided. Result(s): The age-adjusted frequency of skewed X inactivation was not statistically significantly higher in ovarian cancer or familial breast cancer case subjects compared with control subjects. Skewed X inactivation was higher in BRCA1 mutation carriers than in control subjects (odds ratio [OR] = 2.7, 95% confidence interval [CI] = 1.1 to 6.2; P =. 02), particularly among unaffected women (OR = 6.1, 95% CI = 1.5 to 31.8; P =. 005). Among BRCA1 mutation carriers, those with skewed X inactivation were older at diagnosis of breast or ovarian cancer than those without skewed X inactivation (hazard ratio [HR] o

Objective. The extracellular glycosaminoglycan hyaluronan (HA) and its degradative enzymes, hyaluronidases (Hyal), play important roles in tumor metastasis and angiogenesis. HA promotes tumor cell adhesion and migration, while its cleaved fragments stimulate angiogenesis. The aims of this study were to assess the levels of HA and how it might be regulated in endometrial cancer. Methods. Endometrial carcinomas were grouped according to histologic grade (Grade 1-3). HA histochemistry utilized a biotinylated HA binding peptide (n = 15), while HA synthase (HAS) immunohistochemistry utilized an antibody recognizing HAS1, HAS2 HAS3 (n = 24). Real-time RT-PCR was used to determine the mRNA expression of Hyal 1, Hyal 2 (n = 13) and Hyal 3 (n = 11) in endometrial carcinomas. Results. HA, its synthases and degradative enzymes were identified in endometrial carcinomas of all histologic grades. HA was predominantly localized to tumor-associated stroma. Semiquantitative analysis revealed increased HA levels with tumor grade, however, this increase only attained significance in Grade 2 carcinomas (P < 0.05). HA staining intensity scores were significantly associated with the presence of myometrial invasion (P < 0.05). Alternatively, HAS was predominantly localized in tumor epithelial cells, and its levels did not vary with tumor grade. Expression of Hyal 3 and Hyal 2 mRNA were >1000-fold and >30-fold greater respectively than that of Hyal 1 mRNA, the major Hyal expressed in other cancers. No Hyal type varied with tumor grade. Conclusion. This is the first study to demonstrate the cellular localization of HA and its synthases and that Hyal 3 mRNA is predominant in endometrial cancer. The results suggest a role for elevated HA in endometrial cancer progression. © 2005 Elsevier Inc. All rights reserved.

Background/Aims: Optimal delivery of intraperitoneal (IP) chemotherapy is dependent on adequate drug distribution. An accurate understanding of the limitations of IP distribution is critical if we are to improve cytotoxic delivery through this route. Method(s): Using repeated scintigraphic peritoneography we investigated peritoneal fluid distribution in patients receiving IP therapy. Both early (1-6h) and late (24-48h) images were performed. The peritoneal cavity was divided into six regions; pouch of Douglas, left and right paracolic gutters, left and right subphrenic spaces and the right subhepatic space. The distribution in each region was classified as absent (0), faint (1) or intense (2). A total distribution score was calculated from the summation of distribution values for each of the six regions. Distribution was then graded according to the total distribution score as follows: Grade 0 = 0-3; Grade 1 = 4-6; Grade 2 = 7-9; and Grade 3 = 10-12. Result(s): Twenty-six participants were included in the study: all 26 patients had early imaging performed and 21 of these also had late imaging. Thirteen (50%) and 15 (71%) patients had grade 1 or 2 IP distribution on early and late imaging respectively. The most common abdominal regions to show maldistribution were the subphrenic spaces. Conclusion(s): This study highlights the deficiencies of distribution following IP drug delivery, with the majority of patients demonstrating multiple regions of faint or absent uptake on scintigraphic peritoneography imaging. Future large clinical studies investigating IP chemotherapy should include analyses of IP distribution to improve our understanding of optimal drug delivery through this route. © 2011 The Authors. Internal Medicine Journal © 2011 Royal Australasian College of Physicians.

Objective: The Laparoscopic Approach to Cancer of the Endometrium (LACE) randomized trial aims to establish the equivalence of laparoscopic and open surgery (laparotomy) for early-stage endometrial cancer. Seven hundred sixty patients with clinical stage I endometrioid adenocarcinoma of the endometrium, ECOG status 0 or 1, were enrolled between 2005 and 2010. To date, 685 patients completed at least six months of follow-up; 319 were randomly allocated to total abdominal hysterectomy (TAH) and 366 to total laparoscopic hysterectomy (TLH). Three hundred seventy-three patients (49.4%) received pelvic and/or aortic lymph node dissection. Descriptive statistics were used to establish frequency of treatment crossovers (conversions). Serious adverse events or adverse events of grade 3+ were regarded as surgical complications (SCs), and X2 tests were used to examine differences in proportions. Variables that showed significant association with SCs were entered into a multivariate stepwise logistic regression to determine independent predictors of SCs. Result(s): Overall, 26 conversions (3.8%) were recorded, five from TAH to TLH because of patient decision after randomization, and 21 from TLH to TAH (13 for anatomical reasons: Sox needed an abdominal incision to remove the uterus, two for technical reasons, and six due to intraoperative complications). Overall, 112 patients (17%) developed at least one SC (TAH: 64/319, 20.1%; TLH: 48/366, 13.1%; P=0.014). Factors predictive of SCs were TAH (OR=2.1, 95% CI=1.3-3.3), history of myocardial infarction, congestive heart failure, general or systemic conditions, ECOG performance status of 1 and elevated alkaline phosphatase levels (shown in the table). Lymph node dissection was not associated with a greater risk of SCs. Conclusion(s): Within the LACE trial few conversions were observed, and of those, very few were due to surgical complications or anatomical restrictions. Patients receiving TAH experience twice as many SCs as patien

Objectives: To compare the quality of life (QoL) of patients randomized to Total Laparoscopic Hysterectomy (TLH) versus Total Abdominal Hysterectomy (TAH) for stage I endometrial cancer. Method(s): LACE (Laparoscopic Approach to Carcinoma of the Endometrium) is a randomized, controlled, multicentre, stage III trial equivalence trial enrolling 332 patients for the QoL substudy from October 2005 to April 2008 (enrollment for disease free survival from 2005 to 2010), stratified by treating site, FIGO stage and cancer history. Randomization was 2:1 (TLH:TAH) for the first 180 patients and 1:1 from then onwards. Eligibility required a histological diagnosis of endometrioid adenocarcinoma of the endometrium, clinically stage 1 disease, and an ECOG score less than 2. Exclusions included uterine size larger than 10 weeks gestation, enlarged aortic lymph nodes, or being considered unfit for surgery. QoL was measured using the Functional Assessment of Cancer Therapy questionnaire (FACT-G) plus a supplementary endometrial cancer specific subscale, the Body image scale (BIS) and the Euro-QOL visual analogue scale. These were completed at baseline, one week, four weeks (early), three months and six months (late) after surgery. Improvements in QoL from baselines of >5% were defined as clinically significant. Analysis was performed using generalized estimating equations on differences from baseline for the early and late QoL periods using the principal of intention-to-treat. Result(s): 191 and 141 patients were randomised to receive TLH and TAH, respectively. Patients mean age was 62.7 years, and 75% had completed <=12 years of schooling. More than half of the patients (62%) were living with a partner. The majority of patients (85.6%)were overweight or obese. Conversion from assigned treatment was recorded in eight cases (2.4%). Up to four weeks post-surgery, patients undergoing TLH reported clinically and statistically significantly greater improvement frombaseline QoL compared t

Background: Interleukin (IL) 11 is produced by human endometrium and endometrial cancer tissue. It has roles in endometrial epithelial cell adhesion and trophoblast cell invasion, two important processes in cancer progression. This study aimed to determine the levels of IL11 in uterine lavage fluid in women with endometrial cancer and postmenopausal women. It further aimed to determine the levels of IL11 protein and its signaling molecules in human endometrial cancer of varying grades, and endometrium from postmenopausal women and IL11 signalling mechanisms in endometrial cancer cell lines. Method(s): IL11 levels in uterine lavage were measured by ELISA. IL11, IL11 receptor(R) alpha, phosphorylated (p) STAT3 and SOCS3 were examined by immunohistochemistry in endometrial carcinomas and in control endometrium from postmenopausal women and normal cycling women. The effect of IL11 on pSTAT3/STAT3 and SOCS3 protein abundance in endometrial cancer cell lines and non-cancer endometrial epithelial cells was determined by Western blot. Result(s): IL11 was present in uterine flushings and was significantly higher in women with Grade 1 carcinomas compared to postmenopausal women (p < 0.05). IL11 immunostaining was significantly elevated in the endometrial tumour epithelial cells from Grade 1 and 3 compared to endometrial epithelium from postmenopausal and cycling women. IL11Ralpha immunostaining intensity was increased in cancer epithelium in the Grades 1 and 2 tumours compared to epithelium from postmenopausal women. Both IL11 and IL11Ralpha localized to vascular endothelial and smooth muscle cells while IL11 also localized to subsets of leucocytes in the cancer tissues. pSTAT3 was found in both the tumour epithelial and stromal compartments but was maximal in the tumour epithelial cells, while SOCS3 was predominantly found in the tumour epithelial cells. pSTAT3 staining intensity was significantly higher in Grade 1 and 2 tumour epithelial cells compared to epithelial cells f

BACKGROUND: Interleukin (IL) 11 is produced by human endometrium and endometrial cancer tissue. It has roles in endometrial epithelial cell adhesion and trophoblast cell invasion, two important processes in cancer progression. This study aimed to determine the levels of IL11 in uterine lavage fluid in women with endometrial cancer and postmenopausal women. It further aimed to determine the levels of IL11 protein and its signaling molecules in human endometrial cancer of varying grades, and endometrium from postmenopausal women and IL11 signalling mechanisms in endometrial cancer cell lines. METHODS: IL11 levels in uterine lavage were measured by ELISA. IL11, IL11 receptor(R) alpha, phosphorylated (p) STAT3 and SOCS3 were examined by immunohistochemistry in endometrial carcinomas and in control endometrium from postmenopausal women and normal cycling women. The effect of IL11 on pSTAT3/STAT3 and SOCS3 protein abundance in endometrial cancer cell lines and non-cancer endometrial epithelial cells was determined by Western blot. RESULTS: IL11 was present in uterine flushings and was significantly higher in women with Grade 1 carcinomas compared to postmenopausal women (p < 0.05). IL11 immunostaining was significantly elevated in the endometrial tumour epithelial cells from Grade 1 and 3 compared to endometrial epithelium from postmenopausal and cycling women. IL11R alpha immunostaining intensity was increased in cancer epithelium in the Grades 1 and 2 tumours compared to epithelium from postmenopausal women. Both IL11 and IL11R alpha localized to vascular endothelial and smooth muscle cells while IL11 also localized to subsets of leucocytes in the cancer tissues. pSTAT3 was found in both the tumour epithelial and stromal compartments but was maximal in the tumour epithelial cells, while SOCS3 was predominantly found in the tumour epithelial cells. pSTAT3 staining intensity was significantly higher in Grade 1 and 2 tumour epithelial cells compared to epithelial cells fro

Objective: There are currently no programs to assess ovarian health in postmenopausal women. The aim of this study was to describe the ovaries in healthy women at least 5 years after menopause by questionnaire, transvaginal ultrasonography, and blood ovarian cancer markers. Design(s): A total of 515 women who were asymptomatic and at the Stages of Reproductive Aging Workshop +2 stage of menopause (>5 y postmenopause) were recruited by advertisement. Clinical history was obtained by questionnaire, and biophysical assessment by a transvaginal ultrasound investigation and biochemical assessment by serum CA-125 and inhibin were performed. Abnormal findings were confirmed and then reviewed. Result(s): Both ovaries were identified by transvaginal ultrasonography in 71% of women. The right ovary was visualized in 86.3% of these volunteers, and the left ovary was visualized in 78%. The presence of small unilocular cysts and echogenic foci facilitated identification of the ovary in some women. Ovarian/paraovarian lesions were present in 12.6% of women. Abnormalities of the endometrium and uterus were also common, prompting surgery in 7.2% of the women. Total serum inhibin concentrations were normal for postmenopausal women, whereas serum CA-125 was elevated in two women. Conclusion(s): We find that the description and detection of postmenopausal ovaries by transvaginal ultrasonography allows the identification of both ovaries in most postmenopausal women. Ultrasonography-detected abnormalities of the ovary and/or the uterus/endometrium are common in women at this stage of life. The potential need for surgical intervention after the detection of such abnormalities needs to be carefully evaluated when considering transvaginal ultrasonography as a screening tool for ovarian cancer. © 2008 by The North American Menopause Society.