microRNA and Ovarian Cancer.

Ovarian cancer is the fifth most common cancer in women and the leading cause of death from gynaecological malignancy in the Western world. The majority of ovarian cancers are diagnosed at an advanced stage and this is due to lack of a reliable screening test and the vagueness of symptoms. Early diagnosis is key as the 5-year survival rate for women diagnosed with late-stage disease is less than 20% compared to up to 90% for women diagnosed at early-stage disease. Early-stage disease that has a good prognosis cannot be detected easily. Currently, no standardized reliable screening test exists. Lack of a reliable screening test is due to the fact that the underlying molecular biology of oncogenesis in ovarian cancer is a complex pathway. Once the molecular biology of the ovarian cancer is known, more reliable and sensitive screening tests can be established and a better and effective treatment can be found. Current diagnostic tools include imaging and CA125 have their limitations in terms of accuracy. There is a strong need for prognostic and predictive markers to diagnose it early and to help optimize and personalize treatment. microRNAs were recently found to be involved in the pathophysiology of all types of analyzed human cancers mainly by aberrant gene expression. microRNA profiling has allowed the identification of signatures associated with diagnosis, prognosis, and response to treatment of human tumors. Several studies showed that microRNAs are deregulated in ovarian cancer. This chapter reviews the role of microRNAs in ovarian cancer and their utility of microRNAs as diagnostic and prognostic markers for ovarian cancer.

Pre-Treatment of platinum resistant ovarian cancer cells with an MMP-9/MMP-2 inhibitor prior to cisplatin enhances cytotoxicity as determined by high content screening.

Platinum resistance is a major cause of treatment failure in ovarian cancer. We previously identified matrix metalloproteinase 9 (MMP-9) as a potential therapeutic target of chemoresistant disease. A2780cis (cisplatin-resistant) and A2780 (cisplatin-sensitive) ovarian carcinoma cell lines were used. The cytotoxic effect of MMP-9/MMP-2 inhibitor, (2R)-2-[(4-Biphenylsulfonyl) amino]-3 phenylpropionic acid (C21H19NO4S) alone or in combination with cisplatin was determined using high content screening. Protein expression was examined using immunohistochemistry and ELISA. Co-incubation of cisplatin and an MMP-9/MMP-2 inhibitor, (2R)-2-[(4-Biphenylsulfonyl) amino]-3 phenylpropionic acid (C21H19NO4S) resulted in significantly greater cytotoxicity as compared to either treatment alone in a cisplatin resistant MMP-9 overexpressing cell line; A2780cis. In addition, pre-incubating with MMP-9i prior to cisplatin further enhances the cytotoxic effect. No significant difference was observed in MMP-9 protein in tissue but a trend towards increased MMP-9 was observed in recurrent serum. We propose that MMP-9/MMP-2i may be utilized in the treatment of recurrent/chemoresistant ovarian cancers that overexpress MMP-9 mRNA but its role in vivo remains to be evaluated.

Evaluation of maternal and perinatal outcomes in pregnancy with high BMI.

BACKGROUND: Maternal obesity is a significant risk factor for unfavourable outcomes during pregnancy. However, the extent of this relationship is poorly defined in Irish mothers. AIMS: This study was to compare maternal and perinatal outcomes between obese and non-obese mothers in an Irish population. METHODS: A retrospective comparative study was conducted in a secondary level maternity unit for births recorded between January 2018 and January 2019 and 2,793 women were included. BMI calculated at booking visit was used to compare obese (BMI ≥ 30 kg/m2) and non-obese mothers (BMI < 30 kg/m2). RESULTS: Of 2,793 women included in this study, 2111 had a BMI < 30 kg/m2 and 682 had a BMI ≥ 30 kg/m2. Obese women were less likely to experience spontaneous onset of labour (33.4% vs. 48.1%, p < 0.001) and more likely to be induced (37.2% vs. 31.0%, p = 0.002). Obesity was associated with a statistically significant increase in stillbirth, fetal macrosomia and emergency caesarean birth rates, whereas operative vaginal deliveries were significantly decreased. Miscarriage, shoulder dystocia, post-partum haemorrhage and spontaneous vaginal deliveries were reduced while elective caesarean birth and low birth weight incidence were increased in obese mothers; however, these results were not statistically significant. CONCLUSIONS: This study highlights the magnitude of obstetric risks that are associated with maternal obesity within Irish population. Implementation of effective intervention strategies to reduce the number of obese women in pregnancy may have beneficial effects on pregnancy outcomes in Ireland.

Atypical presentation of molar pregnancy.

The classic features of molar pregnancy are irregular vaginal bleeding, hyperemesis, enlarged uterus for gestational age and early failed pregnancy. Less common presentations include hyperthyroidism, early onset pre-eclampsia or abdominal distension due to theca lutein cysts. Here, we present a case of molar pregnancy where a woman presented to the emergency department with symptoms of acute abdomen and was treated as ruptured ectopic pregnancy. The woman underwent laparoscopy and evacuation of retained products of conception. Histological examination of uterine curettage confirmed the diagnosis of a complete hydatidiform mole. The woman was discharged home in good general condition with a plan for serial beta-human chorionic gonadotropin (beta-hCG) follow-up. Complete follow-up includes use of contraception and follow-up after beta-hCG is negative for a year.

Silent uterine rupture in scarred uterus.

Uterine rupture in pregnancy is a rare and catastrophic complication with a high incidence of fetal and maternal morbidity. Very few cases have been reported in the literature. CASE PRESENTATION: A 28-year-old fifth gravid woman with a history of one caesarean section presented to our department at 39 weeks and 6 days gestation with complaints of headache, epigastric pain and nausea. Her blood pressure was elevated and there was proteinuria. Emergency caesarean section was performed in view of symptoms. Uterine rupture was found during the surgery. A live male infant was delivered in good condition. Postnatal recovery was unremarkable and the woman discharged on postoperative day 5. CONCLUSION: Rupture of the uterus can present in third trimester even before labour with minimal or no symptoms.

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

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

Tumour expresion of tissue factor and tissue factor pathway inhibitor in ovarian cancer- relationship with venous thrombosis risk.

INTRODUCTION: Ovarian cancer is known to display a particular association with venous thromboembolism (VTE) with reports up to 42% of patients developing thromboembolic complications. Tissue Factor (TF) and its inhibitor Tissue Factor Pathway Inhibitor (TFPI) have been implicated in VTE risk in cancer. The aim of this study was to measure tumour derived TF and TFPI and to investigate their potential role in VTE in ovarian cancer patients. METHODS: TF and TFPI mRNA expression was measured using TaqMan real time PCR in 99 ovarian tumour samples. Nineteen cases complicated by VTE were matched to 19 cases without VTE. TF and TFPI protein levels were measured using ELISA and immunohistochemistry was used to localize TF expression. The role of TF expression on overall survival was also determined. RESULTS: TF mRNA and protein expression was increased in tumours from patients with clear cell carcinoma (p<0.001). TF protein expression was also increased in endometroid carcinoma (P<0.01) compared with benign tumours. TFPI mRNA expression was increased in clear cell carcinoma (P<0.01). TF mRNA and antigen level was increased in malignant tumours of patients who developed VTE compared with matched malignant õtumours of patients who remained thrombosis free (P<0.01). There was no difference in TFPI expression between the two groups. CONCLUSION: TF expression in ovarian cancer is significantly higher in patients who develop VTE. TF expression was increased in clear cell ovarian cancer and endometroid cancer and this may explain the higher risk of VTE in these subgroups. TF derived from these tumours may be the trigger for VTE in ovarian cancer.