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Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy in the western world. The majority of women presenting with the disease are asymptomatic and it has been dubbed the "silent killer". To date there is no effective minimally invasive method of stratifying those with the disease or screening for the disease in the general population. Recent molecular and pathological discoveries, along with the advancement of scientific technology, means there is a real possibility of having disease-specific liquid biopsies available within the clinical environment in the near future. In this review we discuss these discoveries, particularly in relation to the most common and aggressive form of EOC, and their role in making this possibility a reality.

LISA is a space-based gravitational wave observatory aimed at detecting gravitational waves in the frequency range of 0.1 mHz to 0.1 Hz. The observatory is composed of three spacecraft, each separated by 2.5 million km in an equilateral triangle formation, trailing the Earth in a heliocentric orbit. One of the many crucial components to the mission is the LISA telescope, a bidirectional component used to expand an outgoing laser beam to the far spacecraft as well as compress a large incoming beam to a diameter of a few mm at the optical bench. Since the telescope is in the path of the long-baseline interferometer, its structure must be dimensionally stable at the pm/√Hz level at mHz frequencies. A way to measure the stability of the LISA telescope is with a compact optical truss interferometer (OTI), consisting of three Fabry-Perot cavities mounted along the telescope to monitor structural distortions over time. All three cavities are operated with a common laser source, and each cavity is equipped with an acousto-optic modulator to shift the nominal laser frequency as well as an electro-optical modulator to modulate the laser phase for Pound-Drever-Hall locking. Variations in each cavity’s length create variations in their corresponding laser frequency, which can be measured against a reference frequency that is locked to an external ultra-stable cavity. We will present the design and preliminary results in the fabrication and testing of firstgeneration OTI prototypes.

Background: Rapid response teams (RRTs) are a critical care resource that review deteriorating patients within the hospital. We aimed to describe demographic, preoperative, surgical, anesthetic, and postoperative characteristics of patients who required RRT activation after major hip surgery. We also sought to assess whether these characteristics where associated with mortality during the index hospital admission.Methods: We reviewed an RRT database of adult patients undergoing orthopedic surgery at a university teaching hospital. We then retrospectively reviewed the medical records to extract a priori–defined patient, preoperative, surgical, anesthetic, and postoperative data of major hip surgery admissions between September 2014 and December 2017. Patients who survived the index hospital stay were compared to those who died.Results: Overall, 187 patients had postoperative RRT activations. Median (interquartile range) age was 84.0 (78-90) years; 125 (67%) were female, and most patients had at least one significant comorbidity, median Charlson Comorbidity Index (CCI) 5.0 (4.0-7.0). The majority of patients were frail (68%), American Society of Anesthesiologists physical status Class 3 or greater (91%), and underwent nonelective surgery (88%). Median (interquartile range) time from surgery to RRT activation was 29.4 (11.3–75.0) hours, and 25 (13%) patients had unplanned admissions to intensive care or high dependency units. Compared to patients who survived RRT activation, those who died displayed higher mean CCI (6.5 [1.8] vs. 5.5 [2.1], p = 0.02), were more frail (80.1% vs. 56.5%, OR = 3.2, 95% CI: 1.2,8.1; p = 0.03), and received less intraoperative opioids (intravenous morphine equi-analgesia: median = 5.8 (0.1–8.20 vs. 11.7 (3.7–19.0) mg, p = 0.03). They were also more likely to have received an urgent medical review prior to RRT activation (62% vs. 40%, OR = 2.4, 95% CI: 1.1, 5.6); p = 0.05.Conclusions: Death after RRT activation occurred in 1 in 7 patients undergoing major hip surgery. Common patient characteristics included advanced age (> 82 years), frailty, high CCI, and emergency surgery. Further studies investigating perioperative surveillance teams in the identification of the high-risk patients before surgery and deteriorating patients after major hip surgery are warranted.

Objectives To compare the physiology of apneic oxygenation with low-tidal-volume (VT) ventilation during harvesting of the left internal mammary artery. Design Prospective, single-center, randomized trial. Setting Single-center teaching hospital. Participants The study comprised 24 patients who underwent elective coronary artery bypass grafting surgery. Interventions Apneic oxygenation (apneic group: 12 participants) and low-VT ventilation (low-VT group: 12 participants) (2.5 mL/kg ideal body weight) for 15 minutes during harvesting of the left internal mammary artery. Measurement and Main Results The primary endpoint was an absolute change in partial pressure of arterial carbon dioxide (PaCO2). Secondary endpoints were changes in arterial pH, pulmonary artery pressures (PAP), cardiac index, and pulmonary artery acceleration time and ease of surgical access. The mean (standard deviation) absolute increase in PaCO2 was 31.8 mmHg (7.6) in the apneic group and 17.6 mmHg (8.2) in the low-VT group (baseline-adjusted difference 14.2 mmHg [95% confidence interval 21.0-7.3], p

Background ALM201 is a therapeutic peptide derived from FKBPL that has previously undergone preclinical and clinical development for oncology indications and has completed a Phase 1a clinical trial in ovarian cancer patients and other advanced solid tumours. Methods In vitro, cancer stem cell (CSC) assays in a range of HGSOC cell lines and patient samples, and in vivo tumour initiation, growth delay and limiting dilution assays, were utilised. Mechanisms were determined by using immunohistochemistry, ELISA, qRT-PCR, RNAseq and western blotting. Endogenous FKBPL protein levels were evaluated using tissue microarrays (TMA). Results ALM201 reduced CSCs in cell lines and primary samples by inducing differentiation. ALM201 treatment of highly vascularised Kuramochi xenografts resulted in tumour growth delay by disruption of angiogenesis and a ten-fold decrease in the CSC population. In contrast, ALM201 failed to elicit a strong antitumour response in non-vascularised OVCAR3 xenografts, due to high levels of IL-6 and vasculogenic mimicry. High endogenous tumour expression of FKBPL was associated with an increased progression-free interval, supporting the protective role of FKBPL in HGSOC. Conclusion FKBPL-based therapy can (i) dually target angiogenesis and CSCs, (ii) target the CD44/STAT3 pathway in tumours and (iii) is effective in highly vascularised HGSOC tumours with low levels of IL-6.

Introduction/Background Cervical cancer is one of the most commonly occurring female cancers with increasing incidence worldwide. The mainstay of treatment for locally advanced cervical cancer is primary chemoradiotherapy. Pre-operative imaging alongside laparoscopic extraperitoneal para-aortic node dissection (LEPAND) has been used in order to best target this treatment. This study looked at all the women in the Belfast Trust over the last 9 years who had this investigation done as part of their pre-treatment workup and their outcomes. Methodology Retrospective data was collected for all those who had LEPAND for locally advanced cervical cancer from January 2010 to December 2018. These women all had pre-operative imaging that suggested positive pelvic lymph nodes but negative para-aortic nodes therefore deeming them suitable for the surgery. Results Sixty women were identified in this group with an age range from 23–69 and median age of 39. 93.3% had stage 2b cervical cancer, the remainder were 1b2 or 3b. 17% had adenocarcinoma of the cervix and 83% had squamous cell carcinoma. 70% of the women had primary LEPAND surgery before chemoradiotherapy with the remainder having their primary treatment before surgery. 5% (3/60) had positive para-aortic nodes on histopathology although 100% appeared node negative on MRI or PET imaging. None of those with positive nodes had recurrences but 66% died within 2 years. 15% of the study population died with 90% of these in the two years after diagnosis. 67% of these women had primary LEPAND followed by chemoradiotherapy with the others proceeding straight to primary treatment. The median survival for this group is 5 years. Conclusion 5% of the group had positive para-aortic lymph nodes on histopathological examination. This was despite imaging stating that they were node negative.LEPAND surgery prevented undertreatment in these women by re-targeting their radiotherapy. Disclosure Nothing to disclose.

Introduction/Background Cytoreductive Surgery (CRS) to zero visible residual disease is the strongest independent predictor of survival in advanced ovarian cancer. High-grade serous(HGSC) is the commonest and most aggressive sub-type. Carcinogenesis begins in the distal fallopian tube (NFT), via serous tubal intraepithelial carcinoma (STIC). Management may be through CRS followed by Adjuvant Chemotherapy (ACT) or Neoadjuvant Chemotherapy (NACT) followed by Interval CRS. Determining active visceral disease versus chemotherapeutic effect can be challenging during Interval CRS. A proportion of patients may be inappropriately treated and, therefore, potentially have worse survival or increased morbidity. Tumour-specific molecular alterations in surgical margins can predict risk of local recurrence. However, these assays are time-consuming and cannot be used in the intraoperative setting. The objective of this study was to validate tumour-specific methylated DNA assays using that could be used intra-operatively to assess sites of equivocal visceral disease in HGSC patients treated with NACT. Methodology Six cases of HGSC were identified through the Northern Ireland Gynaecological Cancer Centre. Formalin-fixed paraffin embedded (FFPE) tissue samples were retrieved via the Northern Ireland Biobank (NIB11:005, NIB13:0094). Matched NFT and HGSC samples were analysed by DNA methylation (DNAme) array profiling. Bioinformatic analyses revealed hypermethylation of multiple loci in HGSC compared to NFT. The top differentially methylated targets were further validated in a second cohort using pyrosequencing and qMSP. Results The top differentially methylated DNAme targets were analysed. Four were further validated in a cohort of 48 NFT and 48 HGSC unmatched samples. Pyrosequencing analysis revealed statistically significant differences (p Conclusion Intra-operative tissue biopsy analysis, using qMSP, is technically feasible. This technology may provide a more accurate tool to identify viable, residual HGSC following NACT and therefore assist with more appropriate CRS. Disclosure Nothing to disclose.

Objectives Cervical cancer is one of the most commonly occurring female cancers with increasing incidence. The mainstay of treatment for locally advanced disease is primary chemoradiotherapy. Pre-operative imaging in combination with laparoscopic extraperitoneal para-aortic node dissection (LEPAND) has been used to best target this treatment. This study looked at all women in the Belfast Trust over the last 9 years who had this investigation as part of their pre-treatment workup. Methods Retrospective data was collected for all those who had LEPAND for locally advanced cervical cancer from January 2010 to December 2018. All women had pre-operative imaging that suggested positive pelvic nodes but negative para-aortic nodes. Results Sixty women were identified in this group ageing 23–69 with median age 39. 93.3% had stage 2b cervical cancer, the remainder were 1b2 or 3b. 17% had adenocarcinoma of the cervix and 83% had squamous cell carcinoma. The median survival overall is 5 years. 70% of women had primary LEPAND surgery before chemoradiotherapy with the remainder having primary treatment before surgery. 15% of the study population died, 90% of which died within two years of diagnosis. 67% of these women had primary LEPAND followed by chemoradiotherapy with the others proceeding straight to primary treatment prior to surgery. 5% (3/60) had positive para-aortic nodes on histopathology although 100% appeared node negative on MRI/PET imaging. None with positive nodes had recurrences but 66% died within 2 years. Conclusions Despite having negative nodes on imaging 5% had positive para-aortic lymph nodes on histopathology. LEPAND surgery prevented undertreatment in these women.

Objective. There is a need to develop and validate biomarkers for treatment response and survival in tubo-ovarian high-grade serous carcinoma (HGSC). The chemotherapy response score (CRS) stratifies patients into complete/near-complete (CRS3), partial (CRS2), and no/minimal (CRS1) response after neoadjuvant chemotherapy (NACT). Our aim was to review current evidence to determine whether the CRS is prognostic in women with tubo-ovarian HGSC treated with NACT.Methods. We established an international collaboration to conduct a systematic review and meta-analysis, pooling individual patient data from 16 sites in 11 countries. Patients had stage IIIC/IV HGSC, 3-4 NACT cycles and >6-months follow-up. Random effects models were used to derive combined odds ratios in the pooled population to investigate associations between CRS and progression free and overall survival (PFS and OS).Results. 877 patients were included from published and unpublished studies. Median PFS and OS were 15 months (IQR 5-65) and 28 months (IQR 7-92) respectively. CRS3 was seen in 249 patients (28%). The pooled hazard ratios (HR) for PFS and OS for CRS3 versus CRS1/CRS2 were 0.55 (95% CI, 0.45-0.66; P < 0.001) and 0.65 (95% CI 0.50-0.85, P = 0.002) respectively; no heterogeneity was identified (PFS: Q = 6.42, P = 0.698, I2 = 0.0%; OS: Q = 6.89, P = 0 648, I2 = 0.0%). CRS was significantly associated with PFS and OS in multivariate models adjusting for age and stage. Of 306 patients with known germline BRCA1/2 status, those with BRCA1/2 mutations (n = 80) were more likely to achieve CRS3 (P = 0.027).Conclusions. CRS3 was significantly associated with improved PFS and OS compared to CRS1/2. This validation of CRS in a real-world setting demonstrates it to be a robust and reproducible biomarker with potential to be incorporated into therapeutic decision-making and clinical trial design. (C) 2019 The Authors. Published by Elsevier Inc.

Objective High grade serous carcinoma (HGSC) is the most common and most aggressive, subtype of epithelial ovarian cancer. It presents as advanced stage disease with poor prognosis. Recent pathological evidence strongly suggests HGSC arises from the fallopian tube via the precursor lesion; serous tubal intraepithelial carcinoma (STIC). However, further definition of the molecular evolution of HGSC has major implications for both clinical management and research. This study aims to more clearly define the molecular pathogenesis of HGSC. Methods Six cases of HGSC were identified at the Northern Ireland Gynaecological Cancer Centre (NIGCC) that each contained ovarian HGSC (HGSC), omental HGSC (OMT), STIC, normal fallopian tube epithelium (FTE) and normal ovarian surface epithelium (OSE). The relevant formalin-fixed paraffin embedded (FFPE) tissue samples were retrieved from the pathology archive via the Northern Ireland Biobank following attaining ethical approval (NIB11:005). Full microarray-based gene expression profiling was performed on the cohort. The resulting data was analysed bioinformatically and the results were validated in a HGSC-specific in-vitro model. Results The carcinogenesis of HGSC was investigated and showed the molecular profile of HGSC to be more closely related to normal FTE than OSE. STIC lesions also clustered closely with HGSC, indicating a common molecular origin. Conclusion This study provides strong evidence suggesting that extrauterine HGSC arises from the fimbria of the distal fallopian tube. Furthermore, several potential pathways were identified which could be targeted by novel therapies for HGSC. These findings have significant translational relevance for both primary prevention and clinical management of the disease.

Key content Postpartum ovarian vein thrombosis (POVT) is a rare but potentially fatal condition. Symptoms up to 4 weeks postpartum often include vague abdominal pain and pyrexia. A high index of suspicion is required to make the diagnosis. As there is no consensus regarding management, a multidisciplinary approach is advised. Learning objectives Recognise the symptoms and signs of POVT and formulate a differential diagnosis. Recognise the importance of imaging in confirming the diagnosis and involvement of the multidisciplinary team to plan management. Understand that conservative management with low-molecular-weight heparin is the first-line treatment, and understand the situations that may require vena caval filter insertion or surgical intervention. Ethical issues How can we counsel women about risks of conservative and surgical management of this condition when there is no consensus for this management? Should women who have had an ovarian vein thrombosis in a previous pregnancy be counselled toward avoiding future pregnancy?

For accurate spectral Doppler valvular evaluation, intraoperative sonographers must use transoesophageal echocardiographic (TOE) views that offer optimal incident angles. We hypothesised that views added to the 2013 American Society of Echocardiography/Society of Cardiovascular Anesthesiologists (ASE/SCA) standard views and other novel views we have described of the tricuspid (TV) and pulmonary valves (PV) offered superior incident angles to those included in the origina 1999 ASE/SCA recommendations for comprehensive intraoperative TOE examination. We compared the acquisition feasibility and incident angles obtained by these views in 62 patients undergoing elective cardiac surgery, who received TOE monitoring as standard care. Overall, the 2013 ASE/SCA standard and novel views provided superior incident angles for the TV (28% and 66% of patients) whereas the 1999 ASE/SCA standard views provided superior incident angles for the PV (79% of patients, P 0.11). We conclude that the 2013 ASE/SCA TV standard and novel views obtained superior incident angles for the tricuspid, but not pulmonary valves. We recommend that ntraoperative sonographers consider the use of these views, particularly when incident angles obtained with standard views are suboptimal.

Evidence to support prolonged catheterisation after radical hysterectomy is lacking. We sought to assess feasibility of a new protocol of early post-operative catheter removal following laparoscopic radical hysterectomy for cervical cancer. A retrospective review of post-operative bladder care in patients who underwent laparoscopic radical hysterectomy for cervical cancer was carried out. The post-operative bladder care protocol recommended catheter removal after 24–72 hours. Three consecutive post-void residual scans of less than 150 millilitres (ml) were considered evidence of normal voiding function. First line management of voiding dysfunction was clean intermittent self-catheterisation (CISC). Ninety-eight patients underwent laparoscopic radical hysterectomy for cervical cancer of whom 78 patients had catheter removal 24–72 hours post-operatively. The incidence of post-operative voiding dysfunction in this group was 44%, of whom 88% were managed with CISC and 82% regained normal voiding function. Average hospital stay was 4.2 days. The overall rate of long-term voiding dysfunction was 6%. Early catheter removal after laparoscopic radical hysterectomy appears to be both feasible and effective and compliments the ethos of enhanced patient recovery.

Key content The role of the Fanconi Anaemia-BRCA pathway in hereditary breast-ovarian cancer syndrome. Recent research has led to the identification of further inherited mutations associated with ovarian carcinoma. The improved knowledge of the mismatch repair pathway has led to a greater understanding of how hereditary mutations influence hereditary gynaecological cancer. Unusual carcinomas are often associated with unusual germline mutations. Learning objectives An outline of the incidence, prevalence and inheritance patterns of germline mutations associated with gynaecological cancer. Discussion of the molecular mechanisms that are interrupted due to these mutations and the carcinomas they are likely to influence. Ethical issues The future implications of advanced sequencing technologies on genetic screening.

It is generally assumed that virtually all cervical squamous cell carcinomas are associated with persistent infection by high-risk human papillomavirus (HPV), although it is well known that unusual variants of cervical adenocarcinoma are mostly HPV negative. We report a case of a well-differentiated cervical squamous cell carcinoma in a 54-yr-old woman, the morphologic features of which suggested a non-HPV-related neoplasm. The tumor was p16 negative. HPV was also negative by 2 methods, including the highly sensitive SPF-10 system. Further study of additional cases is needed to establish the etiological and pathogenetic factors that underlie very rare non-HPV-related cervical squamous cell carcinoma.

FKBPL is a secreted protein with well-established anti-angiogenic and anti-cancer stem cell activity. A novel therapeutic peptide, ALM201, derived from this protein has successfully completed a phase I clinical trial and was granted orphan drug status, by the FDA, for the treatment of ovarian cancer. Ovarian cancer is the most lethal gynecological cancer and there are no prognostic biomarkers currently used in the clinic. It is associated with a high incidence of recurrent chemo-resistant disease and this has been attributed to a treatment-resistant subpopulation of CD44+ cancer stem cells (CSCs). Previously, we presented evidence that CD44 is a potential target of ALM201 and here, for the first time, we investigate its ability to target both angiogenesis and CSCs in HGSOC. Tumorsphere and flow cytometry assays demonstrated that ALM201 is effective at reducing CSCs in a range of HGSOC cell lines and primary patient samples in vitro. Clonogenic assays demonstrated that ALM201 is not cytotoxic, but rather mediates ovarian CSC differentiation. In vitro, ALM201 displayed potent anti-CSC activity in the HGSOC cell line, OVCAR3. However, OVCAR3 tumor xenografts are not dependent on angiogenesis for their growth and therefore ALM201 did not elicit a strong response in this model. Furthermore, OVCAR3 xenografts dramatically upregulated the inflammatory cytokines IL-6 and IL-8, which is consistent with the lack of anti-CSC activity of ALM201 in vivo compared to in vitro. In contrast, treatment of highly angiogenic Kuramochi tumor xenografts, another HGSOC cell line, resulted in a statistically significant delay in both tumor growth and tumor initiation. This was associated with disruption of the CD31+ vascular network and a 10 fold decrease in the CSC population. Finally, using HGSOC tissue microarrays we demonstrated that high endogenous expression of FKBPL correlated with increased progression free interval; indicating the potential for FKBPL to be used as a prognostic biomarker in HGSOC. HGSOC cell lines display marked differences in tumor vascularisation in vivo. ALM201, a peptide fragment of FKBPL, has potent anti-CSC and anti-angiogenic activity in an HGSOC xenograft which is dependent on angiogenesis for growth; an important finding for the clinical development of ALM201. Our data also strongly suggest that FKBPL is a potential novel prognostic biomarker in HGSOC, supporting its endogenous anti-tumor activity. Citation Format: Stephanie Annett, Gillian Moore, Amy Short, Neermeen Moustafa, Sudipto Das, Darran O'Connor, Cian McCrudden, Adrien Kissenpfenning, Laura Nelson, Ian Harley, Ken Arthur, Anita Yakkundi, Glen McCluggage, Andrea Marshall, Fiona Furlong, Helen O. McCarthy, Graham Cotton, Timothy Harrison, Lana McClements, Tracy Robson. FKBPL as a novel therapeutic target and prognostic biomarker in high grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-054.