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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.

ObjectivesThe objective of this study was to investigate the relationship between BRCA1 protein expression, as determined by immunohistochemistry, and clinical outcome in uterine serous carcinoma (USC).MethodsA tissue microarray containing duplicate cores of 73 cases of USC was immunohistochemically stained with mouse anti-BRCA1 (Ab-1) mouse monoclonal (MS110) antibody. The cores were scored in a semiquantitative manner evaluating both the distribution and intensity of nuclear staining. BRCA1 protein expression was correlated with progression-free survival.ResultsSeventy-two of 73 cases were assessable, and there was a statistically significant decreased progression-free survival for those cases exhibiting tumor cell nuclei staining of 76% or greater (P = 0.0023).ConclusionsOur study illustrates that a low level of BRCA1 protein expression is a favorable prognostic indicator in USC, similar to what is observed in high-grade serous ovarian carcinoma. Further studies should focus on the BRCA1 status of USCs at a molecular level and also investigate whether BRCA1 protein expression is associated with response to chemotherapy in USC.

ObjectivesThe objectives of this study were to investigate the accuracy of magnetic resonance imaging (MRI) in predicting the depth of myometrial invasion in the preoperative assessment of women with endometrial cancer and to quantify the impact of MRI as an adjunct to predicting patients requiring full surgical staging.MethodsThis was a diagnostic accuracy study of prospective cases in conjunction with STARD guidelines using collected data from a tumor board within a cancer network. Consecutive series of all endometrial cancers in Northern Ireland over a 21-month period was discussed at the Gynaecological Oncology Multidisciplinary Team/tumor board meeting. This study concerns 183 women who met all the inclusion criteria. Main outcome measure was the correlation between the depth of myometrial invasion suggested by preoperative MRI study and the subsequent histopathological findings following examination of the hysterectomy specimen. Secondary end point was how MRI changed management of women who required surgery to be performed at a central cancer center.ResultsFor the detection of outer-half myometrial invasion, overall sensitivity of MRI was 0.73 (95% confidence interval [CI], 0.59–0.83), and specificity was 0.83 (95% CI, 0.76–0.89). The positive predictive value was 0.63 (95% CI, 0.50–0.74), and negative predictive value was 0.89 (95% CI, 0.82–0.93). Positive likelihood ratio was 4.35 (95% CI, 2.87–6.61), and negative likelihood ratio was 0.33 (95% CI, 0.21–0.52). Magnetic resonance imaging improved the sensitivity and negative predictive value of endometrial biopsy alone in predicting women with endometrial cancer who require full surgical staging (0.73 vs 0.65 and 0.80 vs 0.78, respectively).ConclusionsPreoperative pelvic MRI is a moderately sensitive and specific method of identifying invasion to the outer half of myometrium in endometrial cancer. Addition of MRI to preoperative assessment leads to improved preoperative assessment, triage, and treatment.

Purpose To review the role of adjuvant radiotherapy (RT) in the outcome and recurrence patterns of granulosa cell tumors (GCTs) of the ovary. Methods and Materials The records of all patients with GCTs referred to the Princess Margaret Hospital University Health Network between 1961 and 2006 were retrospectively reviewed. The patient, tumor, and treatment factors were assessed by univariate and multivariate analyses using disease-free survival (DFS) as the endpoint. Results A total of 103 patients with histologically confirmed GCTs were included in the present study. The mean duration of follow-up was 100 months (range, 1–399). Of the 103 patients, 31 received adjuvant RT. A total of 39 patients developed tumor recurrence. The tumor size, incidence of intraoperative rupture, and presence of concurrent endometrial cancer were not significant risk factors for DFS. The median DFS was 251 months for patients who underwent adjuvant RT compared with 112 months for patients who did not ( p = .02). On multivariate analysis, adjuvant RT remained a significant prognostic factor for DFS ( p = .004). Of the 103 patients, 12 had died and 44 were lost to follow-up. Conclusion Ovarian GCTs can be indolent, with patients achieving long-term survival. In our series, adjuvant RT resulted in a significantly longer DFS. Ideally, randomized trials with long-term follow-up are needed to define the role of adjuvant RT for ovarian GCTs.

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.

Inherited mutations in the MLH1 gene are associated with a proportion of families with the hereditary non-polyposis colon cancer syndrome (HNPCC). The cardinal features of the syndrome are a predisposition to colon, endometrial and ovarian cancers. Recently, it has been shown that a non-coding polymorphic variant in MLH1 (GA nt-93) predisposes to colon and endometrial cancer, but with much reduced penetrance. We sought to establish whether or not this polymorphic variant also predisposes to ovarian cancer.We genotyped 899 women with invasive ovarian cancer and 931 controls for the GA nt-93 variant.The presence of the variant was associated with a modest, but highly significant risk of ovarian cancer (OR=1.5; 95% CI 1.3-1.9; p=0.00005). The association was present in cancers of all histologies except clear cell, and in all ethnic groups.The GA nt-93 variant of the MLH1 gene is associated with an increased risk of invasive ovarian cancer.

Women with germ-line mutations in the mismatch repair genes (responsible for hereditary nonpolyposis colorectal cancer) face an increased risk of colonic and endometrial cancer. However, these germ-line mutations are rare and are responsible for fewer than 1% of endometrial cancers. Therefore, we examined whether or not common variants of the hereditary nonpolyposis colorectal cancer–associated genes might also be associated with an increased risk of endometrial cancer. Three single-nucleotide polymorphisms were selected in the MLH1 and MSH2 mismatch repair genes. All the various 672 women with endometrial cancer and 880 controls were genotyped. Each of these three single-nucleotide polymorphisms was associated with an increased risk of endometrial cancer. Carriers of the MLH1 nt-93 A allele were at a 1.5-fold increased risk of developing endometrial cancer compared with controls [95% confidence interval (95% CI), 1.2-2.0; P = 0.001]. The risk was higher for homozygote carriers [odds ratio (OR), 1.9; 95% CI, 1.2-3.2; P = 0.009]. For carriers of the MSH2 rs2303428 C allele, the OR was 1.4 (95% CI, 1.0-1.9; P = 0.05), and for carriers of the MSH2 rs2059520 G allele, the OR was 1.3 (95% CI, 1.0-1.7; P = 0.03). More than 9% of endometrial cancer cases carried a variant allele in both MLH1 and MSH2. For these women, the risk of endometrial cancer was particularly high (OR, 2.1; 95% CI, 1.2-3.6; P = 0.005). For patients younger than 50 years at diagnosis who carried both variants, the risk was even higher (OR, 3.4; 95% CI, 1.7-6.6; P = 0.0005). In summary, two common variant alleles of the MLH1 and MSH2 genes make a substantial contribution to endometrial cancer incidence in Ontario. (Cancer Epidemiol Biomarkers Prev 2006;15(9):1636–40)

Aims: Traditionally, advanced stage ovarian carcinoma is treated by debulking surgery followed by chemotherapy. However, in some circumstances preoperative chemotherapy may be given before optimal surgical debulking. This study aims to describe the morphological features found in ovarian carcinoma after chemotherapy because these have not been detailed previously. Methods: Histological sections were examined from 18 cases of ovarian carcinoma that had been treated by preoperative chemotherapy. The morphology was compared with any pre-chemotherapy biopsies that had been performed. Tumours were classified as showing morphological features suggesting a good response to chemotherapy (n = 14) or as showing little or no response (n = 4). Serum CA125 values before and after chemotherapy were compared. In all cases, the mitotic activity index (MAI), volume percentage of epithelium (VPE), and mean nuclear area (MNA) of tumour cells were calculated. Results: The preoperative biopsies were all typical ovarian serous or endometrioid adenocarcinomas. Morphological features present in the group responding to chemotherapy included the presence of small groups or single tumour cells in a densely fibrotic stroma. Tumour cells were characterised by both nuclear and cytoplasmic alteration, making accurate tumour typing and grading impossible. Nuclear features included the presence of bizarre enlargement with hyperchromatism, irregularity of outline, and chromatin clumping or smudging. Cytoplasmic alterations included intense eosinophilia, vacuolation, or foam cell change. There were pronounced stromal changes of fibrosis, inflammation, collections of foamy histiocytes, cholesterol cleft formation, haemosiderin deposition, fat necrosis, and dystrophic calcification, including the presence of many free psammoma bodies. There was no correlation between morphological response and biochemical response, as determined by serum CA125 values. In all nine cases in which pre-chemotherapy and post-chemotherapy biopsies were available, the MNA increased post-chemotherapy (p = 0.007, paired Wilcoxon test) and in six of nine cases the MAI decreased (p = 0.093). Conclusions: Because preoperative chemotherapy is being used increasingly in the management of ovarian cancer, pathologists should be aware of the resultant morphological effects. Accurate tumour typing and grading is impossible. In some cases, it may be difficult to confirm the presence of residual tumour, making it imperative that pre-chemotherapy tissue biopsies are obtained. Definite confirmation of residual tumour may require the examination of multiple histological sections from areas showing pronounced stromal changes, sometimes with multiple levels and immunohistochemistry. In the absence of definite residual tumour, the report should state that the features are consistent with the prior presence of tumour.

An unusual cervical adenocarcinoma is reported in a 50-year-old woman with a history of Peutz Jeghers syndrome. The carcinoma contained two morphologically distinct and spatially separate components, one comprising typical well differentiated adenoma malignum and the other a moderately differentiated neoplasm, in keeping with gastric type adenocarcinoma. Both components were positive for HIK1083 and MUC6 and negative for p16, and did not contain human papillomavirus. It is believed that such a composite tumour has not been described in the literature. It is believed that the component of gastric type adenocarcinoma arose through a process of dedifferentiation within adenoma malignum and we provide circumstantial molecular evidence in support of the interpretation that both components may be clonally related in that they displayed an extra copy of chromosome 7. This raises the possibility of a relationship between these two uncommon types of cervical adenocarcinoma, both of which are thought to exhibit gastric differentiation.

BACKGROUND. The aim of the study was to assess the feasibility, efficacy, and accuracy of the sentinel lymph node (SLN) procedure in vulvar cancer. METHODS. From April 2004 to September 2006, all patients with vulvar cancer, clinical stages I and II, underwent SLN detection, followed by a complete inguinofemoral lymphadenectomy. Demographic, surgical, and pathologic data on all patients were prospectively entered in a database. RESULTS. Forty-two patients underwent the SLN procedure. One patient was excluded from further analysis due to metastases to the vulva. The detection rate for at least 1 SLN per patient was 95%, with bilateral SLNs detected in 46% of patients. There was a trend toward improved ability to detect bilateral SLNs and proximity of the cancer to the midline (r = 0.996; P = .057). No contralateral SLNs were identified in patients with lateral vulvar lesions (>1 cm from the midline). For ‘close-to-midline’ (≤1 cm from the midline) lesions, SLNs were detected in 93% of ipsilateral groins and bilateral SLNs were found in 46% of patients, whereas lesions abutting the midline had unilateral and bilateral SLN detected in 100% and 93%, respectively. Sixteen of 41 patients (39%) and 18 of 68 groins (26%) revealed metastatic disease in the lymph nodes; all were correctly identified by the SLN procedure. There were no false-negative SLN results. CONCLUSIONS. SLN dissection is feasible and safe to perform in vulvar cancer. The ability to identify bilateral sentinel inguinal lymph nodes appears to be related to the proximity of the vulvar cancer to the midline. Cancer 2007. © 2007 American Cancer Society.

Table 1. Effectiveness of PSM compared to UC. PSM Usual care p value Out-of-range INR proportion 36% 41% 4.5) 10/1547 (0.6%) 20/1393 (1.4%) 0.033 a Closed loop non-inferiority testing. The time to first extreme reading was earlier for the UC group (p= 0.052). The rateof serious adverse events including bleeding events between groups was not significantly different. For participants in the PSM group, 76% of those who completed a satisfaction survey indicated that they were self managing their INR levels at least some of the time. Discussion: Self management performed at least as well as usual care in terms of maintenance of INR within target range. This was achieved safely, with high levels of acceptance, and has the potential to change current practice. It would be particularly advantageous for patients living in remote locations or with limited mobility, and will be broadly applicable if proven to be a cost-effective alternative to current practice. doi:10.1016/j.hlc.2010.11.021 The Dor Procedure: Alfred Hospital Experience J. Dimitriou ∗, J. Chan, J. Bhaskar, K. Chaudhuri, D. Esmore, S. Marasco, F. Rosenfeldt CJOB Cardiothoracic Unit, Alfred Hospital, Prahran, Victoria, Australia Introduction: In 2005 the prevalence of heart failure in the Australian population was 263,000. As patients age, the incidence of heart failure increases from 2.5% in those one percent of these showed a reduction in left ventricular volume (usingLVdiastolic diameter as an approximation). Discussion: In conclusion, the Dor procedure can be performed with acceptable morbidity and mortality in appropriately selected patients.