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Mucinous ovarian carcinoma (MOC) is a rare histotype of ovarian cancer, with low response rates to standard chemotherapy, and very poor survival for patients diagnosed at advanced stage. There is a limited understanding of the MOC immune landscape, and consequently whether immune checkpoint inhibitors could be considered for a subset of patients.We performed multicolor immunohistochemistry (IHC) and immunofluorescence (IF) on tissue microarrays in a cohort of 126 MOC patients. Cell densities were calculated in the epithelial and stromal components for tumor-associated macrophages (CD68+/PD-L1+, CD68+/PD-L1-), T cells (CD3+/CD8-, CD3+/CD8+), putative T-regulatory cells (Tregs, FOXP3+), B cells (CD20+/CD79A+), plasma cells (CD20-/CD79a+), and PD-L1+ and PD-1+ cells, and compared these values with clinical factors. Univariate and multivariable Cox Proportional Hazards assessed overall survival. Unsupervised k-means clustering identified patient subsets with common patterns of immune cell infiltration.Mean densities of PD1+ cells, PD-L1- macrophages, CD4+ and CD8+ T cells, and FOXP3+ Tregs were higher in the stroma compared to the epithelium. Tumors from advanced (Stage III/IV) MOC had greater epithelial infiltration of PD-L1- macrophages, and fewer PD-L1+ macrophages compared with Stage I/II cancers (p = 0.004 and p = 0.014 respectively). Patients with high epithelial density of FOXP3+ cells, CD8+/FOXP3+ cells, or PD-L1- macrophages, had poorer survival, and high epithelial CD79a + plasma cells conferred better survival, all upon univariate analysis only. Clustering showed that most MOC (86%) had an immune depleted (cold) phenotype, with only a small proportion (11/76,14%) considered immune inflamed (hot) based on T cell and PD-L1 infiltrates.In summary, MOCs are mostly immunogenically 'cold', suggesting they may have limited response to current immunotherapies.

PURPOSE: Prior studies of menopausal hormone therapy (MHT) and ovarian cancer survival have been limited by lack of hormone regimen detail and insufficient sample sizes. To address these limitations, a comprehensive analysis of 6419 post-menopausal women with pathologically confirmed ovarian carcinoma was conducted to examine the association between MHT use prior to diagnosis and survival. METHODS: Data from 15 studies in the Ovarian Cancer Association Consortium were included. MHT use was examined by type (estrogen-only (ET) or estrogen+progestin (EPT)), duration, and recency of use relative to diagnosis. Cox proportional hazards models were used to estimate the association between hormone therapy use and survival. Logistic regression and mediation analysis was used to explore the relationship between MHT use and residual disease following debulking surgery. RESULTS: Use of ET or EPT for at least five years prior to diagnosis was associated with better ovarian cancer survival (hazard ratio, 0.80; 95% CI, 0.74 to 0.87). Among women with advanced stage, high-grade serous carcinoma, those who used MHT were less likely to have any macroscopic residual disease at the time of primary debulking surgery (p for trend

Objective There are widespread efforts to increase symptom awareness of ‘pelvic/abdominal pain, increased abdominal size/bloating, difficulty eating/feeling full and urinary frequency/urgency’ in an attempt to diagnose ovarian cancer earlier. Long-term survival of women with these symptoms adjusted for known prognostic factors is yet to be determined. This study explored the association of symptoms, routes and interval to diagnosis and long-term survival in a population-based cohort of postmenopausal women diagnosed with invasive epithelial tubo-ovarian cancer (iEOC) in the ‘no screen’ (control) UKCTOCS arm. Methods Of 101,299 women in the control arm, 574 were confirmed on outcome review to have iEOC between randomisation (2001–2005) and 31 December 2014. Data was extracted from medical notes and electronic records. A multivariable model was fitted for individual symptoms, time interval from symptom onset to diagnosis, route to diagnosis, speciality, morphological Type, age at diagnosis, year of diagnosis (period effect), stage, primary treatment, and residual disease. Results Women presenting with symptoms listed in the NICE guidelines (HR1.48, 95%CI1.16–1.89, p = 0.001) or the modified Goff Index (HR1·68, 95%CI1·32–2.13, p, Highlights • This study explored the association of symptoms of ovarian cancer, interval and route to diagnosis with survival. • Focus on ‘high alert’ symptoms: pelvic/abdominal pain, increase abdominal size/bloating and difficulty eating/feeling full • The ovarian cancer ‘high alert’ symptom complexes identify postmenopausal women with a significantly poorer prognosis. • The study could not however exclude the possibility of better outcomes in those who are aware and acted on these symptoms.

Evidence of a mortality benefit continues to elude ovarian cancer (OC) screening. Data from the US Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial which used a screening strategy incorporating CA125 cut-off and transvaginal ultrasound has not shown mortality benefit. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) is using the Risk of Ovarian Cancer (ROC) time series algorithm to interpret CA125, which has shown an encouraging sensitivity and specificity however the mortality data will only be available in 2015. The article explores the impact of growing insights into disease aetiology and evolution and biomarker discovery on future screening strategies. A better understanding of the target lesion, improved design of biomarker discovery studies, a focus on detecting low volume disease using cancer specific markers, novel biospecimens such as cervical cytology and targeted imaging and use of time series algorithms for interpreting markers profile suggests that a new era in screening is underway., Highlights • Ovarian cancer screening using CA125 cut-off has shown no mortality benefit. • Initial results using a time-series algorithm have been encouraging. • Cancer-specific biomarkers, novel biospecimens, targeted imaging to detect precursor lesion/low-volume disease are likely to be central to future screening strategies.

Objectives: Ovarian cancer screening for women at increased genetic risk in the UK involves 4-monthly CA125 tests and annual ultrasound, with further tests prompted by an abnormal result. The study evaluated the longer-term psychological and behavioural effects of frequent ovarian screening. Methods: Women completed T1 questionnaires before their first routine 4-monthly CA125 test, and T2 follow-up questionnaires one week after their result. Women with abnormal results completed a further questionnaire one week after return to routine screening (T3 primary end-point). T4 questionnaires were sent at nine months. Measures included cancer distress, general anxiety/depression, reassurance, and withdrawal from screening. Results: A total 1999 (62%) of 3224 women completed T1 questionnaires. T2 questionnaires were completed by 1384/1609 participants (86%): 1217 (89%) with normal results and 167/242 (69%) with abnormal results. T3 questionnaires were completed by 141/163 (87%) women, with 912/1173 (78%) completing T4 questionnaires. Analysis of covariance indicated that, compared to women with normal results, women with abnormal results reported moderate cancer distress (F = 27.47, p ≤.001, η2 = 0.02) one week after their abnormal result and were significantly more likely to withdraw from screening (OR = 4.38, p ≤.001). These effects were not apparent at T3 or T4. The effect of screening result on general anxiety/depression or overall reassurance was not significant. Conclusions: Women participating in frequent ovarian screening who are recalled for an abnormal result may experience transient cancer-specific distress, which may prompt reconsideration of risk management options. Health professionals and policy makers may be reassured that frequent familial ovarian screening does not cause sustained psychological harm. © 2012 Elsevier Inc. All rights reserved.

Objectives We sought to evaluate the effect of polymorphisms in the VEGF ( Vascular Endothelial Growth Factor ) gene on overall survival in ovarian cancer patients. Methods A sample of 319 women diagnosed with primary invasive epithelial ovarian cancer in Australia between 1985 and 1997, recruited as incident cases, were genotyped for four VEGF single nucleotide polymorphisms (three tagSNPs and one functional SNP) using the Sequenom MassARRAY platform. A SNP found to be associated with ovarian cancer survival in this sample set was then evaluated in two independent datasets in an attempt to replicate the association. Results VEGF tagSNPs rs3025033 and rs2146323 were not associated with ovarian cancer survival in the Australian sample. Ovarian cancer patients homozygous for tagSNP rs833068 or the functional SNP rs2010963 displayed significantly shortened overall survival in the Australian sample (HR 2.09, 95% CI 1.16–3.78), an effect most apparent in the first 5years after diagnosis. This association was not replicated in two independent datasets. Conclusions Findings from this study provide no evidence that rs3025033 and rs2146323 VEGF polymorphisms are associated with ovarian cancer survival. Although homozygous carriers of the tagSNP rs833068 experienced significantly worse survival in our Australian dataset, we were unable to replicate this in two independent datasets.

Objective To define risk thresholds for cost-effectiveness of risk-reducing salpingo-oophorectomy (RRSO) for ovarian cancer (OC) prevention in low/intermediate risk postmenopausal women. Methods A decision-analytic model compares lifetime costs-&-effects of offering ‘RRSO' with ‘no RRSO' to postmenopausal women ≥50years for different lifetime OC-risk thresholds: 2%, 4%, 5%, 6%, 8% and 10%. Well established data from the literature are used to estimate total costs, effects in terms of Quality-Adjusted-Life-Years(QALYs), cancer incidence, incremental cost-effectiveness ratio(ICER) and impact. Costs are reported at 2012 prices; costs/outcomes discounted at 3.5%. Deterministic/probabilistic sensitivity analysis (PSA) evaluate model uncertainty. Results RRSO does not save QALYs and is not cost-effective at the 2% general population lifetime OC-risk. At 4% OC-risk RRSO saves QALYs but is not cost-effective. At risk thresholds ≥5%, RRSO saves more life-years and QALYs and is highly cost-effective. The ICERs for OC-risk levels 5%, 6%, 8% and 10% are £15,247, £9958, £4584, and £1864 respectively. The gain in life-years from RRSO equates to 29.2, 40.1, 62.1 and 80.3days at risk thresholds of 5%, 6%, 8% and 10% respectively. The results are not sensitive to treatment costs of RRSO/OC/cardiovascular events but are sensitive to utility-scores for RRSO. On PSA, 67%, 80%, 84%, 91% and 94% of simulations at risk thresholds of 4%, 5%, 6%, 8% and 10% respectively are cost-effective for RRSO. Conclusion RRSO is highly cost-effective in postmenopausal women aged >50 with ≥5% lifetime OC-risk and increases life-expectancy by ≥29.2days. The results could have significant clinical implications given the improvements in risk prediction and falling costs of genotyping.

OBJECTIVES: To describe our experience of laparoscopic extraperitoneal paraaortic lymphadenectomy and to study the feasibility, safety and applications of this technique in managing cervical, ovarian and endometrial carcinomas. METHODS: Our study included 32 women with cervical, ovarian or endometrial cancers undergoing laparoscopic extraperitoneal paraaortic lymphadenectomy between December 1997 and May 2002. The operating time, nodal yield, hospital stay and complications were recorded prospectively. The impact on the overall management was assessed by comparing the preoperative therapeutic plan with that following surgicopathological staging. RESULTS: The median nodal yield was 12 nodes, median-operating time was 80 min and the median hospital stay was 2 days. The median follow-up was 15.25 months. Lymphadenectomy was successful in all but one woman who had a peritoneal tear causing CO(2) gas leakage. Complications included one case each of pulmonary embolism, umbilical hernia, lymphocoele, pelvic collection and left-thigh cellulitis. In all women, the need for adjuvant chemotherapy or extended field radiotherapy (EFRT) was based on nodal histology. The primary plan of management was changed in 22.6% women. In the endometrial and cervical cancer group, 8.3% women deferred and 20.8% additionally received EFRT. All women with ovarian cancer (stage I) were completely staged and avoided chemotherapy. CONCLUSIONS: Laparoscopic extraperitoneal paraaortic lymphadenectomy is feasible with minimal complications, acceptable nodal yield and short hospital stay. It accurately identifies those cervical and endometrial cancers requiring extended field irradiation as part of their adjuvant therapy. It can be effectively applied in staging early ovarian cancers to determine the need for adjuvant chemotherapy.

Objective A prospective psychological evaluation study of familial ovarian cancer screening (PsyFOCS) is underway in partnership with the UK Familial Ovarian Cancer Screening Study (UK FOCSS Phase 2). One of the aims of PsyFOCS is to examine factors associated with withdrawal from the UK FOCSS prior to the onset of 4-monthly screening. Method 1999 of 3224 women completed a baseline questionnaire. 110 (5.5%) women withdrew from screening prior to their first routine Phase 2 screen, of which 73 (66.4% of withdrawals) had withdrawn because they had undergone removal of their ovaries and fallopian tubes (withdrawn group). The comparison group consisted of 1868 women who remained on screening. The baseline questionnaire included measures of cancer-specific distress, anxiety, depression and illness perceptions. Results Logistic regression analysis indicated that having had prior annual (Phase 1) screening (OR = 13.34, p < .01), past experience of further tests (OR = 2.37, p < .01) and greater cancer-specific distress (OR = 1.38, p < .01) were associated with withdrawal for surgery. Belief in ageing as a cause of ovarian cancer was also associated with withdrawal (OR = 1.32, p = .05). Conclusion These cross-sectional data suggest that withdrawal from familial ovarian cancer screening may be influenced by both clinical and psychological factors. These may reflect women's experience of the drawbacks of screening and increased concern about ovarian cancer risk, as well as having opportunities to consider surgery as an alternative risk management strategy whilst using screening as an interim measure.

Objectives. To examine intra-operative, short and longer term morbidity associated with Radical Trachelectomy (RT) within our cohort of patients, compared with conventional Radical Hysterectomy (RH). Methods. A retrospective case note review comprising 29 RT and 50 RH patients. Patients who required adjuvant treatment were excluded. Operative data, short-term and long-term complications were recorded. Long-term problems were included only if they had been of persistent nature. Results. The median age and follow up period for the RH group were 40 years and 60 months and for RT group 30.5 years and 25 months. There were significant differences between RH and RT groups in median operative time (260 versus 187 min), blood loss (1000 versus 400 ml), transfusion requirement (75% versus 12%), analgesic requirement (8 versus 3.5 days) and hospital stay (11 versus 6 days). Bladder hypotonia requiring prolonged catheterisation was more frequent in RH group ( P = 0.004). There was no apparent difference in psychosexual problems between the two groups (17 versus 16%). Complications of deep dyspareunia ( P = 0.009), excessive vaginal discharge ( P = 0.01), and upper thigh parasthesia ( P = 0.05) were noted to be significantly higher in the RT group. Specific problems encountered in the RT group included; dysmenorrhea (24%), irregular menstruation (17%), recurrent candidiasis (14%), cervical suture problems (14%), isthmic stenosis (10%) and prolonged amenorrhea (7%). Conclusion. RT is associated with less operative and short-term morbidity compared with conventional RH. In addition to specific complications associated with RT, in our experience, there are long-term morbidities that are not as commonly observed in RH.