High performance of the DNA methylation-based WID-qEC test for detecting uterine cancers independent of sampling modalities.

Endometrial cancer (EC) is the most prevalent gynaecological cancer in high-income countries and its incidence is continuing to rise sharply. Simple and objective tools to reliably detect women with EC are urgently needed. We recently developed and validated the DNA methylation (DNAme)-based women's cancer risk identification-quantitative polymerase chain reaction test for endometrial cancer (WID-qEC) test that could address this need. Here, we demonstrate that the stability of the WID-qEC test remains consistent regardless of: (i) the cervicovaginal collection device and sample media used (Cervex brush and PreservCyt or FLOQSwab and eNAT), (ii) the collector of the specimen (gynaecologist- or patient-based), and (iii) the precise sampling site (cervical, cervicovaginal and vaginal). Furthermore, we demonstrate sample stability in eNAT medium for 7 days at room temperature, greatly facilitating the implementation of the test into diagnostic laboratory workflows. When applying FLOQSwabs (Copan) in combination with the eNAT (Copan) sample collection media, the sensitivity and specificity of the WID-qEC test to detect uterine (i.e., endometrial and cervical) cancers in gynaecologist-taken samples was 92.9% (95% confidence interval [CI] = 75.0%-98.8%) and 98.6% (95% CI = 91.7%-99.9%), respectively, whilst the sensitivity and specificity in patient collected self-samples was 75.0% (95% CI = 47.4%-91.7%) and 100.0% (95% CI = 93.9%-100.0%), respectively. Taken together these data confirm the robustness and clinical potential of the WID-qEC test.

Outcomes of minimal access retroperitoneal para-aortic lymphadenectomy in patients with locally advanced cervical cancer.

BACKGROUND: To evaluate outcomes of laparoscopic retroperitoneal para-aortic lymphadenectomy for stage 1b3-3b cervical cancer. METHODS: Pathology databases searched for all para-aortic lymphadenectomy cases 2005-2016. Descriptive statistics were used to analyse baseline characteristics, cox models for treatment affect after accounting for variables, and Kaplan Meier curves for survival (STATA v15). RESULTS: 191 patients had 1b3-3b cervical cancer of which 110 patients had Para-aortic lymphadenectomy. 8 (7.3%) patients stage 1b3, 82 (74.6%) stage 2b, and 20 (18.1%) stage 3b cervical cancer. Mean lymph node count 11.7 (SD7.6). The intra-operative and post-operative 30 day complication rates were 8.8% (CI: 4.3%, 15.7%) and 5.3% (CI: 1.9%, 11.2%) respectively.Para-aortic nodes were apparently positive on CT/MRI in 5/110 (5%) cases. Cancer was found in 10 (8.9%, CI: 4.3%, 15.7%) cases on histology, all received extended field radiotherapy. Only 2 were identified on pre-operative CT/MRI imaging. 3 of 10 suspected node-positive cases on CT/MRI had negative histology. Para-aortic lymphadenectomy led to alteration in staging and radiotherapy management in 8 (8%, CI: 3.7%, 14.6%) patients. Mean overall survival 42.81 months (SD = 31.79 months). Survival was significantly higher for women undergoing PAN (50.57 (SD 30.7) months) compared to those who didn't (31.27 (SD 32.5) months). CONCLUSION: Laparoscopic retroperitoneal para-aortic lymphadenectomy is an acceptable procedure which can guide treatment in women with locally advanced cervical cancer.

We evaluated outcomes for patients with stage 1b3-3b cervical cancer that had lymph nodes removed prior to planning their chemoradiotherapy. There were 3 groups ­ patients that had their lymph nodes removed, those that did not and those that had their procedure abandoned so didn't have their lymph nodes removed. We looked at the lymph nodes down the microscope to see if they contained cancer and compared this to their pre-operative imaging. 8 patients had a change to their staging and treatment because they were found to have cancer in the lymph nodes. We found that the keyhole procedure to remove lymph nodes is an acceptable procedure which can guide treatment in women with locally advanced cervical cancer.

Objective assessment tools in laparoscopic or robotic-assisted gynecological surgery: A systematic review.

INTRODUCTION: There is a growing emphasis on proficiency-based progression within surgical training. To enable this, clearly defined metrics for those newly acquired surgical skills are needed. These can be formulated in objective assessment tools. The aim of the present study was to systematically review the literature reporting on available tools for objective assessment of minimally invasive gynecological surgery (simulated) performance and evaluate their reliability and validity. MATERIAL AND METHODS: A systematic search (1989-2022) was conducted in MEDLINE, Embase, PubMed, Web of Science in accordance with PRISMA. The trial was registered with the Prospective Register of Systematic Reviews (PROSPERO) ID: CRD42022376552. Randomized controlled trials, prospective comparative studies, prospective single-group (with pre- and post-training assessment) or consensus studies that reported on the development, validation or usage of assessment tools of surgical performance in minimally invasive gynecological surgery, were included. Three independent assessors assessed study setting and validity evidence according to a contemporary framework of validity, which was adapted from Messick's validity framework. Methodological quality of included studies was assessed using the modified medical education research study quality instrument (MERSQI) checklist. Heterogeneity in data reporting on types of tools, data collection, study design, definition of expertise (novice vs. experts) and statistical values prevented a meaningful meta-analysis. RESULTS: A total of 19 746 titles and abstracts were screened of which 72 articles met the inclusion criteria. A total of 37 different assessment tools were identified of which 13 represented manual global assessment tools, 13 manual procedure-specific assessment tools and 11 automated performance metrices. Only two tools showed substantive evidence of validity. Reliability and validity per tool were provided. No assessment tools showed direct correlation between tool scores and patient related outcomes. CONCLUSIONS: Existing objective assessment tools lack evidence on predicting patient outcomes and suffer from limitations in transferability outside of the research environment, particularly for automated performance metrics. Future research should prioritize filling these gaps while integrating advanced technologies like kinematic data and AI for robust, objective surgical skill assessment within gynecological advanced surgical training programs.

Racioethnic Disparities in Endometrial Cancer Outcomes.

Black women are twice as likely to die from endometrial cancer (EC) compared with white women. This represents one of the worst racioethnic disparities amongst all cancers globally. Compared with white women, black women are more likely to be diagnosed with advanced EC, have more barriers to accessing care and experience increased delays in obtaining an EC diagnosis and commencing treatment. Histological and molecular differences place black women at higher risk of being diagnosed with more aggressive EC subtypes that carry less favourable outcomes. Furthermore, EC diagnostic pathways are less reliable in black women, and black women are less likely to receive evidence-based treatment for EC. This racioethnic disparity in EC outcomes exists both in the UK and US, despite differences in healthcare systems. This review methodically describes the key factors along the patient journey that contribute to the disparity in black women and proposes multifaceted approaches to lessen these gaps.

Plasma cell-free DNA methylation analysis for ovarian cancer detection: Analysis of samples from a case-control study and an ovarian cancer screening trial.

Analysis of cell-free DNA methylation (cfDNAme), alone or combined with CA125, could help to detect ovarian cancers earlier and may reduce mortality. We assessed cfDNAme in regions of ZNF154, C2CD4D and WNT6 via targeted bisulfite sequencing in diagnostic and early detection (preceding diagnosis) settings. Diagnostic samples were obtained via prospective blood collection in cell-free DNA tubes in a convenience series of patients with a pelvic mass. Early detection samples were matched case-control samples derived from the UK Familial Ovarian Cancer Screening Study (UKFOCSS). In the diagnostic set (ncases = 27, ncontrols = 41), the specificity of cfDNAme was 97.6% (95% CI: 87.1%-99.9%). High-risk cancers were detected with a sensitivity of 80% (56.3%-94.3%). Combination of cfDNAme and CA125 resulted in a sensitivity of 94.4% (72.7%-99.9%) for high-risk cancers. Despite technical issues in the early detection set (ncases = 29, ncontrols = 29), the specificity of cfDNAme was 100% (88.1%-100.0%). We detected 27.3% (6.0%-61.0%) of high-risk cases with relatively lower genomic DNA (gDNA) contamination. The sensitivity rose to 33.3% (7.5%-70.1%) in samples taken <1 year before diagnosis. We detected ovarian cancer in several patients up to 1 year before diagnosis despite technical limitations associated with archival samples (UKFOCSS). Combined cfDNAme and CA125 assessment may improve ovarian cancer screening in high-risk populations, but future large-scale prospective studies will be required to validate current findings.

The oncological and reproductive outcomes of fertility-preserving treatments for stage 1 grade 1 endometrial carcinoma: a systematic review and meta-analysis.

INTRODUCTION: The number of patients desiring fertility-preserving treatment for endometrial cancer rather than standard surgical management continues to increase. OBJECTIVE: We aimed to evaluate the efficacies of fertility-preserving treatments on the live birth rate, remission and relapse rates for women with stage 1a grade 1 endometrial carcinoma to support patient counselling. METHODS: We performed a meta-analysis for our primary outcomes of overall remission and relapse rate, and for secondary analysis, we divided papers into treatment type: systemic progestins, intrauterine progestins or hysteroscopic resection and adjuvant hormonal treatment. RESULTS: Thirty-five observational studies met inclusion criteria, with a total of 624 patients. Overall, conservative treatment of endometrial cancer showed a remission rate of 77% (95% CI: 70-84%), a relapse rate of 20% (95% CI: 13-27%) and a live birth rate of 20% (95% CI: 15-25%) with more favourable outcomes for the hysteroscopic resection group. CONCLUSIONS: Hysteroscopic resection and adjuvant hormonal treatment had the most favourable fertility and oncological outcomes. Further high-quality prospective multi-centre trials are warranted to determine the optimal treatment regimen and dosage and risk stratification for these patients.

The number of women diagnosed with womb cancer who want to preserve their fertility is increasing. Traditional treatment involves surgery to remove the womb and ovaries, rendering women infertile. Fertility-preserving treatments (e.g. hormone therapy, removing only affected areas) exist but their impact on remission, relapse and fertility is not certain. Our team discovered that for women who underwent fertility-preserving treatment: three in four had cancer remission, one in five had cancer relapse and one in five had a successful birth. More research is needed to work out the best fertility-preserving treatment and identify which women are more likely to have successful pregnancies.Overall, our research will help to counsel women diagnosed with womb cancer who want to preserve their fertility or are unsuitable for major surgery more effectively.

Circulating HPV DNA as a Biomarker for Pre-Invasive and Early Invasive Cervical Cancer: A Feasibility Study.

BACKGROUND: High-risk HPV infection is responsible for >99% of cervix cancers (CC). In persistent infections that lead to cancer, the tumour breaches the basement membrane, releasing HPV-DNA into the bloodstream (cHPV-DNA). A next-generation sequencing assay (NGS) for detection of plasma HPV circulating DNA (cHPV-DNA) has demonstrated high sensitivity and specificity in patients with locally advanced cervix cancers. We hypothesised that cHPV-DNA is detectable in early invasive cervical cancers but not in pre-invasive lesions (CIN). METHODS: Blood samples were collected from patients with CIN (n = 52) and FIGO stage 1A-1B CC (n = 12) prior to treatment and at follow-up. DNA extraction from plasma, followed by NGS, was used for the detection of cHPV-DNA. RESULTS: None of the patients with pre-invasive lesions were positive for CHPV-DNA. In invasive tumours, plasma from one patient (10%) reached the threshold of positivity for cHPV-DNA in plasma. CONCLUSION: Low detection of cHPV-DNA in early CC may be explained by small tumour size, poorer access to lymphatics and circulation, and therefore little shedding of cHPV-DNA in plasma at detectable levels. The detection rate of cHPV-DNA in patients with early invasive cervix cancer using even the most sensitive of currently available technologies lacks adequate sensitivity for clinical utility.

Updates on HPV Vaccination.

Cervical cancer still poses a significant global challenge. Developed countries have mitigated this challenge by the introduction of structured screening programmes and, more recently, the HPV vaccine. Countries that have successfully introduced national HPV vaccination programmes are on course for cervical cancer elimination in a few decades. In developing countries that lack structured screening and HPV vaccination programmes, cervical cancer remains a major cause of morbidity and mortality. The HPV vaccine is key to addressing the disproportionate distribution of cervical cancer incidence, with much to be gained from increasing vaccine coverage and uptake globally. This review covers the history and science of the HPV vaccine, its efficacy, effectiveness and safety, and some of the considerations and challenges posed to the achievement of global HPV vaccination coverage and the consequent elimination of cervical cancer.

The WID-EC test for the detection and risk prediction of endometrial cancer.

The incidence of endometrial cancer is rising. Measures to identify women at risk and to detect endometrial cancer earlier are required to reduce the morbidity triggered by the aggressive treatment required for advanced endometrial cancer. We developed the WID-EC (Women's cancer risk IDentification-Endometrial Cancer) test, which is based on DNA methylation at 500 CpG sites, in a discovery set of cervical liquid-based cytology samples from 1086 women with and without an endometrial cancer (217 cancer cases and 869 healthy controls) with a worse prognosis (grade 3 or ≥stage IB). We validated the WID-EC test in an independent external validation set of 64 endometrial cancer cases and 225 controls. We further validated the test in 150 healthy women (prospective set) who provided a cervical sample as part of the routine Swedish cervical screening programme, 54 of whom developed endometrial cancer within 3 years of sample collection. The WID-EC test identified women with endometrial cancer with a receiver operator characteristic area under the curve (AUC) of 0.92 (95% CI: 0.88-0.97) in the external set and of 0.82 (95% CI: 0.74-0.89) in the prospective validation set. Using an optimal cutoff, cancer cases were detected with a sensitivity of 86% and a specificity of 90% in the external validation set, and a sensitivity and specificity of 52% and 98% respectively in the prospective validation set. The WID-EC test can identify women with or at risk of endometrial cancer.

A Simple Cervicovaginal Epigenetic Test for Screening and Rapid Triage of Women With Suspected Endometrial Cancer: Validation in Several Cohort and Case/Control Sets.

PURPOSE: Endometrial cancer (EC) incidence has been rising over the past 10 years. Delays in diagnosis reduce survival and necessitate more aggressive treatment. We aimed to develop and validate a simple, noninvasive, and reliable triage test for EC to reduce the number of invasive diagnostic procedures and improve patient survival. METHODS: We developed a test to screen and triage women with suspected EC using 726 cervical smear samples from women with and without EC, and validated the test in 562 cervicovaginal samples using three different collection methods (cervical smear: n = 248; vaginal swab: n = 63; and self-collection: n = 251) and four different settings (case/control: n = 388; cohort of women presenting with postmenopausal bleeding: n = 63; a cohort of high-risk women with Lynch syndrome: n = 25; and a nested case/control setting from a screening cohort and samples taken up to 3 years before EC diagnosis: n = 86). RESULTS: We describe the Women's cancer risk IDentification - quantitative polymerase chain reaction test for Endometrial Cancer (WID-qEC), a three-marker test that evaluates DNA methylation in gene regions of GYPC and ZSCAN12. In cervical, self-collected, and vaginal swab samples derived from symptomatic patients, it detected EC with sensitivities of 97.2% (95% CI, 90.2 to 99.7), 90.1% (83.6 to 94.6), and 100% (63.1 to 100), respectively, and specificities of 75.8% (63.6 to 85.5), 86.7% (79.3 to 92.2), and 89.1% (77.8 to 95.9), respectively. The WID-qEC identified 90.9% (95% CI, 70.8 to 98.9) of EC cases in samples predating diagnosis up to 1 year. Test performance was similar across menopausal status, age, stage, grade, ethnicity, and histology. CONCLUSION: The WID-qEC is a noninvasive reliable test for triage of women with symptoms suggestive of ECs. Because of the potential for self-collection, it could improve early diagnosis and reduce the reliance for in-person visits.

Hysterectomy with radiotherapy or chemotherapy or both for women with locally advanced cervical cancer.

BACKGROUND: This is an update of the Cochrane Review published in Issue 4, 2015. Cervical cancer is one of the most frequent cause of death from gynaecological cancers worldwide. Many new cervical cancer cases in low-income countries present at an advanced stage. Standard care in Europe and the US for locally advanced cervical cancer (LACC) is chemoradiotherapy. In low-income countries, with limited access to radiotherapy, LACC may be treated with chemotherapy and hysterectomy. It is not certain if this improves survival. It is important to assess the value of hysterectomy with radiotherapy or chemotherapy, or both, as an alternative. OBJECTIVES: To determine whether hysterectomy, in addition to standard treatment with radiotherapy or chemotherapy, or both, in women with LACC (Stage IB2 to III) is safe and effective compared with standard treatment alone. SEARCH METHODS: We searched CENTRAL, MEDLINE via Ovid, Embase via Ovid, LILACS, trial registries and the grey literature up to 3 February 2022. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) that compared treatments involving hysterectomy versus radiotherapy or chemotherapy, or both, in women with LACC International Federation of Gynecology and Obstetrics (FIGO) Stages IB2 to III. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We independently assessed study eligibility, extracted data and assessed the risk of bias. Where possible, we synthesised overall (OS) and progression-free (PFS) or disease-free (DFS) survival in a meta-analysis using a random-effects model. Adverse events (AEs) were incompletely reported and we described the results of single trials in narrative form. We used the GRADE approach to assess the certainty of the evidence. MAIN RESULTS: From the searches we identified 968 studies. After deduplication, title and abstract screening, and full-text assessment, we included 11 RCTs (2683 women) of varying methodological quality. This update identified four new RCTs and three ongoing RCTs. The included studies compared: hysterectomy (simple or radical) with radiotherapy or chemoradiotherapy or neoadjuvant chemotherapy (NACT) versus radiotherapy alone or chemoradiotherapy (CCRT) alone or CCRT and brachytherapy. There is also one ongoing study comparing three groups: hysterectomy with CCRT versus hysterectomy with NACT versus CCRT. There were two comparison groups for which we were able to do a meta-analysis. Hysterectomy (radical) with neoadjuvant chemotherapy versus chemoradiotherapy alone Two RCTs with similar design characteristics (620 and 633 participants) found no difference in five-year OS between NACT with hysterectomy versus CCRT. Meta-analysis assessing 1253 participants found no evidence of a difference in risk of death (OS) between women who received NACT plus hysterectomy and those who received CCRT alone (HR 0.94, 95% CI 0.76 to 1.16; moderate-certainty evidence). In both studies, the five-year DFS in the NACT plus surgery group was worse (57%) compared with the CCRT group (65.6%), mostly for Stage IIB. Results of single trials reported no apparent difference in long-term severe complications, grade 3 acute toxicity and severe late toxicity between groups (very low-quality evidence). Hysterectomy (simple or radical) with neoadjuvant chemotherapy versus radiotherapy alone Meta-analysis of three trials of NACT with hysterectomy versus radiotherapy alone, assessing 571 participants, found that women who received NACT plus hysterectomy had less risk of death (OS) than those who received radiotherapy alone (HR 0.71, 95% CI 0.55 to 0.93; I2 = 0%; moderate-quality evidence). However, a significant number of participants who received NACT plus hysterectomy also had radiotherapy. There was no difference in the proportion of women with disease progression or recurrence (DFS and PFS) between NACT plus hysterectomy and radiotherapy groups (RR 0.75, 95% CI 0.53 to 1.05; I2 = 20%; moderate-quality evidence). The certainty of the evidence was low or very-low for all other comparisons for all outcomes. None of the trials reported quality of life outcomes. AUTHORS' CONCLUSIONS: From the available RCTs, we found insufficient evidence that hysterectomy with radiotherapy, with or without chemotherapy, improves the survival of women with LACC who are treated with radiotherapy or CCRT alone. The overall certainty of the evidence was variable across the different outcomes and was universally downgraded due to concerns about risk of bias. The certainty of the evidence for NACT and radical hysterectomy versus radiotherapy alone for survival outcomes was moderate. The same occurred for the comparison involving NACT and hysterectomy compared with CCRT alone. Evidence from other comparisons was generally sparse and of low or very low-certainty. This was mainly based on poor reporting and sparseness of data where results were based on single trials. More trials assessing medical management with and without hysterectomy may test the robustness of the findings of this review as further research is likely to have an important impact on our confidence in the estimate of effect.

Comparison of Expectant and Excisional/Ablative Management of Cervical Intraepithelial Neoplasia Grade 2 (CIN2) in the Era of HPV Testing.

Objective: To investigate conservative and excisional/ablative treatment outcomes for cervical intraepithelial neoplasia grade 2 (CIN2) following introduction of virological test of cure. Methods: This was a retrospective study of prospectively collected data at a teaching hospital colposcopy unit. 331 sequential biopsy-proved CIN2 cases were involved. CIN2 cases diagnosed between 01/07/2014 and 31/12/2017 were either conservatively managed or treated with excision/ablation and then were followed up until discharge from colposcopy clinic and then using the national cervical cytology database. Outcomes were defined: cytological/histological regression was absence of high-grade CIN on biopsy and/or high-grade dysplasia; virological regression was cytological/histological regression and negative human papillomavirus testing; persistence was biopsy-proven CIN2 and/or moderate dyskaryosis; progression was biopsy-proven CIN3+ and/or severe dyskaryosis. Results: Median follow-up was 22.6 months (range: 1.9-65.1 months). Among 175 (52.9%) patients initially managed conservatively, 77.3% (133/172) regressed, 13.4% (23/172) persisted, 9.3% (16/172) progressed to CIN3+, and 97 (56.4%) patients achieved virological regression. 156 (47.1%) patients underwent initial excision/ablation, with an 89.4% (110/123) virological cure rate. After discharge, 7 (4.0%) and 3 (1.9%) patients redeveloped CIN in the conservative and treatment groups, respectively, during a median period of 17.2 months. Conclusion: Conservative management is a reasonable and effective management strategy in appropriately selected women with CIN2. High rates of histological and virological regression should be expected. The previously mentioned data provide useful information for deciding management options.

Randomized Trial of Cytoreductive Surgery for Relapsed Ovarian Cancer.

BACKGROUND: Treatment for patients with recurrent ovarian cancer has been mainly based on systemic therapy. The role of secondary cytoreductive surgery is unclear. METHODS: We randomly assigned patients with recurrent ovarian cancer who had a first relapse after a platinum-free interval (an interval during which no platinum-based chemotherapy was used) of 6 months or more to undergo secondary cytoreductive surgery and then receive platinum-based chemotherapy or to receive platinum-based chemotherapy alone. Patients were eligible if they presented with a positive Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) score, defined as an Eastern Cooperative Oncology Group performance-status score of 0 (on a 5-point scale, with higher scores indicating greater disability), ascites of less than 500 ml, and complete resection at initial surgery. A positive AGO score is used to identify patients in whom a complete resection might be achieved. The primary end point was overall survival. We also assessed quality of life and prognostic factors for survival. RESULTS: A total of 407 patients underwent randomization: 206 were assigned to cytoreductive surgery and chemotherapy, and 201 to chemotherapy alone. A complete resection was achieved in 75.5% of the patients in the surgery group who underwent the procedure. The median overall survival was 53.7 months in the surgery group and 46.0 months in the no-surgery group (hazard ratio for death, 0.75; 95% confidence interval, 0.59 to 0.96; P = 0.02). Patients with a complete resection had the most favorable outcome, with a median overall survival of 61.9 months. A benefit from surgery was seen in all analyses in subgroups according to prognostic factors. Quality-of-life measures through 1 year of follow-up did not differ between the two groups, and we observed no perioperative mortality within 30 days after surgery. CONCLUSIONS: In women with recurrent ovarian cancer, cytoreductive surgery followed by chemotherapy resulted in longer overall survival than chemotherapy alone. (Funded by the AGO Study Group and others; DESKTOP III ClinicalTrials.gov number, NCT01166737.).

Venous thromboembolism in women with ovarian cancer undergoing neoadjuvant chemotherapy prior to cytoreductive surgery: A retrospective study.

INTRODUCTION: Ovarian cancer is associated with a venous thromboembolism risk of at least 7.2% by 2 years from diagnosis, and although patients undergoing surgery benefit from routine thromboprophylaxis, those undergoing neoadjuvant chemotherapy do not. This study aims to determine the venous thromboembolism incidence in patients with ovarian cancer undergoing neoadjuvant chemotherapy, and explore whether any subset is at higher risk, in order to evaluate whether thromboprophylaxis is justified in some or all of these patients. MATERIAL AND METHODS: This was a retrospective review of all women undergoing neoadjuvant chemotherapy for FIGO radiological stages III and IV primary ovarian, fallopian tube, and primary peritoneal cancer, between 2000 and 2015, in a London tertiary cancer center. The primary outcome was venous thromboembolism rate among women undergoing neoadjuvant chemotherapy. The secondary outcomes were patient or treatment factors associated with venous thromboembolism risk, including age, body mass index, smoking status, performance status, and tumor stage. RESULTS: We identified 278 eligible women from the ovarian cancer database. Fifty-eight women (20.9%) developed venous thromboembolism between initial presentation and the immediate postoperative period, of which 45 (77.6%) developed a pulmonary embolism. In all, 15.1% of women developed venous thromboembolism from the start of neoadjuvant chemotherapy. Age, body mass index, smoking, or other comorbidities were not significantly associated with venous thromboembolism risk. One woman died from massive pulmonary embolism, 27 women underwent inferior vena cava filter insertion, and 10 had surgery delayed. CONCLUSIONS: This study demonstrates an unacceptably high rate of avoidable venous thromboembolism including pulmonary embolism in these women, which complicates and delays treatment. Thromboprophylaxis during neoadjuvant chemotherapy should now be assessed prospectively.

Female Genital Tract Melanoma: 10 Years of Experience at a Single Tertiary Center.

OBJECTIVE: Malignant melanoma of the female genital tract is a rare disease with poor prognosis, with controversies remaining in its staging and management. In this study, we investigate clinical, pathological, and outcome data for patients referred to a tertiary cancer center with female genital tract melanoma over a decade. METHODS: Patients were retrospectively identified using a search of pathology reports to identify all cases of female genital tract melanoma from 2007 to 2019. Electronic patient records were used to record clinical information. Histopathology specimens were reviewed by a gynecological and dermatological pathology specialist. RESULTS: We identified 30 cases of genital tract melanoma, of which 19 were vulvar, 10 were vaginal, and 1 cervical. Overall survival at 1, 3, and 5 years was found to be 80%, 60%, and 57%. Patients who died were not significantly older at presentation than patients who survived (62 y vs 69 y, p = .215). No association was found between mortality and microscopic ulceration, lymphovascular invasion, pigmentation, resection margins, or radical versus local surgery.Nonvulvar lesions were significantly associated with mortality compared with vulvar lesions (p = .0018), despite similar age and Breslow thickness. Five patients were diagnosed at in situ stage, all of these were vulvar. Even after excluding these melanomas in situ, nonvulvar melanomas still had a significantly worse mortality rate (p = .048). A higher proportion of nonvulvar lesions than vulvar lesions displayed loss of pigmentation (p = .026). CONCLUSIONS: Nonvulvar genital tract melanomas carry a significantly worse prognosis. Survival was not related to resection margins, supporting the use of more conservative surgical margins.

Stepped approach to improving sexual function after gynaecological cancer: the SAFFRON feasibility RCT.

BACKGROUND: Women affected by gynaecological cancer are often unaware of the sexual consequences of both the cancer and its treatment. Most do not receive appropriate advice or help to recover sexual function, and the effect on their sexuality may be profound, both physically and emotionally. However, several potential therapies can be effective in helping recover some sexual engagement and change self-perception around sex. A major initial challenge is informing and involving patients in an appropriate and sensitive manner, and a further issue is delivering therapies in busy gynaelogical oncology clinics. This study was conceived in response to a National Institute for Health Research (NIHR) Health Technology Assessment (HTA) call asking for proposals to improve sexual functioning in women treated for gynaecological cancer while taking into account associated issues of mood. Existing evidence-based therapies for improving sexual function after cancer treatment were adapted and placed within a 'stepped care' model for delivering these in the NHS setting. An assessment and treatment stepping algorithm was developed in parallel, both to assign women to a treatment level at assessment and to follow their progress session by session to advise on changing intervention level. The assessment tool was applied to all participants on the principle that the problem was sexual difficulty, not the cancer of origin. PARTICIPANTS: Women aged > 18 years (with partners at their choice) treated for any gynaecological malignancy with surgery and/or chemotherapy and/or radiation at University College London Hospital or Bristol Gynaecological cancer centres, minimally 3 months post end of treatment, of any sexual orientation, with sexual function difficulties identified by three initial screening questions. DESIGN: A feasibility two-arm, parallel-group randomised controlled pilot trial. SETTING: Two NHS gynaecological cancer centres, one in London and one in Bristol. INTERVENTIONS: A three-level stepped care intervention. OBJECTIVE: To assess the feasibility of conducting a full-scale investigation of stepped therapy and indicate the potential benefits to patients and to the NHS generally. PRIMARY OUTCOME MEASURES: Recruitment to study, proportion of women stepping up, number of usable data points of all measures and time points over length of trial, and retention of participants to end of trial. RESULTS: Development of the intervention and accompanying algorithm was completed. The study was stopped before the recruitment stage and, hence, no randomisation, recruitment, numbers analysed, outcomes or harms were recorded. LIMITATIONS: As the study did not proceed, the intervention and its accompanying algorithm have not been evaluated in practice, and the capacity of the NHS system to deliver it has not been examined. CONCLUSIONS: None, as the study was halted. FUTURE WORK: The intervention could be studied within a clinical setting; however, the experience of the study group points to the need for psychosocial studies in medical settings to establish pragmatic and innovative mechanisms to ensure adequate resource when extending staff clinical skills and time to deliver any new intervention for the duration of the trial. TRIAL REGISTRATION: Current Controlled Trials ISRCTN12010952 and ClinicalTrials.gov NCT02458001. FUNDING: This project was funded by the NIHR HTA programme and will be published in full in Health Technology Assessment; Vol. 23, No. 5. See the NIHR Journals Library website for further project information.

Women affected by gynaecological cancer are often unaware of the sexual consequences of the cancer and its treatment. Most do not receive appropriate help to recover sexual function, and the physical and mental impact on their sexuality may be profound. However, several therapies could be effective in helping recovery. A major initial challenge is informing and involving patients appropriately and sensitively, and a further challenge is delivering therapies in busy cancer clinics. This study was conceived in response to the funder's call asking for proposals to improve sexual functioning in women treated for gynaecological cancer while taking into account associated issues of mood. Existing evidence-based therapies for improving sexual function after gynaecological cancer treatment were adapted and a new therapy for complex difficulties was devised. Three levels of intervention were developed and placed into a 'stepped care' model: a self-help intervention, a clinical nurse specialist-delivered intervention and a clinical psychologist high-level intervention for problems not responding to levels 1 and 2. In parallel, an assessment and treatment algorithm was developed to assess women and follow their progress closely to inform whether or not their intervention level should be changed. However, major difficulties were encountered: procedural and logistical delays in setting up the study, both at the beginning across a range of hospitals and, later, at the point of training staff within the NHS to deliver the interventions within their clinical workload. Issues such as maternity leave with untrained locum cover led to nursing staff being unable to free up qualified staff to be part of the study. It is hoped that the existing developments can be tested in a future study to determine (1) if they are effective and (2) whether or not they can be delivered within the NHS.

HPV vaccine in the treatment of usual type vulval and vaginal intraepithelial neoplasia: a systematic review.

BACKGROUND: HPV DNA is found in almost 80% of VIN/VaIN. Current management is inadequate, with high recurrence rates. Our objective was to review the literature regarding the role of HPV vaccine in secondary prevention and treatment of VIN/VaIN. METHODS: Database searches included Ovid Medline, Embase, Web of Science, The Cochrane Library and Clinicaltrials.gov . Search terms included HPV vaccine AND therapeutic vaccine* AND VIN OR VAIN, published in English with no defined date limit. Searches were carried out with a UCL librarian in March 2018. We included any type of study design using any form of HPV vaccine in the treatment of women with a histologically confirmed diagnosis of VIN/VaIN. We excluded studies of other lower genital tract disease, vulval/vaginal carcinoma and prophylactic use of vaccines. The outcome measures were lesion response to vaccination, symptom improvement, immune response and HPV clearance. RESULTS: We identified 93 articles, 7 studies met our inclusion criteria; these were uncontrolled case series. There were no RCTs or systematic reviews identified. Reduction in lesion size was reported by all 7 studies, symptom relief by 5, HPV clearance by 6, histological regression by 5, and immune response by 6. CONCLUSIONS: This review finds the evidence relating to the use of HPV vaccine in the treatment of women with VIN/VaIN is of very low quality and insufficient to guide practice. Further longitudinal studies are needed to assess its use in prevention of progression to cancer.

Outcome of patients with advanced ovarian cancer who do not undergo debulking surgery: A single institution retrospective review.

OBJECTIVE: To assess the outcome of patients with advanced ovarian cancer (OC) who were treated without surgery, having received upfront chemotherapy and no interval debulking surgery (IDS). METHODS: Retrospective analysis of medical and chemotherapy records of consecutive patients with OC between 2005 and 2013 at UCL Hospitals London, UK who received neoadjuvant chemotherapy (NACT) was then found to be unsuitable for IDS following review by the multidisciplinary team. RESULTS: Eighty-three patients (18%) out of 467 receiving NACT did not undergo IDS. Median age was 70years (range 33-88); out of these 83 patients, 43 (51.8%) presented with stage IV disease. Forty-three of these 83 patients received carboplatin and paclitaxel (CP) (51.8%) and 37 received carboplatin alone (C) (44.6%); 3 patients (3.6%) received other platinum-based combinations. Reasons for not proceeding to surgery were: poor response to chemotherapy after 3-4 cycles of NACT (61/83, 73.5%); comorbidities (12/83, 14.5%); patient decision (4/83, 4.8%). Six patients (7.2%) received <3 cycles of NACT due to a worsening clinical condition. The median overall survival (OS) for patients not undergoing IDS was 18months (95% CI 10-20months). Forty-four of 83 patients (53%) received >2 lines of chemotherapy. In a univariate analysis CP, age <70years, and absence of comorbidities were factors influencing OS. In a multivariate analysis only having received CP remained independently associated with OS (HR 0.49, 95% CI 0.29-0.84). CONCLUSIONS: Chemotherapy alone can provide reasonable disease control in patients unsuitable for IDS and CP should be used if possible.

Enumeration and Molecular Characterisation of Circulating Tumour Cells in Endometrial Cancer.

BACKGROUND: This is a feasibility study to determine whether circulating tumour cells (CTCs) are detectable and suitable for molecular profiling in advanced endometrial cancer (aEC). METHOD: Between October 2012 and February 2014, 30 patients with aEC had baseline and up to 3 follow-up samples. CTCs and stathmin expression were evaluated using the CellSearch platform. Epithelial cell adhesion molecule (EpCAM) and stathmin immunohistochemistry were performed on FFPE tumour tissue. RESULTS: Eighteen from 30 (60%) patients had detectable CTCs during study [1 CTC (n = 7), 2 (n = 4), 3 (n = 1), 4 (n = 2), 7 (n = 1), 8 (n = 1), 22 (n = 1), 172 (n = 1) in 7.5 ml blood]. Ten from 18 patients had between 50 and 100% of detectable CTCs that were stathmin positive. More CTC-positive than CTC-negative patients had non-endometrioid versus endometrioid histology, tumour size ≥5 versus <5 cm, higher-stage disease and worse survival [hazard ratio 3.3, p > 0.05, 95% confidence interval 0.7-16.2]. Twenty-one tumour blocks were tested for EpCAM and stathmin immunohistochemistry (IHC). Stathmin tumour immunostaining scores (TIS) on IHC were higher in CTC-positive patients. CONCLUSION: CTC enumeration and molecular profiling with stathmin on the CellSearch platform is feasible in aEC. Stathmin TIS on IHC, a known prognostic marker in EC, was associated with CTC positivity.

DNA Methylation Signatures in Vaginal Fluid Samples for Detection of Cervical and Endometrial Cancer.

OBJECTIVE: A noninvasive tool that allows individuals to be monitored who are at risk of developing a malignancy is an unmet need. Such a test would need to consist of a molecular signature that allows for gradual judgment to assess the efficacy of preventive strategies. Here we performed a proof-of-principle study to test whether a DNA methylation (DNAme) signature in fluid collected from the vagina is able to identify women with cervical or endometrial cancer. MATERIALS AND METHODS: DNA from vaginal fluid samples from 111 women (30, 8, 73 with endometrial cancer, cervical cancer, and benign gynecological conditions, respectively) were analyzed for DNAme using the Illumina 450k DNA methylation bead array assay, which allows the assessment of DNAme at more than 480.000 CpG sites. We developed a cervical and an endometrial cancer DNAme signature by comparing normal and cancerous cervical and endometrial samples from the publicly available The Cancer Genome Atlas data and developed deviation scores to assess the potential of discriminating cancer from a control sample using a vaginal fluid DNAme signature. RESULTS: More than 60% of variations in DNAme in our vaginal fluid cannot be explained by those clinical or technical factors that we were aware of. Both the cervical and the endometrial cancer DNAme signature resulted in receiver operating characteristic area under the curve between 0.75 and 0.83 to discriminate controls and the cancers for which the signature has been designed for. CONCLUSIONS: Whole DNAme signatures based on array technologies in body fluids are able to discriminate cancer cases from controls.