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Objective: To evaluate the association of Jewish cultural and religious identity and denominational affiliation with interest in, intention to undertake and uptake of population‐based BRCA (Breast Cancer Gene)‐testing. Design: Cohort‐study set within recruitment to GCaPPS‐trial (ISRCTN73338115). Setting: London Ashkenazi‐Jewish (AJ) population. Population or sample: AJ men and women, >18 years. Methods: Participants were self‐referred, and attended recruitment clinics (clusters) for pre‐test counselling. Subsequently consenting individuals underwent BRCA testing. Participants self‐identified to one Jewish denomination: Conservative/Liberal/Reform/Traditional/Orthodox/Unaffiliated. Validated scales measured Jewish Cultural‐Identity (JI) and Jewish Religious‐identity (JR). Four‐item Likert‐scales analysed initial 'interest' and 'intention to test' pre‐counselling. Item‐Response‐Theory and graded‐response models, modelled responses to JI and JR scales. Ordered/multinomial logistic regression modelling evaluated association of JI‐scale, JR‐scale and Jewish Denominational affiliation on interest, intention and uptake of BRCA testing. Main outcome measures: Interest, intention, uptake of BRCA testing. Results: In all, 935 AJ women/men of mean age = 53.8 (S.D = 15.02) years, received pre‐test education and counselling through 256 recruitment clinic clusters (median cluster size = 3). Denominational affiliations included Conservative/Masorti = 91 (10.2%); Liberal = 82 (9.2%), Reform = 135 (15.1%), Traditional = 212 (23.7%), Orthodox = 239 (26.7%); and Unaffiliated/Non‐practising = 135 (15.1%). Overall BRCA testing uptake was 88%. Pre‐counselling, 96% expressed interest and 60% intention to test. JI and JR scores were highest for Orthodox, followed by Conservative/Masorti, Traditional, Reform, Liberal and Unaffiliated Jewish denominations. Regression modelling showed no significant association between overall Jewish Cultural or Religious Identity with either interest, intention or uptake of BRCA testing. Interest, intention and uptake of BRCA testing was not significantly associated with denominational affiliation. Conclusions: Jewish religious/cultural identity and denominational affiliation do not appear to influence interest, intention or uptake of population‐based BRCA testing. BRCA testing was robust across all Jewish denominations. Jewish cultural/religious factors do not affect BRCA testing, with robust uptake seen across all denominational affiliations. Jewish cultural/religious factors do not affect BRCA testing, with robust uptake seen across all denominational affiliations. [ABSTRACT FROM AUTHOR]

Objectives: The aims of the study are to explore the range and variation in serum estradiol concentration, and to estimate the prevalence of "poor absorption" (women using licensed estradiol doses with subtherapeutic levels), in perimenopausal and postmenopausal women using transdermal estradiol in the real world., Methods: This is a cross-sectional analysis in a specialist menopause clinic in the UK., Results: Serum samples were obtained from 1,508 perimenopausal and postmenopausal women. A total of 61.87% were using licensed doses. The median estradiol concentration was 355.26 pmol/L (interquartile range 198.44-646.15 pmol/L). A reference interval for the whole cohort was defined as 54.62-2,050.55 pmol/L. There was substantial interindividual variation across the dose range. Variance was greater in younger women ( P = 0.002) and gel users ( P = 0.002). There was a trend toward greater variance in women using higher doses, but the association failed to reach statistical significance ( P = 0.074). One in four women (24.84%) using the highest licensed dose had subtherapeutic levels (<200 pmol/L). Older women (≥50 y) and patch users were more likely to have low levels (odds ratio 1.77, 95% confidence interval 1.22-2.62, P = 0.003; and odds ratio 1.51, 95% confidence interval 1.18-1.95, P = 0.001, respectively)., Conclusions: The reference interval for perimenopausal and postmenopausal women using on-label and off-label doses of transdermal estradiol in the real world is wide, and there is considerable interindividual variation. The number of estradiol users with low estradiol levels (<200 pmol/L) is higher than previously recognized. Measurement of serum estradiol can be helpful to identify women who may benefit from an off-label dose. Dose customization is key to ensure that all women can reap the benefits of HT., Competing Interests: Financial disclosure/conflicts of interest: Lynsey McColl has an ongoing relationship with Newson Health Ltd, via her company Select Statistical Services Ltd providing statistical analysis and support as a consultant. The other authors have nothing to disclose., (Copyright © 2024 by The Menopause Society.)

The burden of uterine cancer is growing and, in the US and UK, mortality rates are poorest among black women. Early detection of these cancers is critical and poor performance of ultrasound in black women may contribute to adverse outcomes. Limited data on this topic are available from Africa. We assessed whether a simple DNA methylation test, the WID-qEC, enables detection of all epithelial uterine (endometrial and cervical) cancers in women presenting with abnormal uterine bleeding (AUB) in Ghana. Among 118 women ≥40 years presenting with AUB, 106 consented to the study and a cervicovaginal sample was obtained for WID-qEC testing. Subsequent to ultrasound assessment 102 women had a cervical or endometrial biopsy. Histopathology, ultrasound and WID-qEC testing were analyzed and compared. Among the 102 volunteers, 8 and 15 were diagnosed with endometrial and cervical cancer (EC and CC), respectively. The receiver operating characteristic (ROC) area under the curve (AUC) was 0.56 (95% confidence interval [CI] 0.25-0.86) for sonographic endometrial thickness (ET) and 0.98 (95% CI 0.94-1.00) for the WID-qEC test. Sensitivity and specificity of the prespecified ET ≥5 mm were 66.7% (95% CI 24.1-94.0) and 22.7 (95% CI 12.0-38.2) and for the prespecified WID-qEC SUM-PMR ≥ 0.3 were 100% (95% CI 56.1-100.0) and 76.1 (96%CI 60.9-86.9), respectively. In addition, 15 CCs were detected by the WID-qEC test [sensitivity 100% (95% CI 74.7-100.0)]. The WID-qEC test accurately detects both EC and CC in black women presenting with AUB., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Purpose: The purpose of this study was to assess the impact of testosterone therapy on mood and cognitive symptoms in perimenopausal and postmenopausal women., Methods: A retrospective cohort study undertaken in a UK specialist menopause clinic. 510 women using hormone replacement therapy (HRT) with persistent low libido, cognitive and negative mood symptoms were treated with testosterone cream or gel for 4 months. A modified version of the Greene Climacteric Scale was used to measure self-reported symptom frequency and severity at baseline and 4 months after initiating treatment., Results: All nine cognitive and mood symptoms significantly improved across the study period. Mood improved more than cognition (47% of women reported an improvement in mood vs. 39% reported an improvement in cognition; 34% vs. 22% decrease in mean symptom scores, respectively). Regarding libido, 52% of women reported an improvement; mean symptom score decreased by 33%., Conclusion: Transdermal testosterone therapy for 4 months was associated with significant improvements in mood and cognition. Further research including randomised clinical trials are needed to establish the long-term efficacy and safety of testosterone for the treatment of menopausal cognitive and psychological symptoms., (© 2024. The Author(s).)

Female genital mutilation is widely recognised as a practice that causes grave, permanent damage to the genital anatomy and function. The literature has documented its impact on physical, sexual, emotional, and mental wellbeing, and this has informed the development of guidelines and recommendations for managing women with female genital mutilation. There has, though, been little, if any, focus on how women with female genital mutilation experience menopause. A literature search did not return any published research on the topic and there are currently no clinical guidelines for managing the menopause in women who have undergone female genital mutilation. This review calls attention to this gap by exploring the clinical implications that the loss of natural hormones has on the vulvovaginal tissues, as well as on urogenital and sexual function. Psychological aspects of the experience of women with female genital mutilation going through menopause are also explored, as well as common barriers they face in accessing adequate healthcare. Finally, we offer a set of recommendations for clinical practice, including the need to improve current care pathways, and potential directions for future research., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

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., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Menopause is a biological process experienced by all people assigned female at birth. A significant number of women experience mental ill health related to the major brain gonadal hormone shifts that occur in their midlife. There is poor understanding and management of the complex mental ill health issues, with the biological brain hormone changes receiving little formal attention. The current treatment advice is to manage this special type of mental ill health in the same way that all mental ill health is managed. This leads to poor outcomes for women and their families. Many women leave the workforce earlier than expected due to menopause-related depression and anxiety, with subsequent loss of salary and superannuation. Others describe being unable to adequately parent or maintain meaningful relationships - all ending in a poor quality of life. We are a large and diverse group of national and international clinicians, lived experience and social community advocates, all working together to innovate the current approaches available for women with menopausal mental ill health. Above all, true innovation is only possible when the woman with lived experience of menopause is front and centre of this debate., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Tissue-specificity for fimbrial fallopian tube ovarian carcinogenesis remains largely unknown in BRCA1 mutation carriers. We aimed to assess the cell autonomous and cell-nonautonomous implications of a germline BRCA1 mutation in the context of cancer immunosurveillance of CD3 - CD56 + natural killer (NK) cells., Methods: Premenopausal BRCA1 mutation carriers versus age-matched non-carriers were compared. Daily urinary 5β-pregnanediol levels were used to determine progesterone metabolomics across an ovarian cycle. Using peripherally acquired NK cells the cell-mediated cytotoxicity of tumor targets (OVCAR-3, K-562) was determined using live cellular impedance (xCELLigence ® ) and multicolor flow cytometry. Hypoxia-inducible factor 1-alpha (HIF-1α) immunohistochemistry of cancer-free fallopian tube specimens allowed a comparison of proximal versus distal portions. Utilizing these findings the role of environmental factors relevant to the fimbrial fallopian tube (progesterone, hypoxia) on NK cell functional activity were studied in an ovarian phase-specific manner., Results: BRCA1 mutation carriers demonstrate a differential progesterone metabolome with a phase-specific reduction of peripheral NK cell functional activity. Progesterone exposure further impairs NK cell-mediated cytotoxicity in a dose-dependent manner, which is reversed with the addition of mifepristone (1.25 µM). The fimbrial fallopian tube demonstrated significantly higher HIF-1α staining, particularly in BRCA1 mutation carriers, reflecting a site-specific 'hypoxic niche'. Exposure to hypoxic conditions (1% O 2 ) can further impair tumor cytotoxicity in high-risk carriers., Conclusions: Phase-specific differential NK cell activity in BRCA1 mutation carriers, either systemically or locally, may favor site-specific pre-invasive carcinogenesis. These cumulative effects across a reproductive lifecycle in high-risk carriers can have a detrimental effect further supporting epidemiological evidence for ovulation inhibition.

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 (n cases  = 27, n controls  = 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 (n cases  = 29, n controls  = 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., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: To detect uterine cancer, simpler and more specific index tests are needed to triage women with abnormal uterine bleeding to a reference histology test. We aimed to compare the performance of conventional index imaging tests with the novel WID-qEC DNA methylation test in terms of detecting the presence or absence of uterine cancers in women with abnormal uterine bleeding., Methods: EPI-SURE was a prospective, observational study that invited all women aged 45 years and older with abnormal uterine bleeding attending a tertiary gynaecological diagnostic referral centre at University College London Hospital (London, UK) to participate. Women meeting these inclusion criteria who consented to participate were included. Pregnant women and those with previous hysterectomy were excluded. A cervicovaginal sample for the WID-qEC test was obtained before standard assessment using index imaging tests (ie, ultrasound) and, where applicable, reference histology (ie, biopsy, hysteroscopy, or both) was performed. Technicians performing the WID-qEC test were masked to the final clinical outcome. The result of the WID-qEC test is defined as the sum of the percentage of fully methylated reference (ΣPMR) of the ZSCAN12 and GYPC regions. Patients were followed until diagnostic resolution or until June 12, 2023. The primary outcome was to assess the real-world performance of the WID-qEC test in comparison with ultrasound with regard to the area under the receiver-operating-characteristic curve (AUC), sensitivity, specificity, and positive and negative predictive values. EPI-SURE is registered with ISRCTN (16815568)., Findings: From June 1, 2022, to Nov 24, 2022, 474 women were deemed eligible to participate. 74 did not accept the invitation to participate, and one woman withdrew after providing consent. 399 women were included in the primary analysis cohort. Based on 603 index imaging tests, 186 (47%) women were recommended for a reference histology test (ie, biopsy, hysteroscopy, or both). 12 women were diagnosed with cancer, 375 were not diagnosed with cancer, and 12 had inconclusive clinical outcomes and were considered study dropouts. 198 reference histology test procedures detected nine cases of cancer and missed two; one further cancer was directly diagnosed at hysterectomy without a previous reference test. The AUC for detection of uterine cancer based on endometrial thickness in mm was 87·2% (95% CI 71·1-100·0) versus 94·3% (84·7-100·0) based on WID-qEC (p=0·48). Endometrial thickness assessment on ultrasound scan was possible in 379 (95%) of the 399 women and a prespecified cut-off of 4·5 mm or more showed a sensitivity of 90·9% (95% CI 62·3-98·4), a specificity of 79·1% (74·5-82·9), a positive predictive value of 11·8% (6·5-20·3), and a negative predictive value of 99·6% (98·0-99·9). The WID-qEC test was possible in 390 (98%) of the 399 patients with a sensitivity of 90·9% (95% CI 62·3-98·4), a specificity of 92·1% (88·9-94·4), a positive predictive value of 25·6% (14·6-41·1), and a negative predictive value of 99·7% (98·3-99·9), when the prespecified threshold of 0·03 ΣPMR or more was applied. When a higher threshold (≥0·3 ΣPMR) was applied the specificity increased to 97·3% (95% CI 95·1-98·5) without a change in sensitivity., Interpretation: The WID-qEC test delivers fast results and shows improved performance compared with a combination of imaging index tests. Triage of women with abnormal uterine bleeding using the WID-qEC test could reduce the number of women requiring histological assessments for identification of potential malignancy and specifically reduce the false positive rate., Funding: The Eve Appeal, Land Tirol, and the European Research Council under the European Union's Horizon 2020 Research and Innovation Programme., Competing Interests: Declaration of interests CH and MW are shareholders of Sola Diagnostics GmbH, which holds an exclusive licence to the intellectual property that protects the commercialisation of the WID-qEC test. DJ is an unpaid advisory board member of the International Society for Ultrasound in Obstetrics and Gynecology. MW received funding from the Land Tirol, The Eve Appeal, and the European Research Council. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

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 W omen's cancer risk ID entification - q uantitative polymerase chain reaction test for E ndometrial C ancer (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., Competing Interests: Chiara HerzogStock and Other Ownership Interests: Sola Diagnostics GmbHPatents, Royalties, Other Intellectual Property: Named inventor on a patent combining epigenetic signatures for detection and risk stratification for breast cancer (WID-qtBC, Women's cancer risk identification—quantitative trait Breast Cancer) Paula Peremiquel-TrillasHonoraria: WerfenTravel, Accommodations, Expenses: Werfen Joan BrunetConsulting or Advisory Role: MSD Oncology, AstraZeneca SpainTravel, Accommodations, Expenses: GlaxoSmithKline Jordi PonceConsulting or Advisory Role: Medtronic, Abex, KCI Xavier Matias-GuiuConsulting or Advisory Role: AstraZeneca, Lilly, Amgen, Janssen, GlaxoSmithKlineTravel, Accommodations, Expenses: GlaxoSmithKline, Roche Laia AlemanyOther Relationship: Integrated DNA Technologies (Inst), Roche (Inst)Uncompensated Relationships: Roche (Inst) Adam RosenthalConsulting or Advisory Role: AbcodiaResearch Funding: Abcodia (Inst) David CibulaConsulting or Advisory Role: AstraZeneca, Sotio, Roche, GlaxoSmithKline, Novocure, Akeso Biopharma, MSD, Mersana Karin SundströmConsulting or Advisory Role: Merck (Inst)Research Funding: Merck (Inst) Laura CostasHonoraria: Roche Sequencing SolutionsOther Relationship: Integrated DNA Technologies (Inst), Roche (Inst)Uncompensated Relationships: Roche (Inst) Martin WidschwendterPatents, Royalties, Other Intellectual Property: I am a shareholder of Sola Diagnostics GmbH, which holds an exclusive license to the intellectual property that protects the commercialization of the WID tests. I am an inventor on pending patents describing the various WID tests. I am a shareholder of BreOva, which aims to license IP for developing and applying cell-free DNA methylation tests. I am an inventor on two pending patents on cell-free DNA methylation analysis for breast and ovarian cancerNo other potential conflicts of interest were reported.

Background: Breast cancer is a leading cause of death in premenopausal women. Progesterone drives expansion of luminal progenitor cells, leading to the development of poor-prognostic breast cancers. However, it is not known if antagonising progesterone can prevent breast cancers in humans. We suggest that targeting progesterone signalling could be a means of reducing features which are known to promote breast cancer formation., Methods: In healthy premenopausal women with and without a BRCA mutation we studied (i) estrogen and progesterone levels in saliva over an entire menstrual cycle (n = 20); (ii) cancer-free normal breast-tissue from a control population who had no family or personal history of breast cancer and equivalently from BRCA1/2 mutation carriers (n = 28); triple negative breast cancer (TNBC) biopsies and healthy breast tissue taken from sites surrounding the TNBC in the same individuals (n = 14); and biopsies of ER+ve/PR+ve stage T1-T2 cancers and healthy breast tissue taken from sites surrounding the cancer in the same individuals (n = 31); and (iii) DNA methylation and DNA mutations in normal breast tissue (before and after treatment) from clinical trials that assessed the potential preventative effects of vitamins and antiprogestins (mifepristone and ulipristal acetate; n = 44)., Results: Daily levels of progesterone were higher throughout the menstrual cycle of BRCA1/2 mutation carriers, raising the prospect of targeting progesterone signalling as a means of cancer risk reduction in this population. Furthermore, breast field cancerization DNA methylation signatures reflective of (i) the mitotic age of normal breast epithelium and (ii) the proportion of luminal progenitor cells were increased in breast cancers, indicating that luminal progenitor cells with elevated replicative age are more prone to malignant transformation. The progesterone receptor antagonist mifepristone reduced both the mitotic age and the proportion of luminal progenitor cells in normal breast tissue of all control women and in 64% of BRCA1/2 mutation carriers. These findings were validated by an alternate progesterone receptor antagonist, ulipristal acetate, which yielded similar results. Importantly, mifepristone reduced both the TP53 mutation frequency as well as the number of TP53 mutations in mitotic-age-responders., Conclusions: These data support the potential usage of antiprogestins for primary prevention of poor-prognostic breast cancers., Trial Registration: Clinical trial 1 Mifepristone treatment prior to insertion of a levonorgestrel releasing intrauterine system for improved bleeding control - a randomized controlled trial, clinicaltrialsregister.eu, 2009-009014-40 ; registered on 20 July 2009. Clinical trial 2 The effect of a progesterone receptor modulator on breast tissue in women with BRCA1 and 2 mutations, clinicaltrials.gov, NCT01898312 ; registered on 07 May 2013. Clinical trial 3 A pilot prevention study of the effects of the anti- progestin Ulipristal Acetate (UA) on surrogate markers of breast cancer risk, clinicaltrialsregister.eu, 2015-001587-19 ; registered on 15 July 2015., (© 2022. The Author(s).)

Transabdominal cerclage (TAC) is a recognised treatment for recurrent spontaneous late miscarriage or preterm birth due to cervical weakness. This can be performed via an open procedure before and during pregnancy, or a laparoscopic technique preconception. Complications include cerclage failure and suture migration. We present a case highlighting these complications where laparoscopic removal of an open TAC and replacement led to two successful term deliveries. A woman in her thirties with a fibroid uterus, adenomyosis and a history of three spontaneous mid-trimester losses, had an open TAC at 13 weeks of gestation. Preterm premature rupture of the membranes occurred shortly after and at 18 weeks of gestation she underwent surgical evacuation of the uterus. Subsequent hysteroscopy confirmed migration of the cerclage through the cervical canal. We demonstrate the application of endoscopic gynaecological surgery to remove and replace the TAC with two successful term births by Caesarean section in the ensuing pregnancies., Competing Interests: Competing interests: MH has received educational expenses from Medtronic Plc and Olympus. ALD, ES and DR report no conflict of interest., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

The vast majority of epithelial ovarian cancer arises from tissues that are embryologically derived from the Müllerian Duct. Here, we demonstrate that a DNA methylation signature in easy-to-access Müllerian Duct-derived cervical cells from women with and without ovarian cancer (i.e. referred to as the Women's risk IDentification for Ovarian Cancer index or WID-OC-index) is capable of identifying women with an ovarian cancer in the absence of tumour DNA with an AUC of 0.76 and women with an endometrial cancer with an AUC of 0.81. This and the observation that the cervical cell WID-OC-index mimics the epigenetic program of those cells at risk of becoming cancerous in BRCA1/2 germline mutation carriers (i.e. mammary epithelium, fallopian tube fimbriae, prostate) further suggest that the epigenetic misprogramming of cervical cells is an indicator for cancer predisposition. This concept has the potential to advance the field of risk-stratified cancer screening and prevention., (© 2022. The Author(s).)

Preventive population genomics offers the prospect of population stratification for targeting screening and prevention and tailoring care to those at greatest risk. Within cancer, this approach is now within reach, given our expanding knowledge of its heritable components, improved ability to predict risk, and increasing availability of effective preventive strategies. Advances in technology and bioinformatics has made population-testing technically feasible. The BRCA model provides 30 years of insight and experience of how to conceive of and construct care and serves as an initial model for preventive population genomics. Population-based BRCA-testing in the Jewish population is feasible, acceptable, reduces anxiety, does not detrimentally affect psychological well-being or quality of life, is cost-effective and is now beginning to be implemented. Population-based BRCA-testing and multigene panel testing in the wider general population is cost-effective for numerous health systems and can save thousands more lives than the current clinical strategy. There is huge potential for using both genetic and non-genetic information in complex risk prediction algorithms to stratify populations for risk adapted screening and prevention. While numerous strides have been made in the last decade several issues need resolving for population genomics to fulfil its promise and potential for maximizing precision prevention. Healthcare systems need to overcome significant challenges associated with developing delivery pathways, infrastructure expansion including laboratory services, clinical workforce training, scaling of management pathways for screening and prevention. Large-scale real world population studies are needed to evaluate context specific population-testing implementation models for cancer risk prediction, screening and prevention., Competing Interests: Disclosures R.M. declares research funding from the British Gynaecological Cancer Society, Barts & the London Charity, Rosetrees Trust and Eve Appeal outside this work, an honorarium for grant review from Israel National Institute for Health Policy Research and honorarium for advisory board membership from Astrazeneca/MSD. R.M. is supported by an NHS Innovation Accelerator (NIA) Fellowship for population testing., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The composition of the microbiome plays an important role in human health and disease. Whether there is a direct association between the cervicovaginal microbiome and the host's epigenome is largely unexplored., Results: Here we analyzed a total of 448 cervicovaginal smear samples and studied both the DNA methylome of the host and the microbiome using the Illumina EPIC array and next-generation sequencing, respectively. We found that those CpGs that are hypo-methylated in samples with non-lactobacilli (O-type) dominating communities are strongly associated with gastrointestinal differentiation and that a signature consisting of 819 CpGs was able to discriminate lactobacilli-dominating (L-type) from O-type samples with an area under the receiver operator characteristic curve (AUC) of 0.84 (95% CI = 0.77-0.90) in an independent validation set. The performance found in samples with more than 50% epithelial cells was further improved (AUC 0.87) and in women younger than 50 years of age was even higher (AUC 0.91). In a subset of 96 women, the buccal but not the blood cell DNA showed the same trend as the cervicovaginal samples in discriminating women with L- from O-type cervicovaginal communities., Conclusions: These findings strongly support the view that the epithelial epigenome plays an essential role in hosting specific microbial communities.

The European Collaborative on Personalized Early Detection and Prevention of Breast Cancer (ENVISION) brings together several international research consortia working on different aspects of the personalized early detection and prevention of breast cancer. In a consensus conference held in 2019, the members of this network identified research areas requiring development to enable evidence-based personalized interventions that might improve the benefits and reduce the harms of existing breast cancer screening and prevention programmes. The priority areas identified were: 1) breast cancer subtype-specific risk assessment tools applicable to women of all ancestries; 2) intermediate surrogate markers of response to preventive measures; 3) novel non-surgical preventive measures to reduce the incidence of breast cancer of poor prognosis; and 4) hybrid effectiveness-implementation research combined with modelling studies to evaluate the long-term population outcomes of risk-based early detection strategies. The implementation of such programmes would require health-care systems to be open to learning and adapting, the engagement of a diverse range of stakeholders and tailoring to societal norms and values, while also addressing the ethical and legal issues. In this Consensus Statement, we discuss the current state of breast cancer risk prediction, risk-stratified prevention and early detection strategies, and their implementation. Throughout, we highlight priorities for advancing each of these areas.

Background: Various factors-including age, family history, inflammation, reproductive factors, and tubal ligation-modulate the risk of ovarian cancer. In this study, our aim was to establish whether women with, or at risk of developing, ovarian cancer have an imbalanced cervicovaginal microbiome., Methods: We did a case-control study in two sets of women aged 18-87 years in the Czech Republic, Germany, Italy, Norway, and the UK. The ovarian cancer set comprised women with epithelial ovarian cancer and controls (both healthy controls and those diagnosed with benign gynaecological conditions). The BRCA set comprised women with a BRCA1 mutation but without ovarian cancer and controls who were wild type for BRCA1 and BRCA2 (both healthy controls and those with benign gynaecological conditions). Cervicovaginal samples were gathered from all participants with the ThinPrep system and then underwent 16S rRNA gene sequencing. For each sample, we calculated the proportion of lactobacilli species (ie, Lactobacillus crispatus, Lactobacillus iners, Lactobacillus gasseri, and Lactobacillus jensenii), which are essential for the generation of a protective low vaginal pH, in the cervicovaginal microbiota. We grouped samples into those in which lactobacilli accounted for at least 50% of the species present (community type L) and those in which lactobacilli accounted for less than 50% of the species present (community type O). We assessed the adjusted association between BRCA1 status and ovarian cancer status and cervicovaginal microbiota community type, using a logistic regression model with a bias reduction method., Findings: Participants were recruited between Jan 2, 2016, and July 21, 2018. The ovarian cancer set (n=360) comprised 176 women with epithelial ovarian cancer, 115 healthy controls and 69 controls with benign gynaecological conditions. The BRCA set (n=220) included 109 women with BRCA1 mutations, 97 healthy controls wild type for BRCA1 and BRCA2 and 14 controls with a benign gynaecological condition wild type for BRCA1 and BRCA2. On the basis of two-dimensional density plots, receiver-operating characteristic curve analysis, and age thresholds used previously, we divided the cohort into those younger than 50 years and those aged 50 years or older. In the ovarian cancer set, women aged 50 years or older had a higher prevalence of community type O microbiota (81 [61%] of 133 ovarian cancer cases and 84 [59%] of 142 healthy controls) than those younger than 50 years (23 [53%] of 43 cases and 12 [29%] of 42 controls). In the ovarian cancer set, women younger than 50 years with ovarian cancer had a significantly higher prevalence of community type O microbiota than did age-matched controls under a logistic regression model with bias correction (odds ratio [OR] 2·80 [95% CI 1·17-6·94]; p=0·020). In the BRCA set, women with BRCA1 mutations younger than 50 years were also more likely to have community type O microbiota than age-matched controls (OR 2·79 [95% CI 1·25-6·68]; p=0·012), after adjustment for pregnancy (ever). This risk was increased further if more than one first-degree family member was affected by any cancer (OR 5·26 [95% CI 1·83-15·30]; p=0·0022). In both sets, we noted that the younger the participants, the stronger the association between community type O microbiota and ovarian cancer or BRCA1 mutation status (eg, OR for community type O for cases aged <40 years in the ovarian cancer set 7·00 [95% CI 1·27-51·44], p=0·025; OR for community type O for BRCA1 mutation carriers aged <35 years in the BRCA set 4·40 [1·14-24·36], p=0·031)., Interpretation: The presence of ovarian cancer, or factors known to affect risk for the disease (ie, age and BRCA1 germline mutations), were significantly associated with having a community type O cervicovaginal microbiota. Whether re-instatement of a community type L microbiome by using, for example, vaginal suppositories containing live lactobacilli, would alter the microbiomial composition higher up in the female genital tract and in the fallopian tubes (the site of origin of high-grade serous ovarian cancer), and whether such changes could translate into a reduced incidence of ovarian cancer, needs to be investigated., Funding: EU Horizon 2020 Research and Innovation Programme, EU Horizon 2020 European Research Council Programme, and The Eve Appeal., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Cancer risk assessment should stratify screening and enable preventive health interventions based on individuals' risk of developing cancer. Studies are underway to develop epigenetic tests, including trials investigating women's risk of female-specific cancers., Objective: Given potential consequences for quality of life and care, women considering such assessment need to be able to make a fully informed choice. It is currently unknown what information they require., Method: We conducted 4 focus groups with 25 women (aged 30-65 years) to explore what they want to know about epigenetic cancer risk assessment, how they evaluate its usefulness, and how they would like to be informed about their risk. Independent coders categorised paraphrases based on transcribed recordings of the group discussions to enable a summarising text analysis., Results: The women in the study wanted to understand how the epigenetic approach is different from established genomic tests, how epigenetic changes relate to cancer, and whether the test enables monitoring of one's cancer risk (n = 11). Furthermore, they desired information about their basic cancer risks (n = 11), about the quality of the assessment (n = 9), and about measures to deal with a risk result (n = 11)., Conclusions: Informed consent in epigenetic cancer risk assessments depends on whether basic cancer risks, uncertainties of testing, and effects of tests on care management are transparently communicated prior to testing. These requirements are not limited to epigenetic testing. Accordingly, physicians and health authorities will have to provide multi-layered information when counselling women on cancer risk assessment., (© 2019 S. Karger AG, Basel.)

The incidence of cancer is continuing to rise and risk-tailored early diagnostic and/or primary prevention strategies are urgently required. The ideal risk-predictive test should: integrate the effects of both genetic and nongenetic factors and aim to capture these effects using an approach that is both biologically stable and technically reproducible; derive a score from easily accessible biological samples that acts as a surrogate for the organ in question; and enable the effectiveness of risk-reducing measures to be monitored. Substantial evidence has accumulated suggesting that the epigenome and, in particular, DNA methylation-based tests meet all of these requirements. However, the development and implementation of DNA methylation-based risk-prediction tests poses considerable challenges. In particular, the cell type specificity of DNA methylation and the extensive cellular heterogeneity of the easily accessible surrogate cells that might contain information relevant to less accessible tissues necessitates the use of novel methods in order to account for these confounding issues. Furthermore, the engagement of the scientific community with health-care professionals, policymakers and the public is required in order to identify and address the organizational, ethical, legal, social and economic challenges associated with the routine use of epigenetic testing.

Background: Monitoring treatment and early detection of fatal breast cancer (BC) remains a major unmet need. Aberrant circulating DNA methylation (DNAme) patterns are likely to provide a highly specific cancer signal. We hypothesized that cell-free DNAme markers could indicate disseminated breast cancer, even in the presence of substantial quantities of background DNA., Methods: We used reduced representation bisulfite sequencing (RRBS) of 31 tissues and established serum assays based on ultra-high coverage bisulfite sequencing in two independent prospective serum sets (n = 110). The clinical use of one specific region, EFC#93, was validated in 419 patients (in both pre- and post-adjuvant chemotherapy samples) from SUCCESS (Simultaneous Study of Gemcitabine-Docetaxel Combination adjuvant treatment, as well as Extended Bisphosphonate and Surveillance-Trial) and 925 women (pre-diagnosis) from the UKCTOCS (UK Collaborative Trial of Ovarian Cancer Screening) population cohort, with overall survival and occurrence of incident breast cancer (which will or will not lead to death), respectively, as primary endpoints., Results: A total of 18 BC specific DNAme patterns were discovered in tissue, of which the top six were further tested in serum. The best candidate, EFC#93, was validated for clinical use. EFC#93 was an independent poor prognostic marker in pre-chemotherapy samples (hazard ratio [HR] for death = 7.689) and superior to circulating tumor cells (CTCs) (HR for death = 5.681). More than 70% of patients with both CTCs and EFC#93 serum DNAme positivity in their pre-chemotherapy samples relapsed within five years. EFC#93-positive disseminated disease in post-chemotherapy samples seems to respond to anti-hormonal treatment. The presence of EFC#93 serum DNAme identified 42.9% and 25% of women who were diagnosed with a fatal BC within 3-6 and 6-12 months of sample donation, respectively, with a specificity of 88%. The sensitivity with respect to detecting fatal BC was ~ 4-fold higher compared to non-fatal BC., Conclusions: Detection of EFC#93 serum DNAme patterns offers a new tool for early diagnosis and management of disseminated breast cancers. Clinical trials are required to assess whether EFC#93-positive women in the absence of radiological detectable breast cancers will benefit from anti-hormonal treatment before the breast lesions become clinically apparent.