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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. 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. 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). 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. EU Horizon 2020 Research and Innovation Programme, EU Horizon 2020 European Research Council Programme, and The Eve Appeal.

The advent of tirzepatide has transformed obesity care; yet, real-world weight loss outcomes necessarily depend on patient engagement with behavioral support. Digital platforms offering coaching, self-monitoring, and automated feedback have the potential to further augment pharmacological efficacy. The aim of the study is to examine associations between digital engagement and weight loss outcomes among adults prescribed tirzepatide in routine care over 12 months and to identify baseline correlates of engagement. In this retrospective cohort study, we included adults (18-75 years; BMI ≥30 or ≥27.5 kg/m with comorbidities) who initiated tirzepatide between February 2024 and August 2025 via a UK digital weight loss service. Engagement was defined by all 3: attendance at ≥1 coaching session AND ≥1 weekly weight log AND ≥1 app login over 12 months. Percent weight loss was analyzed at months 2, 4, 6, 8, 10, and 12 using a mixed model repeated measures adjusted for age, sex, baseline BMI, and comorbidities. Time-to-event analyses (Kaplan-Meier) assessed attainment of ≥5%, ≥10%, ≥15%, and ≥20% weight loss thresholds. Multivariable logistic regression identified correlates of engagement, reporting odds ratios (ORs) per decade of age and per 5 kg/m BMI. Among 126,553 participants, 6746 (5.3%) were maximally engaged. Cohort demographics were a mean age of 42.3 (SD 12.4) years, 78.9% (99,905/126,553) female, and a mean BMI of 35.3 (SD 6.2) kg/m . Engaged users achieved greater adjusted weight loss at month 12 (-22.9%, 95% CI -23.2 to -22.6) versus nonengaged users (-17.5%, 95% CI -17.7 to -17.4), an absolute difference of 5.3 percentage points (P<.001; Cohen d=0.54). Differences emerged by month 2 (-7.4% vs -6.4%; P<.001) and widened steadily. Engaged participants reached all clinically significant weight loss thresholds faster (5%-20%; log-rank P<.001), and engaged participants were nearly 3 times more likely to achieve ≥20% weight loss compared to nonengaged participants (1079/6746, 16% vs 6710/119,807, 5.6%; risk ratio 2.88; P<.001). Older age (OR 1.18 per decade, 95% CI 1.15-1.20; P<.001), higher BMI (OR 1.14 per 5 kg/m , 95% CI 1.12-1.16; P<.001), and the presence of polycystic ovary syndrome (OR 1.59, 95% CI 1.45-1.74; P<.001) or fatty liver disease (OR 1.52, 95% CI 1.32-1.76; P<.001) correlated with engagement. Male sex (OR 0.86, 95% CI 0.81-0.92; P<.001) and diabetes (OR 0.83, 95% CI 0.73-0.95; P=.009) were associated with lower engagement. Digital engagement was associated with substantially greater tirzepatide-associated weight loss in real-world practice. Integrating structured digital support with pharmacotherapy represents a promising strategy for optimizing obesity management.

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. Most ovarian cancers originate from cells originally derived from Müllerian Duct cells. Here, the authors show that the methylation profile of Müllerian Duct cells isolated from cervical samples can predict whether a woman has cervical cancer.

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. 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). 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. 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. The Eve Appeal, Land Tirol, and the European Research Council under the European Union's Horizon 2020 Research and Innovation Programme

Background Despite a myriad of attempts in the last three decades to diagnose ovarian cancer (OC) earlier, this clinical aim still remains a significant challenge. Aberrant methylation patterns of linked CpGs analyzed in DNA fragments shed by cancers into the bloodstream (i.e. cell-free DNA) can provide highly specific signals indicating cancer presence. Methods We analyzed 699 cancerous and non-cancerous tissues using a methylation array or reduced representation bisulfite sequencing to discover the most specific OC methylation patterns. A three-DNA-methylation-serum-marker panel was developed using targeted ultra-high coverage bisulfite sequencing in 151 women and validated in 250 women with various conditions, particularly in those associated with high CA125 levels (endometriosis and other benign pelvic masses), serial samples from 25 patients undergoing neoadjuvant chemotherapy, and a nested case control study of 172 UKCTOCS control arm participants which included serum samples up to two years before OC diagnosis. Results The cell-free DNA amount and average fragment size in the serum samples was up to ten times higher than average published values (based on samples that were immediately processed) due to leakage of DNA from white blood cells owing to delayed time to serum separation. Despite this, the marker panel discriminated high grade serous OC patients from healthy women or patients with a benign pelvic mass with specificity/sensitivity of 90.7% (95% confidence interval [CI] = 84.3–94.8%) and 41.4% (95% CI = 24.1–60.9%), respectively. Levels of all three markers plummeted after exposure to chemotherapy and correctly identified 78% and 86% responders and non-responders (Fisher’s exact test, p  = 0.04), respectively, which was superior to a CA125 cut-off of 35 IU/mL (20% and 75%). 57.9% (95% CI 34.0–78.9%) of women who developed OC within two years of sample collection were identified with a specificity of 88.1% (95% CI = 77.3–94.3%). Sensitivity and specificity improved further when specifically analyzing CA125 negative samples only (63.6% and 87.5%, respectively). Conclusions Our data suggest that DNA methylation patterns in cell-free DNA have the potential to detect a proportion of OCs up to two years in advance of diagnosis and may potentially guide personalized treatment. The prospective use of novel collection vials, which stabilize blood cells and reduce background DNA contamination in serum/plasma samples, will facilitate clinical implementation of liquid biopsy analyses.

The exact timing and contribution of epigenetic reprogramming to carcinogenesis are unclear. Women harbouring BRCA1/2 mutations demonstrate a 30–40-fold increased risk of high-grade serous extra-uterine Müllerian cancers (HGSEMC), otherwise referred to as ‘ovarian carcinomas’, which frequently develop from fimbrial cells but not from the proximal portion of the fallopian tube. Here we compare the DNA methylome of the fimbrial and proximal ends of the fallopian tube in BRCA1/2 mutation carriers and non-carriers. We show that the number of CpGs displaying significant differences in methylation levels between fimbrial and proximal fallopian tube segments are threefold higher in BRCA mutation carriers than in controls, correlating with overexpression of activation-induced deaminase in their fimbrial epithelium. The differentially methylated CpGs accurately discriminate HGSEMCs from non-serous subtypes. Epigenetic reprogramming is an early pre-malignant event integral to BRCA1/2 mutation-driven carcinogenesis. Our findings may provide a basis for cancer-preventative strategies. Women with germline variants in BRCA genes are predisposed to ovarian cancer. In this study, the authors demonstrate that fimbrial tissue from the ovary, the site of ovarian cancer, in BRCA mutant carriers contains marked DNA methylation changes compared with the proximal region of the ovary.

Background Menopausal transition is a period of psychological vulnerability, yet suicidality remains underassessed. Hormone replacement therapy (HRT) may influence mood symptoms, but its mental health effects – particularly regarding suicidality – are poorly understood. Aims To evaluate changes in depressive symptoms, menopause-related distress and suicidality among menopausal women attending a specialist clinic, and explore whether outcomes differed across HRT regimens and baseline risk factors. Method We analysed routinely collected data from 957 women attending a UK menopause clinic. All participants received some form of treatment following their initial consultation. Participants completed the Patient Health Questionnaire-9 (PHQ-9) and Menopause Depression Rating Scale (MENO-D) at baseline and follow-up (2–6 months later). Mixed-design analyses of variance assessed changes over time, including interaction effects for HRT type and baseline risk factors (body mass index (BMI), smoking, suicidality, antidepressant use). Results Depressive symptoms and menopause-related psychological distress significantly declined over time (around 46% reduction on average). The largest improvements were observed among women receiving oestrogen–progesterone–testosterone combinations, although similar gains were also seen in oestrogen–progesterone and oestrogen–testosterone groups. Suicidality (PHQ-9 item 9) decreased by 92% among those with baseline ideation, but this was not moderated by HRT type. Self-worth (MENO-D item 4) also improved, but similarly showed no significant moderation by HRT regimen. Higher BMI was associated with worse baseline mental health, but did not moderate treatment outcomes. Conclusions Combined HRT, including formulations with testosterone, was associated with substantial improvements in mental health outcomes. Suicidality was a distinct symptom profile, often underdetected by general depression scores. However, findings are exploratory and should be interpreted cautiously because of the lack of a control group, observational design and small sample sizes in some subgroups. These results highlight the need for menopause-sensitive mental health assessments and integration of psychological screening into routine menopausal care.

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.

Breast, ovarian and endometrial cancers cause significant morbidity and mortality. Despite the presence of existing screening, diagnostic and treatment modalities, they continue to pose considerable unsolved challenges. Overdiagnosis is a growing problem in breast cancer screening and neither screening nor early diagnosis of ovarian or endometrial cancer is currently possible. Moreover, treatment of the diversity of these cancers presenting in the clinic is not sufficiently personalized at present. Recent technological advances, including reduced representation bisulfite sequencing, methylation arrays, digital PCR, next-generation sequencing and advanced statistical data analysis, enable the analysis of methylation patterns in cell-free tumor DNA in serum/plasma. Ongoing work is bringing these methods together for the analysis of samples from large clinical trials, which have been collected well in advance of cancer diagnosis. These efforts pave the way for the development of a noninvasive method that would enable us to overcome existing challenges to personalized medicine.