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Recent studies in social endocrinology have explored the effects of social relationships on female reproductive steroid hormones-estradiol and progesterone-investigating whether they are suppressed in partnered and parous women. Results have been mixed for these hormones although evidence is more consistent that partnered women and women with young children have lower levels of testosterone. These studies were sequential to earlier research on men, based on Wingfield's Challenge Hypothesis, which showed that men in committed relationships, or with young children, have lower levels of testosterone than unpartnered men or men with older or no children. The study described here explored associations between estradiol and progesterone with partnership and parity among women from two different ethnicities: South Asian and white British. We hypothesized that both steroid hormones would be lower among partnered and/or parous women with children ≤3 years old, regardless of ethnicity. In this study we analyzed data from 320 Bangladeshi and British women of European origin aged 18 to 50 who participated in two previous studies of reproductive ecology and health. Levels of estradiol and progesterone were assayed using saliva and/or serum samples and the body mass index calculated from anthropometric data. Questionnaires provided other covariates. Multiple linear regressions were used to analyze the data. The hypotheses were not supported. We argue here that, unlike links between testosterone and male social relationships, theoretical foundations for such relationships with female reproductive steroid hormones are lacking, especially given the primary role of these steroids in regulating female reproductive function. Further longitudinal studies are needed to explore the bases of independent relationships between social factors and female reproductive steroid hormones., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: While many aspects of female ovarian function respond to environmental stressors, estradiol (E2) appears less sensitive to stressors than progesterone, except under extreme ecological conditions. However, earlier studies relied on saliva samples, considered less sensitive than blood. Here, we investigated E2 variation among 177 Bangladeshi and UK white women, aged 35-59, using single serum samples. Bangladeshi women either grew up in Sylhet, Bangladesh (exposed to poor sanitation, limited health care, and higher pathogen loads but not poor energy availability), or in the UK., Methods: We collected samples on days 4-6 of the menstrual cycle in menstruating women and on any day for post-menopausal women. Participants included: (i) Bangladeshi sedentees (n = 36), (ii) Bangladeshis who migrated to the UK as adults (n = 52), (iii) Bangladeshis who migrated as children (n = 40), and (iv) UK white women matched for neighborhood residence to the migrants (n = 49). Serum was obtained by venipuncture and analyzed using electrochemiluminescence. We collected anthropometrics and supplementary sociodemographic and reproductive data through questionnaires. We analyzed the data using multivariate regression., Results: E2 levels did not differ between migrant groups after controlling for age, BMI, physical activity, psychosocial stress, parity, and time since last birth (parous women). Paralleling results from salivary E2, serum E2 did not differ among women who experienced varying developmental conditions., Conclusion: Our results reinforce the hypothesis that E2 levels are stable under challenging environmental conditions. Interpopulation variation may only arise under chronic conditions of extreme nutritional scarcity, energy expenditure, and/or high disease burdens., (© 2021 Wiley Periodicals LLC.)

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.

Background and Objectives: Low levels of vitamin D among dark-skinned migrants to northern latitudes and increased risks for associated pathologies illustrate an evolutionary mismatch between an environment of high ultraviolet (UV) radiation to which such migrants are adapted and the low UV environment to which they migrate. Recently, low levels of vitamin D have also been associated with higher risks for contracting COVID-19. South Asians in the UK have higher risk for low vitamin D levels. In this study, we assessed vitamin D status of British-Bangladeshi migrants compared with white British residents and Bangladeshis still living in Bangladesh ('sedentees')., Methodology: The cross-sectional study compared serum vitamin D levels among 149 women aged 35-59, comprising British-Bangladeshi migrants ( n  = 50), white British neighbors ( n  = 54) and Bangladeshi sedentees ( n  = 45). Analyses comprised multivariate models to assess serum levels of 25-hydroxyvitamin D (25(OH)D), and associations with anthropometric, lifestyle, health and migration factors., Results: Vitamin D levels in Bangladeshi migrants were very low: mean 25(OH)D = 32.2 nmol/L ± 13.0, with 29% of migrants classified as deficient (<25 nmol/L) and 94% deficient or insufficient (≤50 nmol/L). Mean levels of vitamin D were significantly lower among British-Bangladeshis compared with Bangladeshi sedentees (50.9 nmol/L ± 13.3, P  < 0.001) and were also lower than in white British women (55.3 nmol/L ± 20.9). Lower levels of vitamin D were associated with increased body mass index and low iron status., Conclusions and Implications: We conclude that lower exposure to sunlight in the UK reduces vitamin D levels in Bangladeshi migrants. Recommending supplements could prevent potentially adverse health outcomes associated with vitamin D deficiency., Lay Summary: Vitamin D deficiency is one example of mismatch between an evolved trait and novel environments. Here we compare vitamin D status of dark-skinned British-Bangladeshi migrants in the UK to Bangladeshis in Bangladesh and white British individuals. Migrants had lower levels of vitamin D and are at risk for associated pathologies., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Foundation for Evolution, Medicine, and Public Health.)

Longitudinal CA125 algorithms are the current basis of ovarian cancer screening. We report on longitudinal algorithms incorporating multiple markers. In the multimodal arm of United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), 50,640 postmenopausal women underwent annual screening using a serum CA125 longitudinal algorithm. Women (cases) with invasive tubo-ovarian cancer (WHO 2014) following outcome review with stored annual serum samples donated in the 5 years preceding diagnosis were matched 1:1 to controls (no invasive tubo-ovarian cancer) in terms of the number of annual samples and age at randomisation. Blinded samples were assayed for serum human epididymis protein 4 (HE4), CA72-4 and anti-TP53 autoantibodies. Multimarker method of mean trends (MMT) longitudinal algorithms were developed using the assay results and trial CA125 values on the training set and evaluated in the blinded validation set. The study set comprised of 1363 (2-5 per woman) serial samples from 179 cases and 181 controls. In the validation set, area under the curve (AUC) and sensitivity of longitudinal CA125-MMT algorithm were 0.911 (0.871-0.952) and 90.5% (82.5-98.6%). None of the longitudinal multi-marker algorithms (CA125-HE4, CA125-HE4-CA72-4, CA125-HE4-CA72-4-anti-TP53) performed better or improved on lead-time. Our population study suggests that longitudinal HE4, CA72-4, anti-TP53 autoantibodies adds little value to longitudinal serum CA125 as a first-line test in ovarian cancer screening of postmenopausal women.

Background: Ovarian cancer has a poor survival rate due to late diagnosis and improved methods are needed for its early detection. Our primary objective was to identify and incorporate additional biomarkers into longitudinal models to improve on the performance of CA125 as a first-line screening test for ovarian cancer., Methods: This case-control study nested within UKCTOCS used 490 serial serum samples from 49 women later diagnosed with ovarian cancer and 31 control women who were cancer-free. Proteomics-based biomarker discovery was carried out using pooled samples and selected candidates, including those from the literature, assayed in all serial samples. Multimarker longitudinal models were derived and tested against CA125 for early detection of ovarian cancer., Results: The best performing models, incorporating CA125, HE4, CHI3L1, PEBP4 and/or AGR2, provided 85.7% sensitivity at 95.4% specificity up to 1 year before diagnosis, significantly improving on CA125 alone. For Type II cases (mostly high-grade serous), models achieved 95.5% sensitivity at 95.4% specificity. Predictive values were elevated earlier than CA125, showing the potential of models to improve lead time., Conclusions: We have identified candidate biomarkers and tested longitudinal multimarker models that significantly improve on CA125 for early detection of ovarian cancer. These models now warrant independent validation.

Objectives: This study examined the association of minority religious identification (Hindu or Muslim) with self-reported stress and psychological symptoms among sedentee and immigrant Bangladeshi women., Methods: Women, aged 35-59 (n = 531) were drawn from Sylhet, Bangladesh and London, England. Muslim immigrants in London and Hindu sedentees in Sylhet represented minority religious identities. Muslim sedentees in Sylhet and Londoners of European descent represented majority religious identities. In bivariate analyses, minority religious identity was examined in relation to self-reported measures of stress, nervous tension, and depressed mood. Logistic regression was applied to examine the relationship between these variables while adjusting for marital status, parity, daily walking, and perceived financial comfort., Results: In bivariate analyses, religious minorities reported more stress than religious majorities in all group comparisons (p < .05), and minority Muslims reported more nervous tension and depressed mood than majority Muslims (p < .05). In logistic regression models, minority Muslims had greater odds of high stress than majority Muslims (OR 2.00, 95% CI 1.18-3.39). Minority Muslims had greater odds of stress (OR 3.05, 95% CI 1.51-6.17) and nervous tension (OR 3.37, 95% CI 1.66-6.87) than majority Londoners. Financial comfort reduced odds of stress and symptoms in all models., Conclusions: Socioeconomic situation, immigration history, and minority ethnicity appear to influence the relationship between religious identity and psychosomatic symptoms in Bangladeshi women. Attention to personal and socioeconomic context is important for research examining the association between religion and mental health., (© 2024 Wiley Periodicals LLC.)

Background: Transvaginal ultrasound and serum CA125 are routinely used for differential diagnosis of pelvic adnexal mass. Use of human epididymis 4 was approved in the United States in 2011. However, there is scarcity of studies evaluating the additional value of human epididymis 4., Objective: The objective of the study was to evaluate the performance characteristics of transvaginal ultrasound, CA125, and human epididymis 4 for differential diagnosis of ovarian cancer in postmenopausal women with adnexal masses., Study Design: This was a cohort study nested within the screen arms of the multicenter randomized controlled trial, United Kingdom Collaborative Trial of Ovarian Cancer Screening, based in England, Wales, and Northern Ireland. In United Kingdom Collaborative Trial of Ovarian Cancer Screening, 48,230 women randomized to transvaginal ultrasound screening and 50,078 to multimodal screening (serum CA125 interpreted by Risk of Ovarian Cancer Algorithm with second line transvaginal ultrasound) underwent the first (prevalence) screen. Women with adnexal lesions and/or persistently elevated risk were clinically assessed and underwent surgery or follow-up for a median of 10.9 years. Banked samples taken within 6 months of transvaginal ultrasound from all clinically assessed women were assayed for human epididymis 4 and CA125. Area under the curve and sensitivity for diagnosing ovarian cancer of multiple penalized logistic regression models incorporating logCA125, log human epididymis 4, age, and simple ultrasound features of the adnexal mass were compared., Results: Of 1590 (158 multimodal, 1432 ultrasound) women with adnexal masses, 78 were diagnosed with ovarian cancer (48 invasive epithelial ovarian, 14 type I, 34 type II; 24 borderline epithelial; 6 nonepithelial) within 1 year of scan. The area under the curve (0.893 vs 0.896; P = .453) and sensitivity (74.4% vs 75.6% ;P = .564) at fixed specificity of 90% of the model incorporating age, ultrasound, and CA125 were similar to that also including human epididymis 4. Both models had high sensitivity for invasive epithelial ovarian (89.6%) and type II (>91%) cancers., Conclusion: Our population cohort study suggests that human epididymis 4 adds little value to concurrent use of CA125 and transvaginal ultrasound in the differential diagnosis of adnexal masses in postmenopausal women., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose To establish the performance of screening with serum cancer antigen 125 (CA-125), interpreted using the risk of ovarian cancer algorithm (ROCA), and transvaginal sonography (TVS) for women at high risk of ovarian cancer (OC) or fallopian tube cancer (FTC). Patients and Methods Women whose estimated lifetime risk of OC/FTC was ≥ 10% were recruited at 42 centers in the United Kingdom and underwent ROCA screening every 4 months. TVS occurred annually if ROCA results were normal or within 2 months of an abnormal ROCA result. Risk-reducing salpingo-oophorectomy (RRSO) was encouraged throughout the study. Participants were observed via cancer registries, questionnaires, and notification by centers. Performance was calculated after censoring 365 days after prior screen, with modeling of occult cancers detected at RRSO. Results Between June 14, 2007, and May 15, 2012, 4,348 women underwent 13,728 women-years of screening. The median follow-up time was 4.8 years. Nineteen patients were diagnosed with invasive OC/FTC within 1 year of prior screening (13 diagnoses were screen-detected and six were occult at RRSO). No symptomatic interval cancers occurred. Ten (52.6%) of the total 19 diagnoses were stage I to II OC/FTC (CI, 28.9% to 75.6%). Of the 13 screen-detected cancers, five (38.5%) were stage I to II (CI, 13.9% to 68.4%). Of the six occult cancers, five (83.3%) were stage I to II (CI, 35.9% to 99.6%). Modeled sensitivity, positive predictive value, and negative predictive value for OC/FTC detection within 1 year were 94.7% (CI, 74.0% to 99.9%), 10.8% (6.5% to 16.5%), and 100% (CI, 100% to 100%), respectively. Seven (36.8%) of the 19 cancers diagnosed < 1 year after prior screen were stage IIIb to IV (CI, 16.3% to 61.6%) compared with 17 (94.4%) of 18 cancers diagnosed > 1 year after screening ended (CI, 72.7% to 99.9%; P < .001). Eighteen (94.8%) of 19 cancers diagnosed < 1 year after prior screen had zero residual disease (with lower surgical complexity, P = .16) (CI, 74.0% to 99.9%) compared with 13 (72.2%) of 18 cancers subsequently diagnosed (CI, 46.5% to 90.3%; P = .09). Conclusion ROCA-based screening is an option for women at high risk of OC/FTC who defer or decline RRSO, given its high sensitivity and significant stage shift. However, it remains unknown whether this strategy would improve survival in screened high-risk women.

Introduction: Associations of endogenous sex hormone levels and all as well as estrogen-receptor (ER)-positive breast cancers are well described. However, studies investigating their association with ER-negative tumours are limited and none use accurate assays such as mass spectrometry., Methods: Within the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), a nested case-control study was undertaken of postmenopausal-women who developed ER-negative (n=92) or ER-positive (n=205) breast cancer after sample donation and 297 (1:1) age-matched controls. Androgens (testosterone and androstenedione) were measured using mass spectrometry and estradiol by extraction radioimmunoassay (RIA). Bioavailable estradiol and testosterone were calculated using the total hormone level and the sex hormone-binding globulin concentration. Subjects were classified according to the quartile range among controls. Logistic regression was used to estimate odds-ratio (OR) and 95% confidence-intervals (CI) of the associations between two factors and breast cancer risk. A separate analysis was done by stratifying the women based on whether they provided their samples less than or more than 2years before diagnosis., Results: Estradiol and free estradiol were significantly higher prior to diagnosis of ER-negative breast cancer compared with controls while androgens and SHBG did not show any difference. Estradiol, free estradiol, free testosterone and SHBG were significantly higher before ER-positive breast cancer diagnosis compared with controls. Women had a twofold increased ER-negative breast cancer risk if estradiol and free estradiol were in the top quartile but not androgens (testosterone and androstenedione) or SHBG. These associations remained significant only when samples closer (median 1.1y before) to diagnosis were analyzed rather than farther from diagnosis (median 2.9y before). Women had a 2.34 (95% CI: 1.21-4.61, p=0.001), 2.21 (95% CI: 1.14-4.38, p=0.001), 2 (95% CI: 1.05-3.89, p=0.005) fold increased ER-positive breast cancer risk if estradiol, free estradiol and free testosterone respectively were in the top quartile. These associations remained significant regardless of whether the samples were collected less than or more than 2years prior to diagnosis., Conclusion: In postmenopausal women increased estrogens but not androgens are associated with ER-negative breast cancer. Previously reported associations of estradiol and free testosterone with ER-positive breast cancer are confirmed. The use of mass spectrometry and sensitive RIA add validity to these findings., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Ovarian cancer has a poor prognosis, with just 40% of patients surviving 5 years. We designed this trial to establish the effect of early detection by screening on ovarian cancer mortality., Methods: In this randomised controlled trial, we recruited postmenopausal women aged 50-74 years from 13 centres in National Health Service Trusts in England, Wales, and Northern Ireland. Exclusion criteria were previous bilateral oophorectomy or ovarian malignancy, increased risk of familial ovarian cancer, and active non-ovarian malignancy. The trial management system confirmed eligibility and randomly allocated participants in blocks of 32 using computer-generated random numbers to annual multimodal screening (MMS) with serum CA125 interpreted with use of the risk of ovarian cancer algorithm, annual transvaginal ultrasound screening (USS), or no screening, in a 1:1:2 ratio. The primary outcome was death due to ovarian cancer by Dec 31, 2014, comparing MMS and USS separately with no screening, ascertained by an outcomes committee masked to randomisation group. All analyses were by modified intention to screen, excluding the small number of women we discovered after randomisation to have a bilateral oophorectomy, have ovarian cancer, or had exited the registry before recruitment. Investigators and participants were aware of screening type. This trial is registered with ClinicalTrials.gov, number NCT00058032., Findings: Between June 1, 2001, and Oct 21, 2005, we randomly allocated 202,638 women: 50,640 (25·0%) to MMS, 50,639 (25·0%) to USS, and 101,359 (50·0%) to no screening. 202,546 (>99·9%) women were eligible for analysis: 50,624 (>99·9%) women in the MMS group, 50,623 (>99·9%) in the USS group, and 101,299 (>99·9%) in the no screening group. Screening ended on Dec 31, 2011, and included 345,570 MMS and 327,775 USS annual screening episodes. At a median follow-up of 11·1 years (IQR 10·0-12·0), we diagnosed ovarian cancer in 1282 (0·6%) women: 338 (0·7%) in the MMS group, 314 (0·6%) in the USS group, and 630 (0·6%) in the no screening group. Of these women, 148 (0·29%) women in the MMS group, 154 (0·30%) in the USS group, and 347 (0·34%) in the no screening group had died of ovarian cancer. The primary analysis using a Cox proportional hazards model gave a mortality reduction over years 0-14 of 15% (95% CI -3 to 30; p=0·10) with MMS and 11% (-7 to 27; p=0·21) with USS. The Royston-Parmar flexible parametric model showed that in the MMS group, this mortality effect was made up of 8% (-20 to 31) in years 0-7 and 23% (1-46) in years 7-14, and in the USS group, of 2% (-27 to 26) in years 0-7 and 21% (-2 to 42) in years 7-14. A prespecified analysis of death from ovarian cancer of MMS versus no screening with exclusion of prevalent cases showed significantly different death rates (p=0·021), with an overall average mortality reduction of 20% (-2 to 40) and a reduction of 8% (-27 to 43) in years 0-7 and 28% (-3 to 49) in years 7-14 in favour of MMS., Interpretation: Although the mortality reduction was not significant in the primary analysis, we noted a significant mortality reduction with MMS when prevalent cases were excluded. We noted encouraging evidence of a mortality reduction in years 7-14, but further follow-up is needed before firm conclusions can be reached on the efficacy and cost-effectiveness of ovarian cancer screening., Funding: Medical Research Council, Cancer Research UK, Department of Health, The Eve Appeal., (Copyright © 2016 Jacobs Menon et al. Open Access article published under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.)

Objective: To assess whether the quality of early childhood environments among different groups of Bangladeshi women, including migrants to the United Kingdom (UK), contributes to variation in ovarian reserve and the rate of reproductive aging in later life., Design: Cross-sectional study., Setting: Not applicable., Patient(s): A total of 179 healthy women volunteers aged 35-59 years were divided into four groups: [1] 36 Bangladeshis living in Sylhet, Bangladesh; [2] 53 Bangladeshis who migrated to the UK as adults; [3] 40 Bangladeshis who migrated to the UK as children aged 0-16 years; and [4] a reference group of 50 women of European origin living in London., Intervention(s): None., Main Outcome Measure(s): Levels of serum antimüllerian hormone, inhibin B, FSH, and E2, and anthropometrics derived from biomarkers; reproductive, demographic, and health variables from structured questionnaires., Result(s): Bangladeshi migrants who moved to the UK as children and European women had a highly significantly larger, age-related ovarian reserve compared with migrant Bangladeshis who had moved to the UK as adults or Bangladeshi women still living in Bangladesh. There were no other significant covariates in the model aside from age and menopausal status., Conclusion(s): The study points to the importance of childhood development in considering variation in ovarian reserve across different ethnic groups. Clinical studies and research in assisted reproductive technology have emphasized the role of genes or race in determining inter-population variation in ovarian reserve. Early life developmental factors should be given due consideration when evaluating inter-group differences in response to assisted reproductive technology., (Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: Cancer screening strategies have commonly adopted single-biomarker thresholds to identify abnormality. We investigated the impact of serial biomarker change interpreted through a risk algorithm on cancer detection rates., Patients and Methods: In the United Kingdom Collaborative Trial of Ovarian Cancer Screening, 46,237 women, age 50 years or older underwent incidence screening by using the multimodal strategy (MMS) in which annual serum cancer antigen 125 (CA-125) was interpreted with the risk of ovarian cancer algorithm (ROCA). Women were triaged by the ROCA: normal risk, returned to annual screening; intermediate risk, repeat CA-125; and elevated risk, repeat CA-125 and transvaginal ultrasound. Women with persistently increased risk were clinically evaluated. All participants were followed through national cancer and/or death registries. Performance characteristics of a single-threshold rule and the ROCA were compared by using receiver operating characteristic curves., Results: After 296,911 women-years of annual incidence screening, 640 women underwent surgery. Of those, 133 had primary invasive epithelial ovarian or tubal cancers (iEOCs). In all, 22 interval iEOCs occurred within 1 year of screening, of which one was detected by ROCA but was managed conservatively after clinical assessment. The sensitivity and specificity of MMS for detection of iEOCs were 85.8% (95% CI, 79.3% to 90.9%) and 99.8% (95% CI, 99.8% to 99.8%), respectively, with 4.8 surgeries per iEOC. ROCA alone detected 87.1% (135 of 155) of the iEOCs. Using fixed CA-125 cutoffs at the last annual screen of more than 35, more than 30, and more than 22 U/mL would have identified 41.3% (64 of 155), 48.4% (75 of 155), and 66.5% (103 of 155), respectively. The area under the curve for ROCA (0.915) was significantly (P = .0027) higher than that for a single-threshold rule (0.869)., Conclusion: Screening by using ROCA doubled the number of screen-detected iEOCs compared with a fixed cutoff. In the context of cancer screening, reliance on predefined single-threshold rules may result in biomarkers of value being discarded., (© 2015 by American Society of Clinical Oncology.)

Despite prevention strategies, cervical cancer remains a significant public health issue. Human papillomavirus plays a critical role in its development, and early detection is vital to improve patient outcomes. The incidence of cervical cancer is projected to rise, necessitating better diagnostic tools. Traditional screening methods like the cytological examination and human papillomavirus testing have limitations in sensitivity and reproducibility. Liquid-based cytology offers some improvements, but the need for more reliable and sensitive techniques persists, particularly for detecting precancerous lesions. Liquid biopsy is a non-invasive method that analyzes cancer-derived products in biofluids like blood, offering potential for real-time monitoring of tumor progression, metastasis, and treatment response. It can be based on detection of circulating tumor cells (CTCs), circulating free DNA (cfDNA), and microRNAs (miRNAs). This review particularly underlines the potential of microRNAs, which are transported by extracellular vesicles. Overall, this article underscores the importance of continued research into non-invasive diagnostic methods like liquid biopsy to enhance cervical cancer screening and treatment monitoring. [ABSTRACT FROM AUTHOR]

Lynch syndrome, one of the most common genetic syndromes predisposing to cancer, is associated with a series of malignant conditions, among which the most frequent is colorectal cancer, but gynecologic cancers (especially endometrial) are also quite common. Despite the significant progress made in understanding this condition over time, there are still aspects in managing this condition that have not demonstrated clear benefits. This article aims to summarize the recommendations of international societies and present the latest developments in managing Lynch syndrome, focusing on gynecologic cancer screening and possible prevention strategies. Advances in genetic testing procedures and discoveries related to the association between oncological pathology frequency and the affected pathogenic variant type will probably lead to personalized medicine focused on the individual patient in the coming years. Although various screening methods for gynecological cancers in patients with Lynch syndrome have been used over time, they have not shown significant survival benefits. This highlights the need for studying and implementing new screening and diagnostic methods, which have been under investigation in recent years and are mentioned in this article. [ABSTRACT FROM AUTHOR]

Purpose: Biomarkers for the early detection of pancreatic cancer are urgently needed. The primary objective of this study was to evaluate whether increased levels of serum CA19-9, CA125, CEACAM1, and REG3A are present before clinical presentation of pancreatic cancer and to assess the performance of combined markers for early detection and prognosis., Experimental Design: This nested case-control study within the UKCTOCS included 118 single and 143 serial serum samples from 154 postmenopausal women who were subsequently diagnosed with pancreatic cancer and 304 matched noncancer controls. Samples were split randomly into independent training and test sets. CA19-9, CA125, CEACAM1, and REG3A were measured using ELISA and/or CLIA. Performance of markers to detect cancers at different times before diagnosis and for prognosis was evaluated., Results: At 95% specificity, CA19-9 (>37 U/mL) had a sensitivity of 68% up to 1 year, and 53% up to 2 years before diagnosis. Combining CA19-9 and CA125 improved sensitivity as CA125 was elevated (>30 U/mL) in approximately 20% of CA19-9-negative cases. CEACAM1 and REG3A were late markers adding little in combined models. Average lead times of 20 to 23 months were estimated for test-positive cases. Prediagnostic levels of CA19-9 and CA125 were associated with poor overall survival (HR, 2.69 and 3.15, respectively)., Conclusions: CA19-9 and CA125 have encouraging sensitivity for detecting preclinical pancreatic cancer, and both markers can be used as prognostic tools. This work challenges the prevailing view that CA19-9 is upregulated late in the course of pancreatic cancer development., (©2014 American Association for Cancer Research.)

Background: In current scenario breast cancer measured as one of the dangerous health issues. An effective therapeutic class of drug known as aromatase inhibitors (AIs) is dominant against estrogen receptorpositive breast cancer. However, there is an urgent need to create target-specific AIs with better anti-breast cancer profiles due to the increased toxicity and adverse effects related to currently existing anti-breast cancer drugs., Objectives: In the present study, we have designed of 100 novel tiazole analogues as aromatase inhibitors their pharmacophoric features were explored., Method: Molecular docking was applied to a series of 4-substituted-1, 2, 3-triazoles containing letrozole for their aromatase inhibitory effects. The aromatase inhibitory activity of the compound in a series varies in the range of (IC 50 = 0.008-31.26 μM). A hydrogen atom positioned at R1 of the triazole ring in compound (01) was responsible for the most potent compound (IC 50 = 0.008 μM) in the series of 28 compounds as compared to letrozole. The self-organizing molecular field study was used to assess the molecular characteristics and biological activities of the compounds. The four models were developed using PLS and MLR methods. The PLS method was good for statistical analysis. The letrozole scaffold-based 100 compounds were designed by selecting an effective pharmacophore responsible for aromatase inhibitory activity. The designed compound was placed on the previous model as a test set, and its IC 50 values were calculated., Result: Hydrogen bonds were established between the potent molecule (01) and the essential residues Met 374 and Arg 115, which were responsible for the aromatase-inhibiting action. Cross-validated q2 (0.6349) & noncross- validated r2 (0.7163) were discovered in the statistical findings as having reliable predictive power. Among 100 designed compounds, seven compounds showed good aromatase inhibitory activities., Conclusion: The additional final SOMFA model created for the interactions between the aromatase and the triazole inhibitors may be helpful for future modification and enhancement of the inhibitors of this crucial enzyme., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Postmenopausal women with elevated serum sex steroids have an increased risk of breast cancer. Most of this risk is believed to be exerted through binding of the sex steroids to their receptors. For the first time, we investigate the association of estrogen receptor (ER) and androgen receptor (AR) serum bioactivity (SB) in addition to hormone levels in samples from women with breast cancer collected before diagnosis. Two hundred postmenopausal women participating in the UK Collaborative Trial of Ovarian Cancer Screening who developed ER-positive breast cancer 0.6-5 years after sample donation were identified and matched to 400 controls. ER and AR bioassays were used to measure ERα, ERβ, and AR SB. Androgen and estrogen levels were measured with immunoassays. Subjects were classified according to quintiles of the respective marker among controls and the associations between SB and hormones with breast cancer risk were determined by logistic regression analysis. ERα and ERβ SB were significantly higher before diagnosis compared with controls, while estrogens showed no difference. Women had a twofold increased breast cancer risk if ERα SB (odds ratio (OR), 2.114; 95% confidence interval (CI), 1.050-4.425; P=0.040) was in the top quintile >2 years before diagnosis or estrone (OR, 2.205; 95% CI, 1.104-4.586; P=0.029) was in the top quintile <2 years before diagnosis. AR showed no significant association with breast cancer while androstenedione (OR, 3.187; 95% CI, 1.738-6.044; P=0.0003) and testosterone (OR, 2.145; 95% CI, 1.256-3.712; P=0.006) were significantly higher compared with controls and showed a strong association with an almost threefold increased breast cancer risk independent of time to diagnosis. This study provides further evidence on the association of androgens and estrogens with breast cancer. In addition, it reports that high ER but not AR SB is associated with increased breast risk >2 years before diagnosis.

Objectives: To evaluate the performance of stool methylated syndecan2 (mSDC2), methylated septin9 (mSEPT9), fecal occult blood test (FOBT), carcinoembryonic antigen (CEA), carbohydrate antigen 125 (CA125) and carbohydrate antigen 199 (CA199) in detecting colorectal neoplasia and adenomas. Methods: Blood-borne CEA, CA125, and CA199 levels were measured by electrochemiluminescence. The SDC2 methylation was detected by Methylation Detection Kit for Human SDC2 Gene (Real time PCR), and the SEPT9 methylation was detected by the Septin9 Gene Methylation Detection Kit based on PCR fluorescent probe assay. The colonoscopy combined with tissue biopsy pathology was used as a validation criterion for colorectal neoplasia. Results: In detecting colorectal neoplasia, the AUCs of mSDC2, FOBT and mSEPT9 were 0.935 (95% CI: 0.915-0.956, P<0.001), 0.824 (95% CI: 0.617-1.000, P<0.001) and 0.671 (95% CI: 0.511-0.831, P<0.001), respectively. The sensitivity of mSDC2, FOBT and mSEPT9 were 100.0%, 66.7% and 40.0%, respectively. But the AUC of CEA, CA125 and CA199 were not statistically significant for colorectal neoplasia (all P>0.05). The combined application of mSEPT9 and mSDC2 showed the best predictive performance (AUC: 0.956, 95% CI: 0.887~1.000). For adenomas, the AUC of FOBT was extremely low (AUC: 0.524, 95% CI: 0.502-0.545, P=0.004). The CEA, CA125, CA199, mSEPT9 and mSDC2 were not statistically significant in detecting adenomas (all P>0.05). Conclusions: For individual tests, FOBT and mSDC2 are relatively better indicators for detecting colorectal neoplasia compared to mSEPT9, CEA, CA125 and CA199. The combined form of mSEPT9 and mSDC2 to detect colorectal neoplasia has good predictive performance. However, none of these indicators demonstrated significant predictive power for detecting adenomas in our study. [ABSTRACT FROM AUTHOR]

Objective: To investigate the relationship between the expression of androgen receptor (AR) and clinical characteristics in breast cancer. Patients and methods: The clinical records of all 432 patients tested for AR in our institution between January 2020 and May 2023 were reviewed. Clinical characteristics, age, menopausal status, tumor node metastasis (TNM) stage, distant metastasis, pathological complete response (pCR), histopathological features histological grade, estrogen receptor (ER), progesterone receptor, Her-2, Ki-67, and molecular subtype were registered for all patients. Results: About 377 (87.27%) of the 432 patients had AR expression. No significant difference in AR expression was found with age, menopausal status, TNM stage of primary tumor, or pCR. AR was positively and significantly associated with the histological grade, and recurrence. The AR expression was significantly related with molecular subtypes, including ER, PR Her-2, Ki67 and molecular subtype. ER (OR = 10.489, 95%CI: 5.470–21.569), PR (OR = 7.690, 95%CI: 3.974–16.129, Her-2 (OR = 10.489, 95%CI: 2.779–23.490 and tumor recurrence (OR = 0.110, 95%CI: 0.031–0.377 were significant independent risk factors affecting AR expression. Conclusions: AR expression can serve as a reliable basis for judging the clinical molecular types and poor prognosis for breast cancer. AR may be a novel biomarker and target in AR-positive breast cancer depending on significant difference in AR expression among different molecular types of breast cancer. [ABSTRACT FROM AUTHOR]

Background: The grim (<10% 5-year) survival rates for pancreatic ductal adenocarcinoma (PDAC) are attributed to its complex intrinsic biology and most often late-stage detection. The overlap of symptoms with benign gastrointestinal conditions in early stage further complicates timely detection. The suboptimal diagnostic performance of carbohydrate antigen (CA) 19–9 and elevation in benign hyperbilirubinaemia undermine its reliability, leaving a notable absence of accurate diagnostic biomarkers. Using a selected patient cohort with benign pancreatic and biliary tract conditions we aimed to develop a data analysis protocol leading to a biomarker signature capable of distinguishing patients with non-specific yet concerning clinical presentations, from those with PDAC. Methods: 539 patient serum samples collected under the Accelerated Diagnosis of neuro Endocrine and Pancreatic TumourS (ADEPTS) study (benign disease controls and PDACs) and the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS, healthy controls) were screened using the Olink Oncology II panel, supplemented with five in-house markers. 16 specialized base-learner classifiers were stacked to select and enhance biomarker performances and robustness in blinded samples. Each base-learner was constructed through cross-validation and recursive feature elimination in a discovery set comprising approximately two thirds of the ADEPTS and UKCTOCS samples and contrasted specific diagnosis with PDAC. Results: The signature which was developed using diagnosis-specific ensemble learning demonstrated predictive capabilities outperforming CA19-9, the only biomarker currently accepted by the FDA and the National Comprehensive Cancer Network guidelines for pancreatic cancer, and other individual biomarkers and combinations in both discovery and held-out validation sets. An AUC of 0.98 (95% CI 0.98–0.99) and sensitivity of 0.99 (95% CI 0.98–1) at 90% specificity was achieved with the ensemble method, which was significantly larger than the AUC of 0.79 (95% CI 0.66–0.91) and sensitivity 0.67 (95% CI 0.50–0.83), also at 90% specificity, for CA19-9, in the discovery set (p = 0.0016 and p = 0.00050, respectively). During ensemble signature validation in the held-out set, an AUC of 0.95 (95% CI 0.91–0.99), sensitivity 0.86 (95% CI 0.68–1), was attained compared to an AUC of 0.80 (95% CI 0.66–0.93), sensitivity 0.65 (95% CI 0.48–0.56) at 90% specificity for CA19-9 alone (p = 0.0082 and p = 0.024, respectively). When validated only on the benign disease controls and PDACs collected from ADEPTS, the diagnostic-specific signature achieved an AUC of 0.96 (95% CI 0.92–0.99), sensitivity 0.82 (95% CI 0.64–0.95) at 90% specificity, which was still significantly higher than the performance for CA19-9 taken as a single predictor, AUC of 0.79 (95% CI 0.64–0.93) and sensitivity of 0.18 (95% CI 0.03–0.69) (p = 0.013 and p = 0.0055, respectively). Conclusion: Our ensemble modelling technique outperformed CA19-9, individual biomarkers and indices developed with prevailing algorithms in distinguishing patients with non-specific but concerning symptoms from those with PDAC, with implications for improving its early detection in individuals at risk. Author summary: Pancreatic ductal adenocarcinoma (PDAC) has one of the lowest 5-year survival rates among cancers, primarily due to its complex biology and late-stage diagnosis. Early symptoms often mimic benign gastrointestinal conditions, complicating timely detection. The standard biomarker, carbohydrate antigen (CA) 19–9, is not reliable due to its suboptimal performance and elevation in benign conditions, highlighting the need for better diagnostic tools. In our study, we aimed to develop a biomarker signature to distinguish between benign pancreatic/biliary conditions and PDAC using serum samples from the Accelerated Diagnosis of neuro Endocrine and Pancreatic Tumours and UK Collaborative Trial of Ovarian Cancer Screening studies. We screened 539 patient serum samples with state-of-the-art biomarker panels and developed a robust predictive signature by applying specialized machine learning methods. This new signature significantly outperformed CA19-9 and other panels reported in the literature. Our findings suggest that this new biomarker signature can improve early detection of PDAC in patients with ambiguous clinical symptoms, potentially leading to better outcomes for those at risk. [ABSTRACT FROM AUTHOR]

Manuka honey (MH) exhibits potential antitumor activity in preclinical models of a number of human cancers. Treatment in vitro with MH at concentrations ranging from 0.3 to 5.0% (w/v) led to significant dose-dependent inhibition of proliferation of human breast cancer MCF-7 cells, but anti-proliferative effects of MH were less pronounced in MDA-MB-231 breast cancer cells. Effects of MH were also tested on non-malignant human mammary epithelial cells (HMECs) at 2.5% w/v, and it was found that MH reduced the proliferation of MCF-7 cells but not that of HMECs. Notably, the antitumor activity of MH was in the range of that exerted by treatment of MCF-7 cells with the antiestrogen tamoxifen. Further, MH treatment stimulated apoptosis of MCF-7 cells in vitro, with most cells exhibiting acute and significant levels of apoptosis that correlated with PARP activation. Additionally, the effects of MH induced the activation of AMPK and inhibition of AKT/mTOR downstream signaling. Treatment of MCF7 cells with increased concentrations of MH induced AMPK phosphorylation in a dose-dependent manner that was accompanied by inhibition of phosphorylation of AKT and mTOR downstream effector protein S6. In addition, MH reduced phosphorylated STAT3 levels in vitro, which may correlate with MH and AMPK-mediated anti-inflammatory properties. Further, in vivo, MH administered alone significantly inhibited the growth of established MCF-7 tumors in nude mice by 84%, resulting in an observable reduction in tumor volume. Our findings highlight the need for further research into the use of natural compounds, such as MH, for antitumor efficacy and potential chemoprevention and investigation of molecular pathways underlying these actions. [ABSTRACT FROM AUTHOR]

Aim: The prognosis of high-risk, locally advanced cervical cancer (LACC) remains poor following concurrent chemoradiotherapy (CCRT). We investigated whether the effect of CCRT can be enhanced by programmed cell death protein 1 (PD-1) inhibitor. Methods: A retrospective cohort study was conducted to compare the efficacy and safety of CCRT group (n = 82) and PD-1 inhibitor plus CCRT group (n = 70). Results: Compared with the CCRT group, the PD-1 inhibitor plus CCRT group had significantly higher objective response rate, median progression-free survival, leukopenia and fatigue. The addition of PD-1 inhibitor to CCRT showed a favorable trend in overall survival without statistical significance. Conclusion: PD-1 inhibitor plus CCRT presented a significant survival benefit and a manageable safety profile in high-risk LACC. Article highlights The prognosis of high-risk locally advanced cervical cancer (LACC) (FIGO 2014 stage IB2–IIB with positive para-aortic lymph nodes and stage IIIA–IVA) remains poor after concurrent chemoradiotherapy (CCRT). Programmed death ligand-1 (PD-1) inhibitors have shown efficacy in patients with cervical cancer, and whether the effect of CCRT can be enhanced by PD-1 inhibitor is a hot topic in high-risk LACC research. This retrospective cohort study was conducted to compare the efficacy and safety of CCRT alone (n = 82 patients) and PD-1 inhibitor plus CCRT (n = 70 patients). Compared with the CCRT-alone group, the PD-1 inhibitor plus CCRT group had a significantly higher objective response rate and median progression-free survival (PFS) but also higher incidence of leukopenia and fatigue. The addition of PD-1 inhibitor to CCRT showed a favorable trend in overall survival (OS) without statistical significance. Compared with the PD-L1-negative subgroup, PFS (p = 0.002) and OS (p = 0.032) in the PD-L1-positive subgroup were significantly improved. Multivariate analysis showed that total radiotherapy duration >56 days (hazard ratio [HR]: 4.799), FIGO 2009 stage IVA (HR: 6.464), and combined PD-1 inhibitor (HR: 0.324) were independent determinants of disease progression. PD-1 inhibitor plus CCRT presented a significant survival benefit and a manageable safety profile in high-risk LACC. It can be considered as a new alternative treatment for this patient population. The effects of different timing of PD-1 inhibitor combination with radiotherapy and different duration of PD-1 inhibitor maintenance therapy on survival outcomes need to be further explored in future studies. This is an exploratory study that adds to the literature on high-risk LACC and PD-1 inhibitor, prospective studies are needed to determine the value of PD-1 inhibitor plus CCRT for high-risk LACC. [ABSTRACT FROM AUTHOR]

Metabolomic age models have been proposed for the study of biological aging, however, they have not been widely validated. We aimed to assess the performance of newly developed and existing nuclear magnetic resonance spectroscopy (NMR) metabolomic age models for prediction of chronological age (CA), mortality, and age‐related disease. Ninety‐eight metabolic variables were measured in blood from nine UK and Finnish cohort studies (N ≈31,000 individuals, age range 24–86 years). We used nonlinear and penalized regression to model CA and time to all‐cause mortality. We examined associations of four new and two previously published metabolomic age models, with aging risk factors and phenotypes. Within the UK Biobank (N ≈102,000), we tested prediction of CA, incident disease (cardiovascular disease (CVD), type‐2 diabetes mellitus, cancer, dementia, and chronic obstructive pulmonary disease), and all‐cause mortality. Seven‐fold cross‐validated Pearson's r between metabolomic age models and CA ranged between 0.47 and 0.65 in the training cohort set (mean absolute error: 8–9 years). Metabolomic age models, adjusted for CA, were associated with C‐reactive protein, and inversely associated with glomerular filtration rate. Positively associated risk factors included obesity, diabetes, smoking, and physical inactivity. In UK Biobank, correlations of metabolomic age with CA were modest (r = 0.29–0.33), yet all metabolomic model scores predicted mortality (hazard ratios of 1.01 to 1.06/metabolomic age year) and CVD, after adjustment for CA. While metabolomic age models were only moderately associated with CA in an independent population, they provided additional prediction of morbidity and mortality over CA itself, suggesting their wider applicability. [ABSTRACT FROM AUTHOR]

Cervical cancer (CC) is one of the deadliest gynecological cancers worldwide. Human papillomavirus is the main etiological agent responsible for the initiation and development of most CC cases. The standard method utilized for CC screening in the global population is the cytological Pap smear test. Despite its effective validity in detecting precancerous lesions and its response to layer stages of this disease, greater screening and diagnostic reliability are needed, as well as an improvement in specificity and sensitivity. In this context, the use of liquid biopsies, like blood, for the isolation of circulating tumor DNA (ctDNA) in CC screening, diagnosis, prognosis, and surveillance could fill the gaps that still exist. In the present review, we aim to study the literature in order to collect knowledge on blood-based liquid biopsy based on descriptions of its precious molecular content and its utilization as a potential tool for CC patients' management. We will mainly focus on the important role of the novel ctDNA and the unique possibilities to additionally use HPV-ctDNA in CC at various stages of clinical application. [ABSTRACT FROM AUTHOR]

Purpose: Carcinoembryonic antigen (CEA) is an important prognostic factor for rectal cancer. This study aims to introduce a novel cutoff point for CEA within the normal range to improve prognosis prediction and enhance patient stratification in rectal cancer patients., Methods: A total of 316 patients with stages I to III rectal cancer who underwent surgical tumor resection were enrolled. The Cox proportional hazards regression model was used to evaluate the impact of preoperative CEA level and other co-variates on overall survival (OS). The Youden Index method was used for CEA optimal cutoff estimation., Results: The mean follow-up period was 46.47 months. In risk-adjusted Cox proportional analysis, higher preoperative CEA levels (HR 1.17, CI 1.131.21; P < 0.001), and T-stage were associated with poor OS. The mean preoperative CEA level was significantly higher in patients with positive lymphovascular invasion (LVI) and perineural invasion (PNI) (CI: 1.06-2.45 and 0.75-2.33, respectively, P < 0.001, t test). Pathologic complete response (pCR) occurred in 71 (22.4%) cases. Patients with pCR had lower levels of preoperative CEA than non-pCR group (P = 0.002, CEA pCR -CEA nonpCR  =  - 1.3; t test). Using Youden Index, the estimated optimal CEA cutoff value for predicting OS was 2.8 ng/mL (sensitivity 90%; specificity 78.5%). Lower preoperative CEA levels predict higher pCR rates, aiding patient stratification and planning., Conclusion: Preoperative CEA may play a role in the prediction of pCR in rectal cancer. Considering the CEA level of 2.8 ng/ml, as a newly defined cutoff point, patients with a worse prognosis can be identified prior to operation. PNI, along with LVI as independent predictors, may be contemplated as prognostic indicators to improve treatment strategies., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

One of the greatest challenges in modern gynecological oncology is ovarian cancer. Despite the numerous studies currently being conducted, it is still sometimes detected at late clinical stages, where the prognosis is unfavorable. One significant contributing factor is the absence of sensitive and specific parameters that could aid in early diagnosis. An ideal screening test, in view of the low incidence of ovarian cancer, should have a sensitivity of greater than 75% and a specificity of at least 99.6%. To enhance sensitivity and specificity, diagnostic panels are being created by combining individual markers. The drive to develop better screening tests for ovarian cancer focuses on modern diagnostic methods based on molecular testing, which in turn aims to find increasingly effective biomarkers. Currently, researchers' efforts are focused on the search for a complementary parameter to those most commonly used that would satisfactorily enhance the sensitivity and specificity of assays. Several biomarkers, including microRNA molecules, autoantibodies, cDNA, adipocytokines, and galectins, are currently being investigated by researchers. This article reviews recent studies comparing the sensitivity and specificity of selected parameters used alone and in combination to increase detection of ovarian cancer at an early stage. [ABSTRACT FROM AUTHOR]

Background: N6-methyladenosine (m6A) is dysregulated in various cancers, including colorectal cancer (CRC). Herein, we assess the diagnostic potential of peripheral blood (PB) m6A levels in CRC. Methods: We collected PB from healthy controls (HCs) and patients with CRC, analyzed PB RNA m6A levels and the expression of m6A-related demethylase genes FTO and ALKBH5, cocultured CRC cells with PB mononuclear cells (PBMCs), and constructed an MC38 cancer model. Results: PB RNA m6A levels were higher in the CRC than that in HCs. The area under the curve (AUC) of m6A levels (0.886) in the CRC was significantly larger compared with carbohydrate antigen 199 (CA199; 0.666) and carcinoembryonic antigen (CEA; 0.834). The combination of CEA and CA199 with PB RNA m6A led to an increase in the AUC (0.935). Compared with HCs, the expression of FTO and ALKBH5 was decreased in the CRC. After coculturing with CRC cells, the PBMCs RNA m6A were significantly increased, whereas the expression of FTO and ALKBH5 decreased. Furthermore, m6A RNA levels in the PB of MC38 cancer models were upregulated, whereas the expression of FTO and ALKBH5 decreased. Conclusions: PB RNA m6A levels are a potential diagnostic biomarker for patients with CRC. [ABSTRACT FROM AUTHOR]

Purpose: The preoperative diagnosis of endometriosis associated ovarian cancer (EAOC) remains challenging for lack of effective diagnostic biomarker. We aimed to study clinical characteristics and develop a nomogram for diagnosing EAOC before surgery. Methods: A total of 87 patients with EAOC and 348 patients with ovarian endometrioma (OEM) were enrolled in our study. Least absolute shrinkage and selection operator (LASSO) regression and Logistic regression were utilized to select variables and construct the prediction model. The performance of the model was assessed using receiver operating characteristic (ROC) analyses and calibration plots, while decision curve analyses (DCAs) were conducted to assess clinical value. Bootstrap resampling was used to evaluated the stability of the model in the derivation set. Results: The EAOC patients were older compared to the OEM patients (46.41 ± 9.62 vs. 36.49 ± 8.09 year, P < 0.001) and proportion of postmenopausal women was higher in EAOC group than in the OEM group (34.5 vs. 1.5%, P < 0.001). Our prediction model, which included age at diagnosis, tumor size, cancer antigen (CA) 19–9 and risk of ovarian malignancy algorithm (ROMA), demonstrated an area under the curve (AUC) of 0.858 (95% confidence interval (CI): 0.795–0.920) in the derivation set (N = 304) and an AUC of 0.870 (95% CI: 0.779–0.961) in the validation set (N = 131). The model fitted both the derivation (Hosmer–Lemeshow test (HL) chi-square = 12.600, P = 0.247) and the validation (HL chi-square = 8.210, P = 0.608) sets well. Conclusion: Compared to patients with OEM, those with EAOC exhibited distinct clinical characteristics. Our four-variable prediction model demonstrated excellent performance in both the derivation and validation sets, suggesting its potential to assist with preoperative diagnosis of EAOC. [ABSTRACT FROM AUTHOR]

BACKGROUND The establishment of maternal–fetal crosstalk is vital to a successful pregnancy. Glycosylation is a post-translational modification in which glycans (monosaccharide chains) are attached to an organic molecule. Glycans are involved in many physiological and pathological processes. Human endometrial epithelium, endometrial gland secretions, decidual immune cells, and trophoblasts are highly enriched with glycoconjugates and glycan-binding molecules important for a healthy pregnancy. Aberrant glycosylation in the placenta and uterus has been linked to repeated implantation failure and various pregnancy complications, but there is no recent review summarizing the functional roles of glycosylation at the maternal–fetal interface and their associations with pathological processes. OBJECTIVE AND RATIONALE This review aims to summarize recent findings on glycosylation, glycosyltransferases, and glycan-binding receptors at the maternal–fetal interface, and their involvement in regulating the biology and pathological conditions associated with endometrial receptivity, placentation and maternal–fetal immunotolerance. Current knowledge limitations and future insights into the study of glycobiology in reproduction are discussed. SEARCH METHODS A comprehensive PubMed search was conducted using the following keywords: glycosylation, glycosyltransferases, glycan-binding proteins, endometrium, trophoblasts, maternal–fetal immunotolerance, siglec, selectin, galectin, repeated implantation failure, early pregnancy loss, recurrent pregnancy loss, preeclampsia, and fetal growth restriction. Relevant reports published between 1980 and 2023 and studies related to these reports were retrieved and reviewed. Only publications written in English were included. OUTCOMES The application of ultrasensitive mass spectrometry tools and lectin-based glycan profiling has enabled characterization of glycans present at the maternal–fetal interface and in maternal serum. The endometrial luminal epithelium is covered with highly glycosylated mucin that regulates blastocyst adhesion during implantation. In the placenta, fucose and sialic acid residues are abundantly presented on the villous membrane and are essential for proper placentation and establishment of maternal–fetal immunotolerance. Glycan-binding receptors, including selectins, sialic-acid-binding immunoglobulin-like lectins (siglecs) and galectins, also modulate implantation, trophoblast functions and maternal–fetal immunotolerance. Aberrant glycosylation is associated with repeated implantation failure, early pregnancy loss and various pregnancy complications. The current limitation in the field is that most glycobiological research relies on association studies, with few studies revealing the specific functions of glycans. Technological advancements in analytic, synthetic and functional glycobiology have laid the groundwork for further exploration of glycans in reproductive biology under both physiological and pathological conditions. WIDER IMPLICATIONS A deep understanding of the functions of glycan structures would provide insights into the molecular mechanisms underlying their involvement in the physiological and pathological regulation of early pregnancy. Glycans may also potentially serve as novel early predictive markers and therapeutic targets for repeated implantation failure, pregnancy loss, and other pregnancy complications. [ABSTRACT FROM AUTHOR]

High-grade serous ovarian cancer (HGSOC) is the most lethal tumor of the female genital tract. Despite extensive studies and the identification of some precursor lesions like serous tubal intraepithelial cancer (STIC) or the deviated mutational status of the patients (BRCA germinal mutation), the pathophysiology of HGSOC and the existence of particular risk factors is still a puzzle. Moreover, a lack of screening programs results in delayed diagnosis, which is accompanied by a secondary chemo-resistance of the tumor and usually results in a high recurrence rate after the primary therapy. Therefore, there is an urgent need to identify the substantial risk factors for both predisposed and low-risk populations of women, as well as to create an economically and clinically justified screening program. This paper reviews the classic and novel risk factors for HGSOC and methods of diagnosis and prediction, including serum biomarkers, the liquid biopsy of circulating tumor cells or circulating tumor DNA, epigenetic markers, exosomes, and genomic and proteomic biomarkers. The novel future complex approach to ovarian cancer diagnosis should be devised based on these findings, and the general outcome of such an approach is proposed and discussed in the paper. [ABSTRACT FROM AUTHOR]

Background/Aim: Circulating tumor DNA (ctDNA), which is shed from cancer cells into the bloodstream, offers a potential minimally invasive approach for cancer diagnosis and monitoring. This research aimed to assess the preoperative ctDNA levels in ovarian tumors patients' plasma and establish correlations with clinicopathological parameters and patient prognosis. Patients and Methods: Tumor DNA was extracted from ovarian tumor tissue from 41 patients. Targeted sequencing using a panel of 127 genes recurrently mutated in cancer was performed to identify candidate somatic mutations in the tumor DNA. SAGAsafe digital PCR (dPCR) assays targeting the candidate mutations were used to measure ctDNA levels in patient plasma samples, obtained prior to surgery, to evaluate ctDNA levels in terms of mutant copy number/ml and variant allele frequency. Results: Somatic mutations were found in 24 tumor samples, 17 of which were from ovarian cancer patients. The most frequently mutated gene was TP53. Preoperative plasma ctDNA levels were detected in 14 of the 24 patients. With higher stage, plasma ctDNA mutant concentration increased (p for trend <0.001). The overall survival of cancer patients with more than 10 ctDNA mutant copies/ml in plasma was significantly worse (p=0.008). Conclusion: Pre-operative ctDNA measurement in ovarian cancer patients' plasma holds promise as a predictive biomarker for tumor staging and prognosis. [ABSTRACT FROM AUTHOR]

Background: Methylated stool DNA (sDNA) is a reliable noninvasive biomarker for early colorectal cancer (CRC) diagnosis. However, there are barely any diagnostic panels that can achieve both a sensitivity and specificity exceeding 90% simultaneously., Objective: We aimed to identify a novel methylated sDNA panel and model for the early diagnosis of CRC., Methods: We conducted methyl-CpG binding domain isolated genome sequencing (MiGS) on CpG island methylation phenotype (CIMP)-positive (n = 3) and CIMP-negative CRC tissues (n = 3) and their corresponding normal adjacent tissues. Subsequently, by utilizing both the aforementioned data and public datasets, we identified a set of promising methylated sDNA markers for CRC. Next, we validated 5 of these genes using pyrosequencing in CRC patients (n = 31). Then, we developed a combined diagnostic model (CDM) for CRC based on the methylation status of PRDM12, FOXE1, and SDC2 by a Training cohort (n = 231). Finally, the performance of CDM was evaluated in an independent multicenter Validation cohort (n = 800)., Results: A total of 1062 participants were included in this study. The area under the curve (AUC) of the CDM was 0.979 (95% CI: 0.960-0.997), and the optimal sensitivity and specificity were 97.35% and 99.05%, respectively, in the training cohort (n = 231). In the independent validation cohort (n = 800), the AUC was 0.950 (95% CI: 0.927-0.973), along with the optimal sensitivity of 92.75% and specificity of 97.21%. When CRC and advanced adenoma (AAD) were used as diagnostic targets, the model AUC was 0.945 (95% CI: 0.922-0.969), with an optimal sensitivity of 91.89% and a specificity of 95.21%. The model sensitivity for nonadvanced adenoma patients was 68.66%., Conclusion: The sDNA diagnostic model CDM, developed from both CIMP-P and CIMP-N, exhibited exceptional performance in CRC and could serve as a potential alternative strategy for CRC screening., (© 2024 The Author(s). United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Background: Human papillomavirus (HPV) has emerged as a significant contributor to cancer incidence globally, particularly in the context of oropharyngeal squamous cell carcinoma (OPSCC) and cancer of unknown primary (HNCUP). This study aimed to develop and validate droplet digital PCR (ddPCR) assays for the detection of circulating tumor HPV DNA (ctHPV-DNA) in plasma, focusing on high-risk HPV genotypes associated with these cancers., Methods: ddPCR assays for HPV16, 18, 33, 35, 56, and 59 were developed and tested using gBlocks, HPV cell-free DNA, fragmented tumor HPV+ DNA, and plasma samples from patients with HPV+ OPSCC (n = 110) and HNCUP (n = 9)., Results: Assays demonstrated robust technical sensitivity across all tested HPV genotypes. Clinical application of the assays on a cohort of patients with HPV+ OPSCC and HNCUP revealed high sensitivity (91.6%) and wide variability in ctHPV-DNA levels. Analyses revealed correlations between ctHPV-DNA levels and TNM stage and tumor viral load. The association between ctHPV-DNA and tumor viral load persisted even after adjusting for TNM stage. At posttreatment, 72.5% of samples had reached undetectable ctHPV-DNA levels. Having detectable ctHPV-DNA posttreatment was associated with a higher ctHPV-DNA level at diagnosis and higher viral load at diagnosis., Conclusion: The findings underscore the potential of ctHPV-DNA as a biomarker for monitoring HPV+ cancers and offer insights into tumor dynamics. Implementation of these assays in clinical practice could enhance no-invasive treatment monitoring and recurrence detection in HPV-associated cancers., Clinical Trials: NCT05904327., (© 2024. The Author(s).)

To construct a nomogram for overall survival (OS) in colorectal cancer. Using Cox univariate and multivariate analysis, significant variables were plotted into a nomogram. The predictive accuracy and discriminative ability of the nomogram was determined using the concordance index (C-index), receiver operator characteristic curve and calibration curve. CA125 and tumor node metastasis (TNM) were identified as independent predictors for OS in colorectal cancer patients. Area under the curve (AUC) for 1, 3, and 5 years was 0.89, 0.723, and 0.71 respectively in primary cohort, and C-index was 0.702 (95% CI, 0.610 to 0.794) in validation cohort, which indicated a middle degree of accuracy. High-quality calibration plots were seen in the OS nomogram models. Age, CA125, and TNM were identified as poor predictors of colorectal cancer. This nomogram is a valuable predictive tool for the prognosis of colorectal cancer. [ABSTRACT FROM AUTHOR]

Background: This study aimed to compare the diagnostic performance of carcinogenic antigen (CA) 125, (HE)-4 (Human epididymis protein 4), and ultrasound (International Ovarian Tumor Analysis [IOTA]) Simple Rules individually and to derive a composite score in the differentiating ovarian cancer from benign ovarian mass. Subjects and Methods: Consecutive patients (n = 100) with pelvic mass admitted during February 2018-August 2019 were included prospectively. Patients with either known case of epithelial ovarian cancer (EOC) or metastatic EOC were excluded. The primary outcome was to assess the sensitivity and specificity of CA-125, HE-4, and IOTA Simple Rules in predicting benign from malignant mass independently, while secondary outcome was derivation of a new model incorporating these variables using multivariate logistic regression analysis to predict benign from malignant lesions. Receiver operator curve (ROC) was drawn to redefine the best-performing cutoff values and difference between area under the ROC (AUROC) were compared by DeLong's method. Results: Out of 100 cases of adnexal mass selected, the sensitivity and specificity of CA-125 were 73.8% and 77.6%, HE-4 were 90.5% and 87.9%, and IOTA Simple Rules were 92.9% and 81.0%. CA-125, HE-4, and IOTA Simple Rules were independently associated with the likelihood of malignancy/borderline (P < 0.001). The area under the curve for the "composite score" (AUC = 0.93) was the highest and was significantly better than that of CA-125 (AUC = 0.786) (P = 0.004 using DeLong's test) and comparable with HE-4 (AUROC = 0.90; P = 0.128 using DeLong's Test). Conclusion: The sensitivity and specificity of HE-4 and IOTA Simple Rules for predicting malignant ovarian tumor was better than those of CA-125. The diagnostic performance of "composite score" was comparable to those of either HE-4 or IOTA Simple Rules and significantly better than CA-125. [ABSTRACT FROM AUTHOR]

AGR2 is a secreted protein widely existing in breast. In precancerous lesions, primary tumors and metastatic tumors, the expression of AGR2 is increased, which has aroused our interest. This review introduces the gene and protein structure of AGR2. Its endoplasmic reticulum retention sequence, protein disulfide isomerase active site and multiple protein binding sequences endow AGR2 with diverse functions inside and outside breast cancer cells. This review also enumerates the role of AGR2 in the progress and prognosis of breast cancer, and emphasizes that AGR2 can be a promising biomarker and a target for immunotherapy of breast cancer, providing new ideas for early diagnosis and treatment of breast cancer. [ABSTRACT FROM AUTHOR]

Background Our study aimed to establish ’real-world’ performance and cost-effectiveness of ovarian cancer (OC) surveillance in women with pathogenic germline BRCA1/2 variants who defer risk-reducing bilateral salpingo-oophorectomy (RRSO). Methods Our study recruited 875 female BRCA1/2- heterozygotes at 13 UK centres and via an online media campaign, with 767 undergoing at least one 4-monthly surveillance test with the Risk of Ovarian Cancer Algorithm (ROCA) test. Surveillance performance was calculated with modelling of occult cancers detected at RRSO. The incremental cost-effectiveness ratio (ICER) was calculated using Markov population cohort simulation. Results Our study identified 8 OCs during 1277women screen years: 2 occult OCs at RRSO (both stage 1a), and 6 screen-detected; 3 of 6 (50%) were ≤stage 3a and 5 of 6 (83%) were completely surgically cytoreduced. Modelled sensitivity, specificity, Positive Predictive Value (PPV) and Negative Predictive Value (NPV) for OC were 87.5% (95% CI, 47.3 to 99.7), 99.9% (99.9–100), 75% (34.9–96.8) and 99.9% (99.9–100), respectively. The predicted number of quality-adjusted life years (QALY) gained by surveillance was 0.179 with an ICER costsaving of -£102,496/QALY. Conclusion OC surveillance for women deferring RRSO in a ’real-world’ setting is feasible and demonstrates similar performance to research trials; it down-stages OC, leading to a high complete cytoreduction rate and is cost-saving in the UK National Health Service (NHS) setting. While RRSO remains recommended management, ROCA-based surveillance may be considered for female BRCA-heterozygotes who are deferring such surgery. [ABSTRACT FROM AUTHOR]