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Endometrial cancer is the sixth most common cancer in women, with a rising incidence worldwide. Current approaches for the diagnosis and screening of endometrial cancer are invasive, expensive or of moderate diagnostic accuracy, limiting their clinical utility. There is a need for cost-effective and minimally invasive approaches to facilitate the early detection and timely management of endometrial cancer. We analysed blood plasma samples in a cross-sectional diagnostic accuracy study of women with endometrial cancer (n = 342), its precursor lesion atypical hyperplasia (n = 68) and healthy controls (n = 242, total n = 652) using attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy and machine learning algorithms. We show that blood-based infrared spectroscopy has the potential to detect endometrial cancer with 87% sensitivity and 78% specificity. Its accuracy is highest for Type I endometrial cancer, the most common subtype, and for atypical hyperplasia, with sensitivities of 91% and 100%, and specificities of 81% and 88%, respectively. Our large-cohort study shows that a simple blood test could enable the early detection of endometrial cancer of all stages in symptomatic women and provide the basis of a screening tool in high-risk groups. Such a test has the potential not only to differentially diagnose endometrial cancer but also to detect its precursor lesion atypical hyperplasia&mdash, the early recognition of which may allow fertility sparing management and cancer prevention.

Background An association between BRCA pathogenic variants and an increased endometrial cancer risk, specifically serous-like endometrial cancer, has been postulated but remains unproven, particularly for BRCA2 carriers. Mechanistic evidence is lacking, and any link may be related to tamoxifen exposure or testing bias. Hysterectomy during risk-reducing bilateral salpingo-oophorectomy is, therefore, of uncertain benefit. Data from a large, prospective cohort will be informative. Methods Data on UK BRCA pathogenic variant carriers were interrogated for endometrial cancer diagnoses. Standardised incidence ratios (SIRs) were calculated in four distinct cohorts using national endometrial cancer rates; either from 1/1/1980 or age 20, prospectively from date of personal pathogenic variant report, date of family pathogenic variant report or date of risk-reducing salpingo-oophorectomy. Somatic BRCA sequencing of 15 serous endometrial cancers was performed to detect pathogenic variants. Results Fourteen cases of endometrial cancer were identified in 2609 women (1350 BRCA1 and 1259 BRCA2), of which two were prospectively diagnosed. No significant increase in either overall or serous-like endometrial cancer risk was identified in any of the cohorts examined (SIR = 1.70, 95% confidence interval = 0.74–3.33; no cases of serous endometrial cancer diagnosed). Results were unaffected by the BRCA gene affected, previous breast cancer or tamoxifen use. No BRCA pathogenic variants were detected in any of the serous endometrial cancers tested. Conclusions Women with a BRCA pathogenic variant do not appear to have a significant increased risk of all-type or serous-like endometrial cancer compared with the general population. These data provide some reassurance that hysterectomy is unlikely to be of significant benefit if performed solely as a preventive measure., Highlights • Endometrial cancer risk was not increased in BRCA1/2 pathogenic variant carriers. • Results were unaffected by BRCA gene, previous breast cancer or tamoxifen use. • No specific increase in serous-like endometrial cancer risk was identified. • Sequencing of 15 serous endometrial tumours revealed no pathogenic BRCA1/2 variants.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:. To determine the safety and effectiveness of interventions to improve insulin resistance for the prevention of atypical endometrial hyperplasia or endometrial cancer, or both.

BackgroundHigh expression of Ki67, a proliferation marker, is associated with reduced endometrial cancer-specific survival. Pre-surgical metformin reduces tumour Ki-67 expression in some women with endometrial cancer. Metformin’s anti-cancer activity may relate to effects on cellular energy metabolism. Since tumour hypoxia and glucose availability are major cellular redox determinants, we evaluated their role in endometrial cancer response to metformin.MethodsEndometrial cancer biopsies from women treated with pre-surgical metformin were tested for the hypoxia markers, HIF-1α and CA-9. Endometrial cancer cell lines were treated with metformin in variable glucose concentrations in normoxia or hypoxia and cell viability, mitochondrial biogenesis, function and energy metabolism were assessed.ResultsIn women treated with metformin (n = 28), Ki-67 response was lower in hypoxic tumours. Metformin showed minimal cytostatic effects towards Ishikawa and HEC1A cells in conventional medium (25 mM glucose). In low glucose (5.5 mM), a dose-dependent cytostatic effect was observed in normoxia but attenuated in hypoxia. Tumours treated with metformin showed increased mitochondrial mass (n = 25), while in cultured cells metformin decreased mitochondrial function. Metformin targets mitochondrial respiration, however, in hypoxic, high glucose conditions, there was a switch to glycolytic metabolism and decreased metformin response.ConclusionsUnderstanding the metabolic adaptations of endometrial tumours may identify patients likely to derive clinical benefit from metformin.

Background Endometrial cancer (EC) is a major health concern due to its rising incidence. Whilst early stage disease is generally cured by surgery, advanced EC has a poor prognosis with limited treatment options. Altered energy metabolism is a hallmark of malignancy. Cancer cells drive tumour growth through aerobic glycolysis and must export lactate to maintain intracellular pH. The aim of this study was to evaluate the expression of the lactate/proton monocarboxylate transporters MCT1 and MCT4 and their chaperone CD147 in EC, with the ultimate aim of directing future drug development. Methods MCT1, MCT4 and CD147 expression was examined using immunohistochemical analysis in 90 endometrial tumours and correlated with clinico-pathological characteristics and survival outcomes. Results MCT1 and MCT4 expression was observed in the cytoplasm, the plasma membrane or both locations. CD147 was detected in the plasma membrane and associated with MCT1 (p = 0.003) but not with MCT4 (p = 0.207) expression. High MCT1 expression was associated with reduced overall survival (p = 0.029) and remained statistically significant after adjustment for survival covariates (p = 0.017). Conclusion Our data suggest that MCT1 expression is an important marker of poor prognosis in EC. MCT1 inhibition may have potential as a treatment for advanced or recurrent EC. Electronic supplementary material The online version of this article (10.1186/s12907-017-0067-7) contains supplementary material, which is available to authorized users.

Key contentOf the 20 most common tumour types, endometrial cancer has the strongest association with obesity.Endometrial cancer should be considered in young, obese women with irregular or heavy menstrual bleeding.To reduce the risk of postoperative complications, surgery for endometrial cancer should be performed using minimal access techniques whenever possible.For women who are unfit for, or who decline, surgery, alternative treatments include progestins or radiotherapy, but these have lower efficacy and are associated with a higher risk of disease relapse.Obesity is associated with reduced overall survival following endometrial cancer because of increased cardiovascular mortality; it may also affect disease‐specific survival.Learning objectivesTo further understanding of the mechanisms through which obesity drives endometrial carcinogenesis.To improve understanding of the potential difficulties associated with the management of endometrial cancer in obese women.To increase knowledge of alternative treatment options for women who are unfit for, or who decline, standard endometrial cancer management.Ethical issuesThe number of young, premenopausal women with endometrial cancer is increasing – how should these women be managed?Should super‐obese women with endometrial cancer only be treated in cancer centres?After treating a woman's endometrial cancer, how should she be counselled her about her weight and cardiovascular disease risk?

Advanced endometrial cancer continues to have a poor prognosis, due to limited treatment options, which may be further adversely impacted by obesity. Endometrial cancer stem cells have been reported to drive metastasis, chemotherapy resistance and disease relapse, but have yet to be fully characterised and no specific targeted therapies have been identified. Here, we describe the phenotype and genotype of aldehyde dehydrogenase high (ALDHhigh) and CD133+ve endometrial cancer stem cells and how adipocyte secreted mediators block the inhibitory effect of metformin on endometrial cancer stem cell activity. Ishikawa and Hec-1a cell lines were used to characterise ALDHhigh and CD133+ve endometrial cancer cells using flow cytometry, functional sphere assays and quantitative-Polymerase Chain Reaction. The comparative effect of metformin on endometrial cancer stem cell activity and bulk tumour cell proliferation was determined using an Aldefluor and cytotoxicity assay. The impact of adipocyte secreted mediators on metformin response was established using patient-derived conditioned media. ALDHhigh cells demonstrated greater endometrial cancer stem cell activity than CD133+ve cells and had increased expression of stem cell and epithelial-mesenchymal transition genes. Treatment with 0.5&ndash, 1 mM metformin reduced the proportion and activity of both endometrial cancer stem cell populations (p &le, 0.05), without affecting cell viability. This effect was, however, inhibited by exposure to patient-derived adipocyte conditioned media. These results indicate a selective and specific effect of metformin on endometrial cancer stem cell activity, which is blocked by adipocyte secreted mediators. Future studies of metformin as an adjuvant therapy in endometrial cancer should be adequately powered to investigate the influence of body mass on treatment response.

Endometrial cancer is the most common malignancy of the female genital tract and a major cause of morbidity and mortality in women. Early detection is key to ensuring good outcomes but a lack of minimally invasive screening tools is a significant barrier. Most endometrial cancers are obesity-driven and develop in the context of severe metabolomic dysfunction. Blood-derived metabolites may therefore provide clinically relevant biomarkers for endometrial cancer detection. In this study, we analysed plasma samples of women with body mass index (BMI) ≥30kg/m2 and endometrioid endometrial cancer (cases, n = 67) or histologically normal endometrium (controls, n = 69), using a mass spectrometry-based metabolomics approach. Eighty percent of the samples were randomly selected to serve as a training set and the remaining 20% were used to qualify test performance. Robust predictive models (AUC &gt, 0.9) for endometrial cancer detection based on artificial intelligence algorithms were developed and validated. Phospholipids were of significance as biomarkers of endometrial cancer, with sphingolipids (sphingomyelins) discriminatory in post-menopausal women. An algorithm combining the top ten performing metabolites showed 92.6% prediction accuracy (AUC of 0.95) for endometrial cancer detection. These results suggest that a simple blood test could enable the early detection of endometrial cancer and provide the basis for a minimally invasive screening tool for women with a BMI ≥ 30 kg/m2.

BACKGROUND: Preclinical studies in endometrial cancer (EC) show that metformin reduces cellular proliferation by PI3K-AKT-mTOR inhibition. We tested the hypothesis that short-term presurgical metformin reduces cellular proliferation in atypical endometrial hyperplasia (AEH) and endometrioid EC, and assessed the feasibility of using phosphorylated PI3K-AKT-mTOR proteins as tissue end points.METHODS: Women with AEH or EC received metformin 850 mg twice a day or no drug in the presurgical window between diagnosis and hysterectomy. Before and after the window, tissue samples were obtained; serum markers of insulin resistance (e.g. homeostasis model of assessment of insulin resistance index) were determined; and anthropometrics measured (e.g. BMI). Cell proliferation (Ki-67) and PI3K-AKT-mTOR phosphostatus were assessed by immunohistochemistry and scored blinded to treatment.RESULTS: Twenty-eight metformin-treated and 12 untreated patients, well matched for age and BMI, completed the study. Metformin treatment (median 20 days, range 7-34) was associated with a 17.2% reduction in tumour Ki-67 (95% CI -27.4, -7.0, P=0.002), in a dose-dependent manner. Tumour PI3K-AKT-mTOR protein phosphostatus varied but the effects were not significant after adjusting for changes in controls.CONCLUSIONS: Short-term metformin was associated with reduced Ki-67 expression in EC. Changes in tumour PI3K-AKT-mTOR protein phosphostatus were seen in both groups. Future studies should address the variability attributed to different sampling techniques including devascularisation of the uterus at hysterectomy.

Background Lynch syndrome (LS) predisposes to endometrial cancer (EC), colorectal cancer, and other cancers through inherited pathogenic variants affecting mismatch-repair (MMR) genes. Diagnosing LS in women with EC can reduce subsequent cancer mortality through colonoscopic surveillance and aspirin chemoprevention; it also enables cascade testing of relatives. A growing consensus supports LS screening in EC; however, the expected proportion of test positives, and optimal testing strategy is uncertain. Previous studies from insurance-based healthcare systems were limited by narrow selection criteria, failure to apply reference standard tests consistently, and poor conversion to definitive testing. The aim of this study was to establish the prevalence of LS and the diagnostic accuracy of LS testing strategies in an unselected EC population. Methods and findings This was a prospective cross-sectional study carried out at a large United Kingdom gynaecological cancer centre between October 2015 and January 2017. Women diagnosed with EC or atypical hyperplasia (AH) were offered LS testing. Tumours underwent MMR immunohistochemistry (IHC), microsatellite instability (MSI), and targeted MLH1-methylation testing. Women, Emma Crosbie and colleagues investigate the prevalence of and strategies for identifying Lynch syndrome among women with endometrial cancer., Author summary Why was this study done? Endometrial (womb) cancer (EC) is the most common gynaecological cancer in the developed world, and its incidence is rising. A significant minority (around 3%) of EC are caused by an inherited genetic predisposition called Lynch syndrome (LS). EC may be the first sign that a woman has LS. She is likely to survive this cancer but develop other preventable cancers related to LS later in life. Her family members are also at risk. Identifying women with LS can enable them to reduce their risk of new cancers, for example, through bowel (colorectal) cancer surveillance (colonoscopy). We do not know how many women with EC have LS or how best to identify them; current practice is based on experience in bowel cancer and may not be accurate in EC. What did this research do and find? We tested 500 women with EC treated in a large tertiary referral centre in the North West of England for LS. We did not preselect women to test based on clinical or tumour characteristics. We tested tumours for features of LS called mismatch repair (MMR) deficiency and microsatellite instability (MSI). Women with strongly suggestive clinical or tumour characteristics underwent germline LS testing. In total, 16 of 500 women (3%) had LS, and these women could not always be predicted by their age or family history. MMR deficiency was more accurate than MSI at identifying LS-EC, picking up 16/16 (100%) versus 9/16 (56%). What do these findings mean? In our study, we found that 3% of women with endometrial cancer have LS and can benefit from strategies to reduce their future cancer risk. Our results suggest that it may be best to test everyone because preselecting women to test based on clinical or tumour characteristics misses cases of LS. In this population, tumour MMR deficiency was more accurate than MSI at identifying LS in EC. Our results should be interpreted with caution because we did not do germline testing on all women, and the number of women we tested was relatively small.

This study aimed to evaluate the effectiveness of inpatient care models during induction of labour (IOL). A prospective observational study involving 1,133 women undergoing IOL in a tertiary obstetric centre was conducted between March 2009 and August 2010. Three models of care were evaluated: model A – women were admitted when workload permitted, and cared for by midwives who may also be caring for women in labour. Model B – women were given specific appointments and cared for by dedicated IOL midwives working a total of 40 hours or (model C) 84 hours per week. Model C resulted in a reduction in admission-to-birth interval when compared to models A and B (p

Background: Endometrial cancer is strongly associated with obesity and insulin resistance. Metformin, an insulin sensitizer, reduces endometrial tumour growth in vitro. Pre-surgical window studies allow rapid in vivo assessment of anti-tumour activity. Previous window studies found short-term metformin treatment reduced endometrial cancer proliferation but these lacked methodological rigor, particularly control arms for comparison. PREMIUM was designed to definitively determine the anti-proliferative effect of metformin in vivo using a robust window study design. Methods: A randomised, double-blind, placebo-controlled phase 3 trial was conducted in five hospitals in England. Eligible women had biopsy-proven atypical endometrial hyperplasia or endometrioid endometrial cancer and were not receiving anti-diabetic medication. Women were computer-randomised (1:1) using the permuted block method (block size 30) to metformin (850mg daily for three days, increased to twice daily thereafter) or placebo for 1-5 weeks, until the evening before surgery. Participants and researchers were blinded to treatment group allocation. The primary outcome was post-treatment immunohistochemical expression of Ki-67 in the hysterectomy specimen; a modified intention-to-treat analysis included all women taking at least one dose of study drug and undergoing tumour biopsy within 72 hours of treatment discontinuation. Safety analysis included all women receiving at least one dose of drug. Findings: Between February 2015-2017, 93 women were randomised to metformin (n=47) or placebo (n=46), with five withdrawals (four without taking any drug and one because of no post-treatment biopsy). Eighty-eight women were included in the final analysis (metformin n=45, placebo n=43). There was no overall difference in post-treatment Ki-67 between the metformin and placebo arms, in an ANCOVA analysis adjusting for baseline Ki-67 expression (mean difference -0·57%, 95% CI -7·57% to 6·42%, p=0·87). Women receiving metformin reported significantly more adverse events than those receiving placebo (37 [82·2%] vs. 25 [58·1%], p=0·001), especially nausea and vomiting (17 [37·8%] vs. 6 [13·6%], p=0·015), diarrhoea (23 [51·1%] vs. 6 [13·6%], p=0·0003) and anorexia (9 [20·0%] vs. 0 [0·0%], p=0·003), but did not discontinue treatment.. Interpretation: Short term treatment with standard diabetic doses of metformin does not reduce tumour proliferation in women with endometrial cancer awaiting hysterectomy. This study does not support a biological effect of metformin in endometrial cancer and casts doubt on its potential application in the primary and adjuvant treatment settings. Future studies should focus on primary and secondary prevention of endometrial cancer and pursue longer treatment windows. Clinical Trial Number: The study was registered on UK and European clinical trials databases (ISRCTN 88589234, EudraCT number 2014-000991-25) and is closed to recruitment. Funding Statement: National Institute for Health Research Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: All participants provided written, informed consent. The trial was approved by the North West Research Ethics Committee (14/NW/1236), Medicine and Healthcare Products Regulatory Authority (MHRA, reference 21387/0232/001-0001) and local Research and Development departments.

A role for insulin and its related protein IGF-1 as drivers of endometrial carcinogenesis is now well established, with epidemiological and in vitro evidence demonstrating insulin resistance to be critical to the development of the disease. In addition to a direct effect on the endometrium, stimulating unregulated cell proliferation, insulin also closely interacts with excess adipose tissue, increasing the aromatisation of androgens to oestrogen and decreasing the secretion of the adipokine adiponectin, a major regulator of insulin sensitivity. Interventions aimed at improving the body’s response to insulin would, therefore, be expected to have a positive effect on preventing the development of endometrial cancer. Numerous lifestyle, pharmacological and surgical interventions have been shown to influence insulin resistance, either through weight loss, increased insulin secretion or modulation of signalling through the insulin receptor. This review discusses the mechanisms underpinning these strategies and, in particular, the existing data for their role in endometrial cancer prophylaxis.

The British Gynaecological Cancer Society has issued the first Endometrial (Uterine) Cancer guidelines as recommendation for practice for the UK.

Background Diagnoses of endometrial cancer are increasing secondary to the rising prevalence of obesity. Obesity plays an important role in promoting the development of endometrial cancer, by inducing a state of unopposed oestrogen excess, insulin resistance and inflammation. It also affects treatment, increasing the risk of surgical complications and the complexity of radiotherapy planning, and may additionally impact on subsequent survival. Weight‐loss interventions have been associated with improvements in breast and colorectal cancer‐specific survival as well as a reduction in the risk of cardiovascular disease, a frequent cause of death in endometrial cancer survivors. Objectives To determine the impact of weight‐loss interventions, in addition to standard management of endometrial cancer, on overall survival and the frequency of adverse events. Secondary objectives include an assessment of weight‐loss interventions on endometrial cancer‐specific survival, weight loss achieved, cardiovascular event frequency and quality of life both overall and stratified according to patient body mass index (BMI), where possible. Search methods This review searched Cochrane Central Register of Controlled Trials, MEDLINE, Embase and reference lists of articles, trial registries, and international gynaecological oncology conference abstracts from inception to January 2018. Selection criteria Randomised controlled trials (RCTs) of interventions to facilitate weight loss in overweight or obese women undergoing treatment for, or previously treated for, endometrial cancer were selected. Data collection and analysis Two review authors independently selected studies, assessed trial quality, and extracted data with disagreements resolved by a third review author. Study authors were contacted to obtain missing data, including details of any adverse events. Main results We included three RCTs in the review, randomising a total of 161 overweight and obese women with endometrial cancer. All studies compared combined behavioural and lifestyle interventions to facilitate weight loss through dietary modification and increased physical activity. The included RCTs were of low or very low quality, due to high risk of bias by failing to blind participants, personnel and outcome assessors, and significant loss to follow‐up (attrition rate up to 29%). Combined behaviour and lifestyle interventions were not associated with improved overall survival (risk ratio (RR mortality), 0.23 95% confidence interval (CI) 0.01 to 4.55, P = 0.34, one RCT, 37 participants; very low‐certainty evidence) compared with usual care at 24 months. There was no evidence that such interventions were associated with improvements in cancer‐specific survival or cardiovascular event frequency as no cancer‐related deaths, myocardial infarctions or strokes were reported in the included studies. None of the included RCTs reported data for the outcome of recurrence‐free survival. Combined behaviour and lifestyle interventions were not associated with significant weight loss at either six months (mean difference (MD) ‐1.88 kg, 95% CI ‐5.98 to 2.21 kg, P = 0.37, three RCTs, 131 participants, I2= 0%; low‐certainty evidenc e)or 12 months (MD ‐8.98 kg, 95% CI ‐19.88 to 1.92 kg, P = 0.11, two RCTs, 91 participants, I2= 0%; very low‐certainty evidence) when compared with usual care. Combined behaviour and lifestyle interventions were not associated with increased quality of life, when measured using either the SF‐12 Physical Health questionnaire or FACT‐G at six months (FACT‐G MD 2.51, 95% CI ‐5.61 to 10.64, P = 0.54, two RCTs, 95 participants, I2= 83%; very low‐certainty evidence), or by FACT‐G alone at 12 months (MD 2.77, 95% CI ‐0.65 to 6.20, P = 0.11, two RCTs, 89 participants, I2= 0%; very low‐certainty evidence) when compared with usual care. No serious adverse events, for example hospitalisation or deaths, were reported in included trials. Lifestyle and behavioural interventions were associated with a higher risk of musculoskeletal symptoms (RR 19.03, 95% CI 1.17, 310.52, P = 0.04, two RCTs, 91 participants; low‐certainty evidence). Authors' conclusions There is currently insufficient high‐quality evidence to determine the effect of combined lifestyle and behavioural interventions on survival, quality of life, or significant weight loss in women with a history of endometrial cancer compared to those receiving usual care. The limited evidence suggests that there is little or no serious or life‐threatening adverse effects due to these interventions, although musculoskeletal problems were increased, presumably due to increased activity levels. Our conclusion is based on low‐ and very low‐quality evidence from a small number of trials and very few patients. We therefore have very little confidence in the evidence: the true effect of weight‐loss interventions in obese women with endometrial cancer is currently not known. Further methodologically‐rigorous, adequately‐powered RCTs are required with follow‐up of 5 to 10 years duration. These should focus on the effects of varying dietary modification regimens, pharmacological treatments associated with weight loss and bariatric surgery on survival, quality of life, weight loss and adverse events.

Despite the success of cervical screening, cancer of the cervix is the fourth most common cancer affecting women worldwide (CRUK 2014). Rates are particularly high in developing nations, which lack the requisite infrastructure for cytology and colposcopy-based screening, and in certain demographic groups, where uptake of screening is poor. Recent research has focussed on developing less invasive and potentially more acceptable means of identifying women at high risk of cervical intraepithelial neoplasia (CIN). Urinary HPV testing has received particular attention because of the ease of obtaining samples and the opportunity this affords to overcoming barriers to cervical screening like embarrassment and discomfort. This article is protected by copyright. All rights reserved.

OBJECTIVE: Women with a prior history of polycystic ovary syndrome (PCOS) have an increased risk of endometrial cancer (EC).AIM: To investigate whether the endometrium of women with PCOS possess gene expression changes similar to those found in EC.DESIGN AND METHODS: Patients with EC, PCOS and control women unaffected by either PCOS or EC were recruited into a cross-sectional study at the Nottingham University Hospital, UK. For RNA sequencing, representative individual endometrial biopsies were obtained from women with EC, PCOS and a woman unaffected by PCOS or EC. Expression of a subset of differentially expressed genes identified by RNA sequencing, including NAD(P)H quinone dehydrogenase 1 (NQO1), were validated by quantitative reverse transcriptase PCR validation (n=76) and in the cancer genome atlas UCEC (uterine corpus endometrioid carcinoma) RNA sequencing dataset (n=381). The expression of NQO1 was validated by immuno-histochemistry in EC samples from a separate cohort (n=91) comprised of consecutive patients who underwent hysterectomy at St Mary's Hospital, Manchester between 2011 and 2013. A further 6 postmenopausal women with histologically normal endometrium who underwent hysterectomy for genital prolapse were also included. Informed consent and local ethics approval was obtained for the study.RESULTS: We show for the first that that NQO1 expression is significantly increased in the endometrium of women with PCOS and EC. Immunohistochemistry confirms significantly increased NQO1 protein expression in EC relative to non-malignant endometrial tissue (pCONCLUSIONS: The results obtained here support a previously unrecognized molecular link between PCOS and EC involving NQO1. This article is protected by copyright. All rights reserved.

Already the fourth most common cancer in women in the developed world, the incidence of endometrial cancer is increasing rapidly, in line with the increasing prevalence of obesity. Relatively few studies have been undertaken of risk-reducing interventions aimed at limiting the impact of the disease on both individuals and the health service. Those that have been performed have demonstrated only modest results due to their application in relatively unselected populations. A validated risk prediction model is therefore urgently required to identify individuals at particularly high risk of endometrial cancer who may benefit from targeted primary prevention strategies and to guide trial eligibility. On the basis of a systematic review of the literature, the evidence for inclusion of measures of obesity, reproduction, insulin resistance, and genetic risk in such a model is discussed, and the strength of association between these risk factors and endometrial cancer is used to guide the development of a pragmatic risk prediction scoring system that could be implemented in the general population. Provisional cutoff values are described pending refinement of the model and external validation in large prospective cohorts. Potential risk-reducing interventions are suggested, highlighting the need for future studies in this area if the increasing tide of endometrial cancer is to be stemmed. Cancer Prev Res; 10(1); 1–13. ©2016 AACR.

Ki-67, a marker of cellular proliferation, is increasingly being used in pre-surgical window studies in endometrial cancer as a primary outcome measure. Unlike in breast cancer, however, there are no guidelines standardizing its measurement and its clinical relevance as a response biomarker is undetermined. It is, therefore, imperative that Ki-67 scoring protocols are optimized and its association with patient survival rigorously evaluated, in order to be able to clinically interpret the results of these studies. Using the International Ki-67 in Breast Cancer Working Group guidelines as a basis, whole slide, hot spot and invasive edge scoring protocols were evaluated using endometrial biopsies and hysterectomy specimens from 179 women. Whole sections and tissue microarrays, manual and semi-automated scoring using Definiens Developer software were additionally compared. Ki-67 scores were related to clinicopathological variables and cancer-specific survival in uni- and multivariate analysis. Against criteria of time efficiency, intra- and inter-observer variability and consistency, semi-automated hot spot scoring was the preferred method. Ki-67 scores positively correlated with grade, stage and depth of myometrial invasion (P-values all

Summary Objective Women with a prior history of polycystic ovary syndrome (PCOS) have an increased risk of endometrial cancer (EC). Aim To investigate whether the endometrium of women with PCOS possesses gene expression changes similar to those found in EC. Design and Methods Patients with EC, PCOS and control women unaffected by either PCOS or EC were recruited into a cross‐sectional study at the Nottingham University Hospital, UK. For RNA sequencing, representative individual endometrial biopsies were obtained from women with EC, PCOS and a woman unaffected by PCOS or EC. Expression of a subset of differentially expressed genes identified by RNA sequencing, including NAD(P)H quinone dehydrogenase 1 (NQO1), was validated by quantitative reverse transcriptase PCR validation (n = 76) and in the cancer genome atlas UCEC (uterine corpus endometrioid carcinoma) RNA sequencing data set (n = 381). The expression of NQO1 was validated by immunohistochemistry in EC samples from a separate cohort (n = 91) comprised of consecutive patients who underwent hysterectomy at St Mary's Hospital, Manchester, between 2011 and 2013. A further 6 postmenopausal women with histologically normal endometrium who underwent hysterectomy for genital prolapse were also included. Informed consent and local ethics approval were obtained for the study. Results We show for the first that NQO1 expression is significantly increased in the endometrium of women with PCOS and EC. Immunohistochemistry confirms significantly increased NQO1 protein expression in EC relative to nonmalignant endometrial tissue (P

Background Human papillomaviruses (HPV) are causally associated with ano-genital and a subset of head and neck cancers. Rising incidence of HPV+ anal cancers and head and neck cancers have now been demonstrated in the developed world over the last decade. The majority of published data on HPV prevalence at the anal and oro-pharyngeal sites are from studies of higher-risk populations. There is a paucity of data on the prevalence of HPV at non-cervical sites in lower risk, non-HIV+ women and this study was designed to provide initial pilot data on a population of women recalled for colposcopy as part of the UK cervical screening programme. Methods 100 non-HIV+ women with abnormal cervical cytology, attending clinic for colposcopic examination were recruited. Swabs from the oro-pharyngeal, anal and cervical sites were taken and DNA extracted. HPV detection and genotyping were performed using a standardised, commercially available PCR-line blot assay, which is used to genotype 37 HPV subtypes known to infect the ano-genital and oro-pharyngeal areas. Strict sampling and laboratory precautions were taken to prevent cross-contamination. Results There was a very high prevalence of HPV infection at all three sites: 96.0%, 91.4% and 92.4% at the cervix, anus and oro-pharynx, respectively. Multiple HPV subtype infections were dominant at all 3 mucosal sites. At least one or more HR genotype was present at both the cervix/anus in 39/52 (75.0%) patients; both the cervix/oro-pharynx in 48/56 (85.7%) patients; and both the anus/oro-pharynx in 39/52 (75.0%) patients. HPV 16 infection was highly dominant across all mucosal sites, with over a 2-fold increase over the next most prevalent subtype (HPV 31). Conclusions Women with abnormal smears have widespread infection with high-risk HPV at the cervical, anal and oro-pharyngeal mucosal sites and may represent a higher risk population for HPV disease in the future.

population was significantly more dormant than the original tumor. RNA sequencing analysis of treated and untreated PDX tumors (n = 6 pair) demonstrated that numerous factors with roles in ribosomal synthesis were significantly altered by treatment. In vitro, an inhibitor of ribosomal synthesis, CX-5461, caused significant G2/M-phase arrest, and effects were much more profound in chemoresistant cells than corresponding chemosensitive cells. In vivo, of the five PDX models that were treated with CX-5461, two had progression, one had stable disease, one had a 60% reduction in tumor growth, and one had a complete response to single-agent therapy, still without recurrence after 3 months. Conclusions: The ovarian PDX model exhibits similarity to patient tumors. Postchemotherapy tumors reveal severe alteration of ribosomal synthesis. Treatment with an inhibitor of ribosomal RNA synthesis was highly effective in vitro and in vivo, offering a novel opportunity to specifically target the chemoresistant population in ovarian cancer.