HE4 as a Biomarker for Endometrial Cancer

There are currently no blood biomarkers in routine clinical use in endometrial carcinoma (EC). Human epididymis protein 4 (HE4) is a glycoprotein that is overexpressed in the serum of patients with EC, making it a good candidate for use as a diagnostic and/or prognostic biomarker. HE4 is correlated with poor prognostic factors, including stage, myometrial invasion and lymph node metastases, which means it could be used to guide decisions regarding the extent of surgery and need for adjuvant therapy. Serum HE4 has also shown promise for predicting responses to progestin therapy in early-stage EC. The use of algorithms and indices incorporating serum HE4 and other biomarkers, including clinical and imaging variables, is an area of increasing interest. Serum HE4 levels rise with age and renal dysfunction, which may affect the interpretation of results. This review covers the evidence supporting the use of HE4 as an EC biomarker for diagnosis, prognosis, recurrence monitoring, and prediction of therapy response. The evidence for combining serum HE4 with other biomarkers, including clinical and imaging variables, its value as a biomarker in other biofluids and potential challenges of its clinical use are also discussed

Serum CA125 and HE4 as Biomarkers for the Detection of Endometrial Cancer and Associated High-Risk Features

Early detection of endometrial cancer improves survival. Non-invasive diagnostic biomarkers would improve triage of symptomatic women for investigations. This study aimed to determine the diagnostic accuracy of serum Cancer Antigen 125 (CA125) and Human Epididymis 4 (HE4) for endometrial cancer and associated high-risk features. Serum samples from women investigated for gynaecological symptoms or diagnosed with endometrial cancer were analysed for CA125 and HE4. Conventional diagnostic metrics were calculated. In total, 755 women were included; 397 had endometrial cancer. Serum CA125 and HE4 were significantly elevated in cases compared with controls (both p < 0.001), and with pathological markers of disease severity (p < 0.05). A combination of CA125 and HE4 detected endometrial cancer with an area under the curve (AUC) of 0.77 (95% CI: 0.74–0.81). In a model with body mass index (BMI) and parity, HE4 predicted endometrial cancer in pre-menopausal women with an AUC of 0.91 [sensitivity = 84.5%, specificity = 80.9% (p < 0.001)]. In women with abnormal ultrasound, HE4 ≥ 77 pmol/L improved specificity compared with imaging alone [68.6% (95% CI: 75.0–83.6) vs. 34.4% (95% CI: 27.1–42.3), respectively], but at a cost to sensitivity. HE4 ≥ 77 pmol/L improved the detection of myometrial invasion ≥50% in women with stage I disease compared with magnetic resonance imaging (MRI) alone [sensitivity = 100% (95% CI: 54.1–100)]. CA125 ≥ 35 U/mL did not add to imaging. HE4 is a good predictor of poor prognostic features which could assist staging investigations

HE4 as a Biomarker for Endometrial Cancer

From MDPI via Jisc Publications RouterHistory: accepted 2021-09-17, pub-electronic 2021-09-23Publication status: PublishedFunder: Manchester Biomedical Research Centre; Grant(s): IS-BRC-1215-20007Funder: National Institute for Health Research; Grant(s): NIHR300650There are currently no blood biomarkers in routine clinical use in endometrial carcinoma (EC). Human epididymis protein 4 (HE4) is a glycoprotein that is overexpressed in the serum of patients with EC, making it a good candidate for use as a diagnostic and/or prognostic biomarker. HE4 is correlated with poor prognostic factors, including stage, myometrial invasion and lymph node metastases, which means it could be used to guide decisions regarding the extent of surgery and need for adjuvant therapy. Serum HE4 has also shown promise for predicting responses to progestin therapy in early-stage EC. The use of algorithms and indices incorporating serum HE4 and other biomarkers, including clinical and imaging variables, is an area of increasing interest. Serum HE4 levels rise with age and renal dysfunction, which may affect the interpretation of results. This review covers the evidence supporting the use of HE4 as an EC biomarker for diagnosis, prognosis, recurrence monitoring, and prediction of therapy response. The evidence for combining serum HE4 with other biomarkers, including clinical and imaging variables, its value as a biomarker in other biofluids and potential challenges of its clinical use are also discussed

Comparison of two immunoassays for the measurement of serum HE4 for ovarian cancer.

INTRODUCTION: The use of Human Epididymis Protein 4 (HE4) as a biomarker for ovarian cancer is gaining traction, providing the impetus for development of a high throughput automated HE4 assay that is comparable to the conventional manual enzyme immunometric-assay (EIA). The aim of this study was to compare two immunoassay methods for the measurement of serum HE4. MATERIALS AND METHODS: 1348 serum samples were analysed for serum HE4 using both the EIA and the automated chemiluminescent immunoassay (CLEIA) methods. HE4 values were compared using a Passing-Bablok regression and agreement assessed using Lin's concordance correlation coefficient (CCC). The absolute and percentage bias of the CLEIA compared to EIA was determined. RESULTS: There was moderate agreement between the two methods (CCC 0.929, 95%CI 0.923-0.936). Passing-Bablok regression demonstrated an overestimation of the CLEIA [constant 4.44 (95%CI 2.96-5.68), slope 1.04 (95%CI 1.02-1.07)]. The CLEIA method had a mean percentage bias of 16.25% compared to the EIA method. CONCLUSION: The CLEIA significantly overestimated serum HE4 values compared to the EIA, which could impact clinical interpretation and patient management. Further studies are required to develop an appropriate cut-off depending on the population being investigated and the analytic method being used

DEveloping Tests for Endometrial Cancer deTection (DETECT): protocol for a diagnostic accuracy study of urine and vaginal samples for the detection of endometrial cancer by cytology in women with postmenopausal bleeding.

From Europe PMC via Jisc Publications RouterHistory: ppub 2021-07-01, epub 2021-07-28Publication status: PublishedFunder: Wellcome TrustFunder: Department of Health; Grant(s): NIHR300650Funder: Cancer Research UK; Grant(s): C147/A25254IntroductionPostmenopausal bleeding (PMB), the red flag symptom for endometrial cancer, triggers urgent investigation by transvaginal ultrasound scan, hysteroscopy and/or endometrial biopsy. These investigations are costly, invasive and often painful or distressing for women. In a pilot study, we found that voided urine and non-invasive vaginal samples from women with endometrial cancer contain malignant cells that can be identified by cytology. The aim of the DEveloping Tests for Endometrial Cancer deTection (DETECT) Study is to determine the diagnostic test accuracy of urine and vaginal cytology for endometrial cancer detection in women with PMB.Methods and analysisThis is a multicentre diagnostic accuracy study of women referred to secondary care with PMB. Eligible women will be asked to provide a self-collected voided urine sample and a vaginal sample collected with a Delphi screener before routine clinical procedures. Pairs of specialist cytologists, blinded to participant cancer status, will assess and classify samples independently, with differences settled by consensus review or involving a third cytologist. Results will be compared with clinical outcomes from standard diagnostic tests. A sample size of 2000 women will have 80% power to establish a sensitivity of vaginal samples for endometrial cancer detection by cytology of ≥85%±7%, assuming 5% endometrial cancer prevalence. The primary objective is to determine the diagnostic accuracy of urogenital samples for endometrial cancer detection by cytology. Secondary objectives include the acceptability of urine and vaginal sampling to women.Ethics and disseminationThis study has been approved by the North West-Greater Manchester West Research Ethics Committee (16/NW/0660) and the Health Research Authority. Results will be disseminated through publication in peer-reviewed scientific journals, presentation at conferences and via charity websites.Trial registration numberISRCTN58863784

Does Clinical and Biochemical Thyroid Dysfunction Impact on Endometrial Cancer Survival Outcomes? A Prospective Database Study

From MDPI via Jisc Publications RouterHistory: accepted 2021-10-27, pub-electronic 2021-10-29Publication status: PublishedFunder: Cancer Research UK Manchester Centre; Grant(s): C147/A25254Funder: Medical Research Council; Grant(s): MR/M018431/1Funder: National Institute for Health Research; Grant(s): NIHR300650Endometrial cancer is the commonest gynaecological malignancy in developed countries, and women presenting with high risk or advanced disease have poor outcomes. Thyroid hormones play a key role in cellular metabolism and can influence cancer growth and invasion. Our aim was to evaluate the association between clinical and biochemical thyroid dysfunction and endometrial cancer survival outcomes. This was a prospective cohort study of women treated for endometrial cancer at a specialist centre. Clinical diagnosis of hypothyroidism was based on clinical and biochemical assessment, verified by general practitioner (GP) records. Pre-treatment serum samples were tested for thyrotropin (TSH), thyroid hormones (free T4 and total T3), and thyroid peroxidase antibodies. Kaplan–Meier survival estimates and log-rank tests were used to compare survival between groups, while Cox regression was used for multivariable analysis, adjusting for known confounders and effect modifications. In total, 333 women with median age and body mass index (BMI) of 66 years (interquartile range (IQR) 56, 73) and 33 kg/m2 (IQR 27, 41) respectively were included. A total of 51 (15.3%) women had a diagnosis of hypothyroidism, 39 (11.9%) had biochemical evidence of overt or subclinical hypothyroidism. Median follow-up was 35 months (IQR 21, 45) with 38 (11.7%) relapses and 50 (15.0%) deaths. Women with a diagnosis of hypothyroidism had improved overall survival (adjusted HR = 0.22, 95%CI 0.06–0.74, p = 0.02), cancer-specific survival (adjusted HR = 0.21, 95%CI 0.05–0.98, p = 0.04) and fewer recurrences (adjusted HR = 0.17, 95%CI 0.04–0.77, p = 0.02) than those who did not. Confirmatory studies should explore underlying mechanisms and the potential for therapeutic exploitation

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Lytic activity by temperate phages of Pseudomonas aeruginosa in long-term cystic fibrosis chronic lung infections

Pseudomonas aeruginosa is the most common bacterial pathogen infecting the lungs of cystic fibrosis (CF) patients. The transmissible Liverpool epidemic strain (LES) harbours multiple inducible prophages (LESϕ2; LESϕ3; LESϕ4; LESϕ5; and LESϕ6), some of which are known to confer a competitive advantage in an in vivo rat model of chronic lung infection. We used quantitative PCR (Q-PCR) to measure the density and dynamics of all five LES phages in the sputa of 10 LES-infected CF patients over a period of 2 years. In all patients, the densities of free-LES phages were positively correlated with the densities of P. aeruginosa, and total free-phage densities consistently exceeded bacterial host densities 10–100-fold. Further, we observed a negative correlation between the phage-to-bacterium ratio and bacterial density, suggesting a role for lysis by temperate phages in regulation of the bacterial population densities. In 9/10 patients, LESϕ2 and LESϕ4 were the most abundant free phages, which reflects the differential in vitro induction properties of the phages. These data indicate that temperate phages of P. aeruginosa retain lytic activity after prolonged periods of chronic infection in the CF lung, and suggest that temperate phage lysis may contribute to regulation of P. aeruginosa density in vivo

Measurement of the inclusive isolated-photon cross section in pp collisions at √s = 13 TeV using 36 fb−1 of ATLAS data

The differential cross section for isolated-photon production in pp collisions is measured at a centre-of-mass energy of 13 TeV with the ATLAS detector at the LHC using an integrated luminosity of 36.1 fb. The differential cross section is presented as a function of the photon transverse energy in different regions of photon pseudorapidity. The differential cross section as a function of the absolute value of the photon pseudorapidity is also presented in different regions of photon transverse energy. Next-to-leading-order QCD calculations from Jetphox and Sherpa as well as next-to-next-to-leading-order QCD calculations from Nnlojet are compared with the measurement, using several parameterisations of the proton parton distribution functions. The predictions provide a good description of the data within the experimental and theoretical uncertainties. [Figure not available: see fulltext.