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

Pathological features and clinical behavior of Lynch syndrome-associated ovarian cancer

OBJECTIVE: Lynch syndrome (LS) is an inherited tumor predisposition condition caused by mutations in the mismatch repair (MMR) genes. Mutation carriers are at increased risk of various malignancies, including ovarian cancer (OC). Relatively little is known about the pathological features and clinical behavior of LS associated OC. METHODS: We analyzed the data of 1047 proven MMR mutated individuals from a prospectively maintained database at a large referral center for genomic medicine in the North West of England. Data were crosschecked with pathology reports, the National Cancer Registry and death certificates, where appropriate. Data from gynecological surveillance and risk reducing surgery were analyzed. RESULTS: We identified 53 cases of LSAOC in proven MMR mutated individuals. The cumulative risk of LSAOC was 20% at age 80 in those who retained their ovaries. LSAOC presented at an earlier age (average 51, range 24–70 years) than sporadic OC. The predominant histological subtype was endometrioid adenocarcinoma (53%). Most cases presented early (85% at stage I/II vs. 15% at stage III/IV, p < 0.001) and overall survival was excellent (80% 5-year survival), however, patients with advanced disease had a poor prognosis (40% 5-year survival). Most women were found to have LS after their OC diagnosis, however, two were detected at Stage 1c through gynecological surveillance and a further three were detected following surgery for screen-detected synchronous endometrial pathology. CONCLUSION: The predominance of early stage disease in LSAOC is linked to its good prognosis. We support risk-reducing surgery for women whose families are complete especially if undertaking hysterectomy for endometrial risk, and ovarian surveillance as part of gynecological screening for those who have not

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 &lt; 0.001), and with pathological markers of disease severity (p &lt; 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&ndash;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 &lt; 0.001)]. In women with abnormal ultrasound, HE4 &ge; 77 pmol/L improved specificity compared with imaging alone [68.6% (95% CI: 75.0&ndash;83.6) vs. 34.4% (95% CI: 27.1&ndash;42.3), respectively], but at a cost to sensitivity. HE4 &ge; 77 pmol/L improved the detection of myometrial invasion &ge;50% in women with stage I disease compared with magnetic resonance imaging (MRI) alone [sensitivity = 100% (95% CI: 54.1&ndash;100)]. CA125 &ge; 35 U/mL did not add to imaging. HE4 is a good predictor of poor prognostic features which could assist staging investigations

Magnetic impurities on superconducting Pb surfaces

It has been predicted theoretically and found experimentally that magnetic impurities induce localized bound states within the superconducting energy gap, called Yu-Shiba-Rusinov (YSR) states. Combining symmetry analysis with experimental findings provides a convincing argument for the energy splitting and distribution of the YSR peaks, but the full details of the electronic structure remain elusive and simple models with point scatterers lack the full orbital complexity required to meet this challenge. In this work we combine a Greens function based first-principles method, which incorporates a phenomenological parameterization of the superconducting state, with orbitally complex impurity potentials to make material-specific predictions of realistic systems. We study the effect of 3d transition elements on the superconducting energy gap of a Pb (001) surface. Not only do we find a good agreement with experiment, we also show that the energetic position, strength and orbital composition of the YSR states depend strongly on the chemical makeup of the impurity and its position with respect to the surface. Such quantitative results cannot be derived from simplified models but require full material specific calculations

Could Ovarian Cancer Prediction Models Improve the Triage of Symptomatic Women in Primary Care? A Modelling Study Using Routinely Collected Data.

CA125 is widely used as an initial investigation in women presenting with symptoms of possible ovarian cancer. We sought to develop CA125-based diagnostic prediction models and to explore potential implications of implementing model-based thresholds for further investigation in primary care. This retrospective cohort study used routinely collected primary care and cancer registry data from symptomatic, CA125-tested women in England (2011-2014). A total of 29,962 women were included, of whom 279 were diagnosed with ovarian cancer. Logistic regression was used to develop two models to estimate ovarian cancer probability: Model 1 consisted of age and CA125 level; Model 2 incorporated further risk factors. Model discrimination (AUC) was evaluated using 10-fold cross-validation. The sensitivity and specificity of various model risk thresholds (≥1% to ≥3%) were compared with that of the current CA125 cut-off (≥35 U/mL). Model 1 exhibited excellent discrimination (AUC: 0.94) on cross-validation. The inclusion of additional variables (Model 2) did not improve performance. At a risk threshold of ≥1%, Model 1 exhibited greater sensitivity (86.4% vs. 78.5%) but lower specificity (89.1% vs. 94.5%) than CA125 (≥35 U/mL). Applying the ≥1% model threshold to the cohort in place of the current CA125 cut-off, 1 in every 74 additional women identified had ovarian cancer. Following external validation, Model 1 could be used as part of a 'risk-based triage' system in which women at high risk of undiagnosed ovarian cancer are selected for urgent specialist investigation, while women at 'low risk but not no risk' are offered non-urgent investigation or interval CA125 re-testing. Such an approach has the potential to expedite ovarian cancer diagnosis, but further research is needed to evaluate the clinical impact and health-economic implications.Cancer Research UK [C8640/A23385] National Institute for Health Research (NIHR) School for Primary Care Research (FR17 424

The diagnostic performance of CA125 for the detection of ovarian and non-ovarian cancer in primary care: a population-based cohort study

Background The serum biomarker Cancer Antigen 125 (CA125) is widely used as an investigation for possible ovarian cancer in symptomatic women presenting to primary care. However, its diagnostic performance in this setting is unknown. We evaluated the performance of CA125 in primary care for the detection of ovarian and non-ovarian cancers. Methods and findings We studied women in the UK Clinical Practice Research Datalink with a CA125 test performed between 1 May 2011 – 31 December 2014. Ovarian and non-ovarian cancers diagnosed in the year following CA125 testing were identified from the cancer registry. Women were categorised by age: <50 years and ≥50 years. Conventional measures of test diagnostic accuracy, including sensitivity, specificity and positive predictive value, were calculated for the standard CA125 cut-off (≥35 U/ml). The probability of a woman having cancer at each CA125 level between 1-1000 U/ml was estimated using logistic regression. Cancer probability was also estimated on the basis of CA125 level and age in years using logistic regression. We identified CA125 levels equating to a 3% estimated cancer probability: the ‘risk threshold’ at which the UK National Institute for Health and Care Excellence advocates urgent specialist cancer investigation. 50,780 women underwent CA125 testing; 456 (0.9%) were diagnosed with ovarian cancer and 1321 (2.6%) with non-ovarian cancer. 3.4% of women <50 years and 15.2% of women ≥50 years with CA125 levels ≥35 U/ml, had ovarian cancer. 20.4% of women ≥50 years with a CA125 level ≥35 U/ml, who did not have ovarian cancer, were diagnosed with a non-ovarian cancer. A CA125 value of 53 U/ml equated to a 3% probability of ovarian cancer overall. This varied by age, with a value of 104 U/ml in 40-year-old women and 32 U/ml in 70-year-old women, equating to a 3% probability. The main limitations of our study were that we were unable to determine why CA125 tests were performed and that our findings are based solely on UK primary care data, so caution is need in extrapolating them to other healthcare settings. Conclusions CA125 is a useful test for ovarian cancer detection in primary care, particularly in women ≥50 years old. Clinicians should also consider non-ovarian cancers in women with high CA125 levels, especially if ovarian cancer has been excluded, in order to prevent diagnostic delay. Our results enable clinicians and patients to determine the estimated probability of ovarian cancer and all cancers at any CA125 level and age, which can be used to guide individual decisions on the need for further investigation or referral.National Institute of Health Research (NIHR) School of Primary Care Research [FR17 424]. Cancer Research UK [C8640/A23385]

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