Serum Human Epididymis Protein 4 Levels Research Articles

Human epididymis protein 4 is a useful predictor of post-operative prognosis in patients with severe aortic stenosis.

The human epididymis protein 4 (HE4), a novel fibrosis marker, is expressed only in activated fibroblasts and is thought to reflect ongoing left ventricular (LV) fibrosis. LV fibrosis is a feature of severe aortic stenosis (AS) and is related to the post-operative outcome of patients with AS. We investigated the relationship between serum levels of HE4 and the post-operative prognosis of patients with severe AS. We measured the serum HE4 levels of 55 participants (80.8±8.0years old, male n=26, 46%) with severe AS prior to surgical aortic valve replacement (n=31, 56%) or transcatheter aortic valve implantation (n=24, 44%) at Kumamoto University Hospital in 2018. We followed them for cardiovascular (CV) death or hospitalization for heart failure (HF) for 3years. Serum HE4 levels were positively correlated with computed tomography-extracellular volume (CT-ECV) values (r=0.53, P=0.004). Kaplan-Meier curves demonstrated a significantly higher probability of hospitalization for HF or CV-related death in the patients with high HE4 (greater than the median HE4 value) compared with the patients with low HE4 (lower than the median HE4 value) (log-rank P=0.003). Multivariate analysis showed HE4 (log(HE4)) to be an independent prognostic factor [hazard ratio (HR): 7.50; 95% confidence interval (CI): 1.81-31.1; P=0.005]. Receiver operating characteristic (ROC) curve analysis suggested that HE4 is a marker of increased risk of CV-related death or hospitalization for HF at 3years after surgery, with an area under the curve (AUC) of 0.76 (95% CI: 0.62-0.90; P=0.003). We found that HE4 is a potentially useful biomarker for predicting future CV events in patients scheduled for AS surgery. Measuring serum HE4 values could help consider AS surgery.

Human epididymis protein 4, a novel potential biomarker for diagnostic and prognosis monitoring of lung cancer.

This study aimed to explore the application value of human epididymis protein 4 (HE4) in diagnosing and monitoring the prognosis of lung cancer. First, TCGA (The Cancer Genome Atlas) databases were used to analyze whey-acidic-protein 4-disulfide bond core domain 2 (WFDC2) gene expression levels in lung cancer tissues. Then, a total of 160 individuals were enrolled, categorized into three groups: the lung cancer group (n = 80), the benign lesions group (n = 40), and the healthy controls group (n = 40). Serum HE4 levels and other biomarkers were quantified using an electro-chemiluminescent immunoassay. Additionally, the expression of HE4 in tissues was analyzed through immunohistochemistry (IHC). In vitro cultures of human airway epithelial (human bronchial epithelial [HBE]) cells and various lung cancer cell lines (SPC/PC9/A594/H520) were utilized to detect HE4 levels via western blot (WB). Analysis of the TCGA and UALCAN (The University of Alabama at Birmingham Cancer Data Analysis Portal) databases showed that WFDC2 gene expression levels were upregulated in lung cancer tissues (p < 0.01). Compared with the control group and the benign group, HE4 was significantly higher in the serum of patients with lung cancer (p < 0.001). Receiver operating characteristic (ROC) analysis confirmed that HE4 had better diagnostic efficacy than classical markers in the differential diagnosis of lung cancer and benign lesions and had the highest diagnostic value in lung adenocarcinoma (area under the ROC curve [AUC] = 0.826). HE4 increased in early lung cancer and positively correlated with poor prognosis (p < 0.001). Moreover, the results of WB and IHC revealed that the expression of HE4 was increased in lung cancer cells (SPC/A549/H520) and lung cancer tissues but decreased in PC9 cells with a lack of exon EGFR19 (p < 0.05). Serum HE4 emerges as a promising novel biomarker for the diagnosis and prognosis assessment of lung cancer.

HE4 Serum Levels are Associated with Poor Prognosis in Patients with Acute Heart Failure Combined with Chronic Kidney Disease.

The levels of human epididymis protein 4 (HE4) is associated not only with the prognosis of patients with acute heart failure (AHF), but also with chronic kidney disease (CKD). Our study aims to understand the prediction value of HE4 on prognosis in patients with AHF combined with CKD. This study prospectively enrolled patients diagnosed with AHF combined with CKD at the Department of Cardiology of Hunan Provincial People's Hospital from March 2019 to December 2022. Serum levels of HE4 were measured using a chemiluminescence microparticle immunoassay. The endpoint events included heart failure readmission and cardiovascular death. A total of 130 patients with AHF combined with CKD were included in the stud. The median age is 73 years (interquartile range: 65-79 years). Among the patients, 94 experienced the endpoint events. The multivariable Cox analysis reveals that LnHE4 (HR=2.280, 95% CI 1.300-3.998, P = 0.004) and age (HR=1.024, 95% CI 1.003-1.045, P = 0.025) are independent predictors of the endpoint events. The Kaplan-Meier survival curve demonstrates that patients with HE4 levels>276.15 pmol/L has a significantly higher incidence of endpoint events compared to those with HE4 levels≤276.15 pmol/L (Log rank test: χ2=19.689, P < 0.001). After adjusting for age and gender, the HR is 2.520 (95% CI: 1.626-3.906, P < 0.001). HE4 is an independent predictor of heart failure readmission and cardiovascular death in patients with AHF combined with CKD.

Predicting epithelial ovarian cancer prognosis: correlation of posttreatment 18F-fluorodeoxyglucose positron emission tomography-computed tomography metabolic parameters, serum carbohydrate antigen, and human epididymis protein levels with overall survival.

Identifying reliable prognostic indicators can aid in improving patient care. The aim of this study was to establish the association of 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) whole-body metabolic parameters, serum carbohydrate antigen 125 (CA125), and human epididymis protein 4 (HE4) with overall survival (OS) in patients with epithelial ovarian cancer (EOC) after surgery combined with platinum-based chemotherapy. From May 2014 to May 2019, a total of 79 patients with EOC who underwent posttreatment 18F-FDG PET/CT in the First Affiliated Hospital of Chongqing Medical University were included. Clinical data and laboratory indicators were obtained. The whole-body maximum standardized uptake value (WBSUVmax), whole-body metabolic tumor volume (WBMTV), and whole-body total lesion glycolysis (WBTLG) were measured and calculated on 18F-FDG PET/CT. The follow-up was conducted until February 2023, and the endpoint was death from any cause. Pearson correlation analysis, Kaplan-Meier, and Cox proportional regression were used in this study. The PET-positive (PET-P) patients had significantly decreased OS based on either Kaplan-Meier survival analysis (P<0.001) or univariate Cox regression analysis [hazard ratio (HR) =40.177, 95% confidence interval (CI): 2.690-600.134; P=0.007]. "Ln" is a logarithmic transformation with a base of "e" (natural logarithm). LnWBMTV, lnWBTLG, and therapy after PET were independent predictors of OS in a cohort of 63 PET-P patients. The difference in OS between groups sorted by the median WBMTV (4.16; P<0.001) and WBTLG (14.71; P<0.001) was statistically significant. There were statistically significant differences in CA125 and HE4 levels between patients in the PET-P and PET-negative (PET-N) groups (P<0.001). In the PET-P patient cohort, serum HE4 levels were substantially correlated with WBMTV and WBTLG. Kaplan-Meier survival analysis suggested a reduction in OS after treatment in patients with EOC positive for CA125, HE4, and PET (P<0.001). Post-PET/CT treatment strategy, WBMTV, and WBTLG demonstrated significant prognostic utility in predicting posttreatment OS in patients with EOC. Patients who tested positive for both tumor markers CA125 and HE4 and had a positive PET scan demonstrated a significantly poorer prognosis in terms of posttreatment OS.

Elevated level of serum human epididymis protein 4 (HE4) predicts disease severity and mortality in COVID-19 pneumonia

BackgroundWe retrospectively analyzed serum level of human epididymis protein 4 (HE4) as a pulmonary inflammatory biomarker in patients with COVID-19 pneumonia in association with disease severity and outcome.MethodsNinety-nine (40 critically ill, 40 severe and 19 mild) COVID-19 patients and as controls 25 age- and sex-matched non-COVID-19 bacterial sepsis subjects were included. Serum HE4 was measured by an immunoassay (Architect® i1000SR, Abbott) in the baseline samples of all study participants obtained at intensive care unit (ICU) admission or during outpatient clinic visit and follow-up sera were available in case of 30 COVID-19 subjects with life-threating conditions. Associations were studied between serum HE4, routinely available laboratory parameters, clinical characteristics, and disease progression.ResultsBaseline HE4 level was significantly higher (P < 0.0001) in critically ill (524.7 [300.1–1153.0] pmol/L) than severe COVID-19 subjects (157.4 [85.2-336.9] pmol/L) and in mild SARS-CoV-2 infection (46.7 [39.1–57.2] pmol/L). Similarly increased HE4 concentrations were found in bacterial sepsis (1118.0 [418.3–1953.0] pmol/L, P = 0.056) compared to critically ill COVID-19 individuals. Serum HE4 levels significantly correlated with age, SOFA-score, inflammation-dependent biomarkers, and the degree of lung manifestation evaluated by chest CT examination in ICU COVID-19 individuals. Based on ROC-AUC curve analysis, baseline HE4 independently indicated the severity of COVID-19 with an AUC value of 0.816 (95% CI [0.723–0.908]; P < 0.0001), while binary logistic regression test found HE4 as an independent prognostic parameter for death (OR: 10.618 [2.331–48.354]; P = 0.002). Furthermore, COVID-19 non-survivors showed much higher baseline HE4 levels without a substantial change under treatment vs. survivors (P < 0.0001). Finally, pre-treatment HE4 level of ≥ 331.7 pmol/L effectively predicted a larger risk for mortality (Log-Rank P < 0.0001) due to severe COVID-19 pneumonia.ConclusionElevated serum HE4 level at ICU admission highly correlates with COVID-19 severity and predicts disease outcome.

A predictive and prognostic model for surgical outcome and prognosis in ovarian cancer computed by clinico-pathological and serological parameters (CA125, HE4, mesothelin).

Numerous prognostic models have been proposed for ovarian cancer, extending from single serological factors to complex gene-expression signatures. Nonetheless, these models have not been routinely translated into clinical practice. We constructed a robust and readily calculable model for predicting surgical outcome and prognosis of ovarian cancer patients by exploiting commonly available clinico-pathological factors and three selected serum parameters. Serum CA125, human epididymis protein 4 (HE4) and mesothelin (MSL) were quantified by Lumipulse® G chemiluminescent enzyme immunoassay (Fujirebio) in a total of 342 serum samples from 190 ovarian cancer patients, including 152 paired pre- and post-operative samples. Detection of pre-operative HE4 and CA125 was the optimal marker combination for blood-based prediction of surgical outcome (AUC=0.86). We constructed a prognostic model, computed by serum levels of pre-operative CA125, post-operative HE4, post-operative MSL and surgical outcome. Prognostic performance of our model was superior to any of these parameters alone and was independent from BRCA1/2 mutational status. We subsequently transformed our model into a prognostic risk index, stratifying patients as "lower risk" or "higher risk". In "higher risk" patients, relapse or death was predicted with an AUC of 0.89 and they had a significantly shorter progression free survival (HR: 9.74; 95 % CI: 5.95-15.93; p<0.0001) and overall survival (HR: 5.62; 95 % CI: 3.16-9.99; p<0.0001) compared to "lower risk" patients. We present a robust predictive/prognostic model for ovarian cancer, which could readily be implemented into routine diagnostics in order to identify ovarian cancer patients at high risk of recurrence.

Revised Cut-Off Value of Human Epididymis Protein 4 Enhances Its Use as an Ovarian Tumor Marker

Objectives: Human epididymis protein 4 (HE4), a protein secreted by ovarian tumors, has been used as an ovarian tumor marker. This study aimed to improve the usefulness of HE4 to detect malignant ovarian tumors by reviewing the cut-off values. Design: A retrospective study without intervention was conducted. Participants: One hundred forty-nine healthy women (premenopausal, 126; postmenopausal, 23) and 24 patients with ovarian tumors (malignant, 12; benign, 12) participated in the study. Setting: The study used the Department of Obstetrics and Gynecology of a university hospital in Japan and the university hospital as a workplace from 2016 to 2018. Methods: The basic performance of the HE4 assay was evaluated, and the serum HE4 levels of participants were measured. Receiver operating characteristic analysis was performed using the HE4 data of the patients. Results: There were no significant differences in HE4 levels between the pre- and postmenopausal groups of healthy women. When the global cut-off values (premenopausal, 70 pmol/L; postmenopausal, 140 pmol/L) were adopted, the clinical sensitivity, specificity, positive predictive value, and negative predictive value were 41.7%, 91.7%, 83.3%, and 61.1%, respectively. Based on the results of the receiver operating characteristic analysis, we set the HE4 cut-off level at 60 pmol/L, regardless of the menopausal status. With the newly set cut-off value, the clinical sensitivity, specificity, positive predictive value, and negative predictive value were 66.7%, 91.7%, 88.9%, and 73.3%, respectively. That is, the clinical sensitivity of HE4 was improved without lowering specificity. Limitations: The small number of subjects and the fact that the health status of the healthy women was evaluated based on questionnaires were limitations to the study. Conclusion: A clinically useful cut-off value for HE4 as an ovarian tumor marker was established regardless of the menopausal status of the women, with improved clinical sensitivity, positive predictive value, and negative predictive value without lowering specificity. Currently, different cut-off values for HE4 in pre- and postmenopausal women are used globally. The cut-off value for CA125 was the same between pre- and postmenopausal women. Therefore, with the newly established cut-off value, HE4 can be used more conveniently in a non-specialized setting, especially when it is used in combination with CA125.

Retrospective efficacy analysis of olaparib combined with bevacizumab in the treatment of advanced colorectal cancer

Colorectal cancer (CRC) is a highly prevalent malignancy of the digestive tract worldwide, characterized by a significant morbidity and mortality rate and subtle initial symptoms. Diarrhea, local abdominal pain, and hematochezia occur with the development of cancer, while systemic symptoms such as anemia and weight loss occur in patients with advanced CRC. Without timely interventions, the disease can have fatal consequences within a short span. The current therapeutic options for colon cancer include olaparib and bevacizumab, which are widely utilized. This study intends to evaluate the clinical efficacy of olaparib combined with bevacizumab in the treatment of advanced CRC, hoping to provide insights into advanced CRC treatment.To investigate the retrospective efficacy of olaparib combined with bevacizumab in the treatment of advanced CRC.A retrospective analysis was conducted on a cohort of 82 patients with advanced colon cancer who were admitted to the First Affiliated Hospital of the University of South China between January 2018 and October 2019. Among them, 43 patients subjected to the classical FOLFOX chemotherapy regimen were selected as the control group, and 39 patients undergoing treatment with olaparib combined with bevacizumab were selected as the observation group. Subsequent to different treatment regimens, the short-term efficacy, time to progression (TTP), and incidence rate of adverse reactions between the two groups were compared. Changes in serum-related indicators [vascular endothelial growth factor (VEGF), matrix metalloprotein-9 (MMP-9), cyclooxygenase-2 (COX-2)] and tumor markers [human epididymis protein 4 (HE4), carbohydrate antigen 125 (CA125), carbohydrate antigen 199 (CA199)] levels before and after treatment were compared between the two groups at the same time.The objective response rate was discovered to be 82.05%, and the disease control rate was 97.44% in the observation group, which were significantly higher than the respective rates of 58.14% and 83.72% in the control group (P < 0.05). The median TTP was 24 mo (95%CI: 19.987-28.005) in the control group and 37 mo (95%CI: 30.854-43.870) in the observation group. The TTP in the observation group was significantly better than that in the control group, and the difference held statistical significance (log-rank test value = 5.009, P = 0.025). Before treatment, no substantial difference was detected in serum VEGF, MMP-9, and COX-2 levels and tumor markers HE4, CA125, and CA199 levels between the two groups (P > 0.05). Following treatment with different regimens, the above indicators in the two groups were remarkably promoted (P < 0.05), VEGF, MMP-9, and COX-2 in the observation group were lower than those in the control group (P < 0.05), and HE4, CA125, and CA199 levels were also lower than those in the control group (P < 0.05). Vis-à-vis the control group, the total incidence of gastrointestinal reactions, thrombosis, bone marrow suppression, liver and kidney function injury, and other adverse reactions in the observation group was notably lowered, with the difference considered statistically significant (P < 0.05).Olaparib combined with bevacizumab in the treatment of advanced CRC demonstrates a strong clinical effect of delaying disease progression and reducing the serum levels of VEGF, MMP-9, COX-2 and tumor markers HE4, CA125 and CA199. Moreover, given its fewer adverse reactions, it can be regarded as a safe and reliable treatment option.

Elevated serum levels of human epididymis protein 4 in adult patients with proliferative lupus nephritis.

This study aimed to access whether serum human epididymis protein 4 (HE4) level could identify lupus nephritis (LN) pathological classes in adults and children. The serum HE4 levels of 190 healthy subjects and 182 patients with systemic lupus erythematosus (SLE) (61 adult-onset LN [aLN], 39 childhood-onset LN [cLN], and 82 SLE without LN) were determined using Architect HE4 kits and an Abbott ARCHITECT i2000SR Immunoassay Analyzer. Serum HE4 level was significantly higher in the aLN patients (median, 85.5 pmol/L) than in the patients with cLN (44 pmol/L, P < 0.001) or SLE without LN (37 pmol/L, P < 0.001), or the healthy controls (30 pmol/L, P < 0.001). Multivariate analysis showed that serum HE4 level was independently associated with aLN. Stratified by LN class, serum HE4 level was significantly higher in the patients with proliferative LN (PLN) than in those with non-PLN, and this difference was found only in aLN (median, 98.3 versus 49.3 pmol/L, P = 0.021) but not in cLN. Stratified by activity (A) and chronicity (C) indices, the aLN patients with class IV (A/C) possessed significantly higher serum HE4 levels than those with class IV (A) (median, 195.5 versus 60.8 pmol/L, P = 0.006), and this difference was not seen in the class III aLN or cLN patients. Serum HE4 level is elevated in patients with class IV (A/C) aLN. The role of HE4 in the pathogenesis of chronic lesions of class IV aLN needs further investigation.

Endometrioid adenocarcinoma: combined multiparametric MRI and tumour marker HE4 to evaluate tumour grade and lymphovascular space invasion

To assess the value of semi-quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and quantitative diffusion-weighted imaging parameters combined with human epididymis protein 4 (HE4) in predicting the pathological grade and lymphovascular space invasion (LVSI) of endometrioid adenocarcinoma (EAC). Between October 2018 and December 2021, 60 women (mean age, 55 [range, 32-77] years) with EAC underwent preoperative pelvic MRI and HE4 level measurements. The positive enhancement integral (PEI), time to peak, maximum slope of increase (MSI), and maximum slope of decrease were measured by manually drawing a region of interest on the neoplastic tissue. The receiver operating characteristic curve was used to calculate the diagnostic efficiency of the single parameter and combined factors. Lower apparent diffusion coefficients (ADCs) were observed in high-grade tumours (G3) than in low-grade tumours (G1/G2). PEI, MSI, and HE4 levels were higher in the high-grade tumours than in the low-grade tumours (p<0.05). The area under the curve (AUC) for G3 diagnosis using multiparametric MRI combined with HE4 was 0.929. ADC values were significantly lower in the EAC with LVSI than in those without LVSI. Tumours with LVSI showed higher PEI and HE4 levels than those without LVSI (p<0.05). The AUC for LVSI-positive diagnosis using multiparametric MRI combined with HE4 was 0.814. Semi-quantitative DCE-MRI, ADC values, and serum HE4 levels can be used to predict tumour grade and LVSI, and the prediction efficiency of multiparametric MRI combined with serum HE4 is better than that of any single factor.

Human epididymis protein 4 as a clinical biomarker in identifying interstitial lung disease in patients with idiopathic inflammatory myopathies.

Human epididymis protein 4 (HE4) can differentiate interstitial lung disease from patients with some rheumatic diseases. However, the clinical utility of HE4 in idiopathic inflammatory myopathies (IIM) remains unclear. 80 IIM patients and 91 age and gender-matched healthy controls (HCs) were recruited. Clinical and laboratory data were recorded at baseline and 12weeks. HE4 was tested by the method of electrochemical luminescence. Compared to HCs, the levels of HE4 significantly elevated in IIM patients. Patients with elevated HE4 had a higher interstitial lung disease (ILD) prevalence. Among patients with ILD, histological patterns of organizing pneumonia had higher HE4 levels than non-specific interstitial pneumonia. Further, there was a positive correlation between HE4 and the semi-quantitative CT grade (r=0.778, p<0.001) and a negative relation between HE4 and the percentage of forced vital capacity (p<0.001) and diffusing capacity of the lung for carbon monoxide (DLco) (p=0.001). An optimal cut-off value of HE4 (79.6pmol/L) for distinguishing IIM-ILD was analyzed by ROC analysis with an AUC of 0.733 (p=0.002). Regression analysis revealed that elevated HE4 independently identified IIM-related ILD (OR 34.8, 95%CI, 3.58-338.14, p=0.002). With the improvement after treatment, serum HE4 levels were significantly decreased (p=0.006), accompanied by improved DLco% (p=0.012). Serum HE4 was significantly elevated in patients with IIM and may be utilized as a serum biomarker to evaluate the disease severity and prognosis of IIM-related ILD.

Serum Human Epididymis Protein 4 as a Prognostic Predictor of New-Onset Heart Failure among Women after Acute Coronary Syndrome: A Single-Center Retrospective Study

Introduction: Little is known about the prognostic factors among women with acute coronary syndrome (ACS), partly due to the small number of women included in heart failure (HF) clinical trials. Human epididymis protein 4 (HE4) has been proven to be a new biomarker for acute and chronic HF over the years. We hypothesize that HE4 could be a promising predictor. Methods: This retrospective study analyzed data from Zhejiang Provincial People’s Hospital. This study included 302 female patients with ACS between January 1, 2021, and December 1, 2021. The primary outcome was new-onset HF after ACS during the 12-month follow-up period. We used a logistic regression model to evaluate the association between serum HE4 levels and the incidence of HF. Serum HE4 levels were measured at baseline (within 24 h after admission). Results: Of the 302 female patients, 70 (23.2%) developed new-onset HF within 12 months. Serum HE4 levels in patients with adverse events were significantly higher than those in patients without events (8.9 [7.3–11.5] pmol/dL versus 5.9 [5.0–6.8] pmol/dL, p < 0.001). The levels of HE4, troponin I peak, left ventricular ejection fraction (LVEF), and estimated glomerular filtration rate (eGFR) were validated as independent predictors, with HE4 being the best laboratory predictor (area under the curve, 0.863; 95% confidence interval, 0.817–0.909). Serum HE4 concentrations of >6.93 pmol/dL distinguished patients at risk of HF with 82.9% sensitivity and 78.0% specificity (maximum Youden index J, 0.609). Moreover, HE4 levels were associated with an increased risk of HF. Discussion: We found a strong relationship between HE4 and the occurrence of HF after ACS among women, which might help identify patients at high risk of HF for whom close or intense management should be mandatory.

The Utility of Preoperative Serum CA125 Combined with HE4 to Predict Lymph Node Metastasis in Endometrial Cancer

Objectives: To investigate the diagnostic performance of the serum cancer antigen 125 (CA125), human epididymis protein 4 (HE4), a combination of CA125 and HE4, and a risk of ovarian malignancy algorithm (ROMA) in the preoperative prediction of high-risk lymph node metastasis (LMN) in patients with early stage endometrial cancer (EC). Designs: This is a cross-sectional study. Participants/Materials, Setting, and Methods: A cross-sectional study of data for patients with early stage endometrioid EC treated surgically at Rajavithi Hospital between April 2020 and April 2021 was commenced. The preoperative serum levels of CA125 and HE4 were measured and analyzed. The ROC curves were generated to determine the optimal cutoff values of CA125, HE4, and ROMA with optimum sensitivity and specificity for predicting LMN. Results: Eighty-six patients with surgically staged EC were identified. Lymph node involvement was detected in 9 patients (10.5%). The median serum CA125, HE4, and ROMA levels were significantly higher in EC patients having LMN than in those who did not (p < 0.05). Based on the ROC curve, both serum markers showed good discrimination for the prediction of LMN, with an optimal cutoff value of 35 U/mL for CA125 (AUC 0.789, 95% CI; 0.647–0.932), 200 pMol/L for HE4 (AUC 0.825, 95% CI; 0.700–0.950), and 60% for ROMA (AUC 0.856, 95% CI; 0.720–0.982). Additionally, HE4 showed the highest sensitivity, whereas the combination of CA125 and HE4 had the highest specificity. Limitations: The lack of ultra-staging might have been an important issue in underestimating the rate of nodal metastasis in low-risk patients and made the number of patients who developed LMN low (10.5%) in this study. Conclusions: The preoperative combined CA125 and HE4 levels are associated with an increased risk of having LMN in patients with early stage EC. This biomarker panel can guide identifying EC patients who might most benefit from lymphadenectomy.

The use of CA125, human epididymis protein 4 (HE4), risk of ovarian malignancy algorithm (ROMA), risk of malignancy index (RMI) and subjective assessment (SA) in preoperative diagnosing of ovarian tumors.

To compare utility of CA125, human epididymis protein 4 (HE4), risk of ovarian malignancy algorithm (ROMA), risk of malignancy index (RMI) and subjective assessment (SA) in preoperative diagnosis of ovarian tumors. Research was conducted among 456 patients qualified for surgery due to ovarian tumor. Preoperatively, CA125 and HE4 serum levels were estimated, and transvaginal ultrasound was performed. ROMA and RMI values and SA qualifications were obtained. Results were compared with pathomorphological findings. Receiver Operating Characteristic (ROC)-Area Under Curve (AUC) values for CA125, HE4, ROMA, RMI and SA in preoperative diagnosis of malignant lesions were 0.819, 0.909, 0.911, 0.895 and 0.895, respectively. Combinations of biochemical and sonographic methods increased sensitivity in diagnosis of ovarian tumors. Combinations utilizing serum HE4 concentrations were most useful. CA125, HE4, ROMA, RMI and SA proved to be useful in preoperative diagnosis of ovarian tumors. HE4 and ROMA occurred to be the most useful. Ultrasonographic methods are considerably useful in diagnosis of ovarian tumors. RMI and SA present similar overall diagnostic value.

Human epididymis protein 4 indicates progression of cardiac fibrosis in Heart Failure with preserved Ejection Fraction

Abstract Background Cardiac fibrosis is one of the main causes of diastolic dysfunction in heart failure with preserved ejection fraction (HFpEF). Human epididymis protein 4 (HE4) is a novel pro-fibrotic protein expressed especially in activated fibroblast, so-call myofibroblast [1]. Although our previous study showed that HE4 functioned as a secretory factor promoting cardiac fibrosis in dilated cardiomyopathy [2], little is known about the role of HE4 in HFpEF. Purpose The aim of this study is to evaluate the pathophysiological role of HE4 in HFpEF and the association between serum HE4 levels and clinical course of HFpEF. Methods In basic research, we administered high-fat diet and NOS inhibitor (L-NAME) to mice for 5 weeks to induce HFpEF. We analyzed echocardiographic findings and mRNA expressions of fibrosis-related genes including HE4 by real time PCR. In clinical research, we measured serum HE4 levels of 79 patients with HFpEF and divided these patients into low and high HE4 group using median values of HE4 (102.0 pmol/L). Then, we evaluated their mortality and cardiovascular events retrospectively. Results In vivo, the administration of high fat diet and L-NAME induced significant increase in left ventricular mass on echocardiography compared with control group (p=0.006). The mRNA expressions of aSMA and collagen3a1 in heart tissue was upregulated in HFpEF model mice (p=0.008 and p=0.003, respectively). Furthermore, the mRNA expression of HE4 was also upregulated in HFpEF model mice (n=6) than in control mice (n=5), although these differences did not reach statistical significance (p=0.238). In vitro, recombinant HE4 upregulated mRNA expression of pro-fibrotic genes, such as periostin (p=0.001), collagen3a1 (p=0.037), aSMA (p=0.095), and PAI-1 (p=0.17), indicating HE4 facilitate the activation of fibroblast and cardiac fibrosis although some did not reach statistical significance. In clinical research, Kaplan-Meier curve revealed that the rate of all cause death and rehospitalization for worsening heart failure were significantly higher in the high than the low HE4 group, suggesting HE4 can predicts prognosis in patients with HFpEF. Conclusion HE4 induces the activation of cardiac fibroblasts and is upregulated in the heart of HFpEF model mice. Furthermore, it is a useful biomarker for predicting cardiovascular events in patients with HFpEF. Funding Acknowledgement Type of funding sources: None.

Effect of Serum Level of Human Epididymis Protein 4 and Interleukin-6 as Biomarkers in Patients with Adnexal Mass.

Ovarian carcinoma is one of the most common types of neoplasms in women and the fifth leading cause of cancer death among women worldwide. Adnexal masses are classified as simple or complicated and can be benign or malignant. No single biomarker has demonstrated high sensitivity and specificity for detecting early ovarian cancer. Therefore, the current study was designed to investigate the influence of using two biomarkers as a tool for diagnosis in patients with an adnexal mass. This prospective case-control study was carried out on female patients diagnosed by ultrasound and magnetic resonance imaging with adnexal masses and scheduled for surgery and healthy women as a control group (n=50 each). The patients were in the age range of 16-80 years old and had attended the surgical rooms of Basrah hospitals, Basrah, Iraq, from January to July 2021. The levels of serum biomarkers were quantitatively assessed using the enzyme-linked immunosorbent assay. The serum concentration of the human epididymis protein 4 (HE4) biomarker exhibited significant differences between females with adnexal mass and healthy women. There was no significant association between neither the patient's age nor the menopausal state and the serum level of HE4. The serum level of HE4 had a sensitivity of 92% and a specificity of 66% as a serum marker for the presence of adnexal mass with a positive predictive value of 73% and a negative predictive value of 89%. In this study, serum interleukin-6 (IL-6) had a sensitivity of 30% and specificity of 64% in determining patients with adnexal mass pathology. It was found that the level of IL-6 was similar in all patients, compared to that in the control group. The median levels of serum HE4 showed high value in patients in the age groups of 21-40, 41-50, and >50 than in the control group; however, it was not statistically different (P=0.413). Human epididymis protein 4 was the top biomarker representing a higher concentration in adnexal mass; moreover, it demonstrated the highest performance in all samples with Adnexal mass. The results of our study showed that combining more than one marker measurement increased both the sensitivity and specificity of distinguishing patients with adnexal mass pathology.

Exploring the relationship between preeclampsia and human epididymis protein 4

Background/Aim: The level of human epididymis protein 4 (HE4), a glycoprotein and protease inhibitor, increases under many malignancies and inflammatory conditions. HE4 is also associated with cell invasion, migration, and adhesion. In this study, we compared the HE4 protein levels in pregnant patients with preeclampsia to healthy pregnant and non-pregnant individuals with the aim of finding a biomarker that can be used to recognize preeclampsia. Methods: Our study is a prospective case control study and included 20 pregnant women with preeclampsia, 20 pregnant women without preeclampsia, and 20 healthy non-pregnant women (the control). The participants’ serum HE4 levels were analyzed statistically. Results: Data analysis revealed that the mean HE4 levels were significantly lower in the preeclampsia group than in the other two groups (P = 0.002). Mean HE4 protein levels were also lower in the non-pregnant women than in the pregnant women without preeclampsia; however, this difference was not significant. Conclusion: It is difficult to predict preeclampsia, and there is not any sensitive or specific biomarker for determining the condition. This study may support that HE4 protein may be useful and significant in predicting preeclampsia. The results we achieved provide proof that HE4 levels could be a potential biomarker for preeclampsia. Many more comprehensive studies are needed to support the association between HE4 protein and preeclampsia.

Elevated serum human epididymis protein 4 is associated with disease severity and worse survival in idiopathic pulmonary fibrosis: a cohort study.

BackgroundElevated expression of human epididymis protein 4 (HE4) was previously described in connective tissue disease-associated interstitial lung diseases (CTD-ILDs) and cystic fibrosis (CF), but the clinical significance of HE4 has remained unknown in idiopathic pulmonary fibrosis (IPF), which is a progressive fibrosing ILD with a heterogeneous course that is in urgent need of reliable biomarkers in its clinical practice.MethodsA total of 27 IPF patients with acute exacerbation status (AE-IPF), 32 IPF patients with stable status (S-IPF), and 29 sex-age matched healthy controls were retrospectively included. The levels of serum HE4 and Krebs von den Lungen-6 (KL-6) of the 3 cohorts were measured. In addition, the pulmonary expression of HE4 was evaluated in lung transplant specimens of IPF using immunohistochemistry and Western blot, and noncancerous lung tissue resected from early-stage lung cancer patients as controls. The endpoint of follow-up was March 1st, 2022, and the Cox regression model was used to analyze the prognostic value of HE4.ResultsThe levels of HE4 and KL-6 were obviously elevated in AE-IPF patients compared to S-IPF (296.4 vs. 178.1 pmol/L for HE4, P<0.001; 2,007.0 vs. 990.5 IU/mL for KL-6, P<0.001) or healthy controls (296.4 vs. 51.8 pmol/L for HE4, P<0.001; 2,007.0 vs. 181.0 IU/mL for KL-6, P<0.001). Significant correlations were observed between serum HE4 levels and percent predicted diffusing capacity of the lung for carbon monoxide (DLCO%) (r=−0.526, P<0.001), percent predicted forced vital capacity (FVC%) (r=−0.344, P=0.024), gender-age-physiology (GAP) index (r=0.535, P<0.001), and oxygenation index (r=−0.550, P<0.001) in IPF patients. In histological analysis, overexpression of HE4 in mucosal epithelium of dilated bronchi was observed in IPF patients compared with controls. Multivariate cox regression revealed that serum levels of HE4 [hazard ratio (HR) =1.004, P=0.042] and GAP index (HR =1.374, P=0.010) were associated with worse survival in IPF patients.ConclusionsThe expression of serum HE4 was obviously elevated in IPF patients, especially in AE-IPF patients. In addition, serum HE4 could be utilized as a biomarker of disease severity and poor prognosis of IPF patients. These findings warrant further validation in larger, multi-center, and longitudinal cohorts.

Prognostic values of human epididymis protein 4 expression in patients with endometrial cancer: A systematic review and meta-analysis.

There is no consensus on the correlation between human epididymis protein 4 (HE4) and prognosis of endometrial cancer (EC). Therefore, we performed a meta-analysis to assess the relationship between HE4 and prognosis of EC. In this systematic review and meta-analysis, the databases were searched. Correlation of serum or tissue HE4 with clinicopathological characteristics was determined by odds ratio (OR) or standardized mean difference (SMD) with 95% confidence interval (CI), respectively. The hazard ratio (HR) with 95% CI was calculated to evaluate the correlation between HE4 and survival outcome. A total of 38 published studies were eligible. We found that high levels of serum HE4 were associated with FIGO III-IV stage (SMD=1.58, 95%CI: 1.18-1.98, p < 0.001), grade 3 (SMD=0.66, 95%CI: 0.39-0.93, p=0.001), ≥50% myometrial invasion (SMD=0.78, 95%CI: 0.58-0.99, p < 0.001), lymphovascular space invasion (SMD=0.82, 95%CI: 0.54-1.11, p=0.001), lymph node metastasis (SMD=1.27, 95%CI: 0.84-1.69, p < 0.001), cervical involvement (SMD=0.71, 95%CI: 0.43-0.98, p=0.003), parametrial involvement (SMD=1.03, 95%CI: 0.71-1.35, p < 0.001) and peritoneal cytology (SMD=0.49, 95%CI: 0.22-0.75, p < 0.001). High expression of tissue HE4 was only significantly associated with lymph node metastasis (OR=6.19, 95%CI: 2.07-18.50, p=0.001). High levels of serum HE4 were significantly associated with poor overall survival (univariate: HR=3.77, 95%CI: 1.94-7.32, p < 0.001; multivariate: HR=2.15, 95%CI: 1.65-2.80, p < 0.001) and disease-free survival (univariate: HR=2.89, 95%CI: 2.14-3.88, p < 0.001; multivariate: HR=2.31, 95%CI:1.20-2.67, p < 0.001) in EC. Compared with cancer antigen 125, serum HE4 may be a better prognostic indicator for EC. High HE4 expression is associated with poor prognosis of EC and may be a potential prognostic biomarker for EC.

Comparative study of significance of serum human epididymis protein 4 (HE4) and carbohydrate antigen 125 (CA125) as an early tumour marker in female patients with ovarian cancer

Aim: To determine the usefulness of serum human epididymis protein4 (HE4) along with Carbohydrate Antigen 125 (CA125) as an early tumour marker in female patients with ovarian cancer.Method: The ovarian cancer patients were recruited from OPD/IPD of Surgery and Oncology department of SMS Hospital, and evaluated serum HE4 and CA125. Total 262 subjects were included in this study.131 ovarian cancer Patients were divided according to different stages and 131 control subjects also included.Results: Serum HE4 and CA125 level raised significantly in ovarian cancer patients. Further increases with the advanced stage of the ovarian cancer.Conclusion: Both HE4 and CA125 can be useful diagnostic tumour marker in ovarian cancer.