Human Epididymis Protein 4 Levels Research Articles

Overexpression of Lewis y antigen promotes human epididymis protein 4-mediated invasion and metastasis of ovarian cancer cells.

To study Human epididymis protein 4 (HE4) surface fucosylation and to determine the effects and significance of Lewis y antigen on HE4-mediated invasion and metastasis of ovarian cancer cells, we investigated four types of ovarian cancer cells and found that six fucosylated antigens (Lewis y, Lewis x, Lewis a, Lewis b, sLewis a, and sLewis x) were identified on HE4 in ovarian cancer cells. Moreover, modification of the type II sugar chain (Lewis y, Lewis x, and sLewis x) was significantly higher than the type I sugar chain (Lewis a, Lewis b, sLewis a) of the lactose series. To confirm the effects of Lewis y antigen on HE4-mediated invasion and metastasis of ovarian cancer cells, the CaoV-3 cells with high Lewis y antigen on the HE4 surface and ES-2 cells, with high Lewis x antigen but low Lewis y antigen, were investigated. We found that the expression levels of HE4 and Lewis y increased in both cell lines while the level of Lewis x didn't have any change after transfection. Furthermore, the high expression of Lewis y antigen significantly enhanced the HE4-mediated invasion and metastasis of ovarian cancer cells. The invasion and metastasis capacities were significantly decreased after Lewis y antibody blocking. This study demonstrates that overexpression of the Lewis y antigen on HE4 promotes ovarian cancer cell invasion and metastasis, which is likely to be used as a target for the clinical treatment of ovarian cancer.

HE4, Ca125 and ROMA algorithm for differential diagnosis between benign gynaecological diseases and ovarian cancer.

The aim of this study is to evaluate the diagnostic performance of human epididymis protein 4 (HE4), cancer antigen 125 (Ca125) and the risk of ovarian malignancy algorithm (ROMA) in discriminating ovarian cancer from other benign gynaecological diseases. Serum levels of HE4 and Ca125 were measured in 119 women with benign gynaecological diseases, 29 patients with primary ovarian cancer, 32 patients with ovarian cancer on chemotherapy treatment (18 of them with progressive disease), 6 patients treated and free of disease and 32 healthy women. Sensitivity, specificity, positive and negative predictive values and positive and negative likelihood ratios (LR ±) were calculated. Receiver operator characteristic (ROC) curves were constructed, and the areas under the curve (AUC) were calculated. High serum levels for HE4, Ca125 and ROMA were observed in cancer patients. HE4 was elevated in 12.6 %, Ca125 in 21 % and ROMA in 9.2 % in the benign group, but HE4 was not elevated in endometriosis. The AUC values for HE4, Ca125 and ROMA were 0.92, 0.911 and 0.945 respectively. The sensitivity for discriminating ovarian cancer from benign gynaecological diseases was 86.2 % for HE4 and Ca125 and 93.1 % for ROMA. The specificity was 87.4, 78.9 and 90.7 % for HE4, Ca125 and ROMA. The overall positive likelihood ratio (LR+) was 6.84 for HE4, 4.1 for Ca125 and 10.01 for ROMA. In premenopausal women, LR + was 11.86 for HE4, 5.11 for ROMA and 2.02 for Ca125. HE4 might be significant in the differential diagnosis of ovarian cancer. HE4 seems to be superior to Ca125 in terms of diagnostic performance of all premenopausal women. ROMA could help to discriminate in cases with any doubt with a high diagnostic accuracy.

Can HE4 predict platinum response during first-line chemotherapy in ovarian cancer?

Actually, in literature there are not valid tools able to predict the chemotherapy response during first-line ovarian cancer treatment. CA125 and human epididymis protein 4 (HE4) levels of consecutive single-institution patients with epithelial ovarian cancer (EOC) were measured during first-line chemotherapy and until 6 months follow-up. First, patients were divided into two groups according to a temporal criterion: patients treated during 2009 (group A: training group) and patients treated during 2010 (group B: verification group). At sixth months follow-up, patients were sub-classified, within both groups, as platinum resistant or platinum sensitive/intermediate, according to Response Evaluation Criteria in Solid Tumors criteria, and the serum marker courses were further analyzed in each subgroup. Moreover, we performed a logistic regression analysis to choose CA125 and HE4 levels that are best fitted to predict chemoresponse. A total of 76 patients were divided into two groups: group A (n = 42) and group B (n = 34). After 6 months of follow-up, 40 patients were classified as platinum sensitive/intermediate and 36 as platinum resistant. At third chemotherapy cycle, in platinum-resistant patients, HE4 levels were >70 pmol/L in 36 of 36 cases, although in platinum-sensitive/intermediate patients, HE4 levels were >70 pmol/L only in six of 40 cases (sensitivity 100 %, specificity 85 %). Moreover, HE4 reduction of almost 47 % at third chemotherapy cycle reached the sensitivity of 83 % with a specificity of 87 % (positive predictive value = 0.86, negative predictive value = 0.85) in predicting chemoresponse. On the contrary, CA125 values during chemotherapy did not result statistically significant in predicting platinum response. Our findings suggest that HE4 values during first-line chemotherapy could predict chemotherapy response in EOC patients.

Evaluating the expression and diagnostic value of human epididymis protein 4 (HE4) in small cell lung cancer.

We evaluated the expression and diagnostic value of human epididymis protein 4 (HE4) in small cell lung cancer (SCLC). Serum HE4 level was measured in serum samples from 30 healthy controls and 49 patients with SCLC using enzyme-linked immunosorbent assay. HE4 expression in tumor tissues was analyzed by immunohistochemical staining. The results show that serum HE4 level is significantly higher in SCLC patients than those in healthy controls, which is also the case in tumor tissues where strong intracytoplasmic staining is demonstrable. Using the optimal cutoff value of 84.19 pmol/l, serum HE4 level distinguishes SCLC patients from healthy controls with a sensitivity of 69.4 %, a specificity of 93.3 %, and the area under the receiver operating characteristic curve (AUC) of 0.85. Compared to other well-known tumor markers used in lung cancer diagnosis, HE4 shows the highest sensitivity (69.4 %, 34 of 49) and accuracy (78.5 %, 62 of 79) in diagnosing SCLC, and combinations with other tumor markers further increase the sensitivity and accuracy. These findings suggest that HE4 levels are greatly elevated in sera and tumor tissues of patients with SCLC and serum HE4 is a potential diagnostic marker for patients with SCLC.

Human Epididymis Protein 4 and Secretory Leukocyte Protease Inhibitor in Vaginal Fluid: Relation to Vaginal Components and Bacterial Composition

Human epididymis protein 4 (HE4) is a protease inhibitor and a recently identified serum biomarker for ovarian cancer. Properties of HE4 in the genital tract of healthy women have not been evaluated. We evaluated associations between HE4 and a second vaginal protease inhibitor, secretory leukocyte protease inhibitor (SLPI), with vaginal concentrations of innate immune mediators or proteases and with the types of vaginal bacterial communities. Vaginal secretions were collected from 18 healthy reproductive age women and assayed by enzyme-linked immunosorbent assay for concentrations of HE4, SLPI, kallikrein 5, cathepsin B, interleukin 1β (IL-1), IL-1 receptor antagonist (IL-1 ra), mannose-binding lectin (MBL), the inducible 70-kDa heat shock protein, and matrix metalloproteinase (MMP)-8. The species composition of vaginal bacterial communities in 16 women was characterized by sequencing amplicons derived from 16S bacterial ribosomal RNA genes. Correlations between any 2 assays were analyzed by the Spearman rank correlation tests. Differences in the concentrations of HE4 and SLPI, and between soluble components and vaginal community types, were analyzed by the Mann-Whitney U tests. Vaginal HE4 concentrations, but not SLPI levels, were positively correlated with levels of IL-1β (P = .0152), IL-1ra (P = .0061), MBL (P = .0100), and MMP-8 (P = .0315). The median vaginal HE4 level, as well as concentrations of MBL, IL-1β, IL-1ra, and MMP-8, was highest when Gardnerella vaginalis dominated a vaginal community. The association between HE4, elevated levels of proteases, immune mediators and high proportions of G vaginalis strongly suggests that HE4 is a component of the proinflammatory immune response in the female genital tract.

Serum human epididymis protein 4 (HE4) as a tumor marker in men with lung cancer.

Human epididymis protein 4 (HE4) is a reliable tumor marker for ovarian cancer, but only limited data are available on HE4 levels in lung malignancies. HE4 levels were measured at diagnosis in 98 men with lung cancer at different stages of the disease, and these results were compared to an age-matched healthy male cohort (n=98). The concentrations of classical tumor markers were also determined, and their efficacy was compared to that of HE4. Compared to healthy controls, patients with lung neoplasm showed significantly higher HE4 levels [118.2 (80.6-150.1) pmol/L vs. 62.2 (47.2-76.1) pmol/L; p<0.001]. Although age and smoking modulated HE4 levels in the healthy cohort, no such effect was observed in the patient population. The area under the receiver operating characteristic curve (ROC-AUC) for HE4 was 0.848 (95% CI 0.792-0.904) for differentiating lung cancer patients from healthy controls, with a cut-off value of 97.6 pmol/L (sensitivity: 64.3%, specificity: 95.9%). HE4 levels were significantly elevated in all stages of lung cancer, and even in patients without clinical symptoms (p<0.05), but no difference was found between the different histological subgroups. A significant correlation was found between HE4 values and the tumor size determined by CT/MRI (Spearman's ρ=0.227, p=0.030). The combination of HE4 with CEA and CA 125 considerably enhanced the diagnostic efficacy [ROC-AUC: 0.963 (95% CI 0.937-0.990), sensitivity: 91.8%, specificity: 92.8%]. Our data suggest that serum HE4, especially in combination with CEA and CA 125, qualifies as a surrogate diagnostic marker in men with lung cancer.

HE4 as a Serum Biomarker for ROMA Prediction and Prognosis of Epithelial Ovarian Cancer

Human epididymis protein 4 (HE4) has been suggested to be a novel biomarker of epithelial ovarian cancer (EOC). The present study aimed to evaluate and compare HE4 with the commonly used marker, carbohydrate antigen 125 (CA125), in prediction and therapy-monitoring of EOC. Serum HE4 concentrations from 123 ovarian cancer patients and 174 controls were measured by Roche electrochemiluminescent immunoassay (ECLIA). Risk of ovarian malignancy algorithm (ROMA) values were calculated and assessed. In addition, the prospects of HE4 detection for therapy-monitoring were evaluated in EOC patients. The ROMA score could classify patients into high- and low-risk groups with malignancy. Indeed, lower serum HE4 was significantly associated with successful surgical therapy. Specifically, 38 patients with EOC exhibited a greater decline of HE4 compared with CA125. In contrast, elevation of HE4 better predicted recurrence (of 46, 11 patients developed recurrence, and with it increased HE4 serum concentrations) and a poor prognosis than CA125. This study suggests that serum HE4 levels are closely associated with outcome of surgical therapy and disease prognosis in Chinese EOC patients.

Are serum HE4 or ROMA scores useful to experienced examiners for improving characterization of adnexal masses after transvaginal ultrasonography?

To determine whether serum human-epididymis protein-4 (HE4) levels or Risk of Ovarian Malignancy Algorithm (ROMA) scores are useful second-stage tests for tumors thought to be difficult to characterize as benign or malignant on the basis of ultrasound findings by experienced examiners, and to investigate whether adding information on serum HE4 levels or ROMA scores to ultrasound findings improves diagnostic performance. This was a prospective cross-sectional diagnostic accuracy study conducted in a tertiary referral center that enrolled consecutive women with a known adnexal mass scheduled for surgery. Experienced level III examiners classified each mass as certainly or probably benign, difficult to classify, or probably or certainly malignant after preoperative ultrasound examination. Serum HE4 and CA 125 levels were measured before surgery. The final database comprised 360 women, of whom 216 (60%) had benign and 144 (40%) had malignant disease. Examiners were highly confident in 196 cases (54%), moderately confident in 135 (38%) and completely uncertain about their diagnosis in 29 (8%) cases. With a sensitivity of 67% and specificity of 70%, subjective assessment outperformed HE4 and ROMA in the subgroup of difficult tumors. Both tests had low discriminatory capacity with poor areas under the receiver-operating characteristics curve of 0.536 (95% CI, 0.302-0.771) and 0.565 (95% CI, 0.294-0.836), respectively. A strategy that incorporates sequential testing of serum HE4 or ROMA scores after transvaginal ultrasonography resulted in a deterioration in overall test performance. Measurement of serum HE4 or calculating scores using the ROMA as secondary tests does not seem useful for classifying adnexal tumors after subjective assessment with transvaginal ultrasonography.

Evaluating the clinical significance of serum HE4 levels in lung cancer and pulmonary tuberculosis

To evaluate whether serum human epididymis protein 4 (HE4) levels could be used as a marker to differentiate lung cancer from pulmonary tuberculosis (PTB) and as a prognostic indicator in patients with non-small-cell lung cancer (NSCLC). HE4 levels were measured in serum samples from 106 healthy controls, 190 lung cancer patients, 114 patients with PTB and 24 patients with pneumonia using enzyme-linked immunosorbent assay. Serum HE4 levels in lung cancer patients were significantly higher than those in patients with PTB and healthy controls (P < 0.001). Using the optimal cut-off value of 94.01 pmol/l, HE4 levels distinguished lung cancer from PTB with a sensitivity of 61.6% and a specificity of 93.0%. After adjusting for age and smoking status, a binary unconditional logistic regression model provided a sensitivity of 67.4% and a specificity of 86.0% for differentiating between these two diseases. In the NSCLC group, serum HE4 levels were significantly higher in patients at advanced stages (Stage I-II vs. Stage III-IV, P = 0.02). Higher levels of serum HE4 (≥ 83.90 pmol/l) were significantly correlated with a worse 3-year survival rate for patients with NSCLC (P < 0.05). Serum HE4 may be used as a potential marker to differentiate lung cancer from PTB and healthy controls. In addition, higher levels of HE4 predict poor prognosis in NSCLC patients.

Human epididymis protein 4 (HE4) and secretory leukocyte protease inhibitor (SLPI) are two novel biomarkers predictive of IVF outcome

HE4 and SLPI are protease inhibitors that are expressed in the ovaries and the female genital tract. HE4 is up-regulated by progesterone and is localized in the secretory endometrium during the window of receptivity. We sought to identify serum levels of HE4 and SLPI and their potential as predictive markers of IVF outcome.

Serum HE4 levels combined with CE CT imaging improve the management of monitoring women affected by epithelial ovarian cancer

The aim of the present study was to evaluate human epididymis protein4 (HE4) as a marker of epithelial ovarian cancer (EOC) relapse and the combination of this biomarker with contrast-enhanced high-resolution multidetector row computed tomography CECT imaging to impove the monitoring of EOC patients. Twenty-one patients with advanced EOC (FIGOIII/IV) who underwent surgery and adjuvant chemotherapy were retrospectively selected. Each patient contributed 3serum samples drawn at 3-month intervals: time intervalI (1-3months from surgery), time intervalII (4-6months from surgery) and time intervalIII (7-10months from surgery). Serum HE4 and cancer antigen-125 (CA-125) levels were determined by EIA and IRMA assays, respectively. Nine out of the 21 (GroupA) women had disease relapse while 12 out of the 21 (GroupB) women had stable disease during the follow-up study. Twenty out of the 21 patients underwent at least twoCECT follow-ups with an interval time of ~6months. One patient did not undergo a second CECT. In patients with relapsed EOC, an increase in HE4 was noted in 22, 78 and 89% of patients within the time intervals I, II and III, respectively. Positivity for CA-125 was found later at time intervalIII and only in 44% of patients. Conversely, for EOC patients in remission, increase over the threshold level was observed only for marker CA-125 (4/12). The evaluation of imaging findings at interval timeII showed a significant correlation with high levels of HE4 in 6 out of 9 patients with recurrent disease. This study supports the hypothesis that HE4 may serve as an early biomarker for recurrence of EOC. Moreover, HE4 serum levels combined with CECT imaging may improve the monitoring management of women affected by ovarian cancer.

Expression of serum human epididymis protein 4 in epithelial ovarian cancer and its correlation with prognosis

To study the characteristics of HE4 expression in patients with epithelial ovarian cancer, and to evaluate whether the pre-treatment serum human epididymis protein 4 (HE4) level is an independent prognostic factor in the patients. The clinicopathological characteristics and follow-up information of 112 patients with epithelial ovarian cancer were collected. The pre-treatment serum samples from these patients were measured for HE4 and CA125 expression. Serum HE4 levels were tested by a quantitative enzyme-linked immunosorbent assay (ELISA) and serum CA125 levels were tested using Elecsys kit. The correlation of HE4 and CA125 expressions with overall survival and other clinical data were analyzed. The median level of pre-treatment serum HE4 and CA125 in the 112 patients was 415.5 pmol/L (26.9-3253.5 pmol/L) and 699 U/ml (5-17 694 U/ml), respectively. Serum HE4 level before treatment was significantly related to grade (r = 0.21, P = 0.037), stage (r = 0.40, P = 0.001), amount of ascites (r = 0.39, P = 0.001), serum CA125 level (r = 0.53, P = 0.001) and residual disease after surgery (r = 0.22, P = 0.027), but was not related to menopausal stauts (P = 0.115), revealed by Spearman correlation test.However, logistic multivariate regression analysis indicated that residual tumor size was not significantly correlated with pre-operative HE4 level (P = 0.259). The mean survival of the 112 patients was 53 months. Log rank test indicated that the overall survival in patients with higher HE4 level was significantly shorter than those with lower HE4 level (P = 0.001). Multivariate Cox proportional hazard model analysis revealed that the pre-treatment serum HE4 level and residual tumor size were independent prognostic factors for overall survival (P = 0.044 and P = 0.048). Pre-treatment serum HE4 level is a valuable prognostic factor for the overall survival in patients with epithelial ovarian cancer.

Diagnosis and preoperative predictive value of serum HE4 concentrations for optimal debulking in epithelial ovarian cancer

The aim of this study was to evaluate serum human epididymis protein 4 (HE4) concentrations for the diagnosis and preoperative prediction of optimal debulking in epithelial ovarian cancer. The concentrations of serum HE4 and CA125 in 180 epithelial ovarian cancer patients, 40 benign ovarian tumor patients and 40 healthy female subjects were determined using enzyme-linked immunosorbent assays (ELISAs). The value of determining the serum HE4 concentrations for the diagnosis and preoperative prediction of optimal debulking in epithelial ovarian cancer was also analyzed. The concentration of serum HE4 was 355.2±221.29 pmol/l in ovarian cancer, 43.86±20.87 pmol/l in benign ovarian tumors and 30.22±9.64 pmol/l in healthy individuals, respectively. The serum HE4 levels of patients with ovarian cancer were significantly higher compared with those in the other two groups (P<0.01), although there were no statistically significant differences (P>0.05) between the benign ovarian tumors and healthy individuals. The maximum diagnostic value was identified at an HE4 serum concentration of 67.52 pmol/l and the sensitivity and specificity were 84 and 96%, respectively. The area under the ROC curve was 0.944 (95% CI, 0.912–0.976; P<0.001) and the κ value of the diagnosis of epithelial ovarian cancer according to HE4 was 0.814 (P=0.000). The demarcation criterion was 600 pmol/l, where a value >600 mol/l indicates a lower possibility of optimal debulking. HE4 predicted that the sensitivity of the incomplete cytoreductive surgery was 77% and specificity was 32%. The concentration of serum HE4 is a useful marker for diagnosis and preoperative prediction for the ideal tumor cytoreductive surgery in epithelial ovarian cancer.

Clinical efficacy of serum human epididymis protein 4 as a diagnostic biomarker of ovarian cancer: A pilot study

ObjectiveTo compare accuracy of serum human epididymis protein 4 (HE4) levels with cancer antigen 125 (CA-125) levels as biomarkers for ovarian cancer.MethodsThe study population included 94 Korean women, including 32 patients with a diagnosis of ovarian cancer and 62 patients with a diagnosis of benign ovarian tumor. All diagnoses were confirmed by histopathological analysis. Serum HE4 levels were assessed using an HE4 enzyme immunoassay, which were performed according to the manufacturer's instructions. Serum CA-125 levels were determined using a Modular analytics E170 module.ResultsThe median serum CA-125 and HE4 levels were significantly higher in patients with ovarian cancer than those with other benign tumors (CA-125, 394.1 U/mL vs. 22.7 U/mL; HE4, 56.7 pM vs. 18.5 pM; P < 0.05 in both). An additional comparison revealed that the patients with endometriosis had greater median serum CA-125 levels than those with other benign ovarian tumors (32.0 U/mL vs. 17.9 U/mL, P = 0.03). Conversely, the median serum HE4 levels were similar among the two benign ovarian tumor groups, with no statistically significant difference observed (19.0 pM vs. 18.2 pM, P = 0.49). The receiver operating characteristics curve analysis for the benign ovarian tumor and ovarian cancer patients showed that HE4 showed a greater area under the curve with borderline significance when compared with CA-125 in both groups (0.93 vs. 0.85).ConclusionSerum HE4 levels may not only allow for the detection of ovarian cancer, but also allow for better differentiation of cases of ovarian cancer versus other benign ovarian tumors compared with serum CA-125.

Expression of serum human epididymal secretory protein E4 at low grade and high grade serous carcinomas

ObjectiveTo investigate the value of serum human epididymis protein 4 (HE4) in differential diagnosis of patients with low-grade serous (LGSC) and high-grade serous carcinoma (HGSC) serous ovarian cancer. MethodsLGSC and HGSC serous ovarian cancer were diagnosed by the two-tier grade system, serum levels of HE4 and carbohydrate antigen 125 (CA125) were measured by ELISA and radioisotope method, respectively in 60 serous ovarian cancer patients. HE4 and TP53 protein in cancer tissue were measured by immunohistochemical method. ResultsThe difference in density of HE4 and TP53 protein was significant between LGSC and HGSC tissue, while serum CA125 did not show significant difference between different serum samples. There was significant difference in serum HE4 levels between LGSC and HGSC, and the result was different within FIGO (I+II) stage, suggesting HE4 was not a reliable biomarker for the discrimination between LGSC and HGSC. HE4 had potential as a biomarker for the discrimination between LGSC and HGSC but the role in early diagnosis was limited. ConclusionsHE4 may be a reliable marker for differential diagnosis of LGSC and HGSC. But its role in early diagnosis of LGSC and HGSC need to be confirmed from the perspective of two-tier grade system.

The Prognostic and Predictive Value of Combined HE4 and CA-125 in Ovarian Cancer Patients

A risk-of-ovarian-malignancy algorithm (ROMA) based on human epididymis protein 4 (HE4) and CA-125 has been reported to categorize women with a pelvic mass into high or low risk of ovarian malignancy. Originally, the ROMA score was developed for diagnostic purposes and the clinical application of HE4 for other purposes such as a predictor of survival or platinum resistance has not been extensively investigated. The objective of the present study was to evaluate the prognostic importance of prechemotherapy combined levels of HE4 and CA-125 and prediction of platinum resistance. Furthermore, we wanted to investigate the dynamics of the markers during treatment. Serum from 137 patients with newly diagnosed serous ovarian cancer was analyzed for CA-125 and HE4 using ELISAs in a training data set. Patients with high levels (upper third percentiles) of both HE4 and CA-125 were classified as high-risk patients. Data were validated in an independent data set of an additional 94 patients. HE4 and CA-125 were also analyzed at all cycles of subsequent chemotherapy. The combined score of HE4 and CA-125 was highly predictive of both progression-free and overall survival in univariate as well as multivariate survival analysis. Values in the upper third percentiles (66th) were significantly associated with decreased progression-free and overall survival in both the training and in the validation set (P < 0.05 in all analyses).The positive predictive value in relation to platinum resistance was higher for the combination of markers than for the markers individually. The positive predictive values were 64.3% and 60.7% for combined CA-125/HE4 in the training and validation sets, respectively. The combination of HE4 and CA-125 levels at baseline just before initiation of chemotherapy was significantly associated with decreased progression-free and overall survival and to some extent with platinum resistance.

Human epididymis protein 4 (HE4) and ovarian cancer prognosis

ObjectiveA cohort study was conducted to evaluate whether preoperative plasma HE4 levels could predict the occurrence of death (primary endpoint) and progression (secondary endpoint) in women with ovarian cancer (OC). MethodsBetween 1998 and 2006, we recruited 136 women newly diagnosed with OC of any FIGO stage at the University Hospital, CHUQ-L'Hôtel-Dieu de Québec, Canada. HE4 was measured using the Abbott's ARCHITECT HE4 assay. Dates of death were obtained by record linkage with the Québec mortality files. Progression was evaluated using the CA-125 or the RECIST criteria, as recommended by the Gynecology Cancer Intergroup. Adjusted hazard ratios (HR) of death and progression, as well as their 95% confidence intervals (CI), were estimated using the Cox proportional hazard regression model. ResultsPreoperative levels of HE4 were strongly associated with all OC standard prognostic factors. HE4 levels increased significantly with age (p=0.02), FIGO stage (p<0.0001), grade (p=0.005), preoperative CA-125 levels (p<0.0001), and residual tumor (p<0.0001). HE4 levels above the median value (394pmol/L) were significantly associated with mortality (HR=2.17; 95% CI: 1.42–3.32) and progression (HR=1.81; 95% CI: 1.21–2.72). After adjustment for the FIGO stage, which was the only factor significantly associated with prognosis in multivariate analyses, the association of HE4 with death remained statistically significant (HR=1.67; 95% CI: 1.08–2.59). However, the association with progression was no longer significant (HR=1.32; 95% CI: 0.87–1.99). ConclusionThese results show that preoperative the plasma level of HE4 is a marker of OC aggressiveness and a predictor of death.

Human epididymis protein 4 (HE4) in benign and malignant diseases

Human epididymis protein 4 (HE4) is described as a useful new biomarker in ovarian cancer. As HE4 is neither tumor nor organ specific, we intensively investigated the occurrence of this protein in female and male patients with various benign and malignant diseases in order to avoid misinterpretation and to identify potential additional clinical relevance. We retrospectively investigated HE4(ARCHITECT R , Abbott Diagnostics, US) in the sera of 205 healthy individuals, 654 patients with benign disorders and 720 patients with cancer before initial treatment. The lowest concentrations of HE4 were observed in healthy men (median 26.2 pmol/L) followed by healthy women (median 40.4 pmol/L). In benign diseases, highest HE4 concentrations were seen in both women and men with renal failure (women, median 1041 pmol/L; men, median 1368pmol/L). In women, the highest HE4 levels in malignant diseases were observed in ovarian cancer (median 242 pmol/l),whereas the highest HE4 concentrations in men occurred in lung cancer (median 89.2 pmol/L). The area under the curve(AUC) of HE4 in women was highest in ovarian cancer and borderline tumors as compared to benign gynecological disorders(88.9 % ), with a sensitivity of 67.4 % at 95 % specificity.Also, significantly elevated concentrations of HE4 with reference to the respective group of benign diseases were observed in uterus corpus and breast cancer as well as in lung cancer for men and women. HE4 has the highest relevance in ovarian cancer but can be elevated in a variety of benign and malignant diseases.

Elevated human epididymis protein 4 concentrations in chronic kidney disease

Human epididymis protein 4 (HE4) has recently become an available tumour biomarker for detecting ovarian cancer along with the standard cancer antigen 125 (CA125). However, it is unknown if the levels of HE4 and CA125 may be altered in subjects who have impaired renal function with no ovarian disorders. In 113 female patients at different stages of chronic kidney disease (CKD) with no ovarian and lung cancer and 68 subjects with normal renal and ovarian function, HE4 and CA125 concentrations were analysed by using chemiluminescent microparticle immunoassay (Architect®, Abbott) and electrochemiluminescent immunoassay (Modular E170®, Roche), respectively. Renal function was evaluated by measuring serum creatinine and urea concentrations (Cobas Integra-800®, Roche). Estimated glomerular filtration rate (eGFR in mL/min/1.73 m2) was calculated by the 4v-MDRD formula. Significantly increased HE4 concentrations (P<0.0001) were found in individuals with differently decreased eGFR values (<90 mL/min/1.73 m2) compared with clinical controls. CA125 serum concentration was higher than normal in subjects with CKD3 (eGFR=30-59 mL/min/1.73 m2), but significant elevation (P=0.006) in CA125 concentrations was seen only in those who had severe renal failure (CKD4-5; eGFR<30 mL/min/1.73 m2). These tendencies were independent of age in our study cohort, and seemed to be more evident among women in premenopausal status. HE4 concentrations may be elevated in CKD patients with no ovarian and lung cancer. Thus, HE4 results should be interpreted cautiously in women with renal disorders.

Does HE4 have a role in the recurrence of ovarian cancer?

e15550 Background: Human epididymis protein 4 (HE4) has been recently described as a new marker for early ovarian cancer, with higher sensitivity (76.9%) compared to CA125. This is the third study in literature on the role of HE4 in recurrence of ovarian cancer and the first evaluating the sensitivity of HE4 and CA125 in these patients Methods: Plasma was obtained 24 hours before secondary cytoreductive surgery from consecutive patients with suspicious recurrence ovarian cancer operated from November 2010 to April 2011 at University Campus Bio-Medico of Rome. CA125 levels were evaluated by a one-step "sandwich" radioimmunoassay. HE4 levels were determined using the HE4 enzymatic immune assay. The CA125 cut-off was less than 35 U/mL. Two cut-off were considered for HE4: less than 150 pmol/L (according to the manufacturer's indications) and less than 70 pmol/L. Results: Fourteen patients were histologically confirmed as recurrence ovarian cancer. Mean Ca125 plasma concentration was 31.95 ± 22.09 U/mL (range 1.1 – 64.3). Mean HE4 plasma concentration was 225.83± 286.82 pmol/L (range 21.61- 633.6). The sensitivity of CA125 was 35.7 %. The sensitivity of HE4 was 71.4% and 28.6% above the cut-off of 70 pmol/L and 150 pmol/L, respectively. The dual marker combination of CA125 and HE4 at 70 pmol/L cut-off yielded the highest sensitivity (85.7%) to detect recurrence ovarian cancer. Conclusions: Even if a standard cut-off point has not been determined, this study suggested that HE4 may potentially be a more sensible marker for recurrence ovarian cancer than CA125 and the association between CA125 and HE4 at cut-off of 70 pmol/L seems to yield the highest sensitivity.