Serum Human Epididymis Protein 4 Levels Research Articles

Evaluation of Serum Human Epididymis Protein 4 Levels in Women with Polycystic Ovary Syndrome.

AimThe main purpose of this study is the determination of serum epididymis protein 4 (HE4) levels in women diagnosed with polycystic ovary syndrome (PCOS) and comparison with non-PCOS healthy controls.MethodsAll consecutive women, who applied between January 2017 and June 2017 to the gynecology outpatient clinics at the Zekai Tahir Burak Women's Health Training and Research Hospital and met the study criteria, were included in this cross-sectional study. Serum human epididymis protein 4 (HE4) concentrations were measured in each woman and the mean values were compared between the PCOS and non-PCOS groups.ResultsA total of 90 women (45 with PCOS and 45 without PCOS) were included in the final analysis. There were no statistically significant differences between the groups in terms of age and body mass index (p >0.05). Basal serum HE4 levels were 172.8 ± 139.8 and 131.8 ± 123.1 pmol/L in the PCOS and non-PCOS groups, respectively (p = 0.415).ConclusionThe serum HE4 levels were found to be similar in women with and without PCOS. No significant correlation was observed between PCOS parameters and serum HE4 levels.

Risk factors for pelvic lymph node metastasis in endometrial cancer.

To evaluate the risk factors for pelvic lymph node metastasis (LNM) in endometrial cancer (EC). Clinicopathological characteristics and preoperative laboratory results were retrospectively analyzed in 393 surgically staged patients with EC (January 2014-February 2019). Pelvic LNM was detected in 45 (11.5%) patients. Univariate analysis showed that increased preoperative levels of human epididymis protein 4 (HE4), carbohydrate antigen 125 (CA125), monocyte to lymphocyte ratio (MLR), platelet to lymphocyte ratio (PLR), and decreased absolute lymphocyte count (ALC), as well as non-endometrioid histology, grade 3 tumor, deep myometrial invasion, vaginal or para-uterine involvement, adnexal involvement, positive peritoneal cytology, and lymphovascular space invasion (LVSI) were risk factors for pelvic LNM (All p < 0.05). Multivariate analysis revealed that preoperative serum HE4 ≥ 132pmol/L (odds ratio (OR) 4.25, 95% confidence interval (CI) 1.65-10.94, p = 0.003), serum CA 125 ≥ 27.6U/mL (OR 6.10, 95% CI 2.31-16.07, p = 0.000), non-endometrioid histology (OR 16.64, 95% CI 5.96-46.47, p = 0.000), myometrial invasion ≥ 50% (OR 5.30, 95% CI 2.07-13.55, p = 0.001), positive peritoneal cytology (OR 4.70, 95% CI 1.21-18.27, p = 0.025), and LVSI (OR 3.11, 95% CI 1.09-8.92, p = 0.034) remained as independent risk factors for pelvic LNM in EC. With the increase of these independent risk factors, the rate of pelvic LNM was increased significantly. Higher preoperative levels of serum HE4 and CA125, non-endometrioid histology, deep myometrial invasion, positive peritoneal cytology, and LVSI are independent risk factors for pelvic LNM in EC, which can provide scientific basis for lymphadenectomy.

Diagnostic Performance of Serum Human Epididymis Protein 4 (HE4) for Prediction of Malignancy in Ovarian Masses

Background:Early diagnosis of ovarian cancer is essential for long term disease control and mortality reduction. This has been achieved using tumor markers like cancer antigen 125 (CA-125) which is elevated in malignant as well as non-malignant conditions. This dilemma led to efforts towards development of newer markers like serum human epididymis secretory protein E4 (HE4). Present study aimed to evaluate role of HE4 in diagnosing ovarian cancers and comparing it with CA-125. Methods:Serum samples from 67 patients with ovarian cancer, 42 with benign ovarian masses and 26 healthy controls were collected preoperatively and tested for serum HE4 levels and CA-125 levels. Diagnostic performance of both tumor markers (HE4/CA-125) to diagnose malignancy in ovarian masses was calculated and compared to each other. Results:Mean CA-125 and HE4 levels were significantly higher in patients with ovarian cancer than in those with benign disease (p<0.001) or healthy controls (p< 0.001). Serum HE4 levels significantly increased in epithelial ovarian cancers when compared to non-epithelial ovarian cancers (p<0.01). Using benign control as comparison, receiver operating characteristic curve (ROC) was generated to predict a cut-off value for diagnosing malignancy for serum HE4 and CA-125. Compared to CA-125, HE4 had a similar sensitivity (83.6% vs. 85.10%) and higher specificity (100% vs. 90.48%); combination of serum HE4 and CA-125 improved the sensitivity to detect ovarian cancer to 92.54%. Sensitivity of HE4 to detect early stage ovarian cancer was superior to CA-125 (92.61% vs. 63.41%). Conclusion:Serum HE4, a novel tumor marker, discriminated epithelial ovarian cancer from benign ovarian masses. HE4 levels were related to the stage and histological types with the lowest levels in mucinous epithelial ovarian cancer and non-epithelial malignancy. Measuring serum HE4 levels alongwith CA-125 may provide higher accuracy for detecting epithelial ovarian cancer particularly in the early stages.

CYFRA 21-1 and Placental Growth Factor as Screening Markers for Endometriosis.

BackgroundThis study evaluated the performance of serum CYFRA 21-1 and placental growth factor (PIGF) as screening markers for endometriosis.Material/MethodsIn this prospective study included 81 female patients who underwent laparoscopy to treat benign ovarian tumors. Serum samples were obtained from all study patients before surgery. Serum marker levels, including CYFRA 21-1, PIGF, cancer antigen (CA)125, CA19-9, and human epididymis protein 4 (HE4) were measured using a fluorescence immunoassay technique.ResultsForty of the patients were diagnosed with endometriosis (the study group) and 41 women were diagnosed with other benign ovarian tumors (the control group). Mean serum CYFRA 21-1 and PIGF levels were not different between these 2 groups (P=0.179 and P=0.865, respectively). Elevated serum CA125 levels (>35 U/mL) and lower CYFRA 21-1 levels (≤2.29 ng/mL) were more frequently observed in the endometriosis study group than in the control group (P<0.0001, and P=048, respectively). High serum PIGF levels (>14.2 pg/mL) were observed in both groups (P=0.226). Mean serum CA19-9 levels and HE4 levels, as well as the ROMA (risk of ovarian malignancy Algorithm) score were similar between the 2 groups. Sensitivity (95.0%) and negative predictive value (NPV) (80.0%) of CYFRA 21-1 for diagnosing endometriosis were higher than those of CA125 (sensitivity 67.5%, NPV 74.5%) and PIGF (sensitivity 20.0%, NPV 53.6%). However, the specificity (PIGF 90.2%, CA125 92.7%) and positive predictive value (PPV) (PIGF 66.7%, CA125 87.1%) of PIGF and CA125 for diagnosing endometriosis were higher than those of CYFRA 21-1 (specificity 19.5%, PPV 53.5%).ConclusionsCYFRA 21-1 and PIGF may be promising markers to identify patients with and without ovarian endometriosis.

Cancer Antigen 125 (CA125), Human Epididymis Protein 4 (HE4), Risk of Malignancy Index (RMI), and Risk of Ovarian Malignancy Algorithm (ROMA) as Diagnostic Tests in Ovarian Cancer

Background: Distinguishing between malignant and benign ovarian masses is necessary to refer patients to centers with experience in the surgical. Objectives: The aim of this study was to analyze the diagnostic value of the tumor markers, including risk of malignancy index (RMI), human epididymis protein 4 (HE4), cancer antigen125 (CA125), and risk of ovarian malignancy algorithm (ROMA) in ovarian mass. Methods: One hundred patients with ovarian masses were assessed for the tumor markers ROMA, HE4, RMI, and CA125. The sensitivity and specificity of each parameter were calculated, using receiver-operating characteristic curves (ROCs) according to the area under the curve (AUC) for each method. Results: The median CA125, HE4, RMI, and ROMA serum levels had significant difference between malignant and benign masses in the overall assessment (P < 0.001). The AUCs were 0.83 (CA125), 0.88 (HE4), 0.85 (RMI), and 0.92 (ROMA) for benign vs. malignant masses in all the patients. The comparison of ROC curves was carried out, using a pairwise comparison method, and no differences were found among 4 methods. Conclusions: The results based on the AUC markers of CA125, HE4, RMI, and ROMA revealed that the accuracy trend of ROMA was higher than that of CA125, HE4, and RMI in all the patients and each group of pre- and post-menopausal patients.

Diagnostic value of serum human epididymis protein 4 and carbohydrate antigen 125 combined with risk of ovarian malignancy algorithm index for ovarian cancer

Objective To investigate the clinical value of serum human epididymis protein 4 (HE4), carbohydrate antigen 125 (CA125) combined with risk of ovarian malignancy algorithm (ROMA) index in the diagnosis of ovarian cancer. Methods A total of 541 patients in the Department of Gynaecology in Baoji Central Hospital from August 2016 to February 2018 were collected. The serum HE4 and CA125 levels were measured by using electrochemiluminescence immunoassay in 226 cases of ovarian cancer (ovarian cancer group), 315 cases of ovarian benign disease (ovarian benign disease group) and 100 female healthy people (the control group). ROMA index was calculated according to ROMA model and the results were analyzed statistically. Results The levels of serum HE4, CA125 and ROMA index were significantly different in premenopausal and postmenopausal ovarian cancer group, ovarian benign disease group and the control group (all P < 0.05). The sensitivity and Yonden's index of the three combined diagnosis of serum HE4, CA125 and ROMA for premenopausal ovarian cancer were 97.01% and 77.01% respectively, which were higher than those of a single detection (HE4: 79.37%, 69.11%; CA125: 76.06%, 66.38%; ROMA index: 89.55%, 72.41%; χ2sensitivity=12.35, P=0.000; χ2Yonden's index=6.460, P=0.013. The sensitivity and Yonden's index of the three combined diagnosis of serum HE4, CA125 and ROMA for postmenopausal ovarian cancer were 98.99% and 82.99% respectively, which were higher than those of a single detection (HE4: 86.90%, 79.40%; CA125: 82.98%, 76.31%; ROMA index: 93.54%, 80.64%; χ2sensitivity=14.25, P=0.000; χ2Yonden's index=4.822, P=0.031). The area under the curve of the combined detection of three indicators was higher than that of a single detection (premenopausal group: 0.871 vs. 0.682, 0.626, 0.708; postmenopausal group: 0.981 vs. 0.724, 0.705, 0.833), and there were significant differences (premenopausal group: χ2= 11.24, P= 0.000; postmenopausal group: χ2= 16.38, P= 0.000). Conclusion The combined detection of serum HE4, CA125 and ROMA index can increase the sensitivity and accuracy for diagnosing ovarian cancer, which can provide a more reliable basis for diagnosis and screening of ovarian cancer. Key words: Ovarian neoplasms; Human epididymis protein 4; Carbohydrate antigen 125; Risk of ovarian malignancy algorithm; Diagnosis

HE4 suppresses the expression of osteopontin in mononuclear cells and compromises their cytotoxicity against ovarian cancer cells.

Ovarian cancers are known to evade immunosurveillance and to orchestrate a suppressive immune microenvironment. Here we examine the role of human epididymis protein 4 (HE4), an ovarian cancer biomarker, in immune evasion. Through modified subtractive hybridization analyses we have characterized the gene targets of HE4 in human peripheral blood mononuclear cells (PBMCs), and established a preliminary mechanism for HE4-mediated immune failure in ovarian tumours. Upon exposure of purified PMBCs to HE4, osteopontin (OPN) and dual-specificity phosphatase 6 (DUSP6) emerged as the most suppressed and up-regulated genes, respectively. SKOV3 and OVCAR8, human ovarian carcinoma cell lines, exhibited enhanced proliferation in conditioned media from HE4-exposed PBMCs, an effect that was attenuated by the addition of recombinant OPN or OPN-inducible cytokines [interleukin (IL)-12 and interferon (IFN)-Ɣ]. Additionally, upon co-culture with PBMCs, HE4-silenced SKOV3 cells were found to be more susceptible to cytotoxic cell death. The relationship between HE4 and OPN was reinforced further through the analysis of serous ovarian cancer patient samples. In these biopsy specimens, the number of OPN+ T cells correlated positively with progression free survival (PFS) and inversely with serum HE4 level. Taken together, these findings show that HE4 enhances ovarian cancer tumorigenesis by compromising OPN-mediated T cell activation.

Serum levels of human epididymis protein 4 are more stable than cancer antigen 125 in early and mid-term pregnancy.

Previous studies have shown serum human epididymis protein 4 (HE4) and cancer antigen 125 (CA125) levels could serve as predictive markers in the diagnosis of ovarian cancer. However, HE4 levels have been less well studied during pregnancy, especially in threatened abortion, while CA125 levels were fluctuated. Our study aimed to assess the stability of HE4 and CA125 levels through trimesters and in cases of threatened abortion. Forty-six nonpregnant women (control), 167 healthy pregnant women and 46 pregnant threatened abortion (TA; 8-12 weeks pregnancy) women who visited the Obstetrics and Gynecology Hospital of Fudan University from September to December 2017 were recruited. The healthy pregnant women group included 57 women in the first trimester (T1), 55 in the second (T2) and 55 in the third (T3). Serum levels of HE4 and CA125 were measured by electrochemiluminescent immunoassay. Both HE4 and CA125 levels in the T3 group were significantly higher than in the control group (P < 0.001). There was no difference in HE4 between the control, T1 and T2 groups, while levels of CA125 in T1 group were elevated (P < 0.001). There was no difference in HE4 levels between the TA, control and T1 groups. However, the levels of CA125 in the TA group were much higher (P < 0.05). The level of HE4 was found to be more stable than that of CA125 in early and mid-pregnancy and in cases of threatened abortion.

The diagnostic value of human epididymis protein 4 as a novel biomarker in patients with renal dysfunction.

In this study, we investigated the diagnostic value of human epididymis protein 4 (HE4) in acute and chronic renal dysfunction and analyzed the correlation between HE4 levels and the results of routine renal function tests. We aimed to provide evidence to establish HE4 as a novel biomarker of renal injury and its appropriate application as a marker of ovarian cancer. We collected 259 serum samples from hospitalized patients with different causes of renal damage. HE4 serum levels were detected by chemiluminescence and the levels of serum creatinine, urea, and cystatin C were tested by conventional clinical chemical methods. The levels of HE4 were highest in the acute kidney injury groups and chronic kidney disease groups, although other groups were also significantly higher than the control group. HE4 and creatinine, urea, and cystatin C had a positive linear correlation. In contrast, HE4 and estimated glomerular filtration rate (eGFR) had a negative linear correlation, with a correlation coefficient of - 0.674 (P < 0.01). Area under the receiver-operating characteristic curve analysis showed that HE4 has higher diagnostic value compared with creatinine, urea, and cystatin C in both acute and chronic renal injury patients; however, HE4 and creatinine have a similar diagnostic value. Notably, HE4 concentration gradually increased with a decline of glomerular filtration rate, with significant differences evident between different eGFR stages. HE4 is a potential biomarker of kidney injury in acute and chronic renal dysfunction. Importantly, clinicians should be aware of this when using HE4 to diagnose ovarian cancer.

Clinical analysis of four serum tumor markers in 458 patients with ovarian tumors: diagnostic value of the combined use of HE4, CA125, CA19-9, and CEA in ovarian tumors.

PurposeTo investigate the diagnostic values of human epididymis protein 4 (HE4), carbohydrate antigen 125 (CA125), carbohydrate antigen 19-9 (CA19-9), and carcinoembryonic antigen (CEA) for ovarian tumors.MethodsThe participants were divided into three groups: 386 healthy women (control group), 262 patients with benign ovarian tumors (the benign group), and 196 patients with malignant pelvic tumors (the malignant group). The serum levels of HE4, CA125, CA19-9, and CEA were analyzed by electrochemiluminescent immunoassay.ResultsIt showed that serum levels of HE4, CA125, CA19-9, and CEA of patients with malignant ovarian tumors were significantly higher than those in the control group and benign group (P<0.01). HE4 had a high specificity (96.56%) in malignant ovarian tumors. The tumor markers HE4, CA125, CA19-9, and CEA had a sensitivity of 63.78%, 62.75%, 35.71%, and 38.78%, respectively. The combined use of two or more tumor markers (parallel test) had a higher diagnostic sensitivity but lower specificity than a single tumor marker. The combined efficiency of HE4 and CA125 was the highest, with a sensitivity and specificity of 80.10% and 69.08%, respectively. HE4 and CA125 combined with the Risk of Ovarian Malignancy Algorithm provided an efficient means of screening and diagnosis of ovarian malignancies. The diagnostic sensitivity increased to 88.52% when three or four tumor markers were used but showed no significant difference compared with the combination of HE4 and CA125 (P>0.05).ConclusionThe combination of three or four tumor markers did not improve the diagnostic efficacy when compared with the combination of HE4 and CA125.

Prognostic value of HE4 in patients with ovarian cancer.

Background There is no consensus in the medical community about the prognostic role of preoperative serum levels of human epididymis protein 4 (HE4) in ovarian cancer (OC). The purpose of this meta-analysis was to establish whether preoperative serum levels of HE4 are associated with OC prognosis. Content Eligible studies were searched for in PubMed, ClinicalTrials.gov, CNKI and Wanfang Med Online. We performed a meta-analysis of 1315 OC cases from 14 published articles. Summary Our meta-analysis demonstrated that high HE4 was associated with poor overall survival (OS) (random effects model, hazard ratio [HR]=1.91, 95% confidence interval [CI]=1.40-2.614, p<0.0001; I2=52%, p=0.04) and; progression-free survival (PFS) (random effects model, HR=1.38, 95% CI=1.13-1.69, p=0.002; I2=85%, p<0.00001). However, subgroup analysis showed that high HE4 was not associated with poor OS (fixed effects model, HR=1.86, 95% CI=0.89-3.89, p=0.1; I2=34%, p=0.22) or PFS (random effects model, HR=1.34, 95% CI=0.95-1.88, p=0.1; I2=69%, p=0.007) for studies including only Asian populations. Outlook In conclusion, this meta-analysis shows that high HE4 was associated with poor OC OS and PFS overall. However, the association of high HE4 with poor OS and PFS was not observed for Asians. Large-scale, multi-center investigations should be performed.

Increased HE4 mRNA Expression Correlates with High Level Of eIF3a mRNA And Better Survival in Women with Epithelial Ovarian Cancer.

Human epididymis protein 4 (HE4) is one of the most promising biomarkers for epithelial ovarian cancer (EOC). The majority of previous studies utilized the serum level or tissue protein expression of HE4 based upon immunohistochemistry (IHC) to evaluate the role of HE4 in the diagnosis, prognosis, and surveillance of EOC, but very little is known about HE4 mRNA expression. Eukaryotic translation initiation factor 3a (eIF3a) is implicated in oncogenesis and has been investigated extensively as a potential biomarker for malignancy. We previously reported a positive correlation between IHC expressions of eIF3a and HE4 in EOC. In the present study, we performed RT-PCR to determine mRNA expressions of HE4 and eIF3a in 30 normal ovarian tissues, 45 benign, 20 borderline and 94 malignant ovarian tumors. The association of HE4 and eIF3a mRNA expressions with clinicopathological characteristics and patient survivals was investigated. IHC was also performed in the same participants to investigate the correlation between mRNA and protein levels of HE4. HE4 mRNA level was found to be 48.42 ± 74.55 (mean ± SD, range: 0.01-343.99), significantly higher in primary EOC than in the borderline tumor, benign tumor, and normal ovarian tissue (P<0.001). The cutoff value was 13.99 for HE4 to discriminate malignant from benign tumors at 68.1% sensitivity and 93.0% specificity. By Spearman's correlation test, HE4 mRNA expression was indicated to positively correlate with serum CA125 level (r=0.530, P<0.001). Higher HE4 mRNA expression was associated with decreased frequency of lymph node metastasis (P=0.038) and better overall survival (OS) (P=0.007) in primary EOC. Multivariable analysis showed an independent prognostic value of the relative mRNA level of HE4 greater than one for OS (Hazard Ratio, 0.069, 95%CI, 0.009-0.530, P=0.010). eIF3a mRNA expression in women with primary EOC was 0.95 ± 1.19 (mean ± SD, range: 0.06-7.46), which was in a positive linear correlation with HE4 mRNA expression (r=0.310, P=0.002). In the present study, the HE4 mRNA level was unparalleled with IHC expression of HE4 (P>0.05). Collectively, our study revealed that increased HE4 mRNA expression correlates with high level of eIF3a mRNA and better survival in women with EOC, which calls for further investigations.

Clinical Usefulness of Human Epididymis Protein 4 in Lung Cancer.

Human epididymis protein 4 (HE4) has been suggested as a useful new biomarker of lung cancer; however, few relevant large-scale studies have been published. In this study, we evaluated the utility of serum HE4 for lung cancer detection. HE4 levels were measured in serum samples from 100 lung cancer patients, 57 patients with benign lung diseases, and 274 healthy controls by using a chemiluminescent immunoassay, and variations in HE4 levels were analyzed by clinical status such as lung cancer, benign lung disease, and healthy condition, Tumor, Lymph Nodes, Metastasis (TNM) stage, tumor score, and histological cancer type. Lung cancer patients had significantly higher serum HE4 levels than patients with benign lung diseases and healthy controls (P<0.0001). The area under the ROC curve for HE4 was 0.84 (95% confidence interval, 0.78–0.89; P<0.0001) between lung cancer patients and healthy controls. Serum HE4 levels were significantly higher in patients with advanced disease (according to TNM stage) than in healthy controls (P<0.0001). HE4 levels were significantly elevated in patients with tumors of all types, those of different histological subgroups, and those with the smallest tumors (P=0.002). This report supports the potential of serum HE4 as an ancillary diagnostic marker for lung cancer detection.

Serum human epididymis protein 4 levels in colorectal cancer patients.

Tumour markers are widely used for the diagnosis, staging and monitoring of colorectal cancer (CRC) patients in clinical practice. Carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) are the most frequently used biomarkers in CRC patients. A number of studies have recently investigated the presence of human epididymis protein 4 (HE4) overexpression in certain cancer types. Its significance in ovarian and endometrial cancer has been well-demonstrated. The aim of the present study was to evaluate the significance of serum HE4 levels in CRC patients. A total of 46 newly diagnosed CRC patients and 36 age- and gender-matched healthy subjects were included in the study. The concentrations of CEA and CA19-9 were also determined and compared according to HE4 levels. HE4 positivity was determined in 13 of the 46 cases (28.3%) in the CRC group, but no HE4-positive subjects were identified in the control group (0%; P=0.009). The area under the receiver operating characteristic curve for HE4 positivity was 0.641 (95% CI: 0.523-0.760). HE4 was statistically significantly positive in patients with stage III-IV disease and in those with high CA 19-9 levels (all P<0.01). To the best of our knowledge, this is the first study to investigate HE4 expression in CRC patients, and the findings suggest that it may be a useful biomarker, particularly in stage III-IV patients.

Diagnostic value of urinary-to-serum human epididymis protein 4 ratio in ovarian cancer.

Human epididymis protein 4 (HE4) is one of the best-known tumor markers for ovarian cancer (OC). Emerging evidence indicates that the evaluation of serum HE4 (S-HE4) levels may be problematic when patients have chronic kidney disease (CKD). Assaying urine for HE4 levels is non-invasive alternative for the diagnosis of OC. However, whether the combined detection of S- and urinary HE4 (U-HE4) levels distinguishes OC from CKD remains unknown. To investigate this issue, the present study recruited 31 female patients with OC, 38 female patients with CKD, and 36 healthy control (HC) females. Serum and urine samples were preoperatively collected for HE4 level detection. Receiver operating characteristic (ROC) curves were constructed to assess the diagnostic performance of S-HE4 level, U-HE4 level and the ratio of urinary-to-serum HE4 level (R-HE4). Data from the current study indicated that serum HE4 levels in the OC and CKD groups were significantly higher than that in the HC group. The U-HE4 level in the OC group was significantly higher than that in the CKD and HC groups. The highest R-HE4 was observed in the HC group, followed by the OC group, and the lowest R-HE4 was observed in the CKD group. ROC analysis demonstrated that the R-HE4 was useful in differentiating OC from CKD and HC. Based on the diagnostic interval of optimal cut-off values from 36.85 to 96.15, the sensitivity and specificity of R-HE4 in differentiating OC patients from non-OC patients were 82.6 and 85.4%, respectively. Thus, the combined detection of S- and U-HE4 levels facilitates the diagnosis of OC, and R-HE4 is an effective marker for differentiating OC from CKD.

Correlation of preoperative ROMA scores with clinical stage in epithelial ovarian cancer patients.

The significance of the Risk of Ovarian Malignancy Algorithm (ROMA) in differentiating benign and malignant ovarian lesions has been evidenced. In our clinical work, we found that advanced ovarian cancer were accompanied commonly with high ROMA scores. Thus, this study aimed to clarify the performance of ROMA in different disease stage of epithelial ovarian cancer (EOC) prior to surgery. Carbohydrate antigen (CA125) and human epididymis protein 4 (HE4) levels and ROMA scores in 221 patients with FIGO stage I, II or III/IV stage EOC were analyzed. The positive rates of CA125, HE4 and ROMA at each disease stage were calculated. Their cutoff values, sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) for distinguishing patients with FIGO stage I/II from those with FIGO stage III/IV were estimated via ROC curves. Serum CA125 and HE4 levels and ROMA scores rose significantly with advancing stage. ROMA and CA125 were significantly elevated more frequently in comparing with HE4 in EOC patients at with the same stage. Based on ROC curves, the cutoff values for FIGO stage III/IV EOC were 110IU/mL, 126pmol/L, 78 and 68% for CA125, HE4, premenopausal and postmenopausal ROMA, respectively. ROMA was the strongest predictor of FIGO stage, with the highest specificity, accuracy, and PPV, which were 84.4, 82.5, and 87.0% for postmenopausal patients, 89.3, 85.6, and 74.3% for premenopausal patients. Our data suggest high ROMA scores correlated with advanced ovarian cancer prior to surgery. These observations suggest potential utility of ROMA in the comprehensively preoperative evaluation of EOC patients.

The clinical significance of DJ-1 and HE4 in patients with endometrial cancer.

The non-invasive diagnostic approach for early detection of endometrial cancer (EC) remains limited. To date, human epididymis protein 4 (HE4) has been intensively studied but its diagnostic is controversial in EC. DJ-1 is an oncoprotein secreted by cancer cells, recently identified as a potential diagnostic biomarker for breast cancer, melanoma, and pancreatic cancer. The aim of this study was to compare the diagnostic performances of DJ-1 and HE4 measured in EC patients and healthy controls (HC). Forty-five patients (63.9±12.0years) with EC and 29 (63.2±13.3years) HC were enrolled. Serum concentrations of DJ-1 and HE4 were measured using ELISA kits developed by R&D (Minneapolis, USA) and Fujirebio Diagnostic (Malvern, PA, USA), respectively. Differences between EC patients and HC were assessed by Mann-Whitney test and associations were tested by Spearman's correlation. The diagnostic performance was assessed using receiver operating characteristics (ROC) curves analysis. Serum DJ-1 concentrations were found to be higher in EC patients than in HC (9533.6 vs 1988.5pg/mL; P<.0001). The area under the ROC curve (ROC-AUC) was 0.95 (P<.0001). At the cut-off of 3654pg/mL, the sensitivity and specificity were 0.89 and 0.90, respectively. HE4 serum levels were higher in EC patients than in HC (75.3 vs 56.2pmol/L; P=.019), with an AUC of 0.66 (P=.020). The AUC obtained by the combination of the two markers resulted 0.96 (P<.0001). These results suggest that increased serum DJ-1 levels are associated with EC and that this biomarker may be potentially useful for diagnosing EC.

Diagnostic Performance of Serum Human Epididymis Protein 4 in Endometrial Carcinoma: A Pilot Study.

Endometrial Cancer (EC) is a common female malignant disorder. To date, there are no specific tumour markers for EC that may be routinely used in clinical practice for diagnosis. To evaluate the diagnostic performance of the serum Human Epididymis protein 4 (HE4) as biomarker for EC and to determine its association with clinicopathological variables. The study population included 60 postmenopausal women with a diagnosis of EC and 60 healthy postmenopausal female subjects (control group). Concentrations of serum HE4 and CA-125 in EC patients and control group were determined using Enzyme-Linked Immunosorbent Assays (ELISA). The value of serum HE4 and CA-125 for the diagnosis and prediction of stage, histology, myometrial invasion and lymph nodal metastasis was analysed. The mean serum HE4 and CA-125 levels were significantly higher in patients with EC than those with control group (p<0.05). Comparison for HE4 and CA-125 between different stages showed a statistically significant difference. Stage I EC patients with <50% myometrial invasion had a significantly lower mean serum HE4 value than patients with >50% myometrial invasion (p=0.007). Corresponding values of CA-125 showed a similar trend (p=0.023). There were significantly higher levels of HE4 and CA-125 in cases with lymph node involvement. The levels of serum HE4 and CA-125 were higher in the non-endometroid histology, but the difference was not statistically significant. The Receiver Operating Characteristics (ROC) curve analysis for EC and control group showed that HE4 had greater Area Under Curve (AUC) when compared with CA-125. Using ROC curve, a serum HE4 concentration of 69.8 pmol/l (AUC 0.974) and/or serum CA-125 level of 34.50 U/mL (AUC 0.714) was used to predict malignancy. Sensitivity of combined biomarkers showed no additional improvement in comparison to HE4 or CA-125 alone. Our results show that HE4 is a sensitive diagnostic serum marker for detection of EC patients, exhibiting a better diagnostic performance compared to CA-125. Good performance of HE4 in diagnosis of early stages EC indicates its usefulness as a prognostic marker and also to monitor therapy and detect early recurrence.

HE4 as a predictor of adjuvant chemotherapy resistance and survival in patients with epithelial ovarian cancer.

The aim of this study was to investigate the value of serum human epididymis protein 4 (HE4) and HE4 tissue protein expression to predict tumor resistance to adjuvant chemotherapy, progression-free survival (PFS), and overall survival in patients with epithelial ovarian cancer (EOC). Consecutive inclusion of 198 patients diagnosed with EOC was conducted. Blood samples were collected prior to surgery and tissue samples during surgery. Patient data were registered prospectively in the Danish Gynecologic Cancer Database. The association between serum HE4 and HE4 tissue protein expression, resistance to adjuvant chemotherapy, PFS, and overall survival were analyzed in univariate analyses and in multivariate analyses adjusted for age, performance score, surgical outcome, stage, grade, and histological subtype. Serum HE4 levels predicted chemotherapy resistance, PFS, and overall survival correlated significantly (p < 0.001) in the univariate analyses; but after adjustment in a multivariate model, serum HE4 was insignificant, except in a subgroup analysis of postmenopausal women, where serum HE4 significantly predicted resistance to chemotherapy and progression-free survival. HE4 tissue protein expression predicted PFS (p = 0.022) and overall survival (p = 0.047) in the univariate analysis, while HE4 tissue protein expression failed to predict these outcomes in the adjusted multivariate analyses. Serum HE4 or HE4 tissue protein expression are not independent factors of chemotherapy resistance or survival in patients with EOC, but serum HE4 might predict chemotherapy resistance and PFS in postmenopausal women.

Elevated serum concentrations of HE4 as a novel biomarker of disease severity and renal fibrosis in kidney disease.

BackgroundHuman epididymis protein 4 (HE4), has recently been reported as a mediator of renal fibrosis. However, serum HE4 levels appear in a large number of patient samples with chronic kidney disease (CKD), and the relationship of these levels to disease severity and renal fibrosis is unknown.MethodsIn 427 patients at different stages of CKD excluding gynecologic cancer and 173 healthy subjects, serum HE4 concentrations were tested by chemiluminescent microparticle immunoassay. Renal biopsy was performed on 259 of 427 subjects. Histological findings were evaluated using standard immunohistochemistry.ResultsThe levels of serum HE4 were higher in CKD patients than in healthy subjects, and higher levels were associated with more severe CKD stages. Patients with more severe renal fibrosis tended to have higher HE4 levels, and correlation analysis showed a significant correlation between HE4 and degree of renal fibrosis (r = 0.938, P < 0.0001). HE4 can be a predictor of renal fibrosis in CKD patients; the area under the receiver-operating characteristic curve (AUC-ROC) was 0.99, higher than the AUC-ROC of serum creatinine (0.89).ConclusionElevated levels of serum HE4 are associated with decreased kidney function, and also with an advanced stage of renal fibrosis, suggesting that HE4 may serve as a valuable clinical biomarker for renal fibrosis of CKD.