Difference in the seminal plasma protein expression in unexplained infertile men with successful and unsuccessful in vitro fertilisation outcome.

Unexplained male infertility (UMI) is a condition in which routine semen analysis fails to detect subcellular sperm dysfunctions. In the present research, a comparative proteomics study of seminal plasma (SP) was conducted in men with unexplained infertility whose female partners had undergone in vitro fertilisation (IVF) treatment to find differences in the SP protein profile. Five UMI men with successful and eight with unsuccessful IVF outcome enrolled in this study. Two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) technique was used for protein separation. The differentially expressed proteins were identified using mass spectrometry. Results indicated that at least two different protein spots, including clusterin and epididymal secretory protein E1, were over-expressed (1.5- and 2-fold change, respectively, p < 0.05) while prostate-specific antigen was downregulated (0.3-fold change, p < 0.05) in the successful group as compared with the unsuccessful group. Considering the role of all three identified proteins in the sperm quality, the results of the present study introduced these proteins as new candidate biomarkers for success of IVF in UMI couples.

Post-testicular sperm maturation and identification of an epididymal protein in the Japanese quail (Coturnix coturnix japonica).

The role of the avian epididymis in post-testicular development and capacitation was examined to assess whether avian spermatozoa undergo any processes similar to those characteristic of mammalian sperm development. We found no evidence of a need for quail sperm to undergo capacitation and 90% of testicular sperm could bind to a perivitelline membrane and acrosome react. However, computer-assisted sperm analysis showed that 20% of testicular sperm from the quail were capable of movement and only about 12% of the motile sperm would have a curvilinear velocity greater than the mean for sperm from the distal epididymis. Nevertheless, epididymal transit was associated with increases in mean sperm velocity and the proportion of motile sperm. Together, these findings explain why earlier workers have achieved some fertilizations following inseminations of testicular spermatozoa and also demonstrate the need for some epididymal maturation of avian spermatozoa. Analysis of the electrophoretic profile of quail epididymal luminal proteins revealed that only one major protein (∼16 kDa) is secreted by the epididymis and it was virtually the only protein secreted by the ipsilateral epididymis following unilateral orchidectomy. Mass spectrometry showed that this protein is hemoglobin; this finding was confirmed using anti-hemoglobin antibodies. It is suggested that hemoglobin may support sperm metabolism in the quail epididymis, aid in motility, and/or serve as an antioxidant.

The role of novel biomarker HE4 in endometrial cancer: a case control prospective study.

The aim of the study was to explore the clinical value of serum human epididymis secretory protein E4 (HE4) and CA125 in endometrial carcinoma. From January 2010 to April 2012, serum specimens were collected from consecutive cases of endometrial carcinoma and from cases of uterus benign disease (control group). The CA125 normal value is considered less than 35 U/mL. Two HE4 cutoff are considered: less than 70 pmol/L and less than 150 pmol/L. The specificity analysis was performed using the Mann-Whitney test for the CA125 and HE4 series. The level of statistical significance is set at p < 0.05. The sensitivity of CA125 in detecting endometrial cancer is 19.8 %, whereas the sensitivity of HE4 is 59.4 and 35.6 % for 70 and 150 pmol/L cutoff, respectively. Thus the specificity of HE4 is 100 % (positive predictive value = 100 %, negative predictive value = 71.52 and 61.31 % considering the two HE4 cutoff, respectively), whereas the CA125 specificity is 62.14 % (positive predictive value = 33.9 %, negative predictive value = 44.14 %) in detection of endometrial cancer. Combining CA125 and HE4, the sensitivity to detect endometrial cancer is 60.4 and 34.6 %, at HE4 cutoff of 70 and 150 pmol/L, respectively, with a specificity of 100 %. HE4 may be a new tool for preoperative evaluation and postoperative surveillance of endometrial cancer patients, with a positive predictive value = 100 %. HE4 at cutoff of 70 pmol/L yields the best sensitivity and specificity.

Improving strategies for diagnosing ovarian cancer: a summary of the International Ovarian Tumor Analysis (IOTA) studies.

In order to ensure that ovarian cancer patients access appropriate treatment to improve the outcome of this disease, accurate characterization before any surgery on ovarian pathology is essential. The International Ovarian Tumor Analysis (IOTA) collaboration has standardized the approach to the ultrasound description of adnexal pathology. A prospectively collected large database enabled previously developed prediction models like the risk of malignancy index (RMI) to be tested and novel prediction models to be developed and externally validated in order to determine the optimal approach to characterize adnexal pathology preoperatively. The main IOTA prediction models (logistic regression model 1 (LR1) and logistic regression model 2 (LR2)) have both shown excellent diagnostic performance (area under the curve (AUC) values of 0.96 and 0.95, respectively) and outperform previous diagnostic algorithms. Their test performance almost matches subjective assessment by experienced examiners, which is accepted to be the best way to classify adnexal masses before surgery. A two-step strategy using the IOTA simple rules supplemented with subjective assessment of ultrasound findings when the rules do not apply, also reached excellent diagnostic performance (sensitivity 90%, specificity 93%) and misclassified fewer malignancies than did the RMI. An evidence-based approach to the preoperative characterization of ovarian and other adnexal masses should include the use of LR1, LR2 or IOTA simple rules and subjective assessment by an experienced examiner.

The utility of human epididymal protein 4, cancer antigen 125, and risk for malignancy algorithm in ovarian cancer and endometriosis.

BACKGROUND: In women with pelvic mass, cancer antigen 125 (CA125) had not achieved satisfactory sensitivity and specificity in the detection of ovarian cancer, particularly in patients with underlying endometriosis. The aim of this study was to determine the diagnostic potential of human epididymal protein 4 (HE4), the combination of HE4+CA125, and the Risk of Ovarian Malignancy Algorithm (ROMA) for patients with pelvic mass, particularly in differentiating endometriosis from carcinoma. METHODS: A prospective cross-sectional study was conducted at the Clinic for Gynecology and Obstetrics, Clinical Center of Serbia. Serum samples were obtained preoperatively from 108 women undergoing surgery for pelvic mass; 29 of them had ovarian carcinoma, and 79 had a nonmalignant ovarian disease (39 with benign tumor, 20 with endometriosis, 20 healthy controls). Sera were analyzed for the levels of HE4 and CA125 and were then compared with the final pathologic results. The diagnostic performance of HE4 and CA125 was estimated using receiver operating characteristic curve and area under the receiver operating characteristic curve. RESULTS: The level of HE4 and CA125 was significantly higher among the patients with malignant tumors, compared with patients with nonmalignant disease. At the predefined specificity of 95%, HE4 and CA125 showed sensitivity of 65.5% and 58.6%, respectively, whereas the combination of HE4+CA125 reached 68.9% at the same specificity. Importantly, the level of HE4 did not differ significantly between the patients with endometriosis and with other nonmalignant diseases (which was not the case with CA125). Risk of Ovarian Malignancy Algorithm classified 96% of benign premenopausal cases as at low risk for ovarian cancer. CONCLUSIONS: HE4 showed satisfactory capability of distinguishing endometriosis from ovarian cancer, which CA125 lacked. The Risk of Ovarian Malignancy Algorithm score proved to be useful in excluding malignant diagnosis in premenopausal women.

Systematic mapping and functional analysis of a family of human epididymal secretory sperm-located proteins.

The mammalian spermatozoon has many cellular compartments, such as head and tail, permitting it to interact with the female reproductive tract and fertilize the egg. It acquires this fertilizing potential during transit through the epididymis, which secretes proteins that coat different sperm domains. Optimal levels of these proteins provide the spermatozoon with its ability to move to, bind to, fuse with, and penetrate the egg; otherwise male infertility results. As few human epididymal proteins have been characterized, this work was performed to generate a database of human epididymal sperm-located proteins involved in maturation. Two-dimensional gel electrophoresis of epididymal tissue and luminal fluid proteins, followed by identification using MALDI-TOF/MS or MALDI-TOF/TOF, revealed over a thousand spots in gels comprising 745 abundant nonstructural proteins, 408 in luminal fluids, of which 207 were present on spermatozoa. Antibodies raised to 619 recombinant or synthetic peptides, used in Western blots, histological sections, and washed sperm preparations to confirm antibody quality and protein expression, indicated their regional location in the epididymal epithelium and highly specific locations on washed functional spermatozoa. Sperm function tests suggested the role of some proteins in motility and protection against oxidative attack. A large database of these proteins, characterized by size, pI, chromosomal location, and function, was given a unified terminology reflecting their sperm domain location. These novel, secreted human epididymal proteins are potential targets for a posttesticular contraceptive acting to provide rapid, reversible, functional sterility in men and they are also biomarkers that could be used in noninvasive assessments of male fertility.

HE4 and CA125 as a diagnostic test in ovarian cancer: prospective validation of the Risk of Ovarian Malignancy Algorithm.

BACKGROUND: Recently, a Risk of Ovarian Malignancy Algorithm (ROMA) utilising human epididymis secretory protein 4 (HE4) and CA125 successfully classified patients as presenting a high or low risk for epithelial ovarian cancer (EOC). We validated this algorithm in an independent prospective study. METHODS: Women with a pelvic mass, who were scheduled to have surgery, were enrolled in a prospective study. Preoperative serum levels of HE4 and CA125 were measured in 389 patients. The performance of each of the markers, as well as that of ROMA, was analysed. RESULTS: When all malignant tumours were included, ROMA (receiver operator characteristic (ROC)-area under curve (AUC)=0.898) and HE4 (ROC-AUC)=0.857) did not perform significantly better than CA125 alone (ROC-AUC=0.877). Using a cutoff for ROMA of 12.5% for pre-menopausal patients, the test had a sensitivity of 67.5% and a specificity of 87.9%. With a cutoff of 14.4% for post-menopausal patients, the test had a sensitivity of 90.8% and a specificity of 66.3%. For EOC vs benign disease, the ROC-AUC of ROMA increased to 0.913 and for invasive EOC vs benign disease to 0.957. CONCLUSION: This independent validation study demonstrated similar performance indices to those recently published. However, in this study, HE4 and ROMA did not increase the detection of malignant disease compared with CA125 alone. Although the initial reports were promising, measurement of HE4 serum levels does not contribute to the diagnosis of ovarian cancer.

Diagnostic and prognostic impact of serum HE4 detection in endometrial carcinoma patients.

BACKGROUND: To date, no good marker for screening or disease monitoring of endometrial cancer (EC) is available. The aims of this study were to investigate HE4 gene, protein expression and serum HE4 (sHE4) levels in a panel of ECs and normal endometria (NEs) and to correlate sHE4 with patient clinicopathological characteristics and prognosis. METHODS: Using quantitative real-time PCR we tested 46 ECs and 20 NEs for HE4 gene expression. Protein expression was analysed by immunohistochemistry on tissue microarrays in 153 ECs and 33 NEs. Pre-operative serum samples from 138 EC and 76 NE patients were analysed with HE4-EIA assay. Association between sHE4 and patient clinicopathological characteristics or outcome was evaluated. RESULTS: Protein and HE4 gene were significantly upregulated in EC tissues and sera, compared with controls. High sHE4 levels were significantly associated with worse EC clinical characteristics. By univariate survival analysis, high sHE4 levels significantly correlated with decreased overall survival, progression-free survival and disease-free survival, retaining their independent prognostic value on the poorly differentiated EC cohort. CONCLUSION: We demonstrate, for the first time, that high sHE4 levels correlates with an aggressive EC phenotype and may constitute an independent prognostic factor for poorly differentiated-ECs. Determination of sHE4 could be clinically useful in identifying high-risk EC patients for a more aggressive adjuvant therapy.

Comparison of serum human epididymis protein 4 with cancer antigen 125 as a tumor marker in patients with malignant and nonmalignant diseases.

BACKGROUND: Human epididymis protein 4 (HE4), a precursor of human epididymis protein, has been proposed as a tumor marker for ovarian cancer. We evaluated HE4 in comparison with cancer antigen 125 (CA 125) in healthy individuals and in patients with benign and malignant diseases. METHODS: CA 125 and HE4 serum concentrations were determined in 101 healthy individuals, 535 patients with benign pathologies (292 with benign gynecologic diseases) and 423 patients with malignant diseases (127 with ovarian cancers). CA 125 and HE4 cutoffs were 35 kU/L and 140 pmol/L, respectively. RESULTS: HE4 and CA 125 results were abnormal in 1.1% and 9.9% of healthy individuals and in 12.3% and 37% of patients with benign diseases, respectively. Renal failure was the most common cause of increased HE4 in patients with benign disease, who had significantly higher HE4 concentrations (P = 0.001) than patients with other benign diseases. HE4 showed a higher specificity than CA 125 in patients with benign gynecologic diseases, with abnormal concentrations in 1.3% and 33.2% of the patients, respectively. HE-4 concentrations were abnormal primarily in gynecologic cancer and lung cancer. By contrast, CA 125 was increased in many different nonovarian malignancies, including nonepithelial tumors. A significantly higher area under the ROC curve was obtained with HE4 than with CA 125 for differentiating benign from malignant diseases (0.755 vs 0.643) and in the differential diagnosis of gynecologic diseases (0.874 vs 0.722). CONCLUSIONS: HE4 has significantly higher diagnostic specificity than CA 125, and the combination of CA 125 and HE4 improved the detection of ovarian cancer in all stages and histological types.

Prognostic significance of HE4 expression in pulmonary adenocarcinoma.

We investigated the possibility of human epididymis 4(HE4) to predict survival for patients with pulmonary adenocarcinoma. One hundred and thirty-seven patients with pulmonary adenocarcinoma underwent surgery in our institute from 2000 to 2008. We used immunohistochemical analysis to determine the expression of HE4 and compared with the clinicopathological factors and survival. Serum levels of HE4 in lung adenocarcinoma were investigated by enzyme immunometric assay. Fifty-seven of 137 cases (41.6%) were HE4 positive. It was found that there was no correlation between HE4 expression by immunohistochemistry and clinicopathological factors, however, adenocarcinoma subtype was significantly associated with HE4 expression. Sera in lung adenocarcinoma were significantly higher than in healthy control. Five-year disease-free survival in the HE4-positive group (44.6%) was significantly different from that in the negative group (82.3%, p = 0.001) by immunohistochemistry. The five-year overall survival rate was 60.1% in the HE4-positive group, as compared with 90.8% in the HE4-negative group (p = 0.001). In multivariate Cox regression analysis, positive HE4 protein expression was a worse prognosis factor of disease-free and overall survival (HR = 3.7, 95%CI = [1.7-8.4], p = 0.001; HR = 5.5, 95%CI = [1.8-17.2], p = 0.003, respectively), in addition to nodal status as a powerful value. When HE4 expression in adenocarcinoma cases except the BAC were analyzed, nodal status and HE4 expression were independent prognostic factors in disease-free and overall survivals. These data showed that HE4 expression is associated with a worse prognosis and is a possible prognostic factor of lung adenocarcinoma.

HE4 a novel tumour marker for ovarian cancer: comparison with CA 125 and ROMA algorithm in patients with gynaecological diseases.

The aim of this study is to evaluate a new tumour marker, HE4, in comparison with CA 125 and the Risk of Ovarian Malignancy Algorithm (ROMA) in healthy women and in patients with benign and malignant gynaecological diseases. CA 125 and HE4 serum levels were determined in 66 healthy women, 285 patients with benign gynaecological diseases (68 endometriosis, 56 myomas, 137 ovarian cysts and 24 with other diseases), 33 patients with non-active gynaecological cancer and 143 with active gynaecological cancer (111 ovarian cancers). CA 125 and HE4 cut-offs were 35 U/mL and 150 pmol/L, respectively. ROMA algorithm cut-off was 13.1 and 27.7 for premenopausal or postmenopausal women, respectively. HE4, CA 125 and ROMA results were abnormal in 1.5%, 13.6% and 25.8% of healthy women and in 1.1%, 30.2% and 12.3% of patients with benign diseases, respectively. Among patients with cancer, HE4 (in contrast to CA 125) had significantly higher concentrations in ovarian cancer than in other malignancies (p < 0.001). Tumour marker sensitivity in ovarian cancer was 79.3% for HE4, 82.9% for CA 125 and 90.1% for ROMA. Both tumour markers, HE4 and CA 125 were related to tumour stage and histological type, with the lowest concentrations in mucinous tumours. A significantly higher area under the ROC curve was obtained with ROMA and HE4 than with CA 125 in the differential diagnosis of benign gynaecological diseases versus malignant ovarian cancer (0.952, 0.936 and 0.853, respectively). Data from our population indicate that ROMA algorithm might be further improved if it is used only in patients with normal HE4 and abnormal CA 125 serum levels (cancer risk for this profile is 44.4%). ROMA algorithm in HE4 positive had a similar sensitivity and only increases the specificity by 3.2% compared to HE4 alone.

Progranulin is a potential prognostic biomarker in advanced epithelial ovarian cancers.

OBJECTIVE: There are few validated relapse prediction biomarkers for epithelial ovarian cancer (EOC). We have shown progranulin (PGRN) and secretory leukocyte protease inhibitor (SLPI) are up regulated, overexpressed survival factors in EOC. We hypothesized they would predict presence of occult EOC. METHOD: PGRN, SLPI, and the known biomarker HE4 were measured in EOC patient plasma samples, prospectively collected every 3 months from initial remission until relapse. Clinical data and CA125 results were incorporated into statistical analyses. Exploratory Kaplan-Meier estimates, dividing markers at median values, evaluated association with progression-free survival (PFS) and overall survival (OS). Area-under-the-curve (AUC) statistics were computed from receiver operating characteristic (ROC) curves to evaluate discrimination ability. A Cox proportional hazards model assessed the association between PFS, OS, and biomarkers, adjusting for clinical prognostic factors. RESULTS: Samples from 23 advanced stage EOC patients were evaluated. PGRN at 3 months was the only biomarker independently associated with PFS (P<0.0001) and OS (P<0.003). When used to predict progression by 18 months, sensitivity and specificity were 93% and 100%, respectively, with AUC=0.944. The Cox model hazard ratio for PFS, divided at 59 ng/ml by ROC analysis and adjusted for clinical factors, was 23.5 (95% CI: 2.49-220). Combinations with SLPI, HE4, and/or CA125 did not improve the model. CONCLUSIONS: We report pilot data indicating a potential independent association of PGRN on EOC patient PFS and OS. A validation study will be required to confirm this finding and to inform whether PGRN warrants evaluation as a potential screening biomarker.

No benefit from combining HE4 and CA125 as ovarian tumor markers in a clinical setting.

OBJECTIVE: About 70% of epithelial ovarian cancer patients (EOC) are diagnosed at advanced stage with a five-year survival rate of only 30%. Whilst CA125 detects peritoneally-spread disease, it has limited sensitivity for early cancers, many of which are potentially curable. METHODS: We compared the new commercially available tumor marker HE4 with CA125 individually, in combination, within the risk of malignancy index (RMI) and the newly defined risk of malignancy algorithm (ROMA). Our prospectively-collected cohort of 160 patients consisted of healthy controls, benign diseases, and borderline tumors/adenocarcinomas of ovarian, tubal, peritoneal and endometrial origin. HE4 and CA125 were measured in serum using standardized ELISA. RESULTS: Both markers showed similar diagnostic performance in the detection of EOC at clinically defined thresholds (CA125 35U/ml; HE4 70pM) but HE4 was not elevated in endometriosis. Comparison of non-malignant diagnoses (n=71) versus early stage ovarian and tubal cancers (n=19) revealed that HE4 and ROMA displayed the best diagnostic performance (AUC 0.86/0.87, specificity 85.9%/87.3% and sensitivity 78.9%/78.9%, respectively). Whilst RMICA125 detects peritoneal cancer better than all other models (AUC 0.99, specificity 97.2%, sensitivity 80.0%), there is no other detection benefit from RMI compared to HE4 alone or included in ROMA. CONCLUSIONS: The major advantage of HE4 lies in its specificity and improved detection of borderline tumors and early stage ovarian and tubal cancers. HE4 is superior to CA125 with or without RMI and ROMA indices. However, we see no benefit from combining both markers in clinical practice.

Human epididymis protein 4 offers superior specificity in the differentiation of benign and malignant adnexal masses in premenopausal women.

OBJECTIVE: We sought to assess the ability of human epididymis protein 4 (HE4) and CA-125 to distinguish among benign, borderline, and malignant pelvic masses in premenopausal women. STUDY DESIGN: We conducted a subset analysis of data from a prospective clinical trial that enrolled women undergoing surgery for an adnexal mass. Diagnostic performance of CA-125 and HE4 for epithelial ovarian cancer (EOC) detection in premenopausal women was determined. RESULTS: Of 229 premenopausal patients, 195 (85%) had benign masses, 18 (8%) had EOC, and 16 (7%) had borderline ovarian tumor. The sensitivity of CA-125 and HE4 for EOC detection was 83.3% and 88.9%, respectively. The specificity of CA-125 and HE4 was 59.5% and 91.8%, respectively. A normal HE4 level ruled out invasive cancer in 98% of women with an elevated CA-125. CONCLUSION: HE4 offers superior specificity compared to CA-125 for the differentiation of benign and malignant adnexal masses in premenopausal women.

The diagnostic accuracy of two human epididymis protein 4 (HE4) testing systems in combination with CA125 in the differential diagnosis of ovarian masses.

BACKGROUND: Cancer antigen 125 (CA125) is the best known single tumor marker for ovarian cancer (OC). We investigated whether the additional information of the human epididymis protein 4 (HE4) improves diagnostic accuracy. METHODS: We retrospectively analyzed preoperative sera of 109 healthy women, 285 patients with benign ovarian masses (cystadenoma: n=78, leimyoma: n=66, endometriosis: n=52, functional ovarian cysts: n=79, other: n=10), 16 low malignant potential (LMP) ovarian tumors and 125 OC (stage I: 22, II: 15, III: 78, IV: 10). CA125 was analyzed using the ARCHITECT system, HE4 using the ARCHITECT(a) system and EIA(e) technology additionally. RESULTS: The lowest concentrations of CA125 and HE4 were observed in healthy individuals, followed by patients with benign adnexal masses and patients with LMP tumors and OC. The area under the curve (AUC) for the differential diagnosis of adnexal masses of CA125 alone was not significantly different to HE4 alone in premenopausal (CA125: 86.7, HE4(a): 82.6, HE4(e): 81.6% p>0.05) but significantly different in postmenopausal [CA125: 93.4 vs. HE4(a): 88.3 p=0.023 and vs. HE4(e): 87.8% p=0.012] patients. For stage I OC, HE4 as a single marker was superior to CA125, which was the best single marker in stage II-IV. The combination of CA125 and HE4 using risk of malignancy algorithm (ROMA) gained the highest sensitivity at 95% specificity for the differential diagnosis of adnexal masses [CA125: 70.9, HE4(a): 67.4, HE4(e): 66.0, ROMA(a): 76.6 and ROMA(e): 74.5%], especially in stage I OC [CA125: 27.3, HE4(a): 40.9, HE4(e): 40.9, ROMA(a): 45.5 and ROMA(e): 45.5%]. CONCLUSIONS: CA125 is still the best single marker in the diagnosis of OC. HE4 alone and even more the combined analysis of CA125 and HE4 using ROMA improve the diagnostic accuracy of adnexal masses, especially in early OC.

Evaluation of the accuracy of serum human epididymis protein 4 in combination with CA125 for detecting ovarian cancer: a prospective case-control study in a Korean population.

BACKGROUND: This study aimed to determine the serum concentrations of CA125 and human epididymis protein 4 (HE4) in patients with ovarian cancer, and to evaluate the sensitivity and specificity of these biomarkers for differentiating between patients with benign gynecological disease and those with ovarian cancer, when used alone and in combination in a Korean population. METHODS: We consecutively recruited 159 women with an adnexal mass, including 78 women with ovarian cancer. A total of 224 healthy women served as controls. The serum concentrations of HE4 and CA125 were analyzed using immunochemiluminescence assays. The concentrations of the markers were compared among the different subgroups, and the diagnostic accuracy of each marker and the combination of the two markers was assessed by plotting receiver operating characteristic (ROC) curves. In addition, the Risk of Ovarian Malignancy Algorithm (ROMA) was utilized to categorize patients into low- and high-risk groups for epithelial ovarian cancer. RESULTS: Serum HE4 and CA125 concentrations were significantly higher in the ovarian cancer patients compared with those seen in patients with benign disease or in the healthy controls (p<0.0001 in both). In patients with an adnexal mass, the area under the ROC curve was higher when the combination of the markers was used compared with use of CA125 only. Using ROMA, patients could be successfully classified into high- and low-risk group, with 87.5% sensitivity at a specificity of 93.8%. CONCLUSIONS: These findings suggest that measuring serum HE4 concentrations along with CA125 concentrations may provide higher accuracy for detecting ovarian cancer.

The ROMA (Risk of Ovarian Malignancy Algorithm) for estimating the risk of epithelial ovarian cancer in women presenting with pelvic mass: is it really useful?

BACKGROUND: The study is aimed at evaluating the performance of the predictive model ROMA (Risk of Ovarian Malignancy Algorithm), which utilizes the combination of human epididymis protein 4 (HE4) and CA125 values to assess the risk of epithelial ovarian cancer (EOC) in women with a pelvic mass. METHODS: One hundred and four women diagnosed with a pelvic mass (55 EOC and 49 benign cases) and scheduled to have surgery were enrolled, along with 49 healthy females. Preoperative serum concentrations of HE4 and CA125 were measured. Separate logistic regression algorithms ROMA for pre-menopausal and post-menopausal women were used to categorize patients into low- and high-risk groups for EOC. The area under the curve (AUC), sensitivity and specificity were calculated for HE4, CA125 and ROMA for the diagnosis of ovarian cancer using receiver operating characteristic (ROC) analysis. RESULTS: The median CA125 and HE4 serum concentrations were significantly higher among EOC patients than in healthy females (both p<0.05) and those with a benign mass (both p<0.05). The pre-menopausal group included 36 benign cases (29 of which were classified by ROMA as low-risk with a specificity of 80.6%; 95% CI: 64.0%-91.8%), and 15 EOC (eight of which were classified by ROMA as high-risk, with a sensitivity of 53.3%; 95% CI: 26.6%-78.7%). The post-menopausal group enclosed 13 benign cases (11 of which were classified by ROMA as low-risk with a specificity of 84.6%; 95% CI: 54.6%-98.0%), and 40 EOC (33 of which were classified by ROMA as high-risk with a sensitivity of 82.5%; 95% CI: 67.2%-92.7%). In the pre-menopausal group, the AUC was 0.64 (p=0.12, 95% CI: 0.44-0.83) for CA125, 0.77 (p=0.003, 95% CI: 0.62-0.92) for HE4 and 0.77 (p=0.002, 95% CI: 0.63-0.92) for ROMA. In the post-menopausal group, the AUC was 0.84 (p=0.0003, 95% CI: 0.73-0.94) for CA125, 0.94 (p<0.0001, 95% CI: 0.88-0.99) for HE4 and 0.92 (p<0.0001, 95% CI: 0.85-0.99) for ROMA. CONCLUSIONS: The ROMA is a simple scoring system which shows excellent diagnostic performance for the detection of EOC in post-menopausal women, but not in pre-menopausal women. Moreover, the dual marker combination of HE4 and CA125 (ROMA) does not show better performance than HE4 alone.

Utility of tumor marker HE4 to predict depth of myometrial invasion in endometrioid adenocarcinoma of the uterus.

OBJECTIVE: The purpose of this pilot study was to determine whether the biomarker human epididymis protein 4 (HE4) correlates with depth of myometrial invasion, histologic grade, lymph vascular space invasion, positive cytologic washings, and nodal metastases in patients with endometrioid adenocarcinoma of the uterus. METHODS: This was a prospective, observational study in women with biopsy-proven endometrioid adenocarcinoma. Concentrations of HE4 were assessed before surgery, and all surgical specimens were reviewed by dedicated gynecologic pathologists. RESULTS: Included were a total of 96 women with endometrioid adenocarcinomas of the uterus, most (77%) with stage I disease. Levels of serum HE4 greater than 70 pM displayed a sensitivity of 94% and a negative predictive value of 97% in identifying stage IA (<50% myometrial invasion) versus stage IB (≥ 50% myometrial invasion) tumors and a sensitivity of 82% and negative predictive value of 82% versus all more advanced tumors. CONCLUSIONS: Human epididymis protein 4 may be a useful marker preoperatively in the clinical decision process for determining the need for lymph node dissection in women with endometrioid endometrial cancer.

Human epididymis protein 4 (HE4) as a serum tumor biomarker in patients with ovarian carcinoma.

BACKGROUND: Ovarian cancer remains a leading cause of death from gynecological malignancy. Early diagnosis is the most important determinant of survival. For more than 25 years, cancer antigen 125 (CA 125) has been the criterion standard biomarker for the diagnosis and management of women with epithelial ovarian cancer. This study evaluated human epididymis protein 4 (HE4), a novel ovarian cancer biomarker, both alone and in combination with CA 125 as a diagnostic marker for ovarian cancer in a Chinese population. METHODS: Sera from 491 Chinese women with ovarian cancer or nonmalignant disorders and healthy women were analyzed. Sensitivities and specificities for both biomarkers and the combination were determined using predefined cutoffs (HE4>150 pmol/L and CA 125>35 U/mL) and receiver operator characteristic curves to define cutoffs based on 95% and 98% sensitivities. RESULTS: At baseline, serum HE4 and CA 125 levels were significantly higher in the ovarian cancer group versus the 5 reference groups. Using predefined cutoffs, HE4 specificity for ovarian cancer ranged from 90% to 100%; CA 125 specificity ranged from 36% (benign gynecologic disease) to 99%. Combining both markers yielded specificity for ovarian cancer of 100%. Using receiver operator characteristic curve analysis, the cutoff for 95% and 98% specificity was 102.6 and 150.2 pmol/L for HE4, respectively, and 127.2 and 325.5 U/mL for CA 125, respectively; the sensitivity of CA 125 for distinguishing ovarian cancer from benign gynecologic disease was 54% (95% specificity) and 28% (98% specificity), improving to 78% and 68%, respectively, with the addition of HE4. CONCLUSIONS: Human epididymis protein 4 used in conjunction with CA 125 yields improved specificity for ovarian cancer compared with the use of CA 125 alone, generally similar to results seen in non-Chinese populations.

Comparison of different ovarian cancer detection algorithms.

UNLABELLED: The objective of the study was to evaluate the accuracy of a combined-two step ovarian cancer screening tool consisting of the ovarian cancer symptom index combined with either a risk of ovarian malignancy algorithm (ROMA) or a risk of malignancy index. MATERIAL AND METHODS: The case-control study consisted of 31 patients with ovarian cancer, 30 patients with benign ovarian diseases and 27 age-matched healthy controls. RESULTS: Sensitivity and specificity of the ovarian cancer symptom index among menopausal women were 84.6% and 52.9%, respectively. ROMA revealed the highest discriminative value when compared to others (AUC 98.4%). When the cutoff level of 28 was applied for menopausal women, ROMA revealed sensitivity and specificity of 95.8% and 93.1%, respectively. CONCLUSIONS: The ovarian cancer symptom index could be used as the first step in ovarian cancer screening with subsequent application of ROMA as a second step screening tool. A larger sample size in both control and patient groups should be evaluated to reach clear conclusions.