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.

Does the Risk of Ovarian Malignancy Algorithm Provide Better Diagnostic Performance Than HE4 and CA125 in the Presurgical Differentiation of Adnexal Tumors in Polish Women?

AIM: This study compared the diagnostic performance of the Risk of Ovarian Malignancy Algorithm (ROMA) and HE4 and CA125 for the presurgical differentiation of adnexal tumors. MATERIAL AND METHODS: This prospective study included 302 patients admitted for surgical treatment due to adnexal tumors. The ROMA was calculated depending on CA125, HE4, and menopausal status. RESULTS: Fifty patients were diagnosed with malignant disease. In the differentiation of malignant from nonmalignant adnexal tumors, the area under curve (AUC) was higher for ROMA and HE4 than that for CA125 in both the premenopausal and postmenopausal subgroups. In the differentiation of stage I FIGO malignancies and epithelial ovarian cancer from nonmalignant pathologies, the AUC of HE4 and ROMA was higher than that of CA125. The ROMA performed significantly better than CA125 in the differentiation of all malignancies and differentiation of stage I FIGO malignancies from nonmalignant pathologies (p = 0.043 and p = 0.025, resp.). There were no significant differences between the ROMA and the tumor markers for any other variants. CONCLUSIONS: The ROMA is more useful than CA125 for the differentiation of malignant (including stage I FIGO) from nonmalignant adnexal tumors. It is also as useful as HE4 and CA125 for the differentiation of epithelial ovarian cancer from nonmalignant adnexal tumors.

Comment on "Serum human epididymis protein 4 is associated with the treatment response of concurrent chemo-radiotherapy and prognosis in patients with locally advanced non-small cell lung cancer" by Lan WG et al

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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 is associated with the treatment response of concurrent chemoradiotherapy and prognosis in patients with locally advanced non-small cell lung cancer

Aim: To investigate the role of human epididymis protein 4 (HE4) in the diagnosis and prognosis of patients with locally advanced non-small cell lung cancer (LA-NSCLC) receiving concurrent chemoradiotherapy (CRT). Methods: A total of 218 patients with LA-NSCLC were enrolled. All patients underwent CRT. The treatment response to CRT was evaluated. The prognosis analysis was performed using relapse-free survival (RFS) and overall survival [1]. Results: Our data show that the serum HE4 can discriminate patients who respond well to CRT from those who respond poorly. Higher serum HE4 had dramatically increased risk of being non-responders to CRT. Serum HE4 level is also associated with prognosis of patients after CRT. Patients with high HE4 level had shorter RFS and OS compared to those with low HE4 level. Conclusion: Our data suggest that serum HE4 may be a useful prognostic biomarker for LA-NSCLC patients who underwent CRT (AU)

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Time-specific changes in DNA methyltransferases associated with the leptin promoter during the development of obesity / Cambios en puntos temporales específicos en ADN-metiltransferasas en relación con el promotor de leptina durante el desarrollo de obesidad

Objective: The role of epigenetic modifications on leptin expression during the development of obesity has not been clearly determined. This study aimed to investigatechanges in the expression of DNA methyltransferases (DNMTs) at the leptin promoter and their effect on genetranscription during the development of obesity. Methods: Using a high-fat diet (HFD)-induced obese (DIO) mouse model, we examined adipose expression of leptin, its promoter associated DNMTs and the methyl CpG-binding domain protein 2 (MBD2) at different time points after HFD feeding. Results: The leptin expression levels in epididymal fat were significantly increased after feeding the mice aHFD for 4, 8, 12 and 18 weeks (w), as opposed to feeding them a standard diet (SD). However, the CpG promoter methylation fractions were significantly reduced at 8 w with a decreased association of MBD2 and DNMT1, and increased at 12 w and 18 w with an increased association of MBD2, DNMT3A and DNMT3B, after HFD feeding. Additionally, the binding of RNA polymerase II was increased at 8 w and decreased at 18 w after HFD feeding compared with SD feeding. Conclusions: These data indicate that time-specific changes in promoter associated DNMTs may be associated with the regulation of leptin expression, indicating that a complex and dynamic epigenetic mechanism underlies aberrant leptin expression during the development of obesity (AU)

Objetivo: El objetivo de las modificaciones epigenéticas sobre la expresión de la leptina durante el desarrollo de obesidad no ha podido ser claramente establecido. Este estudio tiene por objetivo investigar los cambios en la expresión de ADN-metiltransferasas (ADNMTs) en el promotor de leptina y su efecto sobre la trascripción génica durante el desarrollo de obesidad. Métodos: Empleando un modelo de ratones con obesidad inducida por dieta rica en grasa (DRG), examinamos la expresión adiposa de leptina, su promotor asociado ADNMTs y la proteína 2 con dominio de unión a metil-CpG (MBD2) en diferentes momentos tras la alimentación DRG. Resultados: Los niveles de expresión de leptina en grasa epididimal aumentaron significativamente tras la alimentación de los ratones con una dieta DRG durante 4, 8, 12 y 18 semanas (s), contrariamente a la alimentación con dieta estándar (DE). Sin embargo, las fracciones de metilación del promotor CpG se redujeron significativamente en la s8 con una menor asociación de MBD2 y DNMT1, y aumentaron en la s12 y s18 con una mayor asociación de MBD2, DNMT3A y DNMT3B, tras la DRG. Además, la unión de ARN polimerasa II aumentó en la s8 y disminuyó en la s18 tras la DRG en comparación con la alimentación de DE. Conclusiones: Estos datos indican que los cambios en puntos temporales específicos en ADNMTs en relación con un promotor podrían estar relacionados con la regulación de la expresión de leptina, indicando que existe un mecanismo epigenético dinámico y complejo subyacente en la expresión de leptina aberrante durante el desarrollo de obesidad (AU)

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.

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 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.

DHEA: el andrógeno más producido pero el menos entendido / DHEA: the androgen produced but least understood

Dehidroepiandrosterona (DHEA) y su derivada sulfatada (DHEAS) son los esteroides más abundantes en el cuerpo humano, pero aún se deconoce su mecanismo de acción y sus implicancias fisiológicas. Se le ha atribuido múltiples efectos antienvejecimiento, antiinflamatorio y antiarteriosclerótico entre otros y en EEUU se vende al público como complemento energético y para aumento del libido, sin restricción de la FDA...

The effect of ghrelin pretreatment on epididymal sperm quality and tissue antioxidant enzyme activities after testicular ischemia/reperfusion in rats

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Ghrelin, the endogenous ligand for growth hormone secretagogue receptor, has been reported to prevent ischemia/reperfusion (I/R) injury in various tissues by its antioxidant activity. Therefore, this study was aimed to investigate the effect of ghrelin on sperm quality and antioxidant enzyme activity in a rat testicular ischemia/reperfusion injury model. Forty-two male Wistar rats were divided into groups control, I/R, and I/R plus ghrelin. The right testes were rotated 720° for 1 h and were allowed to reperfuse for 4 h and 30 days thereafter. Ghrelin (40 nmol/kg IP) or vehicle (physiological saline) was administrated 15 min before reperfusion. After 4 h of reperfusion, a right orchiectomy was performed to measure the biochemical parameters. In addition, the sperm was collected from the epididymis after 30 days of reperfusion, and sperm characteristics were examined. The malondialdehyde levels of the testis tissues were significantly increased, but a statistically significant decrease was found in the superoxide dismutase, glutathione peroxidase, and catalase activities in the I/R group as compared with the control, indicating I/R injury. The sperm evaluation showed a significant reduction in all characteristics resulted from I/R compared with the control. In the ghrelin-treated group, the malondialdehyde values were significantly lowered, and only enzyme activity of glutathione peroxidase showed significant increases compared with the I/R group. Ghrelin significantly enhanced sperm motility, movement, and concentration but did not prevent I/R-induced reduction in membrane integrity in the testes of rats compared to the I/R group. Our results suggest that ghrelin treatment has a protective role on IR-induced testicular injury, and this effect may be due to its antioxidant properties (AU)

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.

HE4 in ovarian cancer: from discovery to clinical application.

Despite the relatively low prevalence, ovarian cancer is the fifth leading cause of death from cancer among women. As such, an early diagnosis for establishing a timely surgical and/or chemotherapeutic treatment is essential for improving the outcome. The most reliable, but not always straightforward, approach to diagnose ovarian cancer relies on multiple, time-consuming and expensive investigative tools. These typically include clinical presentation (i.e., pelvic or abdominal pain, urinary frequency or urgency, increased abdominal size or bloating) with pelvic examination, transvaginal ultrasonography (US), and measurement of carbohydrate antigen 125 (CA125). Although the conventional pathway to develop and market a clinically useful biomarker is challenging, recent advances in genomic and proteomic technologies have led to the identification of previously unknown candidate markers of ovarian cancer. Some of these are currently under clinical validation. The human epididymis protein 4 (HE4) has recently been approved by the Food and Drug Administration for monitoring recurrence or progression of epithelial ovarian cancer. Nevertheless, reliable clinical evidence demonstrates that HE4, used alone or in combination with CA125, substantially improves the accuracy of screening and/or disease monitoring. This chapter will review the current knowledge on biologic and clinical applications of ovarian cancer biomarkers, with particular emphasis on the newly proposed marker, HE4.

Effect of human epididymis protein 4 gene silencing on the malignant phenotype in ovarian cancer.

BACKGROUND: Human epididymis secretory protein 4 (HE4) has been proved to be a promising novel biomarker for the detection of epithelial ovarian carcinomas. Compared with CA125, HE4 assay demonstrated an improved ability to discriminate between pelvic mass with malignant and benign disease. Though it is well known that HE4 is overexpressed in ovarian cancer, however, the role of HE4 in the carcinogenesis and progression of ovarian cancer remains unkown. METHODS: In this study, we explored the role of HE4 in the carcinogenesis and progression of ovarian cancer. We screened nine ovarian cancer cell lines for HE4 expression, and using RNA interference (RNAi), we silenced HE4 gene expression in CaoV3 and SKOV3.ip1 ovarian cancer cell lines. We assessed the effect of HE4 gene silencing on the transformed phenotype by examining the cell cycle, apoptosis, proliferation and transwell migration/invasion in vitro. RESULTS: HE4 gene silencing induces G0/G1 arrest and blocks the progression from the G1 to S phase in CaoV3 and SKOV3.ip1 cells. HE4 knockdown also inhibited cell proliferation, migration and invasion in SKOV3.ip1 cells in vitro. CONCLUSION: HE4 may be involved in the regulation of the cell cycle and promote ovarian cancer migration and invasion.

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.

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.

Potential role of HE4 in multimodal screening for epithelial ovarian cancer.

In screening for epithelial ovarian cancer, unnecessary surgery can be reduced by limiting use of transvaginal ultrasound (TVU) to women with increasing CA125 serum levels. Replacing or augmenting TVU with measurement of a serum marker specific for malignancy might further improve screening performance. Serum samples from 112 invasive ovarian cancer patients and 706 matched control subjects from the Prostate, Lung, Colorectal, and Ovarian trial were used to evaluate human epididymis protein 4 (HE4), mesothelin, matrix metalloproteinase 7 (MMP7), SLPI, Spondin2, and insulin-like growth factor binding protein 2 (IGFBP2) for their potential use in screening. TVU results were available for a subset of 84 patients and 516 control subjects used to compare the best marker with TVU. HE4 was found to perform better than TVU as a second-line screen, confirming 27 of 39 cancers with increasing CA125 serum levels compared with 17 cancers confirmed by TVU (P = .03). Serum HE4 levels were found to increase with age and smoking status, suggesting that a longitudinal algorithm might improve its performance.

Integration of cell phone imaging with microchip ELISA to detect ovarian cancer HE4 biomarker in urine at the point-of-care.

Ovarian cancer is asymptomatic in the early stages and most patients present with advanced levels of disease. The lack of cost-effective methods that can achieve frequent, simple and non-invasive testing hinders early detection and causes high mortality in ovarian cancer patients. Here, we report a simple and inexpensive microchip ELISA-based detection module that employs a portable detection system, i.e., a cell phone/charge-coupled device (CCD) to quantify an ovarian cancer biomarker, HE4, in urine. Integration of a mobile application with a cell phone enabled immediate processing of microchip ELISA results, which eliminated the need for a bulky, expensive spectrophotometer. The HE4 level detected by a cell phone or a lensless CCD system was significantly elevated in urine samples from cancer patients (n = 19) than healthy controls (n = 20) (p < 0.001). Receiver operating characteristic (ROC) analyses showed that the microchip ELISA coupled with a cell phone running an automated analysis mobile application had a sensitivity of 89.5% at a specificity of 90%. Under the same specificity, the microchip ELISA coupled with a CCD had a sensitivity of 84.2%. In conclusion, integration of microchip ELISA with cell phone/CCD-based colorimetric measurement technology can be used to detect HE4 biomarker at the point-of-care (POC), paving the way to create bedside technologies for diagnostics and treatment monitoring.

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.

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.