• Asian Pacific Journal of Cancer Prevention
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• v.13 no.9
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• pp.4695-4698
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• 2012

Objective: To analyze differential diagnostic accuracy of urinary human epidydimis secretory protein 4 (HE4) in patients with ovarian tumors. Materials and methods: In the case-control study 23 patients with ovarian cancer, 37 patients with benign ovarian tumors and 18 women in the control group were included. Serum CA125 values and urinary concentrations of HE4were assessed quantitatively. Urinary creatinine concentrations and glomerular filtration rate were also determined and used to calculate ratios to HE4. Results: Higher urinary HE4 concentrations were observed in patients with late stage ovarian cancer (p=0.001) and also in patients with early stage ovarian cancer when compared to patients with benign ovarian tumors (p=0.044). On analysis where all ovarian cancer patients were included, higher diagnostic accuracy was observed with calculated ratio of HE4 to glomerular filtration rate (GFR) to unchanged urinary HE4 concentrations -AUC 0.861 vs. 0.858. When discriminatory accuracy was calculated for urinary HE4/GFR ratio and unchanged urinary HE4 concentrations, the last demonstrated a higher area under the curve - 0.701 vs. 0.602. The urinary HE4/creatinine ratio had lower discriminatory characteristics than unchanged concentrations of urinary HE4. However, HE4 serum concentration was more accurate for discrimination of patients with benign and malignant ovarian tumors when compared to urinary HE4 and CA125 in sera (AUCs were 0.868 for serum HE4 and 0.856 and 0.653 for urinary HE4 and CA125, respectively). Conclusions: Ovarian cancer patients have higher urinary concentrations of human epidydimis secretory protein 4 than patients with benign ovarian tumors. Urinary HE4 has comparable discriminatory accuracy with serum HE4 for benign and malignant ovarian tumors and can be recommended as a non-invasive ovarian cancer risk assessment method.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.1
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• pp.323-333
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• 2016

Background: Ovarian cancer remains a major worldwide health care issue due to the lack of satisfactory diagnostic methods for early detection of the disease. Prior studies on the role of serum cancer antigen 125 (CA125) and human epididymis protein 4 (HE4) in detecting ovarian cancer presented conflicting results. New tools to improve the accuracy of identifying malignancy are urgently needed. We here aimed to evaluate the diagnostic utility of tissue CA125 and HE4 gene expression in comparison to serum CA125 and HE4 in discriminating benign from malignant pelvic masses. Materials and Methods: One-hundred Egyptian women were enrolled in this study, including 60 epithelial ovarian cancer (EOC) patients and 20 benign ovarian tumor patients, as well as 20 apparently healthy women. Preoperative serum levels of CA125 and HE4 were measured by immunoassays. Tissue expression levels of genes encoding CA125 and HE4 were determined by quantitative real time polymerase chain reaction (qRT-PCR). The diagnostic performance of CA125 and HE4, measured either as mRNA or protein levels, was evaluated by receiver operating characteristic (ROC) curves. Results: The serum CA125+HE4 combination and serum HE4, with area under the curve (AUC) values of 0.935 and 0.932, respectively, performed significantly better than serum CA125 (AUC=0.592; P<0.001). Tissue CA125 and HE4 (AUC=1) performed significantly better than serum CA125 (P<0.001), serum HE4 (P=0.016) and the serum CA125+HE4 combination (P=0.018). Conclusions: Measurement of tissue CA125 and HE4 gene expression not only improves discriminatory performance, but also broadens the range of differential diagnostic possibilities in distinguishing EOC from benign ovarian tumors.

• Journal of Life Science
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• v.20 no.4
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• pp.572-577
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• 2010

The purpose of this study was to find out the Bcl-2 (B-cell leukemia/lymphoma-2), Bax, and caspase-3(cysteine-aspartic proteases-3) protein expression in soleus and EDL muscle according to treadmill exercise intensity in 60 week-old SD rats. The SD rats were randomly divided into four groups (n=10 in each group): control (CON), low intensity exercise (LE), moderate intensity exercise (ME), and high intensity exercise (HE). The exercise was given to the rats for 8 wk, 5 day/wk. The animals underwent treadmill exercise at intensities of 30 min at 8 m/min for the LE group, 15 min at 16 m/min for the ME group, and 9 min at 24 m/min for the HE group. The results were as follows: the expression of Bcl-2 protein was lowest in the HE group and the expression of Bax protein was highest in the HE group. The expression of caspase-3 (cleaved form) protein was observed in the HE group. For the different types of muscle fiber, Bcl-2 protein expression in the soleus muscle was decreased in all groups. Bax protein expression in the soleus muscle was increased in the HE group only. Bcl-2 protein expression in the EDL muscle was decreased in the HE group, and Bax protein expression in the EDL muscle was increased in the ME and HE groups. Consequently, the protein expression related to the aged rats shows a difference according to the intensity of exercise. In addition, caspase-3 protein expression appeared in the HE group; however, in all amounts of intensity, DNA fragmentation was not observed. Therefore, apoptosis on skeletal muscles of aged mice can be intervened with optimal exercise. On the other hand, high intensity exercise can potentially accelerate the apoptosis of muscle fiber in aged rats.

• KSBB Journal
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• v.11 no.4
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• pp.438-444
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• 1996

Using recombinant Vaccinia virus(vSC8) that express ${\beta}$-galactosidase, a model heterologous protein, conditions for virus and protein production were investigated in tissue culture flask. As host animal cells HeLa and HeLa S3 were used. It was demonstrated that cells infected during the exponential growth phase gave higher protein yield than those infected during the stationary growth phase and calf serum concentration after virus infection did not significantly alter protein yield. Pretreatment of cell layer with hypotonic solution enhanced the virus infectivity. Optimum cell growth and recombinant protein production was achieved at $37^{\circ}C$. But, during 2 hours of virus infection period incubation temperature must be lowered to 20∼$30^{\circ}C$ for maximum recombinant protein yield. To enhance virus replication, the effects of adrenal glucocorticoid hormone (Dexamethasone) and silkworm hemolymph were evaluated. Only dexamethasone increased about 20% of ${\beta}$-galactosidase yield in HeLa S3 cells when added with 10-7∼10-5M concentration 24 hours before infection.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.3
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• pp.1489-1492
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• 2016

Background: Although there are no biomarkers that are routinely used in endometrial cancer (EC) management, many studies have found that serum human epididymis protein 4 (HE4) is superior to cancer antigen 125 (CA125) in the detection of EC. The correlation of HE4 with two prognostic factors for EC, primary tumor diameter (PTD) and depth of myometrial invasion (DMI) may be useful in identifying EC patients at high risk of lymphatic dissemination. Objective: To evaluate the correlation of serum HE4 with PTD and DMI in patients with EC. Materials and Methods: A cross-sectional study was conducted on 70 EC patients who were scheduled for elective surgery at Rajavithi Hospital between 1st September 2013 and 30th May 2014. Preoperative serum levels of HE4 and CA125 were investigated, and then gross measurement of PTD was taken and postoperative pathologic slides were reviewed for DMI including histologic types, grading and staging. Results: Preoperative serum HE4 levels were strongly correlated with PTD (r=0.65, p<0.001) and moderately correlated with DMI (r=0.46, p<0.001). Moreover, serum HE4 levels were significantly elevated in EC patients with PTD >2 cm (p<0.001) and DMI > 50% (p=0.004). The performance of serum HE4 in identifying EC patients at low risk and high risk of lymph node metastasis was significantly better than that of CA125 (AUC 0.88 vs. 0.65, p=0.003). At an optimal cut-off value of 70 pM/L, serum HE4 had a sensitivity of 83.3% and a specificity of 80.0%. Conclusions: In EC patients, preoperative serum HE4 is significantly correlated with PTD and DMI. Serum HE4 levels could be useful in identifying endometrial cancer patients at high risk of lymphatic spread who would benefit from systemic lymphadenectomy at the cut-off value of 70 pM/L.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.9
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• pp.4483-4486
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• 2016

Background: Despite the fact that ovarian cancer is the seventh most common cancer in women worldwide and the fifth leading cause of cancer death, It is the most common cause of death due to reproductive cancers in Thailand where epithelial ovarian cancer (EOC) is commonly found. According to a Thai statistical analysis in 2010 by the Department of Medical Services, epithelial ovarian cancer was the sixth most common cancer in Thailand from 2001to 2003.The incidence of 5.1 per 100,000 women per year. Human epididymis protein 4 (HE4) is a novo diagnostic tumor marker for EOC. The combination of HE4 and carcinoma antigen 125 (CA 125) is a tool for detecting epithelial ovarian cancer (EOC) better than using CA 125 alone. Therefore, the researcher is interested in HE4 does have a role to predict recurrent epithelial ovarian cancer. Materials and Methods: The patients who had complete response after diagnosed with epithelial ovarian cancer by pathology, FIGO stage 3 or more had been treated through surgery and chemotherapy at the Sunpasitthiprasong Hospital from June 2014 until March 2016. The patients were followed up every three months, using tumor marker (CA 125, HE4,Carcinoma antigen 19-9) together with other checkup methods, such as rectovaginal examination, CXR every year and other imaging as indication. Afterwards, the data was analyzed for the ability of HE4 to detect recurrence of epithelial ovarian cancer. Results: In 47 patients in this study follow-up for 22 months after complete response treatment from surgery and chemotherapy in epithelial ovarian cancer, 23 had recurrent disease and HE4 titer rising. The patients with recurrent epithelial ovarian cancer demonstrated high levels of both HE4 and CA125 with sensitivity of 91.3% and 52.7% respectively, specificity of 87.5% and 95.6% and positive predictive values of 87.5% and 85.7%. HE4 can predict recurrent epithelial ovarian cancer (p-value=0.02242). Comparing HE4 and CA125 in predicting recurrent epithelial ovarian cancer HE4 had more potential than CA125 (p-value =0.8314). Conclusions: The present study showed HE4 to have a role in predicting recurrent epithelial ovarian cancer and HE4 is potentially better than CA125 as a marker for this purpose.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.1
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• pp.101-105
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• 2014

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

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.8
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• pp.4545-4548
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• 2013

The objective of this study is to assess tissue expression of CA-125 and HE4 protein in primary benign and malignant epithelial tumours of the ovary and correlate with serum CA-125 levels. A total of 100 formalin-fixed, paraffin embedded sections of ovarian tumours which included serous adenoma (11), mucinous adenoma (42), serous carcinoma (20), mucinous carcinoma (12) and endometrioid carcinoma (15), histologically diagnosed between $1^{st}$ January 2004 to $31^{st}$ December 2012 at the University Malaya Medical Centre, were stained for HE4 (rabbit polyclonal antibody, Abcam, UK) and CA-125 (mouse monoclonal antibody clone: OC125, Cell Marque Corporation, Rocklin, California, USA). Pre-operative serum CA-125 levels were obtained from the laboratory information system. Immunoscore (I score) for HE4 and CA-125 was given based on the intensity of staining and percentage of positive tumour cells and considered significant when it was >50 (intensity of staining multiplied by percentage of positive tumour cells). Serum CA-125 levels were compared with the I score of HE4 and CA-125 in tissues. We noted that the CA-125 levels in serum and tissues were significantly raised in malignant compared to benign ovarian tumours (p value<0.05). Tissue expression of HE4 protein was also significantly raised in malignant tumours compared to benign tumours (p value<0.05). We conclude that HE4 can be a useful tissue immunomarker in addition to CA-125.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.11
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• pp.5427-5432
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• 2012

Background and Purpose: Ovarian cancer is the leading cause of death among gynecologic cancers because of the lack of effective early detection methods. Accuracies of the human epididymis protein 4 (HE4) and mesothelin in detecting ovarian cancer have never been systematically assessed. The current systematic review aimed to tackle this issue. Methods: MEDLINE, EMBASE, and Cochrane databases were searched (September 1995-November 2011) for studies on the diagnostic performances of HE4 and mesothelin in differentiating ovarian cancer from other benign gynecologic diseases. QUADAS items were used to evaluate the qualities of the studies. Meta-DiSc software was used to handle data from the included studies and to examine heterogeneity. All included studies for diagnostic performance were combined with sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratios (DORs) with 95% confidence intervals (CIs), summary receiver operating characteristic (SROC) curves, and areas under the SROC curves (AUC). Results: A total of 18 studies and 3,865 patients were eligible for the final analysis. The pooled sensitivity estimates for HE4 (74.4%) were significantly higher than those for mesothelin (49.3%). The pooled specificity estimates for mesothelin (94.5%) were higher than those for HE4 (85.8%). The pooled DOR estimates for HE4 (26.22) were higher than those for mesothelin (24.01). The SROC curve for HE4 showed better diagnostic accuracy than that for mesothelin. The PLR and NLR of HE4 were 6.33 (95% CI: 3.58 to 11.18) and 0.27 (95% CI: 0.21 to 0.34), respectively. The PLR and NLR for mesothelin were 11.0 (95% CI: 6.21 to 19.59) and 0.51 (95% CI: 0.42 to 0.62), respectively. The combination of the two tumor markers or their combination with CA-125 increased sensitivity and specificity to different extents. Conclusion: The diagnostic accuracy of HE4 in differentiating ovarian cancer from other benign gynecologic diseases is better than that of soluble mesothelin-related protein. Combinations of two or more tumor markers show more sensitivity and specificity.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.5
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• pp.2507-2511
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• 2016

Purpose: To study the diagnostic accuracies of serum human epididymis protein 4 (HE-4) levels, virtual organ computer-aided analysis (VOCAL) parameters and endometrial volume in endometrial cancer cases. Materials and Methods: One hundred and seven patients (37 with endometrial cancer and 70 with benign endometrial pathology) were included in this study. VOCAL parameters and serum HE-4 levels were compared between the groups. Results: Area under the curve (AUC) values were 0.702, 0.658, 0.706 for vascularization index (VI), the flow index (FI) and the vascularization flow index (VFI), respectively. A cut off value of 0.568 for VI demonstrated 70% sensitivity, 72% specificity, 56% positive predictive value (PPV) and a81% negative predictive value (NPV). A cut off value of 25.8 for showed a senitivith of 70% and a specificity of 58% with aPPV of 46% and NPV of 78%, and with a cut off value of 0.12 for VFI 70%, 69%, 54% and 81%, respectively. The area under the curve for HE-4 was 0.814. A cut off value of 458 pmol/L was predictive of malignancy with 86% sensitivity and 63% specificity. Conclusions: VOCAL parameters and serum HE-4 levels were statistically significantly higher in the endometrial cancer patients. Serum HE-4 levels provided a greater sensitivity compared to power doppler angiography for predicting malignancy or benign endometrial pathology.