[Establishment and validation of a prediction model for early-stage epithelial ovarian cancer based on LASSO regression].

Objective: To establish and validate a prediction model for early-stage epithelial ovarian cancer based on least absolute shrinkage and selection operator (LASSO) regression. Methods: A total of 509 cases ovarian mass patients who underwent surgical treatment in Tianjin Medical General Hospital from January 2018 to March 2023 were retrospectively analyzed. The patients were randomly divided into modeling group [n=356, M(Q1,Q3) for age were 43 (31, 61) years] and internal validation group [n=153, age 42 (31, 60) years] by 7∶3 ratio. In addition, 86 patients [age 44 (33, 61) years] who underwent surgical treatment for ovarian mass in Tianjin Medical University General Hospital from April to November 2023 were collected as external validation group. The variables were screened by LASSO regression. The nomogram model was established and plotted by multivariate logistic regression. Internal and external validation were then conducted. The model performance and clinical applicability were evaluated using receiver operating characteristic (ROC) curve, calibration curve and decision curve. Results: Five variables including age (OR=1.040,95%CI:1.000-1.050,P=0.002), carbohydrate antigen 125 (CA125) (OR=1.001, 95%CI: 1.000-1.010, P=0.017), human epididymis protein 4 (HE4) (OR=1.020, 95%CI: 1.000-1.030, P=0.002), carbohydrate antigen 199 (CA199) (OR=1.001, 95%CI:1.000-1.020, P=0.023) and lactate dehydrogenase (LDH) (OR=1.020, 95%CI: 1.010-1.022, P=0.001) were screened as risk factors for early-stage epithelial ovarian cancer. The nomogram model was constructed based on these above five risk factors to predict early-stage epithelial ovarian cancer. ROC curves showed the area under curve (AUC) were 0.915(95%CI:0.910-0.932)for modeling group, 0.891(95%CI:0.874-0.905) for internal validation group, and 0.924(95%CI:0.907-0.942) for external verification. The calibration curves and clinical decision curves showed the model exhibited good consistency and clinical practicability. Conclusions: The nomogram model built includes age, CA125, HE4, CA199, and LDH. It can effectively predict early-stage epithelial ovarian cancer and has strong clinical practicability.

Diagnostic Utility of Selected Matrix Metalloproteinases (MMP-2, MMP-3, MMP-11, MMP-26), HE4, CA125 and ROMA Algorithm in Diagnosis of Ovarian Cancer.

Ovarian cancer (OC) has an unfavorable prognosis. Due to the lack of effective screening tests, new diagnostic methods are being sought to detect OC earlier. The aim of this study was to evaluate the concentration and diagnostic utility of selected matrix metalloproteinases (MMPs) as OC markers in comparison with HE4, CA125 and the ROMA algorithm. The study group consisted of 120 patients with OC; the comparison group consisted of 70 patients with benign lesions and 50 healthy women. MMPs were determined via the ELISA method, HE4 and CA125 by CMIA. Patients with OC had elevated levels of MMP-3 and MMP-11, similar to HE4, CA125 and ROMA values. The highest SE, SP, NPV and PPV values were found for MMP-26, CA125 and ROMA in OC patients. Performing combined analyses of ROMA with selected MMPs increased the values of diagnostic parameters. The topmost diagnostic power of the test was obtained for MMP-26, CA125, HE4 and ROMA and performing combined analyses of MMPs and ROMA enhanced the diagnostic power of the test. The obtained results indicate that the tested MMPs do not show potential as stand-alone OC biomarkers, but can be considered as additional tests to raise the diagnostic utility of the ROMA algorithm.

Machine Learning-Enhanced Extraction of Biomarkers for High-Grade Serous Ovarian Cancer from Proteomics Data.

Comprehensive biomedical proteomic datasets are accumulating exponentially, warranting robust analytics to deconvolute them for identifying novel biological insights. Here, we report a strategic machine learning (ML)-based feature extraction workflow that was applied to unveil high-performing protein markers for high-grade serous ovarian carcinoma (HGSOC) from publicly available ovarian cancer tissue and serum proteomics datasets. Diagnosis of HGSOC, an aggressive form of ovarian cancer, currently relies on diagnostic methods based on tissue biopsy and/or non-specific biomarkers such as the cancer antigen 125 (CA125) and human epididymis protein 4 (HE4). Our newly developed ML-based approach enabled the identification of new serum proteomic biomarkers for HGSOC. The performance verification of these marker combinations using two independent cohorts affirmed their outperformance against known biomarkers for ovarian cancer including clinically used serum markers with >97% AUC. Our analysis also added novel biological insights such as enriched cancer-related processes associated with HGSOC.

Human epididymis protein 4, a novel potential biomarker for diagnostic and prognosis monitoring of lung cancer.

OBJECTIVE: This study aimed to explore the application value of human epididymis protein 4 (HE4) in diagnosing and monitoring the prognosis of lung cancer. METHODS: First, TCGA (The Cancer Genome Atlas) databases were used to analyze whey-acidic-protein 4-disulfide bond core domain 2 (WFDC2) gene expression levels in lung cancer tissues. Then, a total of 160 individuals were enrolled, categorized into three groups: the lung cancer group (n = 80), the benign lesions group (n = 40), and the healthy controls group (n = 40). Serum HE4 levels and other biomarkers were quantified using an electro-chemiluminescent immunoassay. Additionally, the expression of HE4 in tissues was analyzed through immunohistochemistry (IHC). In vitro cultures of human airway epithelial (human bronchial epithelial [HBE]) cells and various lung cancer cell lines (SPC/PC9/A594/H520) were utilized to detect HE4 levels via western blot (WB). RESULTS: Analysis of the TCGA and UALCAN (The University of Alabama at Birmingham Cancer Data Analysis Portal) databases showed that WFDC2 gene expression levels were upregulated in lung cancer tissues (p < 0.01). Compared with the control group and the benign group, HE4 was significantly higher in the serum of patients with lung cancer (p < 0.001). Receiver operating characteristic (ROC) analysis confirmed that HE4 had better diagnostic efficacy than classical markers in the differential diagnosis of lung cancer and benign lesions and had the highest diagnostic value in lung adenocarcinoma (area under the ROC curve [AUC] = 0.826). HE4 increased in early lung cancer and positively correlated with poor prognosis (p < 0.001). Moreover, the results of WB and IHC revealed that the expression of HE4 was increased in lung cancer cells (SPC/A549/H520) and lung cancer tissues but decreased in PC9 cells with a lack of exon EGFR19 (p < 0.05). CONCLUSION: Serum HE4 emerges as a promising novel biomarker for the diagnosis and prognosis assessment of lung cancer.

Elevated serum HE4 levels as a novel biomarker of disease severity and hepatic fibrosis in autoimmune hepatitis.

BACKGROUND: Human epididymis protein 4 (HE4) has been identified as a biomarker for renal fibrosis. This study aimed to evaluate the role of HE4 in the diagnosis and determination of disease severity and hepatic fibrosis in autoimmune hepatitis (AIH). METHODS: Serum HE4 levels were determined via electrochemiluminescence immunoassays in 60 healthy controls and 109 AIH patients (43 without liver cirrhosis and 66 with liver cirrhosis). Liver biopsy was performed on 56 of 109 enrolled patients. We conducted a 5-year follow-up survey of 53 enrolled patients. All continuous variables were reported as median (25th-75th percentile). RESULTS: Serum HE4 levels were significantly elevated in autoimmune hepatitis with liver cirrhosis (AIH-LC) patients compared with AIH patients and healthy controls [98.60 (74.15-139.08) vs 73.50 (59.88-82.00) vs 48.75 (43.38-52.93) pmol/L, p = 0.004]. The serum HE4 levels showed a positive correlation with the METAVIR scoring system in patients with liver biopsy (r = 0.711, p < 0.001). Serum HE4 levels were significantly elevated in Child-Pugh class C patients compared with Child-Pugh class B patients and Child-Pugh class A patients [106.50 (83.46-151.25) vs 110.00 (73.83-166.75) vs 77.03 (72.35-83.33) pmol/L, p = 0.006]. The diagnostic sensitivity and specificity of serum HE4 for evaluating liver cirrhosis were 69.7 % and 79.07 %, respectively, with a cutoff value of 82.34 pmol/L in enrolled patients. The logistic regression analysis showed that high levels of HE4 (≥82.34 pmol/L) were associated with AIH-LC (OR = 8.751, 95 % CI = 1.412-54.225, p = 0.020). The Kaplan-Meier curves demonstrated that high levels of serum HE4 (≥82.34 pmol/L) were associated with poor outcome (log-rank p = 0.037, HR = 0.372, 95 % CI = 0.146-0.946). CONCLUSIONS: Serum HE4 levels were found to be elevated in AIH-LC patients and exhibited a strong correlation with the severity of hepatic fibrosis, thus supporting their potential clinical value as a novel biomarker of disease severity and hepatic fibrosis in AIH.

Human epididymal protein 4 and its combined detection show good diagnostic value in lung cancer: A retrospective study.

OBJECTIVES: This study aimed to assess the diagnostic value of human epididymal protein 4 (HE4), a potential novel biomarker for lung cancer, and its combined detection with five other conventional biomarkers in lung cancer diagnosis and subtyping. METHODS: In this retrospective study, 115 lung cancer patients, 50 patients with benign pulmonary disease, and 50 healthy controls were included. Serum HE4, progastrin-releasing peptide (ProGRP), squamous cell carcinoma (SCC) antigen, cytokeratin-19 fragment (CYFRA21-1), neuron-specific enolase (NSE), and carcinoembryonic antigen (CEA) were analyzed using the electrochemiluminescence immunoassay and chemiluminescence immunoassay. The receiver operating characteristic curve was performed to analyze the diagnostic efficacy of individual biomarkers in identifying both lung cancer and its histologic subtypes. RESULTS: All six biomarkers showed significantly elevated levels in the lung cancer group compared to both benign pulmonary disease and control groups (P < 0.05). Among the biomarkers evaluated, HE4 exhibited the highest diagnostic performance for lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma with area under the curve (AUC) values of 0.921, 0.891, and 0.937, respectively. ProGRP was the optimal biomarker for small cell lung cancer with an AUC of 0.973. The combination of all six biomarkers yielded the largest AUCs in the diagnosis of lung cancer subtypes (0.937 for lung adenocarcinoma, 0.998 for lung squamous cell carcinoma, and 0.985 for small cell lung cancer). Furthermore, specific combinations, such as HE4 + CEA, HE4 + SCC, and ProGRP + HE4 + NSE, showed strong diagnostic performance in lung cancer. CONCLUSIONS: HE4 and its combined detection held substantial clinical significance in the diagnosis of lung cancer and its histologic subtyping, especially for lung adenocarcinoma and lung squamous cell carcinoma.

Human epididymis protein 4: Analysis of national health and nutrition examination survey data.

BACKGROUND: Human epididymis protein 4 (HE4) is a tumor marker overexpressed in ovarian cancer and is commonly utilized to aid with diagnosis of an adnexal mass. HE4 levels vary based on pregnancy, age, menopausal status, and tobacco use. OBJECTIVE(S): The objective of this study was to evaluate population-based data to examine factors that affect HE4 among adult women in the United States and stratify levels of HE4 by demographic and gynecologic factors. STUDY DESIGN: A retrospective analysis was conducted using data from 2,480 women aged 20 + who participated in the National Health and Nutrition Examination Survey (2001-2002). From these cross-sectional data, serum HE4 and cotinine, a marker of tobacco exposure, were combined with demographic and interview data. Estimated glomerular filtration rates (eGFR) were based on serum creatinine, age, sex, and race. Other variables of interest included menopausal status, pregnancy, and various gynecologic factors. Summary HE4 data are provided as geometric means with associated 95 % confidence intervals. RESULTS: HE4 levels were independently associated with age, renal function, and nicotine use, all p < 0.001. Pre-menopausal women with a history of endometriosis were found to have elevated HE4 levels compared to those without, p < 0.01; however, we found no such difference among post-menopausal women. Adjusting for age, no differences in HE4 were found based on race/ethnicity, p = 0.29. HE4 levels showed statistically significant associations with income level; however, these were small and clinically irrelevant. CONCLUSION: This study provides evaluation of HE4 levels among a data set representative of 98.5 million non-institutionalized women in the United States and gives insight into extraneous factors that may influence these levels.

Evaluation of serum CA125, HE4 and CA724 and the risk of ovarian malignancy algorithm score in the diagnosis of high-grade serous ovarian cancer.

AIM: To develop a new algorithm for the detection of high-grade serous ovarian cancer (HGSOC). METHODS: Patients diagnosed with HGSOC, borderline ovarian tumours (BOTs) or benign ovarian masses (BOMs) were enrolled between February 2019 and December 2020. Patients with BOTs or BOMs were grouped as non-HGSOC. The cases were divided randomly into a training cohort (two-thirds of cases) and a validation cohort (one-third of cases). Logistic regression was used to find risk factors for HGSOC and to create a new algorithm in the training cohort. Receiver operating characteristic curves were used to compare the diagnostic value of tumour biomarkers. Sensitivity and specificity of tumour markers and the new algorithm were calculated in the training cohort and validation cohort. RESULTS: This study found significant differences in age; BRCA1/2 mutation status; CA125, CA724 and HE4 levels; and Risk of Ovarian Malignancy Algorithm score between the two groups.Logistic regression analysis showed that CA125 and BRCA1/2 were risk factors for HGSOC. A new algorithm combining CA125 and BRCA1/2 increased the specificity of CA125 for diagnosis of HGSOC. The new algorithm had sensitivity of 81.08% and specificity of 93.10% in the training cohort. CONCLUSION: The new algorithm using CA125 and BRCA1/2 helped to distinguish between patients with HGSOC and patients with non-HGSOC.

Evaluating the effectiveness of pre-operative diagnosis of ovarian cancer using minimally invasive liquid biopsies by combining serum human epididymis protein 4 and cell-free DNA in patients with an ovarian mass.

OBJECTIVE: To assess the feasibility of scalable, objective, and minimally invasive liquid biopsy-derived biomarkers such as cell-free DNA copy number profiles, human epididymis protein 4 (HE4), and cancer antigen 125 (CA125) for pre-operative risk assessment of early-stage ovarian cancer in a clinically representative and diagnostically challenging population and to compare the performance of these biomarkers with the Risk of Malignancy Index (RMI). METHODS: In this case-control study, we included 100 patients with an ovarian mass clinically suspected to be early-stage ovarian cancer. Of these 100 patients, 50 were confirmed to have a malignant mass (cases) and 50 had a benign mass (controls). Using WisecondorX, an algorithm used extensively in non-invasive prenatal testing, we calculated the benign-calibrated copy number profile abnormality score. This score represents how different a sample is from benign controls based on copy number profiles. We combined this score with HE4 serum concentration to separate cases and controls. RESULTS: Combining the benign-calibrated copy number profile abnormality score with HE4, we obtained a model with a significantly higher sensitivity (42% vs 0%; p<0.002) at 99% specificity as compared with the RMI that is currently employed in clinical practice. Investigating performance in subgroups, we observed especially large differences in the advanced stage and non-high-grade serous ovarian cancer groups. CONCLUSION: This study demonstrates that cell-free DNA can be successfully employed to perform pre-operative risk of malignancy assessment for ovarian masses; however, results warrant validation in a more extensive clinical study.

HE4 as a serum biomarker for the diagnosis of pelvic masses: a prospective, multicenter study in 965 patients.

BACKGROUND: To evaluate the diagnostic value of adding human epididymis protein 4 (HE4), cancer antigen 125 (CA125) and risk of malignancy algorithm (ROMA) to ultrasound for detecting ovarian cancer in patients with a pelvic mass. METHODS: This was a prospective, observational, multicenter study. Patients aged > 18 years who were scheduled to undergo surgery for a suspicious pelvic mass had CA125 and HE4 levels measured prior to surgery, in addition to a routine transvaginal ultrasound scan. The diagnostic performance of CA125, HE4 and ROMA for distinguishing between benign and malignant adnexal masses was assessed using receiver operating characteristic (ROC) analysis and the corresponding area under the curve (AUC). RESULTS: Of 965 evaluable patients, 804 were diagnosed with benign tumors and 161 were diagnosed with ovarian cancer. In late-stage ovarian cancer, CA125, HE4 and ROMA all had an excellent diagnostic performance (AUC > 0.92), whereas in stage I and II, diagnostic performance of all three biomarkers was less adequate (AUC < 0.77). In the differential diagnosis of ovarian cancer and endometriosis, ROMA and HE4 performed better than CA125 with 99 and 98.1% versus 75.0% sensitivity, respectively, at 75.4% specificity. CONCLUSIONS: ROMA and HE4 could be valuable biomarkers to help with the diagnosis of ovarian cancer in premenopausal patients in order to differentiate from endometriosis, whereas CA125 may be more adequate for postmenopausal patients.

Can serum human epididymis protein 4 (HE4) support the decision to refer a patient with an ovarian mass to an oncology hospital?

INTRODUCTION: The value of serum human epididymis protein 4 (HE4) in guiding referral decisions in patients with an ovarian mass remains unclear, because the majority of studies investigating HE4 were performed in oncology hospitals. However, the decision to refer is made at general hospitals with a low ovarian cancer prevalence. We assessed accuracies of HE4 in differentiating benign or borderline from malignant tumors in patients presenting with an ovarian mass at general hospitals. METHOD: Patients with an ovarian mass were prospectively included between 2017 and 2021 in nine general hospitals. HE4 and CA125 were preoperatively measured and the risk of malignancy index (RMI) was calculated. Histological diagnosis was the reference standard. RESULTS: We included 316 patients, of whom 195 had a benign, 39 had a borderline and 82 had a malignant ovarian mass. HE4 had the highest AUC of 0.80 (95%CI 0.74-0.86), followed by RMI (0.71, 95%CI 0.64-0.78) and CA125 (0.69, 95%CI 0.62-0.75). Clinical setting significantly influenced biomarker performances. Applying age-dependent cut-off values for HE4 resulted in a better performance than one cut-off. Addition of HE4 to RMI resulted in a 32% decrease of unnecessary referred patients, while the number of correctly referred patients remained the same. CONCLUSION: HE4 is superior to RMI in predicting malignancy in patients with an ovarian mass from general hospitals. The addition of HE4 to the RMI improved HE4 alone. Although, there is still room for improvement, HE4 can guide referral decisions in patients with an ovarian mass to an oncology hospital.

BC-DETECT: combined detection of serum HE4 and TFF3 improves breast cancer diagnostic efficacy.

BACKGROUND: Early accurate breast cancer (BC) diagnosis is critical in disease management. Mammography has been widely used. However, its radiation, and high false-negative and -positive results have always been a concern. We evaluated combined detection of human epididymal protein 4 (HE4) and trefoil factor 3 (TFF3) as substitute method to enhance BC diagnosis. METHODS: HE4 and TFF3 blood levels were determined by ELISA in sera of 120 BC patients and 80 women (40 healthy and 40 benign breast disease) as controls. Receiver-operating characteristic curve was applied for evaluation diagnostic power of each biomarker and their combination. RESULTS: In BC patients, serum HE4 [5 (2-11.9) vs. 3.1 (1.8-5.4) and 1 (1-3.5); P = 0.022] and TFF3 [5.3 (4.5-6.7) vs. 4.7 (4-4.8) and 3.9 (3-4.4); P = 0.027] were significantly higher than that in benign and healthy groups, respectively. Both HE4 (AUC = 0.783; P < 0.0001) and TFF3 (AUC = 0.759; P < 0.0001) had superior BC diagnostic ability compared to CEA and CA-15.3. Logistic regression analysis revealed simplified index BC-DETECT = HE4 + TFF3, and its values were significantly (P = 0.0132) elevated in BC (10.9 (8.4-17.2) compared to benign (7.2 (5.4-10.1)) and healthy (5.1 (4-6.3)) controls. AUC of BC-DETECT for BC prediction was (AUC = 0.850; P < 0.0001) with sensitivity, specificity, and positive and negative predictive values and accuracy of 84.2%, 70%, 80.8%, 74.7%, and 78.5%, respectively. High BC-DETECT levels were associated with tumor non-luminal subtypes, late stage, high grade, large size, lymph-node invasion, and multiple lesions. CONCLUSIONS: BC-DETECT is inexpensive, rapid, and easy to perform and reliably guides BC early detection. Moreover, the association between elevated BC-DETECT values and disease severity may propose its potential role as prognostic marker.

Plasma circN4BP2L2 is a promising novel diagnostic biomarker for epithelial ovarian cancer.

BACKGROUND: Circular RNAs (circRNAs) are more stable than linear RNA molecules, which makes them promising diagnostic biomarkers for diseases. By circRNA-sequencing analysis, we previously found that circN4BP2L2 was significantly decreased in epithelial ovarian cancer (EOC) tissues, and was predictive of disease progression. The aim of this study was to evaluate the diagnostic value of plasma circN4BP2L2 in EOC. METHODS: Three hundred seventy-eight plasma samples were acquired prior to surgery. Samples were obtained from 126 EOC patients, 126 benign ovarian cyst patients, and 126 healthy volunteers. CircN4BP2L2 was assessed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cancer antigen 125 (CA125) and human epididymis protein 4 (HE4) were assessed using enzyme-linked immunosorbent assay (ELISA). EOC cells were transfected with small interference RNAs (siRNAs) and cell proliferation, migration, invasion, cell cycle and cell apoptosis were performed to assess the effect of circN4BP2L2 in EOC. Receiver operating curve (ROC), the area under the curve (AUC), sensitivity and specificity were estimated. RESULTS: Plasma circN4BP2L2 was significantly downregulated in EOC patients. Decreased circN4BP2L2 was significantly associated with advanced tumor stage, worse histological grade, lymph node metastasis and distant metastasis in EOC. CircN4BP2L2 inhibited tumor cell migration and invasion in vitro. CircN4BP2L2 could significantly separate EOC from benign (AUC = 0.82, P <  0.01) or normal (AUC = 0.90, P <  0.01) cohort. Early stage EOC vs benign (AUC = 0.81, P <  0.01) or normal (AUC = 0.90, P <  0.01) cohort could also be distinguished by circN4BP2L2. In discrimination between EOC cohort and benign or normal cohort, circN4BP2L2 performed equally well in both pre- and post-menopausal women. The combination of circN4BP2L2, CA125 and HE4 showed high sensitivity and specificity in detecting EOC cases. CONCLUSIONS: Plasma circN4BP2L2 is significantly downregulated in EOC and might serve as a promising novel diagnostic biomarker for EOC patients, especially in early stage EOC cases. CircN4BP2L2 might act as an adjunct to CA125 and HE4 in detecting EOC. Further large-scale studies are warranted to verify our results.

Fibrinogen/albumin ratio as a promising predictor of platinum response and survival in ovarian clear cell carcinoma.

BACKGROUND: This study aims to evaluate the role of the fibrinogen/albumin ratio (FAR) in predicting platinum resistance and survival outcomes of patients with ovarian clear cell carcinoma (OCCC). METHODS: Coagulation function and D-dimer, serum albumin, CA125 and HE4 levels were measured before surgery in OCCC patients undergoing initial surgery in our institution. FAR was calculated as fibrinogen/albumin level. The correlation between these indicators and clinicopathological features, platinum response, and survival outcomes was further analyzed. The Kaplan-Meier method and multivariable Cox regression model were used to assess the effects of FAR on progression-free survival (PFS) and overall survival (OS). RESULTS: Advanced stage patients accounted for 42.1% of the 114 participants. Optimal cytoreductive surgery was achieved in 105 patients, and the complete resection rate was 78.1%. FAR was associated with tumor stage, residual tumor and platinum response. A receiver operating characteristic curve for predicting platinum response showed that the optimal cutoff point of the FAR was 12%. The sensitivity was 73.3% and the specificity was 68.2%. In multivariate analysis, FAR ≥12% (HR = 4.963, P = 0.002) was an independent risk factor for platinum resistance. In addition, FAR and D-dimer proved to be independent negative factors for outcomes including both PFS and OS. The median follow-up time was 52 months. A high FAR (≥ 12%) showed a stronger correlation with poor OS and PFS in the subgroup analysis of advanced and completely resected patients. CONCLUSIONS: The FAR might be a potential preoperative biochemical marker for predicting treatment response and oncological outcomes in OCCC patients.

Quantitative analysis of the MRI features in the differentiation of benign, borderline, and malignant epithelial ovarian tumors.

OBJECTIVE: This study aims to investigate the value of the quantitative indicators of MRI in the differential diagnoses of benign, borderline, and malignant epithelial ovarian tumors (EOTs). MATERIALS AND METHODS: The study population comprised 477 women with 513 masses who underwent MRI and operation, including benign EOTs (BeEOTs), borderline EOTs (BEOTs), and malignant EOTs (MEOTs). The clinical information and MRI findings of the three groups were compared. Then, multivariate logistic regression analysis was performed to find the independent diagnostic factors. The receiver operating characteristic (ROC) curves were also used to evaluate the diagnostic performance of the quantitative indicators of MRI and clinical information in differentiating BeEOTs from BEOTs or differentiating BEOTs from MEOTs. RESULTS: The MEOTs likely involved postmenopausal women and showed higher CA-125, HE4 levels, ROMA indices, peritoneal carcinomatosis and bilateral involvement than BeEOTs and BEOTs. Compared with BEOTs, BeEOTs and MEOTs appeared to be more frequently oligocystic (P < 0.001). BeEOTs were more likely to show mild enhancement (P < 0.001) and less ascites (P = 0.003) than BEOTs and MEOTs. In the quantitative indicators of MRI, BeEOTs usually showed thin-walled cysts and no solid component. BEOTs displayed irregular thickened wall and less solid portion. MEOTs were more frequently characterized as solid or predominantly solid mass (P < 0.001) than BeEOTs and BEOTs. The multivariate logistic regression analysis showed that volume of the solid portion (P = 0.006), maximum diameter of the solid portion (P = 0.038), enhancement degrees (P < 0.001), and peritoneal carcinomatosis (P = 0.011) were significant indicators for the differential diagnosis of the three groups. The area under the curves (AUCs) of above indicators and combination of four image features except peritoneal carcinomatosis for the differential diagnosis of BeEOTs and BEOTs, BEOTs and MEOTs ranged from 0.74 to 0.85, 0.58 to 0.79, respectively. CONCLUSION: In this study, the characteristics of MRI can provide objective quantitative indicators for the accurate imaging diagnosis of three categories of EOTs and are helpful for clinical decision-making. Among these MRI characteristics, the volume, diameter, and enhancement degrees of the solid portion showed good diagnostic performance.

Serum HE4 is associated with clinical prognostic factors and survival outcome in female patients with primary peritoneal carcinoma.

OBJECTIVE: The aim of this study was to investigate whether serum HE4 was associated with clinical risk prognostic factors and survival outcome. METHODS: In this study, 72 patients with primary peritoneal carcinoma (PPC) from January 2011 to October 2019 participated. Serum HE4 and CA125 levels were detected at primary diagnosis, post-surgery, pre-recurrence and the presence of recurrence. The relations between serum HE4 levels with clinical prognostic factors were analyzed, and the hazard ratios between serum HE4 levels with overall survival and recurrence-free survival were also analyzed by univariate and multivariate survival analysis. RESULTS: HE4 and CA125 levels were significantly elevated in serous type, high histological grade, advanced stage and positive lymph node status and residual tumor diameter more than 1 cm, respectively, compared with those in non-serous type, low histological grade, early stage, negative lymph node status and residual tumor diameter no more than 1 cm, respectively. HE4 was an independent prognostic factor for recurrence-free survival and overall survival with hazard ratios of 5.36 (95% confidence interval: 2.19-13.15) and 4.48 (95% confidence interval: 1.87-10.74), respectively. CONCLUSION: HE4 is correlated with clinical risk prognostic factors in PPC and is effective in the recurrence detection and predicting outcome in PPC patients.

A combined strategy of TK1, HE4 and CA125 shows better diagnostic performance than risk of ovarian malignancy algorithm (ROMA) in ovarian carcinoma.

BACKGROUND: The dual marker algorithm Risk of Ovarian Malignancy Algorithm (ROMA) has been widely used in the clinic for the identification of equivocal pelvic masses in ovarian carcinoma. To obtain higher diagnostic efficiency, we created a new diagnostic index, Risk of Ovarian Malignancy Index (ROMI), by combing thymidine kinase 1 (TK1), HE4 and CA125. METHODS: 335 patients with pelvic masses on imaging and 46 healthy controls were enrolled. Serum TK1 was analyzed before further study. ROMI and ROMA were evaluated for diagnostic efficiency. RESULTS: The level of TK1 was elevated in malignant ovarian tumors compared to benign masses (p < 0.001) and healthy controls (p < 0.001). TK1 expression was positively correlated with stage, intrapelvic metastasis, lymphatic metastasis and distant metastasis (all p values < 0.001). The area under the receiver operating characteristic curve (AUC) of ROMI was higher than that of ROMA for both pre- and postmenopausal women. ROMI had better sensitivity, specificity, accuracy, and positive and negative predictive values than ROMA in diagnosis of all-stage or stage I + II ovarian carcinoma for both pre- and postmenopausal women. CONCLUSIONS: TK1 is a potential biomarker in detection of ovarian carcinoma. ROMI shows better diagnostic performance than ROMA in distinguishing malignant ovarian tumors from benign masses.

Measurement of HE4 six months after first-line treatment as optimal time in identifying patients at high risk of progression advanced ovarian cancer.

OBJECTIVES: The objective of the study was to assess the usefulness of determining HE4 and CA125 in ovarian cancer patients, to indicate which of the measurements may be optimal in the prognosis, depending on the treatment scheme. MATERIAL AND METHODS: The concentrations of CA125 and HE4 were performed in 70 patients with advanced ovarian cancer during I-line therapy and after treatment. The subjects were divided based on the treatment scheme: group I - primary surgery and adjuvant chemotherapy, II- neoadjuvant therapy, and surgery. RESULTS: Multivariate analysis showed that HE4 levels six months after treatment was significantly higher in patients with disease progression. ROC analysis in the group of patients treated with neoadjuvant therapy showed that the cut-off values indicating relapse for HE4 and CA125 after six months of follow up, were > 90.4 pmol/L, > 25.6 IU/mL, respectively. In the group of patients not treated with neoadjuvant therapy, the cut-off points differentiating patients with progression were: HE4 > 79.1 pmol/L, CA125 > 30.7 IU/mL. We demonstrated significantly higher HE4 and CA125 at both 6- and 12-months follow-up in patients treated with neoadjuvant therapy. In both groups of patients, the cut-off points were lower than those proposed by the manufacturer of the kits. CONCLUSIONS: Measurement of HE4 six months after treatment may be useful in identifying patients at high risk of progression, especially when CA125 levels may be non-specifically elevated. The cut-off values indicating relapse for HE4 and CA125 after six months of follow up may be lower than the normal range.

Evaluation of Combined Cancer Markers With Lactate Dehydrogenase and Application of Machine Learning Algorithms for Differentiating Benign Disease From Malignant Ovarian Cancer.

BACKGROUND: The differential diagnosis of ovarian cancer is important, and there has been ongoing research to identify biomarkers with higher performance. This study aimed to evaluate the diagnostic utility of combinations of cancer markers classified by machine learning algorithms in patients with early stage ovarian cancer, which has rarely been reported. METHODS: In total, 730 serum samples were assayed for lactate dehydrogenase (LD), neutrophil-to-lymphocyte ratio (NLR), human epididymis protein 4 (HE4), cancer antigen 125 (CA125), and risk of ovarian malignancy algorithm (ROMA). Among them, 53 were diagnosed with early stage ovarian cancer, and the remaining 677 were diagnosed with benign disease. RESULTS: The areas under the receiver operating characteristic curves (ROC-AUCs) of the ROMA, HE4, CA125, LD, and NLR for discriminating ovarian cancer from non-cancerous disease were .707, .680, .643, .657, and .624, respectively. ROC-AUC of the combination of ROMA and LD (.709) was similar to that of single ROMA in the total population. In the postmenopausal group, ROC-AUCs of HE4 and CA125 combined with LD presented the highest value (.718). When machine learning algorithms were applied to ROMA combined with LD, the ROC-AUC of random forest was higher than that of other applied algorithms in the total population (.757), showing acceptable performance. CONCLUSION: Our data suggest that the combinations of ovarian cancer-specific markers with LD classified by random forest may be a useful tool for predicting ovarian cancer, particularly in clinical settings, due to easy accessibility and cost-effectiveness. Application of an optimal combination of cancer markers and algorithms would facilitate appropriate management of ovarian cancer patients.

Analysis of serum HE4 levels in various histologic subtypes of epithelial ovarian cancer and other malignant tumors.

BACKGROUND: The measurement of serum HE4 levels has emerged as a sensitive and specific biomarker for epithelial ovarian cancers (EOCs). However, serum levels in women diagnosed with various histologic subtypes of EOC and in women with metastatic non-ovarian primary malignancies have not been widely reported. OBJECTIVE: The goal of this study was to identify how serum HE4 levels vary in women diagnosed with different histologic subtypes of EOC and non-ovarian malignancies. METHODS: Data from six prospective pelvic mass clinical trials was combined and an evaluation of serum HE4 levels in women diagnosed with a malignancy was performed. For all patients, serum was obtained prior to surgery and final pathology, including primary tumor site, histologic subtype, grade and stage, were recorded. The mean, median, standard deviation, maximum, and minimum HE4 levels were determined for each group. RESULTS: A total of 984 patients were included in this study, with the average patient age being 60 years old. There were 230 premenopausal and 754 postmenopausal patients. Serum HE4 levels were elevated (≥70.0 pMol) in 85%of EOCs, 40%of LMP tumors, 21%of non-EOCs (germ cell tumors), 25%of cervical cancers, and 47%of non-gynecologic metastatic cancers. Analysis of histologic subtypes revealed 90%(n = 391) of serous, 85%(n = 73) of endometrioid, 45%(n = 42) of mucinous, 86%(n = 51) of mixed tumors, and 69%(n = 36) of clear cell tumors had elevated serum HE4 levels. CONCLUSIONS: Serum HE4 levels are most often elevated in women with high grade serous and endometrioid EOCs, and though serum elevations are seen more often with advanced stage disease, HE4 is also often elevated in early stage disease and lower grade tumors.