Characterization of serum biomarkers for detection of early stage ovarian cancer

We have previously reported the identification of three ovarian cancer biomarker panels comprised of SELDI-TOF-MS peaks representing 14 differentially expressed serum proteins for the diagnosis of ovarian cancer. Using micro-LC-MS/MS, we identified five m/z peaks as transthyretin (TTR 13.9 kDa, TTR fragment 12.9 kDa), beta-hemoglobin (Hb, 15.9 kDa), apolipoprotein AI (ApoAI, 28 kDa) and transferrin (TF, 79 kDa). Western and/or ELISA methods confirmed the differential expression of TTR, Hb, and TF, and multivariate analyses resulted in improving the detection of early stage ovarian tumors (low malignant potential and malignant; receiver operating characteristic, ROC 0.933) as compared to cancer antigen CA125 alone (ROC 0.833). Interestingly, when CA125 was included with our markers in the multivariate analysis, the ROC increased to 0.959. Furthermore, multivariate analysis with only the mucinous subtype of early stage ovarian tumors, showed our markers to greatly improve the detection of disease (ROC 0.959) as compared to CA125 alone (ROC 0.613). Interestingly, the combination of CA125 with our markers did not seem to further improve the detection of mucinous tumors (ROC 0.955). We conclude that TTR, Hb, ApoAI and TF, when combined with CA125 should significantly improve the detection of early stage ovarian cancer.     

人附睾蛋白4与血清CA125联合检测在卵巢癌诊断中的应用价值

目的：探讨人附睾蛋白4（HE4）和CA125联合检测在上皮性卵巢癌临床诊断中的应用价值。方法：用化学发光法测定51例卵巢癌患者、64例卵巢良性疾病患者和50例健康对照者血清中的HE4和CA125水平,并对结果进行比较分析。结果：卵巢癌组血清中HE4和CA125水平均显著高于卵巢良性肿瘤组和健康对照组,差异有统计学意义（P〈0．05）,卵巢良性肿瘤组与健康对照组比较无显著性差异;HE4在早期卵巢癌中的阳性率高于CA125,两者联合检测可提高卯巢癌诊断的阳性率;卵巢癌组联合检测ROC曲线下面积大于单项检测曲线下面积。结论：联合检测HE4和CA125有助于卵巢癌的早期诊断。     

Development of multiplexed bead-based immunoassays for the detection of early stage ovarian cancer using a combination of serum biomarkers

CA125 as a biomarker of ovarian cancer is ineffective for the general population. The aim of this study was to evaluate multiplexed bead-based immunoassay of multiple ovarian cancer-associated biomarkers such as transthyretin and apolipoprotein A1, together with CA125, to improve the identification and evaluation of prognosis of ovarian cancer. We measured the serum levels of CA125, transthyretin, and apolipoprotein A1 from the serum of 61 healthy individuals, 84 patients with benign ovarian disease, and 118 patients with ovarian cancer using a multiplex liquid assay system, Luminex 100. The results were then analyzed according to healthy and/or benign versus ovarian cancer subjects. When CA125 was combined with the other biomarkers, the overall sensitivity and specificity were significantly improved in the ROC curve, which showed 95% and 97% sensitivity and specificity, respectively. At 95% specificity for all stages the sensitivity increased to 95.5% compared to 67% for CA125 alone. For stage I+II, the sensitivity increased from 30% for CA125 alone to 93.9%. For stage III+IV, the corresponding values were 96.5% and 91.6%, respectively. Also, the three biomarkers were sufficient for maximum separation between noncancer (healthy plus benign group) and stage I+II or all stages (I-IV) of disease. The new combination of transthyretin, and apolipoprotein A1 with CA125 improved both the sensitivity and the specificity of ovarian cancer diagnosis compared with those of individual biomarkers. These findings suggest the benefit of the combination of these markers for the diagnosis of ovarian cancer.     

Tumor antigen NB/70K and CA 125 levels in the blood of preoperative ovarian cancer patients and controls: a preliminary report of the use of the NB12123 and CA 125 radioimmunoassays alone and in combination

The NB12123 and CA125 radioimmunoassays, murine monoclonal antibody assays for measuring circulating levels of human ovarian tumor associated antigens NB/70K and CA 125, respectively, have been previously described. In the present study, preoperative serum samples were obtained from patients undergoing laparotomy for benign neoplastic ovarian tumors (N = 16), cancer of the cervix (N = 22), cancer of the uterus (N = 20), and cancer of the ovary (N = 47). Controls (N = 50) were obtained from healthy blood bank donors. No correlation was observed between the levels of NB/70K and CA 125 in these samples (r2 = .079, linear regression analysis). In general, increasing levels of both antigens were present with increasing tumor burden and higher histological grade. In addition, both markers were most elevated in the serum of ovarian cancer patients with serous and unclassified adenocarcinomas. Using 40 AU and 35 unit cut-offs for the NB/70K and CA 125 assay, respectively, overall specificity for healthy controls and patients with benign diseases approaches 100%. The combined sensitivity of the assays for ovarian cancer patient sera in this study indicates that the assays may be helpful in establishing a pre operative diagnosis of ovarian cancer. Complementarity of the NB/70K and CA 125 assays has been demonstrated, indicating that one or both assays may be used to monitor as many as 85% of ovarian cancer patients.     

Identification and Confirmation of Differentially Expressed Fucosylated Glycoproteins in the Serum of Ovarian Cancer Patients Using a Lectin Array and LC-MS/MS

In order to discover potential glycoprotein biomarkers in ovarian cancer, we applied a lectin array and Exactag labeling based quantitative glycoproteomics approach. A lectin array strategy was used to detect overall lectin-specific glycosylation changes in serum proteins from patients with ovarian cancer and those with benign conditions. Lectins, which showed significant differential response for fucosylation, were used to extract glycoproteins that had been labeled using isobaric chemical tags. The glycoproteins were then identified and quantified by LC-MS/MS, and five glycoproteins were found to be differentially expressed in the serum of ovarian cancer patients compared to benign diseases. The differentially expressed glycoproteins were further confirmed by lectin-ELISA and ELISA assay. Corticosteroid-binding globulin (CBG), serum amyloid p component (SAP), complement factor B (CFAB), and histidine-rich glycoprotein (HRG) were identified as potential markers for differentiating ovarian cancer from benign diseases or healthy controls. A combination of CBG and HRG (AUC = 0.825) showed comparable performance to CA125 (AUC = 0.829) in differentiating early stage ovarian cancer from healthy controls. The combination of CBG, SAP, and CA125 showed improved performance for distinguishing stage III ovarian cancer from benign diseases compared to CA125 alone. The ability of CBG, SAP, HRG, and CFAB to differentiate the serum of ovarian cancer patients from that of controls was tested using an independent set of samples. Our findings suggest that glycoprotein modifications may be a means to identify novel diagnostic markers for detection of ovarian cancer.     

血清OPN、HE4和CA125检测对卵巢癌的临床意义

目的：探讨联合检测血清OPN、HE4和CA125对卵巢癌的临床意义。方法：选择2010年6月-2012年7月西安市中心医院妇科及陕西省肿瘤医院妇瘤科收治的35例卵巢癌患者、73例卵巢良性肿瘤患者及40例同期体检的健康妇女为研究对象,应用ELISA法检测患者手术前后血清OPN、HE4水平,电化学发光法检测患者手术前后血清CA125水平,计算3种肿瘤标志物单项以及联合检测在卵巢癌诊断中的敏感性及特异性。结果：（1）卵巢癌患者术前血清OPN、HE4和CA125水平分别为94.6±61.06ng/mL、412.3±278.62 pmol/mL和398.64±220.91 U/mL,与卵巢良性肿瘤组及正常对照组比较差异有统计学意义（P〈0.05）;（2）卵巢癌患者手术前与术后1月血清OPN、HE4和CA125水平比较,差异均有统计学意义（P〈0.05）;（3）血清OPN、HE4和CA125水平联合检测诊断卵巢癌的敏感性（94.3%）显著高于血清OPN、HE4和CA125单项指标检测（分别为37.1%、71.4%和77.1%）,联合检测与单项指标检测比较差异均有统计学意义（P〈0.05）,而血清OPN、HE4和CA125联合检测诊断卵巢癌的特异性（78.8%）稍低于血清OPN、HE4和CA125单项指标检测（分别为87.6%、100%和80.5%）,联合检测与单项指标检测的特异性比较差异无统计学意义（P〉0.05）。血清HE4单项指标检测的特异性高达100%。结论：联合检测卵巢癌患者血清OPN、HE4和CA125水平可作为诊断和评估卵巢癌预后的参考指标。     

Clinical evaluation of a new two-site assay for CA125 antigen

As appropriate surgery and chemotherapy can improve both quality of life and survival of patients with ovarian adenocarcinoma, there has been a pressing need for "serodiagnostic" assays to enable close patient monitoring. CA 125 antigen has previously been described as a useful tumor marker of ovarian cancer. This is the first clinical evaluation of a radioimmunoassay using two new monoclonal antibodies, B27.1 and B43.13, that react with separate sites on the glycoprotein marker CA 125. Using the new assay, the majority of patients with clinically or radiologically detectable disease had serum CA 125 antigen levels well above the upper limit seen with random apparently healthy donors, while only three patients who were believed free of disease had elevated levels. Disease progression was associated with increasing values of serum CA 125 antigen, while response to therapy was associated with a steady decline in serum CA 125 antigen levels. Seven patients had steadily rising serum CA 125 antigen levels after initially having normal levels. The mean lead time between rise above normal and clinical or radiological evidence of relapse was 5 months (range 2 to 12 months). The merits of further surgical intervention are illustrated by the serial values of two patients followed after chemotherapy. The assay appears to have value in monitoring response to therapy and in detecting disease relapse at a time when appropriate therapeutic intervention is still possible or likely to be beneficial. Furthermore, monitoring CA 125 antigen was shown to be of benefit in assessing response to chemotherapy in a few patients with metastatic adenocarcinoma of unknown primary, and may be useful in this group of patients in determining those likely to benefit from aggressive chemotherapy.     

Urinary gonadotropin fragment (UGF) measurements in the diagnosis and management of ovarian cancer

UGF is a small peptide present in the urines and tissues of patients with gynecologic cancers. Published research (which, at present, mainly comes from our laboratory) on the general application of UGF as a tumor marker, and on its use in the diagnosis of ovarian cancer, is reviewed, and new studies on its use, alone and with CA125, in the management of patients with ovarian cancer, are presented. In 234 healthy women, 89 with benign disease, and 79 with ovarian cancer, UGF levels were above 3 fmol/ml (low cut-off) in 12 percent, 7 percent, and 82 percent, respectively, and above 8 fmol/ml (high cut-off) in 1.7 percent, less than 1.1 percent, and 59 percent, respectively. Similarly, 11 percent, 14 percent, and 70 percent, respectively, had CA125 levels above 35 U/ml (low cut-off), and less than 1.9 percent, 1.2 percent, and 49 percent had levels above a 200 U/ml (high cut-off). Ideally, the higher UGF and CA125 cut-offs should be used for diagnostic applications, like differentiation of a benign from a malignant pelvic mass (false-positive rate: UGF, less than 1.1 percent; CA125, 1.2 percent), but raising the cut-offs diminishes sensitivities for malignancy (UGF, 59 percent; CA125, 49 percent). The populations detected by the two markers only partially overlap, however, so that, together, UGF or CA125 can identify 75 percent of malignant pelvic masses. Levels of UGF (cut-off, greater than 3 fmol/ml) and CA125 (35 U/ml) were also monitored in 30 women undergoing therapy for ovarian cancer. Clinical observations were reflected at each clinic visit by UGF alone in 67 percent, by CA125 alone in 57 percent, and by UGF and CA125 together in 87 percent of cases. While separately UGF and CA125 levels predicted 71 percent and 57 percent, together they forecast 86 percent of recurrent cancers prior to clinical manifestations. UGF and CA125 should be used together in the detection and management of ovarian cancers.     

CA125、CA199、CEA 联合检测在妇科肿瘤临床诊断中的应用价值

目的：探讨CA125、CA199、CEA联合检测在妇科肿瘤临床诊断中的应用价值。方法：选择妇科恶性肿瘤组65例、妇科良性肿瘤组55例、健康对照组70例,采用自动荧光磁微粒酶免分析法检测血清中CA199、CA125的含量,采用光激化学发光法检测血清中CEA的含量。结果：妇科恶性肿瘤组血清中CA125、CA199、CEA的水平明显高于妇科良性肿瘤组及对照组,差异有统计学意义（P〈0．01）;妇科良性肿瘤组血清中CA125、CA199、CEA的水平高于对照组,差异有统计学意义（P〈0．01）;CA125、CA199、CEA联合检测对早期妇科肿瘤诊断的阳性率较单独检测高,差异有统计学意义（P〈O．05）;良性组、恶性组联合检测ROC曲线下面积大于单项检测曲线下面积。结论：联合检测可提高对妇科肿瘤早期诊断的阳性率,对妇科良恶性的诊断及鉴别诊断有重要价值。     

A multiplex platform for the identification of ovarian cancer biomarkers

Background

Currently, there are no FDA approved screening tools for detecting early stage ovarian cancer in the general population. Development of a biomarker-based assay for early detection would significantly improve the survival of ovarian cancer patients.

Methods

We used a multiplex approach to identify protein biomarkers for detecting early stage ovarian cancer. This new technology (Proseek^® Multiplex Oncology Plates) can simultaneously measure the expression of 92 proteins in serum based on a proximity extension assay. We analyzed serum samples from 81 women representing healthy, benign pathology, early, and advanced stage serous ovarian cancer patients.

Results

Principle component analysis and unsupervised hierarchical clustering separated patients into cancer versus non-cancer subgroups. Data from the Proseek^® plate for CA125 levels exhibited a strong correlation with current clinical assays for CA125 (correlation coefficient of 0.89, 95% CI 0.83, 0.93). CA125 and HE4 were present at very low levels in healthy controls and benign cases, while higher levels were found in early stage cases, with highest levels found in the advanced stage cases. Overall, significant trends were observed for 38 of the 92 proteins (p < 0.001), many of which are novel candidate serum biomarkers for ovarian cancer. The area under the ROC curve (AUC) for CA125 was 0.98 and the AUC for HE4 was 0.85 when comparing early stage ovarian cancer versus healthy controls. In total, 23 proteins had an estimated AUC of 0.7 or greater. Using a naïve Bayes classifier that combined 12 proteins, we improved the sensitivity corresponding to 95% specificity from 93 to 95% when compared to CA125 alone. Although small, a 2% increase would have a significant effect on the number of women correctly identified when screening a large population.

Conclusions

These data demonstrate that the Proseek^® technology can replicate the results established by conventional clinical assays for known biomarkers, identify new candidate biomarkers, and improve the sensitivity and specificity of CA125 alone. Additional studies using a larger cohort of patients will allow for validation of these biomarkers and lead to the development of a screening tool for detecting early stage ovarian cancer in the general population.

     

Clinical evaluation of the simultaneous determination of CA 15-3, CA 125 and sHER2 in breast cancer

Objective We investigated serum levels of CA 15-3, sHER2 and CA 125, and their usefulness in the detection of metastatic disease in breast cancer patients.

Methods The levels of CA 15-3, sHER2 and CA 125 tumour markers were determined in 60 patients, 40 with localized and 20 with metastatic breast carcinoma. The control group consisted of 10 healthy women.

Results We found that, at the time of diagnosis, serum levels of all three tumour markers were elevated in patients with distant metastases, but of minute importance in the detection of any breast cancer. When the data for the individual markers were combined the overall sensitivity of metastases detection with all three markers improved. In this regard, 90% of patients with distant metastases had an increase in serum level of at least one of tested tumour markers. Similar results were obtained using receiver operating characteristic curve (ROC). Moreover, using ROC we defined cut-off values for metastasis detection for each of the tested markers.

Conclusion Our findings indicate that measurement of CA 15-3 serum values in conjunction with sHER2 and CA 15-3 can increase sensitivity in metastasis detection.     

HE4和HE4/CA125并联诊断卵巢癌的系统评价

目的:通过Meta分析方法系统评价血清人附睾蛋白4(HE4)及HE4并联糖类抗原125(CA125)诊断卵巢癌的价值。方法:中国知网期刊数据库(CNKI)、中文科技期刊数据库(中国万方数据库)、中文电子期刊数据库及维普网等数据库检索2005年1月至2015年3月的相关文献,使用Meta-Disc软件进行Meta分析,分析异质性及处理后选择适当效应模型合并效应量,得出合并敏感性、合并特异性及合并似然比,制作SROC曲线并计算曲线下面积(AUC)。对HE4及HE4/CA125并联检测诊断卵巢癌的AUC应用Z检验进行比较。采用STATA13.0软件应用Egger检验法进行发表偏倚检测。结果:16篇文献符合纳入标准,将对照组分为健康人群和良性疾病组,经Meta分析后得出:以健康人群为对照,HE4和HE4/CA125并联检测卵巢癌的AUC分别为0.8611±0.0399、0.8959±0.0237,差异无统计学意义(Z值=0.749871,P0.05)。以良性疾病组为对照,HE4和HE4/CA125并联检测卵巢癌的AUC分别为0.9443±0.0153、0.9328±0.0132,差异无统计学意义(Z值=0.569105,P0.05)。结论:HE4/CA125并联检测提高了卵巢癌检测的灵敏度,而单独检测HE4有良好的特异度,两者对卵巢癌诊断均有较高的AUC,但HE4与HE4/CA125并联检测的诊断价值差异并无统计学意义。     

Immunosuppressive acidic protein (IAP) and CA 125 assays in detection of human ovarian cancer: preliminary results

Serum levels of the immunosuppressive acidic protein (IAP) and CA-125 were measured in 45 patients with ovarian tumors (30 malignant and 15 benign) before surgery. Concentrations of both markers were slightly increased in benign forms but still within the upper limit for controls. The sensitivity of IAP in detecting ovarian cancer was higher than CA-125 (83.4% versus 76.7%). Five false negatives were observed in IAP assay and seven for CA-125. Parallel determination of both markers, however, improved the diagnostic accuracy up to 90.0% of the total malignant cases. Combined measurements of circulating IAP and CA-125 are therefore recommended in the detection of ovarian cancers.     

Roles of CA125 in diagnosis,prediction, and oncogenesis of ovarian cancer

After it was discovered approximately 40 years ago, carbohydrate antigen 125 (CA125) became the most widely used and concerning biomarker in ovarian cancer screening. However, there is still controversy about its role in clinical practice. CA125 is not sufficiently reliable in diagnosis to screen for early-stage ovarian cancer. On the other hand, CA125 has been a valuable indicator for evaluating chemotherapeutic efficacy and prognosis. We still do not know much about its biological role, and several studies have indicated that this marker participates in the occurrence and development of ovarian cancer. Currently, an increasing number of scholars have begun to pay attention to CA125-targeted treatment strategies. In the interest of better design and development of anticancer therapies, a renewed and systematic understanding of the roles of CA125 in diagnosis, prediction, and tumorigenesis is warranted.     

Peritoneal fluid cytokines and the differential diagnosis of benign and malignant ovarian tumors and residual/recurrent disease examination

This study aimed to assess the potential value of peritoneal fluid cytokine examination for the differential diagnosis of ovarian tumors and for evaluating residual or recurrent disease after treatment. The cytokines that are commonly elevated in ovarian cancer, VEGF, IL-6, bFGF, IL-8 and M-CSF, and a reference ovarian tumor marker, CA 125, were measured in peritoneal fluids of 53 previously untreated patients with epithelial ovarian cancer, 18 ovarian cancer patients after surgical treatment and chemotherapy, and 17 patients with benign epithelial ovarian tumors. Non-parametric statistical analysis of data was performed. Ovarian cancer peritoneal fluids, as compared to peritoneal fluids of patients with benign ovarian tumors, contained significantly higher concentrations of IL-6, VEGF and CA 125, and significantly lower concentrations of bFGF and M-CSF, but only the levels of IL-6 and VEGF were significantly higher in peritoneal fluids of stage I and II ovarian cancer patients than of patients with benign ovarian conditions. IL-6 at the cutoff level of 400 pg/mL discriminated benign and malignant ovarian tumors with 92% sensitivity and 60% specificity, while VEGF at the cutoff of 400 pg/mL had 90% sensitivity and 80% specificity. At the cutoff level of 1200 pg/mL, IL-6 had 84% sensitivity and 87% specificity. A radical decrease in local cytokine and CA 125 levels in patients after treatment was independent of therapy outcome. IL-6 and VEGF measurements in peritoneal fluids might be useful for the differential diagnosis of malignant and benign ovarian conditions, but not for residual or recurrent disease examination.     

Clinical evaluation of the simultaneous determination of CA 15-3, CA 125 and sHER2 in breast cancer

Objective We investigated serum levels of CA 15-3, sHER2 and CA 125, and their usefulness in the detection of metastatic disease in breast cancer patients.

Methods The levels of CA 15-3, sHER2 and CA 125 tumour markers were determined in 60 patients, 40 with localized and 20 with metastatic breast carcinoma. The control group consisted of 10 healthy women.

Results We found that, at the time of diagnosis, serum levels of all three tumour markers were elevated in patients with distant metastases, but of minute importance in the detection of any breast cancer. When the data for the individual markers were combined the overall sensitivity of metastases detection with all three markers improved. In this regard, 90% of patients with distant metastases had an increase in serum level of at least one of tested tumour markers. Similar results were obtained using receiver operating characteristic curve (ROC). Moreover, using ROC we defined cut-off values for metastasis detection for each of the tested markers.

Conclusion Our findings indicate that measurement of CA 15-3 serum values in conjunction with sHER2 and CA 15-3 can increase sensitivity in metastasis detection.     

Progress and challenges in screening for early detection of ovarian cancer

Ovarian cancer is characterize by few early symptoms, presentation at an advanced stage, and poor survival. As a result, it is the most frequent cause of death from gynecological cancer. During the last decade, a research effort has been directed toward improving outcomes for ovarian cancer by screening for preclinical, early stage disease using both imaging techniques and serum markers. Numerous biomarkers have shown potential in samples from clinically diagnosed ovarian cancer patients, but few have been thoroughly assessed in preclinical disease and screening. The most thoroughly investigated biomarker in ovarian cancer screening is CA125. Prospective studies have demonstrated that both CA125 and transvaginal ultrasound can detect a significant proportion of preclinical ovarian cancers, and refinements in interpretation of results have improved sensitivity and reduced the false-positive rate of screening. There is preliminary evidence that screening can improve survival, but the impact of screening on mortality from ovarian cancer is still unclear. Prospective studies of screening are in progress in both the general population and high-risk population, including the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), a randomized trial involving 200,000 postmenopausal women designed to document the impact of screening on mortality. Recent advances in technology for the study of the serum proteome offer exciting opportunities for the identification of novel biomarkers or patterns of markers that will have greater sensitivity and lead time for preclinical disease than CA125. Considerable interest and controversy has been generated by initial results utilizing surface-enhanced laser desorption/ionization (SELDI) in ovarian cancer. There are challenging issues related to the design of studies to evaluate SELDI and other proteomic technology, as well as the reproducibility, sensitivity, and specificity of this new technology. Large serum banks such as that assembled in UKCTOCS, which contain preclinical samples from patients who later developed ovarian cancer and other disorders, provide a unique resource for carefully designed studies of proteomic technology. There is a sound basis for optimism that further developments in serum proteomic analysis will provide powerful methods for screening in ovarian cancer and many other diseases.     

Development and Preliminary Evaluation of a Multivariate Index Assay for Ovarian Cancer

Background

Most women with a clinical presentation consistent with ovarian cancer have benign conditions. Therefore methods to distinguish women with ovarian cancer from those with benign conditions would be beneficial. We describe the development and preliminary evaluation of a serum-based multivariate assay for ovarian cancer. This hypothesis-driven study examined whether an informative pattern could be detected in stage I disease that persists through later stages.

Methodology/Principal Findings

Sera, collected under uniform protocols from multiple institutions, representing 176 cases and 187 controls from women presenting for surgery were examined using high-throughput, multiplexed immunoassays. All stages and common subtypes of epithelial ovarian cancer, and the most common benign ovarian conditions were represented. A panel of 104 antigens, 44 autoimmune and 56 infectious disease markers were assayed and informative combinations identified. Using a training set of 91 stage I data sets, representing 61 individual samples, and an equivalent number of controls, an 11-analyte profile, composed of CA-125, CA 19-9, EGF-R, C-reactive protein, myoglobin, apolipoprotein A1, apolipoprotein CIII, MIP-1α, IL-6, IL-18 and tenascin C was identified and appears informative for all stages and common subtypes of ovarian cancer. Using a testing set of 245 samples, approximately twice the size of the model building set, the classifier had 91.3% sensitivity and 88.5% specificity. While these preliminary results are promising, further refinement and extensive validation of the classifier in a clinical trial is necessary to determine if the test has clinical value.

Conclusions/Significance

We describe a blood-based assay using 11 analytes that can distinguish women with ovarian cancer from those with benign conditions. Preliminary evaluation of the classifier suggests it has the potential to offer approximately 90% sensitivity and 90% specificity. While promising, the performance needs to be assessed in a blinded clinical validation study.     

CA 125 in biological fluids

CA 125 is not a specific tumor marker, and is synthesized by normal and malignant cells of different origin (mainly in tissues derived from the müllerian epithelia) in a similar proportion. Abnormal CA 125 levels may be found in fluids of different origin (ascites, pleura, pericardium, amniotic fluid, cyst fluid, bronchoalveolar fluid, etc.) and in serum from patients with these fluids. Differences in serum CA 125 found in malignant or benign diseases may be related to the number of cells that synthesize the marker, and are highly dependent on the access to serum, where the marker is normally determined. Moreover, CA 125 is a very good tumor marker in ovarian and lung cancer. The sensitivity of CA 125 in ovarian cancer is related to stage (40-95%), histological type (lower levels in mucinous adenocarcinoma), and the marker is useful in the early detection of recurrence (sensitivity 80%) and in therapy monitoring. It's sensitivity in lung cancer is lower than in ovarian cancer, 39% in locoregional malignancies and 69% in metastatic disease, but clearly related to stage and histology (mainly in adenocarcinomas and large cell lung cancer) and it is useful in prognosis and disease monitoring.     

血清HE4、FS、SMRP及CA125在卵巢癌患者中的表达及临床意义

目的:探讨血清人附睾蛋白4(HE4)、卵泡抑素(FS)、可溶性间皮素相关蛋白(SMRP)、糖类抗原125(CA125)在卵巢癌患者中的表达水平及临床意义。方法:选取2014年6月-2017年9月我院收治的卵巢癌患者60例作为卵巢癌组,另选取同期收治的卵巢良性肿瘤患者32例作为良性组,选取同期健康体检妇女40例作为对照组,检测三组受试者血清HE4、FS、SMRP、CA125水平,对比三组HE4、FS、SMRP、CA125阳性表达率,并分析血清HE4、FS、SMRP、CA125对卵巢癌的诊断价值。结果:三组受试者的HE4、FS、SMRP、CA125水平整体对比有统计学意义(P0.05),其中卵巢癌组与良性组HE4、FS、SMRP、CA125水平高于对照组,且卵巢癌组高于良性组,差异有统计学意义(P0.05)。三组受试者的HE4、FS、SMRP、CA125阳性表达率整体对比有统计学意义(P0.05),卵巢癌组与良性组HE4、FS、SMRP、CA125阳性表达率高于对照组,且卵巢癌组高于良性组,差异有统计学意义(P0.05)。联合检测的灵敏度高于FS、SMRP单项检测,差异有统计学意义(P0.05),联合检测的特异度高于HE4、FS、SMRP、CA125单项检测,但差异无统计学意义(P0.05)。结论:卵巢癌患者血清HE4、FS、SMRP、CA125水平及阳性表达率均较高,四项指标联合检测可提高诊断卵巢癌的灵敏度及特异度。