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Loss of estrogen receptor/progesterone receptor (ER/PR) in endometrial cancer (EC) is associated with tumor progression and poor outcomes. Elevated pretreatment cancer antigen 125 (CA 125) level is a risk factor for lymph node metastasis (LNM). We evaluated whether the combination of ER/PR expression and CA 125 level could be used as a biomarker to predict LNM. We retrospectively investigated patients with endometrioid EC who underwent complete staging surgery during January 2015 to December 2020. We analyzed ER/PR status using immunohistochemical staining, and quantified its expression using the sum of both ER/PR H -scores. Receiver operating characteristic curves were used to identify optimal cutoff values of H -score and CA 125 levels for predicting LNM. A nomogram for predicting LNM was constructed and validated by bootstrap resampling. In 396 patients, the optimal cutoff values of the ER/PR H -score and CA 125 were 407 (area under the receiver operating characteristic curve: 0.645, P =0.001) and 40 U/mL (area under the receiver operating characteristic curve: 0.762, P <0.001), respectively. Multivariate analysis showed that CA 125 ≥40 UmL (odds ratio: 10.02; 95% CI: 4.74-21.18) and ER/PR H -score <407 (odds ratio: 4.20; 95% CI: 1.55-11.32) were independent predictors. An LNM predictive nomogram was constructed using these 2 variables and our model yielded a negative predictive value and negative likelihood ratio of 98.3% and 0.14, respectively. ER/PR expression with pretreatment CA 125 levels can help estimate LNM risk and aid in decision-making regarding the need for lymphadenectomy in patients with endometrioid EC., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 by the International Society of Gynecological Pathologists.)

Purpose: Gastric cancer is the fifth most common malignant tumor worldwide. Many attempts have been made over the years to investigate the relationship between tumor markers and the risk of recurrence. This study aims to explore the predictive value of tumor markers measured in peritoneal washing during staging laparoscopy, regarding peritoneal carcinomatosis and mortality within 1 year., Methods: Patients with locally advanced gastric cancer, staged as at least usT2anyNM0 were submitted to staging laparoscopy in a Portuguese single center. CA 19.9, CEA, CA 125, and CA 72.4 were measured in the peritoneal washing after being harvested during staging laparoscopy., Results: Thirty-eight patients were enrolled. After 1 year, 20 patients did not recur (52.5%), 11 (28.9%) developed carcinomatosis, and 7 (18.4%) had distant metastasis. Mortality reached 23.7% (n = 9). A statistically significant prediction of carcinomatosis was obtained for CA 125 (cutoff: 107.6 U/mL (p = 0.019)) and CEA (cutoff: 2.0 ng/mL (p = 0.020)) with 87.5% and 75% sensitivity, respectively. Prediction of mortality was significant for CA 125 (cutoff: 103.8 U/mL (p = 0.044)) and CA 125 + CEA (p = 0.030). CEA and CA 125 had NPVs of 87.9% and 93.1% regarding PC, respectively. NPVs of 88.9% and 89.2% were met concerning mortality, for the same tumor markers., Conclusion: Performing the peritoneal liquid harvest during staging laparoscopy makes this analysis cost effective, reproducible, and does not add further morbidity. CA 125 and CEA, individually and in association, are good predictors of progression of disease and mortality within a year of staging laparoscopy in GC patients., (© 2023. The Author(s).)

Objective: CA-125 is widely used as biomarker of ovarian cancer. However, CA-125 suffers low accuracy. We developed a hybrid analytical model, the Ovarian Cancer Decision Tree (OCDT), employing a two-layer decision tree, which considers genetic alteration information from cell-free DNA along with CA-125 value to distinguish malignant tumors from benign tumors., Methods: We consider major copy number alterations at whole chromosome and chromosome-arm level as the main feature of our detection model. Fifty-eight patients diagnosed with malignant tumors, 66 with borderline tumors, and 10 with benign tumors were enrolled., Results: Genetic analysis revealed significant arm-level imbalances in most malignant tumors, especially in high-grade serous cancers in which 12 chromosome arms with significant aneuploidy ( P <0.01) were identified, including 7 arms with significant gains and 5 with significant losses. The area under receiver operating characteristic curve (AUC) was 0.8985 for copy number variations analysis, compared to 0.8751 of CA125. The OCDT was generated with a cancerous score (CScore) threshold of 5.18 for the first level, and a CA-125 value of 103.1 for the second level. Our most optimized OCDT model achieved an AUC of 0.975., Conclusions: The results suggested that genetic variations extracted from cfDNA can be combined with CA-125, and together improved the differential diagnosis of malignant from benign ovarian tumors. The model would aid in the pre-operative assessment of women with adnexal masses. Future clinical trials need to be conducted to further evaluate the value of CScore in clinical settings and search for the optimal threshold for malignancy detection.

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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: At present there is no predictive value univocally associated with the success of chemotherapy. Biomarkers produced by ovarian cancer (HE4 and Ca125) could have a good prognostic significance. The aim of this study is to prove the ability of biomarkers to identify patients with the highest risk of non-optimal response during the chemotherapy, and to predict which patients will most likely develop recurrence of disease., Methods: We analyzed 78 patients with epithelial ovarian cancers who underwent surgery in the biennium 2016-2017. All the patients underwent chemotherapy after surgery or interval debulking surgery following neoadjuvant therapy. Serum levels of HE4 and Ca125 were measured at diagnosis and at each cycle of chemotherapy. We established the degree of response to the treatment by computed tomography scan, and the patients were followed up (median: 10 months). The parameters of progression-free survival and disease-free survival were related to serum levels of biomarkers., Results: Both CA125 and HE4 values became negative at the fourth cycle in the patients with good response to chemotherapy. HE4 increased earlier than Ca125. The parameters that best correlated with a long progression-free survival were: negativization of the marker after the third cycle of chemotherapy (HE4: odds ratio (OR) 5.5; Ca125: OR 9.1) and biomarker serum levels lower than the mean value in the affected population at the time of diagnosis (HE4: OR 3.4; Ca125: OR 3.7)., Conclusions: We can conclude that the monitoring of HE4 and Ca125 during chemotherapy, especially at the third cycle, is recommended, because their variation is a good prognostic factor.

Background: Variation in intercellular methylation patterns can complicate the use of methylation biomarkers for clinical diagnostic applications such as blood-based cancer testing. Here, we describe development and validation of a methylation density binary classification method called EpiClass (available for download at https://github.com/Elnitskilab/EpiClass ) that can be used to predict and optimize the performance of methylation biomarkers, particularly in challenging, heterogeneous samples such as liquid biopsies. This approach is based upon leveraging statistical differences in single-molecule sample methylation density distributions to identify ideal thresholds for sample classification., Results: We developed and tested the classifier using reduced representation bisulfite sequencing (RRBS) data derived from ovarian carcinoma tissue DNA and controls. We used these data to perform in silico simulations using methylation density profiles from individual epiallelic copies of ZNF154, a genomic locus known to be recurrently methylated in numerous cancer types. From these profiles, we predicted the performance of the classifier in liquid biopsies for the detection of epithelial ovarian carcinomas (EOC). In silico analysis indicated that EpiClass could be leveraged to better identify cancer-positive liquid biopsy samples by implementing precise thresholds with respect to methylation density profiles derived from circulating cell-free DNA (cfDNA) analysis. These predictions were confirmed experimentally using DREAMing to perform digital methylation density analysis on a cohort of low volume (1-ml) plasma samples obtained from 26 EOC-positive and 41 cancer-free women. EpiClass performance was then validated in an independent cohort of 24 plasma specimens, derived from a longitudinal study of 8 EOC-positive women, and 12 plasma specimens derived from 12 healthy women, respectively, attaining a sensitivity/specificity of 91.7%/100.0%. Direct comparison of CA-125 measurements with EpiClass demonstrated that EpiClass was able to better identify EOC-positive women than standard CA-125 assessment. Finally, we used independent whole genome bisulfite sequencing (WGBS) datasets to demonstrate that EpiClass can also identify other cancer types as well or better than alternative methylation-based classifiers., Conclusions: Our results indicate that assessment of intramolecular methylation density distributions calculated from cfDNA facilitates the use of methylation biomarkers for diagnostic applications. Furthermore, we demonstrated that EpiClass analysis of ZNF154 methylation was able to outperform CA-125 in the detection of etiologically diverse ovarian carcinomas, indicating broad utility of ZNF154 for use as a biomarker of ovarian cancer.

The aim of this study was to investigate the association between the clinicopathologic factors and either expression or co-expression of mesothelin and cancer antigen (CA) 125 in endometrial serous carcinoma and mixed carcinomas including serous carcinoma. Between 1990 and 2017, patients with endometrial serous carcinoma and mixed carcinoma including serous carcinoma treated by total hysterectomy and bilateral salpingo-oophorectomy at our hospital were identified. The association between either expression or co-expression of mesothelin and CA125 was evaluated by immunochemical analysis and the clinico-pathological features were retrospectively examined. Among the 40 patients included, 19, 31, and 18 patients exhibited single positive mesothelin, single positive CA125, and positive co-expression, respectively. The expression of mesothelin and CA125 was observed to be positively associated (p = 0.021). There was no significant association of age and FIGO stage with individual mesothelin or CA125 expression or their co-expression. Overall survival (OS), but not progression-free survivals (PFS), of only mesothelin-positive patients was worse (p = 0.024). Hence, OS and PFS of patients with positive co-expression were worse (PFS: p = 0.043, OS: p = 0.012). In multivariate analysis, single mesothelin expression and single CA125 expression did not lead to worse prognosis. However, positive co-expression was the worst prognostic factor for OS (hazard ratio: 3.32, p = 0.039). Co-expression of mesothelin and CA125 may accurately predict OS in endometrial serous carcinoma and mixed carcinomas including serous carcinoma. Further studies should examine this relationship.

Carbohydrate antigen 19‑9 (CA19‑9) is the most important biomarker for pancreatic cancer. Approximately 5‑10% of individuals are Lewis antigen negative with scarce secretion of CA19‑9 and fucosylation deficiency. However, the characteristics of Lewis‑negative pancreatic cancer are unidentified. Clinicopathological characteristics of 853 patients with pancreatic cancer were examined. Pancreatic cancer cell lines were sequenced for Lewis status. Morphological and molecular features of pancreatic cancer cells were compared. Orthotopic animal modes were established. Lewis‑negative patients had poorer outcome (P<0.001), higher metastatic rate (P=0.004), lower CA19‑9 expression (P<0.001) and higher MUC16 expression (P<0.001) than Lewis‑positive patients. Lewis‑negative cells (CaPan‑1, MiaPaCa‑2 and Panc‑1) showed a shuttle shape with scarce pseudopods. Overall, Lewis‑negative cells had higher proliferation rate, higher migration ability, lower fucosylation, lower CA19‑9 expression and higher MUC16 expression than Lewis‑positive cells (BxPC‑3, SU8686, SW1990). Lewis‑negative cell line MiaPaCa‑2 corresponded to larger orthotopic tumor than Lewis‑positive cells SU8686. Potential proteoglycans were identified in Lewis‑positive cancer, including EGFR, HSPG2, ADAM17, GPC1, ITGA2, CD40, IL6ST and GGT1. Therefore, Lewis‑negative pancreatic cancer is an aggressive subgroup with special clinical and molecular features.

To determine whether ultrasound features can improve the diagnostic performance of tumor markers in distinguishing ovarian tumors, we enrolled 719 patients diagnosed as having ovarian tumors at Nanfang Hospital from September 2014 to November 2016. Age, menopausal status, histopathology, the International Federation of Gynecology and Obstetrics (FIGO) stages, tumor biomarker levels, and detailed ultrasound reports of patients were collected. The area under the curve (AUC), sensitivity, and specificity of the bellow-mentioned predictors were analyzed using the receiver operating characteristic curve. Of the 719 patients, 531 had benign lesions, 119 had epithelial ovarian cancers (EOC), 44 had borderline ovarian tumors (BOT), and 25 had non-EOC. AUCs and the sensitivity of cancer antigen 125 (CA125), human epididymis-specific protein 4 (HE4), Risk of Ovarian Malignancy Algorithm (ROMA), Risk of Malignancy Index (RMI1), HE4 model, and Rajavithi-Ovarian Cancer Predictive Score (R-OPS) in the overall population were 0.792, 0.854, 0.856, 0.872, 0.893, 0.852, and 70.2%, 56.9%, 69.1%, 60.6%, 77.1%, 71.3%, respectively. For distinguishing EOC from benign tumors, the AUCs and sensitivity of the above mentioned predictors were 0.888, 0.946, 0.947, 0.949, 0.967, 0.966, and 84.0%, 79.8%, 87.4%, 84.9%, 90.8%, 89.1%, respectively. Their specificity in predicting benign diseases was 72.9%, 94.4%, 87.6%, 95.9%, 86.3%, 90.8%, respectively. Therefore, we consider biomarkers in combination with ultrasound features may improve the diagnostic performance in distinguishing malignant from benign ovarian tumors.

Background: To evaluate the diagnostic performance of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) for ovarian cancer., Patients and Methods: A thorough research was conducted in PubMed, Web of Science and Embase (until November 2018) to identify studies evaluating the accuracy of MALDI-TOF-MS for ovarian cancer. Using Meta-Disc1.4, Review Manager 5.3 and Stata 15.1 software to analyze the pooled results: sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and 95% confidence intervals (CI). The summary receiver operating characteristic curves (SROC) and area under the curve (AUC) show the overall performance of MALDI-TOF-MS., Results: Eighteen studies were included in the meta-analysis. Methodological quality analysis of the included studies showed that these articles were at low risk of bias and applicability concerns in total. Summary estimates of the diagnostic parameters were as follows: sensitivity, 0.77 (95% CI: 0.73-0.80); specificity, 0.72 (95% CI: 0.70-0.74), PLR, 2.80 (95% CI: 2.41-3.24); NLR, 0.30 (95% CI: 0.22-0.40) and DOR, 10.71 (95% CI: 7.81-14.68). And the AUC was 0.8336. Egger's test showed no significant publication bias in this meta-analysis., Conclusion: In conclusion, MALDI-TOF-MS shows a good ability for diagnosing ovarian cancer. Further evaluation and optimization of standardized procedures are necessary for complete relying on MALDI-TOF-MS to diagnose ovarian cancer.

Ovarian cancer is a silent cancer which rate survival mainly relays in early stage detection. The discovery of reliable ovarian cancer biomarkers plays a crucial role in the disease management and strongly impact in patient's prognosis and survival. Although having many limitations CA125 is a classical ovarian cancer biomarker, but current research using proteomic or metabolomic methodologies struggles to find alternative biomarkers, using non-invasive our relatively non-invasive sources such as urine, serum, plasma, tissue, ascites or exosomes. Metabolism and metabolites are key players in cancer biology and its importance in biomarkers discovery cannot be neglected. In this chapter we overview the state of art and the challenges facing the use and discovery of biomarkers and focus on ovarian cancer early detection.

Background/aim: The potential of the DNA mismatch repair (MMR) system as a prognostic predictor has been evaluated in several cancer types. However, associations between MMR and the prognostic factors of ovarian cancer are poorly understood., Patients and Methods: MLH1 expression was evaluated by immunohistochemistry in patients with advanced serous ovarian cancer treated with platinum- and taxane-based chemotherapy. Associations between MLH1 expression and clinicopathological factors as well as claudin-4 expression were examined., Results: Low MLH1 expression was significantly associated with increased progression-free and overall survival, and a normalisation of CA125 levels after chemotherapy. Additionally, low claudin-4 expression was more frequently found among the group with low MLH1 expression., Conclusion: Low MLH1 expression was associated with improved prognosis and is a possible predictor of the chemosensitivity of ovarian cancer. Claudin-4 might be involved in the molecular mechanisms underlying how MLH1 influences survival and chemosensitivity in patients with ovarian cancer., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: Management of a woman with a pelvic mass is complicated by difficulty in discriminating malignant from benign disease. Many serum biomarkers have been examined to determine their sensitivity for detecting malignancy. This study was designed to evaluate if the addition of biomarkers to HE4 and CA125, as used in the Risk of Malignancy Algorithm (ROMA), can improve the detection of EOC., Methods: This was an IRB approved, prospective clinical trial examining serum obtained from women diagnosed with a pelvic mass who subsequently underwent surgery. Serum biomarker levels for CA125, HE4, YKL-40, transthyretin, ApoA1, Beta-2-microglobulin, transferrin, and LPA were measured. Logistic regression analysis was performed for various marker combinations, ROC curves were generated, and the area under the curves (AUCs) were determined., Results: A total of 184 patients met inclusion criteria with a median age of 56 years (Range 20-91). Final pathology revealed there were 103 (56.0%) benign tumors, 4 (2.2%) LMP tumors, 61 EOC (33.1%), 2 (1.1%) non-EOC ovarian cancers, 6 (3.3%) gynecologic cancers with metastasis to the ovary and 8 (4.3%) non-gynecologic cancers with metastasis to the ovary. The combination of HE4 and CA125 (i.e. ROMA) achieved an AUC of 91.2% (95% CI: 86.0-96.4) for the detection of EOC vs benign disease. The combination of CA125, HE4, YKL-40, transthyretin, ApoA1, Beta 2 microglobulin, transferrin, LPA and menopausal status achieved the highest AUC of 94.6% (95% CI: 90.1-99.2) but this combination was not significantly better than the HE4 and CA125 combination alone (p = 0.078)., Conclusions: The addition of select further serum biomarkers to HE4 and CA125 does not add to the performance of the dual marker combination for the detection of ovarian cancer., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Circulating tumor cells (CTCs) have received enormous attention as a novel biomarker in various malignant diseases. We investigated the clinical association between the presence of perioperative CTCs and survival outcomes in women with ovarian cancer. In a total of 30 women who were scheduled to undergo a surgical treatment for ovarian cancer, peripheral blood samples were obtained before and after surgery. CTCs were isolated and counted using the optimized tapered-slit filter (TSF) platform. The association between the presence of perioperative CTCs and tumor features was evaluated. The impact of the presence of perioperative CTCs on progression-free survival (PFS) and overall survival (OS) rates were analyzed using a Kaplan-Meier method. The median age was 58 (range, 24-77) years, and the median follow-up period was 31.5 (range, 1-41) months. Overall, the CTC detection rate was not significantly different before and after surgery (76.7% vs 57.1%, P = .673). The presence of postoperative CTCs was not significantly associated with 3-year PFS (29.1% vs 58.3%, P = .130) and OS (84.4% vs 80.0%, P = .559) rates in the whole study population. In advanced stage, PFS rate in patients with postoperative CTCs had lower PFS rates than those without postoperative CTCs, although there was no statistical significance (18.8% vs 57.1%, P = .077). Postoperative CTC was more frequently detected in women who had lymph node involvement than those who did not (7/7 [100%] vs 3/10 [30.0%], P = .010). The presence of postoperative CTCs as detected using the TSF platform seems to be associated with poorer PFS rates in women with ovarian cancer of advanced stage. Further study with a larger population is warranted to validate our study findings.

Background: The correlation between tumor markers (TM) and TNM stage of non-small-cell lung cancer (NSCLC) has not been widely reported., Methods: TM levels (CEA, CA125, CA15-3, CA19-9, CA72-4, CYFRA21-1, and SCC-Ag) in 424 cases of lung adenocarcinoma (LAC), 166 cases of lung squamous cell carcinoma (LSCC), and 103 cases of benign chest disease (BCD) were analyzed before treatment., Results: By Kendall's tau-b correlation analysis, CEA, CA125, CA15-3, CA19-9, CA72-4, CYFRA21-1, and SCC-Ag were correlated with T stage of LAC ( r = 0.235, p < 0.05; r = 0.298, p < 0.05; r = 0.254, p < 0.05; r = 0.063, p < 0.05; r = 0.080, p < 0.05; r = 0.268, p < 0.05; and r = 0.080, p < 0.05). CEA, CA125, CA15-3, CA19-9, CA72-4, and CYFRA21-1 were correlated with N stage of LAC ( r = 0.356, p < 0.05; r = 0.415, p < 0.05; r = 0.340, p < 0.05; r = 0.117, p < 0.05; r = 0.175, p < 0.05; and r = 0.351, p < 0.05). CEA, CA125, CA15-3, CA19-9, CA72-4, and CYFRA21-1 were correlated with M stage of LAC ( r = 0.365, p < 0.05; r = 0.353, p < 0.05; r = 0.293, p < 0.05; r = 0.135, p < 0.05; r = 0.169, p < 0.05; and r = 0.312, p < 0.05). CA125, CYFRA21-1, and SCC-Ag were correlated with T stage of LSCC ( r = 0.202, p < 0.05; r = 0.233, p < 0.05; and r = 0.099, p < 0.05). CA125 and CYFRA21-1 were correlated with N stage of LSCC ( r = 0.178, p < 0.05 and r = 0.284, p < 0.05). CA125, CA15-3, and CYFRA21-1 were correlated with M stage of LSCC ( r = 0.214, p < 0.05; r = 0.152, p < 0.05; and r = 0.213, p < 0.05). Combining hazard ratio, AUC, sensitivity, specificity, NPV, and PPV, it was concluded that CEA and CYFRA21-1were the most related TM of LAC. SCC-Ag and CYFRA21-1 were the most related TM of LSCC., Conclusions: CEA combined with CYFRA21-1 contributed to auxiliary diagnosis of LAC. CYFRA21-1 combined with SCC-Ag contributed to auxiliary diagnosis of LSCC. CEA, CA125, CA15-3, CA19-9, CA72-4, and CYFRA21-1 were correlated with primary tissue and metastasis of LAC. CA125 and CYFRA21-1 were correlated with primary tissue and metastasis of LSCC.

N-glycolylneuraminic acid (Neu5Gc)-containing glycans are a prominent form of aberrant glycosylation found in human tumor cells and have been proposed as cancer biomarkers. The B subunit of the subtilase cytotoxin (SubB) produced by Shiga toxigenic Escherichia coli recognises Neu5Gc containing glycans. We have previously engineered this lectin, SubB2M, for greater specificity and enhanced recognition of Neu5Gc-containing glycans. Here we further explore the utility of SubB2M to detect Neu5Gc tumor biomarkers in sera from patients with ovarian cancer. Using surface plasmon resonance (SPR) we show that SubB2M can detect the established ovarian cancer biomarker, CA125, in a highly sensitive and specific fashion in the context of human serum. These studies established conditions for screening serum samples from patients with ovarian cancer for Neu5Gc glycans. We found that serum from patients with all stages of ovarian cancer had significantly elevated mean levels of Neu5Gc glycans compared to normal controls. Serum from patients with late stage disease (stages IIIC, IV) had uniformly elevated levels of Neu5Gc glycans. Detection of Neu5Gc-glycans using SubB2M has the potential to be used as a diagnostic ovarian cancer biomarker, as well as a tool for monitoring treatment and disease progression in late stage disease., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Ovarian cancer remains the most lethal gynecologic malignancy. This is due to lack of effective screening, diagnosis predominance in late stage of disease, a high recurrence rate after primary therapy, and poor treatment response in platinum-resistant tumor. Thus, unique biomarkers, predictive of individual disease course, and prognosis are urgently needed. The aim of our study was to assess the clinicopathological significance of plasma, peritoneal fluid, and tumor tissue levels of mesothelin in epithelial ovarian cancer patients. Plasma and peritoneal fluid levels of mesothelin were measured by enzyme-linked immunosorbent assay. Tissue expression of MSLN was evaluated using quantitative real-time polymerase chain reaction. Preoperative plasma mesothelin levels were significantly higher in epithelial ovarian cancer patients in comparison to the patients with benign tumor and controls. There have been noticed significant differences in the plasma mesothelin levels based on International Federation of Gynecology and Obstetrics stage, grade, and histology type. No significant changes were observed between Kurman and Shih type I versus type II epithelial ovarian cancer. Interestingly, peritoneal fluid mesothelin levels revealed significant differences based on both grade and Kurman and Shih-type epithelial ovarian cancer. There were no relevant changes in the mesothelin level in peritoneal fluid between different stages and histology types compared to benign tumor. MSLN expression level in tumor tissue was significantly higher based on stage, grade, and Kurman and Shih-type epithelial ovarian cancer than in the benign masses. In addition, data showed significant higher MSLN expression in endometrioid tumors compared to benign masses and serous tumors. Plasma, peritoneal fluid, and tumor tissue levels of mesothelin positively correlated with level of CA125. Low mesothelin concentrations in plasma were also associated with prolonged patient survival. More importantly, we revealed that plasma mesothelin level was correlated with both peritoneal fluid mesothelin level and tumor MSLN expression. This study highlights that plasma mesothelin level may be a useful noninvasive biomarker surrogate for local tumor mesothelin status in monitoring of epithelial ovarian cancer patients.

In recent years, a lot of attention has been paid to quantum dot (QD) nanoparticles as fluorescent sensors for sensitive and accurate detection of cancer biomarkers. Here, using a homemade specific monoclonal antibody against CA125 and QD525- or FITC-labeled probes, expression of this marker in an ovarian cancer cell line and cancer tissues were traced and optical properties of fluorophores were compared qualitatively and quantitatively. Our results clearly showed that besides lower background and exceptionally higher photobleaching resistance, QD525 exhibited higher fluorescent intensity for both ovarian cancer cell and tissues at different exposure times (p<0.0001) and excitation filter sets (p<0.0001) exemplified by significantly higher staining index (p<0.016). More importantly, the FITC-labeled probe detected antigen-antibody complex at minimum concentration of 0.3 mg/mL of anti-CA125, while reactivity limit decreased to 0.078 mg/mL of anti-CA125 when QD525-labeled probe was applied showing four times higher reactivity level of QD525 probe compared to the same probe labeled with FITC. Based on our results, it seems that QDs are inimitable tags for sensitive detection and localization of ovarian cancer micrometastasis and molecular demarcation of cancer tissues in surgical practice, which subsequently figure out accurate therapeutic approaches.

Despite many years of studies, ovarian cancer remains one of the top ten cancers worldwide. Its high mortality rate is mainly due to lack of sufficient diagnostic methods. For this reason, our research focused on the identification of blood markers whose appearance would precede the clinical manifestation of the disease. ITRAQ-tagging (isobaric Tags for Relative and Absolute Quantification) coupled with mass spectrometry technology was applied. Three groups of samples derived from patients with: ovarian cancer, benign ovarian tumor, and healthy controls, were examined. Mass spectrometry analysis allowed for highlighting the dysregulation of several proteins associated with ovarian cancer. Further validation of the obtained results indicated that five proteins (Serotransferrin, Amyloid A1, Hemopexin, C-reactive protein, Albumin) were differentially expressed in ovarian cancer group. Interestingly, the addition of Albumin, Serotransferrin, and Amyloid A1 to CA125 (cancer antigen 125) and HE4 (human epididymis protein4) improved the diagnostic performance of the model discriminating between benign and malignant tumors. Identified proteins shed light on the molecular signaling pathways that are associated with ovarian cancer development and should be further investigated in future studies. Our findings indicate five proteins with a strong potential to use in a multimarker test for screening and detection of ovarian cancer.

Background: Primary cytoreduction surgery followed by chemotherapy is the cornerstone treatment for epithelial ovarian cancer (EOC). In patients with a low probability of optimal primary surgical debulking, neoadjuvant chemotherapy (NACT) followed by interval debulking increases the chance of optimal surgery. The aim of this study was to develop a model to identify preoperative predictors for suboptimal cytoreduction. Methods: Medical records of patients with EOC who underwent primary cytoreductive surgery in a referral tertiary gyneco-oncology center were reviewed from 2007 to 2017. Data were collected on a range of characteristics including demographic features, comorbidities, serum tumor markers, hematologic markers, preoperative imaging, surgical procedures, and pathologic reports. Univariate and multivariate analyses were performed to clarify the ability of preoperative factors to predict suboptimal primary surgery. Results: The majority of patients (71.3%) who underwent primary cytoreductive surgery were optimally debulked. Based on the Youden index, the best cut-off point for the serum CA125 level to distinguish suboptimal debulking was 420U/ml with 0.730 (95%CI:0.559 to 0.862) sensitivity and 0.783 (0.684 to 0.862) specificity. Multiple logistic regression results showed that serum CA125 level >420 U/ ml (p value <0.001), the presence of liver metastasis on preoperative imaging (p value: 0.041) and ascites (p value: 0.032) or massive ascites (p value:0.010) significantly increased the risk of suboptimal debulking (logit p = 2.36 CA125 level +1.85 Liverinvolvement +1.68 presence of Ascites+ 2.28 Massive Ascites). Conclusion:The present study suggests that a serum CA125 level >420 U/ml, the presence of ascites or massive ascites and liver metastasis are strong predictors of suboptimal primary surgery in cases of EOC. Based on the constructed model, with any of these 4 factors, the probability of suboptimal debulking in EOC is more than 80%., (Creative Commons Attribution License)

Using random survival forest, this study was intended to evaluate the prognostic value of serum markers for lung adenocarcinoma patients with brain metastasis (BM), and tried to integrate them into a prognostic model. During 2010 to 2015, the patients were retrieved from two medical centers. Besides the Cox proportional hazards regression, the random survival forest (RSF) were also used to develop prognostic model from the group A (n = 142). In RSF of the group A, the factors, whose minimal depth were greater than the depth threshold or had a negative variable importance (VIMP), were firstly excluded. Subsequently, C-index and Akaike information criterion (AIC) were used to guide us finding models with higher prognostic ability and lower overfitting possibility. These RSF models, together with the Cox, modified-RPA and lung-GPA index were validated and compared, especially in the group B (CAMS, n = 53). Our data indicated that the KSE125 model (KPS, smoking, EGFR-20 (exon 18, 19 and 21) and Ca125) was the best in survival prediction, and performed well in internal and external validation. In conclusions, for lung adenocarcinoma patients with brain metastasis, a validated prognostic nomogram (KPS, smoking, EGFR-20 and Ca125) can more accurately predict 1-year and 2-year survival of the patients.

Background: Among frequently-used tumor markers in lung cancer, carcinoembryonic antigen (CEA) and carbohydrate antigen 125 (CA125), cytokeratin 19 (CYFRA21-1) and squamous carcinoma antigen (SCC), neuron specific enolase (NSE) and pro-gastrin-releasing peptide (ProGRP) are respectively expressed highly in lung adenocarcinoma, lung squamous carcinoma and small cell lung cancer. By comparing patients with multiple increased tumor markers (group A) and patients with increase of CEA and/or CA125 (group B), this study aims to investigate the utility of multiple increased tumor markers in therapeutic evaluation and prediction of disease relapsing in patients with advanced lung adenocarcinoma., Methods: Patients with stage IV lung adenocarcinoma who receiving the first line chemotherapy in Cancer Hospital, Chinese Academy of Medical Sciences were enrolled and retrospectively analyzed. Clinical characteristic, serum tumor markers before chemotherapy, efficacy evaluation, progression-free survival (PFS) were analyzed., Results: Except CEA and CA125, the highest ratio of increased tumor markersin group A was CYFRA21-1 (93%), then was NSE (36%), SCC (13%) and ProGRP (12%). Patients with multiple increased tumor markers tend to have more distant metastasis (P<0.001) and shorter PFS (median PFS 5.3 months vs 7.3 months, P=0.016). The relapse risk was lower in patients who accepted maintenance therapy than those who didn't accept maintenance therapy in both groups (P<0.001)., Conclusions: Patients with multiple increased tumor markers have high risk of relapse, and maintenance therapy can reduce relapse risk.

Galectins are moving closer to center stage in detecting glycosylation aberration in cancer cells. Here, we have investigated the expression of galectins in ovarian cancer (OC) and examined their potential as biomarkers in tissues and blood plasma samples of high grade serous ovarian carcinoma (HGSC) patients. In tissues, we found that increased protein expression of stromal gal-1 and epithelial gal-8/9 was associated with a poor response to treatment of HGSC patients. Gal-8/9 were both independent predictors of chemoresistance and overall survival (OS), respectively. This galectin signature increased the predictive value of the cancer antigen 125 (CA125) on 5-year disease-free survival (DFS), post-chemotherapy treatment and 5-year OS. In CA125 LOW patients, epithelial gal-9 was associated with a lower 5-year OS while stromal gal-1 and epithelial gal-8 were both associated with a lower 5-year DFS. Such negative predictive value of gal-8 and gal-9 was also found using plasma samples. In both cases, high plasma levels of gal-8 and gal-9 was associated with a lower OS and DFS. Overall, these data suggest that galectins may be promising biomarkers to identify subgroups of HGSC patients with poorer prognosis. Our study also contributes to better define the heterogeneity of the disease.

Purpose: To investigate whether vascular differentiation marker von Willebrand factor (vWf) and proliferation marker KI67 expression correlate with MUC4 localization around stromal tumor vascularization in human conjunctival malignant melanoma (CMM)., Materials and Methods: For the purposes of this study, we analyzed samples from human CMMs (n = 4), conjunctival compound nevi (n = 7), and samples from healthy conjunctiva (n = 7) for MUC1, 4, and 16 by immunohistochemistry. To test CMM vessel association of MUC4, we investigated the co-localization of MUC4 with vWf or KI67 in human CMM specimens (n = 10) by immunohistochemistry. Also, we investigated the MUC4 localization around vessels of healthy conjunctiva (n = 10)., Results: The immunohistochemical analysis demonstrated membrane-associated mucin expression in epithelia of CMM, nevi and healthy conjunctiva, whereas only MUC4 was localized perivascular in CMM tissue in this preliminary analysis. Co-staining analysis with vWf and KI67 demonstrated MUC4 localization around stromal vessels in human CMM specimens. In contrast, no MUC4 localization has been seen around healthy conjunctiva stroma vessels., Conclusions: MUC4 was detected around vWf/KI67-positive CMM stromal vascular tissue, but not around healthy conjunctival stroma vessels. Therefore, we assume that MUC4 might play a role in tumor cell migration toward vessels inducing metastasis.

The aim of this study was to assess the usefulness of the human epididymis protein 4 (HE4) serum biomarker in predicting malignant disease in a clinical setting in comparison with other diagnostic tools, such as serum CA125 and ROMA score. A multicentric prospective observational study was carried out between January 2010 and December 2011 in four European centres (Italy, Portugal, Latvia and Spain). Data from 981 healthy controls and patients diagnosed with adnexal pathology were collected. Data on the ROMA index, CA124 and HE4 tumour markers were analysed. The receiver-operator characteristics curve and the area under the curve were analysed to discriminate between malignant and nonmalignant disease. Predictive values were also calculated. In total, 642 (65.4%) patients presented with a pelvic mass, with 324 (33%) of them being diagnosed with malignant disease. Sensitivity for HE4 was 64.1%; specificity was 95.7%; and positive predictive value was 88.1%, with a 4.3% false-positive rate. On comparing malignant disease versus nonmalignant/healthy patients, there was a significant difference (P<0.001) in the area under the curve. The receiver-operator characteristic for CA125 was 0.79 [95% confidence interval (CI): 0.76-0.83], for HE4 was 0.89 (95% CI: 0.87-0.91) and for ROMA was 0.71 (95% CI: 0.68-0.75). The HE4 serum marker showed similar sensitivity, but better specificity, than CA125 and can improve the detection of malignant pathology in women diagnosed with adnexal pathology.

Background and Aims: Bile duct cancer is one of the lethal cancers, presenting difficulties in early diagnosis and limited treatment modalities. Despite current advances in biomarker research, most studies have been performed in Western populations. Therefore, the purpose of this study was to determine a prognostic marker for bile duct cancer, especially in Korean patients, whose incidence of bile duct cancer is high., Results: Comparing cancer and normal bile duct tissue, we identified 29091 differentially expressed genes. CP, SCEL, and MUC16 had positive coefficients with a log2 ratio >1 for advanced T, N stage and perineural invasion cancer tissue. Strong immunohistochemical expression of ceruloplasmin was dominant in tumors with advanced T stage (p>0.999) and perineural invasion (p=0.316)., Patients and Methods: We performed tissue microarray experiment with 79 bile duct cancer tissue samples and 21 normal bile duct tissue samples. Candidate genes that has positive correlation with T, N stage and perineural invasion were drawn with multivariate analysis. Tissue expression of the genes was evaluated with an immunohistochemical study., Conclusions: Ceruloplasmin is supposed to be related with advanced T stage and perineural invasion, having a possibility as a candidate prognostic marker for bile duct cancer.

Background: Ovarian cancer is one of the highest mortality cancers in gynaecology. Discrimination of benign masses from malignant ones may sometimes become a challenge for the clinician since there is not a reliable tumour marker, thus some unnecessary, highly morbid operations can be performed., Aims: To explore the efficacy of human epididymis 4 (HE 4) and cancer antigen 125 (CA 125) markers in differentiating malignant and benign pelvic masses of ovarian origin and to identify the cut-off points for those markers., Study Design: Prospective study., Methods: Fifty-one patients who were diagnosed and planned to undergo surgery for ovarian mass between June 2008 and December 2008 were enrolled into this study. Preoperative venous blood samples were taken and frozen for marker investigation and final diagnoses were concluded by histopathological examination. After recruitment of all cases CA 125 and HE 4 levels were evaluated., Results: The statistical analysis did not indicate any statistically significant difference between the CA 125 levels of the patients with malignant and benign adnexal masses (p=0.105). The HE 4 levels of the patients with malignant adnexal masses were higher at a statistically significant level compared to the patients with benign adnexal masses (p=0.002). For HE 4 tumour marker and at the cut-off point of >25 pM, sensitivity was 1, specificity 0.40, positive cut-off value 0.19, negative cut-off value 1, accuracy 0.47 and positive likelihood ratio 1.65., Conclusion: Human epididymis 4 is a better diagnostic tool than CA 125 in benign-malignant discrimination of adnexal masses. The cut-off value of 25 pmol/L for human epididymis 4 will contribute to providing proper guidance to patients with adnexal masses and applying the proper treatment method.

Circulating tumor cells (CTCs) are viable tumor cells that are released into the circulatory system. CTCs have shown a prognostic value in numerous solid tumors. CTC research in epithelial ovarian carcinoma (EOC) has attracted only little attention. Since the primary route of metastasis in EOC is considered to be direct peritoneal spread in the abdominal cavity and distant metastases only occur in one third of the patients, it was thought that there is not enough shedding of tumor cells in the circulation. Nevertheless recent studies revealed an important role of hematogenous spread in EOC and showed that CTC status is associated with advanced tumor stage, CA-125 levels and residual disease after surgery. Furthermore the presence of CTCs correlates with shorter overall and disease free survival. However this prognostic value of CTCs in EOC seems to depend on the used isolation and detection methods. In EOC function- or density based enrichment methods seem to offer more promising results then epithelial cell adhesion molecule (EpCAM)-based approaches. This can be explained by a low number of EpCAM positive CTCs in EOC and the downregulation of EpCAM during epithelial-to-mesenchymal transition (EMT). The presence of CTCs might also have predictive value as CTC status was associated with treatment response in two studies and CTCs showed to be a better monitoring tool then CA-125 in a small population. The (genotypic) characterization of CTCs might become even more important in the future paving the way for CTCs to a true predictive "liquid tumor biopsy"., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

We examined the prognostic value of normal levels of four serum cancer markers, carcinoembryonic antigen (CEA), carbohydrate associated antigen (CA19-9), alpha-fetoprotein (AFP) and cancer antigen 125 (CA125), in gastric cancer patients. Among 1927 gastric cancer patients enrolled in this study, 1477 were male (76.6%) and 450 were female (23.4%). The median age was 57 years (range 20-86). Clinicopathological features and survival times were recorded, and the association between CEA, CA19-9, AFP, and CA125 levels and patient prognosis was analyzed. The optimal cut-off values were 0.71 for CEA (P=0.317), 9.22 for CA19-9 (P=0.009), 3.76 for AFP (P=0.008) and 15.65 for CA125 (P=0.006). Serum CA19-9 levels correlated with gender, age, and tumor depth (all P<0.05); AFP levels correlated with pathological type (P=0.005); and CA125 levels correlated with gender, tumor size, pathological type, tumor depth and lymph node metastasis (all P<0.05). Relatively high levels of CA19-9, AFP and CA125, still within the normal range, were all associated with poor prognosis (5-year overall survival: 70.6% vs 64.2%, P<0.001. 69.6% vs 54.5%, P=0.011. 70.2% vs 54.9%, P<0.001). However, only CA19-9 and AFP levels were independent prognostic predictors. We conclude that the combined assessment of CA19-9, AFP and CA125 levels could have prognostic value in gastric cancer (P<0.001)., Competing Interests: The authors declare no conflicts of interest.

Objective: The aim of this study was to assess the predictive value of neutrophil/lymphocyte and platelet/lymphocyte ratios for borderline, malignant ovarian tumors, and borderline cases with microinvasion., Methods: Totally 275 women with sonographically detected ovarian tumor were enrolled for this study. All subjects underwent gynecological surgery via endoscopic or conventional approach and ovarian masses were all evaluated histopathologically by the same pathologist. All study population was divided into three groups as group with borderline tumors, benign tumors, or malignant tumors according to the histopathological diagnosis. Just before surgical intervention, a blood sample was obtained from each participant to analyze CA125 level, neutrophil, platelet, and lymphocyte count., Results: Neutrophil/lymphocyte ratio (AUC = 0.604, P = 0.02) was a significant predictor for malignant cases. Optimal cutoff value for the neutrophil/lymphocyte ratio was found to be 2.47 with 63.4% sensitivity and 63.5% specificity for malignancy prediction. Odds ratio of high neutrophil/lymphocyte ratio for malignancy risk was 2.5 (95% CI 1.3-4.8, P = 0.004). Platelet/lymphocyte ratio (AUC = 0.621, P = 0.007) was a significant predictor for malignant cases. Platelet/lymphocyte ratio (AUC = 0.568, P = 0.05) was also predictive for cases without a benign mass. Optimal cutoff value for the platelet/lymphocyte ratio was found to be 144.3 with 54% sensitivity and 59% specificity for malignancy prediction. Odds ratio of high platelet/lymphocyte ratio for malignancy risk was 2.1 (95% CI 1.1-3.8, P = 0.02)., Conclusion: Neutrophil/lymphocyte and platelet/lymphocyte ratios are predictors for malignant ovarian tumors but not borderline tumors even in case of microinvasion.

Transmembrane mucins (TMs) are restricted to the apical surface of normal epithelia. In cancer, TMs not only are over-expressed, but also lose polarized distribution. MUC16/CA125 is a high molecular weight TM carrying the CA125 epitope, a well-known molecular marker for human cancers. MUC16 mRNA and protein expression was mildly stimulated by low concentrations of TNFα (2.5 ng/ml) or IFNγ (20 IU/ml) when used alone; however, combined treatment with both cytokines resulted in a moderate (3-fold or less) to large (> 10-fold) stimulation of MUC16 mRNA and protein expression in a variety of cancer cell types indicating that this may be a general response. Human cancer tissue microarray analysis indicated that MUC16 expression directly correlates with TNFα and IFNγ staining intensities in certain cancers. We show that NFκB is an important mediator of cytokine stimulation of MUC16 since siRNA-mediated knockdown of NFκB/p65 greatly reduced cytokine responsiveness. Finally, we demonstrate that the 250 bp proximal promoter region of MUC16 contains an NFκB binding site that accounts for a large portion of the TNFα response. Developing methods to manipulate MUC16 expression could provide new approaches to treating cancers whose growth or metastasis is characterized by elevated levels of TMs, including MUC16.

Our identification of dysregulation of the AKT pathway in ovarian cancer as a platinum resistance specific event led to a comprehensive analysis of in vitro, in vivo and clinical behaviour of the AKT inhibitor GSK2141795. Proteomic biomarker signatures correlating with effects of GSK2141795 were developed using in vitro and in vivo models, well characterised for related molecular, phenotypic and imaging endpoints. Signatures were validated in temporally paired biopsies from patients treated with GSK2141795 in a clinical study. GSK2141795 caused growth-arrest as single agent in vitro, enhanced cisplatin-induced apoptosis in vitro and reduced tumour volume in combination with platinum in vivo. GSK2141795 treatment in vitro and in vivo resulted in ~50-90% decrease in phospho-PRAS40 and 20-80% decrease in fluoro-deoxyglucose (FDG) uptake. Proteomic analysis of GSK2141795 in vitro and in vivo identified a signature of pathway inhibition including changes in AKT and p38 phosphorylation and total Bim, IGF1R, AR and YB1 levels. In patient biopsies, prior to treatment with GSK2141795 in a phase 1 clinical trial, this signature was predictive of post-treatment changes in the response marker CA125. Development of this signature represents an opportunity to demonstrate the clinical importance of AKT inhibition for re-sensitisation of platinum resistant ovarian cancer to platinum.

Background: galectin-1 has been implicated in tumor invasion and metastasis and is frequently over-expressed in epithelial ovarian cancer (EOC), but its potential as a biomarker remains unclear. In this novel study, we have explored the possible use of galectin-1 as a biomarker for EOC., Methods: galectin-1 in sera was evaluated by ELISA in a pilot panel of EOC patients, healthy volunteers, patients with benign gynecologic tumors or other gynecologic malignancies. We examined galectin-1 expression in EOC tumor samples by Western Blot, qRT-PCR and immunohistochemistry. In vitro experiments were conducted to elucidate the biologic role of galectin-1 in EOC progression using over-expression of galectin-1 in OVCAR-3 cells. We also looked for the association of galectin-1 expression with clinic pathological variables and survival outcomes in EOC., Results: A significant difference was detected in serum galectin-1 between EOC patients with non-metastatic and those with metastatic disease, but not between EOC patients and healthy volunteers. It increased in recurrent cases and decreased after debulking surgery. Both of galectin-1 mRNA and protein levels were increased in 90 % of the examined EOC tissue samples, compared with a wedge resection of a normal ovary. High galectin-1 in peritumor stroma was primarily detected in advanced stages of EOC. Over expression of galectin-1 significantly increased the ability of OVCAR-3 cells' migration and invasion., Conclusions: Our results suggest that galectin-1 might play a role in tumor progression and be associated with poor outcome in EOC. It could be a novel prognostic and progression biomarker in EOC patients.

Background/aim: Aim of the present study was to assess the diagnostic value of unenhanced biparametric magnetic resonance imaging (Bp-MRI) as adjunct to CA125 and human epididymis protein 4 (HE4) in the characterization of large ovarian masses., Patients and Methods: Bp-MRI and dynamic contrast-enhanced (DCE) imaging of 53 patients with large ovarian masses were retrospectively analyzed and compared to histological diagnosis. The results of Bp-MRI and DCE were assessed by two readers in consensus for each technique individually compared to each other and then with HE4 and CA125., Results: Sensitivity, specificity, negative predictive values and positive predictive values for Bp-MRI and DCE were 92.3%, 91.4%, 94.1%, 88.9% and 84.6%, 94.3%, 89.2%, 91.7%, respectively. Both Bp-MRI and DCE were significant predictors of outcome. Among biomarkers, HE4 was significant. Considering the area under receiver operating characteristic curve the model including Bp-MRI and HE4 was not significantly different from the model including DCE and HE4., Conclusion: Bp-MRI in addition to HE4, especially in women of pre-menopausal age, could improve the characterization of large ovarian masses., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Objective: We developed and validated a hybrid risk classifier combining serum markers and epidemiologic risk factors to identify post-menopausal women at elevated risk for invasive fallopian tube, primary peritoneal, and ovarian epithelial carcinoma., Methods: To select epidemiologic risk factors for use in the classifier, Cox proportional hazards analyses were conducted using 74,786 Women's Health Initiative (WHI) Observational Study (OS) participants. To construct a combination classifier, 210 WHI OS cases and 536 matched controls with serum marker measurements were analyzed; validation employed 143 cases and 725 matched controls from the WHI Clinical Trial (CT) with similar data., Results: Analyses identified a combination risk classifier composed of two elevated-risk groups: 1) women with CA125 or HE4 exceeding a 98% specificity threshold; and 2) women with intact fallopian tubes, prior use of menopausal hormone therapy for at least two years, and either a first degree relative with breast or ovarian cancer or a personal history of breast cancer. In the WHI OS population, it classified 13% of women as elevated risk, identifying 30% of ovarian cancers diagnosed up to 7.8years post-enrollment (Hazard Ratio [HR]=2.6, p<0.001). In the WHI CT validation population, it classified 8% of women as elevated risk, identifying 31% of cancers diagnosed within 7years of enrollment (HR=4.6, p<0.001)., Conclusion: CA125 and HE4 contributed significantly to a risk prediction classifier combining serum markers with epidemiologic risk factors. The hybrid risk classifier may be useful to identify post-menopausal women who would benefit from timely surgical intervention to prevent epithelial ovarian cancer., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: To evaluate the use of as an aid in the identification of women who can safely undergo conservative, non-surgical management., Methods: All patients referred to the Program in Women's Oncology for surgery with a pelvic mass are evaluated at a prospective multidisciplinary tumor board (TB) where ROMA and imaging are used for management recommendations. This study evaluated women presented to TB with a pelvic mass between 2009 and 2013 who had either surgical or conservative management., Results: Of the 498 patients assessed, 392 (79%) had benign disease, 22 (4%) had LMP tumors, 28 (6%) had stage I-II epithelial ovarian cancer (EOC), 36 (7%) had stage III-IV EOC and 20 (4%) had non-EOC. Using clinical assessment in conjunction with ROMA, the TB recommended observation in 188 (37.8%) women. All patients diagnosed with an invasive malignancy were recommended for surgery by the TB. In the 315 patients managed surgically, 212 were found to have benign disease and 84 women were diagnosed with an invasive malignancy. The sensitivity for the initial TB recommendations using ROMA in conjunction with clinical judgment for detecting malignancy was 100% with a specificity of 47.7% and a NPV of 100%. When including low malignant potential tumors the sensitivity was 99.1%. For stage I-IV EOC ROMA alone had a sensitivity of 95.3%., Conclusions: ROMA in conjunction with clinical assessment can safely identify women for conservative management., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: The usefulness of tumor markers in the differential diagnosis of cancer in patients with ascites remains a matter of controversy. Few studies have reported the measurement of cancer antigen 125 (CA125) and cytokeratin 19 soluble fragments (CYFRA21-1) in ascitic fluid. The aim of the present study was to evaluate the diagnostic accuracy of these tumor markers in the detection of malignant ascites., Materials and Methods: We analyzed CA125 and CYFRA21-1 from 143 consecutive undiagnosed patients with ascitis., Results: Use of CA125 gave a sensitivity of 39.7% and a specificity of 98.8%, and CYFRA21-1 a sensitivity of 50.0% and a specificity of 97.6% in differential diagnosis of malignant ascites. For combined use of CA125 plus CYFRA21-1, sensitivity was 65.5% and specificity 96.5%. In patients with negative cytology, these two tumor markers had a sensitivity of 50% and a specificity of 96.5%., Conclusion: The determination of tumor markers in ascitic fluid could be useful for the diagnostic assessment of patients with ascites., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Human epididymis protein 4 (HE4) has been proposed as a novel biomarker for the diagnosis of epithelial ovarian cancer. Using HE4 and CA125, the risk of malignancy algorithm (ROMA) has been shown to be effective in the stratification of epithelial ovarian cancer risk., Aims: To determine the effectiveness of HE4 and ROMA in the diagnosis of malignancy of women presenting with a complex pelvic mass in an Australian population and to compare it with CA125 and the risk of malignancy index (RMI)., Materials and Methods: Prospective recruitment of women was conducted between October 2012 and March 2014 (n = 50). CA125 and HE4 serum concentrations were collected and stored for subsequent analysis. Sensitivities, specificities, positive predictive values (PPV) and negative predictive values (NPV) were calculated for HE4, CA125, ROMA and the RMI. Receiver operating characteristic (ROC) area under the curves (AUC) were also calculated for comparison., Results: There was a higher HE4 level in women with ovarian cancer compared with women with benign pathology (P = 0.008), and this observation was seen in benign versus stage 1 ovarian cancer women (P = 0.025). HE4 had a better specificity than CA125 for the diagnosis of ovarian cancer in all women (P = 0.022), and this effect was also observed in premenopausal women (P = 0.012). Furthermore, the ROC-AUC for HE4 was superior than CA125 in all women (P = 0.0451). The ROMA algorithm was not inferior to the RMI calculation in this population., Conclusions: In an Australian population, HE4 and ROMA are useful in the diagnosis of epithelial ovarian cancer., (© 2015 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

The CA125 assay detects circulating MUC16 and is one of the most widely used cancer biomarkers for the follow-up of ovarian cancer. We previously demonstrated that detection of aberrant cancer-associated glycoforms of MUC16 as well as MUC1 in circulation could improve the yield of these serum assays. Our aim was to refine ovarian cancer biomarkers by detection of aberrant glycoforms (Tn, STn, and T) of MUC16 and MUC1 in ovarian cancer tissue using Proximity Ligation Assays (PLA). We studied two series of serous ovarian tumours, a pilot series of 66 ovarian tumours (27 cystadenomas, 16 borderline tumours and 23 adenocarcinomas) from Centro Hospitalar S. João, Porto and a validation series of 89 ovarian tumours (17 cystadenomas, 25 borderline tumours and 47 adenocarcinomas) from the Portuguese Institute of Oncology Francisco Gentil, Lisbon. PLA reactions for MUC16/Tn, MUC16/STn, MUC1/Tn and MUC1/STn were negative in benign lesions but often positive in borderline and malignant lesions, in both series. An even better yield was obtained based on positivity for any of the four glyco-mucin profiles, further increasing sensitivity to 72% and 83% in the two series, respectively, with 100% specificity. The strategy is designated glyco-mucin profiling and provides strong support for development of PLA-based serum assays for early diagnosis., (Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

Objective: To evaluate the values of 4 tumor markers in serum and ascites and their ascites/serum ratios in the identification and diagnosis of benign and malignant ascites., Materials and Methods: A total of 76 patients were selected as subjects and divided into malignant ascites group (45 cases) and benign ascites group (31 cases). Samples of ascites and serum of all hospitalized patients were collected before treatment. The levels of carcinoembryonic antigen (CEA), alpha fetoprotein (AFP), cancer antigen 125 (CA125) and carbohydrate antigen 19-9 (CA19-9) were detected by chemiluminescence (CLIA) ., Results: CEA, AFP and CA19-9 in both serum and ascites as well as CA125 in ascites were evidently higher in the malignant ascites group than in the benign ascites group (P<0.01). Malignant ascites was associated with elevated ascites/serum ratios for AFP and CA125 (P<0.01). The areas under receiver operating characteristic (AUROCs) of CEA and CA125 in ascites and the ratios of ascites/serum of AFP, CEA, CA125 and CA19-9 were all >0.7, suggesting certain values, while those of ascites CA19-9 and serum CEA were 0.697 and 0.629 respectively, indicating low accuracy in the identification and diagnosis of benign and malignant ascites. However, the AUROCs of the remaining indexes were <0.5, with no value for identification and diagnosis. Compared with single index, the sensitivity of combined detection increased significantly (P<0.05), in which the combined detection of CEA, CA19-9 and CA125 in ascites as well as the ratio of ascites/serum of CEA, CA19-9, CA125 and AFP had the highest sensitivity (98.4%) but with relevantly low specificity. Both sensitivity and specificity of combined detection should be comprehensively considered so as to choose the most appropriate index., Conclusions: Compared with single index, combined detection of tumor markers in serum and ascites can significantly improve the diagnostic sensitivity and specificity.

Background: The nationwide external quality assessment (EQA) of tumor markers in China has been launched for years. The quality of the performance of Chinese clinical laboratories on tumor markers is partly reflected through analysis of EQA results. This report presents an 8-year EQA result of the six most common tumor markers from 2006 to 2013., Methods: Ten freeze-dried EQA samples were distributed to participants every year. Satisfactory performance was defined as scores of more than 80% of acceptable responses with the evaluation criterion of ± 25%. The robust coefficient of variability (CV) between laboratories and percentage difference against the target value of each sample were also calculated by year., Results: A total number of 1154 laboratories submitted results in 2013, which was more than threefold of 2006. The proportion of laboratories with satisfactory performance showed an overall rising trend over the years and was up to 95% for the second survey in 2013. The overall decrease of robust CV was observed for all analytes including alpha fetoprotein (AFP), carcinoembryonic antigen (CEA), total prostate specific antigen (t-PSA), cancer antigen 125 (CA 125), cancer antigen 15-3 (CA 15-3), and cancer antigen 19-9 (CA 19-9) except for CEA, which exhibited a rise followed by a flat trend. The percentage difference narrowed gradually and was less than 2% in 2013., Conclusions: The 8-year EQA results showed a significant enhancement of degree of harmonization of tumor markers in China. However, standardization among various testing systems and improvement of harmonization has yet to be achieved.

Objective: This study measured the human epididymis protein 4 (HE4) and CA125 levels in Chinese women with benign gynecological disorders., Material and Methods: Sera were obtained from Chinese women prior to surgery for a pelvic mass and HE4 and CA125 levels were determined. The proportions of patients with HE4 and CA125 levels were compared., Results: There were 68 Chinese women with benign diseases. HE4 levels were less elevated than CA125 (1% V.S. 29%, P<0.001). The significant difference was observed in patients with endometriosis/endometriomas in which HE4 was not elevated patients and CA125 was elevated in 53% (P<0.001). Serum HE4 level was not elevated in patients with cystadenoma (0% V.S. 23%, P<0.001) and in patients with germ cell tumors (0% V.S. 5%, P<0.001)., Conclusion: HE4 was less elevated and more suitable as a biomarker than CA125 in chinese women with benign disease.

Objective: Early prediction of the expected benefit of treatment in recurrent ovarian cancer (ROC) patients may help in drug development decisions. The actual value of 50% CA-125 decrease is being reconsidered. The main objective of the present study was to quantify the links between longitudinal assessments of CA-125 kinetics and progression-free survival (PFS) in treated recurrent ovarian cancer (ROC) patients., Methods: The CALYPSO randomized phase III trial database comparing two platinum-based regimens in ROC patients was randomly split into a "learning dataset" and a "validation dataset". A parametric survival model was developed to associate longitudinal modeled CA-125 changes (ΔCA125), predictive factors, and PFS. The predictive performance of the model was evaluated with simulations., Results: The PFS of 534 ROC patients were properly characterized by a parametric mathematical model. The modeled ΔCA125 from baseline to week 6 was a better predictor of PFS than the modeled fractional change in tumor size. Simulations confirmed the model's predictive performance., Conclusions: We present the first parametric survival model quantifying the relationship between PFS and longitudinal CA-125 kinetics in treated ROC patients. The model enabled calculation of the increase in ΔCA125 required to observe a predetermined benefit in PFS to compare therapeutic strategies in populations. Therefore, ΔCA125 may be a predictive marker of the expected gain in PFS and an early predictive tool in drug development decisions., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Introduction: The diagnosis of malignant ascites is a challenging problem in clinical practice, non-invasive techniques should be developed to improve diagnostic accuracy. The diagnostic performances of tumor markers in malignant ascites remained unsettled. Our aim was to evaluate diagnostic performance of tumor markers in differential diagnosis of benign and malignant ascites., Material and Methods: A total of 437 patients were enrolled, and the relevant parameters of the patients were analyzed for the differentiation of benign ascites from malignant ascites., Results: At the predetermined cutoff values of tumor makers, tumor markers in ascitic fluid showed better diagnostic performance than those in serum. Combined use of tumor markers and the cytology increased the diagnostic yield of the latter by 37%. In cytologically negative malignant ascites, tumor markers provided assistance in differentiating malignant ascites from benign ascites, and the combination of ascitic tumor markers yielded 86% sensitivity, 97% specificity., Conclusion: Use of a panel of tumor markers exhibited excellent diagnostic performance in diagnosing malignant ascites, which indicated the detection of tumor markers may represent a beneficial adjunct to cytology, thus guiding the selection of patients who might benefit from further invasive procedures.

Background: Cytoreductive surgery (CRS) combined with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) is the optimal treatment for Pseudomyxoma Peritonei (PMP). Despite treatment, disease often recurs and may not be amenable to further CRS. Clinical experience suggests a spectrum of disease which may correlate with tumour marker levels. The aim of this study was to analyse the influence of markers on recurrence and survival., Methods: The details of all patients undergoing surgery for PMP of appendiceal origin at a national centre for peritoneal malignancy were recorded in a dedicated prospective database. The data on all patients who had CRS and HIPEC between March 1994 and January 2012 was analysed and recurrence and survival correlated with pre-operative levels of CEA, CA-125 and CA19-9., Results: Overall, 519 (69%) of 752 consecutive patients, underwent complete CRS and HIPEC. The median (range) age was 56 (20-82) years with 342/519 (66%) females. The mean overall (OS) and disease free survival (DFS) in the 131/519 patients who had normal preoperative tumour markers was 168 (128-207) and 125 (114-136) months respectively, significantly higher when compared with the 109/519 (21%) who had all three tumour markers elevated (OS of 65 (42-88) and DFS of 55 (41-70) months respectively) (P = 0.002)., Conclusions: Elevated tumour markers predict an increased risk of recurrence and reduced survival after complete CRS. This may reflect cell biology in low grade tumours and is an independent prognostic feature. Further analysis may help to select patients for post-operative chemotherapy, second look procedures or stratification of follow up., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objectives: Cytokeratin 19 is significant for indicating cancer cells, and Cyfra 21-1 is a fragment of cytokeratin 19. This retrospective study was designed to define the prognostic value of serum Cyfra 21-1 in epithelial ovarian cancers (EOC)., Materials and Methods: Serum Cyfra 21-1 concentration was obtained from 42 patients with EOC prior to treatment. Various prognostic aspects were examined using univariable and multivariable analyses. The standard serum marker cancer antigen 125 was measured simultaneously and compared in this analysis., Results: Serum levels of both Cyfra 21-1 and cancer antigen 125 were associated with positive retroperitoneal lymph nodes and platinum resistance; higher levels of Cyfra 21-1 (3.0 ng/mL as the cut-off) were associated with shorter disease-free survival (16 months vs. 28 months, p = 0.001) and overall survival (29 months vs. 41 months, p = 0.007) than lower levels. Further univariable analysis showed that Cyfra 21-1, poor differentiation, and retroperitoneal lymph node metastasis were related to platinum resistance and mortality. Multivariable analysis indicated retroperitoneal lymph node metastasis and serum Cyfra 21-1 were independent risk factors for both disease-free survival and overall survival., Conclusion: The pretreatment level of serum Cyfra 21-1 had remarkable prognostic significance for EOC, indicating poor survival when it was elevated above 3.0 ng/mL., (Copyright © 2014. Published by Elsevier B.V.)

The application of serum biomarker to ovarian tumors for early stage detection and clinical diagnosis is a rapidly expanding research area. The problem with conventional markers is that they are often released too late or at too low a level to be detected in time to trigger effective treatment. Ultrasound has been used to influence bio-effects in living cells, but there is only one reported case of the use of ultrasound to enhance the release of a biomarker (Carcinoembryonic antigen CEA). In this study we report the use of ultrasound to enhance the release of a combination of ovarian cancer biomarkers (CA125 and CA19-9) to help in the diagnosis of ovarian cancer at an early stage. The results indicated that after 5 min sonication at a frequency of 1 MHz and intensity of 0.3 W cm(-2), the CA125 and CA19-9 levels were increased by 2.02 and 4.21-fold respectively. These findings suggest that ultrasonic treatment can be used to enhance the release of serum biomarkers from ovarian tumors., (Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.)

A label-free and array-based optical liquid-crystal (LC) immunodetection technique for the detection of CA125 antigen, a protein biomarker most frequently used for ovarian cancer detection, was demonstrated with a nematic LC with larger birefringence (Δn) to promote sensitivity in detecting biomolecules. The LC-based immunodetection offers an alternative and sensitive approach for the detection of biomarker proteins, with the potential of replacing conventional immunoassays used in biochemical studies and clinical laboratories.

Determination of the cause of malignant pleural effusions is important for treatment and management, especially in cases of unknown primaries. There are limited biomarkers available for prediction of the cause of malignant pleural effusion in clinical practice. Hence, we evaluated pleural levels of five tumor biomarkers (CEA, AFP, CA125, CA153 and CA199) in predicting the cause of malignant pleural effusion in a retrospective study. Kruskal-Wallis or Mann-Whitney U tests were carried out to compare levels of tumor markers in pleural effusion among different forms of neoplasia - lung squamous cell carcinoma, adenocarcinoma, or small cell carcinoma, mesothelioma, breast cancer, lymphoma/leukemia and miscellaneous. Receiver operator characteristic analysis was performed to evaluate sensitivity and specificity of biomarkers. The Kruskal-Wallis test showed significant differences in levels of pleural effusion CEA (P<0.01), AFP (P<0.01), CA153 (P<0.01) and CA199 (P<0.01), but not CA125 (P>0.05), among the seven groups. Receiver operator characteristic analysis showed that, compared with other four tumor markers, CA153 was the best biomarker in diagnosing malignant pleural effusions of lung adenocarcinoma (area under curve (AUC): 0.838 (95%confidence interval: 0.787, 0.888); cut-off value: 10.2U/ ml; sensitivity: 73.2% (64.4-80.8)%, specificity: 85.2% (77.8-90.8)%), lung squamous cell carcinoma (AUC: 0.716 (0.652, 0.780); cut-off value: 14.2U/ml; sensitivity: 57.6% (50.7-64.3)%, specificity: 91.2% (76.3-98.0)%), and small-cell lung cancer (AUC: 0.812 (0.740, 0.884); cut-off value: 9.7U/ml; sensitivity: 61.5% (55.0-67.8)%, specificity: 94.1% (71.2-99.0)%); CEA was the best biomarker in diagnosing MPEs of mesothelioma (AUC: 0.726 (0.593, 0.858); cut-off value: 1.43ng/ml; sensitivity: 83.7% (78.3-88.2)%, specificity: 61.1% (35.8-82.6)%) and lymphoma/leukemia (AUC: 0.923 (0.872, 0.974); cut-off value: 1.71ng/ml; sensitivity: 82.8% (77.4-87.3)%, specificity: 92.3% (63.9-98.7)%). Thus CA153 and CEA appear to be good biomarkers in diagnosing different causes of malignant pleural effusion. Our findings implied that the two tumor markers may improve the diagnosis and treatment for effusions of unknown primaries.