Machine learning-enhanced immune signatures optimize cancer antigen 125 performance for epithelial ovarian carcinoma detection

BackgroundCancer is widely believed to result from chronic inflammation, and red cell distribution width (RDW) and mean platelet volume (MPV) are considered as inflammatory markers for cancer. We investigated the values of RDW, MPV, and cancer antigen 125 (CA125), alone or in combination, for distinguishing between ovarian cancer and benign ovarian tumors.MethodsThe study included 326 patients with ovarian cancer, 290 patients with benign ovarian tumors, and 162 control subjects. Hematologic tests were performed at initial diagnosis.ResultsRDW was increased and MPV was decreased in the ovarian cancer group compared with the control and benign ovarian tumor groups. RDW was positively correlated and MPV was negatively correlated with cancer stage. Area under the curve (AUC) analysis for ovarian cancer versus benign ovarian tumors revealed that the specificity and sensitivity were increased for the combination of MPV and CA125 compared with either marker alone, and the specificity was increased for the combination of RDW and CA125, compared with either alone. The AUCs for RDW plus CA125 and MPV plus CA125 were significantly larger than for any of the markers alone.ConclusionsIn conclusion, combinations of the markers RDW, MPV, and CA125 may improve the differential diagnosis of ovarian cancer and benign ovarian tumors.

Background: To explore the diagnostic significance of pre-surgery peripheral blood tumor markers cancer antigen 125 (CA125) and human epitope protein 4 (HE4), in conjunction with neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet count-to-lymphocyte ratio (PLR), and systemic immunoinflammatory index (SII), in the differential diagnosis of epithelial ovarian cancer (EOC) and benign ovarian tumors. Determine the best combination of diagnostic indicators for early diagnosis of EOC.Methods: We retrospectively analyzed clinical data from 189 patients with EOC and 202 patients with benign ovarian tumors, comparing levels of CA125, HE4, and inflammatory markers, and evaluated the efficacy of these markers in diagnosing EOC alone or in combination by calculating sensitivity, specificity, and receiver operating characteristic curve (ROC).Results: Serum concentrations of CA125, HE4, NLR, PLR, MLR, and SII were significantly higher in the EOC group than in the benign ovarian tumor group (P < 0.001). In 189 cases of EOC, CA125 and HE4 were significantly higher in advanced stages than in early stages (P = 0.000, P = 0.012). NLR, PLR, MLR, and SII showed no significant difference between early and advanced stages (P>0.05), and this was also the case in 141 patients with high-grade serous ovarian cancer. CA125, HE4, NLR, PLR, MLR, and SII showed no significant differences across age groups, menopausal states, or pathological types (P > 0.05 for all). For diagnosing EOC, both the CA125+HE4+NLR+PLR+MLR+SII and CA125+HE4+PLR+MLR+SII models achieved the highest AUC values (AUC = 0.951 for both). No statistically significant difference was observed between these two models in AUC comparison (P=0.9305). NLR alone showed the lowest AUC at 0.696. The CA125+HE4+PLR+MLR+SII model demonstrated the highest sensitivity (84.66%), while CA125+HE4 showed the highest specificity (95.54%).Conclusion: Preoperative peripheral blood tumor markers combined with inflammatory markers can improve the diagnostic efficiency of EOC. Among these combinations, CA125+HE4+PLR+MLR+SII demonstrated optimal diagnostic performance with the highest efficacy and sensitivity, providing a clinical basis for enhanced EOC diagnosis.

BACKGROUND: The incidence of ovarian cancer ranks 8th in the world, with 295,414 cases and 184,799 death in 2018. Management in ovarian cancer is surgery and chemotherapy. Some studies state that patients who underwent optimal cytoreduction surgery have better survival rates than suboptimal cytoreduction surgery. The pre-operative serum assessed in this study was Cancer Antigen-125 (CA-125), Fatty Acid Synthase (FASN), and Glucose Transporter (GLUT) to predict suboptimal cytoreduction in epithelial ovarian cancer (EOC). AIM: We aimed to use FASN and GLUT1 as other biomarkers, besides CA-125, to predict suboptimal cytoreduction surgery in epithelial ovarian cancer. METHODS: This observational-analytic cross-sectional study included 109 women diagnosed with epithelial ovarian cancer (EOC) between 2017 and 2019, who had serum CA-125, FASN, and GLUT measured preoperatively and underwent cytoreductive surgery. RESULTS: The results of the statistical analysis test in this study obtained p values at CA-125 (p = 0.0001), FASN (p = 0.017), and at GLUT (p = 0.013). While the cutoff point (COP) on CA-125 was 248.55, FASN was 0.445, and GLUT was 0.1980. The value of area under curve (AUC) obtained by the ROC method at CA-125 76.7%, FASN 65.3%, and GLUT 63.8%. The combination of CA-125 and FASN shows AUC value 76.9%, the combination of CA-125 and GLUT shows AUC value 72.2%, and the combination of the three shows AUC value 75.2%. CONCLUSION: The use of CA-125 as a predictor of cytoreduction surgery is still considered to be the best predictor compared to serum biomarkers in this study.

Chemotherapy directly followed by poly(ADP-ribose) polymerase inhibition as an alternative to surgery in patients with BRCA-mutated ovarian cancer: a potential management strategy in the era of coronavirus disease 2019

The aim of this work was to compare and analyze the diagnostic value of serum prostasin, cancer antigen 125 (CA125), lactate dehydrogenase (LDH), alpha-fetoprotein (AFP), and human chorionic gonadotropin (hCG+β) in epithelial ovarian cancer (EOC) and evaluate if their serum levels could be used as a potential diagnostic markers of EOC from benign tumors and healthy women. Preoperative serum samples of 110 women (24 healthy controls, 66 ovarian benign tumors, and 20 EOC) were tested for prostasin, CA125, AFP, and hCG+β. The level of CA125, AFP, and hCG+β serum tumor markers were determined by electro-chemiluminescence immunoassay (ECLIA) and the serum level of prostasin was measured using enzyme-linked immunosorbent assay (ELISA) and LDH activity was measured by spectrophotometer and analyzed using SPSS version. The Area Under the Curve (AUC) values of prostasin, CA125, LDH, AFP, and hCG+β for the discrimination of EOC from benign and healthy controls were, respectively, 0.89, 0.91, 0.77, 0.54, and 0.65, and significant increase in serum levels of prostasin, CA125, and LDH were observed for EOC compared with benign and control groups. The present study showed that CA 125 and LDH levels of serum increased in high stages, while prostasin level was decreased in high stages. The present results indicate that prostasin, CA125, and LDH are differentially expressed in EOC than in benign and healthy control population, that may be an indicative of a better diagnostic value, with higher sen- sitivity and specificity. Here the authors used a multimarker approach, consisting of CA125, AFP, beta hCG, prostasin, and LDH that could provide a more accurate tool for a differential diagnosis of patients with EOC.

State of the art of surgery in advanced epithelial ovarian cancer

Nowadays there still is no sufficient screening tool for ovarian and uterine cancer. The current study aimed to investigate whether cancer antigen 125 (CA-125), tissue polypeptide antigen (TPA) or the combination of both markers are able to act as screening tools for ovarian or uterine cancer. A total of 275 blood samples from different cohorts (ovarian cancer, uterine cancer, benign control group) were prospectively drawn and analyzed. Established biomarkers TPA and CA-125 showed elevated serum concentrations in patients with malignant tumors as compared to healthy women and women with benign diseases. In ROC curve analyses, both biomarkers were well able to discriminate between malignant and healthy, benign or overall non-malignant cases in the whole sample, with AUCs of 0.842 and above. While TPA was the best diagnostic marker in patients with uterine cancer, CA 125 was the best in patients with ovarian cancer. TPA and CA-125 both showed promising results for the detection of gynecologic malignancies. The combination of CA-125 and TPA did not improve sensitivity in comparison to single markers.

<h3>Introduction/Background</h3> The gold standard of serum tumour markers to detect ovarian cancer is cancer antigen 125 (CA125), human epididimis protein-4 (HE-4) and risk of ovarian malignancy algorithm (ROMA). However there is still need to improve its accuracy. Cytokines play a crucial role in tumour growth and progression according to proangiogenic and immunosuppressive acting. The aim of this study was to investigate the potential use of serum levels of selected cytokines in preoperative diagnosing of adnexal mass. <h3>Methodology</h3> The study group consisted of 120 patients: 35 with epithelial ovarian cancer (EOC) and 85 with benign ovarian tumours (24 teratomas, 27 endometriotic and 34 other epithelial). We measured in sera obtained preoperatively the level of CA125, HE-4 and the panel of 6 cytokines: interleukin (IL) 1β, 6, 8, 10, 12, tumour necrosis factor (TNF) using cytometric bead array (CBA) and one chemokine CXCL1/GRO-α by ELISA method. <h3>Results</h3> Serum levels of IL-6, IL-8, IL-10 and CXCL1/GRO-α were significantly higher in patients with ovarian cancer (2045 pg/ml; 208; 32; 356 pg/ml, respectively) than in women with benign ovarian tumours (17 pg/ml; 29; 16; 127 pg/ml, respectively). The similar pattern was present with standard ovarian cancer markers – CA125 (959 vs 43 U/ml) and HE-4 (534 vs 51 pmol/l). Other investigated cytokines had similar levels in all groups of patients. Analyzing the differences in the subgroups of women with benign ovarian tumours we didn't observe any significant except CA125 and IL-8; they were slightly elevated in cases of endometriotic ovarian cysts. <h3>Conclusion</h3> Proinflammatory cytokines (IL-6, IL-8), immunosuppressive (IL-10) and CXCL1/GRO-α were elevated in sera of EOC patients what points on their role in cancer development. Moreover, they might be useful in preoperative differential diagnosis of ovarian tumors, as a supplemental markers especially as they were not elevated in cases of endometriosis. <h3>Disclosures</h3> All authors report no conflict of interest.

Nanomaterials assisted laser desorption ionization for differential diagnosis of ovarian cancer and benign ovarian tumors

Dear Editor, Peritoneal tuberculosis mimics ovarian cancer due to clinical, radiological and laboratory similarities (1). Patients with peritoneal tuberculosis usually have weight loss, abdominal pain and gastrointestinal symptoms similar to ovarian cancer. Serum cancer antigen 125 (CA-125) rises in almost all cases with tuberculosis (1). Radiologically, ascites is present with an abdominopelvic mass that overlaps late-stage ovarian carcinoma leading to unnecessary laparotomy. Human epididymis protein 4 (HE4) has been shown to be overexpressed by epithelial ovarian cancers (2). It is less likely to be elevated falsely in cases of benign neoplasms, unlike serum CA-125, and can be used for the differential diagnosis of ovarian cancer (3). Here we present two cases of peritoneal tuberculosis whose definitive diagnoses were made in the Gynaecological Oncology Clinic of Zeynep Kamil Women’s and Children’s Health Education and Research Hospital, Istanbul. The first case was a 22-year-old virgin female who was admitted to hospital with constant pelvic pain for three months. Abdominal ultrasonography revealed a heterogenous, septated and partially solid cystic mass of 120*80 mm that had filled the posterior pelvic cavity. Abdominal magnetic resonance imaging (MRI) revealed an intra-abdominal mass with papillary projections and omental cake formations, in addition to loculated ascitic fluid. Serum CA-125 level was 471 U/mL (normal < 25 U/mL) while all other markers were within normal limits. HE4 was measured as 4.34 pM (normal < 40 pM). A peritoneal biopsy was taken by mini-laparatomy and reported necrotizing granulomatous inflammation with Langerhans-type giant cells (tuberculosis). The second case was a 21-year-old virgin girl who was admitted to hospital with pelvic pain and nausea. A large mass filling the whole pelvic cavity was detected during physical and radiological examinations. Serum CA-125 level was detected as 561 U/mL whilst the other tumour markers were within normal limits including HE4. A peritoneal biopsy was taken and reported necrotizing granulomatous inflammation with caseifications (tuberculosis). A correct preoperative diagnosis of female peritoneal tuberculosis is usually not possible through clinical findings and laboratory tests. Family and past history, physical examination, routine chest X-ray, ultrasonography and computer tomography (CT) evaluation may not be specific enough for the diagnosis of peritoneal tuberculosis (1). Laboratory studies to diagnose peritoneal tuberculosis such as isolated mycobacteria, an ascitic adenosinedeaminase (ADA) test and a tuberculin skin test are usually ineffective for diagnosing peritoneal tuberculosis. Patients who present with a pelvic mass, ascites and increased CA-125 level must be considered as ovarian cancer in the differential diagnosis until proven otherwise. Suspicion about peritoneal tuberculosis is a must to conclude diagnosis without any laparotomy or laparoscopy, which emphasizes the importance of and need for new markers. Serum CA-125 level can increase both in benign and malign diseases (4). HE4, which has been proven to be a reliable marker specific to ovaries and epididymis, is not influenced by peritoneal diseases. The employment of HE4 tumour markers not only increases the sensitivity and specificity of the diagnosis of ovarian tumours but also differentiates benign diseases such as peritoneal tuberculosis that may be suspected, especially in young patients with normal levels of HE4.

Background:Early diagnosis of ovarian cancer is essential for long term disease control and mortality reduction. This has been achieved using tumor markers like cancer antigen 125 (CA-125) which is elevated in malignant as well as non-malignant conditions. This dilemma led to efforts towards development of newer markers like serum human epididymis secretory protein E4 (HE4). Present study aimed to evaluate role of HE4 in diagnosing ovarian cancers and comparing it with CA-125. Methods:Serum samples from 67 patients with ovarian cancer, 42 with benign ovarian masses and 26 healthy controls were collected preoperatively and tested for serum HE4 levels and CA-125 levels. Diagnostic performance of both tumor markers (HE4/CA-125) to diagnose malignancy in ovarian masses was calculated and compared to each other. Results:Mean CA-125 and HE4 levels were significantly higher in patients with ovarian cancer than in those with benign disease (p<0.001) or healthy controls (p< 0.001). Serum HE4 levels significantly increased in epithelial ovarian cancers when compared to non-epithelial ovarian cancers (p<0.01). Using benign control as comparison, receiver operating characteristic curve (ROC) was generated to predict a cut-off value for diagnosing malignancy for serum HE4 and CA-125. Compared to CA-125, HE4 had a similar sensitivity (83.6% vs. 85.10%) and higher specificity (100% vs. 90.48%); combination of serum HE4 and CA-125 improved the sensitivity to detect ovarian cancer to 92.54%. Sensitivity of HE4 to detect early stage ovarian cancer was superior to CA-125 (92.61% vs. 63.41%). Conclusion:Serum HE4, a novel tumor marker, discriminated epithelial ovarian cancer from benign ovarian masses. HE4 levels were related to the stage and histological types with the lowest levels in mucinous epithelial ovarian cancer and non-epithelial malignancy. Measuring serum HE4 levels alongwith CA-125 may provide higher accuracy for detecting epithelial ovarian cancer particularly in the early stages.

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

Arguments for centralization of EOC treatment: There is considerable debate about whether specialized care has an effect on with the outcome of advanced (stages III–IV) epithelial ovarian cancer (EOC). It is known that the quality of surgery is one of the most important factors affecting the outcome of women with advanced EOC. We have reviewed the European population-based literature, focusing especially on studies published in the last 10 years, and have found that the evidence shows advantages for patients who undergo surgery performed by gynecologic oncologists over general gynecologists and general surgeons in terms of quality of life, morbidity, and survival. Despite this, population-based studies in Europe show that less than 50 % of patients with advanced EOC have their surgery performed by a gynecologic oncologist, and the debate about the benefits of advanced EOC centralization has continued. It is of great importance that EOC be centralized to centers with sufficiently skilled surgeons and the necessary organization to appropriately handle advanced EOC patients. This requires national health systems to secure sufficient education and training for all medical staff involved. Gynecologic cancers make up the second most common cancer among women. Five major gynecologic malignancies include cervical, ovarian, uterine vaginal, and vulvar cancers. All would agree that their management requires a multidisciplinary approach encompassing combinations of surgery, chemotherapy, and radiation treatment and also needing the help of psychologists, social workers, specialized nurses, and others. It has been claimed that centralization of gynecologic cancer improves outcome, but robust evidence is lacking. Most of the available evidence addresses ovarian cancer in developed countries and contains no information on the role of satellite centers or of other care models which can match the outcomes of centralized services. In fact for all gynecologic malignancy, the treatment site does not affect overall survival. All agree that accurate and complete surgical staging is associated with prolonged survival rates in women with early ovarian cancer and that optimal debulking improves progression-free and overall survival rates in advanced disease. But ovarian cancer is but one part of the spectrum of gynecologic malignancy and, indeed, given the epidemic of endometrial cancer due to obesity, which could engulf specialized units, a relatively less common one than previously. The data on surgical outcomes and their importance are still controversial and relate only to ovarian cancers. There are very few studies addressing outcomes in the other more common gynecologic malignancies including cervical and endometrial. It is impossible to prove that centralization is necessary as most of the published evidence is based on retrospective observational studies and therefore is at high risk of bias. To date no randomized trials have been undertaken to confirm this hypothesis

Factors predictive of elevated serum CA125 levels in patients with epithelial ovarian cancer.

Tumor markers have been widely used clinically. Detection of serum CA125 is one of the commonly used clinical methods for early screening and early diagnosis of epithelial ovarian cancer, but it is difficult to diagnose epithelial ovarian cancer with a single specific tumor marker. In this study, the combinatorial tumor marker detection method was used to compare the value of each tumor marker alone and different combinations in the diagnosis of epithelial ovarian cancer. The clinical data of patients with epithelial ovarian cancer (n=65) and ovarian benign disease (n=29) were collected. Multiple tumor marker protein chip was used to detect cancer antigen 125 (CA125), carbohydrate antigen 242 (CA242), alpha-fetoprotein (AFP), beta-human chorionic gonadotropin (β-HCG), carcinoembryonic antigen (CEA), cancer antigen 199 (CA199), neuron-specific enolase (NSE), Ferritin, cancer antigen 153 (CA153), and human growth hormone (HGH) serum levels, and to compare the differences between the benign and malignant ovarian tumors. The correlation between tumor markers and clinicopathologic features for ovarian epithelial carcinoma was analyzed by χ2 test. Spearman rank analysis showed the correlation between CA125 expression level and other tumor markers in epithelial ovarian cancer and the correlation between age and the above 10 tumor markers. Sensitivity, specificity, positive predictive value, negative predictive value, Youden index, and diagnostic efficiency were used to evaluate the diagnostic value of single tumor marker and the combination of tumor markers. The levels of β-HCG, NSE, CA153, and CA125 in the epithelial ovarian cancer group were higher than those in the ovarian benign disease group. The level of NSE in the serum of patients with epithelial ovarian cancer was related to the clinical stage of patients. In addition, the levels of CA242, β-HCG, CEA, NSE, Ferritin, CA153 in the serum of patients with epithelial ovarian cancer were positively correlated with CA125 (rs=0.497, P<0.001; rs=0.612, P<0.001; rs=0.358, P=0.003; rs=0.680, P<0.001; rs=0.322, P=0.009; rs=0.609, P<0.001, respectively), and the levels of β-HCG, Ferritin, CA153 were positively correlated with the patient's age (rs=0.256, P=0.040; rs=0.325, P=0.008; rs=0.249, P=0.046, respectively). In the diagnosis of epithelial ovarian cancer, the sensitivity, Youden index, and diagnostic efficiency of CA125 detection alone were higher than the results of the other 9 separate detections. When CA153, CA199, CA242, Ferritin, and CEA were combined with CA125, the sensitivity of the combined detection of different combinations was higher than that of CA125 alone. The combined detection sensitivities of CA125+CEA and CA125+Ferritin+CEA were 89.2% and 90.8%, respectively, and the diagnostic efficiencies were both 84.1%, which were higher than those of other combinations. The Youden index of CA125+CEA joint detection was 0.616, which was higher than those of other combinations. CA125 has a high diagnostic value in the diagnosis of epithelial ovarian cancer. The detection of combined tumor markers in serum has higher sensitivity and specificity in epithelial ovarian cancer.