Tumour-associated antigens in systemic lupus erythematosus: association with clinical manifestations and serological indicators.

OBJECTIVES: To explore the relationship of tumour-associated antigens (TAAs) with the clinical manifestations and serological markers of SLE. METHODS: This was a retrospective study. Clinical data of SLE patients were extracted from the electronic medical records, including serum levels of TAAs such as alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), cancer antigen (CA) 19-9, CA125, CA15-3 and cytokeratin 19-fragments (CYFRA21-1). TAA positivity was defined as serum level exceeding the upper limit of the corresponding reference range. RESULTS: A total of 149 SLE patients (SLE group) and 149 age- and sex-matched healthy subjects (control group) were enrolled. Compared with healthy controls, the SLE group had higher positivity rates for CA19-9 and CYFRA21-1, and elevated serum levels of CA125, CA15-3 and CYFRA21-1. SLE patients with TAA positivity were older, had a higher prevalence of serous effusion, pericardial effusion, albuminuria and thrombocytopenia, and lower positivity rate for anti-dsDNA than patients without TAA positivity. The levels of serum creatinine (SCR), blood urea nitrogen, glutamic oxalate transaminase and 24-h urinary protein were also higher in SLE patients with TAA positivity, but platelet count and serum albumin levels were lower. On logistic regression, thrombocytopenia and SCR levels were identified as independent risk factors for TAA positivity. CA125 positivity rate and serum levels of CA125 were associated with SLE disease activity. CONCLUSION: The positivity rates and serum levels of some TAAs were elevated in SLE, and thrombocytopenia and SCR levels were independent risk factors for TAA positivity.

An electrochemical immunosensor based on MXene-GQD/AuNPs for the detection of trace amounts of CA-125 as specific tracer of ovarian cancer.

An electrochemical immunoassay system was developed to detect CA-125 using a glassy carbon electrode (GCE) modified with MXene, graphene quantum dots (GQDs), and gold nanoparticles (AuNPs). The combined MXene-GQD/AuNPs modification displayed advantageous electrochemical properties due to the synergistic effects of MXene, GQDs, and AuNPs. The MXene-GQD composite in the modified layer provided strong mechanical properties and a large specific surface area. Furthermore, the presence of AuNPs significantly improved conductivity and facilitated the binding of anti-CA-125 on the modified GCE, thereby enhancing sensitivity. Various analytical techniques such as FE-SEM and EDS were utilized to investigate the structural and morphological characteristics as well as the elemental composition. The performance of the developed immunosensor was assessed using electrochemical impedance spectroscopy (EIS), cyclic voltammetry (CV), square wave voltammetry (SWV), and differential pulse voltammetry (DPV). Under optimized conditions in a working potential range of -0.2 to 0.6 V (vs. Ag/AgCl), the sensitivity, linear range (LR), limit of detection (LOD), and correlation coefficient (R2) were determined to be 315.250 µA pU.mL-1/cm2, 0.1 to 1 nU/mL, 0.075 nU/mL, and 0.9855, respectively. The detection of CA-125 in real samples was investigated using the developed immunoassay platform, demonstrating satisfactory results including excellent selectivity and reproducibility.

The inflammatory markers combined with CA125 may predict postoperative survival in endometrial cancer.

BACKGROUND: Endometrial cancer (EC) has a high latency, making prognosis difficult to predict. Cancer antigen 125 (CA125) is not specific as a tumour marker for EC; however, complete blood count (CBC) inflammatory markers are associated with prognosis in various malignancies. Thus, this study investigated the value of CBC inflammatory markers combined with CA125 levels in predicting the prognosis of patients with EC. METHODS: In this study, 517 patients with EC were recruited between January 2015 and January 2022, and clinical characteristics, CBC inflammatory markers, and CA125 levels were assessed. Differences in each index at different EC stages and the correlation between the index and EC stage were analysed, and the influence of the index on EC prognosis was evaluated. RESULTS: Platelet distribution width (PDW) levels were significantly lower in patients with advanced EC than in those with early EC, whereas the systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), and CA125 levels were significantly higher in patients with advanced EC (all P < 0.05). ROC curve and multivariate logistic regression analyses indicated that decreased PDW and increased CA125 levels were independent risk factors for EC staging progression. In addition, multivariate Cox regression analysis showed that the combination of low PDW and high CA125 (PDW + CA125 = 2) was an independent prognostic factor of survival in EC patients. Kaplan-Meier survival analysis indicated that patients with low PDW and high CA125 had worse overall survival. CONCLUSIONS: The PDW and CA125 score may be an independent prognostic factor for postoperative overall survival in patients with EC and a useful marker for predicting the prognosis of these patients.

Endometrial cancer (EC) has a high latency period, and the prognosis of EC is difficult to predict. The inflammatory response within the tumour microenvironment plays an important role in the occurrence and development of cancer. In our study, various inflammatory indicators in complete blood counts were comprehensively analysed, and cancer antigen 125 (CA125) was further used to predict the stage and prognosis of EC. The results showed that patients with low platelet distribution width (PDW) and high CA125 levels had poorer overall survival. The PDW and CA125 score may be used as a new independent prognostic indicator.

TGFBI as a candidate biomarker for non-invasive diagnosis of early-stage endometriosis.

STUDY QUESTION: Can cartilage oligomeric matrix protein (COMP) and transforming growth factor-ß-induced protein ig-h3 (TGFBI) alone or in combination with cancer antigen 125 (CA-125) be considered as potential blood biomarkers of endometriosis? SUMMARY ANSWER: The results of this study indicate that COMP has no diagnostic value. TGFBI has potential as a non-invasive biomarker of the early stages of endometriosis, while TGFBI together with CA-125 has similar diagnostic characteristics as CA-125 alone for all stages of endometriosis. WHAT IS KNOWN ALREADY: Endometriosis is a common, chronic gynecological disease that significantly affects patient quality of life by causing pain and infertility. The gold standard for diagnosis is visual inspection of pelvic organs by laparoscopy, therefore there is an urgent need for discovery of non-invasive biomarkers for endometriosis to reduce diagnostic delays and allow earlier treatment of patients. The potential biomarkers for endometriosis evaluated in this study (COMP and TGFBI) were previously identified by our proteomic analysis of peritoneal fluid samples. STUDY DESIGN, SIZE, DURATION: This is a case-control study divided into a discovery (n = 56 patients) and a validation phase (n = 237 patients). All patients were treated between 2008 and 2019 in a tertiary medical center. PARTICIPANTS/MATERIALS, SETTING, METHOD: Patients were stratified based on the laparoscopic findings. The discovery phase included 32 endometriosis patients (cases) and 24 patients with confirmed absence of endometriosis (controls). The validation phase included 166 endometriosis and 71 control patients. Concentrations of COMP and TGFBI were measured by ELISA in plasma samples, whereas concentration of CA-125 was measured using a clinically validated assay for serum samples. Statistical and receiver operating characteristic (ROC) curve analyses were performed. The classification models were built using the linear support vector machine (SVM) method with the SVM built-in feature ranking method. MAIN RESULTS AND THE ROLE OF CHANCE: The discovery phase revealed significantly increased concentration of TGFBI, but not COMP, in plasma samples of patients with endometriosis compared to controls. In this smaller cohort, univariate ROC analysis showed fair diagnostic potential of TGFBI, with an AUC value of 0.77, sensitivity of 58%, and specificity of 84%. The classification model built using linear SVM and combining TGFBI and CA-125 showed an AUC value of 0.91, sensitivity of 88% and specificity of 75% in distinguishing patients with endometriosis from controls. The validation phase results revealed similar diagnostic characteristics of the SVM model combining TGFBI and CA-125, with an AUC value of 0.83, sensitivity of 83% and specificity of 67% and CA-125 alone with AUC value of 0.83, sensitivity of 73% and specificity of 80%. TGFBI exhibited good diagnostic potential for early-stage endometriosis (revised American Society for Reproductive Medicine stage I-II), with an AUC value of 0.74, sensitivity of 61% and specificity of 83% compared to CA-125, which had an AUC value of 0.63, sensitivity of 60% and specificity of 67%. An SVM model combining TGFBI and CA-125 showed a high AUC value of 0.94 and sensitivity of 95% for diagnosing moderate-to-severe endometriosis. LIMITATIONS, REASONS FOR CAUTION: The diagnostic models were built and validated from a single endometriosis center, and thus further validation and technical verification in a multicenter study with a larger cohort is needed. Additional limitation was lack of histological confirmation of disease for some patients in the validation phase. WIDER IMPLICATIONS OF THE FINDINGS: This study revealed for the first time increased concentration of TGFBI in plasma samples of patients with endometriosis, particularly those with minimal-to-mild endometriosis, compared to controls. This is the first step in considering TGFBI as a potential non-invasive biomarker for the early stages of endometriosis. It also opens a path for new basic research to investigate the importance of TGFBI in the pathophysiology of endometriosis. Further studies are needed to confirm the diagnostic potential of a model based on TGFBI and CA-125 for the non-invasive diagnosis of endometriosis. STUDY FUNDING/COMPETING INTEREST(S): The preparation of this manuscript was supported by grant J3-1755 from the Slovenian Research Agency to T.L.R and EU H2020-MSCA-RISE project TRENDO (grant 101008193). All authors declare that they have no conflicts of interest. TRIAL REGISTRATION NUMBER: NCT0459154.

Adherence to risk-reducing salpingo-oophorectomy guidelines among gynecologic oncologists compared to general gynecologists.

BACKGROUND: Risk-reducing bilateral salpingo-oophorectomy reduces mortality from high-grade serous carcinoma in patients with hereditary breast and ovarian cancer associated gene mutations. Ideal surgical management includes 5 steps outlined in 2005 by the Society of Gynecologic Oncology and the American College of Obstetricians and Gynecologists. In addition, it is recommended that pathologic examination include serial sectioning of specimens. In practice, risk-reducing salpingo-oophorectomy is performed by both gynecologic oncologists and general gynecologists. To ensure optimal detection of occult malignancy, standardized adherence to outlined guidelines is necessary. OBJECTIVE: This study aimed to evaluate the adherence to optimal surgical and pathologic examination guidelines and to compare the rate of occult malignancy at the time of surgery between 2 provider types. STUDY DESIGN: Institutional review board exemption was obtained. A retrospective review of patients undergoing risk-reducing bilateral salpingo-oophorectomy without hysterectomy from October 1, 2015, to December 31, 2020, at 3 sites within a healthcare system was conducted. The inclusion criteria included age ≥18 years and a documented indication for surgery being a mutation in BRCA1 or BRCA2 or a strong family history of breast and/or ovarian cancer. Compliance with 5 surgical steps and pathologic specimen preparation was based on medical record documentation. Multivariable logistic regression was used to determine differences in adherence between provider groups and surgical and pathologic examination guidelines. A P value of <.025 was considered statistically significant for the 2 primary outcomes after Bonferroni correction was applied to adjust for multiple comparisons. RESULTS: A total of 185 patients were included. Among the 96 cases performed by gynecologic oncologists, 69 (72%) performed all 5 steps of surgery, 22 (23%) performed 4 steps, 5 (5%) performed 3 steps, and none performed 1 or 2 steps. Among the 89 cases performed by general gynecologists, 4 (5%) performed all 5 steps, 33 (37%) performed 4 steps, 38 (43%) performed 3 steps, 13 (15%) performed 2 steps, and 1 (1%) performed 1 step. Gynecologic oncologists were more likely to document adherence to all 5 recommended surgical steps in their surgical dictation (odds ratio, 54.3; 95% confidence interval, 18.1-162.7; P<.0001). Among the 96 cases documented by gynecologic oncologists, 41 (43%) had serial sectioning of all specimens performed, compared with 23 of 89 cases (26%) performed by general gynecologists. No difference in adherence to pathologic guidelines was identified between the 2 provider groups (P=.0489; note: P value of >.025). Overall, 5 patients (2.70%) had occult malignancy diagnosed at the time of risk-reducing surgery, with all surgeries performed by general gynecologists. CONCLUSION: Our results demonstrated greater compliance with surgical guidelines for risk-reducing bilateral salpingo-oophorectomy in gynecologic oncologists than in general gynecologists. No considerable difference was determined between the 2 provider types in adherence to pathologic guidelines. Our findings demonstrated a need for institution-wide protocol education and implementation of standardized nomenclature to ensure provider adherence to evidence-based guidelines.

The value of CA125 in predicting acute complicated colonic diverticulitis.

BACKGROUND: CA125 is a widely used serum marker for epithelial ovarian cancer which levels may also rise in benign conditions involving peritoneal irritation. We aimed to determine if serum CA125 levels can predict disease severity in patients presenting with acute diverticulitis. METHODS: We conducted a single-center prospective observational study, analyzing CA125 serum levels in patients who presented to the emergency department with computerized tomography-proven acute left-sided colonic diverticulitis. Univariate, multivariate, and receiver operating characteristic (ROC) analyses were used to correlate CA125 serum levels at time of initial presentation with the primary outcome (complicated diverticulitis) and secondary clinical outcomes (need for urgent intervention, length of hospital stay (LOS) and readmission rates). RESULTS: One hundred and fifty-one patients were enrolled between January 2018 and July 2020 (66.9% females, median age 61 years). Twenty-five patients (16.5%) presented with complicated diverticulitis. CA125 levels were significantly higher among patients with complicated (median: 16 (7-159) u/ml) vs. uncomplicated (8 (3-39) u/ml) diverticulitis (p < 0.001) and also correlated with the Hinchey severity class (p < 0.001). Higher CA125 levels upon admission were associated with a longer LOS and a greater chance to undergo invasive procedure during the hospitalization. In patients with a measurable intra-abdominal abscess (n = 24), CA125 levels were correlated with the size of the abscess (Spearman's r = 0.46, p = 0.02). On ROC analysis to predict complicated diverticulitis, the area under the curve (AUC) for CA125 (AUC = 0.82) was bigger than for the leukocyte count (AUC = 0.53), body temperature (AUC = 0.59), and neutrophil-lymphocyte ratio (AUC = 0.70) - all p values < 0.05. On multivariate analysis of factors available at presentation, CA125 was found to be the only independent predictor of complicated diverticulitis (OR 1.12 (95% CI 1.06-1.19), p < 0.001). CONCLUSIONS: The results from this feasibility study suggest that CA125 may accurately discriminate between simple and complicated diverticulitis, meriting further prospective investigation.

The Utility of Preoperative Serum CA125 Combined with HE4 to Predict Lymph Node Metastasis in Endometrial Cancer.

OBJECTIVES: To investigate the diagnostic performance of the serum cancer antigen 125 (CA125), human epididymis protein 4 (HE4), a combination of CA125 and HE4, and a risk of ovarian malignancy algorithm (ROMA) in the preoperative prediction of high-risk lymph node metastasis (LMN) in patients with early stage endometrial cancer (EC). DESIGNS: This is a cross-sectional study. PARTICIPANTS/MATERIALS, SETTING, AND METHODS: A cross-sectional study of data for patients with early stage endometrioid EC treated surgically at Rajavithi Hospital between April 2020 and April 2021 was commenced. The preoperative serum levels of CA125 and HE4 were measured and analyzed. The ROC curves were generated to determine the optimal cutoff values of CA125, HE4, and ROMA with optimum sensitivity and specificity for predicting LMN. RESULTS: Eighty-six patients with surgically staged EC were identified. Lymph node involvement was detected in 9 patients (10.5%). The median serum CA125, HE4, and ROMA levels were significantly higher in EC patients having LMN than in those who did not (p < 0.05). Based on the ROC curve, both serum markers showed good discrimination for the prediction of LMN, with an optimal cutoff value of 35 U/mL for CA125 (AUC 0.789, 95% CI; 0.647-0.932), 200 pMol/L for HE4 (AUC 0.825, 95% CI; 0.700-0.950), and 60% for ROMA (AUC 0.856, 95% CI; 0.720-0.982). Additionally, HE4 showed the highest sensitivity, whereas the combination of CA125 and HE4 had the highest specificity. LIMITATIONS: The lack of ultra-staging might have been an important issue in underestimating the rate of nodal metastasis in low-risk patients and made the number of patients who developed LMN low (10.5%) in this study. CONCLUSIONS: The preoperative combined CA125 and HE4 levels are associated with an increased risk of having LMN in patients with early stage EC. This biomarker panel can guide identifying EC patients who might most benefit from lymphadenectomy.

Comparison of the risk of ovarian malignancy algorithm and Copenhagen Index for the preoperative assessment of Japanese women with ovarian tumors.

OBJECTIVE: To compare the risk of ovarian malignancy algorithm (ROMA) and Copenhagen Index (CPH-I) in their ability to distinguish epithelial ovarian cancer (EOC) and malignant ovarian tumors (MLOT) from benign ovarian tumors (BeOT) in Japanese women. METHODS: Patients with pathologically diagnosed ovarian tumors were included in this study. The study validated the diagnostic performance of ROMA and CPH-I. RESULTS: Among the 463 Japanese women included in this study, 312 had BeOT, 99 had EOC, and 52 had other MLOT. The receiver-operator characteristic (ROC) area under the curve (AUCs) of ROMA (0.89) and CPH-I (0.89) for distinguishing EOC from BeOT were significantly higher than that of CA125 (0.82) (CA 125 vs. ROMA; p = 0.002, vs. CPH-I; p < 0.001). The ROC-AUCs of ROMA (0.82) and CPH-I (0.81) for distinguishing MLOT from BeOT were significantly higher than that of CA125 (0.75) (CA 125 vs. ROMA: p = 0.003, vs. CPH-I: p < 0.001). The sensitivity (SN)/specificity (SP) of ROMA and CPH-I for distinguishing EOC from BeOT at standard cut-off points were 69%/90%, and 69%/90%, respectively, those for distinguishing MLOT from BeOT were 54%/90%, and 55%/90%, respectively. CONCLUSION: ROMA and CPH-I performed comparably well and better than CA125 in distinguishing EOC from BeOT in Japanese women. ROMA and CHP-I should be used with caution in practical situations, where all histological possibilities for must be considered, because the SNs of ROMA and CPH-I were only 54% and 55%.

Association of preoperative CA-125 levels with early POAF after heart valve surgery: a single-center, retrospective study.

OBJECTIVE: Cancer antigen-125 (CA-125), a tumor marker, has received increasing attention in recent years for its role in the cardiovascular field. However, no study has reported the association of CA-125 with early postoperative atrial fibrillation (POAF) after heart valve surgery. Therefore, the aim of this study was to assess whether there is a correlation between CA-125 and early postoperative POAF after heart valve surgery. METHODS: Patients who underwent valve surgery at Fujian Heart Medical Center from January 2020 to August 2022 were retrospectively analyzed and divided into postoperative atrial fibrillation group (POAF group) and postoperative non-atrial fibrillation group (NO-POAF), and the differences in clinical data between the two groups were compared, and the variables with statistical significance in the univariate analysis were included in the COX regression analysis, and finally the receivers' operating characteristics (ROC) curves were drawn. RESULTS: From January 2020 to August 2022, a total of 1653 patients underwent valve surgery. A total of 344 patients were finally included, including 52 patients (15.1%) in the POAF group and 292 patients (84.9%) in the NO-POAF group. Univariate analysis showed higher CA-125 levels in patients in the POAF group than in those in the NO-POAF group [27.89 (13.64, 61.54), 14.48 (9.87, 24.08), P = 0.000]. Analysis of the incidence of POAF based on CA-125 quartiles showed an incidence of up to 29.2% in the highest quartile (> 27.88). Multivariate COX regression analysis showed that CA-125 [OR = 1.006, 95% CI (1.002, 1.010), P = 0.001] was an independent predictor of POAF. The final ROC curve plot showed that the area under the curve for CA-125 was 0.669, with an optimal cut-off value of 27.08 U/ml, and the difference in the area under the curve between the two groups was statistically significant (P = 0.000). CONCLUSION: Elevated preoperative CA-125 levels can affect the incidence of POAF and have a predictive value for the occurrence of POAF in the early stage after valve surgery. However, due to the small sample size and single-center retrospective study, further validation of this result is needed.

A portable electrochemical immunosensor for ovarian cancer uses hierarchical microporous carbon material from waste coffee grounds.

A simple label-free electrochemical immunosensor for ovarian cancer (OC) detection was developed using a hierarchical microporous carbon material fabricated from waste coffee grounds (WCG). The analysis method exploited near-field communication (NFC) and a smartphone-based potentiostat. Waste coffee grounds were pyrolyzed with potassium hydroxide and used to modify a screen-printed electrode. The modified screen-printed electrode was decorated with gold nanoparticles (AuNPs) to capture a specific antibody. The modification and immobilization processes were characterized by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). The sensor had an effective dynamic range of 0.5 to 50.0 U mL-1 of cancer antigen 125 (CA125) tumor marker with a correlation coefficient of 0.9995. The limit of detection (LOD) was 0.4 U mL-1. A comparison of the results obtained from human serum analysis with the proposed immunosensor and the results obtained from the clinical method confirmed the accuracy and precision of the proposed immunosensor.

Relationship between the serum cancer antigen 125 level and the weight of surgically enucleated adenomyosis.

Elevated serum levels of cancer antigen 125 (CA125) are known to occur in adenomyosis. However, the relationship between the severity of adenomyosis and serum CA125 levels has not yet been elucidated. The present study aimed to examine the correlation between the weight of adenomyosis and the serum CA125 level. This retrospective study, after applying exclusion criteria, investigated 308 patients who underwent conservative surgery for adenomyosis. Serum CA125 levels were measured before surgery and weights of surgically enucleated adenomyosis were measured in the operating room. Both serum CA125 and surgically enucleated adenomyosis weight showed log-normal distributions. Pearson's product-moment correlation coefficient for the logarithmically converted values was 0.617 (95% confidence interval, 0.54-0.68).The serum CA125 level correlated positively with the weight of adenomyosis. Although the qualitative characteristics and clinical significance of adenomyosis lesions remain unclear, it seems that the investigation of the relative relationship between the serum CA125 level and the size of the affected lesion is useful to observe one of the qualitative features of adenomyosis. Furthermore, the present study supports the use of postoperative serum CA125 levels as an important indicator for determining the therapeutic effects of conservative surgical treatment for adenomyosis and detecting early signs of recurrence. Impact StatementWhat is already known on this subject? Elevated serum cancer antigen 125 (CA125) levels are known to occur in adenomyosis and are widely recognised as helpful in the diagnosis of adenomyosis.What do the results of this study add? There is a positive correlation between the serum CA125 level and the weight of adenomyosis.What are the implications of these findings for clinical practice and/or further research? The postoperative serum CA125 level is an important indicator for evaluating the extent of the affected lesion remaining after conservative surgical treatment for adenomyosis and also helpful for detecting early signs of recurrence. Further study is required to examine whether it is possible to clarify the qualitative characteristics of adenomyosis in each different case based on the CA125-producing ability of the lesion.

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

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

Consideration should be given to smoking, endometriosis, renal function (eGFR) and age when interpreting CA125 and HE4 in ovarian tumor diagnostics.

OBJECTIVES: To evaluate the impact of different biologic, histopathologic and lifestyle factors on serum levels of human epididymis protein 4 (HE4) and Cancer antigen 125 (CA125) in the diagnostic work up of women with an ovarian cyst or pelvic tumor. METHODS: The statistical evaluation was performed on a population of 445 women diagnosed with a benign ovarian disease, included in a large Swedish multicenter trial (ClinicalTrials.gov NCT03193671). Multivariable logistic regression analyses were performed to distinguish between the true negatives and false positives through adjusting for biologic, histopathologic and lifestyle factors on serum samples of CA125 and HE4 separately. The likelihood ratio test was used to determine statistical significance and Benjamini-Hochberg correction to adjust for multiple testing. RESULTS: A total of 31% of the women had false positive CA125 but only 9% had false positive results of HE4. Smoking (OR 6.62 95% CI 2.93-15.12) and impaired renal function, measured by eGFR (OR 0.18 95% CI 0.08-0.39), were independently predictive of falsely elevated serum levels of HE4. Endometriosis was the only variable predictive of falsely elevated serum levels of CA125 (OR 7.96 95% CI 4.53-14.39). Age correlated with increased serum levels of HE4. CONCLUSIONS: Smoking, renal failure, age and endometriosis are factors that independently should be considered when assessing serum levels of HE4 and CA125 in women with an ovarian cyst or pelvic mass to avoid false indications of malignant disease.

Immunoregulatory protein V-set and immunoglobulin domain-containing 4 is overexpressed in patients with endometriosis.

AIM: V-set and immunoglobulin domain-containing 4 (VSIG4) is a potent negative regulator of T-cell responses and is suggested to regulate antitumor immunity. This study investigates whether VSIG4 is significantly expressed in endometriosis patients and the association between VSIG4 levels and serum cancer antigen (CA)-125 levels, VSIG4 levels and endometriosis severity. METHODS: Tumor tissues and peripheral blood samples were obtained during surgery from 42 endometriotic cyst and 21 nonendometriotic tumor patients. The levels of VSIG4 mRNA, VSIG4 protein expression in tumor tissue and serum soluble VSIG4 concentration were compared between the two groups. After dividing the cohort using the optimized cut-off values obtained by receiver operating characteristic curve analysis, we examined the association between VSIG4 levels and serum CA-125 levels, VSIG4 levels and the factors indicating endometriosis severity. RESULTS: The expressions of VSIG4 mRNA, VSIG4 protein and serum VSIG4 concentration were significantly increased in the endometriotic cyst group compared with the control group (P = 0.001, 0.002 and 0.049, respectively). The optimized VSIG4 cut-off values for endometriosis prediction were 0.71, 0.32 and 144.37 pg/mL, respectively. After cohort division using these values, high VSIG4 levels group showed significantly elevated CA-125 compared with low VSIG4 level group (P = 0.010, 0.043 and 0.039, respectively). There was no association between VSIG4 levels and the factors indicating endometriosis severity. CONCLUSION: The expression of VSIG4 in endometriosis patients is increased compared with nonendometriotic tumor patients, and higher VSIG4 levels are significantly associated with higher serum CA-125 levels. VSIG4 may be importantly involved in the immunological alteration of endometriosis.

Value of preoperative neutrophil-lymphocyte ratio and human epididymis protein 4 in predicting lymph node metastasis in endometrial cancer patients.

AIM: To investigate the value of pretreatment neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), serum cancer antigen 125 (CA125) and human epididymis protein 4 (HE4) in predicting lymph node metastasis in patients with endometrial cancer. METHODS: A retrospective analysis of 145 patients with endometrial cancer who were treated at the Peking University Cancer Hospital and Institute between October 2010 and November 2013 was performed. Preoperative NLR, PLR, serum CA125 and HE4 were assessed. Clinicopathological parameters were evaluated for LN metastasis using logistic regression. Receiver operating characteristic (ROC) curves were plotted and the optimal cut-off values of NLR, PLR, CA125 and HE4 were calculated for predicting lymph node metastasis. RESULTS: The levels of NLR, PLR, serum CA125 and HE4 were significantly higher in patients with lymph node metastasis than those without lymph node metastasis. Multivariate analysis showed that only the higher NLR and HE4 were independent predictors for lymph node metastasis (odds ratio, OR = 3.509, P = 0.016; OR = 1.446, P = 0.016). The optimal cut-off values of NLR and HE4 for predicting lymph node metastasis were 2.50 (area under the curve, AUC = 0.809) and 80.4 pmol/L (AUC = 0.713). The sensitivity and specificity were 75.0% and 84.9% for NLR, 86.7% and 73.8% for HE4, respectively. When HE4 was combined with NLR to predict lymph node metastasis, the sensitivity and specificity were significantly improved. CONCLUSION: Preoperative higher NLR and serum HE4 are predictors of lymph node metastasis in endometrial cancer, and the predictive value was superior to that of serum CA125.

What is the predictive value of preoperative CA 125 level on the survival rate of type 1 endometrial cancer?

Background/aim: To investigate the utility of preoperative serum cancer antigen 125 (CA 125) levels in type 1 endometrial carcinoma (EC) as a marker for determining poor prognostic factors and survival. Material and methods: All patients with endometrial cancer, who had been treated between 2012 and 2020, were retrospectively reviewed, and finally, 256 patients with type 1 endometrium carcinoma were included in the study. The relationship between the clinicopathological characteristics, CA 125 level, and survival rates were analyzed. The cut-off value for the preoperative serum CA 125 level was defined as 16 IU/L. Results: The median serum CA 125 levels were significantly higher in patients with deep myometrial invasion, lymph node metastasis, lymphovascular space invasion, cervical stromal and adnexal involvement, advanced stage, positive peritoneal cytology, recurrence, and adjuvant therapy requirement. Serum CA 125 cut-off values determined according to clinicopathologic factors ranged from 15.3 to 22.9 IU/L (sensitivity 61%­77%, specificity 52%­73%). The disease-specific survival rate was significantly higher in patients with CA 125 levels < 16 IU/L (P = 0.047). Conclusion: The data showed that choosing a lower threshold value for the CA 125 level (16 IU/L) instead of 35 IU/L, could be more useful in type 1 EC patients with negative prognostic factors.

Human epididymis protein 4 antigen-autoantibody complexes complement cancer antigen 125 for detecting early-stage ovarian cancer.

BACKGROUND: Early detection of ovarian cancer could significantly improve patient outcomes. Cancer antigen 125 (CA 125) is elevated in sera from approximately 60% of patients with early-stage (I/II) disease. Sensitivity might be improved through the combination of CA 125 with other biomarkers. Among potential biomarkers, antigen-autoantibody (Ag-AAb) complexes have received relatively little attention. METHODS: Luminex-based immunoassays were used to measure human epididymis protein 4 (HE4), anti-HE4 autoantibody, and HE4 Ag-AAb complexes in sera from patients with early- (n = 73) and late-stage ovarian cancers (n = 49) at the time of diagnosis and from asymptomatic women with (n = 15) or without ovarian cancer (n = 212) enrolled in the Normal Risk Ovarian Cancer Screening Study. RESULTS: At 98% specificity for healthy, asymptomatic women, 7% of patients with early-stage (I/II) ovarian cancer and 4% of patients with late-stage (III/IV) disease had elevated levels of HE4 autoantibody, whereas elevated levels of HE4 Ag-AAb complexes were detected in sera from 38% of early-stage cases and 31% of late-stage cases. Complementarity was observed in receiver operating characteristic (ROC) curves between HE4 Ag-AAb complexes and CA 125 levels in early-stage ovarian cancer (P < .001). CA 125 detected 63% of cases, and a combination of CA 125 and HE4 Ag-AAb complexes detected 81%. Complementarity was also observed in ROC curves for an independent validation set with 69 early-stage patients (P = .039). HE4 Ag-AAb complexes were detected in serial preclinical serum samples from women destined to develop ovarian cancer: they correlated with CA 125 but did not provide a lead time. CONCLUSIONS: HE4 Ag-AAb complexes could complement CA 125 in detecting a higher fraction of early-stage ovarian cancers.

Circulating tumor DNA (ctDNA) is not a good proxy for liquid biopsies of tumor tissues for early detection.

The important conclusion that ctDNA is a mediocre proxy for liquid biopsies of tumor tissues for early detection was reached after new data were published recently in Nature Genetics. These data have shown that most mutations found in ctDNA are not related to tumor tissues but rather to the precancerous condition clonal hematopoiesis. Previously, our group has analyzed the sensitivity of the ctDNA test for early detection of cancer and concluded that the achievable sensitivity, especially for small tumors, is not enough to have clinical value. Now, the new data have shown a serious compromise in specificity. We believe that scientists who are interested in early cancer diagnostics should be aware of the limitations of this test, in both sensitivity and specificity. Our work may prompt further work aiming to alleviate these important issues in the cancer diagnostics field.

Risk-reducing Bilateral Salpingo-oophorectomy: Assessing the Incidence of Occult Ovarian Cancer and Surgeon Adherence to Recommended Practices.

STUDY OBJECTIVE: This study aimed to determine the incidence of ovarian cancer diagnosed at the time of risk-reducing bilateral salpingo-oophorectomy in a large cohort of patients with a BRCA mutation. In addition, we aimed to determine the adherence to the recommended practices for performing a risk-reducing bilateral salpingo-oophorectomy as described by the American College of Obstetricians and Gynecologists and the Society of Gynecologic Oncology. We sought to determine if adherence differed by the type of training (i.e., gynecologic oncologists vs benign gynecologists). DESIGN: Descriptive, retrospective analysis. SETTING: Academic medical center. PATIENTS: Two hundred sixty-nine patients with a known BRCA mutation. INTERVENTIONS: Prophylactic risk-reducing bilateral salpingo-oophorectomy performed either by a gynecologic oncologist or a benign gynecologist between July 2007 and September 2018. MEASUREMENTS AND MAIN RESULTS: Among 269 patients who underwent risk-reducing bilateral salpingo-oophorectomies, 220 procedures were performed by gynecologic oncologists, and 49 were performed by benign gynecologists. Washings were not performed in 5% of the procedures performed by gynecologic oncologists and 37% of the procedures performed by benign gynecologists (p <.001). Complete serial sectioning of the adnexa was not performed in 12% of the procedures performed by oncologists, and 13% of the procedures performed by benign gynecologists (p = .714). There were 8 cases (2.9%) of tubal or ovarian cancer diagnosed within this cohort. Of these cases, only 3 (1.1%) were diagnosed at the time of surgery and met the criteria for conversion to a staging procedure. CONCLUSION: Because the incidence of ovarian cancer diagnosis at the time of risk-reducing bilateral salpingo-oophorectomy is low and is often not diagnosed at the time of surgery owing to the presence of only microscopic disease, it may not be necessary for gynecologic oncologists to exclusively perform these procedures. However, this study also revealed that when this procedure is performed by benign gynecologic surgeons, some of the recommended practices are not routinely followed. If general gynecologic surgeons are to routinely perform risk-reducing bilateral salpingo-oophorectomies, it is important to promote better adherence to these practices.

Clinical application of red cell distribution width, mean platelet volume, and cancer antigen 125 detection in endometrial cancer.

BACKGROUND: Red cell distribution width (RDW) and mean platelet volume (MPV) are considered to be associated with tumors. We investigated the diagnostic value of RDW, MPV, and cancer antigen 125 (CA125), alone or in combination, in the diagnosis of endometrial cancer and endometrial hyperplasia. METHODS: This study included 144 patients with endometrial cancer (stage I: 32; II: 42; III: 48; and IV: 22), 104 patients with endometrial hyperplasia, and 80 healthy control subjects. The whole blood cell parameters were analyzed by a Mindray Blood Cell Analyzer (CAL8000), whereas CA125 was analyzed using an Architect i2000 Analyzer (Abbott). RESULTS: Significant differences in RDW, MPV, and CA125 level were observed in the endometrial cancer, endometrial hyperplasia, and control groups (P < .05). Red cell distribution width was positively correlated (r = .735) whereas MPV was negatively correlated with (r = -.736) endometrial cancer staging. The area under the receiver operating characteristic curve of the combined diagnosis of endometrial cancer based on RDW, MPV, and CA125 was 0.924 (95% CI: 0.881-0.955). The sensitivity and specificity of the combined diagnosis were larger than those of the independent detections involving RDW, MPV, and CA125. CONCLUSIONS: The combination of RDW, MPV, and CA125 can improve the differential diagnosis of endometrial cancer and endometrial hyperplasia.