Diagnosing and staging epithelial ovarian cancer by serum glycoproteomic profiling.

BACKGROUND: There is a need for diagnostic tests for screening, triaging and staging of epithelial ovarian cancer (EOC). Glycoproteomics of blood samples has shown promise for biomarker discovery. METHODS: We applied glycoproteomics to serum of people with EOC or benign pelvic masses and healthy controls. A total of 653 analytes were quantified and assessed in multivariable models, which were tested in an independent cohort. Additionally, we analyzed glycosylation patterns in serum markers and in tissues. RESULTS: We identified a biomarker panel that distinguished benign lesions from EOC with sensitivity and specificity of 83.5% and 90.1% in the training set, and of 86.7 and 86.7% in the test set, respectively. ROC analysis demonstrated strong performance across a range of cutoffs. Fucosylated multi-antennary glycopeptide markers were higher in late-stage than in early-stage EOC. A comparable pattern was found in late-stage EOC tissues. CONCLUSIONS: Blood glycopeptide biomarkers have the potential to distinguish benign from malignant pelvic masses, and early- from late-stage EOC. Glycosylation of circulating and tumor tissue proteins may be related. This study supports the hypothesis that blood glycoproteomic profiling can be used for EOC diagnosis and staging and it warrants further clinical evaluation.

Serum biomarkers of inflammation and vascular damage upon SARS-Cov-2 mRNA vaccine in patients with thymic epithelial tumors.

OBJECTIVES: Thymic epithelial tumors (TET) patients are at high risk of autoimmune and hypoimmune complications. Limited evidence is available on the potential risk of immune-related and inflammatory reactions induced by SARS-Cov-2 vaccine in this patient population. METHODS: In order to identify subjects at higher risk for vaccine complications, we prospectively evaluated a panel of serum biomarkers related to inflammation (TNF-α, IL-1ß, -6, -10, -12, and -17A, IFN-α, ß and γ, MPO, MMP-9), and vascular damage (E- and P-selectin, VEGF-A, P-ANCA and MCP-1) in 44 TET patients and in 30 healthy controls along the whole SARS-Cov-2 vaccine cycle. RESULTS: About 50 % of subjects (either TET and controls) showed an increase of serum biochemical markers of inflammation and endothelial damage with a large heterogeneity of values. Such increase appeared early, after the first dose in control subjects and later, after the second dose in TET patients (in which we observed mainly an increase of inflammatory biomarkers). The values normalized after about 3 months and did not increase after the third, booster dose. No autoimmune or vascular complications were observed in the study subjects and no difference was observed in terms of vaccine response among subjects showing serum biomarkers increase and those who experienced no changes. CONCLUSIONS: Our data highlight the relevance of Sars-Cov-2 vaccine in TET patients, as it resulted safe and prevented severe COVID-19. However, further studies are awaited to explore the mechanisms and the potential consequences of the observed increase of serum inflammatory and vascular damage biomarkers.

Potential Prognostic Value of Preoperative Leukocyte Count, Lactate Dehydrogenase and C-Reactive Protein in Thymic Epithelial Tumors.

Thymic epithelial tumors are the most common mediastinal tumors. Surgery is the mainstay of treatment and complete resection provides the best survival rate. However, advanced tumors often require multimodality treatment and thus we analyzed the prognostic potential of routine circulating biomarkers that might help to risk-stratify patients beyond tumor stage and histology. Preoperative values for white blood cell count (WBC), C-reactive protein (CRP) and lactate dehydrogenase (LDH) were analyzed in 220 thymic epithelial tumor patients operated between 1999 and 2018. Increased CRP levels (>1 mg/dl) were significantly more often measured in thymic carcinoma and neuroendocrine tumors when compared to thymoma. LDH serum activity was higher in thymic neuroendocrine tumors when compared to thymoma or thymic carcinoma. The median disease specific survival was significantly longer in thymoma cases than in thymic carcinoma and neuroendocrine tumors. Increased preoperative LDH level (>240 U/L) associated with shorter survival in thymus carcinoma (HR 4.76, p = 0.0299). In summary, higher CRP associated with carcinoma and neuroendocrine tumors, while LDH increased primarily in neuroendocrine tumors suggesting that biomarker analysis should be performed in a histology specific manner. Importantly, preoperative serum LDH might be a prognosticator in thymic carcinoma and may help to risk stratify surgically treated patients in multimodal treatment regimens.

Occurrence of seromucinous borderline tumours in the peritoneal lesions after bilateral salpingo-oophorectomy.

A 65-year-old woman with a previous history of bilateral salpingo-oophorectomy had peritoneal cysts, increasing in size over 15 years and an increasing cancer antigen 19-9 (CA 19-9) level. The size of the cysts eventually reached 86 mm and 70 mm. As malignant transformation of endometriosis was suspected, we performed peritoneal cystectomy and hysterectomy. Histopathology revealed seromucinous borderline tumours (SMBTs) derived from endometriosis. One month after surgery, her CA 19-9 level had decreased. It is rare for SMBT to occur after bilateral salpingo-oophorectomy; surgical management is the best treatment at present.

High Neutrophil Count as a Negative Prognostic Factor for Relapse in Patients with Thymic Epithelial Tumor.

PURPOSE: Preoperative neutrophil count is reportedly associated with poor prognosis in cancer patients. This study aimed to investigate the clinical significance of pre-treatment peripheral blood cell counts in patients with thymic epithelial tumors (TETs). METHODS: A retrospective review of 71 patients with completely resected TETs [64 thymoma, 6 thymic carcinoma, and 1 thymic neuroendocrine tumor] between 2000 and 2018 was conducted. Associations between tumor recurrence and pre-treatment peripheral blood cell counts of leukocytes (WBC), neutrophils (Neut), lymphocytes (Lymph), monocytes (Mono), and platelets (Plt) were analyzed. Optimal cut-off points were selected using receiver operating characteristic curve analysis to predict tumor recurrence. RESULTS: High WBC (≥ 7000), Neut (≥ 4450), and Plt (≥ 226 × 103) counts had significantly poor relapse-free survival (RFS), but high Lymph (≥ 1950) and Mono (≥ 400) did not. High Neut had the strongest correlation with recurrence (area under curve, 0.800); we focused on the analysis between high-Neut and low-Neut groups. High Neut count significantly correlated with smoking history, pre-treatment C-reactive protein level, and advanced stage; high Neut count and aggressive histology tended to show correlations. RFS was significantly poorer in the high-Neut group than in the low-Neut group (p = 0.003), with 5-year RFS rates of 63.8% and 96.8%, respectively. High Neut count was a significant adverse predictor for RFS and cumulative incidence of recurrence (p = 0.005 and p < 0.001, respectively). The risk scoring system comprising high Neut count, advanced stage, and aggressive histology demonstrated better prognostic ability than any prognostic factors alone. CONCLUSIONS: High Neut count significantly correlated with TET recurrence, suggesting a negative prognostic effect of latent inflammation in TET patients.

A phase 1 dose escalation study of the oncolytic adenovirus enadenotucirev, administered intravenously to patients with epithelial solid tumors (EVOLVE).

BACKGROUND: Enadenotucirev is a chimeric adenovirus with demonstrated preclinical tumor-selective cytotoxicity and a short half-life. Further clinical mechanism of action data showed that enadenotucirev can gain access to and replicate within different types of epithelial tumors. This phase 1 dose escalation study assessed intravenous (IV) dose escalation with enadenotucirev to establish the maximum tolerated dose (MTD) and subsequently identify a suitable schedule for repeated cycles. METHODS: Sixty-one patients with advanced epithelial tumors unresponsive to conventional therapy were enrolled and received enadenotucirev monotherapy as part of this study. During the phase 1a dose escalation (n = 22) and expansion (n = 9), delivery of enadenotucirev between 1 × 1010 and 1 × 1013 viral particles (vp) on days 1, 3, and 5 (single cycle) was used to determine an appropriate MTD. Subsequent treatment cohorts (phase 1a, n = 6 and phase 1b, n = 24) examined the feasibility of repeated dosing cycles in either 3-weekly or weekly dosing regimens. RESULTS: Enadenotucirev displayed a predictable and manageable safety profile at doses up to the MTD of 3 × 1012 vp, irrespective of infusion time or dosing schedule. The most commonly reported treatment-emergent adverse events (TEAEs) of grade 3 or higher were hypoxia, lymphopenia, and neutropenia. The frequency of all TEAEs (notably pyrexia and chills) was highest within 24 h of the first enadenotucirev infusion and decreased upon subsequent dosing. Additionally, delivery of three doses of enadenotucirev over 5 days optimized pharmacokinetic and chemokine profiles in the circulation over time. CONCLUSIONS: This study provides key clinical data in patients with solid epithelial tumors following treatment with IV enadenotucirev monotherapy and supports further investigation of enadenotucirev in combination with other therapeutic agents at doses up to the MTD of 3 × 1012 vp. TRIAL REGISTRATION: ( ClinicalTrials.gov Identifier: NCT02028442 ). Trial registration date: 07 January 2014 - Retrospectively registered.

Peri-operative allogeneic blood transfusion is associated with poor overall survival in advanced epithelial ovarian Cancer; potential impact of patient blood management on Cancer outcomes.

BACKGROUND: Transfusion related immune modulation associated with red blood cell (RBC) transfusion is thought to result in decreased cancer survival. Results in epithelial ovarian cancer (EOC) have been mixed however most suggest worse oncologic outcomes in patients who were transfused at the time of debulking surgery. The impact of restrictive transfusion strategies on this patient population is currently not known. METHODS: We conducted a retrospective study of women with EOC. The study population was divided into two groups based on whether they were transfused RBCs during the peri-operative period or not. Clinical characteristics and prognosticators were compared between groups. Overall survival was compared between groups based on transfusion status and other known prognostic factors. Cox proportional hazard modeling was used to examine the association between the prognostic factors and the study endpoint. RESULTS: Sixty-six percent of women were transfused. Transfusion was associated with CA125, the use of neoadjuvant chemotherapy (NACT), surgical blood loss, and anemia. The mean pre-transfusion Hgb was 7.8 + 0.6 g/dL and 94% had a hemoglobin level greater than the transfusion threshold of 7 g/dL. RBC transfusion, suboptimal debulking, anemia, and NACT were associated with decreased survival. Only RBC transfusion and suboptimal debulking status remained significant in a multivariate model. CONCLUSIONS: Peri-operative RBC transfusion compromises survival in ovarian cancer supporting the need to minimize the use of transfusion at the time of debulking surgery. Adherence to evidence-based transfusion guidelines offers an opportunity to reduce transfusion rates in this population with a resulting positive influence on survival.

Prognostic Value of Serum Creatinine Levels in Patients with Epithelial Ovarian Cancer.

AIM: To evaluate preoperative serum creatinine level as a prognostic parameter in patients with primary epithelial ovarian cancer (EOC). PATIENTS AND METHODS: In a retrospective cohort study, serum levels of creatinine were evaluated in 498 patients with EOC. Data were extracted from our prospectively maintained database. Results were correlated with clinicopathological parameters and patient survival. RESULTS: The mean pre-therapeutic serum creatinine level in patients with EOC was 0.84±0.40 mg/dI. A serum creatinine level of 1.2 mg/dl or higher was found in 22 (4.4%) patients and associated with poor survival. In a multivariate logistic regression analysis, the serum creatinine level was a significant independent prognostic parameter of overall survival. CONCLUSION: The preoperative serum level of creatinine may be useful as an additional independent prognostic parameter in patients with EOC.

A multicenter clinical trial validating the performance of HE4, CA125, risk of ovarian malignancy algorithm and risk of malignancy index.

OBJECTIVE: To validate, in a multicenter clinical trial, the performance of biomarkers and algorithms for differential diagnosis in a population of women diagnosed with an unknown ovarian cyst or pelvic tumor. METHODS: Six hospitals in Western Sweden consecutively enrolled 638 women from September 2013 to February 2016. Serum, transvaginal ultrasound data, and basic patient characteristics were collected preoperatively. Biomarker levels, risk of malignancy algorithm (ROMA), and risk of malignancy index (RMI) were calculated and compared with the final pathology report. RESULTS: Our sample of 638 patients had 445 benign, 31 borderline, and 162 malignant tumors recorded, and the overall incidence of epithelial ovarian cancer was 21%. In postmenopausal women, RMI (>200), ROMA (≥29.9), CA125 (>35 U/mL), and HE4 (>140 pmol/L) showed sensitivity at 89%, 91%, 92%, and 72%, respectively, and specificity at 80%, 77%, 80%, and 92%. In premenopausal women, sensitivity of RMI, ROMA (≥11.6), CA125, and HE4 (>70 pmol/L) was 87%, 87%, 96%, and 83%, respectively, and specificity was 90%, 81%, 60%, 91%. Diagnostic accuracy (ROC AUC) of RMI and ROMA in postmenopausal women was 0.85 and 0.84, and in premenopausal women, 0.90 and 0.81. CONCLUSION: Our results suggest that CA125 is superior to HE4 as a biomarker to identify women with ovarian cancer. HE4 more correctly identifies benign lesions, which may help in differential diagnoses to guide the level of care and decrease overtreatment. This study confirms prior results from single-center studies and suggests the implementation of HE4 measurement in daily practice.

Study on early diagnosis of epithelial ovarian cancer by analysis of plasma septin-9 and clusterin level.

BACKGROUND AND AIM: To investigate the value of peripheral blood plasma levels of septin-9 and clusterin protein in the diagnosis of epithelial ovarian cancer (EOC). MATERIALS AND METHODS: The peripheral blood plasma samples were obtained from 137 EOC patients, 12 borderline ovarian tumor patients, 10 benign ovarian tumor patients, 41 benign pelvic lesion patients, and 58 healthy women. The peripheral plasma septin-9 and clusterin proteins levels were measured by enzyme-linked immunosorbent assay. The power of test was evaluated with the area under the receiver operating characteristic curve (ROC) (AUC). RESULTS: The mean levels of plasma septin-9 and clusterin in EOC patients were significantly higher than that in healthy women (P = 0.002, P = 0.021). The mean levels of plasma septin-9 in benign pelvic lesion patients were significantly higher than that in healthy women (P = 0.007). The mean levels of plasma septin-9 in epithelial ovarian carcinoma patients with tumor family history or distant metastases were significantly higher than that of patients without (P = 0.040, P = 0.025). The AUC of septin-9 protein was 0.712, when the optimal cut-off point was 0.28, the sensitivity and diagnostic specificity were 82.5% and 50.0%, respectively; the AUC of clusterin was 0.636, and when the optimal cut-off point was 87.96 ng/ml, the sensitivity and diagnostic specificity was 71.5% and 41.4%, respectively. CONCLUSION: The plasma levels of septin-9 and clusterin in ovarian cancer patients were abnormally elevated, which might be used as potential candidates of peripheral blood tumor biomarkers for early diagnosis of EOC and septin-9 might be related to distal metastases of EOC. The septin-9 might play the promotion role, which protein level relates to not only the distal metastases but also the prognosis of EOC. Due to the limit of sample volume, further enlargement of the sample size and set up of the follow-up system is in need to in-depth study the relationship between plasma protein concentration with the distal metastases, and further explore its correlation with the prognosis of EOC.

[Correlation between Serum Cytokeratin 19 Fragment and the Clinicopathological Features and Prognosis of Thymic Epithelial Tumors].

BACKGROUND: So far there's no tumor maker applied in diagnosis and treatment of thymic epithelial tumors. This study is to assess the correlation between serum cytokine 19 fragment (Cyfra 21-1) and clinicopathological features and prognosis of thymic epithelial tumors (TETs). METHODS: The clinical data of 159 patients with TETs in Shanghai Chest Hospital was retrospectively analysed. Patients were divided into groups according to different tumor stages and histotypes. Serum Cyfra 21-1 was thus compared. In addition, the possible relationship between perioperative serum Cyfra 21-1 level and the recurrent status was carrid out. RESULTS: Preoperative Cyfra 21-1 serum concentrations in patiants with advanced stage (T4) and thymic carcinomas were significantly higher than that in others (P<0.001, P<0.001, respectively). When the preoperative serum level exceeds the out-off of 1.66 ng/mL, it possibly indicates the recurrence during follow up. Furthermore, the sensitivity, specificity, and positive as well as negative predictive value (PPV and NPV) of postoperative Cyfra 21-1 to predict tumor recurrence were evaluated. At a cut-off of Cyfra 21-1 of 2.66 ng/mL, the sensitivity was 0.7, the specificity was 0.925, the PPV was 0.5 and the NPV was 0.966. CONCLUSIONS: The elevated level of preoperative serum Cyfra 21-1 indicates an advanced stage of tumor or a more malignant histotype (thymic carcinoma). It also probably suggests a higher risk of tumor recurrence. During the oncological follow up, in addition to regular imaging examinations, the blood test of serum Cyfra 21-1 is also suggested to improve the diagnosis of tumor recurrence in order to improve the prognosis.

The Role of PAR1 Autoantibodies in Patients with Primary Epithelial Ovarian Cancer.

AIM: This study aimed to analyze the predictive, prognostic and diagnostic value of autoantibodies to coagulation factor II thrombin receptor (F2R; protease-activated receptor 1, PAR1) (PAR1-AB) in patients with primary epithelial ovarian cancer (EOC). MATERIALS AND METHODS: A total of 197 patients with primary EOC and 200 healthy female blood donors were included in the study. Enzyme-linked immunosorbent assay was applied to determine PAR1-AB levels in blood sera taken preoperatively. Correlation of PAR1-AB with clinicopathological outcome, progression-free (PFS) and overall (OS) survival was analyzed and patients were compared with controls. RESULTS: PAR1-AB was significantly negatively correlated with histological grading (p=0.008) and was significantly lower in the patient group compared to healthy controls (p<0.001). There was no significant correlation of PAR1-AB level with PFS or OS. CONCLUSION: This study showed PAR1-AB to significantly decrease in patients with primary EOC and with histological high-grade carcinoma. The relevance of PAR1-AB in early detection of ovarian cancer and follow-up for EOC should be further investigated.

Clinical study of a CT evaluation model combined with serum CA125 in predicting the treatment of newly diagnosed advanced epithelial ovarian cancer.

BACKGROUND: The treatment of newly diagnosed advanced epithelial ovarian cancer (EOC) was predicted by an ovarian cancer computed tomography (CT) evaluation model combined with serum CA125. METHODS: Clinical data for 194 patients with advanced EOC treated with neoadjuvant chemotherapy (NACT) combined with interval debulking surgery (IDS) or primary debulking surgery (PDS) were retrospectively analyzed, and the appropriate treatment was predicted by comparing the subgroup differences in intraoperative situations, postoperative situations and survival rates. RESULTS: There were no significant differences with respect to operation time, intraoperative blood loss, ideal tumor cytoreductive rate or postoperative complication rate between the NACT + IDS group and the PDS group with scores less than 5 (score < 5) (p = 0.764, p = 0.504, p = 0.906, p = 0.176). However, there was a statistically significant difference in overall survival rate between the two groups (p = 0.029), with better survival in the PDS group than in the NACT + IDS group. There were significant differences between the NACT + IDS group and the PDS group with scores greater than or equal to 5 (score ≥ 5). The former was better than the latter in terms of operation time, intraoperative blood loss, ideal tumor cytoreductive rate, and postoperative complication rate (p = 0.002, p = 0.040, p = 0.014, p = 0.021). However, there was no significant difference in overall survival rate between the two groups (p = 0.383). CONCLUSIONS: According to the new evaluation system, for a score < 5, we suggest that patients with newly diagnosed advanced EOC undergo PDS; for a score ≥ 5, we recommend NACT + IDS.

A predictive score for optimal cytoreduction at interval debulking surgery in epithelial ovarian cancer: a two- centers experience.

BACKGROUND: Optimal cytoreduction (macroscopic Residual Tumor, RT = 0) is the best survival predictor factor in epithelial ovarian cancer (EOC). It doesn't exist a consolidated criteria to predict optimal surgical resection at interval debulking surgery (IDS). The aim of this study is to develop a predictive model of complete cytoreduction at IDS. METHODS: We, retrospectively, analyzed 93 out of 432 patients, with advanced EOC, underwent neoadjuvant chemotherapy (NACT) and IDS from January 2010 to December 2016 in two referral cancer centers. The correlation between clinical-pathological variables and residual disease at IDS has been investigated with univariate and multivariate analysis. A predictive score of cytoreduction (PSC) has been created by combining all significant variables. The performance of each single variable and PSC has been reported and the correlation of all significant variables with progression free survival (PFS) has been assessed. RESULTS: At IDS, 65 patients (69,8%) had complete cytoreduction with no residual disease (R = 0). Three criteria independently predicted R > 0: age ≥ 60 years (p = 0.014), CA-125 before NACT > 550 UI/dl (p = 0.044), and Peritoneal Cancer Index (PCI) > 16 (p < 0.001). A PSC ≥ 3 has been associated with a better accuracy (85,8%), limiting the number of incomplete surgeries to 16,5%. Moreover, a PCI > 16, a PSC ≥ 3 and the presence of R > 0 after IDS were all significantly associated with shorter PFS (p < 0.001, p < 0.001 and p = 0.004 respectively). CONCLUSIONS: Our PSC predicts, in a large number of patients, complete cytoreduction at IDS, limiting the rate of futile extensive surgeries in case of presence of residual tumor (R > 0). The PSC should be prospectively validated in a larger series of EOC patients undergoing NACT-IDS.

Monitoring ovarian cancer patients during chemotherapy and follow-up with the serum tumor marker CA125.

Cancer antigen 125 (CA125) is frequently used in the routine monitoring of patients with epithelial ovarian cancer (EOC). The potential benefit is based on the assumption that changes in serial concentrations may provide early and reliable information on tumor growth expediting an early and potentially effective treatment. However, it has remained a challenge to interpret increments in concentrations that correlate with increasing tumor burden in the individual patient. It has been hypothesized that CA125 assessment criteria taking the random variation (analytical and biological) into account may have better accuracy and lead-time potential than criteria based only on an arbitrary percentage of increase.
 The aims of the current PhD project were to i) identify different types of assessment criteria intended to interpret CA125 increments, ii) compare their ability to signal tumor growth, and iii) estimate the time interval between marker progression and clinical progression (lead-time). 
Study 1 was a systematic review of the literature identifying 21 relevant original articles reporting on 37 different assessment criteria to interpret serial CA125 concentrations. Study 2 was a preclinical phase I trial investigating the monitoring potential of seven selected criteria in a computer-based simulation model under standardized conditions. Study 3 was a clinical phase II trial comparing the performances of the seven criteria among 189 patients with EOC stage IC-IV during first-line chemotherapy and the subsequent follow-up period.
 Study 1 reported that the median sensitivity of the investigated criteria for recurrence was 57% (range 33%-95%) during primary therapy and 85% (range 62%-93%) during follow-up. The calculated false positive (FP) and false negative (FN) rates, respectively, were in median 1% (range 0%-13%) and 44% (range 5%-67%) during primary therapy and 9% (range 0%-33%) and 15% (range 7%-38%) during follow-up. Most of the reports were heterogeneous in terms of study design and format of presentation. Study 2 reported that for increments starting from baseline concentrations ≥cut-off, the best performing criterion in terms of low number of FP signals was based on a confirmed increment ≥2.5 times the nadir concentration. For increments starting from baseline concentrations ≤cut-off, the best performing criterion, also in terms of low number of FP signals, was based on a confirmed increment from ≤cut-off to >2 times the cut-off. Accordingly, the best performing criteria in terms of low number of FP events were based on an arbitrary required percentage of change without defining the random variation. Study 3 reported that the accuracy of the seven criteria observed during first-line chemotherapy and follow-up among all histological tumor types and serous tumors only was similar with overlapping 95% confidence intervals. The sensitivities for detecting CA125 increments ranged from 30% to 55%. The FP rates ranged from 0% to 17%; however, the FN rates ranged from 45% to 70%. The median lead-times ranged from 26 days to 87 days. The performances of the CA125 assessment criteria showed low sensitivities and low ability to exclude tumor growth. The chance of developing clinical progression following CA125 progression was high (range of positive predictive value 90%-100%); however, the lead-times were short among several patients. Thus, study 3 questioned the clinical utility of CA125 monitoring. 
Overall, the PhD study showed, that the different CA125 assessment criteria basically provided similar results thus rejecting the hypothesis that criteria based on calculating the random variation would outperform criteria based on a simple percentage of change. The simulated data proved useful for a preclinical evaluation of CA125 assessment criteria. The results suggested that regardless of the approach, fine-tuning of the assessment criteria did not seem to improve the monitoring performance of CA125 probably indicating that CA125 used as a tumor marker for monitoring has inherent limitations in terms of accuracy. Supplementary markers and alternative assessment criteria are needed.

Combination of serum CA19-9 and CA125 levels and contrast-enhanced ultrasound parametric data facilitates to differentiate ovarian serous carcinoma from ovarian malignant epithelial cancer.

Ovarian serous carcinoma (OSC) is semimalignant ovarian tumors that localized in the ovary at the initial presentation, and can be surgically resected in an excellent prognosis. In contrast, surgical treatment plus adjuvant chemotherapy for ovarian malignant epithelial cancer (OMEC) is the standard treatment stratagem that is painful with poor prognosis and cost quite expensively. Thus, the accurate preoperative differentiation of OSC from OMEC is important for determining the treatment methods and decreasing the cost for individual patients. This study aims to determine whether contrast enhanced ultrasound (CEUS) together with CA19-9/CA125 can improve the ability to differentiate ovarian serous carcinoma from ovarian malignant epithelial cancer. The positive rate of cancer antigen (CA) 199 and CA125 in ovarian malignant epithelial tumors was 68% and 94%, respectively, which was a higher incidence than in the serous carcinoma. The mean serum CA19-9 and CA125 concentration was significantly higher in the patients with ovarian malignant epithelial tumors (CA19-9, 514.0 ±â€Š104.8 U/mL; CA125, 440.0 ±â€Š154.8 U/mL) than that in the patients with ovarian serous carcinoma (CA19-9, 58.0 ±â€Š14.3 U/mL; CA125, 63.0 ±â€Š25.8 U/mL). The time to peak in ovarian serous carcinoma was significantly longer than in ovarian malignant epithelial tumors. However, the peak intensity, area under the curve, and washout time in ovarian serous carcinoma were significantly lower than in ovarian malignant epithelial tumors. The addition of CA19-9/CA125 increased the sensitivities from 79% CEUS only to 85% for CEUS plus CA19-9/CA125 data, and increased the specificities from 65% CEUS only to 91% for CEUS plus the CA19-9/CA125 information. Thus, the addition of the serum CA19-9/CA125 levels to parametric CEUS data was of significant diagnostic value for differentiating OSC from OMEC.

A study of clinicopathologic factors as indicators for early prediction of suboptimal debulking surgery after neoadjuvant chemotherapy in advanced ovarian cancer.

AIM: This study aimed to evaluate early clinicopathologic factors predicting gross residual disease after neoadjuvant chemotherapy in patients with advanced epithelial ovarian cancer. METHODS: We analyzed clinicopathologic data of 68 patients with ovarian cancer who were treated with neoadjuvant chemotherapy followed by interval debulking surgery (NAC-IDS) between March 2006 and December 2016. All the patients received three cycles of NAC followed IDS. We evaluated all possible clinicopathologic characteristics, including reduction rates of serum CA-125 after each NAC and seven initial abdominopelvic computed tomography (CT) findings related to disease severity. RESULTS: After IDS, no gross residual disease was found in 46 (67.6%) patients and 22 (33.4%) patients had gross residual disease. Multivariate analysis identified that reduction rate of CA-125 after 2nd NAC, body mass index (BMI) and small bowel lesion in the initial CT findings were significantly associated with gross residual disease after IDS (P = 0.005, 0.030, 0.001, respectively). The optimal cutoff value predicting gross residual disease were less than 50% of CA-125 reduction rate after 2nd NAC and low BMI (<23 kg/m2 ). The combined receiver operating characteristic curve analysis of these factors showed good performance for predicting gross residual disease after IDS (area under the curve = 0.845). CONCLUSION: A model using small bowel mesentery involvement on CT, BMI (<23 kg/m2 ) and less than 50% reduction of the initial CA-125 level after the 2nd NAC is highly predictive of gross residual disease after IDS in advanced ovarian cancer patients. These results may be helpful in further treatment planning and patients counseling.

Validation of the Cut-points Recommended for ROMA Using the Roche Elecsys CA125 and HE4 Assays.

Assessing the risk of malignancy in patients with a pelvic mass helps triage women suspected of ovarian cancer to specialized gynecologic oncologists to improve treatment outcomes. To this end, several algorithms have been proposed; most notably, the Risk of Ovarian Malignancy Algorithm (ROMA) based on CA125, HE4, and menopausal status. However, appropriate decision cut-points for the ROMA score depends on the choice of analytical assays used. This study validates the use of the Roche Elecsys CA125 and HE4 assays for ROMA calculation in a cohort of 207 women who presented to Mayo Clinic with a pelvic mass. Results were compared to a definitive histologic diagnosis in each case. Clinical performance of ROMA scores derived using these assays was similar to stated claims and indicates that recommended cut-points are acceptable for clinical use.

Diagnostic Model of Serum miR-193a-5p, HE4 and CA125 Improves the Diagnostic Efficacy of Epithelium Ovarian Cancer.

Epithelium ovarian cancer (EOC) is currently the prevalent malignant cancer worldwide. However, there is a lack of efficient biomarkers for EOC screening. Accumulating evidence reveals that serum miRNA detectable in various types of cancer. Therefore, we explore the diagnostic value of combined detection of plasma miR-193a-5p, HE4 and CA125 for EOC. Serum samples were collected from 45 patients with primary EOC, 30 patients with benign ovarian tumor patients and 40 healthy controls. The expression of serum miR-193a-5p was detected by real-time quantitative PCR, and serum HE4 and CA125 were detected by chemiluminescent immunoassay. Moreover, a diagnostic model combining miR-193a-5p, HE4 and CA125 or alone in EOC patients was evaluated by ROC curve analysis. The relative expression quantity (RQ) of serum miR-193a-5p in EOC patients, benign ovarian tumor patients and healthy control groups were 0.419 (0.093, 2.215), 3.667 (1.633, 6.691) and 1.130 (1.000, 7.087), respectively. The RQ of serum miR-193a-5p in EOC patients was significantly lower than that in benign ovarian tumor patients and healthy controls (both P < 0.001), and there was no significant difference between benign ovarian tumor patients and healthy controls (both P > 0.05). There was no significant correlation between serum miR-193-5p, HE4 and CA125 levels (both P > 0.05). Additionally a risk model for miR-193a-5p, HE4 and CA125 was correlated with Grading and Lymph node metastasis (P = 0.016, P = 0.029). The area under the receiver operating characteristic curve of a risk model for distinguishing EOC patients from healthy individuals was 0.996, which higher than any single biomarker. Combined detection of miR-193-5p, HE4 and CA125 by logistic regression analysis could greatly improved the diagnostic ability of EOC and may prove to be a candidate biomarker, providing new directions for further investigation.

Immunobiochemical pathways of neopterin formation and tryptophan breakdown via indoleamine 2,3-dioxygenase correlate with circulating tumor cells in ovarian cancer patients- A study of the OVCAD consortium.

OBJECTIVE: Circulating tumor cells (CTCs) may represent a chronic stimulus for the immune system. In the present study we investigated the potential association of CTCs, the immune activation marker neopterin, and the ratio of kynurenine to tryptophan (Kyn/Trp) as a measure for tryptophan breakdown. METHODS: Neopterin, tryptophan and kynurenine levels were measured in plasma samples from patients with benign gynecological diseases (n=65) and with primary advanced epithelial ovarian cancer (EOC) at diagnosis (n=216) and six months after adjuvant platinum-based chemotherapy (n=45) by an enzyme-linked immunosorbent assay and high performance liquid chromatography. The presence of CTCs had been assessed in a previous study by qPCR-based analysis of CTC-related transcripts in the blood. The respective plasma levels in EOC and benign samples were compared using a two-tailed Chi2 or Fisher's exact test. The associations of the analytes and Kyn/Trp with clinicopathological parameters, platinum-sensitivity, and the presence of CTC-related transcripts were assessed using a two-sided t-test. Associations with patient outcome were evaluated using Cox regression analysis. RESULTS: In EOC, elevated Kyn/Trp and neopterin levels were associated with advanced disease, peritoneal carcinomatosis, ascites, sub-optimal debulking, poor response to therapy and worse outcome. Likewise, neopterin and Kyn/Trp were elevated in CTC-positive patients, both at diagnosis and at follow-up in platinum-sensitive disease. CONCLUSIONS: We observed concomitant alterations of CTCs and immune system related biomarkers suggesting that immune responses along with increase of neopterin and Kyn/Trp concentrations are not necessarily only located at the site of the tumor, but may also go on in the circulation.