Veronika Seebacher

Plasma Fibrinogen Levels and Prognosis in Patients with Ovarian Cancer: A Multicenter Study

INTRODUCTION To evaluate pretherapeutic plasma fibrinogen levels as a prognostic parameter in patients with epithelial ovarian cancer (EOC). Materials and Methods. In the present multicenter study, pretherapeutic plasma fibrinogen levels were evaluated in 422 patients with EOC. Plasma fibrinogen levels were correlated with clinicopathological parameters and patient survival. RESULTS The mean (standard deviation) pretherapeutic plasma fibrinogen level was 450.0 (150.1) mg/dl. Elevated plasma fibrinogen levels were associated with advanced tumor stage (p = .01) and the presence of a postoperative residual tumor mass (p < .001), but not with histological grade (p = .1) and histological type (p = .8). In a multivariate Cox regression model, tumor stage (p < .001 and p < .001), postoperative residual tumor mass (p = .001 and p = .008), and plasma fibrinogen level (p < .001 and p = .002), but not histological type (p = .8 and p = .2), patient age (p = .9 and p = .9), and serum cancer antigen 125 (p = 0.2 and p = 0.3) and C-reactive protein (p = .2 and p = .3) levels, were associated with disease-free and overall survival, respectively. Histological grade was associated with overall but not with disease-free survival (p = .01 and p = .8), respectively. CONCLUSIONS Pretherapeutic plasma fibrinogen levels can be used as an independent prognostic parameter in patients with EOC.

Plasma fibrinogen levels in patients with benign and malignant ovarian tumors

OBJECTIVE Plasma fibrinogen is a key acute phase protein and known to be elevated in ovarian cancer. We aimed to investigate the association between plasma fibrinogen and malignant and benign ovarian tumors. METHODS In a retrospective, single-center study, we evaluated preoperative plasma fibrinogen levels in 471 patients with benign and in 224 patients with malignant (borderline ovarian tumor [BOT]: n=36, epithelial ovarian cancer [EOC]: n=188) ovarian tumors. The association between preoperative plasma fibrinogen levels and clinico-pathological parameters was investigated. A multivariate logistic regression model was performed to identify an independent association. RESULTS Mean (standard deviation) preoperative plasma fibrinogen levels in patients with benign ovarian tumors, BOT, and invasive ovarian cancers were 346.7 (99.7), 372.8 (114), and 472.6 (148.4) mg/dL, respectively (p<0.001). Within the EOC cohort, patients with advanced stage disease had higher plasma fibrinogen levels (485.5 [151.3] mg/dL) than patients with early stage disease (430.9 [130.3] mg/dL; p=0.03). In a multivariate model plasma fibrinogen was identified to be independently associated with the presence of BOT and EOC. In the subgroup of patients <50 years, plasma fibrinogen levels remained independently associated with malignant ovarian tumors in CA 125 positive and negative patients. CONCLUSION Plasma fibrinogen levels are independently associated with malignant ovarian tumors. Plasma fibrinogen levels showed an independent association with malignant ovarian tumors in the subgroup of patients <50 years, in whom differential diagnosis of ovarian tumors is particularly challenging.

Accuracy and prognostic value of variant histology and lymphovascular invasion at transurethral resection of bladder

ObjectivesTo evaluate the concordance rate of lymphovascular invasion (LVI) and variant histology (VH) of transurethral resection (TUR) with radical cystectomy (RC) specimens. Furthermore, to evaluate the value of LVI and VH at TUR for predicting non-organ confined (NOC) disease, lymph node metastasis, and survival outcomes.Patients and methodsTwo hundred and sixty-eight patients who underwent TUR and subsequent RC were reviewed. Logistic regression analyses were performed to evaluate the association of LVI and VH with NOC and lymph node metastasis at RC. Cox regression analyses were used to estimate recurrence-free survival (RFS) and cancer-specific survival (CSS).ResultsLVI and VH were detected in 13.8 and 11.2% of TUR specimens, and in 30.2 and 25.4% of RC specimens, respectively. The concordance rate between LVI and VH at TUR and subsequent RC was 69.8 and 83.6%, respectively. They were both associated with adverse pathological features such as lymph node metastasis and advanced stage. TUR LVI and VH were both independently associated with lymph node metastasis and TUR VH was independently associated with NOC. On univariable Cox regression analyses, TUR LVI was associated with RFS and CSS while TUR VH was only associated with RFS. Only TUR LVI was independently associated with RFS.ConclusionDetection of LVI is missed in a third of TUR specimens while VH seems more accurately identified. TUR LVI and VH are associated with more advanced disease and LVI predicts disease recurrence. Assessment and reporting of LVI and VH on TUR specimen are important for risk stratification and decision-making.

Development of a tool for prediction of ovarian cancer in patients with adnexal masses: Value of plasma fibrinogen

Objective To develop a tool for individualized risk estimation of presence of cancer in women with adnexal masses, and to assess the added value of plasma fibrinogen. Study design We performed a retrospective analysis of a prospectively maintained database of 906 patients with adnexal masses who underwent cystectomy or oophorectomy. Uni- and multivariate logistic regression analyses including pre-operative plasma fibrinogen levels and established predictors were performed. A nomogram was generated to predict the probability of ovarian cancer. Internal validation with split-sample analysis was performed. Decision curve analysis (DCA) was then used to evaluate the clinical net benefit of the prediction model. Results Ovarian cancer including borderline tumours was found in 241 (26.6%) patients. In multivariate analysis, elevated plasma fibrinogen, elevated CA-125, suspicion for malignancy on ultrasound, and postmenopausal status were associated with ovarian cancer and formed the basis for the nomogram. The overall predictive accuracy of the model, as measured by AUC, was 0.91 (95% CI 0.87–0.94). DCA revealed a net benefit for using this model for predicting ovarian cancer presence compared to a strategy of treat all or treat none. Conclusion We confirmed the value of plasma fibrinogen as a strong predictor for ovarian cancer in a large cohort of patients with adnexal masses. We developed a highly accurate multivariable model to help in the clinical decision-making regarding the presence of ovarian cancer. This model provided net benefit for a wide range of threshold probabilities. External validation is needed before a recommendation for its use in routine practice can be given.

A phase I, single-arm, open-label, dose escalation study of intraperitoneal cisplatin and doxorubicin in patients with recurrent ovarian cancer and peritoneal carcinomatosis

OBJECTIVE We performed a phase I, single-arm, non-randomized, open-label, dose-escalation trial to determine the dose-limiting toxicity of intraperitoneal cisplatin and doxorubicin applied as pressurized intraperitoneal aerosol chemotherapy (PIPAC) in women with recurrent ovarian cancer. METHODS We used a standard 3 + 3 dose-escalation design with doxorubicin 1.5 mg/m2, cisplatin 7.5 mg/m2 q 4 to 6 weeks for 3 cycles and subsequent dose escalation steps (20% increment per step) in patients with recurrent ovarian cancer and peritoneal carcinomatosis. Toxicity and clinical efficacy were monitored. The primary endpoint was the maximum-tolerable dose. Secondary endpoints included histologic tumor regression and serum parameters. RESULTS 15 evaluable patients (3, 7, and 5 in cohorts 1, 2, and 3, respectively) on average received 2.3 PIPAC cycles. No dose limiting toxicities were found. Adverse side effects were 1 grade 3 event (colon perforation) and 85 grade 1/2 events including fatigue (n = 19), abdominal pain (n = 18), nausea/vomiting (n = 14), sleep disorder (n = 8), diarrhea (n = 5), and fever (n = 2). Liver and renal toxicity was not observed in any of the 3 cohorts (AST 19.1 ± 3.2, 25.8 ± 6.5, and 22.1 ± 4.5 IU/L, respectively; ALT 14.7 ± 3.5, 18.5 ± 5.6, and 23.3 ± 13.0 IU/L, respectively; GGT 45.7 ± 35.1, 25.2 ± 10.3, and 43.9 ± 26.4 IU/L, respectively; serum creatinine 1.06 ± 0.23, 0.80 ± 0.17, and 0.89 ± 0.35 mg/dL, respectively). No systemic hematologic toxicity, alopecia, or neurotoxicity was noted. The maximum tolerable dose was not reached. Histologic tumor regression was observed in 7/11 (64%) patients who underwent ≥2 PIPAC cycles. CONCLUSIONS PIPAC with cisplatin and doxorubicin may be safely used at an intraperitoneal dose of 10.5 mg/m2 and 2.1 mg/m2, respectively. Systemic toxicity of this therapy is low.

Preoperative C-reactive protein serum levels as a predictive diagnostic marker in patients with adnexal masses

OBJECTIVE To evaluate C-reactive protein (CRP) serum levels as a preoperative predictive marker for ovarian cancer in patients with adnexal masses. METHODS CRP serum levels of 1843 adnexal masses and subsequent surgery were investigated (patients with benign ovarian tumors: n=1423; borderline tumor of the ovary [BTO]: n=83; EOC: n=337). Test characteristics and predictive values of CRP serum levels were investigated by univariate analysis and multivariate binary logistic regression models. RESULTS Median (interquartile range) serum CRP levels in patients with benign ovarian tumors, BTO, and EOC were 0.4 (0.1-0.6)mg/dL, 0.5 (0.2-0.9)mg/dL, and 1.6 (0.5-5.4)mg/dL, respectively (p<0.001). Sensitivity and specificity of the combination of CRP and CA-125 was 80.1% and 90.8%, negative predictive value (NPV) and positive predictive value (PPV) was 92.2% and 76.9%, respectively. In univariate and multivariate analysis, CRP serum levels were independently associated with presence of BTO and EOC (HR 6.7 [5.2-8.5], p<0.001 and HR 2.2 [1.4-3.3], p<0.001). The combination of CRP and CA-125 serum levels resulted in a number needed to treat of 2.11 to detect one case of EOC or BTO. CONCLUSION CRP serum levels independently predicted the presence of BTO and EOC in patients with suspicious adnexal masses. CRP serum levels seem to be of additional value to CA-125 in the preoperative differential diagnosis of adnexal masses and might be particularly in combination with CA-125 clinically useful.

AB0 blood groups and rhesus factor expression as prognostic parameters in patients with epithelial ovarian cancer – a retrospective multi-centre study

BackgroundAB0 blood groups and Rhesus factor expression have been associated with carcinogenesis, response to treatment and tumor progression in several malignancies. The aim of the present study was to test the hypothesis that AB0 blood groups and Rhesus factor expression are associated with clinical outcome in patients with epithelial ovarian cancer (EOC).MethodsAB0 blood groups and Rhesus factor expression were evaluated in a retrospective multicenter study including 518 patients with EOC. Their association with patients’ survival was assessed using univariate and multivariable analyses.ResultsNeither AB0 blood groups nor Rhesus factor expression were associated with clinico-pathological parameters, recurrence-free, cancer-specific, or overall survival. In a subgroup of patients with high-grade serous adenocarcinoma, however, blood groups B and AB were associated with a better 5-year cancer-specific survival rate compared to blood groups A and 0 (60.3 ± 8.6% vs. 43.8 ± 3.6%, p = 0.04). Yet, this was not significant in multivariable analysis.ConclusionsAB0 blood groups and Rhesus factor expression are both neither associated with features of biologically aggressive disease nor clinical outcome in patients with EOC. Further investigation of the role of the blood group B antigen on cancer-specific survival in the subgroup of high-grade serous should be considered.

The Impact of the Duration of Adjuvant Chemotherapy on Survival in Patients with Epithelial Ovarian Cancer – A Retrospective Study

Objective The aim of the present study was to investigate the prognostic role of the duration of adjuvant chemotherapy in patients with epithelial ovarian, fallopian tube and primary peritoneal cancer (EOC). Materials and Methods Within the present study we retrospectively evaluated the data of 165 consecutive patients with EOC treated with primary surgery followed by six completed cycles of platinum-taxan based intravenous adjuvant chemotherapy. Medians of total duration of chemotherapy were compared with clinical-pathological parameters. Patients were stratified into four risk groups according to the delay in days of total duration of chemotherapy, and univariate and multivariable survival analyses were performed. Results The median duration of six completed cycles of chemotherapy comprised 113 days (IQR 107–124 days). Uni- and multivariable survival analyses revealed a delay of total duration of chemotherapy of at least 9 days to be associated with progression-free (PFS), cancer-specific (CSS) and overall survival (OS). Hazard ratios (HR), confidence intervals (95% CI) and p-values for PFS, CSS and OS due to delay of chemo-duration were 2.9 (1.6–5.4; p = 0.001), 2.9 (1.3–6.2; p = 0.008) and 2.6 (1.3–5.4; p = 0.008), respectively. Prolonged total chemo-duration was associated with the amount of postoperative residual disease (p = 0.001) and the patients’ age (p = 0.03). Conclusion The present study suggests a prolonged duration of adjuvant chemotherapy after primary surgery to adversely affect PFS, CSS and OS in patients with EOC. Yet larger studies are required to validate our results.

External Validation of the Pathologic Nodal Staging Score for Prostate Cancer: A Population-based Study

Background We sought to externally validate our pathologic nodal staging score (pNSS) model, which allows for quantification of the likelihood that a pathologically node‐negative patient will not have lymph node (LN) metastasis after radical prostatectomy for prostate cancer (PCa) in a population‐based cohort. Patients and Methods We analyzed data from 50,598 patients treated with radical prostatectomy and pelvic LN dissection using the Surveillance, Epidemiology, and End Results database. We estimated the sensitivity of pathologic nodal staging using a &bgr;‐binomial model and developed a novel pNSS model, which represents the probability that a patients PCa has been correctly staged as node negative as a function of the number of examined LNs. These findings were compared against those from the original cohort of 7135 patients. Results The mean and median number of LNs removed was 6.5 and 5, respectively (range, 1‐89; interquartile range, 2‐8), and 96.9% of the patients (n = 49,020) had stage pN0. Similar to the original cohort, the probability of missing a positive LN decreased with the increasing number of LNs examined. In both the validation and the original cohort, the number of LNs needed to correctly stage a patients disease as node negative increased with more advanced tumor stage, higher Gleason sum, positive surgical margins, and higher preoperative prostate‐specific antigen levels. Conclusion We have confirmed that the number of examined LNs needed for adequate nodal staging in PCa depends on the pathologic tumor stage, Gleason sum, surgical margins status, and preoperative prostate‐specific antigen. We externally validated our pNSS in a population‐based cohort, which could help to refine decision‐making regarding the administration of adjuvant therapy. Micro‐Abstract Using a population‐based cohort, data from 50,598 patients treated with radical prostatectomy and pelvic lymph node dissection were used to externally validate our pathologic nodal staging score model. This model allows for quantification of the likelihood that a pathologically node‐negative patient will not have lymph node metastasis after surgery.