Rainer Kimmig

CA-125 glycovariant assays enhance diagnostic sensitivity in the detection of epithelial ovarian cancer

Abstract Objectives Ovarian cancer is the deadliest gynaecologic malignancy. Due to the lack of reliable biomarkers for the detection of the early disease, most patients are diagnosed at an advanced stage resulting in poor survival. We therefore aimed at establishing novel CA-125 glycovariant assays to improve the diagnostic sensitivity and specificity of ovarian cancer. Methods Blood samples of 184 patients with epithelial ovarian cancers (EOC), 127 benign ovarian tumors, and 115 healthy controls were measured using GLYVAR™ Ovarian I and II assays (Uniogen) and the conventional CA-125 protein assay (CanAg CA-125 EIA, Fujirebio). Results The two glycovariant assays differentiated benign and malignant ovarian masses with 88.0 % sensitivity at 99 % specificity, whereas CA-125 showed 72.8 % sensitivity. The improved performance was most evident in patients with borderline or moderately elevated CA-125 concentration at diagnosis, which is a challenging group for differential diagnostics. The CA-125 glycovariant assays showed 2.5 times higher sensitivity (33.3 % with CA-125 vs. 83.3 % with the CA-125 glycovariants) at 94 % specificity. CA-125 glycovariants corrected 82.4 % of false positive results given by CA-125 concentrations with the commonly used cutoff 35 U/mL. Importantly, the CA-125 glycovariant assays detected 63.6 % of early-stage serous carcinomas from benign and healthy controls with very high 99 % specificity, while CA-125 had a sensitivity of only 45.5 %, representing a 40 % increase. Conclusions This is the first study describing the clinical performance of GLYVAR Ovarian I and II assays in ovarian cancer diagnostics. The results indicate that the CA-125 glycovariant assays have remarkable potential to improve ovarian cancer diagnostics.

Peritoneal mesometrial resection with lymphadenectomy following prior hysterectomy in intermediate/high-risk endometrial cancer: feasibility and safety

Abstract Objective Peritoneal mesometrial resection (PMMR) plus targeted compartmental lymphadenectomy (TCL) aims at removal of the locoregional cancer field in endometrial cancer (EC). Optimal locoregional control without adjuvant radiotherapy should be achieved concomitantly sparing systematic lymphadenectomy (LNE) for most of the patients. However, intermediate/high-risk EC is often definitely diagnosed postoperatively in simple hysterectomy specimen. Our aim was to evaluate feasibility and safety of a completing PMMR + TCL in patients following prior hysterectomy. Methods We evaluated data from 32 patients with intermediate/high-risk EC treated with PMMR + TCL or systematic pelvic and periaortic LNE following prior hysterectomy. Perioperative data on disease characteristics and morbidity were collected and patients were contacted for follow-up to determine the recurrence and survival status. Results We report data from 32 patients with a mean follow-up of 31.7 months. The recurrence rate was 12.5% (4/32) without any isolated locoregional recurrences. Only 21.9% of patients received adjuvant radiotherapy. Rates of intra- and postoperative complications were 6.3% and 18.8%, respectively. Conclusion Our data suggest that robotic PMMR can be performed following prior hysterectomy when previously unknown risk factors arise, albeit with a moderate increase in morbidity. Moreover, despite a relevant reduction of adjuvant radiotherapy, follow-up data suggest an excellent locoregional control even without adjuvant radiotherapy.

Cancer-field surgery for endometrial cancer by robotic peritoneal mesometrial resection and targeted compartmental lymphadenectomy (PMMR+TCL)

Cancer-field surgery by peritoneal mesometrial resection and targeted compartmental lymphadenectomy (PMMR+TCL) for the treatment of endometrial cancer (EC) aims at optimal locoregional tumor control without the need for adjuvant radiotherapy. In a previous publication we could demonstrate the feasibility of the method and presented encouraging first oncologic data. Following up our 2021 publication, we present data on the treatment of EC by PMMR+TCL in much larger cohort and with longer follow-up. One hundred and thirty-five patients with EC International Federation of Gynecology and Obstetrics (FIGO) I-IV (75.6% FIGO I) underwent cancer field surgery via PMMR+TCL for EC in the years 2016-2023. Mean follow-up in our cohort was 27.5 months (0, 83; 19.7). The procedure was feasible and safe with favorable intra-and postoperative complication rates. Even though 50.4% of patients had an indication for postoperative radiotherapy following national and international guidelines, the rate of postoperative irradiation administered was 10.4%. The overall recurrence rate was 8.1% and we observed 2 (1.5%) isolated locoregional recurrences. Our results confirm the feasibility and safety of PMMR+TCL in EC patients. Oncologic data are very encouraging and hint at a superior locoregional control without adjuvant irradiation. Larger studies with longer follow-up will be needed to confirm these results.

Cancer field surgery in endometrial cancer: peritoneal mesometrial resection and targeted compartmental lymphadenectomy for locoregional control

Peritoneal mesometrial resection (PMMR) plus targeted compartmental lymphadenectomy (TCL) aims at removal of the locoregional cancer field in endometrial cancer (EC). Optimal locoregional control without adjuvant radiotherapy and acceptable surgical morbidity should be achieved concomitantly sparing systematic lymphadenectomy (LNE) for most of the patients. We evaluated data from 132 patients treated for EC. Out of these, between January 2017 and June 2020 we performed robotic PMMR and TCL on 51 women. We present the first data of feasibility and safety of the procedure as well as preliminary oncological results. The 51 patients treated with robotic PMMR and TCL showed comparable morbidity to classic laparoscopic hysterectomy or PMMR without LNE. One intraoperative complication occurred. Postoperative complications grade 3 and higher occurred in 2 cases (3.9%). One of these (85 years old) experienced grade 5 following pulmonary embolism with lysis therapy. Fifteen patients (29.4%) could be spared complete LNE. The rate of adjuvant radiotherapy was 3.9% in our collective (n=2), compared to 39.2% of patients (n=20) eligible for irradiation according to international guidelines. In a mean follow-up time of 15 months (0-41), no locoregional recurrences were observed, although three patients showed distant relapse. Our data suggest that robotic PMMR and pelvic TCL can be performed regardless of BMI and comorbidities without a relevant increase in surgical morbidity. Moreover, despite a relevant reduction of adjuvant radiotherapy, first follow-up data hint at a favorable locoregional recurrence rate in the reported cohort.

Bevacizumab May Differentially Improve Prognosis of Advanced Ovarian Cancer Patients with Low Expression of VEGF-A165b, an Antiangiogenic VEGF-A Splice Variant

Abstract Purpose: The identification of a robust IHC marker to predict the response to antiangiogenic bevacizumab in ovarian cancer is of high clinical interest. VEGF-A, the molecular target of bevacizumab, is expressed as multiple isoforms with pro- or antiangiogenic properties, of which VEGF-A165b is the most dominant antiangiogenic isoform. The balance of VEGF-A isoforms is closely related to the angiogenic capacity of a tumor and may define its vulnerability to antiangiogenic therapy. We investigated whether the expression of VEGF-A165b could be related to the effect of bevacizumab in advanced ovarian cancer patients. Experimental Design: Formalin-fixed paraffin-embedded tissues from 413 patients of the ICON7 multicenter phase III trial, treated with standard platinum-based chemotherapy with or without bevacizumab, were probed for VEGF-A165b expression by IHC. Results: In patients with low VEGF-A165b expression, the addition of bevacizumab to standard platinum-based chemotherapy significantly improved progression-free (HR: 0.727; 95% CI, 0.538–0.984; P = 0.039) and overall survival (HR: 0.662; 95% CI, 0.458–0.958; P = 0.029). Multivariate analysis showed that the addition of bevacizumab in low VEGF-A165b–expressing patients conferred significant improvements in progression-free survival (HR: 0.610; 95% CI, 0.446–0.834; P = 0.002) and overall survival (HR: 0.527; 95% CI, 0.359–0.775; P = 0.001), independently from established risk factors. Conclusions: We demonstrate for the first time that bevacizumab may differentially improve the prognosis of advanced ovarian cancer patients with low expression of VEGF-A165b, an antiangiogenic VEGF-A splice variant. We envision that this novel biomarker could be implemented into routine diagnostics and may have direct clinical implications for guiding bevacizumab-related treatment decisions in advanced ovarian cancer patients.