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  • EDTA-blood samples were obtained preoperatively from 235 patients with endometrial cancer before primary surgery. During time of follow-up 48 patients developed recurrence and blood samples were collected from 36 of these patients at time of recurrence. In addition, EDTA-blood was collected from 78 patients diagnosed with endometrial hyperplasia. All patients have been diagnosed at Haukeland University Hospital, Norway between 2003 and 2014 and clinical data as well as blood samples were prospectively collected. Patients signed informed consent. Regional Committees for Medical and Health Research Ethics approval: 2009/2315 and 2014/1907. The median follow-up in this cohort is 43 months (range 1–189). Blood samples were centrifuged at 1600 g for 15 min and the plasma was stored at– 80 °C until measurement of GDF-15. Distribution of measured GDF-15 plasma level was not influenced by storage time. Additionally, data regarding GDF-15 plasma levels were also locally available from an independent cohort of 466 endometrial cancer patients previously published [20]. In order to improve statistical power when predicting lymph node metastases and recurrence, the data were merged together with the current cohort when performing regression analyses. Data were missing for recurrence from 47 patients, histological type from 47 patients and myometrial infiltration from 49 patients, and the resulting cohort included 603 patients. Regarding lymph node status, data were missing for 190 patients and preoperative histology missing for 65 patients, and the cohort included 495 patients. GDF-15 in plasma was measured by the Human enzyme linked GDF-15 Quantakine ELISA kit (#DGD150, batch #P153423, R&D Systems, Minneapolis, USA). The ELISA was performed according to the manufacturer´s instructions. Briefly, 50 μL plasma sample or standard was added in a 96-well microplate coated with a monoclonal antibody specific for human GDF-15, and incubated for 2h in room temperature. Following washing, 200 μL human GDF-15 conjugate was added and incubated for 1 hour in room temperature. The wells were washed again before 200 μL of substrate solution were added and incubated for 30 min in room temperature protected from light, followed by 50 μL of stop solution. The absorbance was measured in a microplate reader at the wavelength of 450 nm, and plasma concentration of GDF-15 calculated. To confirm reproducibility, a subset (n = 102) were measured in duplicates. Clinical data were blinded while performing and evaluating laboratory investigations. The assay has a detection limit of 20 ng/L, an intraassay imprecision of 10.6% or less, and an interassay imprecision of 12.2% or less [21]. Preoperative magnetic resonance imaging (MRI): In parallel, preoperative pelvic MRI scans for 141 patients were assessed to derive the following imaging variables: endometrial tumor size, signs of deep myometrial invasion, cervical stroma invasion and lymph node metastases. MRI was conducted on a whole body 1.5-T MRI system (Siemens Avanto running Syngo v. B17, Erlangen, Germany) using a six channel body coil applying a standardized imaging protocol [22]. To reduce motion artefacts 20 mg of butylscopolamine bromide (Buscopan; Boehringer, Ingelheim, Germany) was administered intravenously. Mean time (range) between MRI examination and surgical staging was 1.5 (0–12) weeks. Statistical analyses were conducted applying Statistical Program for the Social Sciences (SPSS), version 24 (IBM Inc. Chicago, IL, USA). All p-values were two sided and p-value of less than 0.05 was considered statistically significant. Pearson Chi-square or Fisher exact test were used for categorical data. Univariate survival analysis was performed using the Kaplan-Meier method and log-rank test, grouping low versus high concentration. Cut-off values for categorization were based on tertiles according to the size of the subgroups and the number of events in each category. The two lower GDF-15 tertiles were merged due to similar survival. Cut-off value based on this method was found to be near identical to our previous study [20] (cut-off in previously published cohort: 1400 ng/L, cut-off in this cohort 1418 ng/L). For analyses where the cohorts were merged, cut-off value was 1418 ng/L. Low-risk patients were defined as endometrioid histologic type and grade 1 and 2 disease, and high risk patients as endometrioid grade 3 and non-endometrioid. Disease-specific survival was defined as time from primary treatment to death from endometrial cancer. Patients who died from other causes or were lost to follow-up were censored at the date of death/last follow-up. Non-parametric tests Mann Whitney U or Wilcoxon Signed Rank were used for comparison of continuous data between study groups. Binary logistic regression was used to evaluate the odds ratio (OR) for lymph node metastases and recurrence.
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