Laparoscopic surgery for endometrial cancer is oncologically safe and improves hospital stay duration: a retrospective single-center study over a 16-year period.

OBJECTIVE: To investigate changes in surgical procedures and patient outcomes of patients diagnosed with endometrial cancer (EC) at a German university hospital between 1998 and 2014. METHODS: A monocentric, retrospective review was conducted to identify patients diagnosed and treated with EC during the aforementioned period at the Department of Gynecology and Obstetrics at the University Hospital Kiel, Germany. RESULTS: 303 patients were identified. Patient demographics, risk factors, histological subtypes and stages of EC remained consistent over time. The most common surgical procedure was total abdominal hysterectomy (TAH) (81.9%). In 2011, the institution carried out its first total laparoscopic hysterectomy (TLH) for EC, resulting in a significant increase in laparoscopic surgical procedures (2011-2014: N = 70; TAH 44.2%; TLH 51.4%). Although the total number of lymph node stagings remained consistent over time, there was a significant increase in the performance of simultaneous pelvic and para-aortic lymphonodectomy (LNE) compared to pelvic LNE alone (2.6 in 2001-2005 vs. 18.0% in 2011-2014, p ≤ 0.001). The duration of hospital stays significantly decreased over time, with a mean of 20.9 days in the first and 8.5 days in the last period. When comparing surgical procedures, TLHs resulted in significantly shorter postoperative stays with an average of 6.58 vs. 13.92 days for TAH. The surgical procedure performed did not affect 5-year overall survival rates in this study (84.9% for TAH and 85.3% for TLH, p = 0.85). CONCLUSIONS: Our retrospective single-center study demonstrates that laparoscopic surgery for endometrial cancer is oncologically safe and shortens hospital stays.

Fluorescence in situ hybridization test for detection of endometrial carcinoma cells by non-invasive vaginal swab.

Endometrial cancer (EC) is the most common gynaecological malignancy with increasing incidence in developed countries. As gold standard, hysteroscopy confirms only 30% of suspected ECs. The detection of EC cells in the vagina by fluorescence in situ hybridization (FISH) after a smear test could reduce invasive procedures in the future. Using array-based comparative genome hybridization (aCGH) on 65 endometrial carcinomas, most frequently imbalanced regions of the tumour genome were identified. Bacterial artificial chromosomes were used to generate FISH-probes homologue to these human regions. The FISH test was hybridized on swabs specimens collected from the vaginal cavity. Samples from six patients without EC were selected as a negative control and on 13 patients with known EC as a positive control. To distinguish between benign and EC cases, the cut-off value has been defined. A first validation of this EC-FISH Test was performed with swabs from 41 patients with suspected EC. The most common genomic imbalances in EC are around the CTNNB1, FBXW7 and APC genes. The cut-off is defined at 32% of analysed cells without diploid signal pattern. This differs significantly between the positive and negative controls (p < 0.001). In a first validation cohort of 41 patients with suspected EC, the EC-FISH Test distinguishes patients with and without EC with a sensitivity of 91% and a specificity of 83%. The negative predictive value is 96%. This is the first report of a non-invasive EC-FISH Test to predict EC in women with suspected EC.

Nectin-4 as Blood-Based Biomarker Enables Detection of Early Ovarian Cancer Stages.

Ovarian cancer is the third most common gynecological malignancy and has the highest mortality rate. Owing to unspecific symptoms, ovarian cancer is not detected until an advanced stage in about two-thirds of cases. Therefore, it is crucial to establish reliable biomarkers for the early stages to improve the patients' prognosis. The aim of this study is to investigate whether the ADAM17 substrates Nectin-4, Heparin-binding EGF-like growth factor (HB-EGF) and Amphiregulin (AREG) could function as potential tumor markers for ovarian cancer. In this study a set of 231 sera consisting of 131 ovarian cancer patients and 100 healthy age-matched controls were assembled. Nectin-4, HB-EGF and AREG levels of preoperatively collected sera were determined by enzyme-linked immunosorbent assay (ELISA). Our analysis revealed that Nectin-4 and HB-EGF were significantly increased compared to the age-matched control group (p < 0.0001, p = 0.016). Strikingly, significantly higher Nectin-4 and HB-EGF levels were detected in early-stage FIGO I/II (p <0.001; p = 0.025) compared to healthy controls. Eighty-four percent (16/19) of patients with low Ca-125 levels showed increased Nectin-4 levels. Our study proposes Nectin-4 and HB-EGF as promising blood-based biomarkers for the detection of early stages of ovarian cancer patients that would not have been detected by Ca-125.

ADAM17 Inhibition Increases the Impact of Cisplatin Treatment in Ovarian Cancer Spheroids.

Chemotherapy resistance is a major challenge in ovarian cancer (OvCa). Thus, novel treatment combinations are highly warranted. However, many promising drug candidates tested in two-dimensional (2D) cell culture have not proved successful in the clinic. For this reason, we analyzed our drug combination not only in monolayers but also in three-dimensional (3D) tumor spheroids. One potential therapeutic target for OvCa is A disintegrin and metalloprotease 17 (ADAM17). ADAM17 can be activated by chemotherapeutics, which leads to enhanced tumor growth due to concomitant substrate cleavage. Therefore, blocking ADAM17 during chemotherapy may overcome resistance. Here, we tested the effect of the ADAM17 inhibitor GW280264X in combination with cisplatin on ovarian cancer cells in 2D and 3D. In 2D, the effect on five cell lines was analyzed with two readouts. Three of these cell lines formed dense aggregates or spheroids (HEY, SKOV-3, and OVCAR-8) in 3D and the treatment effect was analyzed with a multicontent readout (cytotoxicity, viability, and caspase3/7 activation). We tested the combined therapy on tumor spheroids derived from primary patient cells. In 2D, we found a significant reduction in the half minimal (50%) inhibitory concentration (IC50) value of the combined treatment (GW280264X plus cisplatin) in comparison with cisplatin monotherapy in all five cell lines with both 2D readout assays (viability and caspase activation). In contrast, the combined treatment only showed an IC50 reduction in HEY and OVCAR-8 3D tumor spheroid models using caspase3/7 activity or CelltoxTM Green as the readout. Finally, we found an improved effect of GW280264X with cisplatin in tumor spheroids derived from patient samples. In summary, we demonstrate that ADAM17 inhibition is a promising treatment strategy in ovarian cancer.