The immunohistochemical expression of GPER and classical sex hormone receptors differs in adenomyosis and eutopic endometrium.

G protein-coupled estrogen receptor (GPER) has been found to be an important key regulator in the homeostasis of sex hormone-dependent human cells. The aim of this study was to compare the expression of GPER, estrogen receptor alpha (ER-α), estrogen receptor beta (ER-ß) and progesterone receptor (PR) in adenomyosis, eutopic endometrium from the same patients, and eutopic endometrium from patients without adenomyosis. Immunohistochemical analysis of GPER, ER-α, ER-ß and PR was performed to assess the expression levels on samples of hysterectomies using tissue microarrays. 73 adenomyotic tissue probes and corresponding eutopic endometrial specimens, as well as 48 samples of eutopic endometrial control specimens from patients without adenomyosis were included in this study. Mean age of the women with adenomyosis was 51.7 (SD ± 11.1) and 65.8% were premenopausal. We found a higher nuclear stromal expression of GPER in eutopic endometrium of patients with adenomyosis in comparison to control endometrium (p < 0.001). Comparing adenomyosis to eutopic endometrium of patients with adenomyosis and to control, there was a lower expression of nuclear GPER in epithelial cells (p < 0.001 and p = 0.048, respectively). Lower epithelial nuclear ER-α in adenomyosis and higher epithelial nuclear ER-ß in eutopic endometrium of patients with adenomyosis was found in comparison to control endometrium (p = 0.008 and p = 0.017, respectively). This study showed a significant difference in the immunohistochemical expression of GPER in adenomyosis compared to eutopic endometrium of the same patients and to endometrium of control group. GPER in adenomyosis may be a potential therapeutic target for selective agonists and antagonists.

Judging Urgency in 343 Ectopic Pregnancies Prior to Surgery - The Importance of Transvaginal Sonographic Diagnosis of Intraabdominal Free Blood.

OBJECTIVES: Assessing urgency in ectopic pregnancies (ECP) remains controversial since the disorder covers a large clinical spectrum. Severe conditions such as acute abdomen or hemodynamic instability are mostly related to intra-abdominal blood loss diagnosed as free fluid (FF) on transvaginal sonography (TVS). The aims of the current study were to investigate the value of FF and to assess other potentially predictive parameters for judging urgency. METHODS: Retrospective cohort analysis on prospectively collected cases of proven ECP (n = 343). Demographics, clinical and laboratory parameters, and findings on TVS and laparoscopy (LSC) were extracted from the digital patient file. FF on TVS and free blood (FB) in LSC were evaluated. Low urgency was defined as FB (LSC) < 100 ml and high urgency as FB (LSC) ≥ 300 ml. The best subset of variables for the prediction of FB was selected and predictors of urgency were evaluated using receiver operator characteristic (ROC) curves. RESULTS: Clinical symptoms, age, ß-HCG, hemoglobin (HB) preoperative, and FF were examined in multivariate analysis for the cutoff values of 100 ml and 300 ml. FF was the only independent predictor for low and high urgency; HB preoperative was only significant for high urgency offering marginal improvement. ROC analysis revealed FF as an excellent discriminatory parameter for defining low (AUC 0.837, 95% CI 0.794-0.879) and high urgency (AUC 0.902, 95 % CI 0.860-0.945). CONCLUSION: Single assessment of FF on TVS is most valuable for judging urgency. However, the exact cutoff values for a low- and high-risk situation must still be defined.

The Predictive Value of Decisive and Soft Ultrasound Criteria for Ectopic Pregnancy Identification in 321 Preoperative Cases.

PURPOSE: To define the predictive value of morphological types (MTs) and further criteria in diagnosing ectopic pregnancy (ECP) by transvaginal sonography (TVS) prior to operative confirmation and treatment. MATERIALS AND METHODS: Retrospective cohort analysis of 321 consecutive patients with suspected ECP who were advised to undergo operation. RESULTS: ECP was investigated by TVS in all 321 patients. Application of the five selected MTs (blob sign, bagel sign, yolk sac, embryo, heart action) resulted in 85 % of cases receiving a conclusive diagnosis and 12 % receiving a presumed ECP diagnosis. 3 % remained nondiagnostic due to large or multiple ovarian cysts, large myoma, extended hemoperitoneum, or severe pain. ECP diagnosis was confirmed intraoperatively in 97 % of cases and was otherwise (3 %) immediately followed by curettage (CUR). The assessment of free fluid by TVS was achieved in most cases and correlated significantly with free blood. In the majority of cases, free blood was not bound to transmural ECP rupture. Histology confirmed the ECP diagnosis directly or by exclusion in 99 % of cases. Three cases of tubal ECP were diagnosed by TVS but not confirmed by LSC (1 %) and, finally, histology from CUR proved miscarriage (false-positive rate 1 %). CONCLUSION: We confirm the high accuracy of TVS diagnosis of ECP relying on five clearly different MTs, independent of its location. The blob and bagel sign emerged as important types (75 % of all ECPs). Histology from CUR was needed when ECP could not be visualized in LSC. Assessment of free fluid was essential and accurate in predicting free blood.

Phase I Dose-Escalation Study of the Dual PI3K-mTORC1/2 Inhibitor Gedatolisib in Combination with Paclitaxel and Carboplatin in Patients with Advanced Solid Tumors.

PURPOSE: This phase I study evaluated safety, tolerability, pharmacokinetics, and preliminary activity of the PI3K/mTORC1/2 dual inhibitor gedatolisib combined with carboplatin and paclitaxel. PATIENTS AND METHODS: Patients with advanced solid tumors treated with ≤ 2 prior chemotherapies received intravenous gedatolisib on days 1, 8, 15, and 22 (95, 110, or 130 mg according to dose level); carboplatin (AUC5) on day 8 (day 1 following protocol amendment); and paclitaxel at 80 mg/m2 on days 8, 15, and 22 (1, 8, and 15 after amendment), every 28 days. Patients without progressive disease after cycle 6 received maintenance gedatolisib until progression. RESULTS: Seventeen patients were enrolled [11 ovarian (10 clear cell ovarian cancer, CCOC), 4 endometrial, 2 lung cancers]. Median number of prior chemotherapies was 1 (range, 0-2). Median number of administered cycles was 6 (range, 2-16). Dose-limiting toxicities occurred in 4 patients: 2 (cycle 2 delay due to G2-G3 neutropenia) at 110 mg leading to a change in the treatment schedule, 2 at 130 mg (G2 mucositis causing failure to deliver ≥ 75% of gedatolisib at cycle 1). The recommended phase II dose is gedatolisib 110 mg on days 1, 8, 15, and 22 with carboplatin AUC5 on day 1 and paclitaxel 80 mg/m2 on days 1, 8, and 15. The most frequent ≥G3 treatment-related adverse events were neutropenia (35%), anemia (18%), and mucositis (12%). The overall response rate was 65% (80% in CCOC). Pharmacokinetic parameters of gedatolisib were consistent with single-agent results. CONCLUSIONS: Gedatolisib combined with carboplatin and paclitaxel is tolerable, and preliminary efficacy was observed especially in CCOC.

Evaluation of surgical resection in advanced ovarian, fallopian tube, and primary peritoneal cancer: laparoscopic assessment. A European Network of Gynaecological Oncology Trial (ENGOT) group survey.

OBJECTIVE: Laparoscopy is one of the diagnostic tools available for the complex clinical decision-making process in advanced ovarian, fallopian tube, and peritoneal carcinoma. This article presents the results of a survey conducted within the European Network of Gynaecological Oncology Trial (ENGOT) group aimed at reviewing the current patterns of practice at gynecologic oncology centers with regard to the evaluation of resection in advanced ovarian, fallopian tube, and peritoneal carcinoma. METHODS: A 24-item questionnaire was sent to the chair of the 20 cooperative groups that are currently part of the ENGOT group, and forwarded to the members within each group. RESULTS: A total of 142 questionnaires were returned. Only 39 respondents (27.5%) reported using some form of clinical (not operative) score for the evaluation of resection. The frequency of use of diagnostic laparoscopy to assess disease status and feasibility of resection was as follows: never, 21 centers (15%); only in select cases, 83 centers (58.5%); and routinely, 36 centers (25.4%). When laparoscopy was performed, 64% of users declared they made the decision to proceed with maximal effort cytoreductive surgery based on their personal/staff opinion, and 36% based on a laparoscopic score. To the question of whether laparoscopy should be considered the gold standard in the evaluation of resection, 71 respondents (50%) answered no, 66 respondents (46.5%) answered yes, whereas 5 respondents (3.5%) did not provide an answer. CONCLUSIONS: This study found that laparoscopy was routinely performed to assess feasibility of cytoreduction in only 25.4% of centers in Europe. However, it was commonly used to select patients and in a minority of centers it was never used . When laparoscopy was adopted, the treatment strategy was based on laparoscopic scores only in a minority of centers.

NOTCH signalling in ovarian cancer angiogenesis.

The Notch signalling pathway is involved in the new vessel formation process by regulating tip and stalk cells, which are key cells in the sprout formation. This process is essential in both normal ovary and cancer angiogenesis and is regulated by Notch-VEGF crosstalk. Furthermore, Notch has been linked in ovary with stem cell maintenance and epithelial mesenchymal transition processes. Dysregulation of the Notch pathway is frequent in ovarian cancer (OC) and it has been associated with impaired survival and advanced stages or lymph node involvement. Notch also plays a role in chemoresistance to platinum. In this context, this pathway has emerged as an attractive target for precision medicine in OC. Two main targets of this pathway concentrate the clinical development of compounds blocking Notch: gamma secretase and Delta-like ligand 4. Most of the clinical trials including OC patients have been developed in phase I or phase Ib. Despite being in an early phase, both of these compounds, navicixizumab or demcizumab, two monoclonal antibodies targeting Dll4, showed promising efficacy data in platinum-resistant OC patients in recent studies. This review will focus on the mechanisms of the Notch pathway with special interest in angiogenesis regulation and the implication of Notch as a potential therapeutic target in OC.

The ENZIAN score as a preoperative MRI-based classification instrument for deep infiltrating endometriosis.

PURPOSE: Comparison of preoperative magnetic resonance imaging (MRI) with intraoperative findings in patients with deep infiltrating endometriosis (DIE) by means of the ENZIAN score. METHODS: This retrospective two-center study includes 63 patients with deep infiltrating endometriosis, who underwent surgery between 2012 and 2016 at both the University Hospital of Zurich and the Cantonal Hospital of Schaffhausen. Inclusion criteria were a preoperative pelvic MRI and intraoperative or bioptic confirmation of DIE. The preoperative MRI findings were compared with the intraoperative results by means of the ENZIAN score. Furthermore, the various MRI sequences were analyzed for their diagnostic value based on a Likert scale. RESULTS: Sensitivity and negative predictive values of MRI confirmed by surgery were 95.2% and 91.7% (lesions in the vaginal/rectovaginal space), 78.4% and 56% (uterosacral ligaments), 91.4% and 89.7% (rectum/sigmoid colon), 57.1% and 94.1% (myometrium), 85.7% and 98.3% (bladder), and 73.3% and 92.2% (intestine), respectively. T2 axial and sagittal MRI sequences in combination with a T1 sequence were diagnostically sufficient. CONCLUSIONS: The MRI-based ENZIAN score correlates well with the intraoperative findings, enabling a better planning of the surgical procedure for patients and physicians. However, considerable difficulty and a poorer comparability result from the variations in sequences used in the detection of this multifaceted disease. Therefore, a standardization of MRI protocols used in the detection of DIE will be a crucial step towards increased diagnostic validity and the ENZIAN score may be used as an anatomical land map and valuable communication tool between radiologists and gynecologists.

Preclinical evaluation of the PARP inhibitor BMN-673 for the treatment of ovarian clear cell cancer.

PURPOSE: To determine if models of ovarian clear cell carcinomas (OCCCs) harbouring defects in homologous recombination (HR) DNA repair of double strand breaks (DSBs) are sensitive to cisplatin and/or PARP inhibition. EXPERIMENTAL DESIGN: The HR status of 12 OCCC cell lines was determined using RAD51/γH2AX foci formation assays. Sensitivity to cisplatin and the PARP inhibitor BMN-673 was correlated with HR status. BRCA1, BRCA2, MRE11 and PTEN loss of expression was investigated as a potential determinant of BMN-673 sensitivity. A tissue microarray containing 50 consecutive primary OCCC was assessed for PTEN expression using immunohistochemistry. RESULTS: A subset of OCCC cells displayed reduced RAD51 foci formation in the presence of DNA DSBs, suggestive of HR defects. HR-defective OCCC cells, with the exception of KOC-7c, had higher sensitivity to cisplatin/ BMN-673 than HR-competent OCCC cell lines (Log10 SF50 -9.4 (SD +/- 0.29) vs -8.1 (SD +/- 0.35), mean difference 1.3, p < 0.01). Of the cell lines studied, two, TOV-21G and KOC-7c, showed loss of PTEN expression. In primary OCCCs, loss of PTEN expression was observed in 10% (5/49) of cases. CONCLUSIONS: A subset of OCCC cells are sensitive to PARP inhibition in vitro, which can be predicted by HR defects as defined by γH2AX/RAD51 foci formation. These results provide a rationale for the testing of HR deficiency and PARP inhibitors as a targeted therapy in a subset of OCCCs.

Protein expression of cancer testis antigens predicts tumor recurrence and treatment response to imatinib in gastrointestinal stromal tumors.

Cancer testis antigens (CTAs) have been identified in various tumors as immunological tumor targets. In gastrointestinal stromal tumor (GIST), the prediction of malignant potential remains difficult but is crucial in the era of adjuvant imatinib treatment. Here, we analyzed the impact of CTAs on tumor recurrence and its role on the treatment response to imatinib. The expression of the most frequent CTAs MAGE-A1, MAGE-A3, MAGE-A4, MAGE-C1 and NY-ESO-1 was analyzed by immunohistochemistry. The duration between the initial operation and the tumor relapse was defined as recurrence free survival (RFS). All recurrent cases were treated with imatinib. The tumor response to imatinib was graded according to the modified CT response evaluation criteria. Patients with a CTA positive GIST (n = 23, 27%) had a significantly shorter RFS (p = 0.001) compared to negative cases (n = 63, 73%). The median RFS was 25 months in CTA positive patients and was not reached during the study period in CTA negative patients. According to the established staging criteria CTA positive tumors were predominantly high-risk tumors (p = 0.001). The expression of MAGE-A3 (p = 0.018) and NY-ESO-1 (p = 0.001) were associated with tumor progression under imatinib treatment. A tendency for worse tumor response to imatinib was observed in CTA positive tumors (p = 0.056). Our study confirms the expression of CTAs in GIST and their role as prognostic markers. It also draws attention to the potential impact of CTAs on the tumor response to imatinib.