Many of the enhanced recovery after surgery principles initially developed for colorectal surgery can be successfully applied to gynecologic oncology and lead to significant improvements in ...perioperative care. Enhanced recovery after surgery guidelines specific to gynecologic oncology were published in 2016 and provide a framework for the development and implementation of institutional protocols. Identification of key stakeholders and a multidisciplinary approach are critical to identifying which principles are best suited for implementation at a particular institution and for ensuring success of the protocol. Herein, we review our experience with protocol development and implementation on a gynecologic oncology service.
Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer mortality worldwide. Platinum-based therapy is the standard first line treatment and while most patients initially respond, ...resistance to chemotherapy usually arises. Major signaling pathways frequently upregulated in chemoresistant cells and important in the maintenance of cancer stem cells (CSCs) include Wnt/β-catenin, mTOR, and STAT3. The major objective of our study was to investigate the treatment of ovarian cancer with targeted agents that inhibit these three pathways. Here we demonstrate that niclosamide, a salicylamide derivative, and two synthetically manufactured niclosamide analogs (analog 11 and 32) caused significant inhibition of proliferation of two chemoresistant ovarian cancer cell lines (A2780cp20 and SKOV3Trip2), tumorspheres isolated from the ascites of EOC patients, and cells from a chemoresistant patient-derived xenograft (PDX). This work shows that all three agents significantly decreased the expression of proteins in the Wnt/β-catenin, mTOR and STAT3 pathways and preferentially targeted cells that expressed the ovarian CSC surface protein CD133. It also illustrates the potential of drug repurposing for chemoresistant EOC and can serve as a basis for pathway-oriented in vivo studies.
Niclosamide has shown activity against ovarian cancer in vitro; however, it has low bioavailability in vivo. Therefore, we investigated the cytotoxicity of niclosamide analogs in combination with ...carboplatin against ovarian cancer patient ascites cells and tissue slices.
Tumorspheres were isolated from ascites collected from patients undergoing ovarian cancer surgery and plated at 10,000 cells per 50 μL into low attachment plates. Tumor slices were also processed at the time of surgery. These were treated concurrently with niclosamide or analogs (0.1-5 μM) and carboplatin (5-150 μM). At 48 hours, cell viability was assessed with ATPlite assay. Western blotting was used to determine expression of Wnt/β-catenin proteins in ascites cells.
Cytotoxicity of niclosamide and its analogs in combination with carboplatin was demonstrated in 24 patient ascites samples. Increased cytotoxicity was seen with 2 analogs in 23 patient ascites samples when compared with niclosamide. Similar cytotoxicity was produced in an ex vivo tumor slice model. Western blot analysis showed decreased expression of Wnt/β-catenin proteins with niclosamide and analog treatment in a dose-dependent fashion.
The niclosamide-like analogs produced cytotoxicity both alone and in combination with carboplatin against tumorspheres from patient ascites and slices from solid tumor samples. Tumor slices showed similar cytotoxicity to matched ascites samples. Western blots showed down-regulation of Wnt pathway-associated proteins in patient samples treated with niclosamide analogs. These results suggest that more soluble niclosamide analogs may be useful for the treatment of ovarian cancer in combination with chemotherapy.
To evaluate the potential impact of a standardized preoperative algorithm on outcomes of patients with suspected ovarian cancer.
From January 1 to December 31, 2013, patients with suspected ovarian ...cancer were triaged to primary debulking surgery or neoadjuvant chemotherapy/interval debulking surgery (NACT/IDS) based on a comprehensive review of preoperative clinical data as part of a quality improvement project. Demographics, surgical, and postoperative data were collected.
A total of 110 patients with newly diagnosed ovarian cancer were identified: 68 (62%) underwent PDS with an 85% optimal debulking rate. The 30-day readmission rate was 14.7% with a 2.9% 60-day mortality rate. Forty-two patients (38%) underwent NACT. Two patients (4.8%) died before receiving NACT. Thirty-five patients have undergone IDS with an 89% optimal debulking rate. The 30-day readmission rate was 8.5% with a 5.7% 60-day mortality rate after IDS.
Although it is difficult to predict which patients will undergo optimal debulking at the time of PDS, surgical morbidity and mortality can be decreased by using NACT in select patients. The initiation of a quality improvement project has contributed to an improvement in patient outcomes at our institution.
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Background: Studies have shown that adjuvant therapy increases progression free survival, but does not affect overall survival in patients with high-intermediate risk (H-IR) ...endometrial cancer (EMCA). Our objective was to develop a gene expression signature that may help identify H-IR EMCA patients with the highest risk of recurrence to help guide treatment strategies. Methods: Data was collected on all patients that met H-IR EMCA criteria diagnosed between 2000-2010 at UAB (n = 292). Of the patients that did not receive adjuvant treatment, 13 patients that recurred were matched to 13 patients that did not recur and original tumor was compared. Of those that recurred, 5 patients had original and recurrent tumor available for analysis. Gene expression data was collected using the Nanostring nCounter PanCancer Pathway 770 gene panel. Data was analyzed using nSolver Advanced Analysis Software. A fold change (FC) of ≥ ± 2 (p < 0.05) was used to identify genes with a significant expression difference. Results: Comparing the 13 patients that recurred to the 13 that did not, there were 5 genes with FC ≥ +2: BAIAP3, PLCB1, IL1R1, NOS3 and RAD50. There were 29 genes with FC ≥ -2; the top 3 genes with decreased expression (FC ≥ -10) were: BMP7, FGF18, WNT7A. Genes in the Cell Cycle (CC) pathway were significantly different in the patients that recurred (p = 0.02). There were 61 genes with FC ≥ +2 when comparing the original tumor to recurrent tumor; the top 3 genes with increased expression (FC ≥ 10) were: FGF18, CCND1, HIST1H3H (p < 0.05). There were 50 genes with FC ≥ -2; the top 3 genes with decreased expression (FC ≥ -1000) were: HOXA11, LEFTY2 and SFRP4. Wnt, Hedgehog, Chromatin Modification, DNA repair, TGF-β, MAPK, and CC pathways were significantly different in the recurrent samples compared to the original tumor (p < 0.05). Conclusions: Our data suggests that gene expression panels could better identify patients that warrant adjuvant treatment. The CC pathway, which is significantly different in the original tumor from those that recurred and those that did not, was further altered in the recurrent tumor samples. Additional studies are on-going to validate these findings and to further investigate DNA mutation differences in larger cohort of patients.
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