Neoadjuvant chemotherapy is associated with a high rate of perioperative blood transfusion at the time of interval cytoreductive surgery

Abstract Background The oncologic safety of allogeneic blood transfusion in ovarian cancer patients is unknow. We sought to determine the prevalence and oncologic safety of perioperative allogeneic blood transfusion during interval cytoreduction surgery among women receiving neoadjuvant chemotherapy for ovarian cancer. Methods We utilized retrospective chart review to identify a cohort of patients undergoing interval cytoreduction at a large academic tertiary referral center. We compared outcomes in patients who were exposed to perioperative blood transfusion compared with patients who were not exposed. Our primary endpoint was progression free survival; our secondary endpoint was overall survival. Baseline clinical characteristics were collected for patients in each group. Results Sixty-six women were included in the final cohort of women undergoing interval cytoreductive surgery after NACT. A total of 51 women (77%) were exposed to allogeneic perioperative pRBC transfusion. Fifteen women (23%) were not exposed to transfusion. The baseline characteristics were generally well matched. Women who were not exposed to a perioperative blood transfusion were more likely to have a normalized CA125 prior to undergoing cytoreductive surgery. Preoperative hemoglobin concentration was lower in the transfusion group (10.5 g/dLvs 11.5 g/dL, p < 0.009). Perioperative transfusion was not associated with a significant difference in progression free survival (PFS = 7.6 months for transfused, 9.4 months for not transfused; log-rank test p = 0.4617). Similarly, there was no observed difference between groups for overall survival (OS = 23.6 months for transfused, 22.5 months for not transfused; log-rank test p = 0.1723). Conclusions Women undergoing neoadjuvant chemotherapy for ovarian cancer are at high risk of exposure to blood transfusion at the time of interval cytoreductive surgery. Future studies will continue to evaluate the safety and impact of transfusion on ovarian cancer survival in this at risk population.https://deepblue.lib.umich.edu/bitstream/2027.42/146137/1/12885_2018_Article_4882.pd

Rapamycin inhibits cell proliferation in type I and type II endometrial carcinomas: A search for biomarkers of sensitivity to treatment

Our goal was to evaluate the effect of rapamycin, an mTOR inhibitor, in type I and II human endometrial cancer tumor explants

Activated networking of platelet activating factor receptor and FAK/STAT1 induces malignant potential in BRCA1-mutant at-risk ovarian epithelium

Objectives It is essential to understand the molecular basis of ovarian cancer etiology and tumor development to provide more effective preventive and therapeutic approaches to reduce mortality. Particularly, the molecular targets and pathways involved in early malignant transformation are still not clear. Pro-inflammatory lipids and pathways have been reported to play significant roles in ovarian cancer progression and metastasis. The major objective of this study was to explore and determine whether platelet activating factor (PAF) and receptor associated networking pathways might significantly induce malignant potential in BRCA1-mutant at-risk epithelial cells. Methods BRCA1-mutant ovarian epithelial cell lines including (HOSE-636, HOSE-642), BRCA1-mutant ovarian cancer cell (UWB1.289), wild type normal ovarian epithelial cell (HOSE-E6E7) and cancerous cell line (OVCA429), and the non-malignant BRCA1-mutant distal fallopian tube (fimbria) tissue specimens were used in this study. Mutation analysis, kinase microarray, western blot, immune staining, co-immune precipitation, cell cycle, apoptosis, proliferation and bioinformatic pathway analysis were applied. Results We found that PAF, as a potent pro-inflammatory mediator, induced significant anti-apoptotic effect in BRCA1-mutant ovarian surface epithelial cells, but not in wild type HOSE cells. With kinase microarray technology and the specific immune approaches, we found that phosphor-STAT1 was activated by 100 nM PAF treatment only in BRCA1-mutant associated at-risk ovarian epithelial cells and ovarian cancer cells, but not in BRCA1-wild type normal (HOSE-E6E7) or malignant (OVCA429) ovarian epithelial cells. Co-immune precipitation revealed that elevated PAFR expression is associated with protein-protein interactions of PAFR-FAK and FAK-STAT1 in BRCA1-mutant ovarian epithelial cells, but not in the wild-type control cells. Conclusion Previous studies showed that potent inflammatory lipid mediators such as PAF and its receptor (PAFR) significantly contribute to cancer progression and metastasis. Our findings suggest that these potent inflammatory lipids and receptor pathways are significantly involved in the early malignant transformation through PAFR-FAK-STAT1 networking and to block apoptosis pathway in BRCA1 dysfunctional at-risk ovarian epithelium

Oxidative Phosphorylation: A Target for Novel Therapeutic Strategies Against Ovarian Cancer

Aerobic glycolysis is an important metabolic adaptation of cancer cells. There is growing evidence that oxidative phosphorylation is also an active metabolic pathway in many tumors, including in high grade serous ovarian cancer. Metastasized ovarian tumors use fatty acids for their energy needs. There is also evidence of ovarian cancer stem cells privileging oxidative phosphorylation (OXPHOS) for their metabolic needs. Metformin and thiazolidinediones such as rosiglitazone restrict tumor growth by inhibiting specific steps in the mitochondrial electron transport chain. These observations suggest that strategies to interfere with oxidative phosphorylation should be considered for the treatment of ovarian tumors. Here, we review the literature that supports this hypothesis and describe potential agents and critical control points in the oxidative phosphorylation pathway that can be targeted using small molecule agents. In this review, we also discuss potential barriers that can reduce the efficacy of the inhibitors of oxidative phosphorylation

Atovaquone: An Inhibitor of Oxidative Phosphorylation as Studied in Gynecologic Cancers

Oxidative phosphorylation is an active metabolic pathway in cancer. Atovaquone is an oral medication that inhibits oxidative phosphorylation and is FDA-approved for the treatment of malaria. We investigated its potential anti-cancer properties by measuring cell proliferation in 2D culture. The clinical formulation of atovaquone, Mepron, was given to mice with ovarian cancers to monitor its effects on tumor and ascites. Patient-derived cancer stem-like cells and spheroids implanted in NSG mice were treated with atovaquone. Atovaquone inhibited the proliferation of cancer cells and ovarian cancer growth in vitro and in vivo. The effect of atovaquone on oxygen radicals was determined using flow and imaging cytometry. The oxygen consumption rate (OCR) in adherent cells was measured using a Seahorse XFe96 Extracellular Flux Analyzer. Oxygen consumption and ATP production were inhibited by atovaquone. Imaging cytometry indicated that the majority of the oxygen radical flux triggered by atovaquone occurred in the mitochondria. Atovaquone decreased the viability of patient-derived cancer stem-like cells and spheroids implanted in NSG mice. NMR metabolomics showed shifts in glycolysis, citric acid cycle, electron transport chain, phosphotransfer, and metabolism following atovaquone treatment. Our studies provide the mechanistic understanding and preclinical data to support the further investigation of atovaquone&rsquo;s potential as a gynecologic cancer therapeutic