Targeting Fatty Acid Oxidation to Promote Anoikis and Inhibit Ovarian Cancer Progression.

Epithelial-derived high-grade serous ovarian cancer (HGSOC) is the deadliest gynecologic malignancy. Roughly 80% of patients are diagnosed with late-stage disease, which is defined by wide-spread cancer dissemination throughout the pelvic and peritoneal cavities. HGSOC dissemination is dependent on tumor cells acquiring the ability to resist anoikis (apoptosis triggered by cell detachment). Epithelial cell detachment from the underlying basement membrane or extracellular matrix leads to cellular stress, including nutrient deprivation. In this report, we examined the contribution of fatty acid oxidation (FAO) in supporting anoikis resistance. We examined expression Carnitine Palmitoyltransferase 1A (CPT1A) in a panel of HGSOC cell lines cultured in adherent and suspension conditions. With CPT1A knockdown cells, we evaluated anoikis by caspase 3/7 activity, cleaved caspase 3 immunofluorescence, flow cytometry, and colony formation. We assessed CPT1A-dependent mitochondrial activity and tested the effect of exogenous oleic acid on anoikis and mitochondrial activity. In a patient-derived xenograft model, we administered etomoxir, an FAO inhibitor, and/or platinum-based chemotherapy. CPT1A is overexpressed in HGSOC, correlates with poor overall survival, and is upregulated in HGSOC cells cultured in suspension. CPT1A knockdown promoted anoikis and reduced viability of cells cultured in suspension. HGSOC cells in suspension culture are dependent on CPT1A for mitochondrial activity. In a patient-derived xenograft model of HGSOC, etomoxir significantly inhibited tumor progression. IMPLICATIONS: Targeting FAO in HGSOC to promote anoikis and attenuate dissemination is a potential approach to promote a more durable antitumor response and improve patient outcomes.

Multi-Omic Approaches Identify Metabolic and Autophagy Regulators Important in Ovarian Cancer Dissemination.

High-grade serous ovarian cancers (HGSOCs) arise from exfoliation of transformed cells from the fallopian tube, indicating that survival in suspension, and potentially escape from anoikis, is required for dissemination. We report here the results of a multi-omic study to identify drivers of anoikis escape, including transcriptomic analysis, global non-targeted metabolomics, and a genome-wide CRISPR/Cas9 knockout (GeCKO) screen of HGSOC cells cultured in adherent and suspension settings. Our combined approach identified known pathways, including NOTCH signaling, as well as novel regulators of anoikis escape. Newly identified genes include effectors of fatty acid metabolism, ACADVL and ECHDC2, and an autophagy regulator, ULK1. Knockdown of these genes significantly inhibited suspension growth of HGSOC cells, and the metabolic profile confirmed the role of fatty acid metabolism in survival in suspension. Integration of our datasets identified an anoikis-escape gene signature that predicts overall survival in many carcinomas.

Extended left upper quadrant resection during primary cytoreductive surgery for Stage IV ovarian cancer.

OBJECTIVE: The completeness of primary cytoreductive surgery for Stage IV epithelial ovarian cancer is associated with greater progression free survival and overall survival Winter et al. (2008) [1]. Cytoreduction to no gross residual disease in patients with bulky upper abdominal disease presents significant surgical challenges, highlighting the importance of specialized and comprehensive surgical training in the treatment of advanced ovarian cancers Zivanovic et al. (2008) [2]. Extensive upper abdominal surgical procedures have shown to improve the ability to achieve cytoreduction to no gross residual disease Chi et al. (2004) [3]. This film displays an extended left upper quadrant resection in one of our recent patients. METHODS: The patient was a 62-year-old female with a CA-125 of 2,577U/mL, abdominal ascites, and a preoperative CT showing carcinomatosis with a left upper quadrant infiltration. Primary cytoreductive surgery was undertaken with exploratory laparotomy, type 2 radical oophorectomy (en bloc modified radical abdominal hysterectomy, bilateral salpingo-oophorectomy, pan-pelvic peritonectomy, distal colectomy, retosigmoid colectomy), with en bloc omentectomy, transverse colectomy, splenectomy, distal pancreatectomy, and diaphragm peritonectomy. RESULTS: Operative time was 337min with an estimated blood loss of 900mL. The patient was discharged home on post-operative day 10 after a standard prolongation in hospitalization required to meet milestones after extensive upper quadrant cytoreductive surgery. CONCLUSION: Bulky upper abdominal disease can present significant surgical challenges. This film illustrates obtaining cytoreduction to no gross residual disease is feasible. We show transection of the pancreas by reinforced linear staple closure due to its ease of use and surgeon preference, although controversy remains regarding the ideal technique.

Scope of practice and autonomy of physician assistants in rural versus urban emergency departments.

OBJECTIVES: This was a study of the scope of practice and autonomy of emergency medicine (EM) physician assistants (PAs) practicing in rural versus urban emergency departments (EDs). METHODS: Using the American Academy of Physician Assistants (AAPA) Masterfile, a random sample of 200 U.S. EM PAs were surveyed, with oversampling of an additional 200 rural PAs. Location was classified by zip code-based rural-urban commuting area codes, and responses were compared about conditions managed, procedures performed, and physician supervision between rural versus urban groups. RESULTS: A total of 237 responses were received from PAs in 44 U.S. states, of which (201) were valid responses (105 rural, 96 urban) from PAs currently practicing in EDs (59.3% exclusion-adjusted response rate). Compared to urban PAs, rural PAs more frequently managed cardiac arrest (67% vs. 44%), stroke (86% vs. 72%), multisystem trauma (83% vs. 70%), active labor (44% vs. 23%), and critically ill children (82% vs. 65%) in the past year. They were more likely to have performed intubation (65% vs. 44%), needle thoracostomy (21% vs. 8%), and tube thoracostomy (46% vs. 26%). Rural PAs more often reported never having a physician present in the ED (38% vs. 0%) and less often reported always having a physician present (50% vs. 98%). Rural PAs were also less likely to report that a physician evaluates more than 75% of their patients (8% vs. 18%) and more likely that a physician never evaluates all of their patients (19% vs. 7%). CONCLUSIONS: Rural PAs reported a broader scope of practice, more autonomy, and less access to physician supervision than urban PAs.