Dowdy, Sean C.

AbstractEnhanced recovery protocols consist of a bundle of concepts including early feeding, opioid‐sparing multimodal pain management, and euvolemia, with the overarching goal of hastening postoperative recovery. Enhanced recovery after surgery has been shown to reduce hospital length of stay, reduce costs, and decrease perioperative opioid requirements in benign and oncologic gynecologic surgery. Interventions without supporting evidence of benefit, such as the use of mechanical bowel preparation, routine use of nasogastric tubes and surgical drains, caloric restriction, routine use of intravenous opioid analgesics, and over‐vigorous intravenous hydration should be discouraged to improve broader endpoints such as patient satisfaction and overall recovery. Successful implementation requires engagement from a multidisciplinary team including surgeons, anesthesiologists, nurses, and pharmacists.

Abstract Objectives: To investigate the antitumor potential of the widely used anticholesterol drug Atorvastatin (ATV) alone, in combination with Carboplatin (CBPT) and with the glycolytic inhibitor PFK158 (PFKi) in ovarian cancer (OC). Methods: MTT assay and the Chou-Talalay methodology were used to test anticancer activity in vitro; half maximal inhibitory concentration (IC50) and combination index (CI) were calculated. Cellular changes were studied with transmission electron microscopy (TEM). ATV was combined with PFKi as we previously showed that PFKi, in addition to glycolysis, inhibits lipid metabolism by targeting PLA2G3. PLA2G3 expression was studied by western blot given that downregulation in OVCAR8 using two shRNAs (sh33, sh35) induced autophagy, a prodeath condition in OC, and was associated with chemosensitization compared to nontargeted controls (NTC) (unpublished data). A random sample of 10 patient-derived OC xenografts (PDX) was studied by TEM. Results: OVCAR8 exhibited a dose dependent proliferation inhibition when treated with ATV (IC50 8μM). PFKi and CBPT IC50 were 4μM and 78μM. PFKi treatment combined with 4μM and 8μM of ATV resulted in ATV sensitizing cells to PFKi by shifting PFKi IC50 down to 2.7μM and 0.4μM, respectively. When ATV was combined in constant ratio with CBPT, CIs were >1.1 indicating antagonism. Combination of ATV 4μM with PFKi 2μM resulted in greater decrease in PLA2G3 and p62 and greater increase in cleaved PARP compared to PFKi alone suggesting higher levels of autophagy and apoptosis. ATV and combination treatment resulted in increased caveolin-1 levels, previously shown to be associated with apoptotic cell death. TEM analysis of ATV and PFKi treated cells showed greater number of lipid rich multilamellar bodies (MLB) compared to controls. PLA2G3 knockdowns exhibited higher MBL formation, lower p62, and when treated with statin and with PFKi, cleaved PARP was significantly higher compared to NTCs. TEM showed that PDXs clustered in low and high MLB groups suggesting a distinct novel phenotype. Conclusions: ATV could enhance PFKi antitumor activity by jointly targeting PLA2G3 leading to metabolic reprogramming of OC. Importantly, ATV antagonized CBPT. Additional studies are in progress to explore the mechanistic pathway of ATV and characterize the significance of MLB in OC as a prodeath phenotype and biomarker of response. Citation Format: Eleftheria Kalogera, Debarshi Roy, Jamie N. Bakkum-Gamez, William A. Cliby, Sean C. Dowdy, Viji Shridhar. Atorvastatin antagonizes carboplatin, synergizes with the glycolytic inhibitor PFK-158, and induces lipid laden multilamellar bodies in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5821.

Objective: The aim of this study was to conduct a prospective, multicenter survey of patients regarding postoperative opioid use to inform development of standardized, evidence-based, procedure-specific opioid prescribing guidelines. Summary of Background Data: Previous work has shown significant variation in the amount of opioids prescribed after elective procedures, calling for optimization of prescribing. Methods: Adults (n = 3412) undergoing 25 elective procedures were identified prospectively from 3 academic centers (March 2017 to January 2018) to complete a 29-question telephone interview survey 21 to 35 days post-discharge (n = 688 not contacted, n = 107 refused). Discharge opioids were converted into Morphine Milligram Equivalents (MMEs). Results: Of the 2486 patients who completed the survey, 91.2% received opioids at discharge [median 225 (interquartile range, IQR 125 to 381) MME]. A median of 43 (0 to 184) MMEs were consumed after discharge with 77.3% of patients having leftover opioids at the time of the survey. In total, 61.5% of prescribed opioids were unused; 31.4% of patients used no opioids, and 52.6% required <50 MME. Overall, 90.6% of patients were satisfied with their postdischarge pain control. While 28.3% reported being prescribed too many opioids, 9.0% felt they were not prescribed enough. Only 9.6% of patients disposed of remaining opioids. Of the 2068 opioid-naive respondents (83.2%), 33.6% consumed no opioids (range 5.2% to 80.0% by procedure) and 57.0% (65.7% nonorthopedic) consumed <50 MME. Utilization data and predictors of low/high opioid consumption informed development of postoperative prescribing guidelines. Conclusion: A large proportion of postoperative patients reported using no or few opioids following discharge. Guidelines were developed to minimize opioid prescribing and identify patients requiring low doses or additional multimodal pain control.

AbstractEpidemiological, biological, and molecular data suggest links between endometriosis and endometrial cancer, with recent epidemiological studies providing evidence for an association between a previous diagnosis of endometriosis and risk of endometrial cancer. We used genetic data as an alternative approach to investigate shared biological etiology of these two diseases. Genetic correlation analysis of summary level statistics from genomewide association studies (GWAS) using LD Score regression revealed moderate but significant genetic correlation (rg = 0.23, P = 9.3 × 10−3), and SNP effect concordance analysis provided evidence for significant SNP pleiotropy (P = 6.0 × 10−3) and concordance in effect direction (P = 2.0 × 10−3) between the two diseases. Cross‐disease GWAS meta‐analysis highlighted 13 distinct loci associated at P ≤ 10−5 with both endometriosis and endometrial cancer, with one locus (SNP rs2475335) located within PTPRD associated at a genomewide significant level (P = 4.9 × 10−8, OR = 1.11, 95% CI = 1.07–1.15). PTPRD acts in the STAT3 pathway, which has been implicated in both endometriosis and endometrial cancer. This study demonstrates the value of cross‐disease genetic analysis to support epidemiological observations and to identify biological pathways of relevance to multiple diseases.

Tumor-targeted fluorescence imaging for cancer diagnosis and treatment is an evolving field of research that is on the verge of clinical implementation. As each tumor has its unique biologic profile, selection of the most promising targets is essential. In this review, we focus on target finding in ovarian cancer, a disease in which fluorescence imaging may be of value in both adequate staging and in improving cytoreductive efforts, and as such may have a beneficial effect on prognosis. Thus far, tumor-targeted imaging for ovarian cancer has been applied only in animal models. For clinical implementation, the five most prominent targets were identified: folate receptor α, vascular endothelial growth factor, epidermal growth factor receptor, chemokine receptor 4, and matrix metalloproteinase. These targets were selected based on expression rates in ovarian cancer, availability of an antibody or substrate aimed at the target approved by the Food and Drug Administration, and the likelihood of translation to human use. The purpose of this review is to present requirements for intraoperative imaging and to discuss possible tumor-specific targets for ovarian cancer, prioritizing for targets with substrates ready for introduction into the clinic.