BackgroundThis is the first updated Enhanced Recovery After Surgery (ERAS) Society guideline presenting a consensus for optimal perioperative care in gynecologic/oncology surgery.MethodsA database search of publications using Embase and PubMed was performed. Studies on each item within the ERAS gynecologic/oncology protocol were selected with emphasis on meta-analyses, randomized controlled trials, and large prospective cohort studies. These studies were then reviewed and graded according to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system.ResultsAll recommendations on ERAS protocol items are based on best available evidence. The level of evidence for each item is presented accordingly.ConclusionsThe updated evidence base and recommendation for items within the ERAS gynecologic/oncology perioperative care pathway are presented by the ERAS® Society in this consensus review.

OBJECTIVE To investigate the effects of enhanced recovery (a multimodal perioperative care enhancement protocol) in patients undergoing gynecologic surgery. METHODS Consecutive patients managed under an enhanced recovery pathway and undergoing cytoreduction, surgical staging, or pelvic organ prolapse surgery between June 20, 2011, and December 20, 2011, were compared with consecutive historical controls (March to December 2010) matched by procedure. Wilcoxon rank-sum, χ2, and Fisher's exact tests were used for comparisons. Direct medical costs incurred in the first 30 days were obtained from the Olmsted County Healthcare Expenditure and Utilization Database and standardized to 2011 Medicare dollars. RESULTS A total of 241 enhanced recovery women in the case group (81 cytoreduction, 84 staging, and 76 vaginal surgery) were compared with women in the control groups. In the cytoreductive group, patient-controlled anesthesia use decreased from 98.7% to 33.3% and overall opioid use decreased by 80% in the first 48 hours with no change in pain scores. Enhanced recovery resulted in a 4-day reduction in hospital stay with stable readmission rates (25.9% of women in the case group compared with 17.9% of women in the control group) and 30-day cost savings of more than $7,600 per patient (18.8% reduction). No differences were observed in rate (63% compared with 71.8%) or severity of postoperative complications (grade 3 or more: 21% compared with 20.5%). Similar, albeit less dramatic, improvements were observed in the other two cohorts. Ninety-five percent of patients rated satisfaction with perioperative care as excellent or very good. CONCLUSIONS Implementation of enhanced recovery was associated with acceptable pain management with reduced opioids, reduced length of stay with stable readmission and morbidity rates, good patient satisfaction, and substantial cost reductions.

(Abstracted from Int J Gynecol Cancer 2019; doi: 10.1136/ijgc-2019-000356) Enhanced Recovery After Surgery (ERAS) is a global initiative dedicated to improving gynecologic/oncology surgical quality with attention to both clinical outcomes and economic impact. The ERAS guidelines, first published in February 2016, require updates on a regular basis in order to keep up with contemporary literature and evidence.

Metabolic alterations are increasingly recognized as important novel anti-cancer targets. Among several regulators of metabolic alterations, fructose 2,6 bisphosphate (F2,6BP) is a critical glycolytic regulator. Inhibition of the active form of PFKFB3 using a novel inhibitor, PFK158 resulted in reduced glucose uptake, ATP production, lactate release as well as induction of apoptosis in gynecologic cancer cells. Moreover, we found that PFK158 synergizes with carboplatin (CBPt) and paclitaxel (PTX) in the chemoresistant cell lines, C13 and HeyA8MDR but not in their chemosensitive counterparts, OV2008 and HeyA8, respectively. We determined that PFK158-induced autophagic flux leads to lipophagy resulting in the downregulation of cPLA2, a lipid droplet (LD) associated protein. Immunofluorescence and co-immunoprecipitation revealed colocalization of p62/SQSTM1 with cPLA2 in HeyA8MDR cells uncovering a novel pathway for the breakdown of LDs promoted by PFK158. Interestingly, treating the cells with the autophagic inhibitor bafilomycin A reversed the PFK158-mediated synergy and lipophagy in chemoresistant cells. Finally, in a highly metastatic PTX-resistant in vivo ovarian mouse model, a combination of PFK158 with CBPt significantly reduced tumor weight and ascites and reduced LDs in tumor tissue as seen by immunofluorescence and transmission electron microscopy compared to untreated mice. Since the majority of cancer patients will eventually recur and develop chemoresistance, our results suggest that PFK158 in combination with standard chemotherapy may have a direct clinical role in the treatment of recurrent cancer.

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Objective To evaluate the utility of serum (HE4) as a marker for high risk disease in patients with endometrial cancer (EC). Methods Preoperative serum HE4 levels were measured from a cohort of 75 patients surgically treated for EC. Cases were compared to matched controls without a history of cancer. HE4 levels were analyzed as a function of primary tumor diameter, grade, stage and histological subtype. Wilcoxon rank-sum test, ROC curve, Spearman rank correlation coefficient and contingency tables were used for statistical analyses. Results Stage distribution was as follows: 49 stage I, 2 stage II, 20 stage III, 4 stage IV. Type I EC was present in 54 patients, type II in 21. Median HE4 was significantly elevated in both type I and II EC compared to controls (P<0.001 and P=0.019, respectively). There was significant correlation between type I EC, median HE4, deep myometrial invasion (MI) (>50%, P<0.001) and primary tumor diameter (PTD) (>2cm, P=0.002). Low risk patients (type I, MI ≤50% and PTD ≤2cm) had significantly lower median HE4 compared to all other type I EC patients (P<0.01). In comparison to prior investigations, HE4 (cutoff of 8 mfi) was more sensitive than CA125 in detecting advanced stage disease. Conclusion Our data suggest that HE4 is elevated in a high proportion of EC patients, is correlated with PTD and MI, and is more sensitive than CA125 in EC. These observations suggest potential utility of HE4 in the preoperative prediction of high risk disease and the necessity for definitive surgical staging.

A promising new strategy for cancer therapy is to target the autophagic pathway. In the current study, we demonstrate that the antimalarial drug Quinacrine (QC) reduces cell viability and promotes chemotherapy-induced cell death in an autophagy-dependent manner more extensively in chemoresistant cells compared to their isogenic chemosensitive control cells as quantified by the Chou-Talalay methodology. Our preliminary data, in vitro and in vivo, indicate that QC induces autophagy by downregulating p62/SQSTM1 to sensitize chemoresistant cells to autophagic- and caspase-mediated cell death in a p53-independent manner. QC promotes autophagosome accumulation and enhances autophagic flux by clearance of p62 in chemoresistant ovarain cancer (OvCa) cell lines to a greater extent compared to their chemosensitive controls. Notably, p62 levels were elevated in chemoresistant OvCa cell lines and knockdown of p62 in these cells resulted in a greater response to QC treatment. Bafilomycin A, an autophagy inhibitor, restored p62 levels and reversed QC-mediated cell death and thus chemosensitization. Importantly, our in vivo data shows that QC alone and in combination with carboplatin suppresses tumor growth and ascites in the highly chemoresistant HeyA8MDR OvCa model compared to carboplatin treatment alone. Collectively, our preclinical data suggest that QC in combination with carboplatin can be an effective treatment for patients with chemoresistant OvCa.

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