Repurposing quinacrine for treatment-refractory cancer.

Quinacrine, also known as mepacrine, has originally been used as an antimalarial drug for close to a century, but was recently rediscovered as an anticancer agent. The mechanisms of anticancer effects of quinacrine are not well understood. The anticancer potential of quinacrine was discovered in a screen for small molecule activators of p53, and was specifically shown to inhibit NFκB suppression of p53. However, quinacrine can cause cell death in cells that lack p53 or have p53 mutations, which is a common occurrence in many malignant tumors including high grade serous ovarian cancer. Recent reports suggest quinacrine may inhibit cancer cell growth through multiple mechanisms including regulating autophagy, FACT (facilitates chromatin transcription) chromatin trapping, and the DNA repair process. Additional reports also suggest quinacrine is effective against chemoresistant gynecologic cancer. In this review, we discuss anticancer effects of quinacrine and potential mechanisms of action with a specific focus on gynecologic and breast cancer where treatment-refractory tumors are associated with increased mortality rates. Repurposing quinacrine as an anticancer agent appears to be a promising strategy based on its ability to target multiple pathways, its selectivity against cancer cells, and the synergistic cytotoxicity when combined with other anticancer agents with limited side effects and good tolerability profile.

Outcomes and patient perspectives following implementation of tiered opioid prescription guidelines in gynecologic surgery.

OBJECTIVES: To report the impact of implementing standardized guidelines for opioid prescriptions after gynecologic surgery and describe patient perspectives before and after implementation for those undergoing laparotomy for ovarian cancer. METHODS: Patients undergoing gynecologic surgery between October 2017 and May 2018 were prescribed opioids at discharge using tiered guidelines; prescriptions were compared to consecutive historical controls (March 2017-October 2017). A subset of ovarian cancer laparotomy patients were surveyed regarding postoperative opioid consumption and patient experience. RESULTS: A total of 620 women in the tiered guideline cohort were compared with 599 historical controls. Following implementation, 95.8% of prescriptions met guidelines. Median milligram morphine equivalents (MME) prescribed decreased from 150 to 75 (p ≤ 0.001) with no change in opioid refills (7.7 vs 6.9%, p = 0.62). In surveyed ovarian cancer patients, 100% of tiered guideline patients and 92% of historical controls felt satisfied with pain control (p = 0.24), despite a 50% reduction in prescribed MME and 14.6% receiving no opioids at discharge (p = 0.002). The median (IQR) MME consumed after discharge was 15 (0, 75) in tiered guideline patients vs. 24 (0, 135) in historical controls, and 38.2% and 42.4% consumed no opioids, respectively. Mean time between surgery and opioid use cessation was <1 week in both groups; patients' perceptions of opioid prescription appropriateness did not change (p = 0.49). More than 75% of patients kept their remaining opioids rather than dispose of them. CONCLUSIONS: Reducing prescribed opioids after gynecologic surgery using tiered guidelines did not increase opioid refills or worsen patients' perceptions of postoperative pain. Even after laparotomy, very little opioids were required over a short duration after dismissal. Infrequent disposal of leftover opioids highlights the need to avoid over-prescribing.

Use of bowel preparation does not reduce postoperative infectious morbidity following minimally invasive or open hysterectomies.

BACKGROUND: Literature on the use of bowel preparation in gynecologic surgery is scarce and limited to minimally invasive gynecologic surgery. The decision on the use of bowel preparation before benign or malignant hysterectomies is mostly driven by extrapolating data from the colorectal literature. OBJECTIVE: Bowel preparation is a controversial element within enhanced recovery protocols, and literature investigating its efficacy in gynecologic surgery is scarce. Our aim was to determine if mechanical bowel preparation alone, oral antibiotics alone, or a combination are associated with decreased rates of surgical site infections or anastomotic leaks compared to no bowel preparation following benign or malignant hysterectomy. STUDY DESIGN: We identified women who underwent hysterectomy between January 2006 and July 2017 using OptumLabs, a large US commercial health plan database. Inverse propensity score weighting was used separately for benign and malignant groups to balance baseline characteristics. Primary outcomes of 30-day surgical site infection, anastomotic leaks, and major morbidity were assessed using multivariate logistic regression that adjusted for race, census region, household income, diabetes, and other unbalanced variables following propensity score weighting. RESULTS: A total of 224,687 hysterectomies (benign, 186,148; malignant, 38,539) were identified. Median age was 45 years for the benign and 54 years for the malignant cohort. Surgical approach was as follows: benign: laparoscopic/robotic, 27.2%; laparotomy, 32.6%; vaginal, 40.2%; malignant: laparoscopic/robotic, 28.8%; laparotomy, 47.7%; vaginal, 23.5%. Bowel resection was performed in 0.4% of the benign and 2.8% of the malignant cohort. Type of bowel preparation was as follows: benign: none, 93.8%; mechanical bowel preparation only, 4.6%; oral antibiotics only, 1.1%; mechanical bowel preparation with oral antibiotics, 0.5%; malignant: none, 87.2%; mechanical bowel preparation only, 9.6%; oral antibiotics only, 1.8%; mechanical bowel preparation with oral antibiotics, 1.4%. Use of bowel preparation did not decrease rates of surgical site infections, anastomotic leaks, or major morbidity following benign or malignant hysterectomy. Among malignant abdominal hysterectomies, there was no difference in the rates of infectious morbidity between mechanical bowel preparation alone, oral antibiotics alone, or mechanical bowel preparation with oral antibiotics, compared to no preparation. CONCLUSION: Bowel preparation does not protect against surgical site infections or major morbidity following benign or malignant hysterectomy, regardless of surgical approach, and may be safely omitted.

Therapeutic targeting of PFKFB3 with a novel glycolytic inhibitor PFK158 promotes lipophagy and chemosensitivity in gynecologic cancers.

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 PFKFB3ser461 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.

Guidelines for perioperative care in gynecologic/oncology: Enhanced Recovery After Surgery (ERAS) Society recommendations-2019 update.

BACKGROUND: This is the first updated Enhanced Recovery After Surgery (ERAS) Society guideline presenting a consensus for optimal perioperative care in gynecologic/oncology surgery. METHODS: A 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. RESULTS: All recommendations on ERAS protocol items are based on best available evidence. The level of evidence for each item is presented accordingly. CONCLUSIONS: The 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.

Enhanced Recovery after Minimally Invasive Gynecologic Procedures with Bowel Surgery: A Systematic Review.

Enhanced recovery after surgery (ERAS) is an evidence-based approach to perioperative care of the surgical patient. A mounting body of literature in gynecologic surgery has demonstrated that ERAS improves postoperative outcomes, shortens hospital length of stay, and reduces cost without increasing complications or readmissions. Most of the existing literature has concentrated on open surgery, questioning if patients undergoing minimally invasive surgery also derive benefit. Our aim was to systematically review the literature on ERAS after minimally invasive gynecologic surgery (MIGS) with and without bowel surgery. Given the paucity of studies on ERAS in MIGS with bowel surgery (1 study), we expanded our search to include studies of ERAS in patients undergoing minimally invasive colorectal resections alone. Twelve studies were identified through an electronic database search of PubMed, Medline, and Ovid EMBASE. These studies included patients undergoing MIGS for benign and/or malignant indications and showed that ERAS pathways decreased length of stay and/or increased the proportion of same-day discharge surgeries, improved patient satisfaction, and reduced hospital costs while maintaining low postoperative complication and readmission rates. Although limited, data from a single study suggest that ERAS in MIGS with bowel surgery leads to shortened hospital stay, stable postoperative morbidity, and less readmissions. Although the variation between the published protocols underscores the need for standardization, existing literature supports the adoption of ERAS as safe and effective when planning MIGS.

Enhanced Recovery After Surgery and Acute Postoperative Pain Management.

Enhanced recovery pathways were first developed in colorectal surgery and have since been adapted to other surgical subspecialties including gynecologic surgery. Mounting evidence has shown that the adoption of a standardized perioperative pathway based on evidence-based literature reduces length of hospital stay, reduces cost, reduces opioid requirements with stable to improved pain scores, and accelerates return to normal function as measured by validated patient reported outcomes measurements. The many elements of enhanced recovery may be distilled into 3 concepts: (1) optimizing nutrition before and after surgery, recognizing that nutritional status directly impacts healing; (2) opioid-sparing analgesia, considering the current American prescription opioid crisis and the importance of pain control to regaining functional recovery; and (3) maintenance of euvolemia before, during, and after surgery. Evidence supporting enhanced recovery is presented with reference to international guidelines which were formed based on systematic reviews. Change management and the use of auditing are discussed to assure that patients derive the greatest improvement in surgical outcomes from implementation of an enhanced recovery pathway.

Surgical technical evidence review for gynecologic surgery conducted for the Agency for Healthcare Research and Quality Safety Program for Improving Surgical Care and Recovery.

BACKGROUND: The Agency for Healthcare Research and Quality, in partnership with the American College of Surgeons and the Armstrong Institute at Johns Hopkins, developed the Safety Program for Improving Surgical Care and Recovery, which integrates principles of implementation science into adoption of enhanced recovery pathways and promotes evidence-based perioperative care. OBJECTIVE: The objective of this study is to review the enhanced recovery pathways literature in gynecologic surgery and provide the framework for an Improving Surgical Care and Recovery pathway for gynecologic surgery. STUDY DESIGN: We searched PubMed and Cochrane Central Register of Controlled Trials databases from 1990 through October 2017. Studies were included in hierarchical and chronological order: meta-analyses, systematic reviews, randomized controlled trials, and interventional and observational studies. Enhanced recovery pathways components relevant to gynecologic surgery were identified through review of existing pathways. A PubMed search for each component was performed in gynecologic surgery and expanded to include colorectal surgery as needed to have sufficient evidence to support or deter a process. This review focuses on surgical components; anesthesiology components are reported separately in a companion article in the anesthesiology literature. RESULTS: Fifteen surgical components were identified: patient education, bowel preparation, elimination of nasogastric tubes, minimization of surgical drains, early postoperative mobilization, early postoperative feeding, early intravenous fluid discontinuation, early removal of urinary catheters, use of laxatives, chewing gum, peripheral mu antagonists, surgical site infection reduction bundle, glucose management, and preoperative and postoperative venous thromboembolism prophylaxis. In addition, 14 components previously identified in the colorectal Improving Surgical Care and Recovery pathway review were included in the final pathway. CONCLUSION: Evidence and existing guidelines support 29 protocol elements for the Agency for Healthcare Research and Quality Safety Program for Improving Surgical Care and Recovery in gynecologic surgery.

Patterns of Lymph Node Metastases in Apparent Stage I Low-Grade Epithelial Ovarian Cancer: A Multicenter Study.

OBJECTIVE: The aim of this study was to determine oncological outcomes and incidence of lymph node (LN) metastases in women who underwent systematic pelvic and paraaortic lymphadenectomy for surgical staging of apparent stage I low-grade epithelial ovarian cancer (LGEOC). MATERIALS AND METHODS: A retrospective study was performed at nine institutions across Europe and the US, and patients who underwent surgical staging for presumed stage I LGEOC between 2000 and 2016 were included. To ensure surgical quality, a minimum number of ≥10 pelvic and ≥10 paraaortic LNs was required. Patients with preoperative radiologic or clinical evidence of extraovarian or LN disease, and those with nonepithelial histology, were excluded. RESULTS: The overall incidence of LN metastases was 4.3% in the 163 evaluated patients, and the incidence of LN involvement in serous, endometrioid, and mucinous subtypes was 10.7, 1.5, and 0%, respectively. However, Upstaging due to LN involvement alone occurred in only 2.4% of the patients. Eighty-nine (54.6%) patients received adjuvant chemotherapy due to International Federation of Gynecology and Obstetrics stage IC or higher disease. The 5-year progression-free survival (PFS) and overall survival (OS) were 93.2% (95% confidence interval [CI] 89.4-97.1%) and 94.5% (95% CI 90.9-98.0%), respectively. There was no significant difference in PFS or OS between LN-negative and LN-positive patients. However, fewer patients received adjuvant chemotherapy in the LN-negative group. Multivariate analysis did not identify any independent prognostic factor of survival. CONCLUSION: The risk of LN involvement in nonserous apparent stage I LGEOC appears low, with a rate of <1% in this retrospective analysis, raising questions about the value of lymphadenectomy in those patients. Larger-scale prospective studies are warranted to evaluate the oncologic safety of omitting systematic LN staging in apparent stage I nonserous LGEOC.

Quinacrine in endometrial cancer: Repurposing an old antimalarial drug.

OBJECTIVE: Generate preclinical data on the effect of quinacrine (QC) in inhibiting tumorigenesis in endometrial cancer (EC) in vitro and explore its role as an adjunct to standard chemotherapy in an EC mouse model. METHODS: Five different EC cell lines (Ishikawa, Hec-1B, KLE, ARK-2, and SPEC-2) representing different histologies, grades of EC, sensitivity to cisplatin and p53 status were used for the in vitro studies. MTT and colony formation assays were used to examine QC's ability to inhibit cell viability in vitro. The Chou-Talalay methodology was used to examine synergism between QC and cisplatin, carboplatin or paclitaxel. A cisplatin-resistant EC subcutaneous mouse model (Hec-1B) was used to examine QC's role as maintenance therapy. RESULTS: QC exhibited strong synergism in vitro when combined with cisplatin, carboplatin or paclitaxel with the highest level of synergism in the most chemo-resistant cell line. Neither QC monotherapy nor carboplatin/paclitaxel significantly delayed tumor growth in xenografts. Combination treatment (QC plus carboplatin/paclitaxel) significantly augmented the antiproliferative ability of these agents and was associated with a 14-week survival prolongation compared to carboplatin/paclitaxel. Maintenance with QC resulted in further delay in tumor progression and survival prolongation compared to carboplatin/paclitaxel. QC was not associated with weight loss and the yellow skin discoloration noted during treatment was reversible upon discontinuation. CONCLUSIONS: QC exhibited significant antitumor activity against EC in vitro and was successful as maintenance therapy in chemo-resistant EC mouse xenografts. This preclinical data suggest that QC may be an important adjunct to standard chemotherapy for patients with chemo-resistant EC.

Enhanced recovery pathways in gynecologic oncology.

OBJECTIVE: Many commonplace perioperative practices are lacking in scientific evidence and may interfere with the goal of optimizing patient recovery. Individual components of perioperative care have therefore been scrutinized, resulting in the creation of so-called "enhanced recovery" pathways (ERP), with the goal of hastening surgical recovery through attenuation of the stress response. In this review we examine the evidence for ERP in gynecologic oncology using data from our specialty and general surgery. METHODS: We performed a systematic literature search on ERP in gynecologic oncology in June 2014 using PubMed/MEDLINE, EMBASE, and The Cochrane Library. All study types were included. References were hand reviewed to ensure completeness. The Enhanced Recovery After Surgery (ERAS) Society was contacted to identify any unpublished protocols. RESULTS: Seven investigations were identified that examined the role of ERP in gynecologic oncology. Common interventions included allowing oral intake of fluids up to 2 hours before induction of anesthesia, solids up to 6 hours before anesthesia, carbohydrate supplementation, intra- and postoperative euvolemia, aggressive nausea/vomiting prophylaxis, and oral nutrition and ambulation the day of surgery. In addition, bowel preparations, the NPO after midnight rule, nasogastric tubes, and intravenous opioids were discontinued. While no randomized data are available in gynecologic oncology, significant improvements in patient satisfaction, length of stay (up to 4 days), and cost (up to $7600 in savings per patient) were observed in ERP cohorts compared to historical controls. Morbidity, mortality, and readmission rates were no different between groups. CONCLUSION: Enhanced recovery is a safe perioperative management strategy for patients undergoing surgery for gynecologic malignancies, reduces length of stay and cost, and is considered standard of care at a growing number of institutions. Our specialty would benefit from a formalized ERP such as ERAS which audits compliance to protocol care elements to optimize patient outcomes and value.

A Phase I Trial of Nab-Paclitaxel/Bevacizumab (AB160) Nano-Immunoconjugate Therapy for Gynecologic Malignancies.

PURPOSE: AB160 is a 160-nm nano-immunoconjugate consisting of nab-paclitaxel (ABX) nanoparticles noncovalently coated with bevacizumab (BEV) for targeted delivery into tissues expressing high levels of VEGF. Preclinical data showed that AB160 resulted in greater tumor targeting and tumor inhibition compared with sequential treatment with ABX then BEV. Given individual drug activity, we investigated the safety and toxicity of AB160 in patients with gynecologic cancers. PATIENTS AND METHODS: A 3+3 phase I trial was conducted with three potential dose levels in patients with previously treated endometrial, cervical, and platinum-resistant ovarian cancer to ascertain the recommended phase II dose (RP2D). AB160 was administered intravenously on days 1, 8, and 15 of a 28-day cycle (ABX 75-175 mg/m2, BEV 30-70 mg/m2). Pharmacokinetic analyses were performed. RESULTS: No dose-limiting toxicities (DLT) were seen among the three dose levels tested. Grade 3/4 toxicities included neutropenia, thromboembolic events, and leukopenia. DL2 (ABX 150 mg/m2, BEV 60 mg/m2) was chosen as the RP2D. Seven of the 19 patients with measurable disease (36.8%) had confirmed partial responses (95% confidence interval, 16.3%-61.6%). Pharmacokinetic analyses demonstrated that AB160 allowed 50% higher paclitaxel dosing and that paclitaxel clearance mirrored that of therapeutic antibodies. CONCLUSIONS: The safety profile and clinical activity of AB160 supports further clinical testing in patients with gynecologic cancers; the RP2D is DL2 (ABX 150 mg/m2, BEV 60 mg/m2).

Multiple large bowel resections: potential risk factor for anastomotic leak.

OBJECTIVES: Identify risk factors of anastomotic leak (AL) after large bowel resection (LBR) for ovarian cancer (OC) and compare outcomes between AL and no AL. METHODS: All cases of AL after LBR for OC between 01/01/1994 and 05/20/2011 were identified and matched 1:2 with controls for age (±5 years), sub-stage (IIIA/IIIB; IIIC; IV), and date of surgery (±4 years). Patient-specific and intraoperative risk factors, use of protective stomas, and outcomes were abstracted. A stratified conditional logistic regression model was fit to determine the association between each factor and AL. RESULTS: 42 AL cases were evaluable and matched with 84 controls. Two-thirds of the AL had stage IIIC disease and >90% of both cases and controls were cytoreduced to <1cm residual disease. No patient-specific risk factors were associated with AL (pre-operative albumin was not available for most patients). Rectosigmoid resection coupled with additional LBR was associated with AL (OR=2.73, 95% CI 1.13-6.59, P=0.025), and protective stomas were associated with decreased risk of AL (0% vs. 10.7%, P=0.024). AL patients had longer length of stay (P<0.001), were less likely to start chemotherapy (P=0.020), and had longer time to chemotherapy (P=0.007). Cases tended to have higher 90-day mortality (P=0.061) and were more likely to have poorer overall survival (HR=2.05, 95% CI 1.18-3.57, P=0.011). CONCLUSIONS: Multiple LBRs appear to be associated with increased risk of AL and protective stomas with decreased risk. Since AL after OC cytoreduction significantly delays chemotherapy and negatively impacts survival, surgeons should strongly consider temporary diversion in selected patients (poor nutritional status, multiple LBRs, previous pelvic radiation, very low anterior resection, steroid use).

HE4 transcription- and splice variants-specific expression in endometrial cancer and correlation with patient survival.

We investigated the HE4 variant-specific expression patterns in various normal tissues as well as in normal and malignant endometrial tissues. The relationships between mRNA variants and age, body weight, or survival are analyzed. ICAT-labeled normal and endometrial cancer (EC) tissues were analyzed with multidimensional liquid chromatography followed by tandem mass spectrometry. Levels of HE4 mRNA variants were measured by real-time PCR. Mean mRNA levels were compared among 16 normal endometrial samples, 14 grade 1 and 14 grade 3 endometrioid EC, 15 papillary serous EC, and 14 normal human tissue samples. The relationship between levels of HE4 variants and EC patient characteristics was analyzed with the use of Pearson correlation test. We found that, although all five HE4 mRNA variants are detectable in normal tissue samples, their expression is highly tissue-specific, with epididymis, trachea, breast and endometrium containing the highest levels. HE4-V0, -V1, and -V3 are the most abundant variants in both normal and malignant tissues. All variants are significantly increased in both endometrioid and papillary serous EC, with higher levels observed in grade 3 endometrioid EC. In the EC group, HE4-V1, -V3, and -V4 levels inversely correlate with EC patient survival, whereas HE4-V0 levels positively correlate with age. HE4 variants exhibit tissue-specific expression, suggesting that each variant may exert distinct functions in normal and malignant cells. HE4 levels appear to correlate with EC patient survival in a variant-specific manner. When using HE4 as a biomarker for EC management, the effects of age should be considered.

Utility of closed suction pelvic drains at time of large bowel resection for ovarian cancer.

OBJECTIVE: To test the hypothesis that the use of closed suction pelvic drains placed at time of large bowel resection (LBR) for ovarian cancer (OC) decreases morbidity following anastomotic leak (AL). METHODS: Consecutive cases of LBR for OC between 01/01/1994 and 06/20/2011 were retrospectively identified. Drains were routinely used until bowel movement. AL was defined as: 1) feculent fluid from drains/wound/vagina, 2) radiographic evidence of AL, or 3) AL found at reoperation. Descriptive statistics, Wilcoxon rank-sum, Pearson's chi-square and Fisher's exact test were used. RESULTS: 43 cases met inclusion criteria. AL was characterized by method of diagnosis as follows: change in drain output only (DO, n=8); change in drain output associated with ambiguous clinical signs/symptoms (D-SSX, n=11); or clinical signs/symptoms only (SSX, n=24). The sensitivity of drains in diagnosing AL was 50%. Time to diagnosis was earlier in DO/D-SSX (median 7 vs. 11 days, P=0.003), however, no significant differences were observed in rates of reoperation, length of stay, time to chemotherapy (TTC), and 30- and 90-day mortality between DO/D-SSX and SSX. Comparing cases where no drains were placed (n=5) vs. those with drain (n=38), we observed no differences in outcomes. TTC though statistically significant (47 vs. 59 days, P=0.023) was not clinically significant. CONCLUSIONS: Though a change in drain output correlated with earlier diagnosis, this did not appear to impact overall outcomes. We did not find strong evidence supporting routine prolonged drainage after LBR for OC. Additionally, absence of change in drain output does not rule out presence of AL.

Correlation of serum HE4 with tumor size and myometrial invasion in endometrial cancer.

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 types 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) (>2 cm, P=0.002). Low risk patients (type I, MI ≤ 50% and PTD ≤ 2 cm) 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.

Safety of culdotomy as a surgical approach: implications for natural orifice transluminal endoscopic surgery.

OBJECTIVE: To evaluate the efficacy and safety of culdotomy as a surgical approach to access the peritoneal cavity and discuss its implications for natural orifice transluminal endoscopic surgery (NOTES). METHODS: A retrospective chart review of women undergoing culdotomy for tubal sterilization (N 219) between January 1995 and December 2005 was performed. The Accordion Grading System was used for the severity of complications. RESULTS: No intraoperative complications were noted. Postoperative complications occurred in 7 patients (3.2%): 6 infections (grade 2) and 1 case of hemorrhage (grade 3). Conversion to laparoscopy was necessary in 10 patients (2.2%) due to anatomical constraints or pelvic adhesions; however, culdotomy with entry into the abdominal cavity was nevertheless successful in all 10 cases. The difference in the proportion with a history of pelvic surgery between the conversion and nonconversion groups was not statistically significant (P = .068). Patients with BMI ≥30 had a higher conversion rate compared to patients with BMI <30 (11.4% versus 1.5%, P = .011). Tubal sterilization via culdotomy was successfully performed in all 11 women with no prior vaginal deliveries. CONCLUSION: Culdotomy appears to be a safe surgical approach to access the peritoneal cavity and is associated with a low complication rate. These data support the feasibility and safety of utilizing the cul-de-sac as an access portal for natural orifice transluminal endoscopic surgery.

Impact of enhanced recovery implementation in women undergoing abdominal sacrocolpopexy.

OBJECTIVE: To assess the effect of Enhanced Recovery After Surgery (ERAS) with and without liposomal bupivacaine (LB) on opioid use, hospital length of stay (LOS), costs, and morbidity of women undergoing sacrocolpopexy. METHODS: Retrospective cohort of women who underwent abdominal sacrocolpopexy between April 1, 2009 and November 30, 2017. Costs for relevant healthcare services were determined by assigning 2017 charges multiplied by 2017 Medicare Cost Report's cost to charge ratios. Outcomes were compared among periods with multivariable regression models adjusted for age, American Society of Anesthesiologists score, and concurrent hysterectomy and posterior repair. RESULTS: Patients were subdivided into pre-ERAS (G1, n = 128), post-ERAS (G2, n = 83), and post-ERAS plus LB (G3, n = 91). The proportion of patients needing opioids during postoperative days 0-2 was significantly less for G3 (75.8%) compared with G1 (97.7%) and G2 (92.8%); P < 0.001). The median morphine equivalent units (MEU) with interquartile ranges, mean LOS, and adjusted mean standardized costs were significantly lower in G3 compared with the other two groups (35 [20-75] vs. 67 [31-109], and 60 [30-122] MEUs; 1.8 vs. 2.3 vs. 2.9 days; and $2391, $2975, and $3844, for G3, G2, and G1, respectively; P < 0.001). CONCLUSION: Implementation of an ERAS pathway led to significant decreases in opioid use, LOS, and costs. Supplementation with LB further improved these measures.

Inhibition of PFKFB3 induces cell death and synergistically enhances chemosensitivity in endometrial cancer.

The advanced or recurrent endometrial cancer (EC) has a poor prognosis because of chemoresistance. 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a glycolytic enzyme, is overexpressed in a variety of human cancers and plays important roles in promoting tumor cell growth. Here, we showed that high expression of PFKFB3 in EC cell lines is associated with chemoresistance. Pharmacological inhibition of PFKFB3 with PFK158 and or genetic downregulation of PFKFB3 dramatically suppressed cell proliferation and enhanced the sensitivity of EC cells to carboplatin (CBPt) and cisplatin (Cis). Moreover, PFKFB3 inhibition resulted in reduced glucose uptake, ATP production, and lactate release. Notably, we found that PFK158 with CBPt or Cis exerted strong synergistic antitumor activity in chemoresistant EC cell lines, HEC-1B and ARK-2 cells. We also found that the combination of PFK158 and CBPt/Cis induced apoptosis- and autophagy-mediated cell death through inhibition of the Akt/mTOR signaling pathway. Mechanistically, we found that PFK158 downregulated the CBPt/Cis-induced upregulation of RAD51 expression and enhanced CBPt/Cis-induced DNA damage as demonstrated by an increase in γ-H2AX levels in HEC-1B and ARK-2 cells, potentially revealing a means to enhance PFK158-induced chemosensitivity. More importantly, PFK158 treatment, either as monotherapy or in combination with CBPt, led to a marked reduction in tumor growth in two chemoresistant EC mouse xenograft models. These data suggest that PFKFB3 inhibition alone or in combination with standard chemotherapy may be used as a novel therapeutic strategy for improved therapeutic efficacy and outcomes of advanced and recurrent EC patients.