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).

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.

Group III phospholipase A2 downregulation attenuated survival and metastasis in ovarian cancer and promotes chemo-sensitization.

BACKGROUND: Aberrant lipogenicity and deregulated autophagy are common in most advanced human cancer and therapeutic strategies to exploit these pathways are currently under consideration. Group III Phospholipase A2 (sPLA2-III/PLA2G3), an atypical secretory PLA2, is recognized as a regulator of lipid metabolism associated with oncogenesis. Though recent studies reveal that high PLA2G3 expression significantly correlates with poor prognosis in several cancers, however, role of PLA2G3 in ovarian cancer (OC) pathogenesis is still undetermined. METHODS: CRISPR-Cas9 and shRNA mediated knockout and knockdown of PLA2G3 in OC cells were used to evaluate lipid droplet (LD) biogenesis by confocal and Transmission electron microscopy analysis, and the cell viability and sensitization of the cells to platinum-mediated cytotoxicity by MTT assay. Regulation of primary ciliation by PLA2G3 downregulation both genetically and by metabolic inhibitor PFK-158 induced autophagy was assessed by immunofluorescence-based confocal analysis and immunoblot. Transient transfection with GFP-RFP-LC3B and confocal analysis was used to assess the autophagic flux in OC cells. PLA2G3 knockout OVCAR5 xenograft in combination with carboplatin on tumor growth and metastasis was assessed in vivo. Efficacy of PFK158 alone and with platinum drugs was determined in patient-derived primary ascites cultures expressing PLA2G3 by MTT assay and immunoblot analysis. RESULTS: Downregulation of PLA2G3 in OVCAR8 and 5 cells inhibited LD biogenesis, decreased growth and sensitized cells to platinum drug mediated cytotoxicity in vitro and in in vivo OVCAR5 xenograft. PLA2G3 knockdown in HeyA8MDR-resistant cells showed sensitivity to carboplatin treatment. We found that both PFK158 inhibitor-mediated and genetic downregulation of PLA2G3 resulted in increased number of percent ciliated cells and inhibited cancer progression. Mechanistically, we found that PFK158-induced autophagy targeted PLA2G3 to restore primary cilia in OC cells. Of clinical relevance, PFK158 also induces percent ciliated cells in human-derived primary ascites cells and reduces cell viability with sensitization to chemotherapy. CONCLUSIONS: Taken together, our study for the first time emphasizes the role of PLA2G3 in regulating the OC metastasis. This study further suggests the therapeutic potential of targeting phospholipases and/or restoration of PC for future OC treatment and the critical role of PLA2G3 in regulating ciliary function by coordinating interface between lipogenesis and metastasis.

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.

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.

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.

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.

Optimizing Preanesthesia Care for the Gynecologic Patient.

In the past, best practices for perioperative management have been based as much on dogma as science. The creation of optimized perioperative pathways, known as enhanced recovery after surgery, has been shown to simultaneously improve patient outcomes and reduce cost. In this article, we critically review interventions (and omission of interventions) that should be considered by every surgical team to optimize preanesthesia care. This includes patient education, properly managing existing medical comorbidities, optimizing nutrition, and the use of medications before incision that have been shown to reduce surgical stress, opioid requirements, and postoperative complications. Anesthetic techniques, the use of adjunct medications administered after incision, and postoperative management are beyond the scope of this review. When possible, we have relied on randomized trials, meta-analyses, and systematic reviews to support our recommendations. In some instances, we have drawn from the general and colorectal surgery literature if evidence in gynecologic surgery is limited or of poor quality. In particular, hospital systems should aim to adhere to antibiotic and thromboembolic prophylaxis for 100% of patients, the mantra, "nil by mouth after midnight" should be abandoned in favor of adopting a preoperative diet that maintains euvolemia and energy stores to optimize healing, and bowel preparation should be abandoned for patients undergoing gynecologic surgery for benign indications and minimally invasive gynecologic surgery.

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.

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.

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.

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.

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

Enhanced Recovery After Surgery (ERAS) is now firmly established as a global surgical quality improvement initiative that results in both clinical improvements1 and cost benefits to the healthcare system.2 ERAS guidelines are based on the highest quality evidence available and as such require updating on a regular basis.3 The ERAS Gynecologic/Oncology guidelines4 5 were first published in February 2016. This article represents the joint efforts of the ERAS® Society (www.erassociety.org) and authors from the international ERAS Gynecology chapters to present an updated consensus review of perioperative care for gynecologic/oncology surgery based on best current evidence.

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.

Quinacrine upregulates p21/p27 independent of p53 through autophagy-mediated downregulation of p62-Skp2 axis in ovarian cancer.

We have previously shown that the anti-malarial compound Quinacrine (QC) inhibits ovarian cancer (OC) growth by modulating autophagy. In the present study we extended these studies to identify the molecular pathways regulated by QC to promote apoptosis independent of p53 status in OC. QC exhibited strong anti-cancer properties in OC cell lines in contrast to other anti-malarial autophagy inhibiting drugs. QC treatment selectively upregulated cell cycle inhibitor p21, and downregulated F box protein Skp2 and p62/SQSTM1 expression independent of p53 status. Genetic downregulation of key autophagy protein ATG5 abolished QC-mediated effects on both cell cycle protein p21/Skp2 as well as autophagic cargo protein p62. Furthermore, genetic silencing of p62/SQSTM1 resulted in increased sensitivity to QC-mediated apoptosis, downregulated Skp2 mRNA and increased accumulation of p21 expression. Likewise, genetic knockdown of Skp2 resulted in the upregulation of p21 and p27 and increased sensitivity of OC cells to QC treatment. In contrast, transient overexpression of exogenous p62-HA plasmid rescued the QC-mediated Skp2 downregulation indicating the positive regulation of Skp2 by p62. Collectively, these data indicate that QC-mediated effects on cell cycle proteins p21/Skp2is autophagy-dependent and p53-independent in high grade serious OC cells.

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.

Loss of HSulf-1: The Missing Link between Autophagy and Lipid Droplets in Ovarian Cancer.

Defective autophagy and deranged metabolic pathways are common in cancer; pharmacologic targeting of these two pathways could provide a viable therapeutic option. However, how these pathways are regulated by limited availability of growth factors is still unknown. Our study shows that HSulf-1 (endosulfatase), a known tumor suppressor which attenuates heparin sulfate binding growth factor signaling, also regulates interplay between autophagy and lipogenesis. Silencing of HSulf-1 in OV202 and TOV2223 cells (ovarian cancer cell lines) resulted in increased lipid droplets (LDs), reduced autophagic vacuoles (AVs) and less LC3B puncta. In contrast, HSulf-1 proficient cells exhibit more AVs and reduced LDs. Increased LDs in HSulf-1 depleted cells was associated with increased ERK mediated cPLA2S505 phosphorylation. Conversely, HSulf-1 expression in SKOV3 cells reduced the number of LDs and increased the number of AVs compared to vector controls. Furthermore, pharmacological (AACOCF3) and ShRNA mediated downregulation of cPLA2 resulted in reduced LDs, and increased autophagy. Finally, in vivo experiment using OV202 Sh1 derived xenograft show that AACOCF3 treatment effectively attenuated tumor growth and LD biogenesis. Collectively, these results show a reciprocal regulation of autophagy and lipid biogenesis by HSulf-1 in ovarian cancer.