Secondary cytoreductive surgery and oncologic outcomes in the era of targeted maintenance therapy for recurrent, platinum-sensitive ovarian cancer.

OBJECTIVES: To compare oncologic outcomes of secondary cytoreductive surgery (SCS) before and after FDA approval of Poly(ADP-ribose) polymerase inhibitor (PARPi) and bevacizumab maintenance therapies for platinum-sensitive recurrent ovarian cancer (PS-ROC). METHODS: Patients who underwent SCS for first recurrence of PS-ROC from 1/1/2013-1/1/2020 were identified. Exclusion criteria included prior chemotherapy for recurrence, bowel obstruction procedures, and palliative surgery. Data were dichotomized pre/post 1/2017, relative to FDA approval of PARPi and bevacizumab maintenance for ROC. Second progression-free survival (PFS2), the primary endpoint, was estimated using Kaplan-Meier method. RESULTS: Overall, 245 patients underwent SCS-131 (53%) pre- and 114 (47%) post-approval. Most patients had high-grade serous tumors (83% and 90%, respectively; p = 0.13). Deleterious BRCA1/2 alterations were identified in 27% (32/120) and 28% (32/113) of tested patients, respectively (p = 0.88). Disease-free intervals pre- and post-approval were: 6-12 months, 16% and 18%; 12-30 months, 56% and 59%; and >30 months, 28% and 24%, respectively (p = 0.73). Overall, 85% and 86% of patients, respectively, achieved complete gross resection (CGR; p > 0.99). PARPi maintenance use increased from 3.8% to 27% (p < 0.001) following approval, and bevacizumab from 1.5% to 12% (p < 0.001). Median PFS2 was 19 and 20.1 months, respectively. In the post group, 1-year PFS2 rate was 84.5% (95% CI, 75.7-90.4%) for patients with CGR vs 56.2% (95% CI, 29.5-76.2%) for those with residual disease; 3-year PFS2 rates were 31.3% (95% CI, 21.6-41.4%) and 12.5% (95% CI, 2.1-32.8%), respectively (p = 0.001). CONCLUSIONS: CGR during SCS is associated with improved PFS2 compared to suboptimal resection. Prospective randomized trials are warranted to elucidate the role of SCS as more therapeutics become available.

Safety and feasibility of therapeutic anticoagulation for newly diagnosed venous thromboembolism in women who undergo neoadjuvant chemotherapy for advanced ovarian cancer.

OBJECTIVE: We sought to investigate the safety and feasibility of therapeutic anticoagulation for newly diagnosed venous thromboembolism among women who undergo neoadjuvant chemotherapy for the treatment of advanced ovarian cancer. METHODS: A retrospective study using data extrapolated from a prospectively maintained institutional database was used to identify all patients with ovarian cancer who underwent neoadjuvant chemotherapy from April 2015 through September 2018 at our institution. All patients who received therapeutic anticoagulation for newly diagnosed venous thromboembolism at initial diagnosis or during neoadjuvant chemotherapy were included. RESULTS: Of 290 patients who underwent neoadjuvant chemotherapy for advanced ovarian cancer during the study period, 67 (23%) had newly diagnosed venous thromboembolism at the time of initial diagnosis or developed venous thromboembolism during neoadjuvant chemotherapy. Of these 67 patients, 64 (96%) received therapeutic anticoagulation. A total of 13 (20%) of 64 patients who underwent therapeutic anticoagulation experienced a bleeding episode while on anticoagulation; 4 (31%) of the 13 events were of major severity. Three patients developed major internal bleeding in the peritoneal cavity, and one patient suffered from a major vaginal bleeding episode. All four patients were hospitalized (range, 5-11 days) and received ≥2 units of red blood cells for anemia. None of these patients died from fatal bleeding or had to delay starting chemotherapy. Of note, all four patients received low-molecular-weight heparin via subcutaneous injection. Overall, 13 (20%) of 64 patients required an anticoagulant dose reduction, mostly due to weight loss or new bleeding episodes. CONCLUSION: Therapeutic anticoagulation in this setting appeared safe, with a low risk of major bleeding complications. Furthermore, anticoagulation did not result in delay of chemotherapy or cytoreductive surgery.

Feasibility and safety of planned early discharge following laparotomy in gynecologic oncology with enhanced recovery protocol including opioid-sparing anesthesia.

Objective: This study aims to evaluate the feasibility and safety of planned postoperative day 1 discharge (PPOD1) among patients who undergo laparotomy (XL) in the department of gynecology oncology utilizing a modified enhanced recovery after surgery (ERAS) protocol including opioid-sparing anesthesia (OSA) and defined discharge criteria. Methods: Patients undergoing XL and minimally invasive surgery (MIS) were enrolled in this prospective, observational cohort study after the departmental implementation of a modified ERAS protocol. The primary outcome was quality of life (QoL) using SF36, PROMIS GI, and ICIQ-FLUTS at baseline and 2- and 6-week postoperative visits. Statistical significance was assessed using the two-tailed Student's t-test and non-parametric Mann-Whitney two-sample test. Results: Of the 141 subjects, no significant demographic differences were observed between the XL group and the MIS group. The majority of subjects, 84.7% (61), in the XL group had gynecologic malignancy [vs. MIS group; 21 (29.2%), p < 0.001]. All patients tolerated OSA. The XL group required higher intraoperative opioids [7.1 ± 9.2 morphine milligram equivalents (MME) vs. 3.9 ± 6.9 MME, p = 0.02] and longer surgical time (114.2 ± 41 min vs. 96.8 ± 32.1 min, p = 0.006). No significant difference was noted in the opioid requirements at the immediate postoperative phase and the rest of the postoperative day (POD) 0 or POD 1. In the XL group, 69 patients (73.6%) were successfully discharged home on POD1. There was no increase in the PROMIS score at 2 and 6 weeks compared to the preoperative phase. The readmission rates within 30 days after surgery (XL 4.2% vs. MIS 1.4%, p = 0.62), rates of surgical site infection (XL 0% vs. MIS 2.8%, p = 0.24), and mean number of post-discharge phone calls (0 vs. 0, p = 0.41) were comparable between the two groups. Although QoL scores were significantly lower than baseline in four of the nine QoL domains at 2 weeks post-laparotomy, all except physical health recovered by the 6-week time point. Conclusions: PPOD1 is a safe and feasible strategy for XL performed in the gynecologic oncology department. PPOD1 did not increase opioid requirements, readmission rates compared to MIS, and patient-reported constipation and nausea/vomiting compared to the preoperative phase.

Tumor lenvatinib addiction and withdrawal rebound response in patients with advanced endometrial cancer.

Combination therapy of lenvatinib, a multitargeted tyrosine kinase inhibitor (TKI), plus pembrolizumab, a monoclonal antibody targeting programmed death receptor 1 (PD-1), was recently approved by the Food and Drug Administration for therapy of advanced endometrial cancer. This case series highlights three patients with endometrial serous carcinoma who experienced disease stabilization or slow progression on lenvatinib plus pembrolizumab followed by rapid symptomatic growth of disease after lenvatinib discontinuation, and subsequent repeated response and symptom resolution after lenvatinib re-initiation. All patients died of disease complications 3 to 10 months after retreatment with lenvatinib. These observations highlight an important phenomenon of lenvatinib withdrawal rebound, likely driven by oncogenic signaling pathways upregulated in response to lenvatinib therapy. The findings of this case series represent a potential area for further research into the underlying mechanism for rebound and repeated response to lenvatinib, as well as strategies to mitigate disease flare related to lenvatinib withdrawal.

Immunological modifications following chemotherapy are associated with delayed recurrence of ovarian cancer.

Introduction: Ovarian cancer recurs in most High Grade Serous Ovarian Cancer (HGSOC) patients, including initial responders, after standard of care. To improve patient survival, we need to identify and understand the factors contributing to early or late recurrence and therapeutically target these mechanisms. We hypothesized that in HGSOC, the response to chemotherapy is associated with a specific gene expression signature determined by the tumor microenvironment. In this study, we sought to determine the differences in gene expression and the tumor immune microenvironment between patients who show early recurrence (within 6 months) compared to those who show late recurrence following chemotherapy. Methods: Paired tumor samples were obtained before and after Carboplatin and Taxol chemotherapy from 24 patients with HGSOC. Bioinformatic transcriptomic analysis was performed on the tumor samples to determine the gene expression signature associated with differences in recurrence pattern. Gene Ontology and Pathway analysis was performed using AdvaitaBio's iPathwayGuide software. Tumor immune cell fractions were imputed using CIBERSORTx. Results were compared between late recurrence and early recurrence patients, and between paired pre-chemotherapy and post-chemotherapy samples. Results: There was no statistically significant difference between early recurrence or late recurrence ovarian tumors pre-chemotherapy. However, chemotherapy induced significant immunological changes in tumors from late recurrence patients but had no impact on tumors from early recurrence patients. The key immunological change induced by chemotherapy in late recurrence patients was the reversal of pro-tumor immune signature. Discussion: We report for the first time, the association between immunological modifications in response to chemotherapy and the time of recurrence. Our findings provide novel opportunities to ultimately improve ovarian cancer patient survival.

Off-label use of paclitaxel and pembrolizumab in a case of platinum refractory epithelial ovarian cancer and extensive thromboembolism.

•Management of platinum refractory ovarian cancer is challenging.•Extensive venous thromboembolism precludes anti-angiogenic combination chemotherapy.•Weekly paclitaxel and immune-checkpoint inhibitor combination provides a durable tumor control option.

A Low-Cost Platform for Laparoscopic Simulation Training.

BACKGROUND: With the new requirement for Fundamentals of Laparoscopic Surgery certification among graduating obstetrics and gynecology residents, there has been an increased interest in simulation training. The Fundamentals of Laparoscopic Surgery curriculum uses a commercial laparoscopic box trainer to practice and assess laparoscopic skills. We created a low-cost, space-efficient, portable and versatile training platform that allows for the breakdown of complex tasks, and we studied its user acceptability. METHOD: A rectangular piece of pine wood purchased at a hardware store was used as a base; metal eye hooks were used as ports, and a blueprint was created to simulate placement of Fundamentals of Laparoscopic Surgery inserts. In addition to the Fundamentals of Laparoscopic Surgery skills, this platform can be used for any laparoscopic task (such as hysterectomy or cuff closure). Additionally, this platform can be used with or without a camera to allow for task breakdown into simpler components for faster learning. EXPERIENCE: A usability and acceptability survey was administered to a convenient sample of faculty and trainees. Trainees and faculty responded favorably to the model. Residents, fellows, and attendings felt that the laparoscopic platform closely simulated the feel of performing live laparoscopy surgery. CONCLUSION: This is a novel low-cost laparoscopic platform to add to the gynecologic surgical education simulation toolkit.

A Novel Porcine Stomach Tissue Model for Laparoscopic Colpotomy Simulation.

BACKGROUND: Hysterectomies are the most common benign gynecologic surgical procedures performed in the United States. Currently, there are no tissue models that exist to teach trainees the techniques for colpotomy during laparoscopic hysterectomy. To address this educational gap, we have created a laparoscopic colpotomy model using a porcine stomach attached to a uterine manipulator. METHODS: A segment of a porcine stomach is secured onto a uterine manipulator to simulate the cervicovaginal junction. A uterus model created with craft materials and reused in subsequent sessions is placed above the porcine stomach onto the uterine manipulator tip. Porcine stomach was obtained from a local butcher or meat market costing less than $1.00 per model. The tissue can be refrigerated or frozen for storage, then thawed before each use. This model can be used with any energy device and any laparoscopic platform to teach and perform the colpotomy. Usability survey showed that trainees responded positively to the model and attendings thought it was a useful teaching tool. EXPERIENCE: Trainees and faculty responded favorably to the model and stated that the use of actual tissue enhanced the realism of a colpotomy simulation. CONCLUSION: The porcine stomach laparoscopic colpotomy model is an innovative, low-cost teaching tool to add to a gynecologic surgical education simulation toolkit.

Function and regulation of TRPP2 ion channel revealed by a gain-of-function mutant.

Mutations in polycystin-1 and transient receptor potential polycystin 2 (TRPP2) account for almost all clinically identified cases of autosomal dominant polycystic kidney disease (ADPKD), one of the most common human genetic diseases. TRPP2 functions as a cation channel in its homomeric complex and in the TRPP2/polycystin-1 receptor/ion channel complex. The activation mechanism of TRPP2 is unknown, which significantly limits the study of its function and regulation. Here, we generated a constitutively active gain-of-function (GOF) mutant of TRPP2 by applying a mutagenesis scan on the S4-S5 linker and the S5 transmembrane domain, and studied functional properties of the GOF TRPP2 channel. We found that extracellular divalent ions, including Ca(2+), inhibit the permeation of monovalent ions by directly blocking the TRPP2 channel pore. We also found that D643, a negatively charged amino acid in the pore, is crucial for channel permeability. By introducing single-point ADPKD pathogenic mutations into the GOF TRPP2, we showed that different mutations could have completely different effects on channel activity. The in vivo function of the GOF TRPP2 was investigated in zebrafish embryos. The results indicate that, compared with wild type (WT), GOF TRPP2 more efficiently rescued morphological abnormalities, including curly tail and cyst formation in the pronephric kidney, caused by down-regulation of endogenous TRPP2 expression. Thus, we established a GOF TRPP2 channel that can serve as a powerful tool for studying the function and regulation of TRPP2. The GOF channel may also have potential application for developing new therapeutic strategies for ADPKD.

Depo-Provera (depot medroxyprogesterone acetate) use after bariatric surgery.

In the US, obesity rates are increasing greatly. The Centers for Disease Control and Prevention estimates that 68.5% of Americans, including 63.9% of adult women older than 20 years, are overweight (body mass index between 25 kg/m2 and 29.9 kg/m2) or obese (body mass index >30 kg/m2). In light of this, it is not surprising that the rates of bariatric surgery have also been increasing. When considering the metabolic changes associated with both bariatric surgery and contraceptive use, in combination with the unique medical considerations of obese women, it is indisputable that clear guidelines are needed when counseling obese patients of reproductive age after bariatric surgery. In this literature review, we focus on depot medroxyprogesterone acetate (DMPA) and the implications of its use in obese women, preweight and postweight loss following bariatric surgery. Both DMPA use and bariatric surgery are known to cause bone loss, but it is still unclear whether there is an additive effect of the two factors on bone loss and whether either of these factors directly leads to an increased risk of bone fracture. The current consensus guidelines do not impose a restriction on the use of DMPA after bariatric surgery. DMPA use is associated with weight gain, and it is unclear whether weight loss blunting occurs with the use of DMPA after bariatric surgery. Prior studies had demonstrated an association with weight gain in adolescents, and therefore, those prescribing DMPA use after bariatric surgery in adolescents should proceed with caution. Adult women do not have a similar response to the use of DMPA. DMPA use has rarely been associated with increased risk of venous thromboembolism (VTE). The obesity-associated increase in VTE should be mitigated by surgically induced weight loss. The concurrent use of DMPA in the post bariatric surgical period should not further increase the risk of VTE.

A novel green synthesis approach for polymer nanocomposites decorated with silver nanoparticles and their antibacterial activity.

A novel, low-cost and direct green synthesis strategy was developed for the preparation of polymer composite spheres composed of silver nanoparticles (AgNPs) decorated on the polymer colloids in a raspberry-like fashion. The polymer colloids were employed as both the reductant and the substrate support. The environmentally benign reaction system consists of AgNO3, polymer spheres and an ethanol solvent, without any additional reducing agents or stabilizers. The obtained composite spheres are surprisingly stable. The size range of the formed AgNPs is from several to tens of nanometers, dependent on the reaction time, AgNO3 concentration, and the amount of polymer spheres. A four-step mechanism was proposed for the formation of AgNPs-coated polymer spheres emphasizing the role of ethanol for saturating the external surface of the polymer spheres first. These composites exhibit excellent antibacterial activity, which is dependent on both the concentration of the composite spheres and the size of coated AgNPs.

Analysis of the cell surface expression of cytokine receptors using the surface protein biotinylation method.

Cytokines are pleiotropic, low-molecular-weight proteins that regulate the immune responses to infection and inflammation. They stimulate the immune responses by binding to cytokine receptors on the cell plasma membrane. Thus, knowledge of the expression level of particular cytokine receptors on cell surface is crucial for understanding the cytokine function and regulation. One of the techniques to explore the membrane embedded cytokine receptors is cell surface biotinylation. Biotinylated surface proteins can be rapidly purified through the strong interaction between biotin and streptavidin. Here, we describe the procedure for surface biotinylation and purification of biotinylated cytokine receptors for further downstream analysis.

Detection of CXCR2 cytokine receptor surface expression using immunofluorescence.

The interleukin-8 (IL-8, CXCL8) chemokine, also known as the neutrophil chemotactic factor, is a cytokine that plays a key role in inflammatory response, cell proliferation, migration, and survival. IL-8 expression is increased not only in inflammatory disorders, but also in many types of cancer, including prostate cancer. IL-8 acts as a ligand for the C-X-C chemokine receptor 2 (CXCR2) protein present on the cell plasma membrane. Binding of the IL-8 ligand to the CXCR2 receptor results in an intracellular signaling pathway mediated by GTP binding proteins coupled to the receptor itself. Knowledge of the CXCR2 expression levels facilitates the understanding of the role and function of IL-8. In this chapter, we describe a protocol that uses the immunofluorescence method and confocal microscopy to analyze the CXCR2 surface expression in human prostate cancer cells. However, this protocol is easily adaptable to analyze the surface expression of other cytokine receptors in different cell types.