Extended Venous Thromboembolism Prophylaxis after Robotic Staging for Endometrial Cancer.

OBJECTIVES: Our objectives were to estimate the incidence of venous thromboembolism (VTE) after robotic staging for endometrial cancer and to compare the incidence of VTE in patients who received a single dose of preoperative prophylaxis of enoxaparin with those who received extended postoperative prophylaxis. METHODS: This study is a retrospective chart review of patients who underwent robot-assisted surgical staging for endometrial cancer. Patients were categorized into two groups: preoperative prophylaxis (PP), patients who received a single dose of enoxaparin preoperatively, and extended prophylaxis (EP), patients who received 28 days of enoxaparin postoperatively. RESULTS: In total, 148 patients were included, with 117 patients in the PP group and 31 patients in the EP group. The overall incidence of VTE within 30 days postoperatively was 0.67%. No significant difference was found between the PP and the EP groups (0.9% and 0%, respectively; P = 1.00). Most patients in the cohort had endometrioid adenocarcinoma (78%) with low-grade disease (70%), although there were a greater number of patients in the PP group with uterine serous carcinoma compared with the EP group (17% vs 10%; P = 0.034). The PP group had higher estimated blood loss (106 vs 81 mL; P = 0.009) and longer operative times (178 vs 151 min; P = 0.028) compared with the EP group. Significantly more patients in the PP group underwent lymph node dissection compared with the EP group (32% vs 7%; P = 0.008). CONCLUSIONS: The incidence of VTE following robot-assisted surgical staging for endometrial cancer in this study was 0.67%. No significant difference was found in VTE incidence between the PP group compared with the EP group. Mechanical prophylaxis plus a single dose of preoperative pharmacologic prophylaxis may suffice for low-risk patients following robotic surgical staging for endometrial cancer.

Ovarian Vein Thrombosis after Pelvic Surgery in Patient with Recent Coronavirus Disease.

An abundance of literature has demonstrated that coronavirus disease (COVID-19) contributes to a hypercoagulable state that is associated with venous thromboembolic events. Data on postoperative complications after a mild COVID-19 infection are limited. We report a case of ovarian vein thrombosis after pelvic surgery in a patient with a recent mild COVID-19 infection. The patient presented with complaints of fever and worsening right-sided abdominal pain postoperatively and was found to have a right ovarian vein thrombosis. Thrombophilia workup was negative. The hypercoagulable state of patients with COVID-19 may have implications on postoperative complications after gynecologic surgery even in cases of mild infection. Further research is needed to determine the optimal thromboembolic prophylaxis for patients undergoing pelvic surgery after a COVID-19 infection.

Meigs syndrome presenting with severely elevated CA-125 level.

A 64-year-old woman referred to Gynaecological Oncology secondary to the finding of pelvic mass and ascites. Imaging showed multiple pelvic masses, with the largest mass measuring 20 cm in diameter, as well as bilateral pleural effusions and abdominal ascites, suspicious for ovarian carcinoma. Laboratory findings included elevated cancer antigen 125 (CA-125) of 2124 units/mL. The patient underwent an exploratory laparotomy, total abdominal hysterectomy and bilateral salpingo-oophorectomy for pathological evaluation. Postoperatively, the patient had resolution of ascites and pleural effusion. Surgical pathology revealed a 26 cm right ovarian fibroma, confirming the diagnosis of Meigs syndrome. Despite the high suspicion for ovarian carcinoma in patients presenting with elevated CA-125 level, pelvic mass, ascites and pleural effusion, the diagnosis of Meigs syndrome cannot be excluded without pathological evaluation of mass.

Inhibition of EphA/Ephrin-A signaling using genetic and pharmacologic approaches improves recovery following traumatic brain injury in mice.

Primary Objective: Eph/Ephrin signaling is inhibitory for developing axons and blocking Eph pathways enhances regeneration after spinal cord injury. It was hypothesized that inhibition of Eph signaling promotes cellular and behavioral recovery after traumatic brain injury (TBI). Research design: Lateral fluid percussion (LFP) injury was performed on wildtype (WT) and EphA6 knockout (KO) mice. EphA6-Fc, Ephrin-A5-Fc fusion proteins, and sodium orthovanadate were used to alter the signaling pathway. Immunohistochemistry and tissue explants revealed cellular changes. Rotarod tests demonstrated vestibulomotor function. Outcomes: The EphA6 receptor expression is upregulated following LFP. Uninjured EphA6 KO mice exhibit greater neurite density and clustered Ephrin-A5-Fc causes growth cone collapse in vitro. After LFP, EphA6 KO mice demonstrate longer neurites and decreased neuronal cell death and astrocytosis compared to WT mice. Blocking EphA signaling by soluble EphA6-Fc fusion protein reduces cell death and improves motor function following LFP whereas clustered Ephrin-A5-Fc exacerbates cell death and neurodegeneration. Sodium orthovanadate rescues growth cone collapse in vitro as well as cell death and neurodegeneration in vivo. Conclusions: Eph/Ephrin signaling plays an inhibitory role following TBI. Targeting the Eph signaling pathway with Fc fusion proteins and pharmacological agents can be a novel strategy to counter the damaging effects of TBI. Abbreviations: LFP: lateral fluid percussion; TBI: traumatic brain injury; KO: knockout; WT: wildtype; PTP2: protein phosphotyrosine phosphatase 2; Tg: transgenic; YFP: yellow fluorescent protein; ATM: atmospheres; RT-qPCR: Real-time-quantitative PCR; dpi: days post injury; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; DAPI: 4',6-diamidino-2-phenylindole; PBS: phosphate buffered saline; GFAP: glial fibrillary acidic protein; FLJC: fluorojade C; CA: cornu ammonis; SEM: standard error of the mean; ANOVA: analysis of variance; PLSD: posthoc least significant difference.

Neuropeptide VGF Promotes Maturation of Hippocampal Dendrites That Is Reduced by Single Nucleotide Polymorphisms.

The neuropeptide VGF (non-acronymic) is induced by brain-derived neurotrophic factor and promotes hippocampal neurogenesis, as well as synaptic activity. However, morphological changes induced by VGF have not been elucidated. Developing hippocampal neurons were exposed to VGF through bath application or virus-mediated expression in vitro. VGF-derived peptide, TLQP-62, enhanced dendritic branching, and outgrowth. Furthermore, VGF increased dendritic spine density and the proportion of immature spines. Spine formation was associated with increased synaptic protein expression and co-localization of pre- and postsynaptic markers. Three non-synonymous single nucleotide polymorphisms (SNPs) were selected in human VGF gene. Transfection of N2a cells with plasmids containing these SNPs revealed no relative change in protein expression levels and normal protein size, except for a truncated protein from the premature stop codon, E525X. All three SNPs resulted in a lower proportion of N2a cells bearing neurites relative to wild-type VGF. Furthermore, all three mutations reduced the total length of dendrites in developing hippocampal neurons. Taken together, our results suggest VGF enhances dendritic maturation and that these effects can be altered by common mutations in the VGF gene. The findings may have implications for people suffering from psychiatric disease or other conditions who may have altered VGF levels.

VGF (TLQP-62)-induced neurogenesis targets early phase neural progenitor cells in the adult hippocampus and requires glutamate and BDNF signaling.

The neuropeptide VGF (non-acronymic), which has antidepressant-like effects, enhances adult hippocampal neurogenesis as well as synaptic activity and plasticity in the hippocampus, however the interaction between these processes and the mechanism underlying this regulation remain unclear. In this study, we demonstrate that VGF-derived peptide TLQP-62 specifically enhances the generation of early progenitor cells in nestin-GFP mice. Specifically, TLQP-62 significantly increases the number of Type 2a neural progenitor cells (NPCs) while reducing the number of more differentiated Type 3 cells. The effect of TLQP-62 on proliferation rather than differentiation was confirmed using NPCs in vitro; TLQP-62 but not scrambled peptide PEHN-62 increases proliferation in a cell line as well as in primary progenitors from adult hippocampus. Moreover, TLQP-62 but not scrambled peptide increases Cyclin D mRNA expression. The proliferation of NPCs induced by TLQP-62 requires synaptic activity, in particular through NMDA and metabotropic glutamate receptors. The activation of glutamate receptors by TLQP-62 activation induces phosphorylation of CaMKII through NMDA receptors and protein kinase D through metabotropic glutamate receptor 5 (mGluR5). Furthermore, pharmacological antagonists to CaMKII and PKD inhibit TLQP-62-induced proliferation of NPCs indicating that these signaling molecules downstream of glutamate receptors are essential for the actions of TLQP-62 on neurogenesis. We also show that TLQP-62 gradually activates Brain-Derived Neurotrophic Factor (BDNF)-receptor TrkB in vitro and that Trk signaling is required for TLQP-62-induced proliferation of NPCs. Understanding the precise molecular mechanism of how TLQP-62 influences neurogenesis may reveal mechanisms by which VGF-derived peptides act as antidepressant-like agents.

Neuropeptide orphanin FQ inhibits dendritic morphogenesis through activation of RhoA.

Brain-derived neurotrophic factor (BDNF) plays a facilitatory role in neuronal development and promotion of differentiation. Mechanisms that oppose BDNF's stimulatory effects create balance and regulate dendritic growth. However, these mechanisms have not been studied. We have focused our studies on the BDNF-induced neuropeptide OrphaninFQ/ Nociceptin (OFQ); while BDNF is known to enhance synaptic activity, OFQ has opposite effects on activity, learning, and memory. We have now examined whether OFQ provides a balance to the stimulatory effects of BDNF on neuronal differentiation in the hippocampus. Golgi staining in OFQ knockout (KO) mice revealed an increase in primary dendrite length as well as spine density, suggesting that endogenous OFQ inhibits dendritic morphology. We have also used cultured hippocampal neurons to demonstrate that exogenous OFQ has an inhibitory effect on dendritic growth and that the neuropeptide alters the response to BDNF when pre-administered. To determine if BDNF and OFQ act in a feedback loop, we inhibited the actions of the BDNF and OFQ receptors, TrkB and NOP using ANA-12 and NOP KO mice respectively but our data suggest that the two factors do not act in a negative feedback loop. We found that the inhibition of dendritic morphology induced by OFQ is via enhanced RhoA activity. Finally, we have evidence that RhoA activation is required for the inhibitory effects of OFQ on dendritic morphology. Our results reveal basic mechanisms by which neurons not only regulate the formation of proper dendritic growth during development but also control plasticity in the mature nervous system.