Our results demonstrated that endometrial cancer patients continued to gain weight after hysterectomy, and post-treatment weight change had bidirectional effects on survival outcome.

Wait time for surgical staging was not associated with decreased survival outcome in patients with type I endometrial cancer.

No abstract

SummaryPlasma membrane serotonin transporters (SERTs) regulate serotonin (5HT) levels in brain and are a site of action of antidepressants and psychostimulant drugs of abuse. Syntaxin 1A is a component of the synaptic vesicle docking and fusion apparatus and has been shown to interact with multiple plasma membrane neurotransmitter transporters including SERT. Previously we showed that syntaxin 1A regulates the transport stoichiometry of SERT. When not bound to syntaxin 1A, SERT shows both substrate-independent Na + fluxes and substrate-dependent Na + fluxes of variable stoichiometry; these fluxes are eliminated in the presence of syntaxin 1A as Na + flux becomes strictly coupled to 5HT uptake. However, not known are the endogenous signaling molecules that determine the conducting states that SERT exhibits. In the present experiments, we show that inhibitors of calcium/calmodulin-dependent kinase II (CaM kinase II) modulate the stoichiometry of 5HT flux and that this effect requires syntaxin 1A. The modulation correlates with a shift in the affinity of SERT for syntaxin 1A binding. The regulation by CaM kinase II is eliminated by a mutation in the N-terminal domain of SERT. In neonatal thalomocortical neurons that endogenously express SERT and syntaxin 1A, inhibition of CaM kinase II reveals SERT-mediated currents. These data suggest that calcium-mediated signals can serve as a trigger for regulating protein-protein interactions that control SERT conducting states.

BACKGROUND: Though hysterectomy remains the standard treatment for complex atypical hyperplasia, patients who desire fertility or who are poor surgical candidates may opt for progestin therapy. However, the effectiveness of the levonorgestrel-releasing intrauterine device compared to systemic therapy in the treatment of complex atypical hyperplasia has not been well studied. OBJECTIVE: We sought to examine differences in treatment response between local progestin therapy with the levonorgestrel-releasing intrauterine device and systemic progestin therapy in women with complex atypical hyperplasia. METHODS: This single-institution retrospective study examined women with complex atypical hyperplasia who received progestin therapy between 2003 and 2018. Treatment response was assessed by histopathology on subsequent biopsies. Time-dependent analyses of complete response and progression to cancer were performed comparing the levonorgestrel-releasing intrauterine device and systemic therapy. A propensity score inverse probability of treatment weighting model was used to create a weighted cohort that differed based on treatment type but was similar with respect to other characteristics. An interaction-term analysis was performed to examine the impact of body habitus on treatment response, and an interrupted time-series analysis was employed to assess if changes in treatment patterns correlated with outcomes over time. RESULTS: A total of 245 women with complex atypical hyperplasia received progestin therapy (levonorgestrel-releasing intrauterine device n ¼ 69 and systemic therapy n ¼ 176). The mean age and body mass index were 36.9 years and 40.0 kg/m 2 , respectively. In the patient-level analysis, women who received the levonorgestrel-releasing intrauterine

Non-epithelial ovarian tumors are heterogeneous and account for approximately 10% of ovarian malignancies. The most common subtypes of non-epithelial ovarian tumors arise from germ cells or sex cord and stromal cells of the gonads. These tumors are usually detected at an early stage, and management includes surgical staging and debulking. When indicated for advanced disease, most respond to chemotherapy; however, options for patients with refractory disease are limited, and regimens can be associated with significant toxicities, including permanent organ dysfunction, secondary malignancies, and death. Targeted therapies that potentially decrease chemotherapy-related adverse effects and improve outcomes for patients with chemotherapy-refractory disease are needed. Here, we review the molecular landscape of non-epithelial ovarian tumors for the purpose of informing rational clinical trial design. Recent genomic discoveries have uncovered recurring somatic alterations and germline mutations in subtypes of non-epithelial ovarian tumors. Though there is a paucity of efficacy data on targeted therapies, such as kinase inhibitors, antibody–drug conjugates, immunotherapy, and hormonal therapy, exceptional responses to some compounds have been reported. The rarity and complexity of non-epithelial ovarian tumors warrant collaboration and efficient clinical trial design, including high-quality molecular characterization, to guide future efforts.

No abstract

Tumors deficient in DNA mismatch repair are known to display increased susceptibility to immune checkpoint inhibitors due to accumulation of DNA damage and increased neoantigen load. This suggests that deficiency in the BRCA-related DNA repair mechanism may also be a surrogate marker for immunotherapy response. The aim of this study was to examine the efficacy of the immune checkpoint inhibitor, nivolumab, in women with BRCA gene mutations and recurrent müllerian cancer. This retrospective case series followed six BRCA carriers who received nivolumab monotherapy (3.0 mg/kg, intravenous, day 1 and 15, every 4 weeks) as salvage therapy for recurrent epithelial ovarian (n = 5) and fallopian tubal (n = 1) cancers. Toxicity, treatment response, and survival were examined. Median age was 57 (range 51–64). BRCA1 and 2 mutations were equally distributed. All had high-grade serous histology, and all but one had advanced-stage disease at initial diagnosis. The majority had platinum-resistant disease (n = 4). All received salvage therapy prior to nivolumab therapy (median 3 lines), including PARP inhibitors (n = 3). The median number of nivolumab treatment cycles was 9, including 2 women receiving 18 cycles. Three women developed nivolumab-related toxicities, most commonly grade 2 hypothyroidism (n = 2). Median follow-up time was 13.4 months, and there were 3 complete responses, 1 partial response, and 2 patients with progressive disease. Objective response rate was 67% (4 out of 6). In conclusion, our study suggests that nivolumab monotherapy is well-tolerated and may be an effective salvage therapy for BRCA mutation carriers with recurrent epithelial ovarian, fallopian tubal, and primary peritoneal cancers.