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Background: Conservative management of atypical endometrial hyperplasia (AEH) or endometrial cancer (EMCA) often relies on the treatment of synthetic progestins, which show varied success and response rates. We evaluate the correlation between steroid receptor expression and response to progestin therapy in patients with AEH and EMCA. Methods: Retrospective cohort study collected data for patients with AEH or EMCA who had an endometrial sample after receiving conservative therapy utilizing either Megestrol acetate or Levonorgestrel Intrauterine device (IUD). Immunohistochemistry (IHC) was performed on pre- and post- treatment biopsy samples to assess androgen receptor (AR), estrogen receptor (ER), and progesterone receptor (PR) expression. IHC scores (1–12) were calculated based on staining intensity and percentage of positive cells. Results and analysis: We identified 15 patients with AEH and EMCA between 2015 and 2023 with the majority of African American ethnicity (53 %). Fourteen patients (93 %) received Megestrol acetate, and 1 patient received Levonorgestrel IUD alone. Three patients ultimately underwent hysterectomy. Seven (46.6 %) endometrial samples had strong positivity for AR, PR and ER expression on pre-treatment biopsies, and only 3 (20 %) of them maintained strong positivity for the 3 receptors in the post-treatment. Patients who successfully responded to the treatment demonstrated a significantly greater decrease in IHC scores after the treatment compared to those who did not respond (p = 0.009). Conclusion: Steroid receptor expression could be used as a possible biomarker for response to progestin therapy in patients undergoing conservative management for AEH and EMCA.

Objective: Immature CD11b + Gr1+ myeloid cells that acquire immunosuppressive capability, also known as myeloid-derived suppressor cells (MDSCs), are a heterogeneous population of cells that regulate immune responses. Our study's objective was to elucidate the role of ovarian cancer microenvironment in regulating the immunosuppressive function of CD11b+Gr1+ myeloid cells. Methods: All studies were performed using the intraperitoneal ID8 syngeneic epithelial ovarian cancer mouse model. Myeloid cell depletion and immunotherapy were carried out using anti-Gr1 mAb, gemcitabine treatments, and/or anti-PD1 mAb. The treatment effect was assessed by a survival curve, in situ luciferase-guided imaging, and histopathologic evaluation. Adoptive transfer assays were carried out between congenic CD45.2 and CD45.1 mice. Immune surface and intracellular markers were assessed by flow cytometry. ELISA, western blot, and RT-PCR techniques were employed to assess the protein and RNA expression of various markers. Bone marrow-derived myeloid cells were used for ex-vivo studies. Results: The depletion of Gr1+ immunosuppressive myeloid cells alone and in combination with anti-PD1 immunotherapy inhibited ovarian cancer growth. In addition to the adoptive transfer studies, these findings validate the role of immunosuppressive CD11b+Gr1+ myeloid cells in promoting ovarian cancer. Mechanistic investigations showed that ID8 tumor cells and their microenvironments produced recruitment and regulatory factors for immunosuppressive CD11b+Gr1+ myeloid cells. CD11b+Gr1+ myeloid cells primed by ID8 tumors showed increased immunosuppressive marker expression and acquired an energetic metabolic phenotype promoted primarily by increased oxidative phosphorylation fueled by glutamine. Inhibiting the glutamine metabolic pathway reduced the increased oxidative phosphorylation and decreased immunosuppressive markers’ expression and function. Dihydrolipoamide succinyl transferase (DLST), a subunit of α-KGDC in the TCA cycle, was found to be the most significantly elevated gene in tumor-primed myeloid cells. The inhibition of DLST reduced oxidative phosphorylation, immunosuppressive marker expression and function in myeloid cells. Conclusion: Our study shows that the ovarian cancer microenvironment can regulate the metabolism and function of immunosuppressive CD11b + Gr1+ myeloid cells and modulate its immune microenvironment. Targeting glutamine metabolism via DLST in immunosuppressive myeloid cells decreased their activity, leading to a reduction in the immunosuppressive tumor microenvironment. Thus, targeting glutamine metabolism has the potential to enhance the success of immunotherapy in ovarian cancer.

Objectives: The aim of this study was to evaluate the prognostic value of peritoneal cytology status among other clinicopathological parameters in uterine serous carcinoma (USC). Methods: A retrospective study of 148 patients diagnosed with uterine serous carcinoma from 1997 to 2016 at two academic medical centers in the Detroit metropolitan area was done. A central gynecologic pathologist reviewed all available slides and confirmed the histologic diagnosis of each case of USC. We assessed the prognostic impact of various clinicopathological parameters on overall survival (OS) and endometrial cancer-specific survival (ECSS). Those parameters included race, body mass index (BMI), stage at diagnosis, tumor size, lymphovascular invasion (LVSI), peritoneal cytology status, receipt of adjuvant treatment, and comorbidity count using the Charlson Comorbidity Index (CCI). We used Cox proportional hazards models and 95% confidence intervals for statistical analysis. Results: Positive peritoneal cytology had a statistically significant effect on OS (HR: 2.09, 95% CI: [1.19, 3.68]) and on ECSS (HR: 2.02, 95% CI: [1.06 – 3.82]). LVSI had a statistically significant effect on both OS (HR: 2.27, 95% CI: [1.14, 4.53]) and ECSS (HR: 3.45, 95% CI: [1.49, 7.99]). Black or African American (AA) race was also found to have a significant effect on both OS (HR: 1.92, 95% CI: [1.07, 3.47]) and ECSS (HR: 2.01, 95% CI: [1.02, 3.98]). Other factors including BMI and tumor size > 1 cm did not show a statistically significant impact on OS or ECSS. Conclusions: Peritoneal washings with positive cytology and LVSI are important prognostic tools that may have a significant impact on overall survival in USC and can be used as independent negative prognosticators to help guide adjuvant treatment.