Introduction/Purpose: Endometrial cancer (EC) is the most common gynecologic cancer in the US with increasing incidence and mortality. To proliferate and metastasize, tumor cells must evade immune detection and attack. Evasion of immune detection and establishment of immune tolerance is regulated by a specific type of T cells, known as regulatory T cells (Tregs), through activation of the transcription factor, Foxp3. Our previous data indicated that patients with EC exhibited peripheral inflammation, evident by decreased inducible Tregs (iTreg) and total Treg populations and increased inflammatory cytokines (IL-17A, IL-21, IL-22, TNF-α, IL-10 and IL-1β). However, analysis of the immune profiles within EC tumors showed elevated Foxp3 expression, which indicated an immune tolerant tumor microenvironment (TME). Catabolism of the amino acid, tryptophan (Trp), by tumor cells and specific immune cell populations has been reported to alter effector immune cell function by promoting Treg differentiation. Transport of Trp into cells is regulated by SLC3A2, which is part of the heterodimeric LAT1 transporter. Once Trp enters the cytoplasm, intracellular indoleamine 2,3-dioxygenase (IDO1) catabolizes Trp, to produce kynurenine (Kyn). Catabolism of Trp to Kyn can be blocked by BIN1 (a tumor suppressor, Myc interacting protein) which inhibits IDO1 enzymatic activity. Kyn is a known ligand of the aryl hydrocarbon receptor (AhR) which, when activated, can induce the expression of IDO1, in both an autocrine and paracrine fashion. Activation of the AhR by Kyn has been shown to regulate the polarization of CD4+ cells to Tregs through the production of stimulatory cytokines such as IL-4, IL-10 and TGF-b1. Based on our preliminary data and existing literature, we hypothesized that EC tumor cells promote Treg differentiation of infiltrating CD4+ cells, within the tumor microenvironment through cytokine regulation of tryptophan catabolism by IDO1. Methods: The study population (IRB# 16-493) includes postmenopausal patients who underwent a hysterectomy at Southern Illinois University School of Medicine, Department of Ob/Gyn, Division of Gynecologic Oncology. Endometrial tissue biopsies were pathologically analyzed to confirm the presence of EC. A total of 35 patients were analyzed for this study; 8 Controls and 27 EC. Tissue biopsies and plasma samples were collected during surgery. To investigate alterations in the Trp catabolism pathway, tumor expression of AhR, BIN1, IDO1 and SLC3A2 was determined using quantitative real-time PCR (qPCR). Additionally, we used ELISA and qPCR to define the plasma and tissue expression of inflammatory cytokines (IL-1β, IL-4, IL-6 and IFN-γ) which are known regulators of IDO1. To assess Treg infiltration into the TME, we measured FOXp3 expression and performed immunohistochemical staining for FOXp3 in tissue samples. EC patients were categorized by disease stage and tumor histotype was determined by pathological analysis. The Mann-Whitney U test was used to analyze differences among EC and control patients, and within EC tumors we analyzed differences by disease staging. Results: Of the 27 EC patients, 13 were stage I-II and 14 stage were III-IV. Tumor histotypes represented 16 endometrioid EC, 7 serous, 3 carcinosarcoma and 1 mixed EC. Compared to endometrial biopsies from control patients, IDO1 expression was significantly increased (p=0.0159) in stage I-II EC tumors, but no changes in SLC3A2, BIN1 or AhR. Stage III-IV EC tumors had significantly decreased BIN1 and SLC3A2 (p=0.0091 and p=0.0121, respectively), but no alteration in IDO1 or AhR expression. We found no differences in inflammatory cytokine expression in EC tumors compared to control patients. All EC tumors, regardless of stage displayed elevated Foxp3 expression (p=0.0204) compared to RORγt. Consistent with this, EC tumors had increased Treg localization compared to tissue biopsies from control patients. Conclusions: Early stage (I-II) EC tumors had an immune tolerant TME via increased Treg localization, which may be mediated through IDO1 stimulation of Treg differentiation. Late stage (III-IV) EC tumors also expressed increased Treg localization; however, this may not be mediated by IDO1 catabolism of Trp. Together, these data support that EC tumors establish an immune tolerant TME to evade immune recognition and promote tumor survival.

Introduction/Purpose: Considering the significant impact of gynecological cancers on women’s health, timely treatment plays a crucial role in minimizing morbidity and mortality. Endometrial cancer (EC) stands as the most prevalent gynecologic cancer, while ovarian cancer (OC), although less common, carries a higher fatality rate. The referral process from primary care practitioners (i.e., Ob/Gyn and family medicine physicians) and emergency medicine physicians to gynecologic oncologists (Gyn/Onc) serves as a vital link in the healthcare system, ensuring prompt care. Delays in referrals, particularly for EC and OC, result in assessment and treatment delays and ultimately lead to suboptimal outcomes. The coronavirus disease (COVID-19) pandemic prompted alterations in healthcare practices to reduce exposure risks. Although some changes have persisted post stay-at-home orders and mask mandates, the full impact of resource triaging during the pandemic on gynecologic cancer care remains uncertain. This study aims to investigate referral times and the time-to-treat EC and OC. Our hypothesis posits that during-COVID-19, delays in treatment for EC and OC patients occurred. Our specific focus was to assess the influence of COVID-19 on time from transfer of care and time to surgery. Methods: This retrospective chart review included women undergoing surgical management for EC or suspicion of OC at SIU School of Medicine, Department of Ob/Gyn, Division of Gynecologic Oncology (IRB# 23-343). Subjects seen by the Gyn/Onc between January 1, 2019 and March 11, 2020 were categorized as ‘pre-COVID-19’ and those presenting between March 12, 2020 and May 30, 2021 were considered ‘during-COVID-19’. Patients attending any appointments for their cancer work-up, including surgery, that spanned both the pre- and during-COVID-19 timeframes were excluded. Date of presentation to the referring physician, date of referral to the Gyn/Onc, date of surgery, insurance status, race, age, BMI, gravidity, parity, comorbidities and cancer grade were extracted from the Electronic Health Record. Rural-urban commuting area (RUCA) codes were utilized to determine subjects’ geolocation in order to establish potential delays due to differences in access to transportation or commute time. Chi-square (for categorical variables) and T-test or Mann-Whitney U-test (for numerical variables) were utilized for comparisons. Results: A total 151 patients were included in this study. Of these, 58% presented for surgical evaluation pre-COVID-19 and 42% were during-COVID-19. There were no significant differences (all p-values ≥ 0.05) between the pre- and during-COVID-19 groups, respectively, in regards to: Age at time of surgery (62.3 ± 12.0 vs. 60.0 ± 12.6 years); Insurance type (Medicare: 51% vs. 39%, Medicaid: 19% vs 23%, Commercial: 27% vs. 32%, Uninsured: 2% vs. 6%); RUCA codes (Metro: 51% vs. 49%, Micro: 18% vs. 25%, Rural/Small: 31% vs. 26%); Race (White: 90% vs. 79%, African American: 5% vs. 5%, Asian: 0% vs. 3%, American Indian/Alaskan Native: 1% vs. 0%, Other/declined: 5% vs. 13%); BMI (37.0 ± 10.1 vs. 36.2 ± 10.0); Comorbidities at time of presentation (95% vs. 94%), Gravidity (2.5 ± 2.2 vs. 2.1 ± 1.7) or Parity (2.0 ± 1.6 vs. 1.9 ± 1.6). The cohort during-COVID-19 was found to have significantly shorter ‘time from symptom onset to referral’ compared to the pre-COVID-19 group (median [range]: 34 [7 – 111] days vs. 42 [6 – 298] days, respectively, p=0.009). In addition, there was a significantly shorter time period from the time of referral to surgery (8 [2 – 123] days vs.13 [2 – 125] days, respectively, p=0.006). Conclusions: Despite homogeneous patient populations prior to and during the pandemic era, these findings indicate a noteworthy reduction in both the time to transfer care and the duration from referral to surgery during the COVID-19 pandemic period. Although various factors may contribute to this outcome (i.e., elective surgeries were cancelled allowing more operating room access for cancer cases), our findings suggest that the challenges posed by the COVID-19 pandemic compelled the medical field to enhance efficiency in the health care delivery system. Further investigation is necessary to understand the specific modifications in the referral and time-to-treat processes that have resulted in shorter wait times. A thorough exploration of these changes has the potential to unveil strategies pertinent to improving timeliness of care and enhancing outcomes in the surgical treatment of gynecologic cancers, specifically EC and OC.

ABSTRACT Background Effective diagnostic and prognostic tools are critical for early detection and improved outcomes in endometrial cancer (EC). Although metabolic dysregulation plays a key role in EC pathogenesis, the clinical relevance of lipid droplet–associated genes (LDAGs) remains largely unexplored. This study aims to establish LDAG‐based gene signatures with strong diagnostic and prognostic potential in EC. Aims To identify LDAG signatures with prognostic and diagnostic utility in EC. Methods and Results A curated set of LDAGs was systematically analyzed across publicly available EC datasets to identify differentially expressed LDAGs (DE‐LDAGs). Survival‐associated DE‐LDAGs were then identified using univariate Cox regression. A four‐gene prognostic model was developed through LASSO‐based feature selection followed by multivariate Cox regression and validated using Kaplan–Meier survival and time‐dependent receiver operating characteristic (ROC) analyses. From the same pool of survival‐associated DE‐LDAGs, a six‐gene diagnostic model was constructed using LASSO, ROC analysis, and logistic regression. Model performance was evaluated using ROC curves and support vector machine (SVM) classification. Functional enrichment and protein–protein interaction (PPI) network analyses were conducted to assess the biological relevance of the identified genes. Our results demonstrate that the four‐gene prognostic model (LMLN, LMO3, PRKAA2, and RAB10) stratified EC patients into high‐ and low‐risk groups with significantly different survival outcomes (p < 0.05; time‐dependent AUC > 0.70). The six‐gene diagnostic model (AIFM2, ABCG1, LIPG, DGAT2, LPCAT1, and VCP) demonstrated near‐perfect classification of tumor versus normal tissues (AUC ≈0.99 in ROC analysis; 99.8% accuracy in SVM analysis). Functional enrichment linked DE‐LDAGs to lipid metabolism, ER stress response, cholesterol homeostasis, and autophagy, underscoring their biological relevance in EC pathobiology. Conclusion This study provides the first comprehensive analysis of LDAGs in EC, establishing robust prognostic and diagnostic gene signatures with strong biological relevance. These signatures support a metabolism‐driven framework for EC classification and may offer potential clinical utility in early detection, risk stratification, and personalized treatment.

Background:Lipid droplet (LD) dynamics drive cancer cell proliferation, resistance, and aggressiveness. Diacylglycerol O-acyltransferases (DGATs) and perilipins (PLINs) are key LD-associated genes implicated in cancer pathophysiology. Objective:This study aimed to comprehensively analyze the expression and clinical significance of DGATs and PLINs in ovarian cancer (OC), focusing on their correlation with LDs and triglyceride (TG) levels, and to explore their diagnostic and prognostic implications. Methods:LD and TG levels in ovarian cell lines and clinical samples were assessed using BODIPY staining, fluorometric, colorimetric assays, and thin-layer chromatography (TLC). Gene expression profiling of DGATs and PLINs in cell lines and tissue was conducted via RT-qPCR, ELISA, and bioinformatics analysis. Correlation analyses between gene expression, Ki67, and survival data were performed. ROC curve analysis evaluated diagnostic potential. Results:LD accumulation was significantly higher in OC cell lines and tissues compared with normal controls. Diacylglycerol O-acyltransferase 1 (DGAT1) and diacylglycerol O-acyltransferase 2 (DGAT2) were overexpressed in OC cell lines and tissues, particularly in advanced stages (III and IV). Elevated TG levels were observed in OC cell lines and clinical samples, correlating with LD abundance and the expression of DGAT1 and DGAT2. PLIN2 and PLIN3 were significantly upregulated in OC tissues. Bioinformatics analysis identified dysregulation of DGATs and PLINs in OC. Survival analysis indicated DGAT2 is a predictor of poor prognosis. Diagnostic assessments revealed DGAT2 as a potential biomarker for OC detection. Conclusion:DGATs and PLINs are pivotal in LD metabolism and tumor progression in OC, with DGAT2 being a good candidate as prognostic and diagnostic marker. They present promising avenues for therapeutic targeting and diagnostic biomarkers, holding the potential to improve patient outcomes. Further exploration of their mechanistic roles and clinical implications is essential for advancing personalized cancer care.

Endometrial cancer (EC) is a devastating and common disease affecting women’s health. The NCI Surveillance, Epidemiology, and End Results Program predicted that there would be >66,000 new cases in the United States and >13,000 deaths from EC in 2023, and EC is the sixth most common cancer among women worldwide. Regulation of mitochondrial metabolism plays a role in tumorigenesis. In proliferating cancer cells, mitochondria provide the necessary building blocks for biosynthesis of amino acids, lipids, nucleotides, and glucose. One mechanism causing altered mitochondrial activity is mitochondrial DNA (mtDNA) mutation. The polyploid human mtDNA genome is a circular double-stranded molecule essential to vertebrate life that harbors genes critical for oxidative phosphorylation plus mitochondrial-derived peptide genes. Cancer cells display aerobic glycolysis, known as the Warburg effect, which arises from the needs of fast-dividing cells and is characterized by increased glucose uptake and conversion of glucose to lactate. Solid tumors often contain at least one mtDNA substitution. Furthermore, it is common for cancer cells to harbor mixtures of wild-type and mutant mtDNA genotypes, known as heteroplasmy. Considering the increase in cancer cell energy demand, the presence of functionally relevant carcinogenesis-inducing or environment-adapting mtDNA mutations in cancer seems plausible. We review 279 EC tumor-specific mtDNA single nucleotide variants from 111 individuals from different studies. Many transition mutations indicative of error-prone DNA polymerase γ replication and C to U deamination events were present. We examine the spectrum of mutations and their heteroplasmy and discuss the potential biological impact of recurrent, non-synonymous, insertion, and deletion mutations. Lastly, we explore current EC treatments, exploiting cancer cell mitochondria for therapy and the prospect of using mtDNA variants as an EC biomarker.

By Aneesh Chawla, Stacy Parr & 10 more. We hypothesized that socio-economic factors correlate with altered inflammatory profiles (elevated Th17:Treg ratio) and subsequent higher stage and/or grade of EC at the time of surgery.

Epithelial ovarian cancer (OC) is the deadliest female reproductive cancer; an estimated 13,270 women will die from OC in 2023. Platinum-based chemotherapy resistance mechanisms contribute to poor OC 5-year survival rates. Peripheral inflammation is linked to various disease states and we previously identified unique peritoneal microbial features predictive of OC. We hypothesized that unique peripheral immune profiles and peritoneal microbial features may be predictive of disease-free interval (time to recurrence) and response to chemotherapy in participants with OC. We also investigated self-rated health (SRH) scores in the context of peripheral inflammation as a potential screening tool for OC. Blood and peritoneal fluid were collected from participants with OC or a benign adnexal mass (BPM). Lymphocyte populations were analyzed using Fluorescence Activated Cell Sorting, serum cytokine levels were analyzed using the Human Th17 Magnetic Bead Panel assay and peritoneal fluid microbial features were analyzed using Next Generation Sequencing (NGS). Participants completed a standardized questionnaire on self-rated physical and emotional health. Participants were classified into three chemotherapy response categories: platinum-refractory, platinum-resistant or platinum-sensitive. A significant positive correlation was found between elevated inflammatory status on the day of surgery and longer disease-free interval. SRH measures did not correlate with immune status in participants with OC or a BPM. We identified a correlation between peritoneal microbial features and chemotherapy response. We conclude that immune dysbiosis may be useful in predicting OC recurrence. The immune findings reported here set the framework for additional studies utilizing immune profiles to predict platinum-based chemotherapy responsiveness in OC.

Endometrial cancer (EC) is the most prevalent gynecological malignancy. Abnormal accumulation of sterol-O-acyl transferase 1 (SOAT1) and SOAT1-mediated cholesterol ester (CE) contributes to cancer progression in various malignancies, including ovarian cancer. Therefore, it was hypothesized that similar molecular changes may occur in EC. The present study aimed to evaluate the diagnostic and/or prognostic potential of SOAT1 and CE in EC by: i) Determining SOAT1 and CE levels in plasma, peritoneal fluid and endometrial tissue from patients with EC and control subjects; ii) performing receiver operating characteristic curve analysis to determine diagnostic performance; iii) comparing SOAT1 and CE expression to that of the tumor proliferation marker Ki67; and iv) assessing the association between SOAT1 expression and survival. Enzyme-linked immunosorbent assay was used to determine the levels of SOAT1 protein in tissue, plasma and peritoneal fluid. The mRNA and protein expression levels of SOAT1 and Ki67 in tissues were detected by reverse transcription-quantitative polymerase chain reaction and immunohistochemistry, respectively. CE levels were determined colorimetrically in plasma and peritoneal fluid. SOAT1-associated survival data from the cBioPortal cancer genomics database were used to assess prognostic relevance. The results revealed that SOAT1 and CE levels were significantly elevated in tumor tissue and peritoneal fluid samples collected from the EC group. By contrast, the plasma levels of SOAT1 and CE in the EC and control groups were similar. Significant positive associations between CE and SOAT1, SOAT1/CE and Ki67, and SOAT1/CE and poor overall survival in patients with EC suggested that SOAT1/CE may be associated with malignancy, aggressiveness and poor prognosis. In conclusion, SOAT1 and CE may serve as potential biomarkers for prognosis and target-specific treatment of EC.

Legend and description for supplementary figure.

Supplementary Figure 1. Rural and Urban Counties in the United States by U.S. Census Region The Supplementary Figure indicates the rural and urban counties in the United States and indicates the states (Vermont, Maryland, Minnesota, and Kansas) that chose not to include their data in the North American Association of Central Cancer Registries public use dataset.

Endometrial cancer (EC) is one of the most common forms of gynecological cancer, with death rates from this disease doubling over the past 20 years. Most solid tumors harbor at least one mtDNA mutation, and cancer cells can have mixtures of polyploid wild-type and mutant mtDNA genomes, so-called heteroplasmy. We compared mtDNA genomes from three matched sets of peri-normal and EC tumor specimens and determined that each tumor harbors tumor-specific mtDNA mutations. Furthermore, somatic EC mtDNA mutations were investigated in aggregate from several published studies. Using a total of 361 single nucleotide variants from 153 EC patients, we determined that ∼77% of the patients harbor at least one mtDNA mutation allele at 10% (WT 90%) to 90% (WT 10%) heteroplasmy. Of the total mutations, 278 are unique, and transitions are 24-fold higher than transversions. G>A and T>C are the most common transitions, comprising 85.3% of the unique mutations. Mutations occur across the mtDNA genome, but ∼39% of the mutations localize to complex I genes, and nine tRNA genes lack mutations. NGS amplicon sequencing and Southern blotting were used to analyze cell-free serum mtDNA heteroplasmy and tissue-derived topoisomers in the three EC patients. Our preliminary amplicon sequencing data reveals that at least one tumor-specific heteroplasmic substitution can be detected in serum DNA extracts from all patients. Also, relative to matched peri-normal tissues, all tumors had increased levels of catenanes indicative of enhanced mtDNA replication. Our study suggests tumor mtDNA mutations in the bloodstream could be used as an EC biomarker. Endometrial cancer (EC) is one of the most common forms of gynecological cancer, with death rates from this disease doubling over the past 20 years. Most solid tumors harbor at least one mtDNA mutation, and cancer cells can have mixtures of polyploid wild-type and mutant mtDNA genomes, so-called heteroplasmy. We compared mtDNA genomes from three matched sets of peri-normal and EC tumor specimens and determined that each tumor harbors tumor-specific mtDNA mutations. Furthermore, somatic EC mtDNA mutations were investigated in aggregate from several published studies. Using a total of 361 single nucleotide variants from 153 EC patients, we determined that ∼77% of the patients harbor at least one mtDNA mutation allele at 10% (WT 90%) to 90% (WT 10%) heteroplasmy. Of the total mutations, 278 are unique, and transitions are 24-fold higher than transversions. G>A and T>C are the most common transitions, comprising 85.3% of the unique mutations. Mutations occur across the mtDNA genome, but ∼39% of the mutations localize to complex I genes, and nine tRNA genes lack mutations. NGS amplicon sequencing and Southern blotting were used to analyze cell-free serum mtDNA heteroplasmy and tissue-derived topoisomers in the three EC patients. Our preliminary amplicon sequencing data reveals that at least one tumor-specific heteroplasmic substitution can be detected in serum DNA extracts from all patients. Also, relative to matched peri-normal tissues, all tumors had increased levels of catenanes indicative of enhanced mtDNA replication. Our study suggests tumor mtDNA mutations in the bloodstream could be used as an EC biomarker.

BACKGROUND:Abnormal accumulation of acyl-CoA cholesterol acyltransferase-1 (ACAT1) and ACAT1-mediated cholesterol esterified with fatty acids (CE) contribute to cancer progression in various cancers. Our findings of increased CE and ACAT1 levels in epithelial ovarian cancer (EOC) cell lines prompted us to investigate whether such an increase occurs in primary clinical samples obtained from human subjects diagnosed with EOC. We evaluated the diagnostic/prognostic potential of ACAT1 and CE in EOC by: 1) assessing ACAT1 and CE levels in plasma, peritoneal fluid, and ovarian/tumor tissues; 2) assessing diagnostic performance by Receiver Operating Characteristic (ROC) analysis; and 3) comparing expression of ACAT1 and CE with that of tumor proliferation marker, Ki67.METHODS:ACAT1 protein levels in plasma, peritoneal fluid and tissue were measured via enzyme-linked immunosorbent assay. Tissue expression of ACAT1 and Ki67 proteins were confirmed by immunohistochemistry and mRNA transcript levels were evaluated using quantitative real-time polymerase chain reaction (qRT-PCR). CE levels were assessed in plasma, peritoneal fluid (colorimetric assay) and in tissue (thin layer chromatography).RESULTS:Preoperative levels of ACAT1 and CE on the day of surgery were significantly higher in tissue and peritoneal fluid from EOC patients vs. the non-malignant group, which included subjects with benign tumors and normal ovaries; however, no significant differences were observed in plasma. In tissue and peritoneal fluid, positive correlations were observed between CE and ACAT1 levels, as well as between ACAT1/CE and Ki67.CONCLUSIONS:ACAT1 and CE accumulation may be linked to the aggressive potential of EOC; therefore, these mediators may be useful biomarkers for EOC prognosis and target-specific treatments.

Endometrial carcinoma (EC) is the most common type of gynecologic malignant epithelial tumor, with the death rate from this disease doubling over the past 20 years. Mitochondria provide cancer cells with necessary anabolic building blocks such as amino acids, lipids, and nucleotides, and EC samples have been shown to increase mitochondrial biogenesis. In cancer, mitochondrial DNA (mtDNA) heteroplasmy studies suggest that heteroplasmic variants encode predicted pathogenic proteins. We investigated the mtDNA genotypes within peri-normal and tumor specimens obtained from three individuals diagnosed with EC. DNA extracts from peri-normal and tumor tissues were used for mtDNA-specific next-generation sequencing and analyses of mtDNA content and topoisomers. The three tumors harbor heteroplasmic somatic mutations, and at least one mutation in each carcinoma is predicted to deleteriously alter a mtDNA-encoded protein. Somatic heteroplasmy linked to two mtDNA tRNA genes was found in separate tumors, and two heteroplasmic non-coding variants were identified in a single EC tumor. While two tumors had altered mtDNA content, all three displayed increased mtDNA catenanes. Our findings support that EC cells require wild-type mtDNA, but heteroplasmic mutations may alter mitochondrial metabolism to help promote cancer cell growth and proliferation.

Abnormal accumulation of acyl-CoA cholesterol acyltransferase-1 (ACAT-1) mediated cholesterol ester has been shown to contribute to cancer progression in various cancers including leukemia, glioma, breast, pancreatic and prostate cancers. However, the significance of ACAT-1 and cholesterol esters (CE) is relatively understudied in ovarian cancer. In this in vitro study, we assessed the expression and contribution of ACAT-1 in ovarian cancer progression. We observed a significant increase in the expression of ACAT-1 and CE levels in a panel of ovarian cancer cell lines (OC-314, SKOV-3 and IGROV-1) compared to primary ovarian epithelial cells (normal controls). To confirm the tumor promoting capacity of ACAT1, we inhibited ACAT-1 expression and activity by treating our cell lines with an ACAT inhibitor, avasimibe, or by stable transfection with ACAT-1 specific short hairpin RNA (shRNA). We observed significant suppression of cell proliferation, migration and invasion in ACAT-1 knockdown ovarian cancer cell lines compared to their respective controls (cell lines transfected with scrambled shRNA). ACAT-1 inhibition enhanced apoptosis with a concurrent increase in caspases 3/7 activity and decreased mitochondrial membrane potential. Increased generation of reactive oxygen species (ROS) coupled with increased expression of p53 may be the mechanism(s) underlying pro-apoptotic action of ACAT-1 inhibition. Additionally, ACAT-1 inhibited ovarian cancer cell lines displayed enhanced chemosensitivity to cisplatin treatment. These results suggest ACAT-1 may be a potential new target for the treatment of ovarian cancer.

Epithelial ovarian cancer (OC) is the most deadly cancer of the female reproductive system. To date, there is no effective screening method for early detection of OC and current diagnostic armamentarium may include sonographic grading of the tumor and analyzing serum levels of tumor markers, Cancer Antigen 125 (CA-125) and Human epididymis protein 4 (HE4). Microorganisms (bacterial, archaeal, and fungal cells) residing in mucosal tissues including the gastrointestinal and urogenital tracts can be altered by different disease states, and these shifts in microbial dynamics may help to diagnose disease states. We hypothesized that the peritoneal microbial environment was altered in patients with OC and that inclusion of selected peritoneal microbial features with current clinical features into prediction analyses will improve detection accuracy of patients with OC. Blood and peritoneal fluid were collected from consented patients that had sonography confirmed adnexal masses and were being seen at SIU School of Medicine Simmons Cancer Institute. Blood was processed and serum HE4 and CA-125 were measured. Peritoneal fluid was collected at the time of surgery and processed for Next Generation Sequencing (NGS) using 16S V4 exon bacterial primers and bioinformatics analyses. We found that patients with OC had a unique peritoneal microbial profile compared to patients with a benign mass. Using ensemble modeling and machine learning pathways, we identified 18 microbial features that were highly specific to OC pathology. Prediction analyses confirmed that inclusion of microbial features with serum tumor marker levels and control features (patient age and BMI) improved diagnostic accuracy compared to currently used models. We conclude that OC pathogenesis alters the peritoneal microbial environment and that these unique microbial features are important for accurate diagnosis of OC. Our study warrants further analyses of the importance of microbial features in regards to oncological diagnostics and possible prognostic and interventional medicine.

INTRODUCTION: Epithelial ovarian cancer (OC) is typically diagnosed at advanced stages and accounts for more deaths than any other gynecological cancer. Early detection of OC may improve prognosis. Microbial profiling has identified various diseases and may be utilized to detect OC. We hypothesize that patients with OC have a unique microbial profile, which in conjunction with biomarkers Cancer Antigen-125 (CA-125) and Human Epididymis protein 4 (HE4), would enable a novel screening mechanism to effectively detect OC. METHODS: Inclusion: Consented patients ≥30 yrs presenting at SIU Gynecologic/Oncology for management of an adnexal mass or suspected OC. Exclusion: patients with a previous malignancy, pregnant/intending to conceive. CA-125/HE4 were analyzed in serum and peritoneal fluid (PF). Extracted DNA from PF was sequenced (V4 region of bacterial 16S rRNA gene), then identified using Greengenes database and clustered into operational taxonomical units (OTUs). Microbial profile associations with CA-125/HE4 in serum and PF were calculated utilizing machine learning models for biomarker discovery. RESULTS: CA-125 and HE4 levels were elevated in serum and PF from patients with OC. Patients with OC also exhibited microbial profile clustering. Machine learning models identified 37 microbial features correlative with OC. Overall, performance of biological features (age, BMI, serum [CA-125/HE4], PF [CA-125/HE4], OTUs [taxa]), indicated that serum [CA-125/HE4]+age/BMI had the highest (0.96) accuracy for OC detection. Interestingly, OTUs [family/genus level+age/BMI] (0.87) outperformed PF [CA-125/HE4+age/BMI] (0.78). CONCLUSION: Microbial feature analysis may improve OC screening modalities and warrants further investigations into the urogenital and/or gastrointestinal microbiome profiles to improve detection/survival rates for OC.

Objective: The incidence of endometrial cancer (EC) has increased worldwide in recent years. The gastrointestinal (GI) microbiome influences peripheral inflammation, the immune system, as well as estrogen metabolism. An increase in peripheral inflammation, immune system suppression, and increased levels of estrogen play significant roles in the development of EC. Therefore, it is necessary to study the effects of the microbiome on the development of EC; however, this has yet to be explored. We hypothesize there is a unique microbial and/or immunological signature associated with EC that could be utilized for screening and for optimizing treatment strategies.

More than 46 million Americans live in rural areas, but rural populations remain relatively understudied in cancer disparities research. However, several analyses of multistate cancer registry data that describe the rural cancer incidence burden have been recently published. In light of this, our article aims to characterize the utility and generalizability of multistate, population-based cancer registry datasets for rural cancer surveillance research. First, we describe the accessibility, geographic coverage, available variables, and strengths and weaknesses of five data sources. Second, we evaluate two of these data sources—the North American Association of Central Cancer Registries (NAACCR) public use dataset (93% population coverage) and the Surveillance Epidemiology and End Results (SEER) 18 dataset (28% population coverage)—on their characterization of rural–urban cancer incidence rates and sociodemographic representation. The five data sources varied in geographic coverage and extent of available variables. SEER 18′s cancer rates sociodemographic representation differed from the more geographically representative NAACCR data. We suggest that SEER increase its geographic coverage to improve their generalizability and to take advantage of their utility to assess disparities along the cancer control continuum. We also suggest that non-SEER data sources be utilized more frequently to capitalize on their extensive geographic coverage. Cancer Epidemiol Biomarkers Prev; 27(11); 1252–60. ©2018 AACR.

Abstract Background: Cancer incidence and mortality rates in the United States are declining, but this decrease may not be observed in rural areas where residents are more likely to live in poverty, smoke, and forego cancer screening. However, there is limited research exploring national rural–urban differences in cancer incidence and trends. Methods: We analyzed data from the North American Association of Central Cancer Registries' public use dataset, which includes population-based cancer incidence data from 46 states. We calculated age-adjusted incidence rates, rate ratios, and annual percentage change (APC) for: all cancers combined, selected individual cancers, and cancers associated with tobacco use and human papillomavirus (HPV). Rural–urban comparisons were made by demographic, geographic, and socioeconomic characteristics for 2009 to 2013. Trends were analyzed for 1995 to 2013. Results: Combined cancers incidence rates were generally higher in urban populations, except for the South, although the urban decline in incidence rate was greater than in rural populations (10.2% vs. 4.8%, respectively). Rural cancer disparities included higher rates of tobacco-associated, HPV-associated, lung and bronchus, cervical, and colorectal cancers across most population groups. Furthermore, HPV-associated cancer incidence rates increased in rural areas (APC = 0.724, P < 0.05), while temporal trends remained stable in urban areas. Conclusions: Cancer rates associated with modifiable risks—tobacco, HPV, and some preventive screening modalities (e.g., colorectal and cervical cancers)—were higher in rural compared with urban populations. Impact: Population-based, clinical, and/or policy strategies and interventions that address these modifiable risk factors could help reduce cancer disparities experienced in rural populations. Cancer Epidemiol Biomarkers Prev; 27(11); 1265–74. ©2017 AACR.