Active DNA Demethylase, TET1, Increases Oxidative Phosphorylation and Sensitizes Ovarian Cancer Stem Cells to Mitochondrial Complex I Inhibitor.

Ten-eleven translocation 1 (TET1) is a methylcytosine dioxygenase involved in active DNA demethylation. In our previous study, we demonstrated that TET1 reprogrammed the ovarian cancer epigenome, increased stem properties, and activated various regulatory networks, including metabolic networks. However, the role of TET1 in cancer metabolism remains poorly understood. Herein, we uncovered a demethylated metabolic gene network, especially oxidative phosphorylation (OXPHOS). Contrary to the concept of the Warburg effect in cancer cells, TET1 increased energy production mainly using OXPHOS rather than using glycolysis. Notably, TET1 increased the mitochondrial mass and DNA copy number. TET1 also activated mitochondrial biogenesis genes and adenosine triphosphate production. However, the reactive oxygen species levels were surprisingly decreased. In addition, TET1 increased the basal and maximal respiratory capacities. In an analysis of tricarboxylic acid cycle metabolites, TET1 increased the levels of α-ketoglutarate, which is a coenzyme of TET1 dioxygenase and may provide a positive feedback loop to modify the epigenomic landscape. TET1 also increased the mitochondrial complex I activity. Moreover, the mitochondrial complex I inhibitor, which had synergistic effects with the casein kinase 2 inhibitor, affected ovarian cancer growth. Altogether, TET1-reprogrammed ovarian cancer stem cells shifted the energy source to OXPHOS, which suggested that metabolic intervention might be a novel strategy for ovarian cancer treatment.

Periureteral Liposarcoma Causes of Hydroureter and Hydronephrosis: An Unpredictable Diagnosis.

When obstructive lesions from the uterus or ovaries are suspected, patients with hydronephrosis are usually referred to a gynecologist. Here, a case of suspected endometriosis-related hydroureteronephrosis is reported. A 43-year-old woman with hydronephrosis was found to have a left distal periureteral tumor on the computerized tomography scan. Before the operation, the hydroureteronephrosis was suspected caused by the obstruction of ureter, related with ureteral endometriosis; however, the postoperative pathology revealed the diagnosis of retroperitoneal well-differentiated liposarcoma. When female patients have hydronephrosis, gynecologic causes should be considered. Both benign and malignant causes are needed to include when making differential diagnosis. Therefore, robot-assisted surgery is a feasible option because of its lower morbidity rate and more precise dissection of soft tissue than laparotomy in both benign and malignant retroperitoneal tumors.

Endometrial Cancer Detection Using a Cervical DNA Methylation Assay (MPap) in Women with Abnormal Uterine Bleeding: A Multicenter Hospital-Based Validation Study.

BACKGROUND: We describe a DNA methylation assay, named MPap test, using cervical scraping as an alternative technique for endometrial cancer detection. METHODS: A multicenter hospital-based, two-stage validation study was conducted to validate the cancer detection performance of the MPap test. The MPap value was determined from the DNA methylation status of two genes (BHLHE22, CDO1) and combined with two other clinical variables (age, BMI). The cutoff threshold of the MPap value was established in stage 1 and validated in stage 2. A total of 592 women with abnormal uterine bleeding were enrolled from five medical centers throughout Taiwan. RESULTS: In stage 1, the sensitivity, specificity, and positive and negative predictive values of the MPap test for detecting endometrial cancer were 92.9%, 71.5%, 39.8%, and 98.0%, respectively. These values were validated in stage 2, being 92.5%, 73.8%, 40.2%, and 98.1%. Moreover, MPap outperformed transvaginal ultrasound in sensitivity and negative predictive values for detecting endometrial cancer. When we applied the algorithm for triage of endometrial cancer detection by MPap in the Taiwan National Health Insurance dataset, we found that it may reduce invasive procedures by 69~73%. CONCLUSIONS: MPap may provide a feasible alternative for endometrial cancer detection and can be considered as a triage test to reduce unnecessary invasive procedures.

Epigenomic Analysis Reveals the KCNK9 Potassium Channel as a Potential Therapeutic Target for Adenomyosis.

Adenomyosis is linked to dysmenorrhea and infertility. The pathogenesis of adenomyosis remains unclear, and little is known of the genetic and epigenetic changes in the eutopic endometrium in adenomyosis, which may predispose patients to the invasion and migration of endometrial tissues into the myometrium. Transcriptome studies have identified genes related to various cell behaviors but no targets for therapeutic intervention. The epigenetics of the eutopic endometrium in adenomyosis have rarely been investigated. Endometrial tissue was obtained from premenopausal women with (n = 32) or without adenomyosis (n = 17) who underwent hysterectomy aged 34-57 years at a tertiary hospital. The methylome and transcriptome were assessed by using a Methylation 450 K BeadChip array and Affymetrix expression microarray. Protein expression was examined by immunohistochemistry. Differential methylation analysis revealed 53 lowly methylated genes and 176 highly methylated genes with consistent gene expression in adenomyosis, including three genes encoding potassium ion channels. High expression of KCNK9 in the eutopic and ectopic endometria in patients with adenomyosis but not in normal controls was observed. Hormone-free, antibody-based KCNK9 targeting is a potential therapeutic strategy for adenomyosis-related dysmenorrhea, menorrhagia, and infertility.

Epigenomic Profiling of Epithelial Ovarian Cancer Stem-Cell Differentiation Reveals GPD1 Associated Immune Suppressive Microenvironment and Poor Prognosis.

Intraperitoneal metastasis is a challenging clinical scenario in epithelial ovarian cancer (EOC). As they are distinct from hematogenous metastasizing tumors, epithelial ovarian cancer cells primarily disseminate within the peritoneal cavity to form superficially invasive carcinomas. Unfavorable pharmacokinetics for peritoneal tumors and gut toxicity collectively lead to a narrow therapeutic window and therefore limit the opportunities for a favorable clinical outcome. New insights into tumor metastasis in the peritoneal microenvironment are keenly awaited to develop new therapeutic strategies. Epithelial ovarian cancer stem cell (OCSC) seeding is considered to be a critical component of the peritoneal spread. Using a unique and stepwise process of the OCSC differentiation model may provide insight into the intraperitoneal metastasis. The transcriptome and epigenome of OCSC differentiation were characterized by expression array and MethylCap-Seq. The TCGA, AOCS, and KM-Plotter databases were used to evaluate the association between survival outcomes and the methylation/expression levels of candidate genes in the EOC datasets. The STRING database was used to investigate the protein-protein interaction (PPI) for candidates and their associated genes. The infiltration level of immune cells in EOC patients and the association between clinical outcome and OCSCs differentiation genes were estimated using the TIDE and TIME2.0 algorithms. We established an EOC differentiation model using OCSCs. After an integrated transcriptomics and methylomics analysis of OCSCs differentiation, we revealed that the genes associated with earlier OCSC differentiation were better able to reflect the patient's outcome. The OCSC differentiation genes were involved in regulating metabolism shift and the suppressive immune microenvironment. High GPD1 expression with high pro-tumorigenic immune cells (M2 macrophage, and cancer associated fibroblast) had worst survival. Moreover, we developed a methylation signature, constituted by GNPDA1, GPD1, GRASP, HOXC11, and MSLN, that may be useful for prognostic prediction in EOC. Our results revealed a novel role of epigenetic plasticity OCSC differentiation and suggested metabolic and immune intervention as a new therapeutic strategy.

Ovarian mucinous cystadenoma with a mural nodule of osteosarcoma: A case report.

OBJECTIVE: Osteosarcoma as a mural nodule in the ovary is extremely rare. We aimed to describe a case of a mural nodule with features of an osteosarcoma arising in an ovarian mucinous cystadenoma. CASE REPORT: The 65-year-old woman presented with progressive abdominal swelling and poor intake. Image studies showed a huge (diameter, >30 cm) intra-abdominal multiloculated cystic lesion, suspected to be an ovarian tumor. She underwent unilateral salpingo-oophorectomy with no postoperative adjuvant therapy. She was disease-free at 16-month follow-up. CONCLUSION: Osteosarcoma presenting as a primary ovarian neoplasm is rare, either as a pure osteosarcoma or arising from a teratoma. However, two osteosarcoma cases occurring arising from a mural nodule in an ovarian mucinous neoplasm have been reported. There is no consensus regarding the treatment strategy for osteosarcomatous mural nodules in mucinous tumors because of its rarity. More case studies are needed before its pathogenesis can be fully understood.

Comparison of the laparoscopic versus conventional open method for surgical staging of endometrial carcinoma.

OBJECTIVE: Although laparoscopic surgery is widely utilized in the treatment of endometrial cancer, its efficacy in staging the cancer is not well established. The aim of this study was to compare staging endometrial cancer with laparoscopic and conventional open methods. MATERIALS AND METHODS: From January 2002 to June 2012, 151 patients (70 treated by laparoscopy and 81 by laparotomy) diagnosed with endometrial cancer were enrolled. This was a retrospective cohort review of endometrial cancer surgically staged using laparoscopy or laparotomy in the Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan. RESULTS: The two groups did not significantly differ in patient age, body mass index, previous obstetrical history, or amount of previous abdominal surgery. No differences between the surgical cohorts were observed in relation to cancer status, including stage, grade, myometrial invasion, lymphovascular space invasion, lymph node involvement, and recurrence rate. The laparoscopic approach had less intraoperative blood loss, longer operative time, lower uterine weight, number of removed lymph nodes, and shorter hospital stay. CONCLUSION: Our preliminary results showed that the laparoscopic method for staging endometrial cancer was technically feasible and efficient.

Regulatory T Cells Suppress Natural Killer Cell Immunity in Patients With Human Cervical Carcinoma.

OBJECTIVE: To determine the functional attributes of CD4 CD25 regulatory T (Treg) cells by suppressing natural killer (NK) cell activity in human cervical cancer (CC). METHODS: Triple-color flow cytometry was used to study the phenotypic expression of CD4 CD25 Treg cells and NK cells in the peripheral blood lymphocytes (PBLs) and tumor-infiltrating lymphocytes (TILs). In vitro coculture assays were performed to illustrate the cytokine immunoregulations between Treg cells and NK cells. RESULTS: Significantly lower expression ratio of NK cells and higher expression ratio of Treg cells in TILs than PBLs were found. The NK cells displayed significantly higher expression ratio of inhibitory NK receptors (CD158a, CD158b, and NKG2A) and lower expression ratio of activating NK receptors (NKG2D, NKp46, and NKp30) as well as perforin in TILs than PBLs, suggesting the suppressed cytotoxicity of the NK cells in the CC tumor milieu. The expression ratio of transforming growth factor-ß1 (TGF-ß1) on Treg cells as well as TGF-ßRII on Treg cells and NK cells was significantly higher in TILs than PBLs. Further functional in vitro assays demonstrated that NK cell function was suppressed by Treg cells, mimicking the inhibition of TGF-ß on NK cells, and interleukin-2/interleukin-15 stimulation was able to restore the NK cell activity. CONCLUSIONS: These findings indicate that Treg cells in TILs may abrogate NK cell cytotoxicity through TGF-ß pathway, and therefore, Treg cell elimination may enhance NK cell activity and be a novel therapeutic strategy for CC.

Comparison of Laparoscopic Myomectomy in Large Myomas With and Without Leuprolide Acetate.

STUDY OBJECTIVE: To evaluate the efficacy of gonadotropin-releasing hormone analogue (GnRHa) use before laparoscopic myomectomy (LM) in large myomas. DESIGN: Prospective study (Canadian Task Force classification II-1). SETTING: University-affiliated hospital. PATIENTS: Ninety-one women with large myomas (≥10 cm) or more than 2 myomas ≥ 5 cm underwent LM between July 2011 and March 2014. INTERVENTIONS: Forty patients underwent LM after GnRHa use (group A) and 51 underwent LM only (group B). GnRHa was used for 3 doses every 4 weeks before LM in group A. MEASUREMENTS AND MAIN RESULTS: Group A had a significantly smaller maximum diameter of the largest myoma than group B (8.5 ± 2.1 vs 10.7 ± 2.4, p < .001) and fewer patients with myomas larger than 10 cm after GnRHa administration (33% vs 67%, p = .001). In group A, there was a decrease in 2 or more myomas ≥ 5 cm (20% vs 50%) after GnRHa use. Group A also had significantly smaller mean myoma weight (448 vs 567 g, p = .045) and significantly shorter mean operative time (129 ± 30 vs 152 ± 34 minutes, p = .001). Most patients in group A (40%) had an operative time < 119 minutes, whereas most patients in group B (37%) had an operative time between 150 and 179 minutes. Group A also had less intraoperative blood loss (84 ± 53 vs 137 ± 166 mL, p < .001), drop in hemoglobin (1.5 ± 0.8 vs 3.0 ± 1.7 g/dl, p < .001), excessive bleeding (5% vs 33%, p = .001), postoperative hematoma (2.5% vs 9.8%, p = .168), and blood transfusion (7.5% vs 35%, p = .001). CONCLUSION: GnRHa before LM in large myomas may be an effective adjuvant treatment for women with large and multiple myomas. This method is beneficial in decreasing operative time, intraoperative bleeding, postoperative hemorrhage, and need of blood transfusion.