Cytokine and epigenetic regulation of programmed death-ligand 1 in stem cell differentiation and cancer cell plasticity.

Programmed death-ligand 1 (PD-L1), an immune checkpoint ligand, is recognized as a potential target for cancer immunotherapy as well as for the induction of transplantation tolerance. However, how the crosstalk between stem cell programming and cytokine signaling regulates PD-L1 expression during stem cell differentiation and cancer cell plasticity remains unclear. Herein, we reported that PD-L1 expression was regulated by SOX2 during embryonic stem cell (ESC) differentiation and lung cancer cell plasticity. PD-L1 was induced during ESC differentiation to fibroblasts and was downregulated during SOX2-mediated reprogramming of fibroblasts to induced pluripotent stem cells (iPSCs). Furthermore, SOX2 activation affected cancer cell plasticity and inhibited PD-L1 expression in lung cancer cells. We discovered that the H3K27ac signal at the PD-L1 locus was enhanced during ESC differentiation to fibroblasts as well as during cancer plasticity of SOX2-positive lung cancer cells to SOX2-negative counterparts. Romidepsin, an epigenetic modifier, induced PD-L1 expression in lung cancer cells, whereas TGF-ß stimulation downregulated SOX2 but upregulated PD-L1 expression in lung cancer cells. Furthermore, in addition to PD-L1, the expressions of EGFR and its ligand HBEGF were downregulated by activation of endogenous SOX2 expression during lung cancer cell plasticity and iPSC reprogramming, and the activation of EGFR signaling by HBEGF upregulated PD-L1 expression in lung cancer cells. Together, our results reveal the crosstalk between SOX2 programming and cytokine stimulation influences PD-L1 expression, and these findings may provide insights into PD-L1-mediated therapeutics.

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.

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.

The role of EpCAM in tumor progression and the clinical prognosis of endometrial carcinoma.

OBJECTIVE: EpCAM is a transmembrane glycoprotein that functions as an epithelial marker in endometrial tissues. However, the correlation between EpCAM and endometrial carcinoma (EC) is not clear. METHODS: This study investigated the association between EpCAM and EC. Immunohistochemistry staining and bioinformatics analysis disclosed the clinical importance of low EpCAM expression. The migratory ability of cells expressing low EpCAM levels was studied in transwell invasion assays in vitro and an orthotopic intra-uterine tumor injection model in vivo. The Connectivity MAP was used to identify drugs that effectively inhibit cells with low EpCAM expression. RESULTS: According to immunohistochemistry analysis results, low EpCAM expression was associated with an advanced stage and lymph node metastasis in patients with endometrioid EC, and high EpCAM expression favored survival. EpCAM silencing promoted cell invasion, and EpCAM re-expression in EpCAM-silenced EC cells attenuated their invasiveness. EpCAM suppression in an orthotopic uterine implantation model promoted the lymph node metastasis of EC cells. According to quantitative PCR and promoter reporter analyses, estrogen receptor alpha signaling regulated EpCAM expression by enhancing its promoter activity. As shown in the Connectivity MAP analysis, transamin inhibited the invasiveness of EpCAM-silenced EC cells. CONCLUSIONS: The loss of EpCAM may increase the malignancy of EC, and these findings provide new insights into the prognostic role of EpCAM in patients with EC.

Primary surgery versus primary radiation therapy for FIGO stages I-II small cell carcinoma of the uterine cervix: A retrospective Taiwanese Gynecologic Oncology Group study.

OBJECTIVE: To evaluate the role of surgery, radiation therapy and chemotherapy in the management of small cell carcinoma of the uterine cervix (SCCC) through a retrospective study of Taiwanese Gynecologic Oncology Group. METHODS: We reviewed the medical records and histological files of 144 patients with FIGO stages IA-IIB SCCC treated in 11 main hospitals in Taiwan from 1987 to 2009. RESULTS: There were 110 patients receiving primary surgery and 34 primary radiation therapy. Most patients in each group also received chemotherapy as part of primary treatment. A lower loco-regional failure rate was observed in patients who received primary radiation therapy than in those who had primary surgery (6% vs. 27%; P=0.009). The 5-year overall survival (OS) was 89% for 13 surgically treated patients with cervical tumor ≤2cm and no lymphovascular space involvement (LVSI) in whom recurrence was noted in 2 of 4 patients without receiving adjuvant chemotherapy and none in the 9 patients who had chemotherapy. Excluding these 13 patients, primary radiation therapy with at least 5cycles of platinum-based chemotherapy (n=14, including 12 stages IB2-IIB) resulted in a 5-year OS of 78%, better than that of 46% by primary surgery (n=97, including 40 stages IB2-IIB) (P=0.046). CONCLUSIONS: None of the 9 patients with cervical tumor ≤2cm and no LVSI showed disease recurrence after primary surgery and adjuvant chemotherapy. For most patients with stages I-II, primary radiation therapy with aggressive chemotherapy was associated with better survival than surgery.

Methylated ZNF582 gene as a marker for triage of women with Pap smear reporting low-grade squamous intraepithelial lesions - a Taiwanese Gynecologic Oncology Group (TGOG) study.

OBJECTIVE: Our previous work revealed that host genes ZNF582, PTPRR, PAX1, and SOX1 are highly methylated in cervical intraepithelial neoplasias grade 3 or worse (CIN3(+)). In this study, we used a standardized testing assay to evaluate the clinical efficacy of these biomarkers in the triage of cytological diagnoses of low-grade squamous intraepithelial lesions (LSILs), and compared the performance with human papillomavirus (HPV) testing. METHODS: This 2-year multicenter prospective study examined a population of 230 women from 12 medical centers who were diagnosed with LSILs on cervical cytology. Cervical scrapings were obtained prior to a colposcopy-directed biopsy for quantitative methylation analysis of ZNF582, PTPRR, PAX1, and SOX1, and HPV testing. Using logistic regression and receiver operating characteristic curve analyses, the abilities of methylated genes and HPV to predict CIN3(+) were assessed. RESULTS: Fifteen (6.5%) of the 230 women with a cytological diagnosis of LSIL were confirmed to have CIN3(+) after a colposcopy-directed biopsy. Among the 4 methylated genes, ZNF582 was found to be the best biomarker for detecting CIN3(+). The sensitivities for methylated ZNF582 and HPV testing were 73% and 80%, and the specificities were 71% and 28%, respectively. The odds ratio for predicting CIN3(+) using methylated ZNF582 was 6.8 (95% confidence interval (CI) 2.1-22.1), which was much better than HPV testing (OR=1.6, 95% CI 0.4-5.8). CONCLUSION: This is the first study to show that ZNF582 methylation analysis of cervical swabs may be a promising choice in the positive triage of cytological diagnoses of LSILs.

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.

The role of secondary cytoreductive surgery in patients with recurrent epithelial ovarian, tubal, and peritoneal cancers: a comparative effectiveness analysis.

Background. All published reports concerning secondary cytoreductive surgery for relapsed ovarian cancer have essentially been observational studies. However, the validity of observational studies is usually threatened from confounding by indication. We sought to address this issue by using comparative effectiveness methods to adjust for confounding. Methods. Using a prospectively collected administrative health care database in a single institution, we identified 1,124 patients diagnosed with recurrent epithelial, tubal, and peritoneal cancers between 1990 and 2009. Effectiveness of secondary cytoreductive surgery using the conventional Cox proportional hazard model, propensity score, and instrumental variable were compared. Sensitivity analyses for residual confounding were explored using an array approach. Results. Secondary cytoreductive surgery prolonged overall survival with a hazard ratio (95% confidence interval) of 0.76 (range 0.66-0.87), using the Cox proportional hazard model. Propensity score methods produced comparable results: 0.75 (range 0.64-0.86) by nearest matching, 0.73 (0.65-0.82) by quintile stratification, 0.71 (0.65-0.77) by weighting, and 0.72 (0.63-0.83) by covariate adjustment. The instrumental variable method also produced a comparable estimate: 0.75 (range 0.65-0.86). Sensitivity analyses revealed that the true treatment effects may approach the null hypothesis if the association between unmeasured confounders and disease outcome is high. Conclusions. This comparative effectiveness study provides supportive evidence for previous reports that secondary cytoreductive surgery may increase overall survival for patients with recurrent epithelial, tubal, and peritoneal cancers.

Prenatal case of RIT1 mutation associated Noonan syndrome by whole exome sequencing (WES) and review of the literature.

OBJECTIVE: We aimed to identify the genetic cause of one hydrops fetalis with Noonan syndrome (NS) manifestations including increased nuchal translucency (INT) and ascites through prenatal whole exome sequencing (WES). CASE REPORT: The case is a gestational age (GA) 18 fetus of two healthy parents with a normal child. We proceeded the genomic DNA from both fetus amniotic cells and parents to WES and identified a RIT1 mutation (c.268A>G) as the pathogenic cause of the hydrops fetalis by automatic prioritization algorithm after array-comparative genomic hybridization results showing negative. CONCLUSION: Mutations in RIT1 have been reported as the causes for different fetus structural abnormities in the recent years. This case contributes to the summary delineations of the prenatal NS phenotypes related to RIT1 mutation. In addition, the fast WES application, in this case, has demonstrated its advantage in prenatal disorder diagnosis when conventional karyotyping or chromosomal microarray testing result is negative.

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.

Feasibility of single-port laparoscopic cholecystectomy using a homemade laparoscopic port: a clinical report of 50 cases.

AIM: To report the clinical experience of transumbilical single-port laparoscopic cholecystectomy (TUSPLC), using a homemade laparoscopic access port composed of two inexpensive and common pieces of equipment readily available in the operating room. METHODS: Fifty consecutive patients with gallstones, including ten patients (20%) with acute cholecystitis, underwent single-port laparoscopic cholecystectomy (LC) using a homemade single port composed of a segment of corrugated breathing tube and a pair of surgical gloves. The port was inserted into the umbilicus for simultaneous placement of multiple conventional instruments into the abdominal cavity. All patients underwent dome-down LC using traditional instruments with manually angulated shafts; dissection was done using electrocautery or harmonic scalpel. RESULTS: All but two procedures were completed uneventfully. Two patients with acute cholecystitis due to dense adhesions in the triangle of Calot necessitated conversion to two- and four-port laparoscopic procedures, respectively. Operative time averaged 73 ± 2 min for chronic cholecystitis and 95 ± 5 min for acute cholecystitis. There were no perioperative port-related or surgical complications, except for two patients who developed wound seroma and recovered after conservative treatment. We found that healing of the umbilical wound left virtually no scar in all patients. CONCLUSION: The homemade umbilical port reported in this study is useful for multiple instrument access and allows TUSPLC to be performed safely, with its inherent cosmetic and cost advantages. Further studies of this technique are ongoing.

Myomectomy for uterine myomas through ultramini-laparotomy.

Uterine fibroids are the most common benign tumors in the female reproductive tract during the reproductive years. Among the options in the treatment spectrum, myomectomy is always considered one of the best choices in the management of women with symptomatic uterine fibroids who wish to preserve future fertility. Myomectomy through conventional exploratory laparotomy may be the most familiar surgical approach. However, with the advances being made in techniques and instruments, there are many alternative approaches to myomectomy, including mini-laparotomy, ultramini-laparotomy, laparoscopy, laparoscopy-aided, and vaginal and hysteroscopic approaches. The focus of this review article is limited to discussing the use of the ultramini-laparotomy approach to completing myomectomy in the management of the uterine fibroids.

Comparing uterine fibroids treated by myomectomy through traditional laparotomy and 2 modified approaches: ultraminilaparotomy and laparoscopically assisted ultraminilaparotomy.

OBJECTIVE: We sought to compare myomectomy performed by laparotomy (LT), and 2 other modified approaches: ultraminilaparotomy (UMLT) and laparoscopically assisted UMLT for uterine fibroids with a size <8 cm and the number <5. STUDY DESIGN: A cohort study, including 79 (35.3%) women in the LT group, 71 (31.7%) in the UMLT group, and 74 (33.0%) in the laparoscopically assisted UMLT group, was conducted. The outcome was measured by comparing surgical parameters, immediate postoperative recovery, and therapeutic outcomes. RESULTS: The median follow-up was 52 months with similar recurrence rates in the 3 groups. The modified approaches had advantages not only in the surgical parameters, but also in postoperative recovery, compared to LT (all P < .05). CONCLUSION: UMLT and laparoscopically assisted UMLT can be used successfully in place of LT in the management of uterine fibroids.

Neoadjuvant metformin added to conventional chemotherapy synergizes anti-proliferative effects in ovarian cancer.

BACKGROUND: Ovarian cancer is the leading cause of cancer-related death among women. Complete cytoreductive surgery followed by platinum-taxene chemotherapy has been the gold standard for a long time. Various compounds have been assessed in an attempt to combine them with conventional chemotherapy to improve survival rates or even overcome chemoresistance. Many studies have shown that an antidiabetic drug, metformin, has cytotoxic activity in different cancer models. However, the synergism of metformin as a neoadjuvant formula plus chemotherapy in clinical trials and basic studies remains unclear for ovarian cancer. METHODS: We applied two clinical databases to survey metformin use and ovarian cancer survival rate. The Cancer Genome Atlas dataset, an L1000 microarray with Gene Set Enrichment Analysis (GSEA) analysis, Western blot analysis and an animal model were used to study the activity of the AKT/mTOR pathway in response to the synergistic effects of neoadjuvant metformin combined with chemotherapy. RESULTS: We found that ovarian cancer patients treated with metformin had significantly longer overall survival than patients treated without metformin. The protein profile induced by low- concentration metformin in ovarian cancer predominantly involved the AKT/mTOR pathway. In combination with chemotherapy, the neoadjuvant metformin protocol showed beneficial synergistic effects in vitro and in vivo. CONCLUSIONS: This study shows that neoadjuvant metformin at clinically relevant dosages is efficacious in treating ovarian cancer, and the results can be used to guide clinical trials.

Complete remission of heavily treated ovarian clear cell carcinoma with ARID1A mutations after pembrolizumab and bevacizumab combination therapy: a case report.

BACKGROUND: Patients with ovarian clear cell carcinoma (OCCC) have a poor prognosis because they show low sensitivity to platinum-based chemotherapy. New treatments for refractory OCCC are urgently needed. CASE PRESENTATION: We present a patient with refractory OCCC in whom conventional chemotherapy failed. Cachexia was induced by the disseminating recurrent tumors. Tumor tissue staining and genomic analysis revealed PD-L1 negativity, a low tumor burden, stable microsatellite instability, and two mutations in ARID1A. The patient was administered pembrolizumab combined with bevacizumab triweekly. Her serum CA-125 level decreased dramatically after the first cycle. A computerized tomography scan showed marked regression of the recurrent masses after 3 cycles, and the patient reached complete remission after 9 cycles. She showed good recovery from cachexia. We observed no marked side effects except for mild polyarthritis of the small joints. CONCLUSIONS: The therapeutic effect of checkpoint inhibitors combined with angiogenesis inhibitors is very promising in our patient with OCCC. Further clinical trials of tumors including ARID1A mutations are warranted.

Small supernumerary marker chromosome originating from chromosome 10 associated with an apparently normal phenotype.

Small supernumerary marker chromosomes (sSMC) originating from chromosome 10 are rare. Only seven cases have been documented, and among those three cases were diagnosed prenatally. We reported on another prenatal diagnosis of a de novo mosaic sSMC in an apparently normal female fetus whose mother had conceived with assisted reproductive technology (ART) procedures. G-banding analysis of amniotic cells was performed. Spectral karyotyping (SKY) and fluorescence in situ hybridization (FISH) studies with chromosome 10-specific alphoid satellite DNA probe were used to identify the chromosome 10 origin of the sSMC. Further FISH study with telomeric sequence probes showed that the sSMC lacked a hybridization signal, suggesting that the marker could be a ring chromosome. FISH studies using BAC clone probes specific for the regions within 10p11.2, 10q11.1, and 10q11.2 showed that the short arm breakpoint was located between 29.8 and 30.7 Mb from the 10p telomere, and that the long arm breakpoint was located less than 43.6 Mb from the 10p telomere. The karyotype of the fetus was 47,XX,+mar. ish der(10)(SKY+ CEP 10+, CTD-2130I7+, RP11-89J23-)/46,XX. Oligonucleotide microarray-based copy number variations (CNV) analysis was also performed and showed a 6.7 Mb duplication from 10p11.2 to 10q11.2 (36.2-42.9 Mb) with Affymetrix SNP-array 6.0 genotype: arr cgh. 10p11.2q11.2(CN_519687 --> CN_541524) X 3. At the 1-year follow-up, the baby did not have any findings of the trisomy 10p syndrome. This observation provided further credence to the concept that additional chromosome material of proximal 10p11.2 may not contribute to the trisomy 10p syndrome phenotype.

The role of α2,3-linked sialylation on clear cell type epithelial ovarian cancer.

OBJECTIVE: Our previous study has shown that high expression of α2,3-sialytransferase type I was associated with advanced stage serous type epithelial ovarian cancer (EOC). The aim of the current study further attempts to evaluate the altered α 2,3-sialylation on the behavior of clear cell type EOC (C-EOC). MATERIALS AND METHODS: Immunohistochemistry staining, bioinformatics analysis and tissue array were used to disclose the clinical significance of over α2,3-sialylation in C-EOC. An α2,3 sialylation inhibitor, soyasaponin I (SsaI) was used to investigate the behavior change of the C-EOC cell line. RESULTS: We reconfirmed that α2,3-sialylation, instead of α2,6- sialylation, was associated with late-stage C-EOC. Soyasaponin I could inhibit α2,3-sialylation of C-EOC cell lines and increase E-cadherin expression with subsequently suppressing migration of C-EOC cells. CONCLUSIONS: The current study demonstrated the important role of α2,3-linked sialylation in C-EOC and targeting of α2,3-linked sialylation might offer as a potential therapeutic strategy in the future.

A case-control study to compare the outcome of women treated by two minimally invasive procedures-ultraminilaparotomy myomectomy and laparoscopic myomectomy.

OBJECTIVE: Ultraminilaparotomy myomectomy (UMLT-M with less 4 cm transverse skin incision) and conventional 3-port wound laparoscopic myomectomy (LM) approaches were proposed as alternative minimally invasive procedures in the management of women with symptomatic uterine myomas but few studies have compared the outcomes of both procedures. MATERIALS AND METHODS: Between January 2002 and December 2003, 71 patients undergoing UMLT-M were compared with those 71 women undergoing LM. The last data collection for all patients was done on 31 December 2016. The parameters for comparison included the characteristics of the uterine myomas, surgical parameters, morbidities, and outcomes. Surgical parameters included the operative time (minutes), estimated blood loss (milliliters), time for removal of drainage, percentage of blood transfusion and co-morbidities. RESULTS: Mean operative time in the LM group was significantly longer than that in the UMLT-M group (208.7 ± 65.9 vs. 98.0 ± 28.2 min, p < 0.001). Intra-operative blood loss was significantly higher in the LM group than that in the UMLT-M group (210.9 ± 184.5 vs. 111.7 ± 108.4 ml, p < 0.001). However, more patients had postoperative fever in the UMLT-M group (39.4% vs. 8.5%, p < 0.001). The recurrence rate of myoma at 5-year follow-up was significantly different between two groups (35.2% of UMLT-M vs. 57.7% of LM, p = 0.007), but there was no difference when follow-up time was over ten years. The location of the myoma recurrence was different between two groups with higher recurrence rates in the fundal and lateral sides of uterus in the UMLT-M group and in the anterior wall of uterus in the LM group. However, the overall symptom control, the need of repeated myoma-related surgery and subsequent pregnancy outcome of both groups seemed to be similar in both groups. CONCLUSIONS: More operative time and more blood loss reflected that LM demanded skills, experience and equipment. Therefore, UMLT-M might be a feasible alternative choice in the management of uterine myomas, since it is an easy-to-perform and familiar technique, especially in the absence of suitable equipment or skilled operator. A large and randomized study is needed to confirm the above findings.

Crosstalk between SOX2 and cytokine signaling in endometrial carcinoma.

Endometrial carcinoma is a cancer derived from oncogenesis of the regenerating uterine cavity, in which cytokine stimulation shapes cell differentiation and tissue remodeling. Expression of the stem cell factors SOX2, OCT4, NANOG, and MYC has been linked to tumor malignancy in several cancers. However, how these stem cell factors crosstalk with cytokine signaling to promote malignancy in endometrial carcinoma is still elusive. Here we report that the expression of SOX2 and MYC, but not that of OCT4 and NANOG, correlate with poor histological differentiation and prognosis, while SOX2 expression is negatively associated with MYC level. We found that SOX2-high endometrial carcinoma cells possessed a higher colony-forming ability than their SOX2-low counterparts, and knockdown of SOX2 attenuated the colony-forming ability. We observed that SOX2 regulated EGFR expression in a SOX2-EGFR positive feedback loop. EGF stimulation induced SOX2 expression and promoted migration of endometrial carcinoma cells, whereas TGF-ß stimulation inhibited SOX2 expression and attenuated the colony-forming ability. Immunohistochemistry analysis revealed that SOX2 expression correlated with lymph node infiltration of endometrial carcinoma. Our findings support that cytokine-induced stem cell factor SOX2 possesses oncogenic properties, with the potential to serve as a prognostic biomarker in endometrial carcinoma.