Yonsei Medical Journal

DNM3OS Facilitates Ovarian Cancer Progression by Regulating miR-193a-3p/MAP3K3 Axis

Long non-coding RNAs (lncRNAs) are essential regulators in the development of ovarian cancer (OC). Nonetheless, the function of lncRNA DNM3 opposite strand/antisense RNA (DNM3OS) in OC remains unclear. This work aimed to investigate the biological roles and underlying mechanisms of DNM3OS in OC. Quantitative real-time polymerase chain reaction was conducted to examine DNM3OS, microRNA (miR)-193a-3p, and mitogen-activated protein kinase 3 (MAP3K3) mRNA expression in OC tissues and cell lines. Kaplan-Meier survival analysis was employed to analyze the relationship between DNM3OS expression and the prognosis of OC patients. Cell counting kit-8, 5-ethynyl-2'-deoxyuridine, and transwell experiments were conducted to monitor cell proliferation, migration, and invasion, respectively. Western blot was applied to examine epithelial-mesenchymal transition associated protein (E-cadherin and N-cadherin) expression. Luciferase reporter gene and RNA immunoprecipitation experiments were performed to confirm the relationships among DNM3OS, miR-193a-3p, and MAP3K3. Pearson's correlation analysis was adopted to analyze the correlations among DNM3OS, miR-193a-3p, and MAP3K3 mRNA. DNM3OS expression was remarkably increased in OC tissues and cell lines, which was associated with the unfavorable prognosis of the patients. DNM3OS overexpression enhanced OC cell proliferation, migration, and invasion; suppressed E-cadherin protein expression; and facilitated N-cadherin protein expression, while the transfection of miR-193a-3p mimics had the opposite effects. DNM3OS directly interacted with miR-193a-3p, and miR-193a-3p targeted MAP3K3 by directly binding to 3'UTR. DNM3OS could up-regulate the expression of MAP3K3 via repressing miR-193a-3p expression. DNM3OS, as an oncogenic lncRNA, increases the malignancy of OC cells via regulation of an miR-193a-3p/MAP3K3 axis.

Comparative Survival Outcome of Robot-Assisted Staging Surgery Using Three Robotic Arms versus Open Surgery for Endometrial Cancer

There is lack of data on direct comparison of survival outcomes between open surgery and robot-assisted staging surgery (RSS) using three robotic arms for endometrial cancer. The purpose of this study was to compare the overall survival (OS) and disease-free survival (DFS) between open surgery and RSS using three robotic arms for endometrial cancer. Consecutive women with endometrial cancer who underwent surgery between May 2006 and May 2018 were identified. Robotic procedures were performed using the da Vinci robotic system, and the robotic approach consisted of three robotic arms including a camera arm. Propensity score matching, as well as univariate and multivariate Cox regression of OS and DFS were performed according to clinicopathologic data and surgical method. The study cohort included 423 unselected patients with endometrial cancer, of whom 218 underwent open surgery and 205 underwent RSS using three robotic arms. Propensity score-matched cohorts of 146 women in each surgical group showed no significant differences in survival: 5-year OS of 91% vs. 92% and DFS of 86% vs. 89% in the open and robotic cohorts, respectively (hazard ratio, 1.02; 95% confidence interval, 0.82-1.67). In the univariate analysis with OS as the endpoint, surgical method, age, stage, type II histology, grade, and lymph node metastasis were independently associated with survival. Surgical stage, grade, and type II histology were found to be significant independent predictors for OS in the multivariate analysis. RSS using three robotic arms and laparotomy for endometrial carcinoma had comparable survival outcomes.

Robotic Single-Site Plus One-Port Myomectomy versus Robotic Single-Site Plus Two-Port Myomectomy: A Propensity Score Matching Analysis

Robotic single-site plus one-port myomectomy (RSOM) was designed to reduce the number of incision sites for greater cosmetic satisfaction of patients while retaining the benefits of conventional robotic multi-site myomectomy (CRM). Robotic single-site plus two-port myomectomy (RSTM) eliminated one port relative to conventional CRM, and RSOM achieved the same advantage with respect to RSTM. This study aimed to compare RSOM with RSTM in terms of their respective methodologies and surgical outcomes. The medical records of 230 patients who had undergone RSOM and 146 patients who had undergone RSTM were reviewed. The groups' surgical outcomes were compared using propensity score matching (PSM) analysis. In the total data, RSOM had a shorter operative time (135.1±57.4 min vs. 149.9±46.2 min, Compared with RSTM, RSOM was associated with shorter operative time. Additionally, more detailed comparative and prospective studies are needed to evaluate RSOM relative to RSTM.

A Single-Center, Retrospective Study of Bevacizumab-Containing Neoadjuvant Chemotherapy followed by Interval Debulking Surgery for Ovarian Cancer

We evaluated whether adding bevacizumab to current platinum-based chemotherapy could improve clinical outcomes without affecting safety. We retrospectively reviewed medical records of patients with pathologically confirmed ovarian cancer who received neoadjuvant chemotherapy (NAC) at Yonsei Cancer Hospital. We divided the patients into groups based on the use of bevacizumab for NAC (CP group: carboplatin+paclitaxel vs. BCP group: bevacizumab+carboplatin+paclitaxel) and compared patient characteristics, responses to NAC, and surgical and survival outcomes between the two groups. Overall, 88 patients in the CP group and 16 patients in the BCP group received NAC. The primary endpoint was survival outcomes. Complete resection rate after interval debulking surgery (IDS), cancer antigen 125 (CA-125) normalization after NAC, and chemotherapy response score were secondary endpoints. After NAC treatment, all patients underwent IDS. There were no significant differences in adverse events during NAC or postoperative complications between the two groups ( Bevacizumab-containing NAC might be safe and provide longer PFS than chemotherapy alone in patients with advanced ovarian cancer. However, further study is necessary to investigate the impact of bevacizumab-containing NAC on OS.

Development and Validation of a Nomogram Prediction Model for Endometrial Malignancy in Patients with Abnormal Uterine Bleeding

This study aimed to identify the risk factors and sonographic variables that could be integrated into a predictive model for endometrial cancer (EC) and atypical endometrial hyperplasia (AEH) in women with abnormal uterine bleeding (AUB). This retrospective study included 1837 patients who presented with AUB and underwent endometrial sampling. Multivariable logistic regression was developed based on clinical and sonographic covariates [endometrial thickness (ET), resistance index (RI) of the endometrial vasculature] assessed for their association with EC/AEH in the development group (n=1369), and a predictive nomogram was proposed. The model was validated in 468 patients. Histological examination revealed 167 patients (12.2%) with EC or AEH in the development group. Using multivariable logistic regression, the following variables were incorporated in the prediction of endometrial malignancy: metabolic diseases [odds ratio (OR)=7.764, 95% confidence intervals (CI) 5.042-11.955], family history (OR=3.555, 95% CI 1.055-11.971), age ≥40 years (OR=3.195, 95% CI 1.878-5.435), RI ≤0.5 (OR=8.733, 95% CI 4.311-17.692), and ET ≥10 mm (OR=8.479, 95% CI 5.440-13.216). A nomogram was created using these five variables with an area under the curve of 0.837 (95% CI 0.800-0.874). The calibration curve showed good agreement between the observed and predicted occurrences. For the validation group, the model provided acceptable discrimination and calibration. The proposed nomogram model showed moderate prediction accuracy in the differentiation between benign and malignant endometrial lesions among women with AUB.

Real-World Experience with Pembrolizumab Treatment in Patients with Heavily Treated Recurrent Gynecologic Malignancies

We evaluated the efficacy and safety of pembrolizumab in patients with recurrent gynecologic cancers in real-world practice. We conducted a retrospective, single-institution study of patients with recurrent gynecologic malignancies treated with pembrolizumab. The primary endpoints were the objective response rate (ORR) and safety. Thirty-one patients treated with pembrolizumab were included. The primary disease sites were the uterine cervix (n=18), ovaries (n=8), and uterine corpus (n=5). Fifteen of the 31 patients (48%) had an Eastern Cooperative Oncology Group performance status of ≥2. The median number of prior chemotherapy lines was 2 (range, 1-6), and 14 of 31 patients (45%) had received ≥ 3 prior lines of chemotherapy. The overall ORR was 22.6%: specifically, 22.3% (4 of 18 patients), 12.5% (1 of 8 patients), and 40% (2 of 5 patients) for cervical, ovarian, and endometrial cancers, respectively. During a median follow-up of 4.7 months (range, 0.2-35.3), the median time to response was 1.9 months (range, 1.4-5.7). The median duration of response was not reached (range, 8.8-not reached). The median progression-free survival was 2.5 months (95% confidence interval, 1.7-not reached). Adverse events occurred in 20 patients (64.5%), and only 3 (9.7%) were grade ≥3. There was one case of suspicious treatment-related mortality, apart from which most adverse events were manageable. In real-world practice, pembrolizumab was feasible and effective in heavily treated recurrent gynecologic cancer patients with poor performance status who may not be eligible for enrollment in clinical trials.

Risk Factors Associated with Endometrial Pathology in Premenopausal Breast Cancer Patients Treated with Tamoxifen

To evaluate factors associated with endometrial pathology during tamoxifen use in premenopausal breast cancer (BC) patients. We reviewed the medical records of premenopausal BC patients treated with tamoxifen who underwent endometrial biopsy with or without hysteroscopy. Clinical characteristics were compared between women with endometrial pathology (endometrial hyperplasia or cancer) and those with normal histology or endometrial polyps. Among 284 endometrial biopsies, endometrial hyperplasia was diagnosed in 7 patients (2.5%), endometrial cancer was diagnosed in 5 patients (1.8%), normal histology was noted in 146 patients (51.4%), and endometrial polyp was present in 114 patients (40.1%). When comparing women with endometrial cancer (n=5) to women with normal histology, abnormal uterine bleeding was more common ( In premenopausal BC patients treated with tamoxifen, abnormal uterine bleeding, increased endometrial thickness, and chemotherapy for BC were associated with the occurrence of endometrial cancer. These findings may provide useful information for gynecologic surveillance and counseling during tamoxifen treatment in premenopausal BC patients.

Recurrence, Reoperation, Pregnancy Rates, and Risk Factors for Recurrence after Ovarian Endometrioma Surgery: Long-Term Follow-Up of 756 Women

The aims of this study were to evaluate the cumulative recurrence, reoperation, and pregnancy rates after ovarian endometrioma surgery at a single institution for more than a 5-year follow-up period. This study was conducted as a retrospective chart review of patients with ovarian endometrioma who underwent surgery between January 2008 and March 2016. Study subjects included premenopausal women with at least 5 years of follow-up. Exclusion criteria were patients with stage I or II ovarian endometrioma, those who underwent hysterectomy or bilateral oophorectomy, and presence of residual ovarian lesions on the first postoperative ultrasonography at 3-6 months. Recurrence was defined as a cystic mass by ultrasonography. A total of 756 patients were recruited. The median follow-up duration was 85.5 months (interquartile range, 71-107 months). Recurrent endometrioma was detected in 27.9% patients, and reoperation was performed in 8.3% patients. Cumulative rates at 24, 36, 60, and 120 months were 5.8%, 8.7%, 15.5% and 37.6%, respectively, for recurrence and 0.1%, 0.5%, 2.9%, and 15.1%, respectively, for reoperation. After multivariable analysis, age ≤31 years [hazard ratio (HR)=2.108; 95% confidence interval (CI)=1.522-2.921; Considering that longer postoperative hormonal treatment is the sole modifiable factor for recurrent endometrioma, we recommend long-term hormonal treatment until subsequent pregnancy, especially in younger women.

Survival Effects of Cytoreductive Surgery for Refractory Patients after Neoadjuvant Chemotherapy in Advanced Epithelial Ovarian Cancer

Salvage second-line chemotherapy is usually recommended for patients with advanced epithelial ovarian cancer (AEOC) who develop progressive disease (PD) after neoadjuvant chemotherapy (NAC). Herein, we investigated the role of cytoreductive surgery (CRS) for such patients. We retrospectively reviewed the medical records of 36 patients with AEOC who developed PD after receiving NAC at two tertiary academic centers with different treatment strategies between 2001 and 2016. Patients who developed PD after NAC were consistently treated with CRS at one hospital (group A; n=13) and second-line chemotherapy at another (group B; n=23). The clinical characteristics and treatment outcomes were compared between the groups. Overall survival (OS) was longer in group A than in group B (19.4 months vs. 7.9 months; CRS may result in a survival benefit even in patients with AEOC who develop PD after NAC.

Uptake Rate of Risk-Reducing Salpingo-Oophorectomy and Surgical Outcomes of Female Germline BRCA1/2 Mutation Carriers: A Retrospective Cohort Study

This study investigated the uptake rate of risk-reducing salpingo-oophorectomy (RRSO) and surgical outcomes of germline We examined the records of 824 women who underwent germline There were 117 The uptake rate of RRSO in

Comparison of the Prognostic Outcome between High-Grade Ovarian Sertoli-Leydig Cell Tumors (SLCTs) and Low-Grade SLCTs

The purpose of the current study was to compare prognostic outcomes between patients with high-grade ovarian Sertoli-Leydig cell tumors (SLCTs) and those with other low-grade SLCTs. We retrospectively reviewed medical records for 24 patients pathologically diagnosed with SLCTs between 2006 to 2019 at two institutions. The patients were grouped according to pathological grade: SLCT was classified as grade 1, well differentiated; grade 2, intermediated differentiated; or grade 3, poorly differentiated (Meyer's classification). Statistical analysis was performed to compare survival outcomes according to pathological grade. The median patient age was 42.5 years (range 16-75). Eighteen patients (75%) were International Federation of Gynecology and Obstetrics stage I, and none were diagnosed in stage IV. Nine patients (37.5%) were grade 3, and 15 patients (63.5%) were grades 1-2. When comparing clinical baseline characteristics of the grade 1-2 group with those of the grade 3 group, only serum CA125 level at diagnosis was significantly higher in the grade 3 group (38.34 vs. 382.29,

Indocyanine Green-Loaded PLGA Nanoparticles Conjugated with Hyaluronic Acid Improve Target Specificity in Cervical Cancer Tumors

Indocyanine green (ICG) is a promising agent for intraoperative visualization of tumor tissues and sentinel lymph nodes in early-stage gynecological cancer. However, it has some limitations, including a short half-life and poor solubility in aqueous solutions. This study aimed to enhance the efficacy of near-infrared (NIR) fluorescence imaging by overcoming the shortcomings of ICG using a nano-drug delivery system and improve target specificity in cervical cancer. ICG and poly(lactic-co-glycolic acid) (PLGA) conjugated with polyethylenimine (PEI) were assembled to enhance stability. Hyaluronic acid (HA) was coated on PEI-PLGA-ICG nanoparticles to target CD44-positive cancer cells. The manufactured HA-ICG-PLGA nanoparticles (HINPs) were evaluated in vitro and in vivo on cervical cancer cells (SiHa; CD44+) and human dermal cells (ccd986sk; CD44-), respectively, using NIR imaging to compare intracellular uptake and to quantify the fluorescence intensities of cells and tumors. HINPs were confirmed to have a mean size of 200 nm and a zeta-potential of 33 mV using dynamic light scattering. The stability of the HINPs was confirmed at pH 5.0-8.0. Cytotoxicity assays, intracellular uptake assays, and cervical cancer xenograft models revealed that, compared to free ICG, the HINPs had significantly higher internalization by cervical cancer cells than normal cells ( This study demonstrated the successful application of HINPs as nanocarriers for delivering ICG to CD44-positive cervical cancer, with improved efficacy in NIR fluorescence imaging.

Lymph Node Ratio Is a Strong Prognostic Factor in Patients with Early-Stage Cervical Cancer Undergoing Minimally Invasive Radical Hysterectomy

To determine whether the prognostic impact of lymph node ratio (LNR), defined as the ratio between the number of positive lymph nodes and removed lymph nodes, differs between open and minimally invasive surgical approaches for radical hysterectomy (RH) in node-positive, early-stage cervical cancer. We retrospectively identified 2009 International Federation of Gynecology and Obstetrics stage IB1-IIA2 patients who underwent primary type C RH between 2010 and 2018. Among them, only those with pathologically proven lymph node metastases who received adjuvant radiation therapy were included. The prognostic significance of LNR was investigated according to open surgery and minimally invasive surgery (MIS). In total, 55 patients were included. The median LNR (%) was 9.524 (range, 2.083-62.500). Based on receiver operating characteristic curve analysis, the cut-off value for LNR (%) was determined as 8.831. Overall, patients with high LNR (≥8.831%; n=29) showed worse disease-free survival (DFS) than those with low LNR (<8.831%, n=26) ( In patients with node-positive, early-stage cervical cancer, high LNR was associated with a significantly higher disease recurrence rate. This relationship was further consolidated among patients who received MIS RH.