Identification of Prognostic Markers of Gynecologic Cancers Utilizing Patient-Derived Xenograft Mouse Models.

Patient-derived xenografts (PDXs) are important in vivo models for the development of precision medicine. However, challenges exist regarding genetic alterations and relapse after primary treatment. Thus, PDX models are required as a new approach for preclinical and clinical studies. We established PDX models of gynecologic cancers and analyzed their clinical information. We subcutaneously transplanted 207 tumor tissues from patients with gynecologic cancer into nude mice from 2014 to 2019. The successful engraftment rate of ovarian, cervical, and uterine cancer was 47%, 64%, and 56%, respectively. The subsequent passages (P2 and P3) showed higher success and faster growth rates than the first passage (P1). Using gynecologic cancer PDX models, the tumor grade is a common clinical factor affecting PDX establishment. We found that the PDX success rate correlated with the patient's prognosis, and also that ovarian cancer patients with a poor prognosis had a faster PDX growth rate (p < 0.0001). Next, the gene sets associated with inflammation and immune responses were shown in high-ranking successful PDX engraftment through gene set enrichment analysis and RNA sequencing. Up-regulated genes in successful engraftment were found to correlate with ovarian clear cell cancer patient outcomes via Gene Expression Omnibus dataset analysis.

Correction: ΔNp63 to TAp63 expression ratio as a potential molecular marker for cervical cancer prognosis.

[This corrects the article DOI: 10.1371/journal.pone.0214867.].

microRNA-944 overexpression is a biomarker for poor prognosis of advanced cervical cancer.

BACKGROUND: One-third of cervical cancer patients are still diagnosed at advanced stages. The five-year survival rate is decreased in about 50% of advanced stage cervical cancer patients worldwide, and the clinical outcomes are remarkably varied and difficult to predict. One of the miRNAs known to be associated with cancer tumorigenesis is miR-944. However, the prognostic value of miR-944 in cervical cancer has not been fully investigated. The aim of this study was to analyze clinical significance and prognostic value of miR-944 in cervical cancer. METHODS: The expression levels of miR-944 were detected using quantitative reverse transcription polymerase chain reaction in five types of cervical cancer cell lines and 116 formalin-fixed paraffin-embedded (FFPE) cervical tissues. The association between the expression levels of miR-944 and prognostic value was analyzed using the Kaplan-Meier analysis and Cox proportional hazards model. RESULTS: The expression levels of miR-944 in cervical cancer tissues were significantly higher compared with those in normal tissues (P < 0.0001). Moreover, the expression levels of miR-944 in cervical cancer cell lines and FFPE tissues with human papillomavirus (HPV) infection were significantly higher compared to those without HPV infection (P < 0.01 and P = 0.02). High miR-944 expression was also markedly associated with bulky tumor size (P = 0.026), advanced International Federation of Gynecology and Obstetrics (FIGO) stage (P = 0.042), and lymph node metastasis (P = 0.030). In particular, high miR-944 expression group showed shorter overall survival than the low miR-944 expression group in the advanced FIGO stage (84.4% vs. 44.4%, HR = 4.0, and P = 0.01). CONCLUSIONS: These results suggest that miR-944 may be used as a novel biomarker for improving prognosis and as a potential therapeutic target.

ΔNp63 to TAp63 expression ratio as a potential molecular marker for cervical cancer prognosis.

p63 is a transcription factor p53 family. Two major isoforms of p63, TAp63 with transactivation (TA) domain and ΔNp63 with truncated TA domain, have been reported to play opposing roles either in tumor suppression or oncogenic function. Little is known about the association of these two isoforms of p63 in the carcinogenesis of cervical cancer. In this study, the mRNA expression levels of TAp63 and ΔNp63 in 40 normal, 30 low-grade squamous intraepithelial lesions (LSIL), 38 high-grade squamous intraepithelial lesions (HSIL), and 52 cervical cancer formalin-fixed paraffin-embedded tissues were examined using quantitative reverse transcription polymerase chain reaction (RT-qPCR). We analyzed the association between the ΔNp63 and ΔN/TAp63 mRNA expression ratio and clinicopathological parameters and compared disease-specific survival of each ΔNp63 mRNA expression and ΔN/TAp63 mRNA expression ratio. The ΔN/TAp63 mRNA expression ratio in cervical cancer showed higher sensitivity than the mRNA expression levels of ΔNp63 (52.0% vs 44.2%). The level of ΔN/TAp63 mRNA expression ratio in precancerous LSIL and HSIL was higher than in normal tissues (P = 0.01 and P = 0.003) and lower than in cervical cancer tissues (P = 0.03 and P = 0.02). Besides, the positive ΔN/TAp63 mRNA expression ratio was associated with bulky tumor size and high expression of Ki-67, the proliferation marker, in cervical cancer (P = 0.04 and P = 0.02). The cervical cancer patients with the positive ΔN/TAp63 mRNA expression ratio showed worse survival compared to those who with the negative expression ratio of ΔN/TAp63 (HR = 5.7, 95% CI: 1.6-19.9). In conclusion, the balance of TAp63 and ΔNp63 is closely related to the carcinogenesis of cervical cancer. The ΔN/TAp63 mRNA expression ratio could be useful as a diagnostic and prognostic marker of cervical cancer.

Comparison of the clinical outcome of frozen-thawed embryo transfer with and without pretreatment with a gonadotropin-releasing hormone agonist.

OBJECTIVE: To describe the clinical outcomes of frozen-thawed embryo transfer (FET) with artificial preparation of the endometrium, using a combination of estrogen (E2) and progesterone (P4) with or without a gonadotropin-releasing hormone agonist (GnRHa), and the modified natural cycle (MNC) with human chorionic gonadotropin (hCG) trigger. METHODS: In this retrospective study, we evaluated 187 patients during 3 years (February 2012-April 2015). The patients were allocated to the following treatment groups: group A, comprising 113 patients (181 cycles) who received GnRHa+E2+P4; group B, comprising 49 patients (88 cycles) who received E2+P4; and group C, comprising 25 patients (42 cycles) who received hCG+P4. The inclusion criteria were regular menstrual cycles (length 24-35 days) and age 21-45 years. RESULTS: The primary outcome of the study - implantation rate (IR) per embryo transferred - was not statistically different among the 3 groups. Similar results were found for the IRs with fetal heartbeat per embryo transferred (68/181 [37.6%] in group A vs. 22/88 [25.0%] in group B vs. 14/42 [33.3%] in group C) and for the live birth rates (LBRs) per embryo transferred (56/181 [30.9%] in group A vs. 18/88 [20.5%] in group B vs. 11/42 [26.2%] in group C). CONCLUSION: Although the pregnancy outcomes were better in the hormone therapy with GnRHa group, hormone therapy FET with GnRHa for pituitary suppression did not result in significantly improved IRs and LBRs when compared with hormone therapy FET without GnRHa or MNC FET.

Relationship between Regional Body Fat Distribution and Diabetes Mellitus: 2008 to 2010 Korean National Health and Nutrition Examination Surveys.

BACKGROUND: The aim of this study was to investigate the association between regional body fat distribution, especially leg fat mass, and the prevalence of diabetes mellitus (DM) in adult populations. METHODS: A total of 3,181 men and 3,827 postmenopausal women aged 50 years or older were analyzed based on Korea National Health and Nutrition Examination Surveys (2008 to 2010). Body compositions including muscle mass and regional fat mass were measured using dual-energy X-ray absorptiometry. RESULTS: The odds ratios (ORs) for DM was higher with increasing truncal fat mass and arm fat mass, while it was lower with increasing leg fat mass. In a partial correlation analysis adjusted for age, leg fat mass was negatively associated with glycosylated hemoglobin in both sexes and fasting glucose in women. Leg fat mass was positively correlated with appendicular skeletal muscle mass and homeostasis model assessment of ß cell. In addition, after adjusting for confounding factors, the OR for DM decreased gradually with increasing leg fat mass quartiles in both genders. When we subdivided the participants into four groups based on the median values of leg fat mass and leg muscle mass, higher leg fat mass significantly lowered the risk of DM even though they have smaller leg muscle mass in both genders (P<0.001). CONCLUSION: The relationship between fat mass and the prevalence of DM is different according to regional body fat distribution. Higher leg fat mass was associated with a lower risk of DM in Korean populations. Maintaining leg fat mass may be important in preventing impaired glucose tolerance.

Implementation of a multidisciplinary clinical pathway for the management of postpartum hemorrhage: a retrospective study.

OBJECTIVE: To compare the outcomes of postpartum hemorrhage (PPH) episodes before and after the introduction of a clinical pathway known as the Severance Protocol to save postpartum bleeding through Expeditious care Delivery (SPEED). DESIGN: This study was designed as a retrospective analysis. SETTING: The study was conducted in a hospital implementing SPEED. PARTICIPANTS: The non-SPEED group included 74 patients with PPH who were treated before the introduction of SPEED, whereas the SPEED group included 155 patients. METHODS: Differences in outcomes were compared between groups. MAIN OUTCOME MEASURES: Reduction in treatment duration was the primary outcome measure, whereas uterus preservation was the secondary. RESULTS: No significant intergroup differences were observed for hemoglobin levels, hematocrit values and vital signs upon patients' emergency room arrival. The turnaround time for hemoglobin, mean duration until treatment by obstetricians and gynecologists and duration between chest radiography ordering and performance significantly differed between the two groups (SPEED, 10.0 [1.0-30.0], 3.0 [0-25.0] and 23.0 [1.0-86.0] min, respectively; non-SPEED, 17.0 [1.0-37.0], 12.0 [0-62.0] and 46.0 [1.0-580.0] min, respectively; P < 0.001). Similarly, the mean duration until transfusion of cross-matched red blood cells (SPEED, 77.6 ± 58.6 min; non-SPEED, 103.4 ± 64.4 min; P = 0.015) and uterus preservation rate (SPEED, 90.1% [136/151]; non-SPEED, 81.7% [58/71]; P = 0.043) also differed significantly between the groups. CONCLUSIONS: Clinical pathways enable prompt and efficient care for patients experiencing PPH through faster evaluation and access to red blood cell transfusion, resulting in a decrease in maternal mortality.

Maternal age at first delivery is associated with the risk of metabolic syndrome in postmenopausal women: from 2008-2010 Korean National Health and Nutrition Examination Survey.

BACKGROUND: Recent cross-sectional studies demonstrated that earlier maternal age at first childbirth is correlated with a higher risk of diabetes in postmenopausal women. In this study, we evaluated whether the age at first delivery is associated with the risk of metabolic syndrome (MetS) in postmenopausal women. METHODS: A total of 4,261 postmenopausal women aged 45 years or older were analyzed using data generated from Korea National Health and Nutrition Examination Surveys (2008-2010). Subjects were divided into three groups according to the maternal age at first delivery as follows: ≤ 20 years (n=878), 21-25 years (n=2314), and ≥ 26 years (n=1069). RESULTS: Approximately 37% of subjects had MetS. The prevalence of MetS showed a gradual increase as maternal age at first delivery decreased (≥ 26 years = 30.9% vs. 21-25 years = 39.9% vs. ≤ 20 years = 50.8%, respectively, p < 0.001). Central obesity indices such as trunk fat mass and waist circumference were significantly higher in the group aged ≤ 20 years than other groups. After adjustments for confounding factors, the odds ratios (ORs) for predicting the presence of MetS increased gradually as first delivery age decreased (≥ 26 years vs. 21-25 years vs. ≤ 20 years: OR [95% CI] = 1 vs. 1.324 [1.118-1.567] vs. 1.641 [1.322-2.036], respectively). Among components of MetS, younger maternal age at first delivery (≤ 20 years) was significantly associated with increased waist circumference (OR [95% CI] = 1.735 [1.41-2.13]), elevated blood pressure (1.261 [1.02-1.57]), high triglyceride (1.333 [1.072-1.659]), and low HDL-cholesterol (1.335[1.084-1.643]). CONCLUSIONS: Our findings suggest that younger maternal age at first delivery is independently associated with a higher risk of central obesity and MetS in postmenopausal women.

A comparison of clinical and surgical outcomes between laparo-endoscopic single-site surgery and traditional multiport laparoscopic surgery for adnexal tumors.

OBJECTIVE: The purpose of this study was to compare clinical and surgical outcomes between laparo-endoscopic single-site (LESS) surgery and traditional multiport laparoscopic (TML) surgery for treatment of adnexal tumors. METHODS: Medical records were reviewed for patients undergoing surgery for benign adnexal tumors between January 2008 and April 2012 at our institution. All procedures were performed by the same surgeon. Clinical and surgical outcomes for patients undergoing LESS surgery using Glove port were compared with those patients undergoing TML surgery. RESULTS: A review of 129 patient cases undergoing LESS surgery using Glove port and 100 patient cases undergoing TML surgery revealed no significant differences in the baseline characteristics of the two groups. The median operative time was shorter in the LESS group using Glove port at 44 minutes (range, 19-126 minutes) than the TML group at 49 minutes (range, 20-196 minutes) (P=0.0007). There were no significant differences between in the duration of postoperative hospital stay, change in hemoglobin levels, pain score or the rate of complications between the LESS and TML groups. CONCLUSION: LESS surgery showed comparable clinical and surgical outcomes to TML surgery, and required less operative time. Future prospective trials are warranted to further define the benefits of LESS surgery for adnexal tumor treatment.

Random urine protein/creatinine ratio readily predicts proteinuria in preeclampsia.

OBJECTIVE: To assess the diagnostic accuracy of random urine protein-creatinine (P/C) ratio for prediction of significant proteinuria in preeclampsia as an alternative to the time-consuming 24-hour urine protein collection. METHODS: Retrospective record analysis was performed on 140 pregnant women who were admitted with suspicion for preeclampsia from January 2006 to June 2011. Random urine protein and/or 24-hour urine protein levels were assessed and their correlation to random urine P/C ratio and 24-hour urine protein excretion was evaluated. RESULTS: Out of 140 patients, random urine P/C ratio or/and 24-hour urine protein was performed in 79 patients to evaluate significant proteinuria. Of 79 patients, 46 (58%) underwent both tests whereas in 33 women (42%) 24-hour urine collection was not available due to urgent delivery. In 39 cases (85%), significant proteinuria (≥300 mg/24 hr) was detected with 6 cases (13%) having values over 5,000 mg/24 hr, corresponding to the diagnosis of severe preeclampsia. Random urine P/C ratio highly correlated with 24-hour urine protein excretion (r=0.823, P<0.01). The optimal random urine P/C ratio cutoff points were 0.63 and 4.68 for 300 mg/24 hr and 5,000 mg/24 hr of protein excretion, respectively. with each sensitivity, specificity, and positive and negative predictive values of 87.1%, 100%, 100%, and 58.3%; and 100%, 85%, 50%, and 100%, for significant and severe preeclampsia, respectively. CONCLUSION: Random urine P/C ratio is a reliable indicator of significant proteinuria in preeclampsia and may be better at providing earlier diagnostic information than the 24-hour urine protein excretion with more accuracy than the urinary dipstick test.

The ON-Q pain management system in elective gynecology oncologic surgery: Management of postoperative surgical site pain compared to intravenous patient-controlled analgesia.

OBJECTIVE: The goal of this study was to compare postoperative surgical site pain in gynecologic cancer patients who underwent elective extended lower midline laparotomy and managed their pain with either the ON-Q pain management system (surgical incision site pain relief system, ON-Q pump) or an intravenous patient-controlled analgesia pump (IV PCA). METHODS: Twenty gynecologic cancer patients who underwent elective extended lower midline laparotomy were divided into two groups. One group received a 72-hour continuous wound perfusion of the local anesthetic ropivacaine (0.5%, study group) into the supraperitoneal layer of the abdominal incision through the ON-Q pump. The other group received intravenous infusion pump of patient-controlled analgesia (fentanyl citrate 20 mg/mL · kg+ondansetron hydrochloride 16 mg/8 mL+normal saline). Postoperative pain was assessed immediately and at 6, 24, 48, 72, and 96 hours after surgery using the visual analogue scale. RESULTS: Postoperative surgical site pain scores at 24, 48, and 72 hours after surgery were lower in the ON-Q group than the IV PCA group. Pain scores at 24 hours and 48 hours after surgery were significantly different between the two groups (P=0.023, P<0.001). Overall painkiller administration was higher in the ON-Q group but this difference was not statistically significant (5.1 vs. 4.3, P=0.481). CONCLUSION: This study revealed that the ON-Q pain management system is a more effective approach than IV PCA for acute postoperative surgical site pain relief after extended lower midline laparotomy in gynecologic cancer patients.