Application of Immune Checkpoint Inhibitors in Gynecological Cancers: What Do Gynecologists Need to Know before Using Immune Checkpoint Inhibitors?

Standard treatments for gynecological cancers include surgery, chemotherapy, and radiation therapy. However, there are limitations associated with the chemotherapeutic drugs used to treat advanced and recurrent gynecological cancers, and it is difficult to identify additional treatments. Therefore, immune checkpoint inhibitor (ICI) therapy products, including PD-1/PD-L1 inhibitors and CTLA-4 inhibitors, are in the spotlight as alternatives for the treatment of advanced gynecological cancers. Although the ICI monotherapy response rate in gynecological cancers is lower than that in melanoma or non-small cell lung cancer, the response rates are approximately 13-52%, 7-22%, and 4-17% for endometrial, ovarian, and cervical cancers, respectively. Several studies are being conducted to compare the outcomes of combining ICI therapy with chemotherapy, radiation therapy, and antiangiogenesis agents. Therefore, it is critical to determine the mechanism underlying ICI therapy-mediated anti-tumor activity and its application in gynecological cancers. Additionally, understanding the possible immune-related adverse events induced post-immunotherapy, as well as the appropriate management of diagnosis and treatment, are necessary to create a quality environment for immunotherapy in patients with gynecological cancers. Therefore, in this review, we summarize the ICI mechanisms, ICIs applied to gynecological cancers, and appropriate diagnosis and treatment of immune-related side effects to help gynecologists treat gynecological cancers using immunotherapy.

Prevalence and Treatment of Vulvar Cancer From 2014-2018: A Nationwide Population-Based Study in Korea.

BACKGROUND: Vulvar cancer is one of the rare gynecologic malignancies. Despite the recent increasing trend of vulvar cancer in western countries due to the increased infection of human papillomavirus, there has been no study for population-based incidence of vulvar cancer in Korea. We aimed to investigate the prevalence and treatment of vulvar cancer in South Korea between 2014 and 2018. METHODS: Data from patients diagnosed and treated with vulvar cancer between 2014 and 2018 were obtained from the Health Insurance Review and Assessment Service/National Inpatient Sample (National In-Patient Sample) in South Korea. RESULTS: A total of 4,636,542 women were identified through the HIRA-NIS database from 2014 to 2018, of which 259 patients were diagnosed and treated for vulvar cancer. The mean age diagnosed with vulvar cancer was 62.82 (± 14.30) years in 2014, 64.19 (± 16.79) years in 2015, and 67.40 (± 14.41) years in 2016. In terms of treatment modalities, the most frequent treatment was surgery only without chemotherapy or radiation therapy. In the age-specific prevalence analysis, vulvar cancer was the most prevalent among those over 70 years old. According to multiple regression analysis, patients' age was significantly associated with the prevalence of vulvar cancer. Vulvar cancer was more prevalent in women with low socioeconomic status (SES) compared to those with high SES in 2018 (OR, 4.242; P < 0.001). CONCLUSION: Considering the high prevalence of vulvar cancer in the elderly, it is necessary to establish a new strategy for early screening and treatment.

Long-term risks of coronary heart disease and cerebrovascular disease in ovarian, uterine and cervical cancer survivors: a nationwide study in Korea.

Only few studies have evaluated the incidence of coronary heart disease (CHD) and cerebrovascular disease (CVD) among gynaecologic cancer survivors. We selected 26,880 gynaecologic cancer patients who underwent health check-ups within 2 years after diagnosis using the Korean National Health Insurance Service Database. They were compared with 79,830 non-cancer controls. Cox regression models were used to estimate hazard ratios (HRs). There was no significant relationship between gynaecologic cancer survivors and CHD or CVD events. However, 10 years after diagnosing cancers, the risk of angina increased in cancer survivors (adjusted HR = 1.193, 95% CI: 1.013-1.406). After 1 year of diagnosis, cancer patients with no initial comorbidities showed an increased risk of all CHD and CVD events (adjusted HR = 1.101, 95% CI: 1.020-1.189) and CHD alone (adjusted HR = 1.168, 95% CI: 1.055-1.293) compared with controls. CHD risk was also higher in the cancer group with no comorbidities after 10 years of diagnosis (adjusted HR = 1.284, 95% CI: 1.020-1.615). Overall, the risk of CHD or CVD did not increase in gynaecologic cancer survivors. However, cancer patients without any comorbidities showed a higher risk of CHD compared with control, the risk persisting until 10 years after cancer diagnosis.Impact StatementWhat is already known on this subject? Cardiovascular risk and the incidence of stroke increase after cancer diagnosis.What do the results of this study add? The risk of coronary heart disease (CHD) and cerebrovascular disease did not increase in Asian (especially Korean) gynaecologic cancer survivors compared with the general population. However, cancer patients without any comorbidities showed a higher risk of CHD compared with the non-cancer population.What are the implications of these findings for clinical practice and/or further research? Our results imply the importance of surveillance of cardiovascular risks among patients with gynaecologic cancer without comorbidities.

Females with impaired ovarian function could be vulnerable to environmental pollutants: identification via next-generation sequencing of the vaginal microbiome.

The vaginal microbiome has been widely investigated. However, its relationship with impaired ovarian function has not been evaluated. We conducted a next-generation sequencing (NGS) study of the vaginal microbiome in females with normal and decreased ovarian function and analysed its sensitivity to environmental pollutants. Vaginal swabs were collected from 92 individuals (22 with impaired ovarian function). The 16S rDNA sequences were assembled by FLASH and clustered in OTUs. Diversity analysis was performed using QIIME. The impaired function group showed lower AMH (p < .01) and higher FSH (p = .04). Only two species showed significant differences: Propionibacterium acnes and Prevotella copri. Moreover, more environmental pollutants were related to changes in the vaginal microbiome in the impaired ovarian function group than in the normal group. Vaginal microbiomes in young women with decreased ovarian function tended to be more sensitive to environmental pollutants, especially volatile organic compounds.Impact StatementWhat is already known on this subject? In this study, the possible influence of environmental pollutants, especially volatile organic compounds to ovarian function were identified via next-generation sequencing.What do the results of this study add? This is the first study that shows vaginal microbiomes in young women with decreased ovarian function to be more sensitive to environmental pollutants.What are the implications of these findings for clinical practice and/or further research? The association between impaired ovarian function and environmental pollutants from this study could be helpful when counselling patients with POI.

Pregnancy Outcomes Following Laparoscopic and Open Surgery in Pelvis during Pregnancy: a Nationwide Population-based Study in Korea.

BACKGROUND: Non-obstetric surgery during pregnancy is associated with adverse obstetric and fetal outcomes. The aim of this study was to investigate the risk of adverse pregnancy outcomes for women who underwent non-obstetric pelvic surgery during pregnancy compared with that of women that did not undergo surgery. METHODS: Study data from women who gave birth in Korea were collected from the Korea National Health Insurance claims database between 2006 and 2016. We identified pregnant women who underwent abdominal non-obstetric pelvic surgery by laparoscopy or laparotomy from the database. Pregnancy outcomes including preterm birth, low birth weight (LBW), cesarean section (C/S), gestational hypertension, gestational diabetes, and postpartum hemorrhage were identified. The adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the pregnancy outcomes were estimated by multivariate regression models. RESULTS: Data from 4,439,778 women were collected for this study. From 2006-2016, 9,417 women from the initial cohort underwent non-obstetric pelvic surgery (adnexal mass resection, appendectomy) during pregnancy. Multivariate logistic regression analysis indicated that preterm birth (HR, 2.01; 95% CI, 1.81-2.23), LBW (HR, 1.62; 95% CI, 1.46-1.79), C/S (HR, 1.13; 95% CI, 1.08-1.18), and gestational hypertension (HR, 1.35; 95% CI, 1.18-1.55) were significantly more frequent in women who underwent non-obstetric surgery during pregnancy compared to pregnant women who did not undergo surgery. When the laparoscopic and laparotomy groups were compared for risk of fetal outcomes, the risk of LBW was significantly decreased in laparoscopic adnexal resection during pregnancy compared to laparotomy (odds ratio, 0.62; 95% CI, 0.40-0.95). CONCLUSION: Non-obstetric pelvic surgery during pregnancy was associated with a higher risk of preterm birth, LBW, gestational hypertension, placenta previa, placental abruption, and C/S. Although the benefits and safety of laparoscopy during pregnancy appear similar to those of laparotomy in regard to pregnancy outcomes, laparoscopic adnexal mass resection was associated with a lower risk of LBW.

Exploring the prognostic significance of preoperative high normocalcemia in epithelial ovarian carcinoma.

PURPOSE: We investigated the association between serum ionized calcium and prognosis of EOC and determined the optimal cutoff value of ionized calcium level to predict the prognosis of EOC. METHODS: The medical records of patients who were newly diagnosed with EOC from 2001 to 2016 were retrieved. Preoperative ionized calcium test was performed within 2 weeks before surgery, and the cutoff of high normocalcemia was defined based on the receiver operating characteristic (ROC) curve for recurrence. Cox proportional hazards regression models were used to identify independent prognostic factors for progression-free survival (PFS). RESULTS: From 2001 to 2016, 83 patients diagnosed with EOC were identified at a single institution. The optimal cutoff value was set to 4.7 mg/dL (high normocalcemia vs. control group) by plotting the ROC curve for recurrence. Stages III/IV were more frequent in high normocalcemia, with borderline significance (72.9% vs. 52.2%, p = 0.053). Recurrence (67.6% vs. 43.5%, p = 0.029) and death (46.0% vs. 15.2%, p < 0.01) were significantly more frequent in the high normocalcemia group. In multivariate analysis, high normocalcemia (HR 1.9, 95% CI 1.03-3.61, p = 0.04), age (HR 1.04, 95% CI 1.01-1.08, p = 0.02), stage (HR 3.67, 95% CI 1.13-11.92, p = 0.03), residual tumor > 1 cm (HR 3.79, 95% CI 1.61-8.95, p < 0.01), and lymph node metastasis (HR 2.46, 95% CI 1.27-4.78, p < 0.01) were independent risk factors for recurrence. CONCLUSION: This study showed positive association between relatively high level of ionized calcium level and recurrence risk of EOC. High normocalcemia showed the potential as a biomarker for prognosis of EOC.

The impact of previous cesarean section (C/S) on the risk for post-molar gestational trophoblastic neoplasia (GTN).

OBJECTIVE: To investigate the relationship between previous cesarean section (C/S) and risk for post-molar gestational trophoblastic neoplasia (GTN). METHODS: Data from patients who were treated for hydatidiform moles between 1995 and 2016 were retrospectively reviewed. Patient age, gravidity, parity, abortion history, gestational age, pretreatment beta-human chorionic gonadotropin (HCG), previous molar pregnancy, clinical symptoms, enlarged uterus, theca lutein cyst, type of GTN, World Health Organization risk score, chemotherapy, and mode of delivery were recorded. Hazard ratios (HR) and 95% confidence intervals (CI) for variables associated with the occurrence of post-molar GTN and invasive mole were estimated by univariate and multivariate Cox proportional hazards models. RESULTS: From 1995 to 2016, 182 patients were diagnosed with molar pregnancy and underwent treatment. Patients with previous C/S (C/S group) had higher age (37.0 vs 32.8. p = 0.004), gravidity (3.1 vs 2.0, p < 0.001), and parity (1.6 vs 0.9, p < 0.001) than patients without previous C/S (non-C/S group). Post-molar GTN (43.5 vs 26.5%, p < 0.001), invasive mole (21.7 vs 3.7%, p < 0.001), hysterectomy (28.3 vs 6.6%, p < 0.001), and chemotherapy (45.7 vs 28.7%, p = 0.03) were more frequent in the C/S group. In multivariate analysis, independent risk factors for post-molar GTN were previous C/S (HR 5.1, 95% CI 2.1-12.7), abortion history (HR 6.3, 95% CI 2.5-15.6), and pretreatment ß-hCG (HR 1.3, 95% CI 1.1-1.6). CONCLUSIONS: In this study, C/S was a strong risk factor for occurrence of post-molar GTN and invasive mole. Aggressive treatment, such as multi-agent chemotherapy or hysterectomy, can be considered for hydatidiform moles in patients with a C/S history.

Learning curve for sentinel lymph node mapping in gynecologic malignancies.

BACKGROUND AND OBJECTIVES: Only a few studies have reported the learning curve for sentinel lymph node (SLN) detection in gynecologic malignancies. We investigated the learning curve for SLN detection during robot-assisted laparoscopic surgery for endometrial and cervical carcinomas. METHODS: This retrospective analysis included patients with stage IA to IIA1 cervical cancer or stage I to III endometrial cancer who underwent SLN mapping using indocyanine green during robot-assisted laparoscopic surgery performed by a single surgeon. Learning curves were analyzed in consecutive cases using SLN detection rates and the cumulative sum (CUSUM) method. RESULTS: SLN mapping was achieved in 81.25% (65/80), 77.50% (62/80), and 66.25% (53/80) of the cases involving the right, left, and simultaneous bilateral pelvic areas, respectively. Learning curve analysis based on the cumulative detection rate showed initial fluctuations followed by stabilization; the time required for proficiency was discordant among the LN regions. However, the CUSUM method showed proficient mapping of the right, left, and bilateral SLNs after 27 to 28 cases. CONCLUSION: At least 27 cases were required for SLN mapping proficiency in gynecologic cancer; the learning period could influence the surgical quality. Further studies are warranted to confirm the impact of this learning curve on disease outcomes.

Risk of occult atypical hyperplasia or cancer in women with nonatypical endometrial hyperplasia.

AIM: The aim of this study was to identify subsets of patients diagnosed with nonatypical endometrial hyperplasia (NAEH) by endometrial biopsy who had high risk for occult atypical endometrial hyperplasia (AEH) or endometrial cancer (EC). METHODS: We retrospectively reviewed the medical records of 281 patients who underwent hysterectomy within 6 months after a diagnosis of NAEH. We collected data on age, body mass index, menopausal status, tamoxifen use, previous history of NAEH, details of endometrial biopsy (location, curettage vs. pipelle sampling), NAEH subtype (simple vs. complex), interval between endometrial biopsy and hysterectomy, indication of hysterectomy and the presence of occult AEH or EC in hysterectomy specimen. Associations between variables and occult AEH or EC were analyzed. Risk of occult AEH or EC in subsets were calculated and visualized using a heatmap. RESULTS: Among 281 patients, 34 (12.1%) and 9 (3.2%) had occult AEH and EC in hysterectomy specimens, respectively. Using univariate analysis, we found age, menopausal status and subtype were associated with occult AEH or EC. Using multivariate analysis, older age (odds ratio = 1.09, P < 0.01) and complex subtype (odds ratio = 3.34, P < 0.01) were independent risk factors. Patients at an age ≥ 51 years with complex NAEH had about 50% risk of occult AEH or EC. CONCLUSION: Women at an age ≥ 51 years with complex NAEH had high risk for occult AEH or EC and surgical treatment can be considered for these patients.

Effectiveness of adjuvant treatment for morcellated, International Federation of Gynecology and Obstetrics stage I uterine leiomyosarcoma: A Korean multicenter study.

AIM: To evaluate the effectiveness of adjuvant treatment for morcellated, uterus-confined leiomyosarcoma in a multicenter setting. METHODS: We identified patients with International Federation of Gynecology and Obstetrics stage I uterine leiomyosarcoma primarily treated with surgery between 2003 and 2016. Among them, patients who underwent one of the following morcellation methods were included: (i) power morcellation; (ii) intracorporeal morcellation using scalpels or electrocautery; and (iii) vaginal morcellation. Patients' survival outcomes were compared according to the implementation of adjuvant treatment. RESULTS: From 13 institutions, 55 patients were included; 31 for adjuvant treatment group and 24 for surgery only group. The clinicopathological characteristics including the mass size, morcellation methods, extent of surgery, and mitotic count were similar between the groups. In the adjuvant treatment group, 67.7%, 19.4% and 12.9% of patients received chemotherapy, chemoradiation and radiation, respectively. After a median follow-up of 50.5 months, the adjuvant treatment and surgery only groups showed similar overall survival (5-year rate, 92.0% vs 90.4%; P = 0.959). No significant difference in progression-free survival was observed between the two groups (3-year rate, 46.1% vs 78.2%; P = 0.069). On multivariate analyses, adjuvant treatment did not affect progression-free survival (adjusted HR, 2.138; 95% CI, 0.550-8.305; P = 0.273). The adjuvant treatment group showed a trend towards more common distant metastasis, compared to the surgery only group (25.8% vs 4.2%; P = 0.062). The incidences of pelvic, retroperitoneal, and abdominal recurrences were not different between the groups. CONCLUSION: Despite its frequent use in clinical practice, adjuvant treatment did not improve the survival outcomes of patients with morcellated, International Federation of Gynecology and Obstetrics stage I uterine leiomyosarcoma.

Advances in the Treatment and Prevention of Chemotherapy-Induced Ovarian Toxicity.

Due to improvements in chemotherapeutic agents, cancer treatment efficacy and cancer patient survival rates have greatly improved, but unfortunately gonadal damage remains a major complication. Gonadotoxic chemotherapy, including alkylating agents during reproductive age, can lead to iatrogenic premature ovarian insufficiency (POI), and loss of fertility. In recent years, the demand for fertility preservation has increased dramatically among female cancer patients. Currently, embryo and oocyte cryopreservation are the only established options for fertility preservation in women. However, there is growing evidence for other experimental techniques including ovarian tissue cryopreservation, oocyte in vitro maturation, artificial ovaries, stem cell technologies, and ovarian suppression. To prevent fertility loss in women with cancer, individualized fertility preservation options including established and experimental techniques that take into consideration the patient's age, marital status, chemotherapy regimen, and the possibility of treatment delay should be provided. In addition, effective multidisciplinary oncofertility strategies that involve a highly skilled and experienced oncofertility team consisting of medical oncologists, gynecologists, reproductive biologists, surgical oncologists, patient care coordinators, and research scientists are necessary to provide cancer patients with high-quality care.

Doctor and patient awareness of treatment options for cervical intraepithelial neoplasia 1 (CIN 1): a survey questionnaire approach.

The purpose of this study was to investigate doctors' and patients' perceptions of cervical intraepithelial neoplasia 1 (CIN 1) and its treatment methods. A survey questionnaire was offered to obstetrics and gynaecology doctors and patients with CIN 1 in 2017. Only 43% of patients knew of this disease. Regarding perceptions of its aetiology, 64% of the patients perceived human papillomavirus infection to be the main cause of CIN 1. Patients' most preferred treatments were medication (20%), followed by alternative treatment (14%). Among doctors, regular follow-up was the most preferred method for managing CIN 1. The survey showed that current treatment modalities for CIN 1 were satisfactory to only half of doctors (50%) and patients (53%). Overall, 70% of doctors responded that new drug development for CIN 1 is needed. Although, CIN 1 is a low-grade lesion, doctors and patients expressed the desire for new therapeutic agents to manage it.IMPACT STATEMENTWhat is already known on this subject? In general, treatment is not recommended for CIN 1 because lesions are considered indicative of transient HPV infection and spontaneously regress in most patients.What do the results of this study add? Regular follow-up for CIN 1 were satisfactory to only half of doctors and patients. Thirty-six percent of patients wanted active treatment instead of regular follow-up. In addition, 70% of doctors responded that new drug development for CIN 1 is needed.What are the implications of these findings for clinical practice and/or further research? Our results support the need for therapeutic agents for CIN 1.

CXC chemokine ligand 1 mediates adiponectin-induced angiogenesis in ovarian cancer.

OBJECTIVES: Adiponectin is a cytokine secreted from adipose tissue that regulates energy homeostasis, inflammation, and cell proliferation. Obesity is associated with increased risk of various cancers, including ovarian cancer. Adipokines, including adiponectin, have been implicated as a factor linking obesity and carcinogenesis. The oncogenic role of adiponectin is not known with regard to various cancer types. We sought to determine the role of adiponectin in angiogenesis in ovarian cancer in vitro. METHODS: We transfected SKOV3 cells with vascular endothelial growth factor small interfering RNA in order to identify the independent angiogenic role of adiponectin in ovarian cancer. The vascular endothelial growth factor knockdown SKOV3 cell lines were treated with adiponectin for 48 h. The cytokines involved in adiponectin-mediated angiogenesis were explored using the human angiogenesis cytokine array and were verified with the enzyme-linked immunosorbent assay. The angiogenic effect of adiponectin was evaluated using the human umbilical vein endothelial cell tube formation assay. We also investigated the effects of adiponectin treatment on the migration and invasion of SKOV3 cells. RESULTS: The number of tubes formed by human umbilical vein endothelial cell decreased significantly after knockdown of vascular endothelial growth factor (via transfection of vascular endothelial growth factor small interfering RNA into SKOV3 cells). When these vascular endothelial growth factor knockdown SKOV3 cells were treated with adiponectin, there was an increase in the number of tubes in a tube formation assay. Following adiponectin treatment, the CXC chemokine ligand 1 secretion increased in a cytokine array. This was confirmed by both enzyme-linked immunosorbent assay and Western blot. The increased secretion of CXC chemokine ligand 1 by adiponectin occurred regardless of vascular endothelial growth factor knockdown. In addition, the induction of migration and invasion of SKOV3 cells were significantly stronger with adiponectin treatment than they were without. CONCLUSION: Adiponectin treatment of ovarian cancer cells induces angiogenesis via CXC chemokine ligand 1 independently of vascular endothelial growth factor. These findings suggest that adiponectin may serve as a novel therapeutic target for ovarian cancer.

Outcomes of non-high grade serous carcinoma after neoadjuvant chemotherapy for advanced-stage ovarian cancer: a Korean gynecologic oncology group study (OV 1708).

BACKGROUND: Outcomes of patients with ovarian high-grade serous carcinoma (HGSC) treated with neoadjuvant chemotherapy (NAC) have been widely studied, but there is limited information on the outcomes of patients with non-HGSC. This study aimed to evaluate the outcomes of NAC in non-HGSC patients with advanced-stage ovarian cancer. METHODS: We conducted a retrospective cohort study of patients who underwent NAC for advanced stage non-HGSC between 2002 and 2017 in 17 institutions. Demographics, surgical outcomes, and survival rates were evaluated according to histological subtypes. RESULTS: A total of 154 patients were included in this study, comprising 20 cases (13.0%) of mucinous adenocarcinoma, 31 cases (20.1%) of endometrioid adenocarcinoma, 28 (18.2%) cases of clear cell carcinoma, 29 (18.8%) cases of low-grade serous carcinoma and 12 cases (7.8%) of carcinosarcoma. Complete remission/partial remission after the third cycle of NAC was achieved in 100 (64.9%) patients and optimal debulking surgery (residual disease ≤1 cm) at interval debulking surgery was achieved in 103 (66.9%) patients. The most common reason for performing NAC was high tumor burden (n = 106, 68.8%). The median progression-free survival (PFS) was 14.3 months and median overall survival (OS) was 52.9 months. In multivariate analyses, mucinous and clear cell carcinoma were negative prognostic factors for both PFS (p = 0.007 and p = 0.017, respectively) and OS (p = 0.002 and p = 0.013, respectively). CONCLUSIONS: In this study, poor survival outcomes were observed in patients with mucinous and clear cell carcinoma undergoing NAC. Different treatment strategies are urgently required to improve survival outcomes for this disease subset.

Three-Year Recurrence-Free Survival in Patients With a Very Low Risk of Endometrial Cancer Who Did Not Undergo Lymph Node Dissection (Tree Retro): A Korean Multicenter Study.

OBJECTIVE: Randomized studies have not demonstrated a survival benefit of routine lymph node dissection in early-stage endometrial cancer. Many surgeons nevertheless perform lymph node dissection in all patients with early-stage endometrial cancer. This study aimed to ascertain the survival outcomes of very low-risk endometrial cancer patients (by the Korean Gynecologic Oncology Group [KGOG] criteria) who did not undergo lymph node dissection. MATERIALS AND METHODS: Medical records of 156 consecutive patients who underwent surgical staging without lymph node dissection were collected from 10 institutions. All patients fulfilled the KGOG criteria: (1) endometrioid corpus cancer diagnosed by preoperative endometrial biopsy, (2) serum cancer antigen-125 level ≤35 IU/mL, (3) <50% myometrial invasion with no extension beyond the uterine corpus by magnetic resonance imaging (MRI), and (4) no lymph nodes with a short diameter ≥1.0 cm by MRI or computed tomography. Sampling of <5 nodes was allowed at a surgeon's discretion. We evaluated the 3-year recurrence-free survival (RFS) and 5-year overall survival (OS) using the Kaplan-Meier method. RESULTS: The median patient age was 52 years (range, 24-86 years). The median follow-up was 59 months (range, 0-189 months). The 3-year RFS and 5-year OS were 98.6% (95% confidence interval [CI], 96.8%-100.0%) and 98.6% (95% CI, 96.7%-100.0%), respectively. No disease-related mortality occurred. The final pathology report revealed ≥50% myometrial invasion in 29 patients (18.6%) and extension beyond the uterine corpus in 2 patients (1.3%). One patient (0.6%) was diagnosed with lymph node metastasis after lymph node sampling. Eighteen patients (11.5%) received adjuvant therapy after the final pathologic results indicated high risk. CONCLUSIONS: Very low-risk patients who did not undergo lymph node dissection had acceptable survival outcomes. Omitting lymph node dissection may be reasonable in patients satisfying the KGOG criteria.

CXCL11 mediates TWIST1-induced angiogenesis in epithelial ovarian cancer.

To investigate the role of TWIST1 in tumor angiogenesis in epithelial ovarian cancer and to identify key molecules involved in angiogenesis. TWIST1 small interfering RNA was transfected into A2780 cells, while a complementary DNA vector was transfected into non-malignant human ovarian surface epithelial cells to generate a TWIST1-overexpressing cell line. To evaluate how this affects angiogenesis, human umbilical vein endothelial cell tube formation assays were performed using the control and transfected cell lines. An antibody-based cytokine array was used to identify the molecules involved in TWIST1-mediated angiogenesis. After knockdown of TWIST1 via transfection of TWIST1 small interfering RNA into A2780 cells, the number of tubes formed by human umbilical vein endothelial cells significantly decreased in a tube formation assay. In a cytokine array, TWIST1 downregulation did not significantly decrease the secretion of the common pro-angiogenic factor, vascular endothelial growth factor, but instead inhibited the expression of the CXC chemokine ligand 11, which was confirmed by both an enzyme-linked immunosorbent assay and western blotting. In contrast, TWIST1 overexpression resulted in increased secretion of CXC chemokine ligand 11. Conversely, CXC chemokine ligand 11 downregulation did not inhibit the expression of TWIST1. Furthermore, the ability of TWIST1-expressing A2780 cells to induce angiogenesis was found to be inhibited after CXC chemokine ligand 11 knockdown in a tube formation assay. TWIST1 plays an important role in angiogenesis in epithelial ovarian cancer and is mediated by a novel pro-angiogenic factor, CXC chemokine ligand 11. Downregulation of CXC chemokine ligand 11 can inhibit tumor angiogenesis, suggesting that anti-CXC chemokine ligand 11 therapy may offer an alternative treatment strategy for TWIST1-positive ovarian cancer.

Clinical indications for hysteroscopic removal of uterine masses: Time, age at diagnosis, and mass size.

AIM: The aim of this study was to investigate clinical factors associated with abnormal pathologies of uterine masses resected via hysteroscopy. METHODS: Women who underwent hysteroscopic surgery for presumptive diagnoses of abnormal endometrial or endocervical masses, such as polyps or leiomyomas on ultrasonography, between January 2012 and April 2015, were enrolled. Clinical and pathologic data were retrospectively reviewed. RESULTS: Among 189 patients, pathologic diagnoses of the uterine mass were abnormal in 172 (91.0%) cases, including polyps in 119 (63.0%), leiomyomas in 49 (26.0%), endometrial hyperplasia in two (1.0%), and endometrial cancer in two (1.0%). Seventeen (9.0%) women who underwent hysteroscopic removal showed unremarkable results on pathology, and the most common finding among them was the proliferative phase of the normal endometrium. Women aged over 40 years with uterine masses and a time since last menstrual period of over 15 days are four times more likely to be diagnosed with neoplastic masses than others (odds ratio [OR], 4.39, 95% confidence interval [CI], 1.33-14.48 and OR, 4.22, 95%CI, 1.35-13.21, respectively); those with masses over 1.5 cm in size are three times more likely to be neoplastic than others (OR, 3.08, 95%CI, 1.04-9.12). CONCLUSION: Large mass size, longer time after last menstrual period, and older age are risk factors for abnormal histologies of uterine masses resected via hysteroscopy. Clinicians should take particular care when contemplating hysteroscopic removal for women younger than 40 years, and those with masses of <1.5 cm in size in the proliferative phase of the endometrium to avoid an unnecessary surgery.

A gonadotropin-releasing hormone agonist for the prevention of docetaxel-induced gonadal damage.

This study aimed to evaluate the protective effect of a gonadotropin-releasing hormone (GnRH) agonist against docetaxel-induced gonadotoxicity in a mouse model. Forty mice (female B6, 6-8 weeks old, weighing 16-18 g) were divided randomly into four groups. Groups 1 and 2 were treated with a single intraperitoneal dose of 0.1 mL normal saline; Groups 3 and 4 received 30 mg/kg docetaxel. Groups 2 and 4 were pre-treated with a subcutaneous injection of 0.3 mg leuprolide acetate, 2 weeks before the administration of docetaxel. The ovaries were removed 6 weeks after docetaxel or saline injection. Total follicle number decreased in Group 3 compared to Group 1. There was a significant difference between the Groups 3 and 4 in the total follicle number. Many ovarian follicles were stained for Ki-67 in Groups 1, 2, and 4; however, in Group 3, only a small number were stained and destruction of the ovarian structure was observed. There was no immunohistochemistry staining with γ-H2AX in Groups 1, 2, and 4. However, γ-H2AX staining of the primordial follicles was observed in Group 3. GnRH agonists may protect ovarian follicles from docetaxel-induced ovarian damage considering the total follicle number, follicle proliferation, and double-strand DNA breaks. Impact statement Protection of the ovarian reserve and prevention of infertility are the primary quality of life issues in young cancer patients. In this study, ovarian suppression by gonadotropin-releasing hormone agonists protected ovarian follicles from docetaxel-induced ovarian damage considering the total follicle number, follicle proliferation, and double-strand DNA break. The findings of our study will provide useful information for fertility preservation in women with cancer, undergoing chemotherapy with docetaxel.

Reflex Human Papillomavirus Test Results as an Option for the Management of Korean Women With Atypical Squamous Cells Cannot Exclude High-Grade Squamous Intraepithelial Lesion.

BACKGROUND: Current guidelines recommend initial colposcopy with biopsy regardless of human papillomavirus (HPV) test results in women with atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H). The purpose of this study was to evaluate the value of HPV testing in women with ASC-H based on colposcopic pathology results. MATERIALS AND METHODS: A multicenter cross-sectional study was carried out at three academic hospitals and involved 40,847 Korean women who underwent cervical cancer screening with cytology and HPV tests with or without subsequent colposcopic biopsies between January 2007 and December 2013. RESULTS: ASC-H was diagnosed in 276 women (0.7%). Only 6 of 68 (8.8%) women with ASC-H who were HPV negative had cervical intraepithelial neoplasia grade ≥2 (CIN ≥2) lesions, whereas 47.4% of the women with ASC-H who were HPV positive had CIN ≥2 lesions. No cases of invasive cervical cancer were diagnosed among women with ASC-H who were HPV negative. Logistic regression analysis was performed using the group with normal Papanicolaou test results and HPV-negative status as the reference group. Women with ASC-H who were HPV positive had a significantly increased risk of CIN ≥2 lesions, whereas no significant increase was observed in patients with ASC-H and HPV-negative status. CONCLUSION: If the result of the HPV test was negative, the risk of CIN ≥2 lesions in Korean women with ASC-H cytology was low. Reflex HPV testing should be an option for the management of women with cytology showing ASC-H to decrease unnecessary colposcopic biopsies, which are expensive and invasive. IMPLICATIONS FOR PRACTICE: Current American Society for Colposcopy and Cervical Pathology guidelines recommend universal colposcopy for the management of women with atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H) on cytology, regardless of human papillomavirus (HPV) test results. The present study suggested that HPV cotesting in patients with ASC-H cytology can provide more detailed and useful information regarding the risk of high-grade cervical intraepithelial neoplasia (CIN) lesions and the need for further treatment. When the result of the HPV test was negative, the risk of CIN lesions of grade ≥2 in women with ASC-H cytology was low. Consequently, reflex HPV testing, rather than immediately performance of invasive and expensive colposcopy with biopsy, should be an option for the management of women with ASC-H.

Comparing the prevalence of condylomata acuminata between pregnant women and nonpregnant controls in South Korea: a population-based, cross-sectional study.

We analyzed and estimated the prevalence of condylomata acuminata from South Korea claim data in 2009. The prevalence in pregnant women aged 20 to 34 years (46 ± 7 per 100,000 persons) was lower than that in nonpregnant women aged 20 to 34 years (59 ± 1 per 100,000 persons; P < 0.001).