Prevalence and clinical characterization of BRCA1 and BRCA2 mutations in Korean patients with epithelial ovarian cancer.

This study was performed to investigate the prevalence, clinical characteristics, and treatment response according to BRCA1 and BRCA2 (BRCA) mutations in Korean patients with epithelial ovarian cancer (EOC). Two-hundred and ninety-eight Korean women diagnosed with high-grade serous and/or endometrioid EOC from 2010 to 2015 were tested for germline and 86 specimens for somatic BRCA mutations, regardless of the family history. Clinical characteristics including survival outcomes were compared in patients with and without BRCA mutations (NCT02963688). A total of 43 different germline BRCA mutations were identified in 78 patients among 298 patients (26.2%). Somatic BRCA mutations were identified in 11 (12.8%) patients among patients without germline BRCA mutations. Haplotype analysis demonstrated no founder mutations in our Korean patient cohort. Insignificant differences in age at diagnosis, primary site, and residual disease after surgery were observed between patients with and without BRCA mutations. In multivariate analysis for overall survival (OS), the presence of BRCA mutation was significantly associated with OS (P = .049) in addition to platinum sensitivity (P < .001), indicating it is an independent prognostic factor for survival regardless of platinum sensitivity to first-line chemotherapy. In addition, a higher response rate to subsequent chemotherapy after recurrence was observed in EOC patients with BRCA mutations resulting in better OS. In the current study, the prevalence of BRCA mutations in Korean patients with EOC was higher than previously reported in other ethnic groups. We demonstrated characteristics and treatment response in Korean EOC patients with BRCA mutations. These findings may provide valuable information to be considered in future clinical trials including Asian patients.

Chemoradiotherapy response prediction model by proteomic expressional profiling in patients with locally advanced cervical cancer.

OBJECTIVE: Resistance to chemo-radiation therapy is a substantial obstacle that compromises treatment of advanced cervical cancer. The objective of this study was to investigate if a proteomic panel associated with radioresistance could predict survival of patients with locally advanced cervical cancer. METHODS: A total of 181 frozen tissue samples were prospectively obtained from patients with locally advanced cervical cancer before chemoradiation. Expression levels of 22 total and phosphorylated proteins were evaluated using well-based reverse phase protein arrays. Selected proteins were validated with western blotting analysis and immunohistochemistry. Performances of models were internally and externally validated. RESULTS: Unsupervised clustering stratified patients into three major groups with different overall survival (OS, P = 0.001) and progression-free survival (PFS, P = 0.003) based on detection of BCL2, HER2, CD133, CAIX, and ERCC1. Reverse-phase protein array results significantly correlated with western blotting results (R2 = 0.856). The C-index of model was higher than clinical model in the prediction of OS (C-index: 0.86 and 0.62, respectively) and PFS (C-index: 0.82 and 0.64, respectively). The Kaplan-Meier survival curve showed a dose-dependent prognostic significance of risk score for PFS and OS. Multivariable Cox proportional hazard model confirmed that the risk score was an independent predictor of PFS (HR: 1.6; 95% CI: 1.4-1.9; P < 0.001) and OS (HR: 2.1; 95% CI: 1.7-2.5; P < 0.001). CONCLUSION: A proteomic panel of BCL2, HER2, CD133, CAIX, and ERCC1 independently predicted survival in locally advanced cervical cancer patients. This prediction model can help identify chemoradiation responsive tumors and improve prediction for clinical outcome of cervical cancer patients.

Comparison of laparoscopic and abdominal radical hysterectomy in early stage cervical cancer patients without adjuvant treatment: Ancillary analysis of a Korean Gynecologic Oncology Group Study (KGOG 1028).

OBJECTIVE: We compared two groups of early stage cervical cancer patients treated with different surgical methods without adjuvant treatment using retrospective multicenter data previously collected for Korean Gynecologic Oncology Group (KGOG) study designed for developing prognostic models. METHOD: We initially assessed data from the multi-institutional cohort with early stage (IB-IIA) cervical cancer patients treated with radical hysterectomy without adjuvant treatment between 2000 and 2008. Propensity score matching was performed to compare disease-free survival (DFS) and overall survival (OS) of patients with laparoscopic to abdominal radical hysterectomy. Additionally, survival comparison was performed in patients with tumor size <2 cm. RESULTS: After matching, 119 patients with laparoscopic radical hysterectomy were compared with 357 patients with abdominal radical hysterectomy (median follow-up of 63.9 months). Inferior DFS was observed in the laparoscopy group (HR 2.738 [95% CI 1.326-5.650], p = 0.005) with a significant difference in pelvic (HR 5.110 [95% CI 1.817-14.473], p < 0.001) and hematogenous recurrence (HR 3.171 [95% CI 1.059-9.494], p = 0.03), but OS was not significantly different between two groups (p = 0.624). In subgroup analysis in the patient with tumor size <2 cm (laparoscopy 62 vs. laparotomy 186, median follow-up of 69.1 months), laparoscopy was associated with lower rate of DFS (HR 12.987 [95% CI 1.451-116.244], p = 0.003), but no significant difference in OS was observed between groups. Regarding OS, number of events is lacking, and inferior DFS in the laparoscopy group may be compensated by better response to radiation therapy in pelvic recurrence. CONCLUSIONS: In this analysis, laparoscopic radical hysterectomy was associated with lower rates of DFS but not OS in early stage cervical cancer patients without adjuvant treatment. Further larger scale studies are needed.

Response to Combination Chemotherapy With Paclitaxel/Ifosfamide/Platinum Versus Paclitaxel/Platinum for Patients With Metastatic, Recurrent, or Persistent Carcinoma of the Uterine Cervix: A Retrospective Analysis.

OBJECTIVE: Paclitaxel/ifosfamide/cisplatin triplet has shown a higher response rate than paclitaxel/cisplatin doublet, but the toxicity profile hindered the use of the triplet regimen. In this study, we adjusted the dosage of the triplet regimen and introduced carboplatin in cisplatin-intolerable patients. We tested the efficacy and toxicity of the modified triplet regimen in patients with recurrent or persistent cervical cancer. MATERIALS AND METHODS: We retrospectively reviewed the medical records of patients with recurrent or persistent cervical cancer who were treated between 2003 and 2015 at Samsung Medical Center. Response rate, progression-free survival (PFS), overall survival (OS), and toxicity of paclitaxel/ifosfamide/platinum (TIP) and paclitaxel/platinum (TP) were compared. RESULTS: The overall response rate of TIP was significantly higher than that of TP (52.7% vs 36.4%, P = 0.031). In the TP group, response rate was higher in patients with progression-free interval longer than 12 months (P = 0.028) and those with squamous cell histology (P = 0.028). In TIP group, patients with older than 50 years (P = 0.017), progression-free interval longer than 12 months (P = 0.046), and squamous cell carcinoma histology (P < 0.001) showed higher response rates; but TIP showed higher response on all occasions. Median OS and median PFS were similar for TP and TIP (OS, 22.43 months vs 18.5 months, P = 0.44; PFS, 6.37 months vs 8.3 months, P = 0.48). CONCLUSIONS: Paclitaxel/ifosfamide/platinum showed a higher response rate than TP in patients with recurrent cervical cancer without an increase in severe complications. Considering the high response rate, TIP may be an option for persistent or recurrent cervical cancer.

Impact of lymphadenectomy on survival after recurrence in patients with advanced ovarian cancer without suspected lymph node metastasis.

OBJECTIVE: To investigate the impact of pelvic and para-aortic lymphadenectomy during primary debulking surgery (PDS) on recurrence pattern and survival after recurrence in patients with advanced epithelial ovarian cancer (EOC) without suspected lymph node (LN) metastasis in preoperative imaging studies and intraoperative findings. METHODS: A retrospective review of patients with FIGO stage III and IV EOC without suspected lymph node metastasis was performed. Patients with stage III EOC due to LN metastasis without peritoneal disease were excluded from this study. Survival comparisons for progression-free survival (PFS), overall survival (OS), and survival after recurrence were performed between patients with or without lymphadenectomy. RESULTS: Of the 261 EOC patients fulfilling inclusion criteria, 194 (74.3%) experienced relapse and a further 132 (50.6%) died within a median follow-up period of 48months (range, 6-139months). Patterns of recurrence and CA-125 level at recurrence were not different between patients with lymphadenectomy and without lymphadenectomy; however, patients with lymphadenectomy showed longer survival after recurrence than those without lymphadenectomy (43 vs. 32months, p=0.013). This difference was pronounced in the group with residual tumor <1cm (48 vs. 30months, p=0.010). The survival advantage of lymphadenectomy after recurrence remained significant in multivariate analysis (HR 0.57, 95% CI 0.38-0.84, p=0.005). CONCLUSIONS: Lymphadenectomy during PDS was associated with longer survival, especially survival after recurrence. The underlying mechanism should be elucidated in future studies.

Long-term Outcomes of MRI Stage IIB Cervical Cancer.

OBJECTIVE: Magnetic resonance imaging (MRI) can be used to assess parametrial invasion (PMI) in cervical cancer. Discordance between MRI findings and International Federation of Gynecology and Obstetrics (FIGO) staging is not uncommon because FIGO staging depends on physical examination. The purpose of this study was to retrospectively evaluate the long-term outcomes of MRI stage IIB cervical cancer. METHODS: A total of 312 patients with MRI stage IIB cervical cancer were retrospectively found between 2002 and 2011. Of these patients, 171 (group 1) were FIGO stage IIB cervical cancers and 141 (group 2) were MRI stage IIB cervical cancers that were negative PMI on physical examination. Group 1 was treated with chemotherapy and/or radiation therapy, and group 2 was treated with radical hysterectomy and lymph node dissection. The FIGO stages and pathologic findings of group 2 were recorded. Groups 1 and 2 were compared regarding 5-year overall survival rate. RESULTS: The FIGO stages of group 2 were IB1 in 51 (36.2%), IB2 in 28 (19.9%), and IIA in 62 (44%), whereas those of group 1 were all IIB. Group 2 showed lymphovascular space invasion in 71 (50.4%), lymph node metastasis in 48 (34.0%), PMI in 46 (32.6%), and vagina invasion in 9 (6.4%). Five-year overall survival rates of groups 1 and 2 were 73.7% and 84.5%, respectively (P = 0.013). CONCLUSIONS: Magnetic resonance imaging stage IIB cervical cancers with negative PMI on physical examination should be surgically treated because of better survival rate than FIGO stage IIB cervical cancers.

Timing and patterns of recurrence in epithelial ovarian cancer patients with no gross residual disease after primary debulking surgery.

OBJECTIVE: The aim of this study was to analyse patterns and timing of recurrence and their association with clinical outcomes in recurrent epithelial ovarian cancer (EOC) patients with no gross residual disease after primary debulking surgery (PDS). METHODS: This study was conducted on 303 EOC patients with no residual disease after PDS who were treated at the Samsung Medical Center from 2002 to 2012. By reviewing electronic medical records, information on date of clinical/pathological recurrence and pattern of disease presentation for each relapse were retrieved. RESULTS: Within a median follow-up of 53 months (range 3-156), 88 recurrences (29.0%) and 28 cancer-related deaths (9.2%) were observed. Most of the recurrences were distant, discrete and transcoelomic. After complete cytoreduction, the initial stage was associated with location of recurrence, but not with recurrence patterns. Complete cytoreduction reduced the number of recurrences, but it did not affect timing of recurrence. In multivariate analysis for overall survival (OS), patients with distant recurrence, diffuse carcinomatosis and mixed spread pattern of transcoelomic, lymphatic and haematogenous recurrence were found to have higher risk. CONCLUSIONS: We found that timing of recurrence was not affected by complete cytoreduction. Location, type and pattern of recurrence were also significant prognostic factors for OS, in addition to known prognostic predictors such as platinum sensitivity.

Prevalence of Homologous Recombination Deficiency in First-Line PARP Inhibitor Maintenance Clinical Trials and Further Implication of Personalized Treatment in Ovarian Cancer.

Among ovarian cancer patients with BRCA mutation or homologous recombination deficiency (HRD), the efficacy of Poly-ADP-ribose polymerase (PARP) inhibitors such as olaparib, niraparib, veliparib, and rucaparib has been proven in a number of clinical trials. BRCA mutation and HRD are currently indicated for PARP inhibitor maintenance treatment in ovarian cancer. HRD diagnostic tests examine various components, resulting in different HRD status definitions and, as a result, different treatment decisions. A number of HRD diagnostic tests exist, but test results provided by different companies may differ as they use different methods and different cutoffs. HRD prevalence difference was shown between PARP inhibitor maintenance trials. It is important to select an appropriate method that can present accurate HRD phenotypes to predict sensitivity to PARP inhibitors so that patients who are most likely to benefit from treatment are selected. Additionally, in the subset data of the PARP inhibitor maintenance trials, there was a difference in HRD prevalence by race as higher HRD prevalence in Japanese and Chinese ovarian cancer patients was shown. Further large-scale investigations on racial differences in HRD prevalence are needed and this may contribute to changes in determining the treatment plan and personalized treatment in ovarian cancer patients.

Efficacy of a continuous wound infiltration system for postoperative pain management in gynecologic patients who underwent single-port access laparoscopy for adnexal disease.

Introduction: Single-port access (SPA) laparoscopy requires only one incision, unlike conventional laparoscopy. However, its umbilical incision is larger than that of conventional laparoscopy and can be vulnerable to postoperative pain. This study aimed to evaluate whether simultaneous use of a continuous wound infiltration (CWI) system and intravenous patient-controlled analgesia (IV PCA) effectively decreases surgical site pain in patients who underwent SPA laparoscopy due to gynecologic adnexal disease. Methods: A total of 371 patients who underwent SPA laparoscopy and who received IV PCA or CWI was retrospectively reviewed (combined group [CWI + IV PCA, n = 159] vs. PCA group [IV PCA only, n = 212]). To evaluate postoperative pain management, the numeric rating scale (NRS) pain score after surgery, total amount of fentanyl administered via IV PCA, and additional pain killer consumption were collected. Results: The NRS scores at 12 h (1.90 ± 1.11 vs. 2.70 ± 1.08, p < 0.001) and 24 h (1.82 ± 0.82 vs. 2.11 ± 1.44, p = 0.026) after surgery were significantly lower in the combined group than in the PCA group. The total amount of PCA fentanyl was significantly smaller in the combined group than in the PCA group (p < 0.001). The total quantity of rescue analgesics was smaller in the combined group than in the PCA group (p < 0.05). Conclusion: Combined use of the CWI system and IV PCA is an effective postoperative pain management strategy in patient who underwent SPA laparoscopy for adnexal disease.

Changes in subcellular localization of Lysyl-tRNA synthetase and the 67-kDa laminin receptor in epithelial ovarian cancer metastases.

BACKGROUND: Although lysyl-tRNA synthetase (KARS1) is predominantly located in the cytosol, it is also present in the plasma membrane where it stabilizes the 67-kDa laminin receptor (67LR). This physical interaction is strongly increased under metastatic conditions. However, the dynamic interaction of these two proteins and the turnover of KARS1 in the plasma membrane has not previously been investigated. OBJECTIVE: Our objective in this study was to identify the membranous location of KARS1 and 67LR and investigate if this changes with the developmental stage of epithelial ovarian cancer (EOC) and treatment with the inhibitor BC-K01. In addition, we evaluated the therapeutic efficacy of BC-K01 in combination with paclitaxel, as the latter is frequently used to treat patients with EOC. METHODS: Overall survival and prognostic significance were determined in EOC patients according to KARS1 and 67LR expression levels as determined by immunohistochemistry. Changes in the location and expression of KARS1 and 67LR were investigated in vitro after BC-K01 treatment. The effects of this compound on tumor growth and apoptosis were evaluated both in vitro and in vivo. RESULTS: EOC patients with high KARS1 and high 67LR expression had lower progression-free survival rates than those with low expression levels of these two markers. BC-K01 reduced cell viability and increased apoptosis in combination with paclitaxel in EOC cell xenograft mouse models. BC-K01 decreased membranous KARS1 expression, causing a reduction in 67LR membrane expression in EOC cell lines. BC-K01 significantly decreased in vivo tumor weight and number of nodules, especially when used in combination with paclitaxel. CONCLUSIONS: Co-localization of KARS1 and 67LR in the plasma membrane contributes to EOC progression. Inhibition of the KARS1-67LR interaction by BC-K01 suppresses metastasis in EOC.

Single-port access (SPA) laparoscopic myomectomy with uterine artery ligation via a retroperitoneal approach is feasible in women with large uterine leiomyoma.

OBJECTIVE: Uterine artery ligation (UAL) at the time of myomectomy has shown to decrease blood loss during the operation. However, little is known about the efficacy and feasibility of UAL during single-port access (SPA) myomectomy. The present study was performed to investigate the clinical benefits of UAL in SPA myomectomy and to provide details of the surgical techniques. MATERIALS AND METHODS: A retrospective and comparative review on the surgical outcomes of the patients who underwent SPA myomectomy with UAL and those who underwent SPA myomectomy without UAL was conducted. UAL was performed at its origin from the internal iliac artery via a retroperitoneal approach. RESULTS: A total of 56 women who received SPA myomectomy were reviewed (24 patients received SPA myomectomy with UAL while 32 patients received SPA myomectomy only). The median weight of total resected leiomyomas was heavier for the patients who received UAL than those who did not receive UAL [210.0 g (range: 171.5-335.0 g) vs. 119.0 g (62.5-265.0 g), p = 0.023]. However, no differences in total operative time, estimated blood loss, perioperative hemoglobin changes, use of postoperative analgesics and postoperative complications between the two groups were seen. CONCLUSION: Obtaining similar surgical outcomes between the patients who received UAL with larger leiomyomas and those who did not receive UAL with smaller leiomyomas suggests that UAL is a feasible surgical approach to reduce blood loss during SPA myomectomy. Detailed descriptions of the surgical techniques are provided in the present report.

Prognostic Relevance of BRCA1 Expression in Survival of Patients With Cervical Cancer.

OBJECTIVE: BRCA1 expression can be lost by a variety of mechanisms including germline or somatic mutation and promotor hypermethylation. Given the potential importance of BRCA1 loss as a predictive and prognostic biomarker in several cancers, the objective of this study was to investigate BRCA1 expression using immunohistochemistry (IHC) in cervical cancer and its possible prognostic relevance. METHODS: Seventy patients with cervical cancer were enrolled in this study. Samples from each tumor were stained for BRCA1 and reviewed independently by gynecologic pathologists blinded to the BRCA status. Kaplan-Meier methods were used to estimate overall survival according to BRCA1 expression. Differentially expressed genes (DEGs) by BRCA1 expression were selected using GSE44001 dataset, which included 300 samples treated with radical hysterectomy. In addition, cox regression analysis with backward elimination was performed to select independent prognostic markers. Gene set enrichment analysis (GSEA) was done using these DEGs. RESULTS: BRCA1 IHC was positive in 62.9% (44/70) of cases. Patients with BRCA1 expression showed better overall survival (100% vs. 76.2%, HR 0.20, 95% CI 0.04 - 0.99, p = 0.028) than those without BRCA1 expression. Analysis of gene expression profiles according to BRCA1 expression identified 321 differentially expressed mRNAs. Gene set enrichment analysis results showed two dysregulated pathways (VEGF_A_UP.V1_DN and E2F1_UP.V1_UP). Of these DEGs, alterations of 20 gene signatures were found to be independently associated with survival outcomes of patients. CONCLUSIONS: BRCA1 expression in cervical cancer tissue is associated with survival. In addition, the identification of specific gene alterations associated with BRCA1 expression could help to provide individualized prediction in these patients.

Impact of Angiotensin Receptor Blockers, Beta Blockers, Calcium Channel Blockers and Thiazide Diuretics on Survival of Ovarian Cancer Patients.

PURPOSE: We investigated the impact of four types of antihypertensive medications, angiotensin receptor blockers (ARBs), beta blockers (BBs; both selective and non-selective), calcium channel blockers (CCBs), and thiazide diuretics (TDs) on survival outcomes in epithelial ovarian cancer (EOC). MATERIALS AND METHODS: A single-institutional retrospective chart review of 878 patients with EOC was performed. Survival was compared according to use of the four antihypertensive medications during primary treatment. Propensity score matching (ratio 1:3) was performed to control possible associated covariates, such as age, International Federation of Gynecology and Obstetrics stage, residual status after primary debulking surgery, and co-morbidity. RESULTS: Among 878 patients, 56 patients (6.4%) were ARB users, 62 (7.1%) were BB users, 107 (12.2%) were CCBs users and 32 (3.6%) used TDs. Median progression-free survival (PFS) for ARB, BB, and CCB users was 37.8, 27.2, and 23.6 months compared with 33.6 months for non-users. ARB was associated with 35% decreased risk of disease progression (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.42 to 0.99; p=0.046) in multivariate analysis. After propensity score matching, median PFS for ARB users was 37.8 months and ARB use remained to be associated with lower recurrence rate in univariate (p=0.035) and multivariate analysis (HR, 0.60; 95% CI, 0.39 to 0.93; p=0.022). CONCLUSION: In this study, ARBs use during primary treatment is associated with lower recurrence in EOC patients. However, CCBs, BBs, and TDs did not show beneficial impact.

Prognostic Model for Survival and Recurrence in Patients with Early-Stage Cervical Cancer: A Korean Gynecologic Oncology Group Study (KGOG 1028).

PURPOSE: We aimed to develop and validate individual prognostic models in a large cohort of cervical cancer patients that were primarily treated with radical hysterectomy. MATERIALS AND METHODS: We analyzed 1,441 patients with early-stage cervical cancer treated between 2000 and 2008 from the Korean Gynecologic Oncology Group multi-institutional cohort: a train cohort (n=788) and a test cohort (n=653). Models predicting the risk for overall survival (OS), disease- free survival (DFS), lymphatic recurrence and hematogenous recurrence were developed using Cox analysis and stepwise backward selection and best-model options. The prognostic performance of each model was assessed in an independent patient cohort. Model-classified risk groups were compared to groups based on traditional risk factors. RESULTS: Independent risk factors for OS, DFS, lymphatic recurrence, and hematogenous recurrence were identified for prediction model development. Different combinations of risk factors were shown for each outcome with best predictive value. In train cohort, area under the curve (AUC) at 2 and 5 years were 0.842/0.836 for recurrence, and 0.939/0.882 for OS. When applied to a test cohort, the model also showed accurate prediction result (AUC at 2 and 5 years were 0.799/0.723 for recurrence, and 0.844/0.806 for OS, respectively). The Kaplan-Meier plot by proposed model-classified risk groups showed more distinctive survival differences between each risk group. CONCLUSION: We developed prognostic models for OS, DFS, lymphatic and hematogenous recurrence in patients with early-stage cervical cancer. Combining weighted clinicopathologic factors, the proposed model can give more individualized predictions in clinical practice.

Pretreatment Lymph Node Metastasis as a Prognostic Significance in Cervical Cancer: Comparison between Disease Status.

PURPOSE: Lymph node metastasis (LNM) is the most significant prognostic factor in cervical cancer that was recently incorporated into the International Federation of Gynecology and Obstetrics (FIGO) staging system. This study was performed to evaluate whether the prognostic significance of LNM differs according to disease status. MATERIALS AND METHODS: Patients with FIGO stage IB or higher cervical cancer who had pretreatment computed tomography and/or magnetic resonance imaging studies as well as long-term follow-up were enrolled in this retrospective study. The hazard ratio (HR) of Cox regression was used to determine the prognostic significance of LNM. The HRs were compared between the different tumor groups (based on stage, histology, tumor size, primary treatment, age, parametrium involvement, and lymphovascular space invasion). RESULTS: A total of 970 patients treated between January 1999 and December 2007 were included. The pretreatment LNM had prognostic significance in patients with stage IB1/IIA (HR for progression-free survival 2.10, p=0.001; HR for overall survival 1.99, p=0.005). However, the significance gradually decreased or disappeared with advancing stages. Similarly, the prognostic significance of the pretreatment LNM decreased with advancing disease status, including old age, parametrial involvement or lymphovascular space involvement. In contrast, the tumor size was associated with the prognostic significance of LNM with advancing status. The significance of the clinical LNM did not reflect the significance of the clinical stage. In contrast, the tumor size, parametrial involvement, and significance of the pathologic LNM reflected the clinical stage. CONCLUSION: In patients with cervical cancer, pretreatment LNM on imaging has different clinical significance depending on the tumor status.

Chloroquine reverses chemoresistance via upregulation of p21WAF1/CIP1 and autophagy inhibition in ovarian cancer.

Overcoming drug-resistance is a big challenge to improve the survival of patients with epithelial ovarian cancer (EOC). In this study, we investigated the effect of chloroquine (CQ) and its combination with cisplatin (CDDP) in drug-resistant EOC cells. We used the three EOC cell lines CDDP-resistant A2780-CP20, RMG-1 cells, and CDDP-sensitive A2780 cells. The CQ-CDDP combination significantly decreased cell proliferation and increased apoptosis in all cell lines. The combination induced expression of γH2AX, a DNA damage marker protein, and induced G2/M cell cycle arrest. Although the CQ-CDDP combination decreased protein expression of ATM and ATR, phosphorylation of ATM was increased and expression of p21WAF1/CIP1 was also increased in CQ-CDDP-treated cells. Knockdown of p21WAF1/CIP1 by shRNA reduced the expression of γH2AX and phosphorylated ATM and inhibited caspase-3 activity but induced ATM protein expression. Knockdown of p21WAF1/CIP1 partly inhibited CQ-CDDP-induced G2/M arrest, demonstrating that knockdown of p21WAF1/CIP1 overcame the cytotoxic effect of the CQ-CDDP combination. Ectopic expression of p21WAF1/CIP1 in CDDP-treated ATG5-shRNA/A2780-CP20 cells increased expression of γH2AX and caspase-3 activity, demonstrating increased DNA damage and cell death. The inhibition of autophagy by ATG5-shRNA demonstrated similar results upon CDDP treatment, except p21WAF1/CIP1 expression. In an in vivo efficacy study, the CQ-CDDP combination significantly decreased tumor weight and increased expression of γH2AX and p21WAF1/CIP1 in A2780-CP20 orthotopic xenografts and a drug-resistant patient-derived xenograft model of EOC compared with controls. These results demonstrated that CQ increases cytotoxicity in combination with CDDP by inducing lethal DNA damage by induction of p21WAF1/CIP1 expression and autophagy inhibition in CDDP-resistant EOC.

Comparison of Laparoscopy and Laparotomy for Para-Aortic Lymphadenectomy in Women With Presumed Stage I-II High-Risk Endometrial Cancer.

Objective: To compare laparoscopic surgery to laparotomy for harvesting para-aortic lymph nodes in presumed stage I-II, high-risk endometrial cancer patients. Methods: Patients with histologically proven endometrial cancer, presumed stage I-II with high-risk tumor features who had undergone hysterectomy, bilateral salpingoophorectomy, or pelvic and para-aortic lymphadenectomy by either laparoscopy or laparotomy in Samsung Medical Center from 2005 to 2017 were retrospectively investigated. The primary outcome was para-aortic lymph node count. Secondary outcomes were pelvic lymph node count, perioperative events, and postoperative complications. Results: A total of 90 patients was included (35 for laparotomy, 55 for laparoscopy) for analysis. The mean (±SD) para-aortic lymph node count was 10.66 (±7.596) for laparotomy and 10.35 (±5.848) for laparoscopy (p = 0.827). Mean pelvic node count was 16.8 (±6.310) in the laparotomy group and 16.13 (±7.626) in the laparoscopy group (p = 0.664). Lower estimated blood loss was shown in the laparoscopy group. There was no difference in perioperative outcome between the groups. Additional multivariate analysis showed that survival outcome was not affected by surgical methods in presumed stage I-II, high-risk endometrial cancer patients. Conclusions: Study results demonstrate comparable para-aortic lymph node count with less blood loss in laparoscopy over laparotomy. In women with presumed stage I-II, high-risk endometrial cancer, laparoscopy is a valid treatment modality.

Preclinical assessment of the VEGFR inhibitor axitinib as a therapeutic agent for epithelial ovarian cancer.

Axitinib, small molecule tyrosine kinase inhibitor, demonstrates anti-cancer activity for various solid tumors. We investigated anti-cancer effect of axitinib in epithelial ovarian cancer (EOC). We treated EOC cells (A2780, HeyA8, RMG1, and HeyA8-MDR) with axitinib to evaluate its effects on cell viabilty, apoptosis and migration. Western blots were performed to assess VEGFR2, ERK, and AKT levels, and ELISA and FACS to evaluate apoptosis according to axitinib treatment. In addition, in vivo experiments in xenografts using A2780, RMG1, and HeyA8-MDR cell lines were performed. We repeated the experiment with patient-derived xenograft models (PDX) of EOC. Axitinib significantly inhibited cell survival and migration, and increased apoptosis in EOC cells. The expression of VEGFR2 and phosphorylation of AKT and ERK in A2780, RMG1, and HeyA8 were decreased with axitinib treatment in dose-dependent manner, but not in HeyA8-MDR. In in vivo experiments, axitinib significantly decreased tumor weight in xenograft models of drug-sensitive (A2780), and clear cell carcinoma (RMG1) and PDX models for platinum sensitive EOC compared to control, but was not effective in drug-resistant cell line (HeyA8-MDR) or heavily pretreated refractory PDX model. Axitinib showed significant anti-cancer effects in drug-sensitive or clear cell EOC cells via inhibition of VEGFR signals associated with cell proliferation, apoptosis and migration, but not in drug-resistant cells.

Real-World Experience of Olaparib Maintenance in High-Grade Serous Recurrent Ovarian Cancer Patients with BRCA1/2 Mutation: A Korean Multicenter Study.

BACKGROUND: Olaparib maintenance therapy has shown efficacy and tolerability in patients with platinum-sensitive, high-grade serous recurrent ovarian cancer (HSROC) with BRCA1/2 mutation (BRCAm). Our aim was to present real-world experience with olaparib in Korea. METHOD: We included HSROC patients with BRCAm treated with olaparib maintenance at four institutions in Korea between 2016 and 2018. Medical records were reviewed for clinico-pathologic characteristics, objective response, survival outcomes, and safety. RESULTS: One hundred HSROC patients with BRCAm were included. BRCA1 mutation was present in 71 patients (71.0%), and BRCA2 mutation was present in 23 patients (23.0%). In terms of the best objective response with olaparib maintenance in 53 patients with partial remission from most recent chemotherapy, complete remission occurred in 12 (22.6%) and partial remission in four (7.5%), while 33 patients (62.3%) had stable disease. The 24 month progression-free survival was 42.4%, and 24 month overall survival was 82.1%. Grade 3 or more adverse events were as follows: anemia in 14 patients (14.0%), neutropenia in seven patients (7.0%), thrombocytopenia in two patients (2.0%), oral mucositis in one patient (1.0%), and soft tissue infection in one patient (1.0%). CONCLUSIONS: The safety and effectiveness of olaparib maintenance treatment in a real-world study were consistent with those reported in previous clinical trials.

Prognostic factors for recurrence and survival in uterine leiomyosarcoma: Korean single center experience with 50 cases.

OBJECTIVE: The aim of this study was to determine the possible prognostic factors in patients with uterine leiomyosarcoma (LMS). METHODS: This study retrospectively investigated 50 patients with uterine LMS treated at the Samsung Medical Center between 2001 and 2017. To analyze the prognostic significance of factors for recurrence-free survival (RFS), overall survival (OS), and survival after recurrence, the log-rank test and Cox proportional hazards model were used for univariate and multivariate analysis. RESULTS: Of the 50 patients, 30 (60.0%) experienced recurrence and 16 (32.0%) died within a median follow-up period of 21 (range, 3-99) months. Multivariate analysis revealed that older age, absence of residual tumor after surgery, lower mitotic count, and a history of adjuvant radiotherapy at first treatment were significantly associated with better RFS. Presence of residual tumor after surgery and severe nuclear atypia were associated with poor OS. In the analysis of survival after recurrence, hematogenous recurrence, severe nuclear atypia, and presence of residual tumor at primary surgery were significantly associated with worse prognosis. Notably, residual tumor status at primary surgery was associated with RFS, OS, and survival after recurrence. CONCLUSION: We demonstrated the possible prognostic factors for RFS, OS, and survival after recurrence for patients with LMS. These results may provide useful information for patients with LMS.