Purpose: Parkinson disease (PD) is a progressive neurodegenerative disorder in which dopaminergic (DAergic) systems are destroyed (particularly in the nigrostriatal system), causing both motor and nonmotor symptoms. Hippocampal neuroplasticity is altered in PD animal models, resulting in nonmotor dysfunctions. However, little is known about the precise mechanism underlying the hippocampal dysfunctions in PD. Methods: Striatal 6-hydroxydopamine (6-OHDA) infusions were performed unilaterally in adult Sprague Dawley rats. Both motor and nonmotor symptoms alongside the expression of tyrosine hydroxylase (TH) in the substantia nigra and striatum were confirmed in 6-OHDA-lesioned rats. The neuronal architecture in the hippocampus was analyzed by Golgi staining. Results: During the 7–8 weeks after infusion, the 6-OHDA-lesioned rats exhibited motor and nonmotor dysfunctions (especially anxiety/depression-like behaviors). Rats with unilateral 6-OHDA infusion displayed reduced TH+ immunoreactivity in the ipsilateral nigrostriatal pathway of the brain. Golgi staining revealed that striatal 6-OHDA infusion significantly decreased the dendritic complexity (i.e., number of crossing dendrites, total dendritic length, and branch points) in the ipsilateral hippocampal conus ammonis 1 (CA1) apical/basal and dentate gyrus (DG) subregions. Additionally, the dendritic spine density and morphology were significantly altered in the CA1 apical/basal and DG subregions following striatal 6-OHDA infusion. However, alteration of microglial and astrocytic distributions did not occur in the hippocampus following striatal 6-OHDA infusion. Conclusions The present study provides anatomical evidence that the structural plasticity in the hippocampus is altered in the late phase following striatal 6-OHDA infusion in rats, possibly as a result of the prolonged suppression of the DAergic system, and independent of neuroinflammation.

Purpose: Lymph node metastasis (LNM) is the most significant prognostic factor in cervical cancerthat was recently incorporated into the International Federation of Gynecology and Obstetrics(FIGO) staging system. This study was performed to evaluate whether the prognosticsignificance of LNM differs according to disease status. Materials and Methods: Patients with FIGO stage IB or higher cervical cancer who had pretreatment computedtomography and/or magnetic resonance imaging studies as well as long-term follow-upwere enrolled in this retrospective study. The hazard ratio (HR) of Cox regression was usedto determine the prognostic significance of LNM. The HRs were compared between the differenttumor groups (based on stage, histology, tumor size, primary treatment, age, parametriuminvolvement, 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 forprogression-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, theprognostic 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 advancingstatus. The significance of the clinical LNM did not reflect the significance of the clinicalstage. In contrast, the tumor size, parametrial involvement, and significance of the pathologicLNM reflected the clinical stage. Conclusion In patients with cervical cancer, pretreatment LNM on imaging has different clinical significancedepending on the tumor status.

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.
Follow-Up Studies ; Humans ; Leiomyosarcoma ; Multivariate Analysis ; Neoplasm, Residual ; Prognosis ; Proportional Hazards Models ; Radiotherapy, Adjuvant ; Recurrence ; Retrospective Studies ; Uterine Neoplasms

OBJECTIVE: BRCA mutational status is important in the management of ovarian cancer, but there is a lack of evidence supporting genetic testing in Asian populations. This study was performed to investigate the prevalence and prognostic outcomes of BRCA1/2 mutation and variant of unknown significance (VUS) in Korean patients diagnosed with epithelial ovarian cancer (EOC). METHODS: Among patients newly diagnosed with EOC between January 2007 and January 2017, those tested for germline BRCA1/2 mutation were studied, regardless of family history. Overall survival (OS) and progression-free survival (PFS) were compared between the patients with and without BRCA1/2 mutation and VUS. RESULTS: A total of 313 patients underwent BRCA testing: 88 patients had a BRCA1/2 mutation and 48 patients had a BRCA1/2 VUS (28.1% and 15.3%, respectively). There were no significant associations between BRCA1/2 mutation, BRCA1/2 wild-type, or BRCA1/2 VUS with age at diagnosis, histologic distribution, or residual disease status after primary cytoreductive surgery. BRCA1 mutation, including BRCA1 VUS, showed no difference in PFS or OS compared to BRCA1 wild-type. In contrast, BRCA2 mutation showed longer PFS than that of BRCA2 wild-type (P=0.04) or BRCA2 VUS (P=0.02). BRCA2 mutation, including BRCA2 VUS, did not show any difference in OS compared to BRCA2 wild-type. CONCLUSION: BRCA mutation and BRCA VUS had similar clinical characteristics and survival outcomes, except that BRCA2 mutation showed better PFS. The results of this study will help to understand the prognostic significance of BRCA mutation and VUS in Korean patients.
Asian Continental Ancestry Group ; Diagnosis ; Disease-Free Survival ; Genes, BRCA1 ; Genes, BRCA2 ; Genetic Testing ; Humans ; Korea ; Ovarian Neoplasms ; Prevalence

OBJECTIVES: The aim of this study was to develop a new prognostic classification for epithelial ovarian cancer (EOC) patients using gradient boosting (GB) and to compare the accuracy of the prognostic model with the conventional statistical method. METHODS: Information of EOC patients from Samsung Medical Center (training cohort, n=1,128) was analyzed to optimize the prognostic model using GB. The performance of the final model was externally validated with patient information from Asan Medical Center (validation cohort, n=229). The area under the curve (AUC) by the GB model was compared to that of the conventional Cox proportional hazard regression analysis (CoxPHR) model. RESULTS: In the training cohort, the AUC of the GB model for predicting second year overall survival (OS), with the highest target value, was 0.830 (95% confidence interval [CI]=0.802–0.853). In the validation cohort, the GB model also showed high AUC of 0.843 (95% CI=0.833–0.853). In comparison, the conventional CoxPHR method showed lower AUC (0.668 (95% CI=0.617–0.719) for the training cohort and 0.597 (95% CI=0.474–0.719) for the validation cohort) compared to GB. New classification according to survival probability scores of the GB model identified four distinct prognostic subgroups that showed more discriminately classified prediction than the International Federation of Gynecology and Obstetrics staging system. CONCLUSION: Our novel GB-guided classification accurately identified the prognostic subgroups of patients with EOC and showed higher accuracy than the conventional method. This approach would be useful for accurate estimation of individual outcomes of EOC patients.
Area Under Curve ; CA-125 Antigen ; Chungcheongnam-do ; Classification ; Cohort Studies ; Gynecology ; Humans ; Machine Learning ; Methods ; Obstetrics ; Ovarian Neoplasms ; Prognosis

OBJECTIVE: We compared survival outcomes of advanced serous type epithelial ovarian cancer (EOC) patients with normal-sized ovaries and enlarged-ovarian tumors by propensity score matching analysis. METHODS: The medical records of EOC patients treated at Samsung Medical Center between 2002 and 2015 were reviewed retrospectively. We investigated EOC patients with high grade serous type histology and International Federation of Gynecology and Obstetrics (FIGO) stage IIIB, IIIC, or IV who underwent primary debulking surgery (PDS) and adjuvant chemotherapy to identify patients with normal-sized ovaries. Propensity score matching was performed to compare patients with normal-sized ovaries to patients with enlarged-ovarian tumors (ratio, 1:3) according to age, FIGO stage, initial cancer antigen (CA)-125 level, and residual disease status after PDS. RESULTS: Of the 419 EOC patients, 48 patients had normal-sized ovary. Patients with enlarged-ovarian tumor were younger (54.0±10.3 vs. 58.4±9.2 years, p=0.005) than those with normal-sized ovary, and there was a statistically significant difference in residual disease status between the 2 groups. In total cohort with a median follow-up period of 43 months (range, 3–164 months), inferior overall survival (OS) was shown in the normal-sized ovary group (median OS, 71.2 vs. 41.4 months; p=0.003). After propensity score matching, the group with normal-sized ovary showed inferior OS compared to the group with enlarged-ovarian tumor (median OS, 72.1 vs. 41.4 months; p=0.031). In multivariate analysis for OS, normal-sized ovary remained a significant factor. CONCLUSION: Normal-sized ovary was associated with poor OS compared with the common presentation of enlarged ovaries in EOC, independent of CA-125 level or residual disease.
Chemotherapy, Adjuvant ; Cohort Studies ; Female ; Follow-Up Studies ; Gynecology ; Humans ; Matched-Pair Analysis ; Medical Records ; Multivariate Analysis ; Obstetrics ; Ovarian Neoplasms ; Ovary ; Prognosis ; Propensity Score ; Retrospective Studies

PURPOSE: We aimed to develop molecular classifier that can predict lymphatic invasion and their clinical significance in epithelial ovarian cancer (EOC) patients. MATERIALS AND METHODS: We analyzed gene expression (mRNA, methylated DNA) in data from The Cancer Genome Atlas. To identify molecular signatures for lymphatic invasion, we found differentially expressed genes. The performance of classifier was validated by receiver operating characteristics analysis, logistic regression, linear discriminant analysis (LDA), and support vector machine (SVM). We assessed prognostic role of classifier using random survival forest (RSF) model and pathway deregulation score (PDS). For external validation, we analyzed microarray data from 26 EOC samples of Samsung Medical Center and curatedOvarianData database. RESULTS: We identified 21 mRNAs, and seven methylated DNAs from primary EOC tissues that predicted lymphatic invasion and created prognostic models. The classifier predicted lymphatic invasion well, which was validated by logistic regression, LDA, and SVM algorithm (C-index of 0.90, 0.71, and 0.74 for mRNA and C-index of 0.64, 0.68, and 0.69 for DNA methylation). Using RSF model, incorporating molecular data with clinical variables improved prediction of progression-free survival compared with using only clinical variables (p < 0.001 and p=0.008). Similarly, PDS enabled us to classify patients into high-risk and low-risk group, which resulted in survival difference in mRNA profiles (log-rank p-value=0.011). In external validation, gene signature was well correlated with prediction of lymphatic invasion and patients' survival. CONCLUSION: Molecular signature model predicting lymphatic invasion was well performed and also associated with survival of EOC patients.
Disease-Free Survival ; DNA ; Forests ; Gene Expression ; Genome ; Genome, Human ; Humans ; Logistic Models ; Lymphatic Metastasis ; Ovarian Neoplasms* ; RNA, Messenger ; ROC Curve ; Support Vector Machine ; Transcriptome

OBJECTIVE: This retrospective study is to evaluate the efficacy and toxicity of combination chemotherapy with etoposide and ifosfamide (ETI) in the management of pretreated recurrent or persistent epithelial ovarian cancer (EOC). METHODS: Patients with recurrent or persistent EOC who had measurable disease and at least one chemotherapy regimen were to receive etoposide at a dose of 100 mg/m²/day intravenous (IV) on days 1 to 3 in combination with ifosfamide 1 g/m²/day IV on days 1 to 5, every 21 days. RESULTS: From August 2008 to August 2016, 66 patients were treated with ETI regimen. Most patients were heavily pretreated prior to ETI: 53 (80.3%) patients had received 3 or more chemotherapy regimens. The response rate (RR) of ETI chemotherapy was 18.2% and median duration of response was 6.8 months (range, 0–30). Median survival of all patients was 5 months at a median follow up of 7.2 months. Platinum-free interval (PFI) more than 6 months prior to ETI has statistically significant correlation with overall survival (OS; 9.2 vs. 5.6 months; P=0.029) and RR (34.5% vs. 5.4%; P < 0.010). However, treatment free interval before ETI, number of prior chemotherapy regimen, and optimality of primary surgery did not show significant difference for RR or OS. Grade 3 or 4 hematologic toxicities were observed in 7 cases (3%) of the 232 cycles of ETI. CONCLUSION: The ETI combination regimen shows comparatively low toxicity and modest activity in heavily pretreated recurrent or persistent EOC patients with more than 6 months of PFI after last platinum treatment.
Drug Therapy ; Drug Therapy, Combination* ; Etoposide* ; Follow-Up Studies ; Humans ; Ifosfamide* ; Ovarian Neoplasms* ; Platinum ; Recurrence ; Retrospective Studies*

OBJECTIVE: The aim of this investigation is to compare outcomes of patients according to the presence of cancer arising from endometriosis in ovarian clear cell carcinoma (CCC) and endometrioid carcinoma (EC). METHODS: This study retrospectively investigated 224 CCC and EC patients treated in Samsung Medical Center from 2001 to 2015 to identify cancer arising from endometriosis according to Sampson and Scott criteria. Propensity score matching was performed to compare patients arising from endometriosis to patients without endometriosis (ratio 1:1) according to stage, age, lymph node metastasis (LNM), cancer antigen (CA)-125 level, and residual status after debulking surgery. RESULTS: Forty-five cases arising from endometriosis were compared with 179 cases without endometriosis. CCC and EC arising from endometriosis tended to present with early age (mean, 45.2 vs. 49.2 years; p=0.003), early-stage (stages I and II, 92.7% vs. 62.3%; p < 0.001), lower CA-125 level (mean, 307.1 vs. 556.7; p=0.041), higher percentages of no gross residual disease after surgery (87.8% vs.56.8%; p=0.001), and higher percentages of negative LNM (82.9% vs. 59.0%; p=0.008) compared to cases without endometriosis. Kaplan-Meier curves for progression-free survival (PFS) and overall survival (OS) showed better outcomes for groups with cancer arising from endometriosis (p=0.014 for PFS; and p=0.010 for OS). However, the association with endometriosis was not significant in multivariate analysis. Also, after propensity score matching, survival differences between the 2 groups were not significant. CONCLUSION: CCC and EC arising from endometriosis are diagnosed at an earlier age and stage. However, cancer arising from endometriosis was not a significant prognostic factor.
Carcinoma, Endometrioid ; Disease-Free Survival ; Endometriosis* ; Female ; Humans ; Lymph Nodes ; Multivariate Analysis ; Neoplasm Metastasis ; Ovarian Neoplasms* ; Propensity Score ; Retrospective Studies

PURPOSE: This study was conducted to evaluate the prognostic significance of pre-treatment complete blood cell count (CBC), including white blood cell (WBC) differential, in epithelial ovarian cancer (EOC) patients with primary debulking surgery (PDS) and to develop nomograms for platinum sensitivity, progression-free survival (PFS), and overall survival (OS). MATERIALS AND METHODS: We retrospectively reviewed the records of 757 patients with EOC whose primary treatment consisted of surgical debulking and chemotherapy at Samsung Medical Center from 2002 to 2012. We subsequently created nomograms for platinum sensitivity, 3-year PFS, and 5-year OS as prediction models for prognostic variables including age, stage, grade, cancer antigen 125 level, residual disease after PDS, and pre-treatment WBC differential counts. The models were then validated by 10-fold cross-validation (CV). RESULTS: In addition to stage and residual disease after PDS, which are known predictors, lymphocyte and monocyte count were found to be significant prognostic factors for platinum-sensitivity, platelet count for PFS, and neutrophil count for OS on multivariate analysis. The area under the curves of platinum sensitivity, 3-year PFS, and 5-year OS calculated by the 10-fold CV procedure were 0.7405, 0.8159, and 0.815, respectively. CONCLUSION: Prognostic factors including pre-treatment CBC were used to develop nomograms for platinum sensitivity, 3-year PFS, and 5-year OS of patients with EOC. These nomograms can be used to better estimate individual outcomes.
Blood Cell Count* ; Blood Cells* ; Disease-Free Survival* ; Drug Therapy ; Humans ; Leukocytes ; Lymphocytes ; Monocytes ; Multivariate Analysis ; Neutrophils ; Nomograms* ; Ovarian Neoplasms* ; Platelet Count ; Platinum* ; Prognosis ; Retrospective Studies