198 results on '"Soo Young Hur"'
Search Results
2. Postoperative Adjuvant Chemoradiotherapy Versus Chemotherapy Alone for Stage III Endometrial Cancer: A Multicenter Retrospective Study
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Ji Geun Yoo MD, Jin Hwi Kim MD, PhD, Chan Joo Kim MD, PhD, Hae Nam Lee MD, PhD, Min Jong Song MD, PhD, Dong Choon Park MD, PhD, Joo Hee Yoon MD, PhD, Sang Il Kim MD, PhD, Soo Young Hur MD, PhD, and Sung Jong Lee MD, PhD
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Introduction We aimed to evaluate the efficacy and toxicity of the combination of 6 cycles of chemotherapy and radiation therapy compared with chemotherapy alone as postoperative adjuvant therapy for patients with stage III endometrial cancer. Methods This retrospective cohort study included patients with stage III endometrial cancer who received postoperative chemoradiotherapy or chemotherapy alone at 6 hospitals between January 2009 and December 2019. The progression-free survival (PFS) and overall survival (OS) for each treatment group were analyzed using the Kaplan–Meier method. We also assessed differences in toxicity profiles between the treatment groups. Results A total of 133 patients met the inclusion criteria. Of these, 80 patients (60.2%) received adjuvant chemoradiotherapy and 53 (39.8%) received chemotherapy alone. The PFS and OS did not differ significantly between the groups. For patients with stage IIIC endometrioid subtype, the chemoradiotherapy group had significantly longer PFS rate than did the chemotherapy alone group (log-rank test, P = .019), although there was no significant difference in the OS (log-rank test, P = .100). CRT was identified as a favorable prognostic factor for PFS in multivariate analysis (adjusted HR, .37; 95% CI, .16-.87; P = .022). Patients treated with chemoradiotherapy more frequently suffered from grade 4 neutropenia (73.8% vs 52.8%; P = .018) and grade 3 or worse thrombocytopenia (36.3% vs 9.4%; P = .001) compared with the chemotherapy alone group. There were no differences between the 2 treatment groups in the frequency of toxicity-related treatment discontinuation or dose reduction. Conclusion We confirmed that chemoradiotherapy yields longer progression-free survival than does chemotherapy alone for patients with stage IIIC endometrioid endometrial cancer, with an acceptable toxicity profile.
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- 2022
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3. Plasma-derived exosomal miR-4732-5p is a promising noninvasive diagnostic biomarker for epithelial ovarian cancer
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Jingjing Liu, Jigeun Yoo, Jung Yoon Ho, Yuyeon Jung, Sanha Lee, Soo Young Hur, and Youn Jin Choi
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Exosomes ,Exosomal miRNA profiling ,microRNAs ,Epithelial ovarian cancer ,miR-4732-5p ,Gynecology and obstetrics ,RG1-991 - Abstract
Abstract Background Exosomal miRNAs regulate gene expression and play important roles in several diseases. We used exosomal miRNA profiling to investigate diagnostic biomarkers of epithelial ovarian cancer (EOC). Methods In total, 55 individuals were enrolled, comprising healthy (n = 21) and EOC subjects (n = 34). Small mRNA (smRNA) sequencing and real-time PCR (RT-PCR) were performed to identify potential biomarkers. Receiver operating characteristic (ROC) curves were conducted to determine biomarker sensitivity and specificity. Results Using smRNA sequencing, we identified seven up-regulated (miR-4732-5p, miR-877-5p, miR-574-3p, let-7a-5p, let-7b-5p, let-7c-5p, and let-7f-5p) and two down-regulated miRNAs (miR-1273f and miR-342-3p) in EOC patients when compared with healthy subjects. Of these, miR-4732-5p and miR-1273f were the most up-regulated and down-regulated respectively, therefore they were selected for RT-PCR analysis. Plasma derived exosomal miR-4732-5p had an area under the ROC curve of 0.889, with 85.7% sensitivity and 82.4% specificity in distinguishing EOC patients from healthy subjects (p
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- 2021
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4. Genomic, transcriptomic, and viral integration profiles associated with recurrent/metastatic progression in high‐risk human papillomavirus cervical carcinomas
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Jing Jing Liu, Jung Yoon Ho, Jung Eum Lee, Soo Young Hur, Jinseon Yoo, Kyu Ryung Kim, Daeun Ryu, Tae Min Kim, and Youn Jin Choi
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APOBEC ,cervical cancer ,human papillomavirus ,immunoprofiling ,metastasis ,recurrence ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Acquisition of recurrent/metastatic potential by a tumor cell defines a critical step in malignant progression. However, understanding of metastatic progression at the molecular level is scarce for cervical carcinomas (CES). In this study, we performed genomic, transcriptomic, and viral profiling of five pairs of primary (CES‐P) and matched recurrent/metastatic tumors (CES‐R/M) with high risk human papillomavirus. Whole exome sequencing revealed mutation features of CES‐R/M including elevated mutation burdens and prevalent copy number alterations compared to their matched CES‐P. A relative deficit of APOBEC‐related mutation signatures accompanying the transcriptional downregulation of APOBEC3A was observed for CES‐R/M. Mutations in genes encoding epigenetic regulators were commonly observed as CES‐R/M‐specific alterations. Immunoprofiling and gene set analysis revealed CES‐Ps were enriched with transcripts representing activated anticancer immunity such as interferon‐gamma pathway, while CES‐R/M exhibited upregulation of genes involved in epithelial‐mesenchymal transition and angiogenesis. Viral capture sequencing revealed that integration sites remained enriched in viral E1 protein domain during malignant progression. Moreover, we found transcriptional upregulation of POSTN and downregulation of APOBEC3A were associated with unfavorable clinical outcomes in CES. Comprehensive genomic and transcriptomic profiling of a rare cohort including CES‐R/M identified metastases‐specific features to advance the molecular understanding into CES metastatic progression with potential clinical implications.
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- 2020
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5. CKD-602, a topoisomerase I inhibitor, induces apoptosis and cell-cycle arrest and inhibits invasion in cervical cancer
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Sungha Lee, Jung Yoon Ho, Jing Jing Liu, Hyewon Lee, Jae Young Park, Minwha Baik, Minji Ko, Seon Ui Lee, Youn Jin Choi, and Soo Young Hur
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CKD-602 ,Cell cycle arrest ,Cervical cancer ,Topoisomerase inhibitor ,Invasion assay ,Therapeutics. Pharmacology ,RM1-950 ,Biochemistry ,QD415-436 - Abstract
Abstract Background Cervical cancer is the third most common gynecological malignancy. Conventional treatment options are known to be ineffective for the majority of patients with advanced or recurrent cervical cancer. Therefore, novel therapeutic agents for cervical cancer are necessary. In this study, the effects of CKD-602 in cervical cancer were investigated. Methods Three established human, immortalized, cervical cancer cell lines (CaSki, HeLa and SiHa) were used in this study. Following treatment with CKD-602, apoptosis was quantified using fluorescein isothiocyanate Annexin V-FITC and propidium iodide (PI) detection kit and cell cycle analysis was analyzed using fluorescence activated cell sorting (FACS). Transwell chambers were used for invasion assays. Western blot assay was performed to analyze proteomics. CaSki cells were subcutaneously injected into BALB/c-nude mice and cervical cancer xenograft model was established to elucidate the antitumor effect of CKD-602 in vivo. Results Treatment with CKD-602 induced apoptosis and increased expression of the enzyme PARP, cleaved PARP, and BAX. In addition, expression of phosphorylated p53 increased. Cell cycle arrest at G2/M phase and inhibition of invasion were detected after treatment with CKD-602. A significant decrease in cervical cancer tumor volume was observed in this in vivo model, following treatment with CKD-602. Conclusions This is the first report of CKD-602 having an antitumor effect in cervical cancer in both an in vitro and in vivo models. The results of this study indicate that CKD-602 may be a novel potential drug, targeting cervical cancer, providing new opportunities in the development of new therapeutic strategies.
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- 2019
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6. Risk factors for cytological progression in HPV 16 infected women with ASC-US or LSIL: The Korean HPV cohort
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Kyeong A So, Seon Ah Kim, Yoo Kyung Lee, In Ho Lee, Ki Heon Lee, Jee Eun Rhee, Mee Kyung Kee, Chi Heum Cho, Sung Ran Hong, Chang Sun Hwang, Mi Seon Jeong, Ki Tae Kim, Moran Ki, Soo Young Hur, Jong Sup Park, and Tae Jin Kim
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papillomaviridae ,smoking ,epidemiology ,Gynecology and obstetrics ,RG1-991 - Abstract
ObjectiveThis study was to identify the risk factors for cytological progression in women with atypical squamous cells of undetermined significance (ASC-US) or low-grade squamous intraepithelial lesions (LSIL).MethodsWe analyzed data from women infected with the human papillomavirus (HPV) who participated in the Korean HPV cohort study. The cohort recruited women aged 20–60 years with abnormal cervical cytology (ASC-US or LSIL) from April 2010. All women were followed-up at every 6-month intervals with cervical cytology and HPV DNA testing.ResultsOf the 1,158 women included, 654 (56.5%) and 504 (43.5%) women showed ASC-US and LSIL, respectively. At the time of enrollment, 143 women tested positive for HPV 16 (85 single and 58 multiple infections). Cervical cytology performed in the HPV 16-positive women showed progression in 27%, no change in 23%, and regression in 50% of the women at the six-month follow-up. The progression rate associated with HPV 16 infection was higher than that with infection caused by other HPV types (relative risk [RR], 1.75; 95% confidence interval [CI], 1.08–2.84; P=0.028). The cytological progression rate in women with persistent HPV 16 infection was higher than that in women with incidental or cleared infections (P
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- 2018
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7. Identification of large genomic rearrangement of BRCA1/2 in high risk patients in Korea
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Do-Hoon Kim, Hyojin Chae, Irene Jo, Jaeeun Yoo, Hyeyoung Lee, Woori Jang, Joonhong Park, Gun Dong Lee, Dong-Seok Jeon, Keun Ho Lee, Soo Young Hur, Byung Joo Chae, Byung Joo Song, Myungshin Kim, and Yonggoo Kim
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BRCA1 ,BRCA2 ,Breast cancer ,Ovarian cancer ,Genetic testing ,Korea ,Internal medicine ,RC31-1245 ,Genetics ,QH426-470 - Abstract
Abstract Background While the majority of germline inactivating mutations in BRCA1/2 are small-scale mutations, large genomic rearrangements (LGRs) are also detected in a variable proportion of patients. However, routine genetic methods are incapable of detecting LGRs, and comprehensive genetic testing algorithm is necessary. Methods We performed multiplex ligation-dependent probe amplification assay for small-scale mutation negative patients at high-risk for LGR, based on previously published LGR risk criteria. The inclusion criteria for the high-risk subgroup were personal history of 1) early-onset breast cancer (diagnosed at ≤36 years); 2) two breast primaries; 3) breast cancer diagnosed at any age, with ≥1 close blood relatives (includes first-, second-, or third-degree) with breast and/or epithelial ovarian cancer; 4) both breast and epithelial ovarian cancer diagnosed at any age; and 5) epithelial ovarian cancer with ≥1 close blood relatives with breast and/or epithelial ovarian cancer. Results Two LGRs were identified. One was a heterozygous deletion of exon 19 and the other was a heterozygous duplication of exon 4–6. The prevalence of LGRs was 7% among Sanger-negative, high-risk patients, and accounted for 13% of all BRCA1 mutations and 2% of all patients. Moreover, LGRs reported in Korean patients, including our 2 newly identified cases, were found exclusively in families with at least one high-risk feature. Conclusions Our result suggests that selective LGR screening for Sanger-negative, high-risk patients is necessary for Korean patients.
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- 2017
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8. Clinical Significance of an HPV DNA Chip Test with Emphasis on HPV-16 and/or HPV-18 Detection in Korean Gynecological Patients
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Min-Kyung Yeo, Ahwon Lee, Soo Young Hur, and Jong Sup Park
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Human papillomavirus ,DNA chip ,Hybrid capture 2 ,Cervical intraepithelial neoplasia ,Cervical carcinoma ,Pathology ,RB1-214 - Abstract
Background: Human papillomavirus (HPV) is a major risk factor for cervical cancer. Methods: We evaluated the clinical significance of the HPV DNA chip genotyping assay (MyHPV chip, Mygene Co.) compared with the Hybrid Capture 2 (HC2) chemiluminescent nucleic acid hybridization kit (Digene Corp.) in 867 patients. Results: The concordance rate between the MyHPV chip and HC2 was 79.4% (kappa coefficient, κ = 0.55). The sensitivity and specificity of both HPV tests were very similar (approximately 85% and 50%, respectively). The addition of HPV result (either MyHPV chip or HC2) to cytology improved the sensitivity (95%, each) but reduced the specificity (approximately 30%, each) compared with the HPV test or cytology alone. Based on the MyHPV chip results, the odds ratio (OR) for ≥ high-grade squamous intraepithelial lesions (HSILs) was 9.9 in the HPV-16/18 (+) group and 3.7 in the non-16/18 high-risk (HR)-HPV (+) group. Based on the HC2 results, the OR for ≥ HSILs was 5.9 in the HR-HPV (+) group. When considering only patients with cytological diagnoses of “negative for intraepithelial lesion or malignancy” and “atypical squamous cell or atypical glandular cell,” based on the MyHPV chip results, the ORs for ≥ HSILs were 6.8 and 11.7, respectively, in the HPV-16/18 (+) group. Conclusions: The sensitivity and specificity of the MyHPV chip test are similar to the HC2. Detecting HPV-16/18 with an HPV DNA chip test, which is commonly used in many Asian countries, is useful in assessing the risk of high-grade cervical lesions.
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- 2016
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9. Inhibition of Phosphatidylinositol 3-kinase (PI3K) Signaling Synergistically Potentiates Antitumor Efficacy of Paclitaxel and Overcomes Paclitaxel-Mediated Resistance in Cervical Cancer
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Jing Jing Liu, Jung Yoon Ho, Hye Won Lee, Min Wha Baik, Oyoung Kim, Youn Jin Choi, and Soo Young Hur
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cervical cancer ,combination therapy ,paclitaxel resistance ,cell cycle ,invasion ,PI3K inhibitor ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Acquired paclitaxel (PTX) resistance limits its effectiveness and results in advanced cancer progression. This review investigated whether the inhibition of phosphatidylinositol 3-kinase (PI3K) signaling overcomes paclitaxel resistance in cervical cancer. It was established paclitaxel-resistant cell lines (PTX-R ME180/PTX-R HeLa) and determined the combination index for paclitaxel and PI3K inhibitors (BYL-719/ LY294002) by tetrazolium dye assay. Flow cytometry was used to detect the cell cycle and apoptosis. Migration and invasion were explored by wound healing and transwell assays. Genes related to multiple pathways were assessed by a western blot. It was found that the PI3K pathway was significantly activated in paclitaxel-resistant HeLa and ME180 cells compared to parental cells. PTX + PI3K inhibitor combined therapy showed a synergistic effect by strengthening paclitaxel-induced S and G2M arrest in PTX-R cell sublines by the inactivation of cyclin A1, cyclin B1, cyclin E, and Cdc2 expression. Moreover, combination therapy significantly enhanced drug sensitivity and apoptosis through the activation of Bax, and cleavage of poly-(ADP-ribose) polymerase compared with paclitaxel alone. In addition, PI3K inhibition also suppressed tumor migration and invasion by targeting β-catenin and matrix metalloproteinase-2/9. The authors suggest that the combination of a PI3K inhibitor with paclitaxel may enhance antitumor activity through a cascade of PI3K signaling events.
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- 2019
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10. A phase 1/2a, dose-escalation, safety, and preliminary efficacy study of the RKP00156 vaginal tablet in healthy women and patients with cervical intraepithelial neoplasia 2.
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Hyun-Woong Cho, Sohyeon Jeong, Seung Hun Song, Young Tae Kim, Jae-Weon Kim, Chi-Heum Cho, Soo Young Hur, Suk-Joon Chang, Yong Man Kim, and Jae Kwan Lee
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CERVICAL intraepithelial neoplasia ,WOMEN patients ,HUMAN papillomavirus ,VIRAL load ,STATISTICAL power analysis - Abstract
Objective: This study aimed to determine the safety and efficacy of the RKP00156 vaginal tablet, a CDK9 inhibitor, in healthy women and patients with cervical intraepithelial neoplasia grade 2 (CIN2). Methods: We conducted a phase 1/2a clinical trial of RKP00156. In step 1, RKP00156 at a dose of 10, 25, or 50 mg or a placebo tablet was administered transvaginally to 24 healthy women. In step 2, RKP00156 at a dose of 10, 25, or 50 mg or a placebo tablet was administered once daily for 4 weeks in 62 patients with CIN2. The primary endpoints of this trial were the safety of RKP00156 and the change in the human papillomavirus (HPV) viral load. Results: A total of 86 patients were enrolled and randomized. RKP00156 administration did not cause serious drug-associated adverse events (AEs). Although no significant difference in the HPV viral load was found between the experimental and placebo groups, a reduction in the HPV viral load was observed in the 25 mg-dose group (-98.61%; 95% confidence interval=-99.83%, 4.52%; p=0.046) after treatment completion in patients with a high HPV viral load, despite a lack of statistical power. No differences in histologic regression and HPV clearance were observed. Conclusion: The safety of RKP00156 was proved with no serious AEs. Although the study did not show any significance in histologic regression and HPV clearance, our findings indicate that RKP00156 may have a possibility of short-term inhibitory effect on HPV replication in patients with higher viral loads. [ABSTRACT FROM AUTHOR]
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- 2024
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11. Supplementary Data from A Phase II, Prospective, Randomized, Multicenter, Open-Label Study of GX-188E, an HPV DNA Vaccine, in Patients with Cervical Intraepithelial Neoplasia 3
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Jong Sup Park, You Suk Suh, Young Chul Sung, Jung Won Woo, Ki Seok Park, Chi-Heum Cho, Jae Kwan Lee, Sung Ran Hong, Tae-Jin Kim, Soo Young Hur, and Youn Jin Choi
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Supplementary Data Table S1. Characteristics of the patients who participated the clinical trial Table S2. IFN-γ ELISPOT responses. Table S3. List of HPV16 nucleotide variations among 52 patients included at V8 visit Table S4. Association between "average sum of IFN-γ ELISPOT responses/ baseline IFN-γ ELISPOT responses (fold-change)" and HPV variations (Cutoff p-value
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- 2023
12. Figure S1 from A Phase II, Prospective, Randomized, Multicenter, Open-Label Study of GX-188E, an HPV DNA Vaccine, in Patients with Cervical Intraepithelial Neoplasia 3
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Jong Sup Park, You Suk Suh, Young Chul Sung, Jung Won Woo, Ki Seok Park, Chi-Heum Cho, Jae Kwan Lee, Sung Ran Hong, Tae-Jin Kim, Soo Young Hur, and Youn Jin Choi
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Figure S1 Clinical efficacy according at V7 and V8.
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- 2023
13. Data from A Phase II, Prospective, Randomized, Multicenter, Open-Label Study of GX-188E, an HPV DNA Vaccine, in Patients with Cervical Intraepithelial Neoplasia 3
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Jong Sup Park, You Suk Suh, Young Chul Sung, Jung Won Woo, Ki Seok Park, Chi-Heum Cho, Jae Kwan Lee, Sung Ran Hong, Tae-Jin Kim, Soo Young Hur, and Youn Jin Choi
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Purpose:To determine the efficacy of the therapeutic DNA vaccine GX-188E for inducing regression of cervical intraepithelial neoplasia (CIN) 3.Patients and Methods:We conducted a prospective, randomized, multicenter, open-label, phase II clinical trial of GX-188E in CIN3 patients positive for human papillomavirus (HPV) type 16/18. The primary endpoint was to determine the histopathologic regression to ≤CIN1 at visit seven (V7; 20 weeks after the first GX-188E injection), and an extension study was pursued until visit 8 (V8; 36 weeks after the first GX-188E injection). HPV-sequencing analysis and an ex vivo IFNγ ELISpot assay were performed using the collected cervical biopsy and blood samples from patients.Results:In total, 72 patients were enrolled and underwent randomization. Of them, 64 patients were included in per-protocol analysis (V7) and 52 in extension analysis (V8). Our data showed 52% (33/64) of patients at V7 and 67% (35/52) of patients at V8 presented histopathologic regression after receiving the GX-188E injection. We found that 73% (V7) and 77% (V8) of the patients with histologic regression showed HPV clearance. HPV clearance and histopathologic regression were significantly associated at V7 and at V8. Compared with the measurements at V1 (baseline), the patients at V8 with HPV clearance showed significantly higher fold changes in their IFNγ ELISpot responses compared with those without HPV clearance. The HPV sequence analysis revealed that the HPV type 16 E6/E7 variants D25E, V83L, and N29S were inversely associated with histopathologic regression at V8.Conclusions:GX-188E is an effective therapeutic vaccine against a cohort containing only CIN3 patients.
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- 2023
14. Shallow Whole-Genome Sequencing of Cell-Free DNA (cfDNA) Detects Epithelial Ovarian Cancer and Predicts Patient Prognosis
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Seong Eun Bak, Hanwool Kim, Jung Yoon Ho, Eun-Hae Cho, Junnam Lee, Sung Min Youn, Seong-Woo Park, Mi-Ryung Han, Soo Young Hur, Sung Jong Lee, and Youn Jin Choi
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cfDNA ,epithelial ovarian cancer ,shallow whole-genome sequencing ,plasma ,prognosis ,Cancer Research ,Oncology - Abstract
Despite the progress in diagnostics and therapeutics, epithelial ovarian cancer (EOC) remains a fatal disease. Using shallow whole-genome sequencing of plasma cell-free DNA (cfDNA), we investigated biomarkers that could detect EOC and predict survival. Plasma cfDNA from 40 EOC patients and 20 healthy subjects were analyzed by shallow whole-genome sequencing (WGS) to identify copy number variations (CNVs) and determine the Z-scores of genes. In addition, we also calculated the genome-wide scores (Gi scores) to quantify chromosomal instability. We found that the Gi scores could distinguish EOC patients from healthy subjects and identify various EOC histological subtypes (e.g., high-grade serous carcinoma). In addition, we characterized EOC CNVs and demonstrated a relationship between RAB25 amplification (alone or with CA125), and disease-free survival and overall survival. This study identified RAB25 amplification as a predictor of EOC patient survival. Moreover, we showed that Gi scores could detect EOC. These data demonstrated that cfDNA, detected by shallow WGS, represented a potential tool for diagnosing EOC and predicting its prognosis.
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- 2023
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15. MGMT methylation is associated with human papillomavirus infection in cervical intraepithelial neoplasia: a longitudinal study
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Bo Ram Choi, Hanwool Kim, Jung Yoon Ho, Soo Young Hur, Sung Jong Lee, and Youn Jin Choi
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- 2023
16. The serial chemotherapy regimen choice for better prognosis of ovarian cancer patients
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Seong Eun Bak, Soo Young Hur, and Youn Jin Choi
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- 2023
17. 2022-RA-752-ESGO The efficacy of HPV test for cervical cancer screening
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Heekyoung Song, Jiyun Hong, and Soo Young Hur
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- 2022
18. Distinct genomic profiles of gestational choriocarcinoma, a unique cancer of pregnant tissues
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Dongwan Hong, Yeun-Jun Chung, Sug Hyung Lee, Sang Yong Song, Soo Young Hur, Ok Ran Shin, Mi-Ryung Han, Seung-Hyun Jung, Ahwon Lee, Youn Jin Choi, Jeana Kim, Sung Hak Lee, Min Sung Kim, and Hyeon-Chun Park
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Microarray ,ARID1A ,DNA Copy Number Variations ,Clinical Biochemistry ,Loss of Heterozygosity ,Biology ,medicine.disease_cause ,Biochemistry ,Polymorphism, Single Nucleotide ,Chromatin remodeling ,Article ,Gestational choriocarcinoma ,Endometrial cancer ,Pregnancy ,medicine ,Cancer genomics ,Humans ,Choriocarcinoma ,EP300 ,Molecular Biology ,Gene ,Alleles ,Genetic Variation ,Genomics ,medicine.disease ,NLRP7 ,Uterine Neoplasms ,Cancer research ,Molecular Medicine ,Female ,KRAS ,Disease Susceptibility ,Microsatellite Repeats - Abstract
Little is known about genomic alterations of gestational choriocarcinoma (GC), unique cancer that originates in pregnant tissues, and the progression mechanisms from the nonmalignant complete hydatidiform mole (CHM) to GC. Whole-exome sequencing (20 GCs) and/or single-nucleotide polymorphism microarray (29 GCs) were performed. We analyzed copy-neutral loss-of-heterozygosity (CN-LOH) in 29 GCs that exhibited androgenetic CN-LOHs (20 monospermic, 8 dispermic) and no CN-LOH (one with NLRP7 mutation). Most GCs (25/29) harboring recurrent copy number alterations (CNAs) and gains on 1q21.1-q44 were significantly associated with poor prognosis. We detected five driver mutations in the GCs, most of which were chromatin remodeling gene (ARID1A, SMARCD1, and EP300) mutations but not in common cancer genes such as TP53 and KRAS. One patient’s serial CHM/invasive mole/GC showed consistent CN-LOHs, but only the GC harbored CNAs, indicating that CN-LOH is an early pivotal event in HM-IM-GC development, and CNAs may be a late event that promotes CHM progression to GC. Our data indicate that GCs have unique profiles of CN-LOHs, mutations and CNAs that together differentiate GCs from non-GCs. Practically, CN-LOH and CNA profiles are useful for the molecular diagnosis of GC and the selection of GC patients with poor prognosis for more intensive treatments, respectively., Cancer: Mapping markers of maternal malignancy Genomic analysis reveals chromosomal alterations that drive disease progression in a poorly understood class of tumors that form in placental tissue. Gestational choriocarcinoma (GC) arises during pregnancy and can quickly develop into lethal metastatic disease if not treated promptly. To identify the origins of such malignancies, researchers led by Sug Hyung Lee and Yeun-Jun Chung at The Catholic University of Korea, Seoul, profiled genetic aberrations in 29 GC specimens. The researchers did not observe any consistent link between these malignancies and a particular set of ‘driver mutations’ underlying tumor progression as has been seen in other solid tumors. However, these GC samples exhibited striking levels of rearrangement between chromosomes. The researchers propose that the gain or loss of genes resulting from these chromosomal abnormalities may be an important contributor to rapidly progressing forms of this disease.
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- 2020
19. Clinical Implications of Circulating Tumor DNA from Ascites and Serial Plasma in Ovarian Cancer
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Mi-Ryung Han, Jung Yoon Park, Youn Jin Choi, Sug Hyung Lee, Jung Yoon Ho, Soo Young Hur, and Hyosun Hong
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Adult ,0301 basic medicine ,Cancer Research ,endocrine system diseases ,Somatic cell ,Concordance ,Plasma ,03 medical and health sciences ,0302 clinical medicine ,Ascites ,Biomarkers, Tumor ,medicine ,Humans ,Longitudinal Studies ,Tumor marker ,Ovarian Neoplasms ,Circulating tumor DNA ,business.industry ,High-Throughput Nucleotide Sequencing ,Similar time ,Middle Aged ,Prognosis ,medicine.disease ,Debulking ,female genital diseases and pregnancy complications ,Cystadenocarcinoma, Serous ,Survival Rate ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Mutation ,Next-generation sequencing ,Cancer research ,Female ,Original Article ,Neoplasm Recurrence, Local ,medicine.symptom ,Ovarian cancer ,business ,Adenocarcinoma, Clear Cell ,Follow-Up Studies - Abstract
PurposeThe purpose of this study was to identify the clinical utility of circulating tumor DNA (ctDNA) from ascites and serial plasma samples from epithelial ovarian cancer (EOC) patients.Materials and MethodsUsing targeted next-generation sequencing, we analyzed a total of 55 EOC samples including ctDNA from ascites and serial plasma and gDNA from tumor tissues. Tumor tissues and ascites were collected during debulking surgeries and plasma samples were collected before and after the surgeries. Because one EOC patient underwent secondary debulking surgery, a total of 11 tumor tissues, 33 plasma samples, and 11 ascites samples were obtained from the 10 patients.Results Of the 10 patients, nine (90%) contained somatic mutations in both tumor tissues and ascites ctDNA. This mutational concordance was confirmed through correlation analysis. The mutational concordance between ascites and tumor tissues was valid in recurrent/progressive ovarian cancer. TP53 was the most frequently detected gene with mutations. ctDNA from serial plasma samples identified EOC progression/recurrence at a similar time or even more rapidly than cancer antigen 125, an established serum protein tumor marker for EOC.ConclusionOur data suggest that ascites ctDNA can be used to identify the mutational landscape of ovarian cancer for therapeutic strategy planning.
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- 2020
20. Comparison of ovarian cancer patients and people with familial history of ovary/breast cancer for finding ovarian cancer risk factors.
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Youn Jin Choi, Seong Eun Bak, Min Yeop Whang, and Soo Young Hur
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OVARIAN cancer ,BREAST cancer ,DISEASE risk factors ,CANCER patients ,BRCA genes - Abstract
Objective: Risk of developing ovarian cancer increases if there is a family history of ovarian cancer or breast cancer, and one of the causes is mutation in the BRCA1 or BRCA2 genes. Therefore, people with a family history of ovarian cancer or breast cancer may undergo BRCA1/2 genetic testing to prevent ovarian cancer, and if a mutation is discovered, they visit clinic more often than those who do not. However, there are many cases where ovarian cancer occurs even when gene mutations are not identified, we investigate to find factors that affect the development of ovarian cancer other than the BRCA1/2 genes. Methods: We reviewed anonymized data of ovarian cancer 2,176 patients and healthy 273 subjects from clinical data warehouse for finding ovarian cancer risk factor. Familial history, age at menarche, menopause status, pregnancy history, and BRCA1, BRCA2 mutations were also analyzed. Results: In univariate analysis, significant variables with p<0.05 were identified as factors such as number of family cancers(breast/ovary/pancreas), BRCA1 mutant and variants of uncertain significance (VUS), number of BRCA family cancers, pregnancy history, and body mass index 23 kg/m² or higher. When multivariate analysis was performed using the stepwise method, number of family cancers(breast/ovary/pancreas), BRCA1 mutant, and VUS were confirmed as meaningful results. Conclusion: Therefore, continuous follow-up will be necessary for the healthy people with not only for the number of family cancers but also for BRCA1/2 VUS. [ABSTRACT FROM AUTHOR]
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- 2024
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21. Plasma Protein Biomarkers Associated with Higher Ovarian Cancer Risk in BRCA1/2 Carriers
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Kyunggon Kim, Jung Yoon Ho, Soo Young Hur, Hee-Sung Ahn, Yuyeon Jung, Jiyoung Yu, Sanha Lee, Youn Jin Choi, and Jeonghun Yeom
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0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,endocrine system diseases ,medicine.medical_treatment ,proteome ,Population ,Disease ,Proteomics ,Gastroenterology ,Article ,03 medical and health sciences ,0302 clinical medicine ,BRCA1/2 ,Internal medicine ,medicine ,Liquid biopsy ,LC-MS/MS ,skin and connective tissue diseases ,education ,RC254-282 ,plasma ,education.field_of_study ,liquid biopsy ,business.industry ,Oophorectomy ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Blood proteins ,030104 developmental biology ,ovarian cancer ,Oncology ,030220 oncology & carcinogenesis ,Biomarker (medicine) ,biomarker ,ELISA ,Ovarian cancer ,business - Abstract
Ovarian cancer (OC) is the most lethal gynecologic malignancy and in-time diagnosis is limited because of the absence of effective biomarkers. Germline BRCA1/2 genetic alterations are risk factors for hereditary OC, risk-reducing salpingo-oophorectomy (RRSO) is pursued for disease prevention. However, not all healthy carriers develop the disease. Therefore, identifying predictive markers in the BRCA1/2 carrier population could help improve the identification of candidates for preventive RRSO. In this study, plasma samples from 20 OC patients (10 patients with BRCA1/2 wild type (wt) and 10 with the BRCA1/2 variant (var)) and 20 normal subjects (10 subjects with BRCA1/2wt and 10 with BRCA1/2var) were analyzed for potential biomarkers of hereditary OC. We applied a bottom-up proteomics approach, using nano-flow LC-MS to analyze depleted plasma proteome quantitatively, and potential plasma protein markers specific to the BRCA1/2 variant were identified from a comparative statistical analysis of the four groups. We obtained 1505 protein candidates from the 40 subjects, and SPARC and THBS1 were verified by enzyme-linked immunosorbent assay. Plasma SPARC and THBS1 concentrations in healthy BRCA1/2 carriers were found to be lower than in OC patients with BRCA1/2var. If plasma SPARC concentrations increase over 337.35 ng/mL or plasma THBS1 concentrations increase over 65.28 μg/mL in a healthy BRCA1/2 carrier, oophorectomy may be suggested.
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- 2021
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22. Next-generation Sequencing of an Ovarian Spindle Cell Tumor Identified an Ovarian Low-grade Endometrial Stromal Sarcoma
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Ahwon Lee, Jong Sup Park, Jungyoon Ho, Youn Jin Choi, Soo Young Hur, Jigeun Yoo, and Jing Jing Liu
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Somatic cell ,Sarcoma, Endometrial Stromal ,Cell ,Biology ,medicine.disease_cause ,Pathology and Forensic Medicine ,Frameshift mutation ,Fusion gene ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Ovarian Neoplasms ,Mutation ,Endometrial stromal sarcoma ,High-Throughput Nucleotide Sequencing ,Obstetrics and Gynecology ,Middle Aged ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Immunohistochemistry ,Female ,Sarcoma - Abstract
Ovarian spindle cell tumors comprise a heterogeneous group of ovarian neoplasms from benign to malignant. Since this morphologic finding describes a broad category of ovarian neoplasms, it is not easy to determine an accurate diagnosis. Low-grade endometrial stromal sarcoma (LG-ESS) is a rare gynecological malignancy that presents with spindle cell lesions. To identify ovarian LG-ESS, we performed whole-exome sequencing and transcriptome sequencing of a spindle cell tumor. The tumor harbored JAZF1-SUZ12, a well-known gene fusion commonly found in uterine LG-ESS. Moreover, 28 non-silent somatic mutations (13 frameshift, 12 missense, 2 nonsense and 1 splicing mutations) with five cancer-related genes (ACSL3, ATM, DST, HGF and PKHD1) were detected. Our results indicate that next-generation sequencing combined with conventional immunohistochemical analysis may be a better strategy than conventional analysis alone to identify ovarian LG-ESS with spindle cell lesions. Moreover, our data suggest that ovarian LG-ESS can harbor genetic characteristics similar to those of uterine LG-ESS.
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- 2019
23. Cost-Utility of a Two-Dose Human Papillomavirus Vaccination Programme Added to Cervical Cancer Screening Compared with Cervical Cancer Screening Alone in Korea
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Woo Yun Sohn, Soo Young Hur, I-Heng Lee, Byoung Gie Kim, Hyunju Lee, Georges Van Kriekinge, and Hyeongap Jang
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0301 basic medicine ,Adult ,medicine.medical_specialty ,Human papillomavirus ,Cost-Benefit Analysis ,Uterine Cervical Neoplasms ,Genital warts ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,vaccine ,Health care ,Republic of Korea ,Medicine ,Humans ,Papillomavirus Vaccines ,cost-utility ,Child ,Disease burden ,Early Detection of Cancer ,Aged ,Cervical cancer ,Human papillomavirus 16 ,Korea ,Human papillomavirus 18 ,business.industry ,Papillomavirus Infections ,Vaccination ,virus diseases ,General Medicine ,Middle Aged ,medicine.disease ,Prognosis ,Human papillomavirus vaccination ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cost utility ,Female ,Quality-Adjusted Life Years ,business ,Research Article ,Follow-Up Studies - Abstract
Background: Cervical cancer is caused by the human papillomavirus and is a leading cause of cancer death among young Korean women. Current screening programmes could benefit from the addition of HPV vaccination into their schedule to help reduce disease burden. Two-dose vaccination schedules targeting HPV types 16 and 18, which are responsible for most cervical cancer cases, have recently been approved. Of the two available vaccines, AS04-adjuvanted HPV16/18 vaccine (AS04-HPV16/18v) provides greater protection against non-vaccine oncogenic HPV, while HPV-6/11/16/18 vaccine (4vHPVv) provides protection against genital warts. Methods: The health and economic consequences of introducing a two-dose HPV vaccination programme in 12-year-old girls together with screening were assessed in the Korean healthcare setting using a previously-published Markov model. Results: Compared with screening alone, AS04-HPV16/18v was cost-effective (incremental cost-effectiveness ratio below and within the Korean Won [KRW] 20-30 million treshold). When comparing the two vaccines, at 3% discount rate, AS04-HPV16/18v dominated 4vHPVv (i.e., provided 174 more quality-adjusted life-years (QALYs), 304 more life-years (LYs) and cost-savings of KRW 980 million). At a 5% discount rate, AS04-HPV16/18v provided comparable QALYs (albeit 5 fewer), 105 more LYs and cost-savings of KRW 292 million compared with 4vHPVv. Results were particularly sensitive to the discount rate used, as the health benefits of preventing cervical cancer are observed much later than those of preventing genital warts. Conclusion: For the Korean setting, HPV vaccination with a two-dose schedule is a cost-effective option, and AS04-HPV16/18v is likely to offer better health outcomes at a cost-saving compared with 4vHPVv.
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- 2019
24. Whole-Exome Sequencing Reveals Clinical Potential of Circulating Tumor DNA from Peritoneal Fluid and Plasma in Endometrial Cancer
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Hye-Yeon Ju, Jung Yoon Ho, Jun Kang, Soo Young Hur, Sejin Kim, Youn Jin Choi, and Mi-Ryung Han
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endometrial cancer ,circulating tumor DNA ,plasma ,peritoneal fluid ,liquid biopsy ,heterogeneity ,whole-exome sequencing ,somatic mutations ,copy number alterations ,microsatellite instability ,Cancer Research ,Oncology - Abstract
Endometrial cancer (EC) is the most common type of gynecological cancer. Studies comparing tumor gDNA and ctDNA isolated from the plasma and peritoneal fluid of EC patients are limited. Whole-exome sequencing and P53 immunohistochemistry of 24 paired tissue, plasma, and peritoneal fluid samples from 10 EC patients were performed to analyze somatic mutations, copy number alterations, microsatellite instability, and mutational signatures. Mutations in cancer-related genes (KMT2C, NOTCH2, PRKAR1A, SDHA, and USP6) and genes related to EC (ARID1A, CTNNB1, PIK3CA, and PTEN) were identified with high frequencies among the three samples. TP53 and POLE mutations, which are highly related to the molecular classification of EC, were identified based on several key observations. The ctDNA of two patients with negative peritoneal fluid presented TP53 mutations concordant with those in tissues. ctDNA from the plasma and peritoneal fluid of a patient with positive cytology harbored both TP53 and POLE mutations, although none were detected in tissues. Additionally, the patient presented with wild type P53 immunohistochemistry, with a focal “high” expression in a “low” wild type background. The tissues and peritoneal fluid of 75% EC patients showed concordant microsatellite instability. Furthermore, we observed strong mutational concordance between the peritoneal fluid and tumors. Our data suggest that the ctDNA from peritoneal fluid might be a suitable biomarker for identifying the mutational landscape of EC and could complement tumor heterogeneity.
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- 2022
25. Functional profiles of Müllerian inhibiting substance/anti-Müllerian hormone (MIS/AMH) in primarily cultured endometrial cancer cells
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Joo Hee Yoon, Soo Young Hur, and Sang Il Kim
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endocrine system ,Cell cycle checkpoint ,endocrine system diseases ,medicine.medical_treatment ,Targeted therapy ,Wnt signaling pathway ,Downregulation and upregulation ,otorhinolaryngologic diseases ,Medicine ,biology ,business.industry ,urogenital system ,Endometrial cancer ,Anti-Müllerian hormone ,Cell cycle ,medicine.disease ,Müllerian inhibiting substance ,anti-Müllerian hormone ,Oncology ,endometrial cancer ,biology.protein ,Cancer research ,Signal transduction ,business ,Research Paper - Abstract
Background: Mullerian inhibiting substance/anti-Mullerian hormone (MIS/AMH) inhibits proliferation of MIS/AMH receptor-expressing gynecologic tumors in vivo and in vitro, but the underlying mechanisms have not been fully defined. This study aimed to investigate the expression of MIS/AMH type II receptor (MIS/AMHRII) in endometrial cancer, to identify the mechanism of growth inhibition in MIS/AMH-treated endometrial cancer cells, and to evaluate the clinical significance of MIS/AMH as an effective targeted therapy for MIS/AMH receptor-expressing tumors. Methods: We used tissue samples from 10 patients with total hysterectomy for endometrial cancer. To identify involved signaling pathways, we performed western blotting on apoptosis-, cell cycle-, Wnt signaling-, and autophagy-related proteins. Results: MIS/AMHRII was highly expressed on the cell membrane of endometrial cancer tissues and primarily cultured endometrial cancer cells. We also found that MIS/AMH treatment reduced cell viability, induced cell cycle arrest, and increased apoptosis. MIS/AMH treatment induced upregulation of β-catenin-interacting protein (ICAT) and inhibition of the Dvl and Axin complex (IDAX) but downregulation of phospho-c-Jun in the Wnt signaling pathway. Conclusions: MIS/AMH inhibits the growth of MIS/AMH receptor-expressing endometrial cancer cells through regulation of autophagy, apoptosis, and cell cycle pathways, as well as inhibition of Wnt signaling pathways. These data suggest that MIS/AMH functions as a tumor suppressor and may be an effective therapeutic agent in endometrial cancer.
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- 2021
26. Plasma-derived exosomal miR-4732-5p is a promising noninvasive diagnostic biomarker for epithelial ovarian cancer
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Sanha Lee, Youn Jin Choi, Jingjing Liu, Soo Young Hur, Jigeun Yoo, Yuyeon Jung, and Jung Yoon Ho
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0301 basic medicine ,Oncology ,Adult ,medicine.medical_specialty ,Carcinoma, Ovarian Epithelial ,Exosomal miRNA profiling ,Exosomes ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,microRNA ,Gene expression ,medicine ,Biomarkers, Tumor ,Diagnostic biomarker ,Humans ,Epithelial ovarian cancer ,Stage (cooking) ,miR-4732-5p ,Aged ,Receiver operating characteristic ,business.industry ,Research ,Obstetrics and Gynecology ,Gynecology and obstetrics ,Middle Aged ,Microvesicles ,MicroRNAs ,030104 developmental biology ,030220 oncology & carcinogenesis ,RG1-991 ,Biomarker (medicine) ,Female ,business - Abstract
Background Exosomal miRNAs regulate gene expression and play important roles in several diseases. We used exosomal miRNA profiling to investigate diagnostic biomarkers of epithelial ovarian cancer (EOC). Methods In total, 55 individuals were enrolled, comprising healthy (n = 21) and EOC subjects (n = 34). Small mRNA (smRNA) sequencing and real-time PCR (RT-PCR) were performed to identify potential biomarkers. Receiver operating characteristic (ROC) curves were conducted to determine biomarker sensitivity and specificity. Results Using smRNA sequencing, we identified seven up-regulated (miR-4732-5p, miR-877-5p, miR-574-3p, let-7a-5p, let-7b-5p, let-7c-5p, and let-7f-5p) and two down-regulated miRNAs (miR-1273f and miR-342-3p) in EOC patients when compared with healthy subjects. Of these, miR-4732-5p and miR-1273f were the most up-regulated and down-regulated respectively, therefore they were selected for RT-PCR analysis. Plasma derived exosomal miR-4732-5p had an area under the ROC curve of 0.889, with 85.7% sensitivity and 82.4% specificity in distinguishing EOC patients from healthy subjects (pp = 0.018). Conclusions Plasma derived exosomal miR-4732-5p may be a promising candidate biomarker for diagnosing EOC.
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- 2021
27. Peripheral blood BRCA1 methylation profiling to predict familial ovarian cancer
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Yuyeon Jung, Youn Jin Choi, Jing Jing Liu, Soo Young Hur, Byung Soo Kang, Myungshin Kim, and Sanha Lee
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Oncology ,medicine.medical_specialty ,endocrine system diseases ,Bisulfite sequencing ,Carcinoma, Ovarian Epithelial ,Methylation ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,Family history ,Predictive testing ,skin and connective tissue diseases ,Germ-Line Mutation ,BRCA2 Protein ,Ovarian Neoplasms ,030219 obstetrics & reproductive medicine ,business.industry ,BRCA1 Protein ,Ovary ,Obstetrics and Gynecology ,Cancer ,General Medicine ,DNA Methylation ,medicine.disease ,Ovarian Cancer ,Genes BRCA2 ,Editorial ,Genes BRCA1 ,030220 oncology & carcinogenesis ,DNA methylation ,Hereditary Breast and Ovarian Cancer Syndrome ,Original Article ,Female ,business ,Ovarian cancer - Abstract
OBJECTIVE Familial cancer appears at a young age and its incidence is increasing. About 12% of familial ovarian cancer cases are associated with BRCA1/2 mutations (BRCAm). In this study, we investigated BRCA1 methylation may predict ovarian cancer in those with a family history of cancer (FHC) but without BRCA1/2 mutations (BRCAwt). METHODS Using peripheral blood DNA from 55 subjects without a history of cancer [cancer(-)] and 52 ovarian cancer patients, we examined BRCA1 promoter methylation through bisulfite sequencing of the promoter and expressed the results as the cumulative methylation index. Then, we evaluated the BRCA1 promoter methylation according to BRCA1/2 germline mutations. RESULTS BRCA1 methylation was more prevalent in the BRCAm cancer(-) group than in the BRCAwt cancer(-) group and ovarian cancer patients (p=0.031 and p=0.019, respectively). In the BRCAwt cancer(-) group, BRCA1 methylation was more prevalent in those with an FHC than in those without one and in the BRCAm cancer(-) group with an FHC (p=0.001 and p
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- 2021
28. Epigenetic and genetic characteristics of intraepithelial neoplasia of cervix
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Geunyoung Kim, Heekyoung Song, Seongeun Bak, Imhyeon Kim, and Soo Young Hur
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- 2021
29. Pembrolizumab plus GX-188E therapeutic DNA vaccine in patients with HPV-16-positive or HPV-18-positive advanced cervical cancer: interim results of a single-arm, phase 2 trial
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Yoon-Jeong Choi, Sang Soo Seo, So Jin Shin, You Suk Suh, Jae Hong No, Kyungun Kim, Sang Yoon Park, Jin Won Youn, Jung Won Woo, Byoung-Gie Kim, Young Chul Sung, Marya F. Chaney, Jae Kwan Lee, Soo Young Hur, Yong-Man Kim, Jong Sup Park, and Myong Cheol Lim
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0301 basic medicine ,Adult ,medicine.medical_specialty ,Time Factors ,Uterine Cervical Neoplasms ,Pembrolizumab ,Antibodies, Monoclonal, Humanized ,03 medical and health sciences ,0302 clinical medicine ,Antineoplastic Agents, Immunological ,Internal medicine ,Republic of Korea ,Clinical endpoint ,Vaccines, DNA ,Medicine ,Humans ,Papillomavirus Vaccines ,Prospective Studies ,Prospective cohort study ,Adverse effect ,Neoplasm Staging ,Cervical cancer ,Human papillomavirus 16 ,Human papillomavirus 18 ,business.industry ,Papillomavirus Infections ,Middle Aged ,Interim analysis ,medicine.disease ,Clinical trial ,030104 developmental biology ,Treatment Outcome ,Oncology ,Response Evaluation Criteria in Solid Tumors ,030220 oncology & carcinogenesis ,Female ,Neoplasm Recurrence, Local ,business - Abstract
Summary Background Survival outcomes for patients with recurrent or advanced cervical cancer are poor. Pembrolizumab has been approved for the treatment of recurrent or metastatic cervical cancer, with an overall response rate of 14·3%. GX-188E vaccination has been shown to induce human papillomavirus (HPV) E6-specific and E7-specific T-cell responses and cervical lesion regression in patients with cervical precancer. We aimed to investigate whether a combination of GX-188E therapeutic DNA vaccine plus pembrolizumab showed antitumour activity against recurrent or advanced cervical cancer. Methods In this open-label, single-arm, phase 2 trial, patients with recurrent or advanced, inoperable cervical cancer, who were aged 18 years or older with Eastern Cooperative Oncology Group performance status of 0 or 1 and histologically confirmed recurrent or advanced HPV-positive (HPV-16 or HPV-18) cervical cancer, and who had progressed after available standard-of-care therapy were recruited from seven hospitals in South Korea. Patients received intramuscular 2 mg GX-188E at weeks 1, 2, 4, 7, 13, and 19, with one optional dose at week 46 that was at the investigator's discretion, and intravenous pembrolizumab 200 mg every 3 weeks for up to 2 years or until disease progression. The primary endpoint was the overall response rate within 24 weeks assessed by the investigator using Response Evaluation Criteria in Solid Tumors version 1.1 in patients who received at least 45 days of treatment 45 days of treatment with at least one post-baseline tumour assessment, and this is the report of a planned interim analysis. This trial is registered with ClinicalTrials.gov , NCT03444376 . Findings Between June 19, 2018, and March 20, 2020, 36 patients were enrolled and received at least one dose of the study treatment. 26 patients were evaluable for interim activity assessment, with at least one post-baseline tumour assessment at week 10. At the data cutoff date on March 30, 2020, median follow-up duration was 6·2 months (IQR 3·5–8·1). At 24 weeks, 11 (42%; 95% CI 23-63) of 26 patients achieved an overall response; four (15%) had a complete response and seven (27%) had a partial response. 16 (44%) of 36 patients had treatment-related adverse events of any grade and four (11%) had grade 3–4 treatment-related adverse events. Grade 3 increased aspartate aminotransferase, syncope, pericardial effusion, and hyperkalaemia, and grade 4 increased alanine aminotransferase were reported in one patient each. No treatment-related deaths were reported. Interpretation Treatment with GX-188E therapeutic vaccine plus pembrolizumab for patients with recurrent or advanced cervical cancer was safe and treatment-related adverse events were manageable. This combination therapy showed preliminary antitumour activity in this interim analysis, which could represent a new potential treatment option for this patient population. This trial is ongoing. Funding National OncoVenture.
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- 2020
30. Incidence and clinical course of septic shock in neutropenic patients during chemotherapy for gynecological cancers
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Youn Jin Choi, Soo Young Hur, Keun Ho Lee, Yuyeon Jung, Jigeun Yoo, and Jung Hwan Ahn
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Adult ,medicine.medical_specialty ,Neutropenia ,Adjuvant Chemotherapy ,Genital Neoplasms, Female ,medicine.medical_treatment ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Heart rate ,Medicine ,Chemotherapy ,Humans ,Chemotherapy-Induced Febrile Neutropenia ,Aged ,Retrospective Studies ,030219 obstetrics & reproductive medicine ,business.industry ,Septic shock ,Medical record ,Incidence (epidemiology) ,Mortality rate ,Incidence ,Clinical course ,Age Factors ,Obstetrics and Gynecology ,General Medicine ,Middle Aged ,medicine.disease ,Shock, Septic ,Septic Shock ,Oncology ,030220 oncology & carcinogenesis ,Original Article ,Female ,Gynecologic Neoplasms ,business - Abstract
Objective To identify the incidence and clinical course of septic shock combined with neutropenia during chemotherapy in gynecological cancer patients. Methods We retrospectively reviewed the medical records of all gynecological cancer patients who received intravenous chemotherapy between March 2009 and March 2018. Patients diagnosed with neutropenic septic shock (NSS) during the course of chemotherapy were identified. We calculated the overall incidence and mortality rate of NSS, and analyzed risk factors and clinical course. Results A total of 1,009 patients received 10,239 cycles of chemotherapy during the study period. Among these, 30 (3.0%) patients had 32 NSS events, of which 12 (1.2%) died. With respect to patient age during the first course of chemotherapy, the incidence of NSS after the age of 50 was significantly higher than that in patients under 50 (3.9% vs. 1.4%, p=0.034). As the number of chemotherapy courses increased, the incidence of NSS increased, and linear-by-linear association analysis showed a positive correlation (p=0.004). NSS events occurred on average 7.8 days after the last cycle of chemotherapy, and the median duration of vasopressor administration was 23.3 hours. The median age (64.0 vs. 56.5, p=0.017) and peak heart rate (149.5 min-1 vs. 123.5 min-1, p=0.015) were significantly higher in the group of patients who subsequently died of NSS than in those who survived. Conclusion The overall incidence of NSS in gynecological cancer patients receiving chemotherapy was 3.0%, which is higher than previously estimated. Peak heart rate during NSS events may be an indicator for predicting survival.
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- 2020
31. Genomic, transcriptomic, and viral integration profiles associated with recurrent/metastatic progression in high-risk human papillomavirus cervical carcinomas
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Daeun Ryu, Tae Min Kim, Youn Jin Choi, Soo Young Hur, Jung Eum Lee, Jing Jing Liu, Jung Yoon Ho, Jinseon Yoo, and Kyu Ryung Kim
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0301 basic medicine ,Cancer Research ,Angiogenesis ,cervical cancer ,Uterine Cervical Neoplasms ,Alphapapillomavirus ,Metastasis ,Epigenesis, Genetic ,Transcriptome ,0302 clinical medicine ,INDEL Mutation ,Risk Factors ,APOBEC3A ,Neoplasm Metastasis ,human papillomavirus ,Exome sequencing ,Original Research ,Genome ,Neovascularization, Pathologic ,DNA, Neoplasm ,Genomics ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,humanities ,Up-Regulation ,Survival Rate ,Oncology ,030220 oncology & carcinogenesis ,behavior and behavior mechanisms ,Female ,Cancer Prevention ,Adult ,Epithelial-Mesenchymal Transition ,recurrence ,DNA Copy Number Variations ,Virus Integration ,Down-Regulation ,Biology ,lcsh:RC254-282 ,behavioral disciplines and activities ,Disease-Free Survival ,03 medical and health sciences ,Viral Proteins ,Downregulation and upregulation ,Cytidine Deaminase ,Exome Sequencing ,medicine ,immunoprofiling ,Humans ,metastasis ,Radiology, Nuclear Medicine and imaging ,Epigenetics ,Gene ,Sequence Analysis, RNA ,Carcinoma ,Papillomavirus Infections ,APOBEC ,Proteins ,social sciences ,medicine.disease ,030104 developmental biology ,Cancer research ,Neoplasm Recurrence, Local ,Cell Adhesion Molecules - Abstract
Acquisition of recurrent/metastatic potential by a tumor cell defines a critical step in malignant progression. However, understanding of metastatic progression at the molecular level is scarce for cervical carcinomas (CES). In this study, we performed genomic, transcriptomic, and viral profiling of five pairs of primary (CES‐P) and matched recurrent/metastatic tumors (CES‐R/M) with high risk human papillomavirus. Whole exome sequencing revealed mutation features of CES‐R/M including elevated mutation burdens and prevalent copy number alterations compared to their matched CES‐P. A relative deficit of APOBEC‐related mutation signatures accompanying the transcriptional downregulation of APOBEC3A was observed for CES‐R/M. Mutations in genes encoding epigenetic regulators were commonly observed as CES‐R/M‐specific alterations. Immunoprofiling and gene set analysis revealed CES‐Ps were enriched with transcripts representing activated anticancer immunity such as interferon‐gamma pathway, while CES‐R/M exhibited upregulation of genes involved in epithelial‐mesenchymal transition and angiogenesis. Viral capture sequencing revealed that integration sites remained enriched in viral E1 protein domain during malignant progression. Moreover, we found transcriptional upregulation of POSTN and downregulation of APOBEC3A were associated with unfavorable clinical outcomes in CES. Comprehensive genomic and transcriptomic profiling of a rare cohort including CES‐R/M identified metastases‐specific features to advance the molecular understanding into CES metastatic progression with potential clinical implications., Mutations on genes encoding epigenetic regulators were observed as metastatic‐specific alterations. Immunoprofiling and gene set analysis revealed that primary cervical cancers were with activated anticancer immunity. Elevated POSTN and reduced APOBEC3A at transcription level correlated with unfavorable cervical cancer clinical outcomes.
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- 2020
32. Classification of cervical neoplasms on colposcopic photography using deep learning
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Bum-Joo Cho, Ga Hyun Son, Hong Bae Kim, Ju Han Kim, Young Han Park, Sung Ho Park, Myung Je Lee, Byung Soo Kang, Sung Taek Park, Soo Young Hur, Youn Jin Choi, Yeon Ji Joo, Hye Yon Cho, Min Sun Kyung, and Sanha Lee
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0301 basic medicine ,Adult ,medicine.medical_specialty ,Adolescent ,lcsh:Medicine ,Uterine Cervical Neoplasms ,Cervical intraepithelial neoplasia ,Convolutional neural network ,Article ,Cancer screening ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Deep Learning ,Artificial Intelligence ,Medicine ,Humans ,Diagnosis, Computer-Assisted ,lcsh:Science ,Grading (tumors) ,Aged ,Retrospective Studies ,Colposcopy ,Aged, 80 and over ,Gynaecological cancer ,Multidisciplinary ,medicine.diagnostic_test ,business.industry ,Deep learning ,lcsh:R ,Middle Aged ,medicine.disease ,Uterine Cervical Dysplasia ,030104 developmental biology ,Case-Control Studies ,Cervical cancer ,lcsh:Q ,Female ,Artificial intelligence ,Radiology ,Neural Networks, Computer ,business ,030217 neurology & neurosurgery - Abstract
Colposcopy is widely used to detect cervical cancers, but experienced physicians who are needed for an accurate diagnosis are lacking in developing countries. Artificial intelligence (AI) has been recently used in computer-aided diagnosis showing remarkable promise. In this study, we developed and validated deep learning models to automatically classify cervical neoplasms on colposcopic photographs. Pre-trained convolutional neural networks were fine-tuned for two grading systems: the cervical intraepithelial neoplasia (CIN) system and the lower anogenital squamous terminology (LAST) system. The multi-class classification accuracies of the networks for the CIN system in the test dataset were 48.6 ± 1.3% by Inception-Resnet-v2 and 51.7 ± 5.2% by Resnet-152. The accuracies for the LAST system were 71.8 ± 1.8% and 74.7 ± 1.8%, respectively. The area under the curve (AUC) for discriminating high-risk lesions from low-risk lesions by Resnet-152 was 0.781 ± 0.020 for the CIN system and 0.708 ± 0.024 for the LAST system. The lesions requiring biopsy were also detected efficiently (AUC, 0.947 ± 0.030 by Resnet-152), and presented meaningfully on attention maps. These results may indicate the potential of the application of AI for automated reading of colposcopic photographs.
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- 2020
33. An Open-Label, Randomized, Parallel, Phase II Trial to Evaluate the Efficacy and Safety of a Cremophor-Free Polymeric Micelle Formulation of Paclitaxel as First-Line Treatment for Ovarian Cancer: A Korean Gynecologic Oncology Group Study (KGOG-3021)
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Soo Young Hur, Seung Cheol Kim, Byoung-Gie Kim, Chi Heum Cho, Hee-Sug Ryu, Soon Beom Kang, Jae Hoon Kim, Seok Mo Kim, Shin-Wha Lee, Yong Man Kim, and Young Tae Kim
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Paclitaxel ,Polymers ,Urology ,Phases of clinical research ,Gynecologic oncology ,Neutropenia ,Carboplatin ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Genexol ,Internal medicine ,Republic of Korea ,medicine ,Humans ,Micelles ,Ovarian Neoplasms ,business.industry ,Area under the curve ,Middle Aged ,medicine.disease ,Antineoplastic Agents, Phytogenic ,Genexol-PM ,Regimen ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,Original Article ,Female ,Phase II trial ,business ,Ovarian cancer - Abstract
Purpose Genexol-PM is a biodegradable cremophor EL-free polymeric micelle formulation of paclitaxel. Here,we compared efficacy and safety of Genexol-PM plus carboplatin versus Genexol plus carboplatin for ovarian cancer treatment. Materials and methods In this multicenter, randomized, phase II study, patients with International Federation of Gynecology and Obstetrics IC-IV epithelial ovarian cancer were randomly assigned (1:1) to receive Genexol-PM 260 mg/m2 or Genexol 175 mg/m2 with 5 area under the curve carboplatin every 3weeks (6 cycles). The primary endpointwas the carbohydrate antigen 125 and Response Evaluation Criteria In Solid Tumor composite overall response rate (ORR). Results Of 131 enrolled patients, 98 were included in intention-to-treat analysis. Mean dosages were 260.00±0.00 mg/m2 Genexol-PM or 174.24±3.81 mg/m2 Genexol. Median followup was 18.0 months (range, 6.1 to 33.8 months). ORR was 88.0% (95% confidence interval [CI], 80.4 to 95.6) with Genexol-PM, and 77.1% (95% CI, 67.1 to 87.1) with Genexol (noninferiority threshold, 16.3%). Median time to progression was 14.8 months (95% CI, 11.3 to 20.2) with Genexol-PM and 15.4 months (95% CI, 13.2 to 29.6) with Genexol (p=0.550). Overall, six patients died. Neutropenia was the most common toxicity (incidences of 86.0% vs. 77.1%, p=0.120). Peripheral neuropathy incidences were 84.0% versus 64.6% (p= 0.148). Peripheral neuropathy of ≥ grade 3 occurred in one patient receiving Genexol. All toxicities were manageable. Conclusion Genexol-PM plus carboplatin as first-line treatment in patients with epithelial ovarian cancer demonstrated non-inferior efficacy and well-tolerated toxicities compared with the standard paclitaxel regimen. Further studies are warranted to optimize the dose and schedule, and to investigate long-term outcomes.
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- 2018
34. Efficacy and safety results of GX-188E, a therapeutic DNA vaccine, combined with pembrolizumab administration in patients with HPV 16- and/or 18- positive advanced cervical cancer: Phase II interim analysis results (KEYNOTE-567)
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Jung Won Woo, Soo Young Hur, Myong Cheol Lim, Yong Man Kim, Kyungun Kim, Jong Sup Park, Yoon-Jeong Choi, Young Chul Sung, Jae Hong No, Jae Kwan Lee, Dae Hoon Jeong, You Suk Suh, Chi Heum Cho, Sung Hoon Kim, and Byoung-Gie Kim
- Subjects
Cervical cancer ,Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Pembrolizumab ,Interim analysis ,medicine.disease ,DNA vaccination ,Internal medicine ,medicine ,In patient ,business ,Objective response ,Metastatic cervical cancer - Abstract
5511 Background: Pembrolizumab was approved for the treatment of recurrent or metastatic cervical cancer, based on 14.3% of objective response rate (ORR) in patients with PD-L1 expression (CPS≥1). GX-188E vaccination has been shown to induce human papillomavirus (HPV) E6- and E7-specific T-cell responses. We aimed to investigate whether a combination of GX-188E (Tirvalimogene teraplasmid) therapeutic DNA vaccine plus pembrolizumab showed antitumor activity against recurrent or advanced cervical cancer. Methods: In this open-label, single-arm, phase 2 trial, patients with recurrent or advanced cervical cancer, who were aged over 18 years with ECOG PS of 0 or 1, HPV-16 or HPV-18 and histologically confirmed positive cervical cancer, and who had progressed after standard-of-care therapy were recruited from nine hospitals in South Korea. Patients received intramuscular 2 mg GX-188E at weeks 1, 2, 4, 7, 13, 19, and optional dose at week 46, and intravenous pembrolizumab 200 mg every 3 weeks for up to 2 years or until disease progression. The primary endpoint was the Best Overall Response Rate assessed by the investigator using RECIST version 1.1. Results: To date, a total of 52 patients have been enrolled and received at least one study treatment, and this interim analysis was performed after obtaining at least one post-baseline tumor assessment data from 48 patients. Median age was 52 (range, 27-79) years and 46.2% had ECOG PS 1. At the data cutoff date on January 11, 2021, median follow-up duration was 6.2 months (range; 1.7- 24.2 months). According to investigator evaluation, 15 (31.3%) of 48 patients achieved best overall response; 5 (10.4 %) patients had a complete response (CR) and 10 (20.8 %) had a partial response (PR). Especially, this combination treatment showed higher response rate, 48.0 %, in patients with PD-L1 positive, HPV-16 and squamous cell carcinoma. Median PFS was 4.1 months (range; 1.3-24.2) and median OS was 16.7 months (range; 1.7-24.2). In this clinical trial with cervical cancer patients, GX-188E in combination with pembrolizumab has shown an improved median PFS and OS than the monotherapy of pembrolizumab (KEYNOTE-158). 17 (32.7%) of 52 patients had treatment-related adverse events of any grade and two (3.8%) had grade 3 or 4 treatment-related adverse events; increased aspartate aminotransferase or alanine aminotransferase. No treatment-related deaths were reported. Conclusions: GX-188E vaccine combined with pembrolizumab in recurrent/advanced cervical cancer was safe and tolerable, and showed an enhanced clinical response rate compared with pembrolizumab alone in particular in patients with PD-L1 positive, HPV-16 and squamous cell carcinoma. The combination therapy could represent a new potential treatment option for this patient population. Clinical trial information: NCT03444376.
- Published
- 2021
35. Intraindividual genomic heterogeneity of high-grade serous carcinoma of the ovary and clinical utility of ascitic cancer cells for mutation profiling
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Sug Hyung Lee, Youn Jin Choi, Soo Young Hur, Je-Keun Rhee, Sung Hak Lee, Yeun-Jun Chung, Tae-Min Kim, and Min Sung Kim
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,Somatic cell ,Biology ,medicine.disease ,Pathology and Forensic Medicine ,Metastasis ,03 medical and health sciences ,Serous fluid ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Cancer cell ,DNA methylation ,medicine ,Cancer research ,Ovarian cancer ,Gene ,Exome - Abstract
Intraindividual tumoural heterogeneity (ITH) is a hallmark of solid tumours and impedes accurate genomic diagnosis and selection of proper therapy. The aim of this study was to identify ITH of ovarian high-grade serous carcinomas (OSCs) and to determine the utility of ascitic cancer cells as a resource for mutation profiling in spite of ITH. We performed whole-exome sequencing, copy number profiling and DNA methylation profiling of four OSC genomes by using multiregional biopsies from 13 intraovarian lesions, 12 extraovarian tumour lesions (omentum/peritoneum), and ascitic cells. We observed substantial levels of heterogeneity in mutations and copy number alterations (CNAs) of the OSCs. We categorized the mutations into 'common', 'shared' and 'private' according to the regional distribution. Six common, eight shared and 24 private mutations were observed in known cancer-related genes. Common mutations had a higher mutant allele frequency, and included TP53 mutations in all four OSCs. Region-specific chromosomal amplifications and deletions involving BRCA1, PIK3CA and RB1 were also identified. It is of note that the mutations detected in ascitic cancer cells represented 92.3-100% of overall somatic mutations in the given case. Phylogenetic analyses of ascitic genomes predicted a polyseeding origin of somatic mutations in ascitic cells. Our results demonstrate that, despite ITH, somatic mutations, CNAs and DNA methylations in both 'common' category and cancer-related genes were highly conserved in ascitic cells of OSCs, highlighting the clinical relevance of genome analysis of ascitic cells. Ascitic tumour cells may serve as a potential resource for discovering somatic mutations of primary OSC with diagnostic and therapeutic relevance. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
- Published
- 2016
36. Disparate genomic characteristics of concurrent endometrial adenocarcinoma and ovarian granulosa cell tumor, revealed by targeted next-generation sequencing
- Author
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Jungyoon Ho, Youn Jin Choi, Ahwon Lee, Jong Sup Park, Sug Hyung Lee, Yeun-Jun Chung, Hyeon-Chun Park, and Soo Young Hur
- Subjects
Forkhead Box Protein L2 ,0301 basic medicine ,medicine.drug_class ,Somatic cell ,Granulosa cell ,DNA Mutational Analysis ,STK11 ,Adenocarcinoma ,Biology ,medicine.disease_cause ,Germline ,Pathology and Forensic Medicine ,Neoplasms, Multiple Primary ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,medicine ,Humans ,Receptor, Fibroblast Growth Factor, Type 2 ,Granulosa Cell Tumor ,Mutation ,High-Throughput Nucleotide Sequencing ,Cell Biology ,Middle Aged ,medicine.disease ,Endometrial Neoplasms ,030104 developmental biology ,Estrogen ,030220 oncology & carcinogenesis ,Cancer research ,Female ,Tumor Suppressor Protein p53 - Abstract
Concurrence of both endometrial adenocarcinoma and ovarian adult granulosa cell tumor (aGCT) is believed to be related to high estrogen milieu, but genomic alterations of the concurrent endometrial adenocarcinoma and aGCT are not known. For this, we analyzed an uterine endometrial adenocarcinoma and an ovarian aGCT in a same patient by a targeted next generation sequencing (NGS). We found a germline mutation in STK11 (p.L113fs). The endometrial adenocarcinoma harbored FGFR2 and TP53 mutations and the aGCT harbored a FOXL2 (p.C134 W) mutation. These germline and somatic mutations have been reported in non-concurrent tumors. These two tumors harbored 20 CNAs but only one CNA was exactly overlapped in the tumors. Our findings indicate that the concurrent endometrial adenocarcinoma and aGCT in this patient might not be genetically related to each other at germline or somatic level and suggest that such concurrence might be originated from non-genetic backgrounds including stimulated estrogen milieu.
- Published
- 2018
37. Inhibition of Phosphatidylinositol 3-kinase (PI3K) Signaling Synergistically Potentiates Antitumor Efficacy of Paclitaxel and Overcomes Paclitaxel-Mediated Resistance in Cervical Cancer
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Hye Won Lee, Min Wha Baik, Oyoung Kim, Youn Jin Choi, Soo Young Hur, Jung Yoon Ho, and Jing Jing Liu
- Subjects
Cyclin E ,Paclitaxel ,cervical cancer ,Class I Phosphatidylinositol 3-Kinases ,Uterine Cervical Neoplasms ,Antineoplastic Agents ,Apoptosis ,PI3K inhibitor ,Catalysis ,Article ,combination therapy ,Inorganic Chemistry ,HeLa ,lcsh:Chemistry ,chemistry.chemical_compound ,Cell Line, Tumor ,Humans ,LY294002 ,Physical and Theoretical Chemistry ,Enzyme Inhibitors ,Cyclin B1 ,Molecular Biology ,lcsh:QH301-705.5 ,Spectroscopy ,Cyclin-dependent kinase 1 ,biology ,Organic Chemistry ,Cell Cycle ,Genetic Variation ,Drug Synergism ,General Medicine ,Cell cycle ,biology.organism_classification ,invasion ,Computer Science Applications ,paclitaxel resistance ,chemistry ,lcsh:Biology (General) ,lcsh:QD1-999 ,Drug Resistance, Neoplasm ,Cancer research ,Female ,Phosphatidylinositol 3-Kinase ,Cyclin A1 ,Proto-Oncogene Proteins c-akt ,DNA Damage ,Signal Transduction - Abstract
Acquired paclitaxel (PTX) resistance limits its effectiveness and results in advanced cancer progression. This review investigated whether the inhibition of phosphatidylinositol 3-kinase (PI3K) signaling overcomes paclitaxel resistance in cervical cancer. It was established paclitaxel-resistant cell lines (PTX-R ME180/PTX-R HeLa) and determined the combination index for paclitaxel and PI3K inhibitors (BYL-719/ LY294002) by tetrazolium dye assay. Flow cytometry was used to detect the cell cycle and apoptosis. Migration and invasion were explored by wound healing and transwell assays. Genes related to multiple pathways were assessed by a western blot. It was found that the PI3K pathway was significantly activated in paclitaxel-resistant HeLa and ME180 cells compared to parental cells. PTX + PI3K inhibitor combined therapy showed a synergistic effect by strengthening paclitaxel-induced S and G2M arrest in PTX-R cell sublines by the inactivation of cyclin A1, cyclin B1, cyclin E, and Cdc2 expression. Moreover, combination therapy significantly enhanced drug sensitivity and apoptosis through the activation of Bax, and cleavage of poly-(ADP-ribose) polymerase compared with paclitaxel alone. In addition, PI3K inhibition also suppressed tumor migration and invasion by targeting &beta, catenin and matrix metalloproteinase-2/9. The authors suggest that the combination of a PI3K inhibitor with paclitaxel may enhance antitumor activity through a cascade of PI3K signaling events.
- Published
- 2019
38. CKD-602, a topoisomerase I inhibitor, induces apoptosis and cell-cycle arrest and inhibits invasion in cervical cancer
- Author
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Youn Jin Choi, Minji Ko, Sung Ha Lee, Minwha Baik, Seon Ui Lee, Jung Yoon Ho, Hyewon Lee, Soo Young Hur, Jing Jing Liu, and Jae Young Park
- Subjects
0301 basic medicine ,Cell cycle checkpoint ,Uterine Cervical Neoplasms ,Apoptosis ,HeLa ,chemistry.chemical_compound ,0302 clinical medicine ,Cell Movement ,Medicine ,lcsh:QD415-436 ,Fluorescein isothiocyanate ,Genetics (clinical) ,Cervical cancer ,Mice, Inbred BALB C ,biology ,Flow Cytometry ,G2 Phase Cell Cycle Checkpoints ,030220 oncology & carcinogenesis ,Molecular Medicine ,Female ,CKD-602 ,Topoisomerase inhibitor ,Research Article ,medicine.drug_class ,Mice, Nude ,lcsh:Biochemistry ,Cell cycle arrest ,03 medical and health sciences ,In vivo ,Cell Line, Tumor ,Genetics ,Animals ,Humans ,Propidium iodide ,Molecular Biology ,business.industry ,lcsh:RM1-950 ,Invasion assay ,Cell Cycle Checkpoints ,medicine.disease ,biology.organism_classification ,Xenograft Model Antitumor Assays ,lcsh:Therapeutics. Pharmacology ,030104 developmental biology ,chemistry ,Cancer research ,Camptothecin ,Topoisomerase I Inhibitors ,business ,HeLa Cells - Abstract
Background Cervical cancer is the third most common gynecological malignancy. Conventional treatment options are known to be ineffective for the majority of patients with advanced or recurrent cervical cancer. Therefore, novel therapeutic agents for cervical cancer are necessary. In this study, the effects of CKD-602 in cervical cancer were investigated. Methods Three established human, immortalized, cervical cancer cell lines (CaSki, HeLa and SiHa) were used in this study. Following treatment with CKD-602, apoptosis was quantified using fluorescein isothiocyanate Annexin V-FITC and propidium iodide (PI) detection kit and cell cycle analysis was analyzed using fluorescence activated cell sorting (FACS). Transwell chambers were used for invasion assays. Western blot assay was performed to analyze proteomics. CaSki cells were subcutaneously injected into BALB/c-nude mice and cervical cancer xenograft model was established to elucidate the antitumor effect of CKD-602 in vivo. Results Treatment with CKD-602 induced apoptosis and increased expression of the enzyme PARP, cleaved PARP, and BAX. In addition, expression of phosphorylated p53 increased. Cell cycle arrest at G2/M phase and inhibition of invasion were detected after treatment with CKD-602. A significant decrease in cervical cancer tumor volume was observed in this in vivo model, following treatment with CKD-602. Conclusions This is the first report of CKD-602 having an antitumor effect in cervical cancer in both an in vitro and in vivo models. The results of this study indicate that CKD-602 may be a novel potential drug, targeting cervical cancer, providing new opportunities in the development of new therapeutic strategies. Electronic supplementary material The online version of this article (10.1186/s10020-019-0089-y) contains supplementary material, which is available to authorized users.
- Published
- 2019
39. A Phase II, Prospective, Randomized, Multicenter, Open-Label Study of GX-188E, an HPV DNA Vaccine, in Patients with Cervical Intraepithelial Neoplasia 3
- Author
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Sung Ran Hong, Jong Sup Park, Chi Heum Cho, Tae Jin Kim, Jung Won Woo, Young Chul Sung, Youn Jin Choi, Ki Seok Park, You Suk Suh, Jae Kwan Lee, and Soo Young Hur
- Subjects
0301 basic medicine ,Adult ,Cancer Research ,medicine.medical_specialty ,Randomization ,Uterine Cervical Neoplasms ,Cervical intraepithelial neoplasia ,Gastroenterology ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,law ,Internal medicine ,Clinical endpoint ,medicine ,Vaccines, DNA ,Humans ,Papillomavirus Vaccines ,Prospective Studies ,Prospective cohort study ,Human papillomavirus 16 ,Human papillomavirus 18 ,business.industry ,ELISPOT ,Papillomavirus Infections ,medicine.disease ,Uterine Cervical Dysplasia ,Clinical trial ,030104 developmental biology ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Cohort ,Female ,Patient Safety ,business - Abstract
Purpose: To determine the efficacy of the therapeutic DNA vaccine GX-188E for inducing regression of cervical intraepithelial neoplasia (CIN) 3. Patients and Methods: We conducted a prospective, randomized, multicenter, open-label, phase II clinical trial of GX-188E in CIN3 patients positive for human papillomavirus (HPV) type 16/18. The primary endpoint was to determine the histopathologic regression to ≤CIN1 at visit seven (V7; 20 weeks after the first GX-188E injection), and an extension study was pursued until visit 8 (V8; 36 weeks after the first GX-188E injection). HPV-sequencing analysis and an ex vivo IFNγ ELISpot assay were performed using the collected cervical biopsy and blood samples from patients. Results: In total, 72 patients were enrolled and underwent randomization. Of them, 64 patients were included in per-protocol analysis (V7) and 52 in extension analysis (V8). Our data showed 52% (33/64) of patients at V7 and 67% (35/52) of patients at V8 presented histopathologic regression after receiving the GX-188E injection. We found that 73% (V7) and 77% (V8) of the patients with histologic regression showed HPV clearance. HPV clearance and histopathologic regression were significantly associated at V7 and at V8. Compared with the measurements at V1 (baseline), the patients at V8 with HPV clearance showed significantly higher fold changes in their IFNγ ELISpot responses compared with those without HPV clearance. The HPV sequence analysis revealed that the HPV type 16 E6/E7 variants D25E, V83L, and N29S were inversely associated with histopathologic regression at V8. Conclusions: GX-188E is an effective therapeutic vaccine against a cohort containing only CIN3 patients.
- Published
- 2019
40. Secondary Cytoreductive Surgery for Patients with Isolated Lymph Node Recurrence of Gynecologic Cancer
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Soo Young Hur, Keun Ho Lee, Jong Sup Park, and Eun Young Ki
- Subjects
medicine.medical_specialty ,medicine.anatomical_structure ,business.industry ,Gynecologic cancer ,Medicine ,Radiology ,Cytoreductive surgery ,business ,Lymph node - Published
- 2019
41. Effects of Deep Vein Thrombosis on Survival in Patients with Epithelial Ovarian Cancer: A Retrospective Study
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Eun Young Ki, Soo Young Hur, Jang Yong Kim, and Young Ju Suh
- Subjects
medicine.medical_specialty ,business.industry ,Deep vein ,Retrospective cohort study ,medicine.disease ,Gastroenterology ,Thrombosis ,medicine.anatomical_structure ,Deep vein thrombosis (DVT) ,Internal medicine ,medicine ,Epithelial ovarian cancer ,In patient ,Ovarian cancer ,business - Published
- 2019
42. Risk of cervical dysplasia among human papillomavirus-infected women in Korea: a multicenter prospective study
- Author
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Soo Young Hur, Moran Ki, Tae Jin Kim, Jae Kwan Lee, Chang Sun Hwang, Chi Heum Cho, Yoon Hee Park, Dae Hoon Jeong, Mee Kyung Kee, Seok Ju Seong, and Jaehyun Seong
- Subjects
Adult ,medicine.medical_specialty ,Cervix ,Cohort Studies ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Uterine Cervical Dysplasia ,Internal medicine ,Republic of Korea ,Humans ,Medicine ,Cumulative incidence ,Prospective Studies ,Risk factor ,Prospective cohort study ,Cervical cancer ,Uterine Cervical Cancer ,030219 obstetrics & reproductive medicine ,business.industry ,Incidence ,Papillomavirus Infections ,Obstetrics and Gynecology ,General Medicine ,Middle Aged ,medicine.disease ,Squamous intraepithelial lesion ,medicine.anatomical_structure ,Oncology ,Dysplasia ,030220 oncology & carcinogenesis ,Female ,Original Article ,business ,Precancerous Conditions - Abstract
Objective Human papillomavirus (HPV) infection is the most important risk factor for cervical cancer, which progresses from precursor lesions with no symptom if left untreated. We compared the risk of cervical dysplasia among HPV-positive Korean women based on HPV types and infection patterns. Methods We observed participants of a 5-year multicenter prospective cohort study, comprising HPV-positive women with either atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion of the cervix at their enrollment. Follow-ups, comprising cytology and HPV DNA testing results, were included in the final analysis. Incidence was calculated for each infection pattern (persistent infection, incidental infection, and clearance). To investigate cervical dysplasia risk, we used Cox proportional hazard models adjusted for variables that were significantly different among infection patterns. From April 2010 to September 2017, 71 of 1,027 subjects developed cervical dysplasia more severe than high-grade squamous intraepithelial lesion of the cervix. Results Of these 71 subjects, persistent infection, incidental infection, and clearance were noted in 30, 39, and 2 individuals, respectively. Based on changes in DNA results during follow-up, cumulative incidence was 27.2%, 10.4%, and 0.5% for persistent infection, incidental infection, and clearance, respectively. Compared to clearance, the adjusted hazard ratios for cervical dysplasia were 51.6 and 24.1 for persistent and incidental infections, respectively (p
- Published
- 2019
43. Integrative immunologic and genomic characterization of brain metastasis from ovarian/peritoneal cancer
- Author
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Soo Young Hur, Hyeon-Chun Park, Youn Jin Choi, Sug Hyung Lee, Sang-Yeob Kim, and Yeun-Jun Chung
- Subjects
0301 basic medicine ,endocrine system diseases ,Carcinoma, Ovarian Epithelial ,Immunofluorescence ,Pathology and Forensic Medicine ,Metastasis ,Pathogenesis ,Loss of heterozygosity ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,medicine ,Humans ,Neoplasm Metastasis ,Peritoneal Neoplasms ,Aged ,Ovarian Neoplasms ,medicine.diagnostic_test ,business.industry ,Brain Neoplasms ,Ovary ,Brain ,Cell Biology ,Middle Aged ,medicine.disease ,Prognosis ,030104 developmental biology ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,Female ,Ovarian cancer ,business ,Rare disease ,Brain metastasis - Abstract
Brain metastasis from ovarian/peritoneal cancer is a rare disease that has a dismal prognosis. And genomic alterations and immune-profiling in primary ovarian/ peritoneal cancer and brain metastatic tumor tissues have not been fully elucidated. Multiplexed immunofluorescence and whole-exome sequencing of two matched brain metastatic tumor and primary ovarian/peritoneal cancer tissues were performed. The overall density of immune infiltrates in metastatic tissues (brain) was not significantly different from those in primary cancer tissues (case 1 primary: 2.12% and case 1 metastasis: 2.22%; case 2 primary: 1.70%, and case 2 metastasis: 3.46%). Of note, however, PD-L1 expression in the metastases was higher than that in the primary tumors. We found more non-silent mutations, cancer-related genes, loss of heterozygosity (LOH) and longer lengths of copy-number alterations (CNA) in brain metastases compared to primary ovarian/peritoneal cancers. We report immunologic and genomic profiles of primary ovarian/peritoneal cancer with brain metastasis that may not only provide useful information for understanding its pathogenesis, but also clues for further innovative therapeutic treatments for ovarian cancer.
- Published
- 2018
44. Classical HLA class I antigen downregulation and abnormal HLA-G expression in ovarian cancer
- Author
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Soo Young Hur, Min Jong Song, Joon Mo Lee, Hyon Jee Yoon, Eun Young Ki, and Suk Il Jang
- Subjects
Oncology ,Downregulation and upregulation ,business.industry ,HLA-G ,medicine ,Cancer research ,Obstetrics and Gynecology ,HLA class I antigen ,Ovarian cancer ,medicine.disease ,business - Published
- 2021
45. Clinical Significance of an HPV DNA Chip Test with Emphasis on HPV-16 and/or HPV-18 Detection in Korean Gynecological Patients
- Author
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Jong Sup Park, Min-kyung Yeo, Soo Young Hur, and Ahwon Lee
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,Human papillomavirus ,Histology ,Cervical intraepithelial neoplasia ,Pathology and Forensic Medicine ,Hybrid capture 2 ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Cytology ,Genotype ,medicine ,lcsh:Pathology ,Clinical significance ,Genotyping ,DNA chip ,Cervical carcinoma ,Gynecology ,Cervical cancer ,business.industry ,virus diseases ,Cancer ,medicine.disease ,female genital diseases and pregnancy complications ,Hpv testing ,030104 developmental biology ,030220 oncology & carcinogenesis ,Original Article ,business ,lcsh:RB1-214 - Abstract
Human papillomavirus (HPV) is a DNA tumor virus that is an essential causative factor for cervical cancer. Persistent infection, particularly with high-risk (HR) HPV (HR-HPV) genotypes, plays a major role in the progression of precancerous cervical lesions to invasive cancer [1]. The incidence rate of high-grade cervical lesions is reported to be higher in patients infected with HPV-16 and/or HPV-18 (HPV-16/18) than in patients with other HR-HPV strains [2-5], and HPV-16 and HPV-18 cause 71% of HPV infections in cervical cancer patients [6,7]. Although cytology in cervical cancer screening has been successful, it has several limitations, including low sensitivity and reproducibility. Addition of HPV DNA test to the cytology test, so-called co-test, is the preferred screening method for prevention and early detection of cervical cancer according to the 2012 American Cancer Society screening guidelines [8]. For the first time, these recommendations have adopted HPV 16/18 genotyping in the management of women with positive HPV tests and negative cytology. Specifically, these women should undergo subsequent HPV-16/18 genotyping or repeat co-testing in 12 months [8]. The Hybrid Capture 2 (HC2) chemiluminescent nucleic acid hybridization kit (Digene Corp., Gaithersburg, MA, USA) is a frequently used method to detect HR-HPV and is approved by the United States Food and Drug Administration (U.S. FDA). The kit detects 13 HR-HPV types and reports results as either HR-HPV (+) or HR-HPV (–). The HPV DNA chip test (MyHPV chip, Mygene Co., Seoul, Korea) identifies 15 HR and nine low-risk HPV types and is a commercial HPV DNA genotyping tool used in Korea and other Asian countries. Furthermore, the MyHPV chip kit is approved by the Korean Food and Drug Administration (K-FDA). However, no previous study has assessed the association between HPV-16/18 detected using the MyHPV chip and the risk of developing high-grade cervical lesions. In this study, we compared the clinical performance of the MyHPV chip and HC2 tests using a histological cut-off for high-grade squamous intraepithelial lesions (HSILs).
- Published
- 2016
46. Toll-like receptor 2 gene polymorphisms in Korean women with human papillomavirus-related cervical neoplasia
- Author
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Jin Hwi Kim, Eun Young Key, Min Jong Song, Tae Gyu Kim, Jong Sup Park, Sung Jong Lee, Chan Joo Kim, Tae Chul Park, and Soo Young Hur
- Subjects
Adult ,0301 basic medicine ,medicine.medical_specialty ,Genotype ,Uterine Cervical Neoplasms ,Cervical intraepithelial neoplasia ,Polymorphism, Single Nucleotide ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Asian People ,Internal medicine ,Republic of Korea ,medicine ,Humans ,Allele ,Papillomaviridae ,biology ,business.industry ,Papillomavirus Infections ,HPV infection ,Case-control study ,Obstetrics and Gynecology ,General Medicine ,Odds ratio ,Uterine Cervical Dysplasia ,biology.organism_classification ,medicine.disease ,Genotype frequency ,030104 developmental biology ,Case-Control Studies ,Toll-Like Receptor 9 ,030220 oncology & carcinogenesis ,Female ,business - Abstract
INTRODUCTION The aim of this study was to investigate the association between Toll-like receptor 2 (TLR2) gene polymorphisms and human papillomavirus (HPV)-related cervical neoplasia in Korean women. MATERIAL AND METHODS Peripheral blood samples collected from 127 patients with HPV-related cervical neoplasia and 175 healthy women were genotyped for the TLR2 -16934, +1350, intron1, and 3' untranslated region (UTR) polymorphisms using the polymerase chain reaction and restriction fragment length polymorphism method. RESULTS The TLR2 -16934 A/A, intron1 A/A, and +1350 T/C genotypes were more frequent in patients than in controls [odds ratio (OR) = 2.1, 95% CI = 1.302-3.475, p = 0.002; OR = 1.9, 95% CI = 1.168-3.169, p = 0.010; and OR = 1.9, 95% CI = 1.211-3.123, p = 0.006, respectively]. The frequencies of the TLR2 + 1350 C and 3'UTR G alleles were also higher in patients (OR = 2.0, 95% CI = 1.236-3.121, p = 0.004 and OR = 1.7, 95% CI = 1.005-3.076, p = 0.046, respectively). The genotype frequencies of TLR2 -16934 A/A and intron1 A/A increased with increasing oncogenic risk of the HPV genotype, as follows. low-risk type < high-risk type < HPV-16 and/or HPV-18 type (p = 0.008). CONCLUSIONS Our study provides the first evidence that TLR2 gene polymorphisms are associated with high-risk type HPV-related cervical neoplasia and may play an important role in susceptibility to HPV infection. Further large-scale and functional studies are needed to confirm the role of TLR2 gene polymorphisms in HPV-related cervical neoplasia.
- Published
- 2016
47. Affirm VPIII microbial identification test can be used to detect gardnerella vaginalis, Candida albicans and trichomonas vaginalis microbial infections in Korean women
- Author
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Seung Won Byun, Yeon Joon Park, and Soo Young Hur
- Subjects
0301 basic medicine ,Gynecology ,medicine.medical_specialty ,030219 obstetrics & reproductive medicine ,biology ,business.industry ,Obstetrics ,030106 microbiology ,Trichomonas ,Obstetrics and Gynecology ,medicine.disease_cause ,biology.organism_classification ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Trichomonas Vaginitis ,Gardnerella ,medicine ,Gardnerella vaginalis ,Trichomonas vaginalis ,Nugent score ,business ,Candida albicans ,Vaginitis - Abstract
Aim The aim of this study was to compare Affirm VPIII Microbial Identification Test results for Korean women to those obtained for Gardnerella vaginalis through Nugent score, Candida albicans based on vaginal culture and Trichomonas vaginalis based on wet smear diagnostic standards. Methods Study participants included 195 women with symptomatic or asymptomatic vulvovaginitis under hospital obstetric or gynecologic care. A definite diagnosis was made based on Nugent score for Gardnerella, vaginal culture for Candida and wet prep for Trichomonas vaginalis. Affirm VPIII Microbial Identification Test results were then compared to diagnostic standard results. Results Of the 195 participants, 152 were symptomatic, while 43 were asymptomatic. Final diagnosis revealed 68 (37.87%) cases of Gardnerella, 29 (14.87%) cases of Candida, one (0.51%) case of Trichomonas, and 10 (5.10%) cases of mixed infections. The detection rates achieved by each detection method (Affirm assay vs diagnostic standard) for Gardnerella and Candida were not significantly different (33.33% vs 34.8% for Gardnerella, 13.33% vs 14.87% for Candida, respectively). The sensitivity and specificity of the Affirm test for Gardnerella compared to the diagnostic standard were 75.0% and 88.98%, respectively. For Candida, the sensitivity and specificity of the Affirm test compared to the diagnostic standard were 82.76% and 98.80%, respectively. The number of Trichomonas cases was too small (1 case) to be statistically analyzed. Conclusions The Affirm test is a quick tool that can help physicians diagnose and treat patients with infectious vaginitis at the point of care.
- Published
- 2016
48. A Clinicopathological Review of Pulmonary Metastasis from Uterine Cervical Cancer
- Author
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Jong Sup Park, Eun Young Ki, Keun Ho Lee, and Soo Young Hur
- Subjects
Adult ,0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Pathology ,Lung Neoplasms ,Uterine cervical neoplasms ,medicine.medical_treatment ,Hysterectomy ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Radical Hysterectomy ,Survival analysis ,Cervical cancer ,Chemotherapy ,Lung ,business.industry ,Medical record ,Middle Aged ,Prognosis ,medicine.disease ,Survival Analysis ,Surgery ,Treatment Outcome ,Pulmonary metastasis ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Chemotherapy, Adjuvant ,030220 oncology & carcinogenesis ,Female ,Original Article ,business ,Adjuvant - Abstract
Purpose The purpose of this study was to investigate the clinicopathological features of pulmonary metastasis from cervical cancer. Materials and methods We reviewed the medical records of 56 patients with cervical cancer who developed pulmonary metastasis after radical hysterectomy, postoperative concurrent chemoradiation or systemic chemotherapy between January 1990 and March 2014. Results Fifty-six patients were diagnosed with pulmonary metastasis from cervical cancer. The prevalence of pulmonary metastasis was 3.6%. The mean event-free duration was 12 months. Twelve patients underwent surgical removal of metastatic lesions. The overall survival (OS) of patients with ≤ 3 metastatic lung lesions was 40.7 months, longer than those with > 4 lesions (25 months, p=0.034). The OS of patients who underwent surgical resection was 53.8 months, longer than that of those who did not (p=0.006). In addition, the OS of patients with adjuvant platinum-based chemotherapy was 32.6 months (p=0.027). Conclusion In this study, we found that the number of metastatic nodules, surgical resection, and postoperative platinum-based chemotherapy can influence clinical outcome. Further studies on prognostic factors and successful treatment modalities are warranted.
- Published
- 2016
49. Methylation of Cervical Neoplastic Cells Infected With Human Papillomavirus 16
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Eun Young Ki, Soo Young Hur, Mee Kyung Kee, Jong Sup Park, Jee Eun Rhee, Keun Ho Lee, and Chung Kang
- Subjects
0301 basic medicine ,Pathology ,Uterine Cervical Neoplasms ,Cervical Cancer ,medicine.disease_cause ,Polymerase Chain Reaction ,Immunoenzyme Techniques ,HeLa ,0302 clinical medicine ,Gene expression ,Tumor Cells, Cultured ,Paired Box Transcription Factors ,Promoter Regions, Genetic ,Cervical cancer ,Human papillomavirus 16 ,Membrane Glycoproteins ,DNA methylation ,biology ,Obstetrics and Gynecology ,Methylation ,Prognosis ,Oncology ,030220 oncology & carcinogenesis ,Pituitary Adenylate Cyclase-Activating Polypeptide ,Female ,Antibody ,Human papillomavirus ,medicine.medical_specialty ,Immunoglobulins ,Cervical intraepithelial neoplasia ,03 medical and health sciences ,Biomarkers, Tumor ,medicine ,Humans ,business.industry ,Papillomavirus Infections ,Cell Adhesion Molecule-1 ,Receptors, Interleukin-1 ,Uterine Cervical Dysplasia ,medicine.disease ,biology.organism_classification ,030104 developmental biology ,DNA, Viral ,Cancer research ,biology.protein ,Neoplasm Grading ,Carcinogenesis ,business ,Cell Adhesion Molecules - Abstract
ObjectiveThis study was conducted to evaluate the role of methylation of adenylate cyclase activating peptide 1 (ADCYAP1), paired box gene 1 (PAX1), cell adhesion molecule 1 (CADM1), and T-lymphocyte maturation–associated protein (MAL) during carcinogenesis.MethodsWe evaluated the methylation of 4 genes by using the cervical carcinoma cell lines (CaSki, SiHa, HeLa, and C33A) and cervical neoplastic cells from 56 subjects with human papillomavirus 16 (HPV16)–infected low-grade squamous intraepithelial lesions (LSILs), 50 subjects with HPV16-infected high-grade squamous intraepithelial lesions (HSILs), and 24 subjects with HPV16-infected invasive cervical cancer who attended Seoul St. Mary’s Hospital. Methylation of the 4 genes was evaluated using quantitative bisulfate pyrosequencing.ResultsThe ADCYAP1 promoter was hypermethylated in the 4 cell lines (CaSki, 97.40 ± 1.39; SiHa, 82.04 ± 17.02; HeLa, 96.14 ± 2.08; and C33A, 78 ± 10.18). PAX1 and CADM1 were hypermethylated in the HPV16/18-infected cell lines CaSki (PAX1, 91.18 ± 9.91; CADM1, 93.5 ± 7.33), SiHa (PAX1, 96.14 ± 2.08; CADM1, 93.15 ± 8.81), and HeLa (PAX1, 82.04 ± 17.02; CADM1, 92.43 ± 9.95). MAL was hypermethylated in the CaSki cell line (96.04 ± 4.74). Among human cervical neoplastic cells, the methylation indices of ADCYAP1 were 7.8 (95% confidence interval [95% CI], 7.0–8.6) in subjects with LSILs and 39.8 (95% CI, 29.0–54.7) in those with cervical cancer (P < 0.001); for PAX1, 7.2 (95% CI, 6.1–8.5) and 37.8 (95% CI, 27.1–52.7), respectively; for CADM1, 3.5 (95% CI, 3.0–4.0) and 17.7 (95% CI, 10.8–29.1), respectively; for MAL, 2.7 (95% CI, 2.5–3.0) and 13.0 (95% CI, 7.6–22.0), respectively (P < 0.001 for each). Immunohistochemical staining results were positive in the cytoplasm of subjects with low methylation of the 4 gene promoters; however, they were negative in the cytoplasm of those with hypermethylation of the 4 gene promoters.ConclusionsThe results of this study suggest that the methylation of ADCYAP1, PAX1, CADM1, and MAL may be highly associated with the development of cervical cancer, and that gene expression can be suppressed by gene promoter hypermethylation.
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- 2016
50. Abstract CT033: Efficacy and safety results of pembrolizumab combined with GX-188E, a therapeutic DNA vaccine administration in patients with HPV 16- and/or 18- positive advanced cervical cancer: Phase II interim analysis results
- Author
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Myong Cheol Lim, Jong Sup Park, Jung Won Woo, Soo Young Hur, You Suk Suh, Yong-Man Kim, Chi Heum Cho, Yoon-Jeong Choi, Jae Hong No, Jae Kwan Lee, Young Chul Sung, and Byoung-Gie Kim
- Subjects
Cervical cancer ,Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Phases of clinical research ,Cancer ,Pembrolizumab ,medicine.disease ,Interim analysis ,Radiation therapy ,Tolerability ,Internal medicine ,medicine ,business - Abstract
Purpose: Pembrolizumab was approved for the treatment of patients with relapsed or metastatic cervical cancer with disease progression on or after chemotherapy, whose tumors express PD-L1 (CPS≥1), with a 14.3% objective response rate (ORR) by the U.S. FDA in 2018 (KEYNOTE-158). Combination of pembrolizumab with GX-188E, a DNA vaccine targeting HPV 16 and 18 types is expected to show synergistic anti-tumor effects presumably by antigen-specific CD8+ T cell responses induced by GX-188E DNA vaccine. The objectives of this interim analysis are to assess preliminary anti-tumor efficacy, safety and tolerability. Patients and Design: This is a prospective, open-label, phase II study in patients with advanced, inoperable or metastatic cervical cancer, ECOG PS 0-1, positivity for HPV 16 and/or 18 types who have failed all available standard-of-care (SoC) therapies including surgery, chemotherapy and radiotherapy or who have refused those (≥2 lines). Patients received GX-188E 2 mg intramuscularly, seven times at weeks 1, 2, 4, 7, 13, 19, and 46, with pembrolizumab 200 mg IV every three weeks for up to 2 years or until progression. This interim analysis was performed after obtaining at least one post baseline tumor assessment data from 22 patients (approximately 50% of total patients to be enrolled in Phase II). Results: Among 24 patients treated, 22 patients were evaluable for anti-tumor efficacy. Median age was 52 (range, 27-68) years and 37.5% had ECOG PS 1. As of the Dec 11, 2019 data cutoff, the median follow-up duration was 5.3 months (range; 0.9-16.3 months). ORR was 45.5%, with 5 CRs and 5 PRs. Additionally, one patient had SD at week 14. Median PFS was 4.1 months (range; 1.7-not reached). Median DoR and OS have not been reached. Treatment related AEs occurred in 54.2% of patients with grade 1 or 2 and 12.5% of patients with grade 3-4. The most common treatment related AEs classified by system organ class were gastrointestinal disorders (20.8%) and respiratory, thoracic and mediastinal disorders (16.7%), which were similar to those of pembrolizumab monotherapy. In contrast to pembrolizumab monotherapy, combined therapy showed therapeutic effect in PD-L1 negative tumor. Conclusions: Pembrolizumab combined with GX-188E demonstrated a higher response rate than pembrolizumab monotherapy in patients with cervical cancer showing great synergy regardless of PD-L1 expression. The safety profile was manageable and similar to that of pembrolizumab monotherapy. Further evaluation of anti-tumor response and antigen specific immune response is ongoing in a larger number of patients with and without PD-L1 expression. Citation Format: Sooyoung Hur, Jong Sup Park, Yong-Man Kim, Myong Cheol Lim, Jae Hong No, Byoung-Gie Kim, Jae-Kwan Lee, Chi Heum Cho, Yoon-Jeong Choi, You Suk Suh, Jung Won Woo, Young Chul Sung. Efficacy and safety results of pembrolizumab combined with GX-188E, a therapeutic DNA vaccine administration in patients with HPV 16- and/or 18- positive advanced cervical cancer: Phase II interim analysis results [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT033.
- Published
- 2020
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