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1.  Lymphovascular invasion in more than one-quarter of small rectal neuroendocrine tumors 
World Journal of Gastroenterology  2016;22(42):9400-9410.
AIM
To identify the frequency, clinicopathological risk factors, and prognostic significance of lymphovascular invasion (LVI) in endoscopically resected small rectal neuroendocrine tumors (NETs).
METHODS
Between June 2005 and December 2015, 104 cases of endoscopically resected small (≤ 1 cm) rectal NET specimens at Hallym University Sacred Heart Hospital in Korea were retrospectively evaluated. We compared the detected rate of LVI in small rectal NET specimens by two methods: hematoxylin and eosin (H&E) and ancillary immunohistochemical staining (D2-40 and Elastica van Gieson); in addition, LVI detection rate difference between endoscopic procedures were also evaluated. Patient characteristics, prognosis and endoscopic resection results were reviewed by medical charts.
RESULTS
We observed LVI rates of 25.0% and 27.9% through H&E and ancillary immunohistochemical staining. The concordance rate between H&E and ancillary studies was 81.7% for detection of LVI, which showed statistically strong agreement between two methods (κ = 0.531, P < 0.001). Two endoscopic methods were studied, including endoscopic submucosal resection with a ligation device and endoscopic submucosal dissection, and no statistically significant difference in the LVI detection rate was detected between the two (26.3% and 26.8%, P = 0.955). LVI was associated with large tumor size (> 5 mm, P = 0.007), tumor grade 2 (P = 0.006). Among those factors, tumor grade 2 was the only independent predictive factor for the presence of LVI (HR = 4.195, 95%CI: 1.321-12.692, P = 0.015). No recurrence was observed over 28.8 mo regardless of the presence of LVI.
CONCLUSION
LVI may be present in a high percentage of small rectal NETs, which may not be associated with short-term prognosis.
doi:10.3748/wjg.v22.i42.9400
PMCID: PMC5107704  PMID: 27895428
Rectum; Neuroendocrine tumor; Lymphatic; Immunohistochemistry; Prognosis
2.  Endoscopic submucosal dissection for early gastric cancer with undifferentiated-type histology: A meta-analysis 
AIM: To evaluate the efficacy and safety of endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) with undifferentiated-type histology.
METHODS: A systematic literature review was conducted using the core databases. Complete resection, curative resection, en bloc resection, recurrence and adverse event rate were extracted and analyzed. A random effect model was applied. The methodological quality of the enrolled studies was assessed using the Newcastle-Ottawa Scale. Publication bias was evaluated using a funnel plot, the trim and fill method, Egger’s test, and a rank correlation test.
RESULTS: Fourteen retrospective studies between 2009 and 2014 were identified (972 EGC lesions with undifferentiated-type histology). The total en bloc and complete resection rates were estimated as 92.1% (95%CI: 87.4%-95.2%) and 77.5% (95%CI: 69.3%-84%), respectively. The total curative resection rate was 61.4% (95%CI: 44.5%-75.9%). The overall recurrence rate was 7.6% (95%CI: 3.4%-16%). Limited to histologically diagnosed expanded-criteria lesions, the en bloc and complete resection rates were 91.2% and 85.6%, respectively. The curative resection rate was 79.8%.
CONCLUSION: In this analysis, ESD is a technically feasible treatment modality for EGC with undifferentiated-type histology. Long-term studies are needed to confirm these therapeutic outcomes.
doi:10.3748/wjg.v21.i19.6032
PMCID: PMC4438040  PMID: 26019470
Carcinoma; Endoscopic submucosal dissection; Endoscopy; Gastric cancer; Meta-analysis
3.  The relationship between cisplatin resistance and histone deacetylase isoform overexpression in epithelial ovarian cancer cell lines 
Journal of Gynecologic Oncology  2012;23(3):182-189.
Objective
To investigate the relationship between cisplatin resistance and histone deacetylase (HDAC) isoform overexpression in ovarian cancer cell lines.
Methods
Expression of four HDAC isoforms (HDAC 1, 2, 3, and 4) in two ovarian cancer cell lines, SKOV3 and OVCAR3, exposed to various concentrations of cisplatin was examined by western blot analyses. Cells were transfected with plasmid DNA of each HDAC. The overexpression of protein and mRNA of each HDAC was confirmed by western blot and reverse transcriptase-polymerase chain reaction analyses, respectively. The cell viability of the SKOV3 and OVCAR3 cells transfected with HDAC plasmid DNA was measured using the cell counting kit-8 assay after treatment with cisplatin.
Results
The 50% inhibitory concentration of the SKOV3 and OVCAR3 cells can be determined 15-24 hours after treatment with 15 µg/mL cisplatin. The expression level of acetylated histone 3 protein in SKOV3 cells increased after exposure to cisplatin. Compared with control cells at 24 hours after cisplatin exposure, the viability of SKOV3 cells overexpressing HDAC 1 and 3 increased by 15% and 13% (p<0.05), respectively. On the other hand, OVCAR3 cells that overexpressed HDAC 2 and 4 exhibited increased cell viability by 23% and 20% (p<0.05), respectively, compared with control cells 24 hours after exposure to cisplatin.
Conclusion
In SKOV3 and OVCAR3 epithelial ovarian cancer cell lines, the correlation between HDAC overexpression and cisplatin resistance was confirmed. However, the specific HDAC isoform associated with resistance to cisplatin varied depending on the ovarian cancer cell line. These results may suggest that each HDAC isoform conveys cisplatin resistance via different mechanisms.
doi:10.3802/jgo.2012.23.3.182
PMCID: PMC3395014  PMID: 22808361
Cisplatin resistance; Epithelial ovarian cancer cell lines; Histone deacetylase
4.  Asian society of gynecologic oncology workshop 2010 
Journal of Gynecologic Oncology  2010;21(3):137-150.
This workshop was held on July 31-August 1, 2010 and was organized to promote the academic environment and to enhance the communication among Asian countries prior to the 2nd biennial meeting of Australian Society of Gynaecologic Oncologists (ASGO), which will be held on November 3-5, 2011. We summarized the whole contents presented at the workshop. Regarding cervical cancer screening in Asia, particularly in low resource settings, and an update on human papillomavirus (HPV) vaccination was described for prevention and radical surgery overview, fertility sparing and less radical surgery, nerve sparing radical surgery and primary chemoradiotherapy in locally advanced cervical cancer, were discussed for management. As to surgical techniques, nerve sparing radical hysterectomy, optimal staging in early ovarian cancer, laparoscopic radical hysterectomy, one-port surgery and robotic surgery were introduced. After three topics of endometrial cancer, laparoscopic surgery versus open surgery, role of lymphadenectomy and fertility sparing treatment, there was a special additional time for clinical trials in Asia. Finally, chemotherapy including neo-adjuvant chemotherapy, optimal surgical management, and the basis of targeted therapy in ovarian cancer were presented.
doi:10.3802/jgo.2010.21.3.137
PMCID: PMC2948221  PMID: 20922136
ASGO; Workshop; Cervical caner; Endometrial cancer; Ovarian cancer; Clinical trials
5.  Efficacy of taxane and platinum-based chemotherapy guided by extreme drug resistance assay in patients with epithelial ovarian cancer 
Journal of Gynecologic Oncology  2009;20(2):96-100.
Objective
To evaluate the efficacy of taxane and platinum-based chemotherapy guided by extreme drug resistance assay (EDRA) in patients with epithelial ovarian cancer.
Methods
Thirty-nine patients were enrolled, who were diagnosed as epithelial ovarian cancer, tubal cancer or primary peritoneal carcinoma and received both debulking surgery and EDRA in Asan Medical Center between August 2004 and August 2006. Another thirty-nine patients were enrolled, who did not receive EDRA as control. Paclitaxel 175 mg/m2 and carboplatin AUC 5 were administered as primary combination chemotherapy to both EDRA group and the control group. In the EDRA group, paclitaxel was replaced by docetaxel 75 mg/m2 if a patient showed extreme drug resistance (EDR) to paclitaxel and not to docetaxel. Carboplatin was replaced by cisplatin 75 mg/m2 if a patient showed EDR to carboplatin and not to cisplatin. If only one drug showed low drug resistance (LDR), it was allowed to add another drug which showed LDR such as gemcitabine 1,000 mg/m2. CT scan was performed every three cycles and CA-125 was checked at each cycle.
Results
There was no significant difference in overall response rate between EDRA group and the control group (84.5% vs. 71.8%, p=0.107). However, 93.8% of patients in EDRA group did not show EDR to at least one drug and its response rate was significantly higher than that of the control group (93.3% vs. 71.8%, p=0.023).
Conclusion
we could choose a combination of taxane and platinum which did not show EDR and could obtain a good response in the patients with ovarian cancer.
doi:10.3802/jgo.2009.20.2.96
PMCID: PMC2705007  PMID: 19590720
Ovarian neoplasms; Antineoplastic combined chemotherapy protocol; Drug resistance; neoplasm; Biologic assay
6.  Toothpick impaction with sigmoid colon pseudodiverticulum formation successfully treated with colonoscopy 
Foreign bodies in the colon are encountered with increasing frequency, but only sporadic reports concerning their management have appeared in the literature. While most ingested foreign bodies usually pass through the gastrointestinal tract uneventfully, sharp foreign bodies such as toothpicks infrequently cause intestinal perforation and may even result in death. We report our experience with a patient with a sigmoid colon pseudodiverticulum formation, a complication of accidental ingestion of a toothpick that was diagnosed and successfully managed colonoscopically.
doi:10.3748/wjg.14.948
PMCID: PMC2687067  PMID: 18240357
Toothpick; Colon; Colonoscopy; Pseudo-diverticulum
7.  Gallbladder lymphangioma: A case report and review of the literature 
Lymphangiomas are rare, benign tumors of the lymphatic system, usually present in children aged 5 years and younger. Because they are asymptomatic until the mass enlarges to cause symptoms, most lymphangiomas are diagnosed at adulthood incidentally. We experienced a case of a 60-year-old man diagnosed with a cystic lymphangioma of the gallbladder, which was successfully resected without any complication. Magnetic resonance imaging and magnetic resonance cholangiopancreatography were very helpful for the diagnosis of the cystic lesion around the gallbladder as were ultrasonography and computed tomography scan. These showed a multi-lobulated cystic mass with intact cystic duct and bile duct in the gallbladder fossa. The patient underwent an open cholecystectomy and the histological findings were consistent with a cystic lymphangioma of the gallbladder. We here report the case of cystic lymphangioma of the gallbladder with a review of the literature.
doi:10.3748/wjg.v13.i2.320
PMCID: PMC4065967  PMID: 17226918
Lymphangioma; Gallbladder; Cholecystectomy
8.  Enhanced biglycan gene expression in the adipose tissues of obese women and its association with obesity-related genes and metabolic parameters 
Scientific Reports  2016;6:30609.
Extracellular matrix (ECM) remodeling dynamically occurs to accommodate adipose tissue expansion during obesity. One non-fibrillar component of ECM, biglycan, is released from the matrix in response to tissue stress; the soluble form of biglycan binds to toll-like receptor 2/4 on macrophages, causing proinflammatory cytokine secretion. To investigate the pattern and regulatory properties of biglycan expression in human adipose tissues in the context of obesity and its related diseases, we recruited 21 non-diabetic obese women, 11 type 2 diabetic obese women, and 59 normal-weight women. Regardless of the presence of diabetes, obese patients had significantly higher biglycan mRNA in both visceral and subcutaneous adipose tissue. Biglycan mRNA was noticeably higher in non-adipocytes than adipocytes and significantly decreased during adipogenesis. Adipose tissue biglycan mRNA positively correlated with adiposity indices and insulin resistance parameters; however, this relationship disappeared after adjusting for BMI. In both fat depots, biglycan mRNA strongly correlated with the expression of genes related to inflammation and endoplasmic reticulum stress. In addition, culture of human preadipocytes and differentiated adipocytes under conditions mimicking the local microenvironments of obese adipose tissues significantly increased biglycan mRNA expression. Our data indicate that biglycan gene expression is increased in obese adipose tissues by altered local conditions.
doi:10.1038/srep30609
PMCID: PMC4964581  PMID: 27465988
9.  Clinical Role of Adjuvant Chemotherapy after Radical Hysterectomy for FIGO Stage IB-IIA Cervical Cancer: Comparison with Adjuvant RT/CCRT Using Inverse-Probability-of-Treatment Weighting 
PLoS ONE  2015;10(7):e0132298.
Objective
To evaluate the clinical role of adjuvant chemotherapy (AC) in FIGO stage IB-IIA cervical cancer patients.
Study Design
A cohort of 262 patients with cervical cancer who received radical hysterectomy (RH) and adjuvant therapy at Asan Medical Center between 1992 and 2012 was enrolled. In this cohort, 85 patients received adjuvant chemotherapy (AC), and 177 received adjuvant radiotherapy or concurrent chemoradiation therapy (AR). Oncologic outcomes and adverse events in both treatment arms were compared using weighted Cox proportional hazards regression models with inverse-probability-of-treatment weighting (IPTW) to reduce the impact of treatment selection bias and potential confounding factors.
Results
During a 46.8-month median follow-up duration, 39 patients (14.9%) had recurrences, and 18 patients (6.9%) died of disease. In multivariate analysis, the hazard ratio (HR) for recurrence and death was not significantly different in patients in either treatment arm (p=0.62 and 0.12, respectively). Also, after IPTW matching, the HR for recurrence did not significantly differ between the arms (HR 1.57, 95% CI 0.68-3.62, p=0.29). Similarly, disease-free survival and overall survival were not significantly different between the arms (p=0.47 and 0.13, respectively). In addition, patients with AC had a much lower prevalence of long-term complications (lymphedema: n=8 (9.4%) vs. 46 (26.0%), p=0.03; ureteral stricture: n=0 vs. 9 (6.2%), p=0.05).
Conclusion
Patients with FIGO stage IB-IIA cervical cancer can benefit from AC after RH with fewer long-term complications and non-inferior therapeutic effect to AR. Chemotherapy may therefore be an alternative adjuvant treatment option for cervical cancer, particularly in younger patients.
doi:10.1371/journal.pone.0132298
PMCID: PMC4503636  PMID: 26176626
10.  Laparoendoscopic single-site versus conventional laparoscopic surgery for ovarian mature cystic teratoma 
Obstetrics & Gynecology Science  2015;58(4):294-301.
Objective
To compare the intraoperative and postoperative outcomes of laparoendoscopic single-site surgery (LESS) versus conventional laparoscopic surgery in women with ovarian mature cystic teratoma.
Methods
A retrospective review of 303 women who underwent LESS (n=139) or conventional laparoscopic surgery (n=164) due to ovarian mature cystic teratoma was performed. Intra- and postoperative outcomes were compared between the two groups.
Results
There was no intergroup difference in age, body weight, height, body mass index, comorbidities, tumor size, bilaterality of tumor, or the type of surgery. However, more patients in the LESS group had a history of previous abdominal surgery (19.4% vs. 6.7%, P=0.001). Surgical outcomes including operating time (89 vs. 87.8 minutes, P=0.734), estimated blood loss (69.4 vs. 68.4 mL, P=0.842), transfusion requirement (2.2% vs. 0.6%, P=0.336), perioperative hemoglobin level change (1.3 vs. 1.2 g/dL, P=0.593), postoperative hospital stay (2.0 vs. 2.1 days, P=0.119), and complication rate (1.4% vs. 1.8%, P=0.999) did not differ between LESS and conventional groups. Postoperative pain scores measured using a visual analogue scale were significantly lower in the LESS group at 8 hours (P=0.021), 16 hours (P=0.034), and 32 hours (P=0.004) after surgery, and 32 of 139 patients (23%) in the LESS group and 78 of 164 patients (47.6%) in the conventional group required at least one additional analgesic (P<0.001).
Conclusion
LESS was feasible and showed comparable surgical outcomes with conventional laparoscopic surgery for women with ovarian mature cystic teratoma. LESS was associated with less postoperative pain and required less analgesia.
doi:10.5468/ogs.2015.58.4.294
PMCID: PMC4515479  PMID: 26217600
Laparoendoscopic single-site surgery; Laparoscopes; Mature cystic teratoma; Ovary; Single-port
11.  Corrosive Esophagitis Caused by Ingestion of Picosulfate 
Clinical Endoscopy  2015;48(1):66-69.
Corrosive esophagitis is characterized by caustic injury due to the ingestion of chemical agents, mainly alkaline substances such as detergents. Esophageal bleeding, perforation, or stricture can be worsened by high-degree corrosive esophagitis. Picosulfate is a commonly used laxative frequently administered for bowel preparation before colonoscopy or colon surgery. Picosulfate powder should be completely dissolved in water before ingestion because the powder itself may cause chemical burning of the esophagus and stomach. Here, we report a case of corrosive esophagitis due to the ingestion of picosulfate powder that was not completely dissolved in water.
doi:10.5946/ce.2015.48.1.66
PMCID: PMC4323436  PMID: 25674529
Caustics; Esophagitis; Picosulfate
12.  Knockdown of anterior gradient 2 expression extenuates tumor-associated phenotypes of SNU-478 ampulla of Vater cancer cells 
BMC Cancer  2014;14:804.
Background
Anterior gradient 2 (AGR2) has been implicated in tumor-associated phenotypes such as cell viability, invasion and metastasis in various human cancers. However, the tumor promoting activity of AGR2 has not yet been determined in biliary tract cancers. Thus, we examined the expression of AGR2 and its tumor-promoting activity in biliary tract cancer cells in this study.
Methods
Expression of AGR2 mRNA and protein was analyzed by real time RT-PCR and western blotting, respectively. MTT assay was employed to measure cell viability and pulsed BrdU incorporation by proliferating cells was monitored by flow cytometry. Soft agar colony formation assay and transwell invasion assay were employed to determine anchorage-independent growth and in vitro invasion of the tumor cells, respectively. In vivo tumor formation was examined by injection of tumor cells into immunocompromised mice subcutaneously. Statistical analysis was performed with 2-tailed unpaired Student’s t-test for continuous data and with one-way ANOVA for multiple group comparisons. Bonferroni tests were used for post hoc 2-sample comparisons.
Results
AGR2 mRNA was detected in SNU-245, SNU-478, and SNU-1196 cell lines, and its protein expression was confirmed in SNU-478 and SNU-245 cell lines by western blot analysis. Knockdown of AGR2 expression with an AGR2-specific short hairpin RNA (shRNA) in SNU-478, an ampulla of Vater cancer cell line resulted in decreased cell viability and in decreased anchorage-independent growth by 98%. The AGR2 knockdown also increased the sensitivity of the cells to chemotherapeutic drugs, including gemcitabine, 5-fluorouracil and cisplatin. In addition, SNU-478 cells expressing AGR2-shRNA failed to form detectable tumor xenografts in nude mice, whereas control cells formed tumors with an average size of 179 ± 84 mm3 in 3 weeks. Overexpression of AGR2 in SNU-869 cells significantly increased cell viability through enhanced cell proliferation and the number of Matrigel™-invading cells compared with AGR2-negative SNU-869 cells.
Conclusions
Our findings implicate that AGR2 expression augments tumor-associated phenotypes by increasing proliferative and invasive capacities of the ampulla of Vater cancer cells.
doi:10.1186/1471-2407-14-804
PMCID: PMC4228270  PMID: 25367337
AGR2; Tumor promotion; SNU-478; SNU-869; Biliary tract cancer; Ampulla of Vater
13.  Feasibility and Safety of Laparoscopic Surgery for Obese Korean Women with Endometrial Cancer: Long-Term Results at a Single Institution 
Journal of Korean Medical Science  2014;29(11):1536-1543.
The purpose of this study was to evaluate the surgical feasibility of and survival outcome after laparoscopy in obese Korean women with endometrial cancer which has recently been increasing. We reviewed the medical records of the patients treated at our medical institution between 1999 and 2012. The patients were divided into three groups, non-obese (Body Mass Index [BMI]<25.0), overweight (BMI 25-27.99), and obese (BMI≥28.0). These patient groups were compared in terms of their clinical characteristics, treatment methods, as well as surgical and survival outcomes. In total, 55 of the 278 eligible patients were obese women. There were no differences in the three groups in terms of the proportion of patients who underwent lymphadenectomy, their cancer stage, histologic type, type of adjuvant treatment administered, intra-, post-operative, and long-term complications, operative time, number of removed lymph nodes, blood loss, and duration of hospitalization (P=0.067, 0.435, 0.757, 0.739, 0.458, 0.173, 0.076, 0.124, 0.770, 0.739, and 0.831, respectively). The Disease-Free Survival (DFS) times were 139.1 vs. 121.6 vs. 135.5 months (P=0.313), and the Overall Survival (OS) times were 145.2 vs. 124.8 vs. 139.5 months (P=0.436) for each group, respectively. Obese women with endometrial cancer can, therefore, be as safely managed using laparoscopy as women with normal BMIs.
doi:10.3346/jkms.2014.29.11.1536
PMCID: PMC4234922  PMID: 25408586
Endometrial Neoplasms; Obesity; Laparoscopy; Surgical Outcome; Survival Outcome
14.  Analysis and Comparison of Somatic Mutations in Paired Primary and Recurrent Epithelial Ovarian Cancer Samples 
PLoS ONE  2014;9(6):e99451.
The TP53 mutations have been proved to be predominated in ovarian cancer in a study from The Cancer Genome Atlas (TCGA). However, the molecular characteristics of recurrent ovarian cancers following initial treatment have been poorly estimated. This study was to investigate the pattern of somatic point mutations in matched paired samples of primary and recurrent epithelial ovarian cancers, using the OncoMap mutation detection protocol. We have adapted a high-throughput genotyping platform to determine the mutation status of a large panel of known cancer genes. OncoMap v.4.4 was used to evaluate genomic DNA isolated from a set of 92 formalin-fixed, paraffin-embedded (FFPE) tumors, consisting of matched paired samples of initially diagnosed and recurrent tumors from 46 epithelial ovarian cancer (EOC) patients. Mutations were observed in 33.7% of the samples, with 29.3% of these samples having a single mutation and the remaining 4.3% having two or more mutations. Among the 41 genes analyzed, 35 mutations were found in four genes, namely, CDKN2A (2.2%), KRAS (6.5%), MLH1 (8.2%) and TP53 (20.7%). TP53 was the most frequently mutated gene, but there was no correlation between the presence of mutation in any gene and clinical prognosis. Furthermore, somatic mutations did not differ between primary and recurrent ovarian carcinomas. Every mutation present in recurrent samples was detected in the corresponding primary sample. In conclusion, these OncoMap data of Korean EOC samples provide that somatic mutations were found in CDKN2A, KRAS, MLH1, and TP53. No differences in mutational status between primary and recurrent samples were detected. To understand the biology of tumor recurrence in epithelial ovarian cancer, more studies are necessary, including epigenetic modifications or additional mutations in other genes.
doi:10.1371/journal.pone.0099451
PMCID: PMC4060993  PMID: 24936796
15.  Impact of body mass index on the prognosis of Korean women with endometrioid adenocarcinoma of the uterus: A cohort study 
Obstetrics & Gynecology Science  2014;57(2):115-120.
Objective
To analyze how pretreatment body mass index relates to known endometrial cancer prognostic factors and how it impacts the disease-free survival and cause-specific survival of Korean women with endometrial cancer.
Methods
The patients were divided into the non-obese (<25 kg/m2) and obese groups (≥25 kg/m2) according to their pretreatment body mass index. The 25 kg/m2 body mass index cut-off was based on the World Health Organization criteria for Asian people. The two groups were compared in terms of their clinicopathological characteristics and survival outcomes.
Results
A total of 213 consecutive patients with endometrioid adenocarcinoma of the uterus met the eligibility criteria of this study and were included in the analysis. Of these patients, 105 patients had a body mass index less than 25 kg/m2 (non-obese group) and 108 patients had a body mass index equal to or more than 25 kg/m2 (obese group). The two groups did not differ in terms of age, menopause, parity, height, FIGO (International Federation of Obstetrics and Gynecology) stage, tumor grade, tumor size, myometrial invasion, lymphovascular space invasion, cytology, and lymph node metastasis. Body mass index was not a significant factor for disease-free and cause-specific survival in univariate analysis, and after adjusting for all prognostic factors that were significant in univariate analysis, it did not associate significantly with disease-free and cause-specific survival.
Conclusion
In Korean women with endometrioid adenocarcinoma of the uterus, a high pretreatment body mass index did not associate with other prognostic factors and had little impact on the disease-free survival and cause-specific survival of these women.
doi:10.5468/ogs.2014.57.2.115
PMCID: PMC3965694  PMID: 24678484
Body mass index; Endometrial neoplasms; Obesity; Prognosis
16.  Transactivation of bad by vorinostat-induced acetylated p53 enhances doxorubicin-induced cytotoxicity in cervical cancer cells 
Vorinostat (VOR) has been reported to enhance the cytotoxic effects of doxorubicin (DOX) with fewer side effects because of the lower DOX dosage in breast cancer cells. In this study, we investigated the novel mechanism underlying the synergistic cytotoxic effects of VOR and DOX co-treatment in cervical cancer cells HeLa, CaSki and SiHa cells. Co-treatment with VOR and DOX at marginal doses led to the induction of apoptosis through caspase-3 activation, poly (ADP-ribose) polymerase cleavage and DNA micronuclei. Notably, the synergistic growth inhibition induced by the co-treatment was attributed to the upregulation of the pro-apoptotic protein Bad, as the silencing of Bad expression using small interfering RNA (siRNA) abolished the phenomenon. As siRNA against p53 did not result in an increase in acetylated p53 and the consequent upregulation of Bad, the observed Bad upregulation was mediated by acetylated p53. Moreover, a chromatin immunoprecipitation analysis showed that the co-treatment of HeLa cells with VOR and DOX increased the recruitment of acetylated p53 to the bad promoter, with consequent bad transactivation. Conversely, C33A cervical cancer cells containing mutant p53 co-treated with VOR and DOX did not exhibit Bad upregulation, acetylated p53 induction or consequent synergistic growth inhibition. Together, the synergistic growth inhibition of cervical cancer cell lines induced by co-treatment with VOR and DOX can be attributed to the upregulation of Bad, which is induced by acetylated p53. These results show for the first time that the acetylation of p53, rather than histones, is a mechanism for the synergistic growth inhibition induced by VOR and DOX co-treatments.
doi:10.1038/emm.2013.149
PMCID: PMC3944441  PMID: 24525822
bad; cervical cancer cell; doxorubicin; p53 acetylation; vorinostat
17.  Reproductive outcomes after laparoscopic radical trachelectomy for early-stage cervical cancer 
Objective
The objective of this study was to estimate the reproductive outcome of young women with early-stage cervical cancer who underwent fertility-sparing laparoscopic radical trachelectomy (LRT).
Methods
We performed a retrospective review of the medical records of patients with early-stage cervical cancer who underwent LRT. Clinicopathological data were obtained from patient medical records, and reproductive outcome data were obtained from patient medical records and telephone interviews.
Results
Fifty-five patients who underwent successful LRT were included in this study. The median age of patients was 32 years (range, 22 to 40 years), and the median follow-up time after LRT was 37 months (range, 3 to 105 months). Menstruation resumed in all patients after LRT, with fifty patients (90.9%) and five patients (9.1%) reporting regular and irregular menstruation, respectively. Six patients (10.9%) presented with cervical stenosis, which was manifested by regular but decreased menstrual flow and newly-developed dysmenorrhea. These patients underwent cervical cannulation and dilatation. Eighteen patients (32.7%) attempted to conceive, with six out of 18 patients receiving fertility treatments. Fourteen pregnancies (i.e., four missed abortions, six preterm births and four full-term births) occurred in 10 patients after LRT. Nine out of 10 patients gave birth to 10 healthy babies. The pregnancy rate after LRT was 55.6% (10/18). The spontaneous abortion rate and live birth rate were 28.6% (4/14) and 71.4% (10/14), respectively. The preterm birth rate was 60% (6/10).
Conclusion
Pregnancy and live birth rates after LRT were promising; however, the preterm birth rate was relatively high. Cervical stenosis also occurred in a small percentage of patients.
doi:10.3802/jgo.2014.25.1.9
PMCID: PMC3893680  PMID: 24459575
Cervical cancer; Fertility; Laparoscopic radical trachelectomy; Pregnancy outcome; Reproductive outcome
18.  Laparoscopic treatment for post-cholecystectomy Mirizzi syndrome 
The remnant cystic duct or gallbladder neck calculus may rarely result in post-cholecystectomy Mirizzi syndrome. Various managements have been proposed for the treatment of post-cholecystectomy Mirizzi syndrome. Some previous cases of post-cholecystectomy Mirizzi syndrome have been managed with open cholecystectomy and endoscopically. We report a case of a laparoscopic stone removal of post-cholecystectomy Mirizzi syndrome that developed 7 months after laparoscopic cholecystectomy. To our knowledge, this is the first case of laparoscopic management of post-cholecystectomy Mirizzi syndrome. The mechanism, diagnosis and treatment of post-cholecystectomy Mirizzi syndrome are discussed.
doi:10.14701/kjhbps.2013.17.2.79
PMCID: PMC4304496  PMID: 26155219
Mirizzi syndrome; Cholecystectomy; Gallstone
19.  Endoscopic submucosal dissection as a treatment for gastric subepithelial tumors that originate from the muscularis propria layer: a preliminary analysis of appropriate indications 
Surgical Endoscopy  2013;27(9):3271-3279.
Background
Endoscopic submucosal dissection (ESD) is a well-established method for the treatment of gastrointestinal epithelial tumors. However, the treatment of gastric subepithelial tumors (SETs) that originate from the muscularis propria layer still depends primarily on surgical techniques. We evaluated the appropriate indications for ESD in the treatment of SETs that originate from the muscularis propria layer.
Methods
Thirty-five patients with gastric SETs that originate from the muscularis propria layer who underwent ESD were enrolled, and the charts were retrospectively reviewed to investigate the parameters predictive complete resection and complications.
Results
The mean age of the patients was 54.15 ± 9.3 years, and the male/female ratio was 2:3. Twenty-eight of the 35 SETs (85.7 %) were movable, and 15 (45.7 %) had a positive rolling sign. The most frequent location of the SETs was high body (n = 14). The most common pathological diagnoses were leiomyoma (60 %) and gastrointestinal stromal tumor (28.6 %). The complete resection rate was 74.3 %. A positive rolling sign (p = 0.022) and small tumor size (≤20 mm; p = 0.038) were significantly associated with complete resection. Two patients (6.1 %) developed perforations that required surgical treatment; their SMTs were neurogenic tumors with fixed lesion. Tumor mobility was significantly associated with perforation (p = 0.017).
Conclusions
The ESD method appears to be relatively safe for use in the complete resection of SETs that originate from the muscularis propria layer. Small tumor size (≤20 mm) and a positive rolling sign are appropriate indications for ESD.
doi:10.1007/s00464-013-2904-9
PMCID: PMC3751271  PMID: 23519491
Subepithelial tumor; Muscularis propria; Endoscopic submucosal dissection
20.  Comparison of outcomes between radical hysterectomy followed by tailored adjuvant therapy versus primary chemoradiation therapy in IB2 and IIA2 cervical cancer 
Journal of Gynecologic Oncology  2012;23(4):226-234.
Objective
To compare survival outcomes and treatment-related morbidities between radical hysterectomy (RH) and primary chemoradiation therapy (CRT) in patients with bulky early-stage cervical cancer.
Methods
We selected 215 patients with stage IB2 and IIA2 cervical cancer (tumor diameter > 4 cm on magnetic resonance imaging) who underwent RH followed by tailored adjuvant therapy (n=147) or primary CRT (n=68) at two tertiary referral centers between 2001 and 2010.
Results
About twenty nine percent of patients were cured by RH alone and these patients experienced the best survival outcomes with the lowest morbidity rates. After the median follow-up times of 40 months, 27 RH (18.4%) and 20 CRT (29.4%) patients had recurrence (p=0.068) and 23 (15.6%) and 17 (25%) patients died of disease (p=0.101). The 5-year progression-free survival were 77% and 66% (p=0.047), and the 5-year overall survival were 78% and 67% (p=0.048) after RH and primary CRT, respectively. In multivariate analysis, patients who received primary CRT was at higher risk for tumor recurrence (odds ratio [OR], 2.26; 95% confidence interval [CI], 1.24 to 4.14; p=0.008) and death (OR, 3.02; 95% CI, 1.53 to 5.98; p=0.001) than those who received RH. Grade 3-4, early (17% vs. 30.9%, p=0.021) and late (1.4% vs. 8.8%, p=0.007) complications were significantly less frequent after RH than primary CRT.
Conclusion
Thirty percent of patients were cured by RH alone. A treatment outcome was better in this retrospective study in terms of morbidity and survival. Randomized trials are needed to confirm this result.
doi:10.3802/jgo.2012.23.4.226
PMCID: PMC3469857  PMID: 23094125
Bulky early-stage cervical cancer; Chemoradiation therapy; Radical hysterectomy; Stage IB2; Stage IIA2
21.  Safety and Efficacy of Deep Sedation with Propofol Alone or Combined with Midazolam Administrated by Nonanesthesiologist for Gastric Endoscopic Submucosal Dissection 
Gut and Liver  2012;6(4):464-470.
Background/Aims
Endoscopic submucosal dissection (ESD) is accepted as a treatment for gastric neoplasms and usually requires deep sedation. The aim of this study was to evaluate the safety and efficacy profiles of deep sedation induced by continuous propofol infusion with or without midazolam during ESD.
Methods
A total of 135 patients scheduled for ESDs between December 2008 and June 2010 were included in this prospective study and were randomly assigned to one of two groups: the propofol group or the combination group (propofol plus midazolam).
Results
The propofol group reported only one case of severe hypoxemia with no need of mask ventilation or intubation. Additionally, 18 cases of mild hypotension were observed in the propofol group, and 11 cases were observed in the combination group. The combination group had a lower mean total propofol dose (378 mg vs 466 mg, p<0.012), a longer mean recovery time (10.5 minutes vs 7.9 minutes, p=0.027), and a lower frequency of overall adverse events (32.8% vs 17.6%, p=0.042).
Conclusions
Deep sedation induced by continuous propofol infusion was shown to be safe during ESD. The combination of continuous propofol infusion and intermittent midazolam injection can decrease the total dose and infusion rate of propofol and the overall occurrence of adverse events.
doi:10.5009/gnl.2012.6.4.464
PMCID: PMC3493727  PMID: 23170151
Deep sedation; Propofol; Midazolam; Endoscopy; Gastrointestinal
22.  Management of endoscopic retrograde cholangiopancreatography-related perforations 
Purpose
The purpose of this study is to analyze the treatment strategies of patients with endoscopic retrograde cholangiopancreatography (ERCP)-related perforations. This is a retrospective study.
Methods
We experienced 13 perforations associated with ERCP. We reviewed the medical recordsand classified ERCP-related perforations according to mechanism of injury in terms of perforating device. Injury by endoscopic tip or insertion tube was classified as type I, injury by cannulation catheter or sphincterotomy knife as type II, and injury by guidewire as type III.
Results
Of four type I injuries, one case was managed by conservative management after primary closure with a hemoclip during ERCP. The other three patients underwent surgical treatments such as primary closure orpancreatico-duodenectomy. Of five type II injuries, two patients underwent conservative management and the other three cases were managed by surgical treatment such as duodenojejunostomy, duodenal diverticulization and pancreatico-duodenectomy. Of four type III injuries, three patients were managed conservatively and the remaining patient was managed by T-tube choledochostomy.
Conclusion
Type I injuries require immediate surgical management after EPCP or immediate endoscopic closure during ERCP whenever possible. Type II injuries require surgical or conservative treatment according to intra- and retro-peritoneal dirty fluid collection findings following radiologic evaluation. Type III injuries almost always improve after conservative treatment with endoscopic nasobilliary drainage.
doi:10.4174/jkss.2011.81.3.195
PMCID: PMC3204541  PMID: 22066121
Endoscopic retrograde cholangiopancreatography; Perforation; Surgery
23.  The effect of combined treatment with cisplatin and histone deacetylase inhibitors on HeLa cells 
Journal of Gynecologic Oncology  2010;21(4):262-268.
Objective
To investigate the combined effects of cisplatin and the histone deacetylase (HDAC) inhibitors suberoylanilide hydroxamic acid (SAHA) or sirtinol on HeLa cells and assess the mechanism underlying HDAC inhibitor-cisplatin synergy.
Methods
The antineoplastic actions of cisplatin, SAHA and sirtinol, alone and in combination, were evaluated using the tetrazolium dye-based MTT cell proliferation assay, DAPI nuclear staining and cytotoxicity analysis.
Results
Exposure to cisplatin, SAHA or sirtinol alone induced a dose-dependent reduction in HeLa cell viability. Combined treatment with cisplatin and SAHA or sirtinol was significantly more cytotoxic than cisplatin alone. Individually, cisplatin, SAHA and sirtinol activated caspase-3 and induced apoptosis, but the effects of combined treatment were greater. Importantly, both HDAC inhibitors dose-dependently inhibited the expression of the antiapoptotic proteins Bcl-2 and x-linked inhibitor of apoptosis protein (XIAP).
Conclusion
The combination of cisplatin and SAHA or sirtinol had synergistic effect on the HeLa cell viability. This potentiation of cisplatin activity was associated with HDAC inhibitor-mediated down-regulation of Bcl-2 and XIAP. These may result from the relaxation of chromatin by these HDAC inhibitors that increase cisplatin sensitivity by enhancing the accessibility of DNA to cisplatin and transcriptional regulators.
doi:10.3802/jgo.2010.21.4.262
PMCID: PMC3026306  PMID: 21278889
Cervical cancer; Apoptosis; Cisplatin; Suberoylanilide hydroxamic acid; Sirtinol
24.  Proliferation of CD4+CD25high+Foxp3+ regulatory T lymphocytes in ex vivo expanded ascitic fluid from primary and recurrent ovarian carcinoma 
Objective
Regulatory T lymphocytes evoke the immune tolerance by suppressing and inactivating cytotoxic T lymphocytes. The objective of this study was to compare the proportion of regulatory T lymphocytes, precisely defined as CD4+CD25high+Foxp3+ T lymphocytes, in primary and recurrent ovarian carcinoma before and after ex vivo expansion of ascites with interleukin-2 (IL-2).
Methods
Ascitic fluid samples were obtained from 26 patients with ovarian carcinoma. Lymphocytes were isolated from ascites and cell markers were analyzed by flow cytometry using anti-CD3/CD4/CD8/CD16/CD56/CD25 and anti-Foxp3 antibodies. Lymphocytes were incubated for 2 to 3 weeks and expanded ex vivo by IL-2 stimulation and their phenotypes were analyzed by flow cytometry.
Results
Following ex vivo expansion, ascitic fluid lymphocytes increased by a greater extent in the recurrent group than in the primary group. The proportion of ex vivo-expanded lymphocytes changed as follows; CD4+ T lymphocytes increased, CD8+ T lymphocytes decreased, and the proportion of CD3-CD16+56+ NK cells was unchanged. The proportion of CD4+CD25high+Foxp3+ regulatory T lymphocytes in CD4+ T lymphocytes increased after ex vivo expansion in both groups, but to a greater degree in the recurrent group.
Conclusion
This study showed that regulatory T lymphocytes, neither cytotoxic T lymphocytes nor NK cells, were extensively increased after ex vivo expansion, especially in recurrent ovarian carcinoma. These results may provide information that helps to guide the future development of adoptive immunotherapy against ovarian carcinoma.
doi:10.3802/jgo.2010.21.1.38
PMCID: PMC2849947  PMID: 20379446
Regulatory T lymphocyte; Foxp3; Ex vivo expansion; Ovarian carcinoma; Ascites
25.  Hexamethylmelamine as Consolidation Treatment for Patients with Advanced Epithelial Ovarian Cancer in Complete Response after First-Line Chemotherapy 
Journal of Korean Medical Science  2009;24(4):679-683.
The aim of this study was to assess the efficacy of consolidation therapy with hexamethylmelamine (HMM) in patients with advanced epithelial ovarian cancer (EOC). Patients treated at our hospital between January 1997 and November 2006 and in documented clinical complete response from advanced ovarian cancer following front-line platinum-based therapy were retrospectively analyzed. The patients treated with HMM were compared to the patients of matched counterpart without consolidation therapy. Of 102 patients enrolled, 49 were treated with HMM and 53 received no consolidation treatment. For patients with HMM and observed patients, the mean age were 54.6 and 55.6 yr; the distribution of stage was similar (P=0.977); the optimal surgery was performed in 36 (73.5%) and 44 (83%) (P=0.336); the recurrence rate were 27 (55.1%) and 33 (62.3%) (P=0.463); and the median progression-free survival were 38 months and 21 months for patients with HMM and observed patients (P=0.235). No treatment-related adverse events were reported during the follow-up period. Although this study failed to show the significant survival benefit of consolidation therapy with HMM in patients with advanced EOC, we consider that our study can contribute data to investigate the effectiveness of consolidation therapy in epithelial ovarian cancer.
doi:10.3346/jkms.2009.24.4.679
PMCID: PMC2719200  PMID: 19654952
Altretamine; Consolidation Therapy; Advanced Epithelial Ovarian Cancer

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