Sang Kuon Lee

Laparoscopic Nissen Fundoplication in Korean Patients with Gastroesophageal Reflux Disease

Purpose Although the prevalence of gastroesophageal reflux disease (GERD) is relatively low in Korean population, the number is increasing. The aim of this study is to analyze our experience with laparoscopic Nissen fundoplication. Patients and Methods From Sep. 2003 to Mar. 2008, 31 adult Korean patients diagnosed with GERD underwent laparoscopic Nissen fundoplication. A 360° fundoplication was carried out in all patients. Results There were 19 males and 12 females with an average age of 46.8 ± 17.0 years. Typical symptoms were present in 15 (48%) of patients, and atypical symptoms in 16 (51.6%). Both typical and atypical symptoms were present in 4 of patients (12.9%). Preoperative studies showed hiatal hernias in 13 patients (41.9%), Barretts esophagus in 10 (32.3%), and reflux esophagitis in 18 (58.1%). Mean DeMeester score was 17.4 ± 16.7, mean operative time 206.1 ± 47.8 min and mean hospital stay 5.2 ± 2.1 days. Perioperative complications occurred in 5 patients (16.1%), including gastric perforation, subcutaneous emphysema, atelectasis, and prolonged ileus. Gastroesophageal junction stenoses with subsequent endoscopic balloon dilations were required in 5 patients (16.1%). After surgery, symptoms were completely controlled in 17 patients (54.8%), partially improved in 12 patients (38.7%) and not controlled in 2 patients (6.5%). Conclusion In our series, 93.5% of patients had either complete or partial remission of symptom after laparoscopic Nissen fundoplication. Atypical symptoms were more predominant in our Korean patients. Laparoscopic Nissen fundoplication is an efficacious method of controlling symptoms of GERD, even for those who have atypical symptoms.

IWR-1 inhibits epithelial-mesenchymal transition of colorectal cancer cells through suppressing Wnt/β-catenin signaling as well as survivin expression

Aberrant activation of Wnt/β-catenin signaling is frequently observed in patients with colorectal cancer (CRC) and is considered a major determinant of CRC pathogenesis. CRC pathogenesis is particularly accompanied by epithelial-mesenchymal transition (EMT) and survivin expression. Here, we investigated the potential and mechanism of a novel Wnt/β-catenin inhibitor IWR-1 to suppress tumor metastasis in relation with EMT and survivin expression. We first determined the EMT reversal effects of IWR-1 in in vitro (HCT116 and HT29 cells) and ex vivo (specimens of CRC patients) CRC models. It was shown that IWR-1 inhibited cell proliferation and EMT even in the presence of TNF-α-induced cancer cell stimulation. IWR-1 also significantly suppressed cell migration, invasion, and matrix metalloproteinase activities of CRC cell lines. Furthermore, we showed the evidence that IWR-1 provides EMT reversal effects by directly suppressing survivin expression by the followings: 1) IWR-1 could not completely inhibit EMT in survivin-overexpressing HCT116 cells, 2) EMT reversal effects of IWR-1 were more pronounced in survivin-suppressed cells, and 3) Survivin promoter assay directly identified the survivin promoter region responsible for inhibition of survivin transcription by IWR-1. Taken altogether, our results demonstrate that IWR-1 has the potential to suppress tumor metastasis by inhibiting Wnt/β-catenin pathway as well as survivin expression. Therefore, IWR-1 could be considered for future clinical use as a therapeutic agent to treat CRC.

Roux-en-Y Gastric Bypass vs. Sleeve Gastrectomy vs. Gastric Banding: The First Multicenter Retrospective Comparative Cohort Study in Obese Korean Patients

Purpose Bariatric surgery is relatively new in Korea, and studies comparing different bariatric procedures in Koreans are lacking. This study aimed to compare the clinical outcomes of laparoscopic adjustable gastric banding (LAGB), Roux-en-Y gastric bypass (RYGB), and sleeve gastrectomy (SG) for treating morbidly obese Korean adults. Materials and Methods In this multicenter retrospective cohort study, we reviewed the medical records of 261 obese patients who underwent different bariatric procedures. Clinical outcomes were measured in terms of weight loss and resolution of comorbidities, such as diabetes, hypertension, and dyslipidemia. Safety profiles for the procedures were also evaluated. Results In terms of weight loss, the three procedures showed similar results at 18 months (weight loss in 52.1% for SG, 61.0% for LAGB, and 69.2% for RYGB). Remission of diabetes, hypertension, and dyslipidemia was more frequent in patients who underwent RYGB (65.9%, 63.6%, and 100% of patients, respectively). Safety profiles were similar among groups. Early complications occurred in 26 patients (9.9%) and late complications in 32 (12.3%). In the LAGB group, five bands (6.9%) were removed. Among all patients, one death (1/261=0.38%) occurred in the RYGB group due to aspiration pneumonia. Conclusion The three bariatric procedures were comparable in regards to weight-loss outcomes; nevertheless, RYGB showed a higher rate of comorbidity resolution. Bariatric surgery is effective and relatively safe; however, due to complications, some bands had to be removed in the LAGB group and a relatively high rate of reoperations was observed in the RYGB group.

Potentiation of the anticancer effects of everolimus using a dual mTORC1/2 inhibitor in hepatocellular carcinoma cells

There is lots of evidence to support the critical involvement of mTOR signaling in the carcinogenesis of hepatocellular carcinoma (HCC). However, it has not been determined how the roles of individual mTORC1 and mTORC2 inhibitors played in the HCC therapeutics. We thus compared the effects of everolimus, Ku0063794, and a combination of the two therapies on HCC cells, using various in vitro studies (HepG2, Hep3B, and Huh7 cells), ex vivo culturing of HCC tissues obtained from patients, and the in vivo mouse xenograft model of HCC cells. Our in vitro, ex vivo, and in vivo experiments consistently demonstrated that everolimus and Ku0063794 combination therapy was superior to individual monotherapies, as manifested by higher reduction of proliferation, migration, and invasion of HCC cells, and the higher inhibition of EMT process as well. Although individual monotherapies could not inhibit SIRT1 (positive regulator of EMT) expression, the combination therapy significantly inhibited SIRT1 expression. However, overexpression of SIRT1 mitigated the EMT-inhibiting effect of the combination therapy, suggesting that the combination therapy inhibits the EMT by way of suppressing SIRT1 expression. Therefore, when considering everolimus as an anti-HCC agent, the improved anticancer effects provided by combining it with an inhibitor of both mTORC1 and mTORC2 should be recognized.

Does Korea's current diagnosis-related group-based reimbursement system appropriately classify appendectomy patients?

Purpose As several years have passed since the implementation of the Korean diagnosis-related group (DRG) payment system for appendicitis, its early outcomes should be assessed to determine if further improvements are warranted. Methods We retrospectively analyzed clinical data from Korean patients who underwent appendectomy, dividing the sample into 2 groups of those who received services before and after implementation of the DRG system. Based on the DRG code classification, patient data were collected including the amount of DRG reimbursement and the total in-patient costs. We subsequently performed univariate and multivariate analyses to identify independent factors contributing to higher total in-patient cost. Results Although implementation of the DRG system for appendicitis significantly reduced postoperative length of stay (2.8 ± 1.0 days vs. 3.4 ± 1.9 days, P < 0.001), it did not reduce total in-hospital cost. The independent factors related to total inhospital cost included patient age of 70 years or more (odds ratio [OR], 3.214; 95% confidence interval [CI], 1.769–5.840; P < 0.001) and operation time longer than 100 minutes (OR, 3.690; 95% CI, 2.007–6.599, P < 0.001). In addition, older patients (≥70 years) showed a nearly 10 times greater relative risk for having a comorbid condition (95% CI, 5.141–20.214; P < 0.001) and a 3.255 times greater relative risk for having higher total in-hospital cost (95% CI, 1.731–6.119, P < 0.001). Conclusion It appears that older patients (>70 years) have greater comorbidities, which contribute to higher inpatient costs. Thus, our study suggests that patient age be considered as a DRG classification variable.

Determination of optimized oxygen partial pressure to maximize the liver regenerative potential of the secretome obtained from adipose-derived stem cells

BackgroundA hypoxic-preconditioned secretome from stem cells reportedly promotes the functional and regenerative capacity of the liver more effectively than a control secretome. However, the optimum oxygen partial pressure (pO2) in the cell culture system that maximizes the therapeutic potential of the secretome has not yet been determined.MethodsWe first determined the cellular alterations in adipose tissue-derived stem cells (ASCs) cultured under different pO2 (21%, 10%, 5%, and 1%). Subsequently, partially hepatectomized mice were injected with the secretome of ASCs cultured under different pO2, and then sera and liver specimens were obtained for analyses.ResultsOf all AML12 cells cultured under different pO2, the AML12 cells cultured under 1% pO2 showed the highest mRNA expression of proliferation-associated markers (IL-6, HGF, and VEGF). In the cell proliferation assay, the AML12 cells cultured with the secretome of 1% pO2 showed the highest cell proliferation, followed by the cells cultured with the secretome of 21%, 10%, and 5% pO2, in that order. When injected into the partially hepatectomized mice, the 1% pO2 secretome most significantly increased the number of Ki67-positive cells, reduced serum levels of proinflammatory mediators (IL-6 and TNF-α), and reduced serum levels of liver transaminases. In addition, analysis of the liver specimens indicated that injection with the 1% pO2 secretome maximized the expression of the intermediate molecules of the PIP3/Akt and IL-6/STAT3 signaling pathways, all of which are known to promote liver regeneration.ConclusionsThe data of this study suggest that the secretome of ASCs cultured under 1% pO2 has the highest liver reparative and regenerative potential of all the secretomes tested here.

HSP90 inhibitor 17-DMAG exerts anticancer effects against gastric cancer cells principally by altering oxidant-antioxidant balance

Heat shock protein 90 (HSP90) stabilizes numerous oncoproteins and, therefore, its inhibition has emerged as a promising antineoplastic strategy for diverse malignancies. In this study, we determined the therapeutic effects and mechanisms of action of a specific HSP90 inhibitor, 17-dimethylamino-ethylamino-17-demethoxygeldanamycin (17-DMAG), in gastric cancer cell lines (AGS, SNU-1, and KATO-III), patient-derived tissues, and a mouse xenograft model. 17-DMAG exerted anticancer effects against gastric cancer cells, manifested by significantly decreased proliferation rates (P < 0.05) and increased expression of apoptotic markers. Flow cytometry using dichlorofluorescein (DCF) diacetate revealed that 17-DMAG dose-dependently increases reactive oxygen species (ROS) levels in gastric cancer cells. Inhibition of ROS by N-acetyl-L-cysteine (NAC) abrogated the proapoptotic effects of 17-DMAG, as demonstrated by the decreased expression of proapoptotic proteins. In addition, 17-DMAG dose- and time-dependently reduced the expression of antioxidants such as catalase and glutathione peroxidase (GPx). Moreover, 17-DMAG reduced the expression of nuclear respiratory factor (NRF)-1 and NRF-2, and prevented them from migrating from the cytoplasm to the nucleus dose-dependently. Finally, in a nude mouse xenograft model, the shrinkage of tumors was more prominent in mice treated with 17-DMAG than in control mice (P < 0.05). Taken altogether, our results suggest that 17-DMAG exerts potent antineoplastic activity against gastric cancer cells primarily by promoting ROS generation and suppressing antioxidant enzyme activities.

Validation of the Korean version Moorehead-Ardelt quality of life questionnaire II

Purpose To investigate the weight loss effects with higher sensitivity, disease specific quality of life (QoL) instruments were important. The Moorehead-Ardelt quality of life questionnaire II (MA-II) is widely used, because it was simple and validated the several languages. The aims of present study was performed the translation of MA-II Korean version and the validation compared with EuroQol-5 dimension (EQ-5D), obesity-related problems scale (OP-scale), and impact of weight quality of life-lite (IWQoL-Lite). Methods The study design was a multicenter, cross-sectional survey and this study was included the postoperative patients. The validation procedure is translation-back translation procedure, pilot study, and field study. The instruments of measuring QoL included the MA-II, EQ-5D, OP-scale, and IWQoL-lite. The reliability was checked through internal consistency using Cronbach alpha coefficients. The construct validity was assessed the Spearman rank correlation between 6 domains of MA-II and EQ-5D, OP-scale, and 5 domains of IWQoL-Lite. Results The Cronbach alpha of MA-II was 0.763, so the internal consistency was confirmed. The total score of MA-II was significantly correlated with all other instruments; EQ-5D, OP-scale, and IWQoL-Lite. IWQoL-lite (ρ = 0.623, P < 0.001) was showed the strongest correlation compared with MA-II, followed by OP-scale (ρ = 0.588, P < 0.001) and EQ-5D (ρ = 0.378, P < 0.01). Conclusion The Korean version MA-II was valid instrument of measuring the obesity-specific QoL. Through the present study, the MA-II was confirmed to have good reliability and validity and it was also answered simple for investigating. Thus, MA-II could be estimated sensitive and exact QoL in obesity patients.

Everolimus Plus Ku0063794 Regimen Promotes Anticancer Effects against Hepatocellular Carcinoma Cells through the Paradoxical Inhibition of Autophagy

Purpose Everolimus only inhibits mammalian target of rapamycin complex 1 (mTORC1), whereas Ku0063794 inhibits both mTORC1 and mTORC2. Although they have similar anticancer effects, their combination has a synergistic effect against hepatocellular carcinoma (HCC) cells. We aimed to determine the mechanism underlying the synergistic effects of everolimus and Ku0063794 associated with autophagy in HCC cells. Materials and Methods We compared the effects of everolimus and Ku0063794, individually or in combination, on both the in vitro and in vivo models of HCCs. Results HepG2 cells treated with both agents had significantly lower rates of cell proliferation and higher apoptosis than the individual monotherapies (p < 0.05). Autophagic studies consistently indicated that, unlike the monotherapies, the combination therapy significantly reduced autophagy (p < 0.05). Autophagic blockage directly promoted the pro-apoptotic effects of combination therapy, suggesting autophagy as the survival mechanism of HCC cells. Unlike the monotherapies, combination therapy showed the potential to inhibit sirtuin 1 (SIRT1), the positive regulator of autophagy. SIRT1 overexpression abrogated the autophagy-inhibiting and pro-apoptotic effects of combination therapy. In a nude mouse xenograft model, the shrinkage of tumors was more prominent in mice treated with combination therapy than in mice treated with the respective monotherapies (p < 0.05). The immunohistochemical and immunofluorescence stains of the tumor obtained from the xenograft model showed that combination therapy had the potential of reducing autophagy and promoting apoptosis. Conclusion The combination of everolimus and Ku0063794 potentiates anticancer effects on HCCs through a decrease in autophagy, which is prompted by SIRT1 downregulation.

Expression of Matrix Metalloproteinase-2, Cathepsin D and E-cadherin in Human Gastric Adenocarcinomas

Purpose: The prognosis of gastric cancer depends on the depth of invasion, lymph-node metastasis, invasion to adjacent tissues, and distant metastasis. Recently, it is known that tumor-associated proteases and adhesion molecules have been shown to play a relevant role in the process of progression and metastasis. The purpose of our study was to demonstrate the value of MMP-2 (matrix metalloproteinase), cathepsin D and E-cadherin as prognostic factors. Materials and Methods: In this study, formalin-fixed, paraffin-embedded tissue blocks from 69 patients with gastric cancer were immunohistochemically studied using antibodies to MMP-2, cathepsin D, and E-cadherin, and their expressions were analyzed according to the pathologic stage, lymph-node metastasis, histological differentiation, and patient survival. The medical records of these patients were retrospectively reviewed. Results: Increased expression of MMP-2 significantly correlated with advanced pathologic stage (P=0.026). Patients with lymph-node metastasis also had increased expression of MMP-2. Those patients with increased expression of MMP-2 showed a poorer survival; nevertheless, it was not statistically significant. Increased expression of cathepsin D significantly correlated with advanced pathologic stage (p=0.029). However, no correlation was observed between advanced pathologic stage and either lymph-node status or histological differentiation. Patients with increased expression of cathepsin D had a poorer survival, but that result was not statistically significant. No association was found between reduced expression of E-cadherin and pathologic stage, lymph-node status, or histological differentiation. Also, no correlation was found between the expression of E-cadherin and survival. In addition, when a combination of MMP-2 and cathepsin D expressions was analyzed, if both were negative, the survival seems to be longer, but it was not statistically significant. Conclusions: In patients with gastric cancer, expressions of MMP-2 and cathepsin D correlated with tumor stage; therefore, they may be considered as prognostic factors.