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1.  Gentamicin-Loaded Wound Dressing With Polyvinyl Alcohol/Dextran Hydrogel: Gel Characterization and In Vivo Healing Evaluation 
AAPS PharmSciTech  2010;11(3):1092-1103.
To develop a gentamicin-loaded wound dressing, cross-linked hydrogel films were prepared with polyvinyl alcohol (PVA) and dextran using the freezing–thawing method. Their gel properties such as gel fraction, swelling, water vapor transmission test, morphology, tensile strength, and thermal property were investigated. In vitro protein adsorption test, in vivo wound healing test, and histopathology were performed. Dextran decreased the gel fraction, maximum strength, and thermal stability of hydrogels. However, it increased the swelling ability, water vapor transmission rate, elasticity, porosity, and protein adsorption. The drug gave a little positive effect on the gel properties of hydrogels. The gentamicin-loaded wound dressing composed of 2.5% PVA, 1.13% dextran, and 0.1% drug was more swellable, flexible, and elastic than that with only PVA because of its cross-linking interaction with PVA. In particular, it could provide an adequate level of moisture and build up the exudates on the wound area. From the in vivo wound healing and histological results, this gentamicin-loaded wound dressing enhanced the healing effect more compared to conventional product because of the potential healing effect of gentamicin. Thus, this gentamicin-loaded wound dressing would be used as a potential wound dressing with excellent forming and improved healing effect in wound care.
PMCID: PMC2974132  PMID: 20607628
dextran; gentamicin; histological examination; wound dressing; wound healing effect
2.  Comparison of Clinical Outcomes Associated with Pull-Type and Introducer-Type Percutaneous Endoscopic Gastrostomies 
Clinical Endoscopy  2014;47(6):530-537.
Percutaneous endoscopic gastrostomy (PEG) is a method of providing enteral nutrition using endoscopy. The PEG techniques differ according to the insertion method, and include the pull type, push type, and introducer type. The aim of this study was to compare the clinical outcomes associated with the pull-type and introducer-type PEG insertion techniques, which included the adverse events, at our tertiary care center in Korea.
We retrospectively reviewed 141 cases that had undergone PEG insertion at our center from January 2009 to June 2012. The indications for PEG insertion and the acute and chronic complications caused by each type of PEG insertion were analyzed.
The indications for PEG insertion in our cohort included neurologic disease (58.7%), malignancy (21.7%), and other indications (19.6%). Successful PEG insertions were performed on 136 cases (96.5%), and there were no PEG-associated deaths. Bleeding was the most frequent acute complication (12.8%), and wound problems were the most frequent chronic complications (8.8%). There were no statistically significant differences between the pull-type and introducer-type PEG insertion techniques in relation to complication rates in our study population.
PEG insertion is considered a safe procedure. The pull-type and introducer-type PEG insertion techniques produce comparable outcomes, and physicians may choose either of these approaches according to the circumstances.
PMCID: PMC4260101  PMID: 25505719
Percutaneous endoscopic gastrostomy; Pull type; Introducer type; Complication; Indication for PEG
3.  Does antiviral therapy reduce complications of cirrhosis? 
Chronic hepatitis B infection is associated with the development of cirrhosis, hepatocellular carcinoma, and finally liver-related mortality. Each year, approximately, 2%-5% of patients with hepatitis B virus (HBV)-related compensated cirrhosis develop decompensation, with additional clinical manifestations, such as ascites, jaundice, hepatic encephalopathy, and gastrointestinal bleeding. The outcome of decompensated HBV-related cirrhosis is poor, with a 5-year survival of 14%-35% compared to 84% in patients with compensated cirrhosis. Because the risk of disease progression is closely linked to a patient’s serum HBV DNA level, antiviral therapy may suppress viral replication, stabilize liver function and improve survival. This article briefly reviews the role that antiviral therapy plays in cirrhosis complications, particularly, in decompensation and acute-on-chronic liver failure.
PMCID: PMC4064076  PMID: 24966601
Antiviral therapy; Cirrhosis; Complication; Hepatitis B; Decompensation
4.  Efficacy of Adefovir-Based Combination Therapy for Patients with Lamivudine- and Entecavir-Resistant Chronic Hepatitis B Virus Infection 
Antimicrobial Agents and Chemotherapy  2013;57(12):6325-6332.
Treatment strategies for entecavir (ETV)-resistant chronic hepatitis B (CHB) patients are not yet well established. The aim of this study was to evaluate overall antiviral efficacy and to compare the efficacy of combination therapy with adefovir (ADV) plus nucleoside analogues (lamivudine [LAM], telbivudine [LdT], or ETV) in patients infected with LAM- and ETV-resistant hepatitis B virus (HBV) variants. Virologic, biochemical, and serologic responses during combination therapy with ADV plus nucleoside analogues were assessed. Propensity score analysis was used to select a matched group of patients for the comparison of rescue therapy regimens. A total of 67 consecutive patients were analyzed. Complete virologic suppression was achieved in 27 patients. The overall cumulative incidence of complete virologic suppression at month 24 was 47.4%: 44.3% in the LAM or LdT plus ADV group and 51.4% in the group given ETV and ADV. There was no significant difference between these two groups (P = 0.234). The cumulative incidences of complete virologic suppression were still comparable between the two groups selected and matched using the propensity score model (P = 0.419). Virologic breakthrough was observed in 9 patients, and rtA181V substitution was newly detected in one patient. Hepatitis B e antigen (HBeAg) negativity and lower baseline HBV DNA level were associated with complete virologic suppression in univariate analysis. In multivariate analysis, lower baseline HBV DNA level remained an independent predictor. In conclusion, combination therapy with ADV plus nucleoside analogues fails to show sufficient antiviral efficacy in CHB patients with resistance to both LAM and ETV. Further study is warranted to evaluate the efficacy of a more potent tenofovir-based regimen in such patients.
PMCID: PMC3837850  PMID: 24100506
5.  Validation of P2/MS for reflecting hepatic fibrosis in patients with hepatocellular carcinoma 
The Korean Journal of Hepatology  2010;16(4):389-396.
P2/MS is known as a simple, accurate, and noninvasive marker for determination of the degree of hepatic fibrosis in patients with viral hepatitis. We aimed to validate P2/MS in patients with HCC.
Consecutive HCC patients who underwent surgical resection between June 2007 and March 2009 at Seoul National University Hospital were enrolled. Fibrosis stage was reviewed and assessed according to METAVIR scoring. P2/MS values [platelet count (109/L)]2/[monocyte fraction (%)×segmented neutrophil fraction (%)] and other noninvasive fibrosis scoring systems were calculated.
A total of 171 patients were included; seven patients with METAVIR F1, 31 with F2, 41 with F3, and 92 with F4. The area under the receiver-operating characteristic curve of P2/MS was 0.804 [95% confidence interval (CI), 0.681~0.927] for detection of significant fibrosis (F2-F4) and 0.769 (95% CI, 0.698~0.839) for detection of histological cirrhosis (F4). At a value < 62, P2/MS detected significant fibrosis with a specificity of 85.7% (95% CI, 42.0~99.2) and a positive likelihood ratio of 4.268 (95% CI, 0.692~26.309); and at a value > 115, P2/MS ruled out significant fibrosis with a sensitivity of 90.2% (95% CI, 84.4~94.1) and a negative likelihood ratio of 0.34 (95% CI, 0.106~0.095). P2/MS had a superior efficacy for detection of hepatic fibrosis in patients with HCC compared to the other noninvasive panels.
P2/MS can accurately detect fibrosis in patients with HCC. Thus, P2/MS might be utilized as a noninvasive index reflecting the degree of hepatic fibrosis in HCC patients.
PMCID: PMC3304609  PMID: 21415583
P2/MS; Fibrosis; Hepatocellular carcinoma
6.  Endoscopic Resection for Synchronous Esophageal Squamous Cell Carcinoma and Gastric Adenocarcinoma in Early Stage Is a Possible Alternative to Surgery 
Gut and Liver  2015;9(1):59-65.
We investigated the clinical outcomes according to the method of treatment in synchronous esophageal and gastric cancer.
Synchronous esophageal squamous cell carcinoma and gastric adenocarcinoma were diagnosed in 79 patients between 1996 and 2010. We divided the patients into four groups according to treatment; Group 1 received surgical resection for both cancers or surgery for gastric cancer with chemoradiotherapy for esophageal cancer (n=27); Group 2 was treated by endoscopic resection with or without additional treatment (n=14); Group 3 received chemoradiotherapy only (n=18); and Group 4 received supportive care only (n=20).
The median survival times in groups 1 and 2 were 86 and 60 months, respectively. The recurrence rate and mortality were 23% and 48%, respectively, in group 1 and 21% and 4%, respectively, in group 2. The median survival time was 12 months in group 3 and 9 months in group 4. Multivariate analysis showed that age (p<0.001) and treatment group (p=0.019) were significantly associated with death. Compared with group 1, treatment in the intensive care unit (p=0.003), loss of body weight (p=0.042), and decrease in hemoglobin (p=0.033) were worse in group 1.
Endoscopic resection for synchronous esophageal and gastric cancer could be considered as a possible alternative to surgery for early-stage cancer.
PMCID: PMC4282858  PMID: 25170061
Synchronous; Esophageal neoplasms; Stomach neoplasms
7.  A Micro-Fabricated Force Sensor Using an All Thin Film Piezoelectric Active Sensor 
Sensors (Basel, Switzerland)  2014;14(12):22199-22207.
The ability to measure pressure and force is essential in biomedical applications such as minimally invasive surgery (MIS) and palpation for detecting cancer cysts. Here, we report a force sensor for measuring a shear and normal force by combining an arrayed piezoelectric sensors layer with a precut glass top plate connected by four stress concentrating legs. We designed and fabricated a thin film piezoelectric force sensor and proposed an enhanced sensing tool to be used for analyzing gentle touches without the external voltage source used in FET sensors. Both the linear sensor response from 3 kPa to 30 kPa and the exact signal responses from the moving direction illustrate the strong feasibility of the described thin film miniaturized piezoelectric force sensor.
PMCID: PMC4299009  PMID: 25429407
force sensor; tactile sensor; piezoelectric; thin film; MEMS
8.  Comparison of the Effects of Transarterial Chemoembolization for Advanced Hepatocellular Carcinoma between Patients with and without Extrahepatic Metastases 
PLoS ONE  2014;9(11):e113926.
Sorafenib is a standard treatment for advanced hepatocellular carcinoma (HCC) (Barcelona Clinic Liver Cancer [BCLC] stage C). However, transarterial chemoembolization (TACE) has also been widely used as a treatment for patients with advanced HCC, even if they have extrahepatic metastases (EHM). The aim of this study was to determine the efficacy of TACE for advanced HCC patients with EHM upon initial diagnosis, as compared with those patients without EHM.
This cohort study involved consecutive patients who underwent TACE as an initial treatment for advanced HCC. One hundred seventy-seven patients with EHM (the EHM group) and 205 with portal vein invasion without EHM (the non-EHM group) were included. A survival analysis was performed to compare overall survival between the two groups.
The mean age was 54.5±9.9 years, and median follow-up duration was 13.1 months (range, 0.5–111.0). Overall survival was significantly shorter in the EHM group than the non-EHM group (median, 8.3 vs. 19.1 months; P<0.001). A multivariate analysis showed that the presence of EHM was an independent poor prognostic factor for shorter overall survival (adjusted hazard ratio, 1.74; 95% confidence interval, 1.39–2.17; P<0.001) after adjustment for Child-Pugh classification, intrahepatic tumor T classification, tumor response to TACE, and serum alpha-fetoprotein level. Patients administered TACE and systemic therapy demonstrated a better survival rate than those administered TACE alone in both the EHM (median, 13.5 vs. 7.2 months) and non-EHM groups (median, 27.9 vs. 18.2 months) (both, P<0.05).
The prognosis of advanced HCC patients with EHM is significantly worse than those without EHM administered repeated TACE treatments, even if their tumor stage was similar to BCLC stage C. These results suggest that EHM presence means aggressive tumor biology and that BCLC stage C might be subclassified according to EHM presence.
PMCID: PMC4245068  PMID: 25427152
9.  Prior Exposure to Lamivudine Increases Entecavir Resistance Risk in Chronic Hepatitis B Patients without Detectable Lamivudine Resistance 
The efficacy of entecavir (ETV) treatment in chronic hepatitis B (CHB) patients who were exposed to lamivudine (LAM) but had no detectable LAM resistance (LAM-R) is not well evaluated. In this study, we aimed to evaluate whether the probability of developing genotypic resistance to ETV in LAM-exposed patients with or without LAM-R is comparable to that in antiviral-naive patients. This retrospective cohort study included 500 consecutive patients with CHB who started ETV monotherapy at a single tertiary hospital in Korea. The patients were divided into three groups: nucleos(t)ide analogue (NA)-naive patients (group 1, n = 142), patients who were previously exposed to LAM and had no currently or previously detected LAM-R (group 2, n = 233), and patients with LAM-R when starting ETV (group 3, n = 125). The overall median ETV treatment duration was 48.7 months. The probabilities of virologic breakthrough were significantly increased not only in group 3 (hazard ratio [HR] = 14.4, P < 0.001) but also in group 2 (HR = 5.0, P < 0.001) compared to group 1. Genotypic ETV resistance (ETV-R) developed more frequently in group 2 (HR = 13.0, P = 0.013) as well as group 3 (HR = 43.9, P < 0.001) than in group 1: the probabilities of developing ETV-R in groups 1, 2, and 3 were <1.0%, 8.0%, and 28.2%, respectively, at month 48. The results of this study indicate that ETV-R occurred more frequently in LAM-exposed patients, even though they had no detectable LAM-R, than in NA-naive patients. Therefore, LAM-exposed CHB patients, regardless of the presence or absence of LAM-R, should be monitored more cautiously for the development of ETV-R during ETV monotherapy.
PMCID: PMC3957876  PMID: 24395227
10.  A novel prognostic factor for hepatocellular carcinoma: protein disulfide isomerase 
Protein disulfide isomerase (PDI) has been implicated in the survival and progression of some cancer cells, by compensating for endoplasmic reticulum stress by upregulating the protein-folding capacity. However, its prognostic role in patients with hepatocellular carcinoma (HCC) has not been investigated.
We collected HCC tissues from 83 HCC patients who underwent surgical resection for an immunohistochemical study of PDI. Overall survival (OS) was measured from the date of surgical resection until the date of death from any cause. Radiological progression was evaluated using the modified Response Evaluation Criteria in Solid Tumors in an independent radiological assessment.
PDI expression was found to be increased in human HCC compared to adjacent nontumor tissues. Increased immunopositivity for PDI was associated with a high Edmondson-Steiner grade (p = 0.028). Univariate analysis of patients who had undergone surgical resection for HCC showed that tumor PDI upregulation is a significant risk factor for poor OS (p = 0.016; hazard ratio [HR], 1.980) and time to progression (TTP; p = 0.007; HR, 1.971). Multivariate analyses revealed that high PDI expression was an independent predictor of a shorter TTP (p = 0.015; HR, 1.865) and poor OS (p = 0.012; HR, 2.069).
Upregulated PDI expression is associated with aggressive clinicopathological features of HCC; thus, PDI might serve as an independent prognostic factor and a potential therapeutic target for HCC patients.
PMCID: PMC4164721  PMID: 25228833
Protein disulfide isomerases; Endoplasmic reticulum stress; Carcinoma, hepatocellular; Prognosis
11.  Does 18F-FDG Positron Emission Tomography-Computed Tomography Have a Role in Initial Staging of Hepatocellular Carcinoma? 
PLoS ONE  2014;9(8):e105679.
Background and Aim
The utility of fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography (PET/CT) in initial staging of hepatocellular carcinoma (HCC) has yet to be fully explored. We assessed the usefulness of 18F-FDG PET/CT in initial staging of HCC.
A total of 457 consecutive patients initially diagnosed with HCC at Seoul National University Hospital between 2006 and 2012 were evaluated retrospectively to assess the impact of 18F-FDG PET/CT on staging and compliancy with Milan criteria, relative to dynamic CT of liver and chest x-ray.
Seven among the 457 patients studied showed a shift in Barcelona Clinic Liver Cancer [BCLC] stage (A→C: 6 patients; B→C: 1 patient) and 5 patients who had originally met Milan criteria no longer qualified. 18F-FDG PET/CT had value in initial staging of early (stage A) or intermediate (stage B) HCC, as determined by dynamic CT of liver and BCLC or AJCC classifications, whereas BCLC stage 0 and stage C tumors were unchanged (P<0.001). 18F-FDG PET/CT disclosed additional metastases in patients with American Joint Committee on Cancer [AJCC] T2 (2.7%), T3a (5.3%), and T3b (4.8%) classifications.
In initial staging of HCC, 18F-FDG PET/CT provided additional information, impacting the patients with BCLC (stages A and B) and AJCC (T2 and T3) classifications. Its use might be thus appropriate for these patient subsets, especially if hepatic resection or liver transplantation is planned.
PMCID: PMC4143262  PMID: 25153834
12.  Spontaneous Evolution in Bilirubin Levels Predicts Liver-Related Mortality in Patients with Alcoholic Hepatitis 
PLoS ONE  2014;9(7):e100870.
The accurate prognostic stratification of alcoholic hepatitis (AH) is essential for individualized therapeutic decisions. The aim of this study was to develop a new prognostic model to predict liver-related mortality in Asian AH patients. We conducted a hospital-based, retrospective cohort study using 308 patients with AH between 1999 and 2011 (a derivation cohort) and 106 patients with AH between 2005 and 2012 (a validation cohort). The Cox proportional hazards model was constructed to select significant predictors of liver-related death from the derivation cohort. A new prognostic model was internally validated using a bootstrap sampling method. The discriminative performance of this new model was compared with those of other prognostic models using a concordance index in the validation cohort. Bilirubin, prothrombin time, creatinine, potassium at admission, and a spontaneous change in bilirubin levels from day 0 to day 7 (SCBL) were incorporated into a model for AH to grade the severity in an Asian patient cohort (MAGIC). For risk stratification, four risk groups were identified with cutoff scores of 29, 37, and 46 based on the different survival probabilities (P<0.001). In addition, MAGIC showed better discriminative performance for liver-related mortality than any other scoring system in the validation cohort. MAGIC can accurately predict liver-related mortality in Asian patients hospitalized for AH. Therefore, SCBL may help us decide whether patients with AH urgently require corticosteroid treatment.
PMCID: PMC4094461  PMID: 25013906
13.  Clinical Outcomes Associated with Treatment Modalities for Gastrointestinal Bezoars 
Gut and Liver  2014;8(4):400-407.
With technical and instrumental advances, the endoscopic removal of bezoars is now more common than conventional surgical removal. We investigated the clinical outcomes in a patient cohort with gastrointestinal bezoars removed using different treatment modalities.
Between June 1989 and March 2012, 93 patients with gastrointestinal bezoars underwent endoscopic or surgical procedures at the Asan Medical Center. These patients were divided into endoscopic (n=39) and surgical (n=54) treatment groups in accordance with the initial treatment modality. The clinical feature and outcomes of these two groups were analyzed retrospectively.
The median follow-up period was 13 months (interquartile range [IQR], 0 to 77 months) in 93 patients with a median age of 60 years (IQR, 50 to 73 years). Among the initial symptoms, abdominal pain was the most common chief complaint (72.1%). The bezoars were commonly located in the stomach (82.1%) in the endoscopic treatment group and in the small bowel (66.7%) in the surgical treatment group. The success rates of endoscopic and surgical treatment were 89.7% and 98.1%, and the complication rates were 12.8% and 33.3%, respectively.
Endoscopic removal of a gastrointestinal bezoar is an effective treatment modality; however, surgical removal is needed in some cases.
PMCID: PMC4113045  PMID: 25071905
Bezoars; Endoscopy; Surgery
14.  Meta-Analysis of First-Line Triple Therapy for Helicobacter pylori Eradication in Korea: Is It Time to Change? 
Journal of Korean Medical Science  2014;29(5):704-713.
Proton pump inhibitor (PPI)-based triple therapy consisting of PPI, amoxicillin, and clarithromycin, is the recommended first-line treatment for Helicobacter pylori infection. However, the eradication rate of triple therapy has declined over the past few decades. We analyzed the eradication rate and adverse events of triple therapy to evaluate current practices in Korea. A comprehensive literature search was performed up to August 2013 of 104 relevant studies comprising 42,124 patients. The overall eradication rate was 74.6% (95% confidence interval [CI], 72.1%-77.2%) by intention-to-treat analysis and 82.0% (95% CI, 80.8%-83.2%) by per-protocol analysis. The eradication rate decreased significantly from 1998 to 2013 (P < 0.001 for both intention-to-treat and per-protocol analyses). Adverse events were reported in 41 studies with 8,018 subjects with an overall incidence rate of 20.4% (95% CI, 19.6%-21.3%). The available data suggest that the effectiveness of standard triple therapy for H. pylori eradication has decreased to an unacceptable level. A novel therapeutic strategy is warranted to improve the effectiveness of first-line treatment for H. pylori infection in Korea.
Graphical Abstract
PMCID: PMC4024949  PMID: 24851029
Helicobacter pylori; Eradication; Triple Therapy
15.  Serum Insulin-Like Growth Factor-1 Predicts Disease Progression and Survival in Patients with Hepatocellular Carcinoma Who Undergo Transarterial Chemoembolization 
PLoS ONE  2014;9(3):e90862.
Insulin like-growth factor-1 (IGF-1) reflects hepatic synthetic function and plays a major role in the development and progression of various cancers. In the present study, we investigated whether baseline serum IGF-1 levels predict time-to-progression (TTP) and overall survival (OS) in hepatocellular carcinoma (HCC) patients treated with transarterial chemoembolization (TACE). A total of 155 consecutive treatment-naive patients with HCC who had undergone TACE as initial treatment were included from a prospective cohort. Baseline serum IGF-1 levels were analyzed with regard to their associations with disease progression and survival. During a median follow-up period of 41.8 months, patients with low IGF-1 levels showed significantly shorter TTP (median, 6.0 months; 95% confidence interval [CI], 4.5–7.6) than patients with high IGF-1 levels (median, 16.5 months; 95% CI, 4.9–28.1; p = 0.003). In the multivariate analysis, BCLC stage, serum vascular endothelial growth factorlevels, and IGF-1 levels were independent risk factors for disease progression. The hazard ratio (HR) of progression for each 10 ng/mL decrease in IGF-1 level was 1.072 (95% CI, 1.029–1.117; p = 0.001). Furthermore, together with tumor size, stage, and treatment response, IGF-1 levels were an independent predictor of poorer survival (for each 10 ng/mL decrease in IGF-1 level; HR, 1.057; 95% CI, 1.001–1.115; p = 0.045). In conclusion, low baseline IGF-1 levels independently correlated with shorter TTP and poorer OS in patients with HCC who underwent TACE.
PMCID: PMC3942491  PMID: 24595361
16.  Transfer kinetics of perfluorooctane sulfonate from water and sediment to a marine benthic fish, the marbled flounder (Pseudopleuronectes yokohamae) 
The authors investigated the kinetics of transfer of perfluorooctane sulfonate (PFOS) from water, suspended sediment, and bottom sediment to a marine benthic fish, the marbled flounder (Pseudopleuronectes yokohamae). Fish were exposed in 3 treatments to PFOS in combinations of these exposure media for 28 d and then depurated for 84 d. A major part (37–66%) of PFOS in the fish was in the carcass (i.e., whole body minus muscle and internal organs). Three first-order-kinetic models that differed in exposure media, that is, 1) sum of dissolved and particulate phases and sediment; 2) dissolved phase, particulate phase, and sediment; and 3) dissolved phase only, were fitted to the data assuming common rate constants among the treatments. The uptake efficiency of dissolved PFOS at the respiratory surfaces was estimated to be 3.2% that of oxygen, and the half-life of PFOS in the whole body to be 29 d to 31 d. The better fit of models 1 and 2 and the values of the estimated uptake rate constants suggested that the PFOS in suspended and bottom sediments, in addition to that dissolved in water, contributed to the observed body burden of the fish. Based on an evaluation of several possible contributing factors to the uptake of PFOS from suspended and bottom sediments, the authors propose that further investigation is necessary regarding the mechanisms responsible for the uptake. Environ Toxicol Chem 2013;32:2009–2017. © 2013 The Authors. Environmental Toxicology and Chemistry Published by Wiley Periodicals, Inc., on behalf of SETAC. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
PMCID: PMC3881517  PMID: 23636803
Bioconcentration; Persistent organic pollutants; Respiratory uptake; Aquatic organism; Particle
17.  Intralesional Steroid Injection to Prevent Stricture after Near-Circumferential Endosopic Submucosal Dissection for Superficial Esophageal Cancer 
Clinical Endoscopy  2013;46(6):643-646.
Stricture frequently occurs after endoscopic submucosal dissection (ESD) for superficial esophageal carcinoma with near- or whole-circumferential mucosal defects, and post-ESD stricture is difficult to treat and usually requires multiple sessions of endoscopic balloon dilatation. Intralesional steroid injection has previously been used to prevent stricture; however, there have been few experiences with this method after near- or whole-circumferential ESD. We present a case of a single session of intralesional steroid injection performed immediately after near-circumferential ESD to prevent post-ESD stricture. After a follow-up period of 6 months, the patient showed good outcome without dysphagia.
PMCID: PMC3856266  PMID: 24340258
Injections, intralesional; Esophageal stenosis; Endoscopic submucosal dissection; Esophageal neoplasms
18.  Expression of Stem Cell Markers in Primo Vessel of Rat 
Accumulating line of evidence support that adult tissues contain a rare population of pluripotent stem cells (PSCs), which differentiate into all types of cells in our body. Bonghan microcell (primo microcells (PMCs)) discovered in 1960s was reported to have a pluripotency like a stem cell in vivo as well as in vitro condition. Here, we describe the detailed morphology and molecular features of PMCs. PMCs reside in Bonghan duct (primo vessel (PV)) reported as a corresponding structure of acupuncture points and meridian system. We found that PMCs were frequently observed in the liver surface of the rat between 300 g and 400 g from April to June, suggesting that the their detection frequency depends on the weight, the season, and the organ of rat. As reported, PMCs freshly isolated from PVs were spherical ~1-2 μm microsized cells. In contrast, a unique bithread or budding-shaped PMCs emerged during tissue culture around 8 days. RT-PCR analysis demonstrated that PVs-derived cells express the Oct4, the most important PSCs gene, in addition to several PSCs markers (Sox2, Stella, Rex1, and Klf4). Thus, we for the first time provide the evidence about Oct4-expressing stem-like characteristics for cells resident in PVs, a possible novel stem cell enriched niche.
PMCID: PMC3747494  PMID: 23983780
19.  Up-Regulation of Cyclooxygenase 2 and Matrix Metalloproteinases-2 and -9 in Cutaneous Squamous Cell Carcinoma: Active Role of Inflammation and Tissue Remodeling in Carcinogenesis 
Annals of Dermatology  2013;25(2):145-151.
Tissue inflammation and remodeling have been extensively studied in various tumors in relation with their invasiveness and metastasis.
The purpose of this study was to investigate the change in tissue inflammation and remodeling markers in cutaneous squamous cell carcinoma (SCC).
Expression levels of cyclooxygenase-2 (COX-2) as an inflammatory marker and matrix metalloproteinases-2 and -9 (MMPs 2/9) as remodeling markers were studied in mouse and human SCCs. Western blot analysis and RT-PCR for COX-2 and MMPs 2/9 were performed with skin samples from SCC patients and chronic ultraviolet B (UVB)-induced SCC from hairless mice.
mRNA and protein levels of COX-2 and MMPs 2/9 were up-regulated with the higher sensitivity for MMP-9 in mouse SCCs, which were induced by chronic UVB irradiation. Consistently, COX-2 and MMPs 2/9 were up-regulated with the higher sensitivity for MMP-9 in human SCCs.
COX-2 and MMPs 2/9 are up-regulated in well-differentiated cutanous SCC. Our findings indicate that inflammatory and tissue remodeling processes are actively induced during carcinogenesis of cutaneous SCC.
PMCID: PMC3662905  PMID: 23717003
Cyclooxygenase 2; MMP-2; MMP-9; SCC
20.  Identification of a cholangiocarcinoma-like gene expression trait in hepatocellular carcinoma 
Cancer research  2010;70(8):3034-3041.
Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) are the major adult liver cancers. The existence of combined hepatocellular-cholangiocarcinoma (CHC), a histopathological intermediate form between HCC and CC, suggests phenotypic overlap between these tumors. Here, we applied an integrative oncogenomic approach to address the clinical and functional implications of the overlapped phenotype between these tumors. By performing gene expression profiling of human HCC, CHC, and CC, we identified a novel HCC subtype, namely, CC-like HCC (CLHCC), which expressed CC-like traits (CC signature). As like CC and CHC, CLHCC showed aggressive phenotype with shorter recurrence-free and overall survival. In addition, we found that CLHCC coexpressed embryonic stem cell-like expression traits (ES signature) suggesting its derivation from bipotent hepatic progenitor cells. By comparing the expression of CC signature with previous ES-like, hepatoblast-like, or proliferation-related traits, we observed that that the prognostic value of the CC signatures is independent of the expression of those signatures. In conclusion, we suggest that the acquisition of CC like-expression traits play a critical role in the heterogeneous progression of HCC.
PMCID: PMC3498758  PMID: 20395200
microarray; stem cell; prognosis; cholangiocarcinoma-like HCC
21.  Association of Polymorphism in Pri-microRNAs-371-372-373 with the Occurrence of Hepatocellular Carcinoma in Hepatitis B Virus Infected Patients 
PLoS ONE  2012;7(7):e41983.
Micro RNAs-371-372-373 (miRNAs-371-373), originating from the same pri-miRNA transcript, are reported to be upregulated in hepatocellular carcinoma (HCC) and to be related to the regulation of hepatitis B virus (HBV) infection. Our study investigated whether pri-miRNAs-371-373 polymorphisms are associated with the risk of HCC occurrence and HBV clearance.
Genetic variations were identified through direct DNA sequencing using TaqMan assay. Three sequence variants of pri-miRNAs-371-373 were identified. Genetic associations of those with HCC occurrence and HBV clearance among patients with HBV infection were analyzed using logistic regression analyses with adjustment for age and gender (n = 1439).
For the occurrence of HCC, polymorphism rs3859501C>A acted as a protective factor both in chronic carriers (OR = 0.75, P = 0.005 in a codominant model; OR = 0.71, P = 0.02 in a dominant model; OR = 0.66, P = 0.03 in recessive model) and liver cirrhosis patients (OR = 0.69, P = 0.001 in a codominant model; OR = 0.60, P = 0.003 in a dominant model; OR = 0.63, P = 0.03 in a recessive model). The pri-miRNAs-371-373_ht2 [C-A-C] also showed a protective effect on HCC occurrence both in the chronic carrier and liver cirrhosis groups (P<0.05 in both). However, there was no significant association between pri-miRNAs-371-373 polymorphisms and HBV clearance.
In conclusion, among chronic carriers and liver cirrhosis patients, the A allele of rs3859501 and the haplotype pri-miRNAs-371-373_ht2 were more protective to HCC than other genotypes and haplotypes. Further studies into the roles of rs3859501 and pri-miRNAs-371-373_ht2 haplotype in hepatocarcinogenesis are needed.
PMCID: PMC3407047  PMID: 22848681
22.  Regression of Advanced Gastric MALT Lymphoma after the Eradication of Helicobacter pylori 
Gut and Liver  2012;6(2):270-274.
A 66-year-old female presented with a 1-month history of dyspepsia. An initial upper gastrointestinal endoscopy with biopsy revealed a low-grade mucosa-associated lymphoid tissue (MALT) lymphoma. A rapid urease test was positive for Helicobacter pylori. Endoscopic ultrasound (EUS) and computed tomography (CT) revealed a 30×15-mm lymph node (LN) in the subcarinal area. Histopathologic and phenotypic analyses of the biopsy specimens obtained by EUS-guided fine-needle aspiration revealed a MALT lymphoma, and the patient was diagnosed with a stage 4E gastric MALT lymphoma. One year after H. pylori eradication, the lesion had disappeared, as demonstrated by endoscopy with biopsy, CT, fusion whole-body positron emission tomography, and EUS. Here, we describe a patient with gastric MALT lymphoma that metastasized to the mediastinal LN and regressed following H. pylori eradication.
PMCID: PMC3343168  PMID: 22570759
Marginal zone B-cell lymphoma; Stomach
23.  Metastatic hepatocellular carcinoma presenting as facial nerve palsy and facial pain 
The Korean Journal of Hepatology  2011;17(4):319-322.
Facial nerve palsy due to temporal bone metastasis of hepatocellular carcinoma (HCC) has rarely been reported. We experienced a rare case of temporal bone metastasis of HCC that initially presented as facial nerve palsy and was diagnosed by surgical biopsy. This patient also discovered for the first time that he had chronic hepatitis B and C infections due to this facial nerve palsy. Radiation therapy greatly relieved the facial pain and facial nerve palsy. This report suggests that hepatologists should consider metastatic HCC as a rare but possible cause of new-onset cranial neuropathy in patients with chronic viral hepatitis.
PMCID: PMC3304660  PMID: 22310797
Metastasis; Hepatocellular carcinoma; Temporal bone; Cranial nerve palsy
24.  Protein induced by vitamin K absence or antagonist-II production is a strong predictive marker for extrahepatic metastases in early hepatocellular carcinoma: a prospective evaluation 
BMC Cancer  2011;11:435.
Clinicians often experience extrahepatic metastases associated with hepatocellular carcinoma (HCC), even if no evidence of intrahepatic recurrence after treatment is observed. We investigated the pretreatment predictors of extrahepatic metastases in HCC patients.
Patients diagnosed with HCC without evidence of extrahepatic metastases were prospectively enrolled. We evaluated the correlation between extrahepatic metastases and pretreatment clinical variables, including serum tumor markers.
A total of 354 patients were included. Seventy-six patients (21%) had extrahepatic metastases during the observation period (median, 25.3 months; range, 0.6-51.3 months). Cox regression multivariate analysis showed that serum protein induced by vitamin K absence or antagonist-II (PIVKA-II) production levels, the intrahepatic tumor stage, platelet count, and portal vein thrombosis were independent risk factors for extrahepatic metastases. Patients with a PIVKA-II production ≥ 300 mAU/mL had a 2.7-fold (95% confidence interval; 1.5-4.8; P < 0.001) and 3.7-fold (95% confidence interval; 2.0-6.6; P < 0.001) increased risk for extrahepatic metastases after adjustment for stage, platelet count, alpha-fetoprotein ≥ 400 ng/mL, and portal vein thrombosis according to the AJCC and BCLC staging systems, respectively.
PIVKA-II production levels might be a good candidate predictive marker for extrahepatic HCC metastases, especially in patients with smaller and/or fewer tumors in the liver with in stages regardless of serum alpha-fetoprotein.
PMCID: PMC3210108  PMID: 21985636
Protein induced by vitamin K absence or antagonist-II; hepatocellular carcinoma; metastases; predictive marker
25.  Inhibition of hypoxia-inducible carbonic anhydrase-IX enhances hexokinase II inhibitor-induced hepatocellular carcinoma cell apoptosis 
Acta Pharmacologica Sinica  2011;32(7):912-920.
The hypoxic condition within large or infiltrative hypovascular tumors produces intracellular acidification, which could activate many signaling pathways and augment cancer cell growth and invasion. Carbonic anhydrase-IX (CA-IX) is an enzyme lowering pH. This study is to examine whether hypoxia induces CA-IX in hepatocellular carcinoma (HCC) cells, and to evaluate its clinical implication in HCC patients.
Human HCC cell lines (Huh-7 and HepG2 cells) were used, and cell growth was assessed using MTS assay. CA-IX expression and apoptotic/kinase signaling were evaluated using immunoblotting. The cells were transfected with CA-IX-specific siRNA, or treated with its inhibitor 4-(2-aminoethyl) benzenesulfonamide (CAI#1), and/or the hexokinase II inhibitor, 3-bromopyruvate (3-BP). A clinic pathological analysis of 69 patients who underwent an HCC resection was performed using a tissue array.
Incubation of HCC cells under hypoxia (1% O2, 5% CO2, 94% N2) for 36 h significantly increased CA-IX expression level. CAI#1 (400 μmol/L) or CA-IX siRNA (100 μmol/L) did not influence HCC cell growth and induce apoptosis. However, CAI#1 or CA-IX siRNA at these concentrations enhanced the apoptosis induced by 3-BP (100 μmol/L). This enhancement was attributed to increased ER stress and JNK activation, as compared with 3-BP alone. Furthermore, a clinic pathological analysis of 69 HCC patients revealed that tumor CA-IX intensity was inversely related to E-cadherin intensity.
Inhibition of hypoxia-induced CA-IX enhances hexokinase II inhibitor-induced HCC apoptosis. Furthermore, CA-IX expression profiles may have prognostic implications in HCC patients. Thus, the inhibition of CA-IX, in combination with a hexokinase II inhibitor, may be therapeutically useful in patients with HCCs that are aggressively growing in a hypoxic environment.
PMCID: PMC4003119  PMID: 21666701
hepatocellular carcinoma; hypoxia; intracellular acidification; carbonic anhydrase-IX; hexokinase II; apoptosis

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