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1.  Optimal biliary drainage for inoperable Klatskin's tumor based on Bismuth type 
AIM: To investigate differences in the effects of biliary drainage procedures in patients with inoperable Klatskin’s tumor based on Bismuth type, considering endoscopic retrograde biliary drainage (ERBD), external percutaneous transhepatic biliary drainage (EPTBD) and internal biliary stenting via the PTBD tract (IPTBD).
METHODS: The initial success rate, cumulative patency rate, and complication rate were compared retrospectively, according to the Bismuth type and ERBD, EPTBD, and IPTBD. Patency was defined as the duration for adequate initial bile drainage or to the point of the patient’s death associated with inadequate drainage.
RESULTS: One hundred thirty-four patients (93 men, 41 women; 21 Bismuth type II, 47 III, 66 IV; 34 ERBD, 66 EPTBD, 34 IPTBD) were recruited. There were no differences in demographics among the groups. Adequate initial relief of jaundice was achieved in 91% of patients without a significant difference in the results among different procedures or Bismuth types. The cumulative patency rates for ERBD and IPTBD were better than those for EPTBD with Bismuth type III. IPTBD provided an excellent response for Bismuth type IV. However, there was no difference in the patency rate among drainage procedures for Bismuth type II. Procedure-related cholangitis occurred less frequently with EPTBD than with ERBD and IPTBD.
CONCLUSION: ERBD is recommended as the first-line drainage procedure for the palliation of jaundice in patients with inoperable Klatskin’s tumor of Bismuth type II or III, but IPTBD is the best option for Bismuth type IV.
PMCID: PMC4171166  PMID: 17663508
Klatskin's tumor; Palliation; Drainage; Bile ducts; Intervention
2.  Clobenpropit enhances anti-tumor effect of gemcitabine in pancreatic cancer 
AIM: To evaluate the anti-tumor effect of clobenpropit, which is a specific H3 antagonist and H4 agonist, in combination with gemcitabine in a pancreatic cancer cell line.
METHODS: Three kinds of human pancreatic cancer cell lines (Panc-1, MiaPaCa-2, and AsPC-1) were used in this study. Expression of H3 and H4 receptors in pancreatic cancer cells was identified with Western blotting. Effects of clobenpropit on cell proliferation, migration and apoptosis were evaluated. Alteration of epithelial and mesenchymal markers after administration of clobenpropit was analyzed. An in vivo study with a Panc-1 xenograft mouse model was also performed.
RESULTS: H4 receptors were present as 2 subunits in human pancreatic cancer cells, while there was no expression of H3 receptor. Clobenpropit inhibited cell migration and increased apoptosis of pancreatic cancer cells in combination with gemcitabine. Clobenpropit up-regulated E-cadherin, but down-regulated vimentin and matrix metalloproteinase 9 in real-time polymerase chain reaction. Also, clobenpropit inhibited tumor growth (gemcitabine 294 ± 46 mg vs combination 154 ± 54 mg, P = 0.02) and enhanced apoptosis in combination with gemcitabine (control 2.5%, gemcitabine 25.8%, clobenpropit 9.7% and combination 40.9%, P = 0.001) by up-regulation of E-cadherin and down-regulation of Zeb1 in Panc-1 xenograft mouse.
CONCLUSION: Clobenpropit enhanced the anti-tumor effect of gemcitabine in pancreatic cancer cells through inhibition of the epithelial-mesenchymal transition process.
PMCID: PMC4093704  PMID: 25024609
Clobenpropit; Epithelial-mesenchymal transition; Histamine; Histamine receptors; Pancreatic neoplasm
3.  Non-surgical treatment of post-surgical bile duct injury: Clinical implications and outcomes 
AIM: To investigate the prognostic factors determining the success rate of non-surgical treatment in the management of post-operative bile duct injuries (BDIs).
METHODS: The study patients were enrolled from the pancreatobiliary units of a tertiary teaching hospital for the treatment of BDIs after hepatobiliary tract surgeries, excluding operations for liver transplantation and malignancies, from January 1999 to August 2010. A total of 5167 patients underwent operations, and 77 patients had BDIs following surgery. The primary end point was the treatment success rate according to different types of BDIs sustained using endoscopic or percutaneous hepatic approaches. The type of BDI was defined using one of the following diagnostic tools: endoscopic retrograde cholangiography, percutaneous transhepatic cholangiography, computed tomography scan, and magnetic resonance cholangiography. Patients with a final diagnosis of BDI underwent endoscopic and/or percutaneous interventions for the treatment of bile leak and/or stricture if clinically indicated. Patient consent was obtained, and study approval was granted by the Institutional Review Board in accordance with the legal regulations of the Human Clinical Research Center at the Seoul National University Hospital in Seoul, South Korea.
RESULTS: A total of 77 patients were enrolled in the study. They were divided into three groups according to type of BDI. Among them, 55 patients (71%) underwent cholecystectomy. Thirty-six patients (47%) had bile leak only (type 1), 31 patients had biliary stricture only (type 2), and 10 patients had both bile leak and biliary stricture (type 3). Their initial treatment modalities were non-surgical. The success rate of non-surgical treatment in each group was as follows: BDI type 1: 94%; type 2: 71%; and type 3: 30%. Clinical parameters such as demographic factors, primary disease, operation method, type of operation, non-surgical treatment modalities, endoscopic procedure steps, type of BDI, time to diagnosis and treatment duration were evaluated to evaluate the prognostic factors affecting the success rate. The type of BDI was a statistically significant prognostic factor in determining the success rate of non-surgical treatment. In addition, a shorter time to diagnosis of BDI after the operation correlated significantly with higher success rates in the treatment of type 1 BDIs.
CONCLUSION: Endoscopic or percutaneous hepatic approaches can be used as an initial treatment in type 1 and 2 BDIs. However, surgical intervention is a treatment of choice in type 3 BDI.
PMCID: PMC4051933  PMID: 24944484
Endoscopic retrograde cholangiography; Percutaneous transhepatic cholangiography; Percutaneous transhepatic biliary drainage; Bile duct; Biliary stricture.
4.  A Multicenter Phase II Trial of Gemcitabine Plus Oxaliplatin in Unresectable Gallbladder Cancer 
Gut and Liver  2013;7(5):594-598.
No standard chemotherapy has been established for advanced gallbladder cancer. The authors studied the activity and tolerability of a gemcitabine and oxaliplatin (GEMOX) combination in unresectable gallbladder cancer (GBC).
Adult patients with pathologically confirmed unresectable GBC were prospectively recruited at three centers. No patient had received prior chemotherapy or radiotherapy. Patients received cycles of gemcitabine at 1,000 mg/m2 on day 1, followed by oxaliplatin at 100 mg/m2 on day 2, every 2 weeks. The primary study endpoint was time to progression.
Forty patients with unresectable GBC were enrolled. The median age was 60 years (range, 38 to 79 years). All patients showed good performance status. Of the 33 analyzable patients, 12 achieved partial response (36%), 17 stable disease (52%), and four progressive disease (12%). No patient achieved a complete response. The tumor control rate was 88%. At a median follow-up of 6.8 months, the median time to progression was 5.3 months (95% confidence interval [CI], 3.7 to 6.9), and median overall survival was 6.8 months (95% CI, 6.1 to 7.5). Nine of the 40 patients (23%) experienced at least a grade-3 adverse event, but no patient experienced a grade-4 adverse event.
GEMOX combination therapy is a feasible option and is well tolerated in unresectable GBC.
PMCID: PMC3782675  PMID: 24073318
Gallbladder neoplasms; Gemcitabine; Oxaliplatin
5.  Clinical and pathological differences between serum immunoglobulin G4-positive and -negative type 1 autoimmune pancreatitis 
AIM: To identify clinical and pathological differences between serum immunoglobulin G4 (IgG4)-positive (SIP) and IgG4-negative (SIN) type 1 autoimmune pancreatitis (AIP) in South Korea.
METHODS: AIP was diagnosed by the international consensus diagnostic criteria. The medical records and pathology were retrospectively reviewed and IgG4-positive cells were counted in a high power field (HPF). Type I AIP was defined as a high serum level of IgG4 or histological finding. SIN type 1 AIP was defined as a histological evidence of type 1 AIP and a normal serum IgG4 level. The clinical and pathological findings were compared between the two groups. The analysis was performed using Student’s t test, Fischer’s exact test and Mann-Whitney’s U test. A P value of < 0.05 was considered statistically significant. As repeated comparison was made, P values of less than 5% (P < 0.05) were considered significant.
RESULTS: Twenty five patients with definite type 1 AIP (19 histologically and six serologically diagnosed cases) were enrolled. The mean tissue IgG4 concentrations were significantly higher in SIP than SIN group (40 cells per HPF vs 18 cells per HPF, P = 0.02). Among eight SIN patients, the tissue IgG4 concentrations were less than 15 cells per HPF in most of cases, except one. The sensitivity of serum IgG4 was 68% (17 SIP and eight SIN AIP). Other organ involvement was more frequently associated with SIP than SIN AIP (59% vs 26%, P = 0.016). However, the relapse rate and diffuse swelling of the pancreas were not associated with serum IgG4 level. The concentrations of IgG4-positive cells per HPF were higher in SIP than SIN AIP (40 vs 18, P = 0.02).
CONCLUSION: The sensitivity of serum IgG4 was 68% in type 1 AIP. High serum IgG4 level was associated with other organ involvement and tissue IgG4 concentration but did not affect the relapse rate in type 1 AIP.
PMCID: PMC3703191  PMID: 23840149
Autoimmunity; Chronic pancreatitis; Immunoglobulin G4-related systemic disease; Lymphoplasmacytic sclerosing pancreatitis; Immunoglobulin G4
6.  Bladder Wall Thickness is Associated with Responsiveness of Storage Symptoms to Alpha-Blockers in Men with Lower Urinary Tract Symptoms 
Korean Journal of Urology  2012;53(7):487-491.
Bladder wall thickness (BWT) is reported to be related to detrusor overactivity and bladder outlet obstruction. We investigated the relationship between BWT and the responsiveness of storage symptoms to alpha-blockers in men with lower urinary tract symptoms (LUTS).
Materials and Methods
A total of 74 patients with LUTS were enrolled. International Prostate Symptom Score, uroflowmetry with post-void residual urine volume, and transrectal ultrasonography (TRUS) were investigated. BWT was measured by performing TRUS at the midsagittal plane view, and the average value of BWT at the anterior, dome, and trigone areas was used. After 4 weeks of alpha-blocker medication, patients were reevaluated and divided into two groups. The responder group consisted of patients who reported improvement in the storage symptom subscore of 2 points or more; the non-responder group consisted of patients who reported improvement of less than 2 points. Clinical parameters including BWT were compared between the two groups.
A total of 52 patients were followed. BWT was positively correlated with intravesical prostate protrusion (IPP) (9.26±4.99, standardized beta=0.393, p=0.002) and storage symptom subscore (0.35±0.43, standardized beta=0.458, p=0.002). Compared with that in the responder group, BWT was thicker in the non-responder group, and improvement in the storage symptom score was correlated with BWT (0.58±0.09 cm vs. 0.65±0.11 cm, p=0.018) and prostate volume (27.08±16.26 ml vs. 36.44±10.1 ml, p=0.018).
BWT was correlated with IPP, the storage symptom subscore, and the responsiveness of storage symptoms to alpha-blockers in LUTS/benign prostatic hyperplasia (BPH) patients. As BWT increased, the responsiveness of storage symptoms to alpha-blocker decreased in LUTS/BPH patients.
PMCID: PMC3406196  PMID: 22866221
Adrenergic alpha-antagonists; Lower urinary tract symptoms; Muscarinic antagonists
7.  Endoscopic management of occluded metal biliary stents: Metal versus 10F plastic stents 
AIM: To compare the efficacy of self-expandable metal stents (SEMSs) with 10F plastic stents (PSs) in the endoscopic management of occluded SEMSs.
METHODS: We retrospectively reviewed the medical records of 56 patients who underwent SEMS insertion for palliation of unresectable malignant biliary obstruction between 2000 and 2007 and subsequent endoscopic retrograde biliary drainage (ERBD) with SEMS or PS for initial SEMS occlusion between 2000 and 2008.
RESULTS: Subsequent ERBD with SEMS was performed in 29 patients and with PS in 27. The median time to stent occlusion after subsequent ERBD was 186 d in the SEMS group and 101 d in the PS group (P = 0.118). Overall median stent patency was 79 d for the SEMS group and 66 d for the PS group (P = 0.379). The mean number of additional biliary drainage procedures after subsequent ERBD in patients that died (n = 50) during the study period was 2.54 ± 4.12 for the SEMS group and 1.85 ± 1.95 for the PS group (P = 0.457). The mean total cost of additional biliary drainage procedures after the occlusion of subsequent SEMS or PS was $410.04 ± 692.60 for the SEMS group and $630.16 ± 671.63 for the PS group (P = 0.260). Tumor ingrowth as the cause of initial SEMS occlusion was the only factor associated with a shorter time to subsequent stent occlusion (101 d for patients with tumor ingrowth vs 268 d for patients without tumor ingrowth, P = 0.008).
CONCLUSION: Subsequent ERBD with PSs offered similar patency and number of additional biliary drainage procedures compared to SEMSs in the management of occluded SEMS.
PMCID: PMC2980685  PMID: 21072899
Stents; Biliary tract neoplasms; Obstructive jaundice; Endoscopy; Endoscopic retrograde cholangiopancreatography
8.  Metastasis to the gallbladder: A single-center experience of 20 cases in South Korea 
AIM: To evaluate the clinicopathologic characteristics of patients with metastases to the gallbladder (MGBs).
METHODS: We performed a single-center retrospective study of 20 patients with MGBs diagnosed pathologically from 1999 to 2007.
RESULTS: Among 417 gallbladder (GB) malignancies, 20 (4.8%) were MGBs. The primary malignancies originated from the stomach (n = 8), colorectum (n = 3), liver (n = 2), kidney (n = 2), skin (n = 2), extrahepatic bile duct (n = 1), uterine cervix (n = 1), and appendix (n = 1). Twelve patients were diagnosed metachronously, presenting with cholecystitis (n = 4), abdominal pain (n = 2), jaundice (n = 1), weight loss (n = 1), and serum CA 19-9 elevation (n = 1); five patients were asymptomatic. The median survival after the diagnosis of MGB was 8.7 mo. On Cox regression analysis, R0 resection was the only factor associated with a prolonged survival [hazard ratio (HR): 0.01, P = 0.002]; presentation with cholecystitis was associated with poor survival (HR: 463.27, P = 0.006).
CONCLUSION: MGBs accounted for 4.8% of all pathologically diagnosed GB malignancies. The most common origin was the stomach. The median survival of MGB was 8.7 mo.
PMCID: PMC2761559  PMID: 19824115
Gallbladder; Neoplasms; Gastrointestinal neoplasms; Neoplasm metastasis; Biliary tract neoplasms
9.  Risk factors of acute cholecystitis after endoscopic common bile duct stone removal 
AIM: To evaluate the risk factors of acute cholecystitis after endoscopic common bile duct (CBD) stone removal.
METHODS: A total 100 of patients who underwent endoscopic CBD stone removal with gallbladder (GB) in situ without subsequent cholecystectomy from January 2000 to July 2004 were evaluated retrospectively. The following factors were considered while evaluating risk factors for the development of acute cholecystitis: age, gender, serum bilirubin level, GB wall thickening, cystic duct patency, presence of a GB stone, CBD diameter, residual stone, lithotripsy, juxtapapillary diverticulum, presence of liver cirrhosis or diabetes mellitus, a presenting illness of cholangitis or pancreatitis, and procedure-related complications.
RESULTS: During a mean 18-mo follow-up, 28 (28%) patients developed biliary symptoms; 17 (17%) acute cholecystitis and 13 (13%) CBD stone recurrence. Of patients with acute cholecystitis, 15 (88.2%) received laparoscopic cholecystectomy and 2 (11.8%) open cholecystectomy. All recurrent CBD stones were successfully removed endoscopically. The mean time elapse to acute cholecystitis was 10.2 mo (1-37 mo) and that to recurrent CBD stone was 18.4 mo. Of the 17 patients who received cholecystectomy, 2 (11.8%) developed recurrent CBD stones after cholecystectomy. By multivariate analysis, a serum total bilirubin level of
<1.3 mg/dL and a CBD diameter of <11 mm at the time of stone removal were found to predict the development of acute cholecystitis.
CONCLUSION: After CBD stone removal, there is no need for routine prophylactic cholecystectomy. However, patients without a dilated bile duct (<11 mm) and jaundice (<1.3 mg/dL) at the time of CBD stone removal have a higher risk of acute cholecystitis and are possible candidates for prophylactic cholecystectomy.
PMCID: PMC4066164  PMID: 16521227
Sphincterotomy; Choledocholithiasis; Acute cholecystitis; Cholecystectomy
10.  Acute Pancreatitis Due to a Duodenal Ulcer 
Clinical Endoscopy  2014;47(6):579-583.
Duodenal ulcers and acute pancreatitis are two of the most commonly encountered gastrointestinal diseases among the general population. However, duodenal ulcer-induced pancreatitis is very rarely reported worldwide. This report elaborates on a distinct medical treatment that contributes to partial or complete treatment of acute pancreatitis induced by a duodenal ulcer scar.
PMCID: PMC4260110  PMID: 25505728
Duodenum; Ulcer; Scar; Pancreatitis; Stent
11.  The clinical features and treatment modality of esophageal neuroendocrine tumors: a multicenter study in Korea 
BMC Cancer  2014;14(1):569.
Neuroendocrine tumors (NETs) of the esophagus are extremely rare, and few cases have been reported worldwide. Thus, a comprehensive nationwide study is needed to understand the characteristics of and treatment strategy for esophageal NETs.
We collected data on esophageal NET patients from 25 hospitals in Korea from 2002–2012. The incidence, location, clinical symptoms, histopathology, treatment response, and the biochemical, radiologic and endoscopic characteristics of esophageal NETs were surveyed.
Among 2,037 NETs arising in different gastrointestinal sites, esophageal NETs were found in 26 cases (1.3%). The mean patient age was 60.12 ± 9.30 years with a 4:1 male predominance. In endoscopic findings, 76.9% (20/26) of NETs were located in the lower third of the esophagus and the mean size was 2.34 ± 1.63 cm. At diagnosis, more than half the patients (15/26, 57.7%) had regional lymph node metastasis or widespread metastasis. Endoscopic resection was conducted in three cases, and in all three of them, lymph node metastasis was not found and tumor size was below 1.0 cm. All tumors were completely removable through endoscopic procedures and there was no recurrence during the follow-up period. Eighteen other patients received an operation, chemotherapy or both. Among them, nine patients (50.0%) expired because of the progression of their cancer or post-operative complications. In Kaplan-Meier survival analysis, only tumor size (more than 2.0 cm) showed prognostic significance (P = 0.045).
Despite the general assumption that gastrointestinal NETs are benign and slow-growing tumors, the prognosis of advanced esophageal NETs is not favorable.
PMCID: PMC4133602  PMID: 25098730
Esophagus; Neuroendocrine tumor; Treatment; Prognosis
12.  Which Is the Better Treatment for the Removal of Large Biliary Stones? Endoscopic Papillary Large Balloon Dilation versus Endoscopic Sphincterotomy 
Gut and Liver  2014;8(4):438-444.
We evaluated the efficacy and cost-effectiveness of endoscopic papillary large balloon dilation (EPLBD) for large common bile duct (CBD) stone removal compared with endoscopic sphincterotomy (EST).
A total of 1,580 patients who underwent endoscopic CBD stone extraction between January 2001 and July 2010 were reviewed. The following inclusion criteria were applied: choledocholithiasis treated by EPLBD with minor EST or EST with mechanical lithotripsy; and follow-up >9 months after treatment.
Forty-nine patients with EPLBD and 41 with EST were compared. There was no significant difference in the complication rates and stone recurrence rates between the two groups. However, significantly more endoscopic retrograde cholangiopancreatography (ERCP) sessions were required in the EST group to achieve the complete removal of stones (1.7 times vs 1.3 times; p=0.03). The mean cost required for complete stone removal per patient was significantly higher in the EST group compared to the EPLBD group (USD $1,644 vs $1,225, respectively; p=0.04). Dilated CBD was the only significant factor associated with recurrent biliary stones (relative risk, 1.09; 95% confidence interval, 1.02 to 1.17; p=0.02).
EPLBD is the better treatment (compared to EST) for removing large CBD stones because EPLBD requires fewer ERCP sessions and is less expensive.
PMCID: PMC4113053  PMID: 25071911
Choledocholithiasis; Endoscopic papillary large balloon dilation; Sphincterotomy; endoscopic; Mechanical lithotripsy
13.  Is There Any Role of Positron Emission Tomography Computed Tomography for Predicting Resectability of Gallbladder Cancer? 
Journal of Korean Medical Science  2014;29(5):680-684.
The role of integrated 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography computed tomography (PET-CT) is uncertain in gallbladder cancer. The aim of this study was to show the role of PET-CT in gallbladder cancer patients. Fifty-three patients with gallbladder cancer underwent preoperative computed tomography (CT) and PET-CT scans. Their medical records were retrospectively reviewed. Twenty-six patients underwent resection. Based on the final outcomes, PET-CT was in good agreement (0.61 to 0.80) with resectability whereas CT was in acceptable agreement (0.41 to 0.60) with resectability. When the diagnostic accuracy of the predictions for resectability was calculated with the ROC curve, the accuracy of PET-CT was higher than that of CT in patients who underwent surgical resection (P=0.03), however, there was no difference with all patients (P=0.12). CT and PET-CT had a discrepancy in assessing curative resection in nine patients. These consisted of two false negative and four false positive CT results (11.3%) and three false negative PET-CT results (5.1%). PET-CT was in good agreement with the final outcomes compared to CT. As a complementary role of PEC-CT to CT, PET-CT tended to show better prediction about resectability than CT, especially due to unexpected distant metastasis.
Graphical Abstract
PMCID: PMC4024955  PMID: 24851025
Gallbladder Neoplasms; Positron-Emission Tomography; Tomography, X-Ray Computed; Diagnosis
14.  Stabilization of Oxygen-deficient Structure for Conducting Li4Ti5O12-δ by Molybdenum Doping in a Reducing Atmosphere 
Scientific Reports  2014;4:4350.
Li4Ti5O12 (LTO) is recognized as being one of the most promising anode materials for high power Li ion batteries; however, its insulating nature is a major drawback. In recent years, a simple thermal treatment carried out in a reducing atmosphere has been shown to generate oxygen vacancies (VO) for increasing the electronic conductivity of this material. Such structural defects, however, lead to re-oxidization over time, causing serious deterioration in anode performance. Herein, we report a unique approach to increasing the electronic conductivity with simultaneous improvement in structural stability. Doping of LTO with Mo in a reducing atmosphere resulted in extra charges at Ti sites caused by charge compensation by the homogeneously distributed Mo6+ ions, being delocalized over the entire lattice, with fewer oxygen vacancies (VO) generated. Using this simple method, a marked increase in electronic conductivity was achieved, in addition to an extremely high rate capability, with no performance deterioration over time.
PMCID: PMC3950810  PMID: 24618982
15.  The Effect of Terpene Combination on Ureter Calculus Expulsion After Extracorporeal Shock Wave Lithotripsy 
Korean Journal of Urology  2014;55(1):36-40.
Terpene combination (Rowatinex) is known to help with the expulsion of urinary stones. The aim of this study was to determine how Rowatinex affects the expulsion of remnant stones after shock wave lithotripsy (SWL).
Materials and Methods
Clinical data were collected retrospectively from 499 patients with a diagnosis of ureteral stones who underwent SWL from January 2009 to August 2012. Ureteral stones were diagnosed in all patients by kidney, ureter, and bladder x-ray and abdominal computed tomography (CT). The progress of patients was documented every 2 weeks to confirm remnant stones after SWL. The patients with remnant stones underwent SWL again. Group 1 consisted of patients who were prescribed an analgesic, Tamsulosin 0.2 mg, and Rowatinex. Group 2 consisted of patients who were prescribed only an analgesic and Tamsulosin 0.2 mg. The expulsion rate of urinary stones was compared between groups.
The expulsion rate of urinary stones was not significantly different between the two groups after 2 weeks. However, after 4 weeks, group 1 had a significantly higher expulsion rate (72.2% compared with 61.1%, p=0.022). Fifteen patients (10.2%) in group 1 and 40 (11.4%) in group 2 had to undergo ureteroscopic removal of the stone (p=0.756). Acute pyelonephritis occurred in one patient (0.7%) in group 1 and in one patient (0.3%) in group 2 (p=0.503).
The long-term administration of Rowatinex for 4 weeks increased the expulsion rate of urinary stones after SWL.
PMCID: PMC3897628  PMID: 24466395
Lithotripsy; Terpene combination; Urolithiasis
16.  Clinical Significance and Revisiting the Meaning of CA 19-9 Blood Level Before and After the Treatment of Pancreatic Ductal Adenocarcinoma: Analysis of 1,446 Patients from the Pancreatic Cancer Cohort in a Single Institution 
PLoS ONE  2013;8(11):e78977.
Life expectancy of pancreatic ductal adenocarcinoma (PDAC) patients is usually short and selection of the most appropriate treatment is crucial. The aim of this study was to investigate the usefulness of serum CA 19-9 as a surrogate marker under no impress excluding other factors affecting CA 19-9 level other than tumor itself.
We recruited 1,446 patients with PDACs and patients with Lewis antigen both negative or obstructive jaundice were excluded to eliminate the false effects on CA 19-9 level. The clinicopathologic factors were reviewed including initial and post-treatment CA 19-9, and statistical analysis was done to evaluate the association of clinicopathologic factors with overall survival (OS).
The total of 944 patients was enrolled, and205 patients (22%) underwent operation with curative intention and 541 patients (57%) received chemotherapy and/or radiotherapy. The median CA 19-9 levels of initial and post-treatment were 670 IU/ml and 147 IU/ml respectively. The prognostic factors affecting OS were performance status, AJCC stage and post-treatment CA 19-9 level in multivariate analysis. Subgroup analysis was done for the patients who underwent R0 and R1 resection, and patients with normalized post-operative CA 19-9 (≤37 IU/mL) had significantly longer OS and DFS regardless of initial CA 19-9 level; 32 vs. 18 months, P<0.001, 16 vs. 9 months, P = 0.004 respectively.
Post-treatment CA 19-9 and normalized post-operative CA 19-9 (R0 and R1 resected tumors) were independent factors associated with OS and DFS, however, initial CA 19-9 level was not statistically significant in multivariate analysis.
PMCID: PMC3826753  PMID: 24250822
17.  Changes in Demographic Features of Gallstone Disease: 30 Years of Surgically Treated Patients 
Gut and Liver  2013;7(6):719-724.
The aim of this study was to investigate changes in the clinical and demographical characteristics of gallstone disease in Korea, based on 30 years of surgically treated patients at a single institute.
In total, 7,949 gallstone patients who underwent surgery between 1981 and 2010 were analyzed. Patients were divided into six time periods: period I (1981 to 1985, n=831), period II (1986 to 1990, n=888), period III (1991 to 1995, n=1,040), period IV (1996 to 2000, n=1,261), period V (2001 to 2005, n=1,651) and period VI (2006 to 2010, n=2,278).
The total number and mean age of the patients gradually increased, and the male/female ratio decreased. The proportion of gallbladder (GB)-stone cases increased, whereas the proportions of common bile duct (CBD)- and intrahepatic duct (IHD)-stone cases decreased. Differences in patient geographical origins also decreased. Based on the relationship between changes in the prevalence of gallstone disease and socioeconomic status, the prevalence of CBD stones showed a strong correlation with Engel's coefficient (p<0.001).
Our study indicates that although the total number of cases and the mean age of gallstone patients have continuously increased, there are trends of increasing GB-stone cases and decreasing CBD- and IHD-stone cases.
PMCID: PMC3848536  PMID: 24312714
Cholelithiasis; Epidemiology; Surgery
18.  Clinical Usefulness of Plasma Chromogranin A in Pancreatic Neuroendocrine Neoplasm 
Journal of Korean Medical Science  2013;28(5):750-754.
Chromogranin A (CgA) is widely used as an immunohistochemical marker of neuroendocrine neoplasms and has been measurable in plasma of patients. We assessed the clinical role of plasma CgA in diagnosing pancreatic neuroendocrine neoplasm (PNEN). CgA was checked in 44 patients with pancreatic mass who underwent surgical resection from 2009 through 2011. The cutoff value for diagnosing PNEN and the relationships between CgA and clinicopathologic variables were analyzed. Twenty-six patients were PNENs and 18 patients were other pancreatic disorders. ROC analysis showed a cutoff of 60.7 ng/mL with 77% sensitivity and 56% specificity, and the area under the curve (AUC) was 0.679. Among PNEN group, the sensitivity and specificity of diagnosing metastasis were 100% and 90% respectively when CgA cutoff was 156.5 ng/mL. The AUC was 0.958. High Ki-67 index (160.8 vs 62.1 ng/mL, P = 0.001) and mitotic count (173.5 vs 74.6 ng/mL, P = 0.044) were significantly correlated with plasma CgA, but the tumor size was not. In conclusion, CgA has a little value in diagnosing PNEN. However, the high level of CgA (more than 156.5 ng/mL) can predict the metastasis. Also, plasma CgA level correlates with Ki-67 index and mitotic count which represents prognosis of PNENs.
PMCID: PMC3653089  PMID: 23678268
Pancreatic Neuroendocrine Neoplasm; Chromogranin A; Diagnosis; Pancreatic Neoplasms
19.  A Case of Common Bile Duct Cancer That Completely Responded to Combination Chemotherapy of Gemcitabine and TS-1 
Gut and Liver  2013;7(3):371-376.
Common bile duct (CBD) cancer is a relatively rare malignancy that arises from the biliary epithelium and is associated with a poor prognosis. Here, we report a case of advanced metastatic CBD cancer successfully treated by chemotherapy with gemcitabine combined with S-1 (tegafur+gimeracil+oteracil). A 65-year-old male presented with pyogenic liver abscess. After antibiotic therapy and percutaneous drainage, follow-up computed tomography (CT) showed an enhanced nodule in the CBD. Biopsy was performed at the CBD via endoscopic retrograde cholangiopancreatography, which showed adenocarcinoma. Additional CT and magnetic resonance imaging showed multiple small nodules in the right hepatic lobe, which were confirmed as metastatic adenocarcinoma by sono-guided liver biopsy. The patient underwent combination chemotherapy with gemcitabine and S-1. After nine courses of chemotherapy, the hepatic lesion disappeared radiologically. Pylorus-preserving pancreaticoduodenectomy was performed, and no residual tumor was found in the resected specimen. Three weeks after the operation, the patient was discharged with no complications. Through 3 months of follow-up, no sign of recurrence was observed on CT scan. Gemcitabine combined with S-1 may be a highly effective treatment for advanced cholangiocarcinoma.
PMCID: PMC3661972  PMID: 23710321
Cholangiocarcinoma; Gemcitabine; S-1
20.  Antioxidant Dieckol Downregulates the Rac1/ROS Signaling Pathway and Inhibits Wiskott-Aldrich Syndrome Protein (WASP)-Family Verprolin-Homologous Protein 2 (WAVE2)-Mediated Invasive Migration of B16 Mouse Melanoma Cells 
Molecules and Cells  2012;33(4):363-369.
Reactive oxygen species (ROS) generation is linked to dynamic actin cytoskeleton reorganization, which is involved in tumor cell motility and metastasis. Thus, inhibition of ROS generation and actin polymerization in tumor cells may represent an effective anticancer strategy. However, the molecular basis of this signaling pathway is currently unknown. Here, we show that the Ecklonia cava-derived antioxidant dieckol downregulates the Rac1/ROS signaling pathway and inhibits Wiskott-Aldrich syndrome protein (WASP)-family verprolin-homologous protein 2 (WAVE2)-mediated invasive migration of B16 mouse melanoma cells. Steady-state intracellular ROS levels were higher in malignant B16F10 cells than in parental, nonmetastatic B16F0 cells. Elevation of ROS by H2O2 treatment increased migration and invasion ability of B16F0 cells to level similar to that of B16F10 cells, suggesting that intracellular ROS signaling mediates the prometastatic properties of B16 mouse melanoma cells. ROS levels and the cell migration and invasion ability of B16 melanoma cells correlated with Rac1 activation and WAVE2 expression. Overexpression of dominant negative Rac1 and depletion of WAVE2 by siRNA suppressed H2O2-induced cell invasion of B16F0 and B16F10 cells. Similarly, dieckol attenuates the ROS-mediated Rac1 activation and WAVE2 expression, resulting in decreased migration and invasion of B16 melanoma cells. In addition, we found that dieckol decreases association between WAVE2 and NADPH oxidase subunit p47phox. Therefore, this finding suggests that WAVE2 acts to couple intracellular Rac1/ROS signaling to the invasive migration of B16 melanoma cells, which is inhibited by dieckol.
PMCID: PMC3887808  PMID: 22441674
dieckol; invasion; migration; ROS; WAVE2
21.  Risk Factors of Post Endoscopic Retrograde Cholangiopancreatography Bacteremia 
Gut and Liver  2012;7(2):228-233.
Bacteremia following endoscopic retrograde cholangiopancreatography (ERCP) is a severe complication, but the risk factors for this condition have not yet been clearly determined. Thus, the aim of this study was to investigate the risk factors of post-ERCP bacteremia.
Among patients who underwent ERCP from June 2006 to May 2009, we selected patients without any signs of infection prior to the ERCP procedures. Of these patients, we further selected those who experienced bacteremia after ERCP as well as two-fold age and sex-matched controls who did not experience bacteremia after ERCP procedures. We compared clinical, laboratory and technical aspects between these two groups.
There were 70 patients (3.1%) who developed bacteremia after ERCP. In the multivariate analysis, a history of previous liver transplantation, an elevated serum alkaline phosphatase level and an endoscopic retrograde biliary drainage procedure were independent risk factors of post-ERCP bacteremia (p=0.006, p=0.001, and p=0.004, respectively). The microbiologic analysis revealed the presence of gram-negative organisms in 80% of the cases, and 11 patients had infections with bacteria expressing extended spectrum β-lactamases. Pseudomonas infection was significantly more common in patients who received liver transplantation as compared to patients without transplantation (p=0.014).
A history of liver transplantation, elevated serum alkaline phosphatase levels and endoscopic retrograde biliary drainage procedure were independent risk factors of post-ERCP bacteremia and require additional attention in future studies.
PMCID: PMC3607778  PMID: 23560160
Bacteremia; Endoscopic retrograde cholangiopancreatography; Liver transplantation; Alkaline phosphatase; Endoscopic retrograde biliary drainage
22.  Endoscopic Papillectomy for Benign Ampullary Neoplasms: How Can Treatment Outcome Be Predicted? 
Gut and Liver  2013;7(2):239-245.
Endoscopic papillectomy is increasingly performed with curative intent for benign papillary tumors. This study was performed to identify factors that predict the presence of malignancy and affect endoscopic success.
We retrospectively analyzed the medical records of patients who received an endoscopic papillectomy for papillary adenoma from 2006 to 2009.
A total of 43 patients received endoscopic papillectomy. The pathologic results after papillectomy revealed adenocarcinoma in five patients (12%), and the risk of malignancy was high in cases of large lesions, preprocedural pathology of high-grade dysplasia or high serum alkaline phosphatase. Endoscopic success was observed in 37 patients (86%) at the end of follow-up (mean duration, 10.4±9.6 months). The factor significantly affecting success was a complete resection at the initial papillectomy (p=0.007). Two patients experienced recurrence 10 and 32 months after the complete resection, but both achieved endoscopic success with repeated endoscopic treatment. Six patients with endoscopic failure received surgical resection.
Endoscopic papillectomy is a safe and effective method for the curative resection of benign papillary tumors, especially when complete resection is achieved at the initial papillectomy. Follow-up with surveillance should be performed for at least 3 years because of the possible recurrence of tumors during these periods.
PMCID: PMC3607780  PMID: 23560162
Endoscopic sphincterotomy; Benign papillary tumor; Adenocarcinoma; Endoscopic success
23.  Pancreatic Pseudocyst after Endoscopic Ultrasound-Guided Fine Needle Aspiration of Pancreatic Mass 
Clinical Endoscopy  2012;45(4):431-434.
Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is well known as a safe diagnostic procedure. We report the first case of pancreatic pseudocyst after EUS-FNA of the pancreatic body mass. A 60-year-old male underwent EUS-FNA for incidentally detected pancreatic solid mass which was suspected as neuroendocrine tumor. Two weeks later, the patient visited emergency room with acute abdominal pain and right upper quadrant tenderness; leukocytosis and elevated C-reactive protein, amylase, and lipase levels were noted. Computed tomography discovered newly developed 11.5×9.5 cm sized cystic mass communicating with the main pancreatic duct. Cyst fluid analysis revealed amylase level of 3,423 U/L and fluid culture isolated Streptococcus parasanguinis. The cystic mass corresponds with pancreatic pseudocyst. FNA induced main pancreatic duct injury and fluid leakage may cause it. Endoscopists who perform EUS-FNA must remember that pancreatic main duct injury can occur as one of severe complications and that it could be treated successfully with endoscopic internal drainage.
PMCID: PMC3521949  PMID: 23251895
Pancreatic pseudocyst; Endosonography; Fine-needle biopsy; Complications
24.  Proposal of an endoscopic retrograde cholangiopancreatography-related perforation management guideline based on perforation type 
Consensus for endoscopic retrograde cholangiopancreatography (ERCP) related perforation management is lacking. We aimed to identify candidate patients for conservative management by examining treatment results and to introduce a simple, algorithm-based management guideline.
A retrospective review of 53 patients with ERCP-related perforation between 2000 and 2010 was conducted. Data on perforation site (duodenum lateral wall or jejunum, type I; para-Vaterian, type II), management method, complication, mortality, hospital stay, and hospital cost were reviewed. Comparative analysis was done according to the injury types and management methods.
The outcome was greater in the conservative group than the operative group with shorter hospital stay (20.6 days vs. 29.8 days, P = 0.092), less cost (10.6 thousand United States Dollars [USD] vs. 19.9 thousand USD, P = 0.095), and lower morbidity rate (22.9% vs. 55.6%, P = 0.017). Eighty-one percent (17/21) of type I injuries were operatively managed and 96.9% (31/32) of type II injuries were conservatively managed. Between the types, type II showed better results over type I with shorter hospital stay (19.3 days vs. 30.6 days, P = 0.010), less cost (9.5 thousand USD vs. 20.1 thousand USD, P = 0.028), and lower complication rate (18.8% vs. 57.1%, P = 0.004). There was no difference in mortality.
Type II injuries were conservatively manageable and demonstrated better outcomes than type I injuries. The management algorithm suggests conservative management in type II injuries without severe peritonitis or unsolved problem requires immediate surgical correction, including operative management in type I injuries unless endoscopic intervention is possible. Conservative management offers socio-medical benefits. Conservative management is recommended in well-selected patients.
PMCID: PMC3467388  PMID: 23091794
Endoscopic retrograde cholangiopancreatography; Intestinal perforation; Guideline; Algorithms
25.  Long-Term Outcome of Cystic Lesions in the Pancreas: A Retrospective Cohort Study 
Gut and Liver  2012;6(4):493-500.
The management guidelines for cystic lesions of the pancreas (CLPs) are not yet well established. This study was performed to document the long-term clinical outcome of CLPs and provide guidelines for the management and surveillance of CLPs.
In this retrospective cohort study, an additional follow-up was performed in 112 patients with CLPs enrolled from 1998 to 2004 during a previous study.
During follow-up for the median period of 72.3 months, the size of the CLPs increased in 18 patients (16.1%). Six of these patients experienced growth of their CLPs after 5 years of follow-up. Twenty-six patients underwent surgery during follow-up, and four malignant cysts were detected. The overall rate of malignant progression during follow-up was 3.6%. The presence of mural nodules or solid components was independently associated with the presence of malignant CLPs. Seven patients underwent surgery after 5 years of follow-up. The pathologic findings revealed malignancies in two patients. There was only one pancreas-related death during follow-up.
The majority of CLPs exhibit indolent behavior and are associated with a favorable prognosis. However, long-term surveillance for more than 5 years should be performed because of the potential for growth and malignant transformation in CLPs.
PMCID: PMC3493732  PMID: 23170156
Pancreatic cyst; Natural history; Prognosis

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