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1.  Metal Stenting in Benign Biliary Strictures 
Clinical Endoscopy  2014;47(1):5-6.
PMCID: PMC3928492  PMID: 24570877
2.  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
3.  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
4.  Percutaneous Approach for Removal of Difficult Common Bile Duct Stones 
Clinical Endoscopy  2013;46(1):3-4.
PMCID: PMC3572347  PMID: 23424711
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  Recent Advances in the Diagnosis and Management of Autoimmune Pancreatitis: Similarities and Differences in Japan and Korea 
Gut and Liver  2013;7(4):394-400.
Two subtypes (types 1 and 2) of autoimmune pancreatitis (AIP) are currently recognized. Type 1 AIP is related to immunoglobulin G4 (lymphoplasmacytic sclerosing pancreatitis), and type 2 AIP is characterized by neutrophilic infiltration into the epithelium of the pancreatic duct (idiopathic duct-centric pancreatitis). Although type 2 AIP is sometimes observed in the United States and Europe, most cases of AIP in Japan and Korea are type 1. The international consensus diagnostic criteria for AIP were created to be applicable worldwide and to distinguish between the two types of AIP. AIP is diagnosed based on the presence of at least one of the five cardinal features (i.e., imaging, serology, other organ involvement, histology, and response to steroid therapy). Oral steroids are the standard therapy for AIP, but immunomodulatory drugs or rituximab have been successfully used for patients with relapsed AIP in the United States and Europe. Generally, the clinical manifestations and demography of AIP are similar between Japan and Korea. However, there are differences in some aspects of the disease, including the proportion of other organ involvement, the prevalence of type 2 AIP, diagnostic criteria and maintenance therapy between the two countries.
PMCID: PMC3724025  PMID: 23898377
Pancreatitis; Immunoglobulin G; Steroids
12.  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
13.  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
14.  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
15.  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
16.  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
17.  Elevated microRNA miR-21 Levels in Pancreatic Cyst Fluid Are Predictive of Mucinous Precursor Lesions of Ductal Adenocarcinoma 
Pancreatology  2011;11(3):343-350.
Biomarkers for the diagnostic classification of pancreatic cysts are urgently needed. Deregulated microRNA (miRNAs) expression is widespread in pancreatic cancer. We assessed whether aberrant miRNAs in pancreatic cyst fluid could be used as potential biomarkers for cystic precursor lesions of pancreatic cancer.
Cyst fluid specimens were prospectively collected from 40 surgically resected pancreatic cysts, and small RNAs were extracted. The ‘mucinous’ cohort included 14 intraductal papillary mucinous neoplasms (including 3 with an associated adenocarcinoma) and 10 mucinous cystic neoplasms; the ‘nonmucinous’ cohort included 11 serous cystadenomas and 5 other benign cysts. Quantitative reverse transcription PCR was performed for five miRNAs (miR-21, miR-155, miR-221, miR-17-3p, miR-191), which were previously reported as overexpressed in pancreatic adenocarcinomas.
Significantly higher expression of miR-21, miR-221, and miR-17-3p was observed in the mucinous versus nonmucinous cysts (p < 0.01), with the mean relative fold differences being 7.0-, 7.9-, and 5.4-fold, respectively. Receiver operating characteristic curves demonstrated the highest median area under the curve for miR-21, with a median specificity of 76%, at a sensitivity of 80%.
This pilot study demonstrates that profiling miRNAs in pancreatic cyst fluid samples is feasible and can yield potential biomarkers for the classification of cystic lesions of the pancreas.
PMCID: PMC3142103  PMID: 21757972
Pancreatic cyst; Intraductal papillary mucinous neoplasm; Mucinous cystic neoplasm; microRNA; Biomarker
18.  Aberrant MicroRNA-155 Expression Is an Early Event in the Multistep Progression of Pancreatic Adenocarcinoma 
Pancreatology  2010;10(1):66-73.
Pancreatic intraepithelial neoplasia (PanIN) is the most common noninvasive precursor to invasive pancreatic adenocarcinoma. Misexpression of microRNAs (miRNAs) is commonly encountered in invasive neoplasia; however, miRNA abnormalities in PanIN lesions have not been documented.
Three candidate miRNAs (miR-21, miR-155, and miR-221) previously reported as overexpressed in pancreatic cancers were assessed in 31 microdissected PanINs (14 PanIN-1, 9 PanIN-2, 8 PanIN-3) using quantitative reverse transcription PCR (qRT-PCR). Subsequently, miR-155 was evaluated by locked nucleic acid in situ hybridization (LNA-ISH) in PanIN tissue microarrays.
Relative to microdissected non-neoplastic ductal epithelium, significant overexpression of miR-155 was observed in both PanIN-2 (2.6-fold, p = 0.02) and in PanIN-3 (7.4-fold, p = 0.014), while borderline significant overexpression of miR-21 (2.5-fold, p = 0.049) was observed in PanIN-3 only. In contrast, no significant differences in miR-221 levels were observed between ductal epithelium and PanIN lesions by qRT-PCR. LNA-ISH confirmed the aberrant expression of miR-155 in PanIN-2 (9 of 20, 45%) and in PanIN-3 (8 of 13, 62%), respectively, when compared with normal ductal epithelium (0 of 10) (p < 0.01).
Abnormalities of miRNA expression are observed in the multistep progression of pancreatic cancer, with miR-155 aberrations demonstrable at the stage of PanIN-2, and miR-21 abnormalities at the stage of PanIN-3 lesions.
PMCID: PMC2865485  PMID: 20332664
MicroRNA; miR-21; miR-155; Pancreatic intraepithelial neoplasia; PanIN
19.  Concurrent Chemotherapy and Pulsed High-Intensity Focused Ultrasound Therapy for the Treatment of Unresectable Pancreatic Cancer: Initial Experiences 
Korean Journal of Radiology  2011;12(2):176-186.
This study was performed to evaluate the potential clinical value of concurrent chemotherapy and pulsed high intensity focused ultrasound (HIFU) therapy (CCHT), as well as the safety of pulsed HIFU, for the treatment of unresectable pancreatic cancer.
Materials and Methods
Twelve patients were treated with HIFU from October 2008 to May 2010, and three of them underwent CCHT as the main treatment (the CCHT group). The overall survival (OS), the time to tumor progression (TTP), the complications and the current performance status in the CCHT and non-CCHT groups were analyzed. Nine patients in the non-CCHT group were evaluated to determine why CCHT could not be performed more than twice.
The OS of the three patients in the CCHT group was 26.0, 21.6 and 10.8 months, respectively, from the time of diagnosis. Two of them were alive at the time of preparing this manuscript with an excellent performance status, and one of them underwent a surgical resection one year after the initiation of CCHT. The TTP of the three patients in the CCHT group was 13.4, 11.5 and 9.9 months, respectively. The median OS and TTP of the non-CCHT group were 10.3 months and 4.4 months, respectively. The main reasons why the nine patients of the non-CCHT group failed to undergo CCHT more than twice were as follows: pancreatitis (n = 1), intolerance of the pain during treatment (n = 4), palliative use of HIFU for pain relief (n = 1) and a poor physical condition due to disease progression (n = 3). No major complications were encountered except one case of pancreatitis.
This study shows that CCHT is a potentially effective and safe modality for the treatment of unresectable pancreatic cancer.
PMCID: PMC3052608  PMID: 21430934
Pancreatic cancer; High-intensity focused ultrasound ablation; Gemcitabine; Chemotherapy
20.  Prevalence of Gastric and Duodenal Polyps and Risk Factors for Duodenal Neoplasm in Korean Patients with Familial Adenomatous Polyposis 
Gut and Liver  2011;5(1):46-51.
The prevalence of gastric polyps, duodenal adenoma and duodenal cancer has been reported as being high among familial adenomatous polyposis (FAP) patients, but there have been no reports of this association in Korea. This study evaluated the prevalence of gastric and duodenal polyps and risk factors for duodenal neoplasm in FAP patients in Korea.
We reviewed both initial and follow-up endoscopic results from FAP patients. We also investigated the treatment modality of duodenal adenomas and analyzed the risk factors of duodenal neoplasms by logistic regression analysis.
A total of 148 patients with FAP underwent esophagogastroduodenoscopy (EGD), and the fi ndings were as follows: gastric polyp 39.9% (fundic gland polyp 25.7% and gastric adenoma 14.2%), duodenal adenoma 15.5%, gastric cancer 2.7%, and duodenal cancer 0.7%. There were two cases of gastric cancer that developed from benign gastric polyps. There were progressions of duodenal adenomatosis during follow-up, and some degree of relapse occurred after endoscopic resection. Patients with gastric polyps showed a correlation with the occurrence of duodenal neoplasm (odds ratio, 2.814; p=0.024).
In Korean FAP patients, gastric cancer was detected more frequently, but fundic gland polyps, duodenal adenoma and duodenal cancer were detected less frequently than in Western patients. FAP patients with gastric polyps should undergo regular EGD, particularly for the early detection of duodenal neoplasia.
PMCID: PMC3065092  PMID: 21461071
Familial adenomatous polyposis; Duodenal cancer; Polyps; Adenomas; Gastric cancer
21.  Clinical Features of Metastatic Tumors of the Pancreas in Korea: A Single-Center Study 
Gut and Liver  2011;5(1):61-64.
The purpose of this study was to examine the clinical features of metastatic tumors of the pancreas (MTPs) in Korea.
A total of 53 cases (31 males) of pathologically proven MTPs were collected. Clinicopathological characteristics and patient outcomes were evaluated.
The median age at the diagnosis of the MTP was 60 years. The median interval between the diagnoses of primary malignancy and MTP was 2.2 years. Primary malignancies were renal cell carcinoma (RCC) (n=14), gastric cancer (n=11), colorectal cancer (n=5), lymphoma (n=4), non-small cell lung cancer (n=3), gastrointestinal stromal tumor (n=2), melanoma (n=2), small cell lung cancer (n=2), gallbladder cancer (n=2), hepatocellular carcinoma (n=1), thymic carcinoid (n=1), liposarcoma (n=1), cholangiocarcinoma (n=1), osteosarcoma (n=1), breast cancer (n=1), duodenal cancer (n=1), and ovarian cancer (n=1). The median survival after the diagnosis of MTP was 23.1 months. Multivariate analysis showed that prolonged survival was associated with RCC as the primary malignancy, the patient being asymptomatic upon the diagnosis of MTP, the absence of extrapancreatic involvement, and surgery included in the treatment.
MTPs can occur after a prolonged period from the primary diagnosis. RCC as the primary malignancy, the patient being asymptomatic upon the diagnosis of MTP, the absence of extrapancreatic involvement, and surgery included in the treatment are associated with better prognosis.
PMCID: PMC3065095  PMID: 21461074
Pancreas; Neoplasms; Neoplasm metastasis; Renal cell carcinoma; Stomach neoplasms
22.  Secondary Appendiceal Tumors: A Review of 139 Cases 
Gut and Liver  2010;4(3):351-356.
This study evaluated the clinicopathologic characteristics of patients with secondary appendiceal tumors (SATs).
We performed a single-center, retrospective study of patients with pathologically confirmed SATs.
Among 180 cases of appendiceal malignancies diagnosed between 2000 and 2007, 139 cases (77.2%, 46 male) were SATs. The median age at SAT diagnosis was 55 years. The most common primary origin was the ovary. The mode of appendiceal involvement was metastasis in 122 and invasion in 17 patients. Extra-appendiceal involvement was present in 134 patients. The only manifestation that could be attributed to the SAT itself was appendicitis (n=8). Serosal involvement was predominant. The median survival after diagnosis of SAT was 22.6 months. In the Cox regression analysis, chemotherapy included in the treatment was the only factor associated with prolonged survival (hazards ratio, 0.12; 95% confidence interval, 0.06-0.23; p<0.001). Complete resection of the SAT had no influence on survival.
SATs accounted for 77.2% of all pathologically diagnosed appendiceal malignancies. The most common origin was the ovary. SATs were usually associated with widespread disease, and the median survival after SAT diagnosis was 22.6 months. Complete resection of the SAT had no influence on survival.
PMCID: PMC2956347  PMID: 20981212
Neoplasms; Appendix; Secondary
23.  Widespread Activation of the DNA Damage Response in Human Pancreatic Intraepithelial Neoplasia 
Pancreatic intraepithelial neoplasia (PanIN) lesions are the most common non-invasive precursors of pancreatic adenocarcinoma. We postulated that accumulating DNA damage within the PanIN epithelium activates checkpoint mechanisms. Tissue microarrays were constructed from 81 surgically resected primary pancreatic adenocarcinomas, and an independent set of 58 PanIN lesions (31 PanIN-1, 14 PanIN-2, and 13 PanIN-3). Immunohistochemical labeling was performed using anti- γH2AXSer139, anti-phosphoATMSer1981, anti-phosphoChk2Thr68, and anti-p53. A “histologic score” combining area and intensity of labeling in the nuclear compartment was determined for each lesion. A progressive increase in γH2AXSer139 labeling, consistent with escalating DNA damage, was observed in the non-invasive precursor lesions (scores of 4.34, 6.21, and 7.50, respectively for PanIN-1, -2, and -3), compared to pancreatic ductal epithelium (score 2.36) (ANOVA, P<0.0001). In conjunction, activation of the ATM-Chk2 checkpoint pathway was observed in all histological grades of PanIN lesions. Specifically, pATMSer1981 histologic scores for PanIN-1, PanIN-2, and PanIN-3 were 4.83, 5.14, and 7.17, respectively, versus 2.33 for ductal epithelium (ANOVA, P<0.0001); the corresponding scores for pChk2Thr68 were 5.43, 7.64, and 5.44 in PanINs-1, -2, and -3, respectively, versus 2.75 in ductal epithelium (ANOVA, P<0.0001). In contrast, absent to minimal nuclear p53 was observed in ductal epithelium, and in PanINs-1 and 2 (histologic score of 0-1.86), with a significant upregulation (corresponding to mutational inactivation) seen only at the stage of PanIN-3 and invasive neoplasia (histologic score of 4.00 and 4.22). Nuclear p53 accumulation in cancers was associated with attenuation of the ATM-Chk2 checkpoint and a restitution of “baseline” levels. To conclude, activation of the ATM-Chk2 checkpoint pathway is commonly observed in PanINs, likely in response to the accumulating DNA damage from events such as oncogene mutations and telomere dysfunction. Loss of p53 function appears to be a critical determinant for bypassing this checkpoint and the subsequent progression to invasive adenocarcinoma.
PMCID: PMC2784029  PMID: 19668150
Pancreatic cancer; pancreatic intraepithelial neoplasia; DNA damage; ATM; Chk2
24.  Primary Pancreatic Lymphoma in Korea-A Single Center Experience 
Journal of Korean Medical Science  2010;25(4):536-540.
The aim of this study was to report a single center experience of primary pancreatic lymphoma (PPL) in Korea. We analyzed the clinicopathological data from four PPL patients (three male, median age 36 yr) diagnosed from 1997 to 2007 at Seoul National University Hospital. The diagnoses were: diffuse large B cell lymphoma (n=2), Ki-1 (+) anaplastic large cell lymphoma (n=1), and Burkitt lymphoma (n=1). Presenting symptoms and signs were: abdominal pain (n=4), pancreatitis (n=2), weight loss (n=2) and abdominal mass (n=1). No patient underwent surgery. The Ann Arbor stages of the patients were: IEA (n=1), IIEA (n=1), and IVEB (n=2). Two patients underwent treatment. The stage IEA patient underwent chemotherapy and radiation therapy that resulted in a complete remission. The stage IVEB patient who underwent chemotherapy relapsed. This patient underwent subsequent peripheral blood stem cell transplantation and is alive at 30 months. Two patients (stages IVEB and IIEA) without treatment died at 0.8 and 7.0 months, respectively. For PPL patients, chemotherapy-based treatment, and addition of radiation therapy, if possible, may offer good prognosis.
PMCID: PMC2844603  PMID: 20357994
Pancreas; Lymphoma
25.  MicroRNA miR-155 is a biomarker of early pancreatic neoplasia 
Cancer biology & therapy  2009;8(4):340-346.
Intraductal papillary mucinous neoplasms (IPMNs) are non-invasive precursor lesions of pancreatic cancer. Misexpression of microRNAs (miRNAs) is commonly observed in pancreatic adenocarcinoma. In contrast, miRNA abnormalities in pancreatic cancer precursor lesions have not been documented.
Experimental design
Relative expression levels of a panel of twelve miRNAs upregulated in pancreatic cancers were assessed in 15 non-invasive IPMNs, using quantitative reverse transcription PCR (qRT-PCR). Two significantly overexpressed miRNAs—miR-155 and miR-21—were evaluated by locked nucleic acid in situ hybridization (LNA-ISH) in a panel of 64 archival IPMNs. The expression of miR-155 and miR-21 was also evaluated in pancreatic juice samples obtained from ten patients with surgically resected IPMNs and five patients with non-neoplastic pancreato-biliary disorders (“disease controls”).
Significant overexpression by qRT-PCR of ten of the twelve miRNAs was observed in the 15 IPMNs versus matched controls (p < 0.05), with miR-155 (mean 11.6-fold) and miR-21 (mean 12.1-fold) demonstrating highest relative fold-changes in the precursor lesions. LNA-ISH confirmed the expression of miR-155 in 53 of 64 (83%) IPMNs compared to 4 of 54 (7%) normal ducts, and of miR-21 in 52 of 64 (81%) IPMNs compared to 1 of 54 (2%) normal ducts, respectively (p < 0.0001). Upregulation of miR-155 transcripts by qRT-PCR was observed in 6 of 10 (60%) IPMN-associated pancreatic juice samples compared to 0 of 5 (0%) disease controls.
Aberrant miRNA expression is an early event in the multistage progression of pancreatic cancer, and miR-155 warrants further evaluation as a biomarker for IPMNs in clinical samples.
PMCID: PMC2692997  PMID: 19106647
pancreatic cancer; intraductal papillary mucinous neoplasm; microRNA; miR-155

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