Clinical Significance of Sphingosine 1-phosphate Receptor 2 and Takeda G Protein-coupled Receptor 5 in Extrahepatic Cholangiocarcinoma Patients.

BACKGROUND AND AIMS: In biliary epithelial cells, two bile acid receptors, sphingosine 1-phosphate receptor 2 (S1PR2) and Takeda G protein-coupled receptor 5 (TGR5) have been reported to trigger cell proliferation, as well as neoplastic cell invasiveness. In this study, we aimed to investigate the clinical significance of S1PR2/ TGR5 expression in extrahepatic cholangiocarcinoma (CCA) patients. METHODS: Patients who underwent surgical resection of extrahepatic CCA at Korea University Guro Hospital between 2002 and 2018 were included. Data on immunohistochemical staining and H-score of S1PR2 and TGR5 were evaluated using digital image analysis. RESULTS: A total of 115 cases of invasive CCA were analyzed. The H-score of S1PR2 showed a decrease in invasive CCA (p=0.052) but that of TGR5 showed a significant increase (p=0.02). Overall survival and disease-free survival were significantly lower in the low S1PR2 expression group (p<0.05) than in the control group; however, TGR5 expression was not significant (p=0.096). In multivariate analysis, low S1PR2 was only significant for poor prognosis. CONCLUSION: Low S1PR2 level was the only independent poor prognostic factor in patients with resected extrahepatic CCA.

Significance of dysplasia in bile duct resection margin in patients with extrahepatic cholangiocarcinoma: A retrospective analysis.

BACKGROUND: Radical resection is the only indicator associated with survival in extrahepatic cholangiocarcinoma (EHCC). However, limited data are available regarding the implications of dysplasia at the resection margin following surgery. AIM: To evaluate the prognostic significance of dysplasia-positive margins in patients diagnosed with EHCC. METHODS: We reviewed the records of patients who had undergone surgery for EHCC with curative intent between January 2013 and July 2017. We retrospectively analyzed the clinicopathological data of 116 patients followed for longer than 3 years. The status of resection margin was used to classify patients into negative low-grade dysplasia (LGD) and high-grade dysplasia (HGD)/carcinoma in situ (CIS) categories. RESULTS: Based on postoperative status, 72 patients underwent resection with negative margins, 19 had LGD-positive margins, and 25 showed HGD/CIS-positive margins. The mean survival rates of the patients with negative margins, LGD margins, and HGD/CIS margins were 49.1 ± 4.5, 47.3 ± 6.0, and 20.8 ± 4.4 mo, respectively (P < 0.001). No difference in survival was found between groups with LGD margins and negative margins (P = 0.56). In the multivariate analysis, age > 70 years and HGD/CIS-positive margins were significant independent factors for survival (hazard ratio = 1.90 and 2.47, respectively). CONCLUSION: HGD/CIS margin in resected EHCC is associated with a poor survival. However, the LGD-positive resection margin is not a significant indicator of survival in patients with EHCC.

Clinical outcomes of endoscopic papillectomy of ampullary adenoma: A multi-center study.

BACKGROUND: Ampullary adenoma is a rare premalignant lesion, but its incidence is increasing. Endoscopic papillectomy has become the first treatment of choice for ampullary adenomas due to its safety and effectiveness, thereby replacing surgical resection. However, recurrence rates and adverse events after endoscopic papillectomy were reported in up to 30% of cases. AIM: To review the long-term outcomes of endoscopic papillectomy and investigate the factors that affect these outcomes. METHODS: We retrospectively analyzed the data of patients who underwent endoscopic papillectomy for ampullary adenoma at five tertiary hospitals between 2013 and 2020. We evaluated clinical outcomes and their risk factors. The definitions of outcomes were as follow: (1) curative resection: complete endoscopic resection without recurrence; (2) endoscopic success: treatment of ampullary adenoma with endoscopy without surgical intervention; (3) early recurrence: reconfirmed adenoma at the first endoscopic surveillance; and (4) late recurrence: reconfirmed adenoma after the first endoscopic surveillance. RESULTS: A total of 106 patients were included for analysis. Of the included patients, 81 (76.4%) underwent curative resection, 99 (93.4%) had endoscopic success, showing that most patients with non-curative resection were successfully managed with endoscopy. Sixteen patients (15.1%) had piecemeal resection, 22 patients (20.8%) had shown positive/uncertain resection margin, 11 patients (16.1%) had an early recurrence, 13 patients (10.4%) had a late recurrence, and 6 patients (5.7%) had a re-recurrence. In multivariate analysis, a positive/uncertain margin [Odds ratio (OR) = 4.023, P = 0.048] and piecemeal resection (OR = 6.610, P = 0.005) were significant risk factors for early and late recurrence, respectively. Piecemeal resection was also a significant risk factor for non-curative resection (OR = 5.424, P = 0.007). Twenty-six patients experienced adverse events (24.5%). CONCLUSION: Endoscopic papillectomy is a safe and effective treatment for ampullary adenomas. Careful selection and follow-up of patients is mandatory, particularly in cases with positive/uncertain margin and piecemeal resection.

Quantitative proteomic analysis of bile in extrahepatic cholangiocarcinoma patients.

Background and Aims: Extrahepatic cholangiocarcinoma (CCA) without liver-fluke is increasing. Multifactorial carcinogenesis makes it hard to find biomarkers related to CCA. Although there are a few studies of bile proteomics, these showed different protein profiles because of having heterogeneous groups of patients and different sampling methods. Our aim was to identify the specific bile proteins of extrahepatic CCA patients. Methods: We collected bile from 23 patients undergoing endoscopic nasobiliary drainage in Korea University Guro Hospital from May 2018 to January 2019. The CCA group included 18 patients diagnosed with extrahepatic CCA, and the control group included 5 patients with benign biliary conditions. We analyzed bile proteome using liquid chromatography mass spectrometry. We compared the relative abundance of various proteins in the CCA and control groups. Results: In all, we identified a total of 245 proteins in the bile of CCA and control patients. Increased top 14 proteins in CCA patients were immunoglobulin kappa light chain, apolipoprotein B, inter-alpha-trypsin inhibitor heavy chain H4, apolipoprotein E, Mucin 5B, inter-alpha-trypsin inhibitor heavy chain H1, apolipoprotein A-IV, intercellular adhesion molecule 1, complement C7, complement C5, apolipoprotein C-III, albumin, antithrombin-III, and apolipoprotein A-II. However, the significantly increased proteins in bile of CCA patients comparing with control patients were immunoglobulin kappa light chain, apolipoprotein E, albumin, apolipoprotein A-I, antithrombin-III, α1-antitrypsin, serotransferrin, immunoglobulin heavy constant mu, immunoglobulin J chain, complement C4-A, and complement C3 (p<0.05). Conclusions: In this study, we identified several proteins that were significantly increased in the bile of extrahepatic CCA. Further study is needed to validate them as potential tumor-associated proteins that may be potential biomarkers for CCA.

Survival improvement and prognostic factors in recent management of extrahepatic cholangiocarcinoma: A single-center study.

BACKGROUND: Cholangiocarcinoma was considered as a dismal disease with very poor prognosis until recently. Cholangiocarcinoma is increasingly found due to increased life expectancy. Although surgical and medical management were advanced recently, data on the prognosis, especially extrahepatic cholangiocarcinoma (ECC), were limited. This study aimed to identify clinicopathologic features and prognosis of patients with ECC. METHODS: Patients followed up and diagnosed with ECC between January 2014 and December 2016 at a tertiary hospital were included, whereas those with intrahepatic cholangiocarcinoma, gallbladder cancer, and ampullary cancer were excluded. RESULTS: A total of 83 patients were followed after the treatment (49 men and 34 women; median age 73.3 years). Cancer location was classified as distal common bile duct (25 patients), proximal common bile duct (24 patients), common hepatic duct (20 patients), and hilar (14 patients). About 14.5% of patients had history of another malignant neoplasm, and 24.1% patients had chronic illness. Surgical resection was performed in 54 patients (65%) and dysplasia was combined in 63% (34/54). Adjuvant chemotherapy was performed in 54% (29/54), but only 7 underwent palliative chemotherapy in 29 nonsurgical patients. The median overall survival in all patients was 30.9 months. In analyzing the treatment modality, median survival of adjuvant chemotherapy, surgery only, palliative chemotherapy, and supportive care groups were 42.9, 30.9, 12.0, and 8.9 months, respectively (P < 0.05). In the Cox regression analysis of survival, age, surgical resection, chemotherapy, and comorbidity were significant prognostic factors, and the comorbidity was the only significant prognostic factor in the multivariable analysis (hazard ratio [HR] = 2.80; 95% CI: 1.32-5.95; P = 0.007). In a subgroup analysis of surgical patients, the presence of dysplasia was a favorable prognostic factor in the multivariable analysis (HR = 0.29; 95% CI: 0.09-0.91; P = 0.033). CONCLUSIONS: The overall survival of patients with ECC was quite high and increased with chemotherapy. Absence of comorbidity, and presence of dysplasia were good prognostic factors.

Intestinal Epithelial Deletion of Sphk1 Prevents Colitis-Associated Cancer Development by Inhibition of Epithelial STAT3 Activation.

BACKGROUND AND AIMS: Colitis-associated cancer (CAC) is one of the most serious complications in patients with inflammatory bowel disease. Sphingosine kinase 1 (Sphk1) is a key enzyme in the sphingolipid pathway and has oncogene potential for inducing both initiation and progression of tumors. The aim of this work is to characterize the role of epithelial Sphk1 in mouse colitis and CAC models. METHODS: We investigated the roles of Sphk1 in CAC by conditional deletion of Sphk1 in intestinal epithelial cells (IECs). RESULTS: CAC was induced in both Sphk1ΔIEC/ApcMin/+ and Sphk1IEC/ApcMin/+ mice by administration of 2% dextran sodium sulfate (DSS) for 7 days. Genetic deletion of Sphk1 significantly reduced the number and size of tumors in ApcMin/+ mice. Histologic grade was more severe in Sphk1ΔIEC/ApcMin/+ mice compared with Sphk1IEC/ApcMin/+ mice (invasive carcinoma, 71% versus 13%, p < 0.05). Deletion of Sphk1 decreased mucosal proliferation and inhibited STAT3 activation and genetic expression of cyclin D1 and cMyc in tumor cells. Conditional deletion of Sphk1 using CRISPR-Cas9 in HCT 116 cells inhibited interleukin (IL)-6-mediated STAT3 activation. CONCLUSIONS: Epithelial conditional deletion of Sphk1 inhibits CAC in ApcMin/+-DSS models in mice by inhibiting STAT3 activation and its target signaling pathways.

Usefulness of CA 19-9 for pancreatic cancer screening in patients with new-onset diabetes.

BACKGROUND: Generally, carbohydrate antigen 19-9 (CA 19-9) is not useful for screening pancreatic cancer in the asymptomatic general population. This study aimed to evaluate the utility of CA 19-9 level as a screening indicator of pancreatic cancer in asymptomatic patients with new-onset diabetes. METHODS: We retrospectively reviewed the medical records of patients who visited our health promotion center for health check-ups without cancer related symptoms from January 2005 to January 2014, and were newly diagnosed with diabetes mellitus (DM) within 2 years before their visit. RESULTS: Of the 5111 asymptomatic patients with new-onset DM (<2 years) selected for analyses, 87 (1.7%) eventually developed pancreatic cancer after the health check-up. In the subgroup of 322 patients with high total bilirubin levels (>1.7 mg/dL) at the screening time, 42 (73.7%) of 57 patients with high CA 19-9 levels (>37 IU/mL) had been diagnosed as pancreatic cancer during follow-up period and 12 (4.5%) of 265 patients with normal CA 19-9 levels had finally developed pancreatic cancer (OR = 16.3). In the subgroup of 4789 patients with normal bilirubin levels, pancreatic cancer had been detected in 20 (3.8%) of 522 patients with high CA 19-9 level, while only 13 (0.3%) in 4267 patients with normal CA 19-9 levels (OR = 12.6), respectively. CONCLUSION: CA 19-9 levels after a diagnosis of new-onset DM could be a useful biomarker of pancreatic cancer, especially in patients with high serum bilirubin.

Clinicopathologic Study of Biliary Intraepithelial Neoplasia in Cholangiocarcinoma.

BACKGROUNDS AND AIMS: Biliary intraepithelial neoplasia (BilIN) is a precursor of cholangiocarcinoma (CC) and it has been associated with several chronic inflammatory conditions. This study aimed to elucidate the prevalence of BilIN in CC and its clinicopathological significance. METHODS: Medical records of 193 patients with histologically confirmed CC were analyzed. We reviewed the pathology findings of 48 patients who underwent curative surgery for CC. RESULTS: Of the 48 patients analyzed, 34 and 14 patients had extrahepatic and intrahepatic CC respectively. BilIN was detected in 28 patients (58%) and showed a significantly higher prevalence in extrahepatic CC (75%) than in intrahepatic CC (21%; p < 0.001). In the subgroup of 34 patients with extrahepatic CC, 25 and 9 patients were BilIN positive and negative respectively. Poor differentiation and T3 stage were significantly more common in the BilIN-negative group than in the BilIN-positive group (p < 0.05). The expression of MUC5AC, p53, and loss of Smad4 showed no difference between BilIN-positive CC and in BilIN-negative CC, but the Ki-67 expression was significantly higher (p < 0.05). CONCLUSION: BilIN-positive CC showed less invasiveness than negative cases. The Ki-67 expression was significantly higher in BilIN-positive CC.

Can More Aggressive Treatment Improve Prognosis in Patients with Hepatocellular Carcinoma? A Direct Comparison of the Hong Kong Liver Cancer and Barcelona Clinic Liver Cancer Algorithms.

BACKGROUND/AIMS: In addition to the globally endorsed Barcelona Clinic Liver Cancer (BCLC) staging system, other algorithms or staging systems have been developed, including the Hong Kong Liver Cancer (HKLC) staging system. This study aimed to validate the HKLC staging system relative to the BCLC staging system for predicting survival for hepatocellular carcinoma (HCC) patients in Korea. METHODS: From 2004 to 2013, 2,571 patients newly diagnosed with HCC were consecutively enrolled at three Korea University medical centers. RESULTS: Both staging systems differentiated survival well (p＜0.001). However, 1-year and 3-year survival were predicted better using the HKLC system than the BCLC system (area under the receiver operating characteristic curve: 0.869 vs 0.856 for 1 year, p=0.002; 0.841 vs 0.827 for 3 years, p=0.010). In hypothetical survival curves, the HKLC system exhibited better median overall survival than the BCLC system (33.1 months vs 19.2 months). In evaluations of prognosis according to either BCLC or HKLC treatment guidelines, risk of death was reduced in the group following only HKLC guidelines compared with the group following only BCLC guidelines (hazard ratio, 0.601; 95% confidence interval, 0.443 to 0.816; p=0.001). CONCLUSIONS: Although both staging systems predicted and discriminated HCC prognoses well, the HKLC system showed more encouraging survival benefits than the BCLC system.

What is the reasonable option for elderly patients with incidental pancreatic cystic neoplasms? Follow-up observation versus surgical resection.

AIMS: Pancreatic cystic neoplasms (PCN) with malignant potential are thought to be less aggressive than ordinary ductal adenocarcinoma, even in the setting of malignant transformation. Therefore, deciding whether or not to carry out surgery is very difficult, especially in elderly and asymptomatic patients, because of the high risk of perioperative morbidities. The aim of the present study was to examine clinical outcomes of PCN patients aged 65 years or older. METHODS: This retrospective analysis included patients with incidentally detected PCN with follow-up durations >1 year. Patients diagnosed with obvious simple cysts, pseudocysts or pancreatic cancer and patients with a history of pancreatic disease were excluded from the study. RESULTS: The present study included 201 patients (older group 104 patients ≥65 years; younger group 97 patients <65 years). Surgical resections were carried out for 27 patients in the older group and 41 patients in the younger group. There were 133 patients who were followed up without surgery (mean follow-up duration 41 months). Postoperative morbidity occurred in 22.2% of the patients in the older group and 21.9% of the patients in the younger group. Malignancy occurred in one patient in the older group and in two patients in the younger group. The PCN diameter increased in 20 patients during follow up: 16.9% of the older group and 12.5% of the younger group. CONCLUSIONS: The malignancy rate was very low in incidental PCN patients irrespective of age. Follow-up observation without surgery appears to be a safe option in older patients with morbidity. Geriatr Gerontol Int 2017; 17: 256-261.

Radiation recall gastritis secondary to combination of gemcitabine and erlotinib in pancreatic cancer and response to PPI - a case report.

BACKGROUND: Radiation recall gastritis is rare but can be induced after concurrent chemoradiation for pancreatic cancer. We report a patient with pancreatic cancer who developed radiation-recall gastritis related to a combination of gemcitabine and erlotinib. CASE PRESENTATION: A 54-year-old female with unresectable pancreatic cancer received gemcitabine in combination with radiation therapy followed by chemotherapy with gemcitabine and erlotinib. After completing 2 cycles of chemotherapy, the patient had epigastric pain, nausea, and vomiting. Abdominal computed tomography (CT) scan revealed diffuse wall thickening of the stomach, and esophagogastroduodenoscopy (EGD) showed multiple gastric ulcers. The patient was treated with proton pump inhibitors (PPI) and was continued on maintenance chemotherapy. Two months later, the patient presented with the similar symptoms and persistent gastric ulcers were observed during subsequent EGD. Nevertheless, the patient's symptom had resolved with PPI therapy. Thus, the patient underwent maintenance chemotherapy with gemcitabine and erlotinib for additional 4 cycles. Eventually, follow-up abdominal CT Scan and EGD at 6 months demonstrated resolution of the gastric ulcers. CONCLUSIONS: Physicians should be aware of the possibility of radiation recall gastritis associated with a combination of gemcitabine and erlotinib. Administration of PPIs may mitigate the adverse effects of gemcitabine and erlotinib in the presence of radiation recall gastritis; however further studies are warranted.

Application of the Prague C and M criteria for endoscopic description of columnar-lined esophagus in South Korea.

AIM: To ascertain whether the Prague circumferential (C) length and maximal (M) length criteria for grading the extent of Barrett's esophagus can be applied prior to its widespread application in South Korea. METHODS: Two hundred and thirteen consecutive cases with endoscopic columnar-lined esophagus (CLE) were included and classified according to the Prague C and M criteria. RESULTS: Of 213 cases with CLE, the distribution of maximum CLE lengths was: 0.5-0.9 cm in 99 cases (46.5%); 1.0-1.4 cm in 63 cases (29.6%); 1.5-1.9 cm in 15 cases (7.0%); 2.0-2.4 cm in 14 cases (6.6%); 2.5-2.9 cm in 1 case (0.5%); and 7.0 cm in 1 case (0.5%). Twenty cases (9.4%) had columnar islands alone. Two hundred and eight cases (97.7%) lacked the circumferential CLE component (C0Mx). Columnar islands were found in 70 cases (32.9%), of which 20 cases (9.4%) had columnar islands alone. CONCLUSION: In regions where most CLE patients display short or ultrashort tongue-like appearance, more detailed descriptions of CLE's in < 1.0 cm lengths and columnar islands, as well as avoidance of repeating the prefix "C0" need to be considered in parallel with the widespread application of the Prague system in South Korea.

Value of Early Check-Up of Carbohydrate Antigen 19-9 Levels for Pancreatic Cancer Screening in Asymptomatic New-Onset Diabetic Patients.

OBJECTIVES: We evaluated the value of carbohydrate antigen 19-9 (CA 19-9) as a pancreatic cancer (PC) screening tool in an asymptomatic new-onset diabetic patients. METHODS: Medical records of asymptomatic patients newly diagnosed with diabetes mellitus (DM) were reviewed retrospectively at our hospital from January 2004 to January 2013. RESULTS: In total, 2363 asymptomatic diabetic patients with CA 19-9 measurements were enrolled. Of them, 68 (2.9%) were diagnosed with PC. In the 1719 patients who had CA 19-9 measured within 1 year after the DM diagnosis, a total of 51 (3.0 %) patients developed PC and the odds ratio (OR) of PC according to higher CA 19-9 than normal upper limit, 37 IU/mL was 5.57 (P < 0.001). In 248 patients checked CA 19-9 between 1 and 2 years after DM diagnosis, PC was detected in 9 (3.6%) cases and OR of high CA 19-9 was 4.51 (P = 0.019). However, beyond 2 years, the OR for PC showed no statistical significance. The patients with high CA 19-9 levels tended to have more advanced-stage disease. CONCLUSIONS: Early check-up of CA 19-9 could be a useful marker for screening for PC in asymptomatic patients with new-onset DM in the first 2 years.

Small Bowel Metastatic Cancer Observed With Double Balloon Enteroscopy in a Patient With a Past History of Multiple Cancers.

Small bowel tumors are very rare and generally malignant. As a result of the anatomical location and nonspecific manifestations of small bowel tumors, they are very difficult to diagnose. Balloon-assisted enteroscopy is a relatively noninvasive method compared to surgical resection, and allows for real-time observation, tissue confirmation with biopsy, and interventional procedures. Here, we report the case of a 69-year-old woman with a small bowel metastatic carcinoma observed with double balloon enteroscopy (DBE). She had a history of multiple cancers including ovarian cancer, bladder cancer, and breast cancer. The antegrade DBE procedure was performed before surgery for biopsy tissue confirmation. The patient underwent small bowel resection, and the final diagnosis was the same as that determined by preoperative biopsy. The final diagnosis was metastatic small bowel cancer originating from a cancer of the breast. This is the first detailed report of the preoperative diagnosis of small intestinal metastatic breast cancer by DBE.

Digital design of a surgical guide for placement of definitive implants before orthodontic treatment.

Interdisciplinary treatment planning is an essential part of orthodontic therapy for patients with partial edentulism, especially when dental implants are to serve initially as anchorage and ultimately as prosthetic abutments for the definitive fixed restoration. A technique is presented for designing and fabricating a computed tomography-based surgical guide to place definitive implants before orthodontic therapy. First, the diagnostic cast and the orthodontic tooth arrangement and diagnostic waxing cast are scanned with a 3-dimensional optical scanner. Three-dimensional renderings of these scans are then merged and superimposed onto the cone beam computed tomography (CBCT) image with implant planning software to develop definitive implant positions. A custom surgical guide is fabricated from these data.

Disease recurrence patterns and analysis of clinicopathological prognostic factors for recurrence after resection for distal bile duct cancer.

Surgical resection is the treatment of choice for bile duct cancers. The aim of this study was to investigate disease recurrence patterns and prognostic factors for recurrence of distal bile duct cancers after surgical resection. A retrospective study was performed on 122 patients with distal bile duct cancers who underwent R0 or R1 surgical resection at Korea University Guro Hospital from 1991 to 2010. Sites of initial disease recurrence were classified as locoregional or distant. Univariate and multivariate analyses were performed to investigate the factors affecting recurrence. Of the 122 patients, 80 patients developed recurrence. The disease-free survival rate was 63.1 per cent at one year and 36.4 per cent at three years. The patterns of recurrence at diagnosis were locoregional in 25 patients, locoregional and distant metastasis in 14 patients, and distant metastasis in 41 patients. Multivariate analyses revealed that recurrence pattern, lymph node metastasis, and differentiation are independent prognostic factors affecting disease-free survival. R status (marginal significance) and tumor differentiation were independent prognostic factors associated with locoregional recurrence. Differentiation and lymph node metastasis were independent prognostic factors associated with distant metastasis. The prognosis after recurrence was poor with a 1-year survival rate after recurrence of 26.1 per cent. Adjuvant chemo- or radiation therapy, delivered in patients mainly with R1 resection or with presence of lymph node metastasis, did not demonstrate the survival benefit. Significant factors for recurrence were tumor differentiation and lymph node metastasis. Therefore, close follow-up and adjuvant therapy will be necessary in patients with lymph node metastasis or poorly differentiated tumor.

Cholangiocarcinoma Risk as Long-term Outcome After Hepatic Resection in the Hepatolithiasis Patients.

BACKGROUND: Hepatolithiasis is a well-known risk factor of cholangiocarcinoma. Despite advances in diagnostic modalities, diagnosing cholangiocarcinoma in patients with hepatolithiasis still challenging and there are not enough reports on the incidence of cholangiocarcinoma in patient with hepatolithiasis after treatment. We aimed to evaluate the incidence and clinical characteristics of cholangiocarcinoma in patients with hepatolithiasis who underwent liver resection or non-resection. METHODS: Among a total of 257 patients who received treatment for hepatolithiasis, 236 patients were eligible for analysis. Exclusion criteria were follow-up period less than 9 months, preoperative diagnosis of cholangiocarcinoma, occurrence of cholangiocarcinoma within 1 year after treatment. Completeness of stone clearance was defined when there was no intrahepatic duct stone during whole follow-up period. A retrospective study was done to analyze the patients' characteristics, the results and complications of the procedure, and the long-term outcomes for these patients. Kaplan-Meier method and cox proportional regression were used for statistical analysis. RESULTS: 95 patients underwent hepatic resection (resection group) and 144 patients did not (non-resection group). Complete stone clearance was 71% (67/95) in resection group and 41% (58/141) in non-resection group (p < 0.001). The incidence of cholangiocarcinoma was 6.8% (16/236) during follow-up period (mean 41 ± 41 months). Cholangiocarcinoma occurred 6.3% (6/95) and 7.1% (10/141) in resection and non-resection group, respectively. There was no significant difference in survival between two groups (p = 0.254). In analysis of according to completeness of stone clearance regardless of treatment modality, cholangiocarcinoma incidence was higher in patients with residual stone (10.4%) than complete stone removal (3.3%) (p = 0.263). On multivariate analysis, none of the factors (age, gender, CA19-9, stone location, bile duct stenosis, liver atrophy, stone recurrence, residual stone, and hepatic resection) showed relationship with the incidence of cholangiocarcinoma. CONCLUSION: Hepatic resection for hepatolithiasis is considered to have a limited value in preventing cholangiocarcinoma and the patients should be carefully followed even after hepatic resection. A combination of different treatment modalities is necessary to decrease the residual stone and improve the outcome of the patients with hepatolithiasis.

Butein effects in colitis and interleukin-6/signal transducer and activator of transcription 3 expression.

AIM: To evaluate the effects of butein on inflammatory cytokines, matrix metalloproteinase-9 (MMP-9), and colitis in interleukin (IL)-10(-/-) mice. METHODS: To synchronize colitis, 8- to 10-wk-old IL-10(-/-) mice were fed pellet-chow containing piroxicam for 2 wk. Subsequently, phosphate-buffered saline or butein (1 mg/kg per day, ip) was injected for 4 wk. Histologic scores, inflammatory cytokines, MMP-9 and phosphorylated signal transducer and activator of transcription 3 (pSTAT3) expressions were analyzed in IL-10(-/-) mice and in Colo 205 cells. RESULTS: Butein reduced the colonic inflammatory score by > 50%. Expression levels of IL-6, IL-1ß, interferon (IFN)-γ and MMP-9 were decreased in the colons of mice exposed to butein, whereas other inflammatory cytokines (IL-17A, IL-21 and IL-22) were unchanged. Immunohistochemical staining for pSTAT3 and MMP-9 was significantly decreased in the butein-treated groups compared with the controls. Butein inhibited IL-6-induced activation of STAT3 in Colo 205 cells. CONCLUSION: Butein ameliorated colitis in IL-10(-/-) mice by regulating IL-6/STAT3 and MMP-9 activation.

The influence of alcoholic liver disease on serum PIVKA-II levels in patients without hepatocellular carcinoma.

BACKGROUND/AIMS: Prothrombin induced by vitamin K defi-ciency or antagonist II (PIVKA-II) is a widely used diagnostic marker for hepatocellular carcinoma (HCC). We evaluated the correlation between alcoholic liver disease (ALD) and serum PIVKA-II levels in chronic liver disease (CLD) patients. METHODS: We retrospectively reviewed the medical records of 2,528 CLD patients without HCC. Among these patients, 76 exhibited serum high PIVKA-II levels of >125 mAU/mL (group 1). We categorized 76 control patients matched by age, sex, and the presence of liver cirrhosis from the remain-ing patients who were negative for serum PIVKA-II (group 2). RESULTS: Group 1 revealed increased antibiotic usage (23.7% vs 2.6%, p<0.001) and incidence of ALD (60.5% vs 14.5%, p<0.001) as well as elevated aspartate aminotransferase (52.5 IU/L vs 30.5 IU/L, p=0.025) and γ glutamyl transpepti-dase (67.5 IU/L vs 36.5 IU/L, p=0.005) levels compared with group 2. Further, group 1 was significantly associated with a worse Child-Pugh class than group 2. In the multivariate anal-ysis, ALD (odds ratio [OR], 7.151; p<0.001) and antibiotic us-age (OR, 5.846; p<0.001) were significantly associated with positive PIVKA-II levels. CONCLUSIONS: Our study suggests that ALD and antibiotics usage may be confounding factors when interpreting high serum PIVKA-II levels in patients without HCC. Therefore, serum PIVKA-II levels in patients with ALD or in patients administered antibiotics should be interpreted with caution. (Gut Liver, 2015;9224-230).

CpG island promoter hypermethylation of Ras association domain family 1A gene contributes to gastric carcinogenesis.

Methylation rates of the Ras association domain family 1A gene (RASSF1A) have been variously reported as between 7.5 and 66.7% in gastric carcinoma tissues. The role of this gene in gastric cancer also remains to be fully elucidated. The present study aimed to investigate whether promoter hypermethylation of RASSF1A occurs in gastric adenocarcinoma tissues and gastric cancer cell lines, and to determine the effects of RASSF1A in gastric carcinoma cell lines. The results showed a methylation­specific band only in SNU­719, MKN28 and AGS human gastric cancer cells (indicating full methylation), none of which exhibited RASSF1A expression. By contrast, SNU­16, MKN­45 and KATO­III human gastric carcinoma cells exhibited methylation as well as unmethylation­specific bands (indicating partial methylation), and all displayed positive or weakly positive expression of RASSF1A. Bisulfite sequencing in AGS and SNU­719 cells revealed that virtually all CpG sites were densely methylated. When SNU­719, MKN­28 and AGS cells were treated with the demethylating agent 5­aza­2'­deoxycytidine, RASSF1A gene expression was restored and the methylation­specific polymerase chain reaction pattern was altered in all three cell lines. Transfection of a plasmid expressing RASSF1A into AGS and SNU­719 cells significantly inhibited cell proliferation. Exogenous RASSF1A also reduced the expression of cyclin D1 and phospho­retinoblastoma protein, and increased that of p27 as demonstrated by western blot analysis. Furthermore, RASSF1A expression was significantly reduced (P=0.048) and the methylation rate was elevated in gastric adenocarcinoma tissues, compared with those in adjacent healthy intestinal metaplasia (34.6 vs. 66.7%, P=0.029). The present study indicated that epigenetic silencing of RASSF1A is frequently caused by promoter hypermethylation in gastric cancer cell lines as well as in gastric adenocarcinoma tissues, which may contribute to gastric carcinogenesis.