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.

Arsenic trioxide attenuates STAT-3 activity and epithelial-mesenchymal transition through induction of SHP-1 in gastric cancer cells.

BACKGROUND: We investigated the effect of arsenic trioxide (ATO) for inhibition of signal transducer and activator of transcription 3 (STAT3) and epithelial-mesenchymal transition (EMT) in gastric cancer cells, and the role of SH2 domain-containing phosphatase-1 (SHP-1) during this process. METHODS: We used AGS cells, which showed minimal SHP-1 expression and constitutive STAT3 expression. After treatment of ATO, cellular migration and invasion were assessed by using wound closure assay, Matrigel invasion assay and 3-D culture invasion assay. To validate the role of SHP-1, pervanadate, a pharmacologic phosphatase inhibitor, and SHP-1 siRNA were used. Xenograft tumors were produced, and ATO or pervanadate were administered via intraperitoneal (IP) route. RESULTS: Treatment of ATO 5 and 10 µM significantly decreased cellular migration and invasion in a dose-dependent manner. Western blot showed that ATO upregulated SHP-1 expression and downregulated STAT3 expression, and immunofluorescence showed upregulation with E-cadherin (epithelial marker) and downregulation of Snail1 (mesenchymal marker) expression by ATO treatment. Anti-migration and invasion effect and modulation of SHP-1/STAT3 axis by ATO were attenuated by pervanadate or SHP-1 siRNA. IP injection of ATO significantly decreased the xenograft tumor volume and upregulated SHP-1 expression, which were attenuated by co-IP injection of pervanadate. CONCLUSION: Our data suggest that ATO inhibits STAT3 activity and EMT process by upregulation of SHP-1 in gastric cancer cells.

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.

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.

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.

Melanocytic Nevus on the Rectal Mucosa Removed Using Endoscopic Submucosal Dissection.

Melanocytic nevus is the benign proliferation of melanocytes. The most common location of melanocytic nevus is the skin of the extremities; however, there are few case reports of melanocytic nevus at the rectal mucosa. No prior case of malignant melanoma from melanocytic nevus at the rectal mucosa has been reported; therefore, it is unclear whether resection should be performed or close observation is sufficient. However, the potential malignant transformation of melanocytic nevus should be considered, including melanocytic nevus on the rectum. Melanocytic nevus of the skin can be removed by surgical excision; however, due to rare incidence on the mucosa of the gastrointestinal tract, the optimal treatment for rectal melanocytic nevus remains controversial. Here, we report the first case of melanocytic nevus on the rectal mucosa that was removed by endoscopic submucosal dissection. This case report provides useful information about the optimal management of rectal melanocytic nevus.

The roles of HOXB7 in promoting migration, invasion, and anti-apoptosis in gastric cancer.

BACKGROUND AND AIM: The aim of this study was to compare HOXB7 expression level between gastric cancer and non-cancerous gastric tissues. Additionally, the functional effects of HOXB7, including its pro-migration or invasion and anti-apoptosis roles, were evaluated in gastric cancer cells. METHODS: Both gene and protein expression levels of HOXB7 were examined in gastric cancer cell lines, and HOXB7 expression was compared between primary or metastatic gastric cancer tissues and chronic gastritis or intestinal metaplasia tissues. Functional studies included a wound healing assay, a Matrigel invasion assay, and an Annexin-V assay were performed, and Akt/PTEN activity was measured by western blotting. RESULTS: Both gene and protein expression levels of HOXB7 could be clearly detected in various gastric cancer cell lines except MKN-28 cell. HOXB7 expression was significantly higher in primary or metastatic gastric cancer tissues than in chronic gastritis or intestinal metaplasia tissues. HOXB7 knockdown led to inhibition of cell invasion and migration, had an apoptotic effect, downregulated phosphor-Akt, and upregulated PTEN in AGS and SNU-638 cells. Reinforced expression of HOXB7 caused the opposite effects in MKN-28 and MKN-45 cells. CONCLUSION: Our study suggests that HOXB7 has an oncogenic role in gastric cancer, which might be related to the modulation of Akt/PTEN activity to induce cell migration/invasion and anti-apoptotic effects.

Astaxanthin Inhibits Proliferation of Human Gastric Cancer Cell Lines by Interrupting Cell Cycle Progression.

BACKGROUND/AIMS: Astaxanthin is a carotenoid pigment that has antioxidant, antitumoral, and anti-inflammatory properties. In this in vitro study, we investigated the mechanism of anticancer effects of astaxanthin in gastric carcinoma cell lines. METHODS: The human gastric adenocarcinoma cell lines AGS, KATO-III, MKN-45, and SNU-1 were treated with various concentrations of astaxanthin. A cell viability test, cell cycle analysis, and immunoblotting were performed. RESULTS: The viability of each cancer cell line was suppressed by astaxanthin in a dose-dependent manner with significantly decreased proliferation in KATO-III and SNU-1 cells. Astaxanthin increased the number of cells in the G0/G1 phase but reduced the proportion of S phase KATO-III and SNU-1 cells. Phosphorylated extracellular signal-regulated kinase (ERK) was decreased in an inverse dose-dependent correlation with astaxanthin concentration, and the expression of p27(kip-1) increased the KATO-III and SNU-1 cell lines in an astaxanthin dose-dependent manner. CONCLUSIONS: Astaxanthin inhibits proliferation by interrupting cell cycle progression in KATO-III and SNU-1 gastric cancer cells. This may be caused by the inhibition of the phosphorylation of ERK and the enhanced expression of p27(kip-1).

Endoscopic versus surgical resection of GI stromal tumors in the upper GI tract.

BACKGROUND AND AIMS: Endoscopic resection has been performed for treatment of GI stromal tumors (GISTs) in the upper GI tract. However, the therapeutic roles of the endoscopic procedure remain debatable. We aimed in this retrospective study to evaluate the feasibility and long-term follow-up results of endoscopic resection of GISTs in the upper GI tract, compared with surgery. METHODS: Between March 2005 and August 2014, 130 cases of GIST in the upper GI tract were resected. We compared baseline characteristics and clinical outcomes including R0 resection rate and recurrence rate between the endoscopy group (n = 90) and surgery group (n = 40). RESULTS: The most common location of GIST was the stomach body in the endoscopy group, whereas it was the duodenum in the surgery group (P = .001). Tumor size was significantly smaller (2.3 vs 5.1 cm; P < .001), and procedure time (51.8 ± 36.2 vs 124.6 ± 74.7 minutes; P < .001) and hospital stay (3.3 ± 2.4 vs 8.3 ± 5.4 days; P < .001) were significantly shorter in the endoscopy group than in the surgery group. The R0 resection rate was 25.6% in the endoscopy group, whereas it was 85.0% in the surgery group (P = .001), and 50.0% of resected tumors belonged to a very low-risk group in the endoscopy group, whereas 35.0% and 30.0% belonged to low-risk and high-risk in the surgery group (P = .001). However, during 45.5 months of follow-up, the recurrence rate was not significantly different between the 2 groups (2.2% vs 5.0%; P = .586). CONCLUSIONS: Endoscopic resection might be an alternative therapeutic modality for GISTs in the upper GI tract in selective cases.

Epigenetic regulation and anti-tumorigenic effects of SH2-containing protein tyrosine phosphatase 1 (SHP1) in human gastric cancer cells.

SH2-containing protein tyrosine phosphatase 1 (SHP1) is an important negative regulator in cytokine-mediated signal transduction and cell cycling. Recent studies have demonstrated that SHP1 promoter methylation is frequently observed in gastric adenocarcinoma tissues. In this in vitro study, we attempted to reveal promoter hypermethylation and to investigate effects of SHP1 in gastric carcinoma cell lines. We observed that both gene and protein expression of SHP1 were negative in 8 of 10 gastric cancer cell lines (SNU-1, SNU-5, SNU-16, SNU-638, SNU-719, MKN-28, MKN-45, AGS). Methylation-specific PCR (MSP) showed a methylation-specific band only in the 10 gastric cancer lines. Bisulfite pyrosequencing in AGS, MKN-28, and SNU-719 cells indicated that methylation frequency was as high as 94.4, 92.6, and 94.5 %, respectively, in the three cell lines. Treatment of SNU-719, MKN-28, and AGS cells with 5-Aza-2'-deoxycytidine (5-Aza-dc) led to re-expression of SHP1 in these cells. Introduction of exogenous SHP1 in SNU-719 and MKN-28 cells by transient transfection substantially downregulated protein expression of constitutive phosphor-Janus kinase 2 (JAK2) (tyrosine 1007/1008) and phosphor-signal transducers and activators of transcription 3 (STAT3) (tyrosine 705), which in turn decreased expression of STAT3 target genes including those encoding cyclin D1, MMP-9, VEGF-1, and survivin. Induction of SHP1 significantly inhibited cell proliferation, migration and invasion in SNU-719 and MKN-28 cells. Taken together, epigenetic silencing of SHP1 is frequently caused by promoter hypermethylation in gastric carcinoma cells. Overexpression of SHP1 downregulates the JAK2/STAT3 pathway to modulate various target genes and inhibit cell proliferation, migration, and invasion in gastric cancer cells.

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.

Antitumorigenic effect of plumbagin by induction of SH2-containing protein tyrosine phosphatase 1 in human gastric cancer cells.

A recent study reported that plumbagin downregulated the activity of Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) pathway to show various antitumor effects in multiple myeloma cells. We aimed in this in vitro study to demonstrate the inhibition of JAK2/STAT3 pathway by plumbagin through inducing SH2-containing protein tyrosine phosphatase 1 (SHP1) expression in the MKN-28 gastric cancer cell line. We performed western blot analysis to measure SHP1, phosphor-JAK2/STAT3 level, and observed that plumbagin induced SHP1 expression and simultaneously downregulated phosphor-JAK2/STAT3 in MKN-28 cells, with negative SHP1 expression. This effect was consistent when JAK2/STAT3 signaling was activated by interleukin-6 (IL-6), and ameliorated when cells were treated with prevanadate, a protein tyrosin phosphatase inhibitor. Furthermore, plumbagin significantly reduced gene expression of cyclin D1, vascular endothelial growth factor (VEGF)-1, Bcl-xL, survivin and matrix metalloproteinase-9 (MMP-9), known target products of STAT3 activation in gastric carcinogenesis by reverse transcription-polymerase chain reaction (RT-PCR). Several functional studies such as water soluble tetrazolium salt-1 (WST-1) assay, wound closure assay, Matrigel invasion assay and Annexin V assay were also performed, and we validated the functional effect of plumbagin for inhibition of cell proliferation, migration and invasion, and induction of apoptosis. Collectively, our findings suggest that plumbagin is a potential regulator of cellular growth, migration, invasion and apoptosis by inhibiting both constitutive and inducible STAT3 activity through induction of SHP1 in gastric cancer cells.

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.

Hepatolithiasis and intrahepatic cholangiocarcinoma: A review.

Although the incidence of hepatolithiasis is decreasing as the pattern of gallstone disease changes in Asia, the prevalence of hepatolithiasis is persistently high, especially in Far Eastern countries. Hepatolithiasis is an established risk factor for cholangiocarcinoma (CCA), and chronic proliferative inflammation may be involved in biliary carcinogenesis and in inducing the upregulation of cell-proliferating factors. With the use of advanced imaging modalities, there has been much improvement in the management of hepatolithiasis and the diagnosis of hepatolithiasis-associated CCA (HL-CCA). However, there are many problems in managing the strictures in hepatolithiasis and differentiating them from infiltrating types of CCA. Surgical resection is recommended in cases of single lobe hepatolithiasis with atrophy, uncontrolled stricture, symptom duration of more than 10 years, and long history of biliary-enteric anastomosis. Even after resection, patients should be followed with caution for development of HL-CCA, because HL-CCA is an independent prognostic factor for survival. It is not yet clear whether hepatic resection can reduce the occurrence of subsequent HL-CCA. Furthermore, there are no consistent findings regarding prediction of subsequent HL-CCA in patients with hepatolithiasis. In the management of hepatolithiasis, important factors are the reduction of recurrence of cholangitis and suspicion of unrecognized HL-CCA.