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1.  A case of idiopathic colonic varices: A rare cause of hematochezia misconceived as tumor 
Colonic varices are a very rare cause of lower gastrointestinal bleeding. Fewer than 100 cases of colonic varices, and 30 cases of idiopathic colonic varices (ICV) have been reported in the English literature. Among these 30 cases of ICV, 19 cases were diagnosed by angiography, and 7 operated cases were diagnosed later as ileocecal vein deficit, hemangioma, and idiopathic in 1, 1, 5 cases, respectively. We report the case of a 24-year-old man who suffered from multiple episodes of hematochezia of varying degree at the age of 11 years. He had severe anemia with hemoglobin of 21 g/L. On colonoscopy, tortuously dilated submucosal vein and friable ulceration covered with dark necrotic tissues especially at the rectosigmoid region were seen from the rectum up to the distal descending colon. It initially appeared to be carcinoma with varices. Mesenteric angiographic study suggested a colonic hemangioma. Low anterior resection was done due to medically intractable and recurrent hematochezia. Other bowel and mesenteric vascular structures appeared normal. Microscopic examination revealed normal colonic mucosa with dilated veins throughout the submucosa and serosa without representing new vessel growth. Taken all of these findings together, the patient was diagnosed as ICV. His postoperative course was uneventful.
PMCID: PMC4088003  PMID: 16688816
Idiopathic colonic varices; Hematochezia; Colon cancer; Hemangioma
2.  Preoperative CA 125 is significant indicator of curative resection in gastric cancer patients 
AIM: To investigate the correlation among tumor markers, curative resection, and recurrence in gastric cancer.
METHODS: The patients with preoperative tumor makers [Carcinoembryonic antigen, Carbohydrate antigen (CA) 19-9, and CA 125] and elective gastrectomy between January 2000 and December 2009 at Chungbuk National University Hospital were enrolled in this study. We analyzed the relationship among the tumor makers, curative resection and recurrence, retrospectively.
RESULTS: Among the 679 patients with gastric cancer, curative resection was 93.6% (n = 636) and non-curative resection was 6.4% (n = 43). The independent risk factors for the non-curative resection were tumor location and the positivity of preoperative serum CA 19-9 and CA 125 levels. After curative resection, the independent prognostic risk factors for recurrence in curative resection were gender, stage, and preoperative increased serum CA 125 level (HR = 2.431, P =0.020), in a multivariate analysis.
CONCLUSION: Preoperative CA 125 is a useful predictive biomarker for curative resection and prognostic biomarker for recurrence in gastric cancer patients.
PMCID: PMC4306166  PMID: 25632195
Gastric Cancer; Tumor Marker; Carcinoembryonic antigen; Carbohydrate antigen 19-9; Carbohydrate antigen 125
3.  Risk of gastric cancer is associated with PRKAA1 gene polymorphisms in Koreans 
AIM: To evaluate the association between genetic polymorphisms of the gene encoding AMP-activated protein kinase (PRKAA1) and the risk of gastric cancer.
METHODS: The study subjects consisted of 477 age- and sex-matched case-control pairs. Genotyping was performed for 5 tag single nucleotide polymorphisms (SNPs): rs13361707, rs154268, rs3805486, rs6882903, and rs10074991. Associations between gastric cancer and putative risk factors (including the SNPs) were analyzed with multivariate conditional logistic regression models, after adjusting for potential confounding factors. Multiple testing corrections were implemented following methodology for controlling the false discovery rate. Gene-based association tests were performed by using the versatile gene-based association study (VEGAS) method.
RESULTS: In the dominant model, SNPs rs13361707 [odds ratio (OR) = 1.51, 95%CI: 1.07-2.11)], rs154268 (OR = 1.65, 95%CI: 1.22-2.22), rs6882903 (OR = 1.48, 95%CI: 1.09-2.00), and rs10074991 (OR = 1.53, 95%CI: 1.09-2.16) were significantly associated with an increased risk of gastric cancer. In the recessive model, SNPs rs154268 (OR = 1.66, 95%CI: 1.22-2.26), rs3805486 (OR = 0.63, 95%CI: 0.46-0.85), and rs10074991 (OR = 1.47, 95%CI: 1.15-1.88) were significant risk or protective factors for gastric cancer. In the codominant model, the ORs of each of the 5 SNPs were statistically significant. All SNPs in the model showed a dose-response relationship between the minor allele frequency and the risk of gastric cancer. Most notably, subjects with a homozygous minor allele in SNP rs10074991 showed 2.15 times the risk of gastric cancer as subjects without a minor allele. The PRKAA1 gene showed a significant gene-based association with gastric cancer in the VEGAS test.
CONCLUSION: All 5 tested tag SNPs of the PRKAA1 gene (rs13361707, rs154268, rs3805486, rs6882903, and rs10074991) were significantly associated with gastric cancer.
PMCID: PMC4093708  PMID: 25024613
AMP-activated protein kinase; Gastric cancer; PRKAA1; Single nucleotide polymorphism; Case-control study
4.  ITGA1 polymorphisms and haplotypes are associated with gastric cancer risk in a Korean population 
AIM: To evaluate the association between the genetic polymorphisms and haplotypes of the ITGA1 gene and the risk of gastric cancer.
METHODS: The study subjects were 477 age- and sex-matched case-control pairs. Genotyping was performed for 15 single nucleotide polymorphisms (SNPs) in ITGA1. The associations between gastric cancer and these SNPs and haplotypes were analyzed with multivariate conditional logistic regression models. Multiple testing corrections were carried out following methodology for controlling the false discovery rate. Gene-based association tests were performed using the versatile gene-based association study (VEGAS) method.
RESULTS: In the codominant model, the ORs for SNPs rs2432143 (1.517; 95%CI: 1.144-2.011) and rs2447867 (1.258; 95%CI: 1.051-1.505) were statistically significant. In the dominant model, polymorphisms of rs1862610 and rs2447867 were found to be significant risk factors, with ORs of 1.337 (95%CI: 1.029-1.737) and 1.412 (95%CI: 1.061-1.881), respectively. In the recessive model, only the rs2432143 polymorphism was significant (OR = 1.559, 95%CI: 1.150-2.114). The C-C type of ITGA1 haplotype block 2 was a significant protective factor against gastric cancer in the both codominant model (OR = 0.602, 95%CI: 0.212-0.709, P = 0.021) and the dominant model (OR = 0.653, 95%CI: 0.483-0.884). The ITGA1 gene showed a significant gene-based association with gastric cancer in the VEGAS test. In the dominant model, the A-T type of ITGA1 haplotype block 2 was a significant risk factor (OR = 1.341, 95%CI: 1.034-1.741). SNP rs2447867 might be related to the severity of gastric epithelial injury due to inflammation and, thus, to the risk of developing gastric cancer.
CONCLUSION: ITGA1 gene SNPs rs1862610, rs24321
43, and rs2447867 and the ITGA1 haplotype block that includes SNPs rs1862610 and rs2432143 were significantly associated with gastric cancer.
PMCID: PMC3793141  PMID: 24124332
Integrin; ITGA1; Gastric cancer; Polymorphism; Haplotype
5.  Efficacy of cap-assisted endoscopy for routine examining the ampulla of Vater 
AIM: To determine the efficacy of a cap-assisted endoscopy (CAE) to completely visualize the ampulla of Vater (AV) in patients failed by conventional endoscopy.
METHODS: A prospective study was conducted on 120 patients > 20 years of ages who visited the Health Promotion Center of Chungbuk National University Hospital for conscious sedation esophagogastroduodenoscopy (EGD) as a screening test from July to October, 2011. First, forward-viewing endoscopy was performed with reasonable effort using a push and pull method. We considered complete visualization of the AV when we could observe the entire AV including the orifice clearly, and reported the observation as complete or incomplete (partial or not found at all). Second, in cases of complete failure of the observation, an additional AV examination was conducted by attaching a short cap (D-201-10704, Olympus Medical Systems, Tokyo, Japan) to the tip of a forward-viewing endoscope. Third, if the second method failed, we replaced the short cap with a long cap (MH-593, Olympus Medical Systems) and performed a re-examination of the AV.
RESULTS: Conventional endoscopy achieved complete visualization of the AV in 97 of the 120 patients (80.8%) but was not achieved in 23 patients (19.2%). Age (mean ± SD) and gender [male (%)] were not significantly different between the complete observation and the incomplete observation groups. Additional short CAE was performed in patients in whom we could not completely visualize the AV. This group included 13 patients (10.9%) with partial observation of the AV and 10 (8.3%) in which the AV was not found. Short CAE permitted a complete observation of the AV in 21 of the 23 patients (91.3%). Patients in whom visualization of the AV failed with short CAE had satisfactory outcomes by replacing the short cap with a long cap. The additional time for CAE took an average of 141 ± 88 s. There were no complications and no significant mucosal trauma.
CONCLUSION: CAE is safe to use as a salvage method to achieve complete visualization of the AV when a regular EGD examination fails.
PMCID: PMC3623980  PMID: 23599622
Ampulla of Vater; Conventional endoscopy; Cap-assisted endoscopy; Screening test; Complete observation
6.  Evaluation of the relationship between dietary factors, CagA-positive Helicobacter pylori infection, and RUNX3 promoter hypermethylation in gastric cancer tissue 
AIM: To evaluate the relationship among Helicobacter pylori (H. pylori) infection, CagA status, and dietary factors with RUNX3 promoter hypermethylation.
METHODS: Gastric cancer tissue samples were collected from 184 South Korean patients. All patients were interviewed following a semi-quantitative food frequency questionnaire. The average frequencies of intake and portion sizes of 89 common food items were documented, and total intakes of calories, nutrients, vitamins, and minerals were calculated for each subject. DNA was extracted from gastric cancer tissue samples, and amplification of the HSP60 gene was performed to detect H. pylori infection. Nested polymerase chain reaction (PCR) was used to detect the presence of the CagA gene. RUNX3 gene expression was measured by reverse transcription-PCR, and RUNX3 methylation status was evaluated by methylation-specific PCR. The odds ratios (ORs) and 95%CI associated with RUNX3 promoter hypermethylation status were estimated for each of the food groups, lifestyle factors, and the interaction between dietary and lifestyle factors with CagA status of H. pylori infection.
RESULTS: Overall, 164 patients (89.1%) were positive for H. pylori DNA, with the CagA gene detected in 59 (36%) of these H. pylori-positive samples. In all, 106 (57.6%) patients with gastric cancer demonstrated CpG island hypermethylation at the RUNX3 promoter. RUNX3 expression was undetectable in 52 (43.7%) of the 119 gastric cancer tissues sampled. A high consumption of eggs may increase the risk of RUNX3 methylation in gastric cancer patients, having a mean OR of 2.15 (range, 1.14-4.08). A significantly increased OR of 4.28 (range, 1.19-15.49) was observed with a high consumption of nuts in patients with CagA-positive H. pylori infection. High intakes of carbohydrate, vitamin B1, and vitamin E may decrease the risk of RUNX3 methylation in gastric cancer tissue, particularly in CagA- or H. pylori-negative infection, with OR of 0.41 (0.19-0.90), 0.42 (0.20-0.89), and 0.29 (0.13-0.62), respectively. A high consumption of fruits may protect against RUNX3 methylation.
CONCLUSION: These results suggest that the CagA status of H. pylori infection may be a modifier of dietary effects on RUNX3 methylation in gastric cancer tissue.
PMCID: PMC3607754  PMID: 23555166
Gastric cancer; RUNX3; Helicobacter pylori; CagA; Dietary factors
7.  Mechanism of Action of Cholecystokinin on Colonic Motility in Isolated, Vascularly Perfused Rat Colon 
It is generally believed that cholecystokinin (CCK) stimulates colonic motility, although there are controversial reports. It has also been suggested that postprandial peptide YY (PYY) release is CCK-dependent. Using a totally isolated, vascularly perfused rat colon, we investigated: (1) the roles of CCK and PYY on colonic motility, (2) to determine if CCK modulates PYY release from the colon to influence the motility and (3) to clarify whether the action of CCK and PYY on colonic motility is mediated via the influence of cholinergic input.
An isolated whole rat colon was used. Luminal pressure was monitored via microtip catheter pressure transducers from proximal and distal colon. After a control period, CCK-8 or PYY was administerd intraarterially with or without an anti-PYY serum, loxiglumide or atropine at 12, 60 and 240 pM. Each dose was given for a period of 15-minute and the contractile response was expressed as % changes over basal. PYY concentration in the portal effluent was determined by radioimmunoassay.
Exogenous CCK-8 increased colonic motility which paralleled the increase in PYY release in the portal effluent. Exogenous PYY also significantly increased colonic motility although it was less potent than CCK. The stimulating effect of CCK-8 was significantly inhibited by an anti-PYY serum, and was completely abolished by loxiglumide, and almost completely abolished by atropine.
CCK increases colonic motility via CCK1 receptor and it is mediated partly by PYY. Cholinergic input is required for the increased motility by either PYY or CCK.
PMCID: PMC3042223  PMID: 21369495
Cholecystokinin; Colon; Peptide YY
8.  Metachronous bile duct cancer nine years after resection of gallbladder cancer 
We report a rare case of a 74-year-old man with metachronous gallbladder cancer and bile duct cancer who underwent curative resection twice, with the operations nine years apart. At the age of 65 years, the patient underwent a cholecystectomy and resection of the liver bed for gallbladder cancer. This was a well-differentiated adenocarcinoma, with negative resection margins (T2N0M0, stage IB). Nine years later, during a follow-up examination, abdominal computed tomography and MRCP showed an enhanced 1.7 cm mass in the hilum that extended to the second branch of the right intrahepatic bile duct. We diagnosed this lesion as a perihilar bile duct cancer, Bismuth type IIIa, and performed bile duct excision, right hepatic lobectomy and Roux-en-Y hepaticojejunostomy. The histological diagnosis was a well-differentiated adenocarcinoma with one regional lymph node metastasis (T1N1M0, stage IIB). Twelve months after the second operation, the patient is well, with no signs of recurrence. This case is compared with 11 other cases of metachronous biliary tract cancer published in the world medical literature.
PMCID: PMC2712910  PMID: 19610150
Biliary tree; Metachronous double cancer; Gallbladder cancer; Hilar bile duct cancer
9.  Kimchi and soybean pastes are risk factors of gastric cancer 
AIM: This case-control study investigated the effects of kimchi, soybean paste, fresh vegetables, nonfermented alliums, nonfermented seafood, nonfermented soybean foods, and the genetic polymorphisms of some metabolic enzymes on the risk of gastric cancer in Koreans.
METHODS: We studied 421 gastric cancer patients and 632 age- and sex-matched controls. Subjects completed a structured questionnaire regarding their food intake pattern. Polymorphisms of cytochrome P450 1A1 (CYP1A1), cytochrome P450 2E1 (CYP2E1), glutathione S-transferase mu 1 (GSTM1), glutathione S-transferase theta 1 (GSTT1) and aldehyde dehydrogenase 2 (ALDH2) were investigated.
RESULTS: A decreased risk of gastric cancer was noted among people with high consumption of nonfermented alliums and nonfermented seafood. On the other hand, consumption of kimchi, and soybean pastes was associated with increased risk of gastric cancer. Individuals with the CYP1A1 Ile/Val or Val/Val genotype showed a significantly increased risk for gastric cancer. Increased intake of kimchi or soybean pastes was a significant risk factor for the CYP1A1 Ile/Ile, the CYP2E1 c1/c1, the GSTM1 non-null, the GSTT1 non-null, or the ALDH2 *1/*1 genotype. In addition, eating soybean pastes was associated with the increased risk of gastric cancer in individuals with the GSTM1 null type. Nonfermented alliums were significant in individuals with the CYP1A1 Ile/Ile, the CYP2E1 c1/c2 or c2/c2, the GSTT1 null, the GSTT1 non-null, or the ALDH2 *1/*2 or *2/*2 genotype, nonfermented seafood was those with the CYP1A1 Ile/Ile, the CYP2E1 c1/c1, the ALDH2 *1/*1 genotype or any type of GSTM1 or GSTT1. In homogeneity tests, the odds ratios of eating kimchi for gastric cancer according to the GSTM1 or GSTT1 genotype were not homogeneous.
CONCLUSION: Kimchi, soybean pastes, and the CYP1A1 Ile/Val or Val/Val are risk factors, and nonfermented seafood and alliums are protective factors against gastric cancer in Koreans. Salt or some chemicals contained in kimchi and soybean pastes, which are increased by fermentation, would play important roles in the carcinogenesis of stomach cancer. Polymorphisms of the CYP1A1, CYP2E1, GSTM1, GSTT1, and ALDH2 genes could modify the effects of some environmental factors on the risk of gastric cancer.
PMCID: PMC4316045  PMID: 15929164
Kimchi; Soybean pastes; Gastric cancer
10.  Endoscopy for Nonvariceal Upper Gastrointestinal Bleeding 
Clinical Endoscopy  2014;47(4):315-319.
Endoscopy for acute nonvariceal upper gastrointestinal bleeding plays an important role in primary diagnosis and management, particularly with respect to identification of high-risk stigmata lesions and to providing endoscopic hemostasis to reduce the risk of rebleeding and mortality. Early endoscopy, defined as endoscopy within the first 24 hours after presentation, improves patient outcome and reduces the length of hospitalization when compared with delayed endoscopy. Various endoscopic hemostatic methods are available, including injection therapy, mechanical therapy, and thermal coagulation. Either single treatment with mechanical or thermal therapy or a treatment that combines more than one type of therapy are effective and safe for peptic ulcer bleeding. Newly developed methods, such as Hemospray powder and over-the-scope clips, may provide additional options. Appropriate decisions and specific treatment are needed depending upon the conditions.
PMCID: PMC4130885  PMID: 25133117
Nonvariceal upper gastrointestinal bleeding; Hemostasis; Endoscopy
11.  The experience of transumbilical endoscopic appendectomies 
Minimally invasive surgery is being widely accepted in various fields of surgery. Although several appendectomy techniques have been reported but, there is no standardization. We report here the experiences of transumbilical endoscopic appendectomy in humans. Between July 2008 and September 2010, ten patients with appendicitis successfully underwent transumbilical endoscopic appendectomies. There were 7 cases of suppurative, 2 cases of gangrenous and 1 case of perforated in operative findings. The ages of the patients were 13-56 years (mean age, 32.7 ± 15.4 years). Under general anesthesia, a 15-mm port was inserted through the umbilicus and then a two-channel endoscope was inserted in the peritoneal cavity. After appendix identification, counter-traction of the appendix with a direct abdominal wall puncture using a straight round needle prolene was performed to achieve good visualization of the operative field. Tissue dissection was performed using an endoscopic needle knife. Tissue grasping and resected appendix retrieval were done with endoscopic forceps. The average operation time was 79.5 ± 23.6 minutes (range, 45 to 110 minutes). No procedures were converted to laparoscopic or open appendectomy. Hospital stay was 4-6 days. All patients completely recovered without complications. As it is highly maneuverable, we believe transumbilical endoscopic appendectomy can be a feasible method. And, as surgeons want to proceed from laparoscopic surgery to natural orifice transluminal endoscopic surgery, this procedure could be a triable method.
PMCID: PMC4024928  PMID: 24851231
Appendectomy; Transumbilical approach; Endoscopy
12.  A Novel Germline Mutation in Exon 10 of the SMAD4 Gene in a Familial Juvenile Polyposis 
Gut and Liver  2013;7(6):747-751.
Familial juvenile polyposis (FJP) is a rare autosomal dominant hereditary disorder that is characterized by the development of multiple distinct juvenile polyps in the gastrointestinal tract and an increased risk of cancer. Recently, germline mutations, including mutations in the SMAD4, BMPR1A, PTEN and, possibly, ENG genes, have been found in patients with juvenile polyps. We herein report a family with juvenile polyposis syndrome (JPS) with a novel germline mutation in the SMAD4 gene. A 21-year-old man presented with rectal bleeding and was found to have multiple polyps in his stomach, small bowel, and colon. His mother had a history of gastrectomy for multiple gastric polyps with anemia and a history of colectomy for colon cancer. A review of the histology of the polyps revealed juvenile polyps in both patients. Subsequently, mutation screening in DNA samples from the patients revealed a germline mutation in the SMAD4 gene. The pair had a novel mutation in exon 10 (stop codon at tyrosine 413). To our knowledge, this mutation has not been previously described. Careful family history collection and genetic screening in JPS patients are needed to identify FJP, and regular surveillance is recommended.
PMCID: PMC3848546  PMID: 24312718
Familial juvenile polyposis; Mutation; SMAD4; Exon 10
13.  Podoplanin, α-Smooth Muscle Actin or S100A4 Expressing Cancer-Associated Fibroblasts Are Associated with Different Prognosis in Colorectal Cancers 
Journal of Korean Medical Science  2013;28(9):1293-1301.
The interactions between the tumor microenvironment and tumor cells determine the behavior of the primary tumors. Whether cancer-associated fibroblasts (CAF) have a tumor progressive or a protective role likely depends on the type of tumor cells and the CAF subpopulation. In the present study, we analyzed the prognostic significance of CAF subpopulations in colorectal cancer (CRC). CAF phenotypes were analyzed in 302 CRC patients by using antibodies against podoplanin (PDPN), α-smooth muscle actin (α-SMA), and S100A4. The relationship between the CAF phenotypes and 11 clinicopathological parameters were evaluated and their prognostic significance was analyzed from the disease-free and overall survival times. We observed that at the tumor invasive front, PDPN CAFs were present in 40% of the cases, and S100A4 or α-SMA CAFs were detected in all the cases. PDPN/S100A4 and α-SMA/S100A4 dual-stained CAFs were observed in 10% and 40% of the cases, respectively. The PDPN+ CAFs were associated with 6 favorable clinicopathological parameters and prolonged disease-free survival time. The PDPN-/α-SMAhigh CAFs were associated with 6 aggressive clinicopathological parameters and tended to exhibit shorter disease-free survival time. On the other hand, the PDPN-/S100A4high CAFs were associated with 2 tumor progression parameters, but not with disease prognosis. The PDPN+ CAF phenotype is distinct from the α-SMA or S100A4 CAFs in that it is associated with less aggressive tumors and a favorable prognosis, whereas the PDPN-/α-SMAhigh or PDPN-/S100A4high CAFs are associated with tumor progression in CRC. These findings suggest that CAFs can be a useful prognostic biomarker or potential targets of anti-cancer therapy in CRC.
PMCID: PMC3763102  PMID: 24015033
Cancer-Associated Fibroblast; Podoplanin; α-Smooth Muscle Actin; S100A4; Colorectal Neoplasms
14.  Combined aberrant expression of E-cadherin and S100A4, but not β-catenin is associated with disease-free survival and overall survival in colorectal cancer patients 
Diagnostic Pathology  2013;8:99.
Epithelial-to-mesenchymal transition (EMT) in cancers is related to metastasis, recurrence, and poor prognosis. We evaluated whether EMT-related proteins can act as prognostic biomarkers in colorectal cancer (CRC) patients.
We evaluated the expression of E-cadherin, β-catenin, and S100A4 by immunohistochemistry (IHC) in 333 CRC tissues from the tumor center and invasive margin. Tumor budding, cell grade, tumor stage, type of tumor growth, peritumoral lymphocyte infiltration (TLI), and perineural- or lymphovascular invasion were evaluated as pathological parameters. mRNA levels of E-cadherin, N-cadherin, β-catenin, and S100A4 from 68 specimens from the same set were analyzed by real time quantitative RT-PCR.
Loss of E-cadherin, nuclear β-catenin, and gain of S100A4 were higher in the invasive margin than in the tumor center. Loss of E-cadherin was associated with cell grade, macroscopic type, perineural invasion, and tumor budding, β-catenin with microsatellite instability and tumor site, and S100A4 with growth type, macroscopic type, AJCC stage, lymphovascular invasion, and perineural invasion. The aberrant expression of E-cadherin and S100A4 not β-catenin in the invasive margin was a significant and independent risk factor for disease-free and overall-survival by multivariate analysis, along with AJCC stage and perineural invasion. mRNA levels of β-catenin and S100A4 were correlated with the IHC findings at the tumor invasive margin. E-cadherin and N-cadherin showed a weak inverse correlation.
The combination of loss of E-cadherin and gain of S100A4 in the tumor invasive margin can be used to stratify patients with the same AJCC stage into different survival groups.
Virtual slides
The virtual slides for this article can be found here:
PMCID: PMC3728147  PMID: 23783026
Epithelial to mesenchymal transition; E-cadherin; β-catenin; S100A4; Tumor budding; Colorectal cancer
15.  Direct-Acting Antivirals for the Treatment of Chronic Hepatitis C: Open Issues and Future Perspectives 
The Scientific World Journal  2013;2013:704912.
Currently, two direct-acting antivirals (DAAs) show well-established efficacy against hepatitis C virus (HCV), namely, first-wave protease inhibitors telaprevir and boceprevir. Most clinical trials have examined DAAs in combination with standard of care (SOC) regimens. Future therapeutic drugs were divided into three categories. They are second-wave protease inhibitors, second-generation protease inhibitors, and polymerase inhibitors. Second-wave protease inhibitors are more improved form and can be administered once a day. Oral drug combinations can be favored because interferon (IFN) not only has to be given as intradermal injection, but also can cause several serious side effects. Combination of drugs with different mechanisms shows a good sustained virological response (SVR). But several mutations are associated with viral resistance to DAAs. Therefore, genotypic resistance data may provide insights into strategies aimed at maximizing SVR rates and minimizing resistance. Combined drug regimens are necessary to prevent the emergence of drug-resistant HCV. Many promising DAA candidates have been identified. Of these, a triple regimen containing sofosbuvir shows promise, and treatment with daclatasvir plus asunaprevir yields a high SVR rate (95%). Oral drug combinations will be standard of care in the near future.
PMCID: PMC3687480  PMID: 23844410
17.  Extended Spectrum-β-Lactamase or Carbapenemase Producing Bacteria Isolated from Patients with Acute Cholangitis 
Clinical Endoscopy  2012;45(2):155-160.
This study assessed the antibiotic resistance organisms isolated from the blood and bile of acute cholangitis and evaluated risk factors associated with them and their impact on clinical outcomes.
The identities and antibiotic resistance profiles of bacteria isolated from 433 cases of acute cholangitis from 346 patients were analyzed. Risk factors and the outcomes of patients infected with them were assessed.
Microorganisms were isolated from 266 of 419 blood cultures and 256 of 260 bile cultures. Isolates from bile and blood were identical in 71% of the cases. A total of 20 extended spectrum-β-lactamase (ESBL)-producers and 4 carbapenemase-producing organisms were isolated from blood, and 34 ESBL-producers and 13 carbapenemase-producers were isolated from bile. Sixty-four (14.8%) cases were infected with any one of these bacteria isolated from blood or bile. Risk factors associated with them in blood were nosocomial infection and prior biliary intervention. In bile, indwelling biliary device was a risk factor associated with them. Antibiotic-resistant bacteria were associated with mortality, independent of other prognostic factors.
ESBL or carbapenemase-producing bacteria were frequently isolated in acute cholangitis patients especially with prior biliary intervention and nosocomial infection. Isolation of antibiotic-resistant bacteria was an independent risk factor of mortality.
PMCID: PMC3401620  PMID: 22866257
Acute cholangitis; Bile culture; Blood culture; Microbial drug resistance
18.  High efficacy of adefovir and entecavir combination therapy in patients with nucleoside-refractory hepatitis B 
Newly developed and potent antiviral agents suffer from the problem of drug resistance. Multidrug resistance is a major impediment in the treatment of patients with chronic hepatitis B (CHB). In line with American Association for the Study of Liver Diseases guidelines, adefovir dipivoxil (ADV) add-on therapy is recommended in the case of lamivudine resistance, while tenofovir disoproxil fumarate (TDF) is recommended for ADV or entecavir (ETV) resistance. TDF is currently not available in Korea. ADV+ETV combination therapy may be a viable alternative to TDF in patients with either ADV or ETV resistance. However, the efficacy of ADV+ETV combination therapy in patients with CHB and multidrug resistance is unclear. This study investigated the efficacy of ADV+ETV combination therapy in patients with multidrug resistance.
Twenty-five patients were enrolled and were administered ADV+ETV combination therapy for at least 6 months. Blood was drawn at baseline and at 3, 6, 9, and 12 months after commencing treatment, and the following blood parameters were analyzed: alanine transaminase, hepatitis B e-antigen (HBeAg), anti-hepatitis B e-antigen, and hepatitis B virus (HBV) DNA levels. The initial virological response (IVR) was defined as an HBV DNA level of <4 log10 copies/mL after 6 months of combination therapy.
The IVR rate was 76%. The proportion of patients with a high viral load (≥5.0 log) dropped from 76% at baseline to only 5% after 6 months of treatment. The biochemical response rate during the first 6 months was 71%. HBeAg was lost in 2 patients (10%).
ADV+ETV combination therapy induced a good IVR in CHB patients who were refractory to more than 2 antiviral agents. This regimen may be a good alternative to TDF in Korea, where that drug is not available.
PMCID: PMC3326991  PMID: 22511906
Adefovir; Entecavir; Combination drug therapy; Drug resistance; Treatment efficacy
20.  Comparison of Midazolam Alone versus Midazolam Plus Propofol during Endoscopic Submucosal Dissection 
Clinical Endoscopy  2011;44(1):22-26.
For proper sedation during endoscopic submucosal dissection (ESD), propofol has been widely used. This study aimed to compare the levels of sedation and tolerance of patients treated with midazolam (M group) and a combination of midazolam and propofol (MP group) during ESD.
A total of 44 consecutive patients undergoing ESD were randomly assigned to the two groups. In the M group, 2 mg of midazolam was given repeatedly to maintain after a loading dose of 5 mg. The MP group initially received 5 mg of midazolam and 20 mg of propofol. Then, we increased the dosage of propofol by 20 mg gradually.
The average amount of midazolam was 12 mg in the M group. In the M group, 10 patients were given propofol additionally, since they failed to achieve proper sedation. The average amount of propofol was 181 mg in the MP group. Procedure time, vital signs and rates of complications were not significantly different between two groups. Movement of patients and discomfort were lower in the MP group.
During ESD, treatment with propofol and a low dose of midazolam for sedation provides greater satisfaction for endoscopists compared to midazolam alone.
PMCID: PMC3363047  PMID: 22741108
Endoscopic submucosal dissection; Sedation; Midazolam; Propofol
21.  Cholestatic Hepatitis and Thrombocytosis in a Secondary Syphilis Patient 
Journal of Korean Medical Science  2010;25(11):1661-1664.
The incidence of acute hepatitis in syphilis patient is rare. First of all, our patient presented with hepatitis comorbid with thrombocytosis. To our knowledge, this is only the second report of syphilitic hepatitis with thrombocytosis. The 42-yr-old male complained of flulike symptoms and skin eruptions on his palms and soles. Laboratory findings suggested an acute hepatitis and thrombocytosis. Serologic test results were positive for VDRL. He recovered from his symptoms and elevated liver related enzymes with treatment. Because syphilitic hepatitis can present without any typical signs of accompanying syphilis, syphilis should be considered as a possible cause in acute hepatitis patients.
PMCID: PMC2967006  PMID: 21060758
Hepatitis; Syphilis, Cutaneous; Thrombocytosis
22.  Effects of Dietary Factors and the NAT2 Acetylator Status on Gastric Cancer in Koreans 
Environmental dietary carcinogens and genetic polymorphisms in metabolic enzymes have been reported to be risk factors for gastric cancer. This study was undertaken to investigate the effects of the diet, the N-acetyltransferase (NAT) 2 acetylation status, and their interaction on gastric cancer risk. The study population consisted of 471 gastric cancer patients and 471 age- and sex-matched control subjects. NAT2 genotypes were identified using single-nucleotide primer extension reaction methods. Thirty-one alleles related to 12 polymorphism sites were assayed in this study. Significantly increased odds ratios were observed in former smokers (OR = 2.39, 95%CI = 1.57-3.62), heavy drinkers (OR = 1.28, 95%CI = 1.06-1.55), and individuals who eat well-done meat (OR = 1.24, 95%CI = 1.09-1.41). The odds ratios (95% CI) for high intake of kimchi, stews, and soybean paste were 3.27 (2.44-4.37), 1.96 (1.50-2.58), and 1.63 (1.24-2.14), respectively. The NAT2 genotype alone was not associated with gastric cancer risk. A significant gene-environment interaction was observed between environmental carcinogens and NAT2 genotypes. The odds ratios for kimchi, stews, and soybean paste were higher in slow/intermediate acetylators than in rapid acetylators. The odds ratios for slow/intermediate acetylators were 2.28 (95% CI: 1.29-4.04) for light smokers and 3.42 (95% CI: 2.06-5.68) for well-done meat intake. The NAT2 acetylator genotype may be an important modifier of the effects of environmental factors on gastric cancer risk.
PMCID: PMC2766547  PMID: 19350634
gastric cancer; N-acetyltransferase 2; genotype; dietary factor
23.  Relaxation Patterns of Human Gastric Corporal Smooth Muscle by Cyclic Nucleotides Producing Agents 
To elucidate the mechanism of cyclic nucleotides, such as adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5' -cyclic monophosphate (cGMP), in the regulation of human gastric motility, we examined the effects of forskolin (FSK), isoproterenol (ISO) and sodium nitroprusside (SNP) on the spontaneous, high K+ and acetylcholine (ACh)-induced contractions of corporal circular smooth muscle in human stomach. Gastric circular smooth muscle showed regular spontaneous contraction, and FSK, ISO and SNP inhibited its phasic contraction and basal tone in a concentration-dependent manner. High K+ (50 mM) produced sustained tonic contraction, and ACh (10 µM) produced initial transient contraction followed by later sustained tonic contraction with superimposed phasic contractions. FSK, ISO and SNP inhibited high K+-induced tonic contraction and also ACh-induced phasic and tonic contraction in a reversible manner. Nifedipine (1 µM), inhibitor of voltage-dependent L-type calcium current (VDCCL), almost abolished ACh-induced phasic contractions. These findings suggest that FSK, ISO and SNP, which are known cyclic nucleotide stimulators, inhibit smooth muscle contraction in human stomach partly via inhibition of VDCCL.
PMCID: PMC2802313  PMID: 20054499
Gastricintestinal (GI) tract; Human stomach; Relaxation; Forskolin (FSK); Isoproterenol (ISO); Sodium nitorprusside (SNP); Voltage-dependent L-type calcium current (VDCCL)
24.  Voltage-dependent Ca2+ Current Identified in Freshly Isolated Interstitial Cells of Cajal (ICC) of Guinea-pig Stomach 
The properties of voltage dependent Ca2+ current (VDCC) were investigated in interstitial cells of Cajal (ICC) distributed in the myenteric layer (ICC-MY) of guinea-pig antrum. In tissue, ICC-MY showed c-Kit positive reactions and produced driving potentials with the amplitude and frequency of about 62 mV and 2 times min-1, respectively, in the presence of 1 µM nifedipine. Single ICC-MY isolated by enzyme treatment also showed c-Kit immunohistochemical reactivity. These cells were also identified by generation of spontaneous inward current under K+ -rich pipette solution. The voltage clamp experiments revealed the amplitude of - 329 pA inward current at irregular frequency. With Cs+-rich pipette solution at Vh=-80 mV, ICC-MY produced voltage-dependent inward currents (VDIC), and nifedipine (1 µM) blocked VDIC. Therefore, we successfully isolated c-Kit positive single ICC from guinea-pig stomach, and found that ICC-MY potently produced dihydropiridine sensitive L-type voltage-dependent Ca2+ currents (VDCCL).
PMCID: PMC2788654  PMID: 19967074
Gastrointestinal (GI) tract; Stomach; Interstitial cells of Cajal (ICC); Voltage-dependent Ca2+ current (VDCC)
25.  Effects of Polyamines on Contractility of Guinea-Pig Gastric Smooth Muscle 
This study was designed to investigate the effects of polyamines on mechanical contraction and voltage-dependent calcium current (VDCC) of guinea-pig gastric smooth muscle. Mechanical contraction and calcium channel current (IBa) were recorded by isometric tension recording and whole-cell patch clamp technique. Spermine, spermidine and putrescine inhibited spontaneous contraction of the gastric smooth muscle in a concentration-dependent manner. Spermine (2 mM) reduced high K+ (50 mM)-induced contraction to 16±6.4% of the control (n=9), and significantly inhibited IBa in a reversible manner (p<0.05; IC50=0.8 mM). Pre- and post-treatment of tissue with spermine (2-5 mM, n=10) also inhibited acetylcholine (10 µM)-induced phasic contraction to 5±6.4% of the control. Inhibitory effect of spermine on IBa was observed at a wide range of test potentials of current/voltage (I/V) relationship (p<0.05), and steady-state activation of IBa was shifted to the right by spermine (p<0.05). Spermidine and putrescine (1 mM each) also inhibited IBa to 51±5.7% and 81±5.3% of the control, respectively. And putrescine (1 mM) inhibited IBa at whole tested potentials (p<0.05) without significant change of kinetics (p<0.05). Finally, 5 mM putrescine also inhibited high K+-induced contraction to 53±7.1% of the control (n=4). These findings suggest that polyamines inhibit contractions of guinea-pig gastric smooth muscle via inhibition of VDCC.
PMCID: PMC2693568  PMID: 17297251
Muscle, Smooth; myocytes, Smooth Muscle; Gastrointestinal Tract; Calcium Current; Polyamines; Spermine; Spermidine; Putrescine

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