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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  Long-term treatment outcomes of clevudine in antiviral-naive patients with chronic hepatitis B 
AIM: To evaluate the treatment outcomes of clevudine compared with entecavir in antiviral-naive patients with chronic hepatitis B (CHB).
METHODS: We retrospectively analyzed the clinical data of CHB patients treated with clevudine 30 mg/d and compared their clinical outcomes with patients treated with entecavir 0.5 mg/d. The biochemical response, as assessed by serum alanine aminotransferase (ALT) activity, virologic response, as assessed by serum hepatitis B virus DNA (HBV DNA) titer, serologic response, as assessed by hepatitis B e antigen (HBeAg) status, and virologic breakthrough with genotypic mutations were assessed.
RESULTS: Two-hundred and fifty-four patients [clevudine (n = 118) vs entecavir (n = 136)] were enrolled. In clevudine-treated patients, the cumulative rates of serum ALT normalization were 83.9% at week 48 and 91.5% at week 96 (80.9% and 91.2% in the entecavir group, respectively), the mean titer changes in serum HBV DNA were -6.03 and -6.55 log10 copies/mL (-6.35 and -6.86 log10 copies/mL, respectively, in the entecavir group), and the cumulative non-detection rates of serum HBV DNA were 72.6% and 83.1% (74.4% and 83.8%, respectively, in the entecavir group). These results were similar to those of entecavir-treated patients. The cumulative rates of HBeAg seroconversion were 21.8% at week 48 and 25.0% at week 96 in patients treated with clevudine, which was similar to patients treated with entecavir (22.8% and 27.7%, respectively). The virologic breakthrough in the clevudine group occurred in 9 (7.6%) patients at weeks 48 and 15 (12.7%) patients at week 96, which primarily corresponded to genotypic mutations of rtM204I and/or rtL180M. There was no virologic breakthrough in the entecavir group.
CONCLUSION: In antiviral-naive CHB patients, long-term treatment outcomes of clevudine were not inferior to those of entecavir, except for virologic breakthrough.
PMCID: PMC3531678  PMID: 23322992
Chronic hepatitis B; Hepatitis B virus; Clevudine; Entecavir; Treatment outcomes
9.  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
10.  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
11.  Efficacy of Initial Treatment with Clevudine in Naive Patients with Chronic Hepatitis B 
Clevudine, a pyrimidine nucleoside analogue, has potent antiviral effects in patients with chronic viral hepatitis B (CHB). We report the efficacy of initial treatment with clevudine in naïve patients with CHB living in Daejeon and Chungcheong Province, South Korea.
One hundred five adults with CHB were administered 30 mg of clevudine per day for an average of 51 weeks. We evaluated viral markers and liver biochemistry retrospectively every 3 months.
Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and hepatitis B virus (HBV) DNA before the treatment were 184 ± 188 IU/L, 150 ± 138 IU/L, and 7.1 ± 1.2 log copies/mL, respectively. Undetectable rates (< 60 IU/mL) of DNA were 36.2%, 68.9%, 83.6%, 76.2%, and 75.8% at 12, 24, 36, 48, and 60 weeks, respectively. Seroconversion rates were 9.1%, 13.6%, 24.6%, 26.5%, and 26.1% and ALT normalization rates were 64.5%, 78.1%, 87.9%, 90.0% at 12, 24, 36, and 48 weeks, respectively. Six patients (5.7%) had a viral breakthrough.
Clevudine is a useful drug in the initial treatment of patients with CHB, with a potent antiviral effect and low incidence of viral breakthrough.
PMCID: PMC2997965  PMID: 21179274
Clevudine; Drug resistance; HBV seroconversion; Hepatitis B, chronic
12.  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
13.  A Case of Idiopathic Adulthood Ductopenia 
Idiopathic adulthood ductopenia (IAD) is a chronic cholestatic liver disease of unknown etiology characterized by adult onset, an absence of autoantibodies, inflammatory bowel disease, and a loss of interlobular bile ducts. In the present report, a case fulfilling the IAD criteria is described. A 19-year-old man was admitted to the hospital for persistent elevation of transaminases and alkaline phosphatase without clinical symptoms. Viral hepatitis markers and autoantibodies were absent. The patient had a normal extrahepatic biliary tree and had no evidence of inflammatory bowel disease. A liver biopsy specimen showed absence of interlobular bile ducts from 58% of the portal tracts. He was diagnosed with IAD and was treated with ursodeoxycholic acid.
PMCID: PMC2732788  PMID: 19721865
Idiopathic adulthood ductopenia; Cholestasis
14.  Successful Hemostasis with Recombinant Activated Factor VII in a Patient with Massive Hepatic Subcapsular Hematoma 
Recombinant activated coagulation factor VII (rFVIIa) is known to be effective in the management of acquired deficiencies of factor VII and platelet function defects. But recently, rFVIIa has been successfully used to treat ongoing bleeding in disseminated intravascular coagulopathy (DIC) condition. The patient reported here was suspected to be suffering from toxic hepatitis on admission. After percutaneous liver biopsy, bleeding occurred and did not stop even after right hepatic artery embolization. The patient developed a severe hemorrhage that resulted in hypovolemic shock, hemoperitoneum, and a massive subcapsular hematoma. The patient then developed DIC due to massive transfusion, as well as acute liver necrosis. The patient was given 400 μg/kg of rFVIIa. Recombinant factor VIIa was administered in an attempt to control the bleeding. This stabilized the hemoglobin levels of the patient. The patient gradually recovered in 4 months. In conclusion, this case suggests that rFVIIa can be successfully used for the hemostasis of uncontrolled bleeding in DIC.
PMCID: PMC2895169  PMID: 20651958
Recombinant activated coagulation factor VII; Subcapsular hematoma
15.  Tenofovir (TDF) has stronger antiviral effect than adefovir (ADV) against lamivudine (LAM)-resistant hepatitis B virus (HBV) 
Hepatology International  2008;2(2):244-249.
We retrospectively compared the antiviral effect of tenofovir disoproxil fumarate (TDF) with that of adefovir dipivoxil (ADV) for patients with chronic hepatitis B (CHB) who developed resistance to lamivudine (LAM).
Materials and methods
One hundred nine patients (86 males), all Asian-American except 1 Caucasian male, with LAM resistance received TDF or ADV. HBV DNA levels were measured every 3 months. The HBeAg loss and ALT normalization were assessed at 12 months on therapy.
Forty-four patients (37 males) received TDF (12 with LAM) and 65 (49 males) received ADV (18 with LAM). Median ages (years) for TDF and ADV were 49 (32–68) and 45 (22–68), respectively. Median duration of therapy was 13 months (6–38) and 17 months (6–34) for the TDF and ADV groups. Baseline HBV DNA levels (log10 copies/ml) were 6.2 ± 1.7 for the TDF and 6.5 ± 1.6 for ADV groups. Baseline ALT (IU/l) levels were 77.0 ± 86.0 and 100 ± 195 for the TDF and ADV (P = 0.46) groups, respectively. At 12 months, mean levels of log10 HBV DNA were 1.5 ± 1.0 and 4.3 ± 2.2 for TDF and ADV (P = 0.01). HBeAg loss and ALT normalization at 12 months showed no differences. Using a single factor, ANOVA (2-tailed P value), 4 groups, TDF (n = 32), TDF + LAM (12), ADV (47), and ADV + LAM (18), were compared. HBV DNA reduction at 12 months was the greatest for TDF + LAM (P < 0.001).
Our results suggest that for LAM-resistant HBV, TDF, alone or combined with LAM exerts greater viral reduction than ADV. However, no difference in HBeAg loss was observed. It appears that stronger HBV DNA reduction may not necessarily accelerate HBeAg loss.
PMCID: PMC2716857  PMID: 19669311
HBV; Adefovir; Tenofovir; Lamivudine; Viral resistance
16.  Time for an active antiviral therapy for hepatitis B: An update on the management of hepatitis B virus infection 
Significant advances in the management of chronic hepatitis B (CHB) have been made over the past decade. During this period we have witnessed improvements in survival as well as reduction of disease progression in CHB patients due to the introduction of effective antiviral therapy. The need for effective antiviral therapy is underscored by the results of the REVEAL-HBV study in which 3653 hepatitis B virus (HBV) carriers were followed over 12 year period. This study demonstrated that a persistently elevated serum HBV DNA level was the most important risk factor for the development of hepatocellular carcinoma (HCC). The ultimate goal of antiviral therapy for CHB patients should include halting the progression to cirrhosis and its life threatening complications and in preventing/reducing the development of HCC. An earlier study of 651 CHB patients with cirrhosis or advanced fibrosis from countries in Asia also demonstrated that treatment with lamivudine (LVD) not only delayed disease progression but also reduced the development of HCC. These landmark studies reaffirm the need for active antiviral therapy for CHB. Current treatment options for patients with CHB include interferon and nucleos(t)ide analogues. As we gain experience with these agents, it has become increasingly clear that long-term therapy benefits patients with CHB.
PMCID: PMC2374938  PMID: 18472982
pegylated interferon; lamivudine; adefovir; entecavir; tenofovir; telbivudine
17.  Noninvasive predictors of nonalcoholic steatohepatitis in Korean patients with histologically proven nonalcoholic fatty liver disease 
Clinical and molecular hepatology  2013;19(2):120-130.
The aims of this study were (1) to identify the useful clinical parameters of noninvasive approach for distinguishing nonalcoholic steatohepatitis (NASH) from nonalcoholic fatty liver disease (NAFLD), and (2) to determine whether the levels of the identified parameters are correlated with the severity of liver injury in patients with NASH.
One hundred and eight consecutive patients with biopsy-proven NAFLD (age, 39.8±13.5 years, mean±SD; males, 67.6%) were prospectively enrolled from 10 participating centers across Korea.
According to the original criteria for NAFLD subtypes, 67 patients (62.0%) had NASH (defined as steatosis with hepatocellular ballooning and/or Mallory-Denk bodies or fibrosis ≥2). Among those with NAFLD subtype 3 or 4, none had an NAFLD histologic activity score (NAS) below 3 points, 40.3% had a score of 3 or 4 points, and 59.7% had a score >4 points. Fragmented cytokeratin-18 (CK-18) levels were positively correlated with NAS (r=0.401), as well as NAS components such as lobular inflammation (r=0.387) and ballooning (r=0.231). Fragmented CK-18 was also correlated with aspartate aminotransferase (r=0.609), alanine aminotransferase (r=0.588), serum ferritin (r=0.432), and the fibrosis stage (r=0.314). A fragmented CK-18 cutoff level of 235.5 U/L yielded sensitivity, specificity, and positive and negative predictive values of 69.0%, 64.9%, 75.5% (95% CI 62.4-85.1), and 57.1% (95% CI 42.2-70.9), respectively, for the diagnosis of NASH.
Serum fragmented CK-18 levels can be used to distinguish between NASH and NAFL. Further evaluation is required to determine whether the combined measurement of serum CK-18 and ferritin levels improves the diagnostic performance of this distinction.
PMCID: PMC3701844  PMID: 23837136
Nonalcoholic fatty liver disease; Cytokeratin-18; Ferritin

Results 1-17 (17)