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1.  Expression and prognostic role of molecular markers in 99 KIT-positive gastric stromal tumors in Taiwanese 
AIM: To elucidate the prognostic role and relationship of three molecular markers such as tumor suppressor gene p53, proliferating cell nuclear antigen (PCNA) and Ki-67 in gastric stromal tumor.
METHODS: A total of 108 surgically resected gastric smooth muscle tumor specimens were collected from January 1987 to December 1999. Immunohistochemical studies were performed on the paraffin sections of 99 of 108 CD117-positive tumors with antibodies of p53, PCNA, and Ki-67. Immunoreactivity of three molecular markers was recorded by labeling index (LI, %) and was analyzed for clinicopathologic and survival correlation.
RESULTS: Of the 99 cases, immunostaining revealed that 52 patients (52.5%) had p53, and 37 patients (37.3%) had Ki-67 immunoreactivity (defined as >10% of LI). All patients (100%) had PCNA immunoreactivity ranging from 12% to 93% of LI, divided into high or low by median. Statistics revealed that LI of three markers positively correlate to each other (P<0.01) and to microscopic tumor mitotic counts (P <0.001). By combination, patients with ≥2 markers (positive or high) in tumors had early tumor recurrence (P <0.001) and unfavorable outcome (P <0.001). Univariate analysis indicated that patients with tumor size >5 cm (P = 0.003), tumor mitosis >5/50 HPF (P < 0.001), p53 immunoreactivity (P  = 0.001), Ki-67 immunoreactivity (P =0.026), high PCNA LI (P =0.015) and male gender (P =0.036) were six predictors for early disease recurrence. Subsequent multivariate analysis revealed that mitotic counts, tumor size, and p53 immunoreactivity were three independent prognostic factors for both disease free and overall survival of patients. By combination of three independent prognostic factors for grouping, we found higher tumor recurrence rate (P <0.001) and shorter survival (P <0.001) existed in groups with increasing factors.
CONCLUSION: We first provide the prognostic value and linkage of three molecular markers in GISTs. The combination of three factors (p53, tumor size, and tumor mitosis) provides a more powerful prediction of prognosis than any single factor does.
PMCID: PMC4066093  PMID: 16489674
Gastrointestinal stromal tumor; GIST; p53; PCNA; Ki-67; Prognosis
2.  Hepatitis B virus infection and renal transplantation 
Although the prevalence of chronic hepatitis B virus (HBV) infection has declined in renal transplant recipients (RTRs), it remains a relevant clinical problem with high morbidity and mortality in long-term follow up. A thorough evaluation, including liver biopsy as well as assessment of HBV replication in serum (i.e. hepatitis B e antigen and/or HBV DNA) is required before transplantation. Interferon should not be used in this setting because of low efficacy and precipitation on acute allograft rejection. The advent of effective antiviral therapies offers the opportunity to prevent the progression of liver disease after renal transplantation. However, as far as we are aware, no studies have compared prophylactic and preemptive strategies. To date, the majority of RTRs with HBV-related liver disease have had a high virological and biochemical response to lamivudine use. However, lamivudine resistance is frequent with a prolonged course of therapy. Considering long-term treatment, antiviral agents with a high genetic barrier to resistance and lack of nephrotoxicity are suggested. The optimal strategy in RTRs with HBV infection remains to be established in the near future.
PMCID: PMC2923761  PMID: 20712048
Hepatitis B; Renal transplantation; Lamivudine resistance
3.  Clinical characteristics and prognostic factors of splenic abscess: A review of 67 cases in a single medical center of Taiwan 
AIM: To analyze 67 cases of splenic abscess in a medical center of Taiwan during a period of 19 years.
METHODS: From January 1986 to December 2004, a total of 67 patients with splenic abscess were enrolled for the retrospective study. The clinical characteristics, underlying diseases, organism spectra, therapeutic methods, APACHE II scores, and mortality rates were analyzed.
RESULTS: There were 41 males and 26 females with the mean age of 54.1 ± 14.1 years. Multiple splenic abscesses (MSA) account for 28.4% and solitary splenic abscess in 71.6% of the patients. Twenty-six of sixty-seven patients (35.8%) had extrasplenic abscesses, with leading site of liver (34.6%). Microbiological cultures were positive in 58 patients (86.6%), with 71.8% in blood culture and 93.5% in abscess culture. Gram negative bacillus (GNB) infection predominated (55.2%), with leading pathogen of Klebsiella pneumoniae (22.4%), followed by gram positive coccus (GPC) infection (31%). Splenectomy was performed in 26 patients (38.8%), percutaneous drainage or aspiration in 21 (31.3%), and antibiotic therapy alone in 20 patients (29.9%). Eventually, 12 of 67 patients expired (17.9 %). By statistics, spleen infected with GNB was likely to develop multiple abscesses compared with infection with GPC (P = 0.036). Patients with GNB infection (P = 0.009) and multiple abscesses (P = 0.011) experienced a higher mortality rate than patients with GPC infection and solitary abscess. The mean APACHE II score of 12 expired patients (16.3 ± 3.2) was significantly higher than that of the 55 survivals (7.2 ± 3.8) (P < 0.001).
CONCLUSION: MSA, GNB infection, and high APACHE II scores are poor prognostic factors. Early surgical intervention should be encouraged when these risk factors are present.
PMCID: PMC4066069  PMID: 16489650
Splenic abscess; Prognosis; Gram negative bacillus infection; APACHE II scores
4.  Serum hepatitis B surface antigen levels predict treatment response to nucleos(t)ide analogues 
Quantification of hepatitis B surface antigen (HBsAg) has been suggested to be helpful in the management of chronic hepatitis B (CHB) patients. Nucleos(t)ide analogs (NAs) are the therapy of choice for CHB and are used in the majority of CHB patients. NAs are able to induce hepatitis B virus (HBV) viral suppression, normalization of alanine aminotransferase (ALT) levels, and improvement in liver histology. Automated quantitative assays for serum HBsAg have recently become available, facilitating standardized quantification of serum HBsAg. This has led to increased interest in the clinical application of quantitative serum HBsAg for predicting therapeutic response to NAs. Recent studies have shown that a decline in serum HBsAg levels in patients receiving peginterferon may signal successful induction of immune control over HBV, and can therefore be used to predict therapeutic response. NA treatment typically induces a less rapid decline in HBsAg than interferon treatment; it has been estimated that full HBsAg clearance can require decades of NA treatment. However, a rapid HBsAg decline during NA therapy may identify patients who will show clearance of HBsAg. Currently, there is no consensus on the clinical utility of serum HBsAg monitoring for evaluating patient responses to NA therapy. This review focuses on recent findings regarding the potential application of HBsAg quantification in the management of CHB patients receiving NA therapy.
PMCID: PMC4069297  PMID: 24976706
Alanine aminotransferase; Hepatitis B virus; Hepatitis B surface antigen; Nucleos(t)ide analogs; Virological response
5.  Swab culture monitoring of automated endoscope reprocessors after high-level disinfection 
AIM: To conduct a bacterial culture study for monitoring decontamination of automated endoscope reprocessors (AERs) after high-level disinfection (HLD).
METHODS: From February 2006 to January 2011, authors conducted randomized consecutive sampling each month for 7 AERs. Authors collected a total of 420 swab cultures, including 300 cultures from 5 gastroscope AERs, and 120 cultures from 2 colonoscope AERs. Swab cultures were obtained from the residual water from the AERs after a full reprocessing cycle. Samples were cultured to test for aerobic bacteria, anaerobic bacteria, and mycobacterium tuberculosis.
RESULTS: The positive culture rate of the AERs was 2.0% (6/300) for gastroscope AERs and 0.8% (1/120) for colonoscope AERs. All the positive cultures, including 6 from gastroscope and 1 from colonoscope AERs, showed monofloral colonization. Of the gastroscope AER samples, 50% (3/6) were colonized by aerobic bacterial and 50% (3/6) by fungal contaminations.
CONCLUSION: A full reprocessing cycle of an AER with HLD is adequate for disinfection of the machine. Swab culture is a useful method for monitoring AER decontamination after each reprocessing cycle. Fungal contamination of AERs after reprocessing should also be kept in mind.
PMCID: PMC3325533  PMID: 22529696
Automated endoscope reprocessor; Gastrointestinal scope; High-level disinfection; Swab culture; Monitoring; Decontamination
6.  Effect of ginger on gastric motility and symptoms of functional dyspepsia 
AIM: To evaluate the effects of ginger on gastric motility and emptying, abdominal symptoms, and hormones that influence motility in dyspepsia.
METHODS: Eleven patients with functional dyspepsia were studied twice in a randomized double-blind manner. After an 8-h fast, the patients ingested three capsules that contained ginger (total 1.2 g) or placebo, followed after 1 h by 500 mL low-nutrient soup. Antral area, fundus area and diameter, and the frequency of antral contractions were measured using ultrasound at frequent intervals, and the gastric half-emptying time was calculated from the change in antral area. Gastrointestinal sensations and appetite were scored using visual analog questionnaires, and blood was taken for measurement of plasma glucagon-like peptide-1 (GLP-1), motilin and ghrelin concentrations, at intervals throughout the study.
RESULTS: Gastric emptying was more rapid after ginger than placebo [median (range) half-emptying time 12.3 (8.5-17.0) min after ginger, 16.1 (8.3-22.6) min after placebo, P ≤ 0.05]. There was a trend for more antral contractions (P = 0.06), but fundus dimensions and gastrointestinal symptoms did not differ, nor did serum concentrations of GLP-1, motilin and ghrelin.
CONCLUSION: Ginger stimulated gastric emptying and antral contractions in patients with functional dyspepsia, but had no impact on gastrointestinal symptoms or gut peptides.
PMCID: PMC3016669  PMID: 21218090
Ginger (Zinger offinale); Functional dyspepsia; Gastric emptying; Antral contraction; Abdominal ultrasound; Ghrelin; Glucagon-like peptide-1; Motilin
7.  Predictors of rebleeding after initial hemostasis with epinephrine injection in high-risk ulcers 
AIM: To identify the predictors of rebleeding after initial hemostasis with epinephrine injection (EI) in patients with high-risk ulcers.
METHODS: Recent studies have revealed that endoscopic thermocoagulation, or clips alone or combined with EI are superior to EI alone to arrest ulcer bleeding. However, the reality is that EI monotherapy is still common in clinical practice. From October 2006 to April 2008, high-risk ulcer patients in whom hemorrhage was stopped after EI monotherapy were studied using clinical, laboratory and endoscopic variables. The patients were divided into 2 groups: sustained hemostasis and rebleeding.
RESULTS: A total of 175 patients (144, sustained hemostasis; 31, rebleeding) were enrolled. Univariate analysis revealed that older age (≥ 60 years), advanced American Society of Anesthesiology (ASA) status (category III, IV and V), shock, severe anemia (hemoglobin < 80 g/L), EI dose ≥ 12 mL and severe bleeding signs (SBS) including hematemesis or hematochezia were the factors which predicted rebleeding. However, only older age, severe anemia, high EI dose and SBS were independent predictors. Among 31 rebleeding patients, 10 (32.2%) underwent surgical hemostasis, 15 (48.4%) suffered from delayed hemostasis causing major complications and 13 (41.9%) died of these complications.
CONCLUSION: Endoscopic EI monotherapy in patients with high-risk ulcers should be avoided. Initial hemostasis with thermocoagulation, clips or additional hemostasis after EI is mandatory for such patients to ensure better hemostatic status and to prevent subsequent rebleeding, surgery, morbidity and mortality.
PMCID: PMC2988244  PMID: 21086569
Epinephrine injection; High-risk ulcers; Initial hemostasis; Predictors; Rebleeding
8.  Insulin resistance is associated with hepatocellular carcinoma in chronic hepatitis C infection 
AIM: To elucidate the role of insulin resistance (IR) and serum adiponectin level in hepatocellular carcinoma (HCC) associated with chronic hepatitis C.
METHODS: Clinical and biochemical characteristics were collected from 165 consecutive patients with newly diagnosed HCC. Homeostasis model assessment of IR (HOMA-IR) and serum adiponectin level were investigated in 188 patients with different stages of hepatitis C virus (HCV) infection.
RESULTS: Among HCC patients, type 2 diabetics (DM) was more prevalent in HCV subjects (35.6%, n = 59) compared to hepatitis B virus (HBV; 12.7%, n = 63) or non-HBV, non-HCV cases (7.1%, n = 28). In patients with chronic hepatitis C, HCC subjects had higher blood sugar (P < 0.001), insulin level (P = 0.003) and HOMA-IR (P = 0.018) than those with chronic hepatitis and advanced fibrosis. Age, male sex and body mass index were significantly associated with serum adiponectin level, whereas HOMA-IR was not. Based on stepwise logistic regression analysis, age (OR: 1.124, P < 0.001), serum insulin level (OR: 1.585, P < 0.001), HOMA-IR (OR: 0.495, P = 0.001), DM (OR: 11.601, P = 0.002) and male sex (OR: 3.877, P = 0.016) were independently associated with HCC. This result was similar even if the diabetic subjects were excluded for analysis.
CONCLUSION: Insulin resistance measured by HOMA-IR, regardless of the presence of diabetes, is significantly associated with HCC development in patients with chronic HCV infection.
PMCID: PMC2868220  PMID: 20458764
Hepatitis C virus; Hepatocellular carcinoma; Insulin resistance; Diabetes; Adiponectin
9.  Endoscope-guided pneumatic dilation for treatment of esophageal achalasia 
Pneumatic dilation (PD) is considered to be the first line nonsurgical therapy for achalasia. The principle of the procedure is to weaken the lower esophageal sphincter by tearing its muscle fibers by generating radial force. The endoscope-guided procedure is done without fluoroscopic control. Clinicians usually use a low-compliance balloon such as Rigiflex dilator to perform endoscope-guided PD for the treatment of esophageal achalasia. It has the advantage of determining mucosal injury during the dilation process, so that a repeat endoscopy is not needed to assess the mucosal tearing. Previous studies have shown that endoscope-guided PD is an efficient and safe nonsurgical therapy with results that compare well with other treatment modalities. Although the results may be promising, long-term follow-up is required in the near future.
PMCID: PMC2811791  PMID: 20101764
Esophagoscopy; Dilatation; Esophageal achalasia
10.  Delayed presentation of intrathoracic esophageal perforation after pneumatic dilation for achalasia 
Pneumatic dilation (PD) is considered to be a safe and effective first line therapy for achalasia. The major adverse event caused by PD is esophageal perforation but an immediate gastrografin test may not always detect a perforation. It has been reported that delayed management of perforation for more than 24 h is associated with high mortality. Surgery is the treatment of choice within 24 h, but the management of delayed perforation remains controversial. Hereby, we report a delayed presentation of intrathoracic esophageal perforation following PD in a 48-year-old woman who suffered from achalasia. She completely recovered after intensive medical care. A review of the literature is also discussed.
PMCID: PMC2747072  PMID: 19764103
Intrathoracic esophageal perforation; Delayed presentation; Pneumatic dilation; Esophageal achalasia
11.  Pseudoachalasia in a patient after truncal vagotomy surgery successfully treated by subsequent pneumatic dilations 
Pseudoachalasia is a difficult condition for the clinician to differentiate from idiopathic achalasia even by manometry, radiological studies or endoscopy. Its etiology is usually associated with tumors. In most cases, the diagnosis is made after surgical explorations. The proposed pathogenesis of the disease is considered as mechanical obstruction of the distal esophagus or infiltration of the malignancy that affects the inhibitory neurons of the meyenteric plexus in the majority of cases. Surgery has been reported as a cause of pseudoachalasia. We report a 70-year-old man who suffered from deglutination disorder caused by pseudo-achalasia after truncal vagotomy. The patient was symptom-free after a nine-year follow-up and complete recovery of esophageal motility status from pseudoachalasia after pneumatic dilations. We also reviewed the literature of pseudoachalasia.
PMCID: PMC4087422  PMID: 16937515
Truncal vagotomy; Pseudo-achalasia; Deglutination disorder; Pneumatic dilations; Sustain reversed esophageal motility
12.  Neutrophil-to-Lymphocyte Ratio as a Predictor of Response to Peginterferon plus Ribavirin Therapy for Chronic Hepatitis C 
Disease Markers  2014;2014:462958.
We aimed to determine whether neutrophil-to-lymphocyte ratio (NLR) could be a predictor of antiviral response in chronic hepatitis C patients. A total of 602 consecutive patients (genotype 1, n = 263; genotype 2, n = 297; others/unknown, n = 42) receiving response-guided therapy with peginterferon plus ribavirin were recruited. NLR was related to clinical and virological features and to treatment outcome. Rapid virological response (RVR) and sustained virological response (SVR) were achieved in 436 (73%) and 458 (76%) of the patients, respectively. Higher NLR (≥1.42) was found to be associated with higher prevalence of DM (P = 0.039) and higher hepatitis C viral load (P = 0.002) and white cell count (P < 0.001). NLR was significantly lower in patients with RVR and SVR compared to those without (P = 0.032 and 0.034, resp.). However, NLR was not an independent factor by multivariate analysis. In the subgroup analysis, higher NLR (≥1.42) (odds ratio, 0.494, P = 0.038) was an independent poor predictor of SVR in genotype 2 patients but was not in genotype 1 patients. In conclusion, NLR is a simple and easily accessible marker to predict response to peginterferon plus ribavirin therapy for chronic hepatitis C genotype 2.
PMCID: PMC4255057  PMID: 25505815
13.  Quinolone-Containing Therapies in the Eradication of Helicobacter pylori 
BioMed Research International  2014;2014:151543.
Fluoroquinolones, especially levofloxacin, are used in the eradication of Helicobacter pylori worldwide. Many consensus guidelines recommend that the second-line rescue therapy for H. pylori eradication consists of a proton pump inhibitor, a quinolone, and amoxicillin as an option. Unfortunately, quinolone is well associated with a risk of developing bacterial resistance. In this paper, we review quinolone-containing H. pylori eradication regimens and the challenges that influence the efficacy of eradication. It is generally suggested that the use of levofloxacin should be confined to “rescue” therapy only, in order to avoid a further rapid increase in the resistance of H. pylori to quinolone. The impact of quinolone-containing H. pylori eradication regimens on public health issues such as tuberculosis treatment must always be taken into account. Exposure to quinolone is relevant to delays in diagnosing tuberculosis and the development of drug resistance. Extending the duration of treatment to 14 days improves eradication rates by >90%. Tailored therapy to detect fluoroquinolone-resistant strains can be done by culture-based and molecular methods to provide better eradication rates. Molecular methods are achieved by using a real-time polymerase chain reaction to detect the presence of a gyrA mutation, which is predictive of treatment failure with quinolones-containing triple therapy.
PMCID: PMC4163380  PMID: 25243116
14.  The Clinical and Bacteriological Factors for Optimal Levofloxacin-Containing Triple Therapy in Second-Line Helicobacter pylori Eradication 
PLoS ONE  2014;9(8):e105822.
Quinolone has the disadvantage of easily acquired drug resistance. It is important to prescribe it wisely for a high eradication rate. The current study aimed to determine the clinical and bacteriological factors for optimal levofloxacin-containing triple therapies in second-line H. pylori eradication. We enrolled a total of 158 H. pylori-infected patients who failed H. pylori eradication using the 7-day standard triple therapy (proton-pump inhibitor [PPI] twice daily, 500 mg clarithromycin twice daily, and 1 g amoxicillin twice daily). They were prescribed with either a 10-day (group A) or 14-day (group B) levofloxacin-containing triple therapy group (levofloxacin 500 mg once daily, amoxicillin 1 g twice daily, and esomeprazole 40 mg twice daily for 10 days) by their clinicians. Follow-up studies to assess treatment responses were carried out 8 weeks later. The eradication rates attained by groups A and B were 73.6% (95% confidence interval [CI] = 63.9–85.3%) and 90.5% (95% CI = 84.5–98.1%), respectively in the per protocol analysis (P = 0.008 in the per protocol analysis) and 67.1% (95% CI = 56.6–78.5%) and 84.8% (95% CI = 76.8–93.4%), respectively, in the intention-to-treat analysis (P = 0.009). The subgroup analysis revealed that H. pylori eradication rates for group A patients with levofloxacin-susceptible strains were 92.9% (13/14) but it dropped to 12.5% (1/8) when levofloxacin-resistant strains existed. H. pylori was eradicated among all the group B patients with levofloxacin-susceptible strains, but only half of patients with levofloxacin-resistant strains were successfully eradicated. In conclusion, this study confirms the effectiveness of 14-day treatment. Importantly, the results imply that 10-day treatment duration should be optimal if a culture can be performed to confirm the existence of susceptible strains. The duration of H. pylori eradication and levofloxacin resistance were the influencing factors for successful treatment. This study suggests that tailored levofloxacin-containing therapy should be administered only for patients with susceptible strains because it can achieve >90% success rates.
PMCID: PMC4139398  PMID: 25141137
15.  Distinct Patterns of the Lipid Alterations between Genotype 1 and 2 Chronic Hepatitis C Patients after Viral Clearance 
PLoS ONE  2014;9(8):e104783.
The hepatitis C virus (HCV) genotype-specific impacts on the host metabolic alterations remained inconclusive.
A prospective study including 229 (118 genotype 1 (G1) and 111 G2) consecutive chronic HCV patients who had completed a course of anti-HCV treatment and underwent pre- and 24 weeks post-treatment surveys of metabolic profiles was conducted. Patients were stratified according to the therapeutic response, viral genotype and baseline insulin resistance (IR: homeostasis model assessments of IR (HOMA-IR) ≥2.5). Paired t-tests were used to compare the pre- and post-treatment variables.
Significant post-therapeutic increases in cholesterol, triglyceride, HDL, LDL, apolipoprotein A1 and apolipoprotein B were observed in patients with sustained virological response (SVR) but not in those without. Among those with SVR, post-therapeutic increases in HDL (p<0.001) and apolipoprotein A1 (p = 0.012) were only found in G2, whereas increased triglyceride/HDL (p = 0.01) ratios were only found in G1 patients. When stratified by baseline IR among those with SVR, a significant increase in post-treatment HDL (p = 0.019) and apolipoprotein A1 (p = 0.012) but a decrease in HOMA-IR (p = 0.04), C-peptide (p = 0.019) and hemoglobin A1c (p = 0.047) were found in patients with baseline IR; a significant increase in HOMA-IR (p = 0.002) was found in patients without baseline IR. The latter change was observed only in G1 (p = 0.01) but not G2 patients. Although the pre-treatment metabolic profiles of G1 and G2 patients were indifferent, G1 had higher post-treatment triglyceride/HDL ratios (p = 0.041) and triglyceride (p = 0.044) levels than G2 patients.
G2 benefit more than G1 patients from viral clearance in metabolic alterations, particularly in those without baseline IR.
PMCID: PMC4133245  PMID: 25122116
16.  Outcome of Holiday and Nonholiday Admission Patients with Acute Peptic Ulcer Bleeding: A Real-World Report from Southern Taiwan 
BioMed Research International  2014;2014:906531.
Background. Recent findings suggest that patients admitted on the weekend with peptic ulcer bleeding might be at increased risk of adverse outcomes. However, other reports found that there was no “holiday effect.” The purpose of this study was to determine if these findings hold true for a real-life Taiwanese medical gastroenterology practice. Materials and Methods. We reviewed the medical files of hospital admissions for patients with peptic ulcer bleeding who received initial endoscopic hemostasis between January 2009 and March 2011. A total of 744 patients were enrolled (nonholiday group, n = 615; holiday group, n = 129) after applying strict exclusion criteria. Holidays were defined as weekends and national holidays in Taiwan. Results. Our results showed that there was no significant difference in baseline characteristics between the two groups. We also observed that, compared to the nonholiday group, patients in the holiday group received earlier endoscopy treatment (12.20 hours versus 16.68 hours, P = 0.005), needed less transfused blood (4.8 units versus 6.6 units, P = 0.02), shifted from intravenous to oral proton-pump inhibitors (PPIs) more quickly (5.3 days versus 6.9 days, P = 0.05), and had shorter hospital stays (13.05 days versus 17.36 days, P = 0.005). In the holiday and nonholiday groups, the rebleeding rates were 17.8% and 23.41% (P = 0.167), the mortality rates were 11.63% versus 13.66% (P = 0.537), and surgery was required in 2.11% versus 4.66% (P = 0.093), respectively. Conclusions. Patients who presented with peptic ulcer bleeding on holidays did not experience delayed endoscopy or increased adverse outcomes. In fact, patients who received endoscopic hemostasis on the holiday had shorter waiting times, needed less transfused blood, switched to oral PPIs quicker, and experienced shorter hospital stays.
PMCID: PMC4100444  PMID: 25093189
17.  Significance of Vitamin D Receptor Gene Polymorphisms for Risk of Hepatocellular Carcinoma in Chronic Hepatitis C 
Translational Oncology  2014;7(4):503-507.
Biological and epidemiological data suggest that vitamin D levels may influence cancer development. Several single nucleotide polymorphisms have been described in the vitamin D receptor (VDR) gene in association with cancer risk. We aimed to investigate the association of VDR gene polymorphisms with hepatocellular carcinoma (HCC) development in chronic hepatitis C patients.
In a cross-sectional, hospital-based setting, 340 patients (201 chronic hepatitis, 47 cirrhosis and 92 HCC) and 100 healthy controls receiving VDR genotyping (bat-haplotype: BsmI rs1544410 C, ApaI rs7975232 C and TaqI rs731236 A) were enrolled.
Patients with HCC had a higher frequency of ApaI CC genotype (P = 0.027) and bAt[CCA]-haplotype (P = 0.037) as compared to control subjects. There were no differences in BsmI and TaqI polymorphisms between two groups. In patients with chronic hepatitis C, HCC subjects had a higher frequency of ApaI CC genotype and bAt[CCA]-haplotype than those with chronic hepatitis (P = 0.001 and 0.002, respectively) and cirrhosis (P = 0.019 and 0.026, respectively). After adjusting age and sex, logistic regression analysis showed that ApaI CC genotype (odds ratio: 3.02, 95% confident interval: 1.65-5.51) was independently associated with HCC development.
VDR ApaI polymorphism plays a role in the development of HCC among chronic hepatitis C patients. Further explorations of this finding and its implications are required.
PMCID: PMC4202781  PMID: 24894441
18.  MicroRNAs in Hepatocellular Carcinoma: Carcinogenesis, Progression, and Therapeutic Target 
BioMed Research International  2014;2014:486407.
Hepatocellular carcinoma (HCC) is the third leading cause of death from cancer, with dismal outcomes and an increasing incidence worldwide. Hepatocarcinogenesis is a multistep process that progresses from chronic hepatitis through cirrhosis and/or dysplastic nodule to HCC. However, the detailed molecular pathogenesis remains unclear. MicroRNAs (miRNAs), small noncoding RNAs that regulate the translation of many genes, have emerged as key factors involved in several biological processes, including development, differentiation, and cell proliferation. Recent studies have uncovered the contribution of miRNAs to the cancer pathogenesis, as they can behave as oncogenes or tumor suppressor genes. In addition, other studies have demonstrated their potential values in the clinical management of HCC patients as some miRNAs may be used as prognostic or diagnostic markers. In this review, we summarize current knowledge about the roles of miRNAs in carcinogenesis and progression of HCC. We also discuss the potential application of miRNAs as diagnostic biomarkers and their potential roles in the intervention of HCC.
PMCID: PMC3996893  PMID: 24800233
19.  The Changes of Liver Stiffness and Its Associated Factors for Chronic Hepatitis B Patients with Entecavir Therapy 
PLoS ONE  2014;9(3):e93160.
Liver stiffness measurement (LSM) using transient elastography has been proposed to assess liver fibrosis well in various liver diseases. This study was to determine the changes of LSM and its associated factors for chronic hepatitis B (CHB) patients undergoing Entecavir therapy. Consecutive CHB patients underwent Entecavir therapy with two LSMs were enrolled. Patients with aspartate transaminase (AST) and/or alanine transaminase ≧200 IU/L were excluded. The retrospective study enrolled 233 patients including 132 without cirrhosis (group 1) and 101 with cirrhosis (group 2). The mean values of initial liver stiffness were 7.9 and 16.6 kPa for patients in group 1 and group 2, respectively (p<0.001). In addition to the decline of transaminase levels, there was significant reduction of liver stiffness value in a mean interval of 52.8 and 61.9 weeks between the two LSMs for patients in group 1 and 2, respectively (p<0.001). Multivariate analysis showed that higher initial LSM value and presence of hepatitis B e-antigen were associated with a greater decline of LSM value, whereas follow-up AST≧40 IU/L with increased LSM value for group 1 patients. For group 2 patients, longer interval between the two LSMs, higher initial LSM value and AST≧40 IU/L were associated with a greater decline of LSM value, whereas presence of diabetes mellitus (DM) contributed to increased LSM value. In conclusion, CHB patients improved their LSM values after Entecavir therapy. Higher initial LSM value contributed to greater LSM reduction. However, in cirrhotic patients, DM was associated with an increased LSM value after therapy.
PMCID: PMC3969320  PMID: 24682088
20.  Celecoxib suppresses hepatoma stemness and progression by up-regulating PTEN 
Oncotarget  2013;5(6):1475-1490.
Celecoxib, a COX-2 inhibitor and non-steroidal anti-inflammatory drug, can prevent several types of cancer, including hepatocellular carcinoma (HCC). Here we show that celecoxib suppressed the self-renewal and drug-pumping functions in HCC cells. Besides, celecoxib depleted CD44 + /CD133 + hepatic cancer stem cells (hCSC). Prostaglandin E2 (PGE2) and CD133 overexpression did not reverse the celecoxib-induced depletion of hCSC. Also, celecoxib inhibited progression of rat Novikoff hepatoma. Moreover, a 60-day celecoxib program increased the survival rate of rats with hepatoma. Histological analysis revealed that celecoxib therapy reduced the abundance of CD44 + /CD133 + hCSCs in hepatoma tissues. Besides, the hCSCs depletion was associated with elevated apoptosis and blunted proliferation and angiogenesis in hepatoma. Celecoxib therapy activated peroxisome proliferator-activated receptor γ (PPARγ) and up-regulated PTEN, thereby inhibiting Akt and disrupting hCSC expansion. PTEN gene delivery by adenovirus reduced CD44/CD133 expression in vitro and hepatoma formation in vivo. This study suggests that celecoxib suppresses cancer stemness and progression of HCC via activation of PPARγ/PTEN signaling.
PMCID: PMC4039225  PMID: 24721996
hepatocellular carcinoma; hepatic cancer stem cells; celecoxib; prostaglandin E2; phosphatase and tensin homolog
21.  Accuracy of faecal occult blood test and Helicobacter pylori stool antigen test for detection of upper gastrointestinal lesions 
BMJ Open  2013;3(10):e003989.
Highly sensitive guaiac-based faecal occult blood (Hemoccult SENSA) and Helicobacter pylori stool antigen testing might help detect upper gastrointestinal lesions when appended to a colorectal cancer screening programme with faecal immunochemical testing. We evaluated the diagnostic accuracies of two stool tests in detecting upper gastrointestinal lesions.
Cross-sectional design.
Hospital-based and community-based screening settings.
A hospital-based deviation cohort of 3172 participants to evaluate test performance and a community-based validation cohort of 3621 to verify the findings.
Three types of stool tests with bidirectional endoscopy as the reference standard.
Sensitivity, specificity and positive and negative likelihood ratios.
For detecting upper gastrointestinal lesions in cases with negative immunochemical tests, the sensitivity, specificity, and positive and negative likelihood ratios of the guaiac-based and H pylori antigen tests were 16.3% (95% CI 13.3% to 19.8%), 90.1% (88.9% to 91.2%), 1.64 (1.31 to 2.07), and 0.93 (0.89 to 0.97), respectively, and 52.5% (48.1% to 56.9%), 80.6% (79.0% to 82.1%), 2.71 (2.41 to 3.04) and 0.59 (0.54 to 0.65), respectively. For detecting upper gastrointestinal lesions in cases with normal colonoscopy, the results of the guaiac-based and H pylori antigen tests were 17.9% (14.8% to 21.5%), 90.1% (88.9% to 91.2%), 1.81 (1.45 to 2.26) and 0.91 (0.87 to 0.95), respectively, and 53.1% (48.6% to 57.4%), 80.7% (79.1% to 82.2%), 2.75 (2.45 to 3.08) and 0.58 (0.53 to 0.64), respectively. Within the community, positive predictive values of the immunochemical and H pylori antigen tests were 36.0% (26.0% to 46.0%) and 31.9% (28.3% to 35.5%), respectively, for detecting lower and upper gastrointestinal lesions, which were similar to expected values.
The H pylori stool antigen test is more accurate than the guaiac-based test in the screening of upper gastrointestinal lesions in a population with high prevalence of H pylori infection and upper gastrointestinal lesions. It is applicable to add the H pylori antigen test to the immunochemical test for pan detection.
Trial registration
NCT01341197 (
PMCID: PMC3816242  PMID: 24176798
22.  Ten-Day versus 14-Day Levofloxacin-Containing Triple Therapy for Second-Line Anti-Helicobacter pylori Eradication in Taiwan 
Second-line Helicobacter pylori (H. pylori) eradication with fluoroquinolone-containing triple therapy is one of the recommended treatment options, but neither 7-day nor 10-day regimens provide >90% success rates. The current retrospective study aimed to clarify the effects of 10-day and 14-day levofloxacin-containing triple therapies for second-line H. pylori eradication in a Taiwanese cohort and to evaluate the potential clinical factors influencing eradication. A total of 200 patients who failed H. pylori eradication using the standard triple therapy were prescribed with either a 10-day (EAL-10) or a 14-day (EAL-14) levofloxacin-containing triple therapy group (levofloxacin 500 mg once daily, amoxicillin 1 g twice daily, and esomeprazole 40 mg twice daily). Follow-up studies to assess treatment response were carried out 8 weeks later. Eradication rates attained by EAL-10 and EAL-14 were 75.6%; 95% CI = 63.9–85.3% and 92.5%; 95% CI = 84.5–98.1%, P = 0.002 in the per protocol analysis and 68%; 95% CI = 56.6–78.5% and 86%; 95% CI = 76.8–93.4%, P = 0.002 in the intention-to-treat analysis. The duration of H. pylori therapy is the independent risk factor of H. pylori eradication (P = 0.003). In conclusion, 14-day levofloxacin-containing triple therapy can provide a >90% H. pylori eradication rate, but 10-day treatment duration may be suboptimal. The longer duration of H. pylori therapy (14 days) is the independent risk factor.
PMCID: PMC3819765  PMID: 24235968
23.  Impacts of Pretransplant Infections on Clinical Outcomes of Patients with Acute-On-Chronic Liver Failure Who Received Living-Donor Liver Transplantation 
PLoS ONE  2013;8(9):e72893.
Liver transplantation is the only therapeutic modality for patients with acute-on chronic liver failure (ACLF). These patients are at high risk for bacterial infections while awaiting transplantation. The aim of this study was to elucidate whether an adequately treated bacterial infection influences the outcomes after transplantation in this patient population.
Methodology/Principal Findings
54 recipients (median age, 49.5 years [range, 22–60]) of adult-to-adult living donor liver transplant (LDLT) for ACLF were categorized as those with pretransplant infection (Group 1, n = 34) or without pretransplant infection (Group 2, n = 20) for retrospective analyses. With the exception of a higher male-female ratio (P = 0.046) and longer length of pretransplant hospital stay (P = 0.026) in Group 1, similar demographic, laboratory and clinical features were found in both groups. Patients in Group 1 (totally 42 pretransplant infection episodes) were adequately treated with effective antibiotic(s) before receiving LDLT. All included patients were followed up until one year after transplantation or death. Sixty-one posttransplant infection episodes were found in an overall of 44 ACLF patients (27 in Group 1 vs. 15 in Group 2; P = 0.352). Frequently encountered posttransplant infections were intraabdominal infection, pneumonia, bloodstream infection and urinary tract infection. Two patients died in each group (P = 0.622). No significant difference was found in the length of posttransplant ICU stay, and in one-year survival, graft rejection, and posttransplant infection rate between both groups. The longer overall hospital stay (mean day, 89.0 vs. 65.5, P = 0.024) found in Group 1 resulted from a longer pretransplant hospital stay receiving treatment for pretransplant infection(s) and/or awaiting transplantation.
These data suggested that an adequately treated pretransplant infection do not pose a significant risk for clinical outcomes including posttransplant fatality in recipients in adult-to-adult LDLT for ACLF.
PMCID: PMC3759387  PMID: 24023787
24.  Telbivudine and adefovir combination therapy for patients with chronic lamivudine-resistant hepatitis B virus infections 
Archives of Virology  2013;159(1):29-37.
We evaluated second-line salvage therapy with adefovir + telbivudine (group 1), adefovir followed by adefovir + telbivudine (group 2), or lamivudine + adefovir followed by adefovir + telbivudine (group 3) in hepatitis B patients with an inadequate virologic response to lamivudine treatment. Simple linear regression analysis showed that for each additional month of treatment, the most significant reduction in viral load occurred in group 1 (HBV DNA [Log10 IU/mL]: group 1, −0.149; group 2, -0.081; group 3, −0.123). Generalized estimating equation analysis revealed that compared to group 1, hepatitis B virus (HBV) DNA levels were 1.203 and 0.443 Log10 IU/mL higher in groups 2 and 3, respectively. Overall, a significant reduction in viral load (−0.060 Log10 IU/mL) was observed for each additional month of treatment. Adefovir + telbivudine treatment resulted in a significant reduction in HBV DNA levels. Moreover, telbivudine treatment resulted in a significant reduction in viral load (−0.050 Log10 IU/mL) compared to lamivudine treatment after the emergence of lamivudine resistance.
Electronic supplementary material
The online version of this article (doi:10.1007/s00705-013-1786-4) contains supplementary material, which is available to authorized users.
PMCID: PMC3888503  PMID: 23857507
25.  Biological interactions of CYP2C19 genotypes with CYP3A4*18, CYP3A5*3, and MDR1-3435 in living donor liver transplantation recipients 
Polymorphisms in CYP2C19 are related to the metabolic oxidation of drugs to varying degrees. The CYP3A4*18, CYP3A5*3, and MDR1-3435 variant alleles are very important, particularly in tacrolimus metabolism in organ transplant rejection.
The aim of this study is o explore possible interactions among different CYP2C19 genotypes, namely, between homozygous extensive metabolizers (HomEM), heterozygous extensive metabolizers (HetEM), and poor metabolizers (PM), and the CYP3A4*18, CYP3A5*3, and MDR1-3435 variants in living donors and patients who received a living donor liver transplant (LDLT).
This prospective study enrolled 133 living donors and 133 corresponding recipients. On the basis of the HomEM, HetEM, and PM CYP2C19 genotypes, the distributions of CYP3A4*18 (exon 10; T878C), CYP3A5*3 (intron 3; A6986G), and MDR1-3435 (exon 26; C3435T) genotypes were analyzed for single nucleotide polymorphisms among donors and recipients.
Among 102 HomEM genotypes, including 56 donors and 46 recipients, 91.2% of individuals harbored the T/T genotype of CYP3A4*18; 53.9% possessed G/G, and 34.3% had A/G genotypes of CYP3A5*3; and 38.2% had C/C and 50.0% had C/T genotypes at MDR1-3435. Among 130 HetEM genotypes, including 58 donors and 72 recipients, 97.7% of individuals possessed T/T genotype at CYP3A4*18; 50.0% harbored G/G and 41.5% had A/G genotypes at CYP3A5*3; and 40.0% had C/C and 49.2% had C/T genotypes at MDR1-3435. In 34 PMs, including 19 donors and 15 recipients, 88.2% had T/T genotypes at CYP3A4*18; 41.2% had G/G and 58.8% had A/G genotypes at CYP3A5*3; and 47.1% possessed C/C and 47.1% had C/T genotypes at MDR1-3435. On the basis of the CYP2C19 genotypes, no statistically significant distribution of genotypes were observed between donors and recipients for all genotypes of CYP3A4*18, CYP3A5*3, and MDR1-3435 (P >0.05).
In conclusion, the CYP2C19 genotypes do not affect the expression of CYP3A4*18, CYP3A5*3, or MDR1-3435 variants, which are independently distributed among donors and recipients during LDLT.
PMCID: PMC3643843  PMID: 23617933
Living donor liver transplantation; Cytochrome P450; CYP3A4*18; CYP3A5*3; MDR1-3435; CYP2C19 genotypes

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