Cheng-Kun Wu

A Polymorphism in Interferon L3 Is an Independent Risk Factor for Development of Hepatocellular Carcinoma After Treatment of Hepatitis C Virus Infection

BACKGROUND & AIMS Polymorphisms in interferon (IFN)L3 (encodes IFNλ3 or interleukin 28B) are associated with outcomes of treatment for hepatitis C virus (HCV) infection. However, there is controversy regarding how polymorphisms in IFNL3 affect the risk for development of hepatocellular carcinoma (HCC) in patients treated with pegylated interferon and ribavirin. METHODS In a retrospective study, we analyzed data from 1118 patients with HCV infection (589 men; median age, 60 y; 49.9% infected with genotype 1; 51.3% with advanced fibrosis) treated with pegylated interferon and ribavirin from March 2000 through October 2009 at the Chang Gung Memorial Hospital in Kaohsiung, Taiwan (71.64% achieved sustained virologic response [SVR]). Baseline samples were collected before therapy. Starting 24 weeks after treatment, clinical and biochemical features were assessed every 3 to 6 months and patients underwent ultrasound examinations. Lesions detected were examined by computed tomography, angiography, or fine-needle aspiration biopsy analyses. Patients were followed up from the initiation of HCV therapy until a diagnosis of HCC (based on published guidelines), death, or March 31, 2013 (median, 60 mo). DNA samples from each patient were analyzed for rs12979860 in IFNL3. Kaplan-Meier analysis was used to determine the risk for development of HCC. RESULTS The percentages of patients with the IFNL3 rs12979860 CC, CT, and TT genotypes were 86.4%, 13.2%, and 0.3%, respectively. A total of 108 patients (9.66%) developed HCC. The IFNL3 rs12979860 CT and TT genotypes correlated with high baseline levels of α-fetoprotein (AFP; ≥20 ng/mL), advanced stage of fibrosis, diabetes, or lack of an SVR (all P < .05). Based on multivariate Cox regression analysis, age 60 years and older, low platelet count (<15 × 10(9) cells/L), AFP level of 20 ng/mL or greater, advanced stage fibrosis, diabetes, lack of an SVR, and the IFNL3 rs12979860 CT and TT genotypes were significant risk factors for HCC (P < .05). Age 60 years and older, low numbers of platelets or high AFP level, and advanced fibrosis were risk factors for HCC among patients with a SVR. The IFNL3 rs12979860 genotype did not have a significant effect on risk for HCC among patients with SVRs, although some of these patients (with the CT or TT genotype) did develop HCC. Among patients without SVRs, only fibrosis stage and the IFNL3 rs12979860 CT and TT genotypes (hazard ratio, 1.80; 95% confidence interval, 1.06-3.07; P = .030) were independent risk factors for HCC. CONCLUSIONS Based on a retrospective study of patients treated for HCV infection, the IFNL3 rs12979860 CT and TT polymorphisms are associated with a risk for HCC, especially in patients without a SVR.

The Outcome of Prophylactic Intravenous Cefazolin and Ceftriaxone in Cirrhotic Patients at Different Clinical Stages of Disease after Endoscopic Interventions for Acute Variceal Hemorrhage

Antibiotic prophylaxis with norfloxacin, intravenous ciprofloxacin, or ceftriaxone has been recommended for cirrhotic patients with gastrointestinal hemorrhage but little is known about intravenous cefazolin. This study aimed to compare the outcome of intravenous cefazolin and ceftriaxone as prophylactic antibiotics among cirrhotic patients at different clinical stages, and to identify the associated risk factors. The medical records of 713 patients with acute variceal bleeding who had received endoscopic procedures from were reviewed. Three hundred and eleven patients were entered for age-matched adjustment after strict exclusion criteria. After the adjustment, a total of 102 patients were enrolled and sorted into 2 groups according to the severity of cirrhosis: group A (Child’s A patients, n = 51) and group B (Child’s B and C patients, n = 51). The outcomes were prevention of infection, time of rebleeding, and death. Our subgroup analysis results failed to show a significant difference in infection prevention between patients who received prophylactic cefazolin and those who received ceftriaxone among Child’s A patients (93.1% vs. 90.9%, p = 0.641); however, a trend of significance in favor of ceftriaxone prophylaxis (77.8% vs. 87.5%, p = 0.072) was seen among Child’s B and C patients. More rebleeding cases were observed in patients who received cefazolin than in those who received ceftriaxone among Child’s B and C patients (66.7% vs. 25.0%, p = 0.011) but not in Child’s A patients (32% vs. 40.9%, p = 0.376). The risk factors associated with rebleeding were history of bleeding and use of prophylactic cefazolin among Child’s B and C patients. In conclusion, this study suggests that prophylactic intravenous cefazolin may not be inferior to ceftriaxone in preventing infections and reducing rebleeding among Child’s A cirrhotic patients after endoscopic interventions for acute variceal bleeding. Prophylactic intravenous ceftriaxone yields better outcome among Child’s B and C patients.

Dynamic α-fetoprotein, platelets and AST-to-platelet ratio index predict hepatocellular carcinoma in chronic hepatitis C patients with sustained virological response after antiviral therapy

BACKGROUND Hepatitis C virus (HCV)-infected patients who achieve viral eradication may still develop hepatocellular carcinoma (HCC). Little is known about the impact of dynamic change of serum markers on HCC development. METHODS We enrolled 1351 HCV-infected patients who achieved sustained virological response (SVR). Laboratory data were collected at least 1 year after IFN-based therapy and to the latest follow-up. Data on α-fetoprotein (AFP) were obtained >6 months prior to HCC development to exclude HCC-related AFP elevation. RESULTS HCC developed in 49 patients. Risk factors for HCC in SVR patients were old age, liver cirrhosis, higher pre- and post-treatment AFP and high post-treatment AST-to-platelet ratio index (APRI). Patients with pre-AFP ≥15 ng/mL → post-AFP ≥15 ng/mL (at 1 year, 23.1%; 5 years, 42.3%) and pre-AFP <15 ng/mL → post-AFP ≥15 ng/mL (at 1 year, 25%; 5 years, 50%) had the highest risk of HCC development, followed by pre-AFP ≥15 ng/mL → post-AFP <15 ng/mL (at 1 year, 5.2%; 5 years, 7.6%) and pre-AFP <15 ng/mL → post-AFP ng/mL <15 ng/mL (at 1 year, 0.5%; 5 years, 0.9%) (P < 0.001). The pattern was similar for platelets and APRI (P < 0.001). SVR patients with pre-APRI ≥0.7 → post-APRI ≥0.7 had the highest risk of HCC development, followed by comparable risks among the other three groups. CONCLUSIONS SVR patients with a persistently high AFP level (≥15 ng/mL) and a high APRI (≥0.7) before and after treatment had the highest incidence of HCC development. Patients with a reduction of AFP and APRI to the normal range after treatment had a markedly decreased risk of HCC. The risk was lowest for patients who kept persistently normal AFP and APRI before and after treatment.

Outcome of Holiday and Nonholiday Admission Patients with Acute Peptic Ulcer Bleeding: A Real-World Report from Southern Taiwan

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.

Comprehensive Comparison of Multiple-Detector Computed Tomography and Dynamic Magnetic Resonance Imaging in the Diagnosis of Hepatocellular Carcinoma with Varying Degrees of Fibrosis.

Background & Aims Liver computed tomography and dynamic magnetic resonance imaging play an important role in the early detection of hepatocellular carcinoma. However, the American Association for the Study of Liver Diseases (AASLD) recommend the use of applied imaging studies for HCC diagnosis only in cirrhotic patients. This study aimed to comprehensively compare liver CT and dynamic MRI for HCC diagnosis before surgical resection over years in clinical practice, and also to compare the diagnostic differences between liver CT and dynamic MRI in HCCs with varying degrees of fibrosis. Methods 841 patients with liver tumor who had liver CT or dynamic MRI examinations followed by surgical resection were included in the study. We defined typical HCC imaging characteristics as early enhancement in the artery phase and early washout in the venous phase. The tumor size was recorded based on pathological examination after surgery. The pathologic fibrosis score was verified by the METAVIR scoring classification. Results Among the 841 patients, 756 underwent liver CT and 204 underwent dynamic liver MRI before surgery. The etiologies of chronic liver disease included hepatitis B virus, hepatitis C virus, hepatitis B and C virus, and non-hepatitis B or C virus. The sensitivity and accuracy of liver CT or MRI for HCC diagnosis was approximately 80%~90%. Liver CT had a diagnostic accuracy for HCC similar to that of dynamic MRI, and liver fibrosis stage did not influence their diagnostic efficacies. Conclusions The application of 4-phase dynamic CT and MRI exhibit similar diagnostic accuracy for hepatocellular carcinoma, in tumors of sizes 1 to 2 cm and >2 cm. Liver fibrosis status did not affect the diagnostic accuracy of liver CT or MRI for HCC. The AASLD and EASL restrictions of dynamic imaging studies for HCC diagnosis to cirrhotic patients alone are unnecessary.

Medical expenses in treating acute esophageal variceal bleeding: A 15-year nationwide population-based cohort study.

Abstract Acute variceal bleeding in patients with cirrhosis is related to high mortality and medical expenses. The purpose of present studies was to analyze the medical expenses in treating acute esophageal variceal bleeding among patients with cirrhosis and potential influencing clinical factors. A total of 151,863 patients with cirrhosis with International Classification of Diseases-9 codes 456.0 and 456.20 were analyzed from the Taiwan National Health Insurance Research Database from January 1, 1996 to December 31, 2010. Time intervals were divided into three phases for analysis as T1 (1996–2000), T2 (2001–2005), and T3 (2006–2010). The endpoints were prevalence, length of hospital stay, medical expenses, and mortality rate. Our results showed that more patients were <65 years (75.6%) and of male sex (78.5%). Patients were mostly from teaching hospitals (90.8%) with high hospital volume (50.9%) and high doctor service load (51.1%). The prevalence of acute esophageal variceal bleeding and mean length of hospital stay decreased over the years (P < 0.001), but the overall medical expenses increased (P < 0.001). Multiple regression analysis showed that older age, female sex, Charlson comorbidity index (CCI) score >1, patients from teaching hospitals, and medium to high or very high patient numbers were independent factors for longer hospital stay and higher medical expenses. Aged patients, female sex, increased CCI score, and low doctor service volume were independent factors for both in-hospital and 5-year mortality. Patients from teaching hospitals and medium to high or very high service volume hospitals were independent factors for in-hospital mortality, but not 5-year mortality. Medical expenses in treating acute esophageal variceal bleeding increased despite the decreased prevalence rate and length of hospital stay in Taiwan. Aged patients, female sex, patients with increased CCI score from teaching hospitals, and medium to high or very high patient numbers were the independent factors for increased medical expenses.

The Influential Roles of Antibiotics Prophylaxis in Cirrhotic Patients with Peptic Ulcer Bleeding after Initial Endoscopic Treatments

The influential roles of antibiotic prophylaxis on cirrhotic patients with peptic ulcer bleeding are still not well documented. The purpose of this study is to clarify these influential roles and to identify the risk factors associated with rebleeding, bacterial infection and in-hospital mortality. A cross-sectional, chart review study was conducted on 210 cirrhotic patients with acute peptic ulcer hemorrhage who underwent therapeutic endoscopic procedures. Patients were divided into group A (with prophylactic intravenous ceftriaxone, n = 74) and group B (without antibiotics, n = 136). The outcomes were length of hospital days, prevention of infection, rebleeding rate and in-hospital mortality. Our results showed that more patients suffered from rebleeding and infection in group B than group A (31.6% vs. 5.4%; p<0.001 and 25% vs. 10.8%; p = 0.014 respectively). The risk factors for rebleeding were active alcoholism, unit of blood transfusion, Rockall score, model for end-stage liver disease score and antibiotic prophylaxis. The risk factors for infection were active alcoholism, Child-Pugh C, Rockall score and antibiotic prophylaxis. Rockall score was the predictive factor for in-hospital mortality. In conclusions, antibiotic prophylaxis in cirrhotic patients after endoscopic interventions for acute peptic ulcer hemorrhage reduced infections and rebleeding rate but not in-hospital mortality. Rockall score was the predictive factor of in-hospital mortality.

Transient Stress Distributions in NCF-Bonded COG Packages due to Moisture Diffusion

The nonconductive film (NCF) adhesives have potentials to replace the anisotropic conductive film (ACF) adhesive in the chip-on-glass (COG) or other packages in liquid crystal displays (LCDs) due to their feasible features of finer bump pitch and cost reduction. Prior to applying the NCF to the COG packages, reliability issues, such as interfacial delamination and increase of bump contact resistance under thermal and moisture loads, have to be overcome. The objective of this paper is to investigate the effect of moisture ingression on stress field of the COG packages with NCF bonding. The coefficients of moisture diffusion and the hygro-strains of the NCF adhesive have been determined by an innovative approach of measuring the out-of-plane deformation of the bimaterial specimens during moisture absorption at the condition of 30degC/85%RH using Twyman-Green interferometry, associated with a finite element analysis and bimaterial theory. In this study, the results show that the average of the moisture diffusion coefficients and saturated hygro-strains of the NCF under 30degC/85%RH are 1.09 times 10-6 mm2/s and 1.51 times 10-3, respectively. After being validated by the diffusion theory, the moisture- transient finite element analysis reveals that the moisture absorption of the COG package under 30degC/85%RH is nearly saturated after 1000 h. It is also found that there are large tensile stresses at pad corner and mediate ones across bump joint, and these tensile stresses gradually increase with moisture absorption and up to the maximum at the state of moisture saturation. Through the parametric study by the validated finite element model, the results show that the tensile bump-joint and interfacial stresses increase nonlinearly with the NCF elastic modulus and linearly with the saturated moisture-induced strain (SMIS) of the NCFs. Furthermore, the COG package with polyimide bumps is found to have lower moisture-induced tensile stresses than that with gold bumps. It is further shown that the tensile stresses from the longitudinal-section and transverse-section models are similar only with a few percent difference in values. It can be concluded that the stress states of the NCF-bonded COG packages induced by transient moisture ingression have been fully addressed through experimental, theoretical and numerical approaches in this study.

Moisture Ingression Effect on Stress Distributions in NCF-Bonded COG Packages

The objective of this paper is to investigate the effect of moisture ingression on stress field of the COG packages with NCF bonding. The coefficients of moisture diffusion and the hygro-strains of the NCF adhesive have been determined by an innovative approach of measuring the out-of-plane deformation of the bi-material specimens during moisture absorption at the condition of 30degC /85%RH using Twyman-Green interferometry, associated with a finite element analysis and bi-material theory. It can be concluded that the stress states of the NCF-bonded COG packages induced by transient moisture ingression have been fully addressed through experimental, theoretical and numerical approaches in this study.

Diagnostic pitfall of sebaceous gland metaplasia of the esophagus

We investigated the sebaceous gland metaplasia (SGM) of the esophagus and clarified the evidence of misdiagnosis and its diagnosis pitfall. Cases of pathologically proven SGM were enrolled in the clinical analysis and reviewed description of endoscope. In the current study, we demonstrated that SGM is very rare esophageal condition with an incidence around 0.00465% and an occurrence rate of 0.41 per year. There were 57.1% of senior endoscopists identified 8 episodes of SGM. In contrast, 7.7% of junior endoscopists identified SGM in only 2 episodes. Moreover, we investigated the difference in endoscopic biopsy attempt rate between the senior and junior endoscopist (P = 0.0001). The senior endoscopists had more motivation to look for SGM than did junior endoscopists (P = 0.01). We concluded that SGM of the esophagus is rare condition that is easily and not recognized in endoscopy studies omitting pathological review.