Since its approval for the treatment of chronic hepatitis B in 1998, lamivudine (LAM) has been used extensively throughout the world, because of its relatively low costs and favourable tolerability. However, clinical trials and cohort studies have demonstrated that a high rate of resistance to this drug develops and, as a result, it is no longer included as a first-line therapy in most current treatment guidelines. Nevertheless, because of its low cost, this drug continues to be used in many countries and the pool of patients who have developed resistance to LAM continues to increase. Thus, there is a clear need to develop coherent management strategies to treat such patients as well as limit the emergence of resistance in the first instance. The purpose of this review is to highlight the need to aim for long-term treatment success while limiting the emergence of drug resistance and its consequences for the future. In addition to add-on/switch strategies with other nucleos(t)ide analogs, currently available data suggest that interferon-based therapies, with their potential to induce a sustained response, are worthy of consideration not only for reducing de novo resistance but as an option for the management of those patients in whom drug resistance has already developed. © 2010 John Wiley & Sons A/S.

Patrick Marcellin    沈祖堯     Teerha Piratvisuth   

Liver International

2010

Preterm infants are highly susceptible to life-threatening infections that are clinically difficult to detect, such as late-onset septicemia and necrotizing enterocolitis (NEC). Here, we used a proteomic approach to identify biomarkers for diagnosis of these devastating conditions. In a case-control study comprising 77 sepsis/NEC and 77 nonsepsis cases (10 in each group being monitored longitudinally), plasma samples collected at clinical presentation were assessed in the biomarker discovery and independent validation phases. We validated the discovered biomarkers in a prospective cohort study with 104 consecutively suspected sepsis/NEC episodes. Proapolipoprotein CII (Pro-apoC2) and a des-arginine variant of serum amyloid A (SAA) were identified as the most promising biomarkers. The ApoSAA score computed from plasma apoC2 and SAA concentrations was effective in identifying sepsis/NEC cases in the case-control and cohort studies. Stratification of infants into different risk categories by the ApoSAA score enabled neonatologists to withhold treatment in 45% and enact early stoppage of antibiotics in 16% of nonsepsis infants. The negative predictive value of this antibiotic policy was 100%. The ApoSAA score could potentially allow early and accurate diagnosis of sepsis/NEC. Upon confirmation by further multicenter trials, the score would facilitate rational prescription of antibiotics and target infants who require urgent treatment.

Pakcheung Ng    Ang Irene Ling    Rossa wai kwun Chiu    Karen Li    Hugh simon Lam    Raymond Wong    Kitman Chui    Honming Cheung    Ng Eddy W. Y.    霍泰辉    沈祖堯     卢煜明    Poon   

Journal of Clinical Investigation

2010

Background: The Asia-Pacific consensus guidelines for the management of chronic hepatitis B state that the principal indicators for starting therapy are increased HBV DNA levels (≥20,000 IU/ml for hepatitis B e antigen [HBeAg]-positive status and >2,000 IU/ml for HBeAg-negative status) and alanine aminotransferase (ALT) levels >2x the upper limit of normal. We aimed to determine whether clinicians in the Asia-Pacific region are treating patients with chronic hepatitis B according to the Asia-Pacific consensus statement on the management of chronic hepatitis B. Methods: An online survey of chronic hepatitis B treatment practices was prepared, consisting of 14 questions grouped into seven categories: patient statistics, treatment statistics, treatment decision, first-choice treatment, treatment duration, future directions and patient preference. Results: In total, 124 respondents from 12 countries completed the survey. Most respondents indicated that detectable HBV DNA was either the first or second most important factor when deciding whether to initiate therapy. Many physicians were unsure about initiation of treatment in patients >40 years of age when ALT levels were within the normal range. Oral antiviral drugs were the most frequently used medication because of their effectiveness, safety and ability to provide sustained viral suppression. Conversely, the most important reasons for selecting interferon therapy were effectiveness, fixed duration of treatment and lack of drug resistance. Criteria for stopping treatment generally followed the recommendations included in the guidelines. Conclusions: These data suggest that clinicians from the Asia-Pacific region use criteria beyond those advocated in treatment guidelines when deciding whether to initiate treatment in HBV-infected patients. ©2010 International Medical Press.

沈祖堯     Amarapurkar    Henry lik yuen Chan    Cheng Jun    Jiahorng Kao    Kwanghyub Han    Teerha Piratvisuth   

Antiviral Therapy

2010

Background and Aims: In the management of peptic ulcer bleeding, the benefits of second-look endoscopic treatment with thermal coagulation or injections in controlling recurrent bleeding is unsure. This study set out to compare efficacy of routine second-look endoscopy with treatment using either thermal coagulation or injections versus single endoscopy by pooling data from published work. Methods: Full publications in the English-language published work as well as abstracts in major international conferences were searched over the past 10 years, and six trials fulfilling the search criteria were found. Outcome measurements included: (i) recurrent bleeding; (ii) requirement of surgical intervention; and (iii) mortality. We examined heterogeneity of trials and pooled the effects by meta-analysis. The quality of studies was graded according to the prospective randomization, methods of patient allocation, the list of exclusion criteria, outcome definitions and the predefined salvage procedures for uncontrolled bleeding. Results: Among 998 patients recruited in these five randomized trials, 119 received routine second-look endoscopy with thermal coagulation, and 374 received second-look with endoscopic injection and 505 had single endoscopic therapy. Less recurrent bleeding was reported after thermal coagulation (4.2%) than single endoscopy (15.7%) (relative risk [RR] = 0.29; 95% confidence interval [CI] = 0.11-0.73), but no reduction was reported for the requirement of surgical intervention and all-cause mortality. Injection therapy did not reduce re-bleeding (17.6%) when compared to single endoscopy (20.8%; RR = 0.85; 95% CI = 0.63-1.14), requirement for surgery and mortality. Conclusion: Routine second-look endoscopy with thermal coagulation, but not injection therapy, reduced recurrent peptic ulcer bleeding. There is no proven benefit in reducing surgical intervention and overall mortality. © 2010 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.

Kelvin kf Tsoi    Chan Heyson C H    赵伟仁    Pau Carol Y.Y.    James Lau    沈祖堯    

Journal of Gastroenterology and Hepatology (Australia)

2010

OBJECTIVES:Despite advances in endoscopic and pharmacological treatment for peptic ulcer bleeding (PUB), mortality remains at 5-10% worldwide. Our aim was to investigate the causes of death in a prospective cohort of PUB in a tertiary referral center.METHODS:Between 1993 and 2005, all patients with upper gastrointestinal bleeding (UGIB) admitted to the Prince of Wales Hospital were prospectively registered. Demographic data, characteristics of ulcer, and pharmacological, endoscopic, and surgical therapy, were documented. Mortality cases were classified as (A) bleeding-related death (A1: uncontrolled bleeding, A2: within 48 h after endoscopy, A3: during surgery for uncontrolled bleeding, A4: surgical complications or within 1 month after surgery, and A5: endoscopic related mortality) or (B) non-bleeding-related death (B1: cardiac causes, B2: pulmonary causes, B3: cerebrovascular disease, B4: multiorgan failure, and B5: terminal malignancy).RESULTS:In all, 18,508 cases of UGIB were enrolled; among them, 10,428 cases from 9,375 patients were confirmed to have PUB, and 577 (6.2%) patients died. There were significantly more patients who died of non-ulcer bleeding causes (79.7%) than bleeding causes (18.4%). The mean (s.d.) age of those who died of bleeding-related causes was higher (75.4 (12.6) years) than that of those who died of non-bleeding causes (71.7 (13.1) years) (P0.010). Most bleeding-related deaths occurred when immediate control of bleeding failed (29.2%) or when patients died within 48 h after endoscopic therapy (25.5%). Among those who died of non-bleeding-related causes, multiorgan failure (23.9%), pulmonary conditions (23.5%), and terminal malignancy (33.7%) were most common.CONCLUSIONS:The majority of PUB patients died of non-bleeding-related causes. Optimization of management should aim at reducing the risk of multiorgan failure and cardiopulmonary death instead of focusing merely on successful hemostasis. © 2010 by the American College of Gastroenterology.

沈祖堯     Kelvin kf Tsoi    Ma Terry K.W.    Manyee Yung    James Lau    赵伟仁   

American Journal of Gastroenterology

2010

OBJECTIVES:Chronic hepatitis B patients with diabetes and metabolic syndrome are at increased risk of cirrhosis and hepatocellular carcinoma, but the underlying mechanism is unclear. Our objective was to test whether dysregulation of adipokines contributes to liver injury. We also studied whether viral factors affected adipokines, insulin resistance, and hepatic steatosis.METHODS:A prospective cohort of 266 chronic hepatitis B patients undergoing liver biopsy was studied. Fasting blood was taken for the analysis of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), adiponectin, leptin, and resistin. Insulin resistance was assessed by the homeostasis model assessment of insulin resistance (HOMA-IR). Factors associated with significant necroinflammation and cirrhosis were identified.RESULTS:Histological activity index was correlated with serum TNF-α (R0.40, P0.0001) and IL-6 (R0.32, P0.0001) but not with adiponectin, leptin, or resistin. By multivariate analysis, TNF-α was associated with significant necroinflammation after adjusting for age and viral factors (odds ratio (OR) 1.041, 95% confidence interval (CI) 1.002-1.082, P0.04). Serum adiponectin had positive correlation with hepatitis B virus DNA (R0.17, P0.007) and was decreased in patients with insulin resistance and hepatic steatosis. On the other hand, viral load, hepatitis B e-antigen status, and genotypes had no association with insulin resistance, hepatic steatosis, and the levels of TNF-α and IL-6. A total of 68 (25.6%) patients had cirrhosis. HOMA-IR, but not adipokine dysregulation, was independently associated with cirrhosis (OR 1.09, 95% CI 1.02-1.15, P0.006).CONCLUSIONS:TNF-α and/or IL-6 contribute to hepatic necroinflammation in chronic hepatitis B patients. Adiponectin protects against insulin resistance and hepatic steatosis but does not affect liver injury. Adipokines and viral factors contribute to liver injury independently. © 2010 by the American College of Gastroenterology.

Vincent Wong    Grace Wong    于俊    |蔡祥龙    Anthony wing hong Chan    Hoiyun Chan    Eagle Chu    Alfred Cheng    Angel mei ling Chim    Francis Chan    沈祖堯     Henry lik yuen Chan   

American Journal of Gastroenterology

2010

We report acute encephalopathy associated with influenza A infection in 3 adults. We detected high cerebrospinal fluid (CSF) and plasma concentrations of CXCL8/IL-8 and CCL2/MCP-1 (CSF/plasma ratios >3), and interleukin-6, CXCL10/IP-10, but no evidence of viral neuroinvasion. Patients recovered without sequelae. Hyperactivated cytokine response may play a role in pathogenesis.

李礼舜    Chunkwok Wong    Paul Chan    Lindegardh Niklas    Nicholas White    Hayden Frederick G.    Wong Edward H    Wong Ka Shing    Clive stewart Cockram    沈祖堯     David Hui   

Emerging Infectious Diseases

2010

Background: It is uncertain whether aspirin therapy should be continued after endoscopic hemostatic therapy in patients who develop peptic ulcer bleeding while receiving low-dose aspirin. Objective: To test that continuing aspirin therapy with protonpump inhibitors after endoscopic control of ulcer bleeding was not inferior to stopping aspirin therapy, in terms of recurrent ulcer bleeding in adults with cardiovascular or cerebrovascular diseases. Design: A parallel randomized, placebo-controlled noninferiority trial, in which both patients and clinicians were blinded to treatment assignment, was conducted from 2003 to 2006 by using computergenerated numbers in concealed envelopes. (ClinicalTrials.gov registration number: NCT00153725) Setting: A tertiary endoscopy center. Patients: Low-dose aspirin recipients with peptic ulcer bleeding. Intervention: 78 patients received aspirin, 80 mg/d, and 78 received placebo for 8 weeks immediately after endoscopic therapy. All patients received a 72-hour infusion of pantoprazole followed by oral pantoprazole. All patients completed follow-up. Measurements: The primary end point was recurrent ulcer bleeding within 30 days confirmed by endoscopy. Secondary end points were all-cause and specific-cause mortality in 8 weeks. Results: 156 patients were included in an intention-to-treat analysis. Three patients withdrew from the trial before finishing followup. Recurrent ulcer bleeding within 30 days was 10.3% in the aspirin group and 5.4% in the placebo group (difference, 4.9 percentage points [95% CI, -3.6 to 13.4 percentage points]). Patients who received aspirin had lower all-cause mortality rates than patients who received placebo (1.3% vs. 12.9%; difference, 11.6 percentage points [CI, 3.7 to 19.5 percentage points]). Patients in the aspirin group had lower mortality rates attributable to cardiovascular, cerebrovascular, or gastrointestinal complications than patients in the placebo group (1.3% vs. 10.3%; difference, 9 percentage points [CI, 1.7 to 16.3 percentage points]). Limitations: The sample size is relatively small, and only low-dose aspirin, 80 mg, was used. Two patients with recurrent bleeding in the placebo group did not have further endoscopy. Conclusion: Among low-dose aspirin recipients who had peptic ulcer bleeding, continuous aspirin therapy may increase the risk for recurrent bleeding but potentially reduces mortality rates. Larger trials are needed to confirm these findings. © 2010 American College of Physicians.

沈祖堯     James Lau    Jessica Ching    胡志    Yuktong Lee    赵伟仁    Vincent Leung    Vincent Wong    Francis Chan   

Annals of Internal Medicine

2010

Background: Gastrojejunal anastomosis is commonly performed for palliative management of malignant gastric outlet obstruction and bariatric surgery. Natural orifice transluminal endoscopic surgery revolutionized the surgical approach to intra-abdominal surgery. This study explored the possibility of performing gastrojejunostomy (GJ) by using a hybrid natural orifice transluminal endoscopic surgery approach. Objective: To develop a surgical technique for the performance of transgastric endoscopic GJ (TGEJ) in a porcine model. Design: Prospective series of animal experiments. Setting: University hospital animal laboratory. Animals: Thirteen female domestic pigs. Interventions: With the animals under general anesthesia, the endoscope is passed through the gastrotomy and a segment of small bowel is retrieved into the stomach. An enterotomy is then created, and an EndoGIA stapler is introduced through an intragastric port and passed between the small bowel and stomach wall. A GJ is formed after firing of the EndoGIA stapler. The pigs are allowed to resume their diet 1 day after the operation and are allowed to survive for 2 weeks before they are euthanized. The patency of the GJ is confirmed with a repeat endoscopy, contrast study, and postmortem examination. Results: A total of 13 TEGJs were performed, 11 of which were successful. The mean operative time was 53.6 ± 45.7 minutes. The mean time for gastrotomy was 4.7 minutes, and that for GJ was 42.5 minutes. One TEGJ was converted to open surgery because of malpositioning of the intragastric port, and the other failed because the enterotomy was too extensive. Ten of 11 pigs survived for 2 weeks, and endoscopic examination with contrast study confirmed that all the gastrojejunostomies were patent. On postmortem examination, the average size of the GJ was 30 mm. Limitations: The length between duodenojejunal flexure and the site chosen to perform the GJ could not be determined. Conclusions: TEGJ is technically feasible with a patent and sizable anastomosis. © 2010 American Society for Gastrointestinal Endoscopy.

赵伟仁    Wai Ng Enders Kwok    Teoh Anthony Yun Bun    Candice Lam    James Lau    沈祖堯    

Gastrointestinal Endoscopy

2010

Objectives: The association of interleukin-1B (IL-1B)-511 polymorphism with gastric cancer is still controversial, and the association of IL-1B-511 polymorphism with subtypes of gastric cancer is still largely unknown. We investigated whether the association between IL-1B-511 polymorphism and gastric cancer risk varies by clinically important tumor characteristics and the prognostic value of this polymorphism in a large population-based case-control study among Chinese.Methods: A population-based case-control study was conducted between 1999 and 2006 in Guangdong Province, China. A total of 1,010 gastric cancer patients and 1,500 healthy controls were enrolled in this study. Polymorphism in IL-1B-511 was analyzed by PCR-restriction fragment length polymorphism on 501 gastric cancers and 500 healthy controls.Results: Compared with the CC genotype, carriers of IL-1B-511 TT genotype had an increased gastric cancer risk (odds ratio (OR)=1.97, 95% confidence interval (CI)=1.29-3.01, P=0.0016). TT genotype was significantly associated with intestinal type of gastric cancer (OR=3.16, 95% CI1.74-5.71, P=0.0001) but not with diffuse or mixed-type gastric cancer. The test for OR heterogeneity between the intestinal-type and non-intestinal-type gastric cancers was statistically significant (P0.02). In subgroup analyses, TT genotype was found to be associated with poorly differentiated gastric cancer (OR=3.31, 95% CI1.43-3.60, P<0.0001), but not with moderately or well-differentiated gastric cancer. IL-1B-511 genotypes were not associated with the prognosis of gastric cancer patients.Conclustions: IL-1B polymorphism influences certain subtypes of gastric cancer according to the clinical and pathological features. Understanding the etiologic heterogeneity of gastric cancer may result in improvements in controlling this disorder. © 2010 by the American College of Gastroenterology.

Jun Yu    曾志荣    Shiyan Wang    Linwei Tian    Jian Wu    Ling Xue    Chungwa Lee    Zhang Mingdong    William bernard Goggins    陈旻湖    Pinjin Hu    沈祖堯    

American Journal of Gastroenterology

2010