Ming-Shiang Wu

Screening for gastric cancer in Asia: current evidence and practice

Gastric cancer is the second most common cause of death from cancer in Asia. Although surgery is the standard treatment for this disease, early detection and treatment is the only way to reduce mortality. This Review summarises the epidemiology of gastric cancer, and the evidence for, and current practices of, screening in Asia. Few Asian countries have implemented a national screening programme for gastric cancer; most have adopted opportunistic screening of high-risk individuals only. Although screening by endoscopy seems to be the most accurate method for detection of gastric cancer, the availability of endoscopic instruments and expertise for mass screening remains questionable--even in developed countries such as Japan. Therefore, barium studies or serum-pepsinogen testing are sometimes used as the initial screening tool in some countries, and patients with abnormal results are screened by endoscopy. Despite the strong link between infection with Helicobacter pylori and gastric cancer, more data are needed to define the role of its eradication in the prevention of gastric cancer in Asia. At present, there is a paucity of quality data from Asia to lend support for screening for gastric cancer.

A prospective comparative study of narrow-band imaging, chromoendoscopy, and conventional colonoscopy in the diagnosis of colorectal neoplasia

Background: Discrimination between neoplastic and non-neoplastic lesions is crucial in colorectal cancer screening. Application of narrow-band imaging (NBI) in colonoscopy visualises mucosal vascular networks in neoplastic lesions and may improve diagnostic accuracy. Aim: To compare the diagnostic efficacy of NBI in differentiating neoplastic from non-neoplastic colorectal lesions with diagnostic efficacies of standard modalities, conventional colonoscopy, and chromoendoscopy. Methods: In this prospective study, 180 colorectal lesions from 133 patients were observed with conventional colonoscopy, and under low-magnification and high-magnification NBI and chromoendoscopy. Lesions were resected for histopathological analysis. Endoscopic images were stored electronically and randomly allocated to two readers for evaluation. Sensitivity, specificity and diagnostic accuracy of each endoscopic modality were assessed by reference to histopathology. Results: NBI and chromoendoscopy scored better under high magnification than under low magnification in comparison with conventional colonoscopy. The diagnostic accuracy of NBI with low or high magnification was significantly higher than that of conventional colonoscopy (low magnification: p = 0.0434 for reader 1 and p = 0.004 for reader 2; high magnification: p<0.001 for both readers) and was comparable to that of chromoendoscopy. Conclusion: Both low-magnification and high-magnification NBI were capable of distinguishing neoplastic from non-neoplastic colorectal lesions; the diagnostic accuracy of NBI was better than that of conventional colonoscopy and equivalent to that of chromoendoscopy. The role of NBI in screening colonoscopy needs further evaluation.

Metformin decreases hepatocellular carcinoma risk in a dose-dependent manner: population-based and in vitro studies

Objective Type 2 diabetes mellitus is associated with a higher risk of hepatocellular carcinoma (HCC), which is attenuated by the use of metformin. However, there are no studies addressing the effect of metformin on hepatocarcinoma cells from the antitumoural perspective. Design In the nationwide case-control study, the authors recruited 97 430 HCC patients and 194 860 age-, gender- and physician visit date-matched controls. The chemopreventive effects of metformin were examined by multivariate analysis and stratified analysis. The in vitro effects of metformin on cell proliferation and cell cycle were studied in HepG2 and Hep3B hepatoma cell lines. Results The OR of diabetes in HCC patients was 2.29 (95% CI 2.25 to 2.35, p<0.001). Each incremental year increase in metformin use resulted in 7% reduction in the risk of HCC in diabetic patients (adjusted OR=0.93, 95% CI 0.91 to 0.94, p<0.0001). In the multivariate stratified analysis, metformin use was associated with a reduced risk of HCC in diabetic patients in nearly all subgroups. Cell line studies showed that metformin inhibits hepatocyte proliferation and induces cell cycle arrest at G0/G1 phase via AMP-activated protein kinase and its upstream kinase LKB1 to upregulate p21/Cip1 and p27/Kip1 and downregulate cyclin D1 in a dose-dependent manner, but independent of p53. Combined treatment of oral metformin with doxorubicin functioned more efficiently than either agent alone, in vivo. Conclusions Use of metformin is associated with a decreased risk of HCC in diabetic patients in a dose-dependent manner, via inhibition of hepatoma cells proliferation and induction of cell cycle arrest at G0/G1 phase.

Early Helicobacter pylori Eradication Decreases Risk of Gastric Cancer in Patients With Peptic Ulcer Disease

BACKGROUND & AIMS Helicobacter pylori (H pylori) is a risk factor for gastric cancer. We investigated whether early H pylori eradication is associated with gastric cancer risk in patients with peptic ulcer diseases. METHODS This nationwide cohort study was based on the Taiwan National Health Insurance Database (NHID), which provided data on 80,255 patients who were hospitalized for the first time between 1997 and 2004 with a primary diagnosis of peptic ulcer diseases and received H pylori eradication therapy. The patient population was divided into early (within 1 year) and late (after 1 year) eradication cohorts; standardized incidence ratios (SIRs) and hazards ratios (HRs) were determined. RESULTS There was no significant difference in gastric cancer risk between patients who received early H pylori eradication and the general population (SIR, 1.05; 95% confidence interval [CI]: 0.96-1.14), but late eradication was associated with an increased risk (SIR, 1.36; 95% CI: 1.24-1.49). In gastric ulcer patients who received early eradication, SIRs of gastric cancer decreased from 1.60 at 3-4 years to 1.05 at 7-10 years after hospitalization; the SIRs decreased from 0.57 to 0.33 for duodenal ulcer patients over the same period. Among patients who received late eradication, SIRs decreased from 2.14 to 1.32 for those with gastric ulcers and from 0.90 to 0.66 for those with duodenal ulcers. Early H pylori eradication (HR, 0.77) and frequent aspirin or nonsteroidal anti-inflammatory drug use (HR, 0.65) were independent protective factors for gastric cancer. CONCLUSIONS Early H pylori eradication is associated with decreased risk of gastric cancer in patients with peptic ulcer diseases.

Interleukin-10 genotypes associate with the risk of gastric carcinoma in Taiwanese Chinese.

The association of cytokine genotypes with gastric carcinoma (GC) may be influenced by environmental factors and varies among different populations. Few studies have addressed the impact of different cytokine genotypes on the development and progression of GC. We analyzed 11 functional polymorphisms in tumor necrosis factor‐α (TNF‐α), interleukin (IL)‐1, IL‐4 and IL‐10 genes in 220 Taiwanese Chinese with GC and in 230 healthy controls. The risk of genotypes was adjusted with confounding environmental risks. Our results revealed that the frequency of Helicobacter pylori infection [odds ratio (OR) 1.7, 95% confidence interval (CI) 1.19–2.56], cigarette smoking (OR 2.02, 95% CI 1.38–2.95) and high IL‐10 producer genotype (OR 2.67, 95% CI 1.29–5.50) was significantly increased in the entire GC patients. Among different subtypes of GC, a higher risk of developing diffuse type (OR 1.64, 95% CI 1.01–2.67) or cardia cancer (OR 2.44, 95% CI 1.13–2.67) was observed for the CT/CC genotype of IL‐4 at the position −590, whereas the high IL‐10 producer genotype was significantly linked with the risk of cardia cancer (OR 3.21, 95% CI 1.06–9.73) or advanced stage (OR 2.29, 95% CI 1.12–4.64). No association was noted between GC and controls in the distribution of IL‐1 and TNF‐α genotypes. Logistic regression analyses revealed that H. pylori infection (OR 1.7, 95% CI 1.14–2.52), cigarette smoking (OR 1.87, 95% CI 1.27–‐2.96) and IL‐10 genotype (OR 2.54, 95% CI 1.24–5.61) are independent risks for GC. Independent effects of IL‐10 genotype, H. pylori infection and cigarette smoking indicate that carcinogenesis of GC is influenced by a variety of host and environmental factors.

Sequential versus triple therapy for the first-line treatment of Helicobacter pylori: a multicentre, open-label, randomised trial

BACKGROUND Whether sequential treatment can replace triple therapy as the standard treatment for Helicobacter pylori infection is unknown. We compared the efficacy of sequential treatment for 10 days and 14 days with triple therapy for 14 days in first-line treatment. METHODS For this multicentre, open-label, randomised trial, we recruited patients (≥20 years of age) with H pylori infection from six centres in Taiwan. Using a computer-generated randomisation sequence, we randomly allocated patients (1:1:1; block sizes of six) to either sequential treatment (lansoprazole 30 mg and amoxicillin 1 g for the first 7 days, followed by lansoprazole 30 mg, clarithromycin 500 mg, and metronidazole 500 mg for another 7 days; with all drugs given twice daily) for either 10 days (S-10) or 14 days (S-14), of 14 days of triple therapy (T-14; lansoprazole 30 mg, amoxicillin 1 g, and clarithromycin 500 mg for 14 days; with all drugs given twice daily). Investigators were masked to treatment allocation. Our primary outcome was the eradication rate in first-line treatment by intention-to-treat (ITT) and per-protocol (PP) analyses. This trial is registered with ClinicalTrials.gov, number NCT01042184. FINDINGS Between Dec 28, 2009, and Sept 24, 2011, we enrolled 900 patients: 300 to each group. The eradication rate was 90·7% (95% CI 87·4-94·0; 272 of 300 patients) in the S-14 group, 87·0% (83·2-90·8; 261 of 300 patients) in the S-10 group, and 82·3% (78·0-86·6; 247 of 300 patients) in the T-14 group. Treatment efficacy was better in the S-14 group than it was in the T-14 group in both the ITT analysis (number needed to treat of 12·0 [95% CI 7·2-34·5]; p=0·003) and PP analyses (13·7 [8·3-40], p=0·003). We recorded no significant difference in the occurrence of adverse effects or in compliance between the three groups. INTERPRETATION Our findings lend support to the use of sequential treatment as the standard first-line treatment for H pylori infection. FUNDING National Taiwan University Hospital and National Science Council.

The benefit of mass eradication of Helicobacter pylori infection: a community-based study of gastric cancer prevention

Objective To evaluate the benefit of mass eradication of Helicobacter pylori infection in reducing premalignant gastric lesions. Design Mass eradication of H pylori infection was started from 2004 for a Taiwanese population with prevalent H pylori infection, who were >30 years of age. Participants positive for the 13C-urea breath test underwent endoscopic screening and 1-week clarithromycin-based triple therapy. For subjects whose initial treatment failed, 10-day levofloxacin-based triple therapy was administered. The main outcome measures were changes in the prevalence of H pylori infection and premalignant gastric lesions, and changes in the incidence of premalignant gastric lesions and gastric cancer before (1995–2003) and after (2004–2008) chemoprevention using various comparators. Results The reduction in H pylori infection was 78.7% (95% CI 76.8% to 80.7%), and the estimated incidence of re-infection/recrudescence was 1% (95% CI 0.6% to 1.4%) per person-year. The effectiveness of reducing the incidence of gastric atrophy resulting from chemoprevention was significant at 77.2% (95% CI 72.3% to 81.2%), while the reduction in intestinal metaplasia was not significant. Compared with the 5-year period before chemoprevention and in the absence of endoscopic screening, the effectiveness in reducing gastric cancer incidence during the chemoprevention period was 25% (rate ratio 0.753, 95% CI 0.372 to 1.524). The reduction in peptic ulcer disease was 67.4% (95% CI 52.2% to 77.8%), while the incidence of oesophagitis was 6% (95% CI 5.1% to 6.9%) after treatment. Conclusions Population-based eradication of H pylori infection has led to a significant reduction in gastric atrophy at the expense of increased oesophagitis. The ultimate benefit in reducing gastric cancer incidence and its mortality should be validated by a further long-term follow-up. Trial registration number NCT00155389.

Rational Helicobacter pylori Therapy: Evidence-Based Medicine Rather Than Medicine-Based Evidence

Data are available such that choice of Helicobacter pylori therapy for an individual patient can be reliably predicted. Here, treatment success is defined as a cure rate of 90% or greater. Treatment outcome in a population or a patient can be calculated based on the effectiveness of a regimen for infections with susceptible and with resistant strains coupled with the knowledge of the prevalence of resistance (ie, based on formal measurement, clinical experience, or both). We provide the formula for predicting outcome and we illustrate the calculations. Because clarithromycin-containing triple therapy and 10-day sequential therapy are now only effective in special populations, they are considered obsolete; neither should continue to be used as empiric therapies (ie, 7- and 14-day triple therapies fail when clarithromycin resistance exceeds 5% and 15%, respectively, and 10-day sequential therapy fails when metronidazole resistance exceeds 20%). Therapy should be individualized based on prior history and whether the patient is in a high-risk group for resistance. The preferred choices for Western countries are 14-day concomitant therapy, 14-day bismuth quadruple therapy, and 14-day hybrid sequential-concomitant therapy. We also provide details regarding the successful use of fluoroquinolone-, rifabutin-, and furazolidone-containing therapies. Finally, we provide recommendations for the efficient development (ie, identification and optimization) of new regimens, as well as how to prevent or minimize failures. The trial-and-error approach for identifying and testing regimens frequently resulted in poor treatment success. The described approach allows outcome to be predicted and should simplify treatment and drug development.

Antiviral treatment for hepatitis C virus infection is associated with improved renal and cardiovascular outcomes in diabetic patients

Hepatitis C virus (HCV) infection is causally associated with insulin resistance and diabetes mellitus. This population‐based cohort study aimed to investigate whether antiviral therapy for HCV infection was associated with improved clinical outcomes related to diabetes. From the Taiwan National Health Insurance Research Database, 2,267,270 Taiwanese residents diagnosed with diabetes mellitus were screened for eligibility. HCV infection was defined by a specific diagnosis code and measurement of serum antibody. After excluding patients with serious comorbidity, we enrolled a total of 1,411 eligible patients who received pegylated interferon plus ribavirin (treated cohort), and matched them 1:1 with 1,411 untreated controls by propensity scores (untreated cohort). We also matched the treated cohort 1:4 with 5,644 diabetic patients without HCV infection (uninfected cohort). Participants were followed up for the occurrence of endstage renal disease (ESRD), ischemic stroke, and acute coronary syndrome (ACS) after receiving antiviral treatment or the corresponding calendar date. From 2003 to 2011, the 8‐year cumulative incidences of ESRD in the treated, untreated, and uninfected cohorts were 1.1% (95% confidence interval [CI], 0.3‐2.0%), 9.3% (95% CI, 5.9‐12.7%), and 3.3% (95% CI, 2.3‐4.3%), respectively (P < 0.001); those of stroke were 3.1% (95% CI, 1.1‐5.0%), 5.3% (95% CI, 3.0‐7.5%), and 6.1% (95% CI, 4.8‐7.4%), respectively (P = 0.01); and those for ACS were 4.1% (95% CI, 2.1‐6.1%), 6.6% (95% CI, 3.7‐9.5%), and 7.4% (95% CI, 5.9‐9.0%), respectively (P = 0.05). As compared with the untreated cohort, antiviral treatment was associated with multivariate‐adjusted hazard ratios of 0.16 (95% CI, 0.07‐0.33%) for ESRD, 0.53 (95% CI, 0.30‐0.93) for ischemic stroke, and 0.64 (95% CI, 0.39‐1.06) for ACS. Conclusion: Antiviral treatment for HCV infection is associated with improved renal and cardiovascular outcomes in diabetic patients. (Hepatology 2014;59:1293‐1302)

Genetic alterations in gastric cancer: relation to histological subtypes, tumor stage, and Helicobacter pylori infection

BACKGROUND & AIMS A different spectrum of genetic changes including p53, c-erbB-2, c-met, adenomatous polyposis coli (APC), and deleted in colorectal cancer (DCC) is involved in gastric cancer (GC). The aim of this study was to correlate these alterations with histological subtypes, tumor stages, and Helicobacter pylori infection. METHODS Specimens of 163 patients with GC were immunostained for p53, c-erbB-2, and c-met, and polymerase chain reaction was performed in them to determine loss of heterozygosity (LOH) of APC and DCC. RESULTS Overexpression of p53 was more frequent in early intestinal than early diffuse GC and was noted in the stage progression of diffuse but not intestinal GC. Overexpression of c-erbB-2 occurred more commonly in intestinal GC and advanced GC of both types. Overexpression of c-met was greater in diffuse GC, particularly at advanced stage. LOH of APC was more common in intestinal GC irrespective of the stage but rarely in diffuse GC. LOH of DCC occurred primarily in advanced intestinal GC and infrequently in early GC or advanced diffuse GC. Alterations of these five genes were not correlated with H. pylori infection. CONCLUSIONS A distinct genetic pathway exists in gastric carcinogenesis of different histological subtypes and their tumor progression, in which H. pylori infection may play an equal role or no role.