Wk Leung

Increasing incidence of colorectal cancer in Asia: implications for screening

Many Asian countries, including China, Japan, South Korea, and Singapore, have experienced an increase of two to four times in the incidence of colorectal cancer during the past few decades. The rising trend in incidence and mortality from colorectal cancer is more striking in affluent than in poorer societies and differs substantially among ethnic groups. Although changes in dietary habits and lifestyle are believed to be the reasons underlying the increase, the interaction between these factors and genetic characteristics of the Asian populations might also have a pivotal role. Non-polypoidal (flat or depressed) lesions and colorectal neoplasms arising without preceding adenoma (de novo cancers) seem to be more common in Asian than in other populations. The absence of polypoid growth preceding malignancy has posed difficulties in screening for early colorectal cancer by radiological imaging or even endoscopic techniques. Although epidemiological data are scanty, most Asian populations are not aware of the growing problem of colorectal cancer. More work is needed to elucidate the magnitude of the problem in Asia.

Eradication of Helicobacter pylori and risk of peptic ulcers in patients starting long-term treatment with non-steroidal anti-inflammatory drugs: a randomised trial.

BACKGROUND Whether Helicobacter pylori increases the risk of ulcers in patients taking non-steroidal anti-inflammatory drugs (NSAIDs) is controversial. We hypothesised that eradication of H pylori infection would reduce the risk of ulcers for patients starting long-term NSAID treatment. METHODS Patients were enrolled if they were NSAID naïve, had a positive urea breath test, had dyspepsia or an ulcer history, and required long-term NSAID treatment. They were randomly assigned omeprazole triple therapy (eradication group) or omeprazole with placebo antibiotics (placebo group) for 1 week. All patients were given diclofenac slow release 100 mg daily for 6 months from randomisation. Endoscopy was done at 6 months or if severe dyspepsia or gastrointestinal bleeding occurred. The primary endpoint was the probability of ulcers within 6 months. Analyses were by intention to treat. FINDINGS Of 210 arthritis patients screened, 128 (61%) were positive for H pylori. 102 patients were enrolled, and 100 were included in the intention-to-treat analysis. H pylori was eradicated in 90% of the eradication group and 6% of the placebo group. Five of 51 eradication-group patients and 15 of 49 placebo-group patients had ulcers. The 6-month probability of ulcers was 12.1% (95% CI 3.1-21.1) in the eradication group and 34.4% (21.1-47.7) in the placebo group (p=0.0085). The corresponding 6-month probabilities of complicated ulcers were 4.2% (1.3-9.7) and 27.1% (14.7-39.5; p=0.0026). INTERPRETATION Screening and treatment for H pylori infection significantly reduces the risk of ulcers for patients starting long-term NSAID treatment.

Intestinal metaplasia and gastric carcinogenesis

Gastric intestinal metaplasia, an intermediate step in Correas cascade of gastric carcinogenesis, is generally regarded as a pre‐malignant lesion. Epidemiological studies suggest that patients with intestinal metaplasia have more than a 10‐fold increased risk of developing gastric cancer. Within the subclassification of intestinal metaplasia, incomplete or type III intestinal metaplasia appears to be associated with even higher malignant potential. The topographical distribution of intestinal metaplasia may also have prognostic implications. Certain genetic and epigenetic alterations have been demonstrated in gastric intestinal metaplasia which straddle into gastric cancer. These findings suggest that genetic changes occur early in the multistep gastric carcinogenesis process. Unlike Barretts oesophagus and colonic polyp, which have well‐defined surveillance guidelines, there is no widely accepted surveillance programme for gastric intestinal metaplasia. An annual surveillance programme may allow early detection of gastric cancer, which theoretically may improve survival. It remains elusive whether the treatment of Helicobacter pylori infection may reverse gastric intestinal metaplasia or reduce the subsequent risk of cancer development. Further controlled studies with longer follow‐up are needed to resolve this controversy. The role of chemo‐prophylactic agents, e.g. cyclo‐oxygenase‐2 inhibitor, should be investigated.

Association between cyclo-oxygenase-2 overexpression and missense p53 mutations in gastric cancer

Wild-type p53 competitively binds to the promoter region of COX-2 in vitro and inhibits its transcription. We examined the association between p53 mutation and COX-2 expression in gastric cancer. COX-2 over-expression was seen in 19 (48.7%) cases. These tumours had more lymph-node metastasis (P = 0.048) and tended to have a poorer survival (P = 0.07). Missense mutations of p53 were detected in 20 (51.3%) patients and had a significantly stronger COX-2 expression than tumours without p53 mutation (P = 0.016). Our results suggest a link between p53 mutation and COX-2 overexpression in gastric cancer.

Frequent epigenetic inactivation of secreted frizzled-related protein 2 (SFRP2) by promoter methylation in human gastric cancer

The role of secreted frizzled-related protein (SFRP) genes in gastric cancer remains largely unknown. We determined the frequency and functional significance of SFRPs hypermethylation in human gastric cancer. The expression and methylation status of four SFRP members (SFRP1, 2, 4, and 5) in primary gastric cancer samples was screened. The biological effects of SFRP were analysed by flow cytometry, cell viability assay and in vivo tumour growth in nude mice. Among the four SFRPs, only SFRP2 was significantly downregulated in gastric cancer as compared to adjacent non-cancer samples (P<0.01). Promoter hypermethylation of SFRP2 was detected in 73.3% primary gastric cancer tissues, 37.5% of samples showing intestinal metaplasia and 20% adjacent normal gastric tissues. Bisulphite DNA sequencing confirmed the densely methylated SFRP2 promoter region. Demethylation treatment restored the expression of SFRP2 in gastric cancer cell lines. Forced expression of SFRP2 induced cell apoptosis, inhibited proliferation of gastric cancer cells and suppressed tumour growth in vivo. Moreover, methylated SFRP2 was detected in 66.7% of serum samples from cancer patients but not in normal controls. In conclusion, epigenetic inactivation of SFRP2 is a common and early event contributing to gastric carcinogenesis and may be a potential biomarker for gastric cancer.

Prevalence and distribution of Helicobacter pylori in gastroesophageal reflux disease: a study from the East

OBJECTIVES:The relationship between Helicobacter pylori infection and gastroesophageal reflux (H. pylori) disease (GERD) is controversial. In Asian populations, the prevalence of H. pylori infection is high and GERD is relatively uncommon. The aim of this study was 1) to test the hypothesis that H. pylori protects the esophagus against GERD, and 2) to study the pattern of H. pylori colonization and gastritis in GERD.METHODS:We conducted a prospective case-control study in which patients with GERD and asymptomatic controls were compared for the prevalence of H. pylori infection. Diagnosis of GERD was based on symptoms of heartburn that improved with acid-suppressive therapy and/or endoscopic evidence of erosive esophagitis. H. pylori status was determined by serology and, when endoscopy was indicated, was confirmed by rapid urease test and histology. Gastric biopsies were examined under hematoxylin and eosin and Giemsa stains. Density of H. pylori colonization and activity of gastritis at different parts of stomach were graded and compared according to Updated Sydney system.RESULTS:A total of 106 patients with GERD and 120 age- and sex-matched, asymptomatic controls were enrolled. The prevalence of H. pylori infection was significantly lower in GERD patients (31%) compared with controls (61%, p < 0.001, odds ratio 0.229, 95% confidence interval 0.13–0.41). H. pylori-infected GERD patients showed significantly more severe gastritis in the antrum than in other parts of stomach (mean inflammatory scores: antrum; 3.3 ± 1.63*, body; 1.85 ± 1.31; fundus; 1.65 ± 0.58; cardia, 1.65 ± 1.39; *p < 0.005). H. pylori colonization was found less commonly and at lower density at the cardia compared with other parts of the stomach.CONCLUSIONS:H. pylori infection protects against the development of GERD, and carditis is unlikely to play an important role.

Potential diagnostic and prognostic values of detecting promoter hypermethylation in the serum of patients with gastric cancer

While there is no reliable serum biomarker for the diagnosis and monitoring of patients with gastric cancer, we tested the potential diagnostic and prognostic values of detecting methylation changes in the serum of gastric cancer patients. DNA was extracted from the pretherapeutic serum of 60 patients with confirmed gastric adenocarcinoma and 22 age-matched noncancer controls. Promoter hypermethylation in 10 tumour-related genes (APC, E-cadherin, GSTP1, hMLH1, MGMT, p15, p16, SOCS1, TIMP3 and TGF-beta RII) was determined by quantitative methylation-specific PCR (MethyLight). Preferential methylation in the serum DNA of gastric cancer patients was noted in APC (17%), E-cadherin (13%), hMLH1 (41%) and TIMP3 (17%) genes. Moreover, patients with stages III/IV diseases tended to have higher concentrations of methylated APC (P=0.08), TIMP3 (P=0.005) and hMLH1 (P=0.03) in the serum. In all, 33 cancers (55%) had methylation detected in the serum in at least one of these four markers, while three normal subjects had methylation detected in the serum (specificity 86%). The combined use of APC and E-cadherin methylation markers identified a subgroup of cancer patients with worse prognosis (median survival 3.3 vs 16.1 months, P=0.006). These results suggest that the detection of DNA methylation in the serum may carry both diagnostic and therapeutic values in gastric cancer patients.

Predicting Mortality in Patients With Bleeding Peptic Ulcers After Therapeutic Endoscopy

BACKGROUND & AIMS Despite advances in management of patients with bleeding peptic ulcers, mortality is still 10%. This study aimed to identify predictive factors and to develop a prediction model for mortality among patients with bleeding peptic ulcers. METHODS Consecutive patients with endoscopic stigmata of active bleeding, visible vessels, or adherent clots were recruited, and risk factors for mortality were identified in this deprivation cohort by using multiple stepwise logistic regression. A prediction model was then built on the basis of these factors and validated in the evaluation cohort. RESULTS From 1993 to 2003, 3220 patients with bleeding peptic ulcers were treated. Two hundred eighty-four of the patients developed rebleeding (8.8%); emergency surgery was performed on 47 of these patients, whereas others were managed with endoscopic retreatment. Two hundred twenty-nine of these sustained in-hospital death (7.1%). In patients older than 70 years, presence of comorbidity, more than 1 listed comorbidity, hematemesis on presentation, systolic blood pressure below 100 mm Hg, in-hospital bleeding, rebleeding, and need for surgery were significant predictors for mortality. Helicobacter pylori-related ulcers had lower risk of mortality. The receiver operating characteristic curve comparing the prediction of mortality with actual mortality showed an area under the curve of 0.842. From 2004 to 2006, data were collected prospectively from a second cohort of patients with bleeding peptic ulcers, and mortality was predicted by using the model developed. The receiver operating characteristic curve showed an area under the curve of 0.729. CONCLUSIONS Among patients with bleeding peptic ulcers after endoscopic hemostasis, advanced age, presence of listed comorbidity, multiple comorbidities, hypovolemic shock, in-hospital bleeding, rebleeding, and need for surgery successfully predicted in-hospital mortality.

Effect of Helicobacter pylori eradication on oesophageal acid exposure in patients with reflux oesophagitis.

The effect of Helicobacter pylori eradication on reflux oesophagitis is unclear.

False-negative biopsy urease test in bleeding ulcers caused by the buffering effects of blood

Objectives:A false-negative biopsy urease test (BUT) is common in Helicobacter pylori-associated bleeding peptic ulcers. Although blood in the stomach is thought to interfere with the biopsy urease test, the underlying mechanism remains unknown. This in vitro experiment sought to identify the blood component(s) that interfere with the biopsy urease test, and delineate the mechanism of inhibition.Methods:The modified Hazells microtiter test was used to detect the urease activity of H. pylori. A positive result was indicated by a color change of the pH indicator, bromothymol blue, at 630 nm. Human whole blood, sera with and without anti-H. pylori antibody, electrolytes, and enzymes were incubated with H. pylori to identify the blood component(s) causing the inhibition of urease activity. In addition, any interference of the pH color indicator was tested by adding different concentrations of serum albumin to the urease reagent that contained a fixed quantity of ammonia in the absence of H. pylori.Results:The color change of the microtiter urease test was significantly reduced by blood (p < 0.0001), regardless of the presence of anti-H. pylori antibody. Electrolytes and serum enzymes did not interfere with the urease test. The color change of the pH indicator was progressively suppressed by higher concentrations of serum albumin.Conclusions:Blood adversely affects the performance of the BUT. This is mediated by the buffering effect of serum albumin on the pH indicator, rather than by a direct inhibition on the urease activity.