Benjamin C.Y. Wong

A Subpopulation of CD26+ Cancer Stem Cells with Metastatic Capacity in Human Colorectal Cancer

Recent evidence suggests that a subpopulation of cancer cells, cancer stem cells (CSCs), is responsible for tumor growth in colorectal cancer. However, the role of CSCs in colorectal cancer metastasis is unclear. Here, we identified a subpopulation of CD26(+) cells uniformly present in both the primary and metastatic tumors in colorectal cancer patients with liver metastasis. Furthermore, in patients without distant metastasis at the time of presentation, the presence of CD26(+) cells in their primary tumors predicted distant metastasis on follow-up. Isolated CD26(+) cells, but not CD26(-) cells, led to development of distant metastasis when injected into the mouse cecal wall. CD26(+) cells were also associated with enhanced invasiveness and chemoresistance. Our findings have uncovered a critical role of CSCs in metastatic progression of cancer. Furthermore, the ability to predict metastasis based on analysis of CSC subsets in the primary tumor may have important clinical implication as a selection criterion for adjuvant therapy.

ACG practice guidelines: Esophageal reflux testing

Investigations and technical advances have enhanced our understanding and management of gastroesophageal reflux disease. The recognition of the prevalence and importance of patients with endoscopy-negative reflux disease as well as those refractory to proton pump inhibitor therapy have led to an increasing need for objective tests of esophageal reflux. Guidelines for esophageal reflux testing are developed under the auspices of the American College of Gastroenterology and its Practice Parameters Committee and approved by the Board of Trustees. Issues regarding the utilization of conventional, catheter-based pH monitoring are discussed. Improvements in the interpretation of esophageal pH recordings through the use of symptom-reflux association analyses as well as limitations gleaned from recent studies are reviewed. The clinical utility of pH recordings in the proximal esophagus and stomach is examined. Newly introduced techniques of duodenogastroesophageal reflux, wireless pH capsule monitoring and esophageal impedance testing are assessed and put into the context of traditional methodology. Finally, recommendations on the clinical applications of esophageal reflux testing are presented.

Differences in Genotypes of Helicobacter pylori from Different Human Populations

DNA motifs at several informative loci in more than 500 strains of Helicobacter pylori from five continents were studied by PCR and sequencing to gain insights into the evolution of this gastric pathogen. Five types of deletion, insertion, and substitution motifs were found at the right end of the H. pylori cag pathogenicity island. Of the three most common motifs, type I predominated in Spaniards, native Peruvians, and Guatemalan Ladinos (mixed Amerindian-European ancestry) and also in native Africans and U.S. residents; type II predominated among Japanese and Chinese; and type III predominated in Indians from Calcutta. Sequences in the cagA gene and in vacAm1 type alleles of the vacuolating cytotoxin gene (vacA) of strains from native Peruvians were also more like those from Spaniards than those from Asians. These indications of relatedness of Latin American and Spanish strains, despite the closer genetic relatedness of Amerindian and Asian people themselves, lead us to suggest that H. pylori may have been brought to the New World by European conquerors and colonists about 500 years ago. This thinking, in turn, suggests that H. pylori infection might have become widespread in people quite recently in human evolution.

Asia-Pacific consensus on the management of gastroesophageal reflux disease: update.

Background and Aims:  Since the publication of the Asia‐Pacific GERD consensus in 2004, more data concerning the epidemiology and management of gastroesophageal reflux disease (GERD) have emerged. An evidence based review and update was needed.

Famotidine Is Inferior to Pantoprazole in Preventing Recurrence of Aspirin-Related Peptic Ulcers or Erosions

BACKGROUND & AIMS Little is known about the efficacy of H(2)-receptor antagonists in preventing recurrence of aspirin-related peptic ulcers. We compared the efficacy of high-dose famotidine with that of pantoprazole in preventing recurrent symptomatic ulcers/erosions. METHODS We performed a randomized, double-blind, controlled trial of 160 patients with aspirin-related peptic ulcers/erosions, with or without a history of bleeding. Patients were given either famotidine (40 mg, morning and evening) or pantoprazole (20 mg in the morning and placebo in the evening). All patients continued to receive aspirin (80 mg daily). The primary end point was recurrent dyspeptic or bleeding ulcers/erosions within 48 weeks. RESULTS A total of 130 patients (81.1%) completed the study; 13 of 65 patients in the famotidine group reached the primary end point (20.0%; 95% one-sided confidence interval [CI] for the risk difference, 0.1184-1.0) compared with 0 of 65 patients in the pantoprazole group (P < .0001, 95% one-sided CI for the risk difference, 0.1184-1.0). Gastrointestinal bleeding was significantly more common in the famotidine group than the pantoprazole group (7.7% [5/65] vs 0% [0/65]; 95% one-sided CI for the risk difference, 0.0226-1.0; P = .0289), as was recurrent dyspepsia caused by ulcers/erosions (12.3% [8/65] vs 0% [0/65]; 95% one-sided CI for the risk difference, 0.0560-1.0; P = .0031). No patients had ulcer perforation or obstruction. CONCLUSIONS In patients with aspirin-related peptic ulcers/erosions, high-dose famotidine therapy is inferior to pantoprazole in preventing recurrent dyspeptic or bleeding ulcers/erosions.

Gastrointestinal bleeding in patients receiving a combination of aspirin, clopidogrel, and enoxaparin in acute coronary syndrome.

BACKGROUND:The combination of aspirin, clopidogrel, and enoxaparin (combination therapy) is the standard treatment for acute coronary syndrome but is associated with gastrointestinal bleeding. However, information in this area is scarce.AIM:This retrospective study aimed to determine the incidence of upper gastrointestinal bleeding in a real-life situation. The effect of proton pump inhibitor (PPI) treatment was also analyzed.METHOD:From January 2002 to December 2006, all patients receiving combination therapy were analyzed. The end point was the occurrence of upper gastrointestinal bleeding during combination therapy or within 7 days of stopping enoxaparin.RESULTS:The patient group consisted of 666 patients (age 72.1 ± 12.6 yr). Gastrointestinal bleeding occurred in 18 (2.7%) patients. The overall hospital mortality was 4.1% (27 patients). A cardiac event was the major cause (N = 24, 3.6%). Only one patient died of massive gastrointestinal bleeding (0.15%). Multiple logistic regression analysis demonstrated that previous peptic ulcer, cardiogenic shock, and the lack of PPI coprescription were significant risk factors for gastrointestinal bleeding. The age-adjusted odds ratio (95% confidence interval) for gastrointestinal bleeding was 5.07 (1.31–16.58) for previous peptic ulcer, 21.41 (2.56–146.68) for cardiogenic shock, and 0.068 (0.010–0.272) for the coprescription with a PPI.CONCLUSION:In real life, the incidence of gastrointestinal bleeding associated with the combination of aspirin, clopidogrel, and enoxaparin therapy was estimated to be 2.7%. Previous peptic ulcer disease or cardiogenic shock were significant independent risk factors. Coprescription with a PPI can significantly reduce the risk.

Role of Notch signaling in colorectal cancer

Notch signaling is an important molecular pathway involved in the determination of cell fate. In recent years, this signaling has been frequently reported to play a critical role in maintaining progenitor/stem cell population as well as a balance between cell proliferation, differentiation and apoptosis. Thus, Notch signaling may be mechanistically involved carcinogenesis. Indeed, many studies have showed that Notch signaling is overexpressed or constitutively activated in many cancers including colorectal cancer (CRC). Consequently, inactivation of Notch signaling may constitute a novel molecular therapy for cancer. CRC is one of the most common malignancies but the current therapeutic approaches for advanced CRC are less efficient. Thus, novel therapeutic approaches are badly needed. In this review article, the authors reviewed the current understanding and research findings of the role of Notch signaling in CRC and discussed the possible Notch-targeting approaches in CRC.

C-Reactive Protein Promotes Cardiac Fibrosis and Inflammation in Angiotensin II–Induced Hypertensive Cardiac Disease

C-reactive protein (CRP) is a risk factor or biomarker for cardiovascular diseases, including hypertension. The present study investigated the functional importance of human CRP in hypertensive cardiac remodeling by a chronic infusion of angiotensin II (Ang II) into mice that express human CRP. Compared with the wild-type mice, although Ang II infusion caused an equally high systolic blood pressure, levels of human CRP were further elevated, and cardiac remodeling was markedly exacerbated in mice that express human CRP, resulting in a significant reduction in the left ventricular ejection fraction and fractional shortening and an increase in cardiac fibrosis (collagen I and III and &agr;-smooth muscle actin) and inflammation (interleukin 1&bgr; and tumor necrosis factor-&agr;). The enhancement in cardiac remodeling in mice that express human CRP was associated with further upregulation of the Ang II type I receptor and transforming growth factor-&bgr;1 and overactivation of both transforming growth factor-&bgr;/Smad and nuclear factor-&kgr;B signaling pathways. Furthermore, in vitro studies in cardiac fibroblasts revealed that CRP alone was able to significantly induce expression of the Ang II type I receptor, collagen I/III, and &agr;-smooth muscle actin, as well as proinflammation cytokines (interleukin 1&bgr; and tumor necrosis factor-&agr;), which was further enhanced by addition of Ang II. In conclusion, CRP is not only a biomarker but also a mediator in Ang II-mediated cardiac remodeling. Enhanced upregulation of the Ang II type I receptor and activation of the transforming growth factor-&bgr;/Smad and nuclear factor-&kgr;B signaling pathways may be the mechanisms by which CRP promotes cardiac fibrosis and inflammation under high Ang II conditions.

Upper Gastrointestinal Bleeding in Patients with Aspirin and Clopidogrel Co-Therapy

Introduction: The major complication of aspirin and clopidogrel (A+C) co-therapy is upper gastrointestinal bleeding (UGIB). However, data are unavailable for real-life situations. Furthermore, the treatment effect of antisecretory agents is unknown. Aim: This cohort study aimed to determine the occurrence of UGIB. The treatment effect of H2-receptor antagonist (H2RA) and proton pump inhibitor (PPI) was also analyzed. Method: The records of 987 consecutive patients on A+C co-therapy between January 2001 and September 2006 were analyzed. The follow-up ended on the dates of a first occurrence of UGIB, stopping A+C co-therapy, a change in the antisecretory class, death, or March 2007. Results: After a follow-up of 5.8 ± 6.5 months, UGIB occurred in 39 (4.0%) patients. PPI, H2RA and control were prescribed in 213, 287 and 487 patients respectively. After adjustment for age, dose of aspirin, previous UGIB and duration of treatment, the risk was marginally reduced by H2RA (OR = 0.43, 95% CI 0.18–0.91, p = 0.04) and significantly reduced by PPI (OR = 0.04, 95% CI 0.002–0.21, p = 0.002), as compared to control. Conclusion: The occurrence of UGIB associated with A+C co-therapy for a median of 5.8 months was 4.0%. Co-prescription with PPI was associated with a lower risk.

Effects of selective COX-2 inhibitor and Helicobacter pylori eradication on precancerous gastric lesions

Objective Helicobacter pylori infection and overexpression of cyclo-oxygenase-2 (COX-2) are associated with gastric cancer and its precursors. To evaluate the effect of a selective COX-2 inhibitor alone and combined with H pylori eradication on the evolution of precancerous gastric lesions, a randomised, placebo-controlled trial was conducted in Linqu County, Shandong Province, China. Methods A total of 1024 participants aged 35–64 years with H pylori infection and advanced gastric lesions were randomly assigned in a factorial design to two interventions or placebo: anti-H pylori treatment for 7 days, and a COX-2 inhibitor (celecoxib) for 24 months. The effects of the interventions were evaluated by the regression or progression of advanced gastric lesions. Results Of the 1024 participants who received anti-H pylori treatment or placebo, 919 completed a subsequent 24-month treatment with celecoxib or placebo. The H pylori eradication rate by per-protocol analysis was 78.2%. Compared with placebo, the proportions of regression of gastric lesions significantly increased in the celecoxib treatment (52.8% vs 41.2%) and anti-H pylori treatment (59.3% vs 41.2%) group, and OR by per-protocol analysis was 1.72 (95% CI 1.07 to 2.76) for celecoxib and 2.19 (95% CI 1.32 to 3.64) for H pylori eradication. No statistically significant effect was found for H pylori eradication followed by celecoxib on the regression of advanced gastric lesions (OR 1.48, 95% CI 0.91 to 2.40). Conclusion This population-based intervention trial revealed that celecoxib treatment or H pylori eradication alone had beneficial effects on the regression of advanced gastric lesions. No favourable effects were seen for H pylori eradication followed by celecoxib treatment. Trial registration HARECCTR0500053 in accordance with WHO ICTRP requirements.