Silencing of Jagged1 inhibits cell growth and invasion in colorectal cancer.

Dysregulated Notch signaling has a critical role in the tumorigenesis. Jagged1, a Notch ligand, is overexpressed in various human cancers. Recent studies revealed the involvement of Jagged1 in colorectal cancer (CRC) development. These basic studies provide a promising potential for inhibition of the Notch pathway for the treatment of CRC. Herein, we aimed to investigate the consequences of targeting Jagged1 using shRNA on CRC both in vitro and in vivo to test their potential to inhibit this key element for CRC treatment. We found that downregulation of Jagged1 with lentiviral Jagged1-shRNA resulted in decreased colon cancer cell viability in vitro, most likely mediated through reduced cell proliferation. Importantly, Jagged1 knockdown induced G0/G1 phase cell cycle arrest, with reduced Cyclin D1, Cyclin E and c-Myc expression. Silencing of Jagged1 reduced the migration and invasive capacity of the colon cancer cells in vitro. Furthermore, colon cancer cells with knockdown of Jagged1 had much slower growth rate than control cells in a xenograft mouse model in vivo, with a marked downregulation of cell proliferation markers (PCNA, Ki-67, and c-Myc) and metastasis markers (MMP-2 and MMP-9). These findings rationalize a mechanistic approach to CRC treatment based on Jagged1-targeted therapeutic development.

Review article: current management of metastatic colorectal cancer - the evolving impact of targeted drug therapies.

BACKGROUND: The field of colorectal cancer chemotherapy has been transformed by the advent of molecule-specific drugs. Combined use of such drugs enhances tumour response rates, but controlled data quantifying the relative efficacy and cost-effectiveness of different drug combinations on overall survival remain scarce. AIM: To conduct an overview of published clinical trials in advanced colorectal cancer, with the objective of framing provisional approaches to current management. METHODS: An NCBI/PubMed search was performed using the strings, 'colorectal cancer' ('metastatic' or 'advanced' or 'palliative') and ('chemotherapy' or 'drug therapy' or 'targeted' or 'target-specific' or 'molecularly-targeted'). RESULTS: Combinations of target-specific drugs (with or without the DNA-alkylating agent oxaliplatin) have substantially enhanced colorectal cancer time to progression over the last decade and have also expedited surgical resection of liver metastases. Disease-free survival, overall survival and quality of life are favourably influenced. CONCLUSIONS: Target-specific drugs improve palliative efficacy in the setting of advanced colorectal cancer. However, key issues persist as to the cost-effectiveness of these newer drug treatments, and further controlled trials are needed to resolve this important debate.

Clinical trial: levofloxacin-based quadruple therapy was inferior to traditional quadruple therapy in the treatment of resistant Helicobacter pylori infection.

BACKGROUND: The efficacy of levofloxacin-based quadruple therapy in resistant Helicobacter pylori infection is not known. AIM: To test the efficacy of levofloxacin-based quadruple therapy and traditional quadruple therapy in resistant H. pylori infection. METHODS: One hundred and two patients with resistant H. pylori infection were randomized to 1 week of either EBAL (esomeprazole 40 mg b.d., bismuth subcitrate 240 mg b.d., amoxicillin 1 g b.d. and levofloxacin 500 mg b.d.) or EBMT (esomeprazole 40 mg b.d., bismuth subcitrate 240 mg b.d., metronidazole 400 mg t.d.s. and tetracycline 500 mg q.d.s.). (13)C-urea breath test was performed at week 12 to assess post-treatment H. pylori status. RESULTS: In intention-to-treat analysis H. pylori eradication was achieved in 37 of 51 (73%) subjects in EBAL and 45 of 51 (88%) subjects in EBMT groups, respectively (P = 0.046). Per-protocol eradication rates of EBAL and EMBT groups were 78% and 94%, respectively (P = 0.030). The intention-to-treat eradication rate was statistically lower for EBAL than EMBT (56% vs. 90%, P = 0.013) among those who had failed more than one course of eradication therapy. Previous levofloxacin triple therapy did not affect the efficacy of either protocol significantly. CONCLUSIONS: Levofloxacin-based quadruple therapy was inferior to traditional quadruple therapy for resistant H. pylori infection.

The view of gastroenterologists on non-cardiac chest pain in Asia.

BACKGROUND: Non-cardiac chest pain is an important disorder in Asia. The practice and views of gastroenterologists on non-cardiac chest pain in this region are not known. AIMS: To determine the current understanding, diagnostic practice and treatment strategies among gastroenterologists on the management of non-cardiac chest pain in Asia. METHODS: A 24-item questionnaire was sent to gastroenterologists in Mainland China, Hong Kong, Malaysia, Indonesia, Philippines, Singapore, Taiwan and Thailand. RESULTS: 186 gastroenterologists participated with a response rate of 74%. 98% of gastroenterologists managed patients with non-cardiac chest pain over the last 6 months. 64% felt that the number of non-cardiac chest pain patients was increasing and 85% believed that the most common cause of non-cardiac chest pain was GERD. 94% of the gastroenterologists believed that they should manage non-cardiac chest pain patients, but only 41% were comfortable in diagnosing non-cardiac chest pain. The average number of investigations performed was four in non-cardiac chest pain patients, and oesophago-gastro-duodenoscopy was the most commonly used initial test. A proton pump inhibitor was considered the first-line treatment in non-cardiac chest pain and was reported as the most effective treatment by the gastroenterologists. CONCLUSION: Most gastroenterologists were practicing evidence-based medicine, but frequent use of investigations and a lack of awareness of the role of visceral hypersensitivity in non-cardiac chest pain patients were noted.

Positive association between gastro-oesophageal reflux disease and irritable bowel syndrome in a Chinese population.

BACKGROUND: Gastro-oesophageal reflux disease and irritable bowel syndrome are common diseases which may be related. AIM: To examine the association between gastro-oesophageal reflux disease and irritable bowel syndrome in Chinese population in Hong Kong. METHODS: Randomly selected ethnic Chinese were invited to participate in a telephone survey in 1996. Gastro-oesophageal reflux disease was defined as subjects having heartburn and/or acid regurgitation once weekly or more. Irritable bowel syndrome was diagnosed according to the Rome I criteria. The association between gastro-oesophageal reflux disease and irritable bowel syndrome was calculated using a statistical model which allows the odds ratio to be measured. RESULTS: One thousand six hundred and forty-nine subjects completed the interview (response rate 62%). The population prevalence of gastro-oesophageal reflux disease and irritable bowel syndrome were 5% and 4%, respectively. Thirteen per cent of subjects with gastro-oesophageal reflux disease and 11% with irritable bowel syndrome suffered from both gastro-oesophageal reflux disease and irritable bowel syndrome. The OR of having gastro-oesophageal reflux disease and irritable bowel syndrome together was estimated to be 3 (95% CI: 1.05, 6.27) indicating a positive association between the two diseases. This association occurred predominantly in male subjects [OR = 9.3, (95% CI: 2.3, 26.2)] but not as strong in females [OR = 1.5, (95% CI: 0.3, 4.3)]. Younger subjects were statistically more prone to the two diseases. CONCLUSIONS: There is a positive association between gastro-oesophageal reflux disease and irritable bowel syndrome, and their association occurs predominantly in male subjects.

Difference in T helper responses during hepatitis flares in hepatitis B e antigen (HBeAg)-positive patients with genotypes B and C: implication for early HBeAg seroconversion.

The underlying mechanisms for earlier hepatitis B e antigen (HBeAg) seroconversion in patients with chronic hepatitis B virus (HBV) genotype B when compared with genotype C are unknown. We aimed to determine whether there were any differences in the T helper (Th) responses during hepatitis flares in HBeAg-positive patients with genotypes B and C. Proliferative response measured by (3)H-thymidine uptake and Th responses measured by Enzyme-Linked Immunosorbent Spot assays for interleukin (IL)-2, interferon-gamma (IFN-gamma), IL-4, IL-5 and IL-10 were performed in 10 patients with genotype B and 10 with genotype C with hepatitis flares. HBV genotypes, core promoter, precore mutations, sequence of HBV core region and HBV DNA levels were determined. There was no difference in the HBV DNA levels during hepatitis flares between patients with genotypes B and C. Patients with genotype B had a significantly higher number of IFN-gamma producing cells [with hepatitis B core antigen (HBcAg) stimulation] and lower number of IL-10 producing cells (with HBcAg and HBeAg stimulation) compared with patients with genotype C (P = 0.011, =0.043, <0.001 respectively). There was a trend (P = 0.058) that patients with genotype B had a higher cumulative rate of HBeAg seroconversion. Patients with precore mutants also had a significantly higher number of IFN-gamma producing cells (with HBcAg stimulation) and lower number of IL-10 producing cells (with HBeAg stimulation) compared to patients without precore mutant (P = 0.038, =0.016 respectively). HBV genotype B induces a greater Th1 and lesser Th2 response than genotype C. This provides immunologic evidence for the higher chance of HBeAg seroconversion in patients with genotype B.

Efficacy of tegaserod for functional constipation in Chinese subjects: a randomized double-blind controlled trial in a single centre.

BACKGROUND: Tegaserod has been shown to be effective in chronic constipation in Western population. Aim We investigated if tegaserod is equally effective in Chinese population. MATERIALS AND METHODS: Two hundred and fifty patients were randomized to a double-blinded 8-week treatment of tegaserod 6 mg b.d. or placebo. Response during weeks 1-4 was defined as an increase in complete spontaneous bowel motion >/=1/week. Secondary efficacy included response during weeks 1-8, individual symptoms and scores, quality of life and global assessment of bowel habits and constipation. RESULTS: One hundred and nine patients from the treatment group and 107 from the placebo group completed the 8-week treatment. Responder rates was 47.7% vs. 29% for the treatment and placebo groups (P = 0.005). The sustained complete spontaneous bowel motion rate was 29.4% vs. 15.7% in the two groups (P = 0.016). The response rates were higher than that reported previously in the Caucasian studies. There was improvement in the scores for stool form scale, bothersomeness of constipation, abdominal distension/bloating and satisfaction of bowel habit (P < 0.05). The mental score was higher in the treatment group (46.8 +/- 9 vs. 43.6 +/- 10, P = 0.01). CONCLUSIONS: Tegaserod is effective in relieving chronic constipation in Chinese population. The efficacy observed may be higher than that in Western population.

Traditional Chinese medicine causing hepatotoxicity in patients with chronic hepatitis B infection: a 1-year prospective study.

BACKGROUND: Safety of traditional Chinese medicine in patients with chronic hepatitis B is unknown. AIM: To study the clinical outcome of traditional Chinese medicine-induced hepatotoxicity in chronic hepatitis B patients. PATIENTS AND METHODS: All chronic hepatitis B patients in 2004 with liver dysfunction requiring hospitalization were screened prospectively for traditional Chinese medicine intake. The hepatotoxicity of individual traditional Chinese medicine elements was determined by extensive search of both English and Chinese publications. RESULTS: Of 45 chronic hepatitis B patients, the liver dysfunction in seven (15.6%) was attributable to traditional Chinese medicine. All had liver dysfunction pattern resembling those of acute exacerbation of chronic hepatitis B. Three patients had adverse outcomes (two deaths, one liver transplantation). One patient had accelerated course of cirrhosis now awaiting liver transplantation. The identified hepatotoxic components were Polygonum multiflorum Thunb, Cassia obtusifolia L, Melia toosendan Sieb., Rheum palmatum L., Scolopendra subspinipes mutilans L, Alisma orientale Juzepe, Glycyrrhiza uralensis Fisch. and Mentha haplocalyx Briq. One traditional Chinese medicine formula was adulterated with a highly hepatotoxic agent, N-nitrosofenfluramine. CONCLUSIONS: Traditional Chinese medicine-related hepatotoxicity resulted in high mortality in chronic hepatitis B patients. Prospective randomized-controlled trials with the same stringent criteria as western medicine clinical trials are required for Chinese medicines, to document their efficacies and safety before they can be advocated for the treatment of patients.

Clinical features, biochemical parameters, and virological profiles of patients with hepatocellular carcinoma in Hong Kong.

BACKGROUND: Clinical features of hepatocellular carcinoma patients are changing because of screening. AIM: To examine the clinical features of hepatocellular carcinoma patients in Hong Kong and validity of different staging systems. METHODS: A total of 223 Chinese patients with hepatocellular carcinoma were studied. RESULTS: Seventy-eight percent of hepatocellular carcinoma patients had chronic hepatitis B (43% diagnosed by screening). Hepatitis B positivity, weight loss, jaundice, encephalopathy, alpha-fetoprotein level, portal vein thrombosis, extrahepatic metastasis, and treatment were shown to be independent factors affecting survival. Of chronic hepatitis B patients, hepatitis B virus DNA levels (P = 0.001) and portal vein thrombosis (P = 0.008) were independent factors affecting survival. Seventy-six percent of chronic hepatitis B patients with hepatocellular carcinoma were hepatitis B e antigen negative. Screening patients had hepatocellular carcinoma detected at an earlier stage and better survival (median survival: 21 vs. 4 months, P < 0.0001). All staging systems had good stratification of survival. Prognosis and median survival generated were different when compared with the US data. CONCLUSIONS: Chronic hepatitis B was the most common cause of hepatocellular carcinoma in Hong Kong. High-risk chronic hepatitis B patients should be followed irrespective of the hepatitis B e antigen status. Hepatitis B virus DNA levels at the time of diagnosis are an important survival predictor. Screening detected hepatocellular carcinoma at an earlier stage and prolonged survival. Staging systems should be validated in different populations.

Stability of E-cadherin methylation status in gastric mucosa associated with histology changes.

BACKGROUND: We have previously shown reversal of E-cadherin methylation in gastric mucosa from patients with dyspepsia at week 6 after Helicobacter pylori-eradication therapy. But the long-term methylation status of these patients was unknown. AIM: To investigate the methylation status at E-cadherin at year 3 after H. pylori-eradication therapy. METHODS: 35 patients (25 with and 10 without H. pylori eradicated) enrolled in our previous study were recruited into the present study (year 3 analysis). Methylation at E-cadherin was evaluated by methylation-specific polymerase chain reaction method. RESULTS: There was no difference in age and sex distribution in the two groups. Methylation at E-cadherin in patients with H. pylori eradicated at weeks 0, 6 and year 3 were 52%, 20% and 20%, respectively. Concordant methylation status at week 6 and year 3 was 92%. Methylation at E-cadherin in patients without H. pylori at weeks 0, 6 and year 3 were 50%, 60% and 60%, respectively. Concordant methylation status between week 6 and year 3 was 90%. Stability of E-cadherin methylation status was associated with histological changes. No association between E-cadherin methylation status and age was observed. CONCLUSION: The methylation pattern is stable for a long period, thus suggesting the effect of environment on methylation.

Coexistence between colorectal cancer/adenoma and coronary artery disease: results from 1382 patients.

BACKGROUND: Common risk factors exist in colorectal neoplasia (cancer or adenoma) and coronary artery disease. AIM: To investigate in a retrospective study if there is coexistence of the two events in patients > OR =50 years. METHODS: Computer data on colonoscopies performed on symptomatic patients, the corresponding medical record and colonic histology in 1997-2000 were retrieved. History of coronary artery disease was recorded. To adjust for the factors of age and sex, bivariate logistic regression analysis was used to test for coexistence. RESULTS: 1382 patients were recruited. Colorectal neoplasia and history of coronary artery disease were present in 27% (373) and 12% (167) of patients, respectively. The mean age of patients was older in colorectal neoplasia+ (75 +/- 11 vs. 69 +/- 13 years, P < 0.0001) and in coronary artery disease+ (79 +/- 9 vs. 69 +/- 12 years, P < 0.0001) patients. Male was the predominant sex in colorectal neoplasia+: 33% vs. 22% (P < 0.0001), but not in coronary artery disease+ (P = 0.29). Colorectal neoplasia+ patients were more likely to have coronary artery disease+ [21.2% (79/373) vs. 8.8% (89/1098) (P < 0.0001)]. Bivariate logistic regression analysis showed strong association between the two events (OR: 2.12, 95% CI: 1.5, 3.0). CONCLUSION: There is strong coexistence of colorectal neoplasia and coronary artery disease, probably due to exposure to common risk factors.

Update on clarithromycin resistance in Helicobacter pylori in Hong Kong and its effect on clarithromycin-based triple therapy.

AIM: To determine the antibiotic susceptibility of Helicobacter pylori and evaluate the efficacy of a clarithromycin-based triple therapy in relation to antibiotic resistance. METHODS: Consecutive patients referred for upper endoscopy due to dyspeptic symptoms were recruited. Gastric biopsies were obtained for the CLO test, histology and culture. Antibiotic susceptibility was assessed by the E-test. Patients with H. pylori infection received rabeprazole 20 mg, clarithromycin 500 mg, and amoxicillin 1,000 mg, all twice daily for 7 days. RESULTS: Of 234 patients recruited, 124 were H. pylori-positive and culture was successful in 102 patients. The updated prevalences of resistance to clarithromycin, amoxicillin and metronidazole were 7.8, 0 and 39.2%, respectively. A total of 86 patients received 1-week triple therapy with rabeprazole 20 mg, clarithromycin 500 mg, and amoxicillin 1,000 mg, all twice daily, and 81 patients attended the follow-up test. Eradication rates by per-protocol and intention-to-treat analysis were 92.6 and 87.2%, respectively. The eradication rate by per protocol was significantly higher in patients with clarithromycin-susceptible strains than in those with clarithromycin-resistant strains (98.6 vs. 28.6%, p < 0.001). CONCLUSION: Clarithromycin resistance reduces the clinical efficacy of clarithromycin-based triple therapy. However, due to the low prevalence of clarithromycin resistance, clarithromycin-based therapy is still the first choice for clinical use.

Lansoprazole, levofloxacin and amoxicillin triple therapy vs. quadruple therapy as second-line treatment of resistant Helicobacter pylori infection.

AIM: To test the efficacy of levofloxacin-based second-line therapy for resistant Helicobacter pylori infection. METHODS: One hundred and six patients who failed H. pylori eradication were randomized to receive (i) lansoprazole 30 mg, amoxicillin 1 g, levofloxacin 500 mg, all given twice daily for 7 days (LAL); or (ii) lansoprazole 30 mg twice daily, metronidazole 400 mg thrice daily, bismuth subcitrate 120 mg and tetracycline 500 mg four times daily for 7 days (quadruple). Post-treatment H. pylori status was determined by (13)C-urea breath test. RESULTS: Intention-to-treat and per-protocol H. pylori eradication rates were 57/60% for the LAL group and 71/76% for the quadruple group respectively. Metronidazole, clarithromycin, amoxicillin and levofloxacin resistance were found in 76%, 71%, 0% and 18% of patients, respectively. Levofloxacin resistance led to treatment failure in the LAL group. For patients with dual resistance to metronidazole and clarithromycin, the eradication rates were 79% in the LAL group (levofloxacin-sensitive) and 65% in the quadruple group (P=0.34). CONCLUSION: Lansoprazole, amoxicillin plus levofloxacin second-line therapy is comparable with quadruple therapy in efficacy. Subjects, especially those with dual resistance to metronidazole and clarithromycin, may consider levofloxacin-based therapy for levofloxacin-sensitive strains.

Eradication of Helicobacter pylori infection reverses E-cadherin promoter hypermethylation.

BACKGROUND: E-cadherin methylation is important in gastric carcinogenesis. Reversing hypermethylation may halt the carcinogenic process. We have previously reported that Helicobacter pylori infection is associated with E-cadherin methylation in chronic gastritis patients. AIM: To examine if eradication of H pylori could reverse E-cadherin methylation. METHODS: Patients with dyspepsia and positive for H pylori infection, with a mucosal biopsy showing chronic active gastritis, were randomised to receive H pylori eradication therapy (group 1, n = 41) or no treatment (group 2, n = 40), and were followed up prospectively. Gastric mucosae were taken for methylation assay at week 0 (before treatment) and week 6 (after treatment). Archived specimens of intestinal metaplasia with H pylori infection (n = 22) and without (n = 19) were retrieved for methylation analysis. Methylation was assessed using methylation specific polymerase chain reaction and sequencing. RESULTS: Methylation at E-cadherin was detected in 46% (19/41) and 17% (7/41) of patients at weeks 0 and 6, respectively, in group 1 (p = 0.004); 78.9% (15/19) of specimens were unmethylated after eradication of H pylori. Mucosal biopsy showed chronic inactive gastritis in 35 patients, intestinal metaplasia in one, and normal mucosa in five at week 6. Methylation was detected in 47.5% (19/40) and 52.5% (21/40) of patients at weeks 0 and 6, respectively, in group 2 (P = 0.5). Gastric mucosal biopsy showed persistent chronic active gastritis in all cases. Methylation frequency did not differ in H pylori positive or negative intestinal metaplastic specimens (72.7% v 63%; p = 0.5). CONCLUSION: H pylori eradication therapy could reverse methylation in patients with chronic gastritis. This demonstrates an environmental effect on methylation.

CYP2C19 genotype and the PPIs--focus on rabeprazole.

Amongst all the proton pump inhibitors (PPI), the hepatic metabolism of rabeprazole is least dependent on the CYP4502C19 system. Rabeprazole is therefore the PPI least affected by CYP4502C19 genetic polymorphism. This unique feature of rabeprazole complements rabeprazole's fast onset of action, and may lead to profound and consistent inhibition of gastric acid secretion in the treatment of acid-related disorders.