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Colorectal cancer (CRC) incidence is rising among50-year olds. The objective of this study was to determine screening colonoscopy outcomes among 40- to 49-year olds, which are currently limited.Asymptomatic 40- to 49-year olds underwent one time CRC screening colonoscopy at The Chinese University of Hong Kong between 2007 and 2011. Screening outcomes, including prevalence, distribution, and predictive factors for overall and specifically proximal colorectal neoplasia were determined.Among 1133 ethnic Chinese, colorectal neoplasia prevalence was 20.5%. In men, distal adenomas were associated with proximal colorectal neoplasia. Men, advancing age, a first degree relative (FDR) with CRC, and diabetes mellitus were independently associated with colorectal neoplasia. A colorectal neoplasia was three times more likely to be found in a 45- to 49-year-old man with FDR of CRC compared with a 40- to 44-year-old woman without a FDR of CRC. The numbers needed to screen one colorectal neoplasia, and one advanced neoplasm in the highest risk group of 45- to 49-year-old men with FDR with CRC were 2.8 (95% CI: 2.2-4.4) and 18.5 (95% CI: 8.9-39.2), respectively.Colorectal neoplasia prevalence in this 40- to 49-year-old Chinese cohort was higher than previous studies. Men, advancing age, FDR with CRC, and diabetes mellitus, can be used to risk stratify for neoplasia development. Men 45-49 years old with FDR with CRC represented the highest risk subgroup, with the lowest number needed to screen.

Objective To develop and validate a clinical risk score predictive of risk for colorectal advanced neoplasia for Asia. Methods A prospective, cross-sectional and multicentre study was carried out in tertiary hospitals in 11 Asian cities. The subjects comprise 2752 asymptomatic patients undergoing screening colonoscopy. From a development set of 860 asymptomatic subjects undergoing screening colonoscopy, multiple logistic regression was applied to identify significant risk factors for advanced colorectal neoplasia defined as invasive carcinoma or advanced adenoma. The ORs for significant risk factors were utilised to develop a risk score ranging from 0 to 7 (Asia-Pacific Colorectal Screening (APCS) score). Three tiers of risk were arbitrarily defined: 0–1 ‘average risk’ (AR); 2–3 ‘moderate risk’ (MR); and 4–7 ‘high risk’ (HR). Subjects undergoing screening colonoscopy between July 2006 and December 2007 were prospectively enrolled to form an independent validation group. Each subject had a personal APCS score calculated by summing the points attributed from the presence of risk factors in the individuals. The performance of the APCS score in predicting risk of advanced neoplasia was evaluated. Results There were 860 subjects in the derivation set and 1892 subjects in the validation set, with a baseline prevalence of advanced neoplasia of 4.5% and 3%, respectively. Applying the APCS stratification in the validation set, 559 subjects (29.5%) were in the AR tier, 966 subjects (51.1%) in the MR tier and 367 (19.4%) subjects in the HR tier. The prevalence of advanced neoplasia in the AR, MR and HR groups was 1.3, 3.2 and 5.2%, respectively. The subjects in the MR and HR tiers had 2.6-fold (95% CI 1.1 to 6.0) and 4.3-fold (95% CI 1.8 to 10.3) increased prevalence of advanced neoplasia, respectively, than those in the AR tier. Conclusions The APCS score based on age, gender, family history and smoking is useful in selecting asymptomatic Asian subjects for priority of colorectal screening.

Patients with nonalcoholic fatty liver disease (NAFLD) and family history of colorectal cancer (CRC) are at higher risks but how they should be screened remains uncertain. Hence, we evaluated the cost-effectiveness of CRC screening among patients with NAFLD and family history by different strategies. A hypothetical population of 100,000 subjects aged 40-75 years receive: (i) yearly fecal immunochemical test (FIT) at 50 years; (ii) flexible sigmoidoscopy (FS) every 5 years at 50 years; (iii) colonoscopy 10 yearly at 50 years; (iv) colonoscopy 10 yearly at 50 years among those with family history/NAFLD and yearly FIT at 50 years among those without; (v) colonoscopy 10 yearly at 40 years among those with family history/NAFLD and yearly FIT at 50 years among those without and (vi) colonoscopy 10 yearly at 40 years among those with family history/NAFLD and colonoscopy 10 yearly at 50 years among those without. The incremental cost-effectiveness ratio (ICER) was studied by Markov modeling. It was found that colonoscopy, FS and FIT reduced incidence of CRC by 49.5, 26.3 and 23.6%, respectively. Using strategies 4, 5 and 6, the corresponding reduction in CRC incidence was 29.9, 30.9 and 69.3% for family history, and 33.2, 34.7 and 69.8% for NAFLD. Compared with no screening, strategies 4 (US$1,018/life-year saved) and 5 (US$7,485) for family history offered the lowest ICER, whilst strategy 4 (US$5,877) for NAFLD was the most cost-effective. These findings were robust when assessed with a wide range of deterministic sensitivity analyses around the base case. These indicated that screening patients with family history or NAFLD by colonoscopy at 50 years was economically favorable.

In vitro experimental and animal studies have shown that quinolones reduce the adherence of bacteria on a polyethylene tube and prevent stent blockage. Our aim was to see whether ciprofloxacin prevents stent blockage in patients with malignant stricture of the biliary tract.Patients with inoperable biliary or pancreatic tumor not involving the bifurcation of the common hepatic duct were recruited. They were randomized to receive either endoscopic stenting alone or stenting with prophylactic treatment of ciprofloxacin (200 mg i.v. before stenting, followed by 250 mg orally twice per day). In each follow-up visit, clinical symptoms of cholangitis were documented and blood samples taken for blood counts, serum levels of bilirubin, and alkaline phosphatase. Stent blockage was defined as clinical symptom(s) of cholangitis with biochemical or radiological evidence of stent dysfunction.Fifty-eight patients were recruited into the study. Three patients in the stenting group and three in the ciprofloxacin group were excluded after randomization. Eleven patients received stenting alone and five patients receiving ciprofloxacin had previous endoscopic stenting. Thirteen patients (50%) in the ciprofloxacin group and eight patients (31%) in the stenting group died before stent blockage. Ten patients (38%) in each group had stent blockage during the follow-up at 20 wk. The median stent patency was 11.6 wk and 11.9 wk in the ciprofloxacin group and the stenting group, respectively. Kaplan-Meier analysis of stent patency showed no difference between the two groups. Among patients who received endoscopic stenting for the first time, there was a trend favoring ciprofloxacin treatment, but the difference was not significant. The 30-day and 20-wk mortality between the groups were comparable.Long-term use of ciprofloxacin does not prevent blockage of polyethylene biliary stents.

Cathelicidins are a family of bacteriocidal polypeptides secreted by macrophages and polymorphonuclear leukocytes (PMN). LL-37, the only human cathelicidin, has been implicated in tumorigenesis, but there has been limited investigation of its expression and function in cancer. Here, we report that LL-37 activates a p53-mediated, caspase-independent apoptotic cascade that contributes to suppression of colon cancer. LL-37 was expressed strongly in normal colon mucosa but downregulated in colon cancer tissues, where in both settings its expression correlated with terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling-positive apoptotic cells. Exposure of colon cancer cells to LL-37 induced phosphatidylserine externalization and DNA fragmentation in a manner independent of caspase activation. Apoptogenic function was mediated by nuclear translocation of the proapoptotic factors, apoptosis-inducing factor (AIF) and endonuclease G (EndoG), through p53-dependent upregulation of Bax and Bak and downregulation of Bcl-2 via a pertussis toxin–sensitive G-protein–coupled receptor (GPCR) pathway. Correspondingly, colonic mucosa of cathelicidin-deficient mice exhibited reduced expression of p53, Bax, and Bak and increased expression of Bcl-2 together with a lower basal level of apoptosis. Cathelicidin-deficient mice exhibited an increased susceptibility to azoxymethane-induced colon tumorigenesis, establishing pathophysiologic relevance in colon cancer. Collectively, our findings show that LL-37 activates a GPCR-p53-Bax/Bak/Bcl-2 signaling cascade that triggers AIF/EndoG–mediated apoptosis in colon cancer cells. Cancer Res; 72(24); 6512–23. ©2012 AACR.

The role of Epstein-Barr virus (EBV) infection in gastric carcinogenesis remains largely unknown. The authors studied the effects of zinc finger E-box binding factor 1 (ZEB1) on latent-lytic switch of EBV infection in gastric cancer and explored the importance of EBV in gastric carcinogenesis.Loss or gain of ZEB1 function was obtained by ZEB1 small-interfering RNA (siRNA) knock-down or forced ZEB1 re-expression. Cell growth was evaluated by cell viability and colony formation assays, and the cell cycle was assessed by flow cytometry. EBV was detected using quantitative polymerase chain reaction (PCR) and in situ hybridization analyses.ZEB1 knock-down in a latent EBV-infected gastric cancer cell line (YCC10) increased lytic gene BamHI W leftward reading frame 1 (BZLF1) expression and decreased the expression of latent gene EB nuclear antigen 1 (EBNA1) concomitant with the inhibition of cell viability (P.05) and S-phase DNA synthesis (P.01). ZEB1 depletion combined with ganciclovir revealed a further reduction in cell viability (P.001). ZEB1 knock-down induced cell apoptosis and the up-regulation of caspase 3 and poly(adenosine diphosphate-ribose) polymerase cleavage. Conversely, ectopic overexpression of ZEB1 in a lytic EBV-infected gastric cancer cell line (AGS-EBV) inhibited BZLF1 promoter (Zp) activity, BZLF1 expression, and apoptosis and promoted cell growth. EBV infection was detected in 11.3% (80 of 711) of gastric cancers. The presence of EBV was associated with age, men, and intestinal type cancer.ZEB1 was confirmed as a key mediator of the latent-lytic switch of EBV-associated gastric cancer, a distinct subtype with different clinicopathologic features. The current results indicated that inhibition of ZEB1 may be a potential target for EBV-associated gastric cancer therapy.

To study the efficacy and safety of endoscopic ultrasonography-guided fine-needle aspiration in the management of mediastinal diseases in Hong Kong.Retrospective review of prospectively collected data.University teaching hospital, Hong Kong.A total of 125 consecutive patients with various mediastinal and pulmonary lesions that underwent trans-oesophageal endoscopic ultrasonography-guided fine-needle aspiration from July 1998 to June 2007.The diagnostic accuracy and safety of the procedure and its influence in patient management.Malignancy was confirmed in 62 (50%) of the patients and excluded in 42 (34%). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of endoscopic ultrasonography-guided fine-needle aspiration in diagnosing mediastinal malignancies were 75% (95% confidence interval, 64-83%), 100% (90-100%), 100% (93-100%), 67% (54-78%), and 83%, respectively. Eighty-six (69%) of the patients had their initial plan of invasive investigations changed. Only one (0.8%) patient developed a septic complication in a mediastinal cyst after puncturing, and was treated surgically.Trans-oesophageal endoscopic ultrasonography-guided fine-needle aspiration is a minimally invasive, effective, and safe method of diagnosing malignant mediastinal disease. It may reduce the need for other invasive investigations.

Although nucleot(s)ide analogues can effectively suppress hepatitis B virus (HBV) replication, many patients experience relapse of hepatitis after cessation of treatment. We aimed to investigate the efficacy of pegylated interferon alpha2a (PEG-IFN-alpha2a) in these difficult-to-treat patients.Chronic hepatitis B patients who have received antiviral drugs foror =12 months and stopped foror =6 months were treated by 48-week PEG-IFN-alpha2a. Virological response was defined as HBV DNA10,000 copies/ml and hepatitis B e antigen (HBeAg) seroconversion (for HBeAg-positive patients).A total of 40 patients, 29 HBeAg-positive and 11 HBeAg-negative, with median log10 HBV DNA 7.3 copies/ml and alanine aminotransferase 110 IU/ml were studied. The last antiviral treatment was given for 92 +/- 61 weeks and stopped for 176 +/- 88 weeks. At the end of treatment, 22 (12 HBeAg-positive and 10 HBeAg-negative; 55%) patients had virological response and 16 (7 HBeAg-positive and 9 HBeAg-negative; 40%) patients had undetectable HBV DNA (100 copies/ml). At 24 weeks post-treatment, 14 (8 HBeAg-positive and 6 HBeAg-negative; 35%) patients had virological response and 9 (5 HBeAg-positive and 4 HBeAg-negative; 23%) patients had undetectable HBV DNA. Two (5%) patients had lost hepatitis B surface antigen. HBV DNA levels at week 24 best predicted sustained virological response (area under curve 0.76, 95% confidence interval 0.60-0.92, P=0.007). At HBV DNA cutoffs of 3 logs and 5 logs at week 24, the sensitivity/specificity for sustained virological response were 50%/85% and 86%/62%, respectively.PEG-IFN-alpha2a was effective in the treatment of chronic hepatitis B patients who have failed previous antiviral treatment.

Treatment of chronic hepatitis B (CHB) with lamivudine (3TC) is limited by development of drug-resistant mutants at the YMDD motif. We aimed to validate the use of mass spectrometry to detect YMDD mutants and quantify viral subpopulations.A total of 21 Chinese patients with severe acute exacerbation of CHB treated with 3TC were studied. Serial serum samples were tested for wild-type and YMDD mutants using matrix assisted laser desorption/ionization time-of-flight mass spectrometry. INNO-LiPA assay was performed for comparison.At a median follow-up of 192 weeks, 11 patients developed YMDD mutants (six had YIDD, four had YVDD and one had YV/IDD). Mass spectrometry was concordant with INNO-LiPA in all but one patient, in which INNO-LiPA detected coexistence of YIDD and YVDD but mass spectrometry and direct sequencing detected YVDD only. Mass spectrometry was able to reliably detect a minor hepatitis B virus (HBV) subtype at 5% or above. By serial quantitative measurement, several patterns of viral dynamics were observed. In some cases, YMDD mutants dominated the whole viral population. In other cases, the proportion of YMDD mutants fluctuated with time. When more than one mutant was present (that is, YIDD and YVDD), the different mutants might dominate during different time periods.Mass spectrometry is an accurate and cheap method for the detection of YMDD mutants, even in the presence of overwhelming wild-type HBV. We observed some intriguing mutant viral dynamics during 3TC treatment. Further studies are needed to clarify whether they have any clinical significance.

GOALS: To estimate and compare the direct medical cost in the management of chronic hepatitis B (CHB) infection and its complications from the perspective of public health organizations in Hong Kong and Singapore. BACKGROUND: Hong Kong and Singapore are endemic hepatitis B virus areas with about 10% and 5%, respectively, of the population estimated as hepatitis B virus infected. STUDY: The medical histories of 660 patients with CHB who received medical services over 5 years from three major public hospitals in Hong Kong and Singapore were studied retrospectively. Costs were analyzed according to the five disease states and estimated in Hong Kong dollars (HKD) and Singapore dollars (SGD). RESULTS: In both Hong Kong and Singapore, the per-patient total annual cost increased with the severity of the disease. CHB cost HKD 6318 (US 810 dollars) in Hong Kong and SGD 718.15 (US 410.37 dollars) in Singapore. Compensated cirrhosis cost HKD 10,304 (US 1321 dollars) in Hong Kong and SGD 1,175.34 (US 671.62 dollars) in Singapore. Decompensated cirrhosis cost HKD 58,428 (US 7490 dollars) in Hong Kong and SGD 15,389.84 (US 8794.19 dollars) in Singapore. Hepatocellular carcinoma cost HKD 121,822 (US 15,618 dollars) in Hong Kong and SGD 12314.04 (US 7036.59 dollars) in Singapore. Each case of liver transplant was estimated to cost HKD 514,498 (US 65,961 dollars) in Hong Kong and SGD 86,369.28 (US 49,353.87 dollars) in Singapore. CHB in Hong Kong accounted for about 4% of the healthcare expenditure. CONCLUSION: This study confirms that CHB and its liver disease complications are a significant economic burden to the healthcare budgets of Hong Kong and Singapore, and indicates that effective therapy that arrests or reverses the progression of liver disease would be highly cost-effective.

Evidence indicates that cyclooxygenase (COX)-2-derived prostaglandins (PGs) contribute to tumor growth by inducing angiogenesis. We investigated the role of COX-2 in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). COX-2 and vascular endothelial growth factor (VEGF) expressions were examined by immunohistochemistry in 24 HBV-associated HCC. Tumor micro-vessel density (MVD) was assessed using CD34 immunohistochemistry. Hep3B HCC cell line, which carries integrated HBV genome, was stably transfected with human COX-2 cDNA. COX-2 and VEGF expressions were determined by Western blot while PG level was determined by ELISA. The effects of PGs on VEGF expression were also investigated. Expression of COX-2 and VEGF in HCC cells were observed in 19 (79%) and 16 (67%) cases, respectively. Well-differentiated HCC expressed COX-2 more strongly than less-differentiated HCC (p0.001). COX-2 expression was found to correlate with VEGF expression and MVD (p=0.003 and 0.004, respectively). COX-2 overexpressing Hep3B clone had higher VEGF expression as compared to non-COX-2 expressing clone and parental cells. Treatment of the COX-2 overexpressing cells with a COX-2-selective inhibitor, NS-398 (10 microM), decreased PGE2 level and attenuated VEGF expression. Addition of PGE2 (10 microM) and the stable analog of PGI2, carbaprostacyclin (5 microM), to Hep3B cells also increased VEGF expression. Up-regulation of COX-2 correlates with VEGF expression and tumor angiogenesis in HBV-associated HCC. Moreover, COX-2 up-regulates VEGF expression in HCC cells, possibly via PGs production. Selective inhibition of COX-2 may block HCC associated angiogenesis and thus provides a rational approach for treatment of this malignancy.

Overexpression of cyclooxygenase-2 (COX-2) is associated with loss of apoptosis, enhancement of proliferation and tumorigenesis. The role of promoter methylation in the transcriptional silencing of cox-2 gene in human gastric cancer is less determined. We investigated 5 gastric cancer cell lines and 58 primary gastric carcinomas for the presence of promoter hypermethylation in cox-2 gene. Combined methylation-specific polymerase chain reaction analysis and bisulfite sequencing analysis revealed that the cox-2 promoter was methylated in 2 of the gastric cancer cell lines. Treatment with 5-aza-2'-deoxycytidine, a DNA methyltransferase inhibitor, induced COX-2 expression in the methylated gastric cancer cell line. Among the 58 primary gastric cancers, hypermethylation was detected in 25 (43.1%) cases. However, none of the normal gastric tissues showed methylation in cox-2. Promoter hypermethylation was associated with loss of protein expression as determined by immunostaining (p=0.005). Our results indicate that hypermethylation of the CpG island in the cox-2 gene is a major mechanism that mediates transcriptional silencing in a subset of gastric cancers. Thus, gastric cancers with methylation in cox-2 may not be good candidates for treatment with specific COX-2 inhibitors.

To investigate the relationship between H. pylori infection, gastric cancer and other gastric diseases through the changes in gastric mucosa and the status of different gastric diseases within 5 years after H. pylori eradication in H. pylori-positive subjects in a high incidence region of gastric cancer.One thousand and six adults were selected from the general population in Yantai, Shandong province, a high incidence region for gastric cancer in China. Gastroscopy and Campylobacter-like organism (CLO) testing were performed on all subjects. Biopsy samples from the gastric antrum and body were obtained for histology and assessment of H. pylori infection. All H. pylori-positive subjects were then randomly divided into two groups: treatment group receiving Omeprazole Amoxicillin Clarythromycin (OAC) triple therapy and placebo as controls. These subjects were endoscopically followed up in the second and fifth year. We compared the endoscopic appearance and histology of the biopsy specimens from the same site obtained at the first and last visits.All 552 H. pylori-positive subjects were randomly and evenly divided into treatment group or control group. During the five-year follow-up, the numbers of patients who continued to be negative or positive for H. pylori were 161 and 198, respectively. Statistical analysis revealed that: (1) At the initial visit, there were no significant differences in the severity and activity of inflammation, atrophy and intestinal metaplasia between the biopsy specimens from the antrum and body respectively in both groups. (2) The severity and activity of inflammation in both the antrum and body were markedly reduced after H. pylori eradication (P = 0.000). (3) Within five years after H. pylori eradication, intestinal metaplasia in the antrum either regressed or had no progression, while the proportion of intestinal metaplasia in the H. pylori-positive group increased significantly (P = 0.032). (4) After H. pylori eradication, the atrophy in both the antrum and body had no significant regression. The P value was 0.223 and 0.402, respectively.H. pylori eradication results in remarkable reduction in the severity and activity of chronic gastritis, marked resolution of intestinal metaplasia in the antrum. On the other hand, continuous H. pylori infection leads to progressive aggravation of atrophy and intestinal metaplasia.

Aberrant promoter methylation, an alternative mechanism for gene silencing, is frequently detected in gastric cancer. We studied the feasibility of detecting aberrant methylation in serum of gastric cancer patients.Patients (54) with gastric adenocarcinoma were studied. The tumor and the paired serum were examined for aberrant methylation in DAP-kinase, E-cadherin, GSTP1, p15, and p16 by methylation-specific PCR. Serum from 30 age-matched noncancer patients was used as control.Promoter methylation in DAP-kinase, E-cadherin, GSTP1, p15, and p16 were detected in 70.3, 75.9, 18.5, 68.5, and 66.7% of primary tumor. In serum of gastric cancer patients, methylation in DAP-kinase, E-cadherin, GSTP1, p15, and p16 were detected in 48.1, 57.4, 14.8, 55.6, and 51.9%, respectively. None of the control serum showed aberrant methylation. Aberrant methylation in serum DNA was all accompanied with methylation in the corresponding tumor samples. In general,60% of serum from cancers with aberrant methylation demonstrated these epigenetic alterations.Our findings suggest that aberrant promoter methylation in serum can be detected in a substantial proportion of gastric cancer patients, and this strategy should be evaluated in the screening and surveillance of gastric cancer.

One-week bismuth triple therapy has been established to be highly effective in curing H. pylori infection, but patient compliance has been the major factor of success in therapy. For patients hospitalized for ulcer bleeding, an effective regimen that can completed before discharge will ensure full compliance.To compare 2-day versus 1-wk bismuth triple therapy plus omeprazole in curing H. pylori infection and bleeding peptic ulcers.100 patients with non-actively bleeding duodenal (DU) or gastric ulcers (GU) and confirmed H. pylori infection were randomized to receive either bismuth subcitrate 120 mg, tetracycline 500 mg, and metronidazole 400 mg four times daily for 1 wk (OBTM-7) or bismuth subcitrate 240 mg, tetracycline 500 mg, and metronidazole 400 mg four times daily for 2 days (OBTM-2). Both groups of patients also received omeprazole 20 mg twice daily for the first week. In the OBTM-2 group, the anti-Helicobacter therapy was finished during hospitalization. Endoscopy was repeated 5 wk after randomization to monitor ulcer healing and determine H. pylori status. Side effects related to the anti-Helicobacter therapy was graded as follows: A, mild discomfort, which did not affect daily activity; B, moderate discomfort affecting daily activity; and C, severe discomfort and patients discontinued therapy.Forty-six patients in the OBTM-2 group and 50 in the OBTM-7 group returned for follow-up endoscopy. With an intention-to-treat analysis, ulcer healing was achieved in 44 of 46 patients (95.7%) in the OBTM-2 group versus 49 of 50 (98%) in the OBTM-7 group, p = 0.61. H. pylori eradication was successful in 35 of 46 patients (76.1%) in the OBTM-2 and in all 50 patients (100%) in the OBTM-7 group, p = 0.00024. There was no difference in the severity of side effects experienced by the patients in the OBTM-2 group than in the OBTM-7 group (19 vs 32%, p = 0.16). None of the patients had rebled during the period of follow-up.Despite similar efficacy in ulcer healing, the 2-day quadruple therapy is less effective than the 1-wk regimen in curing H. pylori infection.

Cranial nerve involvement has been reported in cryptococcal infection of the central nervous system. We report a case of unilateral internuclear ophthalmoplegia developed in one patient with cryptococcal meningitis. The symptom subsided one week after commencement of antifungal treatment. We believe that this is a vasculitic phenomenon of the disease.