Helicobacter pylori induces promoter methylation of E-cadherin via interleukin-1ß activation of nitric oxide production in gastric cancer cells.

BACKGROUND: Helicobacter pylori infection causes gastric mucosal inflammatory responses, resulting in up-regulation of interleukin-1ß (IL-1ß) and overproduction of mutagenic nitric oxide (NO). The authors previously demonstrated that IL-1ß plays an important role in H. pylori-induced E-cadherin (E-cad) methylation. Here, they extend the study to investigate the downstream effect of IL-1ß on H. pylori-induced gastric inflammation and aberrant DNA methylation. METHODS: Human gastric cancer cell lines (MKN7, MKN74, and TMK-1) with and without pretreatment of IL-1 receptor antagonist (IL-1ra) were treated with IL-1ß or infected with H. pylori. Promoter methylation status of E-cad was examined by methylation-specific polymerase chain reaction (PCR). Expression of E-cad, inducible nitric oxide synthase (iNOS), and nuclear factor κB (NFκB) was assessed by quantitative reverse transcriptase PCR, Western blotting, or immunofluorescence. NO production and total DNA methyltransferase (DNMT) activity were assayed fluorometrically. RESULTS: Both IL-1ß treatment and H. pylori infection-induced E-cad methylation led to a decrease in E-cad expression at both mRNA and protein levels. Total DNMT enzymatic activity was significantly elevated in treated cells, accounting for the observed E-cad methylation induction. Increased expression of NFκB was accompanied by up-regulation of iNOS and production of NO in treated cells. Reversal of all these phenomena in cells pretreated with IL-1ra suggested H. pylori-induced E-cad methylation via IL-1ß stimulation of the NFκB transcriptional system, leading to activation of DNMT activity by NO production. CONCLUSIONS: These findings reveal a previously unknown effect of IL-1ß and NO on H. pylori-induced aberrant DNA methylation. This possible pathway indicates the role of NO in epigenetic modification that links inflammation to carcinogenesis.

Being active or flexible? Role of control coping on quality of life among patients with gastrointestinal cancer.

OBJECTIVES: This study examined the link between coping and quality of life among patients with gastrointestinal (GI) cancer. Two hypotheses were tested. The active-personality hypothesis states that quality of life is associated with the predominant use of primary control coping (PCC) in general. The situational-flexibility hypothesis states that quality of life is related to flexible deployment of PCC and secondary control coping (SCC) according to situational controllability. METHODS: Participants were 180 Chinese adult patients diagnosed with colon or liver cancer. Their perceived controllability of stressors, coping, and quality of life were compared with those of a sex-and age-matched community sample. RESULTS: Three groups with distinct coping patterns were identified: (a) a flexible group characterized by the use of PCC in controllable situations but SCC in uncontrollable situations, (b) an active group characterized by predominant use of PCC in most situations, and (c) a passive group characterized by predominant use of SCC or avoidant coping in most situations. Patients in the active and the flexible groups had higher perceived controllability and psychological well-being scores than those in the passive group. CONCLUSIONS: Our results provide support for both the active-personality and the situational-flexibility hypotheses among GI cancer patients. Clinical and research implications of the findings are discussed.

A new ECG criterion to identify takotsubo cardiomyopathy from anterior myocardial infarction: role of inferior leads.

With the exception of contrast-enhanced cardiovascular magnetic resonance imaging, clear distinction of takotsubo cardiomyopathy from anterior wall myocardial infarction cannot be achieved currently by simple and noninvasive tests. The aim of this study was to examine the role of inferior ECG leads in distinguishing these two conditions. From January 2004 to June 2006, eight female patients suffering from takotsubo cardiomyopathy were identified by the Mayo Clinic criteria. The clinical and ECG features were compared with 27 consecutive sex- and age-matched patients with anterior wall myocardial infarction admitted to the Coronary Care Unit within the same period. The observed ECG features were then verified with that of 62 published cases of takotsubo cardiomyopathy. Takotsubo cardiomyopathy patients had similar left ventricular ejection fraction (35.0% +/- 5.7% vs 38.2% +/- 6.4%, P = 0.829), lower peak creatinine kinase level (461 +/- 330 U/l vs 2723 +/- 1826 U/l, P = 0.020), more ST-segment elevation in the inferior leads (50% vs 7.4%, P = 0.016), and virtually no ST-segment depression in inferior leads (0% vs 48.2%, P = 0.015) compared with patients who had anterior wall myocardial infarction. ST-segment elevation of >or=1.0 mm in lead II had 62.5% sensitivity and 92.6% specificity in detecting takotsubo cardiomyopathy. The observed ECG characteristics were comparable with those in the literature. In patients who present with anterior wall myocardial infarction, the absence of ST-segment depression or ST-segment elevation in inferior leads, especially if the ST-segment in lead II >or= III, is highly suggestive of takotsubo cardiomyopathy.

Angiographic and clinical implications of combined ST-segment elevation in anterior and inferior leads in acute myocardial infarction.

BACKGROUND: The clinical and angiographic findings of patients suffered from acute myocardial infarction (MI) and presented with combined ST elevation in both anterior and inferior leads remain unclear. HYPOTHESIS: These patients might have >/= 1 coronary arteries occluded. METHODS: From January 2002 to December 2006, 49 consecutive patients were found to have ST elevation in both anterior and inferior leads during myocardial infarction. Patients who had left circumflex artery occlusion (acute or chronic) were excluded. These patients were divided into 4 types according to the infarct-related artery (IRA) and status of the contralateral vessel patency: left anterior descending artery (LAD) as the IRA with a patent right coronary artery (RCA) (type 1A, n = 25); LAD as IRA with an occluded RCA (type 1B, n = 1); RCA as IRA with a patent LAD (type 2A, n = 19); and RCA as IRA with an occluded LAD (type 2B, n = 4). RESULTS: Single vessel occlusion (type A angiographic pattern) was found in 90% of patients. Type 1A patients had a larger infarct size than that of 2A. ST elevation in V(2) >/= V(3) identified RCA as the IRA with a high specificity (92%) and sensitivity (74%). Type 2B patients (2-vessel occlusion) had a larger infarct size than that of 2A; however, no electrocardiogram (ECG) criteria could reliably differentiate them. CONCLUSION: In a real world situation, single vessel occlusion is found in the majority of cases of combined ST elevation in anterior and inferior leads. ST elevation in V(2) >/= V(3) distinguishes RCA against LAD as the IRA with high accuracy.

E-cadherin promoter hypermethylation induced by interleukin-1beta treatment or H. pylori infection in human gastric cancer cell lines.

Interleukin-1beta is up-regulated in the presence of Helicobacter pylori infection. H. pylori infection was associated with E-cadherin methylation. In this study, we examined if IL-1beta could induce promoter methylation of E-cadherin in human gastric cancer cell lines TMK-1, MKN-74 and MKN-7. Cells were treated with IL-1beta (0.025, 0.1, 0.25, 1.0, 2.5 ng/mL) for 6, 12 and 24h. Methylation status was determined by MSP and sequencing. The effects of IL-1beta or H.pylori on the cells, and after blockade with interleukin-1 receptor antagonist (IL-1ra) were tested. Promoter methylation of E-cadherin was induced in all three cells treated with IL-1beta or co-cultured with H. pylori. Treatment of IL-1ra could reverse the phenomena. Our study indicated that IL-1beta is an important step in mediating E-cadherin methylation.

Decreasing trend of esophageal adenocarcinoma in Hong Kong.

BACKGROUND: The incidence of esophageal adenocarcinoma was increasing in the Western Europe and United States, but not in East Asian countries. Population based study on the trend of esophageal adenocarcinoma in Hong Kong was not available. MATERIALS AND METHODS: Population-based data of Hong Kong Cancer Registry from 1984 to 2003 were used. Cases were grouped into four 5-year periods. Average age standardized rate (WSR) of each period was calculated by averaging the WSR of the 5 years in each period, basing on the world standard population, with adjustment made for cases with missing histology. RESULTS: 10,751 new cases of esophageal neoplasm were studied (8,637 males and 2,114 females). Esophageal adenocarcinoma declined among both males and females, with the total number decreased from 224 in 1984 to 1988 to 131 in 1998 to 2003. WSR decreased from 1.10 of 100,000 in 1984 to 1988 to 0.34 of 100,000 in 1998 to 2003. The decline was faster than that for esophageal squamous cell carcinoma so that the relative ratio of esophageal adenocarcinoma decreased from 11.7% in 1984 to 1988 to 6.4% in 1998 to 2003. CONCLUSIONS: The incidence of esophageal adenocarcinoma and ratio of esophageal adenocarcinoma versus esophageal squamous cell carcinoma decreased in Hong Kong.

Influence of positive family history on clinical characteristics of functional constipation.

BACKGROUND & AIMS: We observed that there is familial aggregation in patients with functional constipation. Their clinical characteristics have not been studied. The aim of this study was to investigate the clinical characteristics of patients with functional constipation with and without a positive family history. METHODS: Patients with functional constipation satisfying Rome II criteria were recruited. A Rome II questionnaire on constipation was given to the patients' families to identify whether there were any family members with idiopathic constipation. The clinical characteristics between those with and without positive family history were evaluated. RESULTS: There were 118 patients with at least one first-degree relative with idiopathic constipation and 114 patients without a positive family history. The patients in the 2 groups were comparable in mean age (P = .3) and sex distribution (P = .09). Patients with positive family history had a younger age of onset (median, 11-20 years vs 21-30 years, P < .0001); longer duration of constipation (20 +/- 14 vs 15 +/- 13, P = .016); more complications, eg, symptomatic hemorrhoids, anal fissure, and rectal prolapse (54.2% vs 40.4%, P = .034); less precipitating factors leading to the onset of constipation (35.6% vs 49.1%, P = .037); more frequent use of digital evacuation (27.1% vs 13.2%, P = .008), but no difference in the association with psychological disorders (P = .3); transit time (P = .5); or manometric dyssynergia (P = .5). CONCLUSIONS: Patients with idiopathic constipation and with a positive family history exhibited different clinical characteristics. This might be related to the early age of onset of the symptoms, which might, in turn, give clues to the underlying etiology.

Increasing dietary fiber intake in terms of kiwifruit improves constipation in Chinese patients.

AIM: To investigate if increased dietary fiber, in terms of kiwifruit, is effective in Chinese constipated patients. METHODS: 33 constipated patients and 20 healthy volunteers were recruited for a 4-wk treatment of kiwi fruit twice daily. Response during wk 1-4 was defined as an increase in complete spontaneous bowl, motion (CSBM) > or = 1/wk. Secondary efficacy included response during wk 1-4, individual symptoms and scores of bowel habits and constipation. Responses were compared with the baseline run-in period. Colonic transit time and anorectal manometry were performed before and after treatment. RESULTS: Responder rate was 54.5% in the constipated group. The mean CSBM increased after treatment (2.2 +/- 2.6 vs 4.4 +/- 4.6, P = 0.013). There was also improvement in the scores for bothersomeness of constipation (P = 0.02), and satisfaction of bowel habit (P = 0.001), and decreased in days of laxative used (P = 0.003). There was also improvement in transit time (P = 0.003) and rectal sensation (P < 0.05). However, there was no change in the bowel symptoms or anorectal physiology in the healthy subjects. CONCLUSION: Increasing dietary fiber intake is effective in relieving chronic constipation in Chinese population.

Increasing prevalence of advanced colonic polyps in young patients undergoing colonoscopy in a referral academic hospital in Hong Kong.

AIM: To investigate the distribution and frequency of advanced polyps over eight years. METHODS: 6424 colonoscopies were reviewed during the study period 1998 to 2005. The study period was subdivided into period I: 1998 to 2001 and period II: 2002-2005. RESULTS: 1856 polyps (33% advanced polyps) and 328 CRCs were detected. The mean ages of the patients with advanced polyps and cancer were 69.2 +/- 12.0 and 71.6 +/- 13.8 years, respectively. Advanced polyps were mainly left sided (59.5%). Advanced polyps were found in patients 0.05). CONCLUSION: Advanced polyps increased significantly in the younger male group in the most recent period and there seems to be a shift towards a proximal location.

Prevalence of colorectal neoplasm among patients with newly diagnosed coronary artery disease.

CONTEXT: Colorectal neoplasm and coronary artery disease (CAD) share similar risk factors, and their co-occurrence may be associated. OBJECTIVES: To investigate the prevalence of colorectal neoplasm in patients with CAD in a cross-sectional study and to identify the predisposing factors for the association of the 2 diseases. DESIGN, SETTING, AND PARTICIPANTS: Patients in Hong Kong, China, were recruited for screening colonoscopy after undergoing coronary angiography for suspected CAD during November 2004 to June 2006. Presence of CAD (n = 206) was defined as at least 50% diameter stenosis in any 1 of the major coronary arteries; otherwise, patients were considered CAD-negative (n = 208). An age- and sex-matched control group was recruited from the general population (n = 207). Patients were excluded for use of aspirin or statins, personal history of colonic disease, or colonoscopy in the past 10 years. MAIN OUTCOME MEASURES: The prevalence of colorectal neoplasm in CAD-positive, CAD-negative, and general population participants was determined. Bivariate logistic regression was performed to study the association between colorectal neoplasm and CAD and to identify risk factors for the association of the 2 diseases after adjusting for age and sex. RESULTS: The prevalence of colorectal neoplasm in the CAD-positive, CAD-negative, and general population groups was 34.0%, 18.8%, and 20.8% (P < .001 by chi2 test), prevalence of advanced lesions was 18.4%, 8.7%, and 5.8% (P < .001), and prevalence of cancer was 4.4%, 0.5%, and 1.4% (P = .02), respectively. Fifty percent of the cancers in CAD-positive participants were early stage. After adjusting for age and sex, an association still existed between colorectal neoplasm and presence of CAD (odds ratio [OR], 1.88; 95% confidence interval [CI], 1.25-2.70; P = .002) and between advanced lesions and presence of CAD (OR, 2.51; 95% CI, 1.43-4.35; P = .001). The metabolic syndrome (OR, 5.99; 95% CI, 1.43-27.94; P = .02) and history of smoking (OR, 4.74; 95% CI, 1.38-18.92; P = .02) were independent factors for the association of advanced colonic lesions and CAD. CONCLUSIONS: In this study population undergoing coronary angiography, the prevalence of colorectal neoplasm was greater in patients with CAD. The association between the presence of advanced colonic lesions and CAD was stronger in persons with the metabolic syndrome and a history of smoking.

CpG island methylation in precursors of gastrointestinal malignancies.

Gastrointestinal malignancies account for about 20% of all cancers worldwide. It is widely accepted that cancer evolves through several stepwise morphological stages such as the adenoma-carcinoma and hyperplastic polyp-serrated adenoma-carcinoma sequences in colorectal cancers, and the metaplasia-dysplasia-carcinoma sequences in esophageal and gastric cancers. The morphological progression is associated with the accumulation of multiple genetic and epigenetic events. It is now recognized that epigenetic silencing of gene expression by CpG island methylation is an important alternative mechanism of inactivating tumor suppressor genes. Inflammatory conditions of the gastrointestinal and pancreaticobiliary tracts and liver such as Barrett esophagus, Helicobacter pylori gastritis, inflammatory bowel disease and viral hepatitis, are associated with increased frequency of malignancies and CpG methylation. In addition, CpG methylation is present in aberrant crypt foci and pancreatic intraepithelial neoplasia that are considered putative precursors of colon and pancreatic carcinomas, respectively. Understanding of these early genetic and epigenetic changes allows for the discoveries of potential screening, monitoring and therapeutic strategies. Targeting of the epigenetic changes that occur before the development of frank malignancy offers a potential chemopreventive strategy.

A patient with long-standing iron-deficient anemia.

BACKGROUND: A 36-year-old Chinese woman presented with cutaneous lupus and was incidentally found to have iron-deficient anemia. She had a history of iron-deficient anemia 13 years previously, for which extensive investigations were carried out; the results of which were all normal. The patient also had pulmonary tuberculosis at that time, for which she received a full course of treatment. She required periodic blood transfusions and iron supplements to maintain her hemoglobin levels. She was subsequently discharged to a family clinic for follow-up until the current presentation. INVESTIGATIONS: Upper endoscopy, colonoscopy, barium meal follow-through, small-bowel enema, (99m)Tc-labeled red-cell scan and double-balloon enteroscopy. DIAGNOSIS: Iron-deficient anemia due to obscure gastrointestinal bleeding caused by two small-bowel hemangiomas. MANAGEMENT: Laparoscopic surgery.

E-cadherin in gastric cancer.

Cadherin is an adhesion molecule and a superfamily of calcium-mediated membrane glycoproteins. E-cadherin is the prototype of the class E-cadherin that links to catenins to form the cytoskeleton. Recent evidence has shown that E-cadherin not only acts as an adhesive, but also plays important roles in growth development and carcinogenesis. It has been recently viewed as an invasion as well as a growth suppressor gene. This review summarizes the recent discoveries on E-cadherin and its role in gastric cancer. In particular, our work on E-cadherin in gastric cancer, including its relation with Helicobacter pylori and clinical applications, are described in detail.

Prognostic implications of PR-segment depression in inferior leads in acute inferior myocardial infarction.

BACKGROUND: Concurrent atrial ischemia is usually overlooked in acute myocardial infarction (MI) due to its subtle electrocardiographic (ECG) changes, lack of clear-cut clinical picture, and prognostic significance. PR-segment depression in the inferior leads is a simplified ECG sign for detecting possible underlying atrial ischemia. HYPOTHESIS: The purpose of this study was to document the incidence, clinical characteristics, and prognostic implications of this ECG sign in the setting of acute inferior MI. METHODS: Demographics, clinical characteristics, and outcomes of 463 consecutive patients presenting with acute inferior MI were reviewed. The in-hospital ECG was examined by two independent reviewers. The results were then compared between those with and without ECG sign. RESULTS: Profound PR-segment depression > or = 1.2 mm in inferior leads was found in 9 of 463 (1.9%) patients. Patients with atrial ischemia tended to present earlier (2.4 +/- 2.6 vs. 7.0 +/- 8.2 h, p = 0.000) and had a higher frequency of first-degree atrioventricular block (77.8 vs. 30.6%, p = 0.028) and supraventricular arrhythmias (55.5 vs. 20.2%, p = 0.022). Of greater importance, it was significantly associated with an increased rate of cardiac free-wall rupture (33.3 vs. 2.0%, p = 0.001) and in-hospital mortality (44.4 vs. 11.7%, p = 0.015). CONCLUSION: Profound PR-segment depression > or = 1.2 mm in inferior leads was associated with a complicated hospital course and poor short-term outcome in acute inferior MI. These patients were at high risk for the development of atrioventricular block, supraventricular arrhythmias, and cardiac free-wall rupture.

Bottom-up histogenesis of colorectal adenomas: origin in the monocryptal adenoma and initial expansion by crypt fission.

The adenoma:carcinoma sequence is well established. Understanding the molecular pathology of the adenoma is therefore important. There is great controversy within the field. The Vogelstein group champions the "top-down" theory (colorectal adenomas arise and grow across the mucosal surface and down into the crypts), whereas other studies, including our own, propose "bottom-up" spread. Serial sections of 40 small (<3 mm) sporadic colorectal adenomas were stained with H&E, MIB-1, and for beta-catenin. 10 early adenomas were Feulgen-stained and microdissected. We also examined the flat mucosa of three patients who had undergone colectomies for familial adenomatous polyposis (FAP) and specimens from a XO/XY individual with FAP, the latter using in situ hybridization for the Y chromosome. In the earliest sporadic adenomas, there were crypts entirely filled with adenomatous epithelium, which showed proliferative activity and nuclear localization of beta-catenin. There was a sharp cutoff between crypt epithelial cells showing nuclear beta-catenin and surface cells with membrane staining. In slightly larger lesions, adenomatous spread from above was seen. Microdissected adenomas showed multiple fission events, with proliferation distributed equally throughout. In FAP tissue, numerous isolated monocryptal adenomas, which were clonal in origin, were seen. Examination of adenomas in the XO/XY individual showed no instances of XY or XO adenomatous epithelium growing down into crypts of the other genotype. Both sporadic and FAP adenomas start as a unicryptal adenomas and grow initially by crypt fission--a bottom-up pattern. Later, in sporadic adenomas, there is evidence of growth down into adjacent crypts (top-down).

Antisense targeting protein kinase C alpha and beta1 inhibits gastric carcinogenesis.

Protein kinase C (PKC) family, which functions through serine/threonine kinase activity, is involved in signal transduction pathways necessary for cell proliferation, differentiation, and apoptosis. Its critical role in neoplastic transformation and tumor invasion renders PKC a potential target for anticancer therapy. In this study, we investigated the effect of targeting individual PKCs on gastric carcinogenesis. We established gastric cancer cell lines stably expressing antisense PKCalpha, PKCbeta1, and PKCbeta2 cDNA. These stable transfectants were characterized by cell morphology, cell growth, apoptosis, and tumorigenicity in vitro and in vivo. PKCalpha-AS and PKCbeta1-AS transfectants showed a different morphology with flattened, long processes and decreased nuclear:cytoplasmic ratio compared with the control cells. Cell growth was markedly inhibited in PKCalpha-AS and PKCbeta1-AS transfectants. PKCalpha-AS and PKCbeta1-AS cells were more responsive to mitomycin C- or 5-fluorouracil-induced apoptosis. However, antisense targeting of PKCbeta2 did not have any significant effect on cell morphology, cell growth, or apoptosis. Furthermore, antisense inhibition of PKCalpha and PKCbeta1 markedly suppressed colony-forming efficiency in soft agar and in nude mice xenografts. Inhibition of PKCalpha or PKCbeta1 significantly suppressed transcriptional and DNA binding activity of activator protein in gastric cancer cells, suggesting that PKCalpha or PKCbeta1 exerts their effects on cell growth through regulation of activator protein activity. These data provide evidence that targeting PKCalpha and PKCbeta1 by antisense method is a promising therapy for gastric cancer.

Suppression of survivin expression inhibits in vivo tumorigenicity and angiogenesis in gastric cancer.

Survivin plays an important role in cancer development. We aim to show here that suppression of survivin expression or function by antisense and dominant-negative (DN) mutant can inhibit gastric cancer carcinogenesis and angiogenesis in vivo. Plasmid constructs expressing survivin antisense and DN mutant replacing the cysteine residue at amino acid 84 with alanine (Cys84Ala) were prepared and introduced into BCG-823 and MKN-45 gastric cancer cells to establish stable transfectants. We showed that both antisense and DN mutant stable transfectants exhibited abnormal morphology, with decreased cell growth and increased rate of spontaneous apoptosis and mitotic catastrophe. Furthermore, in nude mice xenografts, these cells exhibited decreased de novo gastric tumor formation and reduced development of angiogenesis. Results from these studies strongly suggest that survivin is a promising target for gastric cancer treatment.

Interleukin-1ß increases the risk of gastric cancer through induction of aberrant DNA methylation in a mouse model.

Interleukin-1ß (IL-1ß) has a significant role in chronic gastric inflammation and manifestations of gastric diseases. The present study aimed to elucidate the specific role of IL-1ß in induction of DNA methylation using IL-1 receptor type 1 knockout (IL-1R1-/-) mice. In the present study, wild-type (WT) and IL-1R1-/- mice were injected with IL-1ß (5 µg/kg/day). Serum levels of IL-1ß, interleukin-6 (IL-6) and nitric oxide (NO) were measured by enzyme-linked immunosorbent or NO assays. E-cadherin (E-cad) methylation status and messenger (m)RNA expression of IL-1ß, IL-6, E-cad and inducible nitric oxide synthase (iNOS) were analyzed. Results from the present study indicated significantly higher IL-1ß mRNA expression (P<0.001) in WT mice compared with IL-1R1-/- mice. IL-1ß and IL-6 release was significantly increased in treated WT mice compared with IL-1R1-/- mice at 1 h, 4 h and 8 h (all P<0.005). IL-1ß release was only detected in WT mice following a second dose measured at day 3, week 1 and week 2 when compared with IL-1R1-/- mice. Promoter methylation of E-cad and a decrease in gene expression was observed in treated WT mice. mRNA expression of iNOS in WT mice was significantly increased at week 1 compared with IL-1R1-/- mice (P=0.0411). Furthermore, a significantly increased level of NO production was observed in treated WT mice (P<0.005 at 8 h and week 1; P<0.001 at 4 h and day 3) when compared with IL-1R1-/- mice. The present results indicated that IL-1ß was able to directly induce DNA methylation, which may link inflammation-induced epigenetic changes and the development of gastric diseases.

Burden of upper gastrointestinal symptoms in patients prescribed dabigatran for stroke prevention.

BACKGROUND: Dabigatran, a non-vitamin K antagonist oral anticoagulant, has been shown to prevent stroke in patients with non-valvular atrial fibrillation. Nonetheless, studies show that 10%-30% of those prescribed dabigatran experience dyspepsia that may eventually lead to discontinuation of therapy and loss of clinical benefit. AIM: To evaluate the gastrointestinal tolerability of dabigatran utilizing a validated questionnaire, as well as determining subsequent non-compliance and drug discontinuation. METHOD: This is an observational study. All patients were assessed by a validated questionnaire, Hong Kong dyspepsia index, prior to drug prescription and again 4 weeks later. RESULTS: In this study, 115 patients with non-valvular atrial fibrillation (mean age: 74.6 ± 11.4 years; mean CHA2DS2-VASc score was 3.39 ± 1.59) were prescribed dabigatran. At baseline, the mean Hong Kong dyspepsia index was 12.9 ± 1.6 and nine patients had significant dyspepsia (Hong Kong dyspepsia index ⩾ 16). After 4 weeks, the mean Hong Kong dyspepsia index was similar at 12.6 ± 1.9 (p = 0.23). There was no change in Hong Kong dyspepsia index after initiation of dabigatran in 59 (51.3%) patients, and improvement in 37 (32.2%). Only 19 (16.5%) patients had worsening of Hong Kong dyspepsia index, and among these 19 patients, only 1 patient (0.9%) discontinued dabigatran due to significant dyspepsia. CONCLUSION: Worsening of dyspepsia with dabigatran 110 mg twice daily was uncommon with correct drug administration and clear instructions provided. Systematic assessment of dyspeptic symptoms using a validated questionnaire (i.e. Hong Kong dyspepsia index) before and after treatment initiation allows a more objective comparison of dyspeptic symptoms.

CpG island methylation in carcinoid and pancreatic endocrine tumors.

Carcinoid tumors and pancreatic endocrine tumors (PETs) are uncommon neuroendocrine neoplasms and their genetic alterations are not well characterized. CpG island methylation is a mechanism of gene silencing, and concordant methylation of multiple CpG islands as CpG island methylator phenotype (CIMP) has been described in tumors. The aim of this study was to evaluate CIMP in carcinoid tumors and PETs. We studied 16 carcinoid tumors, 11 PETs, and 22 associated normal mucosa or pancreas. Methylation status of the p14, p16, cyclo-oxygenase 2 (COX2), O(6)-methyl-guanine methyltransferase (MGMT), estrogen receptor (ER), thrombospondin 1 (THBS1), retinoic acid receptor beta 2 (RARbeta), T-type calcium channel (CACNA1G), and multiple endocrine neoplasia type-1 (MEN1) genes, and of MINT1, MINT2, MINT25, MINT27 and MINT31 loci was evaluated by methylation-specific-PCR (MSP) or combined bisulfite restriction analysis (COBRA). Carcinoid tumors were frequently methylated at RARbeta, MGMT, p16, COX2, p14, THBS1, and ER ranging from 25 to 63% of tumors. Other CpG islands were infrequently methylated or unmethylated. The adjoining normal mucosa was also methylated for ER, COX2, and RARbeta, but methylation at p14, p16, THBS1, and MGMT was tumor-specific. By contrast, PETs and normal pancreas were frequently methylated only at ER. Methylation was more frequent in carcinoid tumors than PETs at MGMT (25 versus 0%, p = 0.03), THBS1 (44 versus 9%, p = 0.04), p14 (44 versus 9%, p = 0.04) and RARbeta (25 versus 0%, p = 0.03). Loss of p16 protein expression correlated with methylation of p16 gene in carcinoid tumors (p = 0.006). Our study indicates that methylation profile of carcinoid tumors differs from PETs, reflecting different molecular pathogenesis.