Wai-Keung Leung

The Effect of Endoscopic Therapy in Patients Receiving Omeprazole for Bleeding Ulcers with Nonbleeding Visible Vessels or Adherent Clots: A Randomized Comparison

Context Endoscopic hemostasis plus omeprazole in patients with actively bleeding ulcers prevents recurrent bleeding. Are both needed if endoscopy shows a nonbleeding vessel or nonbleeding clot? Contribution This randomized trial included 156 patients admitted for bleeding whose endoscopies, performed within 24 hours of admission, showed ulcers with nonbleeding vessels or adherent clots. Approximately 12% of patients receiving omeprazole alone had recurrent bleeding within 30 days compared with approximately 1% who received endoscopic hemostasis (thermocoagulation and epinephrine injection) plus omeprazole. Implications Endoscopic hemostasis plus omeprazole better prevents recurrent bleeding than does omeprazole alone in patients who have recently bled from an ulcer but do not have actively bleeding vessels at endoscopy. The Editors Endoscopic hemostasis is effective in controlling bleeding from peptic ulcers. The optimal treatment of ulcers with nonbleeding visible vessels and adherent clots, however, is unclear. The controversy arises from variability in endoscopic diagnosis as well as in the standard treatment strategies adopted by endoscopists for ulcers with adherent clots. At least two studies have shown that even experienced endoscopists have different definitions of stigmata at the ulcer base (1, 2). Among the stigmata of hemorrhage, clot and protuberant vessels are the most difficult to differentiate. After a clot has been diagnosed, approaches to management are quite different. Some clinicians flush the clot with a syringe or oral irrigator, which in general produces rather weak irrigate (3), whereas others advocate targeted irrigation using thermal probes (4). With these methods of irrigation, the success rates for exposing the underlying stigmata range from 9% (3) to 57% (4). Even after removal of blood clots, it is not certain whether endoscopic therapy prevents recurrent bleeding or actually provokes it. Randomized, controlled trials of endoscopic therapy versus no endoscopic therapy have yielded conflicting results (5, 6), and meta-analysis does not support routine use of endoscopic therapy (7). The advent of proton-pump inhibitors changed the standard of practice in the management of bleeding ulcers. Two studies from India have demonstrated the benefit of high-dose oral omeprazole for peptic ulcer bleeding. Khuroo and colleagues (8) demonstrated that a 5-day course of oral omeprazole, 40 mg twice daily, reduced recurrent bleeding even without endoscopic therapy. The benefit of omeprazole was most remarkable among patients with visible vessels or adherent clots at the ulcer bases. Javid and associates (9) showed that the same omeprazole regimen in combination with endoscopic injection prevented recurrent bleeding. Their study, however, failed to demonstrate a distinct advantage of omeprazole in patients with nonbleeding visible vessels and adherent clots. A recent randomized study by Jensen and coworkers (10) compared twice-daily administration of an oral proton-pump inhibitor with endoscopic therapy in 32 patients who were at high risk for ulcer hemorrhage. Six of 17 medically treated patients had recurrent bleeding compared with none of 15 patients treated endoscopically. The study was discontinued prematurely because of the dramatic difference in clinical outcome. Study limitations included small sample size, unequal distribution of confounding factors, and lack of difference in clinical end points (11). The effectiveness of proton-pump inhibitors alone for ulcers that are not actively bleeding but have stigmata of a nonbleeding visible vessel or an adherent clot remains undetermined. We previously demonstrated that high-dose intravenous omeprazole as an adjunct to endoscopic therapy substantially reduced risk for recurrent bleeding, repeated endoscopy, frequency of blood transfusion, and duration of hospitalization (12). Subgroup analysis suggested that actively bleeding ulcers, as well as ulcers with a nonbleeding visible vessel or an adherent clot, benefited from the treatment. In the current study, we compared high-dose intravenous omeprazole infusion plus endoscopic therapy with intravenous omeprazole infusion alone for prevention of recurrent bleeding from ulcers with a nonbleeding visible vessel or an adherent clot. Methods Description of the Study and Patients We performed a single-center randomized trial comparing the combination of endoscopic therapy and high-dose omeprazole infusion with high-dose omeprazole infusion alone for treatment of ulcers with a nonbleeding visible vessel or an adherent clot. This study was conducted at the Endoscopy Center of the Prince of Wales Hospital in Hong Kong. The clinical trials ethics committee of the faculty of medicine of the Chinese University of Hong Kong approved the study protocol. Consecutive patients who presented with signs of upper gastrointestinal bleeding underwent endoscopic examination within 24 hours of hospital admission. Patients who were in shock or were vomiting fresh blood at presentation underwent urgent endoscopy as soon as their hemodynamic conditions stabilized. All endoscopic examinations were performed by using a dual-channel endoscope (Olympus 2T200, Olympus Japan Co., Tokyo, Japan). All participants provided written informed consent before the endoscopic examinations. At endoscopy, gastric or duodenal ulcers were examined to determine whether they were actively bleeding (spurting or oozing) or showed nonbleeding visible vessels or adherent clots. A nonbleeding visible vessel was defined as a protuberant discoloration according to the National Institutes of Health 1989 consensus statement (13). Ulcers with overlying clots were irrigated for 5 minutes with a 3.2-mm heater probe (Olympus CD-10Z, Olympus Japan Co.) to remove loosely attached clots and debris. An adherent clot was defined as a blood clot that remained attached to the ulcer base after the 5-minute period of irrigation (3). Patients met the inclusion criteria if they were at least 16 years of age and had benign gastroduodenal ulcers showing nonbleeding visible vessels or adherent clots at endoscopy. Patients were excluded if they 1) had actively bleeding ulcers, including ulcers in which endoscopic irrigation procedures provoked bleeding before treatment; 2) had had endoscopic therapy for bleeding ulcer within the past 30 days; 3) had a history of gastric surgery; 4) were pregnant; 5) had malignant ulcers; or 6) did not provide written informed consent. Specimens were taken from the antrum for urease biopsy and histologic examination to determine Helicobacter pylori status. Patients found to have malignant ulcers after initial enrollment were excluded from the analysis. Randomization and Treatment Protocol Randomization was performed when ulcers were judged to show a nonbleeding visible vessel or an adherent clot after 5 minutes of irrigation. Patients were randomly assigned to receive endoscopic therapy or sham endoscopic treatment. Randomization was carried out through the use of a computer-generated list of random numbers in blocks of 10. Allocation concealment was performed by an independent research nurse who assigned treatments according to consecutive numbers in sealed opaque envelopes. Patients randomly assigned to endoscopic therapy were treated with epinephrine injection followed by thermocoagulation. Diluted epinephrine (1:10 000 dilution) was injected in 0.5-mL or 1-mL aliquots around the nonbleeding visible vessels or adherent clots to induce tissue blanching and edema. In general, approximately 5 mL of diluted epinephrine was injected. The vessels were then thermocoagulated by using a 3.2-mm heater probe (30 J for 6 seconds). The end point of endoscopic treatment was defined by the flattening or cavitation of protuberances. Adherent clots were removed by cheese-wiring using a mini-snare, and the ulcer base was again examined. Underlying vessels were coagulated in a similar fashion. In the event of provoked bleeding, cessation of bleeding and flattening or cavitation of protuberances constituted successful treatment. Patients randomly assigned to sham endoscopic treatment underwent gentle irrigation of the ulcer base using a syringe but no manipulation with the heater probe, mini-snare, or suction. Any bleeding provoked after randomization was included in the intention-to-treat analysis. All patients received intravenous omeprazole (Losec, AstraZeneca, Molndal, Sweden) after randomization. A bolus injection of omeprazole, 80 mg, was given during the endoscopic procedure and was followed immediately by a continuous infusion of 8 mg/h for 72 hours. Follow-up After the endoscopic procedure, an independent team of physicians who were blinded to treatment assignments monitored the patients in a gastroenterology ward for signs of recurrent bleeding. The endoscopists were not involved in subsequent patient management. A research nurse kept endoscopy records in opaque sealed envelopes that were not accessible to physicians, investigators, or patients. Blood pressure and pulse rate were monitored hourly during the first 24 hours and every 4 hours thereafter until discharge. After finishing 72 hours of omeprazole infusion, patients were prescribed 20 mg of oral omeprazole per day. Those who had no evidence of recurrent bleeding were discharged within 5 days of hospitalization. Patients who had positive results on urease biopsy also received a 1-week course of omeprazole (20 mg twice daily), clarithromycin (500 mg twice daily), and amoxicillin (1 g twice daily). All patients were evaluated for evidence of delayed recurrent bleeding at day 30. End Points The primary end points were recurrent ulcer bleeding before discharge and within 30 days, according to prespecified criteria. Bleeding was considered to have recurred if any of the following were documented: vomiting of fresh blood; shock (defined as a systolic blood pressure < 90 mm Hg or pulse rate > 110 b

Upregulation of heme oxygenase-1 and p21 confers resistance to apoptosis in human gastric cancer cells

Both heme oxygenase-1 (HO-1) and p21WAF1/Cip1 (p21) are involved in the pathogenesis of human cancer and their functions are closely associated with apoptosis. However, how these two molecules regulate apoptosis in human gastric cancer is unknown. In this study, we studied how HO-1 and p21 were regulated in two gastric cancer cell lines, MKN-45 with wild p53 and MKN-28 with mutant p53. The cells were treated with hemin and cadmium to induce HO-1. The result showed that HO-1 protein was significantly induced by hemin and cadmium in both cells tested. Following the HO-1 expression, p21 level was also markedly induced. The cells with increased HO-1 and p21 showed obviously resistantance to apoptotic stimuli. The levels of HO-1 and p21 induced were significantly inhibited by p38 mitogen-activated protein kinase (p38 MAPK) inhibitor (SB203580) and extracellular-regulated kinase (ERK) inhibitor (PD098059). Parallel to decreased HO-1 and p21 expression, the kinase inhibitors also significantly attenuated the resistance of the cells to apoptosis. The elevated HO-1 and p21 was further found to be associated with increase activity of the nuclear NF-κB and the inhibition of NF-κB led to the block of their induction. The elevated HO-1 and p21 were also demonstrated to be related to increased cellular inhibitor of caspase inbitory protein-2 (c-IAP2) and decreased caspapse-3 activity. It was noted that the above changes observed were not different between MKN-45 and MKN-28 cells, suggesting the functions of HO-1 and p21 were irrespective of the status of p53. In conclusion, we demonstrate that the resistance to apoptosis in gastric cancer cells with elevated HO-1 and p21 is independent of p53 status in a p38 MAPK- and ERK-mediated pathway with elevated c-IAP2 and decreased caspase-3 activity and that this pathway is sensitive to the inhibition of NF-κB.

Does eradication of Helicobacter pylori impair healing of nonsteroidal anti-inflammatory drug associated bleeding peptic ulcers? A prospective randomized study

Despite the widely accepted view that Helicobacter pylori is the most important cause of peptic ulcer disease, recent studies have suggested that the microbe protects against nonsteroidal anti‐inflammatory drug (NSAID)‐associated gastroduodenal lesions and promotes ulcer healing. We investigated the effects of H. pylori eradication on the healing of NSAID‐associated bleeding peptic ulcers.

Changes in Crohn's disease phenotype over time in the Chinese population: validation of the Montreal classification system.

Background: Phenotypic evolution of Crohns disease occurs in whites but has never been described in other populations. The Montreal classification may describe phenotypes more precisely. The aim of this study was to validate the Montreal classification through a longitudinal sensitivity analysis in detecting phenotypic variation compared to the Vienna classification. Methods: This was a retrospective longitudinal study of consecutive Chinese Crohns disease patients. All cases were classified by the Montreal classification and the Vienna classification for behavior and location. The evolution of these characteristics and the need for surgery were evaluated. Results: A total of 109 patients were recruited (median follow‐up: 4 years, range: 6 months–18 years). Crohns disease behavior changed 3 years after diagnosis (P = 0.025), with an increase in stricturing and penetrating phenotypes, as determined by the Montreal classification, but was only detected by the Vienna classification after 5 years (P = 0.015). Disease location remained stable on follow‐up in both classifications. Thirty‐four patients (31%) underwent major surgery during the follow‐up period with the stricturing [P = 0.002; hazard ratio (HR): 3.3; 95% CI: 1.5–7.0] and penetrating (P = 0.03; HR: 5.8; 95% CI: 1.2–28.2) phenotypes according to the Montreal classification associated with the need for major surgery. In contrast, colonic disease was protective against a major operation (P = 0.02; HR: 0.3; 95% CI: 0.08–0.8). Conclusions: This is the first study demonstrating phenotypic evolution of Crohns disease in a nonwhite population. The Montreal classification is more sensitive to behavior phenotypic changes than is the Vienna classification after excluding perianal disease from the penetrating disease category and was useful in predicting course and the need for surgery.

Long-term follow-up of ulcerative colitis in the Chinese population.

OBJECTIVES:The incidence of ulcerative colitis (UC) in Asia is increasing but reports on its long-term course are few. We set out determine the incidence, prevalence, and survival rate of UC in the Chinese population and phenotypic stability by longitudinal follow-up.METHODS:A cohort of Chinese UC patients were followed up in a tertiary referral center in Hong Kong between 1985 and 2006. Clinical data were prospectively collected since 2001. Population statistics were obtained from the Census and Statistics Department of Hong Kong for the calculation of age-specific incidence, prevalence, and survival. The disease phenotypes at diagnosis and upon follow-up were documented.RESULTS:A total of 172 patients (51.7% men) with a median age at diagnosis of 37.0 years (range: 12.0–85.0) were included. The cohort was observed for a total of 1,393 person-years with a median follow-up duration of 7.0 years (range: 0.5–22.0). The age-standardized incidence and prevalence rates of UC per 100,000 were 2.1 (95% confidence interval, CI: 1.1–3.7) and 26.5 (95% CI: 22.6–30.9), respectively, in 2006. The 10-year cumulative rate of proximal extension was 23.8%. Only one patient developed colorectal cancer during the observation period. The cumulative colectomy rates were 2.4% and 7.6% at 1 and 10 years of follow-up. Overall survival was similar to that expected (P=0.07).CONCLUSIONS:The incidence of UC has increased sixfold in the past two decades in Hong Kong. The complication, colorectal cancer, and colectomy rates are low in Chinese patients but increase with duration of illness.

Functional role of the KLF6 tumour suppressor gene in gastric cancer

Gastric cancer is the second most common cancer and a leading cause of cancer-related death worldwide. The Kruppel-like factor 6 (KLF6) tumour suppressor gene had been previously shown to be inactivated in a number of human cancers through loss of heterozygosity (LOH), somatic mutation, decreased expression and increased alternative splicing into a dominant negative oncogenic splice variant, KLF6-SV1. In the present study, 37 gastric cancer samples were analysed for the presence of loss of heterozygosity (LOH) of the KLF6 locus and somatic mutation. In total, 18 of 34 (53%) of the gastric cancer samples analysed demonstrated KLF6 locus specific loss. Four missense mutations, such as T179I, R198G, R71Q and S180L, were detected. Interestingly, two of these mutations R71Q and S180L have been identified independently by several groups in various malignancies including prostate, colorectal and gastric cancers. In addition, decreased wild-type KLF6 (wtKLF6) expression was associated with loss of the KLF6 locus and was present in 48% of primary gastric tumour samples analysed. Functional studies confirmed that wtKLF6 suppressed proliferation of gastric cancer cells via transcriptional regulation of the cyclin-dependent kinase inhibitor p21 and the oncogene c-myc. Functional characterisation of the common tumour-derived mutants demonstrated that the mutant proteins fail to suppress proliferation and function as dominant negative regulators of wtKLF6 function. Furthermore, stable overexpression of the R71Q and S180L tumour-derived mutants in the gastric cancer cell line, Hs746T, resulted in an increased tumourigenicity in vivo. Combined, these findings suggest an important role for the KLF6 tumour suppressor gene in gastric cancer development and progression and identify several highly cancer-relevant signalling pathways regulated by the KLF6 tumour suppressor gene.

Intestinal trefoil factor promotes invasion in non-tumorigenic Rat-2 fibroblast cell.

Intestinal trefoil factor (TFF3) is essential in regulating cell migration and maintaining mucosal integrity in gastrointestinal tract. We previously showed that TFF3 was overexpressed in gastric carcinoma. Whether TFF3 possesses malignant potential is not fully elucidated. We sought to investigate the effects of inducting TFF3 expression in a non-malignant rat fibroblast cell line (Rat-2) on the cell proliferation, invasion and the genes regulating cell invasion. Invasiveness and proliferation of transfected Rat-2 cell line were assessed using in vitro invasion chamber assay and colorimetric MTS assay. Differential mRNA expressions of invasion-related genes, namely, metalloproteinases (MMP-9), tissue inhibitors of metalloproteinases (TIMP-1), beta-catenin and E-cadherin, were determined by quantitative real-time polymerase chain reaction (PCR). We showed that TFF3 did not inhibit the proliferation of Rat-2 cells. We also demonstrated that transfection of TFF3 significantly promoted invasion of Rat-2 cells by 1.4- to 2.2-folds. There was an upregulation of beta-catenin (13.1-23.0%) and MMP-9 (43.4-92.2%) mRNA expression levels, and downregulation of E-cadherin (25.6-33.8%) and TIMP-1 (31.5-37.8%) in TFF3-transfected cells compared to controls during 48-h incubation. Our results suggested that TFF3 possesses malignant potential through promotion of cell invasiveness and alteration of invasion-related genes.

Use of chopsticks for eating and Helicobacter pylori infection.

Epidemiological data suggests that ethnic groupsusing chopsticks for eating have a higher prevalence ofH. pylori infection. This study investigated thecarriage of H. pylori in chopsticks after eating. Used chopsticks and saliva were collected fromasymptomatic individuals whose H. pylori status wasdetermined by [13C]urea breath test andserology. Both the saliva specimens and chopsticks werecultured and processed by polymerase chain reaction(PCR) for the detection of H. pylori . Furthermore,chopsticks used by hospital staff in the cafeteria werepooled for the detection of H. pylori by bacteriologic culture and PCR. Sixty-nine volunteers wererecruited in the first study and 45 (65%) were diagnosedto have H. pylori infection. While all cultures werenegative, H. pylori was detected by PCR in the saliva from 15 (33%) infected subjects and in thechopsticks from one (2%). Among the 12 sets of pooledchopstick-washing studied, H. pylori was detected by PCRin two sets. This study showed that H. pylori was rarely detected in chopsticks after eating andhence, the risk of contracting this infection via theuse of chopsticks is low.