S.C.Sydney Chung

Effect of intravenous omeprazole on recurrent bleeding after endoscopic treatment of bleeding peptic ulcers.

BACKGROUND After endoscopic treatment of bleeding peptic ulcers, bleeding recurs in 15 to 20 percent of patients. METHODS We assessed whether the use of a high dose of a proton-pump inhibitor would reduce the frequency of recurrent bleeding after endoscopic treatment of bleeding peptic ulcers. Patients with actively bleeding ulcers or ulcers with nonbleeding visible vessels were treated with an epinephrine injection followed by thermocoagulation. After hemostasis had been achieved, they were randomly assigned in a double-blind fashion to receive omeprazole (given as a bolus intravenous injection of 80 mg followed by an infusion of 8 mg per hour for 72 hours) or placebo. After the infusion, all patients were given 20 mg of omeprazole orally per day for eight weeks. The primary end point was recurrent bleeding within 30 days after endoscopy. RESULTS We enrolled 240 patients, 120 in each group. Bleeding recurred within 30 days in 8 patients (6.7 percent) in the omeprazole group, as compared with 27 (22.5 percent) in the placebo group (hazard ratio, 3.9; 95 percent confidence interval, 1.7 to 9.0). Most episodes of recurrent bleeding occurred during the first three days, which made up the infusion period (5 in the omeprazole group and 24 in the placebo group, P<0.001). Three patients in the omeprazole group and nine in the placebo group underwent surgery (P=0.14). Five patients (4.2 percent) in the omeprazole group and 12 (10 percent) in the placebo group died within 30 days after endoscopy (P=0.13). CONCLUSIONS After endoscopic treatment of bleeding peptic ulcers, a high-dose infusion of omeprazole substantially reduces the risk of recurrent bleeding.

Preventing recurrent upper gastrointestinal bleeding in patients with Helicobacter pylori infection who are taking low-dose aspirin or naproxen

BACKGROUND Many patients who have had upper gastrointestinal bleeding continue to take low-dose aspirin for cardiovascular prophylaxis or other non-steroidal antiinflammatory drugs (NSAIDs) for musculoskeletal pain. It is uncertain whether infection with Helicobacter pylori is a risk factor for bleeding in such patients. METHODS We studied patients with a history of upper gastrointestinal bleeding who were infected with H. pylori and who were taking low-dose aspirin or other NSAIDs. We evaluated whether eradication of the infection or omeprazole treatment was more effective in preventing recurrent bleeding. We recruited patients who presented with upper gastrointestinal bleeding that was confirmed by endoscopy. Their ulcers were healed by daily treatment with 20 mg of omeprazole for eight weeks or longer. Then, those who had been taking aspirin were given 80 mg of aspirin daily, and those who had been taking other NSAIDs were given 500 mg of naproxen twice daily for six months. The patients in each group were then randomly assigned separately to receive 20 mg of omeprazole daily for six months or one week of eradication therapy, consisting of 120 mg of bismuth subcitrate, 500 mg of tetracycline, and 400 mg of metronidazole, all given four times daily, followed by placebo for six months. RESULTS We enrolled 400 patients (250 of whom were taking aspirin and 150 of whom were taking other NSAIDs). Among those taking aspirin, the probability of recurrent bleeding during the six-month period was 1.9 percent for patients who received eradication therapy and 0.9 percent for patients who received omeprazole (absolute difference, 1.0 percent; 95 percent confidence interval for the difference, -1.9 to 3.9 percent). Among users of other NSAIDs, the probability of recurrent bleeding was 18.8 percent for patients receiving eradication therapy and 4.4 percent for those treated with omeprazole (absolute difference, 14.4 percent; 95 percent confidence interval for the difference, 4.4 to 24.4 percent; P=0.005). CONCLUSIONS Among patients with H. pylori infection and a history of upper gastrointestinal bleeding who are taking low-dose aspirin, the eradication of H. pylori is equivalent to treatment with omeprazole in preventing recurrent bleeding. Omeprazole is superior to the eradication of H. pylori in preventing recurrent bleeding in patients who are taking other NSAIDs.

Endoscopic retreatment compared with surgery in patients with recurrent bleeding after initial endoscopic control of bleeding ulcers.

Background and Methods After endoscopic treatment to control bleeding of peptic ulcers, bleeding recurs in 15 to 20 percent of patients. In a prospective, randomized study, we compared endoscopic retreatment with surgery after initial endoscopy. Over a 40-month period, 1169 of 3473 adults who were admitted to our hospital with bleeding peptic ulcers underwent endoscopy to reestablish hemostasis. Of 100 patients with recurrent bleeding, 7 patients with cancer and 1 patient with cardiac arrest were excluded from the study; 48 patients were randomly assigned to undergo immediate endoscopic retreatment and 44 were assigned to undergo surgery. The type of operation used was left to the surgeon. Bleeding was considered to have recurred in the event of any one of the following: vomiting of fresh blood, hypotension and melena, or a requirement for more than four units of blood in the 72-hour period after endoscopic treatment. Results Of the 48 patients who were assigned to endoscopic retreatment, 35 had long-term...

Randomised trial of eradication of Helicobacter pylori before non-steroidal anti-inflammatory drug therapy to prevent peptic ulcers

BACKGROUND Helicobacter pylori infection is common in patients with peptic ulcers caused by the use of non-steroidal anti-inflammatory drugs (NSAIDs). But the pathogenic role of H pylori in this disease is controversial. We studied the efficacy of eradication of H pylori in the prevention of NSAID-induced peptic ulcers. METHODS We recruited patients with musculoskeletal pain who required NSAID treatment. None of the patients had previous exposure to NSAID therapy. Patients who had H pylori infection but no pre-existing ulcers on endoscopy were randomly allocated naproxen alone (750 mg daily) for 8 weeks or a 1-week course of triple therapy (bismuth subcitrate 120 mg, tetracycline 500 mg, metronidazole 400 mg, each given orally four times daily) before administration of naproxen (750 mg daily). Endoscopy was repeated after 8 weeks of naproxen treatment or when naproxen treatment was stopped early because of bleeding or intractable dyspepsia. All endoscopic examinations were done by one endoscopist who was unaware of treatment assignment. The primary endpoint was the cumulative rate of gastric and duodenal ulcers. FINDINGS 202 patients underwent endoscopic screening for enrolment in the trial, and 100 eligible patients were randomly assigned treatment. 92 patients completed the trial (47 in the naproxen group, 45 in the triple-therapy group). At 8 weeks, H pylori had been eradicated from no patients in the naproxen group and 40 (89%) in the triple-therapy group (p < 0.001). 12 (26%) naproxen-group patients developed ulcers: five had ulcer pain and one developed ulcer bleeding. Only three (7%) patients on triple therapy had ulcers, and two of these patients had failure of H pylori eradication (p = 0.01). Thus, 12 (26%) patients with persistent H pylori infection but only one (3%) with successful H pylori eradication developed ulcers with naproxen (p = 0.002). INTERPRETATION Eradication of H pylori before NSAID therapy reduces the occurrence of NSAID-induced peptic ulcers.

Antibacterial Treatment of Gastric Ulcers Associated with Helicobacter pylori

BACKGROUND There is a strong association between infection with Helicobacter pylori and gastric ulcers that are unrelated to the use of nonsteroidal antiinflammatory medications. We studied the efficacy of antibacterial therapy without medication to suppress gastric acid for the treatment of patients with H. pylori infection and gastric ulcers unrelated to the use of nonsteroidal agents. METHODS Patients with gastric ulcers seen on endoscopy and with H. pylori infection confirmed by smear or culture were randomly assigned to receive either a one-week course of antibacterial agents (120 mg of bismuth subcitrate, 500 mg of tetracycline, and 400 mg of metronidazole, each given orally four times a day) or a four-week course of omeprazole (20 mg orally per day). Follow-up endoscopies were performed after five and nine weeks. The patients and their physicians were aware of the treatment assignments, but the endoscopists were not. RESULTS A total of 100 patients were randomly assigned to treatment, and 85 completed the trial. At five weeks, H. pylori had been eradicated in 41 of the 45 patients in the antibacterial-treatment group (91.1 percent; 95 percent confidence interval, 82.9 to 99.3) and in 5 of the 40 in the omeprazole group (12.5 percent; 95 percent confidence interval, 2.3 to 22.7; P < 0.001). The gastric ulcers were healed in 38 of the patients treated with antibacterial drugs (84.4 percent; 95 percent confidence interval, 73.9 to 95.0) and in 29 of those treated with omeprazole (72.5 percent; 95 percent confidence interval, 58.6 to 86.4; P = 0.28). At nine weeks, ulcer healing was confirmed in 43 of the patients receiving antibacterial therapy and in 37 of those receiving omeprazole (P = 1.0). The mean (+/- SD) duration of pain during the first week of treatment was 1.9 +/- 2.6 days in the omeprazole group, as compared with 3.6 +/- 3.0 days in the antibacterial-treatment group (P = 0.004). One year after treatment, recurrent gastric ulcers were detected in 1 of 22 patients (4.5 percent) in the antibacterial-treatment group and in 12 of 23 (52.2 percent) in the omeprazole group (P = 0.001). H. pylori was detected in the 1 patient with a recurrent ulcer who had received antibacterial treatment and in 10 of the 12 patients with recurrent ulcers who had received omeprazole. CONCLUSIONS In patients with H. pylori infection and gastric ulcers unrelated to the use of nonsteroidal antiinflammatory drugs, one week of antibacterial therapy without acid suppression heals the ulcers as well as omeprazole and reduces the rate of their recurrence.

Risk of colonoscopic polypectomy bleeding with anticoagulants and antiplatelet agents: analysis of 1657 cases

BACKGROUND Anticoagulants and antiplatelet agents commonly are used to treat patients with cardiovascular and cerebrovascular diseases. Data on the safety of the use of these drugs before colonoscopic polypectomy are scanty. METHODS An audit was conducted for a 2-year period of consecutive patients undergoing colonoscopy and polypectomy. Patient demographics, site and size of polyps, and the use of anticoagulants and antiplatelet agents were documented from a hospital on-line database. Bleeding episodes were classified as immediate or delayed and were graded as mild, moderate, or severe. Risk factors associated with postendoscopy bleeding were analyzed by multivariate logistic regression analysis. RESULTS A total of 5593 cases were reviewed. Polypectomy was performed in 1657 patients. There were 37 cases of polypectomy-associated bleeding (2.2%); bleeding was immediate in 32 and delayed in 5. Multivariate analysis showed that warfarin use, after adjustment for the effects of each of the other factors, was an independent risk factor for bleeding, with an odds ratio 13.37: 95% CI[4.10, 43.65]. Age; the location and size of polyp; and the use of aspirin, non-steroidal anti-inflammatory drugs, and other antiplatelet agents were not associated with a higher risk of polypectomy-associated bleeding. CONCLUSIONS The use of antiplatelet agents during polypectomy was not associated with an increase in post-polypectomy bleeding. In contrast, treatment with warfarin should be discontinued, because this was associated with a significant increase in post-polypectomy bleeding.

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

Concurrent hypermethylation of multiple tumor-related genes in gastric carcinoma and adjacent normal tissues

Transcriptional silencing by CpG‐island hypermethylation now is believed to be an important mechanism of tumorigenesis. To date, studies on CpG‐island hypermethylation in gastric carcinoma and adjacent normal tissues are few.

Eradication of Helicobacter pylori prevents recurrence of ulcer after simple closure of duodenal ulcer perforation: randomized controlled trial.

OBJECTIVE In this randomized trial, the authors sought to determine whether eradication of Helicobacter pylori could reduce the risk of ulcer recurrence after simple closure of perforated duodenal ulcer. BACKGROUND DATA Immediate acid-reduction surgery has been strongly advocated for perforated duodenal ulcers because of the high incidence of ulcer relapse after simple patch repair. Although H. pylori eradication is now the standard treatment of uncomplicated and bleeding peptic ulcers, its role in perforation remains controversial. Recently a high prevalence of H. pylori infection has been reported in patients with perforations of duodenal ulcer. It is unclear whether eradication of the bacterium confers prolonged ulcer remission after simple repair and hence obviates the need for an immediate definitive operation. METHODS Of 129 patients with perforated duodenal ulcers, 104 (81%) were shown to be infected by H. pylori. Ninety-nine H. pylori-positive patients were randomized to receive either a course of quadruple anti-helicobacter therapy or a 4-week course of omeprazole alone. Follow-up endoscopy was performed 8 weeks, 16 weeks (if the ulcer did not heal at 8 weeks), and 1 year after hospital discharge for surveillance of ulcer healing and determination of H. pylori status. The endpoints were initial ulcer healing and ulcer relapse rate after 1 year. RESULTS Fifty-one patients were assigned to the anti-Helicobacter therapy and 48 to omeprazole alone. Nine patients did not undergo the first follow-up endoscopy. Of the 90 patients who did undergo follow-up endoscopy, 43 of the 44 patients in the anti-Helicobacter group and 8 of the 46 in the omeprazole alone group had H. pylori eradicated; initial ulcer healing rates were similar in the two groups (82% vs. 87%). After 1 year, ulcer relapse was significantly less common in patients treated with anti-Helicobacter therapy than in those who received omeprazole alone (4.8% vs. 38.1%). CONCLUSIONS Eradication of H. pylori prevents ulcer recurrence in patients with H. pylori-associated perforated duodenal ulcers. Immediate acid-reduction surgery in the presence of generalized peritonitis is unnecessary.

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.