The Quebec Association of Gastroenterology position paper on colorectal cancer screening - 2003.

Colorectal cancer is a leading cause of death and the third most common cancer in Canada. Evidence suggests that screening can reduce mortality rates and the cost effectiveness of a program compares favourably with initiatives for breast and cervical cancer. The objectives of the Association des gastro-entérologues du Québec Task Force were to determine the need for a policy on screening for colorectal cancer in Quebec, to evaluate the testing methods available and to propose one or more of these alternatives as part of a formal screening program, if indicated. Fecal occult blood testing (FOBT), endoscopy (including sigmoidoscopy and colonoscopy), barium enema and virtual colonoscopy were considered. Although most clinical efficacy data are available for FOBT and sigmoidoscopy, there are limitations to programs based on these strategies. FOBT has a high false positive rate and a low detection yield, and even a combination of these strategies will miss 24% of cancers. Colonoscopy is the best strategy to both detect and remove polyps and to diagnose colorectal cancer, with double contrast barium enema also being a sensitive detection method. The Task Force recommended the establishment, in Quebec, of a screening program with five- to 10-yearly double contrast barium enema or 10-yearly colonoscopy for individuals aged 50 years or older at low risk. The program should include outcome monitoring, public and professional education to increase awareness and promote compliance, and central coordination with other provincial programs. The program should be evaluated; specific billing codes for screening for colorectal cancer would help facilitate this. Formal feasibility, effectiveness and cost-effectiveness studies in Quebec are now warranted.

Bismuth-based quadruple therapy with bismuth subcitrate, metronidazole, tetracycline and omeprazole in the eradication of Helicobacter pylori.

BACKGROUND: A previous study showed that 14 days of qid bismuth-based triple therapy with tetracycline 500 mg, metronidazole 250 mg and colloidal bismuth subcitrate 120 mg resulted in excellent Helicobacter pylori eradication rates (89.5%). The present study looked at a shorter treatment period by adding omeprazole and by reducing the dose of tetracycline. METHODS: One hundred sixty-one patients with H pylori confirmed by histology and (13)carbon urea breath test were included in the study. They were treated for seven days with bismuth subcitrate 120 mg plus metronidazole 250 mg plus tetracycline 250 mg qid plus omeprazole 20 mg bid (OBMT). Patients were 18 to 75 years of age and had dyspepsia with or without a history of peptic ulcer. Patients with irritable bowel syndrome, active ulcer or previous attempt at eradication, or those who had used antibiotics or antiulcer drugs in the previous 30 days were excluded. Eradication was determined by two (13)carbon urea breath tests done one and three months, respectively, after treatment. Strains with minimal inhibitory concentrations of 8 microg/mL or higher were considered to be resistant to metronidazole. RESULTS: The overall per protocol eradication rate was 84%-89.5% in metronidazole-sensitive and 70.8% in metronidazole-resistant strains. Modified intent-to-treat analysis resulted in a 80% eradication rate--82.5% in metronidazole-sensitive and 66.7% in metronidazole-resistant strains. Only one patient discontinued treatment because of adverse events. CONCLUSIONS: The OBMT regimen used in this study is safe and effective against metronidazole-sensitive H pylori strains.

Meeting review--Helicobacter pylori: basic mechanisms to clinical cure 2000.

The meeting Helicobacter pylori: Basic Mechanisms to Clinical Cure 2000, held in Bermuda from March 26 to 29, 2000, gathered physicians and scientists from all corners of the world. State-of-the-art reviews and the most recent developments in the field were presented. This article summarizes the highlights of this meeting, including important scientific and clinical developments.

Bismuth-based triple therapy with bismuth subcitrate, metronidazole and tetracycline in the eradication of Helicobacter pylori: a randomized, placebo controlled, double-blind study.

OBJECTIVE: To determine the rate of Helicobacter pylori eradication following bismuth-based triple therapy with colloidal bismuth subcitrate, tetracycline hydrochloride and metronidazole. PATIENTS AND METHODS: One hundred and eleven patients were randomly assigned, in a two to one ratio, to colloidal bismuth subcitrate 120 mg qid plus metronidazole 250 mg qid plus tetracycline 500 mg qid (Gastrostat), or matching placebo tablets and capsules for 14 days. Presence or absence of H pylori was documented by histology at entry and at least 28 days after treatment. Patients had dyspeptic symptoms with or without a history of peptic ulcer. Patients with any previous attempt(s) at eradication of H pylori, who used bismuth, antibiotics, H2 receptor antagonists or proton pump inhibitors in the previous four weeks were excluded. RESULTS: Fifty-three of 59 (90%) patients on bismuth-based treatment and only one of 35 (3%) on placebo achieved eradication by per protocol analysis. Fifty-three of 65 (82%) patients on bismuth-based treatment achieved eradication, while only two of 34 (5%) achieved eradication on placebo by intention to treat analysis. Eradication rates for bismuth-based treatment across sites ranged from 83% to 100%. Only two patients in the bismuth-based treatment group (4%) and one in the placebo group (3%) discontinued treatment because of adverse events. CONCLUSIONS: Colloidal bismuth subcitrate plus metronidazole plus tetracycline, given in the doses studied for 14 days, is safe and highly effective against H pylori infection and would be appropriate as a first-line therapy for eradication.

Helicobacter pylori antibiotic resistance: trends over time.

Resistance to antibiotics can be a major problem in the treatment of bacterial infections. As the use of antibiotics increases, bacterial resistance to these agents is rising and in many cases is responsible for the failure of treatment regimens. Although the treatment of Helicobacter pylori infection requires the use of more than one antibiotic to obtain adequate eradication rates, the efficacy of the currently used antibiotic combinations has been shown to be decreased by resistance to one of the antibiotics. The use of antibiotics in regiments for the treatment of H pylori is increasing in many countries, including Canada. This increase is both in the use of these antibiotics alone for the treatment of nongastrointestinal infections and in their use in association with proton pump inhibitors for the treatment of H pylori infection. In several European and Asian countries, where resistance to antibiotics is being monitored, it has been demonstrated the H pylori resistance to metronidazole and to clarithromycin increased throughout the 1990s. Thus far, the data available in Canada do not show increased resistance to either of these antibiotics. As for other antibiotics used in the treatment of H pylori infection such as tetracycline and amoxicillin, the rate of resistance to these agents is still very low and does not constitute a significant problem. Because the efficacy of the regimens used in the treatment of H pylori infection is compromised by resistance to the antibiotics used, it is important that H pylori resistance rate in Canada and throughout the world continue to be monitored. Only with such reliable data can the most optimal regimens be recommended.

Helicobacter pylori and peptic ulcer disease. Current evidence for management strategies.

OBJECTIVE: To review current evidence for primary care physicians who manage Helicobacter pylori in peptic ulcer disease. QUALITY OF EVIDENCE: MEDLINE was searched to August 1997 for randomized controlled trials, systematic overviews, and consensus reports. High-quality recent reviews were often found. Randomized controlled trials presented as abstracts at recent meetings were reviewed. MAIN FINDINGS: Helicobacter pylori is found in most case of duodental and gastric ulcer, and eradication of H pylori leads to "cure" of ulcer disease and prevention of ulcer complications. Eradication of H pylori is not indicated for gastroesophageal reflux disease. No evidence indicates that screening asymptomatic individuals for H pylori infection reduces the risk of subsequent development of gastric cancer. Controversial areas are the role of H pylori in functional dyspepsia and screening for H pylori before initiating nonsteroidal anti-inflammatory drugs. In primary care, H pylori can be detected using serologic tests or urea breath tests (UBT), but only UBTs can be used to confirm eradication. Whether patients suspected of having ulcers can be managed with an H pylori test-and-treat strategy without initial investigation is controversial. The first-line recommended treatment is 1 week of twice daily triple therapy with a proton pump inhibitor, clarithromycin (Biaxin), and amoxicillin (e.g., Amoxil), or metronidazole (Flagyl). CONCLUSIONS: Helicobacter pylori eradication should be first-line therapy in primary care for infected patients with peptic ulcers. Effective H pylori testing methods and treatments are now available.

Methodological validation and clinical usefulness of carbon-14-urea breath test for documentation of presence and eradication of Helicobacter pylori infection.

UNLABELLED: A simple [14C]urea breath test (C-14-UBT) was validated with aims of determining accuracy in documenting both the presence and proof of eradication of Helicobacter pylori infection. METHODS: Fifty-six dyspeptic patients had endoscopy with biopsies and C-14-UBT. Eleven biopsy-proven H. pylori-negative patients allowed C-14-UBT normal value determination. Forty-three patients with recurrent peptic ulcer disease and biopsy-proven H. pylori infection were included in an antimicrobial eradication protocol. Endoscopy with biopsies and C-14-UBT were done again 8 wk after initiation of treatment in 35 patients. For C-14-UBT, 185 kBq (5 microCi) of [14C]urea was swallowed. Breath samples obtained up to 20 min were counted to calculate AS20, [(% 14CO2 dose excreted/mmol of CO2) x kg] at 20 min. Combined histologic and microbiologic analyses of antral biopsies were used as a gold standard. RESULTS: The positivity value was set as AS20 > 0.33% (mean + 3 s.d. of AS20 in H. pylori-negative patients). Diagnosis of H. pylori infection was correct with C-14-UBT in 55/56 patients (44 true-positive, 11 true-negative and 1 false-negative; sensitivity = 98%; specificity = 100%). As a proof of eradication, C-14-UBT correctly classified 33/35 patients (5 true-positive, 28 true-negative and 2 false-positive; sensitivity = 100%; specificity = 93%). The C-14-UBT global performance yielded sensitivity, specificity and accuracy of 98%, 95% and 97%, respectively. A significant correlation (r = 0.84) was found between AS20 and the number of H. pylori colonies on culture. CONCLUSION: This C-14-UBT is highly accurate both for diagnosis and proof of eradication of H. pylori infection and reflects the antral bacterial load. It is simple, fast and inexpensive, and it is therefore suitable for clinical practice.

Percutaneous drainage of intra-abdominal abscesses in Crohn's disease: short and long-term outcome.

OBJECTIVE: To determine whether percutaneous drainage of Crohn's abscesses obviates the need for early surgical drainage. METHODS: All cases of percutaneous drainage of Crohn's abscesses between 1990 and 1995 were reviewed and classified as a success or failure on the basis of the need for surgery within < 30 days of catheter removal. RESULTS: Twenty-seven drainage procedures were performed in 24 patients; 15 (56%) were classified as successes, and 12 (44%) were classified as failures. Successes and failures did not significantly differ with respect to patient demographics and Crohn's disease characteristics. Patients whose abscesses were successfully drained had significantly fewer associated fistulae (46.6 vs 92.0%, p = 0.037), and their abscesses tended more often to be first (vs recurrent), spontaneous (vs postoperative), located in the right lower quadrant, and smaller. Patients whose abscesses were successfully drained also tended to spend more time with the catheter in place and to require more imaging procedures. Complications were noted in four cases (15%), enterocutaneous fistula at the site of catheter insertion in three cases and postprocedure fever in one case. Hospital stay was significantly shorter after successful drainage (16.3 +/- 6.9 vs 31.7 +/- 22.1 days, p = 0.017). After a total of 543.5 patient-months of follow-up, subsequent intra-abdominal Crohn's-related surgery was required in only two of the successes and one failure. CONCLUSIONS: 1) Percutaneous drainage of Crohn's abscess successfully obviates the need for early surgery in approximately 50% of cases, and this benefit is maintained on long term follow-up. 2) Percutaneous drainage shortens hospital stay. 3) Crohn's abscesses in various locations, single or multiple, with or without an associated fistula may be successfully drained percutaneously. 4) Presence of an associated fistula may be a risk factor for failure.

Stimulation of duodenal muscle contraction by porcine or canine motilin in the dog in vivo.

Motilin is a 22 amino acid polypeptide stimulating intestinal muscle contraction. Structure analysis of motilin purified from hog and from dog intestinal mucosa reveals different amino acids in positions 7, 8, 12, 13, and 14. Previous in vitro experiments suggested this species-related structural heterogeneity could generate different bioactive characteristics for these two peptides. This study was designed to compare the stimulatory mechanism of canine and porcine motilins on dog duodenal motility in vivo, testing the hypothesis that canine motilin stimulates a receptor located on the intestinal muscle, while porcine motilin is acting on intrinsic nerves regulating intestinal muscle contraction. Synthetic porcine and canine motilins were administered through a catheter inserted in the caudal pancreatic duodenal artery to stimulate the contraction of a close irrigated duodenal segment. In acute experiments performed on anaesthetized animals, both peptides induced a similar motor stimulation that was inhibited by tetrodotoxin and atropine. In experiments in conscious animals, canine and porcine motilins were equally potent in inducing premature phase III of the migrating motor complex, and the action of both peptides was abolished by atropine or hexamethonium. This study reveals that the structural heterogeneity between porcine and canine motilin does not influence the bioactivity of both peptides in the dog in vivo and suggests that circulating endogenous motilin stimulates intestinal muscle contraction through intrinsic excitatory nerves.

Regulation of plasma motilin by opioids in the dog.

In the first part of this study, we compared the effects of morphine and trimebutine, two opioid receptor agonists, on small intestinal motility and plasma motilin in dogs. Morphine (100 micrograms/kg iv for 10 min) induced first a typical vomiting myoelectric profile followed subsequently by a migrating electrical activity mimicking phase III of the migrating myoelectric complex; trimebutine (5 mg/kg iv for 10 min) initiated only a migrating phase III-like activity. Despite their different initial contractile effects, both agents induced a significant and similar rise in plasma motilin that preceded the beginning of the premature phase III. In the second portion of the study, naloxone, an opioid receptor antagonist, was infused to verify the influence of endogenous opiates on plasma motilin and on the migrating motor complex. Naloxone (2 mg/kg, then 0.5 mg.kg-1.h-1 iv) delayed significantly the cyclic recurrence of plasma motilin peak increases and of the phase IIIs. In some animals, where naloxone abolished the phase IIIs, the amplitude of the motilin peak increases was significantly diminished. These results suggest 1) that opioid administration increases plasma levels of motilin by a mechanism that is independent of the intestinal contractile activity, and 2) that endogenous opioids could be physiological inducers of plasma motilin increases in the conscious dog.

Molecular heterogeneity of human motilinlike immunoreactivity explained by the processing of prepromotilin.

Results of studies on the molecular forms of canine motilin suggest that this hormone might be synthesized as a higher molecular weight precursor, as is the case for most other biologically active peptides. Chromatographic analysis of human duodenal mucosa extracts and of human serum, using motilin-specific antibodies, also shows the presence of multiple forms of motilinlike immunoreactivity. Cell free translation of human duodenal messenger ribonucleic acid (mRNA) and immunoprecipitation of nascent peptides with motilin antibodies confirm that motilin is synthesized as a 14-15-kilodalton polypeptide precursor. Sequence of the human intestinal motilin complementary deoxyribonucleic acid (cDNA) demonstrates that this precursor bears a 25-amino acid signal peptide, a single dibasic cleavage site immediately following the 22 amino acids of human motilin, and a 65-amino acid polypeptide (motilin-related peptide) following this dibasic processing site. Southern analysis of human genomic kilobases DNA demonstrates that only one motilin gene is contained within 3.5-4 of human genomic DNA. Northern analysis of human intestinal RNA reveals one species of motilin mRNA of an estimated 700 nucleotides in length. These results suggest that (a) only one gene encodes the synthesis of human motilin in the different tissues where this polypeptide is synthesized; (b) human intestinal motilin is translated from one mRNA species and the resulting precursor is processed within the duodenal mucosa by sequential proteolytic cleavage first at a site within the motilin-related peptide, which results in the liberation of a 6-kilodalton form of motilinlike immunoreactivity, and then at the dibasic amino acid cleavage site, thus freeing motilin 22 from its precursor.

Indium-111 leukocyte scanning of the abdomen. Analysis of its value for diagnosis and management of inflammatory bowel disease.

Indium-111 leukocyte scanning of the abdomen (IAS) was performed in 10 patients with ulcerative colitis and in 39 patients with Crohn's disease involving the small intestine (in 25 occasions) and/or the colon (17 cases). Radionuclide uptake by the gut was seen in 84% of the patients with active inflammation. We compared the extent of the disease displayed by IAS with the findings obtained by either radiological or endoscopic studies or at surgery. In two-thirds of the patients, the IAS gave an accurate evaluation of the extent of the disease (sensitivity 68%). False-positive IASs were not seen in small bowel disease (specificity 100%), but were observed on 4 occasions on the colon (specificity 86%). The intensity of the radionuclide uptake could not be correlated with the clinical activity of the disease as evaluated by the Crohn's disease activity index. These results suggest that IAS is not superior to the standard procedures used to detect and localize inflammatory bowel disease and that IAS cannot replace these techniques. However, the simplicity of IAS and the complete lack of complications associated with its use render it useful in the evaluation of the extent and distribution of inflammation in some patients, mainly those with severe disease in whom standard diagnostic procedures would be contraindicated.

Effect of parental malnutrition on enzyme content of rat pancreas.

The aim of this study was to assess in rat pups the influence of protein diets ingested by their mothers during gestation and lactation on the enzyme content of the pancreas of the offspring. Rat pups born of either well-nourished mothers or of mothers fed a diet moderately restricted in protein (9% casein w/w) were studied. After weaning, the pups were fed on one of three diets: a well-balanced diet, a 5% casein diet (protein restricted), or a well-balanced diet of a similar caloric value as the protein-restricted diet (pair-fed rat pups). The pups were sacrificed after intervals of one to 25 weeks after weaning. The results showed that the enzyme content of the pancreas increased progressively with time in pups born of malnourished mothers, particularly in pups fed the protein-restricted diet. This suggests prolonged maturation of the pancreas. Pups fed the 5% casein diet had a decreased amylase content per milligram of DNA but not of other enzymes. Malnutrition in the mother increased the ratio of enzymes to DNA and the total pancreatic enzyme content at different times after weaning, indicating that maternal malnutrition had a prolonged effect on the pancreatic enzyme content of the pups' pancreas. This mechanism could play a role in the pathogenesis of tropical chronic calcific pancreatitis in man and explain some of the geographic differences in the incidence of the disease.

Motilin-like-immunoreactivity in intestine and brain of dog.

Motilin-like-immunoreactivity was detected in various regions of canine intestinal tract and brain. Its content in the brain was much smaller than in the gut. Its regional distribution was not uniform in both organs. On gel chromatography (G-50 SF), intestinal extracts revealed a main molecular form of motilin-like-immunoreactivity corresponding to motilin 1-22, while, in the brain, it eluted predominantly with the void volume. Further characterization of this later substance does not suggest it is strongly related to motilin. Putative motilin precursors of 14 kd and 6 kd are detectable in small concentration in intestinal mucosa.

Comparative stimulation of motilin duodenal receptor by porcine or canine motilin.

Motilins purified from porcine and canine intestine differ in their amino acid composition in positions 7-8-12-13-14. We studied in vitro the contractile response of longitudinal duodenal muscles from various animals (guinea pig, rabbit, dog) to porcine and canine synthetic motilins. Both substances failed to elicit contraction of the guinea pig duodenum but were active and equally potent on rabbit muscle. In dogs, porcine motilin was inactive at the concentrations tested (up to 10(-4) M) whereas canine motilin induced duodenal contractions in a dose-response fashion (mean dose required to induce half-maximal response: 4.82 +/- 0.25 X 10(-5) M). The contraction generated by synthetic canine motilin (10(-5) M) was not influenced by atropine, hexamethonium, tetrodotoxin, naloxone, or sodium nitroprusside (all used at 10(-4) M) but was blocked by verapamil (10(-4)). Our study shows that species-related structural alterations in motilin molecules generate different bioactive capacities in some animal species, suggests that the middle portion of the molecule is important for its bioactive expression, suggests the presence of motilin receptors on canine duodenal muscle, and suggests that an influx of extracellular calcium is involved in the canine duodenal muscle contraction elicited by canine motilin.

Effect of trimebutine on intestinal motility and plasma motilin in the dog.

In a previous report, trimebutine was shown to induce premature periods of phase III activity in fasting dogs, and its action was blocked by naloxone. In this study, we observed that trimebutine (5 mg X kg-1 iv) could induce premature phase IIIs in canine small intestine during interdigestive and digestive periods; trimebutine-induced phase IIIs were migrating along the small intestine faster than spontaneous activity fronts and; trimebutine-induced phase IIIs were accompanied by sharp rises in concentrations of plasma motilin. To further elucidate the trimebutine-stimulatory mechanism, we verified its effects on the release of various circulating peptides that influence intestinal motility: short-interval blood sampling during trimebutine infusion revealed that plasma motilin increases induced by trimebutine preceded the beginning of phase III in proximal duodenum; and gastrin and insulin postprandial releases were abolished by trimebutine. Therefore, trimebutine, by its simultaneous but opposite effects on various peptides that individually carry positive (e.g., motilin) or negative (e.g., gastrin and insulin) influences on the generation of activity fronts, could alter the equilibrium between stimulatory and inhibitory forces in such a way that, in some circumstances (e.g., postprandial period), stimulatory mechanisms become predominant.

Nonparallel secretion of enzymes by the rabbit pancreas.

Since nonparallel secretion of enzymes by the exocrine pancreas has been demonstrated with several experimental models, we were interested in verifying a recent claim that enzyme secretion remained strictly proportional (parallel) upon stimulation of the in vivo rabbit pancreas. Pancreatic juice was collected by extraduodenal cannulation of the pancreatic duct, in two different protocols. In the first protocol the administration of pentobarbital induces a mild anesthesia. Under this condition, amylase and chymotrypsin secretion remained parallel after cholecystokinin stimulation. In a second protocol, a deeper and constant anesthesia was attained with Fluothane resulting in a lower basal protein output than in the first protocol. Pancreatic secretion was collected under intravenous secretin perfusion (4.5 clinical units X kg-1 X h-1). After stabilization and basal collection periods, pancreatic secretion was stimulated with an i.v. bolus injection of either cholecystokinin (2 Ivy dog units/kg), caerulein (0.1 micrograms/kg), or carbachol (6 micrograms/kg). Upon stimulation of the pancreas, protein output increased an average of 30-fold and there was a concomitant 20-25% decrease in the ratio of the specific activities of amylase to chymotrypsin which resulted from a greater increase in the specific activity of chymotrypsin in pancreatic juice after stimulation of secretion. Thus, under appropriate conditions, nonparallel secretion of enzymes by the exocrine pancreas can be demonstrated in yet another experimental model. Furthermore, the proportion of amylase and chymotrypsin activities in pancreatic juice are once more shown to be dependent, up to a threshold, upon the rate of protein output by this exocrine gland.