Global DNA demethylation in gastrointestinal cancer is age dependent and precedes genomic damage.

We studied the relationships between genetic and epigenetic alterations in gastrointestinal cancer by integrating DNA copy number changes determined by arbitrarily primed PCR (AP-PCR) with DNA methylation variations estimated by methylation-sensitive amplified fragment length polymorphism (MS-AFLP). We analyzed about 100 different chromosomal regions by AP-PCR and over 150 random CpG loci by MS-AFLP in human colon and gastric carcinomas. DNA hypomethylation and hypermethylation alterations distributed gradually and increased with cancer patient age, in contrast with the age-independent genomic alterations. Increased DNA hypomethylation and hypermethylation correlated with increased genomic damage, but only hypomethylation was highly significant in multivariate analyses. We conclude that age-dependent accumulation of DNA demethylation precedes diploidy loss in a significant subset of gastrointestinal cancers.

Progression of specialized intestinal metaplasia at the cardia to macroscopically evident Barrett's esophagus: an entity of concern in the ProGERD study.

OBJECTIVES AND AIMS: Histological Barrett's esophagus, defined as specialized intestinal metaplasia (SIM+) at the cardia without endoscopic suspicion of columnar epithelium, is found frequently in biopsies at the gastro-esophageal junction although its clinical relevance is unknown. The authors aim was to evaluate prospectively the progression of SIM+ to macroscopically evident Barrett's esophagus (BE/SIM+), and to identify risk factors for this progression. METHODS: Data were obtained from a sub-group of patients (no visible BE at presentation, but SIM+) included in the ProGERD study, a prospective evaluation of the clinical course of GERD under routine clinical care. They had esomeprazole 20-40 mg/day for 2-8 weeks. Symptom assessment was performed annually, and endoscopy with biopsy was planned at baseline, after healing treatment and after 2 and/or 5 years. RESULTS: 128 of 171 (74.8%) patients with unequivocal SIM at the z-line after healing were biopsied again after 2 and/or 5 years. At follow-up, 33 (25.8%) of these patients showed progression to BE/SIM+. Factors significantly associated with progression were smoking, a long history of GERD and severe esophagitis at baseline. Patients who had progressed to BE/SIM+ already at 2 years showed consistent findings at 5 years. CONCLUSION: More than 20% of GERD patients with SIM+ in this study were found to have BE/SIM+ within 2-5 years. This finding supports the hypothesis that SIM+ at the cardia could be the missing link explaining increased cancer risk in GERD patients without overt BE and merits further investigation in a prospective study.

Nighttime heartburn in patients with gastroesophageal reflux disease under routine care.

BACKGROUND: Gastroesophageal reflux disease (GERD) is a common disorder. The aim of our study was to describe the prevalence of nighttime heartburn and its associations with esophagitis, Barrett's esophagus, and extra-esophageal symptoms. METHODS: Data were collected as part of the ongoing Progression of Gastroesophageal Reflux Disease (ProGERD) study. Based on endoscopy results, patients were categorized as having nonerosive GERD, erosive GERD, or Barrett's esophagus. ORs and 95% CIs derived from logistic regression analysis were calculated for the association between nighttime heartburn and GERD complications. RESULTS: The overall prevalence of nighttime heartburn for at least 1 of 3 years was 49%, and 21% of patients reported nighttime heartburn in all 3 years. According to multivariate analysis, chronic nighttime heartburn was associated with globus sensation (OR 1.79, 95% CI 1.29-2.47) and erosive GERD (OR 1.67, 95% CI 1.29-2.15). Compared to continuous proton pump inhibitor (PPI) intake, noncontinuous PPI therapy (OR 2.26, 95% CI 1.73-2.96) and medication other than PPIs (OR 2.46, 95% CI 1.67-3.62) were also associated with chronic nighttime heartburn. CONCLUSIONS: The prevalence of nighttime heartburn in GERD patients under routine care was high, even in patients on continuous PPI therapy. Nighttime heartburn was not associated with Barrett's esophagus or most extra-esophageal symptoms.

On-demand therapy is a valid strategy in GERD patients: pros and cons.

On-demand proton pump inhibitor (PPI) therapy is an attractive option for long-term management of gastroesophageal reflux disease (GERD). Controlled trials in non-erosive reflux disease (NERD) patients have shown sufficient symptom control in most patients with a high rate of willingness to continue treatment and substantial saving on PPI expenditure. However, due to the slow onset of action of PPIs, rescue antacids are often used when symptoms recur and several patients continue to experience some degree of heartburn. On-demand treatment is less cost-saving in patients with esophagitis, and symptomatic/endoscopic relapses occur frequently in severe grades. Data on the prevention of long-term sequelae of on-demand treatment are scarce, only indirect evidence being available. It is suggested that PPI continuous maintenance is more appropriate than on-demand therapy in patients with severe esophagitis, in those with Barrett's esophagus where chronic PPIs may reduce incidence of dysplasia, in uninvestigated elderly patients where esophagitis is more prevalent and it is more frequently complicated with gastrointestinal bleeding and possibly in uninvestigated or NERD patients with frequent clinical relapses. Finally, more appropriate outcome variables should be used in future trials in order to assess efficacy of on-demand treatment adequately.

Prevalence of H pylori associated "high risk gastritis" for development of gastric cancer in patients with normal endoscopic findings.

AIM: To investigate the prevalence of H pylori associated corpus-predominant gastritis (CPG) or pangastritis, severe atrophy, and intestinal metaplasia (IM) in patients without any significant abnormal findings during upper-GI endoscopy. METHODS: Gastric biopsies from 3548 patients were obtained during upper GI-endoscopy in a 4-year period. Two biopsies from antrum and corpus were histologically assessed according to the updated Sydney-System. Eight hundred and forty-five patients (mean age 54.8 +/- 2.8 years) with H pylori infection and no peptic ulcer or abnormal gross findings in the stomach were identified and analyzed according to gastritis phenotypes using different scoring systems. RESULTS: The prevalence of severe H pylori associated changes like pangastritis, CPG, IM, and severe atrophy increased with age, reaching a level of 20% in patients of the age group over 45 years. No differences in frequencies between genders were observed. The prevalence of IM had the highest increase, being 4-fold higher at the age of 65 years versus in individuals less than 45 years. CONCLUSION: The prevalence of gastritis featuring at risk for cancer development increases with age. These findings reinforce the necessity for the histological assessment, even in subjects with normal endoscopic appearance. The age-dependent increase in prevalence of severe histopathological changes in gastric mucosa, however, does not allow estimating the individual risk for gastric cancer development--only a proper follow-up can provide this information.

Esomeprazole-induced healing of gastroesophageal reflux disease is unrelated to the genotype of CYP2C19: evidence from clinical and pharmacokinetic data.

BACKGROUND: The clinical outcome of acid-related disorders treated by proton pump inhibitors (PPIs) might be dependent on the polymorphically expressed cytochrome P450 (CYP) 2C19, which is involved in PPI metabolism. We tested whether esomeprazole-induced healing of gastroesophageal reflux disease (GERD) is related to CYP2C19 genotype. METHODS: Two hundred five patients with GERD (Los Angeles classification grade A or B) were included in a case-control study according to endoscopic outcome (healed versus unhealed group, matched for confounders) after treatment with 40 mg esomeprazole daily for 4 weeks. The frequency of CYP2C19 genotypes was determined as the primary outcome measure for both groups. In a second trial plasma levels of esomeprazole and corresponding CYP2C19 and CYP3A4 metabolites (5-hydroxyomeprazole and omeprazole sulfone) were monitored in 10 CYP2C19 wild-type patients with GERD after the first and last doses (day 7) of 40 mg esomeprazole daily to calculate metabolic ratios. RESULTS: CYP2C19 wild-type (n = 148) and heterozygous (n = 51) or homozygous variant (n = 6) patients did not differ with respect to baseline characteristics. The frequency distribution of CYP2C19 genotypes was not different between patients with complete (75/100) and incomplete (73/105) healing (P = .65). When a single esomeprazole dose and multiple dosing were compared, the low contribution of CYP2C19 to the elimination of esomeprazole decreased further by 50%. In contrast, the CYP3A4-dependent formation of omeprazole sulfone increased by 40%, and consequently, the metabolic ratio of omeprazole sulfone to 5-hydroxyomeprazole was elevated from 7.9 to 19.3 (P = .0004). CONCLUSION: In contrast to other PPIs, esomeprazole-induced healing of GERD is unrelated to the CYP2C19 genotype, which can be explained by the metabolic shift toward the CYP3A4-mediated pathway.

Gastro esophageal reflux disease is associated with absence from work: results from a prospective cohort study.

AIM: To study the association of gastro-esophageal reflux disease (GERD) with the absence from work and to estimate the extent of loss in gross domestic product due to inability to work. METHODS: Analysis was based on the prospectively gathered data of a large European cohort study involving 6 215 symptomatic GERD patients (ProGERD). Among these patients, 2 871 were initially employed. The calculation of the loss of gross domestic product was based on the assumption that the prevalence of GERD was about 15% in Germany. According to the German Federal Statistical Office, the mean gross wage of employees was 150 EUR/d in 2002. RESULTS: The data of 2 078 employed patients who were prospectively followed up for over 2 years were analyzed. At study entry, the patients reported a mean of 1.8 d per year of inability to work. During the prospective follow-up under routine clinical care, the proportion of patients reporting days with inability to work decreased from 14% to 6% and the mean number of days per year with inability to work decreased to 0.9 d. Assuming a prevalence of troublesome GERD of 15% in the employed German population, the loss of gross domestic product amounted to 668 million EUR/year in Germany. CONCLUSION: GERD causes a relevant impairment on the national economics by absence from work. The presented data demonstrate the importance of GERD, not only for patients and health insurance companies, but also for the community at large.

Breath and string test: a diagnostic package for the identification of treatment failure and antibiotic resistance of Helicobacter pylori without the necessity of upper gastrointestinal endoscopy.

AIM: Helicobacter pylori (H pylori) resistance after failed eradication has a major impact on the outcome of a further treatment regimen. The aim of this study was to assess the validity of a non-invasive strategy using the 13C-urea breath test (UBT) and the gastric string test in identifying post-treatment resistance of H pylori. METHODS: The UBT was routinely performed 4 to 6 wk after H pylori eradication therapy. Forty-two patients (24 females, 18 males, mean age 48 years) with a positive UBT were included in the study. A gastric string test using a capsule containing a 90 cm-long nylon fiber was performed. Before the capsule was swallowed, the free end of the string was taped to the cheek. After one hour in the stomach, the string was withdrawn. The distal 20 cm of the string was inoculated onto an agar plate and processed under micro-aerophilic conditions. Following the string test, upper gastrointestinal endoscopy was performed to obtain gastric biopsies for conventional culture. RESULTS: H pylori was successfully cultured from the gastric string in 34 patients (81%), but not in 5 patients due to contamination with oropharyngeal flora. H pylori was cultured from the gastric biopsies obtained at endoscopy in 39 patients (93%). CONCLUSION: The UBT followed by the gastric string test in the case of treatment failure is a valid diagnostic strategy with the aim of determining the post-therapeutic antibiotic resistance of H pylori with little inconvenience to the patient. Upper GI-endoscopy can be avoided in several cases by applying consequently this diagnostic package.

Somatic DNA Hypomethylation in H. pylori-Associated High-Risk Gastritis and Gastric Cancer: Enhanced Somatic Hypomethylation Associates with Advanced Stage Cancer.

OBJECTIVES: Helicobacter pylori-related high-risk gastritis (HRG) is a severe risk factor for gastric cancer (GC). The link between HRG and long-term risk for GC may involve genetic and epigenetic alterations underlying a field defect, i.e. a region of the mucosa prone to cancer development. Global DNA hypomethylation is a pervasive alteration in GC that associates with chromosomal instability and poor prognosis. The aim of this study was to determine the chronology of this alteration along the progression of HRG to GC, to test the hypothesis that it occurs early in the chronology of this pathway and plays a mechanistic role in the long-term cancer risk. METHODS: We comparatively measured the genomic methylation level in gastric biopsies from 94 GC patients and 16 of their cancer-free relatives, 38 HRG patients, and 17 GERD patients, using a quantitative enzymatic method. RESULTS: GC biopsies were hypomethylated compared to their matching non-tumor mucosa (P=9.4 × 10(-12)), irrespective of the tumor location or patients' country of origin. Genome-wide hypomethylation was also found in gastric mucosa of GC (P=1.5 × 10(-5)) and HRG (P=0.004) patients compared with healthy donors and GC relatives, regardless of the biopsy location within the stomach or previous H. pylori eradication therapy. An enhanced hypomethylation, distinguished by a bi-slope distribution of the differences in methylation between tumor and normal tissues, associated with a more invasive (P=0.005) and advanced stage (P=0.017) type of GC. CONCLUSIONS: Universal DNA demethylation in normal gastric mucosa in GC patients appears sporadic rather than familial. Genomic hypomethylation in HRG possibly contributes to a field defect for cancerization that is not reversed by bacterial eradication. Enhanced somatic hypomethylation may stratify GC for prognostic purposes.

Postprandial lipid and carbohydrate responses after the ingestion of a casein-enriched mixed meal.

BACKGROUND: Postprandial lipemia is markedly modulated when carbohydrates are added to a fatty meal. The effect of added protein is less known, however, and the data are controversial. OBJECTIVE: We investigated the effects of casein added to various fat-rich meals in the absence and presence of oligosaccharides. DESIGN: Four different test meals were given to 24 healthy volunteers: 1) fat alone, consisting of 3 g cream/kg body wt; 2) fat plus 75 g oligosaccharides; 3) fat plus 50 g sodium caseinate; and 4) a combination of all 3 components. Blood samples were taken before the meals and 1, 2, 3, 4, 5, 6, 7, and 8 h thereafter. The variables measured were serum free fatty acids, arginine, glucose, insulin, and C-peptide as well as triacylglycerol in serum, in chylomicrons, and in VLDL. Gastric emptying was monitored with the use of a (13)C breath test. RESULTS: Addition of oligosaccharides resulted in the known delay and reduction in postprandial lipemia. Casein caused additional effects: chylomicrons were further reduced and delayed, independently of gastric emptying. C-peptide and insulin, as expressed by their areas under the curves, were raised not only during the early response to the glucose load but also in the postabsorptive state. Concentrations of free fatty acids, which were markedly suppressed by 24% after oligosaccharides alone, were lowered a further 20% after the addition of casein. CONCLUSIONS: Casein added to a fatty meal lowers free fatty acids markedly in the postprandial and postabsorption phases, probably via its insulinotropic activity. Postprandial lipemia is also moderately reduced.

Microarray analysis of gene expression in metastatic gastric cancer cells after incubation with the methylation inhibitor 5-aza-2'-deoxycytidine.

While the exact mechanisms involved in cancer metastasis are not fully clarified, the altered expression of many different genes has been reported. Hypermethylation of the promoters of cancer-related genes is often associated with their inactivation during tumorigenesis and may also be involved in metastasis. Here we used cDNA microarrays to examine the different gene expression profiles of a primary gastric adenocarcinoma cell line RF1 and its derivative metastasis subline RF48. Compared with RF1, 49 genes were down-regulated and 8 genes were up-regulated in RF48. After treatment of RF48 cells with a DNA methylation inhibitor, 5-aza-2'-deoxycytidine, 101 genes were up-regulated and 1 gene was down-regulated in treated RF48 when compared with untreated RF48. Comparing gene expression patterns of untreated RF1, untreated RF48 and treated RF48 cells showed 5 genes expressed in RF1 but silenced in RF48, which were reactivated after 5-aza-2'-deoxycytidine treatment. Two of those 5 genes have CpG islands within their promoter regions, suggesting that those genes activated by 5-aza-2'-deoxycytidine may result from the direct inhibition of promoter methylation. In conclusion, using global gene expression analysis together with inhibition of DNA methylation, we demonstrate that hypermethylation of the promoters of certain cancer-related genes may play a role in cancer metastasis.

Evaluation of a near-patient fecal antigen test for the assessment of Helicobacter pylori status.

The assessment of Helicobacter pylori antigen in stool specimens is widely accepted. Recently a immunochromatographic near-patient test assay has been developed. In this first evaluation in 100 patients before and after H. pylori eradication therapy we observed a sensitivity (76%) and specificity (98%) of this near-patient test.

Antibiotic susceptibility of Helicobacter pylori in Germany: stable primary resistance from 1995 to 2000.

The issue of antibiotic resistance in Helicobacter pylori is of particular concern and has become an important factor leading to eradication failure. This paper reports the prevalence of primary resistance to clarithromycin, amoxicillin, metronidazole and tetracycline among H. pylori isolates in the north-eastern part of Germany. A total of 1644 clinical H. pylori isolates was investigated over a period of 6 years from 1995 to 2000. The MICs were determined by the Etest. The overall rate of primary resistance was 26.2% for metronidazole and 2.2% for clarithromycin. No significant changes in the resistance rates during the period of investigation were observed. No isolate was resistant to amoxicillin or tetracycline. PCR-RFLP analysis for the detection of point mutations associated with clarithromycin resistance was performed with 36 H. pylori isolates. The A --> G transition mutation at position 2143 was detected in 19 H. pylori isolates (52.8%), whereas the mutation at position 2142 was found in 13 isolates (36.1%).

Reduced PTEN expression in gastric cancer and in the gastric mucosa of gastric cancer relatives.

OBJECTIVES: Gastric cancer is a leading cause of cancer-related deaths worldwide, and the genetic and molecular alterations underlying its pathogenesis are largely unknown. PTEN, a tyrosine phosphatase, is frequently mutated in brain and breast cancers but not in gastric cancers. In order to assess the role of PTEN in gastric carcinogenesis, we analysed the expression of PTEN in human gastric cancer and in the gastric mucosa of cancer relatives. METHODS: Gastric cancer tissues were obtained from 26 patients with gastric cancer undergoing upper-gastrointestinal endoscopy or resection for gastric cancer. Furthermore, 21 first-degree relatives of gastric cancer patients and 12 healthy individuals agreed to undergo upper-gastrointestinal endoscopy. In all cases, biopsies were taken from the antrum and corpus. PTEN expression was assessed by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) analysis and immunohistochemistry. RESULTS: PTEN expression was reduced or absent in 21/26 gastric cancers compared with the matched non-malignant gastric biopsy (P < 0.001). Furthermore, PTEN expression was reduced significantly in the antrum biopsy of first-degree relatives compared with healthy controls (P < 0.05). CONCLUSIONS: Reduced expression of PTEN in gastric cancer points to another mechanism apart from PTEN mutation that may be involved in the pathogenesis of gastric cancer. The reduction of PTEN expression was also observed in first-degree relatives.

The effect of Helicobacter pylori infection and eradication in patients with gastro-oesophageal reflux disease: A parallel-group, double-blind, placebo-controlled multicentre study.

OBJECTIVES: This study aimed to resolve controversy regarding the effects of Helicobacter pylori eradication therapy and H. pylori infection in gastro-oesophageal reflux disease. DESIGN: A randomized, double-blind, multicentre trial was performed in patients presenting with reflux symptoms. H. pylori-positive patients were randomized to receive either antibiotics or placebo for 7 days. H. pylori-negative patient controls received placebo. All received esomeprazole 20 mg b.d. for 7 days, followed by 40 mg o.d. to complete an 8-week course, and were followed up for 32 weeks by telephone. RESULTS: In this study, 198/589 (34%) patients were H. pylori-positive and 113 H. pylori-negative patients served as controls. Baseline endoscopy revealed 63% Los Angeles grade 0A and 37% Los Angeles grade BCD oesophagitis with no difference between patient groups. Symptom improvement on esomeprazole was seen in 89%. H. pylori eradication was successful in 82%. H. pylori eradication had no effect on symptomatic relapse (hazard ratio 1.15, 95% CI 0.74-1.8; p = 0.5). Overall, H. pylori-positive patients had a lower probability of relapse compared to H. pylori-negative controls (hazard ratio 0.6, 95% CI 0.43-0.85; p = 0.004). Relapse hazard was modulated also by oesophagitis grade (BCD vs. 0A, hazard ratio 2.1, 95% CI 1.5-3.0). CONCLUSION: Relapse of gastro-oesophageal reflux disease symptoms after a course of high dose acid suppression took longer for H. pylori-positive patients than H. pylori-negative controls; however eradication therapy had no effect on the risk of relapse; ClincialTrials.gov number, NCT00574925.

Interleukin 1 beta (IL1B) gene polymorphisms are not associated with gastric carcinogenesis in Germany.

BACKGROUND: Polymorphisms of interleukin-1 beta gene (IL1B-511C>T) are considered as risk factor for gastric carcinogenesis, but conflicting data have been reported recently. PATIENTS AND METHODS: The distribution of the four major IL1B variants (IL1B-3737C>T, -1464G>C, - 511C>T, -31T>C) were analyzed in 116 and 142 patients with gastric cancer and 'high risk gastritis', respectively, as well as 94 healthy controls. RESULTS: While identified frequencies of genotypes, haplotypes and haplotype pairs corresponded to those of other studies in Caucasians, none were significantly associated with the presence of gastric cancer or premalignant alterations. CONCLUSION: None of the four major polymorphisms is individually or in its haplotype configuration linked to the development of GC in this Caucasian population in Germany.

Performance of epigenetic markers SEPT9 and ALX4 in plasma for detection of colorectal precancerous lesions.

BACKGROUND: Screening for colorectal cancer (CRC) has shown to reduce cancer-related mortality, however, acceptance and compliance to current programmes are poor. Developing new, more acceptable non-invasive tests for the detection of cancerous and precancerous colorectal lesions would not only allow preselection of individuals for colonoscopy, but may also prevent cancer by removal of precancerous lesions. METHODS: Plasma from 128 individuals (cohort I - exploratory study: 73 cases / 55 controls) was used to test the performance of a single marker, SEPT9, using a real-time quantitative PCR assay. To validate performance of SEPT9, plasma of 76 individuals (cohort II - validation study: 54 cases / 22 controls) was assessed. Additionally, improvement of predictive capability considering SEPT9 and additionally ALX4 methylation was investigated within these patients. RESULTS: In both cohorts combined, methylation of SEPT9 was observed in 9% of controls (3/33), 29% of patients with colorectal precancerous lesions (27/94) and 73% of colorectal cancer patients (24/33). The presence of both SEPT9 and ALX4 markers was analysed in cohort II and was observed in 5% of controls (1/22) and 37% of patients with polyps (18/49). Interestingly, also 3/5 (60%) patients with colorectal cancer were tested positive by the two marker panel in plasma. CONCLUSIONS: While these data confirm the detection rate of SEPT9 as a biomarker for colorectal cancer, they also show that methylated DNA from advanced precancerous colorectal lesions can be detected using a panel of two DNA methylation markers, ALX4 and SEPT9. If confirmed in larger studies these data indicate that screening for colorectal precancerous lesions with a blood-based test may be as feasible as screening for invasive cancer.

Optimal timing of oral refeeding in mild acute pancreatitis: results of an open randomized multicenter trial.

OBJECTIVES: The aim of this study was to compare 2 protocols regarding the initiation of oral nutrition in patients with mild acute pancreatitis. METHODS: We randomized 143 patients to the Lipase directed (LIP) (n = 74) and the self selected PAT (n = 69) group. In the (PAT) group, the patients restarted eating through self-selection. In the LIP group, serum lipase had to normalize before eating. RESULTS: The mean time between admission and oral nutrition was 2 days (interquartile range [IQR], 1-3) in the PAT group and 3 days (IQR, 2-4) in the LIP group (P < 0.005). Before and after the first meal, the mean Δ visual analogue scale (VAS) was +3.14 mm (±11.5 mm) in the PAT group and +2.85 mm (±16.4) in the LIP group (P = 0.597). The length of hospital stay was 7 days (median; IQR, 5-10.5) in the PAT group and 8 days (median; IQR, 5.75-12) in the LIP group (P = 0.315). CONCLUSIONS: We were not able to demonstrate a difference in postprandial abdominal pain or in the length of hospital stay. Patients with self-selected eating, however, were able to restart eating 1 day earlier, and this difference was found to be significant. Our data suggest that normalization of serum lipase is not obligatory for enteral nutrition in mild acute pancreatitis.

Efficacy and cost-effectiveness of the 13C-urea breath test as the primary diagnostic investigation for the detection of Helicobacter pylori infection compared to invasive and non-invasive diagnostic tests.

BACKGROUND: Helicobacter pylori (H. pylori) is one of the most common bacterial infections in humans. There is a risk factor for gastric or duodenal ulcers, gastric cancer and MALT (Mucosa Associated Lymphoid Tissue)-Lymphomas. There are several invasive and non-invasive methods available for the diagnosis of H. pylori. The (13)C-urea breath test is a non-invasive method recommended for monitoring H. pylori eradication therapy. However, this test is not yet used for primary assessment of H. pylori in Germany. OBJECTIVES: What are the clinical and health economic benefits of the (13)C-urea breath test in the primary assessment of H. pylori compared to other invasive and non-invasive methods? METHODS: A systematic literature search including a hand search was performed for studies investigating test criteria and cost-effectiveness of the (13)C-urea breath test in comparison to other methods used in the primary assessment of H. pylori. Only studies that directly compared the (13)C-urea breath test to other H. pylori-tests were included. For the medical part, biopsy-based tests were used as the gold standard. RESULTS: 30 medical studies are included. Compared to the immunoglobulin G (IgG) test, the sensitivity of the (13)C-urea breath test is higher in twelve studies, lower in six studies and one study reports no differences. The specificity is higher in 13 studies, lower in three studies and two studies report no differences. Compared to the stool antigen test, the sensitivity of the (13)C-urea breath test is higher in nine studies, lower in three studies and one study reports no difference. The specificity is higher in nine studies, lower in two studies and two studies report no differences. Compared to the urease test, the sensitivity of the (13)C-urea breath test is higher in four studies, lower in three studies and four studies report no differences. The specificity is higher in five studies, lower in five studies and one study reports no difference. Compared to histology, the sensitivity of the (13)C-urea breath test is higher in one study and lower in two studies. The specificity is higher in two studies and lower in one study. One study each compares the (13)C-urea breath test to the (14)C-urea breath test and the polymerase chain reaction (PCR) test, respectively, and reports no difference in sensitivity and specificity with the (14)C-urea breath test, and lower sensitivity and higher specificity compared to PCR. The statistical significance of these differences is described for six of the 30 studies. Nine health economic evaluations are included in the Health Technology Assessment (HTA) report. Among these studies, the test-and-treat strategy using the (13)C-urea breath test is compared to test-and-treat using serology in six analyses and to test and treat using the stool antigen test in three analyses. Thereby, test-and-treat using the breath test is shown to be cost-effective over the serology based strategy in three models and is dominated by a test-and-treat strategy using the stool antigen test in one model. A cost-effectiveness comparison between the urea breath test approach and the empirical antisecretory therapy is carried out in four studies. Of these, two studies report that the strategy using the urea breath test is cost-effective over the empirical antisecretory therapy. In two studies, test-and-treat using the (13)C-urea breath test is compared to the empirical eradication therapy and in five studies to endoscopy-based strategies. The breath test approach dominates endoscopy in two studies and is dominated by this strategy in one study. DISCUSSION: All included medical and economic studies are limited to a greater or lesser extent. Additionally, the results of the studies are heterogeneous regarding medical and economic outcomes respectively. Thus, the majority of the medical studies do not report the statistical significance of the differences in sensitivity and specificity. In direct comparisons the (13)C- urea breath test shows higher sensitivity and specificity than the IgG and stool antigen tests. In comparison to the urease test, results for sensitivity are inconsistent, and the specificity is slightly higher for the (13)C-urea breath test. There are not enough results for comparisons between the (13)C-urea breath test and the (14)C-urea breath test, histology and PCR to describe tendencies. The included economic studies suggest that the test-and-treat strategy using the (13)C-urea breath test is cost-effective compared to test-and-treat using serology as well as empirical antisecretory therapies. Due to a lack of valid studies, it is not possible to assess the breath test approach in comparison to test-and-treat using the stool antigen test and the empirical eradication therapy respectively, regarding the cost-effectiveness. The results of economic analyses comparing test-and-treat using the breath test to endoscopy strategies are too heterogeneous to draw any conclusions. Overall, none of the included economic models is able to completely capture the complexity of managing patients with dyspeptic complaints. CONCLUSIONS/RECOMMENDATIONS: Based on available medical and economic studies, there is no sufficient evidence to recommend test and-treat using (13)C-urea breath testing for the detection of H. pylori infection as the standard procedure for the management of uninvestigated dyspepsia in the German health care system. In addition, it must be considered that the DVGS guidelines of the Deutsche Gesellschaft für Verdauungs- und Stoffwechselkrankheiten (DVGS) recommend endoscopy based methods for the management of patients with dyspeptic complaints.