14-day tailored PCR-guided triple therapy versus 14-day non-Bismuth concomitant quadruple therapy for Helicobacter pylori eradication: A multicenter, open-label randomized noninferiority controlled trial.

BACKGROUND: The systematic use of susceptibility testing and tailored first-line treatment for Helicobacter pylori eradication has yet to be established. AIM: To compare 14-day tailored PCR-guided triple therapy to 14-day non-Bismuth concomitant quadruple therapy for first-line Helicobacter pylori eradication. PATIENTS AND METHODS: We performed a multicenter, parallel-group, randomized noninferiority controlled trial. Naive adult patients with Helicobacter pylori infection were treated with 14-day tailored PCR-guided triple therapy (esomeprazole 40 mg and amoxicillin 1000 mg b.d. plus clarithromycin 500 mg or levofloxacin 500 mg b.d. according to clarithromycin susceptibility) or 14-day non-Bismuth concomitant quadruple therapy (esomeprazole 40 mg, amoxicillin 1000 mg, clarithromycin 500 mg, and metronidazole 500 mg b.d.). The primary endpoint was H. pylori eradication. RESULTS: We screened 991 patients for eligibility and randomized 241 patients. The first-line eradication rate was 99.2% in the tailored PCR-guided group and 95.9% in the control group (ITT population; absolute difference of +3.30%, with a lower bound of CI at -0.68%). Both first-line therapies were well tolerated, with a formally significant difference in favor of the tailored PCR-guided group (61.4% vs. 41.2%, p = 0.003). Economic analyses revealed a lower cost of the tailored PCR-guided arm, with a 92% chance of being jointly more effective and less expensive than the control arm in the ITT population. CONCLUSION: In a country with a high level of clarithromycin resistance, the results of our study demonstrated the noninferiority of 14-day tailored PCR-guided triple therapy as a first-line H. pylori eradication therapy compared to 14-day non-Bismuth quadruple therapy (ClinicalTrials.gov NCT02576236).

Long-term course of precancerous lesions arising in patients with gastric MALT lymphoma.

BACKGROUND AND AIMS: To evaluate the prevalence and the long-term course of gastric precancerous lesions in patients with GML. PATIENTS AND METHODS: In this retrospective single-centre study, we included 179 patients with GML, 70 with gastric diffuse large B-cell lymphoma (GDLBCL) and 152 with Helicobacter pylori-associated gastritis (HpG), from January 1995 to January 2014. The presence of atrophic gastritis, intestinal metaplasia and neoplastic lesion has been assessed at baseline and during follow-up. RESULTS: Atrophic gastritis was more frequent in the GML group whereas there was also a trend for intestinal metaplasia and gastric dysplasia. In patients with GML, atrophic gastritis, intestinal metaplasia and gastric dysplasia were more frequent in the GML area than in other part of the stomach. During follow-up, the prevalence of atrophic gastritis remained stable overtime whereas intestinal metaplasia and dysplasia tend to increase overtime. In multivariate analysis, the occurrence of dysplasia or carcinoma was associated with the presence of intestinal metaplasia at baseline and male gender. CONCLUSION: GML is associated with gastric precancerous lesion to a higher extent than GDLBCL and HpG. Those precancerous lesions do not regress despite achievement of complete remission of GML and tend to increase overtime.

Helicobacter pylori, gastric cancer and other gastrointestinal malignancies.

In a retrospective study performed in California, U.S.A., ca. 3% of patients with gastric intestinal metaplasia (GIM) developed gastric cancer (GC) within a median time period of 4.6 years after diagnosis of GIM. This observation stresses the importance of targeted surveillance even in regions with a low GC prevalence. Patients with alcoholic liver disease as well as survivors of colorectal and lobular breast cancer were found to be at increased risk of secondary GC. A population-based Chinese study confirmed "serologic biopsy" as a useful screening tool for stratifying the individual risk of developing GC. Concerning GC therapy, a post hoc analysis of the MAGIC trial reported that regression of lymph node metastases, but not the tumor regression itself, predicts overall survival. Furthermore, in patients with high microsatellite instable tumors, perioperative chemotherapy leads to an increased risk of mortality. Two studies confirmed that eradication therapy is worthwhile as an initial treatment for gastric mucosa-associated lymphoid tissue (MALT) lymphoma irrespective of the H. pylori infection status and stage. An increased risk of a second primary malignancy including GC was observed in these patients treated with immuno/chemotherapy but not in patients treated solely with an H. pylori eradication treatment. With respect to gastrointestinal malignancies other than GC, discrepant data have been published regarding the association of H. pylori with pancreatic cancer whereas no association has been reported with esophageal squamous cell carcinoma. The majority of published studies still support an association of H. pylori with colon neoplasms.

Second primary malignancies in patients treated for gastric mucosa-associated lymphoid tissue lymphoma.

To assess the risk of second primary malignancy (SPM) in patients with gastric mucosa-associated lymphoid tissue (MALT) Lymphoma (GML), we included 175 patients with GML in the present study. The incidence of SPM in the general population, used for reference, was determined from the French network of cancer registries. During the 1442.9 patient-years of follow-up, 29 patients were diagnosed with incident SPM, including five patients diagnosed with gastric cancer (20.1/1000 patient-years). An increased incidence of SPM was observed in patients with GML (standardized incidence ratios [SIR]: 1.71 [1.14-2.45]) compared to the general French population especially for gastric cancer (SIR: 16.1 [5.19-37.56]). This elevated risk of SPM was significantly increased only in patients treated with immuno/chemotherapy but not in patients treated with Helicobacter pylori eradication alone. Long-term follow-up of patients with GML is mandatory even in patients who have achieved complete remission.

Rescue therapy with bismuth-containing quadruple therapy in patients infected with metronidazole-resistant Helicobacter pylori strains.

BACKGROUND: The emergence of H. pylori strains that are resistant to clarithromycin, metronidazole and fluoroquinolone requires the evaluation of new and effective salvage therapies. AIMS: To test the efficacy of a new formulation of a bismuth-containing quadruple therapy as a rescue therapy in patients who were infected with a H. pylori strain resistant to metronidazole, clarithromycin and fluoroquinolone or who failed multiple lines of treatment using these three antibiotics. METHODS: A total of 103 patients with confirmed H. pylori infection with a resistance profile described above were treated with Pylera(®) (3-in-1 capsules containing bismuth subcitrate potassium 140mg, metronidazole 125mg and tetracycline 125mg) 3 capsules four times a day plus omeprazole 20mg two times a day for 10 days in a named patient program. Eradication was confirmed using a urea breath test at least 28 days after the end of treatment. Efficacy and safety were studied. RESULTS: A total of 103 patients were prospectively included from June 2010 to October 2011. The eradication rate for the intent-to-treat analysis was 83% (CI95%[75-89%]); an 87% eradication rate (CI95%[80-94%]) was found for the per-protocol analysis and 81% (CI95%[80-82%]) for the intent-to-treat analysis in patients with proven resistance to metronidazole. Nine patients discontinued treatment, all due to adverse events. Two serious adverse events (AEs) were reported (memory disorders of unknown significance). Fifty-six (54%) patients reported at least one AE. CONCLUSION: This bismuth-containing quadruple therapy achieved a remarkable eradication rate as a salvage therapy in patients infected with metronidazole-resistant H. pylori strain, despite the frequent occurrence of mild-to-moderate adverse events.

Therapeutic drug monitoring is predictive of loss of response after de-escalation of infliximab therapy in patients with inflammatory bowel disease in clinical remission.

BACKGROUND: There is no evidence that therapeutic drug monitoring is helpful in patients with inflammatory bowel disease patients in clinical remission with infliximab therapy. METHODS: Eighty consecutive inflammatory bowel disease patients in clinical remission on infliximab maintenance therapy were included and followed-up for at least one year. Infliximab trough level and antibody to infliximab concentration were measured prior to enrollment. At the time of enrollment, physicians in charge were free to alleviate infliximab therapy. Discrepancies between blind and therapeutic drug monitoring-based adjustments were assessed at the end of the follow-up period. Relapse-free survival was analyzed using univariate and multivariate analyses. RESULTS: The mean infliximab trough level was 3.1 µg/mL. Antibody to infliximab was found in 15 (19%) patients. At the end of the follow-up period, 18 (22.5%) patients experienced a relapse. The 3, 6, 9 and 12-month relapse-free rates were 98%, 87%, 86% and 80%, respectively. In our multivariate analysis, relapse-free survival was negatively associated with discrepancies between therapeutic drug monitoring-based and blind adjustments of infliximab therapy, absence of concomitant immunomodulator, the absence of mucosal healing, prior use of infliximab, infliximab therapy duration>2 years and C-reactive protein levels>5mg/L at the time of enrollment. CONCLUSION: In patients with inflammatory bowel disease in clinical remission on infliximab therapy, de-escalation of infliximab therapy should be considered based on therapeutic drug monitoring rather than according to symptoms and CRP.

Endoscopic transgastric versus surgical necrosectomy in infected pancreatic necrosis.

Surgical necrosectomy, but is still associated with a high morbidity. Indications of the endoscopic route, a new less invasive technique are not defined yet. To compare characteristics and clinical outcome of patients treated by the two techniques, a bi-centric retrospective comparison of 21 patients treated by surgical necrosectomy in one center (group S) with 11 patients treated in another center by endoscopic transgastric necrosectomy (group E) was performed. Clinical severity scores were significantly higher in group S although CT severity score did not differ between groups. Acute postoperative complications including pancreatic fistula occurred more frequently in group S (86% vs. 27%, P=0.002). ICU and hospital length of stay were higher in group S (84 vs. 4 days; P=0.008 and 58 vs. 15 days; P=0.005 respectively). Long-term complication did not differ between groups. Compared to surgery, endoscopic necrosectomy exhibited lower rate of complications and reduced hospital length of stays. Endoscopic transgastric necrosectomy appears as a safe and effective procedure and has to be included in the therapeutic algorithm of infected pancreatic necrosis.

The detection of the methylated Wif-1 gene is more accurate than a fecal occult blood test for colorectal cancer screening.

BACKGROUND: The clinical benefit of guaiac fecal occult blood tests (FOBT) is now well established for colorectal cancer screening. Growing evidence has demonstrated that epigenetic modifications and fecal microbiota changes, also known as dysbiosis, are associated with CRC pathogenesis and might be used as surrogate markers of CRC. PATIENTS AND METHODS: We performed a cross-sectional study that included all consecutive subjects that were referred (from 2003 to 2007) for screening colonoscopies. Prior to colonoscopy, effluents (fresh stools, sera-S and urine-U) were harvested and FOBTs performed. Methylation levels were measured in stools, S and U for 3 genes (Wif1, ALX-4, and Vimentin) selected from a panel of 63 genes; Kras mutations and seven dominant and subdominant bacterial populations in stools were quantified. Calibration was assessed with the Hosmer-Lemeshow chi-square, and discrimination was determined by calculating the C-statistic (Area Under Curve) and Net Reclassification Improvement index. RESULTS: There were 247 individuals (mean age 60.8±12.4 years, 52% of males) in the study group, and 90 (36%) of these individuals were patients with advanced polyps or invasive adenocarcinomas. A multivariate model adjusted for age and FOBT led to a C-statistic of 0.83 [0.77-0.88]. After supplementary sequential (one-by-one) adjustment, Wif-1 methylation (S or U) and fecal microbiota dysbiosis led to increases of the C-statistic to 0.90 [0.84-0.94] (p = 0.02) and 0.81 [0.74-0.86] (p = 0.49), respectively. When adjusted jointly for FOBT and Wif-1 methylation or fecal microbiota dysbiosis, the increase of the C-statistic was even more significant (0.91 and 0.85, p<0.001 and p = 0.10, respectively). CONCLUSION: The detection of methylated Wif-1 in either S or U has a higher performance accuracy compared to guaiac FOBT for advanced colorectal neoplasia screening. Conversely, fecal microbiota dysbiosis detection was not more accurate. Blood and urine testing could be used in those individuals reluctant to undergo stool testing.

Infliximab as a bridge to remission maintained by antimetabolite therapy in Crohn's disease: A retrospective study.

BACKGROUND: Infliximab withdrawal in patients with Crohn's disease on concomitant antimetabolite therapy is considered to be superior if obtained after a maintenance therapy period compared to induction alone. METHODS: We retrospectively analyzed the outcome of Crohn's disease patients treated with infliximab and an antimetabolite after infliximab was withdrawn using induction alone or induction plus at least 1-year of maintenance therapy. The time to relapse was analyzed using univariate and multivariate analyses. The model was adjusted according to the period of infliximab withdrawal. RESULTS: A total of 92 patients were included, 54 in the induction alone group. The patient characteristics were identical in the two groups except for the period of infliximab withdrawal. After a median follow-up period of 47.1 (interquartile range=4.4-110.2) months, 66 patients (72%) experienced a relapse. After a year-adjustment, no significant difference was observed between the two groups. Based on year-adjusted multivariate analysis, the risk factors for relapse were active smoking, previous antimetabolite failure, and perianal disease. After relapse, 53 patients (80%) were retreated with infliximab. After infliximab retreatment, clinical remission was observed in 47 patients (89%) at weeks 8-10. CONCLUSION: In Crohn's disease patients, the probability of relapse on antimetabolite therapy after infliximab withdrawal was not superior after a 1-year scheduled maintenance therapy as compared with an induction alone.

[Natural history of gastric cancer linked to Helicobacter pylori]. / Histoire naturelle de la carcinogenèse gastrique liée à H. pylori.

Gastric carcinogenesis is related to inflammatory reaction induced by Helicobacter pylori infection. Infection is involved in pathogenesis of both histological types of gastric cancer, intestinal or diffuse. In the first type, cancer is the last step of successive alterations of the gastric mucosa (atrophy, intestinal metaplasia, dysplasia). In the second type, cancer occurs faster due to chromosomic alterations related to oxidative stress. Inflammation and consequently cancer risk are modulated by bacterial virulence and by the immunologica responsiveness of the host. Helicobacter pylori eradication should be proposed to high risk patients: first degree relatives of patients having gastric cancer, patients with preneoplastic lesions. Cancer prevention is more effective when eradication is performed before occurrence of preneoplastic lesions. When preneoplastic lesions are present, eradication decreases but not suppresses the risk of cancer. Therefore periodic follow up with gastroscopy and biopsies should be planned in these patients.

Microbial dysbiosis and colon carcinogenesis: could colon cancer be considered a bacteria-related disease?

Colorectal cancer (CRC) is posing an increasingly important burden on the health care system, with western countries seeing a growing incidence of the disease. Except for germline DNA mutations which have been attributed to less than 5% of patients, little is known about the main causes of CRC. However, environment factors such as food, lifestyle and medication are now suspected to have a major influence on inducing cancers. Today, exhaustive quantitative and qualitative evaluation of all environmental factors is not possible. Various environment-induced diseases have been characterized based on colon microflora, also called microbiota, analyses. Growing data have shown specific changes in microflora (i.e. dysbiosis) in the stools of patients with colon cancer or those adherent to the colonic mucosa. Thus, it appears that microbiota may be considered a platform offering host and environment interactions for studying CRCs. The hypothesis that colon cancer might be a bacteria-related disease is suggested and perspectives are discussed.

Comparative evaluation of 29 commercial Helicobacter pylori serological kits.

BACKGROUND: Serology is a noninvasive diagnostic method for the detection of Helicobacter pylori infection. Many commercial kits are now on the market. It is necessary to assess their performances to help the user to choose the most appropriate. MATERIAL AND METHODS: The performances of 29 commercial serological tests detecting antibodies to Helicobacter pylori (17 enzyme-linked immunosorbent assay and 12 near-patient tests) were evaluated using sera from 108 patients prospectively selected from gastroenterology departments of five French hospital centers. These patients were infected (45) or uninfected (47) by H. pylori, or had doubtful results (16), according to the gold standard (culture or histology plus rapid urease test or urea breath test). The tests were evaluated by determining the usual parameters of performance: sensitivity, specificity, positive predictive value, negative predictive value, and accuracy. Two analyzes were performed including or not the 16 patients with doubtful infection as uninfected or not analyzed. RESULTS: Depending on the type of analysis, four or two of the 17 enzyme-linked immunosorbent assay tests presented excellent results with the five performance parameters >90%. Calculation of the Youden index allowed to show significantly better performances for one of the 4. Performances of the 12 near-patient tests were lower with accuracies <90% for all except one test. CONCLUSION: These data should help the users to choose the kit the most appropriate to their goals.

Rituximab and chlorambucil versus rituximab alone in gastric mucosa-associated lymphoid tissue lymphoma according to t(11;18) status: a monocentric non-randomized observational study.

Forty-nine patients, t(11;18)-positive (n = 31) and t(11;18)-negative (n = 18), were treated without randomization with rituximab-chlorambucil or rituximab alone. Evaluation was performed at week (W) 6, week (W) 25 and every 6 months (Wx). Comparing the rituximab-chlorambucil group to the rituximab-alone group, remission was obtained in 93% vs. 66% at W6 (p = 0.01), in 93% vs. 81% at W25 (p = 0.14) and in 93% vs. 76% at Wx (p = 0.07). Comparing the rituximab-chlorambucil group to the rituximab-alone group in t(11;18)-positive patients, remission was obtained in 100% vs. 45% at W6 (p = 0.0005), in 100% vs. 66% at W25 (p = 0.01) and in 96% vs. 55% at Wx (p = 0.01). Comparing the rituximab-chlorambucil group to the rituximab-alone group in t(11;18)-negative patients, remission was obtained in 66% vs. 83% at W6 (p = 0.32), in 66% vs. 92% at W25 (p = 0.22) and in 83% vs. 92% at Wx (p = 0.47). In conclusion, rituximab-chlorambucil is significantly more rapidly efficient than rituximab alone. In t(11;18)-positive patients, the combination is more efficient than rituximab alone. In t(11;18)-negative patients, rituximab alone is as efficient as rituximab-chlorambucil and may be an alternative treatment.

Infliximab infusion time in patients with inflammatory bowel diseases: is longer really safer?

BACKGROUND AND OBJECTIVE: Infliximab, a monoclonal antibody directed against tumor necrosis factor α (TNFα), is commonly used during flares and on a regular basis to maintain the remission of inflammatory bowel diseases (IBD). It is usually administered in 2-hours infusion and 2 hours of monitoring after as recommended. However, recent reports suggest that infliximab infusions over a shorter period (30 minutes to 1 hour) are well tolerated. We aimed to compare the tolerability of 1-hour and 2-hours infliximab infusions in patients with IBD in our institution. METHODS: We analyzed data from all patients treated with infliximab between 1999 and September 2010. Infliximab was administered in 1-hour infusion and 1 hour monitoring since 2009. Only the early adverse events were analyzed. RESULTS: Adverse events during infusion were compared between one group of patients who had 1-hour infusion (989 infusions) and the other who had 2-hours infusion (2102 infusions). The incidence of adverse events was 10.6% in the 2-hours infusion group versus 6.3% in the 1-hour infusion group (P=0.36). CONCLUSIONS: These results suggest that the occurrence of infliximab infusion-related adverse events is similar across the two groups, regardless of the infusion cycle. One-hour infusion could then be proposed safely for all patients.

Ciclosporin versus infliximab in patients with severe ulcerative colitis refractory to intravenous steroids: a parallel, open-label randomised controlled trial.

BACKGROUND: Ciclosporin and infliximab are potential rescue treatments to avoid colectomy in patients with acute severe ulcerative colitis refractory to intravenous corticosteroids. We compared the efficacy and safety of these drugs for this indication. METHODS: In this parallel, open-label, randomised controlled trial, patients were aged at least 18 years, had an acute severe flare of ulcerative colitis defined by a Lichtiger score greater than 10 points, and had been given an unsuccessful course of high-dose intravenous steroids. None of the patients had previously received ciclosporin or infliximab. Between June 1, 2007, and Aug 31, 2010, patients at 27 European centres were randomly assigned (via computer-derived permutation tables; 1:1) to receive either intravenous ciclosporin (2 mg/kg per day for 1 week, followed by oral drug until day 98) or infliximab (5 mg/kg on days 0, 14, and 42). In both groups, azathioprine was started at day 7 in patients with a clinical response. Neither patients nor investigators were masked to study treatment. The primary efficacy outcome was treatment failure defined by absence of a clinical response at day 7, a relapse between day 7 and day 98, absence of steroid-free remission at day 98, a severe adverse event leading to treatment interruption, colectomy, or death. Analysis was by intention to treat. This trial is registered with EudraCT (2006-005299-42) and ClinicalTrials.gov (NCT00542152). FINDINGS: 115 patients were randomly assigned; 58 patients were allocated to receive ciclosporin and 57 to receive infliximab. Treatment failure occurred in 35 (60%) patients given ciclosporin and 31 (54%) given infliximab (absolute risk difference 6%; 95% CI -7 to 19; p=0·52). Nine (16%) patients in the ciclosporin group and 14 (25%) in the infliximab group had severe adverse events. INTERPRETATION: Ciclosporin was not more effective than infliximab in patients with acute severe ulcerative colitis refractory to intravenous steroids. In clinical practice, treatment choice should be guided by physician and centre experience. FUNDING: Association François Aupetit, Société Nationale Française de Gastroentérologie, and the International Organization for the study of Inflammatory Bowel Disease.

Is elevated gastric tissue NOX2 associated with lymphoma of mucosa-associated lymphoid tissue?

Abstract Helicobacter pylori infection plays a crucial role in the pathogenesis of gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT). However, the host response to this infection is also important in the development of the disease. In particular, NADPH oxidases (NOXs) which generate reactive oxygen species are known to induce cell damage possibly leading to carcinogenesis. We analyze for the first time NOX expression in a series of well characterized gastric MALT lymphoma (GML) patients in comparison with controls. Our observation leads to the hypothesis that NOX2 expression is significantly associated with GML.

[HNPCC (hereditary non-polyposis colorectal cancer) or Lynch syndrome: a syndrome related to a failure of DNA repair system]. / Le syndrome HNPCC (hereditary non polyposis colorectal cancer) ou syndrome de Lynch : un syndrome en rapport avec une défaillance du système de réparation de l'ADN.

The HNPCC syndrome (hereditary non polyposis colon cancer) or Lynch syndrome stands for an autosomic dominant condition leading to the most prevalent hereditary colo-rectal cancers (CCR). MMR (mismatch repair)'s genes are involved in carcinogenesis as they play a role in ADNA mismatch repair. Microsatellite instability (MSI+ phenotype) induced by germline mutations is characteristic of such tumors and is necessary to assert the diagnosis. The HNPCC syndrome is associated with a significant increased risk of CCR altogether with endometrium, upper urinary tract and small bowel carcinomas as well as ovarian, biliary system and gastric cancers although of lesser extent. It is of importance to diagnose HNPCC syndrome prior to the treatment starts because it may influence patient's (as well as her/his relatives) disease management (type of surgery, surveillance and screening exams). New French recommendations, developed in 2009, about prophylactic colo-rectal and gynecologic surgeries and monitoring update latest ones published on 2004.