Frank Zerbib

Esophageal pH-impedance monitoring and symptom analysis in GERD: a study in patients off and on therapy.

INTRODUCTION:Combined esophageal pH-impedance monitoring allows detection of nearly all gastroesophageal reflux episodes, acid as well as nonacid. However, the role of nonacid reflux in the pathogenesis of symptoms is poorly known. The aim of this study was to evaluate the diagnostic yield of this technique in patients with suspected reflux symptoms while on or off PPI therapy.PATIENTS AND METHODS:The recordings of 150 patients recruited at seven academic centers with symptoms possibly related to gastroesophageal reflux were analyzed. Reflux events were detected visually using impedance (Sandhill, CO) and then characterized by pHmetry as acid or nonacid reflux. The temporal relationship between symptoms and reflux episodes was analyzed: a symptom association probability (SAP) ≥95% was considered indicative of a positive association.RESULTS:One hundred fifty patients were included, 102 women (mean age 52 ± 14 yr, range 16–84). Among the 79 patients off PPI, five did not report any symptom during the recording period. A positive SAP was found in 41 of the 74 symptomatic patients (55.4%), including acid reflux in 23 (31.1%), nonacid reflux in three (4.1%), and acid and nonacid in 15 (20.3%). In the group of patients on PPI (N = 71, 46 women, mean age 51 ± 15 yr), 11 were asymptomatic during the study, SAP was positive in 22 of the 60 symptomatic patients (36.7%), including acid reflux in three (5.0%), nonacid reflux in 10 (16.7%), and acid and nonacid in nine (15.0%). The symptoms most frequently associated with nonacid reflux were regurgitation and cough.CONCLUSION:Adding impedance to pH monitoring improves the diagnostic yield and allows better symptom analysis than pHmetry alone, mainly in patients on PPI therapy. The impact of this improved diagnostic value on gastroesophageal reflux disease management remains to be investigated by outcome studies.

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.

Sphincter-Saving Resection for All Rectal Carcinomas: The End of the 2-cm Distal Rule

Objective:To assess oncologic outcome of patients treated by conservative radical surgery for tumors below 5 cm from the anal verge. Summary Background Data:Standard surgical treatment of low rectal cancer below 5 cm from the anal verge is abdominoperineal resection. Methods:From 1990 to 2003, patients with a nonfixed rectal carcinoma at 4.5 cm or less from the anal verge and without external sphincter infiltration underwent conservative surgery. Surgery included total mesorectal excision with intersphincteric resection, that is, removal of the internal sphincter, to achieve adequate distal margin. Patients with T3 disease or internal sphincter infiltration received preoperative radiotherapy. Results:Ninety-two patients with a tumor at 3 (range 1.5–4.5) cm from the anal verge underwent conservative surgery. There was no mortality and morbidity was 27%. The rate of complete microscopic resection (R0) was 89%, with 98% negative distal margin and 89% negative circumferential margin. In 58 patients with a follow-up of more than 24 months, the rate of local recurrence was 2% and the 5-year overall and disease-free survival were 81% and 70%, respectively. Conclusions:The technique of intersphincteric resection permits us to achieve conservative surgery in patients with a tumor close to or in the anal canal without compromising local control and survival. Tumor distance from the anal verge is no longer a limit for sphincter-saving resection.

Diagnosis and management of patients with reflux symptoms refractory to proton pump inhibitors

Approximately a third of patients with suspected gastro-oesophageal reflux disease are resistant or partial responders to proton pump inhibitors (PPIs). Many of these patients do not have gastro-oesophageal reflux disease, but suffer from functional heartburn or dyspepsia. The potential mechanisms underlying failure of PPI treatment in patients with reflux-related symptoms include persistence of isolated or mixed acid, weakly acidic, bile or gas reflux, impaired oesophageal mucosal integrity, chemical or mechanical hypersensitivity to refluxates and psychological comorbidity. After thorough clinical evaluation and failure of empirical changes in PPI dose regime, diagnostic investigations include endoscopy and reflux monitoring with pH or pH-impedance monitoring. If symptoms are clearly related to persistent reflux, baclofen, antireflux surgery or pain modulators can be considered. If not, pain modulators are the only currently available therapy.

Comparison of Functional Results and Quality of Life Between Intersphincteric Resection and Conventional Coloanal Anastomosis for Low Rectal Cancer

PURPOSE:The technique of intersphincteric resection permits sphincter preservation with good oncologic results in very low rectal cancer. This study aimed to investigate functional results and quality of life after intersphincteric resection compared with conventional coloanal anastomoses.METHODS:From 1990 to 2000, 170 patients underwent total mesorectal excision with coloanal anastomosis for low rectal tumors. Questionnaires were obtained from 77 patients alive without colostomy: 37 had a conventional coloanal anastomosis and 40 had intersphincteric resection. Both groups were similar according to age, gender, anastomotic stenosis, colonic pouch, anastomotic leakage, preoperative radiotherapy, and follow-up (median, 56 months). Assessment included one functional and two quality-of-life questionnaires: the SF-36 Health Status and the Fecal Incontinence Quality of Life score.RESULTS:There was no difference in stool frequency, fragmentation, urgency, dyschesia, and alimentary restriction between patients with and without intersphincteric resection. Patients with intersphincteric resection had significantly worse continence (Wexner score, 10.8 vs. 6.9; P < 0.001) and needed more antidiarrheal drugs (60 vs. 35 percent; P = 0.04) than those without. Compared with conventional coloanal anastomoses, quality of life was altered by intersphincteric resection for the subscale embarrassment (P < 0.01) in the Fecal Incontinence Quality of Life score, whereas no difference of quality of life was observed with SF-36.CONCLUSIONS:Compared with conventional coloanal anastomoses, patients with intersphincteric resection have a higher risk of fecal incontinence and a slightly altered quality of life.

Determinants of gastro-oesophageal reflux perception in patients with persistent symptoms despite proton pump inhibitors

Background and aim: Approximately 20% of patients have persistent symptoms of gastro-oesophageal reflux despite proton pump inhibitor (PPI) therapy. The aim of this study was to assess the determinants of reflux perception in patients on PPI therapy. Patients and methods: 20 patients with typical gastro-oesophageal reflux symptoms (heartburn and/or regurgitation) despite double-dose PPIs (twice daily) were included in this study. Ambulatory 24 h pH–impedance studies were performed in all patients. The characteristics of symptomatic and asymptomatic reflux episodes were compared. Symptoms were considered globally and separately for heartburn and regurgitation. Results: A total of 1273 reflux episodes were detected including 243 (19.1%) acidic, 1018 (80.0%) weakly acidic and 12 (0.9%) weakly alkaline reflux episodes. Overall, 312 (24.5%) reflux episodes were symptomatic. The only factor associated with reflux perception was high proximal extent (p = 0.037). Compared with regurgitation, reflux episodes associated with heartburn were more frequently pure liquid (p = 0.009) and acidic (p = 0.027), had a lower nadir pH (p<0.001), were more frequently preceded by acid reflux episodes (p<0.001) and had a longer reflux bolus clearance time (p<0.001). Conclusions: High proximal extent of the refluxate is the only factor associated with reflux perception in patients on double-dose PPI. However, compared with regurgitation, composition of the refluxate, sensitisation of the oesophagus by preceding acid exposure and delayed bolus clearance appear to play a role in heartburn perception.

Repeated Pneumatic Dilations as Long-Term Maintenance Therapy for Esophageal Achalasia

INTRODUCTION:In esophageal achalasia, pneumatic dilations (PD) provide short-term and long-term remission rates of 60–90% and 40–50%, respectively. The aim of this study was to evaluate the long-term efficacy of repeated PD as long-term maintenance therapy.PATIENTS AND METHODS:From 1992 to 2004, 150 patients with esophageal achalasia treated by PD were included in this retrospective study (78 males, mean age 57 ± 20 yr). PD were performed until remission was achieved (symptom score ≤3, each item < 2) and subsequently when symptomatic recurrence occurred. A standardized symptoms questionnaire was sent to patients lost to follow-up. Results are expressed as mean ± SD.RESULTS:Initial remission was achieved in 137 of 150 (91.3%) patients with 2.67 ± 1.59 dilations [range 1–12]. Failure and perforation rates were 7.3% (n = 11) and 1.3% (n = 2), respectively. After initial remission, 48 of 137 (35%) patients had recurrent symptoms; the probability to be in remission at 5 and 10 yr was 67% and 50%, respectively. At the end of follow-up (45 ± 38 months, ext. 2–144) 108 of 137 (78.8%) patients were in remission. Among 112 patients whose symptoms could be treated by repeated PD (per protocol analysis), 108 (96.4%) were in remission (3.5 ± 2.1 PD, ext. 2–12). In this group, the probability of being in remission after repeated PD at 5 and 10 yr was 96.8% and 93.4%, respectively. No pretherapeutic factor influenced long-term remission rate. The overall prevalence of gastroesophageal reflux was 34.7%.CONCLUSION:One-third of the patients with esophageal achalasia treated by PD will experience symptomatic recurrence during a 4-yr period. Long-term remission can be achieved in virtually all the patients treated by repeated PD according to an “on-demand” strategy based on symptom recurrence.

Functional Esophageal Disorders.

Functional esophageal disorders consist of a disease category that present with esophageal symptoms (heartburn, chest pain, dysphagia, globus) not explained by mechanical obstruction (stricture, tumor, eosinophilic esophagitis), major motor disorders (achalasia, EGJ outflow obstruction, absent contractility, distal esophageal spasm, jackhammer esophagus), or gastroesophageal reflux disease (GERD). While mechanisms responsible are unclear, it is theorized that visceral hypersensitivity and hypervigilance play an important role in symptom generation, in the context of normal or borderline function. Treatments directed at improving borderline motor dysfunction or reducing reflux burden to sub-normal levels have limited success in symptom improvement. In contrast, strategies focused on modulating peripheral triggering and central perception are mechanistically viable and clinically meaningful. However, outcome data from these treatment options are limited. Future research needs to focus on understanding mechanisms underlying visceral hypersensitivity and hypervigilance so that appropriate targets and therapies can be developed.

Evaluation of the Association of Nine Helicobacter pylori Virulence Factors with Strains Involved in Low-Grade Gastric Mucosa-Associated Lymphoid Tissue Lymphoma

ABSTRACT Helicobacter pylori has been associated with the development of two malignant diseases: gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Although the cag pathogenicity island, especially the cagA gene, has been linked with adenocarcinoma, few data concerning H. pylori pathogenic factors involved in low-grade gastric MALT lymphoma are available. The goal of this study was to analyze the prevalence of and correlation between genes coding for seven H. pylori virulence factors (cagA, cagE, vacA, iceA, babA, hopQ, and oipA) and two novel adhesins (sabA and hopZ) by comparing a collection of 43 H. pylori strains isolated from patients with low-grade gastric MALT lymphoma to 39 strains isolated from age-matched patients with gastritis only. Our results show that taken individually, none of the nine genes tested can be considered associated with MALT strains and allow us to conclude that MALT pathogenesis is not linked with more proinflammatory H. pylori strains. We demonstrated that in patients infected with strains harboring the iceA1 allele, sabA functional status, and hopZ “off” status, the odds of developing a MALT lymphoma were 10 times higher. However, the low prevalence of such strains (10 of 43 MALT strains) renders this triple association a low-sensitivity marker for MALT strains. Our data confirmed that H. pylori virulence factors are correlated with one another. If the involvement of H. pylori in MALT lymphoma is well established, the pathomechanism by which gastric lymphoma occurs remains to be identified.

Clinical, but not oesophageal pH-impedance, profiles predict response to proton pump inhibitors in gastro-oesophageal reflux disease

Objective Approximately 30% of patients with gastro-oesophageal reflux disease (GORD) do not achieve adequate symptom control with proton pump inhibitors (PPIs). The aim of this study was to determine whether any symptom profile or reflux pattern was associated with refractoriness to PPI therapy. Design Patients with typical GORD symptoms (heartburn and/or regurgitation) were included and had 24 h pH-impedance monitoring off therapy. Patients were considered to be responders if they had fewer than 2 days of mild symptoms per week while receiving a standard or double dose of PPI treatment for at least 4 weeks. Both clinical and reflux parameters were taken into account for multivariate analysis (logistic regression). Results One hundred patients were included (median age 50 years, 42 male), 43 responders and 57 non-responders. Overall, multivariate analysis showed that the factors associated with the absence of response were absence of oesophagitis (p=0.050), body mass index (BMI) ≤25 kg/m2 (p=0.002) and functional dyspepsia (FD) (p=0.001). In patients who reported symptoms during the recording (n=85), the factors associated with PPI failure were BMI ≤25 kg/m2 (p=0.004), FD (p=0.009) and irritable bowel syndrome (p=0.045). In patients with documented GORD (n=67), the factors associated with PPI failure were absence of oesophagitis (p=0.040), FD (p=0.003), irritable bowel syndrome (p=0.012) and BMI ≤25 kg/m2 (p=0.029). Conclusion No reflux pattern demonstrated by 24 h pH-impedance monitoring is associated with response to PPIs in patients with GORD symptoms. In contrast, absence of oesophagitis, presence of functional digestive disorders and BMI ≤25 kg/m2 are strongly associated with PPI failure.