The dynamics of the oesophageal squamous epithelium 'normalisation' process in patients with gastro-oesophageal reflux disease treated with long-term acid suppression or anti-reflux surgery.

BACKGROUND: Proton pump inhibitors and laparoscopic anti-reflux surgery (LARS) offer long-term symptom control to patients with gastro-oesophageal reflux disease (GERD). AIM: To evaluate the process of 'normalisation' of the squamous epithelium morphology of the distal oesophagus on these therapies. METHODS: In the LOTUS trial, 554 patients with chronic GERD were randomised to receive either esomeprazole (20-40 mg daily) or LARS. After 5 years, 372 patients remained in the study (esomeprazole, 192; LARS, 180). Biopsies were taken at the Z-line and 2 cm above, at baseline, 1, 3 and 5 years. A severity score was calculated based on: papillae elongation, basal cell hyperplasia, intercellular space dilatations and eosinophilic infiltration. The epithelial proliferative activity was assessed by Ki-67 immunohistochemistry. RESULTS: A gradual improvement in all variables over 5 years was noted in both groups, at both the Z-line and 2 cm above. The severity score decreased from baseline at each subsequent time point in both groups (P < 0.001, all comparisons), attaining a normal level by 5 years. Corresponding decreases in Ki-67 expression were observed (P < 0.001, all comparisons). No significant differences were found between esomeprazole treatment and LARS. Neither baseline severity score nor Ki-67 expression predicted the risk of treatment failure. CONCLUSIONS: Five years of treatment is generally required before squamous epithelial cell morphology and proliferation are 'normalised' in patients with chronic GERD, despite endoscopic and symptomatic disease control. Control of the acid component of the refluxate seems to play the predominant role in restoring tissue morphology.

Long-term safety of proton pump inhibitor therapy assessed under controlled, randomised clinical trial conditions: data from the SOPRAN and LOTUS studies.

BACKGROUND: Control of chronic gastro-oesophageal reflux disease may be achieved either by anti-reflux surgery (ARS) or by long-term medical therapy with proton pump inhibitors (PPIs). The primary efficacy results of the SOPRAN study, comparing long-term omeprazole use with open ARS, and the LOTUS study, comparing long-term esomeprazole use with laparoscopic ARS, have been reported. A secondary objective of these studies was to address the long-term safety of these respective therapeutic strategies and thereby provide a valid scientific platform for assessing long-term PPI safety. AIM: To assess the safety of long-term PPI therapy with omeprazole and esomeprazole through analyses of data from the randomised SOPRAN and LOTUS studies. METHODS: Safety data were collected from patients during the 12-year period of the SOPRAN study (n = 298) and the 5-year period of the LOTUS study (n = 514). Reported serious adverse events (SAEs) and changes in laboratory variables were analysed. RESULTS: Across both studies, SAEs were reported at a similar frequency in the PPI and ARS treatment groups. Taking the time frames into consideration, the number of fatal SAEs in the two studies was low in both treatment groups. Laboratory results, including routine haematology and tests for liver enzymes, electrolytes, vitamin D, vitamin B12 , folate and homocysteine, showed no clinically relevant changes over time. As expected, gastrin and chromogranin A were elevated in the PPI groups, with the greatest increases observed in the first year. CONCLUSION: No major safety concerns arose during 5-12 years of continuous PPI therapy. (ClinicalTrials.gov: NCT00251927 and NCT00256737).

Gastric exocrine and endocrine cell morphology under prolonged acid inhibition therapy: results of a 5-year follow-up in the LOTUS trial.

BACKGROUND: Sustained acid inhibition with PPI stimulates gastrin secretion, exerting a proliferative drive on enterochromaffin-like cells (ECL cells) of the oxyntic mucosa. It may also accelerate development of gastric gland atrophy in Helicobacter pylori-infected individuals. AIMS: To evaluate gastric exocrine and endocrine cell changes in GERD patients randomised to laparoscopic antireflux surgery (LARS, n = 288) or long-term (5 years) esomeprazole (ESO) treatment (n = 266). METHODS: Antral and corpus biopsies were taken at endoscopy and serum gastrin and chromogranin A levels were assayed, at baseline and after 1, 3 and 5 years' therapy. RESULTS: Biopsies were available at each time point for 158 LARS patients and 180 ESO patients. In H. pylori-infected subjects, antral mucosal inflammation and activity improved significantly (P < 0.001) and stabilised after 3 years on esomeprazole while no change in inflammation was observed after LARS. Oxyntic mucosal inflammation and activity remained stable on esomeprazole but decreased slightly over time after LARS. Neither intestinal metaplasia nor atrophy developed in the oxyntic mucosa. ECL cell density increased significantly after ESO (P < 0.001), corresponding with an increase in circulating gastrin and chromogranin A. After LARS, there was a significant decrease in ECL cell density (P < 0.05), accompanied by a marginal decrease in gastrin and chromogranin. CONCLUSIONS: Antral gastritis improved in H. pylori-infected GERD patients after 5 years on esomeprazole, with little change in laparoscopic antireflux surgery patients, who acted as a control. Despite a continued proliferative drive on enterochromaffin-like cells during esomeprazole treatment, no dysplastic or neoplastic lesions were found and no safety concerns were raised. NCT 00251927.

Colon capsule endoscopy: European Society of Gastrointestinal Endoscopy (ESGE) Guideline.

PillCam colon capsule endoscopy (CCE) is an innovative noninvasive, and painless ingestible capsule technique that allows exploration of the colon without the need for sedation and gas insufflation. Although it is already available in European and other countries, the clinical indications for CCE as well as the reporting and work-up of detected findings have not yet been standardized. The aim of this evidence-based and consensus-based guideline, commissioned by the European Society of Gastrointestinal Endoscopy (ESGE) is to furnish healthcare providers with a comprehensive framework for potential implementation of this technique in a clinical setting.

Colonic mucosal biopsies obtained during confocal endomicroscopy are pre-stained with fluorescein in vivo and are suitable for histologic evaluation.

BACKGROUND AND STUDY AIMS: Confocal laser endomicroscopy (CLE) with intravenous infusion of fluorescein allows noninvasive, real-time in vivo visualization of gastrointestinal mucosa at ~ × 1000 magnification ("virtual biopsy"). Conventional biopsies obtained during these procedures serve as the reference and established diagnostic standard. The aim of the present study was to assess whether the standard histologic biopsies that are obtained during CLE retain fluorescein in the tissues and allow the visualization of mucosal structures without any additional staining. PATIENTS AND METHODS: CLE optical imaging of the mucosa was performed in 16 patients who were undergoing CLE colonoscopy. Standard conventional biopsies were also obtained from both normal colonic mucosa and colonic polyps. De-paraffinized mucosal sections were examined under a fluorescence microscope for the presence and distribution of fluorescein, and then underwent immunostaining for expression of vascular endothelial growth factor (VEGF). RESULTS: Standard mucosal biopsy sections from patients undergoing CLE displayed a strong fluorescence and showed well-delineated mucosal structures. In colonic adenomas, there was a 4.6-fold increased vascular permeability compared with normal mucosa (P<0.001), indicated by fluorescein leakage to the extravascular space. Immunostaining demonstrated an aberrantly increased expression of VEGF in the epithelium of colonic adenomas but not in the epithelium of normal mucosa or hyperplastic polyps. CONCLUSIONS: This study shows for the first time that standard colonic biopsies obtained during CLE retain fluorescein, show excellent delineation of mucosal structures without additional staining, allow the evaluation of mucosal microvasculature and vascular permeability, and are suitable for immunostaining.

Diagnosis and treatment of chronic constipation--a European perspective.

BACKGROUND: Although constipation can be a chronic and severe problem, it is largely treated empirically. Evidence for the efficacy of some of the older laxatives from well-designed trials is limited. Patients often report high levels of dissatisfaction with their treatment, which is attributed to a lack of efficacy or unpleasant side-effects. Management guidelines and recommendations are limited and are not sufficiently current to include treatments that became available more recently, such as prokinetic agents in Europe. PURPOSE: We present an overview of the pathophysiology, diagnosis, current management and available guidelines for the treatment of chronic constipation, and include recent data on the efficacy and potential clinical use of the more newly available therapeutic agents. Based on published algorithms and guidelines on the management of chronic constipation, secondary pathologies and causes are first excluded and then diet, lifestyle, and, if available, behavioral measures adopted. If these fail, bulk-forming, osmotic, and stimulant laxatives can be used. If symptoms are not satisfactorily resolved, a prokinetic agent such as prucalopride can be prescribed. Biofeedback is recommended as a treatment for chronic constipation in patients with disordered defecation. Surgery should only be considered once all other treatment options have been exhausted.

Randomised clinical trial: effects of monotherapy with ADX10059, a mGluR5 inhibitor, on symptoms and reflux events in patients with gastro-oesophageal reflux disease.

BACKGROUND: ADX10059, a metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulator, has been shown to reduce gastro-oesophageal reflux events and oesophageal acid exposure in patients with gastro-oesophageal reflux disease (GERD) and healthy subjects. AIM: To evaluate the effects of ADX10059 monotherapy for 2 weeks on symptom control in patients with GERD. METHODS: This was a double-blind, placebo-controlled, multi-centre trial in GERD patients who were responders to proton pump inhibitors (PPIs). Following PPIs withdrawal, a 2-week baseline washout period was followed by 2-week treatment with either ADX10059 120 mg or placebo b.d. The primary clinical efficacy endpoint was the number of GERD symptom-free days in treatment week 2 compared with the last 7 days of baseline. The effect on reflux events using 24-h impedance-pH monitoring was also determined in a subset of 24 patients. RESULTS: The full analysis set comprised 103 patients ADX10059 (N= 50), Placebo (N=53). In treatment week 2, ADX10059 significantly increased GERD symptom-free days (P=0.045) and heartburn-free days (P=0.037), reduced antacid use (P=0.017), improved total symptom score (P=0.048) including subscale heartburn/regurgitation (P=0.007) and sleep disturbance because of GERD (P= 0.022). ADX10059 significantly reduced total (P=0.034) and acidic reflux events (P=0.003). ADX10059 was well tolerated. Most common adverse events for ADX10059 were mild to moderate dizziness 16% and vertigo 12% (placebo 4% and 2%). CONCLUSIONS: Inhibition of mGluR5 with ADX10059 monotherapy reduces reflux events and improves symptoms in GERD patients. This mechanism has promise for the management of GERD.

Colon capsule endoscopy vs. colonoscopy in patients at average or increased risk of colorectal cancer.

BACKGROUND: Colon capsule endoscopy (CCE) is a new, non-invasive technology. AIM: To conduct a prospective, multicentre trial to compare CCE and colonoscopy in asymptomatic subjects enrolled in screening or surveillance programmes for the detection of colorectal neoplasia. METHODS: Patients underwent CCE on day one and colonoscopy (gold standard) on day two. CCE and colonoscopy were performed by independent endoscopists. RESULTS: A total of 545 patients were recruited. CCE was safe and well-tolerated. Colon cleanliness was excellent or good in 52% of cases at CCE. Five patients with cancer were detected by colonoscopy, of whom two were missed by CCE. CCE accuracy for the detection of polyps ≥ 6 mm was 39% (95% CI 30-48) for sensitivity, 88% (95% CI 85-91) for specificity, 47% (95% CI 37-57) for positive predictive value and 85% (95% CI 82-88) for negative predictive value. CCE accuracy was better for the detection of advanced adenoma, in patients with good or excellent cleanliness and after re-interpretation of the CCE videos by an independent expert panel. CONCLUSIONS: Although well-tolerated, CCE cannot replace colonoscopy as a first line investigation for screening and surveillance of patients at risk of cancer. Further studies should pay attention to colonic preparation (Clinicaltrial.gov number NCT00436514).

Review article: gene therapy, recent developments and future prospects in gastrointestinal oncology.

BACKGROUND: Gene therapy consists of the introduction of genetic material into cells for a therapeutic purpose. A wide range of gene therapy vectors have been developed and used for applications in gastrointestinal oncology. AIM: To review recent developments and published clinical trials concerning the application of gene therapy in the treatment of liver, colon and pancreatic cancers. METHODS: Search of the literature published in English using the PubMed database. RESULTS: A large variety of therapeutic genes are under investigation, such as tumour suppressor, suicide, antiangiogenesis, inflammatory cytokine and micro-RNA genes. Recent progress concerns new vectors, such as oncolytic viruses, and the synergy between viral gene therapy, chemotherapy and radiation therapy. As evidence of these basic developments, recently published phase I and II clinical trials, using both single agents and combination strategies, in adjuvant or advanced disease settings, have shown encouraging results and good safety records. CONCLUSIONS: Cancer gene therapy is not yet indicated in clinical practice. However, basic and clinical advances have been reported and gene therapy is a promising, new therapeutic approach for the treatment of gastrointestinal tumours.

In vivo real-time imaging of human duodenal mucosal structures in celiac disease using endocytoscopy.

BACKGROUND AND AIMS: Celiac disease is a gluten-induced enteropathy whose diagnosis is based on histological evidence of villous atrophy. The diagnosis may be difficult if the orientation of histological sections is other than optimal. During upper gastrointestinal endoscopy we studied in vivo duodenal mucosa in patients with celiac disease using endocytoscopy, a novel diagnostic technique allowing in vivo real-time visualization of mucosa under x 450 magnification. METHODS: Sixteen patients with documented celiac disease and seven controls without celiac disease were studied. Endocytoscopic images obtained from several fields were compared in a blinded fashion to standard histology. RESULTS: Endocytoscopy showed three different patterns of in vivo histology: (1) the presence of normal-appearing, long, thin villi, lined with clearly distinguishable surface epithelial cells, considered to be normal duodenal mucosa (n = 15, all controls and eight celiac disease patients); (2) the presence of thick, shortened villi, reflecting partial villous atrophy (n = 4); and (3) the total absence of villi and the presence of enlarged crypt orifices, reflecting total villous atrophy (n = 4). Good concordance between endocytoscopy and standard histology was found in all 16 patients with celiac disease. CONCLUSIONS: Endocytoscopy allows in vivo, real-time, noninvasive visualization and characterization of villous architecture and may be a promising method for in vivo evaluation of duodenal mucosa in celiac disease.

Endoscopic ultrasound-guided fine-needle aspiration for the diagnosis of solid pancreatic masses: the impact on patient-management strategy.

BACKGROUND: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is a safe and accurate technique for diagnosing pancreatic cancer. However, its impact for management of these patients is poorly investigated. AIMS: To investigate the diagnostic yield and the therapeutic impact of EUS-FNA in the management of solid pancreatic masses. METHODS: One hundred consecutive patients who underwent EUS-FNA for a solid pancreatic mass were included. Aspirates were placed onto glass slides for cytological examination and microbiopsies were fixed in formaldehyde for histology. The impact on clinical management was analysed retrospectively according to different endpoints, such as its impact on indications for chemotherapy, surgery or appropriate follow-up modality. RESULTS: Eight procedures were considered failures and two patients were lost to follow-up. A final diagnosis was obtained in 90 patients. The sensitivity, specificity and accuracy of combined cytology and histology for the diagnosis of malignant or potentially-malignant tumours were 78%, 75%, and 78% respectively. The sensitivity and accuracy of cytology alone were significantly higher than those of histology alone (P = 0.0003). By intention-to-diagnose analysis, EUS-FNA directly influenced the management strategy in 62 of 100 patients. CONCLUSIONS: In patients with pancreatic mass and suspected malignancy, EUS-FNA provides an accurate diagnosis in approximately 80% of cases. EUS-FNA directly influences the management in two-thirds of patients.

[Future prospects in digestive endoscopy: wireless capsule endoscopy]. / Nouvelles perspectives en endoscopie diagnostique: la vidéocapsule.

Since the beginning of the millennium, the development of wireless capsule endoscopy has represented a major technological advance. The capsule is ingested by the patient and images are transmitted via several sensors positioned on the skin of the patient and downloaded in a computer system. The first applications were focused on the exploration of the small bowel which was previously considered as an obscure area for conventional endoscopy. Wireless capsule endoscopy of the small bowel is now an established technique with many acknowledged indications for the diagnosis of obscure bleeding, anemia of presumed digestive origin, Crohn's disease and small bowel tumors. Recently, thanks to technological progresses, novel capsules have been developed for specific segments of the gut namely the oesophagus and the colon. Recent data suggest that these new capsules could have potential applications for the diagnosis of oesophageal varices, Barrett's oesophagus and for the screening and/or surveillance of polyps of the colon. However, further studies are required before such strategies could be approved for clinical use or even replace conventional endoscopic modalities. In the long-term, progresses in signal processing as well as in the miniaturisation of sensors or markers may lead to a new generation of endoscopic robots. This technological breakthrough may ultimately result in new concepts and change current practice of digestive endoscopy.

Impaired intestinal barrier integrity in the colon of patients with irritable bowel syndrome: involvement of soluble mediators.

BACKGROUND: Growing evidence suggests that patients with irritable bowel syndrome (IBS) have increased intestinal permeability. In addition, mucosal soluble mediators are involved in the pathophysiology of pain in IBS. We aimed to investigate (1) paracellular permeability in colonic biopsies of patients with IBS; and (2) the ability of soluble factors from colonic biopsies to reproduce these alterations in vitro. METHODS: Paracellular permeability in colonic biopsies of healthy subjects and patients with IBS was measured by mounting the biopsies in Ussing chambers. Cleared supernatant (SUP) of the culture from colonic biopsies was collected and applied to Caco-2 cells for 48 h. Paracellular permeability and transepithelial resistance (TER) were evaluated. mRNA expression of the tight junction proteins, zonula occludens (ZO)-1 and occludin, was assessed in colonic biopsies. Abdominal pain was assessed using a validated questionnaire. RESULTS: Permeability of colonic biopsies was significantly higher in patients with IBS compared to healthy subjects. These changes were associated with significantly lower expression of ZO-1 mRNA in biopsies of IBS as compared to healthy subjects. Compared to healthy subjects, SUP of IBS markedly reduced TER and significantly increased permeability in Caco-2 cells. SUP of IBS patients induced a significant decrease of ZO-1 mRNA in Caco-2 as compared to healthy subjects. SUP-induced increased paracellular permeability correlated with the severity of abdominal pain. CONCLUSIONS: Our study shows that colonic soluble mediators are able to reproduce functional (permeability) and molecular (ZO-1 mRNA expression) alterations observed in IBS patients. These findings might pave the way both to identify novel biomarkers as well as new therapeutic targets in IBS.

Medical or surgical management of GERD patients with Barrett's esophagus: the LOTUS trial 3-year experience.

INTRODUCTION: The long-term management of gastroesophageal reflux in patients with Barrett's esophagus (BE) is not well supported by an evidence-based consensus. We compare treatment outcome in patients with and without BE submitted to standardized laparoscopic antireflux surgery (LARS) or esomeprazole treatment. METHODS: In the Long-Term Usage of Acid Suppression Versus Antireflux Surgery trial (a European multicenter randomized study), LARS was compared with dose-adjusted esomeprazole (20-40 mg daily). Operative difficulty, complications, symptom outcomes [Gastrointestinal Symptom Rating Scale (GSRS) and Quality of Life in Reflux and Dyspepsia (QOLRAD)], and treatment failure at 3 years and pH testing (after 6 months) are reported. RESULTS: Of 554 patients with gastroesophageal reflux disease, 60 had BE-28 randomized to esomeprazole and 32 to LARS. Very few BE patients on either treatment strategy (four of 60) experienced treatment failure during the 3-year follow-up. Esophageal pH in BE patients was significantly better controlled after surgical treatment than after esomeprazole (p = 0.002), although mean GSRS and QOLRAD scores were similar for the two therapies at baseline and at 3 years. Although operative difficulty was slightly greater in patients with BE than those without, there was no difference in postoperative complications or level of symptomatic reflux control. CONCLUSION: In a well-controlled surgical environment, the success of LARS is similar in patients with or without BE and matches optimized medical therapy.

Clinical trial: Radiofrequency energy delivery in proton pump inhibitor-dependent gastro-oesophageal reflux disease patients.

BACKGROUND: Radiofrequency (RF) energy delivery is an endoscopic procedure developed for the treatment of gastro-oesophageal reflux disease. AIM: To compare RF and a proton pump inhibitor strategy (PPI) in PPI-dependent patients by carrying out a prospective, randomized trial. METHODS: Patients with PPI-dependent typical reflux symptoms were randomly allocated to either RF or PPI regimen alone. The primary endpoint, evaluated at 6-month, was defined as the possibility for the patient to stop or to decrease PPI use to <50% of the effective dose required at baseline. RESULTS: In the RF group, 18/20 patients stopped (n = 3) or decreased (n = 15) PPI use as compared to eight of 16 in the PPI group (P = 0.01). None of the control patients could stop PPI. Health-related quality of life scores were not different between groups. No significant change in oesophageal acid exposure (OAE) was noted between baseline and 6-months after RF. No severe complication was reported. CONCLUSIONS: Radiofrequency energy delivery is a safe and effective therapeutic option, allowing reduction in or discontinuation of PPI therapy in patients with PPI-dependent symptoms, without loss of quality of life. However, in a majority of patients, PPI therapy cannot be completely stopped. The efficacy of RF does not seem to be related to a decrease in OAE.

Comparing laparoscopic antireflux surgery with esomeprazole in the management of patients with chronic gastro-oesophageal reflux disease: a 3-year interim analysis of the LOTUS trial.

BACKGROUND: With the introduction of laparoscopic antireflux surgery (LARS) for gastro-oesophageal reflux disease (GORD) along with the increasing efficacy of modern medical treatment, a direct comparison is warranted. The 3-year interim results of a randomised study comparing both the efficacy and safety of LARS and esomeprazole (ESO) are reported. METHODS: LOTUS is an open, parallel-group multicentre, randomised and controlled trial conducted in dedicated centres in 11 European countries. LARS was completed according to a standardised protocol, comprising a total fundoplication and a crural repair. Medical treatment comprised ESO 20 mg once daily, which could be increased stepwise to 40 mg once daily and then 20 mg twice daily in the case of incomplete GORD control. The primary outcome variable was time to treatment failure (Kaplan-Meier analysis). Treatment failure was defined on the basis of symptomatic relapse requiring treatment beyond that stated in the protocol. RESULTS: 554 patients were randomised, of whom 288 were allocated to LARS and 266 to ESO. The two study arms were well matched. The proportions of patients who remained in remission after 3 years were similar for the two therapies: 90% of surgical patients compared with 93% medically treated for the intention to treat population, p = 0.25 (90% vs 95% per protocol). No major unexpected postoperative complications were experienced and ESO was well tolerated. However, postfundoplication complaints remain a problem after LARS. CONCLUSIONS: Over the first 3 years of this long-term study, both laparoscopic total fundoplication and continuous ESO treatment were similarly effective and well-tolerated therapeutic strategies for providing effective control of GORD.

Review article: respiratory manifestations of gastro-oesophageal reflux disease.

BACKGROUND: Respiratory manifestations represent one of the most prevalent and difficult-to-manage extra-oesophageal syndromes of gastro-oesophageal reflux disease. AIMS: To review the epidemiology, pathophysiological mechanisms and therapeutic outcomes of reflux-related respiratory disorders. METHODS: Search of the literature published in English using PubMed database. RESULTS: There is a discrepancy between the high prevalence of reflux in asthmatics and the limited efficacy of antireflux therapies. Asthma per se may cause reflux. Patients with difficult-to-treat asthma and/or nocturnal symptoms should be screened for reflux. Reflux can induce chronic cough through different mechanisms including micro-aspiration and both local and central reflexes. Cough and reflux may precipitate each other. A meta-analysis found no significant difference between placebo and proton pump inhibitors in the resolution of cough. Encouraging results have been reported, following antireflux surgery in patients selected on the basis of pH-impedance monitoring. Attention has been drawn to obstructive sleep apnoea syndrome. CONCLUSIONS: The role of gastro-oesophageal reflux disease in the pathogenesis of miscellaneous respiratory disorders has been discussed for decades and established in asthma and cough. However, no major therapeutic advances have been reported recently. Future trials should concentrate on patient selection and the control of efficacy using recently developed technologies, such as pH-impedance monitoring.