Peroral endoscopic myotomy: is it better to perform it in naive patients or as second-line therapy? Results of an open-label-controlled study in 105 patients.

BACKGROUND: Whether Peroral Endoscopic Myotomy (POEM) can be proposed as a second-line treatment in patients with achalasia remains to be confirmed in real-life series. OBJECTIVE: This study aimed to compare the efficacy, feasibility and safety of POEM between treatment-naïve patients and patients who had prior endoscopic or surgical therapies for achalasia. METHODS: All consecutive patients who underwent a POEM procedure for achalasia in our centre from June 2015 to September 2018 were included in this retrospective study. They were classified into treatment-naïve patients (POEM1) and patients who had at least one previous endoscopic and/or surgical treatment for achalasia (POEM2). RESULTS: A total of 105 patients were included, 52 in the POEM1 group and 53 in the POEM2 group. Clinical success (defined as an Eckardt score ≤ 3) at 6 months was observed in 93% of POEM1 patients and 84% of POEM2 patients (p = 0.18). Technical success rate was not significantly different between the two groups (100% vs 96%, respectively; p = 0.50). No significant difference was noted in terms of adverse event rate (19% vs 19%, respectively; p = 1.00). Post-procedure pain occurred in 12% of treatment-naive and 9% of non-naïve patients (p = 0.76). The median length of hospital stay was 3 days in both groups (p = 0.17). Symptomatic gastroesophageal reflux occurred in 25% of POEM1 patients and 16% of POEM2 patients (p = 0.24). CONCLUSION: Efficacy, feasibility and safety of POEM are not different between treatment-naïve and non-naïve patients. POEM is a valuable second-line approach in patients with persistent symptoms of achalasia after surgical or endoscopic treatments.

Pneumatic dilation versus laparoscopic Heller's myotomy for idiopathic achalasia.

BACKGROUND: Many experts consider laparoscopic Heller's myotomy (LHM) to be superior to pneumatic dilation for the treatment of achalasia, and LHM is increasingly considered to be the treatment of choice for this disorder. METHODS: We randomly assigned patients with newly diagnosed achalasia to pneumatic dilation or LHM with Dor's fundoplication. Symptoms, including weight loss, dysphagia, retrosternal pain, and regurgitation, were assessed with the use of the Eckardt score (which ranges from 0 to 12, with higher scores indicating more pronounced symptoms). The primary outcome was therapeutic success (a drop in the Eckardt score to ≤3) at the yearly follow-up assessment. The secondary outcomes included the need for retreatment, pressure at the lower esophageal sphincter, esophageal emptying on a timed barium esophagogram, quality of life, and the rate of complications. RESULTS: A total of 201 patients were randomly assigned to pneumatic dilation (95 patients) or LHM (106). The mean follow-up time was 43 months (95% confidence interval [CI], 40 to 47). In an intention-to-treat analysis, there was no significant difference between the two groups in the primary outcome; the rate of therapeutic success with pneumatic dilation was 90% after 1 year of follow-up and 86% after 2 years, as compared with a rate with LHM of 93% after 1 year and 90% after 2 years (P=0.46). After 2 years of follow-up, there was no significant between-group difference in the pressure at the lower esophageal sphincter (LHM, 10 mm Hg [95% CI, 8.7 to 12]; pneumatic dilation, 12 mm Hg [95% CI, 9.7 to 14]; P=0.27); esophageal emptying, as assessed by the height of barium-contrast column (LHM, 1.9 cm [95% CI, 0 to 6.8]; pneumatic dilation, 3.7 cm [95% CI, 0 to 8.8]; P=0.21); or quality of life. Similar results were obtained in the per-protocol analysis. Perforation of the esophagus occurred in 4% of the patients during pneumatic dilation, whereas mucosal tears occurred in 12% during LHM. Abnormal exposure to esophageal acid was observed in 15% and 23% of the patients in the pneumatic-dilation and LHM groups, respectively (P=0.28). CONCLUSIONS: After 2 years of follow-up, LHM, as compared with pneumatic dilation, was not associated with superior rates of therapeutic success. (European Achalasia Trial Netherlands Trial Register number, NTR37, and Current Controlled Trials number, ISRCTN56304564.).

Diet-induced obesity has neuroprotective effects in murine gastric enteric nervous system: involvement of leptin and glial cell line-derived neurotrophic factor.

Nutritional factors can induce profound neuroplastic changes in the enteric nervous system (ENS), responsible for changes in gastrointestinal (GI) motility. However, long-term effects of a nutritional imbalance leading to obesity, such as Western diet (WD), upon ENS phenotype and control of GI motility remain unknown. Therefore, we investigated the effects of WD-induced obesity (DIO) on ENS phenotype and function as well as factors involved in functional plasticity. Mice were fed with normal diet (ND) or WD for 12 weeks. GI motility was assessed in vivo and ex vivo. Myenteric neurons and glia were analysed with immunohistochemical methods using antibodies against Hu, neuronal nitric oxide synthase (nNOS), Sox-10 and with calcium imaging techniques. Leptin and glial cell line-derived neurotrophic factor (GDNF) were studied using immunohistochemical, biochemical or PCR methods in mice and primary culture of ENS. DIO prevented the age-associated decrease in antral nitrergic neurons observed in ND mice. Nerve stimulation evoked a stronger neuronal Ca(2+) response in WD compared to ND mice. DIO induced an NO-dependent increase in gastric emptying and neuromuscular transmission in the antrum without any change in small intestinal transit. During WD but not ND, a time-dependent increase in leptin and GDNF occurred in the antrum. Finally, we showed that leptin increased GDNF production in the ENS and induced neuroprotective effects mediated in part by GDNF. These results demonstrate that DIO induces neuroplastic changes in the antrum leading to an NO-dependent acceleration of gastric emptying. In addition, DIO induced neuroplasticity in the ENS is likely to involve leptin and GDNF.

A comparison between rectal and colonic biopsies to detect Lewy pathology in Parkinson's disease.

We have shown that routine biopsies of the ascending colon obtained at colonoscopy allow the detection of Lewy neurites (LN) in the enteric nervous system (ENS) of Parkinson's disease (PD) patients. Although colonoscopy is a relatively safe procedure, it requires colon preparation and anesthesia. The present study was therefore undertaken to evaluate whether descending colon and rectal biopsies that are obtainable by rectosigmoidoscopy allow the detection of Lewy pathology in the ENS. A total of 9 controls and 26 PD patients were included and analyzed. Two biopsies were taken from the ascending, descending colon and rectum during the course of a total colonoscopy. Immunohistochemical analysis was performed using antibodies against phosphorylated alpha-synuclein to detect LN and neurofilaments 200 kDa to label the neuronal structures. Biopsies from ascending, descending colon and rectum were morphologically comparable. LN were detected in the biopsies of ascending colon in 17 PD patients (65%), of descending colon in 11 patients (42%) and of rectum in only 6 patients (23%). No LN were seen in control biopsies. Our results show that Lewy pathology follows a rostrocaudal distribution in the colon and rectum of PD patients. Therefore, rectal biopsies have substantially lower sensitivity than ascending colon biopsies to detect Lewy pathology in the gut.

Colonic endoscopic full-thickness biopsies: from the neuropathological analysis of the myenteric plexus to the functional study of neuromuscular transmission.

BACKGROUND: Better understanding of the pathophysiological mechanisms involved in severe dysmotility disorders is crucial to improve patient management and identify novel therapeutic targets. Recent studies suggested that endoscopic full-thickness biopsies (eFTBs) could be developed as an alternative to surgical biopsies. However, currently it remains unknown whether eFTBs would allow myenteric plexus analysis on whole mounts and the evaluation of neuromuscular transmission. OBJECTIVE: To determine with eFTB specimens the ability to analyze on whole mounts the key parameters of the myenteric plexus, ie, ganglia and neurons, and to perform functional evaluation of neuromuscular transmission. DESIGN: An experimental pilot study in 6 pigs was conducted in accordance with French institutional guidelines. INTERVENTION: Under general anesthesia, pigs underwent a rectosigmoidoscopy. In each pig, an eFTB was performed at 25, 30, and 35 cm from the anal margin with an EMR-based technique. Tissue specimens were immediately processed for immunohistochemical and/or functional ex vivo analysis of neuromuscular transmission. In 2 pigs, over-the-scope clips were used to seal the perforation. MAIN OUTCOME MEASUREMENTS: Feasibility of obtaining specimens containing myenteric plexus and muscularis propria, quantitative and standardized immunohistochemical evaluation of ganglia and myenteric neurons, ex vivo assessment of neuromuscular transmission and its pharmacology, and closure rate (ancillary study). RESULTS: Adequate tissue specimens were obtained in 100% of the procedures, on average, in 6±2 minutes. Immunohistochemical analysis of a whole mount of the myenteric plexus showed that each eFTB contained 14±5 ganglia and 1562±1066 myenteric neurons. In circular muscle strips, electrical field stimulation or exposure to a pharmacological agent induced a specific tissue response. A successful closure was achieved in 50% of cases. LIMITATIONS: Nonsurvival study; safety of the procedure needs to be specifically assessed and compared with recently published data. CONCLUSIONS: We demonstrate, for the first time, that full-thickness biopsy specimens obtained by using an endoscopic approach allow the performance of a precise study of the ENS phenotype on whole mounts of the myenteric plexus and the performance of functional studies such as evaluation of neuromuscular transmission. However, further studies are warranted to identify the optimal and safest endoscopic procedure before application of eFTB in humans.

Factors associated with dental erosions in gastroesophageal reflux disease: a cross-sectional study in patients with heartburn.

BACKGROUND AND AIM: Dental erosion (DE) represents a frequent condition in adults and the elderly. The gastroesophageal reflux disease (GERD) is considered an important endogenous factor causing dental erosions. The objective of this study was to assess the prevalence of DE in GERD patients and to establish the correlation between pathogenic intrinsic and extrinsic factors of DE and their relation to GERD. METHODS: A cross-sectional study was conducted on 263 patients (median age 43). Patients with heartburn were recruited in two countries with different prevalence of GERD. Patients were recruited from France (n=158, 60%) and Romania (n=105, 40%) including 163 females and 100 males. The Basic Erosive Wear Examination (BEWE) index for diagnosis and evaluation of dental erosion was used. Based on the value of BEWE score, each patient was included in a risk group for DE development (low risk: BEWE=3-8, medium risk: BEWE=9-13, high risk: BEWE ≥14). Patients filled a questionnaire regarding GERD symptoms, medications, life style. Salivary parameters (pH and buffering capacity) were also assessed and analyzed. RESULTS: DE was significantly more frequent and more severe in GERD subjects than in the non-GERD controls. Low salivary pH but not salivary buffering capacity was associated with BEWE scores. Buffering capacity however was significantly more altered in patients with BEWE score over 9 (medium DE) than in patients with mild DE (BEWE <9). Although extrinsic factors (consumption of citrus fruits, soda drinks) were associated with DE in GERD, there was no statistical correlation with the BEWE score. From the total of 263 patients, 229 (87.1%) presented BEWE score <9, and 34 (12.9%) presented BEWE ≥9. The DE was significantly associated with the presence of GERD (p<0.001). BEWE score >9 was more frequently present in GERD patients (30 patients: 21.3%) than in non GERD patients (4 patients: 3.3%). DE were more frequent in French subjects compared to Romanian subjects. Romanians had lower BEWE scores than the French. CONCLUSIONS: DE is more frequent and more severe with GERD vs. non-GERD. DE in GERD is associated with extrinsic dietary factors like citrus fruits and soda drinks.

Rabeprazole test for the diagnosis of gastro-oesophageal reflux disease: results of a study in a primary care setting.

AIM: To determine the diagnostic value of the rabeprazole test in patients seen by general practitioners. METHODS: Eighty-three patients with symptoms suggestive of GERD were enrolled by general practitioners in this multi-centre, randomized and double-blind study. All patients received either rabeprazole (20 mg bid) or a placebo for one week. The diagnosis of GERD was established on the presence of mucosal breaks at endoscopy and/or an abnormal esophageal 24-h pH test. The test was considered to be positive if patients reported at least a "clear improvement" of symptoms on a 7-point Likert scale. RESULTS: The sensitivities of the test for rabeprazole and the placebo were 83% and 40%, respectively. The corresponding specificity, positive and negative predictive values were 45% and 67%, 71% and 71%, and 62% and 35%, respectively. A receiver operating characteristics (ROC) analysis confirmed that the best discriminatory cut-off corresponded to description of "clear improvement". CONCLUSION: The poor specificity of the proton-pump inhibitor (PPI) test does not support such an approach to establish a diagnosis of GERD in a primary care setting.

Treatment of GORD: Three decades of progress and disappointments.

The treatment of GORD has been revolutionized by the introduction, in the 1980s, of proton-pump inhibitors as the mainstay of medical therapy and by the development of laparoscopic antireflux surgery which has definitively replaced open surgery. However, despite these major advances, many unmet therapeutic needs still persist and justify novel therapeutic approaches. The aim of this historical review is to recall the main discoveries in the treatment of GORD that have occurred during the last three decades and to discuss why some initially promising drugs or techniques have not translated into clinical applications. A careful analysis of these previous disappointing experiences should help to identify high priorities and better research programmes on the management of GORD.

Probe-based confocal laser endomicroscopy: a new method for quantitative analysis of pit structure in healthy and Crohn's disease patients.

BACKGROUND: Probe-based confocal laser endomicroscopy enables microscopic examination of the digestive mucosa. AIMS: (1) To identify and validate quantitative endomicroscopic criteria for evaluation of the colonic mucosa and (2) to compare these criteria between healthy and Crohn's disease patients in clinical remission. METHODS: Six healthy controls and ten Crohn's disease patients in clinical remission were included in this prospective study. Methylene blue-stained biopsies of the right colon and corresponding endomicroscopic images were analyzed. Major axis, minor axis, and major axis/minor axis ratio of crypt lumens were quantified. RESULTS: Quantitative assessment was performed on 21 ± 4 crypt lumens per patient. Major axis/minor axis ratio values measured with endomicroscopy or methylene blue-stained biopsies were linearly correlated (r=0.63, p=0.01). All macroscopically inflamed mucosa had values of major axis/minor axis ratio higher than the median of controls. Interestingly, 50% (3/6) of Crohn's disease patients with macroscopically normal mucosa had also a higher ratio than pooled controls. Histological analysis showed that 6/7 patients with major axis/minor axis ratio superior to 1.7 had microscopic inflammation. CONCLUSION: Probe-based confocal laser endomicroscopy allows quantitative analysis of colonic pit structure. Endomicroscopic analysis of major axis/minor axis ratio allows the detection of microscopic residual inflammation with greater accuracy than standard endoscopy in Crohn's disease patients in clinical remission.

The digestive neuronal-glial-epithelial unit: a new actor in gut health and disease.

The monolayer of columnar epithelial cells lining the gastrointestinal tract--the intestinal epithelial barrier (IEB)--is the largest exchange surface between the body and the external environment. The permeability of the IEB has a central role in the regulation of fluid and nutrient intake as well as in the control of the passage of pathogens. The functions of the IEB are highly regulated by luminal as well as internal components, such as bacteria or immune cells, respectively. Evidence indicates that two cell types of the enteric nervous system (ENS), namely enteric neurons and enteric glial cells, are potent modulators of IEB functions, giving rise to the novel concept of a digestive 'neuronal-glial-epithelial unit' akin to the neuronal-glial-endothelial unit in the brain. In this Review, we summarize findings demonstrating that the ENS is a key regulator of IEB function and is actively involved in pathologies associated with altered barrier function.

Pharyngeal pH alone is not reliable for the detection of pharyngeal reflux events: A study with oesophageal and pharyngeal pH-impedance monitoring.

BACKGROUND: Pharyngeal pH probes and pH-impedance catheters have been developed for the diagnosis of laryngo-pharyngeal reflux. OBJECTIVE: To determine the reliability of pharyngeal pH alone for the detection of pharyngeal reflux events. METHODS: 24-h pH-impedance recordings performed in 45 healthy subjects with a bifurcated probe for detection of pharyngeal and oesophageal reflux events were reviewed. Pharyngeal pH drops to below 4 and 5 were analysed for the simultaneous occurrence of pharyngeal reflux, gastro-oesophageal reflux, and swallows, according to impedance patterns. RESULTS: Only 7.0% of pharyngeal pH drops to below 5 identified with impedance corresponded to pharyngeal reflux, while 92.6% were related to swallows and 10.2 and 13.3% were associated with proximal and distal gastro-oesophageal reflux events, respectively. Of pharyngeal pH drops to below 4, 13.2% were related to pharyngeal reflux, 87.5% were related to swallows, and 18.1 and 21.5% were associated with proximal and distal gastro-oesophageal reflux events, respectively. CONCLUSIONS: This study demonstrates that pharyngeal pH alone is not reliable for the detection of pharyngeal reflux and that adding distal oesophageal pH analysis is not helpful. The only reliable analysis should take into account impedance patterns demonstrating the presence of pharyngeal reflux event preceded by a distal and proximal reflux event within the oesophagus.

Clinical impact of fluorodeoxyglucose-positron emission tomography scan/computed tomography in comparison with computed tomography on the detection of colorectal cancer recurrence.

BACKGROUND AND AIMS: Early detection is an essential prognostic factor in colorectal cancer (CRC) recurrence. Our aim was to evaluate diagnostic performances of (18)F-fluorodeoxyglucose-positron emission tomography ((18)F-FDG-PET)/computed tomography (CT) as compared with CT in the detection of CRC recurrence. METHODS: Data of patients with suspected CRC recurrence and in whom both FDG-PET/CT and CT were performed were analyzed. All detected lesions were characterized according to their number, size, and localization. Positive histological or radiological follow-up was considered as the 'gold standard'. Diagnostic performances of FDG-PET/CT and CT were calculated by lesion, globally and with respect to the site of recurrence. RESULTS: One hundred and seventy-six true-positive lesions were identified in 71 patients. CT scan was positive in 58 (82%) patients and FDG-PET/CT in 70 (98%) patients. In per lesion analysis, the global accuracy of FDG-PET/CT in detection of lesions was of 88% (sensitivity = 95%, specificity = 54%), which was higher than that of CT (53%, sensitivity = 55%, specificity = 43%), particularly in case of lymph nodes metastases (100 vs. 35%) and locoregional lesions (100 vs. 39%) (P<0.0001). FDG-PET/CT modified the clinical management in 31 patients. CONCLUSIONS: FDG-PET/CT is more sensitive than CT for diagnosis of CRC recurrence and can modify the management in 40% of patients.

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) > or =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.

Colonic fermentation influences lower esophageal sphincter function in gastroesophageal reflux disease.

BACKGROUND & AIMS: Colonic fermentation of carbohydrates is known to influence gastric and esophageal motility in healthy subjects. This study investigated the effects of colonic fermentation induced by oral administration of fructooligosaccharides (FOS) in patients with gastroesophageal reflux disease (GERD). METHODS: In the cross-over design used in the study, 9 patients with symptomatic GERD were administered a low-residue diet (i.e., 10 g fiber/day) during 2, 7-day periods, receiving either 6.6 g of FOS or placebo 3 times daily after meals. Each period was separated by a wash out of at least 3 weeks. On day 7, esophageal motility and pH were recorded in fasting conditions and after a test meal containing 6.6 g of FOS or placebo. Breath hydrogen concentrations (reflecting colonic fermentation) and plasma concentrations of glucagon-like peptide 1 (GLP-1), peptide YY, and cholecystokinin were monitored. RESULTS: Compared with placebo, FOS led to a significant increase in the number of transient lower esophageal sphincter relaxations (TLESRs) and reflux episodes, esophageal acid exposure, and the symptom score for GERD. The integrated plasma response of GLP-1 was significantly higher after FOS than placebo. CONCLUSIONS: Colonic fermentation of indigestible carbohydrates increases the rate of TLESRs, the number of acid reflux episodes, and the symptoms of GERD. Although different mechanisms are likely to be involved, excess release of GLP-1 may account, at least in part, for these effects.