Proton pump inhibitor and selective serotonin reuptake inhibitor therapy for the management of noncardiac chest pain.

INTRODUCTION: Although gastroesophageal reflux disease is the main cause of noncardiac chest pain (NCCP), proton pump inhibitors (PPIs) benefit a minority of patients. Our prospective study evaluated the effect of PPI and selective serotonin reuptake inhibitors on the different subtypes of NCCP characterized by impedance-pH monitoring. METHODS: All NCCP patients underwent impedance-pH monitoring and on the basis of the results, those with abnormal distal esophageal acid exposure received PPIs twice daily (group A), those with a positive symptom index for chest pain received citalopram 20 mg and PPI once daily (group B), and those with a negative symptom index for chest pain received citalopram 20 mg once daily (group C). Therapy was administered for 12 weeks and treatment success was defined as complete disappearance of chest pain. RESULTS: From March 2015 to March 2016, 63 patients were included (group A=9, group B=18, group C=36). After 12 weeks of therapy, complete resolution of chest pain was noted in 8/9 (88.9%) group A, 13/18 (72.2%) group B, and 24/36 (66.7%) group C patients. CONCLUSION: Combined impedance-pH monitoring identifies different subtypes of NCCP patients who can receive tailored management. Targeted therapy with PPIs and/or citalopram offers complete symptom relief in the great majority of them.

Proteomics and irritable bowel syndrome.

INTRODUCTION: Irritable bowel syndrome (IBS) is a gastrointestinal disease that according to Rome IV criteria is subdivided into four subtypes. The pathophysiology of this disease is not well understood due to numerous factors playing multiple roles in disease development, such as diet, stress and hormones. IBS has a variety of symptoms and overlaps with many other gastrointestinal and non-gastrointestinal diseases. Area covered: This review aims to present an overview of implementation of proteomics in experimental studies in the field of IBS. Expert commentary: Proteomics is commonly used for biomarker discovery in and has also been extensively used in IBS research. The necessity of a sensitive and specific biomarker for IBS is apparent, but despite the intensive research performed in this field, an appropriate biomarker is not yet available.

Comparative Study of Mutations in Single Nucleotide Polymorphism Loci of KRAS and BRAF Genes in Patients Who Underwent Screening Colonoscopy, With and Without Premalignant Intestinal Polyps.

AIM: Our aim was to perform a comparison study of the mutation rate of V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), and v-Raf murine sarcoma viral oncogene homolog-B (BRAF) genes between blood-based cell-free DNA (cfDNA), and tissue sample biopsies in individuals undergoing screening colonoscopy. MATERIALS AND METHODS: All specimens were collected from January 2015 to January 2016. A total of 92 blood samples and colonic biopsy specimens were collected from healthy individuals with no polyps undergoing screening colonoscopy (group A, n=35), patients with colorectal cancer (group B, n=27), and patients with neoplastic intestinal polyps (group C, n=30). Peripheral blood was collected from each patient and a focal tissue biopsy was conducted. RESULTS: We only found a limited statistically significant difference (p=0.046) in the mutation analysis for codon 12 of the KRAS gene when we compared tissue biopsies from patients in group B to those from group C. In the blood samples, only the rate of mutation in codon 12 of the KRAS gene in samples of group B was significantly higher than that in group A (p=0.013). CONCLUSION: Blood cfDNA may be a promising tool in CRC screening as it may discriminate patients with CRC compared to healthy individuals and those with colonic polyps, even though it does not appear useful in predicting the presence of colonic polyps.

Predictors of tissue healing in ulcerative colitis patients treated with anti-TNF.

AIM: To identify factors predicting mucosal healing in ulcerative colitis patients treated with anti-TNFα agents with or without azathioprine. METHODS: In a prospective, multicenter, one-year study biologic naïve patients aged 25-65 years, with corticosteroid-dependent or refractory colitis received combination treatment with anti-TNFα and azathioprine for 6 months followed by anti-TNFα monotherapy. Patients who denied combination therapy or were outside this age range received anti-TNFα monotherapy (controls). Before and at weeks 12 and 54 of treatment the total Mayo score was calculated. Mucosal healing was defined as endoscopic subscore of 0. Mucosal expression of T helper (Th) cell-lineage specific transcription factors (Tbet, Gata3, Rorc, FoxP3) before treatment was also associated with mucosal healing. RESULTS: Of 67 patients, 58 (86.6%) received combination and 9 (13.4%) anti-TNFα monotherapy. Overall 29 (43.3%) patients achieved mucosal healing; rates were higher in patients receiving combination therapy vs. monotherapy (p=0.03) and in azathioprine naïve vs. exposed patients in the combination group (p=0.01). Mucosal healing was associated with lower pre-treatment mucosal expression of transcription factor Th1-Tbet (p<0.05) and higher expression of Th17-Rorc (p<0.05). CONCLUSIONS: Mucosal healing was associated with combination therapy, especially in biologic and azathioprine-naïve patients and pre-treatment mucosal expression of specific Th specific transcripting factors (Tbet and Rorc).

Impact of ß-glucan on the Fecal Water Genotoxicity of Polypectomized Patients.

The aim of the study was to determine the effect of ß-glucan on the cytotoxicity and genotoxicity of polypectomized patient's fecal water (FW). Polypectomized volunteers (n = 69) were randomly assigned to consume bread with or without ß-glucan, for 3 months. FW was collected at the beginning (t = 0), the 30th and 90th day and 2 wk after the intervention. Cytotoxicity and genotoxicity were estimated on Caco-2 cells, using trypan blue exclusion test and comet assay, respectively. Gastrointestinal symptoms were recorded and subjects kept a 3-day food diary at baseline and after completion. Trypan blue exclusion test revealed cell survival of approximately 87% after incubation with FW. The FW samples showed 49% genotoxicity at the baseline. Genotoxicity in the intervention group decreased during the trial reaching statistical significance on the 90th day compared to control. An increase was noticed 2 wk after the trial, but it still remained significantly lower compared to control. Group-specific analysis for ß-glucan also revealed significant decrease in the genotoxicity on the 90th day compared to baseline. ß-glucan ingestion in polypectomized patients significantly decreased the genotoxicity of their FW. Our findings suggest that ß-glucan consumption could possibly provide protection against colon cancer development.

Effective colonoscopy training techniques: strategies to improve patient outcomes.

Colonoscopy has substantially evolved during the last 20 years and many different training techniques have been developed in order to improve the performance of endoscopists. The most known are mechanical simulators, virtual reality simulators, computer-simulating endoscopy, magnetic endoscopic imaging, and composite and explanted animal organ simulators. Current literature generally indicates that the use of simulators improves performance of endoscopists and enhances safety of patients, especially during the initial phase of training. Moreover, newer endoscopes and imaging techniques such as high-definition colonoscopes, chromocolonoscopy with dyes spraying, and third-eye retroscope have been incorporated in everyday practice, offering better visualization of the colon and detection of polyps. Despite the abundance of these different technological features, training devices are not widely used and no official guideline or specified training algorithm or technique for lower gastrointestinal endoscopy has been evolved. In this review, we present the most important training methods currently available and evaluate these using existing literature. We also try to propose a training algorithm for novice endoscopists.

Prevalence and Characteristics of Extra-intestinal Manifestations in a Large Cohort of Greek Patients with Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Extraintestinal manifestations [EIMs] are common in inflammatory bowel disease [IBD]. Data on epidemiology and risk factors of EIMs in IBD patients are limited. The aim of this study was to investigate the prevalence of EIMs in a large cohort of Greek IBD patients and identify risk factors for their development. METHODS: The study population consisted of IBD patients, who were followed in eight tertiary Greek hospitals. Demographic and clinical characteristics of patients were analysed. The diagnosis of EIMs was based on standard criteria and on specialist consultation. RESULTS: In total, 1860 IBD patients (1001 with Crohn's disease [CD], 859 with ulcerative colitis [UC]) were registered. Among them 615 [33.1%] exhibited at least one EIM; 238 patients [38.6%] developed an EIM before IBD diagnosis. An association between active IBD and presence of an EIM was established in 61.1% of the patients. Arthritic [peripheral arthritis], mucocutaneous [erythema nodosum], and ocular [episcleritis] were the most common manifestations. EIMs were more prevalent in females, patients with CD, smokers [for all p <0.0001], patients with extensive UC [p = 0.007], and patients with a previous appendectomy [p < 0.0001] or a major IBD-related surgery [p = 0.012]. CONCLUSIONS: About one-third of Greek IBD patients developed at least one EIM. Of those, more than one-third had their EIM diagnosed before IBD, and in about two-thirds it was related to disease activity. EIMs were more frequently present in females and patients with extensive UC in multivariate analysis.

Azathioprine discontinuation earlier than 6 months in Crohn's disease patients started on anti-TNF therapy is associated with loss of response and the need for anti-TNF dose escalation.

OBJECTIVES: A high proportion of Crohn's disease (CD) patients lose response to antitumor necrosis factor (anti-TNF) and therapy needs to be intensified. We aimed to prospectively determine the predictors and frequency of anti-TNF loss of response and therefore the need for dose escalation and de-escalation in CD patients treated with infliximab or adalimumab. METHODS: All patients were anti-TNF naive while concomitant azathioprine was administered for 6 months. In patients initially responding to anti-TNF and subsequently losing clinical response after the first 14 weeks of therapy, dose escalation was scheduled. During the follow-up period and after 1 year of intensified administration, anti-TNF was de-escalated in patients in remission. RESULTS: A total of 161 patients were started on infliximab (n=96) or adalimumab (n=65); however, 29 patients (18.0%) did not respond to therapy and were excluded from further analysis. From the remaining 132 patients (infliximab=77, adalimumab=55), 31 (23.5%) needed a dose escalation for maintenance of remission during a median 28-month follow-up period. Factors associated with loss of response and therefore the need for anti-TNF dose escalation were azathioprine discontinuation earlier than 6 months and smoking. Most patients achieved clinical remission (n=25, 80.6%) without other interventions and among these, 16 patients (64%) were successfully de-escalated to the standard maintenance infliximab or adalimumab dose schedule after 1 year of intensified anti-TNF administration. CONCLUSION: Azathioprine discontinuation earlier than 6 months and smoking in CD patients started on anti-TNF therapy is associated with loss of response and the need for anti-TNF dose escalation.

Cold snare polypectomy with pull technique of flat colonic polyps up to 12 mm: a porcine model.

BACKGROUND: Most colonoscopic complications are polypectomy-related and occur more frequently during the removal of numerous small polyps. Therefore, it is important to have the best polypectomy approach of small polyps. The aim of the present animal study was to investigate the effectiveness and safety of cold snare polypectomy (CSP) technique combined with light pull of the snare in order to peel the mucosal and upper submucosal layer, namely pull CSP (PCSP), for the removal of polyps sized up to 12 mm in porcine models. METHODS: We performed a series of polypectomies in the pig colon with a double-channel experimental gastroscope using PCSP technique. RESULTS: Thirty cases of "polyps" larger than 7 mm and up to 12 mm were treated using PCSP technique. No sign of perforation or bleeding was observed in all cases performed with PCSP. CONCLUSIONS: According to our preliminary results in this animal model, PCSP could be a safe and effective technique for flat colonic polyp removal up to 12 mm in size consistent with the basic polypectomy principles.

Intestinal neuronal dysplasia type B in adults: a controversial entity.

Intestinal neuronal dysplasia (IND) is a well-defined entity which raises controversy among authors, described as a congenital malformation of gastrointestinal innervation and caused by dysplastic embryonal development of the enteric nervous system. It is potentially associated with mild and chronic gastrointestinal motility disturbances. IND is rarely reported in adults and especially elderly patients. The present study reports on the case of a 71-year-old man suffering from longstanding idiopathic constipation and who was misdiagnosed for more than 60 years, despite several hospital admissions and a sigmoidectomy in the meantime. On the last admission, the patient presented with megacolon, abdominal pain and X-ray finding of bowel obstruction. Due to massive large bowel dilatation, an exploratory laparotomy failed to reveal any obvious mechanical cause, and a subtotal colectomy and Hartmann's procedure was performed. Bowel continuity was performed 3 months later. Analysis of full-thickness biopsies revealed enlarged myenteric and submucosal neurons as well as an increased number of giant cells and increased acetylcholinesterase activity in the mucosa. The diagnosis of IND was established. The main diagnostic criteria, the underlining pathophysiology and the recommended therapeutic approach of this rare entity are extensively reviewed.

Refractory GERD: increased body mass index is associated with persisting acid exposure but not hypersensitive esophagus or functional heartburn.

OBJECTIVE: To compare the incidence of persistent abnormal acid exposure, hypersensitive esophagus (HE), and functional heartburn (FH) in obese/overweight and normal-weight patients referred for impedance-pH monitoring, because of persisting gastroesophageal reflux disease (GERD) symptoms despite therapy with proton pump inhibitors (PPIs). ΜETHODS: Patients with normal endoscopy and typical GERD symptoms, despite PPI therapy twice daily, underwent 24-h impedance-pH monitoring while on therapy. Distal esophageal acid exposure (% time pH<4) was measured and reflux episodes were classified into acid or nonacid. A positive symptom index was defined when at least 50% of symptom events were preceded by reflux episodes. Patients were categorized as those with persistent abnormal acid exposure, those with HE, and those with FH. The incidence of persistent abnormal acid exposure, HE, and FH between overweight/obese patients (BMI≥25 kg/m) and normal-weight patients (BMI<25 kg/m) was subsequently evaluated. RESULTS: A total of 246 patients (women: 158, men: 88, increased BMI: 151, normal BMI: 95, mean age 55, range 18-75 years) were included. Persistent abnormal acid exposure was found in 39 patients (increased BMI: 31, normal BMI: 8), HE in 77 patients (increased BMI: 43, normal BMI: 34), and FH in 118 patients (increased BMI: 69, normal BMI: 49). When comparing BMI among all three groups, patients with increased BMI were more likely to have acid reflux than HE or FH (P=0.03). CONCLUSION: In patients with GERD symptoms refractory to double-dose PPI therapy, those with increased BMI are more likely to have persistent abnormal acid exposure than HE or FH.

Long term benefit of one year infliximab administration for the treatment of chronic refractory pouchitis.

BACKGROUND-AIM: The aim of this study is to identify the long term benefit of one year infliximab administration for the treatment of chronic refractory pouchitis following ileo-pouch anal anastomosis (IPAA) for ulcerative colitis (UC). METHODS: Seven patients with chronic refractory pouchitis diagnosed by clinical, endoscopic and histological criteria received infliximab 5 mg/kg at 0, 2, and 6 weeks and thereafter every 2 months for 1 year. Three patients had fistulae (1 pouch-bladder, 2 perianal) and 4 extraintestinal manifestations (2 erythema nodosum, 2 arthralgiae). All patients were refractory to antibiotics and 3 to azathioprine. Crohn's disease was excluded after re-evaluation of the history and small bowel examination with enteroclysis or capsule endoscopy. Clinical response was classified as complete, partial and no response. Fistulae closure was classified as complete, partial and no closure. The pouchitis disease activity index (PDAI) was used as an outcome measure. All patients were followed up for 3 years after discontinuation of infliximab therapy. RESULTS: After 1 year of infliximab administration 5 patients had complete clinical response, 1 partial clinical response and 1 no response, while 2 out of the 3 patients with fistulae had a complete closure. The median PDAI dropped from 11 (baseline) (range, 10-14) to 5 (range, 3-8). Extraintestinal manifestations were in complete remission too. Three years after completion of therapy, all patients with complete clinical response at one year remained in remission. CONCLUSIONS: One year infliximab administration is associated with a long term benefit in patients with chronic refractory pouchitis following IPAA for UC.

Long-term administration of rifaximin improves the prognosis of patients with decompensated alcoholic cirrhosis.

BACKGROUND AND AIM: Cirrhotic patients are predisposed to intestinal bacterial overgrowth with translocation of bacterial products which may deteriorate liver hemodynamics. Having shown that short-term administration of rifaximin improves liver hemodynamics in decompensated cirrhosis, we conducted this study to investigate the effect of intestinal decontamination with rifaximin on the long-term prognosis of patients with alcohol-related decompensated cirrhosis (Child-Pugh > 7) and ascites. METHODS: Patients who had received rifaximin and showed improved liver hemodynamics were enrolled in the current study and continued to receive rifaximin (1200 mg/day). Each patient was matched by age, sex, and Child-Pugh grade to two controls and followed up for up to 5 years, death or liver transplantation. Survival and risk of developing portal hypertension-related complications were compared between rifaximin group and controls. RESULTS: Twenty three patients fulfilled the inclusion criteria and matched with 46 controls. Patients who received rifaximin had a significant lower risk of developing variceal bleeding (35% vs. 59.5%, P = 0.011), hepatic encephalopathy (31.5% vs. 47%, P = 0.034), spontaneous bacterial peritonitis (4.5% vs. 46%, P = 0.027), and hepatorenal syndrome (4.5% vs. 51%, P = 0.037) than controls. Five-year cumulative probability of survival was significantly higher in patients receiving rifaximin than in controls (61% vs. 13.5%, P = 0.012). In the multivariate analysis, rifaximin administration was independently associated with lower risk of developing variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis, hepatorenal syndrome, and higher survival. CONCLUSIONS: In patients with alcohol-related decompensated cirrhosis, long-term rifaximin administration is associated with reduced risk of developing complications of portal hypertension and improved survival.

Inflammatory bowel disease: Greek patients' perspective on quality of life, information on the disease, work productivity and family support.

BACKGROUND: The aim of this study was to identify inflammatory bowel disease (IBD) patients' perspectives regarding everyday life issues. METHODS: From October 2010 till April 2011, 1,181 IBD patients completed an anonymous questionnaire through the internet (827 cases) or at the outpatient clinic of the participating centers (354 cases), aiming to identify: a) the impact of disease on social life, emotional status and work productivity; b) the source of disease information; and c) the level of support from family members and friends. RESULTS: Fifty-five percent of the patients reported that IBD interferes with their social life, while 65% felt stressed, 60% depressed and 19% tired because of it. Disease information (physician/ internet) was reported only by 31%, while 26% admitted not discussing their therapy with their gastroenterologist. Forty percent felt that the health service they receive is not satisfactory, with 76% desiring more gastroenterologists, 67% more outpatient clinics, 49% more dieticians and 42% more psychologists specialized in IBD. IBD interfered with working capacity in 40% of the participants, while 57% needed time off of work (ranging from 1-20 days per year). One of three patients (32%) has not informed his work environment about the disease; however, 88% had the support of their family and friends for coping with it. CONCLUSIONS: Greek IBD patients claim that health-related social life, emotional status and work productivity are severely affected by their disease, whereas they complain about lack of information regarding the therapy. These unmet demands call for immediate action by healthcare providers and society.

Selective serotonin reuptake inhibitors for the treatment of hypersensitive esophagus: a randomized, double-blind, placebo-controlled study.

OBJECTIVES: Ambulatory 24-h pH-impedance monitoring can be used to assess the relationship of persistent symptoms and reflux episodes, despite proton pump inhibitor (PPI) therapy. Using this technique, we aimed to identify patients with hypersensitive esophagus and evaluate the effect of selective serotonin reuptake inhibitors (SSRIs) on their symptoms. METHODS: Patients with normal endoscopy and typical reflux symptoms (heartburn, chest pain, and regurgitation), despite PPI therapy twice daily, underwent 24-h pH-impedance monitoring. Distal esophageal acid exposure (% time pH <4) was measured and reflux episodes were classified into acid or non-acid. A positive symptom index (SI) was declared if at least half of the symptom events were preceded by reflux episodes. Patients with a normal distal esophageal acid exposure time, but with a positive SI were classified as having hypersensitive esophagus and were randomized to receive citalopram 20 mg or placebo once daily for 6 months. RESULTS: A total of 252 patients (150 females (59.5%); mean age 55 (range 18-75) years) underwent 24-h pH-impedance monitoring. Two hundred and nineteen patients (86.9%) recorded symptoms during the study day, while 105 (47.9%) of those had a positive SI (22 (20.95%) with acid, 5 (4.76%) with both acid and non-acid, and 78 (74.29%) with non-acid reflux). Among those 105 patients, 75 (71.4%) had normal distal esophageal acid exposure time and were randomized to receive citalopram 20 mg (group A, n=39) or placebo (group B, n=36). At the end of the follow-up period, 15 out of the 39 patients of group A (38.5%) and 24 out of the 36 patients of group B (66.7%) continue to report reflux symptoms (P=0.021). CONCLUSIONS: Treatment with SSRIs is effective in a select group of patients with hypersensitive esophagus.

Selective-serotonin reuptake inhibitors for the treatment of hypersensitive esophagus.

In patients with proton-pump inhibitor (PPI) resistant reflux symptoms, ambulatory 24 h pH impedance monitoring can be used to assess whether a relationship exists between symptoms and reflux episodes. Using this technique it has been suggested that patients with typical reflux symptoms and a normal upper endoscopy should be subclassified as follows: normal endoscopy and abnormal distal acid esophageal exposure (patients with acid reflux); normal endoscopy, with normal distal acid esophageal exposure and a positive symptom association for either acid or nonacid reflux (patients with hypersensitive esophagus); and normal endoscopy, normal distal acid esophageal exposure and a negative symptom association for acid and nonacid reflux (patients with functional heartburn). Although for patients with a normal endoscopy and abnormal distal acid esophageal exposure more aggressive acid suppression can be recommended, managing patients with hypersensitive esophagus and functional heartburn remains a real challenge.Therefore, investigators have evaluated the role of tricyclic antidepressants or selective-serotonin reuptake inhibitors (SSRIs) in influencing esophageal perception. Imipramine has been shown to decrease pain perception in healthy male volunteers and improve symptoms of patients with chest pain and normal coronary angiograms. Trazodone improved symptoms in patients with esophageal contraction abnormalities, while administration of SSRIs lowered chemical and mechanical sensitivity and benefited patients with diffuse esophageal spasm. Furthermore, in a recent study conducted by our group, citalopram administered once daily for 6 months was effective in a select group of patients with hypersensitive esophagus, suggesting that there is a role for SSRIs in the treatment of this disorder.

Bleeding lesions within reach of conventional endoscopy in capsule endoscopy examinations for obscure gastrointestinal bleeding: is repeating endoscopy economically feasible?

BACKGROUND: Most tertiary gastroenterology centers currently offer an open-access capsule endoscopy (CE) service, including patients with obscure gastrointestinal bleeding. However, CE may identify lesions missed by conventional endoscopy. AIMS: To determine the incidence of bleeding lesions missed by the preceding gastroscopy/colonoscopy that were revealed by CE and compare potential differences in the rate of identifying such lesions in patients that we investigated as opposed to those investigated elsewhere. METHODS: We prospectively reviewed data from patients subjected to CE for obscure bleeding. We analyzed all cases where a source of bleeding was located in the stomach, duodenum, or colon. RESULTS: A total of 317 consecutive patients were subjected to CE for obscure gastrointestinal bleeding within 28 months. Prior to CE examination, 174 patients had gastroscopy and colonoscopy in our institutions and 143 were referrals, all with negative endoscopic investigation. We identified 11 (3.5%) cases where the source of bleeding was found in the stomach (n = 4) or the cecum (n = 7). There was a significant difference of extra small intestinal lesions diagnosed by CE between referrals (9/143, 6.3%) and endoscopic investigation performed in our institutions (2/174, 1.15%), (p = 0.026). The estimated cost of re-endoscoping in our institution all CE referrals would be 50,050 euro (143 patients × 350 euro), to avoid unnecessary CE examinations (9 patients × 600 euro = 5,400 euro). CONCLUSIONS: Reading the whole CE video is important, because small-bowel CE may identify lesions responsible for obscure bleeding missed by the preceding gastroscopy and colonoscopy. Repeating conventional endoscopy by experts before CE is not a cost-effective approach.