Expanded allogeneic adipose-derived stem cells (eASCs) for the treatment of complex perianal fistula in Crohn's disease: results from a multicenter phase I/IIa clinical trial.

PURPOSE: The management of perianal fistula in patients with Crohn's disease is an extremely challenging medical problem as many fistulas do not respond to available treatments. The objectives were to assess the safety and efficacy of a suspension of expanded adipose-derived allogeneic mesenchymal stem cells (eASCs) for the treatment of complex perianal fistula in Crohn's disease METHODS: An open-label, single-arm clinical trial was conducted at six Spanish hospitals. Twenty-four patients were administered intralesionally with 20 million eASCs in one draining fistula tract. A subsequent administration of 40 million eASCs was performed if fistula closure was incomplete at week 12. Subjects were followed until week 24 after the initial administration. RESULTS: Treatment-related adverse events did not indicate any clinical safety concerns after 6 months follow-up. The full analysis of efficacy data at week 24 showed 69.2 % of the patients with a reduction in the number of draining fistulas, 56.3 % of the patients achieved complete closure of the treated fistula achieved, and 30 % of the cases presenting complete closure of all existing fistula tracts. Of note, closure was strictly defined as: absence of suppuration through the external orifice and complete re-epithelization, plus absence of collections measured by magnetic resonance image scan (MRI). Furthermore, MRI Score of Severity showed statistically significant differences at week 12 with a marked reduction at week 24. CONCLUSIONS: Locally injected eASCs appear to be a simple, safe, and beneficial therapy for perianal fistula in Crohn's disease patients. Additional studies are needed to further confirm the efficacy of the eASCs.

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.

Normal values in ambulatory oesophageal pH monitoring at two levels in Spain.

AIM: Upper oesophageal pH monitoring may play a significant role in the study of extra-oesophageal GERD, but limited normal data are available to date. Our aim was to develop a large series of normal values of proximal oesophageal acidification. METHODS: 155 healthy volunteers (74 male) participated in a multi-centre national study including oesophageal manometry and 24 hours oesophageal pH monitoring using two electrodes individually located 5 cm above the LOS and 3 cm below the UOS. RESULTS: 130 participants with normal manometry completed all the study. Twelve of them were excluded for inadequate pH tests. Twenty-seven subjects had abnormal conventional pH. The remaining 91 subjects (37 M; 18-72 yrs age range) formed the reference group for normality. At the level of the upper oesophagus, the 95th percentile of the total number of reflux events was 30, after eliminating the meal periods 22, and after eliminating also the pseudo-reflux events 18. Duration of the longest episodes was 5, 4 and 4 min, respectively (3.5 min in upright and 0.5 min in supine). The upper limit for the percentage of acid exposure time was 1.35, 1.05 and 0.95%, respectively. No reflux events were recorded in the upper oesophagus in 8 cases. CONCLUSION: This is the largest series of normal values of proximal oesophageal reflux that confirm the existence of acid reflux at that level in healthy subjects, in small quantity and unrelated to age or gender. Our data support the convenience of excluding pseudo-reflux events and meal periods from analysis.

Recurrence of Helicobacter pylori infection after several eradication therapies: long-term follow-up of 1000 patients.

AIM: To study the incidence of Helicobacter pylori recurrence, its chronological aspects, and the variables that might influence it. METHODS: A total of 1000 patients in whom H. pylori had been eradicated were prospectively studied. Therapies were classified as low and high efficacy regimens. Four to eight weeks after completion of therapy, 13C-urea-breath-test was performed, and it was repeated yearly up to 5 years. In some patients, endoscopy with biopsies was also performed to confirm H. pylori eradication. RESULTS: A total of 1000 patients were included, giving 2744 patient-years of follow-up. Seventy-one H. pylori recurrences were observed (2.6% per patient-year). Probability of being H. pylori-negative at 1 year was 94.7%, and at 5 years 90.7%. In the multivariate analysis, low age (OR: 1.84; 95% CI: 1.04-3.26) and low efficacy therapies (OR: 2.5; 1.23-5.04) correlated with 1-year H. pylori recurrence. Differences were observed when Kaplan-Meier curves were compared depending on age and therapy regimen. CONCLUSION: Risk of posteradication H. pylori recurrence is higher during the first year, which suggests that most recurrences during this period are recrudescence and not true reinfections. H. pylori recurrence is more frequent in younger patients and in those treated with low efficacy therapies, but is exceptional if high efficacy therapies are used, in which case post-therapy eradication can be safely confirmed at 4 weeks with 13C-urea-breath-test.

Modification of pepsinogen I levels and their correlation with gastrointestinal injury after administration of dexibuprofen, ibuprofen or diclofenac: a randomized, open-label, controlled clinical trial.

OBJECTIVE: To assess the effect of a 2-week treatment with dexibuprofen, in comparison with ibuprofen and diclofenac, on pepsinogen plasma concentrations and gastrointestinal mucosa, as well as the correlation of these changes with gastrointestinal mucosal injury. METHODS: 60 patients with rheumatologic disease in chronic therapy with NSAID, were included. After a 7-day run-in period patients were randomly assigned to receive a 14-day treatment with dexibuprofen (Group A; Day 1 - 3 = 400 mg t.i.d; Day 4 - 14 = 400 mg b.i.d.), ibuprofen (Group B; Day 1 - 3 = 800 mg t.i.d; Day 4 -14 = 800 mg b.i.d.) or diclofenac (Group C; Day 1 - 3 = 50 mg t.i.d; Day 4 - 14 = 50 mg b.i.d.). Upper gastrointestinal endoscopy (Day 15), capsule-endoscopy (Day 16, 7 patients of each group) and determination of pepsinogen plasma concentrations were performed (basal and Day 15). A semiquantitative scale was designed for the assessment of the gastrointestinal mucosa. RESULTS: No differences in plasma pepsinogen were found between treatment groups or gastrointestinal injury grades or between basal and post-therapy determinations. Dexibuprofen showed gastroduodenal mucosal injury in fewer patients (42.1%) than was the case with ibuprofen (5%; p = 0.003) and diclofenac (30%; p = N.S.). Dexibuprofen administration was also associated with more patients having no intestinal mucosal damage (42.86% vs. 28.7% in the diclofenac group and 14.29% in the ibuprofen group; p = 0.0175). The rate of clinical adverse events was similar in Groups A, B and C (28%, 38% and 34%). CONCLUSIONS: Dexibuprofen showed a lower rate of gastroduodenal and intestinal mucosal injury. This effect was not mediated by modifications of plasma pepsinogen levels.

Antiinflamatory agents less dangerous for gastrointestinal tract.

NSAIDs represent one of the most commonly used therapeutic drug groups world wide. 1.5% of the world's population is estimated as taking NSAIDs. However, their use is not risk free and gastrointestinal (GI) lesions do appear, which is indeed the main reason for their toxicity. Frequently (50%) NSAID-induced GI lesions are asymptomatic, and perforations or hemorrhages could occur without any previous symptoms. 71% of GI perforations and 50% of upper gastric hemorrhages (UGH) are associated with taking NSAIDs. How frequent GI lesions appear is directly related to whether the patient is in a risk group or not. Factors increasing the risk of GI lesions occurring are the following: being older than 60, using corticoids or other NSAIDs concomitantly, having a history of duodenal ulcer, alcohol consumption, smoking or taking oral anticoagulants. As the toxicity and how frequent the lesions appear depend on which drug is used, there is a need for research into new drugs which are both clinically effective and safer to use. GI toxicity of NSAIDs is mediated by two mechanisms, direct toxicity and prostaglandin synthesis inhibition or sistemic mechanism. Due to the relatively recent discoveries concerning the physiopathology of inflammation and gastric physiology, research into new NSAID derivatives is taking place. Such derivatives are prodrugs, galenic buffer forms, selective COX-2 inhibitors, isomeric compounds, NO-donors, and as a future possibility, phosphodiesterase inhibitors.

Mediterranean diet and health: biological importance of olive oil.

Olive oil, the main fatty component of the Mediterranean diet, is characterized by consisting of monounsaturated fatty acids as well as by its elevated content in antioxidant agents. This oil exhibits numerous biological functions which are beneficial for the state of health. A diet rich in monounsaturated fatty acids provides an adequate fluidity to the biological membranes, diminishing the hazard of lipid peroxidation which affects polyunsaturated fatty acids. Moreover, the antioxidants present in olive oil are able to scavenge free radicals and afford an adequate protection against peroxidation. Regarding the heart, olive oil decreases the plasmatic levels of LDL-cholesterol and increases those of HDL-cholesterol, hence diminishing the risk of suffering from heart complaints. In this context, it has been suggested that increased consumption of monounsaturated fatty acids in place of polyunsaturated fatty acids will render circulating lipoproteins less sensitive to peroxidation and thereby diminish the development of atherosclerosis. Olive oil has also been proven to contribute to a better control of the hypertriglyceridemia accompanying diabetes and may reduce the risk of breast cancer and colorectum. On the other hand, several investigations have suggested that olive oil can be beneficial in inflammatory and autoimmune diseases, such as rheumatoid arthritis. In this sense, some reports have indicated that olive oil modifies inflammatory cytokines production. As for the digestive system, olive oil enhances gallbladder emptying consequently reducing cholelithiasis risk, decreases the pancreatic exocrine secretion and gastric secretory function in response to food. Finally, it has been demonstrated that a diet rich in olive oil is associated with a high percentage of gastric ulcer healing and affords a higher resistance against non steroidal antiinflammatory drugs-induced gastric ulcerogenesis.

Role of L-arginine in ibuprofen-induced oxidative stress and neutrophil infiltration in gastric mucosa.

It has been proposed that neutrophil and oxygen dependent microvascular injuries may be important prime events in gastrointestinal (GI) toxicity of non-steroidal antiinflammatory drugs (NSAIDs). L-arginine (L-ARG) is an essential amino acid which participates in many important biochemical reactions associated to the normal physiology of the organism. In these experimentations, we studied the role of L-ARG, aminoacid precursor of NO synthesis, on ibuprofen (IB) induced gastric lesions, and also on the inflammatory and oxidative mechanisms related to mucosal damage. Oral administration of IB (100 mg kg(-1)), produced severe damage on gastric mucosa, which was more important after 6 h test-period, and was accompanied by a significant increment in myeloperoxidase (MPO) activity, as index of neutrophil activation, as well as lipid peroxidation (LP) levels and xanthine oxidase (XO) activity. However, no changes were observed in total mucosal glutathione (tGSH), nor glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activity. Simultaneous treatment with equimolar doses of L-ARG (oral and i.p.), considerably reduced the number and intensity of lesions, and at the same time (6 h) the maximum protection was also observed. In addition, L-ARG inhibited the IB-induced LP and XO enhancement, but did not produce changes in leukocyte infiltration, tGSH, GSH-Px and SOD activity. These findings suggest that (1) L-ARG protective effect on gastric mucosa against IB-induced mucosal lesions could be explained by a local effect and also might be due to the systemic action of the aminoacid; (2) the active oxygen species, derived both from XO and activated neutrophils, could play a role in the pathogenesis of gastric injury induced by IB, (3) L-ARG exhibit a protective effect against IB-induced mucosal damage, probably through the inhibition of oxidative stress derived via xanthine-XO, but it does not block the oxygen free radical production through polymorphe nuclear leukocytes.

Long-term management of GERD. Why using endoscopy just now?

Early results with the use of endoscopic techniques in the treatment of gastro-oesophageal reflux disease (GERD) have been recently reported. Methods used are an injection of biocompatible substances within the lower oesophageal sphincter (LES), LES ablation using radio-frequency, and suture of folds in the area distal to the Z-line. The latter--endoscopic gastroplasty--is most difficult, but this technique has been most widely accepted by gastroenterologists to this date. Effectiveness of these endoscopic management systems in the long-term control of GERD has never been compared to a control group. This fact, together with the proven efficacy of anti-secretory drugs and the refinement of laparoscopic surgery during the past few years, has led physicians to be more demanding regarding early results. This review will discuss each method available, and issues answered by reported studies to this day are approached.

Usefulness of capsule endoscopy in patients with suspected small bowel disease.

AIM: To study the usefulness and safety of capsule endoscopy as a diagnostic tool in various small bowel disorders. DESIGN: A retrospective analysis of a series of cases. MATERIAL AND METHODS: Between August 2001 and August 2002, 92 capsule endoscopy procedures were performed in 88 patients (53M/39F, age: 43.87 +/- 16.78). Indications included: chronic diarrhea (n=33); unknown abdominal pain (n=29); occult gastrointestinal bleeding or iron-deficiency anemia (n=13); abdominal discomfort in NSAID takers (n=7); staging of gastrointestinal tumors (n=4), and asymptomatic controls (n=2). Previously performed gastroscopy, colonoscopy, and small-bowel follow-through were not conclusive in all patients. RESULTS: Most frequently relevant findings included: jejuno-ileal aphtas and ulcerations (29 patients), vascular malformations (13 patients), and intestinal neoplasm (6 patients). The groups with a higher rate of findings related to this indication were occult gastrointestinal bleeding (76.92%) and chronic diarrhea (67.85%), with the lowest rate in the abdominal pain group (34.48%). Therapeutic strategy was directly changed in 36 of 88 patients (40.90%) because of capsule-endoscopic findings. The only observed complication was the failed excretion of one of the capsules because of an unknown ulcerated intestinal stricture. CONCLUSIONS: Capsule endoscopy is a safe procedure which can study the entire small bowel, meaning a valuable tool for the management of patients with suggestive signs and symptoms of intestinal disorders.

[Hepatitis B virus (HBV) and the inflammatory/immune response. I. The natural environment of the antigen presentation and immunologic chaos induced by the virus]. / Virus de la hepatitis B (VHB) y la respuesta inflamatoria/inmunológica (I): el entorno natural de la presentación antigénica y el caos inmunológico inducido por el virus.

In this paper, the authors update on the immunopathology of hepatitis B virus (HBV) infection, with special reference to the roles of inflammatory and natural immune responses (macrophages and NK cells) in the viral clearance. The role of specific immune responses being related to the influence of the environment of the antigen presentation (macrophages, NK cells, and their related cytokines IL-12 and IFN-gamma) on Th cells within the liver. The viral scape leading to chronic hepatitis B is thought to be due (a) to the suppressive actions of the virus on NK cells and IFN-gamma production (b) to the downregulation of IL-12/IL-15 production provoked by the inflammatory response (factor C3 of the complement system) on IL-12-producing macrophages: immunologic chaos.

[Self-expanding esophageal metal stents in the palliative treatment of esophageal cancer]. / Prótesis metálicas esofágicas autoexpandibles en el tratamiento paliativo del cáncer de esófago.

We report our experience of two years (February 1993-February 1995) in the endoscopic treatment with self-expanding prosthesis (Ultraflex) of 21 patients with inoperable malignant oesophageal stenosis. 23 prosthesis were implanted enabling swallowing in less than 24 h. There were no major complications. In two occasions the prosthesis was obstructed by tumoral growth needing replacement. The prosthesis was occluded by solid food in four cases, which were resolved endoscopically.

[Hepatitis B virus and the inflammatory/immunologic response (II): a new opportunity for the treatment of chronic hepatitis B and a suggestion for the treatment of other persistent viral diseases]. / Virus de la hepatitis B y la respuesta inflamatoria/inmunológica (II): Una nueva oportunidad de tratamiento de la infección crónica y una sugerencia para el tratamiento de otras enfermedades víricas persistentes.

With the immunologic rationale exposed in the first part of this paper, the authors analyze a new experimental treatment which includes the combination of an antiviral (ribavirin) and an immunomodulator (AM3) in a model of hepatotoxic viral-infection in mice. Rationale for this associated treatment is based on the ability of AM3 to restore the natural immunity through the induction of IL-12 and IFN-gamma. Furthermore, the treatment with AM3 decreases factor C3 of the complement system which appears to be implied in IL-12 downregulation. Experimental and clinical results showed herein suggest a new approach to the treatment of viral hepatitis which combines the use of antivirals in combination with immunomodulators able to restore the "immunologic chaos" induced by some viruses.

Posterior laryngitis: effects of treatment with omeprazole alone.

OBJECTIVE: To evaluate the effect of omeprazole treatment on the symptoms and lesions of patients with posterior laryngitis (PL). PATIENTS AND METHOD: Twenty-one patients with a clinical and laryngoscopic diagnosis of PL were studied. Results for each laryngeal symptom (dysphonia, hoarseness, cough, foreign body sensation, and burning) and laryngoscopic finding (mucus stasis, erythema, oedema, hypertrophy, ulceration, and granulation) at baseline, 12 weeks after treatment with omeprazole, 20 mg twice daily, and 12 weeks after treatment discontinuation were compared. No changes in their hygienic-dietary or postural habits were recommended. RESULTS: A reduction in symptom severity and frequency was observed (p < 0.05), as well as in the severity of laryngoscopic findings (p < 0.05)--except for granulation--immediately after treatment discontinuation. A relapse of laryngoscopic findings was seen at 12 weeks after treatment discontinuation (p < 0.01). The trend towards symptom recurrence was not significant. CONCLUSION: Treatment with omeprazole alone modifies clinical manifestations and endoscopic findings in patients with PL. Controlled clinical trials with a high number of patients and longer-term follow-up are needed to define the best therapeutic regimen for these patients.

Short- and medium-term clinical efficacy of three endoscopic therapies for achalasia: a single-blinded prospective study.

OBJECTIVE: to compare the efficacy of three endoscopic therapies for achalasia and to identify predictors of response. DESIGN: prospective, single-blinded study at short and medium term. MATERIAL AND METHODS: 22 patients (9M/13 F; mean age: 47.45 +/- 21.01 years) with confirmed clinical and manometric achalasia were randomised in three groups: intrasphincteric injections of botulinum toxin (group 1: 10 patients ), injections of 1% polidocanol (group 2:6 patients), and a combined therapy with both of them (group 3: 6 patients). Clinical response was evaluated by a score (0-5) of tested symptoms (dysphagia, regurgitation and chest pain) at 1 and 24 weeks post-treatment. RESULTS: at 24 weeks post-treatment group 2 had the best complete response (CR) rate (33.33%), whereas CR in both the botulinum toxin and combined therapy groups was 10 and 0%, respectively. Groups 1 and 2 got an overall improvement in clinical score at 1 (p= 0.02) and 24 weeks (p= 0.04). Five patients (50%) in group 1, two patients (33.33%) in group 2, and three patients (50%) in group 3 needed other therapies (dilation or surgery) because of treatment failure. Separately, neither age nor sex, time from diagnosis or type of therapy could distinguish responders from non-responders in these three groups. However, absence of response within the first week, and an initial clinical score above 7 were predictive factors of poor response at six months. CONCLUSIONS: short- and medium-term clinical response to these endoscopic therapies was limited. The absence of response at seven days and a severe initial clinical score were predictive factors of poor medium-term response.

[Endoscopic treatment of pain in patients with chronic pancreatitis]. / Tratamiento endoscópico del dolor en los pacientes con pancreatitis crónica.

INTRODUCTION: Chronic Pancreatitis is a recurrent disease, frequently alcohol intake related and tend to occur in the third and the fourth decades. Stenoses and lithiasis in the main pancreatic duct causes obstruction and subsequently pain. Therefore endoscopic or surgical decompression of main pancreatic duct results in pain relief. SUBJECTS AND METHODS: Review our experience in the endoscopic management in patients suffering from chronic pancreatitis. 42 patients underwent ERCP for management of their chronic pancreatitis. Therapeutic options were sphincterotomy alone, prostheses and "do nothing". Follow-up was made by phone call and outpatient office visits. Mean follow-up was 47.8 (27.2) months. RESULTS: 22 patients underwent therapeutic ERCP. In 8 patients we performed sphincterotomy and in 14 patients, a sphincterotomy and prostheses intubation. 8 patients are asymptomatic after a mean follow-up of 10.8 (11.6) months. 2 of them, underwent sphincterotomy and six of them, underwent sphincterotomy and prostheses intubation. CONCLUSION: Therapeutic ERCP is a tool that relieves pain in a fifth of patients suffering from chronic pancreatitis.