Randomised clinical trial: colestyramine vs. hydroxypropyl cellulose in patients with functional chronic watery diarrhoea.

BACKGROUND: Idiopathic bile acid malabsorption (BAM) has been suggested as a cause of chronic watery diarrhoea, with a response to colestyramine in 70% of patients. However, the efficacy of this drug has never been investigated in placebo-controlled trials. AIM: To evaluate the efficacy of colestyramine as compared with hydroxypropyl cellulose in the treatment of functional chronic watery diarrhoea. METHODS: Patients with chronic watery diarrhoea were randomly assigned to groups given colestyramine sachets 4 g twice daily (n = 13) or identical hydroxypropyl cellulose sachets (n = 13) for 8 weeks. The primary end-point was clinical remission defined as a mean of 3 or fewer stools per day during the week before the visit, with less than 1 watery stool per day. A secondary end-point was the reduction in daily watery stool number. SeHCAT test was performed in all patients, but an abnormal test was not a prerequisite to be included. RESULTS: All included patients had a SeHCAT 7-day retention ≤20%. There were no statistical differences in the percentage of patients in clinical remission at week 8 between colestyramine and hydroxypropyl cellulose with either intention-to-treat (53.8% vs. 38.4%; P = 0.43) or per-protocol (63.6% vs. 38.4%; P = 0.22) analyses. However, the mean per cent decrease in watery stool number was significantly higher with colestyramine than with hydroxypropyl cellulose (-92.4 ± 3.5% vs. -75.8 ± 7.1%; P = 0.048). The rate of adverse events related to study drugs did not differ between groups. CONCLUSIONS: Colestyramine (4 g twice daily) is effective and safe for short-term treatment of patients with chronic watery diarrhoea presumably secondary to BAM. Clinical Trials Register number EudraCT 2009-011149-14.

Optimised empiric triple and concomitant therapy for Helicobacter pylori eradication in clinical practice: the OPTRICON study.

BACKGROUND: Empiric triple therapy for Helicobacter pylori should be abandoned when clarithromycin resistance rate is >15-20%. Optimisation of triple therapy (high-dose acid suppression and 14-day duration) can increase eradication rates by 10%. AIM: To compare the efficacy and safety of optimised triple (OPT-TRI) and nonbismuth quadruple concomitant (OPT-CON) therapies. METHODS: Prospective multicentre study in 16 Spanish centres using triple therapy in clinical practice. In a 3-month two-phase fashion, the first 402 patients received an OPT-TRI therapy [esomeprazole (40 mg b.d.), amoxicillin (1 g b.d) and clarithromycin (500 mg b.d) for 14 days] and the last 375 patients an OPT-CON treatment [OPT-TRI therapy plus metronidazole (500 mg b.d)]. RESULTS: Seven-hundred seventy-seven consecutive patients were included (402 OPT-TRI, 375 OPT-CON). The OPT-CON therapy achieved significantly higher eradication rates in the per-protocol [82.3% (95% CI = 78-86%) vs. 93.8% (91-96%), P < 0.001] and intention-to-treat analysis [81.3% (78-86%) vs. 90.4% (87-93%), P < 0.001]. Adverse events (97% mild/moderate) were significantly more common with OPT-CON therapy (39% vs. 47%, P = 0.016), but full compliance with therapy was similar between groups (94% vs. 92%, P = 0.4). OPT-CON therapy was the only significant predictor of successful eradication (odds ratio, 2.24; 95% CI: 1.48-3.51, P < 0.001). The rate of participating centres achieving cure rates ≥ 90% favoured OPT-CON therapy (OPT-TRI 25% vs. OPT-CON 62%). CONCLUSIONS: Empiric OPT-CON therapy achieved significantly higher cure rates (>90%) compared to OPT-TRI therapy. Addition of metronidazole to OPT-TRI therapy increased eradication rates by 10%, resulting in more mild adverse effects, but without impairing compliance with therapy.

Helicobacter pylori second-line rescue therapy with levofloxacin- and bismuth-containing quadruple therapy, after failure of standard triple or non-bismuth quadruple treatments.

BACKGROUND: The most commonly used second-line Helicobacter pylori eradication regimens are bismuth-containing quadruple therapy and levofloxacin-containing triple therapy, both offering suboptimal results. Combining bismuth and levofloxacin may enhance the efficacy of rescue eradication regimens. AIMS: To evaluate the efficacy and tolerability of a second-line quadruple regimen containing levofloxacin and bismuth in patients whose previous H. pylori eradication treatment failed. METHODS: This was a prospective multicenter study including patients in whom a standard triple therapy (PPI-clarithromycin-amoxicillin) or a non-bismuth quadruple therapy (PPI-clarithromycin-amoxicillin-metronidazole, either sequential or concomitant) had failed. Esomeprazole (40 mg b.d.), amoxicillin (1 g b.d.), levofloxacin (500 mg o.d.) and bismuth (240 mg b.d.) was prescribed for 14 days. Eradication was confirmed by (13) C-urea breath test. Compliance was determined through questioning and recovery of empty medication envelopes. Incidence of adverse effects was evaluated by questionnaires. RESULTS: 200 patients were included consecutively (mean age 47 years, 67% women, 13% ulcer). Previous failed therapy included: standard clarithromycin triple therapy (131 patients), sequential (32) and concomitant (37). A total of 96% took all medications correctly. Per-protocol and intention-to-treat eradication rates were 91.1% (95%CI = 87-95%) and 90% (95%CI = 86-94%). Cure rates were similar regardless of previous (failed) treatment or country of origin. Adverse effects were reported in 46% of patients, most commonly nausea (17%) and diarrhoea (16%); 3% were intense but none was serious. CONCLUSIONS: Fourteen-day bismuth- and levofloxacin-containing quadruple therapy is an effective (≥90% cure rate), simple and safe second-line strategy in patients whose previous standard triple or non-bismuth quadruple (sequential or concomitant) therapies have failed.

Third-line rescue therapy with bismuth-containing quadruple regimen after failure of two treatments (with clarithromycin and levofloxacin) for H. pylori infection.

BACKGROUND: Helicobacter pylori eradication therapy with a proton pump inhibitor (PPI), clarithromycin, and amoxicillin fails in >20 % of cases. A rescue therapy with PPI-amoxicillin-levofloxacin still fails in >20 % of patients. AIM: To evaluate the efficacy and tolerability of a bismuth-containing quadruple regimen in patients with two consecutive eradication failures. METHODS: Prospective multicenter study of patients in whom 1st treatment with PPI-clarithromycin-amoxicillin and 2nd with PPI-amoxicillin-levofloxacin had failed. A 3rd eradication regimen with a 7- to 14-day PPI (standard dose b.i.d.), bismuth subcitrate (120 mg q.i.d. or 240 mg b.i.d.), tetracycline (from 250 mg t.i.d. to 500 mg q.i.d.) and metronidazole (from 250 mg t.i.d. to 500 mg q.i.d.). Eradication was confirmed by (13)C-urea-breath-test 4-8 weeks after therapy. Compliance was determined through questioning and recovery of empty medication envelopes. Adverse effects were evaluated by means of a questionnaire. RESULTS: Two hundred patients (mean age 50 years, 55 % females, 20 % peptic ulcer/80 % uninvestigated-functional dyspepsia) were initially included, and two were lost to follow-up. In all, 97 % of patients complied with the protocol. Per-protocol and intention-to-treat eradication rates were 67 % (95 % CI 60-74 %) and 65 % (58-72 %). Adverse effects were reported in 22 % of patients, the most common being nausea (12 %), abdominal pain (11 %), metallic taste (8.5 %), and diarrhea (8 %), none of them severe. CONCLUSION: A bismuth-containing quadruple regimen is an acceptable third-line strategy and a safe alternative after two previous H. pylori eradication failures with standard clarithromycin- and levofloxacin-containing triple therapies.

Development and characterization of an isogenic cell line with a radioresistant phenotype

INTRODUCTION: Radiation resistance is a major cause of death in cancer patients. Cancer cells react during radiotherapy by re-programming specific cell functions that may confer resistance to radiation. The understanding of this complex process is hindered due to the lack of appropriate study models. We describe an experimental development of a radioresistant isogenic cancer cell line, and its molecular characterization. MATERIALS AND METHODS: A431-cultured cells were irradiated for 7 month until 85 Gy. Then, a selected single cell was left to grow as stable A431-R cell line. Clonogenic assay was used to determine cell survival, the α and β parameters of the LQ model, and the mean inactivation dose. The DNA repair ability of cells was evaluated by pulsed-field electrophoresis method. Differential effect of fractionated radiation was ultimately tested in xenografts. Furthermore, we used a wound healing assay, Western blot for EGFR, AKT and ERK1/2 and ELISA test for vascular endothelial growth factor (VEGF) secretion. Finally we explored CD44 marker and cell cycle distribution. RESULTS: The established A431-R cell line showed radiation resistance in clonogenic assays, repair of radiation-induced DNA fragmentation and xenografted tumours. The radiation resistance was associated with in vitro higher cell growth and migration, increased levels of former oncoproteins, and secretion of VEGF. CONCLUSIONS: In this model, the emergence of radiation resistance was associated with the acquisition of biological traits that support more aggressive behaviour of cancer cells. We have generated a model that will be useful for mechanistic studies and development of rational treatments against radiation resistance in cancer (AU)

Fourth-line rescue therapy with rifabutin in patients with three Helicobacter pylori eradication failures.

BACKGROUND: In some cases, Helicobacter pylori infection persists even after three eradication treatments. AIM: To evaluate the efficacy of an empirical fourth-line rescue regimen with rifabutin in patients with three eradication failures. DESIGN: Multicentre, prospective study. PATIENTS: In whom the following three treatments had consecutively failed: first (PPI + clarithromycin + amoxicillin); second (PPI + bismuth + tetracycline + metronidazole); third (PPI + amoxicillin + levofloxacin). INTERVENTION: A fourth regimen with rifabutin (150 mg b.d.), amoxicillin (1 g b.d.) and a PPI (standard dose b.d.) was prescribed for 10 days. OUTCOME: Eradication was confirmed by (13) C-urea breath test 4-8 weeks after therapy. Compliance and tolerance: Compliance was determined through questioning and recovery of empty medication envelopes. Adverse effects were evaluated using a questionnaire. RESULTS: One-hundred patients (mean age 50 years, 39% men, 31% peptic ulcer/69% functional dyspepsia) were included. Eight patients did not take the medication correctly (in six cases due to adverse effects). Per-protocol and intention-to-treat eradication rates were 52% (95% CI = 41-63%) and 50% (40-60%). Adverse effects were reported in 30 (30%) patients: nausea/vomiting (13 patients), asthenia/anorexia (8), abdominal pain (7), diarrhoea (5), fever (4), metallic taste (4), myalgia (4), hypertransaminasemia (2), leucopenia (<1,500 neutrophils) (2), thrombopenia (<150,000 platelets) (2), headache (1) and aphthous stomatitis (1). Myelotoxicity resolved spontaneously in all cases. CONCLUSIONS: Even after three previous H. pylori eradication failures, an empirical fourth-line rescue treatment with rifabutin may be effective in approximately 50% of the cases. Therefore, rifabutin-based rescue therapy constitutes a valid strategy after multiple previous eradication failures with key antibiotics, such as clarithromycin, metronidazole, tetracycline and levofloxacin.

Interobserver variability in target volume delineation in postoperative radiochemotherapy for gastric cancer. A pilot prospective study

INTRODUCTION: The aim of this study is to determine the interobserver variability (IV) between radiation oncologists (RO) in target volume delineation for postoperative gastric cancer (GC) radiotherapy planning. MATERIALS AND METHODS: Four physicians were asked to delimitate clinical target volume (CTV) on the same 3D CT images in 9 postoperative radiochemotherapy GC patients. Instructions were given to include tumour bed, remaining stomach, anastomosis, duodenal loop and local lymph nodes. The principal variable was spatial volume discrepancy between the main observer (called "A") and other observers (all called "B"), which were compared using the mathematical formula A⌣B/A⌢B, applied to the 3D CT images using Boolean operators. Analysis of variance with two random effects (observers and patients) was performed. RESULTS: Mean volumes were 1410 cm(3) for OBA, 1231 cm(3) for OB2, 734.6 cm(3) for OB3 and 1350 cm(3) for OB4. Discrepancies were 519.9±431.6 cm(3) for OB2, 652.1±294.36 cm(3) for OB3 and 225.90±237.07 cm(3) for OB4. Standard deviation ascribed to patients as random effect was 898.6 cm(3) and that ascribed to observers was 198.10 cm(3), considered as a statistically significant difference. CONCLUSIONS: A significant IV in target delineation that can be attributed to many factors depends more on patients' characteristics than RO delineating decisions (AU)

[Gastroesophageal reflux and obstructive sleep apnea syndrome]. / Reflujo gastroesofágico proximal y sindrome de la apnea obstructiva del sueño. Datos preliminares de un estudio prospectivo.

INTRODUCTION: Patients with mild or moderate Sleep Apnea Syndrome (SAS) need wider therapeutic scope options according to their disease severity. AIM: To consider including proton pump inhibitors (PPI) to the therapeutical alternatives of these patients. MATERIAL AND METHODS: A prospective study was designed, among patients with SAS. Nocturnal polysomnography and double channel pHmetry were performed simultaneously. RESULTS: From the 18 patients included in this preliminary phase, in three (16.7%) nocturnal proximal ph monitoring was positive. These 3 patients were treated with PPI during at least 3 months with a very satisfactory outcome in two of them. CONCLUSIONS: Treatment with PPI may be a useful therapeutical alternative in patients with mild to moderate SAS.

Reflujo gastroesofágico proximal y síndrome de la apnea obstructiva del sueño. Datos preliminares de un estudio prospectivo / Gastroesophageal reflux and obstructive sleep apnea syndrome

Introducción: Los pacientes con síndrome de apnea del sueño (SAOS) leve o moderado precisan una ampliación de la oferta terapéutica acorde con la intensidad de su enfermedad. Objetivo: Valorar la posibilidad de incluir los inhibidores de la bomba de protones (IBP) al arsenal terapéutico de estos pacientes. Material y métodos: Se diseña un estudio prospectivo entre pacientes con cuadro clínico de SAOS registrando de forma simultánea polisomnografía (PSG) nocturna y pHmetría de 24 horas de dos canales. Resultados: En esta primera fase del estudio se han recogido un total de 18casos, de los que en tres (16,7%) la pHmetría proximal durante la noche resultó positiva. Estos tres pacientes fueron tratados con IBP durante un mínimo de 3 meses siendo el resultado satisfactorio en dos. Conclusión: El tratamiento con IBP puede ser una alternativa terapéutica útil en algunos pacientes con SAOS de intensidad leve o moderada (AU)

Introduction: Patients with mild or moderate Sleep Apnea Syndrome (SAS) need wider therapeutic scope options according to their disease severity. Aim: To consider including proton pump inhibitors (PPI) to the therapeutical alternatives of these patients. Material and methods: A prospective study was designed, among patients with SAS. Nocturnal polysomnography and double channel pHmetry were performed simultaneously. Results: From the 18 patients included in this preliminary phase, in three (16.7%) nocturnal proximal ph monitoring was positive. These 3 patients were treated with PPI during at least 3 months with a very satisfactory outcome in two of them. Conclusions: Treatment with PPI may be a useful therapeutical alternative in patients with mild to moderate SAS (AU)

Digestive system involvement in cystic fibrosis.

Cystic fibrosis is a hereditary disease well known to paediatricians. Over recent years, its prevalence among the adult population has dramatically increased; thus becoming a disease increasingly seen in adult practice. Cystic fibrosis is a multi-organ disease, with a wide spectrum of clinical manifestations involving many organs. The aim of this article is to review the digestive system manifestations of this disease: the involvement of the gastrointestinal tract, liver, biliary system and pancreas, with a special emphasis on the adult population.

Gastrointestinal, liver, and pancreatic involvement in adult patients with cystic fibrosis.

BACKGROUND: The clinical prevalence of cystic fibrosis (CF) in adults continues to rise, with a consequent impact on adult gastroenterology practice. AIM: To characterize the gastrointestinal manifestations of CF in adult patients. PATIENTS AND METHODS: The clinical records of 89 adult CF patients treated at our institution from 1992 to 1999 were reviewed. Patients were distributed into two groups: group A (39 patients), which consisted of patients who were diagnosed with CF at when they were younger than 14 years old and who survived into adulthood; and group B (50 patients), who were diagnosed with CF at the age of 14 years or older. Data on CF genetic mutations, nutritional state, evidence of pulmonary, gastrointestinal, liver, or pancreatic involvement were collected for each patient. RESULTS: The most prevalent genetic mutation in our series was deltaF508, present in 50 patients (56.2%), 29 of whom belonged to group A and 21 who belonged to group B. In group A, the deltaF508 mutation was associated with exocrine pancreatic insufficiency (PI) in 26 of 29 patients (89.6%), whereas in group B it was associated with PI in only four patients (19%). Overall, PI was present in 33 of 39 patients (84.6%) in group A and in eight of 50 patients (16%) in group B. Four patients in group B had experienced previous episodes of acute pancreatitis; two of them had associated PI. Of the 89 patients, 12 (10 in group A) were malnourished. Malnutrition was invariably associated with PI. Hepatic and biliary tree abnormalities were particularly prevalent in patients in group A and was usually associated with PI. Intestinal manifestations were uncommon. CONCLUSIONS: Diagnosis of CF before the age of 14 years is associated with greater gastrointestinal compromise than diagnosis at an older age, particularly with regard to PI. CF carriers of the deltaF508 mutation have an increased risk of developing gastrointestinal manifestations.

Pharyngo-esophageal motility disturbances in patients with myotonic dystrophy.

BACKGROUND: Esophageal motility is often disturbed in patients with myotonic dystrophy. The esophageal motor derangement pattern and its correlation with esophageal and peripheral motor symptoms is not well defined. Our aims were to evaluate: 1) pharyngo-esophageal motor abnormalities in these patients; 2) the relationship between motor involvement and clinical manifestations; and 3) the correlation between pharyngo-esophageal motility abnormalities and peripheral neuromuscular involvement. METHODS: We compared data from 18 patients and 18 healthy controls. Neuromuscular affectation was quantified with a five-point muscular disability rating scale. Pharyngo-esophageal symptoms were assessed with a directed questionnaire, whereas motility was evaluated by means of manometry. RESULTS: Myotonic dystrophy patients had diminished pharyngeal contraction amplitude, upper esophageal sphincter basal pressure, and esophageal body contraction amplitude compared with the control group (P < 0.001). No signs of esophageal myotony were evident. Simultaneous esophageal waves after more than 40% of liquid swallows were found in 80% of patients. No relationship between esophageal manometric alteration and esophageal or peripheral motility symptoms was elicited. CONCLUSION: In patients with myotonic dystrophy pharyngo-esophageal motility is severely deranged in both amplitude and coordination. These abnormalities may be present even if symptoms referred by the patient or the severity of the disease is not remarkable.

Vagaries of clinical presentation of pancreatic and biliary tract cancer.

Pancreatic and biliary carcinomas remain a challenge to clinicians and investigators, as diagnosis is rarely achieved while the tumor is still in a curative stage. Clinical symptoms and signs of these neoplasias are non-specific and heterogeneous. We review the clinical presentation of these tumors, with an emphasis on their pathophysiology and relationship with survival. Abdominal pain is the most common presenting complaint in pancreatic and biliary tract carcinomas, regardless of their size; although severe back pain usually indicates neural compromise, and is associated with a short survival. Jaundice may also be an early sign, in fact, pancreatic tumors that present as painless jaundice have been ascribed, a relatively more favorable prognosis. Weight loss is a common finding in most patients, being usually associated with malabsorption. These neoplasias may also present as diabetes, as an acute pancreatitis episode, with venous thrombosis or malignant thrombophlebitis, as a gastrointestinal hemorrhage, with mental disturbances, or skin manifestations.

Acute pancreatitis as a triggering factor for thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) constitutes a poorly understood multisystemic disease of vascular origin that may involve any organ by thrombotic occlusions of the small vessels. Treatment with plasmapheresis is the best therapeutic option at this present moment. Involvement of the pancreas is a well established feature of this disease, which has generally been interpreted as a consequence of pancreatic vascular compromise. However, there are a few cases in the literature in which the clinical signs of TTP developed well after the clinical and laboratory demonstration of acute pancreatitis (AP). Therefore, the possibility of pancreatic inflammation as a triggering factor of TTP may need to be considered. This cause-effect relationship between AP and TTP remains unclear. We report a patient with chronic pancreatitis presenting with two episodes of TTP, triggered by acute relapses of pancreatitis. TTP may, thus, constitute a hematological complication of AP. We discuss the pathophysiological aspects of this association, along with therapeutical options.