Efficacy of Hepatitis B Virus Vaccines HBVaxpro40© and Fendrix© in Patients with Chronic Liver Disease in Clinical Practice.

Chronic liver disease results in a low response rate to the hepatitis B virus vaccine. Information on the efficacy of the double adjuvanted vaccine FENDRIX® (3-O-desacyl-4'-monophosphoryl lipid A and aluminum phosphate) and single adjuvant HBVAXPRO®40 (aluminum hydroxyphosphate sulfate) in chronic liver disease is scarce. The primary aim of this prospective study in clinical practice was to evaluate the effectiveness of HBVAXPRO®40 and FENDRIX® in this setting. Patients received HBVAXPRO® (0, 1 and 6 months) or FENDRIX® (0, 1, 2 and 6 months) depending on availability. Clinical data and anti-HBs levels were collected at 2, 6 and 12 months. A total of 125 patients were included (mean age 61.8 years; 57.6% males; 43.2% liver cirrhosis; 75.9% Child A and 24.1% Child B): 76 were vaccinated with HBVAXPRO® and 49 with FENDRIX®. There were no significant differences between the two vaccines. The overall response rates at 2, 6 and 12 months were 76.8, 72.8 and 59.2%, respectively. In the univariate analysis, active alcohol intake, alcohol etiology, liver cirrhosis and ultrasound signs of portal hypertension were associated with a lower response to vaccination, whereas in the multivariate analysis, liver cirrhosis was the only factor that significantly increased the likelihood of nonresponse (OR 10.5). HBVAXPRO® and FENDRIX® are good options for HBV vaccination in patients with chronic liver disease.

Deep-sequencing reveals broad subtype-specific HCV resistance mutations associated with treatment failure.

A percentage of hepatitis C virus (HCV)-infected patients fail direct acting antiviral (DAA)-based treatment regimens, often because of drug resistance-associated substitutions (RAS). The aim of this study was to characterize the resistance profile of a large cohort of patients failing DAA-based treatments, and investigate the relationship between HCV subtype and failure, as an aid to optimizing management of these patients. A new, standardized HCV-RAS testing protocol based on deep sequencing was designed and applied to 220 previously subtyped samples from patients failing DAA treatment, collected in 39 Spanish hospitals. The majority had received DAA-based interferon (IFN) α-free regimens; 79% had failed sofosbuvir-containing therapy. Genomic regions encoding the nonstructural protein (NS) 3, NS5A, and NS5B (DAA target regions) were analyzed using subtype-specific primers. Viral subtype distribution was as follows: genotype (G) 1, 62.7%; G3a, 21.4%; G4d, 12.3%; G2, 1.8%; and mixed infections 1.8%. Overall, 88.6% of patients carried at least 1 RAS, and 19% carried RAS at frequencies below 20% in the mutant spectrum. There were no differences in RAS selection between treatments with and without ribavirin. Regardless of the treatment received, each HCV subtype showed specific types of RAS. Of note, no RAS were detected in the target proteins of 18.6% of patients failing treatment, and 30.4% of patients had RAS in proteins that were not targets of the inhibitors they received. HCV patients failing DAA therapy showed a high diversity of RAS. Ribavirin use did not influence the type or number of RAS at failure. The subtype-specific pattern of RAS emergence underscores the importance of accurate HCV subtyping. The frequency of "extra-target" RAS suggests the need for RAS screening in all three DAA target regions.

Leukocytes from obese individuals exhibit an impaired SPM signature.

Specialized proresolving mediators (SPMs) biosynthesized from docosahexaenoic acids (DHAs) including resolvins (Rvs), protectins, and maresins are potent endogenous autacoids that actively resolve inflammation, protect organs, and stimulate tissue regeneration. Our hypothesis was that failure of resolution programs may lead to unremitting inflammation in obesity, contributing to the development of metabolic comorbidities in this condition. Obese individuals with persistent low-grade systemic inflammation showed reduced leukocyte production of the DHA-derived monohydroxy fatty acid 17-hydroxy-DHA (HDHA) and unbalanced formation of SPMs (in particular D-series Rvs) accompanied by enhanced production of proinflammatory lipid mediators such as leukotriene B4. Mechanistic studies attributed this impairment to reduced 15-lipoxygenase (LOX) activity rather than altered DHA cellular uptake. Moreover, leukocytes from obese individuals exhibited decreased 5-LOX levels and reduced 5-LOX Ser271 phosphorylation and distinct intracellular 5-LOX redistribution. However, 15-LOX appears to be the most critical factor for the deficient production of SPMs by obese leukocytes because the formation of D-series Rvs was completely rescued by incubation with the intermediate precursor 17-HDHA. These data provide proof of concept that administration of intermediate precursors of SPM biosynthesis (e.g., 17-HDHA) could be more efficient in overriding impaired formation of these proresolving lipid mediators in conditions characterized by dysfunctional LOX activity, such as obesity.-López-Vicario, C., Titos, E., Walker, M. E., Alcaraz-Quiles, J., Casulleras, M., Durán-Güell, M., Flores-Costa, R., Pérez-Romero, N., Forné, M., Dalli, J., Clària, J. Leukocytes from obese individuals exhibit an impaired SPM signature.

Analysis of survival and prognostic factors in treatment of hepatocellular carcinoma in Spanish patients with drug-eluting bead transarterial chemoembolization.

BACKGROUND AND AIM: Drug-eluting bead transarterial chemoembolization (DEB-TACE) improves the survival of patients with hepatocellular carcinoma (HCC), intermediate stage [i.e. Barcelona Clinic Liver Cancer-B (BCLC-B)]. The aim of our study was to analyse the overall survival (OS) and prognostic factors of patients with HCC treated with DEB-TACE. PATIENTS AND METHODS: Patients' clinical course was recorded from January 2005 to July 2014. The median OS was obtained by the Kaplan-Meier method and compared using the log-rank test. The prognosis factors associated with OS were determined by a multivariate Cox regression analysis and the accuracy of the OS prediction was determined by calculation of the assessment for retreatment with TACE score (ART score). RESULTS: A cohort of 147 consecutive patients treated with DEB-TACE was included. Median age of the patients was 73.4 years. Overall, 68.7% were men, and all had cirrhosis, with 68.8% being hepatisis C virus positive. Moreover, 35.2% were staged as BCLC-A and 60.2% as BCLC-B. After a median follow-up of 19.2 months, 29.3% were alive, 4.3% needed treatment with sorafenib and 56.1% underwent DEB-TACE retreatment. Median OS was 22.8 [95% confidence interval (CI)=19.6-25.9]. After censoring for ascites and more than one nodule, OS was 23.87 (95% CI =20.72-27.01) and 26.89 (95% CI =21.00-32.78), respectively. The risk of death decreased by 22.3% with the number of DEB-TACE sessions (hazard ratio=0.777) and increased by 25.9% with higher Child-Pugh score (hazard ratio=1.259). Overall, 61.2% of the cohort had an ART score between 0 and 1.5. There were no statistical differences in OS between cohort groups with ART of 0-1.5 and at least 2.5. CONCLUSION: The results validate the efficacy and safety of DEB-TACE in patients with HCC and the importance of some prognostic factors for patient survival.

Características clínicas del carcinoma hepatocelular en España. Comparación con el período 2008-2009 y análisis de las causas del diagnóstico fuera de cribado. Estudio de 686 casos en 73 centros / Clinical characteristics of hepatocellular carcinoma in Spain. Comparison with the 2008-2009 period and analysis of the causes of diagnosis out of screening programs. Analysis of 686 cases in 73 centers

Antecedentes y objetivo: En 2010 publicamos que en España el 53% de los carcinomas hepatocelulares (CHC) se diagnostican fuera de programas de cribado, lo que conlleva una menor supervivencia. El objetivo del presente estudio es evaluar la situación actual y las causas del diagnóstico fuera de cribado. Material y métodos: Registro prospectivo entre el 1 de octubre de 2014 y el 31 de enero de 2015 en 73 centros asistenciales españoles de segundo/tercer nivel. Se registraron las características basales y el primer tratamiento de los tumores primarios hepáticos incidentales de ese período. Resultados: Se incluyeron 720 pacientes: CHC (n=686), colangiocarcinoma intrahepático (n=29), hepatocolangiocarcinoma (n=2), otros (n=3). Los pacientes con CHC fueron varones en el 82% de los casos; media de 67 años; cirrosis en el 87%; etiología: alcohol 35%, VHC 30%, alcohol y VHC 15%, enfermedad hepática por depósito de grasa 6%; estadio tumoral: BCLC-0 11%, A 43%, B 19%, C 16% y D 11%; tratamiento inicial: quimioembolización transarterial (23%), ablación percutánea (22%), tratamiento sintomático (20%), resección (11%), sorafenib (11%). Se diagnosticaron fuera de cribado 356 pacientes (53%). Los motivos principales fueron la ausencia de diagnóstico previo de hepatopatía (76%) y la mala adherencia al cribado (18%). Estos pacientes eran predominantemente varones (p<0,001), de etiología alcohólica (p<0,001), con consumo activo de alcohol (p<0,001) y se diagnosticaron en estadios más avanzados (p<0,001), recibiendo menos tratamientos radicales (p<0,001). Conclusiones: En España, la principal causa del diagnóstico de CHC fuera del cribado es la ausencia de diagnóstico previo de enfermedad hepática, principalmente en varones con consumo de alcohol. La detección de hepatopatía en población asintomática y la mejora de la adherencia al cribado son los principales aspectos para mejorar la detección precoz (AU)

Background and objective: In 2010 we published that 53% of cases of hepatocellular carcinoma (HCC) detected in Spain were diagnosed outside the context of standard screening programs, which consequently leads to lower survival rates. The aim of this study was to analyze the current situation and the causes of diagnosis out of screening programs. Material and methods: Prospective registry of 73 second- and third-level Spanish healthcare centers carried out between October 1, 2014 and January 31, 2015. The baseline characteristics of the disease and the first treatment administered for the incidental primary liver tumors during such period were recorded. Results: A total of 720 patients were included in the study: HCC (n=686), intrahepatic cholangiocarcinoma (n=29), hepatic cholangiocarcinoma (n=2), other (n=3). HCC characteristics: male 82%; mean age 67 years; cirrhosis 87%; main etiologies: alcohol 35%, HCV 30%, alcohol and HCV 15%, non-alcoholic fatty liver disease 6%; tumor stage: BCLC-0 11%, A 43%, B 19%, C 16% and D 11%; first treatment: transarterial chemoembolization (23%), percutaneous ablation (22%), symptomatic treatment (20%), resection (11%), sorafenib (11%). Three hundred and fifty-six patients (53%) were diagnosed outside of screening programs, mainly owing to the fact that they suffered from an undiagnosed liver disease (76%) and to the poor adherence to the screening program (18%). These patients were mainly male (P<.001), with an alcoholic etiology (P<.001) and active alcohol consumption (P<.001). Moreover, the disease was predominantly diagnosed at more advanced stages (P<.001) and was addressed with less radical treatments (P<.001). Conclusions: In Spain, the main cause of diagnosis of a HCC outside the context of a screening program is the absence of a prior diagnosis of a liver disease, particularly in alcohol-consuming men. Detecting a liver disease in asymptomatic populations and improving adherence to screening programs are the main areas that must be subject to improvement in order to improve the early detection of HCC (AU)

Escasa eficacia de metronidazol en la erradicación de Blastocystis hominis en pacientes sintomáticos: serie de casos y revisión sistemática de la literatura / Low efficacy of metronidazole in the eradication of Blastocystis hominis in symptomatic patients: Case series and systematic literature review

Introducción: El Blastocystis hominis (B. hominis) es un protozoo comúnmente encontrado en el tracto gastrointestinal. Existen dudas sobre su significado clínico. El metronidazol (MTZ) es el tratamiento aconsejado de primera línea. Material y métodos: Se realizó una revisión retrospectiva entre 2011 y 2012. Se seleccionaron de forma aleatoria 151 de 383 muestras positivas para B. hominis. Los criterios de inclusión fueron: clínica sugestiva, indicación de tratamiento y realización de control microbiológico. Se realizó una revisión sistemática de los estudios que evalúan el efecto de MTZ sobre la infestación por B. hominis. Resultados: Cuarenta y seis pacientes cumplían criterios de inclusión (el 64% eran mujeres; edad, 44,2±2 años). Se utilizó MTZ en 39 pacientes, de los cuales 31 obtuvieron respuesta clínica (79,5%) pero solo 15 respuesta microbiológica (48,4%). No se apreció una relación dosisefecto. Veinte pacientes sin respuesta microbiológica inicial recibieron una segunda tanda de tratamiento (MTZ, cotrimoxazol, paramomicina, otros), con una respuesta microbiológica del 70%. De forma global, se consiguió la curación de B. hominis en un 72% (IC95%: 57-83%). De 54 tratamientos asociados a respuesta clínica, se produjo respuesta microbiológica en 31 (57%); mientras que de los 12 que se siguieron de ausencia de respuesta clínica solo se observó la curación microbiológica en 2 (17%) (p = 0,022). La tasa de erradicación en la revisión sistemática osciló entre 0 y 100%. Conclusiones: Parece existir relación entre la respuesta clínica y microbiológica al tratamiento de B. hominis. En nuestro entorno geográfico la respuesta microbiológica al tratamiento con MTZ es insuficiente. La revisión sistemática muestra que la respuesta a MTZ es muy variable (AU)

Introduction: Blastocystis hominis (B. hominis) is a protozoan commonly found in the gastrointestinal tract. There are doubts about its clinical significance. Metronidazole (MTZ) is the recommended first-line treatment. Materials and methods: A retrospective review was carried out between 2011 and 2012. A total of 151 samples were randomly selected from 383 samples positive for B. hominis. Inclusion criteria were: suggestive symptoms, treatment indication and microbiological follow-up. A systematic review was performed of all studies that evaluated the effect of MTZ on B. hominis infection. Results: Forty-six patients met the inclusion criteria (64% women; age, 44.2±2 years). MTZ was used in 39 patients, 31 of whom obtained a clinical response (79.5%) but only 15 a microbiological response (48.4%). No dose-effect relationship was observed. Twenty patients with no initial microbiological response received a second round of treatment (MTZ, cotrimoxazole, paramomycin, others), with a microbiological response in 70%. Overall, B. hominis was cured in 72% (95% CI: 57%-83%). Of 54 treatments associated with a clinical response, a microbiological response occurred in 31 (57%), while in the remaining 12 with no clinical response, microbiological cure was observed in only 2 (17%) (P = .022). The eradication rate in the systematic review varied between 0% and 100%. Conclusions: There seems to be a relationship between the clinical and microbiological response to B. hominis treatment. The microbiological response to MTZ treatment is insufficient in our geographical setting. The systematic review shows that the response to MTZ is very variable (AU)

Interferon-Free Therapy in Elderly Patients With Advanced Liver Disease.

OBJECTIVES: Interferon-free therapies have an improved safety and efficacy profile. However, data in elderly patients, who have frequently advanced liver disease, associated comorbidities, and use concomitant medications are scarce. The im of this study was to assess the effectiveness and tolerability of all-oral regimens in elderly patients in real-life clinical practice. METHODS: Retrospective analysis of hepatitis C virus (HCV) patients aged ≥65 years receiving interferon-free regimens within the Spanish National Registry (Hepa-C). RESULTS: Data of 1,252 patients were recorded. Of these, 955 (76%) were aged 65-74 years, 211 (17%) were aged 75-79 years, and 86 (7%) were aged ≥80 years at the start of antiviral therapy. HCV genotype-1b was predominant (88%) and 48% were previous non-responders. A significant proportion of patients had cirrhosis (922; 74%), of whom 11% presented decompensated liver disease. The most used regimens were SOF/LDV (33%), 3D (28%), and SOF/SMV (26%). Ribavirin was added in 49% of patients. Overall, the sustained virological response (SVR12) rate was 94% without differences among the three age categories. Albumin ≤3.5 g/dl was the only independent negative predictor of response (0.25 (0.15-0.41); P<0.01). Regarding tolerability, the rate of severe adverse events increased with age category (8.8, 13, and 14%; P=0.04). In addition, the main predictors of mortality (2.3%) were age ≥75 years (2.59 (1.16-5.83); P =0.02) and albumin ≤3.5 (17 (6.3-47); P <0.01). CONCLUSIONS: SVR rates with interferon-free regimens in elderly patients are high and comparable to the general population. Baseline low albumin levels (≤3.5 g/dl) was the only predictor of treatment failure. Importantly, the rate of severe adverse events and death increased with age. Elderly patients (≥75 years) or those with advanced liver disease (albumin ≤3.5) presented higher mortality. Thus a careful selection of patients for antiviral treatment is recommended.

High efficacy of Sofosbuvir plus Simeprevir in a large cohort of Spanish cirrhotic patients infected with genotypes 1 and 4.

BACKGROUND AND AIMS: Hepatitis C (HCV) therapy with Sofosbuvir (SOF)/Simeprevir (SMV) in clinical trials and real-world clinical practice, showed high rates of sustained virological response (SVR) in non-cirrhotic genotype (GT)-1 and GT-4 patients. These results were slightly lower in cirrhotic patients. We investigated real-life effectiveness and safety of SOF/SMV with or without ribavirin (RBV) in a large cohort of cirrhotic patients. METHODS: This collaborative multicentre study included data from 968 patients with cirrhosis infected with HCV-GT1 or 4, treated with SOF/SMV±RBV in 30 centres across Spain between January-2014 and December-2015. Demographic, clinical, virological and safety data were analysed. RESULTS: Overall SVR was 92.3%; the majority of patients were treated with RBV (62%) for 12 weeks (92.4%). No significant differences in SVR were observed between genotypes (GT1a:94.3%; GT1b:91.7%; GT4:91.1%). Those patients with more advanced liver disease (Child B/C, MELD≥10) or portal hypertension (platelet count≤100×109 /L, transient elastography≥21 Kpa) showed significantly lower SVR rates (84.4%-91.9%) than patients with less advanced liver disease (93.8%-95.9%, P<.01 in all cases). In the multivariate analysis, the use of RBV, female gender, baseline albumin≥35 g/L, MELD<10 and lack of exposure to a triple therapy regimen were independent predictors of SVR (P<.05). Serious adverse events (SAEs) and SAE-associated discontinuation events occurred in 5.9% and 2.6%. CONCLUSIONS: In this large cohort of cirrhotic patients managed in the real-world setting in Spain, SOF/SMV±RBV yielded to excellent SVR rates, especially in patients with compensated liver cirrhosis. In addition, this combination showed to be safe, with low rates of SAEs and early discontinuations.

Low efficacy of metronidazole in the eradication of Blastocystis hominis in symptomatic patients: Case series and systematic literature review. / Escasa eficacia de metronidazol en la erradicación de Blastocystis hominis en pacientes sintomáticos: serie de casos y revisión sistemática de la literatura.

INTRODUCTION: Blastocystis hominis (B. hominis) is a protozoan commonly found in the gastrointestinal tract. There are doubts about its clinical significance. Metronidazole (MTZ) is the recommended first-line treatment. MATERIALS AND METHODS: A retrospective review was carried out between 2011 and 2012. A total of 151 samples were randomly selected from 383 samples positive for B. hominis. Inclusion criteria were: suggestive symptoms, treatment indication and microbiological follow-up. A systematic review was performed of all studies that evaluated the effect of MTZ on B. hominis infection. RESULTS: Forty-six patients met the inclusion criteria (64% women; age, 44.2±2 years). MTZ was used in 39 patients, 31 of whom obtained a clinical response (79.5%) but only 15 a microbiological response (48.4%). No dose-effect relationship was observed. Twenty patients with no initial microbiological response received a second round of treatment (MTZ, cotrimoxazole, paramomycin, others), with a microbiological response in 70%. Overall, B. hominis was cured in 72% (95% CI: 57%-83%). Of 54 treatments associated with a clinical response, a microbiological response occurred in 31 (57%), while in the remaining 12 with no clinical response, microbiological cure was observed in only 2 (17%) (P=.022). The eradication rate in the systematic review varied between 0% and 100%. CONCLUSIONS: There seems to be a relationship between the clinical and microbiological response to B. hominis treatment. The microbiological response to MTZ treatment is insufficient in our geographical setting. The systematic review shows that the response to MTZ is very variable.

Clinical characteristics of hepatocellular carcinoma in Spain. Comparison with the 2008-2009 period and analysis of the causes of diagnosis out of screening programs. Analysis of 686 cases in 73 centers. / Características clínicas del carcinoma hepatocelular en España. Comparación con el período 2008-2009 y análisis de las causas del diagnóstico fuera de cribado. Estudio de 686 casos en 73 centros.

BACKGROUND AND OBJECTIVE: In 2010 we published that 53% of cases of hepatocellular carcinoma (HCC) detected in Spain were diagnosed outside the context of standard screening programs, which consequently leads to lower survival rates. The aim of this study was to analyze the current situation and the causes of diagnosis out of screening programs. MATERIAL AND METHODS: Prospective registry of 73 second- and third-level Spanish healthcare centers carried out between October 1, 2014 and January 31, 2015. The baseline characteristics of the disease and the first treatment administered for the incidental primary liver tumors during such period were recorded. RESULTS: A total of 720 patients were included in the study: HCC (n=686), intrahepatic cholangiocarcinoma (n=29), hepatic cholangiocarcinoma (n=2), other (n=3). HCC characteristics: male 82%; mean age 67 years; cirrhosis 87%; main etiologies: alcohol 35%, HCV 30%, alcohol and HCV 15%, non-alcoholic fatty liver disease 6%; tumor stage: BCLC-0 11%, A 43%, B 19%, C 16% and D 11%; first treatment: transarterial chemoembolization (23%), percutaneous ablation (22%), symptomatic treatment (20%), resection (11%), sorafenib (11%). Three hundred and fifty-six patients (53%) were diagnosed outside of screening programs, mainly owing to the fact that they suffered from an undiagnosed liver disease (76%) and to the poor adherence to the screening program (18%). These patients were mainly male (P<.001), with an alcoholic etiology (P<.001) and active alcohol consumption (P<.001). Moreover, the disease was predominantly diagnosed at more advanced stages (P<.001) and was addressed with less radical treatments (P<.001). CONCLUSIONS: In Spain, the main cause of diagnosis of a HCC outside the context of a screening program is the absence of a prior diagnosis of a liver disease, particularly in alcohol-consuming men. Detecting a liver disease in asymptomatic populations and improving adherence to screening programs are the main areas that must be subject to improvement in order to improve the early detection of HCC.

Regional Specialisation of T Cell Subsets and Apoptosis in the Human Gut Mucosa: Differences Between Ileum and Colon in Healthy Intestine and Inflammatory Bowel Diseases.

BACKGROUND AND AIMS: There is very limited information regarding region-specific immunological response in human intestine. We aimed to determine differences in immune compartmentalisation between ileum and colon in healthy and inflamed mucosa. METHODS: T cell profile and its apoptosis were measured by flow cytometry, Th1, Th17, Treg [CD4(+)CD25(+)FOXP3(+)], double positive [DP, CD3(+)CD4(+)CD8(+)] and double negative T cells [DN, CD3(+)CD4(-)CD8(-)], immunohistochemistry [FOXP3, caspase-3], and real-time polymerase chain reaction [PCR] [IFN-γ, IL-17-A, and FOXP3] on biopsies from different regions of healthy intestine and of intestine in inflammatory bowel diseases. RESULTS: Healthy colon showed higher percentages of Treg, Th17, and DN, and lower numbers of DP T cells compared with ileum [p < 0.05]. Some but not all region-specific differences were lost in inflammatory conditions. Disease-specific patterns were found: a Th1/Th17 pattern and a Th17 pattern in Crohn's disease and ulcerative colitis respectively, whereas a reduction in Th1/Th17 was found in microscopic colitis. In colonic Crohn's disease and microscopic colitis, DN T cells had a pattern inverse to that of Th1/Th17 (increase in microscopic colitis [p < 0.05] and decrease in Crohn's disease [p < 0.005]). Higher levels of lymphocyte apoptosis were found in healthy colon compared with the ileal counterparts [p = 0.001]. All forms of colonic inflammation presented a dramatic decrease in apoptosis compared with healthy colon. By contrast ileal Crohn's disease showed higher levels of cleaved-Caspase(+) CD3(+) cells. CONCLUSIONS: Immunological differences exist in healthy gastrointestinal tract. Inflammatory processes overwhelm some location-specific differences, whereas others are maintained. Care has to be taken when analysing immune response in intestinal inflammation, as location-specific differences may be relevant.

Accuracy of GastroPanel for the diagnosis of atrophic gastritis.

BACKGROUND: It has been suggested that GastroPanel might be a useful tool for the diagnosis of chronic atrophic gastritis (CAG) measuring four biomarkers in blood: basal gastrin-17 (G17), pepsinogen I and II (PGI and PGII), and Helicobacter pylori antibodies. AIM: To determine the accuracy of GastroPanel for the diagnosis of CAG. METHODS: This was a prospective, blinded, multicenter study that included dyspeptic patients. G17, PGI, and PGII were determined by enzyme immunoassays. Three antrum and two corpus biopsies were obtained for standard histological analysis and rapid urease test. Biopsies were analyzed by a single blinded expert pathologist. RESULTS: Ninety-one patients were included (77% women, mean age 44 years, 51% H. pylori positive, 17% with CAG). G17 was reduced in patients with antrum CAG (5.4 vs. 13.4 pmol/l; P<0.01) and increased in patients with corpus CAG (11 vs. 24 pmol/l; P<0.05), but its accuracy was only acceptable in the case of corpus localization [area under the receiver operating characteristic curve (AUC), 74%]; PGII difference was almost statistically significant only when testing for corpus atrophy (33 vs. 21 µg/l; P=0.05; AUC=72%). The PGI and PGI/PGII ratio showed no significant differences (AUCs were all unacceptably low). Helicobacter pylori antibody levels were higher in H. pylori-infected patients (251 vs. 109 EIU, P=0.01; AUC=70). The accuracy of GastroPanel for the diagnosis of CAG was as follows: sensitivity 50%; specificity 80%; positive 25% and negative 92% predictive values; and positive 2.4 and negative 0.6 likelihood ratios. CONCLUSION: GastroPanel is not accurate enough for the diagnosis of CAG; thus, its systematic use in clinical practice cannot be recommended.

Randomised clinical trial comparing sequential and concomitant therapies for Helicobacter pylori eradication in routine clinical practice.

OBJECTIVES: No trial has compared non-bismuth quadruple 'sequential' and 'concomitant' regimens in settings with increasing clarithromycin rates. The study aims to compare the effectiveness and safety of these therapies for Helicobacter pylori treatment. DESIGN: Prospective randomised clinical trial in 11 Spanish hospitals. Patients naïve to eradication therapy with non-investigated/functional dyspepsia or peptic ulcer disease were included. Randomised (1:1) to sequential (omeprazole (20 mg/12 h) and amoxicillin (1 g/12 h) for 5 days, followed by 5 days of omeprazole (20 mg/12 h), clarithromycin (500 mg/12 h) and metronidazole (500 mg/12 h)), or concomitant treatment (same drugs taken concomitantly for 10 days). Eradication was confirmed with (13)C-urea breath test or histology 4 weeks after treatment. Adverse events (AEs) and compliance were evaluated with questionnaires and residual medication count. RESULTS: 338 consecutive patients were randomised. Mean age was 47 years, 60% were women, 22% smokers and 20% had peptic ulcer. Concomitant and sequential eradication rates were, respectively, 87% vs 81% by intention-to-treat (p=0.15) and 91% vs 86% (p=0.131) per protocol. Respective compliances were 83% vs 82%. Treatment-emergent AEs were reported in 59% of patients (no differences found between treatments). AEs were mostly mild (60%), and average length was 6.1 days, causing discontinuation only in 12 patients. Multivariate analysis: 'concomitant' treatment showed an OR of 1.5 towards better eradication rate in a borderline significance CI (95% CI 0.9 to 2.8). CONCLUSIONS: Concomitant therapy led to a non-statistically significant advantage (5%) over sequential therapy, coming closer to 90% cure rates. Both therapies showed an acceptable safety profile. ClincialTrials.gov: NCT01273441.

Helicobacter pylori infection as a cause of iron deficiency anaemia of unknown origin.

AIM: To assess the aetiological role of Helicobacter pylori (H. pylori) infection in adult patients with iron-refractory or iron-dependent anaemia of previously unknown origin. METHODS: Consecutive patients with chronic iron-deficient anaemia (IDA) with H. pylori infection and a negative standard work-up were prospectively evaluated. All of them had either iron refractoriness or iron dependency. Response to H. pylori eradication was assessed at 6 and 12 mo from follow-up. H. pylori infection was considered to be the cause of the anaemia when a complete anaemia resolution without iron supplements was observed after eradication. RESULTS: H. pylori was eradicated in 88 of the 89 patients. In the non-eradicated patient the four eradicating regimens failed. There were violations of protocol in 4 patients, for whom it was not possible to ascertain the cause of the anaemia. Thus, 84 H. pylori eradicated patients (10 men; 74 women) were available to assess the effect of eradication on IDA. H. pylori infection was considered to be the aetiology of IDA in 32 patients (38.1%; 95%CI: 28.4%-48.8%). This was more frequent in men/postmenopausal women than in premenopausal women (75% vs 23.3%; P < 0.0001) with an OR of 9.8 (95%CI: 3.3-29.6). In these patients, anaemia resolution occurred in the first follow-up visit at 6 mo, and no anaemia or iron deficiency relapse was observed after a mean follow-up of 21 ± 2 mo. CONCLUSION: Gastric H. pylori infection is a frequent cause of iron-refractory or iron-dependent anaemia of previously unknown origin in adult patients.

Comparison of lymphocyte isolation methods for endoscopic biopsy specimens from the colonic mucosa.

An ideal method of immune cell isolation should provide maximum cell yield without disturbing functional properties. Intestinal endoscopic biopsies, in contrast to surgical samples, allow the study of all disease stages but have the drawback of a minimum amount of tissue available, making protocol optimization mandatory. We compared for the first time two methods of separation of colonic epithelium and five methods of lamina propria cell isolation for colonic biopsy specimens (mechanical, enzymatic and organ culture protocols). Lymphocyte number, viability and phenotype (CD45+, CD103+, CD3+, CD4+, CD8+, CD19+, CD16-56+) were analyzed by flow cytometry. Neither of the two epithelial detachment protocols achieved proper epithelial separation, though the high intensity ion chelation method was more accurate. Maximum cell yield of lamina propria lymphocytes without phenotypic modification was obtained with overnight smooth enzymatic digestion. High dose collagenase incubation caused a marked decrease in CD4+ lymphocytes of the lamina propria as compared to low enzymatic method (p=0.004). Mechanical and biopsy culture are not advisable methods because of the low cell yield, and phenotypic alterations and high contamination rate, respectively.

Paracetamol in therapeutic dosages and acute liver injury: causality assessment in a prospective case series.

BACKGROUND: Acute liver injury (ALI) induced by paracetamol overdose is a well known cause of emergency hospital admission and death. However, there is debate regarding the risk of ALI after therapeutic dosages of the drug.The aim is to describe the characteristics of patients admitted to hospital with jaundice who had previous exposure to therapeutic doses of paracetamol. An assessment of the causality role of paracetamol was performed in each case. METHODS: Based on the evaluation of prospectively gathered cases of ALI with detailed clinical information, thirty-two cases of ALI in non-alcoholic patients exposed to therapeutic doses of paracetamol were identified. Two authors assessed all drug exposures by using the CIOMS/RUCAM scale. Each case was classified into one of five categories based on the causality score for paracetamol. RESULTS: In four cases the role of paracetamol was judged to be unrelated, in two unlikely, and these were excluded from evaluation. In seven of the remaining 26 cases, the RUCAM score associated with paracetamol was higher than that associated with other concomitant medications. The estimated incidence of ALI related to the use of paracetamol in therapeutic dosages was 0.4 per million inhabitants older than 15 years of age and per year (99%CI, 0.2-0.8) and of 10 per million paracetamol users-year (95% CI 4.3-19.4). CONCLUSIONS: Our results indicate that paracetamol in therapeutic dosages may be considered in the causality assessment in non-alcoholic patients with liver injury, even if the estimated incidence of ALI related to paracetamol appears to be low.

Apoptosis resistance of mucosal lymphocytes and IL-10 deficiency in patients with steroid-refractory Crohn's disease.

BACKGROUND: Apoptosis resistance of T-cells is considered an abnormality of immune pathways in Crohn's disease (CD). It has been previously shown that corticosteroids induce apoptosis of cells involved in inflammation. Thus, our aim was to assess the apoptosis of mononuclear cells and pro/antiinflammatory cytokines in the intestinal mucosa of patients with active CD, related to steroid response, and identify cellular and molecular factors that may predict this response to therapy. METHODS: Patients with CD (n = 26), ulcerative colitis (UC) (n = 32), and controls (n = 10) were prospectively studied with mucosal biopsies before and 7-10 days after corticosteroid treatment. Immunophenotype and apoptosis of T and B lymphocytes, plasma cells, and macrophages were assessed by flow cytometry, immunohistochemistry, and immunofluorescence. The cytokine expression pattern was evaluated by quantitative polymerase chain reaction (PCR). RESULTS: Apoptosis resistance of T and B lymphocytes was observed only in steroid-refractory and -dependent CD patients as compared to responsive patients (P = 0.032; P = 0.004, respectively), being evident after steroid treatment. Interleukin (IL)-10 was markedly increased at baseline in steroid-responsive patients compared to the nonresponders (P = 0.006; sensitivity: 88.8%; specificity: 66.6% to predict steroid response). CONCLUSIONS: Apoptosis resistance of mucosal T and B cells in steroid-refractory and -dependent CD patients appears during the evolution of the acute phase, limiting its clinical application as a predictor marker. In contrast, increased expression of IL-10 at an early stage of active steroid-sensitive CD patients supports its usefulness at predicting a good steroid response. Steroid-dependent and -refractory CD patients share similar molecular and cellular pathophysiological mechanisms.

Evolution of the incidence of collagenous colitis and lymphocytic colitis in Terrassa, Spain: a population-based study.

BACKGROUND: Previous studies suggest an increase in the incidence rate of microscopic colitis in recent decades. The aim was to evaluate changes in the population-based incidence rate of microscopic colitis and its subtypes over time in Terrassa, Spain. METHODS: This was a prospective study during the period 2004-2008, with a comparison of data from the period 1993-1997. The catchment area was a mixed rural-urban type, with nearly 290,000 inhabitants. All patients with nonbloody chronic diarrhea referred for a diagnostic colonoscopy were included. Multiple biopsy specimen samples were obtained when the macroscopic appearance of the colonic mucosa was normal to rule out microscopic colitis. Crude and adjusted incidence rates based on either the year of diagnosis or the date of onset of symptoms were calculated. RESULTS: Forty patients with collagenous colitis (CC) and 32 with lymphocytic colitis (LC) were identified. The mean annual incidence of CC and LC based on the year of onset of symptoms was 2.6/10(5) inhabitants (95% confidence interval [CI], 1.9-3.3), and 2.2/10(5) inhabitants (95% CI, 1.5-3.0), respectively. Incidence rates for CC based on the year of onset of symptoms were significantly higher in the period 2004-2008 than in 1993-1997 (2.6 versus 1.1/10(5) ; P = 0.012). The increase in CC incidence was more marked in women (P = 0.047) than in men (P = 0.19). CONCLUSIONS: The annual incidence of CC in Terrassa increased over time, mainly in women. Nevertheless, the rates were much lower than those observed in northern Europe, suggesting that there is a north-south difference in the incidence of microscopic colitis.