Long Non-Coding RNA Signatures in the Ileum and Colon of Crohn's Disease Patients and Effect of Anti-TNF-α Treatment on Their Modulation.

Biological therapies only benefit one-third of patients with Crohn's disease (CD). For this reason, a deeper understanding of the mechanisms by which biologics elicit their effect on intestinal mucosa is needed. Increasing evidence points toward the involvement of long noncoding RNAs (lncRNAs) in the pathogenesis of CD, although their role remains poorly studied. We aimed to characterize lncRNA profiles in the ileum and colon from CD patients and evaluate the effect of anti-TNF-α treatment on their transcription. Terminal ileum and left colon samples from 30 patients (active CD = 10, quiescent CD = 10, and healthy controls (HCs) = 10) were collected for RNA-seq. The patients were classified according to endoscopic activity. Furthermore, biopsies were cultured with infliximab, and their transcriptome was determined by Illumina gene expression array. A total of 678 differentially expressed lncRNAs between the terminal ileum and left colon were identified in HCs, 438 in patients with quiescent CD, and 468 in patients with active CD. Additionally, we identified three new lncRNAs in the ileum associated with CD activity. No differences were observed when comparing the effect of infliximab according to intestinal location, presence of disease (CD vs. HC), and activity (active vs. quiescent). The expression profiles of lncRNAs are associated with the location of intestinal tissue, being very different in the ileum and colon. The presence of CD and disease activity are associated with the differential expression of lncRNAs. No modulatory effect of infliximab has been observed in the lncRNA transcriptome.

Differential Effects of Anti-TNFα and Anti-α4ß7 Drugs on Circulating Dendritic Cells Migratory Capacity in Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is an idiopathic and chronic disorder that includes ulcerative colitis (UC) and Crohn's disease (CD). Both diseases show an uncontrolled intestinal immune response that generates tissue inflammation. Dendritic cells (DCs) are antigen-presenting cells that play a key role in tolerance maintenance in the gastrointestinal mucosa. Although it has been reported that DC recruitment by the intestinal mucosa is more prominent in IBD patients, the specific mechanisms governing this migration are currently unknown. In this study, the expression of several homing markers and the migratory profile of circulating DC subsets towards intestinal chemo-attractants were evaluated and the effect of biological drugs with different mechanisms of action, such as anti-TNFα or anti-integrin α4ß7 (vedolizumab), on this mechanism in healthy controls (HCs) and IBD patients was also assessed. Our results revealed that type 2 conventional DCs (cDC2) express differential homing marker profiles in UC and CD patients compared to HCs. Indeed, integrin ß7 was differentially modulated by vedolizumab in CD and UC. Additionally, although CCL2 displayed a chemo-attractant effect over cDC2, while biological therapies did not modulate the expression of the homing markers, we paradoxically found that anti-TNF-treated cDC2 increased their migratory capacity towards CCL2 in HCs and IBD. Our results therefore suggest a key role for cDC2 migration towards the intestinal mucosa in IBD, something that could be explored in order to develop novel diagnostic biomarkers or to unravel new immunomodulatory targets in IBD.

Ecoendoscopia con punción-aspiración intermitente en el diagnóstico de lesiones sólidas pancreáticas. Estudio piloto / Intermittent endoscopic ultrasound guided fine-needle aspiration for the diagnosis of solid pancreatic lesions. A pilot study

Antecedentes y objetivo: la ecoendoscopia con punción-aspiración con aguja fina (USE-PAAF) es el método de elección para la toma de muestras de lesiones sólidas pancreáticas. Sin embargo, existe una heterogeneidad significativa en cuanto a la técnica utilizada. La aspiración intermitente no ha sido evaluada en lesiones sólidas pancreáticas y podría mejorar el rendimiento diagnóstico.Métodos: estudio piloto de no inferioridad, simple ciego. Se incluyeron de forma prospectiva pacientes con lesiones sólidas pancreáticas e indicación de USE-PAAF. Los pacientes fueron asignados aleatoriamente para el método de aspiración intermitente (AI) o continua (AC). Se evaluaron el rendimiento diagnóstico, la celularidad, la contaminación hemática y el número de pases necesarios para llegar al diagnóstico.Resultados: treinta y tres pacientes fueron asignados a AC (16 pacientes) o AI (17 pacientes). El rendimiento diagnóstico fue del 87,5 % en AC y del 94,1 % en AI (OR 2,29, IC 95 %: 0,19-27,99, p = 0,51). En el grupo de AI las muestras tuvieron mayor celularidad (OR 1,83, IC 95 %: 0,48-6,91, p = 0,37) y menor contaminación hemática (OR 0,38, IC 95 %: 0,09-1,54, p = 0,18). El número de pases necesarios para llegar al diagnóstico fue de 2,12 en AC y 1,94 con AI (p = 0,64). Se obtuvo citología líquida en el 73,3 % de AI y en el 61,5 % de AC (OR 1,72, IC 95 % 0,35-8,50).Conclusiones: la técnica de AI no fue inferior a la AC en términos de precisión diagnóstica, con tendencia a obtener mayor celularidad, menor contaminación hemática y frecuente presencia de bloque celular en la evaluación de lesiones sólidas pancreáticas. (AU)

Intermittent endoscopic ultrasound guided fine-needle aspiration for the diagnosis of solid pancreatic lesions. A pilot study.

BACKGROUND AND PURPOSE: endoscopic ultrasound guided fine-needle aspiration (EUS-FNA) is the method of choice for sampling pancreatic solid lesions. However, there is significant heterogeneity in terms of the technique used. Intermittent aspiration has not been evaluated in pancreatic solid lesions and could improve the diagnostic performance. METHODS: a single-blind, non-inferiority pilot study was performed. Patients with solid pancreatic lesions and an indication for EUS-FNA were prospectively included. Patients were randomly assigned to intermittent (IS) or continuous (CS) suction techniques. Diagnostic performance, cellularity, blood contamination and the number of passes required to reach a diagnosis were evaluated. MAIN RESULTS: thirty-three patients were assigned to CS (16 patients) or IS (17 patients). Diagnostic performance was 87.5 % for CS and 94.1 % for IS (OR 2.29, 95 % CI: 0.19-27.99, p = 0.51). In the IS group, samples had a higher cellularity (OR 1.83, 95 % CI: 0.48-6.91, p = 0.37) and lower blood contamination (OR 0.38, 95 % CI: 0.09-1.54, p = 0.18). The number of passes required to reach a diagnosis was 2.12 for CS and 1.94 for IS (p = 0.64). Liquid cytology was obtained in 73.3 % of IS and 61.5 % of CS (OR 1.72, 95 % CI: 0.35-8.50). CONCLUSIONS: the IS technique was not inferior to CS in terms of diagnostic accuracy in the evaluation of pancreatic solid lesions, with a tendency to obtain higher cellularity, lower blood contamination and the frequent presence of cell block.

Lunasin Peptide is a Modulator of the Immune Response in the Human Gastrointestinal Tract.

INTRODUCTION: Lunasin is a soybean bioactive peptide with a variety of beneficial properties against chronic disorders. However, its effect in human primary intestinal cells remains unknown. Hence, this study aims to characterize its ex vivo biological activity in the human intestinal mucosa. METHODS AND RESULTS: Human intestinal biopsies, obtained from healthy controls, are ex vivo conditioned with lunasin both in the presence/absence of lipopolysaccharide (LPS). Peptide maintains its stability during biopsy culture by HPLC-MS/MS analysis. Lunasin is bioactive in the human mucosa, as it induces IL-1ß, TNF-α, IL-17A, CCL2, and PGE2/COX-2 gene expression together with an increased expression of tolerogenic IL-10 and TGFß, while it also downregulates the expression of iNOS and subunit p65 from NF-κB. Indeed, lunasin also abrogates the LPS-induced pro-inflammatory response, downregulating IL-17A, IFNγ, and IL-8 expression, and inducing IL-10 and TGFß expression. These results are also mirrored in the cell-free culture supernatants at the protein level by Multiplex. Moreover, lunasin further induces a regulatory phenotype and function on human intestinal conventional dendritic cell and macrophage subsets as assessed by flow cytometry. CONCLUSIONS: We hereby have characterized lunasin as an immunomodulatory peptide with potential capacity to prevent immune and inflammatory-mediated disorders in the human gastrointestinal tract.

Effectiveness of rectal indomethacin in the prevention of acute pancreatitis after endoscopic retrograde cholangiopancreatography in unselected patients

BACKGROUND AND AIMS: several studies have shown that rectal indomethacin decreases the risk of acute pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). However, in recent studies, its effectiveness is being questioned, especially in average risk patients. Our principal aim was to evaluate the efficacy of rectal indomethacin prophylaxis in the development of post-ERCP pancreatitis (PEP). METHODS: a retrospective cohort study was conducted at a third-level university hospital. Data was collected from every patients who underwent ERCP between January 2014 and June 2016. After February 2015, all patients received 100 mg of rectal indomethacin prior to ERCP. We analyzed groups, with indomethacin and without indomethacin, in unselected patients. RESULTS: a total of 524 patients were analyzed, with a mean age of 71.1 ± 17.0 (standard deviation [SD]) years. Of the total number of patients, 393 (75%) had an average risk; 277 received rectal indomethacin prior to ERCP, while 247 did not. In the group with indomethacin, 12 patients developed PEP (4.33%) versus ten in the indomethacin-free group (4.04%) (OR 1.33; 95% confidence interval [CI], 0.52-3.40; p = 0.56). Severe-moderate PEP developed in seven patients (2.52%) in the indomethacin group and in two patients (0.81%) in the indomethacin-free group (p = 0.24). Previous sphincterotomy was a protective factor (OR 0.02; 95% CI, 0.02-0.2; p = 0.001) and age < 45 years was a risk factor: (OR 3.43; 95% CI, 1.14-10.32; p = 0.03). CONCLUSIONS: rectal indomethacin does not appear to decrease the risk of developing PEP in unselected patients

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Effectiveness of rectal indomethacin in the prevention of acute pancreatitis after endoscopic retrograde cholangiopancreatography in unselected patients.

BACKGROUND AND AIMS: several studies have shown that rectal indomethacin decreases the risk of acute pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). However, in recent studies, its effectiveness is being questioned, especially in average risk patients. Our principal aim was to evaluate the efficacy of rectal indomethacin prophylaxis in the development of post-ERCP pancreatitis (PEP). METHODS: a retrospective cohort study was conducted at a third-level university hospital. Data was collected from every patients who underwent ERCP between January 2014 and June 2016. After February 2015, all patients received 100 mg of rectal indomethacin prior to ERCP. We analyzed groups, with indomethacin and without indomethacin, in unselected patients. RESULTS: a total of 524 patients were analyzed, with a mean age of 71.1 ± 17.0 (standard deviation [SD]) years. Of the total number of patients, 393 (75%) had an average risk; 277 received rectal indomethacin prior to ERCP, while 247 did not. In the group with indomethacin, 12 patients developed PEP (4.33%) versus ten in the indomethacin-free group (4.04%) (OR 1.33; 95% confidence interval [CI], 0.52-3.40; p = 0.56). Severe-moderate PEP developed in seven patients (2.52%) in the indomethacin group and in two patients (0.81%) in the indomethacin-free group (p = 0.24). Previous sphincterotomy was a protective factor (OR 0.02; 95% CI, 0.02-0.2; p = 0.001) and age < 45 years was a risk factor: (OR 3.43; 95% CI, 1.14-10.32; p = 0.03). CONCLUSIONS: rectal indomethacin does not appear to decrease the risk of developing PEP in unselected patients.

Immunomodulatory Effect of Gut Microbiota-Derived Bioactive Peptides on Human Immune System from Healthy Controls and Patients with Inflammatory Bowel Disease.

Bioactive peptides secreted by probiotic Bifidobacterium longum (peptide B7) and opportunistic pathogen Bacteroides fragilis (peptide B12) modulate the intestinal cytokine milieu in health. Here, we characterized their capacity to modulate both the mucosal cytokine production and the phenotype of circulating antigen presenting cells (APCs) in active inflammatory bowel disease (IBD). The IBD mucosa produced higher levels of pro-inflammatory cytokines referred to healthy controls (HCs). Peptides B7 and B12, however, did not ameliorate the mucosal cytokine milieu in IBD. Human circulating APCs (B-cells, monocytes, plasmacytoid dendritic cells (pDCs), and conventional dendritic cells (cDCs)) were characterized by flow cytometry in presence/absence of the peptides. Circulating B-cells, monocytes, and cDCs from IBD patients were more activated than those from HCs. Peptide B7, but not B12, decreased CCR2 expression on all APC subsets from HC, but not IBD patients. Moreover, both peptides tend to further increase their pro-inflammatory profile in IBD. In summary, IBD patients display mucosal and circulating APC pro-inflammatory properties. Peptide B7 immunomodulatory capacity elicited over circulating APCs from HC, but not IBD patients, suggests the presence of disrupted modulatory mechanisms for this peptide in IBD. Future studies should address the effect of bacteria-derived immunomodulatory peptides in non-inflamed (quiescent) IBD patients.

Linfomas de colon: análisis de nuestra experiencia en los últimos 23 años / Colon lymphomas: an analysis of our experience over the last 23 years

Introducción: el linfoma de colon (LC) es una variedad poco frecuente de los linfomas no Hodgkin (LNH) que representa menos del 0,6% de todas las neoplasias primarias del colon. Realizar un diagnóstico precoz es difícil debido a que las manifestaciones clínicas son inespecíficas. El objetivo de esta revisión fue presentar nuestra experiencia en los últimos años en cuanto a características clínicas, endoscópicas, histológicas, diagnóstico, tratamiento y evolución de los LC. Pacientes y métodos: se realizó un análisis retrospectivo y descriptivo de pacientes con LC diagnosticados desde 1994 hasta 2016 en el Hospital Universitario de la Princesa, Madrid. Resultados: se identificaron 29 pacientes con LC (mediana de edad 67 años, 18 hombres [62%]). Las manifestaciones clínicas más comunes fueron dolor abdominal, síndrome constitucional, diarrea y masa abdominal palpable. Ocho (27,6%) pacientes se encontraban asintomáticos y seis (20,6%) debutaron con complicaciones quirúrgicas. En 24 pacientes se realizó colonoscopia y los hallazgos más frecuentes fueron infiltración difusa y tumoración. La localización más común fue el colon descendente y sigma. Los subtipos histológicos más frecuentes fueron: LNH de células B del manto y linfoma difuso de células grandes tipo B. Se trató con quimioterapia a 28 pacientes (96,5%), con cirugía a seis (20,7%) y uno recibió quimio y radioterapia. La mediana del tiempo de supervivencia fue de 156 meses. La supervivencia al año fue del 100,0% y a los diez años, del 55,0%. Conclusiones: debido al aspecto endoscópico variable del LC, es necesario el estudio histológico de todos los segmentos del colon. El tratamiento de elección es la quimioterapia y en casos de complicaciones es necesaria la cirugía urgente con quimioterapia posterior. Los principales factores asociados a peor supervivencia son la edad mayor de 65 años, la existencia de recidiva y las respuestas parciales o nulas

Introduction: colon lymphoma (CL) is an uncommon variety of non-Hodgkin lymphoma (NHL) that represents less than 0.6% of all primary colonic neoplasms. Early diagnosis is challenging as clinical manifestations are non-specific. The goal of this review was to discuss our experience over the last few years regarding the clinical, endoscopic, histological, diagnostic, therapeutic and evolutionary characteristics of CL. Patients and methods: a retrospective, descriptive analysis of patients with CL diagnosed from 1994 to 2016 at the Hospital Universitario de La Princesa (Madrid, Spain) was performed. Results: a total of 29 patients with CL were identified, with a median age of 67 years; 18 were male (62%). The most common clinical manifestations included abdominal pain, constitutional syndrome, diarrhea and a palpable abdominal mass. Eight (27.6%) patients were asymptomatic and six (20.6%) initially presented with surgical complications. A colonoscopy was performed in 24 patients and the most common findings included diffuse infiltration and solid growth. The most common location was the descending and sigmoid colon. The most common histological subtypes included mantle B-cell NHL and diffuse large B-cell lymphoma. Chemotherapy was administered to 28 patients (96.5%), surgery was performed in six (20.7%) and combined chemo-radiotherapy was administered to one patient. Median survival was 156 months. Survival was 100.0% at one year and 55.0% at ten years. Conclusions: due to the variable aspects of CL on endoscopy, a histological study of all colonic segments is required. Chemotherapy is the treatment of choice and emergency surgery followed by chemotherapy is required for complications. Primary factors associated with poorer survival include age above 65 years, relapsing disease and partial or nil responses

Colon lymphomas: an analysis of our experience over the last 23 years.

INTRODUCTION: colon lymphoma (CL) is an uncommon variety of non-Hodgkin lymphoma (NHL) that represents less than 0.6% of all primary colonic neoplasms. Early diagnosis is challenging as clinical manifestations are non-specific. The goal of this review was to discuss our experience over the last few years regarding the clinical, endoscopic, histological, diagnostic, therapeutic and evolutionary characteristics of CL. PATIENTS AND METHODS: a retrospective, descriptive analysis of patients with CL diagnosed from 1994 to 2016 at the Hospital Universitario de La Princesa (Madrid, Spain) was performed. RESULTS: a total of 29 patients with CL were identified, with a median age of 67 years; 18 were male (62%). The most common clinical manifestations included abdominal pain, constitutional syndrome, diarrhea and a palpable abdominal mass. Eight (27.6%) patients were asymptomatic and six (20.6%) initially presented with surgical complications. A colonoscopy was performed in 24 patients and the most common findings included diffuse infiltration and solid growth. The most common location was the descending and sigmoid colon. The most common histological subtypes included mantle B-cell NHL and diffuse large B-cell lymphoma. Chemotherapy was administered to 28 patients (96.5%), surgery was performed in six (20.7%) and combined chemo-radiotherapy was administered to one patient. Median survival was 156 months. Survival was 100.0% at one year and 55.0% at ten years. CONCLUSIONS: due to the variable aspects of CL on endoscopy, a histological study of all colonic segments is required. Chemotherapy is the treatment of choice and emergency surgery followed by chemotherapy is required for complications. Primary factors associated with poorer survival include age above 65 years, relapsing disease and partial or nil responses.

Long-term outcome of chronic hepatitis C patients with sustained virological response to peginterferon plus ribavirin.

AIM: To assess the clinical, biochemical and virological long-term outcome in chronic hepatitis C (CHC) patients with a sustained virological response (SVR) after peginterferon (PEG-IFN) plus ribavirin combination therapy. METHODS: One hundred and fifty three patients with a SVR after treatment with PEG-IFN plus ribavirin were included in a 5-year follow-up study in a single Spanish center, based on standard clinical practice. Clinical anamnesis, biochemical analysis, hepatitis C virus RNA and alpha-fetoprotein measurement, ultrasonography and transient elastography were performed annually. RESULTS: The mean follow-up period of the 153 patients was 76 ± 13 mo after they obtained a SVR. Five patients (3.26%) presented with cirrhosis before treatment and 116 (75.8%) had genotype 1. No patient showed evidence of hepatic decompensation. One patient (0.65%) developed a hepatocellular carcinoma at month 30 after achieving SVR. There were no virological relapses during this follow-up period. Persistently elevated alanine aminotransferase was found in only one patient (0.65%). At the end of the 5-year follow-up, the mean value of transient elastography was 7 ± 4.3 kPa (F1). There were no deaths and no other tumors. CONCLUSION: The long-term outcome of 153 CHC patients with SVR to PEG-IFN plus ribavirin was good. No evidence of a virological relapse was seen. One patient (0.65%) developed a hepatocellular carcinoma.

[Hepatic involvement in celiac disease]. / Afectación hepática en la enfermedad celíaca.

Celiac disease (CD) is an autoimmune enteropathy triggered by gluten ingestion in genetically susceptible individuals. Hypertransaminasemia has been observed in up to 40% of untreated celiac patients and is usually resolved by a gluten-free diet. The most common type of liver disease associated with CD is non-specific reactive hepatitis, while association with viral hepatitis or autoimmune-mediated liver diseases such as autoimmune hepatitis, primary biliary cirrhosis or primary sclerosing cholangitis is less frequent. Therefore, a practical recommendation would be to look for liver disfunction in patients with CD as well as to perform diagnostic tests for CD in patients with hypertransaminasemia or cholestasis of unknown etiology.

Afectación hepática en la enfermedad celíaca / Hepatic involvement in coeliac disease

La enfermedad celíaca (EC) es una enteropatía autoinmune desencadenada por la ingestión de gluten en individuos con susceptibilidad genética. Se ha observado la existencia de una hipertransaminasemia en aproximadamente el 40% de los pacientes celíacos no tratados, que suele resolverse al excluir el gluten de la dieta. La forma más frecuente de afectación hepática en estos pacientes es una hepatitis reactiva inespecífica, y es menos común su asociación con las hepatitis virales o las hepatopatías autoinmunes, como la hepatitis autoinmune, la cirrosis biliar primaria o la colangitis esclerosante primaria. Por tanto, sería recomendable la búsqueda de hepatopatía en enfermos celíacos y, de igual modo, la realización de pruebas diagnósticas de EC en pacientes con hipertransaminasemia o colestasis de causa no filiada

Celiac disease (CD) is an autoimmune enteropathy triggered by gluten ingestion in genetically susceptible individuals. Hypertransaminasemia has been observed in up to 40% of untreated celiac patients and is usually resolved by a gluten-free diet. The most common type of liver disease associated with CD is non-specific reactive hepatitis, while association with viral hepatitis or autoimmune-mediated liver diseases such as autoimmune hepatitis, primary biliary cirrhosis or primary sclerosing cholangitis is less frequent. Therefore, a practical recommendation would be to look for liver disfunction in patients with CD as well as to perform diagnostic tests for CD in patients with hypertransaminasemia or cholestasis of unknown etiology