Jordi Guardiola

A prognostic index of the survival of patients with unresectable hepatocellular carcinoma after transcatheter arterial chemoembolization.

Transcatheter arterial chemoembolization (TACE) has been used as a palliative treatment for patients with unresectable hepatocellular carcinoma (HCC), but its prognostic usefulness has not previously been clarified.

DNA Methylation Biomarkers for Noninvasive Diagnosis of Colorectal Cancer

DNA methylation biomarkers for noninvasive diagnosis of colorectal cancer (CRC) and precursor lesions have been extensively studied. Different panels have been reported attempting to improve current protocols in clinical practice, although no definite biomarkers have been established. In the present study, we have examined patient biopsies starting from a comprehensive analysis of DNA methylation differences between paired normal and tumor samples in known cancer-related genes aiming to select the best performing candidates informative for CRC diagnosis in stool samples. Five selected markers were considered for subsequent analyses in independent biologic cohorts and in silico data sets. Among the five selected genes, three of them (AGTR1, WNT2 and SLIT2) were validated in stool DNA of affected patients with a detection sensitivity of 78% [95% confidence interval (CI), 56%–89%]. As a reference, DNA methylation of VIM and SEPT9 was evaluated in a subset of stool samples yielding sensitivities of 55% and 20%, respectively. Moreover, our panel may complement histologic and endoscopic diagnosis of inflammatory bowel disease (IBD)-associated neoplasia, as it was also efficient detecting aberrant DNA methylation in non-neoplastic tissue samples from affected patients. This novel panel of specific methylation markers can be useful for early diagnosis of CRC using stool DNA and may help in the follow-up of high-risk patients with IBD. Cancer Prev Res; 6(7); 656–65. ©2013 AACR.

A new rapid quantitative test for fecal calprotectin predicts endoscopic activity in ulcerative colitis.

Background:Fecal calprotectin (FC) determined by the enzyme-linked immunosorbent assay (ELISA) test has been proposed as a promising biomarker of endoscopic activity in ulcerative colitis (UC). However, data on its accuracy in predicting endoscopic activity is scarce. Besides, FC determined by the quantitative-point-of-care test (FC-QPOCT) that provides rapid and individual results could optimize its use in clinical practice. The aims of our study were to evaluate the ability of FC to predict endoscopic activity according to the Mayo score in patients with UC when determined by FC-QPOCT and to compare it with the ELISA test (FC-ELISA). Methods:FC was determined simultaneously by FC-ELISA and FC-QPOCT in patients with UC undergoing colonoscopy. Clinical disease activity and endoscopy were assessed according to the Mayo score. Blood tests were taken to analyze serological biomarkers. Results:A total of 146 colonoscopies were performed on 123 patients with UC. FC-QPOCT correlated more closely with the Mayo endoscopic subscore (Spearman’s correlation coefficient rank r = 0.727, P < 0.001) than clinical activity (r = 0.636, P < 0.001), platelets (r = 0.381, P < 0.001), leucocytes (r = 0.300, P < 0.001), and C-reactive protein (r = 0.291, P = 0.002). The prediction of “endoscopic remission” (Mayo endoscopic subscore ⩽1) with FC-QPOCT (280 µg/g) and FC-ELISA (250 µg/g) presented an area under the curve of 0.906 and 0.924, respectively. The interclass correlation index between both tests was 0.904 (95% confidence interval, 0.864–0.932; P < 0.001). Conclusions:FC determined by QPOCT was an accurate surrogate marker of “endoscopic remission” in UC and presented a good correlation with the FC-ELISA test.

Novel Methylation Panel for the Early Detection of Colorectal Tumors in Stool DNA

BACKGROUND Previous studies showed that the assessment of promoter hypermethylation of a limited number of genes in tumor biopsies may identify the majority of colorectal tumors. This study aimed to assess the clinical usefulness of a panel of methylation biomarkers in stool DNA in the identification of colorectal tumors, using methylation-specific melting curve analysis (MS-MCA), a technique that simultaneously analyzes all cytosine-phosphate-guanine (CpG) residues within a promoter. MATERIALS AND METHODS The promoter methylation status of 4 tumor-related genes (RARB2, p16INK4a, MGMT, and APC) was analyzed in DNA stool samples and corresponding tissues in an initial set of 12 patients with newly diagnosed primary colorectal carcinomas and 20 patients with newly diagnosed colorectal adenomas, using methylation-specific polymerase chain reaction. Results were replicated in a set of 82 patients (20 healthy subjects, 16 patients with inflammatory bowel disease (IBD), 20 patients with adenomas, and 26 patients with carcinomas), using MS-MCA analyses. RESULTS In the initial set, >or= 1 positive methylation marker was detected in the stools of 9 of 12 patients (75%) with carcinomas and 12 of 20 patients (60%) with adenomas, with no false-positive results. Stool analyses missed 7 methylated lesions (25%). In the replication set, stool DNA testing detected 16 of 26 carcinomas (62%) and 8 of 20 adenomas (40%). The MS-MCAs missed 14 methylated tumors (37%). No aberrant methylation was evident in healthy subjects, but the RARB2 marker was positive in 2 of 15 stool samples (13%) of patients with IBD. CONCLUSION Analysis via MS-MCA of a panel of methylation markers in stool DNA may offer a good alternative in the early, noninvasive detection of colorectal tumors.

Recurrence and virulence of colonic diverticulitis in immunocompromised patients

BACKGROUND To evaluate the probability of recurrence and the virulence of colonic diverticulitis correlated with immunocompromised status. METHODS Nine hundred thirty-one patients admitted in a single tertiary referral university hospital over a 14-year period were included. Patients were divided into 2 groups: group 1, 166 immunosuppressed patients, and group 2, 765 nonimmunosuppressed patients. The variables studied were sex, age, American Society of Anesthesiologist status, reasons of immunosuppression (eg, chronic use of corticosteroids, transplant recipients, and diseases affecting the immune system), severity of the diverticulitis episode, recurrence, emergency and elective surgery, and morbidity and mortality rates. RESULTS Two hundred thirteen patients underwent an emergency operation during the first hospitalization and 26 patients in further episodes. One hundred thirty-six patients developed 1 or more recurrent episodes of diverticulitis. The overall recurrence rate was similar in both groups. Patients in group 1 with a severe first episode presented significantly higher rates of recurrence and severity without needing more emergency surgery. Mortality after emergency surgery was 33.3% in group 1 and 15.9% in group 2 (P = .004). CONCLUSIONS After successful medical treatment of acute diverticulitis, patients with immunosuppression need not be advised to have an elective sigmoidectomy.

Recomendaciones para el diagnóstico y el tratamiento de la hemorragia digestiva alta aguda no varicosa

Se define como hemorragia digestiva alta aquella que se origina en una lesión situada por encima del ángulo de Treitz. Clínicamente, se manifiesta en forma de hematemesis de sangre fresca o en «poso de café», de melenas, de ambas o, con menor frecuencia, como hematoquecia. La causa más frecuente de hemorragia digestiva alta no varicosa es la úlcera péptica gastroduodenal, que representa alrededor del 70% de los casos, pero también puede ser debida a lesiones agudas de la mucosa gástrica, esofagitis, síndrome de Mallory-Weiss, tumores o lesiones vasculares. La hemorragia digestiva alta no varicosa es una emergencia médica frecuente, con una incidencia anual que oscila entre 50 y 150 casos por 100.000 habitantes1. Ello representa un elevado número de ingresos anuales y un consumo muy elevado de recursos sanitarios. A pesar de los importantes avances de los últimos años, la mortalidad asociada a la hemorragia digestiva alta no varicosa todavía es elevada en algunas series (10%)2,3, aunque en estudios más recientes ha descendido hasta valores del 2%4. La reducción de la mortalidad observada en las series más recientes se debe, principalmente, al mejor conocimiento de los factores pronósticos en la hemorragia digestiva alta2,3,5-9 y, sobre todo, a la introducción y el desarrollo de diferentes técnicas de terapéutica endoscópica que ha condicionado un notable descenso de la incidencia de recidiva de la hemorragia y de la necesidad de tratamiento quirúrgico10. No obstante, existen otros factores que han contribuido a este descenso de mortalidad, y entre ellos debemos destacar el tratamiento de estos pacientes en «unidades de sangrantes». En ellas, los pacientes son atendidos por un equipo médico multidisciplinario (formado por gastroenterólogo, cirujano, endoscopista y radiólogo) y personal de enfermería especializado y altamente cualificado en el manejo de la hemorragia digestiva alta. Estas unidades también favorecen la concentración de recursos terapéuticos y la aplicación de protocolos que conducirán a un manejo más homogéneo de los pacientes. En cualquier caso, es fundamental tratar a los pacientes con hemorragia digestiva alta en centros que dispongan del personal y los recursos necesarios para tratar adecuadamente a estos pacientes. La hemorragia digestiva alta no varicosa es una entidad idónea para la confección de una guía clínica, porque tiene una elevada incidencia y ocasiona un importante consumo de recursos. A pesar de la abundante información acumulada en los últimos años sobre su pronóstico y tratamiento, todavía existe una importante heterogeneidad en el manejo de los pacientes, lo que puede ocasionar resultados clínicos diferentes. En este sentido, un estudio realizado recientemente en hospitales universitarios de nuestro país11 pone de manifiesto el diferente manejo de la hemorragia digestiva en función del servicio de ingreso del paciente (gastroenterología, cirugía o medicina interna). Si bien no se observan diferencias significativas en la mortalidad, la estancia media y el coste de la hospitalización fueron significativamente inferiores en los pacientes ingresados en el servicio de gastroenterología, que en los de cirugía o medicina interna. Estos hechos ponen de manifiesto la necesidad de una guía clínica para la hemorragia digestiva alta no varicosa, que permita homogeneizar la conducta, mejorar la calidad de la asistencia que reciben los pacientes y optimizar la utilización de recursos sanitarios. Por iniciativa de la Junta de Gobierno de la Societat Catalana de Digestologia, se constituyó un grupo de trabajo formado por 11 especialistas con amplia experiencia en el diagnóstico y el tratamiento de la hemorragia digestiva, entre los cuales había gastroenterólogos, endoscopistas y cirujanos, con el objetivo de confeccionar una guía clínica para la hemorragia digestiva alta aguda no varicosa. Cada uno de los miembros del grupo desarrolló diferentes temas de la guía, que fueron discutidos conjuntamente en las 10 reuniones de trabajo que se realizaron a lo largo de algo más de un año. Las recomendaciones que se exponen a continuación son fruto de la revisión de la mejor evidenCorrespondencia: Dr. F. Feu. Servicio de Gastroenterología. Hospital Clínic. Villarroel, 170. 08036 Barcelona. España. Correo electrónico: ffeu@clinic.ub.es

Diagnosis of tuberculosis infection by tuberculin skin test and a whole-blood interferon-γ release assay in patients considered for anti–tumor necrosis factor-α therapy

To assess the performance of QuantiFERON®-TB Gold in-Tube (QFT-GIT; Cellestis, Carnegie, Australia) and tuberculin skin test (TST) in patients with immune-mediated inflammatory diseases (IMID), before anti-tumor necrosis factor-α (TNF-α) therapy, and to compare the results with those from the healthy population. Three hundred fourteen subjects (214 with IMID and 100 controls) underwent simultaneous QFT-GIT and TST. QFT-GIT was positive in 21% of IMID patients and in 16% of controls (P = 0.29). Among IMID patients, 21% tested positive by QFT-GIT and 24%, by TST (P = 0.30). Positive QFT-GIT results were not affected by immunosuppressive therapy (odds ratio, 0.78; 95% confidence interval [CI], 0.36-1.68; P = 0.52). Agreement between both tests in those patients who tested positive by one of the tests was 50% (95% CI, 37.2-62.8). QFT-GIT is useful for identifying IMID patients requiring treatment of latent tuberculosis before anti-TNF therapy. However, given the poor agreement between TST and QFT-GIT, we advocate a strategy of simultaneous testing to optimize diagnostic sensitivity.

External validation of a prognostic model for predicting survival of cirrhotic patients with refractory ascites

OBJECTIVE:Cirrhotic patients with refractory ascites (RA) have a poor prognosis, although individual survival varies greatly. A model that could predict survival for patients with RA would be helpful in planning treatment. Moreover, in cases of potential liver transplantation, a model of these characteristics would provide the bases for establishing priorities of organ allocation and the selection of patients for a living donor graft. Recently, we developed a model to predict survival of patients with RA. The aim of this study was to establish its generalizability for predicting the survival of patients with RA.METHODS:The model was validated by assessing its performance in an external cohort of patients with RA included in a multicenter, randomized, controlled trial that compared large-volume paracentesis and peritoneovenous shunt. The values for actual and model-predicted survival of three risk groups of patients, established according to the model, were compared graphically and by means of the one-sample log-rank test.RESULTS:The model provided a very good fit to the survival data of the three risk groups in the validation cohort. We also found good agreement between the survival predicted from the model and the observed survival when patients treated with peritoneovenous shunt and with paracentesis were considered separately.CONCLUSION:Our survival model can be used to predict the survival of patients with RA and may be a useful tool in clinical decision making, especially in deciding priority for liver transplantation.

Novel methylation panel for the early detection of neoplasia in high-risk ulcerative colitis and Crohn's colitis patients†

Background:Patients with ulcerative colitis and Crohns colonic disease are at increased risk of developing colorectal cancer (CRC). The aim of the study was to analyze the methylation status of selected genes as a risk marker for CRC in inflammatory bowel disease (IBD) patients. Methods:We evaluated the methylation status of four genes (TGFB2, SLIT2, HS3ST2, and TMEFF2) in biopsies of four groups of patients: 60 patients with sporadic CRC, 32 patients with IBD-associated neoplasia, 85 patients with IBD without associated neoplasia (20 at high risk and 65 at low risk), and 28 healthy controls. Methylation-specific melting curve analysis (MS-MCA) was used. Methylation status of these genes was also assessed in stool DNA from 60 IBD patients without neoplasia. Results:Methylation of the panel of genes analyzed was a very common phenomenon (78%) in IBD-associated neoplasia. The prevalence of methylation in adjacent nonneoplastic mucosa was also high (12/30). This prevalence was higher than in mucosa from healthy controls (2/28;7.1%; P < 0.05). Methylation of SLIT2 and TMEFF2 was more frequently detected in the mucosa of IBD patients at high risk of dysplasia or cancer (15/20) than patients at low risk (32/63) (P = 0.05 and P = 0.03, respectively). When stool samples were assessed, only SLIT2 gene methylation was more frequently methylated in the group of patients at high risk of dysplasia or cancer (4/16) compared to low risk (0/37) (P = 0.006). Conclusions:Analysis of a panel of methylation markers may help in the early identification of colorectal dysplasia or cancer in high-risk IBD patients.

Identification of candidate susceptibility genes for colorectal cancer through eQTL analysis

In this study, we aim to identify the genes responsible for colorectal cancer risk behind the loci identified in genome-wide association studies (GWAS). These genes may be candidate targets for developing new strategies for prevention or therapy. We analyzed the association of genotypes for 26 GWAS single nucleotide polymorphisms (SNPs) with the expression of genes within a 2 Mb region (cis-eQTLs). Affymetrix Human Genome U219 expression arrays were used to assess gene expression in two series of samples, one of healthy colonic mucosa (n = 47) and other of normal mucosa adjacent to colon cancer (n = 97, total 144). Paired tumor tissues (n = 97) were also analyzed but did not provide additional findings. Partial Pearson correlation (r), adjusted for sample type, was used for the analysis. We have found Bonferroni-significant cis-eQTLs in three loci: rs3802842 in 11q23.1 associated to C11orf53, COLCA1 (C11orf92) and COLCA2 (C11orf93; r = 0.60); rs7136702 in 12q13.12 associated to DIP2B (r = 0.63) and rs5934683 in Xp22.3 associated to SHROOM2 and GPR143 (r = 0.47). For loci in chromosomes 11 and 12, we have found other SNPs in linkage disequilibrium that are more strongly associated with the expression of the identified genes and are better functional candidates: rs7130173 for 11q23.1 (r = 0.66) and rs61927768 for 12q13.12 (r = 0.86). These SNPs are located in DNA regions that may harbor enhancers or transcription factor binding sites. The analysis of trans-eQTLs has identified additional genes in these loci that may have common regulatory mechanisms as shown by the analysis of protein-protein interaction networks.