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Background and aims Cholangiocarcinoma (CCA) is a devastating disease often detected at advanced stages when surgery cannot be performed. Conventional and targeted systemic therapies perform poorly, and therefore effective drugs are urgently needed. Different epigenetic modifications occur in CCA and contribute to malignancy. Targeting epigenetic mechanisms may thus open therapeutic opportunities. However, modifications such as DNA and histone methylation often coexist and cooperate in carcinogenesis. We tested the therapeutic efficacy and mechanism of action of a class of dual G9a histone-methyltransferase and DNA-methyltransferase 1 (DNMT1) inhibitors. Approach and results Expression of G9a, DNMT1, and their molecular adaptor, ubiquitin-like with PHD and RING finger domains-1 (UHRF1), was determined in human CCA. We evaluated the effect of individual and combined pharmacological inhibition of G9a and DNMT1 on CCA cell growth. Our lead G9a/DNMT1 inhibitor, CM272, was tested in human CCA cells, patient-derived tumoroids and xenograft, and a mouse model of cholangiocarcinogenesis with hepatocellular deletion of c-Jun-N-terminal-kinase (Jnk)-1/2 and diethyl-nitrosamine (DEN) plus CCl4 treatment (JnkΔhepa + DEN + CCl4 mice). We found an increased and correlative expression of G9a, DNMT1, and UHRF1 in CCAs. Cotreatment with independent pharmacological inhibitors G9a and DNMT1 synergistically inhibited CCA cell growth. CM272 markedly reduced CCA cell proliferation and synergized with Cisplatin and the ERBB-targeted inhibitor, Lapatinib. CM272 inhibited CCA tumoroids and xenograft growth and significantly antagonized CCA progression in JnkΔhepa + DEN + CCl4 mice without apparent toxicity. Mechanistically, CM272 reprogrammed the tumoral metabolic transcriptome and phenotype toward a differentiated and quiescent status. Conclusions Dual targeting of G9a and DNMT1 with epigenetic small molecule inhibitors such as CM272 is a potential strategy to treat CCA and/or enhance the efficacy of other systemic therapies.

Objective: despite significant progresses in imaging and pathological evaluation, early differentiation between benign and malignant biliary strictures remains challenging. Endoscopic retrograde cholangiopancreatography (ERCP) is used to investigate biliary strictures, enabling the collection of bile. We tested the diagnostic potential of next-generation sequencing (NGS) mutational analysis of bile cell-free DNA (cfDNA). Design: a prospective cohort of patients with suspicious biliary strictures (n=68) was studied. The performance of initial pathological diagnosis was compared with that of the mutational analysis of bile cfDNA collected at the time of first ERCP using an NGS panel open to clinical laboratory implementation, the Oncomine Pan-Cancer Cell-Free assay. Results: an initial pathological diagnosis classified these strictures as of benign (n=26), indeterminate (n=9) or malignant (n=33) origin. Sensitivity and specificity of this diagnosis were 60% and 100%, respectively, as on follow-up 14 of the 26 and eight of the nine initially benign or indeterminate strictures resulted malignant. Sensitivity and specificity for malignancy of our NGS assay, herein named Bilemut, were 96.4% and 69.2%, respectively. Importantly, one of the four Bilemut false positives developed pancreatic cancer after extended follow-up. Remarkably, the sensitivity for malignancy of Bilemut was 100% in patients with an initial diagnosis of benign or indeterminate strictures. Analysis of 30 paired bile and tissue samples also demonstrated the superior performance of Bilemut. Conclusion: implementation of Bilemut at the initial diagnostic stage for biliary strictures can significantly improve detection of malignancy, reduce delays in the clinical management of patients and assist in selecting patients for targeted therapies. Funding: we thank the financial support of CIBERehd; grants PI16/01126 and PI19/00163 from Instituto de Salud Carlos III (ISCIII) cofinanced by ’Fondo Europeo de Desarrollo Regional’ (FEDER) ’Una manera de hacer Europa’; grants 58/2017 and 55/2018 from Gobierno de Navarra Salud; grant 0011-1411-2020-000010 from AGATA Strategic Project from Gobierno de Navarra; grant 2020/101 from Euroregion Nouvelle Aquitaine-Euskadi-Navarra; Fundación Eugenio Rodríguez Pascual; Fundación Mario Losantos, Fundación M Torres; grant 2018/117 from AMMF, the Cholangiocarcinoma Charity; the COST Action CA181122 Euro-cholangio-Net; POSTD18014AREC postdoctoral fellowship from AECC to MA; and Ramón y Cajal Program contracts RYC-2014-15242 and RYC-2018-024475-1 to FJC and MGFB.

Liver fibrosis, a common hallmark of chronic liver disease (CLD), is characterized by the accumulation of extracellular matrix secreted by activated hepatic fibroblasts and stellate cells (HSC). Fibrogenesis involves multiple cellular and molecular processes and is intimately linked to chronic hepatic inflammation. Importantly, it has been shown to promote the loss of liver function and liver carcinogenesis. No effective therapies for liver fibrosis are currently available. We examined the anti-fibrogenic potential of a new drug (CM414) that simultaneously inhibits histone deacetylases (HDACs), more precisely HDAC1, 2, and 3 (Class I) and HDAC6 (Class II) and stimulates the cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) pathway activity through phosphodiesterase 5 (PDE5) inhibition, two mechanisms independently involved in liver fibrosis. To this end, we treated Mdr2-KO mice, a clinically relevant model of liver inflammation and fibrosis, with our dual HDAC/PDE5 inhibitor CM414. We observed a decrease in the expression of fibrogenic markers and collagen deposition, together with a marked reduction in inflammation. No signs of hepatic or systemic toxicity were recorded. Mechanistic studies in cultured human HSC and cholangiocytes (LX2 and H69 cell lines, respectively) demonstrated that CM414 inhibited pro-fibrogenic and inflammatory responses, including those triggered by transforming growth factor &beta, (TGF&beta, ). Our study supports the notion that simultaneous targeting of pro-inflammatory and fibrogenic mechanisms controlled by HDACs and PDE5 with a single molecule, such as CM414, can be a new disease-modifying strategy.

Cholangiocarcinoma (CCA) and pancreatic adenocarcinoma (PDAC) may lead to the development of extrahepatic obstructive cholestasis. However, biliary stenoses can also be caused by benign conditions, and the identification of their etiology still remains a clinical challenge. We performed metabolomic and proteomic analyses of bile from patients with benign (n = 36) and malignant conditions, CCA (n = 36) or PDAC (n = 57), undergoing endoscopic retrograde cholangiopancreatography with the aim of characterizing bile composition in biliopancreatic disease and identifying biomarkers for the differential diagnosis of biliary strictures. Comprehensive analyses of lipids, bile acids and small molecules were carried out using mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (1H-NMR) in all patients. MS analysis of bile proteome was performed in five patients per group. We implemented artificial intelligence tools for the selection of biomarkers and algorithms with predictive capacity. Our machine-learning pipeline included the generation of synthetic data with properties of real data, the selection of potential biomarkers (metabolites or proteins) and their analysis with neural networks (NN). Selected biomarkers were then validated with real data. We identified panels of lipids (n = 10) and proteins (n = 5) that when analyzed with NN algorithms discriminated between patients with and without cancer with an unprecedented accuracy., This research was funded by: Instituto de Salud Carlos III (ISCIII) co-financed by Fondo Europeo de Desarrollo Regional (FEDER) Una manera de hacer Europa, grant numbers: PI16/01126 (M.A.A.), PI19/00819 (M.J.M. and J.J.G.M.), PI15/01132, PI18/01075 and Miguel Servet Program CON14/00129 (J.M.B.); Fundación Científica de la Asociación Española Contra el Cáncer (AECC Scientific Foundation), grant name: Rare Cancers 2017 (J.M.U., M.L.M., J.M.B., M.J.M., R.I.R.M., M.G.F.-B., C.B., M.A.A.); Gobierno de Navarra Salud, grant number 58/17 (J.M.U., M.A.A.); La Caixa Foundation, grant name: HEPACARE (C.B., M.A.A.); AMMF The Cholangiocarcinoma Charity, UK, grant number: 2018/117 (F.J.C. and M.A.A.); PSC Partners US, PSC Supports UK, grant number 06119JB (J.M.B.); Horizon 2020 (H2020) ESCALON project, grant number H2020-SC1-BHC-2018–2020 (J.M.B.); BIOEF (Basque Foundation for Innovation and Health Research: EiTB Maratoia, grant numbers BIO15/CA/016/BD (J.M.B.) and BIO15/CA/011 (M.A.A.). Department of Health of the Basque Country, grant number 2017111010 (J.M.B.). La Caixa Foundation, grant number: LCF/PR/HP17/52190004 (M.L.M.), Mineco-Feder, grant number SAF2017-87301-R (M.L.M.), Fundación BBVA grant name: Ayudas a Equipos de Investigación Científica Umbrella 2018 (M.L.M.). MCIU, grant number: Severo Ochoa Excellence Accreditation SEV-2016-0644 (M.L.M.). Part of the equipment used in this work was co-funded by the Generalitat Valenciana and European Regional Development Fund (FEDER) funds (PO FEDER of Comunitat Valenciana 2014–2020). Gobierno de Navarra fellowship to L.C. (Leticia Colyn); AECC post-doctoral fellowship to M.A.; Ramón y Cajal Program contracts RYC-2014-15242 and RYC2018-024475-1 to F.J.C. and M.G.F.-B., respectively. The generous support from: Fundación Eugenio Rodríguez Pascual, Fundación Echébano, Fundación Mario Losantos, Fundación M Torres and Mr. Eduardo Avila are acknowledged. The CNB-CSIC Proteomics Unit belongs to ProteoRed, PRB3-ISCIII, supported by grant PT17/0019/0001 (F.J.C.). Comunidad de Madrid Grant B2017/BMD-3817 (F.J.C.).

Introduction Large serrated polyps (SP), proximal SP, SP with dysplasia and the presence of multiple sessile serrated adenomas/polyps (SSA/P), which we refer to as SP with increased risk of metachronous lesions (SPIRML), have been associated with an increased risk of advanced colon lesions on follow-up. It is unclear, however, whether SPIRML are also associated with an increased risk of synchronous advanced colorectal neoplasia (ACN). Aim The aim of this study was to estimate the prevalence of SPIRML and to evaluate the association between SPIRML and synchronous ACN. Methods A cross-sectional population-based study in all patients (1538) with histological diagnosis of SP obtained from colonoscopies, sigmoidoscopies and colonic surgery performed in Navarra Health Service hospitals (Spain) in 2011. Demographic parameters and synchronous colonic lesions (adenomas, advanced adenomas [AA] and ACN) were analysed. Results One fourth of the sample (384 patients) presented SPIRML. These were older patients, with a slight predominance of women, and with no differences in body mass index (BMI) compared to patients without SPIRML. In the univariate analysis, patients with SPIRML showed an increased risk of adenoma, AA and ACN. In the multivariate analysis, the SPIRML group had a higher risk of synchronous AA and ACN (odds ratio [OR]: 2.38 [1.77–3.21] and OR: 2.29 [1.72–3.05], respectively); in the case of ACN, this risk was statistically significant in both locations (proximal or distal), with OR slightly higher for the proximal location. Different subtypes of SPIRML had a higher risk of AA and synchronous NA. Conclusion SPIRML were common in patients with SP, and their presence was associated with an increased risk of synchronous ACN.

Resumen Introduccion Los polipos serrados (PS) grandes, PS proximales, PS con displasia y la presencia de multiples adenomas sesiles serrados (P/ASS), que englobamos bajo el termino PS con riesgo aumentado de lesiones metacronicas (PSRALM), se asocian a un mayor riesgo de presentar dichas lesiones, pero desconocemos si tambien se asocian a un mayor riesgo de neoplasia avanzada de colon (NA) sincronica. Objetivo Estimar la prevalencia de PSRALM y evaluar la asociacion con NA sincronica. Metodos Se trata de un estudio transversal de base poblacional que incluyo a todos los pacientes (1.538) con diagnostico histologico de PS de muestras procedentes de colonoscopias, rectosigmoidoscopias e intervenciones quirurgicas de los hospitales publicos del Servicio Navarro de Salud durante el ano 2011. Se analizaron parametros demograficos y presencia de lesiones sincronicas de colon (adenomas, adenomas avanzados [AA] y NA) Resultados La cuarta parte de los pacientes (384) presentaron PSRALM, con una edad media mas avanzada, un ligero predominio en mujeres y sin diferencias en cuanto al IMC respecto a los pacientes sin PSRALM. En el analisis multivariante el grupo PSRALM presento un mayor riesgo de AA y NA sincronicos (OR: 2,38 [1,77-3,21] y OR: 2,29 [1,72-3,05] respectivamente) y en el caso de NA, este riesgo fue estadisticamente significativo en ambas localizaciones (proximal y distal), con OR superior para la proximal. Los distintos subtipos de PSRALM presentaron un mayor riesgo de AA y NA sincronicos. Conclusion Los PSRALM fueron frecuentes entre los pacientes con PS y se asociaron a un mayor riesgo de presentar NA sincronica.

Introduction Alteration of mismatch repair system protein expression detected by immunohistochemistry (IHQ) in tumoural tissue is a useful technique for Lynch Syndrome (LS) screening. A recent review proposes LS screening through immunohistochemical study not only in all diagnosed cases of colorectal cancer (CRC) but also in advanced adenomas, especially in young patients. Objective To assess the prevalence of altered IHQ carried out in all adenomas with high-grade dysplasia (HGD) diagnosed in our community in 2011, as well as the variables associated with this alteration. Methods We included all the cases of adenomatous polyps with HGD diagnosed in the three public pathology laboratories of Navarre during 2011 and performed a statistical study to assess the association between different patient and lesion characteristics and altered IHQ results. Results A total of 213 colonic adenomas with HGD were diagnosed, and 26 (12.2%) cases were excluded from the final analysis (2 known LS, 22 without IHQ study and 2 with inconclusive IHQ studies). The final number of adenomas included was 187. Pathologic results were found in 10 cases (5.35%)–6 cases in MLH1 and PMS2, 2 cases in PMS2, 1 case in MSH6 and 1 case in MSH2 and MSH6. The factors showing a statistically significant association with the presence of abnormal proteins were the synchronous presence of CRC, the presence of only one advanced adenoma, proximal location of HGD and age Conclusions The percentage of pathologic nuclear expression found in IHQ is high. Consequently, screening of all diagnosed HGD could be indicated, especially in young patients, with a single AA and proximal HGD.

Resumen Introduccion La alteracion en la expresion nuclear de proteinas de los genes reparadores del ADN valorada mediante inmunohistoquimica (IHQ) en el tejido tumoral es una tecnica util como cribado de sindrome de Lynch (SL). Una revision reciente propone realizar este cribado no solo sobre todos los canceres colorrectales (CCR) diagnosticados, sino tambien sobre adenomas avanzados (AA), especialmente en pacientes jovenes. Objetivo Evaluacion de la prevalencia de IHQ alterada realizada sobre todos los adenomas con displasia de alto grado (DAG) diagnosticados en nuestra comunidad durante 2011, y descripcion de las variables asociadas a su alteracion. Metodos Se incluyeron todos los casos de polipos adenomatosos con DAG diagnosticados desde los 3 laboratorios de anatomia patologica publicos de Navarra durante el ano 2011, y se realizo un estudio estadistico para medir la asociacion de diferentes variables, tanto de los pacientes como de las lesiones con la presencia de IHQ alterada. Resultados Se diagnosticaron 213 adenomas de colon con DAG, excluyendose del analisis posterior 26 (12,2%) casos (2 SL ya diagnosticados, 22 casos sin estudio IHQ y 2 casos con IHQ no valorable), siendo el numero final 187. Se encontraron hallazgos patologicos en 10 casos, suponiendo el 5,35%: 6 casos en MLH1 y PMS2, 2 casos en PMS2, un caso en MSH6 y un caso en MSH2 y MSH6. La presencia sincronica de CCR, la presencia de un unico AA, la localizacion proximal de la DAG y la edad Conclusiones El porcentaje de expresion nuclear patologica hallado en la IHQ es elevado, por lo que podria estar indicado realizar screening de rutina con IHQ en todas las DAG diagnosticadas, especialmente en pacientes jovenes, con un unico AA y con DAG proximal.

Summary The analysis of biological fluids to identify proteins that may indicate a disease setting, state and progression, is an increasingly explored field. Despite the expectatives created, there are several hurdles that must be solved to reach an extensive proteome coverage using mass spectrometry, mainly due to the complex composition of the matrices. In this regard, bile is specially challenging and yet, very attractive, as a proximal fluid that might provide valuable information for the management of liver and pancreas associated diseases. Proteins account for less than 5% of bile organic components and, although optimized protocols for protein extraction have been developed, only partial descriptions of bile proteome have been achieved. In this manuscript a new procedure is described that significantly improves protein recovery from rat bile, which reduces by a factor of six the sample amount required for a typical proteomics analysis. Moreover, the number of proteins reliably identified in a single nanoLC-MS/MS run from 1 μg protein was increased by three-fold. This procedure provides a valuable resource to dig deeper into the molecular composition of bile and open new avenues to identify new hallmarks of disease such as cholangiocarcinoma, hepatocellular carcinoma and pancreatic cancer for their better clinical management.

Chronic liver diseases (CLD) represent a worldwide health problem. While CLDs may have diverse etiologies, a common pathogenic denominator is the presence of liver fibrosis. Cirrhosis, the end-stage of CLD, is characterized by extensive fibrosis and is markedly associated with the development of hepatocellular carcinoma. The most important event in hepatic fibrogenesis is the activation of hepatic stellate cells (HSC) following liver injury. Activated HSCs acquire a myofibroblast-like phenotype becoming proliferative, fibrogenic, and contractile cells. While transient activation of HSCs is part of the physiological mechanisms of tissue repair, protracted activation of a wound healing reaction leads to organ fibrosis. The phenotypic changes of activated HSCs involve epigenetic mechanisms mediated by non-coding RNAs (ncRNA) as well as by changes in DNA methylation and histone modifications. During CLD these epigenetic mechanisms become deregulated, with alterations in the expression and activity of epigenetic modulators. Here we provide an overview of the epigenetic alterations involved in fibrogenic HSCs transdifferentiation with particular focus on histones acetylation changes. We also discuss recent studies supporting the promising therapeutic potential of histone deacetylase inhibitors in liver fibrosis.

Resumen Introduccion La albumina forma parte de la respuesta sistemica inflamatoria antitumoral, por lo que analizaremos su valor en el pronostico pre-operatorio del carcinoma colorrectal (CCR). Pacientes y metodos Estudio retrospectivo y observacional de una serie de CCR resecados consecutiva y programadamente. Efectuamos un analisis estadistico univariante y multivariante de la supervivencia entre los casos con y sin hipoalbuminemia pretratamiento ( II . Adicionalmente, comparamos el indice de mortalidad debida al tumor a los 5 anos entre los casos con y sin hipoalbuminemia. Resultados Revisamos 207 pacientes (mediana de seguimiento: 81 meses). En el analisis multivariante global los casos con normoalbuminemia presentaron unas curvas de supervivencia superiores a las de los pacientes con hipoalbuminemia: (HR = 2,82; IC 95% = [1,54-5,19]; p = 0,001). Este mejor pronostico de la normoalbuminemia se mantiene en el estadio pTNM II : (HR = 3,76; IC 95% = [1,40-10,08]; p = 0,009). El indice de mortalidad a los 5 anos fue inferior en los casos con normoalbuminemia: global = 18,8 versus 42,9% (OR = 3,24; IC 95% = [1,48-7,12]; p = 0,001); estadio pTNM II = 13,3 versus 44,4% (OR = 5,2; IC 95% = [1,36-20,34]; p = 0,004). Conclusion Una hipoalbuminemia pre-tratamiento II . De confirmarse estos resultados la hipoalbuminemia constituiria un sencillo y significativo marcador de mal pronostico, disponible desde el momento del diagnostico.

Fundamento . En el cancer colorrectal se discute la posible relacion entre la expresion patologica de proteinas reparadoras (EPPR) y la infiltracion linfocitica tumoral (ILT), asi como el posible efecto pronostico de ambos factores. Material y metodos. Se han revisado 243 canceres colorrectales, resecados consecutivamente. Estudiamos inmunohistoquimicamente la EPPR de MLH1, MSH2 y MSH6. La ITL se valoro mediante la tincion de CD3 en el epitelio tumoral. Comparamos la mortalidad y progresion tumoral post-operatoria entre los casos con y sin EPPR y con y sin ITL. Adicionalmente estudiamos la mortalidad y progresion tumoral entre los casos EPPR (+), segun presentaran o no ITL. Resultados. El 13,6% tumores expresaron EPPR (+) y el 25,5% ITL (+). El seguimiento fue: 73,8±34,6 meses. La frecuencia de ITL (+) resulto similar entre tumores EPPR (+): 27,3% y EPPR (-): 25,2% (p = 0,80). Los casos EPPR (+) mostraron menor mortalidad: 12,1% versus 23,3% (p = 0,15) y menor progresion tumoral: 21,2% versus 29% (p = 0,35). Las neoplasias ITL (+) tuvieron menor mortalidad: 9,7% versus 26% [p = 0,007; OR = 3,27(1,25-9,05)] y progresion tumoral: 12,9% versus 33,1% [p = 0,002; OR = 3,35 (1,42-8,15)]. Los 9 tumores EPPR (+) e ILT (+) no presentaron mortalidad ni progresion tumoral, frente a una mortalidad: 16,7% y progresion: 29,2% de los 24 casos EPPR (+) e ITL (-) p = 0,19 y p = 0,07 respectivamente. Conclusiones. No se ha encontrado relacion entre EPPR e ITL, con tasas muy similares de ILT (+) entre casos con y sin EPPR. La ILT (+) mostro un efecto pronostico favorable superior a la EPPR (+). La combinacion de ILT (+) e EPPR (+) parece tener un efecto protector acumulativo, aunque su escasa frecuencia resta significacion al hallazgo.

The presence of subdiaphragmatic thyroid tissue is a very rare finding. We reviewed the literature and found only 15 published cases. The most appropriate management of this entity has not been established, but surgical removal is common to exclude malignancy. We present the case of a 76-year-old woman with an ectopic mesenteric thyroid gland forming a retroperitoneal mass that was surgically removed. Outcome was favorable.

To evaluate the diagnostic yield of endoscopic ultrasonography (EUS) in patients with idiopathic acute pancreatitis (IAP), find factors predictive of a positive EUS finding in these patients and investigate whether these etiological findings are maintained during follow-up.We performed EUS in patients with IAP between July 2004 and August 2007. We recorded epidemiological data, the number and severity of previous bouts of pancreatitis and gallbladder status.A total of 44 patients were included in the study. EUS was normal in seven patients (16%). In the remaining 37 patients (84%) we found cholelithiasis (n = 3), microlithiasis (n = 20), chronic pancreatitis (n = 14), pancreas divisum (n = 3), pancreatic mass (n = 1), apudoma (n = 1), cystic tumor of the pancreas (n = 2) and choledocholithiasis (n = 2). Positive EUS findings were not influenced by sex, severity of pancreatitis or recurrent disease. Patients aged65 years (ageor65 years: 73.9% versus 95.2%; P = 0.097) and patients with gallbladder in situ (cholecystectomy versus non-cholecystectomy: 63.6% versus 90.9%; P = 0.054) showed a tendency to have positive EUS findings. Mean follow-up was 28.95 +/- 10.86 months (range 12-64 months; median 28 months). During follow-up the etiological diagnosis was changed in two patients, lowering the diagnostic yield to 79%.EUS identified the cause of IAP in 79% of patients. Patients with gallbladder in situ and patients aged65 years showed a tendency to have positive EUS findings. The majority of the diagnoses provided by EUS are maintained during follow-up and seem to be reliable.

Spontaneous bacterial peritonitis (SBP) is frequently associated with renal failure. This study assessed if systemic and hepatic hemodynamics are also affected by this condition. Standard laboratory tests, tumor necrosis factor alpha (TNF-alpha) in plasma and ascitic fluid, plasma renin activity (PRA) and norepinephrine (NE), and systemic and hepatic hemodynamics were determined in 23 patients with SBP at diagnosis and after resolution of infection. Eight patients developed renal failure during treatment. At diagnosis of infection, patients developing renal failure showed significantly higher values of TNF-alpha, blood urea nitrogen (BUN), PRA and NE, peripheral vascular resistance, and hepatic venous pressure gradient (HVPG) and lower cardiac output than patients not developing renal failure. During treatment, a significant reduction in cardiac output and arterial pressure and increase in PRA and NE, HVPG, and Child-Pugh score were observed in the first group but not in the second. Peripheral vascular resistance remained unmodified in both groups. Changes in PRA and NE correlated inversely with changes in arterial pressure and directly with changes in BUN, Child-Pugh score, and HVPG. Five patients in the renal failure group developed encephalopathy, and 6 died. In the group without renal failure, none of the patients developed encephalopathy or expired. In conclusion, patients with SBP frequently develop a rapidly progressive impairment in systemic hemodynamics, leading to severe renal and hepatic failure, aggravation of portal hypertension, encephalopathy, and death. This occurs despite rapid resolution of infection and is associated with an extremely poor prognosis.

Introduccion: El tratamiento de la disrupcion ductal pancreatica (DDP) mediante protesis pancreaticas transpapilares (PT) resuelve la DDP en el 44 – 92% de los casos, especialmente si la PT puentea la DDP, lo cual es tecnicamente muy complejo. Objetivo: Analizar los resultados del tratamiento de DDP mediante PT e influencia de diversos factores en el exito terapeutico. Material y Metodo: Analizamos retrospectivamente una base de datos prospectiva identificando pacientes sometidos a tratamiento endoscopico de DDP entre enero/09-junio/14. Analizamos tipo de DDP (parcial/completa), pancreatopatia (estenosis/pancreatolitiasis/coleccion), localizacion de PT (“en puente” cuando la PT conecto el conducto proximal y distal a DDP; “intradisrupcion” cuando la PT se coloco dentro de la DDP; “distal” cuando la PT quedo por debajo de la DDP) y resultado terapeutico. Obtuvimos aprobacion por CEIC local. Resultados: Incluimos 29 pacientes: 21 con DDP parcial y 8 completa. Asociada: pancreatolitiasis (2 casos), estenosis (17) y coleccion (27). En todos los pacientes se coloco PT: en puente (13 pacientes: 11 con DDP parcial y 2 completa), intradisrupcion (8 pacientes: 4 parcial, 4 completa) y distal (8 pacientes: 6 parcial, 2 completa). Asociamos esfinterotomia pancreatica mayor (19 pacientes) y minor (3). En dos pacientes no pudimos analizar el resultado terapeutico por cirugia y exitus. En los 27 restantes comprobamos resolucion de la disrupcion en 20 (74,1%): 14/19 parciales, 6/8 completas. La PT en puente resolvio la DDP en el 100%, la intradisrupcion en 75% y la distal en 28%. La colocacion en puente o intradisrupcion fueron significativamente mas resolutivas que la distal (90% vs. 28%; p = 0,005). El resto de variables no influyeron en el resultado. Conclusiones: El tratamiento mediante PT resuelve la DDP en el 74% de los casos. Las PT en puente o intradisrupcion son la mejor opcion subiendo el exito terapeutico al 90%.

A 63-year-old man was admitted with aortic dissection and acute thrombosis of the superior mesenteric artery in May 2013. After urgent surgical arterial bypass, he experienced postoperative mesenteric ischemia, pancreatitis, and bleeding, requiring 2 additional surgical interventions. Subsequently, he experienced pancreaticocutaneous fistula and abdominal sepsis; after a lengthy hospital stay, he was discharged in September. One day after discharge he was readmitted for fever related to Pseudomona and Serratia spp infection of a peribypass collection, which was treated with percutaneous drainage twice, and 4 courses of antibiotics for recurrent bacteriemia until April 2014, when recurrence of the peribypass collection was diagnosed. Because of the patient’s unacceptable surgical risk, EUS-guided transgastric drainage of the collection with the arterial bypass floating inside (Fig. 1) was completed (Video 1, available online at www.giejournal. org). A double pigtail stent was inserted, followed by a nasocystic catheter for continuous lavage during 1 week. After 4 weeks, a CT scan confirmed resolution of the collection, and the transgastric double-pigtail stent was retrieved uneventfully. He has been asymptomatic except for an episode of fever, which resolved with antibiotics without recurrence of fluid collection during 9 months of follow-up.

s / Pancreatology 15 (2015) e1ee17 e3 Introduction: Exocrine pancreatic insufficiency (EPI) is a consequence of multiple diseases, but chronic pancreatitis is its main cause. Recognizing this entity is crucial to prevent malnutrition. Pancreatic enzyme replacement therapy can not be optimized based solely on clinical parameters. The 13C-mixed triglyceride breath test (Pancreo-kit®) is a validated test for obtaining information about exocrine pancreatic activity. Objective: Assess the modifications made in the treatment of patients with suspected EPI depending on the result of the 13C-mixed triglyceride breath test.Material and Methods: Retrospective descriptive study of patients with suspected EPI who underwent the breath test to assess the beginning / removal / increased doses of enzyme replacement therapy. Outpatients attending in the Digestive-Pancreatic examination room from December 2013 to October 2014 were included. Results: The analysis included 30 patients, 22 (73%) men, with an average age of 58 (limits: 2878) years old. The main indications of the test were: chronic pancreatitis, 27 (90%); acute necrotizing pancreatitis, 2 (6%) and resected pancreatic neuroendocrine tumor, 1 (3%). The test was abnormal in 11 patients (36%): in 2 (6%) patients, replacement therapy was initiated; in 7 (23%) patients, dosage was increased and in 2 (6%) patients, treatment was not started because of history of intolerance. Patients with negative test: in 5 (16%) patients, replacement therapy was discontinued; in 12 (40%), treatment was not started and in 2 (6%), treatment was initiated because of symptoms. The results of the test led us to do a change in the treatment in 14 (46%) patients. Conclusions: The implementation of the Pancreo-kit® test in patients with pancreatic diseases could allow enzyme replacement therapy to be adapted to a substantial number of patients. Further prospective studies are needed to find the real implication of the test.

Fundamento: El índice de Onodera (IO) combina los valores de los linfocitos circulantes y de la albúmina sérica y se ha utilizado como marcador del estado nutricional, postulándose recientemente en Japón y China su posible valor pronóstico en el cáncer colorrectal. Todavía no disponemos de datos sobre el valor predictivo del IO en una población occidental. Pacientes y métodos: Se revisaron 207 cánceres colorrectales resecados programada y consecutivamente, con intención curativa. Se calculó el IO pre-tratamiento mediante la fórmula: [10 x albúmina sérica (g/dl) + 0,005 x cifra de linfocitos circulantes/mm²]. Consideramos bajos los valores de IO menores de 40. Se efectuó un análisis univariable y multivariable de las curvas de supervivencia entre los casos con valores de IO menores de 40 (modelo de Cox, stepwise), todo ello en la serie global y en el estadio pTNM II. Resultados: El seguimiento clínico tuvo una mediana de 81 meses (rango intercuartílico 60-96). Veintiséis pacientes (12,6%) presentaron un IO bajo (< 40). En el análisis multivariable, los pacientes con IO bajo mostraron unas curvas de supervivencia más desfavorables, tanto en la serie global: [p < 0,001; HR = 3,16; IC 95% = 1,67-5,94)] como en los 78 casos en estadio pTNM II: [p < 0,004; HR = 4,36; IC 95% = 1,61-11,76)]. Conclusiones: También en pacientes europeos, un índice de Onodera pre-tratamiento bajo (< 40) tiene un valor predictivo independiente y desfavorable sobre la supervivencia en el cáncer colorrectal resecado, tanto en la serie global como en el estadio pTNM II.

Albuminemia is part of the antitumoral systemic inflammatory response. We therefore analyzed its possible value in establishing the preoperative prognosis of colorectal carcinoma (CRC).We conducted a retrospective, observational study of a series of consecutive patients who underwent CRC resection. Univariate and multivariate analyses of survival curves were performed in patients with and without pre-treatment hypoalbuminemia (3.5g/dl), both in the overall group of patients and in the subgroup of those with pTNM stage ii tumors. In addition, we compared the 5-year tumor-related mortality in patients with and without hypoalbuminemia.A total of 207 patients were reviewed (median follow-up: 81 months). In the overall multivariate analysis, survival curves were better in patients with normal albumin levels than in those with hypoalbuminemia (HR=2.82; CI 95%=[1.54-5.19]; P=.001). This better prognostic value of normal albumin levels was also significant in pTNM stage ii tumors: (HR=3.76; CI 95%=[1.40-10.08]; P=.009). The 5-year mortality index was lower in patients with normal albumin levels: overall series=18.8% vs 42.9% (OR=3.24; CI 95%=[1.48-7.12]; p=0.001); pTNM stage ii=13.3% vs 44.4% (OR=5.2; CI 95%=[1.36-20.34]; P=0.004).Pre-treatment hypoalbuminemia (3.5g/dl) was independently related to shorter survival after tumor resection, both in the overall series of patients and in pTNM stage ii CRC. If these results are confirmed, hypoalbuminemia would be a simple and significant marker of poor prognosis, available at the initial diagnosis.

Introduction accurate preoperative localization of colorectal cancer (CRC) is very important, with a wide range of published error rates. Aims to determine accuracy of endoscopic localization of CRC in comparison with preoperative computed tomography (CT). To analyse variables that could be associated with a wrong endoscopic localization. Patients and methods endoscopic and CT localization of a series of CRC without previous surgery were reviewed. We studied the concordance between endoscopic and radiologic localization against operative findings comparing accuracy of endoscopy and CT. We analysed the frequency of wrong endoscopic diagnoses with regard to a series of patient, endoscopy and tumor variables. Results two hundred thirty seven CRC in 223 patients were studied. Concordance with surgical localization was: colonoscopy = 0.87 and CT = 0.69. Endoscopic localization accuracy was:91.1%; CT: 76.2%: p = 0.00001; OR = 3.22 (1.82-5.72). Obstructive cancer presented a higher rate of wrong localization: 18 vs. 5.7% in non-obstructive tumors (p = 0.0034; OR = 3.65 (1.35-9.96). Endoscopic localization mistakes varied depending on tumor location, being more frequent in descending colon: 36.3%, p = 0.014; OR = 6.23 (1.38-26.87) and cecum: 23.1%, p = 0.007; OR = 3.92 (1.20-12.43). Conclusions endoscopic accuracy for CRC localization was very high and significantly better than CT accuracy. Obstructive tumor and those located in the descending colon or cecum wereassociated with a significant increase of the error risk of CRC endoscopic localization.

s / Pancreatology 15 (2015) S1eS141 S53 remains a challenge to assess the accurate indications for ERCP in patients with suspected choledocholithiasis and to select high risk PEP patients for appropriate prevention. Aims: The aim was to evaluate PEP prevalence and analyse patient's predictive factors of PEP in suspected choledocholithiasis prior ERCP. Patients & methods: 270 patients undergone ERCP due to suspected choledocholithiasis from 2012-2014y. Mean age was 65y (range 21-96y), 66% were females. The PEP prevalence were analysed. Patients were grouped using American Society of Gastrointestinal Endoscopy (ASGE,2010) outlined predictive factors, risk groups of choledocholithiasis prior ERCP. Univariate, multivariate analysis of choledocholithiasis and PEP risk factors were made. Results: Overall 16 patient's(6%) had PEP, 2(0,7%) hyperamylasemia. 2 cases were severe PEP with one lethal outcome. Choledocholithiasis was confirmed in 139(51%) patients, 10 occured PEP. All patients were in high risk group of PEP (according to ESGE,2014). 195(72%) patients had high risk, 75 intermediate risk of choledocholithiasis according to ASGE guidelines. PEP occured in 13 cases of high(p1⁄40,067), 3 intermediate group(p1⁄40,04). No risk factor significantly increased risk of PEP by univariate analysis. Abnormal liver biochemical test other than bilirubin (OR 0,857, p1⁄40,0001) and age>55y (OR 0,664, p1⁄40,020) increased risk by multivariate analysis. PEP was in 19% of age 18-45y, 17% 46-65y, 25% 66-85y. Choledocholithiasis mostly was in age 66-85y(28%). Conclusion: Patients with high risk of choledocholithiasis have higher risk of PEP comparing to intermediated risk. Patient's age >55y in suspected choledocholithiasis is additional predictive factor of PEP.

s / Pancreatology 15 (2015) e1ee17 e10 brush cytology of the common bile duct was negative for malignancy. Tumor markers were negative and IgG4 levels were not measured. Results: A cephalic pancreaticoduodenectomy was performed and a pancreatic head tumor was found. Histology revealed plasmacytic infiltration of the pancreatic parenchyma, gallbladder and bile and cystic ducts with a predominance of IgG4-positive plasma cells (90/high-power field). Final diagnosis was a lymphoplasmacytic sclerosing pancreatitis with biliary involvement. Discussion: IgG4-associated cholangitis is a rare type of AIP associated with bile duct involvement with or without pancreatic affection that responds well to steroids therapy, so it is important to rule out AIP in the diagnostic work-up of an EC to avoid unnecessary surgeries.

Introduction: Technical success for endoscopic wirsung-gastrostomy (EWG) is about 40% with a complication rate >20%. Long-term results are scarce. Case: A 46 year old patient with alcoholic liver and pancreatic chronic disease with active consumption referred recurrent pancreatic like type pain requiring intensive analgesic therapy. CT scan showed pancreatic duct dilation proximal to the head of the pancreas with distal pancreatic duct stenosis and severe perigastric collateral vessels related to portal hypertension. The patient was considered as high surgical risk so in October 2011 pancreatic stent placement was attempted but failed because of impossibility of pancreatic duct cannulation. EUS-guided transgastric pancreatic duct access was performed. Wirsungraphy was accomplished through the transgastric EUS guided needle showing a severe pancreatic duct stenosis in the pancreatic isthmus hindering guidewirenavigation and the EWGwas completed by insertion of a 5F pancreatic stent connecting the pancreatic duct and the gastric lumen. The patient had a favourable outcome and could stop taking analgesics. In may 2012 a second transgastric 7F stent placement was scheduled uneventfully to ensure pancreatic drainage. The patient remained asymptomatic thereafter despite keeping toxic habits, until august 2013 when he was admitted for a septic clinical picture with abdominal pain. A CT scan showed two abdominal collections with transgastric pancreatic stents correctly placed. The patient was diagnosed of acute relapse over chronic pancreatitis and percutaneous drainage of both collections was performed. In order to rule out origin of those collections from the EWG, the transgastric fistula was cannulated showing no leakage and improvement of the pancreatic head stenosis. Three plastic pancreatic stents were placed through the gastric wall into the pancreatic duct. The patient remains asymptomatic 40 months after initial EWG. Conclusion: In our experience, the EWG offers good clinical long-term outcomes in patients with high surgical risk.

s / Pancreatology 15 (2015) S1eS141 S129 Results: 102 patients underwent pancreaticoduodenectomy (PD), 30 distal pancreatectomy (DP), 15 total pancreatectomy (TP). All patients in the study underwent a subcostal incision. Age was 69[15] years, BMI 24.5 [3.9], 15.1% were ASA3-4. WC was placed in 98.7% cases.11.5% required use of opioids. Only 13.4% had a mean NRS up to 3 in POD1, 8.3% in POD2. NRS at rest was 2[3] in POD1, 0[2] POD2, 0[1] POD3. Wound infection rate was 7.4%. 92.4% stay more than 4 hours out of bed in POD3, 59% on POD2. Major complications (Clavien score>II) were 11.5%. Pancreatic fistula rate was 39%. Patients were fit for discharge POD 10[9] after PD, POD 6[2] after DP, 8 [2] after TP. Length of stay for uncomplicated PD was 8[3]. Readmission rate was 4.3%. Conclusion: Postoperative pain control trough continuous local anesthetic wound infiltration after pancreatic surgery guarantee a good pain control and adherence to an ERAS protocol.

s / Pancreatology 15 (2015) S1eS141 S60 Patients&methods:We evaluated 234 patients with first onset of SAP appears in last twenty fourhours. A total of 77 (33%)patientsdied. SIRS score and serum IL-4 concentration were measured in first hour after admission. Results: In 105 patients with SIRS score 3 and higher, initial measured IL-4 levels were significantly higher than in the group of remaining 129 patients. All nonsurvivals were in the first group, with SIRS score 3 and 4 and initial high level IL-4 concentration. The values of C reactive protein (CRP) measured after 48h, Acute Physiology and Chronic Health Evaluation (APACHE II) score on admission and Ranson score showed the similar correlation, but serum amylase level did not correlate significantly with Ranson score, IL-4 concentration and APACHE II score. Conclusion: The combinationof SIRS score on admission and IL-4 serum concentration can be early, predictor of illness severity and outcome in SAP.

Introduction: type 1 diabetes mellitus (T1DM) has been described as a cause of exocrine pancreatic exocrine (EPI). However, the value of Pancreatic Elastase-1 in stools (PE-1) in these patients has been discussed. Aim: to analyze the levels of PE-1 in a group of T1DM patients and to establish its clinical implications. Methods: cross-sectional study approved by de ethics committee of our centre. T1DM and LADA (Latent Autoimmune Diabetes in Adults) aged 18 or older were referred to our department from the Endocrinology Service. All participants signed an informed consent. We analyzed the levels of PE-1 (ELISA with monoclonal antibodies, normal value > 200 mcg/g) in all patients. Then, we tried to define the relationship between those levels with demographic variables and variables related to the diabetes evolution such as age at diagnosis, years since diagnosis was made, levels of HbA1c, presence of gastrointestinal symptoms or complications (nephropathy, neuropathy or retinopathy). Finally we compared the results of PE-1 with those of the mixed 13Ctriglyceride (13C-MTG) breath test (normal value > 29%). Data were analyzed using the independent-samples t-test, the Mann-Whitney U test and the chi-square test. Correlation between quantitative variables was made using the Pearson's correlation coefficient (r). To analyze the agreement between the categorical results of both test we used the kappa coefficient (κ). Results: 100 patients (50 male). Mean age: 45.8 + 11.75. T1DM/LADA: 93/ 7. 71 were smokers and 20 recognized alcohol consumption > 20 g/day. Mean PE-1 level: 249.5 + 158.3. In 43 cases its level was below the cutoff value. 22 of them had levels < 100. The PE-1 level was not correlated with age, years since diagnosis or C-Peptide levels. An inverse correlation was found between PE-1 and HbA1c levels (r: -0.30, p=0.003). No statistically significant differences were found in PE-1 levels comparing sex, type of diabetes, presence of symptoms, smoking or alcohol consumption. However PE-1 levels were 98.6 mcg/g (95% CI: 38.8-159.5, p=0.002) lower in patients diagnosed with diabetes-related complications. 13C-MTG breath test were performed in 86 patients. It was altered in 5 cases (5.8%). Only two of them had also a pathologic PE-1. There was no agreement between both tests (κ=0.005, p=0.93). The same way, no correlation was found (r=0.06, p=0.58). Conclusions: Low PE-1 levels are frequent (43%) in T1DM patients. PE-1 levels are lower in patients with diabetes-related complications and in those with poor glycemic control. Despite low PE-1 levels, fat absorption seems to be preserved in most cases. Therefore, low PE-1 levels in T1DM should be taken cautiously since they may not mean real EPI.

INTRODUCTION: Onodera index (OI) combines circulating lymphocytes and albumin levels. It has been used as a nutritional and immunological marker and it has been recently proposed in Eastern literature its possible value as a predictive variable of prognosis in colorectal cancer (CRC). AIMS: To analyse the prognostic value of OI, assessed at initial diagnosis, on survival of patients with resected CRC. PATIENTS AND METHODS: We present a retrospective observational study including 207 consecutive patients with CRC and surgically treated on elective basis. Clinical follow-up was performed, documenting all cases of tumor-related deaths. OI was calculated according to the equation: [10 x serum albumin (g/dl) + 0.005 x circulating lymphocytes/mm2]. OI values 6 mcg/l, OI < 40 and OI ≥ 40. Univariant and multivariant analysis were performed [Cox model, stepwise, determining hazard ratio (HR) and 95% confidence interval (CI 95%)]. Finally, Fisher and square chi tests were used to compare 5-year mortality rates between groups with OI < 40 and OI ≥ 40, calculating odds ratio (OR) and CI. RESULTS: 26 patients (12.6%) presented a low OI. Median follow up was 81 months, with an interquartile range of 60-96. Overall tumor-related mortality was 23.7% and 19.8% 5 years after surgery. Variables with independent prognostic value in multivariant analysis are summarised in the following table below. 5-year mortality rate was significantly higher in patients with low OI: 42.3% vs 16.7% [OR = 3.69; CI = (1.42-9.58); p=0.002]. CONCLUSIONS: 1. A low Onodera index, assessed at initial CRC diagnosis, is associated with a worse survival curve after tumor resection. 2. This negative prognostic significance of an Onodera index < 40 has proved to have an independent predictive value. 3. Post-surgery 5-year mortality is higher in patients with a low Onodera index. Variables with independent prognostic value in multivariant analysis

absent; however, in 9/14 patients the OTSC was removed endoscopically or surgically. OTSC status was unknown in 9 (18%) patients. Without procedural intervention, overall OTSC retention was greater than 70%. Conclusions: OTS Clip retention occurs in approximately 2/3 of patients, likely due to attachment to the submucosa and muscularis propria. Patients need to be aware of OTSC retention as these clips are MRI conditional. Prospective studies with larger numbers of patients are needed to confirm these findings.