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Pancreaticoduodenectomy (PD) is a very complex operation. Its development took place very slowly at the most prestigious centers in the world. The aim of this investigation is to know who were the first surgeons to perform a PD in Spain as well as its historical circumstances. Despite all kinds of difficulties and very few resources, the first PD in Spain were carried out in Barcelona at the Hospital de la Santa Creu i Sant Pau where from the mid-50s a school of gastrointestinal surgery emerged with surgeons soon to become the spearhead of the Spanish surgery and a reference for the whole country: Pi-Figueras, Vicente Artigas, Antonio Soler-Roig and Antonio Llaurado. Almost simultaneously, in Oviedo, Luis Estrada also introduced the PD and total pancreaticoduodenectomy after a period of training with the pioneers of pancreatic surgery in the United States.

Objective: To provide evidence-based recommendations for the management of exocrine pancreatic insufficiency (EPI) after pancreatic surgery. Background: EPI is a common complication after pancreatic surgery but there is certain confusion about its frequency, optimal methods of diagnosis, and when and how to treat these patients. Methods: Eighteen multidisciplinary reviewers performed a systematic review on 10 predefined questions following the GRADE methodology. Six external expert referees reviewed the retrieved information. Members from Spanish Association of Pancreatology were invited to suggest modifications and voted for the quantification of agreement. Results: These guidelines analyze the definition of EPI after pancreatic surgery, (one question), its frequency after specific techniques and underlying disease (four questions), its clinical consequences (one question), diagnosis (one question), when and how to treat postsurgical EPI (two questions) and its impact on the quality of life (one question). Eleven statements answering those 10 questions were provided: one (9.1%) was rated as a strong recommendation according to GRADE, three (27.3%) as moderate and seven (63.6%) as weak. All statements had strong agreement. Conclusions: EPI is a frequent but under-recognized complication of pancreatic surgery. These guidelines provide evidence-based recommendations for the definition, diagnosis, and management of EPI after pancreatic surgery.

Pancreatic neuroendocrine tumors represent less than 5% of all pancreatic tumors. They are a heterogeneous group of neoplasms with a diverse behavior and prognosis. Pancreatic vasoactive intestinal polypeptide tumor (VIPoma) is an exceptional tumor within this group due to its low incidence. The presence of pancreatic VIPoma should be clinically suspected in all patients with watery diarrhea, particularly when accompanied by a loss of potassium and bicarbonate and a pancreatic mass on imaging. There are other pathologies with similar symptoms; therefore, a correct differential diagnosis with an adequate treatment is essential for its management. We present the case of a 46-year-old patient who developed a prerenal kidney failure secondary to severe watery diarrhea after a diagnosis of pancreatic VIPoma. Thus, a resection was performed as the patient was rapidly deteriorating and required an intervention.

Background: The fusion fascia of Toldt is a well-known landmark used by colorectal surgeons. On the contrary, the fusion fascia of Fredet (the plane between the ascending mesocolon and the visceral duodenal-pancreatic peritoneum) still remains a neglected embryological structure. Aim of this study was to provide an anatomic description of this fascia and its application to minimally invasive D3-lymphadenectomy (D3-L) and complete mesocolic excision (CME) for right colon cancer. Methods: First phase: Cadaveric dissection and anatomic description of the fascia of Fredet. Second phase: prospective evaluation of its surgical application ina consecutive series of laparoscopic right hemicolectomies with CME and D3-L at a tertiary hospital. Results: The fascia of Fredet was identified and dissected in one fresh and two formalin-fixed cadavers. The trunk of Henle and the medial border of the superior mesenteric vein defined the medial limit of this embryologic plane. Seventeen patients were operated on. Laparoscopic dissection of the fascia of Fredet was possible in every patient. Median operative time was 210 (120–380) min. There were no major postoperative complications. All cases were adenocarcinomas, except one adenomatous polyp. T stage was Tis in three, T2 in two, T3 in seven, and T4 in five patients. Median number of harvested lymph nodes was 24 (9–39). Lymphatic invasion was found in six patients. All resections were classified as satisfactory mesocolic excision and R0. Median postoperative length of stay was 6 (4–20) days. Median follow-up time was 28 (16–41) months. Local and distal recurrence rate was 0. Conclusion: The fusion fascia of Fredet is useful to achieve CME and D3-L in right colon cancers with reduced risk of intraoperative complications. This structure is particularly suitable for minimally invasive surgery; therefore, we encourage awareness of the fascia of Fredet by colorectal surgeons.

"Artery-first approach" encompasses different aspects for the surgical treatment of pancreatic cancer. It is a surgical technique or set of techniques which share in common the dissection of the main arterial vasculature involved in pancreatic cancer, before any irreversible surgical step is performed. On the other hand it represents the need for a meticulous dissection of the arterial planes and clearing of the retropancreatic tissue between the superior mesenteric artery, the common hepatic artery and portal vein in an attempt to achieve R0 resections. The recent expansion of this approach is based mainly on three factors: venous involvement should not be considered a contraindication for resection, most of the pancreatic resections performed with a standard procedure may be in fact non-oncological (R1) resections and the postero-medial or vascular margin is the most frequently invaded by the tumor. This review aimed to summarize and update the artery-first approach in pancreaticoduodenectomy.

[Objective]: To compare the rates of R0 resection in pancreatoduodenectomy (PD) for pancreatic and periampullary malignant tumors by means of standard (ST-PD) versus artery-first approach (AFA-PD). [Background]: Standardized histological examination of PD specimens has shown that most pancreatic resections thought to be R0 resections are R1. “Artery-first approach” is a surgical technique characterized by meticulous dissection of arterial planes and clearing of retropancreatic tissue in an attempt to achieve a higher rate of R0. To date, studies comparing AFA-PD versus ST-PD are retrospective cohort or case-control studies. [Methods]: A multicenter, randomized, controlled trial was conducted in 10 University Hospitals (NCT02803814, ClinicalTrials.gov). Eligible patients were those who presented with pancreatic head adenocarcinoma and periampullary tumors (ampulloma, distal cholangiocarcinoma, duodenal adenocarcinoma). Assignment to each group (ST-PD or AFA-PD) was randomized by blocks and stratified by centers. The primary end-point was the rate of tumor-free resection margins (R0); secondary end-points were postoperative complications and mortality. [Results]: One hundred seventy-nine patients were assessed for eligibility and 176 randomized. After exclusions, the final analysis included 75 ST-PD and 78 AFA-PD. R0 resection rates were 77.3% (95% CI: 68.4–87.4) with ST-PD and 67.9% (95% CI: 58.3–79.1) with AFA-PD, P=0.194. There were no significant differences in postoperative complication rates, overall 73.3% versus 67.9%, and perioperative mortality 4% versus 6.4%. [Conclusions]: Despite theoretical oncological advantages associated with AFA-PD and evidence coming from low-level studies, this multicenter, randomized, controlled trial has found no difference neither in R0 resection rates nor in postoperative complications in patients undergoing ST-PD versus AFA-PD for pancreatic head adenocarcinoma and other periampullary tumors.

espanolIntroduccion: la lesion yatrogenica de la via biliar (LYVB) es una complicacion con elevada morbilidad tras la colecistectomia. En los ultimos anos la endoscopia ha adquirido un papel fundamental en el manejo de esta patologia. Metodos: estudio retrospectivo de LYVB tras colecistectomia abierta (CA) o colecistectomia laparoscopica (CL) tratadas en nuestro centro entre 1993 y 2017. Se analizaron los datos referentes a las caracteristicas clinicas, tipo de lesion segun la clasificacion de Strasberg-Bismuth, diagnostico, tecnica de reparacion y seguimiento. Resultados: se estudian 46 pacientes. La incidencia LYVB fue de 0,48%, 0,61% para las CL y 0,24% para las CA. El diagnostico se realizo de forma intraoperatoria en 12 casos (26%) y mediante colangiopancreatografia retrograda endoscopica (CPRE) en 10 (21,7%). Las caracteristicas mas comunes a todos los pacientes con LYVB fueron la colecistitis aguda (20/46, 43,5%), ingreso previo por patologia biliar (16/46, 43,2%) y realizacion de CPRE previa a la colecistectomia (7/46, 18,9%). Los tipos de LYVB mas frecuentes fueron el D (17/46, 36,9%) y el A (15/46, 32,6%). El tratamiento mas empleado fue sutura primaria (13/46, 28,3%) seguido de CPRE (11/46, 23,9%) con esfinterotomia y/o endoprotesis. Ademas, la CPRE se utilizo en el postoperatorio inmediato de 6 pacientes (13%) con reparacion quirurgica de la LYVB para solucionar complicaciones inmediatas. Conclusion: la CPRE es util en el manejo de la LYVB no diagnosticada intraoperatoriamente. Permite localizar la zona lesionada de la via biliar, realizar maniobras terapeuticas y tratar de manera satisfactoria algunas complicaciones postoperatorias. EnglishIntroduction: iatrogenic bile duct injury (IBDI) is a complication with a high morbidity after cholecystectomy. In recent years, endoscopy has acquired a fundamental role in the management of this pathology. Methods: a retrospective study of IBDI after open cholecystectomy (OC) or laparoscopic cholecystectomy (LC) of patients treated in our center between 1993 and 2017 was performed. Clinical characteristics, type of injury according to the Strasberg-Bismuth classification, diagnosis, repair techniques and follow-up were analyzed. Results: 46 patients were studied and IBDI incidence was 0.48%, 0.61% for LC and 0.24% for OC. A diagnosis was made intraoperatively in 12 cases (26%) and by endoscopic retrograde cholangiopancreatography (ERCP) in 10 (21.7%) cases. The most common IBDI patient characteristics were acute cholecystitis (20/46, 43.5%), previous admission due to biliary pathology (16/46, 43.2%) and ERCP prior to cholecystectomy (7/46, 18.9%). The most frequent types of IBDI were D (17/46, 36.9%) and A (15/46, 32.6%). The most commonly used treatment was primary suture (13/46, 28.3%) followed by ERCP (11/46, 23.9%) with sphincterotomy and/or stents. In addition, ERCP was performed during the immediate postoperative period in 6 (13%) patients with a surgical IBDI repair in order to resolve immediate complications. Conclusion: ERCP is useful in the management of IBDI that is not diagnosed intraoperatively. This procedure facilitates the localization of the injured area of the bile duct, therapeutic maneuvers and successful outcomes in postoperative complications.

Pancreatic cancer is a dismal disease with an increasing incidence. Despite the majority of patients are not candidates for curative surgery, a subgroup of patients classified as borderline resectable pancreatic cancer can be selected in whom a sequential strategy of neoadjuvant therapy followed by surgery can provide better outcomes. Multidisciplinary approach and surgical pancreatic expertise are essential for successfully treating these patients. However, the lack of consensual definitions and therapies make the results of studies very difficult to interpret and hard to be implemented in some settings. In this article, we review the challenges of borderline resectable pancreatic cancer, the complexity of its management and controversies and point out where further research and international cooperation for a consensus strategy is urgently needed.

Pancreatic specimens have always been a great challenge for surgical pathologists due to their anatomic complexity and the difficulty of becoming familiar with these specimens. However, pancreatic specimens are becoming more and more common in many hospitals because of the improvements in surgical techniques and perioperative care that have dramatically reduced the postoperative mortality rate.

Acute pancreatitis is an inflammatory process of the pancreatic gland that eventually may lead to a severe systemic inflammatory response. A key event in pancreatic damage is the intracellular activation of NF-κB and zymogens, involving also calcium, cathepsins, pH disorders, autophagy, and cell death, particularly necrosis. This review focuses on the new role of redox signaling in acute pancreatitis. Oxidative stress and redox status are involved in the onset of acute pancreatitis and also in the development of the systemic inflammatory response, being glutathione depletion, xanthine oxidase activation, and thiol oxidation in proteins critical features of the disease in the pancreas. On the other hand, the release of extracellular hemoglobin into the circulation from the ascitic fluid in severe necrotizing pancreatitis enhances lipid peroxidation in plasma and the inflammatory infiltrate into the lung and up-regulates the HIF–VEGF pathway, contributing to the systemic inflammatory response. Therefore, redox signaling and oxidative stress contribute to the local and systemic inflammatory response during acute pancreatitis. Keywords: Acute pancreatitis, Oxidative stress, Glutathione, Acute inflammation

Purpose To compare postoperative complications in patients who underwent pancreatoduodenectomy after either endoscopic or percutaneous biliary drain (BD). Material and Methods Data from studies comparing the rate of postoperative complications in patients who underwent endoscopic BD or percutaneous BD before pancreatoduodenectomy were extracted independently by 2 investigators. The primary outcome compared in the meta-analysis was the risk of postoperative complications. Secondary outcomes were the risks of procedure-related complications, postoperative mortality, postoperative pancreatic fistula, severe complications, and wound infection. For dichotomous variables, the odds ratio (OR) with 95% confidence interval (CI) was calculated. Results Thirteen studies, including 2334 patients (501 in the percutaneous BD group and 1833 in the endoscopic group), met the inclusion criteria. Postoperative and procedure-related complication rates were significantly lower in the percutaneous BD group (OR = .7, 95% CI = .52–.94, P = .02 and OR = .44, 95% CI = .23–.84, P = .01, respectively). No significant differences were observed when severe postoperative complications, postoperative mortality, postoperative pancreatic fistula, and wound infection rates were compared. Conclusions In patients awaiting pancreatoduodenectomy, preoperative percutaneous BD is associated with fewer procedure-related or postoperative complications than endoscopic drain.

A high body mass index increases the risk of severe pancreatitis and associated mortality. Our aims were: (1) To determine whether obesity affects the release of extracellular nucleosomes in patients with pancreatitis; (2) To determine whether pancreatic ascites confers lipotoxicity and triggers the release of extracellular nucleosomes in lean and obese rats. DNA and nucleosomes were determined in plasma from patients with mild or moderately severe acute pancreatitis either with normal or high body mass index (BMI). Lipids from pancreatic ascites from lean and obese rats were analyzed and the associated toxicity measured in vitro in RAW 264.7 macrophages. The inflammatory response, extracellular DNA and nucleosomes were determined in lean or obese rats with pancreatitis after peritoneal lavage. Nucleosome levels in plasma from obese patients with mild pancreatitis were higher than in normal BMI patients; these levels markedly increased in obese patients with moderately severe pancreatitis vs. those with normal BMI. Ascites from obese rats exhibited high levels of palmitic, oleic, stearic, and arachidonic acids. Necrosis and histone 4 citrullination—marker of extracellular traps—increased in macrophages incubated with ascites from obese rats but not with ascites from lean rats. Peritoneal lavage abrogated the increase in DNA and nucleosomes in plasma from lean or obese rats with pancreatitis. It prevented fat necrosis and induction of HIF-related genes in lung. Extracellular nucleosomes are intensely released in obese patients with acute pancreatitis. Pancreatitis-associated ascitic fluid triggers the release of extracellular nucleosomes in rats with severe pancreatitis.

Resumen Introduccion La afectacion microscopica de los margenes de reseccion es un factor pronostico fundamental en la cirugia del cancer de pancreas. Sin embargo, su definicion anatomopatologica no esta estandarizada. Este estudio pretende identificar el porcentaje real de pacientes con resecciones R1 al analizar las piezas quirurgicas con un protocolo estandarizado y evaluar sus implicaciones sobre la supervivencia. Pacientes y metodos Serie de 100 pacientes consecutivos intervenidos por adenocarcinoma ductal de pancreas y resecciones macroscopicamente completas, divididos en 2 grupos: pre- y posprotocolo, segun se intervinieran antes o despues de la aplicacion de un protocolo estandarizado de las piezas de reseccion. Resultados En el grupo preprotocolo la tasa de resecciones R0 fue del 78%, mientras que tras la aplicacion del mismo, se redujo al 47% (p = 0,003). El margen posterior retroperitoneal es el que se encuentra afectado con mayor frecuencia. En los casos con tumores localizados en cabeza de pancreas y analizados con el protocolo estandarizado, la deteccion del margen retroperitoneal afecto (R1) influye de forma negativa en la supervivencia. La mediana de supervivencia del grupo R0 fue de 22 meses frente a 16 meses en los que presentaban margen afecto (HR: 2,044; IC 95% 1,00-4,16; p = 0,043). Conclusiones La aplicacion de un protocolo estandarizado para el estudio del margen retroperitoneal en el cancer de pancreas incrementa la proporcion de pacientes R1. En los pacientes con cancer de cabeza de pancreas, la afectacion del margen posterior retroperitoneal reduce significativamente la supervivencia.

Introduction Involvement of surgical resection margins is a fundamental prognostic factor in pancreatic oncological surgery. However, there is a lack of standardized histopathology definition. The aims of this study are to investigate the real rate of R1 resections when surgical specimens are evaluated according to a standardized protocol and to study its survival implications. Patients and methods One hundred consecutive surgically resected patients with pancreatic ductal adenocarcinoma were included in the study. They were further divided into 2 groups: pre-protocol, evaluated before the introduction of the standardized protocol and post-protocol, analyzed with the standardized protocol. Results R0 resection rate in the pre-protocol group was 78%, falling to 47% after the introduction of the standardized protocol ( P =.003). The posterior retroperitoneal margin was the most frequently involved margin. In cases with tumors located at the pancreatic head and analyzed according to the standardized protocol R1 involvement negatively affected survival. Median survival in the R0 group was 22 months versus 16 in those with the margin involved (HR: 2.044; IC 95% 1.00–4.16; P =.043). Conclusions Standardized evaluation of the retroperitoneal margins in pancreatic cancer increases the rate of R1 patients. In cases with pancreatic cancer located at the pancreatic head involvement of posterior retroperitoneal margin significantly decreases survival.

Background Since the Atlanta Symposium several guidelines and consensus conferences have been published to improve the management and understanding of patients with acute pancreatitis. Herein, a review of the most recent guidelines on acute pancreatitis is carried out, trying to find differences and similarities.

Background Anastomotic leakage of pancreaticojejunostomy (PJ) remains the single most important source of morbidity after pancreaticoduodenectomy (PD). The primary aim of this randomized clinical trial comparing PG with PJ after PD was to test the hypothesis that invaginated PG would result in a lower rate and severity of pancreatic fistula. Methods Patients undergoing PD were randomized to receive either a duct-to-duct PJ or a double-layer invaginated PG. The primary endpoint was the rate of pancreatic fistula, using the definition of the International Study Group on Pancreatic Fistula. Secondary endpoints were the evaluation of severe abdominal complications (Clavien–Dindo grade IIIa or above), endocrine and exocrine function. Results Of 123 patients randomized, 58 underwent PJ and 65 had PG. The incidence of pancreatic fistula was significantly higher following PJ than for PG (20 of 58 versus 10 of 65 respectively; P = 0·014), as was the severity of pancreatic fistula (grade A: 2 versus 5 per cent; grade B–C: 33 versus 11 per cent; P = 0·006). The hospital readmission rate for complications was significantly lower after PG (6 versus 24 per cent; P = 0·005), weight loss was lower (P = 0·025) and exocrine function better (P = 0·022). Conclusion The rate and severity of pancreatic fistula was significantly lower with this PG technique compared with that following PJ. Registration number: ISRCTN58328599 (http://www.controlled-trials.com).

Objectives This study aimed to compare primary surgical versus nonsurgical treatment in a series of patients with infected pancreatic necrosis (IPN) and to investigate whether the success of nonsurgical approach is related to a less severe disease. Methods Thirty-nine consecutive patients with IPN have been included and further subdivided into two groups: primary surgical (n = 21) versus nonsurgical (n = 18). Outcome measures were the differences in mortality, morbidity, and pancreatic function. Comorbidity, organ failure, and other severity indexes were compared between the two groups. Results Mortality occurred in 16.7% of cases in the nonsurgical group versus 42.9% in the surgical group. In the primary nonsurgical group, seven were operated on due to failure of initial conservative treatment. In this latter group, mortality was 28.6% and was performed significantly later than in the primary surgical group. The group of primary surgical treatment was associated with a significant higher rate of multiple organ failure (MOF) at IPN diagnosis, new onset or worsening of organ failure, and MOF and nosocomial infection after surgery. Conclusions Initial nonsurgical approach in IPN is associated with better results both in cases which respond to this treatment as well as in those who, failing this conservative approach, have to be operated on after a delayed period. Primary surgically treated patients had a more severe disease at the time of IPN.

The objectives of this work are to study angiogenesis in pancreatic ductal adenocarcinoma using computerized morphometric and image analysis and to compare the microvascular density in intratumoral and peritumoral areas and normal pancreatic tissue. Microvascular density was analyzed in 60 cases of pancreatic ductal adenocarcinoma and 30 samples of normal pancreatic tissue using an avidin-biotin immunoperoxidase technique with an anti-CD31 antibody. Microvascular density (MVD) was analyzed through digital microimaging and computerized analysis. The blood vessel density in the tumor was significantly higher than in peritumoral areas and in normal pancreatic tissue. Well differentiated pancreatic ductal adenocarcinomas contained higher MVD than poorly differentiated carcinomas. In pancreatic adenocarcinoma, MVD is higher than in peritumoral tissue or normal pancreatic tissue.

Resumen El hepatocolangiocarcinoma combinado (HCC) es un tumor primario hepatico poco frecuente. Se caracteriza por mostrar elementos inequivocos tanto de hepatocarcinoma (HC) como de colangiocarcinoma (CC), intimamente relacionados entre si. Presentamos 2 casos clinicos recientes, en los que el diagnostico preoperatorio fue de CC en el caso 1 y de HC en el caso 2. Tras la reseccion quirurgica el estudio histologico en ambos casos mostro un doble componente de hepatocarcinoma y colangiocarcinoma. Ademas, en el caso 2 existian areas donde las celulas se hacian mas indiferenciadas y expresaban marcadores de celula madre. La clasificacion histologica de este tipo de tumores ha estado sometida a revision recientemente y seria conveniente disponer de unas claves diagnosticas anatomopatologicas. En el presente trabajo se realiza una revision de la literatura y se analizan lo que se consideran claves diagnosticas.

Chronic pancreatitis (CP) is a relatively uncommon, complex and heterogeneous disease. The absence of a gold standard applicable to the initial phases of CP makes its early diagnosis difficult. Some of its complications, particularly chronic pain, can be difficult to manage. There is much variability in the diagnosis and treatment of CP and its complications amongst centers and professionals. The Spanish Pancreatic Club has developed a consensus on the management of CP. Two coordinators chose a multi-disciplinary panel of 24 experts on this disease. A list of questions was drafted, and two experts reviewed each question. Then, a draft was produced and shared with the entire panel of experts and discussed in a face-to-face meeting. This first part of the consensus addresses the diagnosis of CP and its complications. Copyright (C) 2012, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.

Different diseases lead, during their advanced stages, to chronic or acute liver failure, whose unique treatment consists in organ transplantation. The success of intervention is limited by host immune response and graft rejection. The use of immunosuppressant drugs generally improve organ transplantation, but they cannot completely solve the problem. Also, their management is delicate, especially during the early stages of treatment. Thus, new tools to set an efficient modulation of immune response are required. The local expression of interleukin (IL) 10 protein in transplanted livers mediated by hydrodynamic gene transfer could improve the organ acceptance by the host because it presents the natural ability to modulate the immune response at different levels. In the organ transplantation scenario, IL10 has already demonstrated positive effects on graft tolerance. Hydrodynamic gene transfer has been proven to be safe and therapeutically efficient in animal models and could be easily moved to the clinic. In the present work, we evaluated efficacy of human IL10 gene transfer in human liver segments and the tissue natural barriers for gene entry into the cell, employing gold nanoparticles. In conclusion, the present work shows for the first time that hydrodynamic IL10 gene transfer to human liver segments ex vivo efficiently delivers a human gene into the cells. Indexes of tissue protein expression achieved could mediate local pharmacological effects with interest in controlling the immune response triggered after liver transplantation. On the other hand, the ultrastructural study suggests that the solubilized plasmid could access the hepatocyte in a passive manner mediated by the hydric flow and that an active mechanism of transportation could facilitate its entry into the nucleus. Liver Transplantation 23:50-62 2017 AASLD.

The most frequent complications after pancreaticoduodenectomy are analysed in this review. These include, delayed gastric emptying, pancreatic fistula, post-operative bleeding, and the complications after vascular reconstruction in the cases of locally extended pancreatic cancer. For this, randomised prospective studies, systematic meta-analyses and clinical guidelines on the definition, clinical severity grade and treatment of these complications have been evaluated.

Item does not contain fulltext Reactive oxygen species are considered mediators of the inflammatory response and tissue damage in acute pancreatitis. We previously found that the combined treatment with oxypurinol - as inhibitor of xanthine oxidase- and pentoxifylline - as inhibitor of TNF-alpha production-restrained local and systemic inflammatory response and decreased mortality in experimental acute pancreatitis. Our aims were (1) to determine the time-course of glutathione depletion and oxidation in necrotizing pancreatitis in rats and its modulation by oxypurinol and pentoxifylline; (2) to determine whether TNF-alpha is responsible for glutathione depletion in acute pancreatitis; and (3) to elucidate the role of oxidative stress in the inflammatory cascade in pancreatic AR42J acinar cells. We report here that oxidative stress and nitrosative stress occur in pancreas and lung in acute pancreatitis and the co-treatment with oxypurinol and pentoxifylline prevents oxidative stress in both tissues. Oxypurinol was effective in preventing glutathione oxidation, whereas pentoxifylline abrogated glutathione depletion. This latter effect was independent of TNF-alpha since glutathione depletion occurred in mice deficient in TNF-alpha or its receptors after induction of pancreatitis. The beneficial effects of oxypurinol in the inflammatory response may also be ascribed to a partial inhibition of MEK1/2 activity. Pentoxifylline markedly reduced the expression of Icam1 and iNos induced by TNF-alpha in vitro in AR42J cells. Oxidative stress significantly contributes to the TNF-alpha-induced up-regulation of Icam and iNos in AR42J cells. These results provide new insights into the mechanism of action of oxypurinol and pentoxifylline as anti-inflammatory agents in acute pancreatitis.

Cancer of the pancreas is the fourth cause of death due to cancer in developed countries and surgeons and oncologists are showing an increasing interest in the improvement of survival. This has prompted pathologists to develop better, standardized protocols for the evaluation of surgical specimens from pancreatectomies. The different problems that the pathologist may encounter when examining surgical specimens from pancreatoduodenectomies, as well as the different nomenclature used to define resection margins and infiltration are discussed. The protocol followed at the University Hospital of Valencia, based on European and American protocols as well as our own experience, is described.

Salvador Navarro a, , Eva Vaquero , Joan Maurel , Josep Antoni Bombi , Carmen De Juan , Jaime Feliu , Laureano Fernandez Cruz , Angels Gines , Enrique Girela , Ricardo Rodriguez j y Luis Sabater , en representacion del Grupo Espanol de Consenso en Cancer de Pancreas, el Club Espanol Biliopancreatico (CEBP), Grupo Espanol Multidisciplinar de Cancer Digestivo (GEMCAD), Sociedad Espanola de Diagnostico por Imagen del Abdomen (SEDIA), Sociedad Espanola de Endoscopia Digestiva (SEED) y la Sociedad Espanola de Anatomia Patologica (SEAP) a Servicio de Gastroenterologia, CIBERehd, IDIBAPS, Hospital Clinic, Universitat de Barcelona, Barcelona, Espana b Servicio de Gastroenterologia, Hospital Clinic, Universitat de Barcelona, Barcelona, Espana c Servicio de Oncologia Medica y Radioterapica, CIBERehd, IDIBAPS, Hospital Clinic, Universitat de Barcelona, Barcelona, Espana d Servicio de Anatomia Patologica, IDIBAPS, Hospital Clinic, Universitat de Barcelona, Barcelona, Espana e Servicio de Radiologia, Hospital Clinic, Universitat de Barcelona, Barcelona, Espana f Servicio de Oncologia Medica y Radioterapica, Hospital La Paz, Madrid, Espana g Servicio de Cirugia, Hospital Clinic, Universitat de Barcelona, Barcelona, Espana h Seccion de Endoscopia Digestiva, Hospital Clinic, Universitat de Barcelona, Barcelona, Espana i Servicio de Radiologia, Hospital Morales Meseguer, Murcia, Espana j Servicio de Radiologia, Hospital Clinico, Madrid, Espana k Servicio de Cirugia, Hospital Clinico, Valencia, Espana

Resumen La rotura hepatica espontanea asociada a sindrome de HELLP (hemolisis, elevacion de enzimas hepaticas y plaquetopenia) es extremadamente rara y se acompana de una elevada tasa de complicaciones y mortalidad maternofetal. Es necesario un tratamiento urgente basado en la finalizacion del embarazo, reposicion de hemoderivados y hemostasia hepatica. Presentamos el caso de una paciente con sindrome HELLP y rotura hepatica espontanea tratada mediante cesarea urgente y packing hepatico.

Introduction In recent months we have witnessed an update of the residents training program and the regulation of important training aspects. Teaching units are an important aspect of the training process, which should be required to comply with the prerequisites adapted to changing times as a guarantee of quality. Aim To identify areas for improvement in training, and the baseline resources of the units to deal with the implementation of the new training program. Material and methods The study was carried out in all units with accredited educational programs in the Valencian Community with questionnaires answered by tutors and residents, and meetings held with them. Results The participation rate was high (100% of tutors and 92% of residents). Some deficiencies in the requirements of the surgical units and in the quality of the training felt by the residents are detected, mainly in the research and educational activity fields. Huge differences between hospitals are found. Conclusions More attention must be paid to fulfilling all the requirements needed for the accreditation of the teaching units, with an emphasis on educational and research activities. The implementation of the new training program requires monitoring to minimise the differences found between the units.

Resumen Introduccion En los ultimos meses se ha asistido a una actualizacion del programa formativo de los residentes y a una regulacion de los aspectos importantes de su formacion. Un elemento fundamental del proceso de formacion son las unidades docentes, a las que se debe exigir que cumplan con los requisitos indispensables adaptados a los nuevos tiempos, como garantia de calidad. Objetivo Identificar los aspectos mejorables en la formacion y conocer con que recursos parten las unidades docentes para afrontar el cumplimiento del nuevo programa de formacion. Material y metodo El estudio se ha realizado en todas las unidades docentes acreditadas para la formacion de residentes en la Comunidad Valenciana mediante formularios enviados tanto a los tutores como a los residentes y reuniones mantenidas con los residentes. Resultados La tasa de participacion fue elevada (el 100% de tutores y el 92% de residentes). Se han detectado deficiencias en los requisitos de las unidades docentes y en la calidad de la formacion percibida por los residentes, sobre todo en los campos de la investigacion y en la actividad docente. Se constatan importantes diferencias entre hospitales. Conclusiones Se debe incidir en el cumplimiento de todos los requisitos necesarios para la acreditacion de las unidades docentes y hacer hincapie en la actividad docente e investigadora. La implementacion de los nuevos planes de formacion requiere de una supervision que corrija las diferencias encontradas entre los distintos servicios.

Resumen Objetivos Evaluar la morbimortalidad postoperatoria, el estado funcional y la supervivencia a largo plazo de pacientes con tumores de pancreas o periampulares a los que se intervino quirurgicamente. Pacientes y metodos Cohorte de 160 pacientes a los que se intervino consecutivamente: 80 duodenopancreatectomias cefalicas (DPC), 30 resecciones corporocaudales (RCC), 7 duodenopancreatectomias totales, 4 resecciones centrales y 3 ampulectomias; en 36 pacientes no se realizo reseccion. La funcion pancreatica se evaluo mediante test de sobrecarga oral a la glucosa, grasas en heces y elastasa fecal. Resultados La tasa de resecabilidad fue del 77,5%. En los pacientes resecados (n = 124) la morbilidad fue del 38,7% (con una tasa de fistulas pancreaticas del 6,4%) y la mortalidad del 4%. En las DPC la funcion endocrina pancreatica ha empeorado en el 41%, con esteatorrea en el 58,6% de los casos; en las RCC estos valores fueron del 53,6 y del 21,7%. En los 36 pacientes no resecados la morbilidad fue del 27,7% y la mortalidad del 8,3%. La supervivencia a 2 a 5 anos en los pacientes resecados por adenocarcinoma ductal fue del 42 y del 9%; en los ampulomas del 71 y del 53%; en los adenocarcinomas mucinosos, del 83 y del 33%; en los adenocarcinomas duodenales, del 100 y del 75%, y en el colangiocarcinoma distal, del 50 y del 50%. Conclusiones La morbilidad de la cirugia resectiva pancreatica continua siendo alta, aunque la mortalidad perioperatoria es baja. Las alteraciones de la funcion exocrina y endocrina son muy frecuentes y dependen del tipo de reseccion. A pesar de estar gravada con frecuentes complicaciones y alteraciones funcionales, la cirugia resectiva ofrece una posibilidad de supervivencia a largo plazo en determinados casos.

Mitogen-activated protein kinases (MAPKs) are considered major signal transducers early during the development of acute pancreatitis. Pentoxifylline is a phosphodiesterase inhibitor with marked anti-inflammatory properties through blockade of extracellular signal regulated kinase (ERK) phosphorylation and tumor necrosis factor alpha production. Our aim was to elucidate the mechanism of action of pentoxifylline as an anti-inflammatory agent in acute pancreatitis. Necrotizing pancreatitis induced by taurocholate in rats and taurocholate-treated AR42J acinar cells were studied. Phosphorylation of ERK and ERK kinase (MEK1/2), as well as PP2A, PP2B, and PP2C serine/threonine phosphatase activities, up-regulation of proinflammatory genes (by reverse transcription-polymerase chain reaction and chromatin immunoprecipitation), and recruitment of transcription factors and histone acetyltransferases/deacetylases to promoters of proinflammatory genes (egr-1, atf-3, inos, icam, il-6, and tnf-alpha) were determined in the pancreas during pancreatitis. Pentoxifylline did not reduce MEK1/2 phosphorylation but prevented the marked loss of serine/threonine phosphatase PP2A activity induced by taurocholate in vivo without affecting PP2B and PP2C activities. The rapid loss in PP2A activity induced by taurocholate in acinar cells was due to a decrease in cAMP levels that was prevented by pentoxifylline. Pentoxifylline also reduced the induction of early (egr-1, atf-3) responsive genes and abrogated the up-regulation of late (inos, icam, il-6, tnf-alpha) responsive genes and recruitment of transcription factors (nuclear factor kappaB and C/EBPbeta) and histone acetyltransferases to their gene promoters during pancreatitis. In conclusion, the beneficial effects of pentoxifylline--and presumably of other phosphodiesterase inhibitors--in this disease seem to be mediated by abrogating the loss of cAMP levels and PP2A activity as well as chromatin-modifying complexes very early during acute pancreatitis.

Aims To evaluate postoperative morbidity and mortality, pancreatic function and long-term survival in patients with surgically treated pancreatic or periampullar tumours. Patients and methods Cohort study including 160 patients consecutively operated on: 80 pancreaticoduodenectomies (PD), 30 distal pancreatectomies (DP), 7 total pancreatectomies, 4 central pancreatic resections, and 3 ampullectomies. The tumour was not resected in 36 patients. Pancreatic function was evaluated by oral glucose tolerance test, faecal fat excretion, and elastase. Results Resectability rate was 77.5%. In resected patients (n = 124), 38.7% had complications with a pancreatic fistula rate of 6.4% and a mortality rate of 4%. In PD, endocrine function worsened in 41% and 58.6% had steatorrhoea; these figures in DP were 53.6% and 21.7% respectively. In the 36 non-resected patients, postoperative morbidity was 27.7% and mortality 8.3%. Two and 5-year survival rates in resected patients with pancreatic cancer were 42% and 9% respectively; in malignant ampulloma 71% and 53%; in mucinous adenocarcinomas 83% and 33%; in duodenal adenocarcinoma 100% and 75%; and in distal cholangiocarcinoma 50% and 50%. Conclusions Morbidity associated with resective pancreatic surgery is still high, but perioperative mortality is low. Endocrine and exocrine disturbances are very common depending on the type of resection. Despite the associated morbidity and functional disorders, surgery provides long-term survival in selected cases.

Glutathione depletion is a key factor in the development of acute pancreatitis. Our aim was to study the regulation of glutamate cysteine ligase, the rate-limiting enzyme in glutathione synthesis, in edematous or necrotizing pancreatitis in rats. Glutathione levels were kept low in necrotizing pancreatitis for several hours, with no increase in protein or mRNA levels of glutamate cysteine ligase subunits, despite binding of RNA polymerase II to their promoters and coding regions. The survival signal pathway mediated by ERK and c-MYC was activated, and c-MYC was recruited to the promoters. The failure in gene up-regulation seems to be due to a marked increase in cytosolic ribonuclease activity. In contrast, in edematous pancreatitis glutathione levels were depleted and rapidly restored, and protein and mRNA expression of glutamate cysteine ligase increased markedly due to enhanced transcription mediated by recruitment of c-MYC, NF-kappaB, and SP-1 to the promoters. No increase in cytosolic ribonuclease activity was found in this case. We propose a novel pathophysiological mechanism to differentiate necrotizing from edematous pancreatitis, which is the inefficient up-regulation of glutamate cysteine ligase caused by increased cytosolic ribonuclease activity in the severe form of the disease. This mechanism would abrogate a rapid recovery of glutathione levels.

Resumen Introduccion La cirugia es el tratamiento de eleccion de los pacientes con metastasis hepaticas de cancer colorrectal, pero solo un 10-20% de los casos son resecables. El uso de quimioterapia neoadyuvante puede rescatar para la cirugia a pacientes inicialmente considerados irresecables. El objetivo de este trabajo es comparar los resultados de la reseccion de metastasis hepaticas de origen colorrectal en pacientes con y sin quimioterapia neoadyuvante. Pacientes y metodo Se ha estudiado a 105 pacientes intervenidos por metastasis hepaticas de cancer colorrectal, divididos en dos grupos segun la estrategia de tratamiento: cirugia en los pacientes inicialmente considerados resecables (grupo C) y quimioterapia neoadyuvante mas cirugia (grupo QT+C) en los que inicialmente se considero irresecables y que tras quimioterapia se convirtieron en resecables. Se ha comparado la edad y el sexo, el origen del tumor primario, el tiempo de aparicion, el numero, el tamano maximo y la localizacion de las metastasis, CEA, el margen de reseccion, la morbilidad y la mortalidad postoperatorias, el tiempo de ingreso, la tasa de recidivas y la supervivencia en general y la libre de enfermedad. Resultados Al comparar a los dos grupos, C y QT+C, han resultado significativas la presencia de metastasis sincronicas (el 30,8 y el 77,4%), la distribucion bilobar (el 13,5 y el 58,5%), el numero y el tamano de las metastasis (1 contra 3 nodulos y 4 contra 2 cm), la tasa de resecabilidad (el 96,1 y el 81,1%), el intervalo libre de enfermedad (25 y 11 meses) y la supervivencia actuarial a 1, 3 y 5 anos (el 93, el 67 y el 36% contra el 78, el 26 y el 12%). Sin embargo, no hemos encontrado diferencias en cuanto a la morbilidad y la mortalidad postoperatorias, que fueron del 28,8 y el 0%, respectivamente, en el grupo C y del 22,6 y el 1,8% en el grupo QT+C. Conclusiones La quimioterapia neoadyuvante no tuvo relacion con mayor morbimortalidad postoperatoria tras la reseccion de metastasis hepaticas de origen colorrectal, pero la supervivencia general a largo plazo en el grupo de pacientes que recibieron este tratamiento fue inferior a la del grupo de pacientes considerados inicialmente resecables.

Los insulinomas son tumores neuroendocrinos que se manifiestan por episodios de hipoglucemia de ayuno. El diagnostico se basa en la sospecha clinica, que debe ir seguida de la demostracion de hiperinsulinismo y la localizacion tumoral. Sin embargo, la localizacion no siempre es posible con las tecnicas de imagen habituales, por lo que se debe recurrir a otras mas complejas. Presentamos 2 casos de insulinomas cuya localizacion tumoral no fue posible con tecnicas de imagen convencionales, pero si con ultrasonografia endoscopica.

The rate of choledocholithiasis at the time of elective surgery after mild acute biliary pancreatitis is still unclear because it decreases rapidly after the onset. The aims of this study are as follows: (1) To investigate whether the incidence of choledocholithiasis in mild biliary pancreatitis is higher than in patients with symptomatic cholelithiasis. (2) To evaluate the usefulness of intraoperative cholangiography in the diagnosis of unsuspected choledocholithiasis in mild pancreatitis. Prospective study including 130 patients undergoing laparoscopic surgery and classified into two groups: mild biliary pancreatitis (n = 44) and symptomatic cholelithiasis (n = 86). Choledocholithiasis was evaluated by endoscopic cholangiopancreatography, magnetic resonance, and intraoperative cholangiography. Preoperatively, choledocholithiasis was identified in five patients with symptomatic cholelithiasis and two with biliary pancreatitis (5.81 vs 4.54%; p = 0.472). In 117 cases (90%), intraoperative cholangiography was successfully performed, identifying unsuspected choledocholithiasis in five patients of the colelithiasis group and in three in the group of pancreatitis (5.81 vs 6.81%; p = 0.492). The total number of patients with choledocholithiasis in the whole series was 15 (11.5%); 11.6% in colelithiasis group vs 11.4% in biliary pancreatitis group; p = 0.605. The rate of choledocholithiasis was not significantly different between the groups of patients with mild acute biliary pancreatitis and symptomatic cholelithiasis. Intraoperative cholangiography identified unsuspected choledocholithiasis in 6.81% of patients with mild acute biliary pancreatitis.

Acute pancreatitis is an inflammation initially localized in the pancreatic gland which may lead to local and systemic complications. The development of severe acute pancreatitis is mediated by pathophysiological mechanisms involved in the systemic inflammatory response, cytokines and oxidative stress being their components of major importance. Nevertheless, it is still unknown why an episode of acute pancreatitis remains mild or progresses to a severe form. Activated leukocytes are the main source of cytokines. Interleukin 1beta and tumor necrosis factor alpha (TNF-alpha) initiate and propagate almost all the consequences of the systemic inflammatory response syndrome, leading to amplification of the inflammatory response. It is noteworthy that the systemic inflammatory response is restrained and the rate of mortality decreased in acute pancreatitis when TNF-alpha is blocked with specific antibodies or in knock-out mice deficient in its receptors. A synergy between pro-inflammatory cytokines and oxidative stress occurs in the development of the inflammatory response in acute pancreatitis. Pro-inflammatory cytokines and oxidative stress trigger common signal transduction pathways that lead to amplification of the inflammatory cascade, mainly through activation of mitogen-activated protein kinases (MAPK) and nuclear factor kappaB (NF-kappaB). Furthermore, pro-inflammatory cytokines, particularly TNF-alpha, and oxidative stress promote each other generating a vicious circle in acute pancreatitis. This cross-talk that arises between pro-inflammatory cytokines and oxidative stress greatly contributes to amplification of the uncontrolled inflammatory cascade through MAPK and NF-kappaB.