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Bleeding is an intraoperative and postoperative complication of liver surgery of concern, and yet evidence to support utility and reproducibility of bleeding scales for liver surgery is limited. We determined the reproducibility of the clinician-reported validated intraoperative bleeding severity scale and its clinical value of implementation in liver surgery.In this descriptive and observational multicenter study, we assessed the performance of liver surgeons instructed on the clinician-reported intraoperative bleeding severity scale using training videos that covered all 5 grades of bleeding severity. Surgeons were stratified according to years of surgical experience and number of surgeries performed per year based on a median split in low and high values. Intraobserver and interobserver agreement was assessed using Kendall's coefficient of concordance (Kendall's W).Forty-seven surgeons from 10 hospitals in Spain participated in the study. The overall intraobserver concordance was 0.985, and the overall interobserver concordance was 0.929. For "high experience" surgeons, the intraobserver and interobserver agreement values were 0.990 and 0.941, respectively. For "low experience" surgeons, the intraobserver and interobserver agreement was 0.981 and 0.922, respectively. Regarding the annual number of surgeries, intraobserver and interobserver agreement values were 0.995 and 0.940, respectively, for surgeons performing35 surgeries per year, with 0.979 and 0.923, respectively, for surgeons who perform ≤35 surgeries year.The clinician-reported intraoperative bleeding severity scale shows high interobserver and intraobserver concordance, suggesting it is a useful tool for assessing severity of bleeding during liver surgery; years of surgical experience and number of annual procedures performed did not affect the applicability of the clinician-reported intraoperative bleeding severity scale.

Background Annual hospital volume of pancreatoduodenectomies could influence postoperative outcomes. The aim of this study is to establish with a non-arbitrary method the minimum threshold of yearly performed pancreatoduodenectomies in order to improve several postoperative quality outcomes. Method Prospective follow-up of patients submitted to pancreatoduodenectomy in participating hospitals during 1 year. The influence of hospital volume on quality outcomes was analyzed by univariable and multivariable models. The minimum threshold of yearly performed pancreatoduodenectomies to improve outcomes was established by Akaike’s information criteria. Results Data from 877 patients operated in 74 hospitals were analyzed. Of 12 quality outcomes, 9 were influenced by hospital pancreatoduodenectomy volume on multivariable analysis. To decrease the risk of complications and the risk of retrieving an insufficient number of lymph nodes at least 31 pancreatoduodenectomies per year should be performed. To decrease the risk of prolonged length of stay, postoperative death, and affected surgical margins, at least 37, 6, and 14 pancreatoduodenectomies per year should be performed, respectively. Conclusion Several postoperative quality outcomes are influenced by the number of yearly performed pancreatoduodenectomies and could be improved by establishing a minimum threshold of procedures. Number of procedures needed to improve quality outcomes has been established by a non-arbitrary method.

Background and objectives Postoperative complications (POCs) after hepatic resection for colorectal liver metastases (CRLM) adversely affect long-term survival. The aim of this study was to analyze the effect of POC etiology and severity on overall survival (OS) and disease-free survival (DFS). Methods A retrospective study of 254 consecutive hepatectomies for CRLM was performed. Univariate and multivariate analyses were performed to determine the effects of demographic, tumor-related and perioperative variables on OS and DFS. A 1:1 propensity score matching (PSM) was then used to compare patients with different POC etiology: infective (Inf-POC), noninfective (Non-inf POC), and no-complications (No-POC). Results Inf-POC, Non-inf POC, and No-POC patients represented 18.8%, 19.2%, and 62% of the sample, respectively. In univariate and multivariate analyses infectious POC were independent risk factors for decreased OS and DFS. After PSM, Inf-POC group presented decreased OS and DFS when compared with Non-inf POC (5-year OS 31.8% vs 51.6%; P = .05 and 5-year DFS 13.6% vs 31.9%; P = .04) and with No-POC (5-year OS 29.4% vs 58.7%; P = .03 and 5-year DFS 11.8% vs 39.7%; P = .03). There were no differences between Non-inf POC and No-POC patients. POC severity calculated using the Comprehensive Complications Index did not influence OS and DFS before and after PSM. Conclusion The negative oncological impact of POCs after CRLM resection is determined by infective etiology not by severity.

OBJECTIVE To study the effect of postoperative complications (POC) on overall survival (OS) and disease-free survival (DFS) after surgical resection of colorectal liver metastases (CRLM). SUMMARY BACKGROUND DATA Morbidity rates after liver resection can reach 45%. The negative impact of POC on oncologic outcomes has been reported in various types of cancer, especially colorectal. However, data on the consequences of POC after CRLM resection on long-term survival are scarce. METHODS Eligible studies examining the association between POC after CRLM resection and OS/DFS were sought using the PubMed and Web of Science databases. A random-effects model was used to calculate pooled effect estimate for OS and DFS hazard ratios (HR), estimating between-study variance with restricted maximum likelihood estimator with Hartung-Knapp adjustment. Subgroup analysis was used to control the effect of POC on OS and DFS for: 1) Method used to define postoperative complications, 2) Exclusion of early postoperative death from survival analysis, 3) Method of data extraction used, and 4) Tumor and treatment characteristics. RESULTS Forty-one studies were deemed eligible, including 12,817 patients. POC patients had a significant risk of reduced OS compared with no POC group (HR 1.43 [95% CI: 1.3, 1.57], P < 0.0001). POC had also a negative impact on DFS. The HR for reduced DFS was 1.38 [95% CI 1.27, 1.49], P < 0.0001. The negative impact of POC on survival and recurrence was confirmed in subgroup analysis. CONCLUSIONS Our findings evidence the negative impact of POC on survival and recurrence after CRLM resection.

Next-generation three-dimensional modelling software for personalized surgery allows spatially accurate depiction of the hepatic and vasculature anatomy based on the complexity and individual variation in each patient, and could facilitate decision-making about preoperative strategy in perihilar cholangiocarcinoma.

Purpose Liver metastases are the most common malignant solid liver lesions, approximately 40% of which stem from colorectal tumors. Liver resection is currently the only curative treatment for colorectal cancer liver metastases (CRLM). However, there is a lack of consensus criteria to assess the results of this treatment. In order to evaluate the quality of surgical outcomes, it is necessary to identify quality indicators (QIs) and their corresponding quality standards (QS). We propose a simple method to determine QI and QS in CRLM surgery (CRLMS) and establish acceptable quality limits (AQL) for each QI. Material and methods A systematic review of CRLMS results published from 2006 to 2016. Clinical guidelines, consensus conferences, and publications related to the CRLMS were reviewed to identify and select QIs. Once selected, a new review of the papers including the results of at least one of the QIs was performed. Statistical process control (SPC) method was applied to calculate the QS and AQL of each QI. The limits of variability were established from mean and confidence intervals at 95% and 99.8%. Results The most relevant QIs and its AQLs were postoperative mortality (2%, < 4.5%), overall postoperative morbidity (33%, < 41%), liver failure (5%, < 8%), postoperative hemorrhage (1%, < 3%), biliary fistula (6%, < 10%), reoperation (3%, < 6%), R1 resection margins (18%, < 25%), and overall survival at 12 and 60 months (84%, > 77%; and 34%, > 25%, respectively). Conclusions Despite its limitations, the present study constitutes the most extensive scientific evidence to date on QI and AQL in CRLMS and may constitute a reference in future studies.

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.

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.

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.

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.

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.

Fundamento La relacion entre la funcion endocrina y exocrina en la pancreatitis cronica es controvertida. El objetivo de este trabajo fue evaluar el estado funcional del pancreas endocrino en relacion con el grado de insuficiencia exocrina, comparar el valor de la prueba de sobrecarga oral a la glucosa (SOG) frente a la glucemia basal y estudiar los diferentes grados de alteracion funcional exocrina y endocrina en funcion del tiempo de evolucion. Pacientes y Metodo Se ha estudiado a 73 pacientes con pancreatitis cronica. Las funciones exocrina y endocrina se han investigado mediante la prueba de secretina-CCK (PSC), grasas en heces y SOG. Resultados De los 8 pacientes con PSC normal, la mitad presentaba alteraciones del metabolismo hidrocarbonado y 2 eran diabeticos. De los 50 con insuficiencia exocrina moderada, la excrecion de grasas en heces fue patologica en el 20%, mientras que un 54% presentaba alteraciones endocrinas, con diabetes en el 40%. Todos los pacientes con insuficiencia exocrina grave eran diabeticos. La SOG demostro alteraciones en un 42% de los pacientes con glucemia basal normal. La mediana de evolucion de la pancreatitis cronica en los pacientes con alteraciones del metabolismo hidrocarbonado fue menor que en los pacientes con esteatorrea Conclusiones Segun el grado de reserva funcional exocrina, en la pancreatitis cronica hay una mayor proporcion de pacientes con alteraciones del metabolismo hidrocarbonado que de esteatorrea. La SOG detecta alteraciones en un alto porcentaje de pacientes con glucemia basal normal. La disfuncion del metabolismo de los hidratos de carbono aparece mas tempranamente que la excrecion patologica de grasas fecales.

Foregut cystic malformations are common lesions in the mediastinum but are rarely found in subdiaphragmatic locations. Only a few cases have been described within the pancreas where they can easily be misdiagnosed as cystic neoplasms.We herein present the case of a 37-year-old female with acute cholangitis in whom a diagnostic work-up revealed a 1 cm solid-cystic heterogeneous lesion located at the head of the pancreas. The patient underwent a pancreaticoduodenectomy. Pathological evaluation demonstrated a cystic cavity lined by pseudostratified tall columnar ciliated epithelium with goblet cells, but lacking cartilage or smooth muscle bundles. Thus, the final diagnosis of the lesion was a ciliated foregut cyst of the pancreas.A review of the cases published regarding these lesions shows great variability in the taxonomy and a lack of accuracy in the definitions of each different subtype. An easy to use algorithm for the diagnosis of foregut cystic malformations subtypes, based on epithelial lining and wall features, is presented.

Background Hydrodynamic injection has demonstrated to be very efficient in the liver of small animals, although this procedure must be translated to the clinical practice in a milder but no less efficient way. The present study evaluates the capacity of non-invasive interventional catheterization as a procedure for naked DNA delivery to the heart in large animals. Methods Two catheters were placed in the coronary sinus: one of them to block blood circulation and the other to retrogradely inject 50 ml of a saline solution of DNA (20 µg/ml) containing the enhanced green fluorescent protein (EGFP) gene, at a flow rate of 5 ml/s. Results The results obtained show that EGFP protein, identified by immunohistochemistry, was present and widely distributed throughout the atrial and ventricular cardiac tissue. This observation agrees with the efficiency of EGFP gene delivery resulting in 1–200 EGFP gene copies per endogenous haploid genome. However, the transcription efficiency of the exogenous EGFP gene was at a ratio of 0.2–10 copies with respect to the endogenous GAPDH gene, suggesting that optimized gene constructs for expression in cardiac tissue could increase the final efficacy of gene transfer. Conclusions We conclude that the retrovenous injection of naked DNA in the coronary sinus employing the catheterization technique is an easy and probably safe method for whole cardiac gene transfer. Copyright © 2010 John Wiley & Sons, Ltd.

Extracellular haemoglobin (EHb) is considered a toxic molecule due to its cytotoxicity and peroxidase activity. EHb may release free hemin that increases vascular permeability, leukocyte recruitment, and adhesion molecule expression. Pancreatitis-associated ascitic fluid is reddish and may contain cell-free hemoglobin. Our aim was to determine the role of EHb in the local and systemic inflammatory response during severe acute pancreatitis in rats. To this end, taurocholate-induced necrotizing pancreatitis in rats was used. EHb levels were quantified in ascites and plasma and the hemolytic action of ascitic fluid was tested. Furthermore, we assessed if peritoneal lavage prevented the increase in EHb levels in plasma during pancreatitis. Finally, hemoglobin was purified from rat erythrocytes and administered i.p. to assess the local and systemic effects of ascitic-associated EHb during acute pancreatitis. EHb levels markedly increased in ascitic fluid and plasma during necrotizing pancreatitis. Peroxidase activity was very high in ascites. The peritoneal lavage abrogated the increase in cell-free hemoglobin in plasma. The administration of EHb enhanced ascites, dramatically increased abdominal fat necrosis, up-regulated tumor necrosis factor-a, interleukin 1ß and interleukin 6 gene expression and decreased expression of interleukin 10 in abdominal adipose tissue during pancreatitis. EHb enhanced the gene expression and protein levels of vascular endothelial growth factor (VEGF) and other hypoxia inducible factor-related genes [inducible nitric oxide synthase (inos), endothelial nitric oxide synthase (enos) and hexokinase 2] in the lung. EHb also increased myeloperoxidase activity in the lung. In conclusion, extracellular hemoglobin contributes to the inflammatory response in severe acute pancreatitis through abdominal fat necrosis and inflammation and increasing VEGF and leukocyte infiltration in the lung.