Abdominal normothermic regional perfusion in controlled donation after circulatory determination of death liver transplantation: Outcomes and risk factors for graft loss.

Postmortem normothermic regional perfusion (NRP) is a rising preservation strategy in controlled donation after circulatory determination of death (cDCD). Herein, we present results for cDCD liver transplants performed in Spain 2012-2019, with outcomes evaluated through December 31, 2020. Results were analyzed retrospectively and according to recovery technique (abdominal NRP [A-NRP] or standard rapid recovery [SRR]). During the study period, 545 cDCD liver transplants were performed with A-NRP and 258 with SRR. Median donor age was 59 years (interquartile range 49-67 years). Adjusted risk estimates were improved with A-NRP for overall biliary complications (OR 0.300, 95% CI 0.197-0.459, p < .001), ischemic type biliary lesions (OR 0.112, 95% CI 0.042-0.299, p < .001), graft loss (HR 0.371, 95% CI 0.267-0.516, p < .001), and patient death (HR 0.540, 95% CI 0.373-0.781, p = .001). Cold ischemia time (HR 1.004, 95% CI 1.001-1.007, p = .021) and re-transplantation indication (HR 9.552, 95% CI 3.519-25.930, p < .001) were significant independent predictors for graft loss among cDCD livers with A-NRP. While use of A-NRP helps overcome traditional limitations in cDCD liver transplantation, opportunity for improvement remains for cases with prolonged cold ischemia and/or technically complex recipients, indicating a potential role for complimentary ex situ perfusion preservation techniques.

Time-Course Changes of Serum Keratin Concentrations after Liver Transplantation: Contrasting Results of Keratin-18 and Keratin-19 Fragments.

OBJECTIVE: Under normal conditions, adult hepatocytes express only keratin-8 (K8) and keratin-18 (K18), whereas cholangiocytes also express K19. In this study, we delineate the pattern of normal time-course changes in serum K19 and K18 levels after liver transplantation. Patients and Methods. Serum levels of the K19 fragment CYFRA 21-1 and the K18 fragments tissue polypeptide specific antigen (TPS) and M30 (a neoepitope that is generated after caspase cleavage during apoptosis) were measured at baseline and at regular intervals (up to 6 months) after liver transplantation in 11 adult patients. RESULTS: There was a gradual decrease in serum K19 concentrations from baseline values after transplantation, following a time-course pattern similar to that of serum bilirubin. In contrast, serum concentrations of K18 fragments increased markedly shortly after transplantation and gradually decreased thereafter, following a time-course pattern similar to that of serum transaminases. The increase in TPS tended to occur earlier than that in M30, suggesting an initial predominance of hepatocyte necrosis followed by a predominance of apoptosis in the first days after transplantation. Five patients presented posttransplant complications (acute rejection in three cases and HCV recurrence in two cases). An early increase in serum K19 concentrations was observed in all cases. An increase in serum concentrations of K18 fragments (M30 and TPS) was observed in the two cases with HCV recurrence and was more variable in the three cases with acute rejection. CONCLUSIONS: Serum concentrations of K19 and K18 fragments follow a dissimilar pattern of time-course changes after liver transplantation. The diagnostic value of variations in these normal patterns should be addressed in future studies.

Results of a survey on peri-operative nutritional support in pancreatic and biliary surgery in Spain / Resultados de una encuesta sobre el soporte nutricional perioperatorio en la cirugía pancreática y biliar en España

INTRODUCTION: a survey on peri-operative nutritional support in pancreatic and biliary surgery among Spanish hospitals in 2007 showed that few surgical groups followed the 2006 ESPEN guidelines. Ten years later we sent a questionnaire to check the current situation. METHODS: a questionnaire with 21 items sent to 38 centers, related to fasting time before and after surgery, nutritional screening use and type, time and type of peri-operative nutritional support, and number of procedures. RESULTS: thirty-four institutions responded. The median number of pancreatic resections (head/total) was 29.5 (95% CI: 23.0-35; range, 5-68) (total, 1002); of surgeries for biliary malignancies (non-pancreatic), 9.8 (95% CI: 7.3-12.4; range, 2-30); and of main biliary resections for benign conditions, 10.4 (95% CI: 7.6-13.3; range, 2-33). Before surgery, only 41.2% of the sites used nutritional support (< 50% used any nutritional screening procedure). The mean duration of preoperative fasting for solid foods was 9.3 h (range, 6-24 h); it was 6.6 h for liquids (range, 2-12). Following pancreatic surgery, 29.4% tried to use early oral feeding, but 88.2% of the surveyed teams used some nutritional support; 26.5% of respondents used TPN in 100% of cases. Different percentages of TPN and EN were used in the other centers. In malignant biliary surgery, 22.6% used TPN always, and EN in 19.3% of cases. CONCLUSIONS: TPN is the commonest nutrition approach after pancreatic head surgery. Only 29.4% of the units used early oral feeding, and 32.3% used EN; 22.6% used TPN regularly after surgery for malignant biliary tumours. The 2006 ESPEN guideline recommendations are not regularly followed 12 years after their publication in our country

INTRODUCCIÓN: realizamos una encuesta sobre soporte nutricional perioperatorio en cirugía pancreática y biliar en hospitales españoles en 2007, que mostró que pocos grupos quirúrgicos seguían las guías de ESPEN 2006. Diez años después enviamos un cuestionario para comprobar la situación actual. MÉTODOS: treinta y ocho centros recibieron un cuestionario con 21 preguntas sobre tiempo de ayunas antes y después de la cirugía, cribado nutricional, duración y tipo de soporte nutricional perioperatorio, y número de procedimientos. RESULTADOS: respondieron 34 grupos. La mediana de pancreatectomías (cabeza/total) fue de 29,5 (IC 95 %: 23,0-35; rango, 5-68) (total, 1002), la de cirugías biliares malignas de 9,8 (IC 95 %: 7,3-12,4; rango, 2-30) y la de resecciones biliares por patología benigna de 10,4 (IC 95 %: 7,6-13,3; rango, 2-33). Solo el 41,2 % de los grupos utilizaban soporte nutricional antes de la cirugía (< 50 % habian efectuado un cribado nutricional). El tiempo medio de ayuno preoperatorio para sólidos fue de 9,3 h (rango, 6-24 h), y de 6,6 h para líquidos (rango, 2-12). Tras la pancreatectomía, el 29,4 % habían intentado administrar una dieta oral precoz, pero el 88,2 % de los grupos usaron algún tipo de soporte nutricional y el 26,5 % usaron NP en el 100 % de los casos. Los demás grupos usaron diferentes porcentajes de NP y NE en sus casos. En la cirugía biliar maligna, el 22,6 % utilizaron NP siempre y NE en el 19,3 % de los casos. CONCLUSIONES: la NP es el soporte nutricional más utilizado tras la cirugía de cabeza pancreática. Solo el 29,4 % de las unidades usan nutrición oral precoz y el 32,3 % emplean la NE tras este tipo de cirugía. El 22,6 % de las instituciones usan NP habitualmente tras la cirugía de tumores biliares malignos. Las guías ESPEN 2006 no se siguen de forma habitual en nuestro país tras más de 10 años desde su publicación

Post-operative stress hyperglycemia is a predictor of mortality in liver transplantation.

BACKGROUND: A significant association is known between increased glycaemic variability and mortality in critical patients. To ascertain whether glycaemic profiles during the first week after liver transplantation might be associated with long-term mortality in these patients, by analysing whether diabetic status modified this relationship. METHOD: Observational long-term survival study includes 642 subjects undergoing liver transplantation from July 1994 to July 2011. Glucose profiles, units of insulin and all variables with influence on mortality are analysed using joint modelling techniques. RESULTS: Patients registered a survival rate of 85% at 1 year and 65% at 10 years, without differences in mortality between patients with and without diabetes. In glucose profiles, however, differences were observed between patients with and without diabetes: patients with diabetes registered lower baseline glucose values, which gradually rose until reaching a peak on days 2-3 and then subsequently declined, diabetic subjects started from higher values which gradually decreased across the first week. Patients with diabetes showed an association between mortality and age, Model for End-Stage Liver Disease score (MELD) score and hepatitis C virus; among non-diabetic patients, mortality was associated with age, body mass index, malignant aetiology, red blood cell requirements and parenteral nutrition. Glucose profiles were observed to be statistically associated with mortality among patients without diabetes (P = 0.022) but not among patients who presented with diabetes prior to transplantation (P = 0.689). CONCLUSIONS: Glucose profiles during the first week after liver transplantation are different in patients with and without diabetes. While glucose profiles are associated with long-term mortality in patients without diabetes, after adjusting for potential confounding variables such as age, cause of transplantation, MELD, nutrition, immunosuppressive drugs, and units of insulin administered, this does not occur among patients with diabetes.

Pharmacokinetics of prolonged-release tacrolimus versus immediate-release tacrolimus in de novo liver transplantation: A randomized phase III substudy.

BACKGROUND: With the same dose of tacrolimus, lower systemic exposure on the first day of dosing has been reported for prolonged-release tacrolimus compared with immediate-release tacrolimus, prompting investigation of differing initial doses. METHODS: This substudy of a double-blind, randomized, phase III trial in de novo liver transplant recipients compared the pharmacokinetics of once-daily prolonged-release tacrolimus (initial dose: 0.2 mg/kg/day) versus twice-daily immediate-release tacrolimus (initial dose: 0.1 mg/kg/day) during the first 2 weeks post-transplant. RESULTS: Pharmacokinetic data were analyzed from patients receiving prolonged-release tacrolimus (n=13) and immediate-release tacrolimus (n=12). Mean systemic exposure (AUC0-24 ) was higher with prolonged-release versus immediate-release tacrolimus. Dose-normalized AUC0-24 (normalized to 0.1 mg/kg/day) showed generally lower exposure with prolonged-release tacrolimus versus immediate-release tacrolimus. There was good correlation between AUC0-24 and concentration at 24 hours after the morning dose (r=.96 and r=.86, respectively), and the slope of the line of best fit was similar for both formulations. CONCLUSIONS: Doubling the initial starting dose of prolonged-release tacrolimus compared with immediate-release tacrolimus overcompensated for lower exposure on Day 1. A 50% higher starting dose of prolonged-release tacrolimus than immediate-release tacrolimus may be required for similar systemic exposure. However, doses of both formulations can be optimized using the same trough-level monitoring system. (ClinicalTrials.gov number: NCT00189826).

Impact of Cytomegalovirus Infection on Severe Hepatitis C Recurrence in Patients Undergoing Liver Transplantation.

BACKGROUND: The influence of cytomegalovirus (CMV) on recurrent hepatitis C virus (HCV) in liver grafts is controversial. Our aim was to investigate the association between CMV infection and disease and severe HCV recurrence (composite variable of presence of stage 3 to 4 fibrosis, need for retransplantation or death due to liver disease) in the first year after transplantation. METHODS: An observational, prospective, multicenter study was performed. The CMV replication was monitored by determining CMV viral load weekly during hospitalization after transplantation, twice monthly in the first 3 months after discharge, and at each follow-up visit until month 12. Liver fibrosis was assessed histologically by liver biopsy or transient elastometry. Pretransplant, intraoperative, and posttransplant variables were recorded. Multiple logistic regression was performed to study the impact of CMV on severe HCV recurrence. RESULTS: Ninety-eight patients were included. The CMV infection was detected in 48 patients (49%) in the first year posttransplant, of which 11 patients (22.9%) had CMV disease. Twenty-three patients (23.5%) had severe HCV recurrence. Of these, 17 (73.9%) developed stage 3 to 4 fibrosis, 4 (17.4%) died, and 2 (8.7%) underwent retransplantation. Only 7 of 12 (58.3%) seronegative recipients of a seropositive donor (positive donor/negative recipient [D+/R-]) received universal prophylaxis, and 10 of 12 (83.3%) D+/R- patients developed CMV replication. In the multivariate analysis, the presence of CMV D+/R- serodiscordance (odds ratio, 6.87; 95% confidence interval, 1.89-24.99; P = 0.003), and detection of a higher peak HCV viral load (odds ratio, 3.85; 95% confidence interval, 1.49-9.94; P = 0.005) were associated with severe HCV recurrence. CONCLUSIONS: Our results support an association between CMV D+/R- serodiscordance and severe HCV recurrence in patients undergoing liver transplantation for HCV liver disease.

Impact of tacrolimus and mycophenolate mofetil regimen vs. a conventional therapy with steroids on cardiovascular risk in liver transplant patients.

The aim of this study was to evaluate the impact of a steroid-free regimen with tacrolimus and mycophenolate mofetil (modified therapy) vs. a standard regimen of tacrolimus and steroids on the cardiovascular risk score of liver transplant recipients. Patients who received a liver transplant were randomized to a modified therapy (n = 58) or a standard regimen (n = 59). Both groups were balanced at baseline, except for a higher prevalence of diabetes mellitus (DM) (p < 0.01) and a higher serum creatinine concentration (p < 0.05) in the modified therapy group. After 12 months, the prevalence of new-onset DM, arterial hypertension, hypercholesterolemia, hypertriglyceridemia, and changes in cardiovascular risk factors was similar in both groups. The increase in serum creatinine (mg/dL) compared to baseline at one yr post-transplantation was numerically lower in the modified therapy group (0.22 ± 0.42) than in the standard regimen group (0.41 ± 0.67) (p = 0.068). Although estimated cardiovascular risk score did not vary significantly compared to baseline in either group, there was a slight reduction in the modified regimen (-0.27 ± 2.87) vs. a mild increase (0.17 ± 2.94) in the standard regimen (p = 0.566). In conclusion, a steroid-free regimen with tacrolimus and mycophenolate mofetil was associated with a trend toward better preservation of kidney function and reduction of cardiovascular risk score.

Underestimation of chronic renal dysfunction after liver transplantation: ICEBERG study.

AIM: To compare prevalence of chronic renal dysfunction (CRD) according to serum creatinine (sCr) vs estimated glomerular filtration rate (eGFR) among maintenance liver transplant patients. METHODS: The ICEBERG study was an observational, retrospective, cross-sectional, and multicenter study. Consecutive adult patients (aged 18 years or older) with liver transplantation (LT) performed at least two years previously were recruited. Multi-organ transplant recipients were excluded. Chronic renal dysfunction was defined according to sCr based criteria in routine clinical practice (≥ 2 mg/dL) and eGFR using MDRD-4 equation (< 60 mL/min per 1.73 m(2)). Agreement between sCr definition and eGFR assessment was evaluated using the Kappa index. Cox regression analysis was applied to identify predictive factors for developing CRD after LT. RESULTS: A total of 402 patients were analyzed (71.6% males). Mean ± SD age at transplant was 52.4 ± 9.8 years. Alcoholic cirrhosis without hepatocellular carcinoma was the most common reason for LT (32.8%). Mean time since LT was 6.9 ± 3.9 years. Based on sCr assessment, 35.3% of patients (95%CI: 30.6-40.0) had CRD; 50.2% (95%CI: 45.3-55.1) according to eGFR. In 32.2% of cases, sCr assessment had underestimated CRD. Multivariate analysis showed the following factors associated with developing CRD: eGFR < 60 mL/min per 1.73 m(2) at three months post-transplant [hazard ratio (HR) = 4.76; 95%CI: 2.78-8.33; P < 0.0001]; calcineurin inhibitor use (HR = 2.31; 95%CI: 1.05-5.07; P = 0.0371); male gender (HR = 1.98; 95%CI: 1.09-3.60; P = 0.0260); and ≥ 10 years post-transplantation (HR = 1.95; 95%CI: 1.08-3.54; P = 0.0279). CONCLUSION: Seven years after LT, CRD affected half our patients, which was underestimated by sCr. An eGFR < 60 mL/min per 1.73 m(2) three months post-LT was predictive of subsequent CRD.

Acute cellular rejection versus recurrent hepatitis C after liver transplantation: Clinical and pathological features driving a rational diagnostic approach.

AIM: The aim of our study was develop and validate an algorithm system based on morphological features for finding the differences between recurrent hepatitis C virus (HCV) and acute cellular rejection (ACR) in liver biopsies of HCV-transplanted patients. METHODS: Two hundred and eighty-eight liver biopsies were analyzed from 121 patients transplanted for HCV. A diagnostic consensus was reached between clinicians and pathologists in 214 biopsies for the diagnosis of recurrent HCV or ACR. A random sample of 114 liver biopsies (derivation cohort) was taken to generate the diagnostic tree and was subsequently evaluated using the validation cohort in 100 liver biopsies by recursive partitioning analysis of morphological variables and time since transplantation. RESULTS: The presence of endotheliitis together with a time of less than 6 weeks since LT definitely excluded recurrent HCV. After obtaining the regression tree, diagnostic accuracy was 96% and 93% in the derivation and validation cohort, respectively. Both cases surpassed the pathologist's original diagnosis, which had a diagnostic accuracy of 91% (P < 0.05, for both comparisons). CONCLUSION: A recursive partitioning analysis of the morphological features in liver biopsies from HCV-transplanted patients may be useful for easily distinguishing between recurrent HCV and ACR.

Use of artificial intelligence as an innovative donor-recipient matching model for liver transplantation: results from a multicenter Spanish study.

BACKGROUND & AIMS: There is an increasing discrepancy between the number of potential liver graft recipients and the number of organs available. Organ allocation should follow the concept of benefit of survival, avoiding human-innate subjectivity. The aim of this study is to use artificial-neural-networks (ANNs) for donor-recipient (D-R) matching in liver transplantation (LT) and to compare its accuracy with validated scores (MELD, D-MELD, DRI, P-SOFT, SOFT, and BAR) of graft survival. METHODS: 64 donor and recipient variables from a set of 1003 LTs from a multicenter study including 11 Spanish centres were included. For each D-R pair, common statistics (simple and multiple regression models) and ANN formulae for two non-complementary probability-models of 3-month graft-survival and -loss were calculated: a positive-survival (NN-CCR) and a negative-loss (NN-MS) model. The NN models were obtained by using the Neural Net Evolutionary Programming (NNEP) algorithm. Additionally, receiver-operating-curves (ROC) were performed to validate ANNs against other scores. RESULTS: Optimal results for NN-CCR and NN-MS models were obtained, with the best performance in predicting the probability of graft-survival (90.79%) and -loss (71.42%) for each D-R pair, significantly improving results from multiple regressions. ROC curves for 3-months graft-survival and -loss predictions were significantly more accurate for ANN than for other scores in both NN-CCR (AUROC-ANN=0.80 vs. -MELD=0.50; -D-MELD=0.54; -P-SOFT=0.54; -SOFT=0.55; -BAR=0.67 and -DRI=0.42) and NN-MS (AUROC-ANN=0.82 vs. -MELD=0.41; -D-MELD=0.47; -P-SOFT=0.43; -SOFT=0.57, -BAR=0.61 and -DRI=0.48). CONCLUSIONS: ANNs may be considered a powerful decision-making technology for this dataset, optimizing the principles of justice, efficiency and equity. This may be a useful tool for predicting the 3-month outcome and a potential research area for future D-R matching models.

Estudios volumétricos y anatómicos en el donante vivo / No disponible

No disponible

Immunosuppressant treatment adherence, barriers to adherence and quality of life in renal and liver transplant recipients in Spain.

To assess the adherence to immunosuppressant therapy (IST) and perceived barriers affecting IST adherence and quality of life (QOL) in patients who had received a renal (RT) or liver transplant (LT), a questionnaire was sent to over 9000 RT and LT recipients in Spain. Questionnaire comprised questions about patient's socio-demographic, organ transplant and medication characteristics; IST adherence and patient's perceived barriers to adherence; and patient's QOL using the EuroQol. Data from 1983 RT patients and 1479 LT patients were analyzed. Self-reported adherence to IST in RT (92.6%) and LT (88.5%) recipients was high. Daily medication intake (mean of 2-3 doses/d per patient) was considered a lifestyle restriction in about 25% of transplant recipients and was the most common barrier to adherence perceived by over 30% of RT and LT patients. Overall, high-intensity treatment regimens were associated with poorer QOL (EuroQol <70) compared with low-intensity treatment regimens. Most RT (71.0%) and LT (61.4%) patients would prefer to suppress the evening dose if they were able to. Although high adherence rates to IST were reported in this first large Spanish survey in RT and LT patients, adjustment of daily treatment intensity by less frequent dosing may be an adequate strategy to minimize barriers to adherence and improve QOL.

Profilaxis de la infección por citomegalovirus en el trasplante hepático / Prophylaxis of cytomegalovirus infection in liver transplantation

En los receptores de trasplante hepático, las estrategias de prevención de la enfermedad por citomegalovirus (CMV) deben estratificarse según el status serológico. En los receptores D–/R– no se recomienda profilaxis ni tratamiento anticipado. En el resto, la profilaxis universal y el tratamiento anticipado son las estrategias más utilizadas. Frente a placebo ambas son eficaces, pero no se han comparado entre sí mediante ensayos clínicos bien diseñados. El tratamiento anticipado es la estrategia preferida en los pacientes de bajo riesgo, mientras que la profilaxis es la más utilizada en los pacientes de alto riesgo.La enfermedad tardía por CMV es una consecuencia adversa de la profilaxis universal; su prolongación de 100 a 200 días no reduce la incidencia de enfermedad por CMV. La inmunidad celular específica frente a CMV, facilitada por el tratamiento anticipado y demorada por la profilaxis, tiene un efecto terapéutico reduciendo la replicación por CMV. Valganciclovir es el fármaco de elección en sendas estrategias, pero las dosis y la duración son distintas en cada una de ellas. Si se elige el tratamiento anticipado es necesario monitorizar la viremia durante los 4 primeros meses. Para ello, la PCR cuantitativa es la técnica diagnóstica de elección. A falta de datos concluyentes, la elección de una u otra estrategia en estos pacientes debe individualizarse en cada centro y en cada paciente, en función de los recursos disponibles y de la facilidad para el seguimiento (AU)

CMV prevention strategies in liver transplant recipients should be stratified according to serological status. In donor (D)-/recipient (R)- combinations, no prophylaxis or preemptive therapy is recommended. In the remaining combinations, the most widely used strategies are universal prophylaxis and preemptive therapy. Both strategies are effective compared with placebo but have not been compared with each other in welldesigned clinical trials. Preemptive therapy is the preferred strategy in low-risk patients while prophylaxis is the most widely used option in those at high-risk. Delayed CMV disease is an adverse consequence of universal prophylaxis. Prolongation of prophylaxis from 100 to 200 days does not reduce the incidence of CMV disease. CMV-specific cell mediated immunity, facilitated by preemptive therapy and delayed by prophylaxis, has a therapeutic effect by reducing CMV replication. The drug of choice in both strategies is valganciclovir but the duration and dose differ. When preemptive therapy is used, viremia monitoring is required for the first 4 months. The technique of choice is quantitative polymerase chain reaction. Given the lack of conclusive data, the choice of one or other strategy in these patients should be individualized in each patient and center according to the available resources and possibilities of follow-up (AU)

Recomendaciones GESITRA-SEIMC/REIPI para el manejo de la infección por citomegalovirus en pacientes trasplantados de órgano sólido / GESITRA-SEIMC/REIPI recommendations for the management of cytomegalovirus infection in solid-organ transplant patients

La infección por citomegalovirus (CMV) constituye una complicación importante en los pacientes sometidos a trasplante de órgano sólido (TOS). En el año 2005 el Grupo de Estudio de Infección en el Trasplante (GESITRA) de la Sociedad Española de Microbiología Clínica y Enfermedades Infecciosas (SEIMC) elaboró un documento de consenso para la profilaxis y el tratamiento de la infección por CMV en pacientes sometidos a TOS. Desde entonces han sido numerosas las publicaciones que o bien han aclarado, o bien han planteado nuevas dudas respecto a los aspectos tratados en el anterior documento. Entre estos aspectos se encuentran las situaciones y poblaciones que deben recibir profilaxis y su duración, la elección de la mejor técnica para el diagnóstico y monitorización y la elección de la mejor estrategia terapéutica. Todo ello justifica la necesidad de elaborar un nuevo documento de consenso que incluya las últimas recomendaciones en el manejo de la infección por CMV post-trasplante en base a las nuevas evidencias disponibles (AU)

Abstract Cytomegalovirus infection remains a major complication of solid organ transplantation. In 2005 the Spanish Transplantation Infection Study Group (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) developed consensus guidelines for the prevention and treatment of CMV infection in solid organ transplant recipients. Since then, numerous publications have clarified or questioned the aspects covered in the previous document. These aspects include the situations and populations who must receive prophylaxis and its duration, the selection of the best diagnosis and monitoring technique and the best therapeutic strategy. For these reasons, we have developed new consensus guidelines to include the latest recommendations on post-transplant CMV management based on new evidence available (AU)

GESITRA-SEIMC/REIPI recommendations for the management of cytomegalovirus infection in solid-organ transplant patients.

Cytomegalovirus infection remains a major complication of solid organ transplantation. In 2005 the Spanish Transplantation Infection Study Group (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) developed consensus guidelines for the prevention and treatment of CMV infection in solid organ transplant recipients. Since then, numerous publications have clarified or questioned the aspects covered in the previous document. These aspects include the situations and populations who must receive prophylaxis and its duration, the selection of the best diagnosis and monitoring technique and the best therapeutic strategy. For these reasons, we have developed new consensus guidelines to include the latest recommendations on post-transplant CMV management based on new evidence available.

Clinical relevance of epidermal growth factor receptor (EGFR) alterations in human pancreatic tumors.

Pancreatic cancer is a malignant neoplasm with an extremely poor prognosis. The mechanisms of aggressive growth and metastasis are currently not well understood. Expression of epidermal growth factor receptor (EGFR) has been suggested to be associated with the malignant transformation of pancreatic cancer. In this study, we examined the EGFR status of 52 pancreatic tumors by PCR-sequencing (exons 19 and 21), immunohistochemistry and FISH probes. We subsequently investigated the relationship between EGFR status and clinicopathological factors. Somatic alterations in EGFR (R841R, T571T and R831C) were observed only in ductal adenocarcinoma (3/34). In 4 (8%) of the 52 tumors analyzed EGFR was overexpressed, 6 (12%) of the tumors showed moderate expression while 19 (32%) were weakly stained. EGFR overexpression (3+ score) was frequently found in endocrine tumors (29%) followed of ampullary tumors (13%; p < 0.01). No significant correlation was observed between the presence of a somatic EGFR mutation and clinicopathological variables. Fluorescence in situ hybridization (FISH) analysis did not demonstrate amplification in any tumors. Only three somatic mutations in the EGFR gene were detected in pancreatic ductal adenocarcinoma and no association was observed with the clinical variables. Our results suggest that EGFR mutations are rare in pancreatic tumors and not associated with clinical prognosis, and treatment response.

Severe, non-bacteremic infections in ICU patients.

The present article is an update of the literature on various types of infections in ICU patients: ventilator-associated pneumonia, community-acquired pneumonia, the impact of the increasing vancomycin MIC in Staphylococcus aureus in the treatment of infections caused by this microorganism and the usefulness of biomarkers in identifying or ruling out septic complications in ICU patients. A multidisciplinary group of Spanish physicians with an interest in infections in critically-ill patients selected the most important recently published papers produced in the field. One of the members of the group discussed the content of each of the selected papers, with a critical appraisal by other members of the panel.

Severe, non-bacteremic infections in ICU patients

ResumenEl artículo presente recoge una actualización bibliográfica de varios tipos de infecciones en pacientes de cuidados intensivos: la neumonía asociada a ventilación mecánica, la neumonía adquirida en la comunidad, la repercusión del incremento de la CMI a vancomicina en el tratamiento de las infecciones causadas por Staphylococcus aureus y la utilidad de los biomarcadores en el diagnóstico de las complicaciones infecciosas en estos pacientes. Un grupo multidisciplinario de clínicos españoles con experiencia en las infecciones en enfermos críticos seleccionó las publicaciones más importantes en este campo aparecidas recientemente. El contenido de cada uno de los artículos seleccionados fue expuesto y discutido por uno de los miembros del grupo, después de lo cual los miembros restantes efectuaron una revisión crítica (AU)

The present article is an update of the literature on various types of infections in ICU patients: ventilatorassociatedpneumonia, community-acquired pneumonia, the impact of the increasing vancomycin MIC inStaphylococcus aureus in the treatment of infections caused by this microorganism and the usefulness ofbiomarkers in identifying or ruling out septic complications in ICU patients. A multidisciplinary group ofSpanish physicians with an interest in infections in critically-ill patients selected the most importantrecently published papers produced in the field. One of the members of the group discussed the content ofeach of the selected papers, with a critical appraisal by other members of the panel (AU)

Pharmacokinetics for once-daily versus twice-daily tacrolimus formulations in de novo liver transplantation: a randomized, open-label trial.

Tacrolimus, a cornerstone immunosuppressant, is available as a twice-daily formulation (tacrolimus bid). A once-daily prolonged-release formulation (tacrolimus qd) has been developed. This 6-week, randomized, phase 2, multicenter, open-label, prospective trial in primary liver transplant recipients investigated and compared the pharmacokinetics (PK) of tacrolimus for qd and bid formulations. All patients received tacrolimus-based immunosuppression (tacrolimus qd, n = 67; bid, n = 62). PK data were available for 77 patients (tacrolimus qd, n = 45; bid, n = 32). Tacrolimus area under the curve (AUC) from 0 to 24 hours (AUC(0-24) ) at equivalent doses was approximately 50% lower for tacrolimus qd than for bid on day 1 (146 versus 264 ng · h/mL, respectively), but by day 14 was comparable between treatments (324 and 287 ng · h/mL, respectively) with higher tacrolimus qd doses. There was a strong correlation between AUC(0-24) and concentration at 24 hours for tacrolimus qd and bid (r = 0.92 and r = 0.76, respectively). Furthermore, the relationship between these 2 parameters (ie, the slope of the line) was also similar for the 2 formulations. Efficacy endpoints were comparable for both formulations at 6 weeks with no marked differences in incidence, nature, or severity of adverse events between treatments (although the study was not powered to draw efficacy conclusions). These results suggest that targeting the same trough levels will achieve similar total AUC over 24 hours for both tacrolimus qd and tacrolimus bid in de novo liver transplant recipients.

Ductal adenocarcinoma of the pancreas: Expression of growth factor receptors, oncogenes and suppressor genes, and their relationship to pathological features, staging and survival.

Pancreatic ductal adenocarcinoma results in high short-term mortality despite recent advances in diagnostics, surgery and chemotherapy. Modern chemotherapeutic agents directed to specific tumor receptors have higher therapeutic efficacy and lower adverse effects. However, few studies exist that evaluate the clinical impact in pancreatic cancer. The expression of tumor growth factor receptors, oncogenes and tumor suppressor oncogenes in surgical pancreatic cancer specimens as related to pathological characteristics, staging and prognosis was evaluated. Data were recorded for 50 patients who underwent a pancreatic cancer resection and were suitable for immunohistochemical evaluation (32 male, mean age 61 years, range 44-78) with regard to pTN, tumor size and location, histological differentiation grade, vascular and perineural invasion, adjuvant chemotherapy and survival time. Tumor specimens and normal pancreatic tissue were deparaffinized and the expression of vascular epidermal growth factor (VEGF) receptors (R)-1 and -2, epidermal growth factor receptor (EGFR), Her-2/neu, COX-2, p16, p21 and p53 was immunohistochemically evaluated using tissue microarrays. Associations between molecular marker expression and clinicopathological tumor characteristics were evaluated using the Chi-square test (SPSS) and the survival time was defined. The Kaplan-Meier method was utilized to analyze survival curves, verified by the log-rank test. No molecular markers evaluated were expressed in normal tissue. Tumor expression data included VEGF-R1 (74%), EGFR (52%), Her-2/neu (7.84%), COX-2 (21.5%), p16 (29.4%), p21 (21.7%) and p53 (50%). Tumors expressing VEGF-R1, EGFR and/or p53 were larger (p<0.02), frequently poorly differentiated (p<0.05) and more frequently associated with perineural and lymph node invasion (p<0.05). Marker expression did not correlate with pathological tumor characteristics. The median post-surgery survival was 15 months; 60 and 27% patients survived to 12 and 24 months, respectively, with a longer survival time in patients receiving adjuvant chemotherapy (n=20) (median 36 vs. 15 months, p<0.02). Growth factor receptors, oncogenes and tumor suppressor genes were frequently expressed in pancreatic cancer tissue. VEGF-R1, EGFR and p53 expression were associated with poor tissue differentiation and perineural and lymph node infiltration. Only VEGF-R1 expression was associated with a longer survival time and a more favorable response to adjuvant chemotherapy.