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 sub-study 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: 0.2mg/kg/day) versus twice-daily immediate-release tacrolimus (initial dose: 0.1mg/kg/day) during the first 2 weeks post-transplant. Results Pharmacokinetic data were analysed 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 0.1mg/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=0.96 and r=0.86, 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) Discipline liver transplantation/hepatology, immunosuppression/immune modulation. This article is protected by copyright. All rights reserved

Recent advances in gastrointestinal stromal tumors: Where are we going?

Tumores del estroma gastrointestinal; Inhibidores de la tirosina cinasa; LaparoscopiaGastrointestinal stromal tumors; Tyrosine kinase inhibitors; LaparoscopyTumors de l'estroma gastrointestinal; Inhibidors de la tirosina cinasa; LaparoscòpiaLos tumores del estroma gastrointestinal (GIST) suponen el 1-2% de los tumores digestivos, siendo su localización más frecuente el estómago (55-60%) y el intestino delgado (30%). Los avances más importantes sucedidos en los últimos años se centran en cuatro áreas: biología molecular, abordaje quirúrgico laparoscópico, manejo técnico del GIST en localizaciones inusuales y tratamiento e integración de la cirugía en el manejo del GIST avanzado. Los avances en el conocimiento de la biología molecular del GIST han dado lugar a la progresiva identificación de nueva mutaciones oncogénicas que hacen del concepto wild type obsoleto. Estos avances han permitido el desarrollo de dos nuevos fármacos, avapritinib y ripretinib, lo que permite el tratamiento de pacientes con mutaciones resistentes a las tres líneas terapéuticas clásicas. El tratamiento quirúrgico del GIST se rige por unos principios técnicos bien establecidos que el abordaje laparoscópico debe cumplir, abordaje que queda limitado por dos factores clave: localización y tamaño. El GIST de localización infrecuente (esófago, duodeno o recto, o extradigestivo) supone un reto terapéutico. Estos pacientes deben ser manejados en un contexto multidisciplinario. La cirugía queda integrada en el manejo del GIST avanzado, considerándose como adyuvante a los inhibidores de la tirosina cinasa.Gastrointestinal Stromal Sarcomas (GIST) are mesenchymal neoplasms whose incidence accounts for 1-2% of digestive tumors, being located in the stomach (55-60%) and small intestine (30%). The advances in its knowledge and management succeeded in the last years have being spectacular. This review aims to summarize the most important of them for surgeons. We identified four areas of interest: molecular oncology, laparoscopic approach, management of GIST located at unusual locations, and management of advanced GIST. Advances in the field of molecular oncology lead to the discovery of new oncogenic mutations making the term Wil Type GIST obsolete. Moreover, these advances allow for the development of 2 new drugs: Avapritinib and Ripretinib, that added to the previous 3 commercially available drugs (imatinib, sunitinib and regorafenib) make possible the management of GIST with resistant mutations. The principles of the surgical management of primary GIST are well stablished which laparoscopic approach must accomplish. This approach is limited by 2 main factors: location and size. The diagnosis of GIST in unusual locations as esophagus, duodenum, rectum of out of the gastrointestinal tract (EGIST), implies an extraordinary therapeutic challenge, being imperative to manage them by surgeons and oncologist among others in the setting of a multidisciplinary team. The management of advanced/metastatic GIST has changed in a revolutionary fashion because surgery is now part of its treatment as adjuvant to tyrosine kinase inhibitors

Everolimus plus minimized tacrolimus on kidney function in liver transplantation: REDUCE, a prospective, randomized controlled study

Background and aim: reduction in calcineurin inhibitor levels is considered crucial to decrease the incidence of kidney dysfunction in liver transplant (LT) recipients. The aim of this study was to evaluate the safety and impact of everolimus plus reduced tacrolimus (EVR + rTAC) vs. mycophenolate mofetil plus tacrolimus (MMF + TAC) on kidney function in LT recipients from Spain. Methods: the REDUCE study was a 52-week, multicenter, randomized, controlled, open-label, phase 3b study in de novo LT recipients. Eligible patients were randomized (1:1) 28 days post-transplantation to receive EVR + rTAC (TAC levels <_ 5 ng/mL) or to continue with MMF + TAC (TAC levels = 6-10 ng/mL). Mean estimated glomerular filtration rate (eGFR), clinical benefit in renal function, and safety were evaluated. Results: in the EVR + rTAC group (n = 105), eGFR increased from randomization to week 52 (82.2 [28.5] mL/min/1.73 m2 to 86.1 [27.9] mL/min/1.73 m2) whereas it decreased in the MMF + TAC (n = 106) group (88.4 [34.3] mL/min/1.73 m2 to 83.2 [25.2] mL/min/1.73 m2), with significant (p < 0.05) differences in eGFR throughout the study. However, both groups had a similar clinical benefit regarding renal function (improvement in 18.6 % vs. 19.1 %, and stabilization in 81.4 % vs. 80.9 % of patients in the EVR + rTAC vs. MMF + TAC groups, respectively). There were no significant differences in the incidence of acute rejection (5.7 % vs. 3.8 %), deaths (5.7 % vs. 2.8 %), and serious adverse events (51.9 % vs. 44.0 %) between the 2 groups. Conclusion: EVR + rTAC allows a safe reduction in tacrolimus exposure in de novo liver transplant recipients, with a significant improvement in eGFR but without significant differences in renal clinical benefit 1 year after liver transplantation

Results of a survey on peri-operative nutritional support in pancreatic and biliary surgery in Spain

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

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 (&lt; 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