Effects of 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.

Avances en tumores del estroma gastrointestinal: ¿hacia dónde vamos?

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.

Los 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.

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

INTRODUCTION: 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: 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.

A multidrug LC-MS/MS method for the determination of five immunosuppressants in oral fluid.

Aim: This study aimed: to develop and validate an LC-MS/MS method for mycophenolic acid, tacrolimus, sirolimus, everolimus and cyclosporin A in oral fluid (OF), as an essential tool to study the usefulness of OF as an alternative matrix for immunossuppressants' therapeutic drug monitoring; and to find the best OF collector for these analytes. Materials & Methods: Chromatographic separation was achieved using an XBridge® Shield RP18 analytical column maintained at 65ºC, using 2 mM ammonium formate and 0.1% formic acid in water (A) and acetonitrile (B) as mobile phase. OF sample was extracted with solid phase extraction after sonication and protein precipitation. Results & Conclusions: Method validation met all the acceptance criteria. LODs were 0.05-1 ng/ml, and LOQs 0.1-5 ng/ml. Silanized tubes offered the best recoveries. The method was successfully applied to 31 OF specimens, describing everolimus detection in OF for the first time. Conclusion: The proposed method is sensitive enough for the detection of OF trough concentrations in patients receiving immunosuppressants when using an appropriate OF collector.

Recomendaciones de uso de everolimus en el trasplante hepático / Recommendations of everolimus use in liver transplant

Los fármacos inhibidores de la mTOR, everolimus (EVL) y sirolimus, son inmunosupresores con muy poco efecto nefrotóxico, limitado al desarrollo de proteinuria en algunos casos. En la prevención del rechazo agudo EVL combinado con tacrolimus a dosis reducidas tiene una eficacia y seguridad comparables a la inmunosupresión estándar con tacrolimus. La aplicación temprana de una inmunosupresión basada en EVL con minimización de la exposición al inmunosupresor calcineurínico en trasplantados hepáticos permite mejorar los resultados de la función renal, con tasas similares de eficacia y seguridad, tanto en el período de novo como de mantenimiento. En pacientes con disfunción renal establecida la introducción de EVL permite minimizar la exposición al inmunosupresor calcineurínico, con la consiguiente mejoría en la función renal. Aunque no hay evidencia suficiente para recomendar su uso para prevenir la recurrencia del hepatocarcinoma y la progresión de tumores de novo, es práctica clínica habitual utilizarlos en este contexto (AU)

Mammalian target of rapamycin (mTOR) inhibitors, everolimus (EVL) and sirolimus are immunosuppressive agents with a minor nephrotoxic effect, limited to the development of proteinuria in some cases. The combination of EVL and low-dose tacrolimus has proven to be as safe and effective as standard therapy with tacrolimus for the prevention of acute cellular rejection. Early initiation of EVL-based immunosuppressive regimens with reduced exposure to calcineurin inhibitors has been shown to significantly improve renal function of LT recipients during induction and maintenance phases, with comparable efficacy and safety profiles. In patients with established kidney failure, initiating EVL may enable clinicians to reduce calcineurin inhibitors exposure, thereby contributing to the improved renal function of these patients. Although there is not sufficient evidence to recommend their use to prevent the recurrence of hepatocellular carcinoma and the progression of de novo tumours, they are used in this context in routine clinical practice (AU)

Recommendations of everolimus use in liver transplant. / Recomendaciones de uso de everolimus en el trasplante hepático.

Mammalian target of rapamycin (mTOR) inhibitors, everolimus (EVL) and sirolimus are immunosuppressive agents with a minor nephrotoxic effect, limited to the development of proteinuria in some cases. The combination of EVL and low-dose tacrolimus has proven to be as safe and effective as standard therapy with tacrolimus for the prevention of acute cellular rejection. Early initiation of EVL-based immunosuppressive regimens with reduced exposure to calcineurin inhibitors has been shown to significantly improve renal function of LT recipients during induction and maintenance phases, with comparable efficacy and safety profiles. In patients with established kidney failure, initiating EVL may enable clinicians to reduce calcineurin inhibitors exposure, thereby contributing to the improved renal function of these patients. Although there is not sufficient evidence to recommend their use to prevent the recurrence of hepatocellular carcinoma and the progression of de novo tumours, they are used in this context in routine clinical practice.

Leiomiomatosis intravascular con extensión intracardiaca: cirugía abdominal y cardíaca en un solo tiempo / Intravascular leiomyomatosis with cardiac extension: Simultaneous abdominal and cardiac surgery

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Utilidad de la canulación de la aorta torácica con perfusión anterógrada en la extracción de órganos abdominales / Thoracic aortic cannulation with antegrade perfusion for the procurement of abdominal organs

La aceptación definitiva de un órgano como válido depende del equipo quirúrgico que realiza la extracción multiorgánica, que tendrá de enfrentarse en muchas situaciones a dificultades inesperadas. Las características demográficas de los donantes han cambiado, se aceptan donantes de órganos que hace no muchos años considerábamos subóptimos, lo que implica muchas veces una técnica quirúrgica difícil y una toma de decisión acerca de la validez del órgano u órganos muy arriesgada. Se propone un método alternativo a la canulación de la aorta abdominal cuando se evidencie enfermedad de la aorta infra-renal durante la realización de la extracción multiorgánica. Se realiza la canulación de la aorta torácica descendente retrocardíaca con una perfusión anterógrada, esta técnica permite aumentar el número de órganos a trasplantar

The definitive acceptance of an organ as valid for transplant depends on the surgical team performing the multiorgan recovery; and unexpected difficulties can occur. The demographic characteristics of donors has changed, and some accepted donors can present difficulties in surgical technique and risky decisions on the validity of the retrieved organ or organs. An alternative method to the cannulation of the abdominal aorta is proposed when there is evidence of disease in the infrarenal aorta during the multiorgan procurement. The retrocardiac descending thoracic aorta is cannulated using an antegrade perfusion; this technique allows an increase in organ recovery

Grado de homogeneidad de los grupos españoles de trasplante hepático en el tratamiento del hepatocarcinoma / Degree of uniformity in the treatment of hepatocellular carcinoma in the Spanish teams of liver transplantation

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Basiliximab en el tratamiento del rechazo celular agudo resistentea los corticoides postrasplante hepático / Basiliximab in the treatment of acute steroid-resistant rejection after liver transplantation

Se presenta el caso de un receptor de un trasplante hepático con la indicación de cirrosis hepática alcohólica y carcinoma hepatocelular en estadio inicial que presentó un rechazo celular agudo resistente a los corticoides demostrado por biopsia a los 3 meses del trasplante. Tras la ausencia de mejora analítica o histológica con 6-metil-prednisolona intravenosa y la conversión del régimen inmunosupresor a tacrolimus y micofenolato mofetil, se administraron 2 dosis de basiliximab intravenoso separadas por 4 días, asistiendo a la normalización clínica, analítica e histológica. No se detectaron episodios adversos relacionados con el tratamiento con basiliximab. El basiliximab puede representar una opción terapéutica en el rechazo celular agudo resistente a los corticoides tras el trasplante hepático, sin que se hayan observado infecciones, neoplasias ni otros efectos adversos potencialmente relacionados en este caso (AU)

We present the case of a liver transplant recipient with alcoholic liver cirrhosis and early-stage hepatocellular carcinoma who developed biopsy-proven acute steroid-resistant rejection 3 months after liver transplantation. After the failure of immunosuppressive therapy with intravenous boluses of 6-methyl-prednisolone and switching of the immunosuppressive regimen to tacrolimus plus mycophenolate mofetil, two doses of intravenous basiliximab were administered four days apart. Clinical, analytical, and biopsy-proven histological response was complete. No basiliximab-related adverse events were detected. Basiliximab may represent an alternative in liver transplantation immune suppression to treat acute steroid-resistant rejection, without increasing the incidence of infections, neoplasms, or other adverse events, as shown by this case (AU)

[Basiliximab in the treatment of acute steroid-resistant rejection after liver transplantation]. / Basiliximab en el tratamiento del rechazo celular agudo resistente a los corticoides postrasplante hepático.

We present the case of a liver transplant recipient with alcoholic liver cirrhosis and early-stage hepatocellular carcinoma who developed biopsy-proven acute steroid-resistant rejection 3 months after liver transplantation. After the failure of immunosuppressive therapy with intravenous boluses of 6-methyl-prednisolone and switching of the immunosuppressive regimen to tacrolimus plus mycophenolate mofetil, two doses of intravenous basiliximab were administered four days apart. Clinical, analytical, and biopsy-proven histological response was complete. No basiliximab-related adverse events were detected. Basiliximab may represent an alternative in liver transplantation immunosuppression to treat acute steroid-resistant rejection, without increasing the incidence of infections, neoplasms, or other adverse events, as shown by this case.

[Influence of donor age and recipient gender on survival in transplantation due to hepatocarcinoma]. / Influencia de la edad del donante y del sexo del receptor en la supervivencia de los pacientes trasplantados por hepatocarcinoma.

Hepatocarcinoma (HCC) is one of the most frequent indications for liver transplantation. Survival in patients undergoing transplantation due to HCC is similar to that in patients undergoing this procedure for other indications. However, the current shortage of donors has led to longer waiting lists with a consequent risk of tumor progression. The use of older donors in these patients could increase the donor pool and shorten the time spent on the waiting list. We analyzed the influence of donor age on survival in 78 patients with HCC who underwent transplantation in the Santiago de Compostela Hospital between 1994 and 2003.

Influencia de la edad del donante y del sexo del receptoren la supervivencia de los pacientes trasplantadospor hepatocarcinoma / Influence of donorage and recipient gender on survival in transplantarion due to hepatocarcinoma

En la actualidad el hepatocarcinoma (HCC) es una de las indicacionesmás frecuentes de trasplante hepático. La supervivenciade los pacientes trasplantados por HCC es similar aotras indicaciones. Sin embargo, la escasez de donante conllevaun aumento del tiempo en lista de espera, con el consiguienteriesgo de progresión tumoral. En estos pacientes, lautilización de donantes añosos podría aumentar el pool dedonantes y acortar el tiempo en lista de espera. En este estudioanalizamos la influencia de la edad del donante en la supervivenciade 78 pacientes con HCC trasplantados en elHospital Clínico de Santiago entre 1994 y 2003 (AU)

Hepatocarcinoma (HCC) is one of the most frequent indicationsfor liver transplantation. Survival in patients undergoingtransplantation due to HCC is similar to that in patientsundergoing this procedure for other indications.However, the current shortage of donors has led to longerwaiting lists with a consequent risk of tumor progression.The use of older donors in these patients could increase thedonor pool and shorten the time spent on the waiting list.We analyzed the influence of donor age on survival in 78 patientswith HCC who underwent transplantation in the Santiagode Compostela Hospital between 1994 and 2003 (AU)

Lista única nacional o autonómica: pros y contras / No disponible

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Dos casos de hipertensión portal segmentaria en relación con la enfermedad no pancreática / Two cases of segmental portal hypertension associated with pancreatic disease

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