Feasibility of steroid-free tacrolimus-basiliximab immunosuppression in pediatric liver transplantation and predictors for steroid requirement.

Avoidance of steroids in pediatric liver transplantation may reduce toxicity and morbidity. The aim of this study was to analyze the feasibility of a steroid-free tacrolimus-basiliximab immunosuppression scheme, the risk factors associated with steroid requirement, and safety parameters. Patients who underwent liver transplantation for biliary atresia between 2011 and 2019 were included and followed for 6 months after transplantation. Immunosuppression consisted of tacrolimus-based treatment with basiliximab induction. Steroid-free survival was estimated, and risk factors for steroid requirement were evaluated using multivariate Cox regression analysis. A total of 76 patients were included, of whom 42 (55.3%) required steroids (>14 d) due to biopsy-proven acute rejection (47.6%, n = 20), instability in liver function tests (35.7%, n = 15), tacrolimus-related adverse drug reactions (14.3%, n = 6), or other reasons (bronchospasm episode, n = 1). Steroid-free survival was 45.9% (95% CI, 35.9-58.8). Independent factors associated with steroid requirement included tortuosity in tacrolimus trough levels (≥1.76 vs. <1.76: HR 5.8, 95% CI, 2.6-12.7; p < 0.001) and mean tacrolimus trough levels (≥ 6.4 ng/mL vs. < 6.4 ng/mL: HR 0.4, 95% CI, 0.2-0.7; p = 0.002). The rate of bacterial and viral infections was comparable between patients with and without steroids, although in the former group, cytomegalovirus infection developed earlier ( p = 0.03). Patients receiving steroids had higher total cholesterol, LDL, and HDL levels ( p < 0.05) during follow-up, but no changes in the height Z-score were observed 1 year after transplantation. Basiliximab induction in combination with tacrolimus-based treatment avoided steroid requirements in 45% of the patients. Tacrolimus variability and trough levels below 6.4 ng/mL independently increased the risk of steroid requirement. Further efforts should be focused on personalizing immunosuppressive treatment.

Pancreatectomía izquierda laparoscópica: ¿la sistematización de la técnica es de utilidad? / Laparoscopic left pancreatectomy: is systematization of the technique useful?

RESUMEN Antecedentes: la pancreatectomía izquierda laparoscópica es un procedimiento de alta complejidad que debe ser sistematizado para reducir complicaciones y tiempos quirúrgicos. Objetivo: Describir los resultados con una técnica sitematizada de esplenopancreatectomía laparoscópica. Material y métodos: se seleccionaron pacientes candidatos a realizar esplenopancreatecomía distal en el período comprendido entre 2007 y 2022. Se excluyeron pacientes con enfermedad sistémica. La técnica quirúrgica laparoscópica consiste en ligar los vasos cortos como primer paso, luego disecar y cortar la arteria esplénica, dejando la sección de la vena como último gesto quirúrgico. Esto evita la congestión venosa del bazo. Se analizaron variables preoperatorias, intraoperatorias y posoperatorias. Resultados: sobre un total de 155 pacientes, 90 fueron intervenidos por vía laparoscópica y 65 por vía convencional. El tiempo quirúrgico promedio fue 168 minutos. Cuando se analizó el tiempo quirúrgico en los abordajes laparoscópicos, se observó una disminución del tiempo a partir del caso número 30. La mortalidad fue del 1,12%. La incidencia de fístula pancreática total fue 41%. La necesitad de transfusión intraoperatoria ocurrió en el 10,7% de los pacientes y la tasa de conversión fue del 13,3%. Conclusión: la sistematización de la técnica de la pancreatectomía laparoscópica permite la reducción de los tiempos quirúrgicos, adquirir mayor seguridad en la disección y realizar procedimientos cada vez más complejos.

ABSTRACT Background: Laparoscopic left pancreatectomy is a high complexity procedure that should be systematized to reduce complications and operative time. Objective: To describe the results achieved with a systematized technique for laparoscopic pancreatectomy and splenectomy. Materials and methods: We selected patients who were candidates for distal pancreatectomy and splenectomy between 2007 and 2022. Patients with systemic diseases were excluded. The laparoscopic technique consists of ligating the short vessels as a first step, then dissecting and cutting the splenic artery, leaving the section of the vein as the last surgical gesture to avoid venous congestion of the spleen. Perioperative, intraoperative and postoperative variables were analyzed. Results: A total of 155 patients were analyzed, 90 underwent laparoscopy and 65 underwent conventional surgery. Mean operative time was 168 minutes The operative time in the laparoscopic approach decreased from case 30 onwards. Mortality rate was 1.12%. The incidence of pancreatic fistula was 41%. Need for intraoperative transfusion occurred in 10.7% of the patients and the conversion rate was 13.3%. Conclusion: The systematization of the technique of pancreatic laparoscopy is essential to reduce surgical times, ensure safe dissections and performe more complex procedures.

Population pharmacokinetics of sublingually administered tacrolimus in infants and young children with liver transplantation.

AIMS: Pharmacokinetics of tacrolimus after sublingual administration is not characterized in paediatric liver transplant patients. Therefore, we aimed to develop a population pharmacokinetic model of sublingually administered tacrolimus in patients who cannot swallow the capsules due to their age, sedation status and/or mechanical ventilation during the first weeks post-transplantation. METHODS: Demographic, clinical and pharmacological variables, including tacrolimus whole blood concentrations obtained from therapeutic drug monitoring and data from dense-sampling pharmacokinetic profiles, were recorded in 26 paediatric patients with biliary atresia who underwent liver transplantation between 2016 and 2021. Population pharmacokinetic analysis was performed with NONMEM v7.4. RESULTS: Disposition of tacrolimus was best characterized by a 2-compartment model with clearance achieving half of the maximum elimination capacity (CLMAX  = 4.1 L/h) at 4.6 days post-transplantation (T50 ). Compared to sedated patients, nonsedated status showed an increased first-order absorption rate constant (1.1 vs. 0.1 h-1 ) and a 24% reduction in bioavailability (FNS ) at 14 days post-transplant. The model was able to explain the oral absorption pattern in nonsedated patients as the result of gut bioavailability (0.9) and hepatic extraction ratio, with the latter being responsible for first-pass effects. Estimates of interindividual variability remained moderate (25.9% for the gut bioavailability) to high (79.8% for the apparent volume of distribution of the central compartment, and 101% for T50 ). CONCLUSION: A population pharmacokinetic model of sublingually administered tacrolimus in paediatric patients was developed to characterize different absorption mechanisms. Once the model is externally validated, the effect of post-transplant time on clearance and the sedation status may be considered in routine dosing management.

An International Expert Delphi Consensus on Defining Textbook Outcome in Liver Surgery (TOLS).

OBJECTIVE: To reach global expert consensus on the definition of TOLS in minimally invasive and open liver resection among renowned international expert liver surgeons using a modified Delphi method. BACKGROUND: Textbook outcome is a novel composite measure combining the most desirable postoperative outcomes into one single measure and representing the ideal postoperative course. Despite a recently developed international definition of Textbook Outcome in Liver Surgery (TOLS), a standardized and expert consensus-based definition is lacking. METHODS: This international, consensus-based, qualitative study used a Delphi process to achieve consensus on the definition of TOLS. The survey comprised 6 surgical domains with a total of 26 questions on individual surgical outcome variables. The process included 4 rounds of online questionnaires. Consensus was achieved when a threshold of at least 80% agreement was reached. The results from the Delphi rounds were used to establish an international definition of TOLS. RESULTS: In total, 44 expert liver surgeons from 22 countries and all 3 major international hepato-pancreato-biliary associations completed round 1. Forty-two (96%), 41 (98%), and 41 (98%) of the experts participated in round 2, 3, and 4, respectively. The TOLS definition derived from the consensus process included the absence of intraoperative grade ≥2 incidents, postoperative bile leakage grade B/C, postoperative liver failure grade B/C, 90-day major postoperative complications, 90-day readmission due to surgery-related major complications, 90-day/in-hospital mortality, and the presence of R0 resection margin. CONCLUSIONS: This is the first study providing an international expert consensus-based definition of TOLS for minimally invasive and open liver resections by the use of a formal Delphi consensus approach. TOLS may be useful in assessing patient-level hospital performance and carrying out international comparisons between centers with different clinical practices to further improve patient outcomes.

Valoración de la linfadenectomía en una serie consecutiva de pacientes tratados por cáncer biliar / Evaluation of lymphadenectomy in a consecutive series of patients treated for biliary cancer

Resumen Introducción: Si bien actualmente la 8a edición de la clasificación del AJCC para cáncer biliar, recomienda una linfadenectomía con 6 o más GL, su aplicación es escasa. Objetivo: Analizar la aplicabilidad y los resultados de la linfadenectomía en pacientes resecados con fines curativos por cáncer biliar. Materiales y Método: Análisis retrospectivo de pacientes operados por cáncer biliar de 2001 a 2018. Se analizaron variables perioperatorias referidas a la linfadenectomía (número de GL, GL+, morbilidad), comparando supervivencia en pacientes con < 6 y ≥ 6 GL resecados. Resultados: en 72 pacientes resecados por cáncer biliar (46 CaV, 26 CC), se realizaron 66 (91.7%) linfadenectomías N1. En 62.1% (n = 41) se obtuvieron < 6 GL y en el 37.9% (n = 25) ≥ 6 GL. El promedio de GL resecados fue de 5. En 16 (24,2%) linfadenectomías se hallaron GL+ sin diferencias entre ambos grupos. La morbimortalidad global fue de 30,3%, con una mortalidad del 4.5% sin diferencias. Con un seguimiento de 36.9 meses, la supervivencia a 5 años fue 43,7% (n = 17), 7 pacientes con ≥ 6 GL, y 10 pacientes con < 6 GL (p = NS). La supervivencia media en pacientes con GL+ fue 15 meses (6-34 meses). Conclusión: la linfadenectomía ocupa un rol primordial en la cirugía curativa del cáncer biliar, tanto para definir una estadificación y un pronóstico adecuados como para optimizar los resultados de la resección curativa en esta entidad. Su indicación debe ser sistemática con la obtención de un número adecuado de GL acorde a las recomendaciones actuales.

Introduction: Currently the 8th edition of the AJCC classification recommends the resection of 6 or more lymph nodes (LN) in gallbladder cancer and cholangiocarcinoma. However, its implementation is universally scarce. Aim: The goal is to analyze the applicability and results of lymphadenectomy in patients resected with curative purposes in biliary cancer. Materials and Method: a retrospective analysis of patients with biliary cancer (gallbladder carcinoma, intrahepatic and hilar cholangiocarcinoma) treated by curative resection from 2001 to 2018 was performed. Perioperative variables related to lymphadenectomy (LN number, LN positive, related morbidity) were analyzed, comparing survival in patients with < 6 and ≥ 6 resected LN. Results: 72 patients resected for biliary cancer (46 gallbladder cancer, 26 cholangiocarcinoma) were included with 66 (91.7%) N1 lymphadenectomies corresponding to the hepatoduodenal ligament nodes performed. In 62.1% (n = 41) < 6 LN and in 37.9% (n = 25) ≥ 6 LN were resected. Average LN count was 5. In 16 (24.2%) patients positive LN were found, 7 in the group with ≥ 6 LN (28%) vs. 9 in the group with < 6 LN (22%) (p = NS). Overall morbimortality was 30.3% (n = 20). Average follow-up was 36.9 months. Survival at 5 years was 43.7% (n = 17), 7 patients with lymphadenectomy ≥ 6 LN, and 10 patients with < 6 LN (p = NS). Survival mean in patients who had positive LN was 15 months. Conclusión: Lymphadenectomy has a primary role in the radical resection with curative intention for biliary cancer. Systematic indication of lymphadenectomy should be prioritized, with the achievement of an adequately number of LN according to the actual recommendations. Lymphadenectomy is crucial for an adequate staging and prognosis, as well as to optimize the results of curative resection in this entity.

Which cava anastomotic techniques are optimal regarding immediate and short-term outcomes after liver transplantation: A systematic review of the literature and expert panel recommendations.

BACKGROUND: It has long been debated whether cava anastomosis should be performed with the piggyback technique or cava replacement, with or without veno-venous bypass (VVB), with or without temporary portocaval shunt (PCS) in the setting of liver transplantation. OBJECTIVES: To identify whether different cava anastomotic techniques and other maneuvers benefit the recipient regarding short-term outcomes and to provide international expert panel recommendations. DATA SOURCES: Ovid MEDLINE, Embase, Scopus, Google Scholar, and Cochrane Central. METHODS: A systematic review following PRISMA guidelines and recommendations using the GRADE approach derived from an international expert panel (CRD42021240979). RESULTS: Of 3205 records screened, 307 publications underwent full-text assessment for eligibility and 47 were included in qualitative synthesis. Four studies were randomized control trials. Eighteen studies were comparative. The remaining 25 were single-center retrospective noncomparative studies. CONCLUSION: Based on existing data and expert opinion, the panel cannot recommend one cava reconstruction technique over another, rather the surgical approach should be based on surgeon preference and center dependent, with special consideration toward patient circumstances (Quality of evidence: Low | Grade of Recommendation: Strong). The panel recommends against routine use of vevo-venous bypass (Quality of evidence: Very Low | Grade of Recommendation: Strong) and against the routine use of temporary porto-caval shunt (Quality of evidence: Very Low | Grade of Recommendation: Strong).

Intensive Safety Monitoring of Rituximab (Biosimilar Novex® and the Innovator) in Pediatric Patients With Complex Diseases.

Although rituximab is widely used off-label for complex pediatric diseases, safety reports are limited. We aimed to report evidence of its use in clinical practice, to describe the incidence of adverse drug reactions (ADR) to rituximab biosimilar Novex® and innovator, and to identify risk factors for the development of ADR in a real-life follow-up cohort of pediatric patients with complex diseases. We conducted a prospective, longitudinal, observational, single-centre study in patients that received rituximab for any complex disease, and as part of an intensive pharmacovigilance program. Demographic, pharmacological, clinical, and drug-related data were collected for all patients. ADR-free survival, including infusion-related reactions (IRR) and delayed ADR (dADR), was estimated using Kaplan-Meier curves. Risk factors were evaluated by multivariable Cox regression models. In total, 77 patients (<19 y.o.) received 187 infusions of rituximab Novex® (n = 155) or innovator rituximab (n = 32) for neurologic (Neu), immune-hematologic-rheumatic (IHR), oncologic (O) diseases, and hematopoietic stem-cell transplantation (HSCT) or solid-organ transplantation (SOT). We recorded 29 IRR and 58 dADR that occurred in 27 (35.1%) and 29 (37.7%) patients, respectively. The respiratory tract was the most affected during IRR (29.6%) and hypogammaglobulinemia (37.9 %) was the most frequent dADR. First versus subsequent infusions (HR 5.4, CI95% 2.4-12.1, p<0.05), sex (boys vs. girls, HR 0.3, CI95% 0.1-0.8, and p<0.05), and diagnosis (Neu-IHR diseases vs. O-HSCT-SOT, HR 2.3, CI95% 1.02-5.4, and p < 0.05) were significantly associated with the development of IRR. For dADR, risk factors were diagnosis (Neu-IHR diseases vs. O-HSCT-SOT, HR 0.4, CI95% 0.2-0.9, and p < 0.05) and cumulative body surface area-normalized dosage (HR 1.0003, CI95% 1.0001-1.0006, and p < 0.05). The present is the largest real-world safety assessment of rituximab in Latin-American children with complex diseases supporting its use based on the overall acceptable safety. Identification of risk factors may contribute to optimization of off-label rituximab treatment in pediatrics.

Impacto de la pandemia por COVID-19 sobre el trasplante hepático en la argentina. Otro daño colateral / Impact of COVID-19 pandemic in liver transplantation in Argentina. Other collateral damage

Resumen La pandemia COVID-19 declarada en marzo del 2020, ha generado preocupación mundial por su efecto en la salud de la población y el potencial colapso sanitario. La estrategia de "aplanar la curva" mediante el distanciamiento social permitió adaptar los recursos del sistema de salud a pacientes con COVID-19, pero no se pudo prever su repercusión en otras áreas de la salud. El objetivo de este trabajo fue analizar las consecuencias de la pandemia sobre el trasplante hepático en general y por hepatocarcinoma (HCC). Fueron realizados los siguientes estudios: a) un análisis retrospectivo utilizando datos del CRESI/INCUCAI para comparar ingreso en lista de espera, mortalidad en lista, donación y trasplante hepático desde 20/03 a 15/08, 2019 e igual periodo de 2020, y b) una encuesta a los centros de trasplante de mayor actividad trasplantológica para valorar el efecto de las medidas tomadas en diferentes situaciones institucionales y regionales. El primer análisis evidenció una disminución del 55% de los trasplantes hepáticos, con una reducción similar en la donación y en el ingreso a lista de espera hepática; mientras que el trasplante por HCC ascendió de 10% en 2019 a 22% en 2020. El segundo análisis, mostró que la tasa de ocupación de camas por pacientes COVID-19/semana fue variable: de 0.4% al 42.0%. El número de cirugías, hepato-bilio-pancreática, resección de HCC y trasplante hepático, se redujeron en 47%, 49%, 31% y 36% respectivamente. La reducción de la actividad trasplantológica afectó mayormente los centros con alta ocupación por COVID-19. El impacto final a largo plazo deberá evaluarse.

Abstract The COVID-19 pandemic declared in March 2020, has generated worldwide concern due to its effect on the health of the population and the potential health collapse. The strategy of "flattening the curve" through social distancing made it possible to adapt the resources of the health system to patients with COVID-19, but results in other areas of health could not be predicted. The objective of this work was to analyze the consequences of the pandemic on liver transplantation in general and for hepatocarcinoma (HCC). The following studies were carried out: a) a retrospective analysis using data from the CRESI / INCUCAI to compare admission to the waiting list, mortality on the list, donation and liver transplantation from 03/20 to 08/15, 2019 and the same period in 2020, and b) a survey of the transplant centers with the highest transplant activity to assess the effect of the measures taken in different institutional and regional situations. The first analysis showed a 55% decrease in liver transplants, with a similar reduction in donation and admission to the liver waiting list; while HCC transplantation rose from 10% in 2019 to 22% in 2020. The second analysis showed that the occupancy rate of beds by COVID-19 patients / week was variable: from 0.4% to 42.0%. The number of surgeries, hepato-bilio-pancreatic, resection of HCC and liver transplantation, were reduced by 47%, 49%, 31% and 36% respectively. The reduction in transplant activity mainly affected centers with high occupancy due to COVID-19. The final long-term outcome will need to be assessed.

Pancreatitis aguda posduodenopancreatectomía cefálica con complicaciones locales / Acute pancreatitis with local complications after cephalic pancreaticoduodenectomy

RESUMEN Antecedentes: la pancreatitis aguda posduodenopancreatectomía cefálica inmediata es una complica ción cuya frecuencia puede llegar al 55% y condiciona la aparición de fístula pancreática. Objetivo: describir el manejo de 3 pacientes que presentaron pancreatitis aguda posduodenopancrea tectomía con complicaciones locales y realizar una revisión de la literatura. Material y métodos: se revisó una base de datos prospectiva de resecciones pancreáticas. Se identifi caron los pacientes con diagnóstico de pancreatitis aguda con lesiones locales posterior a la realización de duodenopancreatectomía. Se definió fístula pancreática de acuerdo con la clasificación del ISGPF y pancreatitis como la elevación de la amilasa o lipasa tres veces por encima del máximo valor sérico normal en asociación con dolor abdominal o confirmación radiológica. Resultados: entre 2008 y 2019 los autores realizaron 260 duodenopancreatectomías. Tres pacientes presentaron pancreatitis posoperatoria con complicaciones locales. Conclusiones: la pancreatitis aguda posoperatoria es una complicación de una frecuencia elevada. La mayoría de ellas se resuelven en forma espontánea. Pocos pacientes presentan complicaciones locales que pueden requerir tratamiento percutáneo o quirúrgico, predisponiendo al desarrollo de fístulas a veces de difícil manejo. No hay forma de prevenir la aparición de la fístula pancreática. El tratamiento de las complicaciones locales se realizará de acuerdo con su aparición y repercusión, pudiendo requerir desde la colocación de un drenaje percutáneo hasta la pancreatectomía total.

ABSTRACT Background: The incidence of acute pancreatitis immediately after cephalic pancreaticoduodenec tomy is up to 55% and is associated with the development of pancreatic fistula. Objective: The aim of this study is to report three cases of acute pancreatitis after pancreaticoduode nectomy with local complications with a review of the literature. Material and methods: The information about pancreatic resections was retrieved from a prospective database. Patients with diagnosis acute pancreatitis with local lesions immediately after pancreatico duodenectomy were identified. Pancreatic fistula was defined according to the International Study Group on Pancreatic Fistula (ISGPF) Definition and pancreatitis was defined as serum amylase or lipase >3x upper limit of normal associated with abdominal pain or imaging criteria. Results: A total of 260 pancreaticoduodenectomies were performed between 2008 and 2019. Three patients developed postoperative acute pancreatitis with local complications. Conclusions: Postoperative acute pancreatitis is a common complication that solves spontaneously in most cases. Few patients present local complications that may require percutaneous or surgical treatment, which may predispose to the development of fistulas that are sometimes difficult to mana ge. There is no way to prevent pancreatic fistulas. Local complications will be treated according to their occurrence and impact, and may require a variety of procedures, ranging from percutaneous drainage to total pancreatectomy.

An international multicenter study of protocols for liver transplantation during a pandemic: A case for quadripartite equipoise.

BACKGROUND & AIMS: The outbreak of COVID-19 has vastly increased the operational burden on healthcare systems worldwide. For patients with end-stage liver failure, liver transplantation is the only option. However, the strain on intensive care facilities caused by the pandemic is a major concern. There is an urgent need for ethical frameworks to balance the need for liver transplantation against the availability of national resources. METHODS: We performed an international multicenter study of transplant centers to understand the evolution of policies for transplant prioritization in response to the pandemic in March 2020. To describe the ethical tension arising in this setting, we propose a novel ethical framework, the quadripartite equipoise (QE) score, that is applicable to liver transplantation in the context of limited national resources. RESULTS: Seventeen large- and medium-sized liver transplant centers from 12 countries across 4 continents participated. Ten centers opted to limit transplant activity in response to the pandemic, favoring a "sickest-first" approach. Conversely, some larger centers opted to continue routine transplant activity in order to balance waiting list mortality. To model these and other ethical tensions, we computed a QE score using 4 factors - recipient outcome, donor/graft safety, waiting list mortality and healthcare resources - for 7 countries. The fluctuation of the QE score over time accurately reflects the dynamic changes in the ethical tensions surrounding transplant activity in a pandemic. CONCLUSIONS: This four-dimensional model of quadripartite equipoise addresses the ethical tensions in the current pandemic. It serves as a universally applicable framework to guide regulation of transplant activity in response to the increasing burden on healthcare systems. LAY SUMMARY: There is an urgent need for ethical frameworks to balance the need for liver transplantation against the availability of national resources during the COVID-19 pandemic. We describe a four-dimensional model of quadripartite equipoise that models these ethical tensions and can guide the regulation of transplant activity in response to the increasing burden on healthcare systems.

Prognostic Factors in Pediatric Early Liver Retransplantation.

The most common indications for early liver retransplantation (eRe-LT) are vascular complications and primary nonfunction (PNF). These patients are usually in a critical clinical condition that can affect their chances of survival. In fact, the survival of these patients is usually lower compared with the patients undergoing a first transplant. To the best of our knowledge, no specific series of pediatric patients undergoing eRe-LT has been published to date. Therefore, the aim of this study is to report the results of eRe-LT and to analyze factors potentially related to success or failure. Our work is of a retrospective cohort study of patients who underwent eRe-LT at the Juan P. Garrahan Pediatric Hospital of Buenos Aires, Argentina, between May 1995 and December 2018 (n = 60). Re-LT was considered early when performed ≤30 days after the previous LT. A total of 40 (66.7%) patients were enrolled due to vascular causes and 20 (33.3%) were enrolled because of PNF. Of all the relisted patients, 36 underwent eRe-LT, 14 died on the waiting list, and 10 recovered without eRe-LT. A total of 23 (63.9%) patients died after eRe-LT, most of them due to infection-related complications. Survival rates at 1 and 5 years were 42.4% and 33.9%, respectively. On univariate logistic regression analysis, Pediatric End-Stage Liver Disease (PELD)/Model for End-Stage Liver Disease (MELD) scores, transplant era, and advanced life support at eRe-LT were found to be related to 60-day mortality. However, on multivariate analysis, era (odds ratio [OR], 9.3; 95% confidence interval [CI], 1.19-72.35; P = 0.033) and PELD/MELD scores (OR, 1.07; 95% CI, 1-1.14; P = 0.036) were significantly associated with 60-day patient mortality. This study found that the level of acuity before retransplant, measured by the requirement of advanced life support and the PELD/MELD score at eRe-LT, was significantly associated with the chances of post-eRe-LT patient survival.

[Impact of COVID-19 pandemic in liver transplantation in Argentina. Other collateral damage]. / Impacto de la pandemia por COVID-19 sobre el trasplante hepático en la Argentina. Otro daño colateral.

The COVID-19 pandemic declared in March 2020, has generated worldwide concern due to its effect on the health of the population and the potential health collapse. The strategy of "flattening the curve" through social distancing made it possible to adapt the resources of the health system to patients with COVID-19, but results in other areas of health could not be predicted. The objective of this work was to analyze the consequences of the pandemic on liver transplantation in general and for hepatocarcinoma (HCC). The following studies were carried out: a) a retrospective analysis using data from the CRESI / INCUCAI to compare admission to the waiting list, mortality on the list, donation and liver transplantation from 03/20 to 08/15, 2019 and the same period in 2020, and b) a survey of the transplant centers with the highest transplant activity to assess the effect of the measures taken in different institutional and regional situations. The first analysis showed a 55% decrease in liver transplants, with a similar reduction in donation and admission to the liver waiting list; while HCC transplantation rose from 10% in 2019 to 22% in 2020. The second analysis showed that the occupancy rate of beds by COVID-19 patients / week was variable: from 0.4% to 42.0%. The number of surgeries, hepato-bilio-pancreatic, resection of HCC and liver transplantation, were reduced by 47%, 49%, 31% and 36% respectively. The reduction in transplant activity mainly affected centers with high occupancy due to COVID-19. The final long-term outcome will need to be assessed.

La pandemia COVID-19 declarada en marzo del 2020, ha generado preocupación mundial por su efecto en la salud de la población y el potencial colapso sanitario. La estrategia de "aplanar la curva" mediante el distanciamiento social permitió adaptar los recursos del sistema de salud a pacientes con COVID-19, pero no se pudo prever su repercusión en otras áreas de la salud. El objetivo de este trabajo fue analizar las consecuencias de la pandemia sobre el trasplante hepático en general y por hepatocarcinoma (HCC). Fueron realizados los siguientes estudios: a) un análisis retrospectivo utilizando datos del CRESI/INCUCAI para comparar ingreso en lista de espera, mortalidad en lista, donación y trasplante hepático desde 20/03 a 15/08, 2019 e igual periodo de 2020, y b) una encuesta a los centros de trasplante de mayor actividad trasplantológica para valorar el efecto de las medidas tomadas en diferentes situaciones institucionales y regionales. El primer análisis evidenció una disminución del 55% de los trasplantes hepáticos, con una reducción similar en la donación y en el ingreso a lista de espera hepática; mientras que el trasplante por HCC ascendió de 10% en 2019 a 22% en 2020. El segundo análisis, mostró que la tasa de ocupación de camas por pacientes COVID-19/semana fue variable: de 0.4% al 42.0%. El número de cirugías, hepato-bilio-pancreática, resección de HCC y trasplante hepático, se redujeron en 47%, 49%, 31% y 36% respectivamente. La reducción de la actividad trasplantológica afectó mayormente los centros con alta ocupación por COVID-19. El impacto final a largo plazo deberá evaluarse.

Changing Etiologies and Prognostic Factors in Pediatric Acute Liver Failure.

After the implementation of universal hepatitis A virus vaccination in Argentina, the outcome of pediatric acute liver failure (PALF) remains unknown. We aimed to identify variables associated with the risk of liver transplantation (LT) or death and to determine the causes and short-term outcomes of PALF in Argentina. We retrospectively included 135 patients with PALF listed for LT between 2007 and 2016. Patients with autoimmune hepatitis (AIH), Wilson's disease (WD), or inborn errors of metabolism (IEM) were classified as PALF-chronic liver disease (CLD), and others were classified as "pure" PALF. A logistic regression model was developed to identify factors independently associated with death or need of LT and risk stratification. The most common etiologies were indeterminate (52%), AIH (23%), WD (6%), and IEM (6%). Overall, transplant-free survival was 35%, whereas 50% of the patients underwent LT and 15% died on the waiting list. The 3-month risk of LT or death was significantly higher among patients with pure PALF compared with PALF-CLD (76.5% versus 42.5%; relative risk, 1.8 [1.3-2.5]; P < 0.001), and 3 risk factors were independently associated with worse outcome: international normalized ratio (INR) ≥3.5 (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.3-7.2]), bilirubin ≥17 mg/dL (OR, 4.4; 95% CI, 1.9-10.3]), and pure PALF (OR, 3.8; 95% CI, 1.6-8.9). Patients were identified by the number of risk factors: Patients with 0, 1, or ≥2 risk factors presented a 3-month risk of worse outcome of 17.6%, 36.6%, and 82%, respectively. In conclusion, although lacking external validation, this simple risk-staging model might help stratify patients with different transplant-free survival rates and may contribute to establishing the optimal timing for LT.

Prognostic factors for event-free survival in liver transplantation for hepatoblastoma: A single-center experience.

Hepatoblastoma (HB) is the most common malignant liver tumor in children. Twenty percent of the cases may remain unresectable after neoadjuvant chemotherapy and, for these patients, liver transplant (LT) is an accepted therapeutic option. To analyze the risk factors to event-free survival (EFS) that influence the clinical outcome of patients with HB receiving LT, we retrospectively analyzed 21 patients with HB who underwent LT between January 1, 2005, and May 1, 2018. Overall survival (OS) was 90%. The univariate analysis shows that the AFP level at the time of LT was associated with a higher risk of EFS. With a ROC curve analysis, we established a cutoff point value of AFP levels at 16 000 ng/dL, with a sensitivity of 71.43% and a specificity of 85.71%. Multivariate analysis showed that patients with higher values of pretransplant AFP (>16 000 ng/dL) had a significantly higher risk of EFS than those transplanted with lower levels (HR: 10.180; 95% CI: 1.54-66.97; P = .02). Efforts should be made to improve the selection of candidates for LT for unresectable HB, aiming at a better definition of chemoresistance as a risk factor of poor outcomes.

Identification of Factors Affecting Tacrolimus Trough Levels in Latin American Pediatric Liver Transplant Patients.

Tacrolimus is the cornerstone in pediatric liver transplant immunosuppression. Despite close monitoring, fluctuations in tacrolimus blood levels affect safety and efficacy of immunosuppressive treatments. Identifying the factors related to the variability in tacrolimus exposure may be helpful in tailoring the dose. The aim of the present study was to characterize the clinical, pharmacological, and genetic variables associated with systemic tacrolimus exposure in pediatric liver transplant patients. De novo transplant patients with a survival of more than 1 month were considered for inclusion and were genotyped for cytochrome P450 3A5 (CYP3A5). Peritransplant clinical factors and laboratory covariates were recorded retrospectively between 1 month and 2 years after transplant, including alanine aminotransferase (ALT), aspartate aminotransferase, hematocrit, and tacrolimus predose steady-state blood concentrations collected 12 hours after tacrolimus dosing. A linear mixed effect (LME) model was used to assess the association of these factors and the log-transformed tacrolimus dose-normalized trough concentration (logC0/D) levels. Bootstrapping was used to internally validate the final model. External validation was performed in an independent group of patients who matched the original population. The developed LME model described that logC0/D increases with increases in time after transplant (ß = 0.019, 95% confidence interval [CI], 0.010-0.028) and ALT values (ß = 0.00030, 95% CI, 0.00002-0.00056), whereas logC0/D is significantly lower in graft CYP3A5 expressers compared with nonexpressers (ß = -0.349, 95% CI, -0.631 to -0.062). In conclusion, donor CYP3A5 genotype, time after transplant, and ALT values are associated with tacrolimus disposition between 1 month and 2 years after transplant. A better understanding of tacrolimus exposure is essential to minimize the occurrence of an out-of-range therapeutic window that may lead to adverse drug reactions or acute rejection.

Incidental Gallbladder Cancer: How Residual Disease Affects Outcome in Two Referral HPB Centers from South America.

BACKGROUND: Residual disease (RD) has been described as one of the most relevant prognostic factors after radical surgical resection for incidental gallbladder cancer (IGC). The purpose of the present study was to analyze patterns of RD and determinant prognostic factors in patients undergoing re-resection for IGC. METHODS: Patients undergoing re-exploration due to IGC between 1990 and 2014 were identified in two referral centers from different South-American countries. Patients submitted to a radical definitive operation were included in the study. Demographics and tumor-treated related variables were analyzed in correlation with RD and survival. The site of RD, local (gallbladder bed) or regional (lymph nodes and bile duct) was correlated with disease-specific survival (DSS). RESULTS: Of 265 patients with IGC submitted to surgery, 168 underwent a radical re-resection and RD was found in 58 (34.5%). Demographic, clinical and surgical variables were compared between both centers showing differences in type of resection, laparoscopic approach, T stages and disease stage. Location of RD was regional in 34 (20.2%) and local in 24 (14.3%), and no residual disease was found in 110 (65.5%) patients. T stage (T1b = 20%, T2 = 23.8%, T3 = 71.7%, p < 0.001) and disease stage (p < 0.001) were independent predictors of RD. Finding RD at any location reduced the DSS in comparison with non-RD patients (19.6 months vs. 62.7 months p < 0.001). No differences in DSS according to the location of RD were found, and all anatomic sites were equally poor (p = 0.27). RD at any site predicted DSS (p < 0.001), independently of all other IGC variables. CONCLUSIONS: IGC presented similar clinical parameters in two different countries of South America. RD was demonstrated as the most critical prognostic variable in patients with IGC treated by a radical resection. The presence of RD was associated with poor outcome, independently of any anatomic location. Future studies incorporating neoadjuvant chemotherapy in the treatment of patients with prognostic factors for RD are required to improve survival in this entity.

Intrahepatic cholangiocarcinoma surgery: the impact of lymphadenectomy.

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignant tumor and its incidence is increasing over the world. At present times, radical liver resection is still the most effective treatment for ICC patients to achieve long term survival. Pathological lymph node metastases (LMN), found in 15% to 45% of the patients, have been recognized as an extremely poor prognostic risk factor, even if curative resection is performed. So, considering this issue, it acquires relevance to determine the validity of surgical resection for LNM cases that are diagnosed in the preoperative setting, or whether a routine lymphadenectomy should be performed systematically in all hepatectomies for ICC. The role of routine lymphadenectomy in the surgical treatment of ICC remains controversial, with some centers considering it standard whereas other surgeons perform lymphadenectomy only as a selective indication. Recently, a growing widespread adoption of lymphadenectomy was demonstrated that nearly doubled its commonly reported execution rate. The newly updated eight edition of the American Joint Committee on Cancer (AJCC) staging system now recommends that six nodes need to be analyzed to stage patients with ICC. In this review, we analyzed and summarized some anatomic considerations of the lymphatic anatomy of the liver and the current knowledge and potential advantages of performing a routine lymphadenectomy in patients with ICC, especially looking at pathological staging, prognosis, prevention of local recurrence and outcome. New areas like lymphadenectomy in cirrhotic patients and laparoscopic lymphadenectomy are also discussed.

Survival Time to Biopsy-Proven Acute Rejection and Tacrolimus Adverse Drug Reactions in Pediatric Liver Transplantation.

BACKGROUND: Despite advances in surgical procedures and the optimization of immunosuppressive therapies in pediatric liver transplantation, acute rejection (AR) and serious adverse drug reaction (ADR) to tacrolimus still contribute to morbidity and mortality. Identifying risk factors of safety and efficacy parameters may help in optimizing individual immunosuppressive therapies. This study aimed to identify peritransplant predictors of AR and factors related to the risk of ADR to tacrolimus in a large Latin American cohort of pediatric liver transplant patients. METHODS: We performed a retrospective cohort study in a pediatric liver transplant population (n = 72). Peritransplant variables were collected retrospectively including demographic, clinical, laboratory parameters, genomic (CYP3A5 donor and recipients polymorphism), and tacrolimus trough concentrations (C0) over a 2-year follow-up period. Variability in tacrolimus C0 was calculated using percent coefficient of variation and tortuosity. ADR- and AR-free survival rates were calculated using the Kaplan-Meier method, and risk factors were identified by multivariate Cox regression models. RESULTS: Cox-proportional hazard models identified that high tortuosity in tacrolimus C0 was associated with an 80% increased risk of AR [hazard ratio (HR), 1.80; 95% confidence interval (CI), 1.01-3.22; P < 0.05], whereas steroid in maintenance doses decreased this risk (HR, 0.56; 95% CI, 0.31-0.99; P < 0.05). Forty-six patients experienced at least one ADR including hypomagnesemia, nephrotoxicity, hypertension, malignancies, and tremor as a first event. Multivariate analysis showed that C0 values 10 days before the event (HR, 1.25; 95% CI, 1.21-1.39; P < 0.0001) and CYP3A5 expresser recipients (HR, 2.05; 95% CI, 1.03-4.06; P < 0.05) were independent predictors of ADR. CONCLUSIONS: Tacrolimus C0 values, its variability, and CYP3A5 polymorphisms were identified as risk factors of AR and tacrolimus ADR. This knowledge may help to control and reduce their incidence in pediatric liver transplant patients. Prospective studies are important to validate these results.

Waiting list outcome of Peld/Meld exceptions: A single-center experience in Argentina.

As PELD/MELD-based allocation policy was adopted in Argentina in 2005, a system of exception points has been in place in order to award increased waitlist priority to those patients whose severity of illness is not captured by the PELD/MELD score. We aimed to investigate the WL outcome of patients with granted PELD/MELD exceptions. A retrospective cohort study was conducted in children under 18 years old. WL outcomes were evaluated using univariable analysis. From 07/2005 to 01/2014, 408 children were listed for LT. There were 304 classified by calculated PELD/MELD. During this time, 85 (30%) PELD/MELD exceptions were granted. In this cohort, 89.4% (76 of 85) were transplanted and 7.1% (6 of 85) died while on the WL. The remaining 3 pts (3.5%) were removed from the WL due to other causes. We compared the impact of PELD/MELD exceptions in those 85 patients to outcomes in 87 non-exception patients with PELD/MELD ≥19 points. Patients with the exception had significantly better access to WL and lower WL mortality. Our data suggest that children listed by PELD/MELD exceptions had an advantage compared to children with CLD with equivalent PELD/MELD listing priorities.

Intrahepatic and peripheral blood phenotypes of natural killer and T cells: differential surface expression of killer cell immunoglobulin-like receptors.

Deep characterization of the frequencies, phenotypes and functionalities of liver and peripheral blood natural killer (NK), natural killer T (NKT) and T cells from healthy individuals is an essential step to further interpret changes in liver diseases. These data indicate that CCR7, a chemokine essential for cell migration through lymphoid organs, is almost absent in liver NK and T cells. CD56bright NK cells, which represent half of liver NK cells, showed lower expression of the inhibitory molecule NKG2A and an increased frequency of the activation marker NKp44. By contrast, a decrease of CD16 expression with a potential decreased capacity to perform antibody-dependent cellular cytotoxicity was the main difference between liver and peripheral blood CD56dim NK cells. Liver T cells with an effector memory or terminally differentiated phenotype showed an increased frequency of MAIT cells,T-cell receptor-γδ (TCR-γδ) T cells and TCR-αß CD8+ cells, with few naive T cells. Most liver NK and T cells expressed the homing markers CD161 and CD244. Liver T cells revealed a unique expression pattern of killer cell immunoglobulin-like receptors (KIR) receptors, with increased degranulation ability and higher secretion of interferon-γ. Hence, the liver possesses a large amount of memory and terminally differentiated CD8+ cells with a unique expression pattern of KIR activating receptors that have a potent functional capacity as well as a reduced amount of CCR7, which are unable to migrate to regional lymph nodes. These results are consistent with previous studies showing that liver T (and also NK) cells likely remain and die in the liver.