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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

Livers for transplantation from donation after circulatory death donors are relatively more prone to early and ongoing alterations in graft function that might ultimately lead to graft loss and even patient death. In consideration of this fact, this working group of the International Liver Transplantation Society has performed a critical evaluation of the medical literature to create a set of statements regarding the assessment of early allograft function/dysfunction and complications arising in the setting of donation after circulatory death liver transplantation.

Background Recent radiologic advances have made endovascular treatment a very successful option for arterial complications after liver transplant. This article presents our experience of using endovascular treatments during the first week after liver transplant. Methods This study is a retrospective, single-center analysis. Liver transplants performed between 2010 and 2018 were analyzed. All patients underwent Doppler ultrasonography on days 1 and 7. Endovascular therapy was indicated in hepatic artery thrombosis diagnosed early after transplant and in stenosis when hepatic narrowing was > 70%. Patients were treated with subcutaneous anticoagulant therapy and with antiplatelet agents after endovascular therapy. Results Seven patients (1.1%) were included in the study. Stenosis was the reason in 5 patients while 2 patients had symptoms of thrombosis. The first 2 patients were initially treated with angioplasty; both had restenosis and were treated with angioplasty and stent placement, respectively. The 5 most recent patients received stenting as a primary treatment. Two of these patients developed a new stenosis. No patient developed any hepatic artery complication related to the procedure, and only 1 patient experienced a postprocedure complication (femoral artery pseudoaneurysm), which was managed conservatively. No patient required retransplant. After a median follow-up of 48 months (range, 35-85 months) 1 patient had died, and the rest were alive and asymptomatic. Conclusions Although there is scant experience of the use of endovascular therapy very shortly after liver transplant, recent advances in interventional radiology have made the technique feasible and safe, and it achieves a high success rate.

Although good results have been reported with the use of normothermic regional perfusion (NRP) in controlled donation after circulatory death (cDCD) liver transplantation (LT), there is a lack of evidence to demonstrate similar results to donation after brain death (DBD). We present a single-center retrospective case-matched (1:2) study including 100 NRP cDCD LTs and 200 DBD LTs and a median follow-up of 36 months. Matching was done according to donor age, recipient Model for End-Stage Liver Disease score, and cold ischemia time. The following perioperative results were similar in both groups: alanine transaminase peaks of 909 U/L in the DBD group and 836 U/L in the cDCD group and early allograft disfunction percentages of 21% and 19.2%, respectively. The 1-year and 3-year overall graft survival for cDCD was 99% and 93%, respectively, versus 92% and 87%, respectively, for DBD (P = 0.04). Of note, no cases of primary nonfunction or ischemic-type biliary lesion were observed among the cDCD grafts. Our results confirm that NRP cDCD LT meets the same outcomes as those obtained with DBD LT and provides evidence to support the idea that cDCD donors per se should no longer be considered as "marginal donors" when recovered with NRP.

We would like to thank Dr Muller et al. for their interest in our paper and their important comments. Based on our results, the authors present three interesting questions to discuss.

Background Tacrolimus trough levels (TTL) during the first weeks after liver transplantation (LT) have been related with long-term renal function and hepatocellular carcinoma recurrence. Nevertheless, the significance of trough levels of tacrolimus during the early post-transplant period for the long-term outcome is under debate. Aim To evaluate the effect of TTL during the first month on the long-term outcomes after LT. Methods One hundred fifty-five LT recipients treated de novo with once-daily tacrolimus were retrospectively studied. Patients with repeated LT or combined transplantation were excluded as well as those who presented renal dysfunction prior to transplantation and/or those who needed induction therapy. Patients were classified into 2 groups according to their mean TTL within the first month after transplantation: ≤ 10 (n = 98) and > 10 ng/mL (n = 57). Multivariate analyses were performed to assess risk factors for patient mortality. Results Mean levels within the first month post-transplant were 7.4 ± 1.7 and 12.6 ± 2.2 ng/mL in the ≤ 10 and > 10 groups, respectively. Donor age was higher in the high TTL group 62.9 ± 16.8 years vs 45.7 ± 17.5 years (P = 0.002) whilst mycophenolate-mofetil was more frequently used in the low TTL group 32.7% vs 15.8% (P = 0.02). Recipient features were generally similar across groups. After a median follow-up of 52.8 mo (range 2.8-81.1), no significant differences were observed in: Mean estimated glomerular filtration rate (P = 0.69), hepatocellular carcinoma recurrence (P = 0.44), de novo tumors (P = 0.77), new-onset diabetes (P = 0.13), or biopsy-proven acute rejection rate (12.2% and 8.8%, respectively; P = 0.50). Eighteen patients died during the follow-up and were evenly distributed across groups (P = 0.83). Five-year patient survival was 90.5% and 84.9%, respectively (P = 0.44), while 5-year graft survival was 88.2% and 80.8%, respectively (P = 0.42). Early TTL was not an independent factor for patient mortality in multivariate analyses. Conclusion Differences in tacrolimus levels restricted to the first month after transplant did not result in significant differences in long-term outcomes of LT recipients.

COVID-19, the illness caused by the SARS-CoV-2 virus originated in December 2019 in Wuhan, China and has caused more 3,3 million cases and more than 230,000 deaths throughout the world, with 25,000 of them only in Spain, where the first case was diagnosed on January 31st, 2020. As COVID-19 is a "new" disease, we still do not have data on prognosis or treatment in transplant patients or on how to manage immunosuppression in this complex scenario. We present a case of COVID-19 diagnosed during the early postoperative period in a recipient whose liver transplantation was performed on late March during the lockdown in Spain, with donor and recipient previously negative rRT-PCR to SARS-CoV-2. In the first post-operative week the patient suffered COVID-19 pneumonia that was treated with immunosuppression minimization, oral Hydroxycloroquine and Azithromycin with favorable outcome. The patient was discharged on POD 21 without complications. To date, few early post-liver transplantation SARS-CoV-2 infected recipients have been published, but only one was an early postoperative infection. In our case the outcome was favorable, even though it was an early post -liver transplantation COVID-19 in a frail patient.

Background & Aims The incidence and outcomes of coronavirus disease 2019 (Covid-19) in immunocompromised patients are a matter of debate. Methods Prospective nationwide study including a consecutive cohort of liver transplant patients with Covid-19 recruited during the Spanish outbreak from February 28th to April 7th, 2020. The primary outcome was severe Covid-19, defined as the need for mechanical ventilation, intensive care, and/or death. Age- and gender-standardized incidence and mortality ratios (SIR and SMR) were calculated using data from the Ministry of Health and the Spanish liver transplant registry. Independent predictors of severe Covid-19 among hospitalized patients were analyzed using multivariate Cox regression. Results A total of 111 liver transplant patients were diagnosed with Covid-19 (SIR=191.2 [95%CI 190.3-192.2]). The epidemiological curve and geographic distribution overlapped widely between liver transplant and general populations. After a median follow-up of 23 days, 96 patients (86.5%) were admitted to hospital and 22 patients (19.8%) required respiratory support. Twelve patients were admitted to the ICU (10.8%). The mortality rate was 18%, being lower compared to the matched general population (SMR=95.5 [95%CI 94.2-96.8]). Thirty-five patients (31.5%) met criteria of severe Covid-19. Baseline immunosuppression containing mycophenolate was an independent predictor of severe Covid-19 (RR=3.94; 95%CI 1.59-9.74; p=0.003), particularly at doses higher than 1,000 mg/day (p=0.003). This deleterious effect was not observed with calcineurin inhibitors or everolimus and complete immunosuppression withdrawal showed no benefit. Conclusions Being chronically immunosuppressed, liver transplant patients have an increased risk of acquiring Covid-19 but their mortality rates are lower than matched general population. Upon hospital admission, mycophenolate dose reduction or withdrawal could help in preventing severe Covid-19. However, complete immunosuppression withdrawal should be discouraged., Graphical abstract, HIGHLIGHTS • The incidence of Covid-19 is increased in liver transplant patients. • Mortality rates are lower than those observed in matched general population. • Immunosuppression withdrawal may not be justified. • Mycophenolate may increase the risk of severe Covid-19 in a dose dependent-manner. • Calcineurin inhibitors and everolimus are not deleterious for Covid-19., In liver transplant patients, chronic immunosuppression increases the risk of acquiring Covid-19 but it could reduce disease severity. Complete immunosuppression withdrawal may not be justified. However, mycophenolate withdrawal or temporary conversion to calcineurin inhibitors or everolimus until disease resolution could be beneficial in hospitalized patients.

Renal dysfunction is related to short- and long-term survival after liver transplantation. We present herein a retrospective analysis of our experience with liver transplantation in recipients with pretransplant renal dysfunction treated with induction therapy followed by delayed/reduced de novo once-daily tacrolimus.Liver transplantations performed between April 2008 and August 2011 were included in this study. Pretransplant renal dysfunction was defined as estimated glomerular filtration rate 60 mL/min. Interleukin-2 receptor antagonists were used for induction therapy. Initial once-daily tacrolimus dose was 0.10 mg/kg/day or 0.07 mg/kg/day if combined with mycophenolate mofetil (MMF). Tacrolimus target trough levels were 4 to 6 ng/mL during the first post-transplant year and 4 ng/mL the rest of the follow-up.Nineteen patients comprised the study cohort with a median follow-up of 56.4 months (range, 11-78). Median day of tacrolimus introduction was 7 (range, 3-12). Once-daily tacrolimus was withdrawn in 6 patients (31.6%) due to evolution of renal dysfunction in all cases. At 5 years, 30% of the patients were under MMF monotherapy. Mean tacrolimus trough levels were maintained under 5 ng/mL. Mean estimated glomerular filtration rate at 5 years was 55.3 ± 12.7 mL/min. No patient needed hemodialysis or renal transplantation over the follow-up. Patient survival at 5 years was 78.9%.Induction therapy followed by delayed/reduced de novo once-daily tacrolimus and maintenance of low tacrolimus exposition during the follow-up is effective to maintain long-term renal function and to achieve favorable patient survival in liver transplant recipients with pretransplant renal dysfunction.

Background Hepatic artery avulsion following politrauma is an extremely rare condition with a very high mortality rate. Management is based on damage control surgery given the precarious situation of these patients. Ligating the artery is one option under such circumstances, despite potential consequences including ischemic cholangiopathy (IC). Ischemic cholangiopathy, which can be caused by an insufficient blood supply to the bile duct, generally results in stricture and recurrent cholangitis, and the need for a liver transplant in extreme cases. Case presentation We present the case of a 37-year-old male with multiple traumas after falling from the third floor of a building. He was hemodynamically unstable upon arrival at the emergencies department, with no improvement on administration of aggressive fluid therapy. A Echo-FAST exam evidenced fluid in all quadrants, so the patient was transferred to the operating room where a 4-litre hemoperitoneum secondary to total avulsion of the proper hepatic artery was observed. The patient required massive transfusion and vasoactive drugs, with instability throughout the intervention; therefore, we decided to ligate the proper hepatic artery. Hepatic dysfunction and diffuse IC with multiple episodes of recurrent cholangitis were observed during the postoperative period. Given the irreversible clinical picture, we opted for a liver transplant 70 days after the patient’s initial admission. The patient died on Day 34 post-transplant due to irreversible ischemic brain damage and a right occipital hemorrhage. Conclusions Hepatic artery avulsion due to trauma is very rare and its management very complex, and in certain situations the artery must be ligated. The main consequence of ligating the hepatic artery is IC, which is more frequently observed secondary to iatrogenic lesions or systemic diseases, while very few cases have been published in which IC is secondary to hepatic artery avulsion caused by hepatic trauma. Treatment depends on the extent of ischemia, and when the damage is diffuse, as in our case, it may involve a liver transplant.

Our aim was to study the safety and efficacy of immunosuppression with everolimus (EVL) within the 1st month after orthotopic liver transplantation (LT) when calcineurin inhibitors are not recommended. For this purpose, 28 recipients who had been treated with EVL within the 1st month after adult LT were eligible to enter in a retrospective multicenter study. Patients were followed up for 12 months after LT. EVL therapy was initiated at a median of 14 days (range, 4-24) after LT. The reason for early EVL was neurotoxicity in 14 cases, renal dysfunction in 12, and acute cellular rejection combined with renal impairment in 2. In 23 patients, immunosuppression was EVL + mycophenolate mofetil/mycophenolate sodium + steroids, and EVL + tacrolimus + steroids/mycophenolate sodium was used in 4 cases. Neurotoxicity disappeared in all patients. Renal function in patients with renal impairment improved from a median of 32 mL/min/1.73 m2 at the moment of implementation of EVL to 62 mL/min/1.73 m2 at 1 year. Four patients (14.3%) developed acute cellular rejection. We observed incisional hernia in 4 patients (14.3%), hematologic complications in 6 (21.4%), proteinuria in 2 (7.1%), edema and/or effusions in 8 (28.6%), and dyslipidemia in 12 (42.8%). No arterial complications were observed. EVL was withdrawn in 5 patients during the 1st year after LT. One-year patient survival was 92.7%. In conclusion, use of EVL within the 1st month after LT when calcineurin inhibitors are not recommended seems to be an effective therapeutic option with an acceptable safety profile.

Based on two clinical cases that developed subcapsular hematoma after ERCP procedure and resolved each one differently (conservative management and surgery, respectively) we have made a brief review of current status, risk factors and treatment options. We also summarize the cases that required surgery. With the increase of endoscopic procedures, it is important to consider this type of major and severe complication.

[Background & Aims] Although there is increasing interest in its use, definitive evidence demonstrating a benefit for postmortem normothermic regional perfusion (NRP) in controlled donation after circulatory death (cDCD) liver transplantation is lacking. The aim of this study was to compare results of cDCD liver transplants performed with postmortem NRP vs. super-rapid recovery (SRR), the current standard for cDCD., [Methods] This was an observational cohort study including all cDCD liver transplants performed in Spain between June 2012 and December 2016, with follow-up ending in December 2017. Each donor hospital determined whether organ recovery was performed using NRP or SRR. The propensity scores technique based on the inverse probability of treatment weighting (IPTW) was used to balance covariates across study groups; logistic and Cox regression models were used for binary and time-to-event outcomes., [Results] During the study period, there were 95 cDCD liver transplants performed with postmortem NRP and 117 with SRR. The median donor age was 56 years (interquartile range 45–65 years). After IPTW analysis, baseline covariates were balanced, with all absolute standardised differences, [Conclusions] The use of postmortem NRP in cDCD liver transplantation appears to reduce postoperative biliary complications, ischaemic type biliary lesions and graft loss, and allows for the transplantation of livers even from cDCD donors of advanced age., [Lay summary] This is a propensity-matched nationwide observational cohort study performed using livers recovered from donors undergoing cardiac arrest provoked by the intentional withdrawal of life support (controlled donation after circulatory death, cDCD). Approximately half of the livers were recovered after a period of postmortem in situ normothermic regional perfusion, which restored warm oxygenated blood to the abdominal organs, whereas the remainder were recovered after rapid preservation with a cold solution. The study results suggest that the use of postmortem normothermic regional perfusion helps reduce rates of post-transplant biliary complications and graft loss and allows for the successful transplantation of livers from older cDCD donors.

Background Controlled donation after circulatory death (cDCD) has been associated with a high incidence of ischemic cholangiopathy and other perioperative complications. In an attempt to avoid these complications, we implemented an active protocol of cDCD liver transplant (LT) with normothermic regional perfusion (NRP) preservation. Methods This is a descriptive analysis of data collected from a prospective date base of cDCD LT preserved with NRP from January 2015 to June 2017 with a minimum follow up of 9 months. Results Fifty-seven potential cDCD donors were connected to the NRP system. Of these, 46 livers were transplanted over a 30-month period (80% liver recovery rate). The median posttransplant peak in alanine transaminase was 1136 U/L (220-6683 U/L). Seven (15%) patients presented postreperfusion syndrome and 11 (23%) showed early allograft dysfunction. No cases of ischemic cholangiopathy were diagnosed, and no graft loss was observed over a medium follow-up period of 19 months. Of note, 13 donors were older than 65 years, achieving comparable perioperative and midterm results to younger donors. Conclusions As far as we know, this represents the largest published series of cDCD LT with NRP preservation. Our results demonstrate that cDCD liver grafts preserved with NRP appear far superior to those obtained by the conventional rapid recovery technique.

A retrospective cohort multicenter study was conducted to analyze the risk factors for tumor recurrence after liver transplantation (LT) in cirrhotic patients found to have an intrahepatic cholangiocarcinoma (iCCA) on pathology examination. We also aimed to ascertain whether there existed a subgroup of patients with single tumors 2cm (very early) in which results after LT can be acceptable. Twenty-nine patients comprised the study group, eight of whom had a very early iCCA (four of them incidentals). The risk of tumor recurrence was significantly associated with larger tumor size as well as larger tumor volume, microscopic vascular invasion and poor degree of differentiation. None of the patients in the very early iCCA subgroup presented tumor recurrence compared to 36.4% of those with single tumors >2cm or multinodular tumors, p=0.02. The 1-, 3- and 5-year actuarial survival of those in the very early iCCA subgroup was 100%, 73% and 73%, respectively. The present is the first multicenter attempt to ascertain the risk factors for tumor recurrence in cirrhotic patients found to have an iCCA on pathology examination. Cirrhotic patients with iCCA 2cm achieved excellent 5-year survival, and validation of these findings by other groups may change the current exclusion of such patients from transplant programs. This multicenter study analyzes the outcome of patients transplanted for hepatocellular carcinoma who were found to have an intrahepatic cholangiocarcinoma at pathology examination, and focuses on the excellent posttransplant outcome of patients with single intrahepatic cholangiocarcinomas 2 cm.

Introduction Due to the disparity between the number of patients on the list for liver transplantation and the availability of organs, the use of older donors has become necessary. The aim of this study was to investigate the outcomes of liver transplantation using octogenarian donors. Methods From December 2003 to February 2016, 777 liver transplantations were performed at our institution, 33 of them (4.2%) with donors 80 years old and above. Our policy for the acceptance of these donors is based on preoperative liver function tests, donor hemodynamic stability, and intraoperative normal gross aspect. Octogenarian grafts were deliberately not assigned to retransplantations or to recipients with multiple previous surgical procedures or extensive portal thrombosis. Results Mean donor age was 82.7 ± 2.1 years, with a range between 80 and 88. Only 12.1% suffered hemodynamic instability during the intensive care unit stay. Three donors (9.1%) had a history of diabetes mellitus. The mean Model for End-Stage Liver Disease score among recipients was 14.7 ± 5.6. Mean cold ischemia time was 302 ± 61 minutes. After a median follow-up of 18.5 months (range 7.5 to 47.5), no graft developed primary nonfunction. We observed hepatic artery thrombosis in 1 patient (3%) and biliary complications in 4 patients (12.5%). There was 1 case of ischemic-type biliary lesion, although it was related to hepatic artery thrombosis. Patient survival at 1 and 3 years was 90.3%, whereas graft survival was 92.6% and 86.4%, respectively. Conclusions Excellent mid-term results can be obtained after liver transplantation with octogenarian donors with strict donor selection and adequate graft allocation.

The once-daily prolonged-release formulation of tacrolimus has been recently related with significant graft and patient mid-term survival advantages; however, practical information on the de novo administration after liver transplantation and longterm outcomes is currently lacking. This study is a 5-year retrospective analysis of a single-center cohort of liver transplant recipients treated de novo with once-daily tacrolimus (April 2008/August 2011). The study cohort consisted of 160 patients, including 23 with pretransplant renal dysfunction, with a median follow-up of 57.6 months (interquartile range, 46.6-69.0). Tacrolimus target trough levels were 5-10 ng/mL during the first 3 months after transplant, reducing progressively to7 ng/mL after the first posttransplant year. Once-daily tacrolimus was withdrawn in 35 (21.8%) patients during follow-up, mostly due to renal dysfunction and/or metabolic syndrome. The biopsy-proven acute rejection rate was 12.5% with no cases of steroid-resistant rejection. The cumulative incidence of de novo diabetes, hypertension, and dyslipidemia were 16.9%, 31.2%, and 6.5%, respectively. Hepatocellular carcinoma recurrence rate was 2.8%. Renal function remained stable after the sixth month after transplant with a mean estimated glomerular filtration rate of 77.7 ± 19.6 mL/minute/1.73 m(2) at 5 years. None of our patients developed chronic kidney disease stage 4 or 5. Patient survival at 1, 3, and 5 years was 96.3%, 91.9%, and 88.3%, respectively. Overall survival of patients with Model for End-Stage Liver Disease (MELD) score 25 points was not significantly different. In conclusion, our study suggests that immunosuppression based on de novo once-daily tacrolimus is feasible in routine clinical practice, showing favorable outcomes and outstanding longterm survival even in patients with high MELD scores. Liver Transplantation 22 1391-1400 2016 AASLD.

To define and validate a pharmacokinetic (PK) model for tacrolimus (TAC) that includes patient pathophysiology and has clinical applicability in the first 2 weeks post-liver transplantation (PLT). Routine monitoring records [dose, trough levels (Cmin), demographics, biochemistry] from 75 patients treated with TAC (Prograf®) PLT were used to develop a population PK model (employing NONMEM®) testing for predictors of oral clearance (CL/F) according to bedside evidence and primarily with aspartate aminotransferase (AST), albumin (ALB), and hematocrit (HCT). Patients were catergorized into subgroups with above and below “normal” thresholds for AST (500 U/L), ALB (2.5 g/dL), and HCT (28 %), respectively. The model was validated with ten patients from the same period and 15 more recent patients. An empirical Bayes method was developed and applied to the prediction of individual profiles serving as a dose adjustment tool. The number of days PLT (Days PLT) was a key variable during the first 2 weeks, with a dichotomy in the mono-compartmental parameters for 0–3 Days PLT and 4–15 Days PLT. During 0–3 Days PLT, AST levels, indicative of allograft functionality (and TAC metabolism), were crucial predictors of elimination. Three groups were identified with the following clearances: CL/F0-3 = 8.93 L/h for AST ≥500 U/L and CL/F0-3 = 11.0 L/h for AST

Hepatic venous outflow obstruction (HVOO) is a rare complication after orthotopic liver transplantation (OLT) usually related to technical issues or to malposition or kinking of the hepatic graft. When HVOO is diagnosed during the early post-transplant period, surgical options are technically very demanding and outcomes discouraging. Therefore, angioplasty and stent placement have been indicated to avoid a chronic lesion of the graft. Three cases of HVOO after OLT are reported. HVOO was diagnosed during the early post-transplant period and was due to graft malposition in two patients and kinking of the vena cava anastomosis in one. All patients were successfully treated with a 300-cc gel-filled breast implant surgically placed in the right hepatic fossa with the liver graft resting on it. Massive ascites in all three patients disappeared and renal impairment resolved within two wk post-implant placement. No prosthesis-related complications have been observed after a follow-up ranging from 30 to 58 months. We describe a simple and effective method of maintaining the liver graft in an adequate position to achieve prolonged relief of the outflow obstruction for the whole graft and discuss the advantages of a breast implant over stent placement or the use of different balloon catheters.

To explore the main factors that make it difficult to empirically monitor tacrolimus (TAC) in the early period post-liver transplantation (LTx), with a specific focus on those aspects related to patient idiosyncrasy and clinical status as well as to the pharmacokinetic (PK) assumptions on which drug individualization in clinical practice is based.Retrospective monitoring data from 75 de novo liver transplant patients treated with twice daily with TAC and followed for up to 15 days were analyzed. An extensive battery of laboratory measurements were available. Dose adjustment was performed empirically using trough levels (C(min)). The population was separated into two major background groups according to low or high values of aspartate aminotransferase (AST) (Group 1 and 2, respectively) based on AST measurements made during the first 4 days post-LTx. Each of these two major groups was then further subdivided into two subgroups based on elevated (Groups 1A, 2A) or reduced (Groups 1B, 2B) combined albumin (cut-off 2.5 g/dl) and hematocrit (cut-off 28%).The C(min)/Dose ratio [inversely proportional to systemic clearance (CL)] had a variability [coefficient of variation (CV)80%) that was incongruently higher for the ratio than for C(min) and Dose separately. This was attributed to most patients not being at steady state or physiologically stable in the early post-LTx period. Group 1 patients were more predictable than Group 2 patients, who were responsible for the variability in the ratio. C(min) was lower in the reduced ALB and HCT patient groups when AST conditions were similar (1A vs. 1B and 2A vs. 2B), likely due to increased TAC metabolic clearance (reduced C(min)/Dose). This situation existed for two periods: 0-15 days post-LTx and 4-15 days post-LTx observations. Group 2A patients were the main source of the paradoxical variability in C(min)/Dose (higher ratio of 2.7; CV = 100%), suggesting a lower clearance and difficulty in the recovery of stability. In contrast, Group 2B patients had the lower ratio (1.4; 47%) but required the highest number of dose adjustments as the variability was hard to identify clinically. Group 1A patients were the most predictable empirically. When observations from 15 new patients who entered the clinic in 2007 and 2008 were used for the analysis, the same sub-groups existed in the same proportions in both years.The difficulty in empirical dose adjustment of TAC is associated to the inevitable non-fulfillment of PK assumptions early post-LTx and also to the inherent complexity of the clinical condition, leading to increased uncertainty for the clinician regarding dose selection. Identifying these sub-categories provides a rational means of classifying patients akin to a phenotype. The complexity of the kinetics in LTx and TAC treatment does not invalidate C(min) as a biomarker, but a Bayes algorithm including a full PK structure and these covariates would be optimal.

Despite significant advances in orthotopic liver transplantation (OLT), biliary tract reconstruction is still a major source of complications. Choledochocholedochostomy with a T-tube used to be the standard procedure for biliary reconstruction after OLT. However, many centers currently avoid use of the T-tube because of the high incidence of complications. Our aim was to study the biliary complications occurring at our center when end-to-end choledochocholedochostomy (EE-CC) over a T-tube was used as the standard procedure for biliary reconstruction. A retrospective review was conducted of all patients who underwent liver transplantation from February 1, 1996, to April 30, 2010. Only patients requiring any therapy to treat biliary complications were considered, whereas those with concomitant hepatic artery complications were excluded. The study cohort consisted of 743 patients who had EE-CC with a T-tube. Of these, 73 patients (9.8%) experienced any biliary complication. Anastomotic strictures occurred in 17 patients (2.3%), and non-anastomotic strictures in 2 (0.3%). Fifteen patients with anastomotic strictures were successfully treated by dilatation and stenting. Bile leakage was diagnosed in 39 patients (5.2%). Leakage occurred at the anastomosis in 15 patients (2%), and at the exit site of the T-tube in 24 patients (3.2%). Tube opening was the only treatment used in 30 patients with bile leakage (76.9%). Seven patients experienced leaks after elective T-tube removal (1%). Overall, repeat surgery to manage biliary complications was needed in 9 patients (1.2%). The mortality rate from biliary complications was 0.13%. In conclusion, EE-CC with a T-tube was followed by a low incidence of biliary complications. The complication rate after elective T-tube removal and the repeat surgery rate were extremely low. These results might challenge the current trend to avoid T-tube stenting in OLT.

Fig. Sagittal sequence of computed tomography revealed the hepatic hydatid cyst ruptured into the thoracic cavity. Arrow shows the transdiaphragmatic fistula. A 32 YEAR-OLD MAN presented to the emergency department with fever and right thoracic pain. Thoracic auscultation upon admission revealed tachypnea with cracking and respiratory murmur. Arterial gasometry revealed PO2, 61 mmHg; PCO2, 47 mmHg; Sat O2, 92%; HCO3, 32.7 mmol/L; and pH, 7.45. Laboratory investigations revealed leukocytes, 28 3 10/mL; total bilirubin, 6 mmol/L; alkaline phosphatase, 308 U/L; gamma glutamyl transpeptidase, 244 U/L; and C-reactive protein, 29.7 mg/dL. Serum was screened with an indirect hemagglutination assay for Echinococcus granulosus with positive titers of 1:2,560. Contrast-enhanced computed tomography revealed 3 hepatic cystic lesions with high attenuation wall partially calcified.Extrahepatic extensionof the cyst in segment VII was observed with thoracic involvement through a transdiaphragmatic fistula (Fig). The case was compatible with hepatic hydatid disease with thoracic involvement. The patient underwent surgery with combined thoracic and abdominal access through different incisions: Posterolateral thoracotomy and bilateral subcostal laparotomy. The surgical steps proceeded as follows: Evacuation of the pleural cavity, pulmonary decortication, inferior right lobectomy, dissection of the diaphragm breach, right hepatectomy including 2 cysts, segmentectomy of hepatic segment II, closure of the diaphragm breach, and drainage of both the chest and the subphrenic spaces. The patient was discharged home under medical treatment with albendazole. After 3 years

Despite recent advances in organ preservation, surgical procedures, and immunosuppression, biliary reconstruction after orthotopic liver transplantation (OLT) remains as a major source of morbidity. The purpose of this study was to identify risk factors for the development of biliary complications (BCs) after end-to-end choledochocholedochostomy (EE-CC) with a T-tube as the standard technique for biliary reconstruction after OLT.A total of 833 consecutive liver transplantations that took place from February 1996 to April 2010 were retrospectively reviewed. Patients with concomitant hepatic artery complications were excluded, as were those who underwent urgent retransplantation or died within 1 week after transplantation. Finally, the study group comprised 743 patients.The overall BC rate was 9.8% (73 patients), including stricture in 19 patients (2.6%) and bile leakage in 39 patients (5.2%). After univariate analysis, significant risk factors for BCs were surgery time5 hours, arterial ischemia time30 minutes, use of a classic transplant technique, transfusion of red blood cells ≥5 units, anti-cytomegalovirus treatment, and period of transplantation between 1996 and 2002. Stepwise logistic regression study was performed, including those variables with a value of P.200. Multivariate analysis showed that pretransplant serum creatinine (odds ratio = 1.27; 95% confidence interval [CI], 1.03-1.57; P = .025) and arterial ischemia time30 minutes (odds ratio = 2.44; 95% CI, 1.45-4.12; P = .001) were the only independent risk factors related to the development of BCs after biliary reconstruction with the T-tube.The performance of different variables in predicting occurrence of BCs was assessed with the use of receiver operating characteristic analysis. The area under the receiver operating characteristic curve of our model was 0.637 (95% CI, 0.564-0.710), and therefore we must conclude that other variables not included in our model may have influence in the development of BCs after OLT with an EE-CC with a T-tube as the procedure for biliary reconstruction.

Management of patients with hepatocellular carcinoma (HCC) recurrence after liver transplantation (OLT) is not well established. We conducted a retrospective analysis of our results in the treatment of HCC recurrence after OLT Patients. The 23 HCC recurrences developed after 182 OLT performed for HCC within Milan criteria, had an average follow-up of 60 months.The median time to recurrence was 23.4 months. Surgical resection of the recurrence was possible in 11 patients, but an R-0 resection was obtained in 8 patients. Four of these 8 patients developed another recurrence, with 3 succumbing due to tumor recurrence and 1 alive at 12 months with recurrence. The other 4 patients without recurrences, include 3 who are alive at 19, 31, and 86 months and 1 who died at 32.6 months due to hepatitis C recurrence. The 3 patients with palliative resections developed recurrences. Twelve patients were rejected for surgery: 8 were treated symptomatically, 2 with systemic chemotherapy, and 2 with everolimus and sorafenib. This last treatment was also prescribed for 2 patients after R-0 surgery who are alive at 19 and 31 months and for 1 patient after R-1 surgery who is alive at 19 months. Of 15 patients who died, 13 succumbed to HCC recurrence. The average survival from transplantation was 61.7 +/- 37.5 and 48 +/- 34.3 months for patients without and with recurrence, respectively (P.001). The survival from the recurrence was significantly higher among patients with R-0 surgery: 32.3 +/- 21.5 versus 11.9 +/- 6.9 months (P = .006).HCC recurrence after OLT of patients within Milan criteria was low but had a great impact on survival. Few cases are amenable to R-0 resection, but when possible it was associated with a significantly increased survival, although with an high incidence of a new recurrence. There is a rationale for the use of sorafenib and mammalian target of rapamycin based immunosuppression, which warrants randomized studies.

Objective. Postoperative infection is considered one of the most important causes of morbidity and mortality after liver transplantation. We prospectively studied the incidence and significance of infections in preservation solutions for liver transplantation. Materials and Methods. From March 2007 to March 2008, we cultured the University of Wisconsin preservation solution for 60 consecutive liver transplantations. Fluid samples were obtained at the beginning and at the end of the back table procedure. Our posttransplant infection prophylactic protocol consisted of ampicillin and cefotaxime for 48 hours. Results. Cultures were positive in 59 patients (98.4%). Seventy-five percent of the isolates were superficial saprophytic flora (SSF; Staphylococcus coagulase negative, Streptococcus viridans, and Corynebacterium), nevertheless in 15 cases (25.1%) we isolated high virulence pathogens (Staphylococcus aureus, Klebsiella, Escherichia coli, Enterobacter, and Pseudomonas aeruginosa). There were neither anaerobic nor fungal isolates. Sixteen patients (36%) from the group with SSF developed postoperative fever, including 12 with negative posttransplant cultures, while 4 patients showed positive cultures for various microorganisms distinct from those isolated from the preservation solution. Five patients (30%) with high virulence pathogens in the preservation solution developed posttransplant fever, although no pathogen was isolated. Conclusions. Positive cultures of preservation fluids were observed in 98% of patients, although most of them (75%) were SSF. Microorganisms isolated from posttransplant cultures did not match the ones obtained from the preservation solution. Our results did not support routine culturing of the preservation solution provided that one administrator an adequate posttransplant antibiotic prophylactic regimen.

Introduction Posttransplant hepatitis C virus (HCV) recurrence has been shown to negatively impact graft and patient survivals. It has been suggested that HCV recurrence among HIV- and HCV-coinfected transplant recipients is even more aggressive. Objective To compare the histological severity and survival of posttransplant HCV recurrence between HIV- and HCV-coinfected and HCV-monoinfected patients. Patients and methods Among 72 adult patients who underwent primary liver transplantation at our institution for HCV-related cirrhosis between October 2001 and April 2007. We excluded one coinfected patient who died on postoperative day 5 leaving 12 HIV- and HCV-coinfected patients for comparison with 59 monoinfected patients. When listed, all coinfected patients fulfilled the criteria of the Spanish Consensus Document for transplantation in HIV patients. Immunosuppression did not differ between the two groups: all were treated with tacrolimus + steroids (slow tapering). Aggressive HCV recurrence was defined as cholestatic hepatitis and/or a fibrosis grade ≥2 during the first posttransplant year. Results Coinfected patients were younger than monoinfected patients: 45 ± 6 years vs 55 ± 9 years (P = .0008). There were no differences in Child score, Model for End-stage Liver Disease score, donor age, graft steatosis, ischemia time, HCV pretransplant viral load or genotype between the groups. Significant rejection episodes were also equally distributed (25% vs 14%; P = .38). Seven coinfected patients and 29 monoinfected patients developed aggressive HCV recurrences (58% vs 49%; P = .75). Median follow-up was 924 days. Global survival at 3 years was 80%. Survivals at 1, 2, and 3 years were 83%, 75%, 62% in the coinfected vs 98%, 89%, 84% in the monoinfected patients, respectively (log-rank test = 0.09). Conclusions The severity of histological recurrence was similar among HIV- and HCV-coinfected and monoinfected HCV liver recipients in the first posttransplant year. Mortality attributed to recurrent HCV was similar in the groups. There were no short-term (3-year) differences in survival between the two groups of patients.

OBJECTIVE To evaluate the outcome of patients with hepatocellular-cholangiocarcinoma (HCC-CC) or intrahepatic cholangiocarcinoma (I-CC) on pathological examination after liver transplantation for HCC. BACKGROUND Information on the outcome of cirrhotic patients undergoing a transplant for HCC and with a diagnosis of HCC-CC or I-CC by pathological study is limited. METHODS Multicenter, retrospective, matched cohort 1:2 study. STUDY GROUP 42 patients undergoing a transplant for HCC and with a diagnosis of HCC-CC or I-CC by pathological study; and control group: 84 patients with a diagnosis of HCC. I-CC subgroup: 27 patients compared with 54 controls; HCC-CC subgroup: 15 patients compared with 30 controls. Patients were also divided according to the preoperative tumor size and number: uninodular tumors 2 cm or smaller and multinodular or uninodular tumors 2 cm or larger. Median follow-up: 51 (range, 3-142) months. RESULTS The 1-, 3-, and 5-year actuarial survival rate differed between the study and control groups (83%, 70%, and 60% vs 99%, 94%, and 89%, respectively; P < 0.001). Differences were found in 1-, 3-, and 5-year actuarial survival rates between the I-CC subgroup and their controls (78%, 66%, and 51% vs 100%, 98%, and 93%; P < 0.001), but no differences were observed between the HCC-CC subgroup and their controls (93%, 78%, and 78% vs 97%, 86%, and 86%; P = 0.9). Patients with uninodular tumors 2 cm or smaller in the study and control groups had similar 1-, 3-, and 5-year survival rate (92%, 83%, 62% vs 100%, 80%, 80%; P = 0.4). In contrast, patients in the study group with multinodular or uninodular tumors larger than 2 cm had worse 1-, 3-, and 5-year survival rates than their controls (80%, 66%, and 61% vs 99%, 96%, and 90%; P < 0.001). CONCLUSIONS Patients with HCC-CC have similar survival to patients undergoing a transplant for HCC. Preoperative diagnosis of HCC-CC should not prompt the exclusion of these patients from transplant option.

Aim To determine how changes in tacrolimus (TAC) immunosuppression clinical practice, in the first 15 days post liver transplantation (LT) and across a decade, impact a clinical covariate - pharmacokinetic (PK) model, developed in data from 1998, thus testing its utility in dose individualization across time. Patient cohorts from 1998 (Reference: R-1998) and 2007 (EVALUATION: E-2007) were compared. Methods Analysis of monitoring observations (Cmin and Cmin/dose) and the biochemical variables aspartate aminotransferase (AST), hematocrit (HCT), albumin (ALB) and serum creatinine (SCr) was done for 0 - 3 and 4 - 15 days post transplantation (PT). The population PK model developed for R-1998 [1] was re-evaluated for the two cohorts. Results Significant differences in R-1998 vs. E-2007 existed in Cmin and Cmin/dose and in covariates AST (as hepatic function marker) and SCr (as toxicity marker). E-2007 had lower levels of Cmin and Cmin/dose (1/CL), lower AST with faster recovery and lower variability in Cmin/dose for similar dose. AST was a covariate on CL/F in the 0 - 3 day PT period. In 4 - 15 days PT for E-2007, low levels of HCT and ALB as CL/F predictors confirmed a subgroup with higher CL/F (23.8 l/h vs. 19.3 l/h). The R-1998 model's original structure was confirmed. Conclusions Ten years of use of TAC shows gain in therapeutic targeting efficiency, due to improvement in LT methods, knowledge of the drug and consideration of PK steady state. The remaining uncertainty with TAC monitoring in LT can be resolved with application of PK principles combined with patients' diosyncrasies in the model developed for TAC dose individualization in R-1998. The applicability of the model as nucleus in Bayes individualization remains intact across a decade.

Advagraf, a prolonged release formulation of tacrolimus, is administered once daily in the morning. The aim of this study was to show the results obtained in our center, analyzing the safety, efficacy, blood trough levels, and drug doses. Methods. We analyzed 50 consecutive recipients of a first liver transplantation with 6 months follow-up. Efficacy and safety variables were collected as the incidence of acute rejection episodes, patient and graft survivals, kidney function as well as incidences of diabetes mellitus and arterial hypertension de novo. Results. The incidence of biopsy proven acute rejection episodes was 10% (n = 5), none 7 of which were steroid resistant and all resolved favorably. The rate of diabetes mellitus de novo was 22% (n = 11), 7 of whom required insulin. Hypertension developed in 9 patients (18%), all of whom were treated with a single drug. The mean serum creatinine level was 1.08 ± 0.25 mg/dL, with 3 patients (6%) displaying a value ≥ 1.5 mg/dL. Patient and graft survivals were 100%. Conclusion. Advagraf is an effective immunosuppressant in liver transplantation with a low incidence of biopsy-confirmed acute rejection episodes. The good results for patient and graft survival with few side effects make it a useful drug for de novo liver transplantation.

Introduction. Expansion of donor criteria has become necessary with the increasing number of liver transplantation candidates, as aged donors who have been considered to yield marginal organs. Methods. Our database of 477 liver transplants (OLT) included 55 cases performed from donors at least 70 years old vs 422 with younger donors. We analyzed pretransplantation donor and recipient characteristics as well as evolution of the recipients. Results. The old donor group showed significantly lower ALT (23 17 vs 48.9 67; P .0001) and LDH (444 285 vs 570 329; P .01). There was a trend toward fewer hypotensive events in the aged donor group (27.2% vs 40.5%; P .07). No steatosis (10%) was accepted in the old donor group. Cold ischemia time was statistically shorter for the aged donors (297 90 minutes vs 346 139 minutes; P .03). With these selected donors, the results were not different for primary nonfunction, arterial and biliary complications, hospitalization, acute reoperation or acute retransplantation, and hospital mortality when donors 70 years old were compared to younger donors. Functional cholestasis, neither related to rejection nor to biliary complications, was seen more frequently in old donor recipients (40% vs 22%; P .03). No differences in 1, and 3 year survivals were observed between recipients of donors over 70 years old and these of younger organs: 93.8% and 90.6% vs 90.7% and 82.8%, respectively. Conclusion. When using selected donors 70 years old the outcomes were comparable to those obtained with younger donors. Strict selection is necessary to achieve good long-term survival.

A consecutive series of 88 patients underwent transplantation for hepatocellular carcinoma with cirrhosis over a 7-year period. Liver transplantation was indicated because of the tumor in 75 cases (85.2%); tumor was an incidental finding in 13 cases (14.8%). One patient was retransplanted due to primary nonfunction. The perioperative mortality was 4.5%. Tumor recurrence was observed in seven patients (7.95%) with incidental tumor recurrence in one case. As in patients with known primary liver tumors pretransplant, a thorough follow-up is advisable to establish an early diagnosis of recurrence. The actuarial survival for nonincidental hepatocellular carcinoma at 1, 3, and 5 year was 92%, 77%, and 75%, respectively. The differences in actuarial survival between hepatitis C negative and positive hepatocellular carcinoma were not significant (log-rank test P = .27), though there was a clear improvement in results (94%, 85%, and 78% vs 90%, 71%, and 71%), at 1, 3, and 5 years meaning that HCV infection is an important prognostic factor. Although transplantation for HCC has the advantages of removing the tumor and the cirrhotic liver, it remains a controversial topic. In our experience patients showing lesions less than 5 cm or three or fewer lesions experience an equivalent survival to transplanted patients who do not have cancer.