Mireia Caralt

Indications and management of everolimus after liver transplantation.

OBJECTIVE Our aim was to assess our experience with the use and management of everolimus after orthotopic liver transplantation (OLT). MATERIALS AND METHODS Among the 759 patients who underwent transplantation from 1988 to 2008, 25 (3.2%) received immunosuppression with everolimus. Their mean age was 55.6 years. We analyzed indications for use, time between transplantation and introduction of everolimus, as well as its efficacy, side effects, and patient survival. RESULTS The indications for everolimus treatment were: extended hepatocellular carcinoma (HCC) in the explanted liver (n = 6; 24%); HCC recurrence during follow-up (n = 4; 16%); de novo tumor (n = 6; 24%); refractory rejection (n = 3; 12%); side effects of calcineurin inhibitors (CNI; n = 3; 12%); and other causes (n = 3; 12%). Mean time between OLT and everolimus treatment was 40 +/- 33 months (range, 10 days-178 months). Mean follow-up after conversion was 10 +/- 9 months (range, 1.5-25 months). More than half of the patients resolved the event for which the drug was indicated: 75% of patients with refractory rejection; 60% of those with renal insufficiency; and 100% of those converted for neurotoxicity or hepatotoxicity. Two patients with recurrent HCC and 1 with extended HCC died at a mean time of 10.5 months. The 6 cases of de novo tumors were operated and are healthy. Side effects were dyslipidemia in 8 and infection in 2. Five patients (20%) discontinued the drug. CONCLUSIONS In the early posttransplantation period, everolimus is indicated for refractory rejection or as prophylaxis for recurrence of extended tumors. In any time but especially in the late period, everolimus is indicated for patients with serious side effects due to a CNI or to a de novo tumor.

Liver bioengineering: from the stage of liver decellularized matrix to the multiple cellular actors and bioreactor special effects.

Liver bioengineering has been a field of intense research and popular excitement in the past decades. It experiences great interest since the introduction of whole liver acellular scaffolds generated by perfusion decellularization1–3. Nevertheless, the different strategies developed so far have failed to generate hepatic tissue in vitro bioequivalent to native liver tissue. Even notable novel strategies that rely on iPSC-derived liver progenitor cells potential to self-organize in association with endothelial cells in hepatic organoids are lacking critical components of the native tissue (e.g., bile ducts, functional vascular network, hepatic microarchitecture, etc)4. Hence, it is vital to understand the strengths and short comes of our current strategies in this quest to re-create liver organogenesis in vitro. To shed some light into these issues, this review describes the different actors that play crucial roles in liver organogenesis and highlights the steps still missing to successfully generate whole livers and hepatic organoids in vitro for multiple applications.

Safety of bevacizumab in metastatic breast cancer patients undergoing surgery

BACKGROUND Evaluate the safety of surgery in relation to bevacizumab in the first-line treatment of metastatic breast cancer (mBC) in two international trials. PATIENTS AND METHODS The incidence, type and timing of post-surgical bleeding events and wound-healing complications were assessed in surgical patients in the AVastin And DOcetaxel (AVADO) (NCT00333775) and Avastin THErapy for advaNced breAst cancer (ATHENA) (NCT00448591) trials. Both study protocols followed recommendations to withhold bevacizumab for at least 6 weeks before elective surgery and to wait 28 days (or until the wound was fully healed) after major surgery before recommencing bevacizumab therapy. RESULTS In AVADO, 221 surgical procedures (55 major, 166 minor) were performed in 155 patients. In ATHENA, 1190 surgical procedures (435 major, 755 minor) were performed in 672 patients. One bevacizumab-treated AVADO patient (0.9%) who underwent surgery experienced a grade 3 bleeding event. In ATHENA, six patients (0.9%) who underwent surgery experienced grade 3 bleeding events and one patient (0.1%) experienced a grade 4 bleeding event. No grade 5 bleeding events in patients undergoing surgery were reported in either study. One grade 3 wound-healing complication was reported in each of the AVADO arms: placebo (n=46, 2.2%), bevacizumab 7.5mg/kg (n=57, 1.8%) and bevacizumab 15mg/kg (n=52, 1.9%). Incidence of grade 3-4 wound-healing complications in ATHENA was 2.2% and 1.3% in patients undergoing minor or major surgery, respectively. CONCLUSIONS Surgery can be performed on patients with mBC undergoing bevacizumab therapy with a low risk of severe bleeding or wound-healing complications post surgery, if current labelling recommendations are adhered to.

Outcome of patients following hepatic resection for metastatic cutaneous and ocular melanoma

Background/purposeThe aim of this study was to analyze the outcome of patients undergoing hepatic resection for melanoma liver metastases.MethodsPatients undergoing liver resection for melanoma metastases at the Hospital Vall d’Hebron and Hospital Clinic, Barcelona, were reviewed. Selection criteria were: good performance status, feasibly complete and safe resection, and absence of visceral extrahepatic metastases.ResultsBetween 1994 and 2007, 14 liver resections were performed for melanoma liver metastases. The primary tumor was cutaneous in 8 patients and ocular in 6. Two patients underwent urgent liver surgery due to tumor bleeding. In these patients, complete melanoma staging was not performed and extrahepatic metastases were found during surgery or during the postoperative course. Six of 13 patients (46.2%) developed liver recurrence during follow-up. One- and 3-year actuarial patient survivals were 77 and 49%, respectively. Excluding the patients who underwent urgent liver surgery, the 1- and 3-year actuarial patient survivals in those with primary ocular and cutaneous melanoma were 83 and 56% and 80 and 60%, respectively.ConclusionsLiver resection may be considered as part of oncosurgical treatment in patients with melanoma liver metastases, since prolonged survival was observed, albeit with a high recurrence rate. Nevertheless, it should be taken into account that our study included only a small number of patients.

Severe Rhabdomyolysis and Acute Renal Failure Secondary to Concomitant Use of Simvastatin With Rapamycin Plus Tacrolimus in Liver Transplant Patient

OBJECTIVE To report a severe interaction between simvastatin and rapamycin resulting in rhabdomyolysis and acute renal failure in a liver transplant patient. BACKGROUND A 56-year-old man with hepatitis C virus cirrhosis (Child B) was diagnosed with hepatocellular carcinoma and underwent liver transplantation in April 2007. He was immunosuppressed with tacrolimus (FK) and mycophenolate mofetil (MMF). Postoperative complications were arterial hypertension and renal insufficiency. In June 2007, liver dysfunction was detected and acute rejection was diagnosed by biopsy. He received three 500-mg boluses of methylprednisolone and FK levels were maintained between 10 and 12 ng/mL. Laboratory values revealed persistent rejection and MMF was stopped with initiation of rapamicin. One month later, hyperlipidemia appeared as a consequence of rapamicin therapy; simvastatin was administered. In August 2007, the patient was readmitted due to severe muscule pain and the inability to ambulate. Laboratory values were: total bilirubin 16 mg/dL, serum creatinine 4.3 mg/dL, and total creatine kinase (CK) 42,124 U/L. With the suspicion of rhabdomyolysis, leading to worsening of his basal renal insufficiency, rapamycin and tacrolimus were stopped. Hemodialysis was initiated owing to renal failure and hyperkalemia. Some hours later, the patient developed ventricular fibrillation and respiratory failure and succumbed. DISCUSSION Calcineurin inhibitors (CNI), corticosteroids, and mammalian target of rapamycin (m-TOR) inhibitors are associated with adverse dyslipidemic effects. To reduce the overall cardiovascular risk in these patients, lipid-lowering drugs, especially 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, have been widely used. CNI and m-TOR inhibitors, as well as most statins, are metabolized by cytochrome P450 (CYP)3A4; thus, pharmacokinetic interactions between these drugs are possible. Previous reports have indicated an increased risk of rhabdomyolysis in the presence of concomitant drugs that inhibit simvastatin metabolism. CONCLUSIONS Concomitant administration of statin therapy and drugs that inhibit cytochrome P450 (CYP)3A4 increased the risk of rhabdomyolysis in a patient suffering liver and renal dysfunction.

Multiple indications for everolimus after liver transplantation in current clinical practice

AIM To assess our experience with the use and management of everolimus-based regimens post-liver transplantation and to redefine the potential role of this drug in current clinical practice. METHODS From October 1988 to December 2012, 1023 liver transplantations were performed in 955 patients in our Unit. Seventy-four patients (7.74%) received immunosuppression with everolimus at some time post-transplantation. Demographic characteristics, everolimus indication, time elapsed from transplantation to the introduction of everolimus, doses and levels administered, efficacy, side effects, discontinuation and post-conversion survival were analyzed. RESULTS Mean age at the time of conversion to everolimus was 57.7 ± 10 years. Indications for conversion were: refractory rejection 31.1%, extended hepatocellular carcinoma in explanted liver 19%, post-transplant hepatocellular carcinoma recurrence 8.1%, de novo tumour 17.6%, renal insufficiency 8.1%, severe neurotoxicity 10.8%, and others 5.4%. Median time from transplantation to introduction of everolimus was 6 mo (range: 0.10-192). Mean follow-up post-conversion was 22 ± 19 mo (range: 0.50-74). The event for which the drug was indicated was resolved in 60.8% of patients, with the best results in cases of refractory rejection, renal insufficiency and neurotoxicity. Results in patients with cancer were similar to those of a historical cohort treated with other immunosuppressants. The main side effects were dyslipidemia and infections. Post-conversion acute rejection occurred in 14.9% of cases. The drug was discontinued in 28.4% of patients. CONCLUSION Everolimus at low doses in combination with tacrolimus is a safe immunosuppressant with multiple early and late indications post-liver transplantation.

Evolution of Biliary Complications After Liver Transplantation: A Single European Series

BACKGROUND The aim of this study was to analyze the evolution of biliary complications over 20 years among adult patients undergoing liver transplantation (OLT) at our institution. PATIENTS AND METHODS Between 1985 and 2007, we performed 1000 OLT in 789 adults and 211 children. To ascertain the evolution of biliary complications among adult OLT from October 1988 to September 2007, we compared the first 100 to with the last 200 adult OLT. RESULTS Duct-to-duct was the most common biliary anastomosis performed in both periods (1st; 89% and 2nd; 94%; P = NS). However, a T-tube was used more frequently in the first period (1st; 46% vs 2nd; 6.6%; P < .001). The remaining cases underwent a hepaticojejunostomy (1st; 11% vs 2nd; 7.6%). Biliary complications were more frequent in the first period (1st; 20% vs 2nd; 9%; P < .01). In the first period, the use of a T-tube caused 32% of complications, all of them being bile leaks; but there were none in the second period. Arterial thrombosis or strictures were related to biliary complications in 10% and 33.3% among the first and second periods, respectively. The severity of complications according to the Clavien classification was similar in both periods: IIIa, 15% versus 33.3%; IIIb, 55% versus 55.5%; and IV, 15% versus 11.1%, respectively (P = NS). CONCLUSION The biliary complication rate among adult patients post-OLT decreased over 20 years at our institution, probably owing to the abandonment of the routine use of a T-tube as well as to advances in immunosuppressive protocols, organ preservation, and preoperative patient management.

A Prospective, Multicenter Study of Once-Daily Extended-Release Tacrolimus in De Novo Liver Transplant Recipients

To minimize noncompliance in organ transplantation, a new formulation was developed of once-daily extended-release (EXTD) tacrolimus. To analyze the efficacy and safety of this new drug formulation in de novo liver transplant recipients, a prospective, multicenter study was performed in six centers in Spain. The primary objective of the study was to evaluate the incidence of biopsy-proven acute rejection episodes (BPAR) according to the BANFF criteria during the first 3 months of immunosuppression with the EXTD formulation of tacrolimus. Fifty-two patients received a mean initial dose of 10.0 ± 3.8 mg that was gradually reduced to 7.1 ± 4.0 mg, achieving stable mean blood levels of 8.6 ± 3.7 ng/mL at 3 months. BPAR was reported in seven (13%) patients, but patient and graft survivals were 100%. After transplantation liver function improved and was stably maintained throughout the study. At 3 months, mean bilirubin levels were 2.1 ± 5.5 mg/dL and mean alanine aminotransferase and aspartate aminotransferase were 61.6 ± 75.2 U/L and 55.2 ± 76.9 U/L, respectively. Mean serum creatinine of 0.8 ± 0.3 mg/dL pretransplant increased to 1.1 ± 0.4 mg/dL after 3 months (P < .0001). There was no significant increase in the rate of hypertension from pretransplant levels: 30% at baseline versus 31% at 3 months. Mean glucose levels did not change significantly throughout the study. There were no cases of hepatitis C virus relapse. EXTD tacrolimus demonstrated excellent stability in blood trough levels with a good efficacy and safety profile in de novo liver transplant recipients that was similar to the well-described properties of standard-release twice-daily formulation of tacrolimus.

Does Matching Donor-Recipient Age Affect Long-Term Survival in Liver Transplantation?

BACKGROUND The characteristics of liver donors have changed over the last decade owing to the shortage of organs and high mortality on the waiting list, leading to wider use of extended-criteria donors, including older donors. The aim of this study was to evaluate the effect of matching donor-recipient age on morbidity at 1 year post-transplant and on long-term patient and graft survival. MATERIAL AND METHODS Retrospective study from a prospectively-obtained database including adult patients who had received a primary liver transplant (LT) from whole graft of brain-dead donors. Recipients were divided into 2 age groups: <60 years and ≥60 years. Both groups were sub-divided according to donor age (younger than 60 years and 60 years or older). A propensity score analysis was performed to further adjust for baseline differences between recipients and donors. RESULTS We analyzed 642 patients who had LT performed between January 2000 and December 2013. No differences were observed in 1-year morbidity (hospital stay, rejection, surgical complications, and retransplant) between groups. Although patient and graft survival was significantly impaired in the older donor/older recipient group on Kaplan-Meier analysis (p=0.004), the propensity score analysis showed that donor age ≥60 years did not increase the risk of death for recipients aged ≥60 (HR1.40, p 0.074) and <60 years (HR 1.47, p 0.070). CONCLUSIONS Older donor age did not negatively affect survival regardless of recipient age, and comparable outcomes were achieved without an increased rate of complications.

Resultados a largo plazo de la duodenopancreatectomía cefálica con resección de la vena mesentérica superior y vena porta por adenocarcinoma de la cabeza de páncreas

INTRODUCTION The benefit of pancreaticoduodenectomy (PD) with superior mesenteric-portal vein resection (PVR) for pancreatic adenocarcinoma (PA) is still controversial in terms of morbidity, mortality and survival. We conducted a retrospective study to analyze outcomes of PD with PVR in a Spanish tertiary centre. METHODS Between 2002 and 2012, 10 patients underwent PVR (PVR+ group) and 68 standard PD (PVR- group). Morbidity, mortality, overall survival (OS) and disease-free survival (DFS) were compared between PVR+ and PVR- group. Prognostic factors were identified by a Cox regression model. RESULTS Postoperative mortality was 5% (4/78), all patients in PVR- group. Morbidity was higher in the PVR- group compared to PVR+ (63 vs. 30%, P=.004). OS at 3 and 5 years was 43 and 43% in PVR+ group, 35 and 29% in PVR- group (P=.07). DFS at 3 and 5 years DFS were 28 and 15% in PVR+ group, 25 and 20% in PVR- group (P=.84). Median survival was 23.1 months in PVR- group, and 22.8 months in PVR+ group (P=.73). Factors related with OS were absence of adjuvant treatment (OR 2.9, 95%IC: 1.39-6.14, P=.003), R1 resection (OR 2.3, 95%IC: 1.2-4.43, P=.006), preoperative CA 19.9 level ≥ 170 UI/mL (OR 2.3, 95%IC: 1.22-4.32, P=.01). DFS risk factors were R1 resection (OR 2.6, 95%IC: 1.41-4.95, P=.002); moderate or poor tumor differentiation grade (OR 2.7, 95%IC: 1.23-6.17, P=.01); N1 lymph node status (OR 1.8, 95%IC: 1.02-3.19, P=.04); CA 19.9 level ≥ 170 UI/mL (OR 2.4, 95%IC: 1.30-4.54, P=.005). CONCLUSIONS PVR for PA can be performed safely. Patients with PVR have a comparable survival to patients undergoing standard PD if disease-free margins can be obtained.