Evaristo Varo

Spanish Experience in Liver Transplantation for Hilar and Peripheral Cholangiocarcinoma

Objective:To assess the real utility of orthotopic liver transplantation (OLT) in patients with cholangiocarcinoma, we need series with large numbers of cases and long follow-ups. The aim of this paper is to review the Spanish experience in OLT for hilar and peripheral cholangiocarcinoma and to try to identify the prognostic factors that could influence survival. Summary Background Data:Palliative treatment of nondisseminated irresectable cholangiocarcinoma carries a zero 5-year survival rate. The role of OLT in these patients is controversial, due to the fact that the survival rate is lower than with other indications for transplantation and due to the lack of organs. Methods:We retrospectively reviewed 59 patients undergoing OLT in Spain for cholangiocarcinoma (36 hilar and 23 peripheral) over a period of 13 years. We present the results and prognostic factors that influence survival. Results:The actuarial survival rate for hilar cholangiocarcinoma at 1, 3, and 5 years was 82%, 53%, and 30%, and for peripheral cholangiocarcinoma 77%, 65%, and 42%. The main cause of death, with both types of cholangiocarcinoma, was tumor recurrence (present in 53% and 35% of patients, respectively). Poor prognosis factors were vascular invasion (P < 0.01) and IUAC classification stages III–IVA (P < 0.01) for hilar cholangiocarcinoma and perineural invasion (P < 0.05) and stages III-IVA (P < 0.05) for peripheral cholangiocarcinoma. Conclusions:OLT for nondisseminated irresectable cholangiocarcinoma has higher survival rates at 3 and 5 years than palliative treatments, especially with tumors in their initial stages, which means that more information is needed to help better select cholangiocarcinoma patients for transplantation.

Influence of superimposed alcoholic hepatitis on the outcome of liver transplantation for end-stage alcoholic liver disease

BACKGROUND/AIMS Alcoholic cirrhosis is a common indication for liver transplantation. The present study was aimed to assess the influence of superimposed alcoholic hepatitis on the outcome of liver transplantation in patients with alcoholic cirrhosis. METHODS Survival rates of 68 patients transplanted for alcoholic cirrhosis were compared with those of 101 patients transplanted for miscellaneous causes. Within the alcoholic group, explanted livers were searched for data of acute alcoholic hepatitis. The survival rate of patients with alcoholic hepatitis superimposed on liver cirrhosis was compared to that of patients with liver cirrhosis alone. Clinical severity of alcoholic hepatitis was assessed with Maddreys score. RESULTS Survival was similar in alcoholics and patients with other causes of liver disease. Among patients transplanted for alcoholic cirrhosis, survival was similar in patients with superimposed alcoholic hepatitis (n=36) and in cases with liver cirrhosis alone (n=32). There was no difference in survival between patients with mild (n=26) and severe (n=10) alcoholic hepatitis. Seven alcoholics (10%) returned to ethanol consumption. Recidivism was not associated with either alcoholic hepatitis in the explanted liver or graft loss. CONCLUSIONS Survival after liver transplantation in patients with alcoholic cirrhosis plus alcoholic hepatitis detected in the explanted liver is similar to that of patients transplanted for other reasons. Even the presence of severe alcoholic hepatitis does not worsen the outcome of liver transplantation for end-stage alcoholic liver disease.

GESITRA-SEIMC/REIPI recommendations for the management of cytomegalovirus infection in solid-organ transplant patients

Cytomegalovirus infection remains a major complication of solid organ transplantation. In 2005 the Spanish Transplantation Infection Study Group (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) developed consensus guidelines for the prevention and treatment of CMV infection in solid organ transplant recipients. Since then, numerous publications have clarified or questioned the aspects covered in the previous document. These aspects include the situations and populations who must receive prophylaxis and its duration, the selection of the best diagnosis and monitoring technique and the best therapeutic strategy. For these reasons, we have developed new consensus guidelines to include the latest recommendations on post-transplant CMV management based on new evidence available.

Recomendaciones GESITRA-SEIMC y RESITRA sobre prevención y tratamiento de la infección por citomegalovirus en pacientes trasplantados

La infeccion por citomegalovirus (CMV) es una complicacion importante del trasplante. La ultima decada se ha caracterizado por los avances en su tratamiento, reduciendo su morbilidad y la mortalidad. Estos avances han sido decisivos en el diagnostico y prevencion. Se han desarrollado tecnicas de diagnostico rapidas y sensibles. Entre las estrategias de prevencion destaca el uso correcto de los productos sanguineos, las inmunoglobulinas y los farmacos antivirales, empleados en profilaxis o en terapia anticipada. El reciente desarrollo de farmacos eficaces por via oral como el valganciclovir permitira el tratamiento ambulatorio de los pacientes infectados. Es necesario trasladar este conocimiento a la practica clinica diaria. Con este objetivo el Grupo de Estudio de la Infeccion en el Trasplante (GESITRA) de la Sociedad Espanola de Microbiologia Clinica y Enfermedades Infecciosas (SEIMC) ha desarrollado este documento de consenso que incluye las ultimas recomendaciones en el tratamiento de la infeccion por CMV postrasplante.

Intrahepatic cholangiocarcinoma or mixed hepatocellular-cholangiocarcinoma in patients undergoing liver transplantation: a Spanish matched cohort multicenter study.

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.

Improvement of renal function after the switch from a calcineurin inhibitor to everolimus in liver transplant recipients with chronic renal dysfunction

Chronic renal dysfunction is a frequent and severe complication in solid‐organ transplant recipients. Calcineurin inhibitors (CNIs) are the main pathogenic factors of renal dysfunction. Switching from CNIs to nonnephrotoxic drugs, such as mammalian target of rapamycin inhibitors (everolimus and sirolimus), can improve renal function in these patients, but available data about the efficacy and safety of everolimus in liver transplant recipients are scarce. Twenty‐one liver transplant recipients (19 males, mean age = 60.6 ± 7.8 years) with chronic renal dysfunction (creatinine ≥ 1.5 mg/dL) were prospectively included. The basal creatinine values were 1.79 ± 0.39 mg/dL (range = 1.50–2.90 mg/dL). The basal creatinine clearance, evaluated with the Cockroft‐Gault formula, was 54.64 ± 12.47 mL/minute. Everolimus was initiated at a dosage of 0.75 mg twice daily, with target levels of 3 to 8 ng/mL. The withdrawal of CNIs was initiated after the target levels of everolimus were reached. Periodic controls of the weight, arterial pressure, liver function tests, serum creatinine, everolimus levels, proteinuria, creatinine clearance, and glomerular filtration rate at days 30, 90, 180, and 360 were made. After a median follow‐up of 19.8 months, the respective creatinine values at 30, 90, 180, and 360 days were 1.68 ± 0.40 (P = 0.012 with respect to basal values), 1.67 ± 0.34 (P = 0.107), 1.70 ± 0.41 (P = 0.521), and 1.57 ± 0.30 mg/dL (P = 0.047). The respective creatinine clearance values at 30, 90, 180, and 360 days were 58.64 ± 16.50 (P = 0.013 with respect to basal values), 59.49 ± 13.27 (P = 0.028), 59.82 ± 16.83 (P = 0.124), and 64.46 ± 16.79 mL/minute (P = 0.025). CNIs were withdrawn in 20 recipients (95.2%). Rejection was not detected in any case. In conclusion, the application in liver transplant recipients with chronic renal dysfunction of an immunosuppressive protocol with everolimus and the withdrawal of CNIs was associated with an initial improvement of renal function tests without an increase in the risk of rejection. Liver Transpl 15:1792–1797, 2009.

“Very Early” Intrahepatic Cholangiocarcinoma in Cirrhotic Patients: Should Liver Transplantation Be Reconsidered in These Patients?

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 ≤2 cm (“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 >2 cm 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 ≤2 cm achieved excellent 5‐year survival, and validation of these findings by other groups may change the current exclusion of such patients from transplant programs.

Diminished anticoagulant and fibrinolytic activity following liver transplantation

This study analyzed the coagulation changes in twenty patients after orthotopic liver transplantation. The procoagulant, anticoagulant, and fibrinolytic systems were studied during the first two postoperative weeks. Within the first postoperative day all extrinsic and intrinsic pathway factors became normal except factors IX, VII, and X, which recovered within the next 24 hr. Of interest are the changes in factor VIII, which reached a high concentration with an increase in its antigenic fraction during the study. However, coagulation inhibitors showed a different pattern. In fact, antithrombin III (AT-III) and protein C (PC) needed from 7 to 14 days to reach normal values. Total protein S (TPS) and free protein S (FPS) did not recover until day 7, whereas heparin cofactor II (HC-II) remained at subnormal levels throughout the study. Thrombin-antithrombin III complex (TAT) values were strikingly elevated in the immediate postoperative period. Fibrinolysis parameters showed plasminogen (PL) levels in the normal range until day 4. Antiplasmin (AP) followed a curve parallel to that of plasminogen but its levels were higher during this observation period. Similarly the initial elevation in plasminogen activator inhibitor 1 endothelial type (PAI-1) levels remained high until days 4 and 7. In summary, it can be concluded that during the postoperative phase after OLT a hypercoagulable state is developed as a result of diminished anticoagulant and fibrinolytic activity. This coagulation might be a nontechnical factor contributing to the thrombotic vascular complications of some liver recipients.

Pharmacokinetics for once-daily versus twice-daily tacrolimus formulations in de novo liver transplantation: a randomized, open-label trial.

Tacrolimus, a cornerstone immunosuppressant, is available as a twice‐daily formulation (tacrolimus bid). A once‐daily prolonged‐release formulation (tacrolimus qd) has been developed. This 6‐week, randomized, phase 2, multicenter, open‐label, prospective trial in primary liver transplant recipients investigated and compared the pharmacokinetics (PK) of tacrolimus for qd and bid formulations. All patients received tacrolimus‐based immunosuppression (tacrolimus qd, n = 67; bid, n = 62). PK data were available for 77 patients (tacrolimus qd, n = 45; bid, n = 32). Tacrolimus area under the curve (AUC) from 0 to 24 hours (AUC0‐24) at equivalent doses was approximately 50% lower for tacrolimus qd than for bid on day 1 (146 versus 264 ng·h/mL, respectively), but by day 14 was comparable between treatments (324 and 287 ng·h/mL, respectively) with higher tacrolimus qd doses. There was a strong correlation between AUC0‐24 and concentration at 24 hours for tacrolimus qd and bid (r = 0.92 and r = 0.76, respectively). Furthermore, the relationship between these 2 parameters (ie, the slope of the line) was also similar for the 2 formulations. Efficacy endpoints were comparable for both formulations at 6 weeks with no marked differences in incidence, nature, or severity of adverse events between treatments (although the study was not powered to draw efficacy conclusions). These results suggest that targeting the same trough levels will achieve similar total AUC over 24 hours for both tacrolimus qd and tacrolimus bid in de novo liver transplant recipients. Liver Transpl 17:167–177, 2011.

Immunosuppressant treatment adherence, barriers to adherence and quality of life in renal and liver transplant recipients in Spain

Morales JM, Varo E, Lázaro P. Immunosuppressant treatment adherence, barriers to adherence and quality of life in renal and liver transplant recipients in Spain. 
Clin Transplant 2011 DOI: 10.1111/j.1399‐0012.2011.01544.x. 
© 2011 John Wiley & Sons A/S.