J. Ignacio Herrero

De Novo neoplasia after liver transplantation: An analysis of risk factors and influence on survival

Immunosuppression increases the risk of posttransplant malignancy and it may increase posttransplant mortality. The finding of factors related to the development of posttransplant malignancy may serve as a guide to avoid those risk factors and to develop strategies of posttransplant surveillance. The incidence and risk factors of malignancy were studied in 187 consecutive liver transplant recipients surviving more than 3 months. None of the 12 patients surviving less than 3 months had de novo neoplasia. The impact of malignancy on survival was studied in a case‐control study. After a median follow‐up of 65 months, 49 patients developed 63 malignancies: 25 patients had 35 cutaneous neoplasias and 27 patients had 28 noncutaneous malignancies. The 5‐ and 10‐year actuarial rates of cutaneous neoplasia were 14 and 24% and the rates of noncutaneous neoplasia were 11 and 22%, respectively. Risk factors for the development of cutaneous malignancy were older age and Child‐Turcotte‐Pugh A status. Risk factors for the development of noncutaneous malignancy were older age, alcoholism, and smoking. Cutaneous neoplasia had no effect on survival, whereas patients with noncutaneous malignancy had a significant reduction of survival. The overall relative risk of cutaneous and noncutaneous neoplasia, as compared with the general population were 16.91 (95% confidence interval: 11.78‐23.51) and 3.23 (95% confidence interval: 2.15‐4.67), respectively. The relative risk of cancer‐related mortality (after excluding recurrent malignancy) was 2.93 (95% confidence interval: 1.56‐5.02). Multivariate analysis showed that noncutaneous malignancy was an independent risk factor for posttransplant mortality. In conclusion, liver transplant recipients have a higher risk of cancer‐related mortality than the general population. This increased risk is due to the development of noncutaneous neoplasia. Older age, alcoholism, and smoking increase the risk of de novo noncutaneous neoplasia. (Liver Transpl 2005;11:89–97.)

Liver transplantation in patients with hepatocellular carcinoma across Milan criteria

Milan criteria are the most frequently used limits for liver transplantation (LT) in patients with hepatocellular carcinoma (HCC), but our previous experience with expanded criteria showed encouraging results. The aim of this study was to investigate whether our expanded Clinica Universitaria de Navarra (CUN) criteria (1 nodule up to 6 cm or 2–3 nodules up to 5 cm each) could be used to select patients with HCC for LT. Eighty‐five patients with HCC fulfilling CUN criteria were included as candidates for LT. Survival of transplanted HCC patients was compared with survival of patients without HCC (n = 180). After the exclusion of 2 patients with tumor seeding of the chest wall due to pre‐LT tumor biopsy, survival and recurrence rates were compared according to tumor staging. Twenty‐six out of 85 (30%) patients exceeded Milan criteria. Twelve patients had tumor progression on the waiting list. Patients exceeding Milan criteria had a higher dropout rate due to tumoral progression. One‐, 3‐, 5‐, 7‐, and 10‐year survival rates of the 73 transplanted HCC patients were 86%, 74%, 70%, 61%, and 50%, respectively. Survival of patients with HCC was significantly lower than that of patients without HCC, but by multivariate analysis, HCC was not associated with lower survival. Tumor recurrence and survival rates were similar for patients fulfilling Milan and CUN criteria. Pathological staging showed 55 patients within Milan criteria, 7 patients exceeding them but within CUN criteria, and 9 patients exceeding CUN criteria. Tumor recurrence rates were 2/55 (4%), 0/7 (0%), and 4/9 (44%) in each of these groups, respectively. In conclusion, following CUN criteria could increase the number of HCC patients who could benefit from LT, without worsening the results. Because of the short number of patients in this series, these data need external validation. Liver Transpl 14:272–278, 2008.

Liver Transplant Recipients Older Than 60 Years Have Lower Survival and Higher Incidence of Malignancy

Older age is not considered a contraindication for liver transplantation, but age‐related morbidity may be a cause of mortality. Survival and the incidence of the main post‐transplant complications were assessed in 111 adult liver transplant recipients. They were divided in two groups according to their age (patients younger than 60 years, n=54; patients older than 60 years, n=57) and both groups were compared. Older patients were more frequently transplanted for hepatitis C (p= 0.03) and hepatocellular carcinoma (p= 0.05) and their liver disease was less advanced (Child‐Pugh and MELD scores were significantly lower; p=0.004 and p=0.05, respectively). After transplantation, older patients had a significantly lower survival (p=0.02). Higher age was independently associated with mortality (hazard ratio for each 10‐year increase: 2.1; 95% confidence interval: 1.1‐ 4.0; p=0.02). The incidence of de novo neoplasia and nonskin neoplasia were higher in older patients (p=0.02 and p =0.007, respectively). Malignancy was the cause of death in one patient younger than 60 years and in 12 patients older than 60 years (p =0.002). In multivariate analysis, a higher age and smoking were independently associated with a higher risk of dying of de novo neoplasia. In conclusion, older liver transplant recipients have a significantly lower survival than younger patients. Malignancy is responsible for this decreased survival.

De novo malignancies following liver transplantation: Impact and recommendations

Key Points

Nonmelanoma skin cancer after liver transplantation. Study of risk factors

Nonmelanoma skin cancer (NMSC) is a frequent complication after liver transplantation, but the risk factors of posttransplant NMSC have not been well defined. In a prospectively followed series of 170 liver transplant recipients, we assessed the incidence of NMSC, compared it with the expected incidence in the general population, and investigated which risk factors were related to NMSC. After a median follow‐up of 62 months, 27 patients developed 43 NMSC. The relative risk of NMSC was 20.26 (95% confidence interval: 14.66‐27.29) as compared with sex‐ and age‐matched population. In univariate analysis, older age, male sex, Child‐Turcotte‐Pugh A or B at transplantation, treatment with mycophenolate mofetil, skin type, and total pretransplant sun burden were associated to the development of NMSC. In multivariate analysis, only skin type and total sun burden were independently related to NMSC. In conclusion, risk of posttransplant NMSC may be estimated combining skin type and an easy estimation of total sun burden. No individual immunosuppression regimen seems to be related to a higher risk of NMSC. (Liver Transpl 2005;11:1100–1106.)

Herpes zoster after liver transplantation: Incidence, risk factors, and complications

Herpes zoster is the consequence of the reactivation of latent varicella‐zoster infection. Immunosuppression may be a predisposing factor for herpes zoster. We have retrospectively assessed the risk of herpes zoster, the risk factors for its occurrence, and its evolution in a population of 209 consecutive liver transplant recipients. Herpes zoster developed in 25 (12%) of patients. One‐, 3‐, 5‐, and 10‐year actuarial rates of herpes zoster were 3%, 10%, 14%, and 18%, respectively. In a case‐control study, patients developing herpes zoster were younger, received a higher number of immunosuppressive drugs, and were more frequently receiving mycophenolate mofetil or azathioprine. In multivariate analysis, the only factor related to herpes zoster occurrence was treatment with mycophenolate mofetil or azathioprine. Eight patients (31%) developed postherpetic neuralgia. In conclusion, herpes zoster is a relateively common complication after liver transplantation. It is related to immunosuppressive therapy. Postherpetic neuralgia develops in one third of patients with posttransplant herpes zoster. (Liver Transpl 2004;10:1140–1143.)

Trial of complete weaning from immunosuppression for liver transplant recipients: Factors predictive of tolerance

Recipients of liver transplantation (LT) may develop immunological tolerance. Factors predictive of tolerance are not clearly understood. Transplant recipients with normal liver function tests and without active viral hepatitis or autoimmune disease who presented with side effects of immunosuppression or a high risk of de novo malignancies were selected to participate in this prospective study. Twenty‐four patients fulfilled the inclusion criteria and, therefore, underwent a gradual reduction of immunosuppression. Tolerance was defined as normal liver function tests after immunosuppression withdrawal. Basal clinical and immunological characteristics, including lymphocyte counts and subpopulations (T, B, natural killer, CD4+, CD8+, and regulatory T cells) and the phytohemagglutinin stimulation index (SI), were compared for tolerant and nontolerant patients. Fifteen of the 24 patients (62.5%) were tolerant at a median of 14 months (interquartile range = 8.5‐22.5 months) after complete immunosuppression withdrawal. Tolerant patients had a longer median interval between transplantation and inclusion in the study (156 for tolerant patients versus 71 months for nontolerant patients, P = 0.003) and a lower median SI (7.49 for tolerant patients versus 41.73 for nontolerant patients, P = 0.01). We identified 3 groups of patients with different probabilities of tolerance: in the first group (n = 7 for an interval > 10 years and an SI < 20), 100% reached tolerance; in the second group (n = 10 for an interval > 10 years and an SI > 20 or an interval < 10 years and an SI < 20), 60% reached tolerance; and in the third group (n = 7 for an interval < 10 years and an SI > 20), 29% reached tolerance. In conclusion, a high proportion of select LT recipients can reach tolerance over the long term. Two simple basal variables—the time from transplantation and the SI—may help to identify these patients. Liver Transpl 19:937–944, 2013.

Graft-versus-host disease after liver transplantation

We describe a case of graft-versus-host disease that developed in the recipient of an orthotopic liver transplant. A maculopapular eruption developed on postoperative day 25. After the diagnosis of graft-versus-host disease was made aggressive therapy was instituted, which resulted in a complete recovery.

Radioembolization of hepatocellular carcinoma activates liver regeneration, induces inflammation and endothelial stress and activates coagulation

Radioembolization may rarely induce liver disease resulting in a syndrome that is similar to veno‐occlusive disease complicating bone marrow transplantation where inflammation, endothelial cell activation and thrombosis are likely involved. We hypothesized that similar mechanisms could be implicated in radioembolization‐induced liver disease (REILD). Moreover, lobar radioembolization may induce hypertrophy of the non‐treated hemiliver most probably by inducing liver regeneration.

An open, randomized, multicenter clinical trial of oral tacrolimus in liver allograft transplantation: A comparison of dual vs. triple drug therapy

Triple therapy combining an anticalcineurin agent, corticosteroids, and azathioprine (AZA) in liver transplantation has been frequently applied, particularly in Europe. Debates have arisen concerning the use of a third drug (AZA), mainly in patients receiving tacrolimus (TAC). An open‐label, multicenter, prospective, and randomized trial was performed to assess the efficacy and safety of TAC and corticosteroids (dual therapy [D]) vs. TAC, corticosteroids, and AZA (triple therapy [T]) in liver transplantation. A total of 180 patients were randomized, 92 in D and 88 in T group. Patients were followed during 3 months for efficacy and safety and up to 24 months for patient and graft survival assessments. The rate of biopsy‐proven acute rejection was higher in D than in T group (40.7% vs. 24.4%; P = 0.021). A higher incidence of positive HCV status in D group (55.6% vs. 40.7%; P = 0.049) may explain this difference, since significantly more patients of this HCV subpopulation experienced acute rejection when treated with D therapy (48% vs. 20%; P = 0.008). No treatment differences were apparent for HCV‐negative patients. The 24‐month graft survival tended to be inferior in T group, 69.8% vs. 75.8% (P = 0.283). Similar results were observed regarding patient survival at the same time point, with values of 72.9% vs. 76.9% (P = 0.573), favoring D group. Both regimens showed comparable safety profiles with the exception of hematological abnormalities, which were more frequently observed in T group. In conclusion, both regimens were shown to be effective although increased toxicity and a trend towards a lower graft and patient survival were observed in T group. (Liver Transpl 2005;11:515–524.)