The falling incidence of hematologic cancer after heart transplantation.

BACKGROUND: A number of changes in the management of heart transplantation (HT) patients have each tended to reduce the risk of post-HT hematologic cancer, but little information is available concerning the overall effect on incidence in the HT population. METHODS: Comparison of data from the Spanish Post-Heart-Transplantation Tumour Registry for the periods 1991-2000 and 2001-2010. RESULTS: The incidence among patients who underwent HT in the latter period was about half that observed in the former, with a particularly marked improvement in regard to incidence more than five yr post-HT. CONCLUSIONS: Changes in HT patient management have jointly reduced the risk of hematologic cancer in the Spanish HT population. Long-term risk appears to have benefited more than short-term risk.

Influence of steroid dosage, withdrawal, and reinstatement on survival after heart transplantation: results from the RESTCO study.

BACKGROUND: Little information is available regarding the consequences of steroid withdrawal following heart transplantation (HT) in Spain. METHODS: We analyzed the records of 1068 patients (81.6% men) who underwent HT between 2000 and 2005 in 13 Spanish centers who were aged ≥ 18 years and who survived at least 1 year. Death rates and Kaplan-Meier survival curves for 1 to 5 years post-HT were compared among four groups: groups A and B, patients on steroids throughout the first 5 years post-HT at dosages of ≤ 5 mg/d between 1-year and 5-year follow-up (group A; n = 148), or >5 mg/d for some part of this period (group B; n = 578). Groups C and D were patients from whom steroids were at some point withdrawn including group D (n = 73) with and group C (n = 269) without subsequent reintroduction into the maintenance regimen. RESULTS: Steroids were withdrawn at 1.6 ± 0.9 years post-HT in group C, and 1.7 ± 1.2 years post-HT in group D. The death rate between 1- and 5-year follow-up (deaths per 1000 person-years) was 44.3% (95% confidence interval 26.2-62.5) in group A, 42.6% (33.7-51.4) in group B, 30.5% (19.6-41.4) in group C, and 47.8% (21.8-73.7) in group D. There was no significant difference among them or among Kaplan-Meier survival curves of the four groups (P = .34 in both cases). Comparison of combined groups C + D with groups A + B showed no evidence of a greater mortality among combined groups C + D. CONCLUSIONS: The late withdrawal of steroids following HT was not associated with increased mortality.

The prognosis of noncutaneous, nonlymphomatous malignancy after heart transplantation: data from the Spanish Post-Heart Transplant Tumour Registry.

INTRODUCTION: Malignancy is a major complication in the management of solid organ transplant patients. Skin cancers show a better prognosis than other neoplasms, but not all others are equal: Ideally, patient management must take into account the natural history of each type of cancer in relation to the transplanted organs. We sought to determine the prognosis of various groups of noncutaneous nonlymphomatous (NCNL) cancers after heart transplantation (HT). METHODS: We retrospectively analyzed the records of the Spanish Post-Heart-Transplant Tumour Registry, which collects data on posttransplant tumors in all patients who have undergone HT in Spain since 1984. Data were included in the study up to December 2008. We considered only the first NCNL post-HT tumors. RESULTS: Of 4359 patients, 375 developed an NCNL cancer. The most frequent were cancers of the lung (n=97; 25.9%); gastrointestinal tract (n=52; 13.9%); prostate gland (n=47; 12.5%; 14.0% of men), bladder (n=32; 8.5%), liver (n=14; 3.7%), and pharynx (n=14; 3.7%), as well as Kaposi's sarcoma (n=11; 2.9%). The corresponding Kaplan-Meier survival curves differed significantly (P<.0001; log-rank test), with respective survival rates of 47%, 72%, 91%, 73%, 36%, 64%, and 73% at 1 year versus 26%, 62%, 89%, 56%, 21%, 64%, and 73% at 2 years; and 15%, 51%, 77%, 42%, 21%, 64%, and 52% at 5 years post-diagnosis, respectively. CONCLUSION: Mortality among HT patients with post-HT NCNL solid organ cancers was highest for cancers of the liver or lung (79%-85% at 5 years), and lowest for prostate cancer (23%).

Superior prevention of acute rejection by tacrolimus vs. cyclosporine in heart transplant recipients--a large European trial.

We compared efficacy and safety of tacrolimus (Tac)-based vs. cyclosporine (CyA) microemulsion-based immunosuppression in combination with azathioprine (Aza) and corticosteroids in heart transplant recipients. During antibody induction, patients were randomized (1:1) to oral treatment with Tac or CyA. Episodes of acute rejection were assessed by protocol biopsies, which underwent local and blinded central evaluation. The full analysis set comprised 157 patients per group. Patient/graft survival was 92.9% for Tac and 89.8% for CyA at 18 months. The primary end point, incidence of first biopsy proven acute rejection (BPAR) of grade >/= 1B at month 6, was 54.0% for Tac vs. 66.4% for CyA (p = 0.029) according to central assessment. Also, incidence of first BPAR of grade >/= 3A at month 6 was significantly lower for Tac vs. CyA; 28.0% vs. 42.0%, respectively (p = 0.013). Significant differences (p < 0.05) emerged between groups for these clinically relevant adverse events: new-onset diabetes mellitus (20.3% vs. 10.5%); post-transplant arterial hypertension (65.6% vs. 77.7%); and dyslipidemia (28.7% vs. 40.1%) for Tac vs. CyA, respectively. Incidence and pattern of infections over 18 months were comparable between groups, as was renal function. Primary use of Tac during antibody induction resulted in superior prevention of acute rejection without an associated increase in infections.

[Tacrolimus blood levels and incidence of graft rejection in heart transplantation]. / Relación entre los niveles de tacrolimus en sangre y la incidencia de rechazo en enfermos trasplantados de corazón.

OBJECTIVE: To determine the relationship between pharmacokinetic parameters and clinical outcomes after heart transplantation and to determine the range of tacrolimus blood levels which provides the most effective protection against graft rejection. To study other factors that predict graft rejection. METHOD: We retrospectively analyzed the clinical outcomes of all adult patients who received a heart transplant between January 2000 and October 2003 and had routine monitoring of tacrolimus trough levels at the time of scheduled endomyocardial biopsy. Rejection was defined as Grade = 3, based on the International Society for Heart and Lung Transplantation (ISHLT) criteria. The follow-up period was 1 year. All patients were on a triple therapy regimen of Tacrolimus (TAC), Corticosteroids and Azatioprine/Micophenolate Mofetil. Data were analyzed by Student s t-test, univariate logistic regression and ROC curve. RESULTS: Tacrolimus blood levels measured at day +5 postransplant were the strongest predictor of acute graft rejection over a 1-year follow-up period (rejection 5.76 +/- 3.4 ng/ml vs no rejection 9.66 +/- 2.73 ng/ml, p = 0.016). A decrease of one unit in TAC trough level values at day +5 postransplant implied a 1.58 greater risk of rejection (p = 0.05). Overall incidence of treated acute rejection was lower for patients with trough levels higher than 8 ng/ml on day +5 postransplant (33 vs 80%, p = 0.055, Fisher s exact test). CONCLUSIONS: Data suggest that in heart transplant patients it may be crucial to achieve tacrolimus levels of at least 8 ng/ml during the first days postsurgery to avoid rejection.

Detection of transplant heart rejection by analysis of endomyocardial voltage.

These studies seek an alternative method with myocardial biopsy for rejection diagnosis. A pacemaker (Biotronik model Logos) was implanted into 16 patients to detect intramyocardial voltage. The recordings were classified in two groups according to results of myocardial biopsy. The results of the biopsy were classified according to the recommendations of the International Society for Heart and Lung Transplantation: namely, Group I: rejection < 2 (52 recordings) and Group II: rejection > or = 2 (9 recordings). The sensitive parameter for rejection detection was Tslew, which was deduced from the paced intracardial potential in the monopolar mode. The results were significant in both groups; the medium value of Tslew in group I was 96.7%, and the value for group II was 87.13% (P=.022). The sensitivity value in our patient group for detection of treatedable rejection was 78%; the negative predictive value was 95%. In conclusion the method is useful for rejection detection, but is necessary to make several recordings for the same patients during the first month post transplant, to obtain an individual baseline value.

New strategies of cyclosporine monitoring in heart transplantation: initial results.

The aim of this study was to evaluate cyclosporine (CyA) absorption profiles in heart transplantation to establish the most adequate monitoring strategy and determine the optimal therapeutic range for AUC(0-4) or C2 levels. A total of 22 full pharmacokinetic studies were performed at steady-state in 22 adult heart transplant recipients (18 men, 4 women). Twelve studies were performed during the first month posttransplant (group I), and 10 studies were done after 1 month (group II). In 9 outpatients we performed an abbreviated AUC(0-4). The mean age of the patients was 49+/-15 years (range, 15-72 years), and the mean weight was 70.4+/-10.8 kg (mean, 54-98 kg). The CyA dosage had been adjusted to maintain trough levels (C0) in the putative target ranges of 200 to 400 ng/mL in group I and between 100 to 300 ng/mL in group II. Blood samples were drawn prior to and at 0.5, 1, 2, 4, 6, 8, and 12 hours after the morning dose. The CyA blood levels were measured by the AxSYM cyclosporine assay. The AUC was calculated by the trapezoidal rule. Multiple linear regression was done to evaluate the predictive ability of various limited sampling strategies. The C0 correlated poorly, either with the full AUC (r2=0.64) or the AUC(0-4) (r2=0.43), while C2 seemed to be the most accurate single predictor of drug exposure (r2=0.92 for AUC(0-12); r2=0.74 for AUC(0-4)). For both AUC(0-4) and AUC(0-12), all 2- or 3-point strategies had r2 values approaching that of the C2 value. In conclusion, C2 is a simple, fast, and accurate value to predict AUC(0-4) in routine clinical practice. Its implementation must focus on ensuring the commitment of all unit staff, thus ensuring that patients are sampled on time and minimizing the impact on workload.

Clinical pharmacokinetics of tacrolimus in heart transplantation: new strategies of monitoring.

The aim of this study was to investigate the absorption profile of tacrolimus (TAC) in heart transplant patients in order to find the best sampling time to predict the total exposure and to explore the target range for optimal clinical immunosuppression. Twenty-five full pharmacokinetic studies were performed in 22 heart transplant patients (11 men and 7 women) at less than 1 year posttransplant. The immunosuppressive treatment was steroids plus azathioprine or mycophenolate mofetil and TAC. The mean age was 55 years (36-64 years) and the mean weight 70.49 kg (50-111 kg). After three days of receiving the same dose, eight blood samples were collected at 0.5, 1, 2, 4, 6, 8, and 12 hours postmorning dose. TAC concentrations were measured by microparticle enzyme immunoassay (IMx). Area under the concentration-time curve(AUC(0-12)) was calculated by the trapezoidal rule. Using 0-4 hours TAC blood concentrations, a projected 12 hours AUC (extrapolated AUC(0-4)) was calculated assuming C0 and C12 were comparable. A high interpatient TAC pharmacokinetics variability that was greater during the absorption phase was observed. A Cmax (30.5+/-13.8 ng/mL) was reached at 2.3+/-1.5 h. When target trough levels were achieved (10-20 ng/mL), the mean tacrolimus exposure was 230.6+/-59.2 ng h/mL (120.14-327.7) (n=19). Correlation between AUC(0-12) and C0 was relatively good (r2=0.74). Between individual time points, C4 showed the best correlation (r2=0.88). In any case the best strategy to monitor is to obtain the extrapolated AUC(0-4) (r2=0.98), as a good approach to patients with a poor response to treatment.

[Mobile thrombus in the right cardiac cavities in patients with severe pulmonary thromboembolism. Importance of echocardiography]. / Trombos móviles en cavidades cardíacas derechas en pacientes con tromboembolismo pulmonar grave. Importancia de la ecocardiografía.

The pulmonary thromboembolism is a frequent and severe disease, usually difficult to recognize, specially in patients with thrombotic material trapped within right heart cavities. We present our experience in three patients with severe pulmonary thromboembolism where echocardiographic study demonstrated the presence of huge mobile thrombus in right heart cavities, which demanded urgent therapy with excellent results. We would like to stress that echocardiographic study in these patients could be elective diagnostic procedure, avoiding the realization of pulmonary arteriography, which could bring risk of possible thrombus mobilization.

[National Registry of Heart Transplantation. 8th Report (1984-1996)]. / Registro Nacional de Trasplante Cardíaco. VIII Informe (1984-1996).

As in previous years, the results of the Spanish Registry for Heart Transplantation are presented by the Section of Heart Transplantation of the Spanish Society of Cardiology. There are 12 participating hospitals with heart transplantation program. Two hospitals have got infants and adults programs; one hospital have got only infants program. In 1996, 282 procedures were performed, all orthotopic, which represents similar results to one or two years ago, with 292 and 277 operations respectively; this problem is important and should oblige to change the politics of National Network of Transplant (ONT). The early mortality was 12%. The actuarial survival is 53% at 8 years, similar to the International Society for Heart and Lung Transplantation (ISHLT). The survival depends of donor age, receptor age, receptor sex, ischemic time, elective or urgent intervention, extracorporeal circulation time, etiology of cardiac dysfunction, period time of intervention, renal function and donor dead etiology.

[National registry of heart transplantation. Seventh report (1984-1995)]. / Registro Nacional de Trasplante Cardíaco. Séptimo Informe (1984-1995).

As in previous years, the results of the Spanish Registry for Heart Transplantation are presented by the Section of Heart Transplantation of the Spanish Society of Cardiology. There are 12 participating Hospitals with Heart Transplantation Programs. Two Hospitals have infant and adult programs; one hospital has only an infant programs. In 1995, 278 procedures were performed, all orthotopic, which represents a 12% decrease from 1994. This is important and should force a reevaluation of to raise again the policy of the National Transplantation Network (ONT). The early mortality was 12%. The actuarial survival rate is 58% at 8 years, similar to the International Society for Heart and Lung Transplantation (ISHLT). Survival depends on donor age, receptor age, receptor sex, ischemic time, extracorporeal circulation time, etiology of cardiac dysfunction and the period of time of the intervention.

[National Registry of Heart Transplantation. 6th Report (1984-1994)]. / Registro nacional de trasplante cardíaco. Sexto informe (1984/1994).

As in previous years, the results of the Spanish Registry for Heart Transplantation are presented by the Section of Heart Transplantation of the Spanish Society of Cardiology. There are 12 participating Hospitals with Heart Transplantation Program. The activity of the different centres depends on the geographic situation and the years of activity. In 1994, 292 procedures were performed, all orthotopics, which represents a 2% increase from 1993. The early mortality was 12%. The actuarial survival is 53% at 8 years, similar to the International Society for Heart and Lung Transplantation (ISHLT). The survival depends on donor age, receptor age, receptor sex, ischemic time, etiology of cardiac dysfunction and period of time of intervention.

[Immunosuppressive guidelines. The differences and advantages]. / Pautas inmunosupresoras. Diferencias y ventajas.

There is nowadays a revolution of immunosuppressive regimens for trasplantation. The investigation of new drugs on experimental and clinical protocols is very important because is intended to find a better immunosuppressive drug. This activity is based on a better knowledge of immunology and physiopathology of rejection. Alternative non pharmacological methods are used for the control of severe and repetitive rejection and the study of quimerism and xenotransplantation.