Occult nonhematopoietic malignancies present at autopsy in solid organ transplant patients who died within 100 days.

BACKGROUND: Patients are at an increased risk for developing malignancies after transplantation. Lymphomas, skin malignancies, Kaposi's sarcomas, and cervical/vulvar neoplasms are the most common, but visceral malignancies are also well documented, with a reported frequency ranging from 1% to 6%. These visceral tumors represent a mix of neoplasms that were clinically occult at the time of transplantation and those that arise de novo after transplantation. Little information, however, is available on the frequency of clinically occult malignancies at the time of transplantation and their contribution to the number of posttransplant malignancies. METHODS: A retrospective study was performed of all patients who received an organ transplant from January 1981 to June 1997 and died within 100 days, a time interval in which epithelial malignancies found at autopsy were presumed to have been present, but clinically occult, at the time of transplantation. RESULTS: A total of 375 patients were studied who received the following organ transplants: 231 liver, 52 heart, 26 heart and lung, 32 lung, and 34 kidney. Eleven malignancies were identified for an overall frequency of 2.9% and included three thyroid carcinomas, three carcinoids of the small bowel, two lung carcinomas, one laryngeal carcinoma, one renal cell carcinoma, and one seminoma. CONCLUSION: The 2.9% frequency of malignancies seen in this study suggests that a small, but significant, number of patients have occult malignancies at the time of transplantation and that these occult tumors contribute substantially to the number of malignancies that present clinically after transplantation.

Central venulitis in the allograft liver: a clinicopathologic study.

BACKGROUND: Central venulitis denotes a histologic lesion of the allograft liver characterized by perivenular and subendothelial mononuclear inflammation of the terminal hepatic venules associated with varying degrees of perivenular hepatocyte dropout. Although this lesion has generally been considered a manifestation of acute rejection, some have suggested that it instead represents tacrolimus hepatotoxicity. METHODS: We therefore compared the clinicopathologic features of 30 episodes of isolated central venulitis with 22 episodes of combined central venulitis and typical portal acute rejection occurring in 27 patients. Nineteen of the patients received tacrolimus and eight received cyclosporine as primary immunosuppression. RESULTS: No significant differences were found between the two groups, except that isolated central venulitis more often displayed a mild inflammatory component (P=0.007) with small lymphocytes as the predominant cell type (P=0.002). None of the patients had tacrolimus or cyclosporine levels that exceeded the therapeutic range, and none had other clinical evidence of drug toxicity. Usual antirejection therapy was instituted in all but two episodes; response was evident in 93% (28 of 30) of the isolated central venulitis and 86% (19 of 22) of the central venulitis-portal acute rejection group, with histologic regression documented in all follow-up specimens (four and five, respectively). Due to persistent central venulitis, two cyclosporine patients were switched to tacrolimus, with prompt resolution. CONCLUSIONS: These findings are inconsistent with the concept that central venulitis represents drug toxicity and indicate instead that it is a form of acute allograft rejection.

Comparative incidence of de novo nonlymphoid malignancies after liver transplantation under tacrolimus using surveillance epidemiologic end result data.

BACKGROUND: An increased incidence of de novo nonlymphoid malignancies has been shown in immunocompromised patients. However, the true risk over time compared to the general population has not been determined. METHODS: One thousand consecutive patients were carefully followed for an average of 77.8+/-11.1 (range, 56.3-96.3) months after primary liver transplantation at a single center. All de novo nonlymphoid malignancies were recorded. Each malignancy was compared with a standard Occupational Cohort Mortality Analysis Program population matched for age, sex, and length of follow-up using modified life table technique and surveillance epidemiology end result (SEER) data. RESULTS: Fifty-seven patients accounted for de novo malignancies and contributed 4795.3 total person years, a mean+/-SD of 36+/-21 (median, 36; range, 6-74) months after liver transplantation. Twenty-two of these malignancies were skin malignancies including two melanomas. Oropharyngeal cancers (n=7) were found to be 7.6 times higher (P<0.05) and respiratory malignancies (n=8) were 1.7 times higher (P>0.05) compared to the SEER incidence rate. Female reproductive system malignancies including breast cancer (n=3) were 1.9 times lower (P>0.05) and genitourinary malignancies were (n=5) 1.5 times lower (P>0.05) than their matched cohorts. No differences was observed in gastrointestinal malignancies (n=5). There was a significant difference in survival of the patients after diagnosis of malignancy depending on the type of cancer. There were two Kaposi's sarcomas, two metastatic unknown primaries, one thyroid, one brain, and one ophthalmic malignancies in the series. Mortality for Kaposi's and metastatic disease of unknown primary was 100% within 5 months, while the 1-year mortality for oropharyngeal cancer was 57.1% and that for lung cancers was 62.5%. Long-term survival for skin cancer was highest: 86.4% at 3 years (P=0.015 by log-rank test). CONCLUSION: An increased incidence of de novo cancers in the chronically immunocompromised patient demands careful long-term screening protocols which will help to facilitate the diagnosis at an early stage of the disease. This is particularly true for oropharyngeal cancers where the risk is more than 7 times higher compared to SEER incidence data matched for age, sex, and length of follow-up.

A prospective randomized trial of tacrolimus and prednisone versus tacrolimus, prednisone, and mycophenolate mofetil in primary adult liver transplant recipients: an interim report.

BACKGROUND: Tacrolimus (Tac) and mycophenolate mofetil (MMF) are newly approved immunosuppressive agents. However, the safety and efficacy of the combination of MMF and Tac in primary liver transplantation has not been determined. METHODS: An Institutional Review Board-approved, open-label prospective randomized protocol was initiated to study the efficacy and toxicity of Tac and steroids (double-drug therapy) versus Tac, steroids, and MMF (triple-drug therapy) in primary adult liver transplant recipients. Both groups of patients began on the same doses of Tac and steroids. Patients randomized to triple-drug therapy also received 1 g of MMF twice a day. RESULTS: Between August 1995 and January 1997, 200 patients were enrolled, 99 in double-drug therapy and 101 in triple-drug therapy. All patients were followed until May 1997, with a mean follow-up of 12.7 months. During the study period, 28 of 99 patients in double-drug therapy received MMF to control ongoing acute rejection, nephrotoxicity, and/or neurotoxicity. On the other hand, 61 patients in triple-drug therapy discontinued MMF for infection, myelosuppression, and/or gastrointestinal disturbances. By an "intention-to-treat analysis," the actuarial 1-year patient survival rate was 85.1% in double-drug therapy and 83.1% in triple-drug therapy (P=0.77). The actuarial 1-year graft survival rate was 80.2% for double-drug therapy and 79.2% for triple-drug therapy (P=0.77). Forty-one patients (41.4%) in double-drug therapy and 32 (31.7%) in triple-drug therapy had at least one episode of rejection, but this was not statistically significant (P=0.15). The mean maintenance dose of corticosteroids was slightly lower in triple-drug compared with double-drug therapy. CONCLUSION: Patient and graft survival rates were similar in both groups. There was a trend to a lower incidence of rejection, reduced nephrotoxicity, and a lesser amount of maintenance corticosteroids in triple-drug therapy compared with double-drug therapy.

Kidney transplantation for end-stage renal failure in liver transplant recipients with hepatitis C viral infection.

BACKGROUND: End-stage renal failure after successful liver transplantation (LTx) has been described in up to 5% of patients. Kidney transplantation (KTx) has been the treatment of choice in these cases. However, in recipients infected with hepatitis C virus (HCV), the augmentation of immunosuppression after KTx may result in an increased viral load. This, in turn, may adversely affect the liver allograft. METHOD: The present study retrospectively examined the outcome in 17 patients (3 females and 14 males, mean age 51.1+/-11.3 years) who received KTx after LTx. The mean interval from LTx to KTx was 57.6+/-32.1 months. The mean follow-up was 41.7+/-20.5 months after KTx, and 99.6+/-37.7 months after LTx. Sixteen of the 17 patients received tacrolimus-based immunosuppression at the time of KTx. RESULTS: During the follow-up period, one patient underwent combined liver and kidney retransplantation 3.7 years after KTx and 12.7 years after LTx. She subsequently died secondary to primary nonfunction. Four other patients died, two of lung cancer, one of pancreatitis/sepsis, and one of severe depression leading to noncompliance. A total of 29 episodes of biopsy-proven acute renal allograft rejection (1.7 episodes/ patient) were encountered and treated with steroids. Seven patients experienced a rise in liver function tests during the period of increased steroid dosage. Four patients received no treatment, and their liver function returned to baseline. The remaining three were treated with interferon. Overall 1- and 3-year actuarial patient and liver allograft survival was 88% and 71% (after renal transplantation); corresponding 1- and 3-year actuarial graft survival was 88% and 61%. Twelve patients are alive with normal liver function. One patient is on dialysis, because of renal allograft loss to noncompliance. CONCLUSION: In this series, LTx recipients with HCV infection were able to undergo KTx with a reasonable degree of success. KTx should be offered for end-stage renal failure after LTx, even in the presence of HCV infection, to individuals with stable liver function and no signs of liver failure.

Capillary blood versus arterial or venous blood for tacrolimus monitoring in liver transplantation.

Tacrolimus has been found to be useful in clinical solid organ transplantation. A very careful monitoring of the tacrolimus levels and dose adjustments are essential, at least in the immediate post-liver transplantation, situation. However, quite often after liver transplantation, patients have limited venous access for daily monitoring of tacrolimus levels. When the blood is sampled from a multilumen central venous catheter, used also for intravenous administration of tacrolimus, falsely elevated concentrations of tacrolimus have been observed. The present study examines the concentration of tacrolimus in capillary blood samples obtained from finger stick and compares its concentrations in simultaneously drawn samples from arterial line, peripheral venous puncture, and multilumen centrally placed venous catheter from the port used for tacrolimus infusion and the port not used for tacrolimus infusion. Ten adult post-liver transplantation recipients were studied. Whole blood concentration of tacrolimus in capillary blood was comparable to that of arterial blood, as well as to that of peripheral venous blood samples (r2 = 0.99; P = 0.72). Concentrations of tacrolimus in venous blood drawn from the port of the multilumen catheter used for intravenous tacrolimus infusion were 3-23 times higher (P = 0.0015), while the concentrations of venous blood drawn from the port not used for tacrolimus infusion were 1.7-4.5 times higher (P = 0.016), as compared with arterial, capillary, or peripheral venous whole blood concentrations.

An analysis of pretransplantation variables associated with long-term allograft outcome in pediatric liver transplant recipients receiving primary tacrolimus (FK506) therapy.

BACKGROUND: The present study analyzes pretransplantation variables associated with long-term liver allograft survival in 278 children who underwent transplantation under primary tacrolimus (FK506) therapy at a single center between October 1989 and October 1996. METHODS: The influence of 17 pretransplantation variables on long-term liver allograft outcome was analyzed. Donor variables included age, weight, gender, and cold ischemia time. Recipient variables included age, weight, gender, original liver disease, pretransplantation waiting time, previous abdominal surgery, United Network of Organ Sharing (UNOS) status, ABO blood group, bilirubin level, prothrombin time, ammonia level, creatinine level, and reduced-size/split liver grafts. RESULTS: Overall actuarial graft survival was 79.9% at 1 year, 79.1% at 2 years, and 78.3% at 3, 4, and 5 years. Retransplantation rate was 10.8%. Pretransplantation variables with a significant adverse effect on graft survival by univariate analysis were donor age < or = 1 year (P<0.004), donor weight < or = 10 kg (P<0.003), UNOS status I and II (P<0.007), ABO type O, B, and AB (P<0.03), and reduced-size/split liver grafts (P<0.02). Pretransplantation variables significant by multivariate analysis and therefore independent predictors of inferior graft outcome were donor weight '10 kg (relative risk [RR] 2.91, confidence interval [CI] 1.53-5.51); reduced-size/split liver grafts (RR 2.53, CI 1.30-5.64); and UNOS status I (RR 2.22, CI 1.11-4.43). CONCLUSIONS: Pediatric liver transplant recipients receiving primary tacrolimus therapy have long-term graft survival rates approaching 80%. UNOS status, donor weight, and the use of reduced-size/split liver grafts are the most important factors affecting survival.

A prospective trial of tacrolimus (FK 506) in clinical heart transplantation: intermediate-term results.

Between January 1, 1989, and December 31, 1994, we have treated 122 primary heart recipients with FK 506 (group I) and 121 with cyclosporine (group II). Fifty patients in the cyclosporine (CyA) group received no lympholytic induction (CyA alone) and 71 others received lympholytic induction with either rabbit antithymocyte globulin or OKT3 (CyA+LI). The mean follow-up was longer in the FK 506 group than in the CyA groups (3.2 +/- 1.3 vs 2.3 +/- 1.8 years; p< 0.01). Patient survival did not differ on the basis of the type of immunosuppression used. At 3 months after transplantation, the freedom from rejection in the FK 506 group was higher than that of the CyA-alone group (47% vs 22%, p < 0.01) but similar to that of the CyA+LI group (47% vs 53%). The linearized rejection rate (episodes/100 patient-days) of the FK 506 group (0.09 episodes) was lower (p < 0.05) than that of the CyA-alone group (0.26) and the CyA+LI group (0.13). The requirement for pulsed steroids to treat rejection was less in common in the FK 506 group than in either CyA group. Eighteen patients in the CyA group had refractory rejections; all resolved with FK 506 rescue. Two patients in the FK 506 group had refractory rejection that resolved with total lymphoid irradiation (n=1) and methotrexate therapy (n=1). Patients receiving FK 506 had a lower risk of hypertension and required a lower dose of steroids. Although the mean serum creatinine concentration at 1 year was higher in the FK 506 group, this difference disappeared after 2 years. No patients required discontinuation of FK 506 because of its side effects. Our intermediate-term results indicate that FK 506 compares favorably with CyA as a primary immunosuppressant in heart transplantation.

P-glycoprotein (P-gp) is upregulated in peripheral T-cell subsets from solid organ transplant recipients.

Immunosuppressive agents such as cyclosporine, tacrolimus, sirolimus, and corticosteroids are substrates for the transmembrane multidrug resistance pump P-glycoprotein (P-gp). Experience in oncologyhas suggested that chronic exposure to P-gp substrates induces upregulation of P-gp activity, which could result in resistance to immunosuppressive drugs. The authors investigated P-gp function in CD4+ and CD8+ T cells from the peripheral blood of solid organ transplant recipients (SOTX). Subjects included 14 stable SOTX (10 liver, 4 lung) and 16 healthy controls. Four-color flow cytometry was used to simultaneously measure intracellular concentration of the fluorescent P-gp substrate Rhodamine 123 (Rh123) and surface expression of CD45RO (nominal memory/effector), CD45RA (naive), and either CD4 or CD8. P-glycoprotein function was measured by a dye efflux assay in which activity was inferred from a decrease in Rh123 fluorescence. CD4+ and CD8+ T cells from patients and control subjects eliminated Rh123, and this activity was inhibited by verapamil, a known P-gp substrate. CD8+ T cells had greater P-gp activity than CD4+ cells, and naive and transitional T cells displayed greater activity than memory T cells. Activity was bimodal in CD8+ CD45RO+ T cells, with a subset of these cells expressing the greatest P-gp activity. Patient CD8+ naive and transitional T cells had upregulated P-gp activity compared to control subjects. We conclude that (1) P-gp activityis significantly upregulated in specific T-cell subsets (CD8+/CD45RA+) in the peripheral blood of SOTX, and (2) the bimodal nature of P-gp response in CD8+ T cells complicates analysis of the effect of chronic administration of P-gp substrates to SOTX.

Pharmacokinetics of FK506 in liver transplant recipients after continuous intravenous infusion.

The first-dose pharmacokinetics of FK506 was studied in nine orthotopic liver transplant patients receiving continuous intravenous infusion of 0.15 mg/kg/day. Multiple blood samples were obtained during the infusion and plasma FK506 concentrations were measured by enzyme-linked immunosorbent assay. The plasma clearance ranged from 0.47 to 5.8 L/minute, and the half-life ranged from 4.5 hours to 33.1 hours. These results indicate the pharmacokinetics of FK506 to be highly variable between patients. FK506 is extensively distributed outside the plasma compartment. FK506 is extensively metabolized in the body, with less than 1% of the administered dose being excreted in the urine as unchanged FK506. The large variability in FK506 kinetics during the immediate post-operative period is attributed to the variability in the functional status of the liver in the transplant patients. Because of the long half-life of FK506, it takes more than 45 hours to reach steady-state concentrations after continuous infusion. Based on the estimated kinetic parameters, it appears that a combination of a bolus or a rapid infusion of .02 mg/kg with a continuous infusion of 0.05 mg/kg/day will provide and maintain a concentration of more than 2 ng/mL from the beginning of the drug treatment.

Primary angiosarcoma of the spleen: a diagnosis to consider.

We discuss a case of angiosarcoma of the spleen. Splenomegaly was discovered on a routine examination. At a later date it increased further in size and became painful. Peripheral smear and radio-isotope scannings suggested non-functioning spleen with haemorrhage within the tumour. Characteristic features of microangiopathic haemolysis, suggested in previous reports, was not found in our case.

Staghorn calculus in a renal allograft.

A case of staghorn calculus in a transplanted kidney associated with tertiary hyperparathyroidism in the presence of infection has been described. Possible mechanisms of pathophysiology have been discussed.

Incidence and treatment of rejection episodes in primary orthotopic liver transplantation under FK 506.

FK 506 therapy with low doses of steroids was adequate to control rejection in most liver recipients. Rejection episodes were readily reversed with single IV doses of methylprednisone or hydrocortisone. Short courses of OKT3 (3 to 5 days 5-10 mL) controlled severe rejections. The rate of retransplantation directly due to rejection was low (1.6%). There was a limited need for steroids either early or out to 6 to 12 months.