Timothy C. Lee

Quantitative EBV viral loads and immunosuppression alterations can decrease PTLD incidence in pediatric liver transplant recipients

Epstein–Barr virus (EBV) is a common viral infection in pediatric liver transplant patients and can lead to development of post‐transplant lymphoproliferative disorder (PTLD). Differing studies have used immunosuppression reduction, antiviral medications or i.v. CMV‐immunogloublin for EBV prevention and treatment. The purpose of this study was to determine whether implementation of a protocol for frequent EBV monitoring and EBV viral load‐driven immunosuppression reduction could decrease the incidence of PTLD in our patient population. All data were prospectively collected between 2001 and 2004 at a single institution. Seventy‐three patients were entered into the study. Patients were divided into a historical control group (pre‐2001, 30 patients) and a treatment group (post‐2001, 43 patients). Approximately 1271 blood samples of 73 patients were collected between 2001 and 2004. Eleven out of 43 patients received immunosuppression tapering due to high EBV viral loads (>4000 copies/μg DNA). One patient developed allograft rejection after immunosuppression modulation. Prior to 2001, the incidence of PTLD at our institution was 16%. After instituting a protocol for EBV monitoring, the incidence of PTLD decreased to 2% (p‐value < 0.05). These findings illustrate that frequent EBV viral load monitoring and preemptive immunosuppression modulation have an integral role in preventing PTLD in the pediatric liver transplant population.

Fontan operation in the current era: a 15-year single institution experience.

Objective:Evaluate current risk factors for mortality and morbidity in patients undergoing the Fontan procedure at a single institution in the current era. Summary Background Data:An emphasis on early relief of volume and pressure overload culminating in the Fontan procedure has improved patient outcomes for patients with a single ventricle. Methods:A cross-sectional retrospective study was performed for 636 primary Fontan procedures between July 1992 and June 2007. Results:Anatomy included left ventricular hypoplasia in 64% and right ventricular hypoplasia in 36%. A lateral tunnel (LT) was performed in 92% and an extracardiac conduit (EC) in 8%. Hospital survival was 96%. Long-term survival was 97% at a mean follow-up of 50 months (range, 0–173 months). Ventricular anatomy and preoperative hemodynamics did not predict early or late survival. Longer aortic cross clamp (XC) time was associated with decreased late survival (P = 0.01). Fontan takedown was required in 3% and protein-losing enteropathy (PLE) developed in 6%. At follow-up, 98% of patients were either NYHA class I or II and 87% were in normal sinus rhythm. Patients with chest tube drainage >2 weeks had an increased risk of PLE (P < 0.0001) and diminished short- and long-term survival (P = 0.026 and P < 0.0001, respectively). Conclusions:The Fontan procedure can be performed with low risk regardless of ventricular anatomy. Duration of XC time is associated with survival. Prolonged CT drainage correlates with late PLE and diminished survival. There was a low prevalence of late rhythm disturbances and other complications.

Biocompatibility of electroactive polymers in tissues

The biocompatibility of ethylene-vinyl acetate copolymer (EVAc), polyethylene (PE), and polyaniline (PANi) films in the emeraldine (EM), nigraniline (NA) and leucoemeraldine (LM) intrinsic oxidation states were assessed through subcutaneous implantation into male Sprague-Dawley rats beneath the dorsal skin, for a period ranging from 19 to 90 weeks. Histological examination, interstitial pressure measurement, and X-ray photoelectron spectroscopy (XPS) were employed to determine the biocompatibility of the polymers. The polymers did not provoke inflammatory responses in the subcutaneous tissues over the entire implantation period. Characteristics features associated with tissue-implant incompatibility were not evident near the implantation. Interstitial pressure was measured to evaluate the development of tissue. Low interstitial pressure readings on the region of implantation confirmed the biocompatibility of these polymer types. The surface composition of the electroactive aniline polymers before and after the implantation was characterized by XPS.

The delivery of BCNU to brain tumors.

This paper reports the development of three-dimensional simulations to study the effect of various factors on the delivery of 1-3-bis(2-chloroethyl)-1-nitrosourea (BCNU) to brain tumors. The study yields information on the efficacy of various delivery methods, and the optimal location of polymer implantation. Two types of drug deliveries, namely, systemic administration and controlled release from polymers, were simulated using fluid dynamics analysis package (FIDAP) to predict the temporal and spatial variation of drug distribution. Polymer-based delivery provides higher mean concentration, longer BCNU exposure time and reduced systemic toxicity than bolus injection. Polymer implanted in the core gives higher concentration of drug in both the core and viable zone than the polymer in the viable zone case. The penetration depth of BCNU is very short. This is because BCNU can get drained out of the system before diffusing to any appreciable distance. Since transvascular permeation is the dominant means of BCNU delivery, the interstitial convection has minor effect because of the extremely small transvascular Peclet number. The reaction of BCNU with brain tissues reduces the drug concentration in all regions and its effect increases with rate constant. The implantation of BCNU/ethylene-vinyl acetate copolymer (EVAc) matrix at the lumen of the viable zone immediately following the surgical removal of 80% of the tumor may be an effective treatment for the chemotherapy of brain tumors. The present study provides a quantitative examination on the working principle of Gliadel wafer for the treatment of brain tumors.

Cellular immunity to Epstein-Barr virus in liver transplant recipients treated with Rituximab for post-transplant lymphoproliferative disease

The evaluation of long‐term cellular immunity to EBV in pediatric orthotopic liver transplant (OLT) recipients after treatment with the humanized anti‐CD20 monoclonal antibody (Rituximab) has not yet been explored. At our institution, one child with EBV‐related mononucleosis‐like syndrome and five children with polymorphic‐EBV‐PTLD occurring 6–88 months after OLT were treated with Rituximab. Treatment was well tolerated. All children achieved complete remission. After Rituximab, B‐lymphocytes were undetectable in the peripheral blood and EBV‐load, monitored with real‐time PCR, decreased to undetectable levels in all children from >4000 copies/μg DNA at diagnosis. Four to eight months after Rituximab, EBV‐load increased (>4000 copies/μg DNA) in four children, and PTLD recurred in three. Their frequency of EBV‐specific T‐cell precursors, measured by Elispot analysis, remained lower than in healthy controls. Rituximab effectively induced regression of PTLD in OLT recipients. However, EBV‐specific T‐cell immunocompetence, which may be crucial for the long‐term control of EBV‐mediated proliferation, did not improve.

Orthotopic liver transplantation for biliary atresia: The U.S. experience

Biliary atresia is the most common indication for orthotopic liver transplantation (OLT) in the pediatric population. The outcomes of liver transplantation for biliary atresia, however, have not been formally examined on a national scale. The objective of this study was to identify pretransplant variables that predict patient survival after primary liver transplantation for biliary atresia. A cohort of 1,976 pediatric patients undergoing primary liver transplantation for biliary atresia between 1/1988 to 12/2003 was enrolled from the United Network for Organ Sharing database after excluding patients with a history of multiorgan transplant or previous liver transplant. Follow‐up data up to 16 years post‐OLT was available. The 5‐ and 10‐year actuarial survival rates of patients that underwent liver transplantation for biliary atresia in the United States are 87.2% and 85.8%, respectively, and the 5‐ and 10‐year graft actuarial survival rates are 76.2% and 72.7%, respectively. Early deaths (≤90 days post‐OLT) were more often caused by graft failure (P = 0.01), whereas late deaths (>90 days post‐OLT) were more often due to malignancy (P < 0.01). An analysis of outcomes over time demonstrated a decrease in post‐OLT survival and an increase in the number of OLTs done for biliary atresia at an increasing number of centers. A multivariate analysis revealed that cadaveric partial/reduced liver grafts, a history of life support at the time of OLT, and decreased age were independent predictors of increased post‐OLT mortality. In conclusion, OLT is an effective treatment for biliary atresia. Certain pretransplant variables may help predict patient survival following liver transplantation for biliary atresia. (Liver Transpl 2005;11:1193–1200.)

Painting blood vessels and atherosclerotic plaques with an adhesive drug depot

The treatment of diseased vasculature remains challenging, in part because of the difficulty in implanting drug-eluting devices without subjecting vessels to damaging mechanical forces. Implanting materials using adhesive forces could overcome this challenge, but materials have previously not been shown to durably adhere to intact endothelium under blood flow. Marine mussels secrete strong underwater adhesives that have been mimicked in synthetic systems. Here we develop a drug-eluting bioadhesive gel that can be locally and durably glued onto the inside surface of blood vessels. In a mouse model of atherosclerosis, inflamed plaques treated with steroid-eluting adhesive gels had reduced macrophage content and developed protective fibrous caps covering the plaque core. Treatment also lowered plasma cytokine levels and biomarkers of inflammation in the plaque. The drug-eluting devices developed here provide a general strategy for implanting therapeutics in the vasculature using adhesive forces and could potentially be used to stabilize rupture-prone plaques.

Population pharmacokinetics of intravenous caffeine in neonates with apnea of prematurity

To study the population pharmacokinetics of caffeine after intravenous administration to premature infants with apnea.

Population Pharmacokinetic Modeling in Very Premature Infants Receiving Midazolam during Mechanical Ventilation: Midazolam Neonatal Pharmacokinetics

BACKGROUND Midazolam is used widely as a sedative to facilitate mechanical ventilation. This prospective study investigated the population pharmacokinetics of midazolam in very premature infants. METHODS Midazolam (100 microg/kg) was administered as a rapid intravenous bolus dose every 4-6 h to 60 very premature neonates with a mean (range) gestational age of 27 weeks (24-31 weeks), a birth weight of 965 g (523-1,470 g), and an age of 4.5 days (2-15 days). A median (range) of four (one to four) blood samples, 0.2 ml each, were drawn at random times after the first dose or during continuous treatment, and concentrations of midazolam in serum were assayed by high-performance liquid chromatography. A population analysis was conducted using a two-compartment pharmacokinetic model using the NONMEM program. RESULTS Average parameter values (interpatient percent coefficient of variation) for infants with birth weights 1,000 g or less were total systemic clearance (Cl(T)) = 0.783 ml/min (83%), intercompartmental clearance (Cl(Q)) = 6.53 ml/min (116%), volume of distribution of the central compartment (V1) = 473 ml (70%), and volume of distribution of the peripheral compartment (V2) = 513 ml (146%). For infants with birth weights more than 1,000 g they were as follows: Cl(T) = 1.24 ml/min (78%), Cl(Q) = 9.82 ml/min (98%), V1 = 823 ml (43%), and V2 = 1,040 ml (193%). The intrapatient variability (percent coefficient of variation) in the data was 4.5% at the mean concentration midazolam in serum of 121 ng/mL. CONCLUSIONS Serum concentration-time data were used in modeling the population pharmacokinetics of midazolam in very premature, ventilated neonates. Clearance of midazolam was markedly decreased compared with previous data from term infants and older patients. Infants weighing less than 1,000 g at birth had significantly lower clearance than those weighing more than 1,000 g.

Risk stratification of adult patients undergoing orthotopic liver transplantation for fulminant hepatic failure.

Background. Orthotopic liver transplantation (OLT) is an effective treatment for fulminant hepatic failure (FHF), but postOLT mortality is higher for patients with FHF than for patients with other indications for OLT. In the current study, a large cohort of patients who underwent OLT for FHF was evaluated to develop and validate a system useful for estimating postOLT patient survival. Methods. The 1,457 patients who underwent OLT for FHF in the United States between 1988 and 2003 were enrolled through the UNOS database. This group was divided into a modeling group (n=972) and a crossvalidation group (n=486). With a multivariate regression analysis, the modeling group was used to identify clinical parameters that had a significant association with postOLT survival. This regression analysis was used to create a scoring system that was subsequently assessed in the crossvalidation group. Results. Four risk factors were identified with the multivariate analysis: 1) body mass index ≥30 kg/m2; 2) serum creatinine >2.0 mg/dL; 3) recipient age >50 years old; and 4) history of life support. By assigning points based on the number of risk factors present, the scoring system was able to differentiate between low-risk patients (5-year survival, 81%) and high-risk patients (5-year survival, 42%). The relative risk of postOLT mortality increased by approximately 150% for each additional point. Conclusion. The scoring system risk-stratified the crossvalidation group and accurately predicted postOLT survival. A scoring system utilizing clinical and demographic information readily available prior to OLT may help predict the probability of survival after OLT for FHF.