Prediction of key milk biomarkers in dairy cows through milk mid-infrared spectra and international collaborations.

At the individual cow level, suboptimum fertility, mastitis, negative energy balance, and ketosis are major issues in dairy farming. These problems are widespread on dairy farms and have an important economic impact. The objectives of this study were (1) to assess the potential of milk mid-infrared (MIR) spectra to predict key biomarkers of energy deficit (citrate, isocitrate, glucose-6 phosphate [glucose-6P], free glucose), ketosis (ß-hydroxybutyrate [BHB] and acetone), mastitis (N-acetyl-ß-d-glucosaminidase activity [NAGase] and lactate dehydrogenase), and fertility (progesterone); (2) to test alternative methodologies to partial least squares (PLS) regression to better account for the specific asymmetric distribution of the biomarkers; and (3) to create robust models by merging large datasets from 5 international or national projects. Benefiting from this international collaboration, the dataset comprised a total of 9,143 milk samples from 3,758 cows located in 589 herds across 10 countries and represented 7 breeds. The samples were analyzed by reference chemistry for biomarker contents, whereas the MIR analyses were performed on 30 instruments from different models and brands, with spectra harmonized into a common format. Four quantitative methodologies were evaluated to address the strongly skewed distribution of some biomarkers. Partial least squares regression was used as the reference basis, and compared with a random modification of distribution associated with PLS (random-downsampling-PLS), an optimized modification of distribution associated with PLS (KennardStone-downsampling-PLS), and support vector machine (SVM). When the ability of MIR to predict biomarkers was too low for quantification, different qualitative methodologies were tested to discriminate low versus high values of biomarkers. For each biomarker, 20% of the herds were randomly removed within all countries to be used as the validation dataset. The remaining 80% of herds were used as the calibration dataset. In calibration, the 3 alternative methodologies outperform the PLS performances for the majority of biomarkers. However, in the external herd validation, PLS provided the best results for isocitrate, glucose-6P, free glucose, and lactate dehydrogenase (coefficient of determination in external herd validation [R2v] = 0.48, 0.58, 0.28, and 0.24, respectively). For other molecules, PLS-random-downsampling and PLS-KennardStone-downsampling outperformed PLS in the majority of cases, but the best results were provided by SVM for citrate, BHB, acetone, NAGase, and progesterone (R2v = 0.94, 0.58, 0.76, 0.68, and 0.15, respectively). Hence, PLS and SVM based on the entire dataset provided the best results for normal and skewed distributions, respectively. Complementary to the quantitative methods, the qualitative discriminant models enabled the discrimination of high and low values for BHB, acetone, and NAGase with a global accuracy around 90%, and glucose-6P with an accuracy of 83%. In conclusion, MIR spectra of milk can enable quantitative screening of citrate as a biomarker of energy deficit and discrimination of low and high values of BHB, acetone, and NAGase, as biomarkers of ketosis and mastitis. Finally, progesterone could not be predicted with sufficient accuracy from milk MIR spectra to be further considered. Consequently, MIR spectrometry can bring valuable information regarding the occurrence of energy deficit, ketosis, and mastitis in dairy cows, which in turn have major influences on their fertility and survival.

Teaching humanitarian surgery: Filling the gap between NGO needs and subspecialized surgery through a novel inter-university certificate.

Background: Access to surgical care is a global health burden. A broad spectrum of surgical competences is required in the humanitarian context whereas current occidental surgical training is oriented towards subspecialties. We proposed to design a course addressing the specificities of surgery in the humanitarian setting and austere environment.Method: The novelty of the course lies in the implication of academic medical doctors alongside with surgeons working for humanitarian non-governmental organizations (NGO). The medical component of the National Defense participated regarding particular topics of war surgery. The course is aimed at trained surgeons and senior residents interested in participating to humanitarian missions.Results: The program includes theoretical teaching on surgical knowledge and skills applied to the austere context. The course also covers non-medical aspects of humanitarian action such as international humanitarian law, logistics, disaster management and psychological support. It comprises a large-scale mass casualty exercise and a practical skills lab on surgical techniques, ultrasonography and resuscitation. Attendance to the four teaching modules, ATLS certification and succeeding final examinations provide an interuniversity certificate.30 participants originating from 11 different countries joined the course. Various surgical backgrounds, training levels as well as humanitarian experience were represented.Feedback from the participants was solicited after each teaching module and remarks were applied to the following session. Overall participant evaluations of the first course session are presented.Conclusion: Teaching humanitarian surgery joining academic and field actors seems to allow filling the gap between high-income country surgical practice and the needs of the humanitarian context.

Development of Fourier transform mid-infrared calibrations to predict acetone, ß-hydroxybutyrate, and citrate contents in bovine milk through a European dairy network.

To manage negative energy balance and ketosis in dairy farms, rapid and cost-effective detection is needed. Among the milk biomarkers that could be useful for this purpose, acetone and ß-hydroxybutyrate (BHB) have been proved as molecules of interest regarding ketosis and citrate was recently identified as an early indicator of negative energy balance. Because Fourier transform mid-infrared spectrometry can provide rapid and cost-effective predictions of milk composition, the objective of this study was to evaluate the ability of this technology to predict these biomarkers in milk. Milk samples were collected in commercial and experimental farms in Luxembourg, France, and Germany. Acetone, BHB, and citrate contents were determined by flow injection analysis. Milk mid-infrared spectra were recorded and standardized for all samples. After edits, a total of 548 samples were used in the calibration and validation data sets for acetone, 558 for BHB, and 506 for citrate. Acetone content ranged from 0.020 to 3.355mmol/L with an average of 0.103mmol/L; BHB content ranged from 0.045 to 1.596mmol/L with an average of 0.215mmol/L; and citrate content ranged from 3.88 to 16.12mmol/L with an average of 9.04mmol/L. Acetone and BHB contents were log-transformed and a part of the samples with low values was randomly excluded to approach a normal distribution. The 3 edited data sets were then randomly divided into a calibration data set (3/4 of the samples) and a validation data set (1/4 of the samples). Prediction equations were developed using partial least square regression. The coefficient of determination (R(2)) of cross-validation was 0.73 for acetone, 0.71 for BHB, and 0.90 for citrate with root mean square error of 0.248, 0.109, and 0.70mmol/L, respectively. Finally, the external validation was performed and R(2) obtained were 0.67 for acetone, 0.63 for BHB, and 0.86 for citrate, with respective root mean square error of validation of 0.196, 0.083, and 0.76mmol/L. Although the practical usefulness of the equations developed should be further verified with other field data, results from this study demonstrated the potential of Fourier transform mid-infrared spectrometry to predict citrate content with good accuracy and to supply indicative contents of BHB and acetone in milk, thereby providing rapid and cost-effective tools to manage ketosis and negative energy balance in dairy farms.

Dynamics of allograft fibrosis in pediatric liver transplantation.

Progressive liver allograft fibrosis (LAF) is well known to occur long term, as shown by its high prevalence in late posttransplant liver biopsies (LBs). To evaluate the influence of clinical variables and immunosuppression on LAF progression, LAF dynamic was assessed in 54 pediatric liver transplantation (LT) recipients at 6 months, 3 and 7 years post-LT, reviewing clinical, biochemical data and protocol LBs using METAVIR and the liver allograft fibrosis score, previously designed and validated specifically for LAF assessment. Scoring evaluations were correlated with fibrosis quantification by morphometric analysis. Progressive LAF was found in 74% of long-term patients, 70% of whom had unaltered liver enzymes. Deceased grafts showed more fibrosis than living-related grafts (p = 0.0001). Portal fibrosis was observed in correlation with prolonged ischemia time, deceased grafts and lymphoproliferative disease (p = 0.001, 0.006 and 0.012, respectively). Sinusoidal fibrosis was correlated with biliary complications (p = 0.01). Centrilobular fibrosis was associated with vascular complications (p = 0.044), positive autoantibodies (p = 0.017) and high gamma-globulins levels (p = 0.028). Steroid therapy was not associated with reduced fibrosis (p = 0.83). LAF could be viewed as a dynamic process with mostly progression along the time. Peri- and post-LT-associated factors may condition fibrosis development in a specific area of the liver parenchyma.

Population pharmacokinetic analysis of tacrolimus in the first year after pediatric liver transplantation.

PURPOSES: Tacrolimus (TAC) is the most widely used immunosuppressant for the prevention of acute rejection after solid organ transplantation. Its pharmacokinetics (PK) show considerable variability, making TAC a good candidate for therapeutic drug monitoring (TDM). The principal aim of the study was to describe the PK of TAC in pediatric patients during the first year after transplantation. METHODS: Routine TDM trough levels of TAC were obtained from 42 pediatric liver allograft recipients during the first year after transplantation. A population PK model was developed using nonlinear mixed-effects modeling to describe TAC PK during this period and to explain the observed variability by means of patients' demographics, biochemical test results and physiological characteristics. RESULTS: The PK of TAC were best described by a two-compartment model with first-order elimination. Apparent volumes of the central compartment, intercomparmental clearance and maximum blood clearance estimates were 253 L, 115 L/day and 314 L/day, respectively. The absorption first-order rate and volume of peripheral compartment were fixed to 4.5 h(-1) and 100 L, respectively. While hematocrit levels, time after transplantation and bodyweight influenced TAC clearance, bodyweight was the only covariate retained on volume of distribution. CONCLUSIONS: We developed a TAC population PK model in pediatrics covering the first year after liver transplantation that may serve as a tool for TAC dose individualization as part of TDM.

Acquired antithrombin type IIb deficiency after liver transplantation: a case report.

A 3-year-old girl with multifocal hepatoblastoma was referred to our clinic for living-donor liver transplantation, the patient's father being the donor. Pretransplant evaluation revealed that the father presented partial asymptomatic antithrombin (AT) deficiency, with no inherited AT deficiency found in the girl. The genetic testing showed an AT type IIb deficiency responsible for a defect in the heparin-binding region of AT which is less thrombogenic but more common than the other AT qualitative defects. Her mother was ABO incompatible. Despite the thrombophilia on the father's side, transplantation was successfully performed under replacement therapy with intravenous AT concentrate and low-molecular-weight heparin thromboprophylaxis given to both the recipient and the donor. No thrombotic complications occurred. In the posttransplantation course, acquired partial AT deficiency was detected in the recipient, who received adjuvant chemotherapy without thrombotic complications. This case report highlights the relevance of full thrombophilic work-up before liver transplantation from a living donor, while illustrating that the procedure can be successfully performed in the case of AT deficiency on the donor's side provided that appropriate AT supplementation and thromboprophylaxis are administered to both the recipient and the donor.

Novel histologic scoring system for long-term allograft fibrosis after liver transplantation in children.

The existing systems for scoring fibrosis were not developed to evaluate transplanted livers. Our aim was to design and validate a novel fibrosis scoring system specifically adapted to assess liver allograft fibrosis (LAF). Clinical data, histology, transient elastography (TE) and AST/platelet ratio index (APRI) were reviewed in 38 pediatric liver transplant (LT) recipients. Protocol liver biopsies performed at 6 months and 7 years post-LT were reviewed by three pathologists who assessed LAF using the METAVIR and Ishak systems. LAF was also scored separately in portal (0-3), sinusoidal (0-3) and centrolobular areas (0-3). Scoring evaluations were correlated with fibrosis quantification using morphometry, and also with TE and APRI. Statistical correlations between morphometry and METAVIR were 0.571 (p < 0.000) and 0.566 (p < 0.000) for the Ishak system. The novel score (0-9) for separate assessment of portal, sinusoidal and centrolobular fibrosis showed a better correlation with morphometry (0.731; p < 0.000) and high intra-/interobserver agreement (0.966; p < 0.000 and 0.794; p < 0.000, respectively). No correlation was found between TE or APRI and morphometry or the three histologic scores. In conclusion, this novel semiquantitative fibrosis scoring system seems to more accurately reflect LAF than the existing scoring system and may become a practical tool for staging fibrosis in LT.

Living related liver transplant following bone marrow transplantation from same donor: long-term survival without immunosuppression.

We report long-term (seven yr) immunological tolerance in a 16-yr-old boy, to a liver allograft donated by his father following a bone marrow transplant at age 2.5 yr from the same donor. The bone marrow transplant was complicated by severe GVHD leading to liver failure and the ensuing need for a liver transplant, performed under planned avoidance of immunosuppression. At one wk post-transplant, although a liver biopsy was histologically compatible with acute rejection, favorable clinical and biochemical evolution precluded initiating immunosuppressive therapy, thus highlighting the need for caution when interpreting early histological changes so that administration of unnecessary immunosuppression can be avoided. Induction of tolerance in transplant recipients remains an elusive goal. In those patients who had received conventional bone marrow transplants and had endured the consequences of GVHD, development of macrochimerism may allow immunosuppression-free solid organ transplantation from the same donor.

[A ten year university cooperation program in pediatric surgery in Saigon, Vietnam. Lessons and perspectives]. / Dix ans de coopération universitaire en chirurgie pédiatrique a Saigon, Viêt-nam. Des leçons et des perspectives.

A university cooperation in the field of the medico-surgical management of pediatric digestive pathology was set up since 1999 at Children's Hospital no 2 in Saigon, Vietnam. Supported by the Belgian Commission for University Development (CUD), this program focused on postgraduate teaching and research regarding the early detection of neonatal malformations. Replying to a request of Vietnamese health authorities, a pediatric liver transplant program with parental living donors was also launched. Six children were successfully transplanted since 2005, an achievement which required the elaboration of new standards of clinical care in this eight hundred beds pediatric hospital. The direct and indirect improvements promoted through this program should contribute to enhance the overall medico-surgical management of children in this major Southern institution.

Liver transplantation using non-heart-beating donors: Belgian experience.

UNLABELLED: Mortality on liver transplantation (OLT) waiting lists has increased dramatically. Until recently, non-heart-beating donors (NHBD) were not considered suitable for OLT, because of a higher risk of primary graft nonfunction (PNF) and biliary strictures. However, recent experimental/clinical evidence has indicated that NHBD-OLT is feasible when the period of warm ischemia is short. PURPOSE: To characterize the results of NHBD-OLT in Belgium, a survey was sent to all Belgian OLT centers. RESULTS: Between January 2003 and November 2005, 16 livers originating from NHBD were procured and transplanted. The mean donor age was 48.8 years, including 9 males and 7 females with mean time of stop-therapy to cardiac arrest being 18 minutes and from cardiac arrest to liver cold perfusion, 10.5 minutes. Mean recipient age was 52.2 years including 12 males and 4 females. Mean cold ischemia time was 7 hours 15 minutes. No PNF requiring re-OLT was observed. Mean post-OLT peak transaminase was 2209 IU/L, which was higher among imported versus locally procured grafts. Biliary complications occurred in 6 patients requiring re-OLT (n = 2), endoscopic treatment (n = 2), surgical treatment (n = 1), or left untreated (n = 1). These tended to be more frequent after prolonged warm ischemia. Graft and patient survivals were 62.5% and 81.3%, respectively, with a follow-up of 3 to 36 months. CONCLUSION: This survey showed acceptable graft/patient survivals after NHBD-LT. The NHBD-liver grafts suffered a high rate of ischemic injury and biliary complications and therefore should be used carefully, namely with no additional donor risk factors, lower risk recipients, and short cold/warm ischemia.

Progressive Fibrosis Is Driven by Genetic Predisposition, Allo-immunity, and Inflammation in Pediatric Liver Transplant Recipients.

AIM: To determine predisposing factors of idiopathic allograft fibrosis among pediatric liver transplant recipients. BACKGROUND: Protocol biopsies (PB) from stable liver transplant (LT) recipient children frequently exhibit idiopathic fibrosis. The relation between allograft inflammation, humoral immune response and fibrosis is uncertain. Also the role of HLA-DRB1 genotype has not been evaluated, though it's associated with fibrosis in autoimmune hepatitis. PATIENTS AND METHODS: This observational study, included 89 stable LT recipient transplanted between 2004-2012 with mean follow-up of 4.3years, 281 serial PBs (3.1 biopsy/child) and human leukocyte antigen (HLA) antibody data. PBs were taken 1-2, 2-3, 3-5, 5-7, and 7-10years post-LT, and evaluated for inflammation and fibrosis using liver allograft fibrosis score (LAFSc). The evolution of fibrosis, inflammation and related predisposing factors were analysed. FINDINGS: HLA-DRB1*03/04 allele and Class II DSA were significantly associated with portal fibrosis (p=0.03; p=0.03, respectively). Portal inflammation was predisposed by Class II DSA (p=0.02) and non-HLA antibody presence (p=0.01). Non-portal fibrosis wasn't predisposed by inflammation. Lobular inflammation was associated with non-HLA antibodies. INTERPRETATION: We conclusively demonstrated that allograft inflammation results in fibrosis and is associated with post-LT Class II DSA and non-HLA antibodies. The HLA-DRB1*03/04 allele caused genetic predisposition for fibrosis. FUNDING: None.

Evaluation of a new immunoassay to measure sirolimus blood concentrations compared to a tandem mass-spectrometric chromatographic analysis.

A new immunoassay of sirolimus based on the microparticle enzyme immunoassay (MEIA) principle has been developed with collaboration of Abbott Diagnostics. Laboratories and Axis-Shield. Our laboratory evaluated this new assay on 153 whole blood samples (EDTA) drawn from a population of renal (n = 141) and hepatic (n = 12) transplant patients. Each blood sample was analyzed simultaneously by MEIA (Y) and by a reference method (X) used routinely in our laboratory, namely, liquid chromatography tandem mass spectrometry (LC-MS/MS). The statistical analysis of Passing-Bablok produced the following results: Spearman r value = 0.95, slope = 1.15 and intercept with the Y axis = +0.2 ng/mL. The observed global overestimation of 15% compared to the reference method could be explained by the cross-reactivity of sirolimus metabolites with the antibody. A complementary analysis taking into account the transplanted organ (kidney versus hepatic) did not show any significant difference between the populations, most likely owing to the low number of hepatic transplantation samples. The analytical performance of the MEIA method showed CV < or =10% and a limit of quantification of 1.5 ng/mL, which were acceptable for routine clinical monitoring. In conclusion, the MEIA method has shown robust, stable, reproducible, features with an excellent correlation with the reference LC-MS/MS method.

[Contribution to the study of mechanisms of rejection and tolerance in organ transplantation: minimizing immunosuppression as a strategy for graft tolerance in pediatric liver transplantation]]. / Contributions a l'étude des mécanismes de rejet et de tolérance en transplantation d'organes: la minimisation de l'immunosuppression comme stratégie tolérogénique en greffe hépatique pédiatrique.

Basic concepts in transplantation immunology have been recently revisited. Accordingly, the immune response towards an allograft is not anymore considered as necessarily harmful, but could participate, under certain conditions, to graft acceptation through active mechanisms. This novel paradigm was progressively evaluated in clinical liver transplantation, with the aim to minimize the immunosuppressive regimens and, as a first step, to completely withdraw steroids from the immunoprophylactic regimen. The development of laboratory tests to reproducibly assess the immune reactivity of a recipient towards his/her transplanted organ should allow the identification of operationally tolerant patients, and the elective withdrawal of maintenance immunosuppression in this subgroup.

Steroid withdrawal in liver transplantation: benefits, risks, and unanswered questions.

Since the early days of clinical liver transplantation, steroid therapy has constituted the mainstay of maintenance immunosuppression and is still currently combined with cyclosporine or tacrolimus worldwide. Nevertheless, the side effects of long-term steroid administration, particularly diabetes, hypercholesterolemia, arterial hypertension, infections, and bone diseases, including growth retardation in children, have focused the interest on the feasibility of steroid-free immunosuppression. The benefits and the risks of steroid withdrawal (SW) after liver transplantation are overviewed. In adults, early (3 months after transplantation) SW has been validated by several studies, whereas in pediatric recipients, the timing and selection criteria to optimize the risk/benefit ratio of SW still constitute a matter of debate. The identification of the unanswered questions in this field may serve as a framework for future studies to better assess steroid-free immunosuppression after liver transplantation.

Epstein-Barr virus serology and Epstein-Barr virus-associated lymphoproliferative disorders in pediatric liver transplant recipients.

Epstein-Barr virus serology was performed before and after transplantation in 116 patients of a total series of 261 pediatric OLT recipients. Thirty-nine percent had no immunity before OLT, but this percentage decreased to 11.2% at 6 months and 10.5% at 2 years after transplantation. In this series, 10 children developed a B cell lymphoproliferative disease. Four had adenotonsillar involvement, 2 of them with associated digestive tract invasion. Three of these are alive, 2 after retransplantation for chronic rejection subsequent to arrest of immunosuppression. The fourth died from bone marrow aplasia. Three patients with multiorgan involvement died from multisystemic failure. The remaining 3 patients had a pseudotumoral mass. Two of these are alive, 1 after retransplantation for hepatic localization and secondary vascular and biliary complication. The last died from cachexia. Four patients developed the syndrome after viral reactivation, and 6 after primo infection. Four patients were under FK506 rescue therapy. We conclude that a high rate of EBV primo infection is observed in the first months after transplantation. A significant percentage will develop EBV-associated lymphoproliferative disease, which causes death in half of the patients, including all these with multiorgan involvement. Half of the patients may survive, but because immunosuppression must be stopped, retransplantation for chronic rejection is often necessary in survivors.

Impact of innovative techniques on the waiting list and results in pediatric liver transplantation.

The wide application of liver transplantation in children is hampered by the shortage of size-matched pediatric donors; this results in high mortality rate on the waiting list, a long waiting time, worsening of the clinical condition of the waiting patient, deterioration of the overall results, and an increase in the cost. Reduced-size liver transplants have been shown to be a safe way to alleviate the shortage of size-matched organs. We have retrospectively analyzed the impact of the reduced-size liver transplants on the waiting list and the results in a consecutive series of 314 transplants performed in 261 children over an 8-year period (1984-1991). Among these 314 grafts, 160 (51%) were innovative techniques including 86 reduced livers (stricto senso), 66 partial livers (with preservation of the recipient vena cava), and 8 split livers. Such an extensive use of these technical variants allowed a sharp decrease in the waiting list mortality: from 14.9% between 1984 and 1989 to 6.6% in 1990 and 5% in 1991; the corresponding figures for infants registered under the age of 1 year were 25%, 13.3%, and 8.3%, respectively. Results obtained with a full-size graft or a technical variant were similar regarding surgical complications (with a significantly lower incidence of arterial thrombosis for the reduced transplants), graft loss, and patient survival. The 5-year survival of the whole group was 78.1% without any significant difference regarding type of transplant, indications (with the best results: 89.4% 5-year survival obtained in 41 children grafted for metabolic diseases), or age (the 5-year survival was 82.2% for the 41 infants transplanted under the age of 1 year, 78.9% for the 124 children transplanted between 1 and 3 years, and 81.3% for the 96 children transplanted between 6 and 15 years). This series of reduced-size liver transplants, which is the largest worldwide single institutional experience, confirms that the extensive use of reduced transplants in children is safe; this study also shows that innovative techniques, including the split liver, allow a drastic decrease of the waiting list mortality of candidates in the pediatric age range without alterations of the results.

Indications and results of chemotherapy in children with posttransplant lymphoproliferative disease after liver transplantation.

Among 39 posttransplant lymphoproliferative diseases (PTLD) in a cohort of 450 pediatric liver transplant recipients, 3 had a malignant lymphoma, unresponsive to arrest of immunosuppression and to gancyclovir, interferon, and anti-interleukin 6 antibodies. Lymphoma appeared 20, 46, and 96 months posttransplantation and 16, 43, and 90 months after primary Epstein-Barr virus infection. In one case, the patient had histological progression from plasmacytic hyperplasia PTLD, concomitant with symptomatic primary infection, to Burkitt-like lymphoma 43 months later. These three patients received five courses of chemotherapy, after a cyclophosphamide, doxorubicin, vincristine, and prednisone regimen for Burkitt-like or LH 89 scheme for Hodgkin-like PTLDs. Chemotherapy was well tolerated, and all three were free of disease and without immunosuppression 19, 14, and 4 months after chemotherapy. In Burkitt-like or Hodgkin-like PTLDs, immunomodulatory or antiviral drugs were inefficient. Chemotherapy is indicated and can be safely and successfully used. Long-term arrest of immunosuppression seems feasible without graft rejection.

Use of mycophenolate mofetil as rescue therapy after pediatric liver transplantation.

BACKGROUND: Mycophenolate mofetil (MMF) has been increasingly used after liver transplantation (LT) in adults. We report our preliminary experience with MMF as rescue therapy after pediatric LT. METHODS: A total of 19 children received MMF for 21 indications. Median age at LT was 30 months (range 7-149). The median initial oral dose of MMF was 23 mg/kg/day (range 12-43) orally. Median follow-up after initiation of MMF therapy was 642 days (range 229-1606). RESULTS: 1) EFFICACY: MMF was indicated for rejection or insufficient immunosuppression in 16 cases, with normalization of both liver function tests and liver histology in 10 (62%). MMF was successfully used in one patient with post-LT immmune hepatitis and one patient with corticodependence. In three patients with renal function impairment, MMF allowed reduction of cyclosporine A or tacrolimus blood levels, without subsequent rejection. 2) Tolerance: Six patients (32%) experienced eight side effects, mainly gastrointestinal and hematological, which resolved after cessation of MMF in five cases and dose reduction in three. One case of posttransplant lymphoproliferative disease (PTLD) occurred under MMF therapy (5.2%). Four patients had EBV primary infection, while under MMF therapy, without subsequent PTLD. Three patients had CMV primary infection, and five CMV reactivation, under MMF therapy. Seven remained asymptomatic, and one presented with CMV enteritis. CONCLUSIONS: These preliminary results suggest that MMF is an effective and safe immunosuppressant in pediatric LT recipients. Its use is hampered by frequent gastrointestinal and hematological side-effects. MMF does not seem to increase the risk of PTLD nor CMV disease.

Monoclonal antibodies in prophylactic immunosuppression after liver transplantation. A randomized controlled trial comparing OKT3 and anti-IL-2 receptor monoclonal antibody LO-Tact-1.

A prospective trial was conducted to assess the efficacy of induction immunosuppression with antilymphocyte monoclonal antibodies in 129 primary liver transplant patients who were randomly divided into three groups according to immunosuppression during the first 10 days post-OLT: triple drug therapy only (TDIS: cyclosporine, steroids, azathioprine) (group I: n = 42); TDIS with a 10-day course of OKT3 (group II: n = 44); and LO-Tact-1 (anti-IL-2 receptor mAb) (group III: n = 43). Biopsy-proved acute rejection (AR) was treated using the same biopsy-guided protocol in the 3 groups. One-year patient survival rates were 67%, 84%, and 93% in groups I, II, and III, respectively (I vs. II, NS; I vs. III, P = 0.001; II vs. III, P = 0.044). Incidences of AR were studied in the subgroup of 100 patients who were exposed to the risk of developing rejection, with an overall rate of 89% during the first 3 months post-OLT, similar in the 3 groups. However, incidences of steroid-resistant rejection diagnosed during the 10 first days post-OLT were 54%, 24%, and 34% in groups I, II, and III and 46%, 26%, and 11%, respectively, during the 10-90 days interval. Sixteen patients with CMV had received OKT3, whereas the 5 remaining CMV cases had not (P = 0.019). In summary: (1) mAbs did not modify crude incidence of AR; (2) in the early period (< 10 days), TDIS immunoprophylaxis combined with OKT3 was more efficient than TDIS alone; (3) when compared with groups I and II, LO-Tact-1 apparently better prevented steroid-resistant rejection during the 10-90 days post-OLT; (4) OKT3 significantly increased incidence of CMV infection. In conclusion, TDIS with LO-Tact-1 seemed to achieve the better risk-benefit ratio in induction immunosuppression after OLT.