Search

Myelodysplastic syndromes (MDS), a spectrum of heterogeneous hematopoietic stem cell diseases, vary in clinical severity, response to therapy, and propensity toward progression to acute myeloid leukemia. These are acquired clonal disorders resulting from somatic mutations within the hematopoietic stem or progenitor cell population. Understanding the natural history and the risk of developing leukemia and other adverse outcomes is dependent on access to well-annotated biospecimens linked to robust clinical and molecular data. To facilitate the acquisition and distribution of MDS biospecimens to the wider scientific community and support scientific discovery in this disease, the National MDS Natural History study was initiated by the National Heart, Lung, and Blood Institute (NHLBI) and is being conducted in collaboration with community hospitals and academic medical centers supported by the National Cancer Institute (NCI). The study will recruit up to 2000 MDS patients or overlapping myeloproliferative neoplasms (MDS/MPN) and up to 500 cases of idiopathic cytopenia of undetermined significance (ICUS). The National MDS Natural History Study (NCT02775383) will offer the world's largest disease-focused tissue biobank linked to longitudinal clinical and molecular data in MDS. Here, we report on the study design features and describe the vanguard phase of 200 cases. The study assembles a comprehensive clinical database, quality of life results, laboratory data, histopathology slides and images, genetic information, hematopoietic and germline tissues representing high-quality biospecimens and data from diverse centers across the United States. These resources will be available to the scientific community for investigator-initiated research.

Hepatitis C virus (HCV) infection is the leading cause of liver disease in hemophilia patients. In those with human immunodeficiency virus (HIV)/HCV coinfection, the rate of liver disease progression is greater than in HCV monoinfected individuals. Despite antiretroviral therapy, which slows HCV liver disease progression, some require transplantation. Whether transplant outcomes are worse in hemophilic (H) rather than nonhemophilic (NH) candidates is unknown. In order to determine rates and predictors of pretransplant and posttransplant survival, we conducted a retrospective observational study using United Network for Organ Sharing national transplant registry data, comparing HCV+ H and NH candidates. We identified 2502 HCV+ liver transplant candidates from 8 US university-based transplant centers, between January 1, 2004 to December 31, 2010, including 144 HIV+ (6%) and 2358 HIV-; 36 H (1%) and 2466 NH; 1213 (48%) transplanted and 1289 not transplanted. Other than male predominance and younger age, each were P < 0.001. Baseline data were comparable between H and NH. In univariate analysis, 90-day pretransplant mortality was associated with higher baseline Model for End-Stage Liver Disease (MELD; hazard ratio [HR] = 1.15; P < 0.001), lower baseline platelet count (HR = 0.9 per 25,000/µL; P = 0.04), and having HIV/HCV+ hemophilia (P = 0.003). In multivariate analysis, pretransplant mortality was associated with higher MELD (P < 0.001) and was significantly greater in HIV+ than HIV- groups (P = 0.001). However, it did not differ between HIV+ H and NH (HR = 1.7; P = 0.36). Among HIV/HCV+, posttransplant mortality was similar between H and NH, despite lower CD4 in H (P = 0.04). In conclusion, this observational study confirms that hemophilia per se does not have a specific influence on transplant outcomes and that HIV infection increases the risk of mortality in both H and NH patients. Liver Transplantation 23 762-768 2017 AASLD., (© 2016 by the American Association for the Study of Liver Diseases.)

The recombinant ALVAC vaccine coupled with the monomeric gp120/alum protein have decreased the risk of HIV and SIV acquisition. Ab responses to the V1/V2 regions have correlated with a decreased risk of virus acquisition in both humans and macaques. We hypothesized that the breadth and functional profile of Abs induced by an ALVAC/envelope protein regimen could be improved by substituting the monomeric gp120 boost, with the full-length single-chain (FLSC) protein. FLSC is a CD4-gp120 fusion immunogen that exposes cryptic gp120 epitopes to the immune system. We compared the immunogenicity and relative efficiency of an ALVAC-SIV vaccine boosted either with bivalent FLSC proteins or with monomeric gp120 in alum. FLSC was superior to monomeric gp120 in directing Abs to the C3 α2 helix, the V5 loop, and the V3 region that contains the putative CCR5 binding site. In addition, FLSC boosting elicited significantly higher binding Abs to V2 and increased both the Ab-dependent cellular cytotoxicity activity and the breadth of neutralizing Abs. However, the FLSC vaccine regimen demonstrated only a trend in vaccine efficacy, whereas the monomeric gp120 regimen significantly decreased the risk of SIVmac251 acquisition. In both vaccine regimens, anti-V2 Abs correlated with a decreased risk of virus acquisition but differed with regard to systemic or mucosal origin. In the FLSC regimen, serum Abs to V2 correlated, whereas in the monomeric gp120 regimen, V2 Abs in rectal secretions, the site of viral challenge, were associated with efficacy., (Copyright © 2016 by The American Association of Immunologists, Inc.)

A recombinant vaccine containing Aventis Pasteur's canarypox vector (ALVAC)-HIV and gp120 alum decreased the risk of HIV acquisition in the RV144 vaccine trial. The substitution of alum with the more immunogenic MF59 adjuvant is under consideration for the next efficacy human trial. We found here that an ALVAC-simian immunodeficiency virus (SIV) and gp120 alum (ALVAC-SIV + gp120) equivalent vaccine, but not an ALVAC-SIV + gp120 MF59 vaccine, was efficacious in delaying the onset of SIVmac251 in rhesus macaques, despite the higher immunogenicity of the latter adjuvant. Vaccine efficacy was associated with alum-induced, but not with MF59-induced, envelope (Env)-dependent mucosal innate lymphoid cells (ILCs) that produce interleukin (IL)-17, as well as with mucosal IgG to the gp120 variable region 2 (V2) and the expression of 12 genes, ten of which are part of the RAS pathway. The association between RAS activation and vaccine efficacy was also observed in an independent efficacious SIV-vaccine approach. Whether RAS activation, mucosal ILCs and antibodies to V2 are also important hallmarks of HIV-vaccine efficacy in humans will require further studies.

Background: Enterotoxigenic Escherichia coli (ETEC) is a major cause of travellers' diarrhoea. We investigated the efficacy and safety of a skin-patch vaccine containing the pathogen's heat-labile toxin (LT) in a population of travellers to Mexico and Guatemala., Methods: In this phase 3, randomised, double-blind, placebo-controlled field trial, healthy adults (aged 18-64 years) travelling from Germany or the UK to Mexico or Guatemala were assigned in a 1:1 ratio by a dynamic electronic randomisation system to receive transcutaneous immunisation with a patch containing 37.5 μg of ETEC LT or a placebo patch. Participants, site staff, and the investigators who did the analyses were masked to group assignment. Participants were vaccinated before travel, with two patches given 14 days apart. In the destination country, participants tracked stool output in a diary and provided stool samples for pathogen identification if diarrhoea occurred. The primary endpoint was the proportion of participants with at least one episode of moderate-to-severe diarrhoea (defined as four or more unformed stools in a 24 h period) in which either or both ETEC enterotoxins (LT and heat-stable toxin [ST]) were detected. The study is registered at ClinicalTrials.gov, number NCT00993681., Findings: 2036 participants were recruited and randomly assigned between Oct 14, 2009, and Aug 13, 2010, with 1016 allocated to receive the LT patch and 1020 the placebo patch. 821 participants in the LT-patch group and 823 in the placebo group received both vaccinations and were analysed in the per-protocol population. 30 (3.7%, 95% CI 2.5-5.2) participants in the LT-patch group and 46 (5.6%, 4.1-7.4) in the placebo group had moderate or severe ETEC diarrhoea (vaccine efficacy 34.6%, -2.2 to 58.9; p=0.0621). 9333 local (ie, patch-site) adverse events (including erythema, rash, pruritus, hyperpigmentation, pain, hypopigmentation, and oedema) occurred in 943 (93%) of 1015 participants in the LT-patch group, compared with 1444 local adverse events in 574 (56%) of 1019 participants in the placebo group (p<0.0001). Serious adverse events occurred in 25 participants (14 in the LT-patch group and 11 in the placebo group), with all regarded as either unrelated or possibly related to treatment. Vaccine-induced hyperpigmentation persisted for at least 180 days after vaccination in 150 (18%) of the 849 participants who received both vaccinations and returned for final assessment in the LT-patch group, compared with none of the 842 participants in the placebo group. The vaccine was immunogenic, with a post-vaccination geometric mean titre of LT-specific serum immunoglobulin G of 3400.29, compared with 315.41 in the placebo group., Interpretation: Although the LT antigen was delivered effectively by the skin patch, the vaccine did not protect travellers against diarrhoea caused by ETEC or other organisms. Future vaccines against travellers' diarrhoea might need to include several antigens against various diarrhoeal pathogens, and might need to be able to generate mucosal and higher systemic immunity., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Hepatitis C virus (HCV) is a controversial indication for liver transplantation (LT) in human immunodeficiency virus (HIV)-infected patients because of reportedly poor outcomes. This prospective, multicenter US cohort study compared patient and graft survival for 89 HCV/HIV-coinfected patients and 2 control groups: 235 HCV-monoinfected LT controls and all US transplant recipients who were 65 years old or older. The 3-year patient and graft survival rates were 60% [95% confidence interval (CI) = 47%-71%] and 53% (95% CI = 40%-64%) for the HCV/HIV patients and 79% (95% CI = 72%-84%) and 74% (95% CI = 66%-79%) for the HCV-infected recipients (P < 0.001 for both), and HIV infection was the only factor significantly associated with reduced patient and graft survival. Among the HCV/HIV patients, older donor age [hazard ratio (HR) = 1.3 per decade], combined kidney-liver transplantation (HR = 3.8), an anti-HCV-positive donor (HR = 2.5), and a body mass index < 21 kg/m(2) (HR = 3.2) were independent predictors of graft loss. For the patients without the last 3 factors, the patient and graft survival rates were similar to those for US LT recipients. The 3-year incidence of treated acute rejection was 1.6-fold higher for the HCV/HIV patients versus the HCV patients (39% versus 24%, log rank P = 0.02), but the cumulative rates of severe HCV disease at 3 years were not significantly different (29% versus 23%, P = 0.21). In conclusion, patient and graft survival rates are lower for HCV/HIV-coinfected LT patients versus HCV-monoinfected LT patients. Importantly, the rates of treated acute rejection (but not the rates of HCV disease severity) are significantly higher for HCV/HIV-coinfected recipients versus HCV-infected recipients. Our results indicate that HCV per se is not a contraindication to LT in HIV patients, but recipient and donor selection and the management of acute rejection strongly influence outcomes., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Post-transplant lymphoproliferative disorder (PTLD) has been associated with high mortality, but recent anecdotal survival appeared better. From 1988 to 2010, the NAPRTCS registry had 235 registered PTLD cases. We sent a special 25-point questionnaire study to the NAPRTCS centers with the most recent 150 cases to obtain additional follow-up data not collected in the master registry, our objective being to determine the recent outcomes after PTLD and determine prognostic factors. We received 92 completed responses, in which only 12 (13%) deaths were reported, 2 from nonmedical causes, 10 with a functioning graft. Kaplan-Meier-calculated patient survival was 90.6% at 1 year and 87.4% at 3, 4 and 5 years post-PTLD. Graft survival post-PTLD was 81.8% at 1 year, 68.0% at 3 years and 65.0% at 5 years. Seven patients received a retransplant after PTLD, with no PTLD recurrence reported. Using all 235 PTLD cases, the covariates associated with better patient survival were more recent year of PTLD diagnosis (adjusted hazard ratio AHR 0.86, p < 0.001), and with worse survival were late PTLD (AHR 1.98, p = 0.0176) and patient age above 13 at PTLD (AHR 3.43, p value 0.022). In children with kidney transplants, patient survival has improved with more recent PTLDs., (©2011 The Authors Journal compilation©2011 The American Society of Transplantation and the American Society of Transplant Surgeons.)

NAPRTCS data were analyzed to assess outcome of TX recipients from YDs (<5 yr) in comparison with IDs (6-35 yr) and ODs (36-55 yr). Of 9854 TX in NAPRTCS (1987-2003), 469 were YD. Patient survival (PS) and graft survival (GS) were compared between DD TX after 1995; 81YD, 1324 ID, and 429 OD and eGFR were compared among functioning grafts (YD 31, ID 439, OD 174) at three yr. PS was comparable in all groups; GS at one, two, and three yr in TX of YD (91.1%, 83.8%, 79.7%), ID (93.5%, 89.7%, 83.6%), and OD (92.2%, 87.2%, 82.4%) was comparable. The eGFR in YD was comparable to ID but better than OD (86.5 vs. 79.7 vs. 67.2 mL/min/1.73 m2, p 0.139 and<0.0003). Primary graft non-function was more frequent in TX from YD than ID and OD (3.7% vs. 0.3 and 0.7%, p=0.004); the incidence of vascular thrombosis was similar. The aforementioned data show that pediatric recipients of YD had equivalent patient and graft survival. Although primary graft non-function was higher, eGFR of functioning grafts was comparable to ID. With further improvements in care, kidneys from YD may present a viable option for transplantation., (© 2010 John Wiley & Sons A/S.)

Background: The outcomes of kidney transplantation and immunosuppression in people infected with human immunodeficiency virus (HIV) are incompletely understood., Methods: We undertook a prospective, nonrandomized trial of kidney transplantation in HIV-infected candidates who had CD4+ T-cell counts of at least 200 per cubic millimeter and undetectable plasma HIV type 1 (HIV-1) RNA levels while being treated with a stable antiretroviral regimen. Post-transplantation management was provided in accordance with study protocols that defined prophylaxis against opportunistic infection, indications for biopsy, and acceptable approaches to immunosuppression, management of rejection, and antiretroviral therapy., Results: Between November 2003 and June 2009, a total of 150 patients underwent kidney transplantation; survivors were followed for a median period of 1.7 years. Patient survival rates (±SD) at 1 year and 3 years were 94.6±2.0% and 88.2±3.8%, respectively, and the corresponding mean graft-survival rates were 90.4% and 73.7%. In general, these rates fall somewhere between those reported in the national database for older kidney-transplant recipients (≥65 years) and those reported for all kidney-transplant recipients. A multivariate proportional-hazards analysis showed that the risk of graft loss was increased among patients treated for rejection (hazard ratio, 2.8; 95% confidence interval [CI], 1.2 to 6.6; P=0.02) and those receiving antithymocyte globulin induction therapy (hazard ratio, 2.5; 95% CI, 1.1 to 5.6; P=0.03); living-donor transplants were protective (hazard ratio, 0.2; 95% CI, 0.04 to 0.8; P=0.02). A higher-than-expected rejection rate was observed, with 1-year and 3-year estimates of 31% (95% CI, 24 to 40) and 41% (95% CI, 32 to 52), respectively. HIV infection remained well controlled, with stable CD4+ T-cell counts and few HIV-associated complications., Conclusions: In this cohort of carefully selected HIV-infected patients, both patient- and graft-survival rates were high at 1 and 3 years, with no increases in complications associated with HIV infection. The unexpectedly high rejection rates are of serious concern and indicate the need for better immunotherapy. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00074386.).

Short-term graft survival has improved in renal transplants without significant effect on long-term graft survival. As GFR decline precedes graft loss, an understanding of variables affecting eGFR after TX may help improve graft survival. NAPRTCS data were analyzed to assess effects of donor, recipient, and other variables on Schwartz eGFR after transplantation. For 8438 children with a functioning graft at day 30, data were censored for children dying with a functioning graft, and those with <3 yr follow-up. Multivariate linear regression and repeated measures analyses identified factors related to eGFR at day 30 after TX and during follow-up. Young, female, non-black, children without ATN and acute rejection in the first 30 days, TX after 1995, those with better eGFR at day 30, and receiving tacrolimus had better long-term eGFR. Transplant from ideal (6-35 yr) donors had best short-term eGFR, young donors (<5 yr) had lower eGFR and poor graft survival. After one yr, eGFR improved in surviving grafts of young donors and matched ideal donors. Acute rejection, BP medications, and hospitalizations in prior six months had negative association with subsequent eGFR. Regardless of variables, eGFR deteriorated with time. Slope of eGFR decline has not changed in the recent era indicating the need for innovative therapies.

rhGH, widely used to optimize linear growth in children with ESRD, also modulates B-cell precursor development and may be associated with malignancy development. To determine if rhGH use in children was associated with higher risk of PTLD, we analyzed retrospectively collected data on children with CRI, on dialysis or with renal transplants in a large multi-center registry of children with ESRD. Of the 194 LPD patients currently listed in the registry, 41 were previously enrolled in the CRI registry and 18/41 (43.9%) used rhGH during their period with CRI. Among CRI patients who later received a transplant, rates of PTLD post-transplant were significantly higher among rhGH users (18/407 or 4.4%) compared to patients who never used rhGH during their CRI follow-up and received a transplant (23/1240 or 1.9%, p = 0.009). After adjusting for the confounders of recipient age (at CRI and at transplant) and transplant era, the use of rhGH pretransplant was associated with a borderline higher risk for PTLD (odds ratio 1.88, 95% CI = 1.00-3.55, p = 0.05). In contrast, use of rhGH during dialysis or post-transplant only was not associated with a higher risk for PTLD. Continued monitoring is recommended.

Improvements in human immunodeficiency virus (HIV)-associated mortality make it difficult to deny transplantation based upon futility. Outcomes in the current management era are unknown. This is a prospective series of liver or kidney transplant recipients with stable HIV disease. Eleven liver and 18 kidney transplant recipients were followed for a median of 3.4 years (IQR [interquartile range] 2.9-4.9). One- and 3-year liver recipients' survival was 91% and 64%, respectively; kidney recipients' survival was 94%. One- and 3-year liver graft survival was 82% and 64%, respectively; kidney graft survival was 83%. Kidney patient and graft survival were similar to the general transplant population, while liver survival was similar to the older population, based on 1999-2004 transplants in the national database. CD4+ T-cell counts and HIV RNA levels were stable; and there were two opportunistic infections (OI). The 1- and 3-year cumulative incidence (95% confidence intervals [CI]) of rejection episodes for kidney recipients was 52% (28-75%) and 70% (48-92%), respectively. Two-thirds of hepatitis C virus (HCV)-infected patients, but no patient with hepatitis B virus (HBV) infection, recurred. Good transplant and HIV-related outcomes among kidney transplant recipients, and reasonable outcomes among liver recipients suggest that transplantation is an option for selected HIV-infected patients cared for at centers with adequate expertise.

This summary of the NAPRTCS 2006 Annual Report of the Transplant Registry highlights the significant impact the registry has had in advancing knowledge in pediatric renal transplantation worldwide. This cooperative group has collected clinical information on children undergoing a renal transplantation since 1987 and now includes over 150 participating medical centers in the USA, Canada, Mexico, and Costa Rica. Currently, the NAPRTCS transplant registry includes information on 9837 renal transplants in 8990 patients (NAPRTCS 2006 Annual Report). Since the first data analysis in 1989, NAPRTCS reports have documented marked improvements in outcome after renal transplantation in addition to identifying factors associated with both favorable and poor outcomes. The registry has served to document and influence practice patterns, clinical outcomes, and changing trends in renal transplantation.

Membranoproliferative glomerulonephritis type II (MPGN II) is an uncommon form of complement-dependent acquired renal disease. Although it has been recognized since the 1970s that MPGN II recurs almost universally in renal transplants, data regarding the long-term consequences of disease recurrence are limited. Therefore, a retrospective comparative analysis of 75 patients with MPGN II contained in the North American Pediatric Renal Transplant Cooperative Study transplantation database was performed. Five-year graft survival for patients with MPGN II was significantly worse (50.0 +/- 7.5%) compared with the database as a whole (74.3 +/- 0.6%; P < 0.001). Living related donor organs had a significantly better 5-yr survival (65.9 +/- 10.7%) compared with cadaveric donor organs (34.1 +/- 9.8%; P = 0.004). The primary cause of graft failure in 11 (14.7%) patients was recurrent disease. Supplemental surveys were obtained on 29 (38%) of 75 patients. Analysis of these data indicated that recurrent disease occurred in 12 (67%) of the 18 patients with posttransplantation biopsies. Although there was no correlation between pretransplantation presentation, pre- or posttransplantation C3 levels, and either disease recurrence or graft failure, there was a strong association between heavy proteinuria and disease recurrence. The presence of glomerular crescents in allograft biopsies had a significant negative correlation with graft survival. At last follow-up, patients with recurrent disease had significantly higher serum creatinine and qualitatively more proteinuria than patients without biopsy-proven disease. These data indicate that recurrent MPGN II has a significant negative impact on renal allograft function and survival.

Acute rejection leading to renal graft failure is more frequent among children. In patients treated with T cell antibody induction, retrospective data from the pediatric registry show a 22% reduction in the risk of graft failure. We conducted a randomized trial (n = 287) using OKT3 mAbs in one (OKT3) arm and intravenous cyclosporine in the other arm (CYS). Maintenance therapy consisted of randomized, double blind Sandimmune or Neoral together with prednisone and either azathioprine (AZA) or mycophenolate mofetil (MMF). Morbidity, mortality, rejection rates and adverse reactions in the two study arms were similar. Through 4 yr, graft failure was 27% in OKT3 and 19% in CYS (p = 0.15). One-year graft survival was 89.1% in OKT3 and 89.2% in CYS (p = .19). In multivariate analysis, OKT3 had a numerically inferior graft survival (RR = 1.4, CI 0.8-2.2, p = 0.22). In OKT3 graft survival was inferior for children aged 6 yr or younger. Our trial demonstrates that the incidence of acute rejection or graft failure in pediatric patients is not improved by OKT3 induction therapy relative to cyclosporine induction.

This study assessed hemodialysis adequacy in pediatric centers. Monthly adequacy data were requested in NAPRTCS enrollees on hemodialysis for at least 6 mo. Data forms were returned for 147 children from 32 centers. Data are presented for the 138 children (57% boys, 45% black) that were dialyzed 3 times/wk, representing 2282 patient-months of follow-up. Pre- and postdialysis BUN levels were reported in all children. Kt/V values were reported in 76 children; however, sufficient data were obtained to calculate Kt/V in 129 children. On average, 14.9 Kt/V and 15.2 urea reduction ratio (URR) values were calculated per child. Aggregate dialysis dose was defined as adequate if Kt/V was >1.2 in at least 75% of calculated Kt/V measures within a subject. Mean +/- SD age was 11.3 +/- 3.7 yr (median, 12.0 yr). Hemodialysis dose was variable within subjects (median CV%: URR 8.2, Kt/V 16.9). Aggregate dialysis dose was adequate in 70% of subjects. Multivariate logistic regression showed male gender (OR, 0.41; 95% CI, 0.16 to 0.98), black race (OR, 0.28; 95% CI, 0.11 to 0.67), larger body surface area (fourth versus first quartile: OR, 0.22; 95% CI, 0.05 to 0.80), and absence of reported Kt/V at the treating center (OR, 0.26; 95% CI, 0.10 to 0.62) were significant predictors of inadequate dialysis dose. Age, renal diagnosis, and center size were not associated with adequacy. Racial and gender disparities in hemodialysis dose existed among children at specialized academic pediatric centers and a substantial proportion received inadequate hemodialysis.

Newer immunosuppressive agents have dramatically reduced the rates of acute graft rejection (AR) over the last decade but may have exacerbated the problem of post-transplant infections (PTI). We analyzed data from the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) to determine the risks of hospitalization from PTI vs. AR in the years 1987-2000. For patients transplanted in 1987, the AR-associated hospitalization rate exceeded the equivalent hospitalization rate for PTI at both early (1-6 months) and later time points (6-24 months). In contrast, for patients transplanted in the year 2000, the PTI-associated hospitalization rate was twice that for AR-associated hospitalization during each time period. During the first two years post-transplant, rates of AR hospitalization trended significantly downwards (p < 0.001) while rates of PTI-associated hospitalization stayed constant. In the 6-24-month time period post-transplant, the risk of bacterial and viral infection-related hospitalization rose significantly from 1987 to 2000 (p < 0.001 for trend by transplant year). We conclude that the causes of hospitalization at all times up to 24 months post-transplant, including the critical early 6 months, have shifted away from AR to PTI.

Tacrolimus (FK506) and mycophenolate mofetil (MMF) have been reported to increase PTLD risk. The NAPRTCS registry database now has several years of data on FK506 and MMF use in pediatric kidney transplantation. We analyzed the data registry to determine if the risk of PTLD was enhanced by the use of MMF or tacrolimus in initial immunosuppression. Data on day 30 therapy in the PTLD group were compared to corresponding data in patients who did not develop PTLD. Data were analyzed using SAS software and a log-rank test for significance. As of October 2000, there were 108 cases of PTLD in 6720 total transplants(1.60%). The use of MMF at day 30 was not a significant risk factor (0. 78% PTLD rate vs. 1.78% in cohort, RR = 1.05, p = 0.89). The relationship of FK506 with PTLD was linked to transplant era, 1987-95 or 1996-2000. In the earlier era, use of FK506 at day 30 was associated with PTLD (seen in 7/15 patients given FK506, RR = 47.7, p < 0.001). However, in the more recent era, there was no such significant association (seen in 3/313 patients given FK506, RR = 1.28, p = 0.692). There have been no cases of PTLD in 197 patients who received both FK506 and MMF at day 30. We conclude that FK506 and MMF use are not currently associated with increased risk of PTLD in pediatric kidney transplants.

Background: The safety and immune tolerance potential of donor marrow infusion with cadaveric source renal transplants was evaluated in a series of non-randomized multicenter pilot trials by the NIH Cooperative Clinical Trials in Transplantation (CCTT) Group., Patients and Methods: Three strategies were tested: (1) immunosuppression with cyclosporin, azathioprine and prednisone with a single post-transplant day 1 infusion of 5 x 107 viable cells/kg, (2) OKT3 induction with triple drug therapy and marrow transfusion on day 1, or (3) same therapy as (2) but with an additional marrow transfusion on day 10-12., Results: Thirty-eight marrow recipients and 35 contemporaneous controls were entered with a mean follow-up of over 5 yr. Graft survival was initially better in the marrow recipients than the controls but was similar after 5 yr. Microchimerism rates were similar for the marrow infusion and control groups throughout the follow-up period, regardless of the immunosuppression strategies., Discussion: Bone marrow infusions were well tolerated by a group of cadaver renal allograft recipients. There were no complications from the infusion(s), no episodes of graft-vs.-host disease (GVHD) and no increase in infections or other complications. There was a trend toward early improved graft survival in marrow recipients. Decreased rejection rates were observed in black recipients.

Chronic rejection accounted for 32% of all graft losses in 7123 pediatric transplants. In a previous study acute, multiple acute and late acute rejections were risk factors for the development of chronic rejection. We postulated that the recent decrease in acute rejections would translate into a lower risk for chronic rejection among patients with recent transplants. We reviewed our data on patients transplanted from 1995 to 2000, and using multivariate analysis and a proportional hazards model developed risk factors for patients whose grafts had failed due to chronic rejection. A late initial rejection increased the risk of chronic rejection graft failure 3.6-fold (p < 0.001), while a second rejection resulted in further increase of 4.2-fold (p < 0.001). Recipients who received less than 5 mg/kg of cyclosporine at 30 days post-transplant had a relative risk (RR) of 1.9 (p = 0.02). Patients transplanted from 1995 to 2000 had a significantly lower risk (RR = 0.54, p < 0.001) of graft failure from chronic rejection than those who received their transplants earlier (1987-94). Since we were able to demonstrate that there is a decreased risk of chronic rejection graft failure in our study cohort, we would conclude that the goal of future transplants should be to minimize acute rejections.

Background: The incidence of renal post transplant diabetes mellitus (PTDM) in adults varies from 3-46%., Methods: We did a retrospective analysis of 1365 children in The North American Pediatric Renal Transplant Cooperative Study with renal transplant (Tx) reported between January 92 and July 1997. PTDM, defined as >2 weeks of insulin therapy after Tx, developed in 36 patients. A control group of 153/1329 non-PTDM patients was selected and matched for age at Tx and primary diagnosis., Results: African-Americans were overrepresented (36.1 vs. 17.6%, P=0.017) and Hispanics were underrepresented (5.6 vs. 26.1%, P=0.019) among cases. Although prednisone dose 30 days post-Tx was higher among cases (0.89 mg/kg/day) versus controls (0.71 mg/kg/day), P=0.019, cyclosporine dose was similar. No differences in prednisone or cyclosporine doses were observed at 6, 12, or 24 months post-Tx. Tacrolimus use in PTDM group was high (45%). The estimated incidence of first acute rejection at 1, 3, and 12 months was higher among cases, 0.41+/-0.08, 0.52+/-0.08, 0.61+/-0.08, compared to controls, 0.23+/-0.02, 0.37+/-0.02, and 47+/-0.02 (P=0.058). Crude graft failure rates of 13.5% (5/36) and 12.4% (19/153) were similar between the two groups, so was the calculated creatinine clearance at 12 and 24 months and post-Tx hospitalization days., Conclusion: PTDM occurs in <3% of children. African-Americans are at higher risk and Hispanics at lower risk for PTDM. Tacrolimus is a significant risk factor for PTDM. Children with PTDM had a higher incidence of acute rejection, but graft survival, kidney function, and hospitalization rates were similar to selected controls.

Historically, higher acute rejection rates, earlier first rejection, and an inability to reverse the rejection characterize pediatric renal transplantation. In recent years, short-term (1-year) graft survival of pediatric renal transplants has steadily improved. To test the hypothesis that these improvements were mediated by changes in acute rejection, we considered the rejection profile of patients who received a renal allograft between 1987 and 1989 (cohort A) and compared it with recipients transplanted between 1997 and 1999 (Cohort B). Cohort A comprised 1469 transplants and cohort B comprised 1189 transplants. Restricting the data to the first year of follow-up, rejection ratios were 1.6 and 0.7, respectively (p < 0.001). Sixty per cent of the later cohort (B) were rejection free at 1 year, compared with 29% for the earlier cohort (A) (p < 0.001). Controlling for donor source, the rejection reversal rate for the later cohort was significantly better than that of the early cohort (p < 0.001). Cumulative distribution of times to first rejection was significantly better for cohort B (p < 0.001). One-year graft survival for cohort B at 94% was significantly better than 80% for cohort A (p < 0.001). We conclude that the improved short-term graft survival is mediated by improvements in the rejection profile in more recently transplanted patients and that this may translate into a better half-life for pediatric renal transplant recipients who received an allograft in the years 1997-99.

Background: Posttransplant lymphoproliferative disorder (PTLD) is an important complication of transplantation. The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) database has documented 56 cases of PTLD, the largest such series to date., Methods: We analyzed the available longitudinal and multicenter data in the NAPRTCS database to evaluate the demographic and therapeutic risk factors and the temporal trends for PTLD in children after renal transplantation., Results: The overall incidence of PTLD was 1.2% of all patients or 298/100,000 posttransplantation years of follow-up. However, this incidence increased from 254/100,000 years between 1987 and 1991 to 395/100,000 years from 1992 onwards. In the same periods, the time to PTLD decreased from a median of 356 days (range 843048) to a median of 190 days (range 42-944). PTLD occurred with greater frequency in white children (P=0.003) and in cadaver donor transplants (P=0.019), but there was no significant predilection for gender, younger children (0-5 years), or primary diagnosis. No significant difference was found in the use of anti-T-cell antibodies or in doses of CsA, azathioprine, or prednisone at 1 month, 6 months, and 1 year. Between 1996 and 1997, 69 patients were initiated with tacrolimus. Eight cases of PTLD were identified in these recipients to date (prevalence rate 11.5%), compared with 46/4084 (1.1%) where cyclosporine was used (P<0.0001)., Conclusions: There is a trend towards increasing incidence and earlier occurrence of PTLD in the pediatric renal transplant population. White race and cadaver donor sources are risk factors not reported before. Continued monitoring of tacrolimus immunosuppression is important.

Background: Because of concerns of increased risk of graft loss with recurrent disease, living donor (LD) transplantation in children with focal segmental glomerulosclerosis (FSGS) has been controversial., Methods: The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) database from January 1987 to January 2000 was examined to determine differences in demographics, treatment, and outcomes in children with FSGS compared with other renal diseases., Results: Data on 6484 children, 752 (11.6%) with FSGS, demonstrated that FSGS patients were more likely to be older and black, and were less likely to receive either pre-emptive or LD transplant (P < 0.001). No differences existed in human lymphocyte antigen (HLA) matching or immunosuppression regimens. Acute tubular necrosis occurred in more FSGS patients following LD (11.8 vs. 4.6%) or cadaveric (CD; 27.9 vs. 16.3%) transplants (P < 0.001). Graft survival was worse for LD FSGS patients (5 years 69%) compared with no FSGS (82%, P < 0.001) and was not significantly different than CD graft survival in the FSGS (60%) and No FSGS groups (67%). The LD to CD ratios of relative risk of graft failure were higher in FSGS patients (test for interaction, P = 0.01). Recurrence of original disease was the only cause of graft failure that differed between groups (P < 0.001). A greater percentage of LD FSGS graft failures was attributed to recurrence (P = 0.06)., Conclusions: The impact of FSGS on graft survival in children is greatest in LD transplants, resulting in loss of expected LD graft survival advantage. The rationale for LD grafts in children with FSGS should be based on factors other than better outcomes typically associated with LD transplantation.

Antibodies generated by candidate HIV-1 vaccines in a phase I clinical trial were assessed for neutralizing activity with a panel of eight well-characterized, genetically diverse clade B primary isolates having an R5 phenotype. The vaccines consisted of one of three different recombinant canarypox vectors expressing membrane-anchored HIV-1(MN)gp120 (ALVAC vCP205, vCP1433, and vCP1452) followed by boosting with a soluble gp160 hybrid consisting of MNgp120 and the majority of gp41 from strain IIIB. Serum samples from a subset of volunteers in each arm of the trial, containing moderate to high titers of neutralizing antibodies to HIV-1 MN, were analyzed. Competition assays with peptides revealed that the majority of neutralizing activity was specific for the MN-V3 loop. Despite MN-specific neutralization titers that sometimes exceeded 1:500, no neutralization of primary isolates was detected and, in some cases, mild infection enhancement was observed. In addition, little or no neutralization of the HIV-1 IIIB heterologous T cell line-adapted strain of virus was detected. These results reinforce the notion that monovalent HIV-1 ENV is a poor immunogen for generating cross-reactive neutralizing antibodies.

An inverse relationship between mortality and center volume has been established for several surgical procedures. Given the distinctiveness of pediatric renal transplantation and the large variation in center volume, investigation for relationships between center volume and graft outcome was pursued using the North American Pediatric Transplant Cooperative Study database. Center volume groups were based on the total number of pediatric transplants reported from 1987 to 1995. Centers reporting > 100, 51-100, or < or = 50 transplants were grouped as high- (n=11), moderate- (n=28), or low-volume (n=65), respectively. Differences between groups included increasing rates of cadaver donor graft thrombosis (2.4%, 4.3%, and 5.7%, P<0.01) and acute tubular necrosis (ATN) (10.2%, 11.5%, and 14.0%, P<0.01) with decreasing center volume. Treatment differences included a higher rate of induction with an anti-T-cell antibody preparation in the larger-volume groups, 60.2%, 51.8%, and 39.2% (P<0.001). Decreasing graft survival for decreasing center size groups was noted at 3 months post transplant, 90.4%, 90.2%, and 88.4%. These differences were significant only with the exclusion of anti-T-cell induction from the proportional hazards model (relative risk=0.81 and =0.70 for the moderate- and high-volume groups, P<0.02). Superior graft survival in the high-volume centers noted at 3 months post transplant appears predominantly the result of lower rates of cadaver donor graft thrombosis and ATN. Analysis points to the need for low-volume centers to identify risk factors influencing these outcomes.

This report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS), covering the years 1987-96 (January 15, 1997), analyzed data on 4898 patients who received 5362 transplants. Over the 10 yr of the study, 21.3% of the patients were under the age of 6 yr. Of the disorders that lead to end-stage renal disease (ESRD), structural and developmental anomalies of aplasia, dysplasia, and obstructive uropathy accounted for over 1500 patients. Despite the potential therapies for focal segmental glomerulosclerosis (FSGS), there has been little change in its incidence and this lesion continues to be the most common cause of renal failure and transplantation among acquired diseases. Eighty-nine per cent of patients with a functioning graft continue to receive cyclosporin A (CsA) 5 yr post-transplantation, and 84% of patients continue to receive azathioprine (AZA), whereas 26% of patients receive alternate-day steroid therapy at 4 yr post-transplant. Thirty-seven per cent of the living donor (LD) recipients and 47% of cadaver donor (CD) recipients were treated with the polyclonal T-cell antibody ATG/ALG for induction, and the monoclonal T-cell antibody, OKT3, was utilized for induction in 12% of LD patients and in 19% of CD patients. Twenty-five per cent of the 5362 transplants (1333) have failed over the 10-yr period. Graft survival is 90% at 1 yr and 74% at 6 yr for LD kidneys, and is 80% at 1 yr and 58% at 6 yr for CD patients. The most common cause for graft failure (30%) is chronic rejection. For recipients of LD grafts, relative risk (RR) factors for graft survival are African-American race (RR = 2.1, p < 0.001) and greater than five prior transfusions (RR = 1.6, p < 0.001). Prophylactic anti-T-cell antibody reduces the risk of graft failure (RR = 0.76, p = 0.009). For recipients of cadaver kidneys, risk factors are: recipient age < 2 yr (RR = 2, p < 0.001), donor age < 6 yr (RR = 1.3, p = 0.005), and absence of induction T-cell antibody (RR = 1.31, p < 0.001).

This report of pediatric renal transplantation covers the years 1987-1998. Since its inception in 1987, the NAPRTCS has collected data on 6,038 transplants performed in 5,516 patients provided by 73 renal centers across the country. FSGS, together with developmental lesions of dysplasia and obstructive uropathy, account for 40% of all transplants. There has been a steady increase in the use of LD donors among children with 54% of all transplants in 1996 and 1997 being live-related. About 72% of LD transplants are performed in Caucasian children, with African-American children unfortunately receiving a disproportionate percentage of CD kidneys. There has been a steady decline in the use of CD kidneys recovered from young individuals and a gradual decline in the number of transplants performed in young recipients (< 6 years old). Graft survival for LD recipients was 91%, 84% and 79% at one, 3 and 5 years, respectively, and the comparative figures for CD recipients were 81%, 72% and 64%, respectively. Acute and chronic rejections account for most of the graft losses, with chronic rejection accounting for more than 30%. There has been a steady improvement in one-year graft survival of CD recipients with the 1997-1998 cohort exhibiting an improvement of 16% over the 1987-1988 cohort. This improvement has been brought about by eliminating the use of infant donor kidneys, reducing the number of random transfusions and increasing the maintenance dose of cyclosporine. Posttransplant growth continues to be poor, with catch-up growth being exhibited only in children under age 6.

Acute rejection is a frequent event in pediatric transplantation. In addition to graft loss, acute rejection episodes stimulate the development of chronic rejection and inhibit growth in children post-transplantation. In this study, we analyzed our data from 1987 through 1996 to identify acute rejection episodes in children. In 2,520 living donor (LD) transplants there were 2,540 rejection episodes (rejection ratio: 1.1), and in 2,579 cadaver donor (CD) transplants 3,653 episodes were observed (rejection ratio: 1.32). For LD recipients the first rejection occurred sooner when there was at least one HLA-DR mismatch (RR=1.6, p<0.001) and prophylactic T-cell antibody was not used (RR=1.4, p<0.001). For CD transplants absence of prophylactic T-cell antibody (RR=1.2, p<0.001) and donor age below five years were risk factors (RR=1.5, p<0.001). Late initial acute rejections were seen in 327 of 1,471 patients (22.2%) who were rejection free at one year. At risk for the development of late rejections were children over the age of six years at transplantation (RR=1.7, p<0.001) and children of non-white origin (RR=1.5, p <0.002). For LD transplant recipients in the age range of 0-5 years, irreversible rejection was observed in 8.7% compared to 4.1% for older children (RR=1.46, p<0.001). Similar results for CD transplants were 12.6% versus 6.6% (RR=1.5, p<0.00). The high frequency of rejection episodes in children and the greater irreversibility in younger children suggest pediatric patients may have a more robust immune response. Current ongoing studies in the molecular mechanisms of the pathogenesis of rejection in surveillance biopsies of children may help determine if this hypothesis is valid.

Using the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) database, we performed a retrospective cohort study of 1,552 pediatric renal transplant patients who had received a graft from a biological parent to determine if parental donor sex influences the development of rejection. There were 102/675 (15.1%) graft failures in paternal grafts compared to 144/877 (16.4%) graft failures in maternal grafts. Overall graft survival (p=0.48) and time to first rejection (p>0.9) were not different in patients receiving paternal versus maternal grafts. The overall frequency of graft loss to rejection was also not different. However, maternal donation was associated with a significantly longer time to first rejection in patients less than one year of age at the time of transplantation (p=0.01). Time to first rejection was not different between maternal and paternal grafts in older recipients. In summary, the present study did not demonstrate a difference in graft survival between maternal and paternal donations, but the youngest patients may experience a longer time to first rejection with maternal donation. The number of young patients is small, however, and further data are necessary to confirm this observation.

We investigated the safety and immunogenicity of a candidate HIV-1 vaccine, Env 2-3 (Chiron Biocine Co.), in combination with an adjuvant emulsion, MF59, with or without an additional immune modulator, MTP-PE 78 healthy HIV-1-seronegative adults. Sixteen subjects participated in a dose escalation study of MTP-PE in MF59 without Env 2-3, given at 0 and 1 months; 48 subjects participated in a study of a fixed dose of 30 micrograms of Env 2-3 in MF59 with increasing doses of MTP-PE (0, 5, 10, 25, 50, and 100 micrograms), and 14 subjects participated in a study of 100 micrograms of Env 2-3 in MF59 without MTP-PE. Subjects were assigned to study groups under a randomized, double-blind allocation. Subjects received immunization at 0, 1, and 6 months, and had the option of receiving a fourth dose at 12-18 months. Env 2-3 in MTP-PE/MF59 was associated with significant reactogenicity, in that severe, although self-limited systemic and/or local reactions occurred in 15 of 30 vaccinees. In contrast, Env 2-3 in MF59 without MTP-PE was relatively well tolerated, and severe local and/or systemic reactions occurred in only 2 of 18 subjects. Env 2-3 stimulated serum antibodies to HIV-1 envelope protein (gp120) as detected by Western blot in 39 of 43 subjects and to HIV-1 virus lysate by EIA in 28 of 43 subjects after three injections. The majority of subjects also developed EIA antibodies to recombinant gp120 (SF-2), gp120 (LAI), and V3 peptide (SF-2). Neutralizing antibodies to the homologous SF-2 strain developed in 30 of 43 and 27 of 34 subjects, and fusion inhibition antibodies in 25 of 43 and 15 of 36 subjects after three and four injections, respectively. Lymphoproliferative responses to the immunogen, Env 2-3 were observed in over 80% of the vaccinees examined, and CD4+ cytotoxic T cell activity directed against HIV-1 was noted transiently in 2 of 20 vaccinees. Addition of MTP-PE to Env 2-3 or increasing the dose of Env 2-3 from 30 to 100 micrograms did not augment immunogenicity. Env 2-3 in MF59 was well tolerated and immunogenic in HIV-1-seronegative individuals. The addition of MTP-PE significantly increased reactogenicity, but had little, if any, effect on immunogenicity.

The data base of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) was used to examine the effect of primary diagnosis on the outcome of renal transplantation in children. The relative risk of graft failure for eight diagnostic groups was determined, with patients with congenital and structural anomalies of the urinary tract serving as the reference group. Covariate analysis was used to control for the effects of age, race and transfusion history in recipients of living-related donor kidneys, and for age, donor age, antilymphocyte prophylaxis, prior transplantation, prior dialysis and cold ischemia time in recipients of cadaver kidneys. In recipients of living-related donor kidneys, the lowest graft failure rates were associated with the diagnoses of cystinosis, familial nephritis and hemolytic uremic syndrome (HUS), while the highest failure rates were observed in patients with a primary diagnosis of congenital nephrotic syndrome (CNS) or focal segmental glomerulosclerosis (FSGS). In cadaver allograft recipients, the lowest graft failure rates were associated with primary diagnoses of glomerulonephritis, congenital/structural disease and cystinosis, while patients with FSGS, HUS and CNS had the highest graft failure rates. This study suggests that patients with a primary diagnosis of cystinosis have superior outcomes, while the diagnoses of FSGS and CNS carry with them the highest risks of graft failure.

Changes in height deficit and standard deviation score (SDS) were evaluated in 524 recipients who were growth retarded at transplantation (SDS > -2.00) and were followed for at least 2 years post transplant. At 2 years the delta SDS was 0.32 +/- 0.04 and the delta height deficit was 0.75 +/- 0.23. Therefore despite improvement in the SDS at 2 years post transplant, the change in height deficit was < 1 cm. Change in height deficit may be a better indication of "catch-up" growth following transplantation.

We examined the safety and immunogenicity of a baculovirus-derived recombinant HIV-1 envelope glycoprotein vaccine candidate, rgp160 (VaxSyn; MicroGeneSys, Meriden, CT), administered at doses of 160 or 640 micrograms to 56 healthy, HIV-1-seronegative adults, in a randomized, double-blind, placebo-controlled study. Immunizations were given intramuscularly at 0, 1, 6, and 12 months. Both doses were generally well tolerated, although self-limited local reactions were frequent. No other clinical or laboratory toxicities were noted, and no effects on CD4 or CD8 lymphocyte counts or percentages were noted. Serum antibody responses to HIV proteins were detected by Western blot (WB) in 19 of 20 and in 19 of 19 recipients of four doses of 160 and 640 micrograms, respectively. Western blot responses developed more rapidly in the 640-micrograms group. High rates of EIA antibody responses to HIV-1 lysate were also present in both groups, and developed more rapidly in the 640-micrograms group. Enzyme immunoassay antibody responses to the immunogen (rgp160) were also frequent, but were infrequent to V3 to gp41 peptides. Neutralizing antibodies against the homologous HIV-1 LAI isolate were seen in 3 of 20 subjects (GMT = 11) who received four doses of 160 micrograms, and in 10 of 19 subjects who received four doses of 640 micrograms (GMT = 32). Fusion inhibiting antibody was not detected. CD4 blocking activity was seen in 3 of 19 subjects who received four doses of 640 micrograms. Complement-mediated antibody-dependent enhancement was found in sera from 11 of 19 volunteers in the 640-micrograms group. Lymphocyte proliferative responses to the immunogen were detected in 4 of 4 subjects tested, but no cytotoxic T cell activity was noted in 11 subjects. Administration of the 640-micrograms dose of this rgp160 vaccine candidate relative to the lower doses was associated with increased immunogenicity, including higher rates of homologous neutralizing antibody responses, although at low titer.

The purpose of this randomized, double-blind study was to test the safety and immunogenicity of an HIV-1LAI recombinant gp160 (rgp160) vaccine in healthy, uninfected volunteers using accelerated dosing schedules. Thirty volunteers were randomly assigned to receive 50-micrograms doses of rgp160 in one of two immunization schedules. Group 1 received rgp160 at times 0, 1, 2 and 5 months; and group 2 received rgp160 at times 0, 1, 2, 3 and 4 months. The vaccine was safe and stimulated high levels of HIV-1 envelope-specific binding antibody and T cell memory. There was a trend (P < 0.10) suggesting neutralizing antibodies were better induced by the regimen incorporating a rest period before the final immunization in group 1 volunteers. Both accelerated immunization schedules induced immune responses at levels similar to or better than those achieved by four rgp160 vaccine injections given over 12-18 months in other studies.

Background and Methods: The safety of long-term immunosuppression with cyclosporine in renal-transplant recipients is not well understood. This drug may cause a progressive toxic nephropathy, but it also preserves renal function because it prevents rejection. To determine the effect of cyclosporine on renal function and graft rejection, we conducted a retrospective analysis of data on 1663 renal-transplant recipients at six centers., Results: The rate of graft survival was 78 percent (median follow-up, 36 months). Grafts were was lost in 279 patients (17 percent), mostly because of acute rejection (68 patients) or chronic graft dysfunction that was unresponsive to a reduction in the dose of cyclosporine (125 patients); 92 patients died with functioning grafts. The median change in the serum creatinine concentration in all patients after transplantation was less than 0.001 mg per deciliter per month (< 0.09 mumol per liter per month). Patients who had episodes of rejection had decreased rates of long-term graft function and survival. Eight percent of patients with functioning grafts at one year had first episodes of rejection more than one year after transplantation. These late first rejections were associated with noncompliance with therapy (in 34 percent), blood cyclosporine concentrations that were marginally lower than those of patients who had no episodes of rejection, and a low rate of successful reversal of rejection (77 percent, vs. 97 percent in patients with rejection during the first year; P < 0.001)., Conclusions: The majority of renal-transplant patients tolerate long-term cyclosporine therapy without evidence of progressive toxic nephropathy. Graft failure is most often due to rejection.

During 1992 the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) began to develop a pediatric Dialysis Patient Data Base by collecting data on pediatric patients who had received either hemodialysis (HD) or peritoneal dialysis (PD), or both, at a participating NAPRTCS center. This preliminary report describes study methods and contains detailed, though short-term observations reported by 64 of 87 NAPRTCS centers on 762 patients who were < 21 years of age at enrollment and who received treatment between January 1, 1992 and September 15, 1992. In these 762 patients, a total of 810 independent courses of dialysis therapy were identified (PD = 534 [65.9%]; HD = 276 [34.1%]). Patients age groupings showed a significantly greater proportion of PD patients among younger age groups. Automated peritoneal dialysis was used by about 75% of registered PD patients at one and six months after registration. A total of 196 peritonitis episodes were reported, yielding a peritonitis rate of one episode every 7.1 patient-months. Ten percent of PD catheters were replaced, primarily for mechanical malfunction and leaks. Percutaneous catheters were used for vascular access in about one-half of the HD patients, with the remainder almost equally divided between arteriovenous fistulae and grafts. Vascular access revision was reported in 28% of HD patients, with about one-third of these revisions performed to create a more permanent access. Recombinant human erythropoietin therapy was used in 89% of PD and 94% of HD patients at six months. Recombinant human growth hormone therapy was used in 9% of PD and 5% of HD patients at six months.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: To compare the relative safety and efficacy of azathioprine (AZA), methotrexate (MTX), and the combination of both in the treatment of active rheumatoid arthritis (RA)., Methods: Two hundred twelve patients with active RA were entered into a 24-week prospective, controlled, double-blind, multicenter trial and were randomly assigned to 1 of 3 treatment groups., Results: One hundred fifty-eight patients finished 24 weeks of the study. There were no remissions seen but response rates were greater than 30% for all outcome measures. Combination therapy was not statistically superior to MTX therapy alone, but both combination therapy and MTX alone were superior to AZA alone when patients were analyzed by intent-to-treat and with withdrawals treated as therapy failures. If only patients who continued taking the therapy were analyzed, the mean improvement was greater for AZA therapy than for MTX, while the combination remained the most active. Adverse effects on the gastrointestinal tract and elevations of liver enzyme levels were the most frequent causes for discontinuations., Conclusion: Both combination therapy and MTX alone were superior to therapy with AZA alone for active RA but were not statistically different in their effect on outcome assessment.

Background: Previous studies of renal transplantation in children have focused on the survival of grafts and patients. Little information is available about the cause of renal disease, the sources of donated organs, or children's growth after transplantation. The North American Pediatric Renal Transplant Cooperative Study was organized to identify the diseases that require transplantation and to analyze factors that affect the success of transplantation in children., Methods: We collected data from 73 pediatric transplantation centers from 1987 through 1990. These data included information about demographic characteristics of patients, graft function, and therapy one month after transplantation and every six months thereafter for each patient 17 years of age or younger., Results: Altogether, 1550 children received 1667 renal allografts during this period; 31 percent of the children were five years of age or younger. Forty-three percent of the transplanted kidneys came from a living related donor, and 57 percent from a cadaver. The two most common causes of renal disease leading to transplantation were congenital malformations of the kidneys and urinary tract (42 percent of the patients) and focal segmental glomerulosclerosis (12 percent). One year after transplantation, the rate of graft survival in recipients of a kidney from a living related donor was 89 percent; it was 80 percent after three years. For recipients of cadaver kidneys, the comparable rates were 74 percent and 62 percent, respectively (P less than 0.001). The best growth was observed in patients who were no more than five years old at the time of transplantation. During follow-up, 79 patients died, and cancer developed in 12 patients., Conclusions: The most common causes of end-stage renal disease in children and adolescents are congenital malformations of the kidneys and urinary tract and focal segmental glomerulosclerosis. The rates of graft survival at one and three years are better in children and adolescents who receive a kidney from a living related donor than in those who receive a kidney from a cadaver.

Adult studies have shown a high renal graft survival if the donor and recipient match for each antigen of the human lymphocyte antigen (HLA)-A, B and DR loci (six-antigen match). The 4 yr of data from the North American Pediatric Renal Transplant Cooperative Study Registry show a statistically beneficial effect of DR matching for cadaver graft outcome. No antigen matching clearly has a worse outcome, 72% at 1 yr versus those with one or more antigen matching at each loci with a 1-yr graft survival of 81% and 2-yr graft survival of 69%. The long-term improved outcome from better antigen matching suggests that cadaver donor allograft organ assignment should address both the need of the center-driven and patient-driven concepts of recipient selection to achieve the best use of this scarce resource and an improved quality of life.

Purpose: The purpose of this study is to evaluate the risk of acute vascular events in patients receiving cisplatin-based chemotherapy for testicular cancer., Patients and Methods: A questionnaire assessing cardiovascular toxicity was distributed to all participants in the Testicular Cancer Intergroup study and details of toxicity from the chemotherapy flow sheets were reviewed. Patients with pathologic stage I testicular cancer were registered on to the study and observed after retroperitoneal lymphadenectomy. Patients with pathologic stage II disease were randomized to receive two postoperative courses of adjuvant cisplatin-based chemotherapy or observation. Any patient who had disease recurrence after observation or adjuvant therapy was given four cycles of cisplatin-based chemotherapy., Results: Review treatment-related toxicity for those patients receiving adjuvant chemotherapy (n = 97) or chemotherapy for recurrent disease (n = 83) showed no cases of acute cardiovascular toxicity. The median follow-up period after study enrollment was 5.1 years; 459 questionnaires were mailed and 270 were returned. The percent return was equal among the observed adjuvant and recurrent groups (59%, 54%, and 64%). There was a significant increase in the incidence of extremity paresthesias in the two groups receiving chemotherapy. Fatal myocardial infarction was reported in two patients in the observation group and one nonfatal infarction was reported in the adjuvant treatment group. No patient in any group reported an incidence of stroke. Three patients in the observation group and one patient in the recurrent group experienced a thromboembolic event., Conclusion: Despite sporadic case reports suggesting a causal association between chemotherapy for testicular cancer and acute vascular events, this retrospective analysis provides no evidence of an increased risk for subsequent cardiovascular disease in this patient population.

Purpose: The Testicular Cancer Intergroup Study (TCIS) was undertaken to evaluate the pathologic findings in early-stage testicular cancer as determined by central pathology review, to compare these findings with the interpretation by the contributing pathologists, and to make correlations with various clinical parameters and outcomes., Patients and Methods: The prospective study of non-seminomatous germ cell testicular cancer staged surgically involved 459 eligible patients with stage I (node-negative) or stage II (node-positive) disease. Pathologic materials from both the orchiectomy and lymphadenectomy specimens were submitted to a central laboratory for evaluation., Results: Central and local pathologists differed significantly in their identification of certain cellular histologies (primarily yolk sac tumors [YST]) and recognition of invasion into vascular structures. In contrast to our prior findings with local pathologic assessment, venous/lymphatic invasion as determined by central review predicted relapse in both stages. In pathologic stage I disease, the relapse rate was 19.4% (12 of 62 cases) for those with invasion versus 6.0% (10 of 168 cases) for those without invasion. In pathologic stage II disease, the respective relapse rates were 63.5% (40 of 63 cases) and 24.0% (six of 25 cases). Vascular invasion was jointly predictive with nodal stage for risk of relapse. The percentage of embryonal carcinoma (EC) in the primary tumor was predictive of nodal stage and relapse in a univariate, but not a multivariate, analysis. In a large substudy, immunohistochemical staining identified a correlation between stain intensity in YST and serum alpha-fetoprotein (AFP) levels. In a similar fashion human chorionic gonadotropin (HCG) staining reactivity occurred exclusively in patients with syncytiotrophoblasts and correlated with serum levels of beta-HCG., Conclusions: A number of tumor histology correlates with clinical parameters have been identified or confirmed. Careful pathologic scrutiny of the primary testicular tumor, especially for vascular invasion, provides important prognostic information.

The Testicular Cancer Center Intergroup Study entered surgically staged patients with nonseminomatous tumor and metastases limited to the regional lymph nodes into a previously reported cooperative trial of immediate versus delayed therapy for positive retroperitoneal node disease. Patients with negative nodes (stage I) were placed in an observation registry with specified treatment strategy upon relapse. Of 264 stage I cancer patients 27 (10.2%) had recurrence: 5 of these 27 patients died after recurrence of the testicular malignancies, while 4 other nontumor-related deaths have occurred. Pre-lymphadenectomy staging characteristics observed to predict significantly node positivity are the results of radiological examinations, presence of tumor invasion, vascular invasion and tumor histology. In a multiple logistic regression analysis with these variables, misclassification still occurs in more than a fourth of the patients. Future refinements in diagnosis may allow for better prediction of these patients at risk to have positive lymph nodes and ultimately recurrence. Presently, if assessment of nodal involvement is the objective, noninvasive procedures are not an adequate substitute for surgical staging with modified lymphadenectomy.

Eighteen patients with unresectable localized adenocarcinoma of the pancreas were treated by a combination of chemotherapy plus hyperfractionated radiation therapy to the pancreas for 4080 cGy with an additional 960 cGy to the pancreatic tumor and a surrounding margin. One hundred and twenty cGy were given twice daily 4 to 6 hours apart. High-energy photon or electron beams were used with treatment planning based on computed tomographic (CT) scans. Patients were given chemotherapy in the form of 5-fluorouracil (5-FU) at 350 mg/m2 on the first 3 and last 3 days of radiation therapy. On day 53, chemotherapy was given that included 600 mg/m2 IV of 5-FU, 1 gm/m2 of streptozotocin, and 10 mg/m2 IV of mitomycin C. The 5-FU and streptozotocin were repeated on days 60, 81, and 88, and the stretozotocin and mitomycin (SMF) cycles were repeated every 8 weeks until progression. Radiation toxicity was generally tolerable with one of 18 evaluable patients having severe nausea and vomiting and two of 18 patients having severe diarrhea. One patient had total liver failure and died 3 months after initiation of therapy. Six patients had severe hematopoietic toxicity during chemotherapy. Overall, the severe toxicity rate was higher (67%) than in previous studies. Median survival was 35 weeks, the 1-year survival rate was 39%, and the patient who survived the longest died at 68 months. Although this schedule of hyperfractionated radiation and chemotherapy was disappointing, combined experimental radiation approaches plus chemotherapy for localized unresectable adenocarcinoma of the pancreas deserve additional research.

In this multi-institutional study of advanced gastric cancer, 73 patients were evaluable for response or survival. Patients were treated with either triazinate (Baker's antifol), standard-dose methotrexate, or ICRF-159 (razoxane). Objective responses were seen in four patients receiving Baker's antifol, in three receiving methotrexate, and in none receiving razoxane. Baker's antifol produced a median survival of 18 weeks and methotrexate and razoxane produced a median survival of 8 and 9 weeks, respectively. Seventy of the 73 patients entered in this study had been previously treated, most frequently with combination chemotherapy regimens containing 5-FU or doxorubicin. This study appears to demonstrate that Baker's antifol is an active drug for patients with advanced gastric cancer, according to both response and survival criteria. Examination of the pretreatment prognostic characteristics of the patients further suggests that a possible survival advantage is due to treatment with Baker's antifol rather than the prognostic characteristics of the patients.

Determining the prognostic significance of clinical factors for patients with severe head injury can lead to an improved understanding of the pathophysiology of head injury and to improvement in therapy. A technique known as the sequential Bayes method has been used previously for the purpose of prognosis. The application of this method assumes that prognostic factors are statistically independent. It is now known that they are not. Violation of the assumption of independence may produce errors in determining prognosis. As an alternative technique for predicting the outcome of patients with severe head injury, a logistic regression model is proposed. A preliminary evaluation of the method using data from 115 patients with head injury shows the feasibility of using early data to predict outcome accurately and of being able to rank input variables in order of their prognostc significance.