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We analyzed the outcomes of 283 patients receiving unrelated donor allogeneic hematopoietic cell transplantation for non-Hodgkin lymphoma (NHL) facilitated by the Center for International Blood and Marrow Transplant Research/National Marrow Donor Program (CIBMTR/NMDP) between 1991 and 2004. All patients received myeloablative conditioning regimens. The median follow-up of survivors is 5 years. Seventy-three (26%) patients are alive. The day 100 probability of death from all causes is estimated at 39%. The cumulative incidence of developing grade III-IV acute graft-versus-host disease (aGVHD) at day 100 is 25%. The estimated 5-year survival and failure free survival are 24% (95% confidence interval [CI]: 19-30) and 22% (95% CI: 17-28), respectively. Factors adversely associated with overall survival (OS) included increasing age, decreased performance status, and refractory disease. Follicular lymphoma (FL) and peripheral T cell lymphoma had improved survival compared to aggressive B cell lymphomas. Factors adversely associated with progression-free survival (PFS) included performance status, histology, and disease status at transplant. Long-term failure-free survival is possible following unrelated donor transplantation for NHL, although early mortality was high in this large cohort.

Reporting transplant center-specific survival rates after hematopoietic cell transplantation is required in the United States. We describe a method to report 1-year survival outcomes by center, as well as to quantify center performance relative to the transplant center network average, which can be reliably used with censored data and for small center sizes. Each center’s observed 1-year survival outcome is compared to a predicted survival outcome adjusted for patient characteristics using a pseudovalue regression technique. A 95% prediction interval for 1-year survival assuming no center effect is computed for each center by bootstrapping the scaled residuals from the regression model, and the observed 1-year survival is compared to this prediction interval to determine center performance. We illustrate the technique using a recent center specific analysis performed by the Center for International Blood and Marrow Transplant Research, and study the performance of this method using simulation.

The National Marrow Donor Program (NMDP) has facilitated unrelated donor hematopoietic cell transplants for more than 20 years. In this time period, there have been many changes in clinical practice, including improvements in HLA typing and supportive care, and changes in the source of stem cells. Availability of banked unrelated donor cord blood (incorporated into the NMDP registry in 2000) as a source of stem cells has become an important option for children with leukemia, offering the advantages of immediate availability for children with high-risk disease, the need for a lesser degree of HLA match, and expanding access for those with infrequent HLA haplotypes. Overall survival (OS) in children with acute leukemia transplanted with unrelated donor bone marrow (BM) is markedly better in more recent years, largely attributable to less treatment-related mortality (TRM). Within this cohort, 2-year survival was markedly better for patients with acute lymphoblastic leukemia (ALL) in first complete response (CR1) (74%) versus second complete response (CR2) (62%) or more advanced disease (33%). Similar findings are observed with patients with AML, suggesting earlier referral to bone marrow transplant (BMT) is optimal for survival. Notably, this improvement over time was not observed in unmodified peripheral blood stem cell (PBSC) recipients, suggesting unmodified PBSC may not be the optimal stem cell source for children.

Matching for HLA class I alleles, including HLA-C, is an important criterion for outcome of unrelated donor transplantation. However, haplotype-mismatched transplantations for myeloid malignancies, mismatched for killer immunoglobulin-like receptor (KIR) ligands in the graft-versus-host (GVH) direction, is associated with lower rates of graft-versus-host disease (GVHD), relapse, and mortality. This study investigated the effect of KIR ligand mismatching on the outcome of unrelated donor transplantation. The outcomes after 1571 unrelated donor transplantations for myeloid malignancies where donor–recipient pairs were HLA-A, -B, -C, and -DRB1 matched (n = 1004), GVH KIR ligand–mismatched (n = 137), host-versus-graft (HVG) KIR ligand–mismatched (n = 170), and HLA-B and/or –C–mismatched but KIR ligand–matched (n = 260) were compared using Cox regression models. Treatment-related mortality (TRM), treatment failure, and overall mortality were lowest after matched transplantations. Patients who received grafts from donors mismatched at the KIR ligand in the GVH or HVG direction and mismatched at HLA-B and/or C but matched at the KIR ligand had similar rates of TRM, treatment failure, and overall mortality. There were no differences in leukemia recurrence between the 4 groups. These results do not support the choice of an unrelated donor on the basis of KIR ligand mismatch determined from HLA typing.

Allogeneic bone marrow transplantation (BMT) offers the only curative therapy for chronic myelogenous leukemia. We compared prospectively collected results of 2464 unrelated donor (URD) transplantations with 450 HLA-identical, matched sibling donor (MSD) transplantations performed at collaborating National Marrow Donor Program institutions. A total of 63% of URDs were matched at HLA-A, -B, and at -DRB1 alleles; all MSDs were genotypically identical at major histocompatibility loci. URD recipients were younger (median 36 vs 39, P = .001) than MSDs and underwent BMT later after diagnosis (median 17 [0-325 months] vs 7 [1-118 months],P = .001) and less often in chronic phase (CP) (67% vs 82%, P = .001). Multivariate analysis demonstrated a significantly increased risk of graft failure and acute graft versus host disease after URD BMT. The risk of hematologic relapse was low after either matched URD or MSD transplantations. We observed significantly though modestly poorer survival and disease-free survival (DFS) after URD transplantations. However, for those undergoing transplantation during CP within 1 year from diagnosis, 5-year DFS was similar or only slightly inferior after matched URD versus MSD transplantation (age < 30: URD 61% ± 8% vs MSD 68% ± 15%,P = .18; 30-40: URD 57% ± 9% vs MSD 67% ± 10%,P = .05; > 40: URD 46% ± 9% vs MSD 57% ± 9%,P = .02). Delay from diagnosis to BMT in CP patients led to substantially poorer 5-year DFS after matched URD than MSD BMT (CP 1-2 years: URD 39% ± 6% vs MSD 63% ± 12%; beyond 2 years: URD 33% ± 7% vs MSD 50% ± 20%). Outcome of matched URD BMT for early CP chronic myelogenous leukemia yields survival and DFS approaching that of MSD transplantation. However, delay may compromise URD outcomes to a greater extent. Improvements in URD and MSD transplantation are still needed, and results of newer, nontransplantation therapies should be evaluated against the established curative potential of URD and MSD marrow transplantation.

Children with juvenile myelomonocytic leukaemia (JMML) have a poor outcome, with survival in a minority of patients. The major limitation on success of sibling donor bone marrow transplantation for JMML has been reported to be relapse. A total of 46 children with a diagnosis of JMML underwent unrelated donor marrow (URD) transplantation facilitated by the National Marrow Donor Program. Forty-three of 46 patients had neutrophil engraftment at a median of 20 d post transplant, with platelet recovery in 28 of 40 evaluable patients at a median of 34.5 d. Thirty-two of 44 evaluable patients developed acute graft-versus-host-disease (GVHD) (Grades 2-4) and chronic GVHD developed in 14 of 35 evaluable patients. At a median follow-up of 2.0 years, probabilities of survival and disease-free survival were 42% and 24% respectively. The probability of relapse was 58% at 2 years and represents the major cause of treatment failure. Multivariate analysis revealed that chronic GVHD was associated with reduced relapse [risk ratio 0.20 (95% CI 0.04-1.02, P=0.05)] improved survival [risk ratio 0.13 (95% CI 0.03-0.68, P=0.02)] and event-free survival [risk ratio 0.23 (95% CI 0.06-0.94, P=0.04)]. This study demonstrates that relapse is the major cause of treatment failure in patients with JMML undergoing URD transplantation. With lower relapse observed in patients with chronic GVHD, new treatment strategies that focus on enhancing the graft-versus-leukaemia effect may improve survival.

For more than 20 years the National Marrow Donor Program has facilitated unrelated donor hematopoietic cell transplants for adult recipients. In this time period, the volunteer donor pool has expanded to nearly 12 million adult donors worldwide, improvements have occurred in the understanding and technology of HLA matching, there have been many changes in clinical practice and supportive care, and the more common graft source has shifted from bone marrow (BM) to peripheral blood stem cells (PBSCs). The percentage of older patients who are receiving unrelated donor transplants is increasing; currently over 1 in 10 adult transplant recipients is over the age of 60 years. Chronic myelogenous leukemia (CML) was previously the most common diagnosis for unrelated donor transplantation, but it now comprises less than 10% of transplants for adult recipients. Transplants for acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL), and myelodysplastic syndromes (MDS) all outnumber CML. Treatment-related mortality (TRM) has declined significantly over the years, particularly in association with myeloablative transplant preparative regimens. Correspondingly, survival within each disease category has improved. Particularly gratifying are the results in severe aplastic anemia (AA) where 2-year survival has doubled in just 10 years.

The allelic diversity and associated human leukocyte antigen (HLA) disparity of 1775 bone marrow recipients and their unrelated donors, matched for six of six (1361/1775,77%), five of six (397/1775, 22%), or four of six (17/1775, 1%) HLA-A, -B, -DR antigens, were retrospectively evaluated. The comprehensive HLA analysis included the class I (A, B, C) and II (DRB1, DQA1, DQB1, DPA1, DPB1) loci. Most (>66%) of the predominantly Caucasian study population carried one or two of five to seven common alleles at each HLA locus. In spite of this limited diversity, 29% of the six of six antigen-matched transplants carried allele mismatches at HLA-A, -B, and/or -DRB1, and 92% carried at least one allele mismatch at one of the eight HLA loci tested. Of the 968 HLA-A,-B,-DRB1 allele-matched pairs, 89% carried mismatches at other HLA loci, predominantly at DP loci. The substantially greater than expected HLA allelic disparity between donor and recipient suggests extensive haplotypic diversity and underscores the importance of enhancing approaches to mitigate the deleterious effect of HLA mismatches.

Children with juvenile myelomonocytic leukaemia (JMML) have a poor outcome, with survival in a minority of patients. The major limitation on success of sibling donor bone marrow transplantation for JMML has been reported to be relapse. A total of 46 children with a diagnosis of JMML underwent unrelated donor marrow (URD) transplantation facilitated by the National Marrow Donor Program. Forty-three of 46 patients had neutrophil engraftment at a median of 20 d post transplant, with platelet recovery in 28 of 40 evaluable patients at a median of 34.5 d. Thirty-two of 44 evaluable patients developed acute graft-versus-host-disease (GVHD) (Grades 2-4) and chronic GVHD developed in 14 of 35 evaluable patients. At a median follow-up of 2.0 years, probabilities of survival and disease-free survival were 42% and 24% respectively. The probability of relapse was 58% at 2 years and represents the major cause of treatment failure. Multivariate analysis revealed that chronic GVHD was associated with reduced relapse [risk ratio 0.20 (95% CI 0.04-1.02, P=0.05)] improved survival [risk ratio 0.13 (95% CI 0.03-0.68, P=0.02)] and event-free survival [risk ratio 0.23 (95% CI 0.06-0.94, P=0.04)]. This study demonstrates that relapse is the major cause of treatment failure in patients with JMML undergoing URD transplantation. With lower relapse observed in patients with chronic GVHD, new treatment strategies that focus on enhancing the graft-versus-leukaemia effect may improve survival.

KIR ligand incompatibility in the graft-versus-host (GvH) direction has been associated with a significant reduction in relapse, graft rejection and graft-versus-host disease (GvHD) in patients with high-risk acute myeloid leukemia (AML)undergoing full haplotype-mismatched, T-cell depleted transplants. The effect in UDT has been less consistent. This study investigates the effect of KIR ligand mismatching on the outcome of UDT in a large combined data set from the National Marrow Donor Program and the European Group for Blood and Marrow Transplantation, comparing the outcome of 1,816 KIR ligand matched and mismatched transplants for AML (n=501), chronic myelogenous leukemia (n=1024), and myelodysplasia (n=291). All cases had high-resolution HLA typing, and were matched for HLA-A, and -DRB1 alleles. Based on HLA typing for -B and -C alleles, cases were divided into one of 4 groups for comparison of outcome: KIR ligand incompatible in GvH direction (n=156), KIR ligand incompatible in host-versus-graft (HvG) direction (n=185), HLA mismatched for -B and/or -C, KIR ligand compatible (n=301), and fully HLA matched (n=1174). All received myeloablative preparative regimens, and ex-vivo T-cell depletion of the graft was performed in 18%, 22%, 16% and 15% of patients in the 4 groups, respectively. Overall, a beneficial effect of KIR ligand incompatibility in the GvH direction could not be demonstrated. KIR ligand incompatibility was associated with increased risk of grade III/IV acute GvHD and worse overall survival (OS). However, the effect varied according to whether or not ex-vivo T-cell depletion of the graft was performed (see Table). Our results suggest a detrimental effect of KIR ligand incompatibility in unmanipulated UDT, whereas this negative effect is lost with ex-vivo T-cell depletion. With ex-vivo T-cell depletion, KIR ligand incompatibility in the GvH direction may be associated with a reduced risk of severe acute GvHD and improved OS compared to HLA mismatched, KIR ligand matched transplants, with the outcome approaching that of fully HLA matched transplants. Therefore, full MHC class I matching remains the best option in UDT. KIR ligand mismatching in the GvH direction may be considered if only HLA-B and or -C incompatible donors are available and ex-vivo T-cell depletion is performed. This requires validation in prospective studies. | | GvH KIR ligand mismatch | HvG KIR ligand mismatch | No KIR ligand mismatch, HLA mismatch | HLA matched | P-value | |:----------------------- | ----------------------- | ----------------------- | ------------------------------------ | ----------- | ------- | | T-cell depleted UDT | | Treatment mortality | 51% ± 17% | 64% ± 14% | 61% ± 13% | 47% ± 7% | 0.12 | | Grade III/IV acute GvHD | 14% ± 13% | 25% ± 13% | 37% ± 13% | 17% ± 6% | 0.04 | | Chronic GvHD at 3 years | 50% ± 21% | 39% ± 17% | 32% ± 15% | 53% ± 8% | 0.09 | | Relapse | 18% ± 14% | 12% ± 9% | 22% ± 11% | 20% ± 6% | 0.49 | | OS | 31% ± 17% | 27% ± 14% | 18% ± 11% | 38% ± 7% | 0.06 | | T cell replete UDT | | Treatment mortality | 63% ± 8% | 63% ± 8% | 54% ± 6% | 44% ± 3%

Matched unrelated donor hematopoietic stem cell transplantation (MUD HSCT) is a potentially curative treatment for patients with acute myeloid leukemia (AML). The graft-versus-leukemia (GVL) effect may be potent enough to overcome the otherwise poor prognosis associated with AML though its efficacy for high risk cytogenetic subgroups is uncertain. To test this hypothesis, we analyzed outcomes by cytogenetic risk group in 324 patients in first complete remission (CR1), and 440 in CR2 undergoing NMDP-facilitated MUD HSCT between 1988–2002. Using the SWOG/ECOG classification of cytogenetic risk groups (Slovak et al. Blood, 2000) cytogenetics were classified as favorable in 14% of patients, intermediate in 71% and unfavorable in 16%. 56% of the patients were male and 42% were > 35 years at HSCT. 76% of patients and donors were matched at HLA-A, -B and -DRB1, 17% were mismatched at one or more loci and 7% were potentially matched (serologically matched at HLA-A and -B and potentially allele matched at -DR). Disease Status N Kaplan-Meier Estimate for Survival at 5 years Kaplan-Meier Estimate for Disease-Free Survival at 5 years Cumulative Incidence for 100 Day Transplant-Related Mortality Cumulative Incidence for Relapse at 5 years * p-value indeterminate; ** p=0.01 CR1 324 32 ± 6% 32 ± 5% 32 ± 5% 18 ± 4% Intermediate 227 33 ± 7% 32 ± 7% 31 ± 6% 16 ± 5%* Unfavorable 85 31 ± 11% 31 ± 10% 29 ± 10% 23 ± 9%* CR2 440 36 ± 5% 35 ± 5% 25 ± 4% 16 ± 3% Favorable 93 46 ± 10% 44 ± 10% 25 ± 9% 10 ± 6%** Intermediate 313 33 ± 6% 32 ± 5% 27 ± 5% 16 ± 4%** Unfavorable 34 37 ± 17% 38 ± 16% 15 ± 12% 32 ± 15%** These data suggest that with the exception of the 5-year relapse rate, results of cytogenetics have little apparent influence on the outcome for patients undergoing MUD HSCT for AML in CR1. In CR2, results in patients with favorable cytogenetics appear to be better than those with intermediate or unfavorable cytogenetics, but are not statistically significantly different. Effective GVL and protection against relapse is observed, even in high risk cytogenetic subgroups. In this retrospective study, other prognostic factors may influence the outcome, but overall survival for patients with unfavorable cytogenetics appears at least as good as previously reported for matched sibling HSCT.

Developments over the last few years have focused increased interest on the risk inherent in farm decision making. In part this is a renewal of emphasis from the 1950s (Thair, Johnson, Schichele), but it also reflects contemporary phenomena such as increased variation in foreign demand for U.S. grain, changes in governmental agricultural programs, and drought in some of the major agricultural areas of the nation. The "teachable moment" for farm decision making under risk has arrived. The need for educational programs in this area includes both existing farm producers participating in extension programs and potential farm managers studying in the classroom. A review of the literature (Walker and Nelson), contrasted with a survey of farm management instructors and extension specialists (Walker), indicates the existence of a large gap between theory and practice in risky-farm decision making. The emphasis of this paper is on the estimation and use of personal probabilities in the decision-making process. The purpose is to describe the rationale and process followed in developing an instructional package dealing with this topic.1 This paper first reviews the theory and methodology for incorporating probabilities into the decision-making process, i.e., the existing body of knowledge. This is followed by an analysis of the audience and the specification of the instructional objectives which, together with the existing body of knowledge, determine the content for the teaching module. The alternative teaching methods are then discussed, followed by a description of the characteristics of the final package and some preliminary observations regarding evaluation.

A simulation model was developed to study voluntary forage intake, energy requirements for maintenance, liveweight change and calving rate of grade Zebu cows in the Llanos of Colombia. Multiplicative correction factors were fitted to intake and maintenance requirement prediction equations researched from the literature to account for reduced intake due to sparse regrowth of recently burned native savanna and to conditions of mineral deficiency, increased intake and decreased maintenance requirement during periods of high compensatory gain during the rainy season, and increased intake and maintenance requirement due to the effects of lactation and gestation. A frequency distribution was constructed relating liveweight at time of mating to subsequent calving rate, and this was used to simulate the calving rates of cow herds in the Llanos. Use of the model would allow prediction of the amount of improved pasture or supplemental feed that would be necessary to raise calving rates in a particular herd to an acceptable level, defined as at least three calves per cow every four years. The model was fitted by computer and was then run on programmable calculators. This type of simulation is suited to regions of the world in which computer time is expensive or unavailable. Verifications, validations and experimentation with the model are presented in a companion paper.

Estimation of a supply and demand model of the hog economy is presented for analyzing the possible effects of high-lysine com. Changes in hog marketings and prices are predicted as a function of the feed cost savings resulting from the successful introduction of high-lysine corn.

Unrelated donor (URD) hematopoietic cell transplantation (HCT) can eradicate chronic myelogenous leukemia (CML). It has been postulated that greater donor-recipient histoincompatibility can augment the graft-versus-leukemia (GVL) effect. We previously reported similar, but not equivalent, outcomes of URD versus sibling donor HCT for CML using an older, less precise classification of HLA matching. Here, we used our recently refined HLA-matching classification, which is suitable for interpretation when complete allele-level typing is unavailable, to reanalyze outcomes of previous HCT for CML. We found that using our new matching criteria identifies substantially more frequent mismatching than older, less precise "6 of 6 antigen-matched" URD-HCT. Under the new criteria, only 37% of those previously deemed "HLA- matched" were HLA well matched, and 44% were partially matched. Using our refined matching criteria confirms the greater risk of graft failure in partially matched or mismatched URD-recipient pairs compared with either sibling or well-matched URD-recipient pairs. Acute and chronic graft-versus-host disease (aGVHD, cGVHD) are significantly more frequent with all levels of recategorized URD HLA matching. Importantly, overall survival (OS) and leukemia-free survival (LFS) remain significantly worse after URD-HCT at any matching level. No augmented GVL effect accompanied URD HLA mismatch. Compared with sibling donor transplants, we observed only marginally increased (not statistically significant) risks of relapse in well-matched, partially matched, and mismatched URD-HCT. These data confirm the applicability of revised HLA-matching scheme in analyzing retrospective data sets when fully informative, allele-level typing is unavailable. In this analysis, greater histoincompatibility can augment GVHD, but does not improve protection against relapse; thus the best donor remains the most closely matched donor.

The purpose of this note is to review the results of past AAEA-sponsored commodity outlook surveys and to evaluate forecasting accuracy and performance. We discuss the methodology for conducting such a review and suggest some factors that seem to affect the accuracy of responses. How does the span of the forecast affect accuracy? Is it easier to forecast prices for some commodities than others? Are some forecasters more accurate than others?

S EAGRAVES AND PASOUR (hereafter S-P) offer a strong argument for accepting a cost-oriented definition of the "uneconomic regions" of the production function in the theory of the firm [3]. We hope in this note to make a few amendments to the S-P argument and, in so doing, to cast further doubt on the usefulness of the traditional "stages of production" notion as a pedagogical device. To illustrate the problems with conventional definitions of "economic region," S-P have employed a homogeneous production function. They also, implicitly at least, assumed the "fixed factor" to be perfectly divisible.1 We shall argue that: 1. In the case of a two-input production function, when one input is fixed and indivisible, the firm facing constant input and product prices will choose not to produce if output price falls below average variable costs. The reason for this is not that the marginal physical productivity of the "fixed input" is zero at the output corresponding to minimum average variable costs (this is true, however, for linear and homogeneous production functions), but rather that if the firm produces when product price is less than average variable costs, it will earn a negative quasi-rent. For some functions, the marginal physical productivity of the "fixed factor" may be negative at the minimum average variable cost output. The firm may wish to employ fewer units of that factor but is unable to do so because of its indivisible nature. Thus, production where the marginal physical productivity of an input is negative need not imply "uneconomic" production. 2. In the case of a two-input production