Electronic transport, structure, and energetics of endohedral Gd@C82 metallofullerenes

Electronic structure and transport properties of the fullerene C$_{82}$ and the metallofullerene Gd@C$_{82}$ are investigated with density functional theory and the Landauer-Buttiker formalism. The ground state structure of Gd@C$_{82}$ is found to have the Gd atom below the C-C bond on the C$_2$ molecular axis of C$_{82}$. Insertion of Gd into C$_{82}$ deforms the carbon chain in the vicinity of the Gd atoms. Significant overlap of the electron distribution is found between Gd and the C$_{82}$ cage, with the transferred Gd electron density localized mainly on the nearest carbon atoms. This charge localization reduces some of the conducting channels for the transport, causing a reduction in the conductivity of the Gd@C$_{82}$ species relative to the empty C$_{82}$ molecule. The electron transport across the metallofullerene is found to be insensitive to the spin state of the Gd atom.Comment: 13 pages, 7 figures, submitted Nano Let

Post-Transplant Outcomes in High-Risk Compared with Non-High-Risk Multiple Myeloma: A CIBMTR Analysis.

Conventional cytogenetics and interphase fluorescence in situ hybridization (FISH) identify high-risk multiple myeloma (HRM) populations characterized by poor outcomes. We analyzed these differences among HRM versus non-HRM populations after upfront autologous hematopoietic cell transplantation (autoHCT). Between 2008 and 2012, 715 patients with multiple myeloma identified by FISH and/or cytogenetic data with upfront autoHCT were identified in the Center for International Blood and Marrow Transplant Research database. HRM was defined as del17p, t(4;14), t(14;16), hypodiploidy (-Y) or chromosome 1 p and 1q abnormalities; all others were non-HRM. Among 125 HRM patients (17.5%), induction with bortezomib and immunomodulatory agents (imids) was higher compared with non-HRM (56% versus 43%, P \u3c .001) with similar pretransplant complete response (CR) rates (14% versus 16%, P .1). At day 100 post-transplant, at least a very good partial response was 59% in HRM and 61% in non-HRM (P = .6). More HRM patients received post-transplant therapy with bortezomib and imids (26% versus 12%, P = .004). Three-year post-transplant progression-free (PFS) and overall survival (OS) rates in HRM versus non-HRM were 37% versus 49% (P \u3c .001) and 72% versus 85% (P \u3c .001), respectively. At 3 years, PFS for HRM patients with and without post-transplant therapy was 46% (95% confidence interval [CI], 33 to 59) versus 14% (95% CI, 4 to 29) and in non-HRM patients with and without post-transplant therapy 55% (95% CI, 49 to 62) versus 39% (95% CI, 32 to 47); rates of OS for HRM patients with and without post-transplant therapy were 81% (95% CI, 70 to 90) versus 48% (95% CI, 30 to 65) compared with 88% (95% CI, 84 to 92) and 79% (95% CI, 73 to 85) in non-HRM patients with and without post-transplant therapy, respectively. Among patients receiving post-transplant therapy, there was no difference in OS between HRM and non-HRM (P = .08). In addition to HRM, higher stage, less than a CR pretransplant, lack of post-transplant therapy, and African American race were associated with worse OS. In conclusion, we show HRM patients achieve similar day 100 post-transplant responses compared with non-HRM patients, but these responses are not sustained. Post-transplant therapy appeared to improve the poor outcomes of HRM

Specific Class I HLA Supertypes but Not HLA Zygosity or Expression Are Associated with Outcomes following HLA-Matched Allogeneic Hematopoietic Cell Transplant: HLA Supertypes Impact Allogeneic HCT Outcomes

Maximizing the probability of antigen presentation to T cells through diversity in HLAs can enhance immune responsiveness and translate into improved clinical outcomes, as evidenced by the association of heterozygosity and supertypes at HLA class I loci with improved survival in patients with advanced solid tumors treated with immune checkpoint inhibitors. We investigated the impact of HLA heterozygosity, supertypes, and surface expression on outcomes in adult and pediatric patients with acute myeloid leukemia (AML), myelodysplastic syndrome, acute lymphoblastic leukemia, and non-Hodgkin lymphoma who underwent 8/8 HLA-matched, T cell replete, unrelated, allogeneic hematopoietic cell transplant (HCT) from 2000 to 2015 using patient data reported to the Center for International Blood and Marrow Transplant Research. HLA class I heterozygosity and HLA expression were not associated with overall survival, relapse, transplant-related mortality (TRM), disease-free survival (DFS), and acute graft-versus-host disease following HCT. The HLA-B62 supertype was associated with decreased TRM in the entire patient cohort (hazard ratio [HR], 0.79; 95% CI, 0.69 to 0.90; P = .00053). The HLA-B27 supertype was associated with worse DFS in patients with AML (HR = 1.21; 95% CI, 1.10 to 1.32; P = .00005). These findings suggest that the survival benefit of HLA heterozygosity seen in solid tumor patients receiving immune checkpoint inhibitors does not extend to patients undergoing allogeneic HCT. Certain HLA supertypes, however, are associated with TRM and DFS, suggesting that similarities in peptide presentation between supertype members play a role in these outcomes. Beyond implications for prognosis following HCT, these findings support the further investigation of these HLA supertypes and the specific immune peptides important for transplant outcomes

Human leukocyte antigen supertype matching after myeloablative hematopoietic cell transplantation with 7/8 matched unrelated donor allografts: a report from the Center for International Blood and Marrow Transplant Research

The diversity of the human leukocyte antigen (HLA) class I and II alleles can be simplified by consolidating them into fewer supertypes based on functional or predicted structural similarities in epitope-binding grooves of HLA molecules. We studied the impact of matched and mismatched HLA-A (265 versus 429), -B (230 versus 92), -C (365 versus 349), and -DRB1 (153 versus 51) supertypes on clinical outcomes of 1934 patients with acute leukemias or myelodysplasia/myeloproliferative disorders. All patients were reported to the Center for International Blood and Marrow Transplant Research following single-allele mismatched unrelated donor myeloablative conditioning hematopoietic cell transplantation. Single mismatched alleles were categorized into six HLA-A (A01, A01A03, A01A24, A02, A03, A24), six HLA-B (B07, B08, B27, B44, B58, B62), two HLA-C (C1, C2), and five HLA-DRB1 (DR1, DR3, DR4, DR5, DR9) supertypes. Supertype B mismatch was associated with increased risk of grade II-IV acute graft-versus-host disease (hazard ratio =1.78, P=0.0025) compared to supertype B match. Supertype B07-B44 mismatch was associated with a higher incidence of both grade II-IV (hazard ratio=3.11, P=0.002) and III-IV (hazard ratio=3.15, P=0.01) acute graft-versus-host disease. No significant associations were detected between supertype-matched versus -mismatched groups at other HLA loci. These data suggest that avoiding HLA-B supertype mismatches can mitigate the risk of grade II-IV acute graft-versus-host disease in 7/8-mismatched unrelated donor hematopoietic cell transplantation when multiple HLA-B supertype-matched donors are available. Future studies are needed to define the mechanisms by which supertype mismatching affects outcomes after alternative donor hematopoietic cell transplantation

GRFS and CRFS in alternative donor hematopoietic cell transplantation for pediatric patients with acute leukemia.

We report graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) (a composite end point of survival without grade III-IV acute GVHD [aGVHD], systemic therapy-requiring chronic GVHD [cGVHD], or relapse) and cGVHD-free relapse-free survival (CRFS) among pediatric patients with acute leukemia (n = 1613) who underwent transplantation with 1 antigen-mismatched (7/8) bone marrow (BM; n = 172) or umbilical cord blood (UCB; n = 1441). Multivariate analysis was performed using Cox proportional hazards models. To account for multiple testing, P \u3c .01 for the donor/graft variable was considered statistically significant. Clinical characteristics were similar between UCB and 7/8 BM recipients, because most had acute lymphoblastic leukemia (62%), 64% received total body irradiation-based conditioning, and 60% received anti-thymocyte globulin or alemtuzumab. Methotrexate-based GVHD prophylaxis was more common with 7/8 BM (79%) than with UCB (15%), in which mycophenolate mofetil was commonly used. The univariate estimates of GRFS and CRFS were 22% (95% confidence interval [CI], 16-29) and 27% (95% CI, 20-34), respectively, with 7/8 BM and 33% (95% CI, 31-36) and 38% (95% CI, 35-40), respectively, with UCB (P \u3c .001). In multivariate analysis, 7/8 BM vs UCB had similar GRFS (hazard ratio [HR], 1.12; 95% CI, 0.87-1.45; P = .39), CRFS (HR, 1.06; 95% CI, 0.82-1.38; P = .66), overall survival (HR, 1.07; 95% CI, 0.80-1.44; P = .66), and relapse (HR, 1.44; 95% CI, 1.03-2.02; P = .03). However, the 7/8 BM group had a significantly higher risk for grade III-IV aGVHD (HR, 1.70; 95% CI, 1.16-2.48; P = .006) compared with the UCB group. UCB and 7/8 BM groups had similar outcomes, as measured by GRFS and CRFS. However, given the higher risk for grade III-IV aGVHD, UCB might be preferred for patients lacking matched donors. © 2019 American Society of Hematology. All rights reserved

Incidence, Risk Factors, and Outcomes of Patients Who Develop Mucosal Barrier Injury-Laboratory Confirmed Bloodstream Infections in the First 100 Days after Allogeneic Hematopoietic Stem Cell Transplant

Importance: Patients undergoing hematopoietic stem cell transplant (HSCT) are at risk for bloodstream infection (BSI) secondary to translocation of bacteria through the injured mucosa, termed mucosal barrier injury-laboratory confirmed bloodstream infection (MBI-LCBI), in addition to BSI secondary to indwelling catheters and infection at other sites (BSI-other). Objective: To determine the incidence, timing, risk factors, and outcomes of patients who develop MBI-LCBI in the first 100 days after HSCT. Design, Setting, and Participants: A case-cohort retrospective analysis was performed using data from the Center for International Blood and Marrow Transplant Research database on 16875 consecutive pediatric and adult patients receiving a first allogeneic HSCT from January 1, 2009, to December 31, 2016. Patients were classified into 4 categories: MBI-LCBI (1481 [8.8%]), MBI-LCBI and BSI-other (698 [4.1%]), BSI-other only (2928 [17.4%]), and controls with no BSI (11768 [69.7%]). Statistical analysis was performed from April 5 to July 17, 2018. Main Outcomes and Measures: Demographic characteristics and outcomes, including overall survival, chronic graft-vs-host disease, and transplant-related mortality (only for patients with malignant disease), were compared among groups. Results: Of the 16875 patients in the study (9737 [57.7%] male; median [range] age, 47 [0.04-82] years) 13686 (81.1%) underwent HSCT for a malignant neoplasm, and 3189 (18.9%) underwent HSCT for a nonmalignant condition. The cumulative incidence of MBI-LCBI was 13% (99% CI, 12%-13%) by day 100, and the cumulative incidence of BSI-other was 21% (99% CI, 21%-22%) by day 100. Median (range) time from transplant to first MBI-LCBI was 8 (<1 to 98) days vs 29 (<1 to 100) days for BSI-other. Multivariable analysis revealed an increased risk of MBI-LCBI with poor Karnofsky/Lansky performance status (hazard ratio [HR], 1.21 [99% CI, 1.04-1.41]), cord blood grafts (HR, 2.89 [99% CI, 1.97-4.24]), myeloablative conditioning (HR, 1.46 [99% CI, 1.19-1.78]), and posttransplant cyclophosphamide graft-vs-host disease prophylaxis (HR, 1.85 [99% CI, 1.38-2.48]). One-year mortality was significantly higher for patients with MBI-LCBI (HR, 1.81 [99% CI, 1.56-2.12]), BSI-other (HR, 1.81 [99% CI, 1.60-2.06]), and MBI-LCBI plus BSI-other (HR, 2.65 [99% CI, 2.17-3.24]) compared with controls. Infection was more commonly reported as a cause of death for patients with MBI-LCBI (139 of 740 [18.8%]), BSI (251 of 1537 [16.3%]), and MBI-LCBI plus BSI (94 of 435 [21.6%]) than for controls (566 of 4740 [11.9%]). Conclusions and Relevance: In this cohort study, MBI-LCBI, in addition to any BSIs, were associated with significant morbidity and mortality after HSCT. Further investigation into risk reduction should be a clinical and scientific priority in this patient population

Tacrolimus versus Cyclosporine after Hematopoietic Cell Transplantation for Acquired Aplastic Anemia

AbstractCombinations of cyclosporine (CSP) with methotrexate (MTX) have been widely used for immunosuppression after allogeneic transplantation for acquired aplastic anemia. We compared outcomes with tacrolimus (TAC)+MTX versus CSP+MTX after transplantation from HLA-identical siblings (SIB) or unrelated donors (URD) in a retrospective cohort of 949 patients with severe aplastic anemia. Study endpoints included hematopoietic recovery, graft failure, acute graft-versus-host disease (GVHD), chronic GVHD, and mortality. TAC+MTX was used more frequently in older patients and, in recent years, in both SIB and URD groups. In multivariate analysis, TAC+MTX was associated with a lower risk of mortality in URD recipients and with slightly earlier absolute neutrophil count recovery in SIB recipients. Other outcomes did not differ statistically between the 2 regimens. No firm conclusions were reached regarding the relative merits of TAC+MTX versus CSP+MTX after hematopoietic cell transplantation for acquired aplastic anemia. Prospective studies would be needed to determine whether the use of TAC+MTX is associated with lower risk of mortality in URD recipients with acquired aplastic anemia

Comparative Analysis of Calcineurin Inhibitor-Based Methotrexate and Mycophenolate Mofetil-Containing Regimens for Prevention of Graft-versus-Host Disease after Reduced-Intensity Conditioning Allogeneic Transplantation

The combination of a calcineurin inhibitor (CNI) such as tacrolimus (TAC) or cyclosporine (CYSP) with methotrexate (MTX) or with mycophenolate mofetil (MMF) has been commonly used for graft-versus-host disease (GVHD) prophylaxis after reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (alloHCT), but there are limited data comparing efficacy of the 2 regimens. We evaluated 1564 adult patients who underwent RIC alloHCT for acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), and myelodysplastic syndrome (MDS) from 2000 to 2013 using HLA-identical sibling (matched related donor [MRD]) or unrelated donor (URD) peripheral blood graft and received CYSP or TAC with MTX or MMF for GVHD prophylaxis. Primary outcomes of the study were acute and chronic GVHD and overall survival (OS). The study divided the patient population into 4 cohorts based on regimen: MMF-TAC, MMF-CYSP, MTX-TAC, and MTX-CYSP. In the URD group, MMF-CYSP was associated with increased risk of grade II to IV acute GVHD (relative risk [RR], 1.78; P <.001) and grade III to IV acute GVHD (RR, 1.93; P =.006) compared with MTX-TAC. In the URD group, use of MMF-TAC (versus MTX-TAC) lead to higher nonrelapse mortality. (hazard ratio, 1.48; P =.008). In either group, no there was no difference in chronic GVHD, disease-free survival, and OS among the GVHD prophylaxis regimens. For RIC alloHCT using MRD, there are no differences in outcomes based on GVHD prophylaxis. However, with URD RIC alloHCT, MMF-CYSP was inferior to MTX-based regimens for acute GVHD prevention, but all the regimens were equivalent in terms of chronic GVHD and OS. Prospective studies, targeting URD recipients are needed to confirm these results