Acquired severe aplastic anemia (SAA) is a rare hematologic disease associated with significant morbidity and mortality. Immune destruction of hemopoietic stem cells plays an important role in ...pathogenesis, as shown by successful treatment with immunosuppressive agents, leading to transfusion independence or complete recovery of peripheral blood counts in a proportion of patients. Growth factors can be combined with immunosuppressive therapy (IST) and may improve response rates, as recently shown with thrombopoietin analogs. Anabolic steroids may still play a role in combination with IST. The problem with IST is failure to respond and the development of late clonal disorders. Bone marrow transplantation (BMT) is the other therapeutic option: a matched sibling donor remains the best choice. For patients lacking a matched family donor, unrelated donors can be readily found, although mostly for patients of Caucasian origin. Other BMT options include unrelated cord blood or mismatched family donors. Acute and chronic graft-versus-host disease remain important complications of BMT. Patient age is a strong predictor of outcome for both IST and BMT, and must be considered when designing therapeutic strategies. Early diagnosis and treatment, as well as long-term monitoring, remain crucial steps for successful treatment of SAA.
Allogeneic hematopoietic stem-cell transplantation remains the only curative treatment for patients with acquired severe aplastic anemia (SAA). When a matched sibling is not available, one can search ...for a matched unrelated donor or a cord blood unit (CB) in the international registries or, more recently, for an HLA haploidentical (HAPLO) family member. International guidelines call for a course of antithymocyte globulin (ATG) and cyclosporine before a patient with SAA receives a transplant from a donor other than an HLA identical sibling, but whether this is necessary for patients age <20 years is less clear. Here I will examine the rapid increase in HAPLO transplantations for SAA, showing encouraging early results both in children and young adults. Graft-versus-host disease prophylaxis remains of primary importance in patients with SAA, and in vivo T-cell depletion with either ATG or alemtuzumab offers a significant survival advantage. Finally, I will discuss the strong age effect, which is particularly evident at >40 and 50 years of age for reasons not entirely clear and which should be taken into account when designing a treatment strategy for a given patient.
In this paper a second-order homogenization approach for periodic material is derived from an appropriate representation of the down-scaling that correlates the micro-displacement field to the ...macro-displacement field and the macro-strain tensors involving unknown perturbation functions. These functions take into account of the effects of the heterogeneities and are obtained by the solution of properly defined recursive cell problems. Moreover, the perturbation functions and therefore the micro-displacement fields result to be sufficiently regular to guarantee the anti-periodicity of the traction on the periodic unit cell. A generalization of the macro-homogeneity condition is obtained through an asymptotic expansion of the mean strain energy at the micro-scale in terms of the microstructural characteristic size
ɛ
; the obtained overall elastic moduli result to be not affected by the choice of periodic cell. The coupling between the macro- and micro-stress tensor in the periodic cell is deduced from an application of the generalised macro-homogeneity condition applied to a representative portion of the heterogeneous material (cluster of periodic cell). The correlation between the proposed asymptotic homogenization approach and the computational second-order homogenization methods (which are based on the so called
quadratic ansätze
) is obtained through an approximation of the macro-displacement field based on a second-order Taylor expansion. The form of the overall elastic moduli obtained through the two homogenization approaches, here proposed, is analyzed and the differences are highlighted. An evaluation of the developed method in comparison with other recently proposed in literature is carried out in the example where a three-phase orthotropic material is considered. The characteristic lengths of the second-order equivalent continuum are obtained by both the asymptotic and the computational procedures here analyzed. The reliability of the proposed approach is evaluated for the case of shear and extensional deformation of the considered two-dimensional infinite elastic medium subjected to periodic body forces; the results from the second-order model are compared with those of the heterogeneous continuum.
Summary
Acute graft‐versus‐host disease (GvHD) is a frequent complication of allogeneic haemopoietic stem cell transplantation (HSCT) and donor lymphocyte infusions (DLI). Its incidence and severity ...depends on several factors, such as prophylaxis method, donor/recipient matching, intensity of the conditioning regimen and composition of the graft. Significant progress has been made in recent years in understanding the pathogenesis of the disease, and some of these advances have been translated into clinical trials. First‐line treatment of acute GvHD is based on corticosteroids, and produce sustained responses in 50–80% of patients depending on the initial severity. Non‐responders are offered second‐line therapy, with combinations of immunosuppressive agents, but 1‐year survival is 30% in most large trials. New strategies explored include infusion of expanded mesenchymal stem cells (MSC), down regulation of antigen‐presenting cells (APC) and suicide gene transduced T cells. Acute GvHD is complicated by severe immunodeficiency causing life‐threatening infections. To date, GvHD has not been differentiated from the graft‐versus‐leukaemia effect. The present review will discuss some of these aspects.
The outcome of allogeneic stem cell transplantation has improved over the past decades due to a significant reduction of nonrelapse mortality, whereas our ability to control underlying malignant ...diseases has remained unchanged. Reduction of nonrelapse mortality has been achieved in matched sibling donor transplantation, but perhaps more so with unrelated donor transplantation, in part due to the advances in HLA matching between donor and recipient, but also as a result of improved supportive care, better GVHD prophylaxis, and tailored conditioning regimens. Therefore, over the past decade, results of matched sibling donor and unrelated donor grafts have grown more similar, and the difference in 1-year survival for patients with leukemia has gone from 21% in 1988 in favor of MSD to 9% in 2008. However, due to the significant and combined effect of patient, transplantation, and donor variables, comparisons are made here in the context of defined subsets of patients and specific diseases and in some circumstances also looking at separate studies in children and adults.
Microstructured honeycomb materials may exhibit exotic, extreme and tailorable mechanical properties, suited for innovative technological applications in a variety of modern engineering fields. The ...paper is focused on analysing the directional auxeticity of tetrachiral materials, through analytical, numerical and experimental methods. Theoretical predictions about the global elastic properties have been successfully validated by performing tensile laboratory tests on tetrachiral samples, realized with high precision 3D printing technologies. Inspired by the kinematic behaviour of the tetrachiral material, a newly-design bi-layered topology, referred to as bi-tetrachiral material, has been theoretically conceived and mechanically modelled. The novel topology virtuously exploits the mutual collaboration between two tetrachiral layers with opposite chiralities. The bi-tetrachiral material has been verified to outperform the tetrachiral material in terms of global Young modulus and, as major achievement, to exhibit a remarkable auxetic behaviour. Specifically, experimental results, confirmed by parametric analytical and computational analyses, have highlighted the effective possibility to attain strongly negative Poisson ratios, identified as a peculiar global elastic property of the novel bi-layered topology.
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•A novel layered topology of auxetic cellular materials based on the tetrachiral honeycomb microstructure, named bi-tetrachiral material, is proposed.•The global elastic properties of 3D printed samples of the bi-tetrachiral material are experimentally identified from quasi-static tensile tests.•Computational finite element models and beam lattice models efficiently reproduce the experimental response of the bi-tetrachiral material.•The mutual collaboration of two tetrachiral layers with opposite chirality prevents the development of global angular strains under tensile loads.•Parametric analyses show that Poisson ratios close to −1 are achievable by regulating the distance between the interlayer constraints.
We studied adults with acute myeloid leukemia (AML) after haploidentical (n = 192) and 8/8 HLA-matched unrelated donor (n = 1982) transplantation. Haploidentical recipients received calcineurin ...inhibitor (CNI), mycophenolate, and posttransplant cyclophosphamide for graft-versus-host disease (GVHD) prophylaxis; 104 patients received myeloablative and 88 received reduced intensity conditioning regimens. Matched unrelated donor transplant recipients received CNI with mycophenolate or methotrexate for GVHD prophylaxis; 1245 patients received myeloablative and 737 received reduced intensity conditioning regimens. In the myeloablative setting, day 30 neutrophil recovery was lower after haploidentical compared with matched unrelated donor transplants (90% vs 97%, P = .02). Corresponding rates after reduced intensity conditioning transplants were 93% and 96% (P = .25). In the myeloablative setting, 3-month acute grade 2-4 (16% vs 33%, P < .0001) and 3-year chronic GVHD (30% vs 53%, P < .0001) were lower after haploidentical compared with matched unrelated donor transplants. Similar differences were observed after reduced intensity conditioning transplants, 19% vs 28% (P = .05) and 34% vs 52% (P = .002). Among patients receiving myeloablative regimens, 3-year probabilities of overall survival were 45% (95% CI, 36-54) and 50% (95% CI, 47-53) after haploidentical and matched unrelated donor transplants (P = .38). Corresponding rates after reduced intensity conditioning transplants were 46% (95% CI, 35-56) and 44% (95% CI, 0.40-47) (P = .71). Although statistical power is limited, these data suggests that survival for patients with AML after haploidentical transplantation with posttransplant cyclophosphamide is comparable with matched unrelated donor transplantation.
•Lower GVHD after haploidentical transplant with posttransplant cyclophosphamide compared with HLA-matched unrelated donor transplant.•Comparable overall survival after haploidentical compared with matched unrelated donor transplant for AML.
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