The paper is focused on a homogenization procedure for the analysis of wave propagation in materials with periodic microstructure. By a reformulation of the variational-asymptotic homogenization ...technique recently proposed by Bacigalupo and Gambarotta (2012a), a second-gradient continuum model is derived, which provides a sufficiently accurate approximation of the lowest (acoustic) branch of the dispersion curves obtained by the Floquet–Bloch theory and may be a useful tool for the wave propagation analysis in bounded domains. The multi-scale kinematics is described through micro-fluctuation functions of the displacement field, which are derived by the solution of a recurrent sequence of cell BVPs and obtained as the superposition of a static and dynamic contribution. The latters are proportional to the even powers of the phase velocity and consequently the micro-fluctuation functions also depend on the direction of propagation. Therefore, both the higher order elastic moduli and the inertial terms result to depend by the dynamic correctors. This approach is applied to the study of wave propagation in layered bi-materials with orthotropic phases, having an axis of orthotropy parallel to the direction of layering, in which case, the overall elastic and inertial constants can be determined analytically. The reliability of the proposed procedure is analysed by comparing the obtained dispersion functions with those derived by the Floquet–Bloch theory.
The aim of this work is to produce recommendations on the management of allogeneic stem cell transplantation (allo-SCT) in primary myelofibrosis (PMF). A comprehensive systematic review of articles ...released from 1999 to 2015 (January) was used as a source of scientific evidence. Recommendations were produced using a Delphi process involving a panel of 23 experts appointed by the European LeukemiaNet and European Blood and Marrow Transplantation Group. Key questions included patient selection, donor selection, pre-transplant management, conditioning regimen, post-transplant management, prevention and management of relapse after transplant. Patients with intermediate-2- or high-risk disease and age <70 years should be considered as candidates for allo-SCT. Patients with intermediate-1-risk disease and age <65 years should be considered as candidates if they present with either refractory, transfusion-dependent anemia, or a percentage of blasts in peripheral blood (PB) >2%, or adverse cytogenetics. Pre-transplant splenectomy should be decided on a case by case basis. Patients with intermediate-2- or high-risk disease lacking an human leukocyte antigen (HLA)-matched sibling or unrelated donor, should be enrolled in a protocol using HLA non-identical donors. PB was considered the most appropriate source of hematopoietic stem cells for HLA-matched sibling and unrelated donor transplants. The optimal intensity of the conditioning regimen still needs to be defined. Strategies such as discontinuation of immune-suppressive drugs, donor lymphocyte infusion or both were deemed appropriate to avoid clinical relapse. In conclusion, we provided consensus-based recommendations aimed to optimize allo-SCT in PMF. Unmet clinical needs were highlighted.
In the present work, the evolution of damage in periodic composite materials is investigated through a novel finite element-based multiscale computational approach. The proposed methodology is ...developed by means of the original combination of asymptotic homogenization with the phase field approach to nonlocal damage. This last is applied at the macroscale level on the equivalent homogeneous continuum, whose constitutive properties are obtained in closed form via a two-scale asymptotic homogenization scheme. The formulation considers different assumptions on the evolution of damage at the microscale (e.g., damage in the matrix and not in the inclusion/fiber), as well as the role played by the microstructural reinforcement, i.e. its volumetric content and shape. Numerical results show that the proposed formulation leads to an apparent tensile strength and a post-peak branch of unnotched and notched specimens dependent not only on the internal length scale of the phase field approach, as for homogeneous materials, but also on microstructural features. Down-scaling relations provide the full reconstruction of the microscopic fields at any point of the macroscopic model, as a simple post-processing operation.
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.
•Concomitant radio-chemotherapy remain the standard of care in locally advanced HNSCC.•Immunotherapy leads to better oncological results in R/M HNSCC.•Immunotherapy in first line treatment failed to ...improve outcomes.•Design of trials should be based on patients selection or predictive biomarkers.
Immunotherapy represents an effective therapeutic option in the management of recurrent/metastatic head and neck squamous cell carcinoma, along with chemotherapy in metastatic disease or radiotherapy/re-irradiation for (locoregionally confined) recurrent disease.
On the other hand, concomitant chemo-radiation remains the primary treatment modality in many patients with locally advanced disease. In spite of promising preclinical, it is difficult to clearly establish the role of immunotherapy in the upfront management of locally advanced head and neck squamous cell carcinoma and its integration with the standard of care. In this paper, we discuss/review the main results thus far available and outline some unanswered questions that might help design future clinical trials.
In this paper an asymptotic homogenization method for the analysis of composite materials with periodic microstructure in presence of thermodiffusion is described. Appropriate down-scaling relations ...correlating the microscopic fields to the macroscopic displacements, temperature and chemical potential are introduced. The effects of the material inhomogeneities are described by perturbation functions derived from the solution of recursive cell problems. Exact expressions for the overall elastic and thermodiffusive constants of the equivalent first order thermodiffusive continuum are derived. The proposed approach is applied to the case of a two-dimensional bi-phase orthotropic layered material, where the effective elastic and thermodiffusive properties can be determined analytically. Considering this illustrative example and assuming periodic body forces, heat and mass sources acting on the medium, the solution performed by the first order homogenization approach is compared with the numerical results obtained by the heterogeneous model.
GVHD remains the major impediment to broader application of allogeneic haematopoietic SCT. It can be prevented completely, but at the expense of other complications, rejection, relapse or delayed ...immune reconstitution. No optimal prevention or treatment method has been defined. This is reflected by enormous heterogeneity in approaches in Europe. Retrospective comparisons between different policies, although warranted, do not give definite answers. In order to improve the present situation, an European Group for Blood and Marrow Transplantation and the European LeukemiaNet working group has developed in a Delphi-like approach recommendations for prophylaxis and treatment of GVHD in the most common allogeneic transplant setting, transplantation from an HLA-identical sibling or unrelated donor for standard risk malignant disease. The working group proposes these guidelines to be adopted as routine standard in transplantation centres and to be used as comparator in systematic studies evaluating the advantages and disadvantages of practices differing from these recommendations.
This is a report of 148 patients with hematologic malignancies who received an unmanipulated haploidentical bone marrow transplant (BMT), followed by post-transplant high-dose cyclophosphamide ...(PT-CY). All patients received a myeloablative conditioning consisting of thiotepa, busulfan, fludarabine (n=92) or TBI, fludarabine (n=56). The median age was 47 years (17-74); 47 patients were in first remission (CR1), 37 in second remission (CR2) and 64 had an active disease; all patients were first grafts. The diagnosis was acute leukemia (n=75), myelodisplastic syndrome (n=24), myelofibrosis (n=16), high-grade lymphoma (n=15) and others (n=18). GVHD prophylaxis consisted in PT-CY on days +3 and +5, cyclosporine (from day 0), and mycophenolate (from day +1). The median day for neutrophil engraftment was day +18 (13-32). The cumulative incidence of grades II-IV acute GVHD was 24%, and of grades III-IV GVHD 10%. The incidence of moderate-severe chronic GVHD was 12%. With a median follow-up for the surviving patients of 313 days (100-1162), the cumulative incidence of transplant-related mortality (TRM) is 13%, and the relapse-related death is 23%. The actuarial 22 months overall survival is 77% for CR1 patients, 49% for CR2 patients and 38% for patients grafted in relapse (P<0.001). Major causes of death were relapse (22%), GVHD (2%) and infections (6%). We confirm our initial results, suggesting that a myeloablative conditioning regimen followed by unmanipulated haploidentical BMT with PT-CY, results in a low risk of acute and chronic GVHD and encouraging rates of TRM and overall survival, also for patients with active disease at the time of transplant.
Antilymphocyte/thymocyte globulins (ALGs/ATGs) have now been used for over 30 years in the setting of hemopoietic stem cell transplants (HSCT), with the aim of preventing graft-versus-host disease ...(GvHD). This is true especially for transplants from alternative donors. In this review, we will be discussing available published and unpublished data on the advantages and disadvantages of using ALG/ATG before or after an allogeneic HSCT. These studies show that ALG/ATG significantly reduce the incidence and severity of acute and chronic GvHD. Unfortunately, they also show that immune deficiency is a more prolonged and infectious complication more frequent in patients receiving ALG/ATG, suggesting the importance of aggressive monitoring of viral and fungal infections. In particular, the emerging problem of Epstein-Barr virus (EBV) infections and EBV-related lymphoproliferative disorders will be discussed, together with the use of pre-emptive therapy with rituximab. I personally believe ALG/ATG has an important role in allogeneic HSCT, especially today with the increasing use of peripheral blood transplants and the consequent high risk of chronic GvHD. ALG/ATG should be used with caution, and the negative consequences must be understood and possibly prevented.
The paper is focused on the multi-scale modeling of shear banding in a two-phase linear elastic periodically layered strip with damaging interfaces. A two-dimensional layered strip is considered ...subjected to transverse shear and is assumed to have a finite thickness along the direction of the layers and an infinite extension along the direction perpendicular to layering. The strip is analyzed as a second-gradient continuum resulting from a second-order homogenization procedure developed by the Authors, here specialized to the case of layered materials. This analysis is also aimed to understand the influence on the strain localization and post-peak structural response of the displacement boundary conditions prescribed at the strip edges. To this end, a first model representative of the strip with warping allowed at the edges is analyzed in which the strain localization process is obtained as a results of a bifurcation in analogy to the approach by Chambon et al. (1998). A second model is analyzed in which the warping of the edge is inhibited and the damage propagates from the center of the specimen without exhibiting bifurcation phenomena. For this latter case the effects of a possible interaction between the shear band and the boundary shear layer are considered, which are influenced mainly by the characteristic lengths of the model and the strip length. For realistic values of the relevant parameters it is shown that the boundary conditions have a small effects on the elastic response and on the overall strength of the model. Conversely, the boundary conditions have a significant effect on the shear band location, the post-peak response and the structural brittleness. Since the model parameters directly depend on the material microstructure as a result of the homogenization process, both the extension of the shear band and the occurrence of snap-back in the post-peak phase may be controlled in terms of the constitutive parameters and of the geometry of the phases.
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