Rabbit Anti T-Lymphocyte Globulin Induces Apoptosis in Peripheral Blood Mononuclear Cell Compartments and Leukemia Cells, While Hematopoetic Stem Cells Are Apoptosis Resistant

AbstractPolyclonal anti-T-lymphocyte globulins (ATG) are used in allogeneic stem cell transplantation (SCT) for the prophylaxis of graft versus host disease (GVHD) by in vivo T cell depletion. In this study we investigated the complement independent induction of apoptosis by rabbit ATG in peripheral blood mononuclear cell (PBMNC) compartments and hematopoetic stem cells (HSC). We also detected antileukemic activity of ATG by measuring apoptosis in myeloid and lymphatic leukemia cell lines and primary leukemia cells. We found ATG to induce apoptosis in T-lymphocytes (CD4+, CD8+), B-lymphocytes (CD20+), natural killer (NK)-cells (CD56+), and monocytes (CD14+). HSC, in contrast, were apoptosis resistant and could be growth stimulated by low-dose ATG in the presence of bystander cells. The human leukemia cell lines Jurkat, Daudi, DG-75 (lymphoblastic), and K562, HL-60, KG1, and U937 (myeloblastic) underwent ATG-induced apoptosis, whereas the NK-cell line YT was resistant. Primary leukemia cells from 6 investigated patients with acute lymphoblastic leukemia, 9 of 10 patients with chronic lymphocytic leukemia, and 4 of 8 patients with acute myeloblastic leukemia underwent ATG-induced apoptosis. We conclude apoptosis induction in all PBMNC compartments contributes to GVHD prophylaxis. ATG might support engraftment. Finally, antileukemic activity of ATG could positively influence the transplantation outcome

Intensive Chemotherapy with Autologous Peripheral Blood Stem Cell Transplantation During a 10-Year Period in 64 Patients with Germ Cell Tumor

AbstractDespite gratifying cure rates in germ cell tumors, conventional-dose chemotherapy achieves long-term remissions in less than 50% of patients at high risk. High-dose chemotherapy followed by autologous (auto) peripheral blood stem cell transplantation (PBSCT) has shown impressive remission rates in high-risk and relapsed germ cell tumors. We report on 64 consecutive patients with high- (n = 39), intermediate- (n = 18), and refractory or relapsed low- (n = 7) risk germ cell tumors who underwent auto-PBSCT between January 1993 and February 2003. PBSCTs were performed as a single (n = 40) or repeated (n = 24) transplantation using either etoposide, ifosfamide, and carboplatin (n = 80) or related protocols (paclitaxel, ifosfamide, carboplatin, etoposide [n = 7]; carboplatin, etoposide, thiotepa [n = 4]). With a median follow-up of 6 years, estimated 2- and 5-year overall survivals were 77.2% (95% confidence interval [CI] 66.7-87.7) and 73.1% (95% CI 61.7-84.5), respectively. We observed unfavorable results in those patients showing refractoriness to cisplatin (hazard ratio 20.36; 95% CI 6.64-62.47) or no response to induction chemotherapy (hazard ratio 10.67; 95% CI 1.37-83.37). Auto-PBSCT was well tolerated, showed objective antitumor activity, and achieved long-term survival in patients at high risk and with relapse. Our data suggest that auto-PBSCT can increase response rates and may improve the outcome in these patients

Macroscopic Analysis to identify Stage Boundaries in Multi-Stage Arrival Management

Accommodating the air traffic growth, reducing arrival delay is one of the most important functions of designing the ATM system. One of the newest concepts to further optimize arrival flows is multi-stage arrival management, proposed by DLR, in which different guidance principles to manage the arriving traffic are implemented in different stages. These stages are optimized to the core management task to be done in a certain area of the arrival stream and the conditions of the surrounding environment. This paper discusses this concept through a macroscopic analysis on the overall arrival traffic flows. Further, this paper analyzes parts of the multi-stage arrival management concept applied to Tokyo International Airport as a case study. A stochastic characteristic of arrival trajectories will be discussed as a counterpart of conventional deterministic trajectorybased operation based on data-driven analysis and arrival procedures at the airport. The best strategies of shifting arrival flow control to time-based management is analyzed based on the stochastic data analysis. Impacts of pop-up aircraft are discussed as one of the causes to increase uncertainties in aircraft trajectory management

Marrow versus Blood-Derived Stem Cell Grafts for Allogeneic Transplantation from Unrelated Donors in Patients with Active Myeloid Leukemia or Myelodysplasia

Peripheral blood stem cells (PBSCs) are increasingly used as the graft source in allogeneic hematopoietic cell transplantation. We compared long-term outcome after unrelated donor transplantation of 85 consecutive patients with acute myelogenous leukemia or myelodysplastic syndrome regarding disease status (early disease [CR1, refractory anemia); n = 25 and advanced/active disease [>CR1, >refractory anemia]; n = 60) who were treated with conventional conditioning regimens followed by bone marrow (BM) or PBSC grafts. Graft-versus-host disease prophylaxis consisted mainly of cyclosporine A, short-course methotrexate, and anti-T-lymphocyte globulin. After a median follow-up of 118 months (68-174), the 10-year event-free survival rate after peripheral blood stem cell transplantation (PBSCT) was 54.8% (95% confidence interval [CI], 39.7%-69.8%), and after bone marrow transplantation (BMT), it was 27.9% (14.5%-41.3%; P < .004). In the advanced/active disease group, the 10-year event-free survival rate after PBSCT was 50% (30.8%-69.2%), and after BMT, it was 23.5% (9.3%-37.8%; P < .007). Non relapse mortality was less after PBSCT than BMT (14.3% vs 30.2%), respectively. In multivariate Cox regression analysis, PBSCT showed a better overall survival (OS; hazard ratio [HR], 0.43; 95% CI, 0.23-0.79; P = .007) compared to BMT; unfavorable/unknown prognostic impact cytogenetic abnormalities were an adverse factor for all patients (HR, 2.202; 95% CI, 1.19-4.06; P = .011). In patients with advanced disease, the use of PBSCs showed a significant favorable outcome via multivariate analysis (HR, 0.49; 95% CI, 0.24-0.99; P = .046). Outcome of acute myelogenous leukemia/myelodysplastic syndrome after unrelated hematopoietic cell transplantation is adversely affected by cytogenetic abnormalities and state of remission at hematopoietic cell transplantation. PBSC as a graft source has a significant favorable influence on survival

Reliable multicast in heterogeneous mobile ad-hoc networks

In disaster scenarios, communication infrastructure could be damaged or completely failed. Mobile Ad-hoc Networks (MANETs) can be used to substitute failed communication devices and thus to enable communication. As group communication is an important part in disaster scenarios, multicast will be used to address several nodes. In this paper, we propose our new reliable multicast protocol RMDA (Reliable Multicast over Delay Tolerant Mobile Ad hoc Networks). We introduce an efficient group management approach and a new method for reliable multicast delivery over Delay Tolerant Networks. We show, that our protocol is adaptive to different kinds of MANETs, e.g. with or without clusterheads, respectively. For those without, we use our name resolution over adaptive routing approach

Mocravimod, a Selective Sphingosine-1-Phosphate Receptor Modulator, in Allogeneic Hematopoietic Stem Cell Transplantation for Malignancy

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the sole curative option for patients with acute myelogenous leukemia. Outcomes are limited by leukemia relapse, graft-versus-host disease (GVHD), and abnormal immune reconstitution. Mocravimod (KRP203) is an oral sphingosine-1-phosphate receptor (S1PR) modulator that blocks the signal required by T cells to egress from lymph nodes and other lymphoid organs. Mocravimod retains T cell effector function, a main differentiator to immunosuppressants. In preclinical models, mocravimod improves survival by maintaining graft-versus-leukemia (GVL) activity while reducing GVHD. In patients undergoing allo-HSCT for hematological malignancies, mocravimod is postulated to prevent GVHD by redistributing allogeneic donor T cells to lymphoid tissues while allowing a sufficient GVL effect in the lymphoid, where malignant cells usually reside. The primary objective of this study was to assess the safety and tolerability of mocravimod in patients undergoing allo-HSCT for hematologic malignancies. Secondary objectives were to determine the pharmacokinetic profiles of mocravimod and its active metabolite mocravimod-phosphate in this patient group, as well as to assess GVHD-free, relapse free survival at 6 months after the last treatment. In this 2-part, single- and 2-arm randomized, open-label trial, we evaluated the safety, tolerability, and pharmacokinetics of mocravimod in allo-HSCT recipients (ClinicalTrials.gov identifier NCT01830010). Patients received either 1 mg or 3 mg mocravimod per day on top of standard of care GVHD prophylaxis with either cyclosporine A/methotrexate or tacrolimus/methotrexate. We found that mocravimod can be safely added to standard treatment regimens in patients with hematologic malignancies requiring allo-HSCT. Mocravimod resulted in a significant reduction of circulating lymphocyte numbers and had no negative impact on engraftment and transplantation outcomes. Our results indicate that mocravimod is safe and support a larger study to investigate its efficacy in a homogeneous acute myelogenous leukemia patient population undergoing allo-HSCT