New approaches to graft engineering for haploidentical bone marrow transplantation.

Haploidentical transplantation opens the possibility to offer this treatment to a large number of patients with an otherwise incurable disease, such as some hematologic or oncologic malignancies, inborn or acquired bone marrow failure syndromes, hemoglobinopathies, immunodeficiencies, or other genetic diseases. Initial attempts at haploidentical transplantation using unmanipulated bone marrow were associated with a high transplant-related mortality. However, recent insights into the biology of haploidentical transplantation, the availability of effective in vivo large-scale graft-manipulation technology, and improved supportive care strategies have led to and are still leading to significantly better outcomes compared to previous decades.

Adoptive transfer of epstein-barr virus (EBV) nuclear antigen 1-specific t cells as treatment for EBV reactivation and lymphoproliferative disorders after allogeneic stem-cell transplantation.

Purpose: Reactivation of Epstein-Barr virus (EBV) after allogeneic stem-cell transplantation (SCT) can lead to severe life-threatening infections and trigger post-transplantation lymphoproliferative disease (PTLD). Since EBV-specific T cells could prevent PTLD, cellular immunotherapy has been a promising treatment option. However, generation of antigen-specific T-cell populations has been difficult within a short time frame.

CD133-Positive Hematopoietic Stem Cells: From Biology to Medicine.

Lifelong hematopoiesis is sustained by a very small number of hematopoietic stem cells capable of self-renewal and differentiation into multiple hematopoietic lineages. The sialomucin CD34 has been, and is currently, used for the identification and purification of primitive hematopoietic progenitors. Depending on the source of stem cells, CD34 may not be expressed on all progenitor cells.

Allo-SCT using BU, CY and melphalan for children with AML in second CR.

Based on the results from the AML-BFM 98 trial, hematopoietic SCT (HSCT) is recommended for children with AML in second CR only. Here, we retrospectively analyze interphase data of children who underwent HSCT after myeloablative conditioning with BU, CY, and melphalan (BuCyMel) for AML in second remission (CR2) between 1998 and 2009. Out of 152 children, transplant data were available on 109 individuals.

Induction of Thelper1-driven antiviral T-cell lines for adoptive immunotherapy is determined by differential expression of IFN-γ and T-cell activation markers.

Viral infections with cytomegalovirus (CMV) or human adenovirus (HAdV) after stem cell transplantation are still associated with a high morbidity and mortality. Transfer of T-cell immunity from a healthy individual to a stem cell transplant recipient, known as adoptive T-cell transfer, has been shown to be effective to prevent viral complications. Treatment efficacy will depend on the availability of functional T-cell lines with a strong T(helper)1 response.

Analysis of posaconazole as oral antifungal prophylaxis in pediatric patients under 12 years of age following allogeneic stem cell transplantation.

Background: Pediatric patients undergoing hematopoietic stem cell transplantation (HSCT) are at high risk of acquiring fungal infections. Antifungal prophylaxis shortly after transplantation is therefore indicated, but data for pediatric patients under 12 years of age are scarce. To address this issue, we retrospectively assessed the safety, feasibility, and initial efficacy of prophylactic posaconazole in children.

Juvenile metachromatic leukodystrophy 10 years post transplant compared with a non-transplanted cohort.

Metachromatic leukodystrophy (MLD) is a rare inborn error of metabolism leading to severe neurological symptoms and early death. Hematopoietic SCT (HSCT) is considered a treatment option, but results are inconsistent and comparison with natural history is practically missing. We compare a girl with juvenile MLD 10 years after allogeneic HSCT not only with her untreated sister, but also with a large cohort of untreated patients.

Negative depletion of CD3(+) and TcRαβ(+) T cells.

Purpose Of Review: In contrast to CD34(+) positive selection, negative depletion strategies retain large numbers of effector cells in allogeneic peripheral stem cell grafts, such as natural killer (NK) and other cells. This review summarizes the clinical experience obtained using negative depletion approaches of CD3(+) and T-cell receptor (TcR)αβ(+) T lymphocytes.

Recent Findings: Attempts to improve immune reconstitution and to better exploit the graft-versus-malignancy effect after transplantation of T-cell-depleted grafts through the preservation of immune effector cells led to the development of CD3-, CD3/CD19- and more recently TcRαβ/CD19-negative depletion strategies of mobilized peripheral stem cell grafts.

Immune reconstitution and strategies for rebuilding the immune system after haploidentical stem cell transplantation.

Haploidentical hematopoietic stem cell transplantation is a curative alternative option for patients without an otherwise suitable stem cell donor. In order to prevent graft-versus-host disease (GvHD), different in vitro and in vivo T cell-depletion strategies have been developed. A delayed immune reconstitution is common to all these strategies, and an impaired immune function after haploidentical transplantation with subsequent infections is a major cause of deaths in these patients.

EVI-1 modulates leukemogenic potential and apoptosis sensitivity in human acute lymphoblastic leukemia.

The transcriptional regulator ecotropic viral integration site-1 (EVI-1) has mainly been studied for its role in myeloid malignancies, in which high EVI-1 levels are associated with particularly aggressive disease. The role of EVI-1 in lymphoid cells, however, is largely unknown. Here we show that EVI-1 is indeed expressed in lymphoid malignancies such as acute lymphoblastic leukemia (ALL) and a subset of chronic lymphocytic leukemia.

Human leukocyte antigen distribution in German Caucasians with advanced Ewing's sarcoma.

Background: Risk stratification criteria for patients with Ewing's sarcoma family of tumors (ESFT) are still limited. We hypothesized divergent human leukocyte antigen (HLA) patterns in ESFT patients and compared HLA-A, -B and -DR phenotype frequencies of patients with advanced ESFT with those of healthy controls.

Patients: HLA types of all German Caucasian patients with advanced ESFT and available HLA-A, -B and -DR data registered in the European Group for Blood and Marrow Transplantation, Paediatric Registry for Stem Cell Transplantation and the MetaEICESS data bases (study group, n=30) were retrospectively compared with HLA types of healthy German stem cell donors (control group, n=8 862 for single HLA frequencies and n=8 839 for allele combinations).

Caspofungin as antifungal prophylaxis in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation: a retrospective analysis.

Background: Pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) often receive intravenous liposomal amphotericin B (L-AmB) as antifungal prophylaxis. There are no guidelines for antifungal prophylaxis in children in this situation. Caspofungin (CAS), a broad-spectrum echinocandin, could be an effective alternative with lower nephrotoxicity than L-AmB.

Characterisation of the cell line HC-AFW1 derived from a pediatric hepatocellular carcinoma.

Current treatment of paediatric hepatocellular carcinoma (HCC) is often inefficient due to advanced disease at diagnosis and resistance to common drugs. The aim of this study was to generate a cell line derived from a paediatric HCC in order to expand research in this field. We established the HC-AFW1 cell line from a liver neoplasm of a 4-year-old boy through culturing of primary tumor specimens.

Siglec-7 tetramers characterize B-cell subpopulations and leukemic blasts.

Cell surface glycosylation has important regulatory functions in the maturation, activation, and homeostasis of lymphocytes. The family of human sialic acid-binding immunoglobulin-like lectins (siglecs) comprises inhibitory as well as activating receptors intimately involved in the regulation of immune responses. Analyses of the interaction between siglecs and glycans are hampered by the low affinity of this interaction.

Surgical management of stem cell transplantation-related complications in children.

HSCT is an established treatment option for some children with life-threatening diseases, but complications remain a major cause of morbidity and mortality. This retrospective data analysis addresses the surgical issues of children with HSCT-related complications. Between 2002 and 2008, HSCT was performed in 240 children for leukemias/lymphomas (n=135), solid tumors (n=59), immunodeficiencies (n=20), lipid storage diseases (n=10), autoimmune diseases (n=9), and others (n=7).

Detectable minimal residual disease before hematopoietic cell transplantation is prognostic but does not preclude cure for children with very-high-risk leukemia.

In patients with acute leukemia, detection of minimal residual disease (MRD) before allogeneic hematopoietic cell transplantation (HCT) correlates with risk of relapse. However, the level of MRD that is most likely to preclude cure by HCT is unclear, and the benefit of further chemotherapy to reduce MRD before HCT is unknown. In 122 children with very-high-risk acute lymphoblastic leukemia (ALL; n = 64) or acute myeloid leukemia (AML, n = 58), higher MRD levels at the time of HCT predicted a poorer survival after HCT (P = .

Influence of dichloroacetate (DCA) on lactate production and oxygen consumption in neuroblastoma cells: is DCA a suitable drug for neuroblastoma therapy?

Many cancer cells metabolize glucose preferentially via pyruvate to lactate instead to CO(2) and H(2)O (oxidative phosphorylation) even in the presence of oxygen (Warburg effect). Dichloroacetate (DCA) is a drug which is able to shift pyruvate metabolism from lactate to acetyl-CoA (tricarboxylic acid cycle) by indirect activation of pyruvate dehydrogenase (PDH). This can subsequently lead to an increased flow of oxygen in the respiratory chain, associated with enhanced generation of reactive oxygen species (ROS) which may cause apoptosis.

Haploidentical allogeneic hematopoietic cell transplantation in adults using CD3/CD19 depletion and reduced intensity conditioning: a phase II study.

Background: We report a prospective multicenter phase II study of haploidentical hematopoietic stem cell transplantation using CD3/CD19-depleted grafts after reduced intensity conditioning with fludarabine, thiotepa, melphalan and OKT-3.

Design And Methods: Sixty-one adults with a median age of 46 years (range 19-65 years) have been enrolled. Diagnoses were acute myeloid leukemia (n=38), acute lymphoblastic leukemia (n=8), non-Hodgkin's lymphoma (n=6), myeloma (n=4), chronic myeloid leukemia (n=3), chronic lymphatic leukemia (n=1) and myelodysplastic syndrome (n=1).

Bacterial reprogramming of PBMCs impairs monocyte phagocytosis and modulates adaptive T cell responses.

Septic diseases are characterized by an initial systemic, proinflammatory phase, followed by a period of anti-inflammation. In the context of the latter, monocytes have been described to display altered functions, including reduced TNF secretion and T cell-stimulating capacities in response to recall antigens. This hyporesponsiveness is supposed to be detrimental for coping with secondary infections.

A phase I/II study of CY and topotecan in patients with high-risk malignancies undergoing autologous hematopoietic cell transplantation: the St Jude long-term follow-up.

Fifty-eight consecutive children with high-risk malignancies were treated with CY, and targeted topotecan followed by autologous hematopoietic cell transplantation (AHCT) in a phase I/II Institutional Review Board-approved study. Twelve participants enrolled in phase I; 5 received dose level 1 of topotecan 3 mg/m(2) per day, with subsequent doses targeted to total systemic exposure of 100±20 ng h/mL and CY 750 mg/m(2) per day. Seven participants received dose level 2.

Monocytes derived from humanized neonatal NOD/SCID/IL2Rγ(null) mice are phenotypically immature and exhibit functional impairments.

Trials of immune-modulating drugs in septic patients have mostly failed to demonstrate clinical efficacy. Thus, we sought to generate a surrogate model of myelomonocytic lineage differentiation that would potentially allow sepsis induction and preclinical testing of anti-inflammatory drugs. Comparing transplantation of cord blood-derived stem cells in neonatal NOD/SCID/IL2Rγ(null) (neonatal huNSG) mice with transplantation of adult peripheral mobilized stem cells into adult NSG (adult huNSG) recipients, we demonstrate that myelomonocytic lineage differentiation in neonatal huNSG mice is retarded and monocytes are phenotypically immature with respect to HLA-DR expression and the emergence of CD80(+)CD86(+) monocytes.

New strategies for haploidentical transplantation.

Haploidentical transplantation in children opens the possibility to offer this treatment to every child with an otherwise incurable disease, such as some hematological or oncological malignancies, inborn or acquired bone marrow-failure syndromes, hemoglobinopathies, immunodeficiencies, or other genetic diseases. Although initial attempts at haploidentical transplantation were associated with a high transplant-related mortality, recent insights into the biology of haploidentical transplantation, the availability of effective in vivo large-scale graft-manipulation technology, and improved supportive care strategies have led to and are still leading to significantly better outcomes of haploidentical transplantation as compared with previous decades. In addition, expensive and time-consuming searches for matched unrelated donors (MUDs) as well as the expensive establishment and maintenance of cord blood banks are not necessary.