The impact of donor factors on primary non-engraftment in recipients of reduced intensity conditioned transplants from unrelated donors.

Background And Objectives: Primary graft failure is a serious complication following hematopoietic cell transplants, particularly when using unrelated donors. We analyzed factors affecting primary graft failure in recipients of hematopoietic cell transplants from unrelated donors, which were performed using reduced intensity conditioning.

Design And Methods: This was a retrospective analysis of 144 patients whose transplants took place between March 1998 and October 2004.

Conjugation of lentivirus to paramagnetic particles via nonviral proteins allows efficient concentration and infection of primary acute myeloid leukemia cells.

Nonviral producer cell proteins incorporated into retroviral vector surfaces profoundly influence infectivity and in vivo half-life. We report the purification and concentration of lentiviral vectors using these surface proteins as an efficient gene transduction strategy. Biotinylation of these proteins and streptavidin paramagnetic particle concentration enhances titer 400- to 2,500-fold (to 10(9) CFU/ml for vesicular stomatitis virus G protein and 5 x 10(8) for amphotropic murine leukemia virus envelope).

Humoral detection of leukaemia-associated antigens in presentation acute myeloid leukaemia.

The serological analysis of recombinant cDNA expression libraries (SEREX) technique was used to immunoscreen a testes cDNA expression library with sera from newly diagnosed acute myeloid leukaemia (AML) patients. We used a testis cDNA library to aid our identification of cancer-testis (CT) antigens. We identified 44 antigens which we further immunoscreened with sera from AML, chronic myeloid leukaemia (CML), and normal donors.

Detection and clinical significance of bone marrow micrometastases in patients undergoing liver transplantation for hepatocellular carcinoma.

Background: Existing methods of selecting patients with hepatocellular carcinoma (HCC) for liver transplantation rely on computed tomography and magnetic resonance imaging, which fail to detect vascular invasion or micrometastases. Vascular invasion cannot be assessed pretransplant because of the risks of tumor biopsy. Pretransplant detection of micrometastases in bone marrow is an alternative method that may identify patients at risk of recurrence and permit better organ allocation.

Liver transplantation for HCV-related cirrhosis in a patient with gastric mucosa-associated lymphoma (MALToma) pretreated with rituximab.

End-stage liver disease due to chronic hepatitis C virus (HCV) infection is now the most frequent indication for liver transplantation. HCV infection is associated with extrahepatic disease including cryoglobulinemia and lymphoma. The number of patients requiring liver transplantation (LT) for cirrhosis secondary to HCV infection has increased over the past 10 years; consequently, associated extrahepatic manifestations (in particular hematological malignancies) will be more commonly observed in this patient group.

Microarray analysis of tumour antigen expression in presentation acute myeloid leukaemia.

Acute myeloid leukaemia (AML) is a difficult to treat disease, especially for those patients who have no eligible haematopoietic stem cell (HSC) donor. One of the most promising treatment options for these patients is immunotherapy. To investigate the expression of known tumour antigens in AML, we analysed microarray data from 124 presentation AML patient samples and investigated the present/absent calls of 82 tumour-specific or -associated antigens.

Development of a whole cell vaccine for acute myeloid leukaemia.

We describe the modification of tumour cells to enhance their capacity to act as antigen presenting cells with particular focus on the use of costimulatory molecules to do so. We have been involved in the genetic modification of tumour cells to prepare a whole cell vaccine for nearly a decade and we have a particular interest in acute myeloid leukaemia (AML). AML is an aggressive and difficult to treat disease, especially, for patients for whom haematopoietic stem cell (HSC) transplant is not an option.

Direct transcriptional regulation of Bim by FoxO3a mediates STI571-induced apoptosis in Bcr-Abl-expressing cells.

In this study, we have used the human BV173 and the mouse BaF3/Bcr-Abl-expressing cell lines as model systems to investigate the molecular mechanisms whereby STI571 and FoxO3a regulate Bim expression and apoptosis. FoxO3a lies downstream of Bcr-Abl signalling and is constitutively phosphorylated in the Bcr-Abl-positive BV173 and BaF3/Bcr-Abl cells. Inhibition of Bcr-Abl kinase by STI571 results in FoxO3a activation, induction of Bim expression and apoptosis.

IL-2/B7.1 (CD80) fusagene transduction of AML blasts by a self-inactivating lentiviral vector stimulates T cell responses in vitro: a strategy to generate whole cell vaccines for AML.

Combined expression of costimulatory factors and proinflammatory cytokines stimulate effective immune-mediated tumor rejection in a variety of murine tumor models. Specifically, syngeneic tumor cells genetically modified to express B7.1 (CD80) have been shown to induce rejection of previously established murine solid tumors, and transduction with IL-2 can further increase survival.

Antiapoptotic microenvironment of acute myeloid leukemia.

We showed previously that tumor-derived supernatant (TSN) from acute myeloid leukemia (AML) myeloblasts inhibits peripheral blood T cell activation and proliferation, rendering the T cells functionally incompetent. We show here that the AML TSN also significantly delays apoptosis of both resting and stimulated T cells, as judged by reduction in annexin V/propidium iodide staining. In addition, we show that this is not unique to T cells and that AML TSN inhibits apoptosis of peripheral B cells, neutrophils, and monocytes.

Pathobiology, classification, and diagnosis of myelodysplastic syndrome.

Recent advances in molecular genetics have advanced the knowledge regarding the mechanisms leading to myelodysplastic syndrome (MDS), secondary acute myeloid leukemia, and therapy-induced MDS. Unfavorable cytogenetics associated with this group of disorders includes monosomy or deletion of the long arm of chromosomes 5 or 7, inversions of chromosome 3, translocations, deletions, and trisomies involving several other chromosomes. These unbalanced chromosomal aberrations result in hemizygosity and unmasking of oncogenes, changes in levels of expressed genes, or inactivation of tumor suppressor genes.

Reduced-intensity allogeneic hematopoietic stem cell transplantation for myelodysplastic syndrome and acute myeloid leukemia with multilineage dysplasia using fludarabine, busulphan, and alemtuzumab (FBC) conditioning.

Reduced-intensity conditioned (RIC) hematopoietic stem cell transplantation (HSCT) has improved the accessibility of transplantation in patients previously ineligible. We report the results of allografting following conditioning with fludarabine, busulphan, and alemtuzumab in 62 patients with myelodysplastic syndromes (MDSs) (matched sibling donors [24] or volunteer unrelated donors [VUDs, 38]). The median age for sibling recipients was 56 years (range, 41-70 years) and for VUD recipients, 52 years (range, 22-65 years), with a median follow-up (survivors) of 524 days (range, 93-1392 days) and 420 days (range, 53-1495 days), respectively.

Targeted therapies in myeloid leukemia.

Targeted therapies for hematological malignancies have come of age since the advent of all trans retinoic acid (ATRA) for treating APL and STI571/Imatinib Mesylate/Gleevec for CML. There are good molecular targets for other malignancies and several new drugs are in clinical trials. In this review, we will concentrate on individual abnormalities that exist in the myelodysplastic syndromes (MDS) and myeloid leukemias that are targets for small molecule therapies (summarised in Fig.

Role of 4-1BB:4-1BB ligand in cancer immunotherapy.

The activation of T cells plays a central role in antitumor immunity. In order to activate naïve T cells, two key signals are required. Signal one is provided through the T-cell receptor (TCR) while signal two is that of costimulation.

Constitutive DNA damage is linked to DNA replication abnormalities in Bloom's syndrome cells.

Bloom's syndrome (BS) is an autosomal recessive disorder associated with an elevated incidence of cancers. The gene mutated in BS, BLM, encodes a RecQ helicase family member. BS cells exhibit genomic instability, including excessive homologous recombination and chromosomal aberrations.

The myelodysplastic syndromes: a matter of life or death.

Apoptosis is upregulated in early myelodysplastic syndromes (MDS) and may contribute to the peripheral cytopenias commonly observed. Conversely, leukemic progression is associated with abrogation of programmed cell death (PCD). The stage of hematopoietic cell maturation at which defects in PCD arise and the underlying causes of apoptosis dysregulation remain unknown.

Myelodysplastic syndrome.

The last decade has witnessed a multistep evolution in the understanding of the natural history, clinical manifestations, and some of the molecular mechanisms that underlie the ineffective hematopoiesis and leukemic transformation in the myelodysplastic syndrome (MDS). The international prognostic scoring system, FAB, and WHO classifications have helped define specific subgroups with their characteristic cytogenetic, molecular and immunological abnormalities. Until recently the mainstay of the treatment has been entirely supportive with blood and platelet transfusions.

Cyclin D2 controls B cell progenitor numbers.

Cyclin D2 affects B cell proliferation and differentiation in vivo. It is rate-limiting for B cell receptor (BCR)-dependent proliferation of B cells, and cyclin D2-/- mice lack CD5+(B1) B lymphocytes. We show here that the bone marrow (BM) of cyclin D2-/- mice contains half the numbers of Sca1+B220+ B cell progenitors but normal levels of Sca1+ progenitor cells of other lineages.

BEAM-alemtuzumab reduced-intensity allogeneic stem cell transplantation for lymphoproliferative diseases: GVHD, toxicity, and survival in 65 patients.

We report the outcomes of reduced-intensity allogeneic stem cell transplantation using BEAM-alemtuzumab conditioning (carmustine, etoposide, cytosine arabinoside, melphalan, and alemtuzumab 10 mg/d on days -5 to -1) in 6 United Kingdom transplant centers. Sixty-five patients with lymphoproliferative diseases underwent sibling (n = 57) or matched unrelated donor (n = 8) transplantation. Sustained donor engraftment occurred in 60 (97%) of 62 patients.

Apoptosis in the myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are neoplastic dyscrasias characterized by peripheral cytopenia, despite a normocellular or hypercellular bone marrow. In the past decade, it has become apparent that this ineffective hemopoiesis is largely caused by excessive apoptosis of myeloid precursors. There is no evidence for gain-of-function mutations within the apoptotic machinery in MDS.