Marrow fibrosis and its relevance during imatinib treatment of chronic myeloid leukemia.

In chronic myeloid leukemia (CML), imatinib may reverse bone marrow fibrosis (MF). Whether the unfavorable prognosis of MF is also reversed and whether imatinib guarantees against evolution of MF are unclear as yet. Fifty-nine patients with Ph+ CML treated with > or = 400 mg imatinib/day were examined for MF in 6- to 12-month intervals.

Remarkable leukemogenic potency and quality of a constitutively active neurotrophin receptor, deltaTrkA.

Neurotrophins and their receptors play a key role in neurogenesis and survival. However, we and others have recently obtained evidence for a potential involvement of this receptor system in leukemia. To investigate mechanisms underlying the leukemogenic potential of activated neurotrophin receptor signaling, we analyzed in vivo leukemogenesis mediated by deltaTrkA, a mutant of TRKA (tropomyosin-related kinase A) isolated from a patient with acute myeloid leukemia (AML).

Risks and benefits of erythropoiesis-stimulating agents in cancer management.

Anemia is frequently diagnosed in patients with cancer and its treatment is an important clinical problem. The deficiency in red blood cells (RBCs) can be a debilitating problem, and anemia correlates with poor performance status, deteriorates quality of life, and may negatively influence the prognosis of cancer patients. The development of recombinant human erythropoietins (rhEPO) provides a therapeutic option in patients with mild to moderate anemia.

Use of colony-stimulating factors for chemotherapy-associated neutropenia: review of current guidelines.

Chemotherapy-associated neutropenia is often dose-limiting and may compromise treatment efficacy. Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage-colony-stimulating factor (GM-CSF) are increasingly used to prevent febrile neutropenia (FN) or to increase dose-density. This review discusses recent changes in treatment guidelines for chemotherapy-associated neutropenia.

Hematopoietic growth factors in the treatment of acquired bone marrow failure states.

In severe aplastic anemia (SAA), the use of hematopoietic growth factors (HGFs) to support blood counts is of limited value, as predicted by in vitro studies and measurement of endogenous serum levels of hematopoietic growth factors (HGF), which are markedly elevated. Benefit is usually only seen in those with less severe disease who are unlikely to require HGFs in practice. HGFs administered alone play no role in the treatment of SAA.

Prognosis of acute myeloid leukemia patients up to 60 years of age exhibiting trisomy 8 within a non-complex karyotype: individual patient data-based meta-analysis of the German Acute Myeloid Leukemia Intergroup.

Background And Objectives: Trisomy 8 (+8) is among the commonest genetic aberrations seen in acute myeloid leukemia (AML). However, the prognostic significance of this aberration and the best consolidation strategy for patients with it are still not resolved. Additional prognostic indicators are needed to further classify these patients and determine their appropriate management.

MN1 overexpression induces acute myeloid leukemia in mice and predicts ATRA resistance in patients with AML.

Overexpression of wild-type MN1 is a negative prognostic factor in patients with acute myeloid leukemia (AML) with normal cytogenetics. We evaluated whether MN1 plays a functional role in leukemogenesis. We demonstrate using retroviral gene transfer and bone marrow (BM) transplantation that MN1 overexpression rapidly induces lethal AML in mice.

Gene-expression profiling identifies distinct subclasses of core binding factor acute myeloid leukemia.

Core binding factor (CBF) leukemias, characterized by either inv(16)/t(16;16) or t(8;21), constitute acute myeloid leukemia (AML) subgroups with favorable prognosis. However, there exists substantial biologic and clinical heterogeneity within these cytogenetic groups that is not fully reflected by the current classification system. To improve the molecular characterization we profiled gene expression in a large series (n = 93) of AML patients with CBF leukemia [(inv (16), n = 55; t(8;21), n = 38)].

Comparison between molecularly defined and conventional therapeutics in a conditional BCR-ABL cell culture model.

Accumulating knowledge about the molecular mechanisms causing human diseases can support the development of targeted therapies such as imatinib, a BCR-ABL-specific tyrosine kinase inhibitor to treat chronic myeloid leukemia (CML). Here, we use lentivirus-mediated RNA interference (RNAi) targeting BCR-ABL and the downstream signaling molecules SHP2, STAT5, and Gab2 to compare the efficacy and specificity of molecularly defined therapeutics with that of conventional cytotoxic drugs (cytarabine, doxorubicin, etoposide) in a conditional BCR-ABL cell culture model. IC(50) values were determined for each drug in TonB cells cultured either with interleukin-3 (IL-3) or BCR-ABL, and molecularly defined therapies were studied using lentivirally expressed shRNAs.

Therapeutic use of erythropoietin in dermatooncology.

Erythropoietin has been successfully used in Europe since 1997 in the treatment of anemia induced by chemotherapy of solid tumors. There is only limited experience with regard to its use when treating dermatologic tumors such as metastatic melanoma. We review here current guidelines on the use of erythropoietin in cancer patients and report on our own melanoma patients treated with erythropoietin for chemotherapy-induced anemia.

Good manufacturing practice-compliant validation and preparation of BM cells for the therapy of acute myocardial infarction.

Background: Intracoronary application of BM-derived cells for the treatment of acute myocardial infarction (AMI) is currently being studied intensively. Simultaneously, strict legal requirements surround the production of cells for clinical studies. Thus good manufacturing practice (GMP)-compliant collection and preparation of BM for patients with AMI was established by the Cytonet group.

Targeting vascular endothelial growth factor (VEGF)-receptor-signaling in renal cell carcinoma.

Metastatic renal cell carcinoma (RCC) is resistant to conventional chemotherapy. Combined data for a variety of immunotherapies resulted in an overall chance of partial (PR) or complete remission (CR) of only 12.9%.

Proteomic patterns predict acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

Acute graft-versus-host disease (aGvHD) contributes significantly to morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Diagnosis of GvHD is mainly based on clinical features and tissue biopsies. A noninvasive, unbiased laboratory test for GvHD diagnosis does not exist.

Targeting the RAS signaling pathway in malignant hematologic diseases.

Molecularly targeting signaling pathways that are involved in the pathogenesis of hematopoietic malignancies may lead to more specific and efficacious therapies. Activation of the RAS signal transduction cascade is a common feature in the molecular pathogenesis of hematologic malignancies. A number of novel agents targeting RAS signaling have been developed over the past decade.

Efficacy, safety and tolerability of recombinant factor VIII (REFACTO) in patients with haemophilia A: interim data from a postmarketing surveillance study in Germany and Austria.

An open-label, multicentre, postmarketing surveillance study conducted in Germany and Austria with recombinant factor VIII (REFACTO) has enrolled 217 patients (mean age 26.3 years) from 38 haemophilia centres during the first 4.8 years.

Expression of the miR-17-92 polycistron in chronic myeloid leukemia (CML) CD34+ cells.

Aberrant micro RNA (miRNA) expression has been described in human malignancies including B-cell lymphomas. We here report BCR-ABL- and c-MYC-dependent regulation of miRNA expression in chronic myeloid leukemia (CML) using microarray analysis (miCHIP) and miRNA-specific quantitative real-time reverse transcriptase-polymerase chain reaction (miR-qRT-PCR). In 3 bcr-abl-positive cell lines, expression of miRNAs encoded within the polycistronic miR-17-92 cluster is specifically down-regulated (2- to 5-fold) by both imatinib treatment and anti-BCR-ABL RNA interference (RNAi).

An in Vivo Experimental Comparison of Stainless Steel and Titanium Schanz Screws for External Fixation.

Objective: To compare the clinical benefits of stainless steel (SS) to titanium (Ti) on reducing pin track irritation/infection and pin loosening during external fracture fixation.

Methods: A tibial gap osteotomy was created in 17 sheep and stabilized with four Schanz screws of either SS or Ti and an external fixation frame. Over the 12 week observation period, pin loosening was assessed by grading the radiolucency around the pins and measuring the extraction torque on pin removal at sacrifice.

Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation.

Telomere shortening limits the proliferative lifespan of human cells by activation of DNA damage pathways, including upregulation of the cell cycle inhibitor p21 (encoded by Cdkn1a, also known as Cip1 and Waf1)) (refs. 1-5). Telomere shortening in response to mutation of the gene encoding telomerase is associated with impaired organ maintenance and shortened lifespan in humans and in mice.

Initial chemotherapy with mitoxantrone, chlorambucil, prednisone impairs the collection of stem cells in patients with indolent lymphomas--results of a randomized comparison by the German Low-Grade Lymphoma Study Group.

Myeloablative radio-chemotherapy with subsequent autologous stem cell transplantation (ASCT) significantly prolongs progression free and probably overall survival in follicular lymphoma (FL) in first remission. The current trial explored prospectively the rate of successful stem cell mobilization in patients with advanced stage FL after initial therapy with either Mitoxantrone, Chlorambucil, Prednisone (MCP) or Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (CHOP) as part of a prospective randomized comparison of both regimens. ASCT patients received Dexa-BEAM (Dexamethasone, BCNU, Melphalan, Etoposide, Cytarabine) for mobilization of stem cells.

Identification of novel regulators in T-cell differentiation of aplastic anemia patients.

Background: Aplastic anemia (AA) is a bone marrow failure syndrome mostly characterized by an immune-mediated destruction of marrow hematopoietic progenitor/stem cells. The resulting hypocellularity limits a detailed analysis of the cellular immune response. To overcome this technical problem we performed a microarray analysis of CD3+ T-cells derived from bone marrow aspirates and peripheral blood samples of newly diagnosed AA patients and healthy volunteers.

Classical Hodgkin's lymphoma: molecular evidence for specific alterations in circulating T lymphocytes.

Objective: Impairment in cell-mediated immunity has long been recognized in classical Hodgkin's lymphoma (cHL). The immunosuppressive environment at the tumor site and/or a primary T-cell defect may contribute to an ineffective immune clearance of Hodgkin/Reed-Sternberg (H/R-S) cells. Here, we analyzed whether circulating T lymphocytes of cHL patients show specific alterations in gene expression with possible impact on anti-tumor immunity.

High meningioma 1 (MN1) expression as a predictor for poor outcome in acute myeloid leukemia with normal cytogenetics.

The translocation t(12;22) involves MN1 and TEL and is rarely found in acute myeloid leukemia (AML). Recently, it has been shown in a mouse model that the fusion protein MN1-TEL can promote growth of primitive hematopoietic progenitor cells (HPCs) and, in cooperation with HOXA9, induce AML. We quantified MN1 expression by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) in 142 adult patients with AML with normal cytogenetics treated uniformly in trial AML-SHG 01/99.