Therapeutic efficacy of platelet transfusion in patients with acute leukemia: an evaluation of methods.

Background: Clinical effect of platelet (PLT) transfusion is monitored by measures of PLT viability (PLT recovery and survival) and functionality. In this study we evaluate and compare transfusion effect measures in patients with chemotherapy-induced thrombocytopenia due to treatment of acute leukemia.

Study Design And Methods: Forty transfusions (28 conventional gamma-irradiated and 12 pathogen-inactivated photochemical-treated PLT concentrates [PCs]) were investigated.

Primary human acute myelogenous leukemia cells release matrix metalloproteases and their inhibitors: release profile and pharmacological modulation.

Objectives: Angiogenesis seems important for both leukemogenesis and chemosensitivity in acute myelogenous leukemia (AML). Angiogenesis is regulated by the balance between pro- and antiangiogenic cytokines, which also indicates an important role of matrix metalloproteases (MMPs) and their natural inhibitors, tissue inhibitors of metalloproteases (TIMPs). We investigated the constitutive release of MMPs and TIMPs for a large group of consecutive AML patients.

Connexin-based signaling in acute myelogenous leukemia (AML).

Normal and malignant hematopoiesis are regulated by intercellular communication in the hematopoietic microenvironments, and both soluble mediators as well as direct cell-cell contact play important functional roles. Gap junctions are complex membrane structures that transfer molecules between neighboring cells and thereby alter intracellular signaling and metabolism. The gap junction building blocks, the connexins, are also involved in gap junction-independent intercellular communication by forming hemichannels that transfer substances between the intra- and extracellular spaces.

Use of different DMSO concentrations for cryopreservation of autologous peripheral blood stem cell grafts does not have any major impact on levels of leukocyte- and platelet-derived soluble mediators.

Background Aims: Infusion of stem cell autografts can be associated with adverse effects. Necrotic normal leukocytes, cytokines or intracellular mediators released from leukocytes and platelets or the cryo-protectant dimethyl sulfoxide (DMSO) may contribute to this. Cryopreservation using 5% instead of 10% DMSO improves CD34(+) cell viability and therefore we investigated whether using less DMSO had favorable outcomes on leukocyte viability and levels of various soluble mediators in the graft supernatant.

Heat shock protein 90 - a potential target in the treatment of human acute myelogenous leukemia.

Heat shock proteins (HSPs) are molecular chaperones that stabilize folding and conformation of normal as well as oncogenic proteins. These chaperones thereby prevent the formation of protein aggregates. HSPs are often overexpressed in human malignancies, including AML.

Should low-dose mycophenolate mofetil be used to prolong the response after rituximab therapy in patients with immune thrombocytopenic purpura? A case report.

Rituximab and mycophenolate mofetil are used in the treatment of resistant immune thrombocytopenic purpura (ITP). Both therapeutic approaches can induce responses in subsets of patients, but these responses are usually of limited duration and often lasting for less than one year. Mycophenolate mofetil 250 mg twice daily was insufficient to induce a prolonged response.

Long-term cryopreservation of autologous stem cell grafts: a clinical and experimental study of hematopoietic and immunocompetent cells.

Background: Autologous stem cell transplantation(ASCT) is used in the treatment of several malignancies.Harvesting sufficient peripheral blood progenitor cells (PBPCs) for a potential second autotransplantation at the time of relapse several years after diagnosis is becoming an increasingly common practice.

Study Design And Methods: Cryopreserved PBPCs were prepared with different concentrations of dimethyl sulfoxide (DMSO; 2, 4, 5, and 10%) and stored for at least 5 years before the recovery of CD34+ cells and various T- and natural killer (NK)-cell subsets were analyzed by flow cytometry.

The protein kinase C agonist PEP005 increases NF-kappaB expression, induces differentiation and increases constitutive chemokine release by primary acute myeloid leukaemia cells.

Acute myeloid leukaemia (AML) cells show constitutive release of several chemokines that occurs in three major clusters: (I) chemokine (C-C motif) ligand (CCL)2-4/chemokine (C-X-C motif) ligand (CXCL)1/8, (II) CCL5/CXCL9-11 and (III) CCL13/17/22/24/CXCL5. Ingenol-3-angelate (PEP005) is an activator of protein kinase C and has antileukaemic and immunostimulatory effects in AML. We investigated primary AML cells derived from 35 unselected patients and determined that PEP005 caused a dose-dependent increase in the release of chemokines from clusters I and II, including several T cell chemotactic chemokines.

Connexins are active participants of hematopoietic stem cell regulation.

Intercellular communication participates in the regulation of normal hematopoiesis and possibly in neoplastic transformations in the hematopoietic niches. The role of gap junctions (GJs) and their connexins (Cxs) on hematopoietic tissues have been studied since the 1970s. Clearly, GJs are involved in different functional characteristics and connexin expression seems to be thoroughly regulated in hematopoietic tissues, suggesting that these molecules participate in the physiology of hematopoiesis.

Targeted therapy in acute myeloid leukaemia: current status and future directions.

Background: The limit of acceptable toxicity for standard chemotherapeutic drugs used in acute myeloid leukaemia (AML) therapy has been reached. New therapeutic strategies are therefore needed.

Objective: This review summarizes development in new strategies, and gives an overview of the clinical status on new drugs for non-promyelocytic AML in adults.

Genes of cell-cell interactions, chemotherapy detoxification and apoptosis are induced during chemotherapy of acute myeloid leukemia.

Background: The molecular changes in vivo in acute myeloid leukemia cells early after start of conventional genotoxic chemotherapy are incompletely understood, and it is not known if early molecular modulations reflect clinical response.

Methods: The gene expression was examined by whole genome 44 k oligo microarrays and 12 k cDNA microarrays in peripheral blood leukocytes collected from seven leukemia patients before treatment, 2-4 h and 18-24 h after start of chemotherapy and validated by real-time quantitative PCR. Statistically significantly upregulated genes were classified using gene ontology (GO) terms.

[Granulocyte transfusion].

Background: Granulocyte transfusion is used in the treatment of severe, sustained or complicated infection and neutropenia. In recent years, the method's efficacy has improved and its availability increased. After the introduction of granulocyte colony-stimulating factor (G-CSF) there has been a growing interest for granulocyte transfusion, and effective methods for collection and transfusion of granulocytes are now in clinical use.

Anticancer immunotherapy in combination with proapoptotic therapy.

Induction of immune responses against cancer-associated antigens is possible, but the optimal use of this strategy remains to be established and especially the combination of T cell therapy and the use of new targeted therapeutic agents should be investigated. The design of future clinical studies then has to consider several issues. Firstly, induction of anticancer T cell reactivity seems most effective in patients with low disease burden.

Primary human acute myeloid leukaemia cells increase the proliferation of microvascular endothelial cells through the release of soluble mediators.

Bone marrow angiogenesis is suggested to play a role in the pathogenesis of acute myeloid leukaemia (AML) and endothelial cells may mediate chemosensitivity. This study investigated in vitro endothelial effects of coculture of microvascular endothelial cells (MVEC) with AML cells derived from 33 consecutive AML patients. A proliferation assay showed that (i) AML cells from the majority of patients examined increased endothelial cell proliferation, while cytokine neutralizing experiments had divergent effects on proliferation and (ii) the angiopoietin/Tie2 system was important for growth of AML cells, and angiopoietin-1 induced phosphorylation of signal transducers and activators of transcription (STAT) proteins in AML cells.

A subset of patients with high-risk acute myelogenous leukemia shows improved peripheral blood cell counts when treated with the combination of valproic acid, theophylline and all-trans retinoic acid.

Acute myelogenous leukemia (AML) patients (24 consecutive patients, median age 71 years, 17 high-risk disease) were treated with all-trans retinoic acid, theophylline and valproic acid. Among 22 evaluable patients 9 responded with increased normal peripheral blood cell counts. The responses could be classified as hematological improvement according to response criteria for patients with myelodysplastic syndromes (MDS) for four patients only.

Hematopoietic engraftment of dimethyl sulfoxide-depleted autologous peripheral blood progenitor cells.

Background: Autologous stem cell transplantation with cryopreserved autografts is a prerequisite for high-dose chemotherapy in treatment of several malignancies. Adverse effects due to the cryoprotectant dimethyl sulfoxide (DMSO) vary from mild to severe. DMSO-associated adverse effects can be reduced by DMSO depletion before autograft infusion.

In vivo biological effects of ATRA in the treatment of AML.

Background: All-trans retinoic acid (ATRA) is mandatory in the treatment of acute promyelocytic leukaemia (APL). Experimental studies suggest that ATRA can induce differentiation and apoptosis in leukaemia cells also for other acute myelogenous leukaemia (AML) subtypes, but the clinical observations are conflicting.

Design And Methods: Twenty-two AML patients with non-APL disease received oral ATRA alone (22.

[Changes in smoking habits among medical students in Bergen 2004-2006].

Background: Smoking and snuff habits among medical students are of interest because they may reflect the attitude to smoking and snuff among future doctors, but few longitudinal studies have been performed.

Material And Method: A standard questionnaire, developed by Statistics Norway, was handed out to all medical students at the University of Bergen during plenum lectures in the spring 2004 and 2006. The questionnaires were marked by personal codes to enable follow-up of smoking and snuff habits for each individual student during the study period.

In vitro induction of a dendritic cell phenotype in primary human acute myelogenous leukemia (AML) blasts alters the chemokine release profile and increases the levels of T cell chemotactic CCL17 and CCL22.

Immunotherapy is now considered in acute myelogenous leukemia (AML). A dendritic cell (DC) phenotype can be induced in primary human AML cells by in vitro culture in the presence of various cytokine combinations. The aim was to investigate whether this phenotypic alteration is associated with altered chemokine release.

Autologous peripheral blood progenitor cells cryopreserved with 5 and 10 percent dimethyl sulfoxide alone give comparable hematopoietic reconstitution after transplantation.

Background: Previous in vitro studies have demonstrated decreased apoptosis and necrosis in peripheral blood progenitor cells (PBPCs) cryopreserved with 5 percent instead of 10 percent dimethyl sulfoxide (DMSO). This study was carried out to investigate whether these in vitro findings were supported by clinical data concerning hematopoietic engraftment after autologous stem cell transplantations with PBPCs cryopreserved with 5 and 10 percent DMSO.

Study Design And Methods: During a 6-year period, 103 consecutive patients with newly diagnosed multiple myeloma (MM; n = 58) and lymphoma (n = 45) were transplanted with autologous PBPCs.

Platelet-released supernatants enhance hematopoietic stem cell proliferation in vitro.

Peripheral blood stem cell transplantation (PBSCT) is used to reconstitute normal hematopoiesis after myeloablative chemotherapy. The hematopoietic stem cells are collected from the blood by apheresis machines using density gradient centrifugation. Because of density similarities the grafts contain high levels of leukocytes and platelets that release various mediators into the grafts.

Epigenetic targeting in acute myeloid leukemia: use of flow cytometry in monitoring therapeutic effects.

Flow cytometric techniques have emerged as a powerful tool in hematology allowing fast, sensitive and reproducible multi-parametric analyses at the single cell level of heterogeneous samples. Small subsets of cells can be studied with high degree of accuracy, and a broad and constantly increasing specter of antibodies is available. Flow cytometry has therefore become the method of choice for evaluation of therapeutic effects at single cell level.

Histone deacetylase inhibitors in cancer treatment: a review of the clinical toxicity and the modulation of gene expression in cancer cell.

Characterization of epigenetic events in carcinogenesis has led to the discovery of a new class of oncogenes and thereby a new class of therapeutic targets. Among the new therapeutic approaches are modulation of protein lysine acetylation through inhibition of histone deacetylases (HDACs). HDACs deacetylate histones as well as transcription factors and can modulate gene expression through both these mechanisms in normal and malignant cells.

Global gene expression in classification, pathogenetic understanding and identification of therapeutic targets in acute myeloid leukemia.

Global gene expression analysis by way of DNA microarrays and real time quantitative PCR provides an important supplement to established diagnosis and classification of malignant disease. A comprehensive molecular understanding of the regulatory modules involved in carcinogenesis should also be important for improved identification of therapeutic targets and thus for future individualized therapy, e.g.