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This study has investigated quantification of chimerism in sex-mismatched transplantations by quantitative real time PCR (RQ-PCR) using FTA paper for blood sampling. First, we demonstrate that the quantification of DNA from EDTA-blood which has been deposit on FTA card is accurate and reproducible. Secondly, we show that fraction of recipient cells detected by RQ-PCR was concordant between the FTA and salting-out method, reference DNA extraction method. Furthermore, the sensitivity of detection of recipient cells is relatively similar with the two methods. Our results show that this innovative method can be used for MC assessment by RQ-PCR.

We have assessed the possibility that rare allelic variants of the c-Ha-ras-1 locus may be linked to a susceptibility to malignancy [1]. c-Ha-ras-1 genotypes were scored in 41 patients with myelodysplasia (MDS), 51 patients with acute myeloid leukaemia (AML) and 52 normal subjects. The incidence of rare alleles in the MDS patients was 4.8% and in AML an incidence of 15.7% was found. No rare alleles were found in the normal subjects. We conclude that rare alleles in MDS are not a common predisposing factor.

Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative option for patients with Myelodysplastic syndromes (MDS). For many years, the selection of patients to allogeneic HSCT has been largely based on use of the International Prognostic Scoring System-Revised (IPSS-R). However, the recent broader application of next generation sequencing in clinical practice provided an abundance of molecular data and led to the introduction of molecular prognostic scores as IPSS-Molecular (IPSS-M). In this paper, we retrospectively analyzed the outcomes of 57 consecutive MDS patients treated with allogeneic HSCT in our center. Re-stratification from IPSS-R to IPSS-M occurred in almost half of patients. The application of IPSS-M to our cohort demonstrated a stronger prognostic separation compared to IPSS-R and improved the C-index. Very high-risk IPSS-M patients showed worse outcomes following HSCT compared to high-risk patients. This study provides data supporting the need of integrating molecular information in the transplant decision making of patients with MDS. This allows an earlier and better identification of patients to whom the transplant should be advised. • IPSS-R is commonly used to allocate MDS patients to HSCT. • Novel scores as IPSS-M taking into account the molecular data have been introduced. • This is a retrospective single-center study on MDS patients treated with HSCT. • Re-stratification from IPSS-R to IPSS-M occurred in almost half of patients. • IPSS-M demonstrated a stronger prognostic separation compared to IPSS-R. [ABSTRACT FROM AUTHOR]

Highlights • Inter-laboratory tests showed a degree of concordance of 84% in MRD assessment. • Variability in MRD assessment is for a large part due to subjective interpretation. • Immunophenotypic MRD assessment is a complex process, requiring specific experience. • Laboratories involved in MRD detection need to follow standardized protocols. Abstract Flow-cytometric detection of now termed measurable residual disease (MRD) in acute myeloid leukemia (AML) has proven to have an independent prognostic impact. In a previous multicenter study we developed protocols to accurately define leukemia-associated immunophenotypes (LAIPs) at diagnosis. It has, however, not been demonstrated whether the use of the defined LAIPs in the same multicenter setting results in a high concordance between centers in MRD assessment. In the present paper we evaluated whether interpretation of list-mode data (LMD) files, obtained from MRD assessment of previously determined LAIPs during and after treatment, could reliably be performed in a multicenter setting. The percentage of MRD positive cells was simultaneously determined in totally 173 LMD files from 77 AML patients by six participating centers. The quantitative concordance between the six participating centers was meanly 84%, with slight variation of 75%–89%. In addition our data showed that the type and number of LAIPs were of influence on the performance outcome. The highest concordance was observed for LAIPs with cross-lineage expression, followed by LAIPs with an asynchronous antigen expression. Our results imply that immunophenotypic MRD assessment in AML will only be feasible when fully standardized methods are used for reliable multicenter assessment. [ABSTRACT FROM AUTHOR]

Highlights • The ALC/AMC ratio is positively correlated with survival of PTCL-NOS patients. • The ALC/AMC ratio is an independent prognostic factor predicting survival. • The ALC/AMC ratio combined with PTCL-U score may be a better guide for the prognosis of PTCL-NOS patients. Abstract Peripheral T-cell lymphomas-not otherwise specified (PTCL-NOS) generally have poor patient outcomes, with a 5-year survival rate of ∼32%. The most common prognostic system for patients with PTCL-NOS, the PTCL-U score, is often inadequate because it does not take into consideration the role of host immunity or the microenvironment induced by the tumor. In this paper we aimed to determine the correlation between the Absolute Lymphocyte Count/Absolute Monocyte Count (ALC/AMC) ratio and the prognosis of PTCL-NOS. Retrospective data from 58 patients diagnosed with PTCL-NOS were analyzed. We found that PTCL-NOS patients with lower ALC/AMC ratios (ALC/AMC < 2) had shorter overall survival (OS) and progression-free survival (PFS) periods (OS: P < 0.001; PFS: P = 0.001) compared with other patients (ALC/AMC ≥ 2). When we combined ALC/AMC ratio and PTCL-U scores, patients could be clearly divided into 3 groups with significantly different prognoses. This study suggests that the ALC/AMC ratio may be a simple, effective, and independent prognostic factor for OS and PFS, and may be helpful to identify high-risk PTCL-NOS patients. Since the ALC/AMC ratio is related to host immunity and tumor microenvironment and reflects immune status and individual differences, combining ALC/AMC with PTCL-U may be a better prognostic guide for PTCL-NOS patients. [ABSTRACT FROM AUTHOR]

Diagnosis of myelodysplastic syndromes (MDS) is not straightforward when objective data, such as blast excess and abnormal cytogenetics, are lacking. Expert laboratories use flow cytometry (FCM) to help diagnose MDS. However, most of FCM protocols for MDS are complex, requiring a high level of expertise and high cost. We have reported a FCM mini-panel consisting of four FCM parameters (so-called Ogata score), which is simple to conduct and inexpensive. In this paper, to refine this mini-panel, we have introduced a new FCM parameter, which quantifies CD33 expression on CD34+ cells (called Granulocyte/CD34 cell CD33 ratio). Bone marrow cells from MDS without blast excess (low-grade MDS) and controls were stained with CD34, CD45, and CD33 and analyzed for five parameters (“Granulocyte/CD34 cell CD33 ratio” plus four parameters in the Ogata score). By a multivariate logistic regression model, only three parameters, including “Granulocyte/CD34 cell CD33 ratio” had statistically significant power for diagnosing low-grade MDS. Based on the results, we constructed a new scoring system, which showed approximately 50% sensitivity and more than 95% specificity in diagnosing low-grade MDS. Our revised mini-panel is suitable for screening samples suspected for MDS and provides a basis for further improvement in diagnostic FCM protocols for MDS. [ABSTRACT FROM AUTHOR]

Invasive fungal disease (IFD) is a major complication in patients with acute myeloid leukemia (AML) receiving intensive induction chemotherapy, and the use of anti-mold prophylaxis is considered standard of care. On the other hand, the use of anti-mold prophylaxis in AML patients receiving less-intensive venetoclax-based regimens is not well established, basically because the incidence of IFD may not be high enough to justify primary antifungal prophylaxis. Furthermore, dose adjustments in venetoclax are needed because of drug interactions with azoles. Finally, the use of azoles is associated with toxicity, including liver, gastrointestinal and cardiac (QT prolongation) toxicity. In a setting of low incidence of invasive fungal disease, the number needed to harm would be higher than the number needed to treat. In this paper we review the risk factors for IFD in AML patients receiving intensive chemotherapeutic regimens, the incidence and risk factors for IFD in patients receiving hypomethylating agents alone, and in patients receiving less-intensive venetoclax-based regimens. We also discuss potential problems with the concomitant use of azoles, and present our perspective on how to manage AML patients receiving venetoclax-based regimens without primary antifungal prophylaxis. • Antifungal prophylaxis is standard of care in patients with AML receiving intensive chemotherapy. • The need for antifungal prophylaxis in patients receiving venetoclax-based regimens is uncertain. • Antifungal prophylaxis may be associated with side effects and potential drug interactions with venetoclax. • A risk-based approach can help the decision to give antifungal prophylaxis in patients receiving venetoclax-based regimens. [ABSTRACT FROM AUTHOR]

Abstract: It is almost axiomatic that chronic lymphocytic leukemia (CLL) is not caused by ionizing radiation. This assumption has been challenged recently by a critical re-appraisal of existing data. A recent paper implicated radon exposure in Czech uranium miners as a possible cause of CLL and in this issue of Leukemia Research the first paper examining the incidence of CLL among those exposed to radiation from the accident at the nuclear power plant in Chernobyl is published. It suggests that CLL occurring among the clean-up workers was of a more aggressive form than is normally seen in the community. [Copyright &y& Elsevier]

In biomedical image analysis, segmentation of cell nuclei from microscopic images is a highly challenging research problem. In the computer-assisted health care system, the segmented microscopic cells have been used by many biological researchers for the early prediction of various diseases. Multiple myeloma is one type of disease which is also term as a plasma cell cancer. The segmentation of the nucleus and cell is a very critical step for multiple myeloma detection. Here, In this work, we have designed two modules. One is for recognizing the nucleus of myeloma cells with a deep IEMD neural network, and the other is for differentiating the cell i.e cytoplasm. The different IMFs provides detailed frequency component of an image which are used for feature extraction. This will significantly improves the performance. We proposed a new counting algorithm for counting the myeloma-affected plasma cells in this paper. An algorithm for counting overgrowth plasma cells within the myeloid tissue has been developed using the Python TensorFlow framework. Experimental outcomes on SegPC datasets substantiate that, the proposed deep learning approach outperforms other competitive methods in myeloma recognition and detection. The result of this research indicates that, the proposed image segmentation mechanism can recognize multiple myeloma with superiority. Early detection of multiple myeloma at the initial stage increases the chances to cure patients. • Proposed two modules: for recognizing the nucleus of MM cells and for differentiating the cell membrane i.e cytoplasm. • In-depth feature extraction with IEMD and IMFs which step will significantly improve the performance. • Developed new counting algorithm with Python for counting overgrowth plasma cells within the myeloid tissue. • Validation with publicly available SegPC datasets for various imaging modalities. [ABSTRACT FROM AUTHOR]

Targeting components of the B-cell receptor (BCR) pathway have dramatically improved clinical outcomes in a variety of B-cell malignancies. Despite the well-documented pathogenic role of BCR precursor (pre-BCR) pathway in B-cell acute lymphoblastic leukemia (B-ALL), there is limited available data of therapies that aim to disrupt this pathway. To investigate the role of protein kinase Cβ (PKCβ), a crucial mediator of BCR and pre-BCR signaling, in B-ALL survival, we studied the activity of the PKCβ selective inhibitor enzastaurin (ENZ) in seven B-ALL cell lines. Treatment with ENZ resulted in a dose- and time-dependent growth inhibition in all cell lines with a relatively higher efficacy in pro-B ALL with translocation t(4;11)(q21;q23). The mechanism of growth inhibition was by apoptotic induction and cell cycle arrest. A rapid reduction in phosphorylation of AKT and its downstream target glycogen synthase kinase 3β (GSK3β) were observed at 30 min after treatment and remaining for 48 h. The reduction in GSK3β phosphorylation was associated with a paradoxical accumulation of β-catenin, which was due to a transient loss of β-catenin phosphorylation at ser33-37. In addition, accumulation of β-catenin was associated with downregulation of c-Myc, upregulatiuon of c-Jun, and a subsequent protective effect on the tumor suppressor p73. Data in this paper were presented in part at 2012 American Society of Hematology Annual Meeting, abstract 1350. [ABSTRACT FROM AUTHOR]

Abstract: The cellular and molecular genetic aberrations of hematopoietic and lymphoid tissues are increasingly important in leukemia classification and are prognostically significant. Although some recurrent molecular cytogenetic abnormalities in AML have been extensively studied, others including t(7;11)(p15;p15) have not been well characterized. In this paper, seventeen AML patients with t(7;11)(p15;p15) were retrospectively reviewed for cell morphology, immuno-phenotype, cytogenetics as well as clinical features and prognosis. Among them, thirteen were female; nine were AML-M2. Six patients who were newly diagnosed were alive, one was lost for followed up and ten died. The median survival was 8 months. Taking together, AML with t(7;11)(p15;p15) is a rare and distinct disease. Most patients with this translocation are female at younger age and have special clinical and hematological characteristics such as M2-subtype of AML, easy to relapse and poor prognosis. [Copyright &y& Elsevier]

Abstract: Cytarabine combined with an anthracycline or an anthracenedione represents the usual intensive induction therapy for the treatment of AML. However, this protocol induces severe side effects and treatment-related mortality due to the lack of selectivity of these cytotoxic agents. In this paper, we present the study of the first galactosidase-responsive molecular “Trojan Horse” programmed for the delivery of doxorubicin exclusively inside AML blasts over-expressing the folate receptor (FR). This targeting system allows the selective killing of AML blasts without affecting normal endothelial, cardiac or hematologic cells from healthy donors suggesting that FDC could reduce adverse events usually recorded with anthracyclines. [Copyright &y& Elsevier]

Abstract: Changes in classical and non-classical human leukocyte antigen expression by tumor cells can play a critical role in the generation of tumor antigen-specific immune responses and can modulate the interactions of natural killer cells and T cell subpopulations with target cells. Recently, several studies have investigated the relations between HLA molecules and prognosis in B-CLL, suggesting a potential clinical relevance of tumor escape mechanisms. In this paper, we will summarize conflicting information about the role of HLA-related prognostic factors in B-CLL, such as downregulation of HLA class I antigen expression, interactions between natural killer cell receptor and certain ligands and the role of HLA-G expression. [Copyright &y& Elsevier]

Abstract: The main objective of this systematic review is to quantify and to summarize all studies that have included health-related quality of life (HRQOL) or, any other type of patient-reported outcomes (PROs), in patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs). Nine papers were found and none of these were published before 2003. Overall, 3290 CML patients were enrolled in the studies reviewed. Four studies reported HRQOL data on patients treated with imatinib only. The most solid data in this area indicate that CML patients receiving TKIs have a worse HRQOL profile when compared to their peers, without cancer, in the general population and interventions to improve HRQOL outcomes are thus needed. Our review revealed the paucity of evidence-based data in this area. However, HRQOL assessment in these studies emphasize the unique information provided by the patient''s perspective. Urgent efforts are needed to provide solid PROs data to complement current knowledge on clinical efficacy of TKIs. [Copyright &y& Elsevier]

Abstract: The purpose of any classification of hematologic neoplasms is to provide reliable criteria for their diagnosis and their classification into clinically relevant disease entities. In 1982, the French – American – British (FAB) group introduced such a classification for the myelodysplastic syndromes (MDS), a heterogenous group of diseases that prior to the FAB scheme was often referred to only as “preleukemia.” Over the ensuing two decades, the FAB classification facilitated hundreds of morphologic, clinical, and genetic studies that helped to clarify the disease process and its management. The World Health Organization (WHO) classification of MDS is a consensus classification first introduced in 2001 and revised in 2008. It maintains much of the structure and philosophy of the FAB classification, but draws upon more recently acquired biologic and clinical information to refine the diagnostic criteria and improve its prognostic value. This paper outlines the evolution from the FAB to the WHO classification of MDS and gives a glimpse of what might lie beyond. [Copyright &y& Elsevier]

Abstract: Although Georg Hegel quipped, “We learn from history that we do not learn from history”, Aldous Huxley expressed a more nuanced view: “The charm of history and its enigmatic lesson consist in the fact that, from age to age, nothing changes and yet everything is completely different.” In order to understand present-day positions and peculiarities in any field of human endeavor, familiarity with the past is essential. Those of us who study myelodysplastic syndromes (MDS) or care for patients diagnosed with these troublesome conditions may wonder also how the current state of affairs evolved with respect to our narrow area of focus, and how we know what we think we know now about these still-enigmatic bone marrow diseases. Here, I review a number of developments that collectively represent a brief “history of MDS.” I first highlight a few landmark observations that preceded any concept of MDS by hundreds of years. Twentieth-century case descriptions and series with hypotheses about the etiology and nature of disorders described as “refractory anemia”, “preleukemia”, and with other terminology culminated in the efforts of the French-American-British (FAB) Co-operative Group of morphologists, whose landmark 1976 and 1982 papers provided the first widely-used classification of MDS. More recent developments in the MDS field include new mechanistic biological insights, regulatory approval of several somewhat-effective treatments, and improved organizational support and advocacy. The history of a disease concept like MDS, as for history in general, provides both inspiration and cautionary tales that can inform present and future work. [Copyright &y& Elsevier]

Abstract: This paper speculates on the role of infection in modifying a young child''s risk of promoting precursor B-cell acute lymphoblastic leukemia (ALL). It is suggested that the heat shock instigated by infections, particularly in infancy, stimulates Th1 pro-inflammatory cytokines and an apoptosis-inhibitory environment. This infective stress also increases the number of cooperating oncogenic mutations in pre-leukemic cells, especially if the primary adaptive immune response is delayed. The glucocorticoid release that follows leads to acute thymic involution, a decline in antitumor immunity, and maturation arrest of B-lymphocytes. The infective lymphoid recovery hypothesis addresses an apparent contradiction–that a non-hygienic environment primes the adaptive immune response and is protective against childhood ALL, while multiple infections occurring later increase the risk of childhood ALL. In affluent (compared to less-affluent) societies, the characteristic ALL incidence peak in early childhood, and the shortened time to diagnosis, arise from surviving recurrent infections and the accumulated loss and recovery of lymphoid tissue. Evidence supporting the hypothesis, such as the role of lymphoid tissue reconstitution cytokines that stimulate proliferation stress on B-cell progenitors, comes from the study of children with congenital syndromes that are susceptible to leukemia. [Copyright &y& Elsevier]

Abstract: Dequalinium, an amphiphilic quinolinium derivative, selectively accumulates in mitochondria and displays anticancer activity in cells from different malignancies. Previous studies indicate a differential DQA-induced cytotoxicity in NB4 and K562 human leukemia cells as a consequence of an early disturbance in mitochondrial function. Results in this paper show that DQA induces a concentration-dependent oxidative stress by decreasing GSH level and increasing ROS in a cell type specific way. Inhibitors of the JNK and p38 stress regulated kinases potentiate DQA-induced NB4 cell death suggesting a protective function for these enzymes. K562 cells with relatively high GSH levels remained resistant to DQA action. [Copyright &y& Elsevier]

Abstract: Resistance to chlorambucil in chronic lymphocytic leukemia (CLL) has been associated with increased DNA repair. Specifically, inhibition of either c-abl, which modulates Rad51 directed homologous recombination or DNA-PK dependent nonhomologous end joining has been shown to sensitize primary CLL lymphocytes to chlorambucil. Here we report that inhibition of c-abl can result in a compensatory increase in DNA-PK and thus inhibition of both c-abl and DNA-PK optimally sensitizes CLL lymphocytes to chlorambucil. In this paper we report a drug-induced compensatory change between two DNA repair pathways with potential therapeutic implications in CLL therapy. [Copyright &y& Elsevier]

Abstract: Establishment of a leukemia plasmacytoid dendritic cell line (PMDC05) and intra-lineage transformation from pDCs to mDCs in PMDC05 has been reported. In this paper, we show the applicability of PMDC05 for cellular immunotherapy. By stimulation with LPS, PMDC05 showed enhancement in expression of antigen presentation-associated surface molecules and production of cytokines (IL-12p70 and TNF-α). The antigen presenting ability was markedly increased in PMDC05 stimulated with LPS. By co-culturing of CD8+ T cells with LPS-stimulated and WT1/CMVpp65 peptide-pulsed PMDC05, WT1/CMVpp65 tetramer+ cytotoxic T lymphocytes were efficiently generated. These findings reveal the applicability of PMDC05 in cellular immunotherapy for tumor and severe viral infections. [Copyright &y& Elsevier]

Abstract: Increased levels of kynurenic acid (KYNA) have been detected in patients with neurological, autoimmune and tumor diseases. The aim of this paper was to determine KYNA levels in the blood and bone marrow plasma of MGUS and MM patients and to find out common events which are characteristic for both pathological stages and correlates with diagnostic markers of MGUS and MM. We also examined whether bone marrow stromal cells (BMSCs) and MM cells could produce KYNA. The levels of KYNA present in plasma and in cell culture media were examined by HPLC. An increased level of KYNA was detected in the blood and marrow plasma of MGUS patients and in the blood plasma of the MM group. In the MM group, the blood KYNA level was the highest in patients with monoclonal IgG protein and with free light chains of immunoglobulins and correlated positively with blood levels of creatinine and urea. In the MGUS group, KYNA correlated positively with the C-reactive protein (CRP) level, and in both groups KYNA correlated positively with the β2-microglobulin. We detected KYNA production in BMSCs of control and MM patients and by two myeloma cell lines used in the experiments. The results suggest that the increased KYNA level in MGUS patients was mainly caused by a dysfunction of the immune system, as it correlated positively with CRP and β2-microglobulin levels. In MM patients, the increased KYNA level may have been a result of a dysfunction of the immune system, KYNA production by myeloma cells, and decreased KYNA excretion by kidneys. [Copyright &y& Elsevier]

Abstract: We have investigated the production of metalloproteinases (MMP-1, MMP-2, MMP-9) and tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) in bone marrow stromal cells (BMSCs) of patients with multiple myeloma (MM) and a healthy control. The new findings of this paper is that BMSCs of the MM patients exhibited intrinsic MMP-1, MMP-2 and TIMP-2 overproduction. Production of MMP-1, TIMP-2 and activation of MMP-2 was additionally enhanced in co-cultures of BMSCs with RPMI8226 cells. The ratio between MMP-2 and TIMP-2 was significantly higher in BMSCs of the MM patients than in control. BMSCs of both the control and the MM patients exhibited the presence of MMP-9 latent form, but in co-cultures RPMI8226 cells were the main producers of this metalloproteinase. [Copyright &y& Elsevier]

Abstract: We investigated the effects of a single s.c. injection of peg-filgrastim in 32 patients with multiple myeloma who underwent autologous stem cell transplantation (AuSCT) as first line treatment. For comparison, 32 myeloma patients with similar characteristics and receiving standard daily administration of filgrastim were matched. Overall, there were no statistically significant differences between peg-filgrastim and filgrastim in terms of tolerability, marrow recovery, severity of neutropenia, incidence and duration of febrile neutropenia, documented infections and transfusions. However, some favourable trends or effects in favour of peg-filgrastim were observed. This was confirmed by a review of the published papers about this topic. [Copyright &y& Elsevier]

Abstract: Etanercept is a commercially available pharmaceutical protein approved for treatment of rheumatoid arthritis, RA. Given subcutaneously, etanercept binds and inactivates soluble tumor necrosis factor-alpha, TNF. Etanercept has a good safety record and is of benefit in lowering pain, inflammation, and joint destruction in RA. RA is mediated by many factors, TNF among them. Malignant myeloma, MM, is a malignant clonal expansion of a post-germinal center B lymphocyte. Since TNF is a necessary growth factor for expansion and maintenance of MM cells, and etanercept binds soluble TNF and is of clinical benefit in RA, etanercept was tried experimentally in MM. Contrary to expectations, etanercept resulted in increased levels of TNF and possibly shortened survival. This paper presents an hypothesis of how this happened. There are two cognate receptors for TNF, termed R1 and R2 and two forms of TNF, soluble and transmembrane. Soluble TNF has greater affinity for TNF-R1 than for TNF-R2. Transmembrane TNF has equal affinity for the two receptors. Since TNF-R2 signaling tends to be more anti-apoptotic and activating of nuclear factor kappa B, NFkB, than is TNF-R1, and TNF-R1 tends to be more pro-apoptotic than is TNF-R2, by inactivating soluble TNF while leaving transmembrane TNF signaling relatively unchanged, etanercept changed the balance in TNF signaling from TNF-R1 towards TNF-R2 weighting. Anti-apoptosis and TNF synthesis would have been up-regulated by that shift. Early data indicates that the common generic antidepressant bupropion may ameliorate Crohn''s disease course by down regulating TNF synthesis, maybe it will slow the course of MM as well. [Copyright &y& Elsevier]

Abstract: Granulocyte function may be altered after in vivo G-CSF administration and this has been related to both an immaturity of mobilized cells and to a defect in F-actin polymerization. In this paper we show that in resting Filgrastim (non-glycosylated G-CSF)-pulsed cells, F-actin polymerization, membrane-linked RhoA and cell polarization are enhanced compared to those found in resting Lenograstim (glycosylated G-CSF)-cells. The basal hyper-activation of RhoA could be responsible for the morphological and functional modifications of Filgrastim-mobilized cells. Moreover, Filgrastim-mobilized cells, but not Lenograstim-mobilized cells, are unable to correctly respond to LPS stimulation, as demonstrated by minor further RhoA activation and cell elongation. [Copyright &y& Elsevier]

Abstract: Evidence suggests that amelioration of childhood immune thrombocytopenic purpura and some other autoimmune states by intravenous normal IgG is due to the following chain of events: (1) cross-linking of Fcγ-receptors on blood effector cells; (2) release of mediators from these cells, often yielding an infusion-related reaction; (3) mediator-induced development of a cytokine field characterized by a mutually stabilizing Th2 polarization of CD4 T lymphocytes and alternative activation of macrophages; (4) selective quiescence of these macrophages towards targets coated with IgG autoantibody, due to increased expression of the macrophage Fcγ-receptor IIB. In this paper it is postulated that in the field of antibody therapy of tumor, an undesirable delayed or absent subsidence of antibody-coated tumor is due to immunomodulation of the same type as yields amelioration of autoimmunity, and arising from a similar chain of events. If the postulate is correct the chain could usefully be broken at the level of mediator action, possibly by blocking that increased synthesis of prostaglandin E2 which is catalyzed by the enzyme cyclooxygenase-2. [Copyright &y& Elsevier]

The increase of megakaryocytes and platelets that characterizes essential thrombocythemia (ET) appears to be secondary to a deregulation of megakaryocytopoiesis. The carboxy-terminal fragment of osteogenic growth peptide (OGP10–14) promotes bone formation and hemopoiesis, while it inhibits megakaryocytopoiesis. In this paper we show that treatment with synthetic OGP10–14 (sOGP10–14) induces a significant reduction of mid and large colony-forming unit-megakaryocytes (CFU-Mk) in ET patients as well as in controls, and is associated with a significant inhibition of thrombopoietin (TPO)-primed MO-7e megakaryoblastic cells proliferation. These actions appear to be related to sOGP10–14 modulation of TGF-β1 synthesis and/or secretion, although a direct effect on TGF-β receptor expression cannot be excluded. [Copyright &y& Elsevier]

Telomere length and telomerase have an important role in normal and malignant hematopoiesis. Telomere erosion can lead to chromosome end fusion and thereby contribute to genomic instability during tumorigenesis. Thus, like complex chromosomal aberrations, telomere length may be a prognostic factor in hematopoietic malignancies. A paper by Sieglova et al. in this issue of Leukemia Research reports on the prognostic impact of telomere shortening in bone marrow (BM) and peripheral blood (PB) specimens of myelodysplastic syndrome (MDS) and MDS converted-AML patients (pts). Their results underline the importance to study telomere biology together with cytogenetics, genomic and proteomic profiling as prognostic factors, in order to improve risk-adapted therapy of MDS and AML pts. [Copyright &y& Elsevier]

The t(12;21)(p12;q22) is the most frequent chromosomal rearrangement observed in acute lymphoblastic leukaemia (ALL) and is associated with favourable prognosis and good response to initial treatment. The translocation-Ets-leukaemia (TEL) and AML1 genes are very often involved in chromosomal translocations in haematopoietic malignances.This review presents the structure, roles of TEL and AML1 genes, and their proteins in haematopoiesis and in leukaemiogenesis as well. Aspects such as: the mechanism of translocation t(12;21)(p12;q22), function of TEL/AML1 fusion gene and chimeric protein, clinical significance of this abnormality and methods allowing to detect this translocation and its transcript are also discussed in this paper. [Copyright &y& Elsevier]

In the present paper a case of a 65-year-old man diagnosed as suffering from a lymphoplasmacytic lymphoma, resistant to conventional chemotherapy, associated to a bone marrow (BM) mastocytosis, who was successfully treated with cladribine is reported. In this patient cladribine induced not only clinical remission of the lymphoplasmacytic lymphoma but it was also associated with immunophenotypical changes in the BM mast cells (MCs) compartment. Such changes were consistent with a decrease in the number of phenotypically aberrant (CD2+/CD25++/CD35++/CD69++/CD117++) MCs and the reappearance in the BM of MCs displaying a normal phenotype (CD2−/CD25−/CD35−/CD69+/CD117+++). Despite the potential utility of cladribine in the treatment of mastocytosis, our observations should be considered as preliminary and caution should be taken as regards the exact indications of the use of this purine analog in mastocytosis. [Copyright &y& Elsevier]

Extensive research into mechanisms of cytotoxic drug and irradiation resistance have produced few clinically encouraging results. In this report, we apply correlation analyses to drug and irradiation response results from a cohort of 36 classical B chronic lymphocyte leukemia (CLL) patients. Nine drugs and two types of irradiation were selected according to their usefulness in CLL therapy or on the basis of their otherwise interesting mechanisms of action. Part of the results concerning individual drugs have been previously published, but new correlation analyses are presented in this paper. Altogether 2376 duplicate cultures were performed in order to determine ID80 values, i.e. doses causing an 80% inhibition in 4-day cultures when leucine incorporation was used as an indicator of cells vitality. Non-parametric Spearman’s rank order correlation confirmed a tight relationship between 2-chlorodeoxyadenosine and fludarabine, as expected. Surprisingly, correlation between two P-glycoprotein-dependent drugs, vincristine and doxorubicin, was not demonstrable. A number of entirely unexpected correlations were identified between drugs with very different mechanisms of action: (i) chlorambucil and γ-irradiation; (ii) 2-chlorodeoxyadenosine and vincristine; (iii) 2-chlorodeoxyadenosine and γ-irradiation; (iv) fludarabine and cis-platin; (v) doxorubicine and γ-irradiation; (vi) prednisolone and cyclosporin A; (vii) vincristine and verapamil. Our findings emphasize: (i) the usefulness of fresh tumor cells instead of cell lines in cytotoxicity studies; (ii) the great variation in cytotoxicity in individual patients, i.e. tumor cell heterogeneity, as well as patient heterogeneity; and (iii) an entirely unexpected finding that there were tight relationships in drug and irradiation responses between substances supposed to act with very different mechanisms. [Copyright &y& Elsevier]

The purpose of this editorial is to highlight the findings reported herein in the paper by Wun et al. on the connection between expression of the cyclooxygenase-2 (COX-2) enzyme and B-cell lymphoma [Leuk. Res., in press]. We will first briefly review key aspects of the COX-2 enzyme, the newly discovered prostaglandin (PG) synthases and their PG products, and their roles both in inflammation and in the pathogenesis of cancer. Having placed the COX pathway in this context, the discussion will then return to the provocative findings of Wun et al. [Leuk. Res., 28, 2004]. [Copyright &y& Elsevier]