British Journal of Haematology via MedWorm.com

Reduction of imatinib dose and persistence of complete molecular response after p210 multipeptide vaccine in chronic myeloid leukaemia treated with dose escalation for acquired resistance

British Journal of Haematology — Sat, 20 Mar 2010 00:00:00 +0100

(Source: British Journal of Haematology)

Successful treatment of disseminated intravascular coagulation in a child with acute myelogenous leukaemia using recombinant thrombomodulin

British Journal of Haematology — Fri, 19 Mar 2010 00:00:00 +0100

(Source: British Journal of Haematology)

Necrobiotic xanthogranuloma, a rare complication of a persistently high paraprotein

British Journal of Haematology — Fri, 19 Mar 2010 00:00:00 +0100

(Source: British Journal of Haematology)

Development of romiplostim for the treatment of patients with chronic immune thrombocytopenia: from bench to bedside

British Journal of Haematology — Thu, 18 Mar 2010 00:00:00 +0100

Immune thrombocytopenia (ITP) is an autoimmune disorder characterised by abnormally low platelet counts ( (Source: British Journal of Haematology)

Artificial contact pathway activation masks the haemostatic potential of rFVIIa and NN1731 in thrombocytopenic whole blood

British Journal of Haematology — Wed, 17 Mar 2010 00:00:00 +0100

(Source: British Journal of Haematology)

Diagnosis of severe Type 1 Gaucher's disease before irreversible damage occurs : is HDL cholesterol the answer?

British Journal of Haematology — Tue, 16 Mar 2010 00:00:00 +0100

(Source: British Journal of Haematology)

Advances in understanding the pathogenesis of chronic thromboembolic pulmonary hypertension

British Journal of Haematology — Tue, 16 Mar 2010 00:00:00 +0100

Chronic thromboembolic pulmonary hypertension (CTEPH) comprises organizing thrombotic obstructions in the pulmonary arteries. While roughly 40% of CTEPH cases are not preceded by a venous thromboembolic event, 0·1[ndash]5·1% of acute pulmonary thromboemboli evolve into organized obstructions of the pulmonary artery. In patients with predominantly proximal disease, surgical pulmonary endarterectomy provides a potential cure of the disease. For years, the scientific debate of CTEPH was mainly focused around its thromboembolic nature because of striking dissimilarities to classical venous thromboembolism, for example, the lack of risk factors for venous thrombosis, the lack of clinically apparent pulmonary embolism in many patients, the difficulty to reproduce the disease in animal models o...

Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus

British Journal of Haematology — Tue, 16 Mar 2010 00:00:00 +0100

Tumour lysis syndrome (TLS) is a life-threatening oncological emergency characterized by metabolic abnormalities including hyperuricaemia, hyperphosphataemia, hyperkalaemia and hypocalcaemia. These metabolic complications predispose the cancer patient to clinical toxicities including renal insufficiency, cardiac arrhythmias, seizures, neurological complications and potentially sudden death. With the increased availability of newer therapeutic targeted agents, such as rasburicase (recombinant urate oxidase), there are no published guidelines on the risk classification of TLS for individual patients at risk of developing this syndrome. We convened an international TLS expert consensus panel to develop guidelines for a medical decision tree to assign low, intermediate and high risk to patient...

Anti-thymocyte globulin plus etanercept as therapy for myelodysplastic syndromes (MDS): a phase II study

British Journal of Haematology — Tue, 16 Mar 2010 00:00:00 +0100

Immunosuppressive therapies have proven valuable in treating patients with myelodysplastic syndromes (MDS). We evaluated the combination of equine anti-thymocyte globulin (ATGAM®) and the soluble tumour necrosis factor receptor, etanercept (Enbrel®), in a phase II trial. Twenty-five patients with MDS [4-refractory anaemia (RA), 2-RA with ring sideroblasts, 15-refractory cytopenia with multilineage dysplasia (RCMD), 3-RCMD and ring sideroblasts, 1-RA with excess blasts type 1] in International Prognostic Staging System risk groups low (n = 11) or intermediate-1 (n = 14) were enrolled. All patients were platelet or red cell transfusion-dependent. Nineteen patients completed therapy with ATG at 40 mg/kg per day for four consecutive days, followed by etanercept, 25 mg subcutaneous twice a we...

Flow cytometric scoring system (FCMSS) assisted diagnosis of myelodysplastic syndromes (MDS) and the biological significance of FCMSS-based immunophenotypes

British Journal of Haematology — Tue, 16 Mar 2010 00:00:00 +0100

In the myelodysplastic syndromes (MDS), the haematopoietic cells show various levels of abnormal maturation and differentiation, which can be detected by flow cytometry. Testing the anomalies of stage- or lineage-specific surface antigens in CD34+ blasts can distinguish MDS from non-clonal cytopenic diseases, and also reflect the pathological characteristics of MDS as a class of clonal diseases for providing new clues to basic research. The present study established a flow cytometric scoring system (FCMSS) based on theproportion and antigenic co-expression of CD34+ blasts. This FCMSS showed good sensitivity and specificity (77·8% and 100%) in the assisted diagnosis of low-risk MDS without chromosome anomalies, ringed sideroblasts and excess marrow blasts. Moreover, we explored and reporte...

Systematic review of the addition of vincristine plus steroid pulses in maintenance treatment for childhood acute lymphoblastic leukaemia – an individual patient data meta-analysis involving 5659 children

British Journal of Haematology — Tue, 16 Mar 2010 00:00:00 +0100

Vincristine plus steroid pulses have long been a part of maintenance treatment in many protocols for childhood acute lymphoblastic leukaemia (ALL). A collaborative individual patient data meta-analysis of all randomised trials of the addition of vincristine plus prednisone/prednisolone (VP) pulses in childhood ALL was updated and extended to include trials comparing vincristine plus dexamethasone (VD) pulses to maintenance without pulses. VP pulses improved event-free survival (EFS) (70·1% vs. 62·0% at 5 years; odds ratio (OR) = 0·71; 95% confidence interval (CI) = 0·61[ndash]0·84; P = 0·00004); VD pulses did not have a significant effect (80·9% vs. 79·9% 5 year EFS; OR = 0·94; 95% CI = 0·80[ndash]1·11; P = 0·5). Heterogeneity between groups (VP or VD) was significant (P = 0·0...

Regulation of the human HBA genes by KLF4 in erythroid cell lines

British Journal of Haematology — Mon, 15 Mar 2010 00:00:00 +0100

KLF1/EKLF and related Krueppel-like factors (KLFs) are variably implicated in the regulation of the HBB-like globin genes. Prompted by the observation that four KLF sites are distributed in the human [alpha]-globin gene (HBA) promoter, we investigated if KLFs could also act to modulate the expression of the HBA genes. Among the KLFs tested, only KLF4/GKLF bound specifically to three out of four [alpha]-globin KLF sites. The occupancy of the same sites by KLF4 in vivo was confirmed by chromatin immunoprecipitation assays with KLF4-specific antibodies. In luciferase reporter assays in MEL cells, high levels of the wild type HBA promoter, but not mutated promoters bearing point mutations that disrupted KLF4-DNA binding, were transactivated by over-expression of KLF4. In K562 cells, induced KL...

MiRNA profiling in B non-Hodgkin lymphoma: a MYC-related miRNA profile characterizes Burkitt lymphoma

British Journal of Haematology — Mon, 15 Mar 2010 00:00:00 +0100

(Source: British Journal of Haematology)

Guideline for investigation and management of adults and children presenting with a thrombocytosis

British Journal of Haematology — Mon, 15 Mar 2010 00:00:00 +0100

(Source: British Journal of Haematology)

Preclinical anti-myeloma activity of the novel HDAC-inhibitor JNJ-26481585

British Journal of Haematology — Mon, 15 Mar 2010 00:00:00 +0100

This study preclinically evaluated the effects of the 'second generation' pan-HDAC inhibitor JNJ-26481585 on human multiple myeloma (MM) cells from established cell lines and primary MM samples (n = 42). Molecular responses in both groups of MM cells included histone acetylation, a shift in Bcl2-family members towards proapoptotic bias, attenuation of growth and survival pathway activity and Hsp72 induction. Mcl-1 depletion and Hsp72 induction were the most reliable features observed in JNJ-26481585-treated primary MM samples. The drug alone effectively induced myeloma cell death at low nanomolar concentrations. In vitro combination of JNJ-26481585 with anti-myeloma therapeutic agents generally resulted In effects close to additivity. In view of the favourable activity of this novel HDAC-i...

Impaired lymphocyte mitochondrial antioxidant defences in variegate porphyria are accompanied by more inducible reactive oxygen species production and DNA damage

British Journal of Haematology — Sat, 13 Mar 2010 00:00:00 +0100

In conclusion, lymphocytes from VP women showed impaired expression of mitochondrial antioxidant defences but no significant signs of oxidative stress were evidenced in basal, non-stressing conditions; however, lymphocytes of VP women were more susceptible to producing mitochondrial ROS and to suffering oxidative damage when submitted to stressful situations. (Source: British Journal of Haematology)

Blockade of the MEK/ERK signalling cascade by AS703026, a novel selective MEK1/2 inhibitor, induces pleiotropic anti-myeloma activity in vitro and in vivo

British Journal of Haematology — Fri, 12 Mar 2010 00:00:00 +0100

This study investigated the cytotoxicity and mechanism of action of AS703026, a novel, selective, orally bioavailable MEK1/2 inhibitor, in human multiple myeloma (MM). AS703026 inhibited growth and survival of MM cells and cytokine-induced osteoclast differentiation more potently (9- to 10-fold) than AZD6244. Inhibition of proliferation induced by AS703026 was mediated by G0-G1 cell cycle arrest and was accompanied by reduction of MAF oncogene expression. AS703026 further induced apoptosis via caspase 3 and Poly ADP ribose polymerase (PARP) cleavage in MM cells, both in the presence or absence of bone marrow stromal cells (BMSCs). Importantly, AS703026 sensitized MM cells to a broad spectrum of conventional (dexamethasone, melphalan), novel or emerging (lenalidomide, perifosine, bortezomib...

Pharmacodynamic and efficacy studies of the novel proteasome inhibitor NPI-0052 (marizomib) in a human plasmacytoma xenograft murine model

British Journal of Haematology — Fri, 12 Mar 2010 00:00:00 +0100

Our previous study showed that the novel proteasome inhibitor NPI-0052 induces apoptosis in multiple myeloma (MM) cells resistant to conventional and bortezomib (Velcade[trade], Takeda, Boston, MA, USA) therapies. In vivo studies using human MM-xenografts demonstrated that NPI-0052 is well tolerated, prolongs survival, and reduces tumour recurrence. These preclinical studies provided the basis for an ongoing phase-1 clinical trial of NPI-0052 in relapsed/refractory MM patients. Here we performed pharmacodynamic (PD) studies of NPI-0052 using human MM xenograft murine model. Our results showed that NPI-0052: (i) rapidly left the vascular compartment in an active form after intravenous (i.v.) administration, (ii) inhibited 20S proteasome chymotrypsin-like (CT-L, [beta]5), trypsin-like (T-L, ...

Hairy cell leukaemia-variant and splenic red pulp lymphoma: a single entity?

British Journal of Haematology — Fri, 12 Mar 2010 00:00:00 +0100

(Source: British Journal of Haematology)

A United Kingdom Haemophilia Centre Doctors' Organization guideline approved by the British Committee for Standards in Haematology: guideline on the use of prophylactic factor VIII concentrate in children and adults with severe haemophilia A

British Journal of Haematology — Thu, 11 Mar 2010 00:00:00 +0100

Consensus-based guidelines supported by the literature are presented on the role of prophylactic administration of factor VIII concentrate in children and adults with severe haemophilia A. The timing of initiation of prophylaxis, the choice of prophylactic regimen, monitoring, management of breakthrough bleeding and education of the patient and family are discussed. (Source: British Journal of Haematology)

Monitoring heparin anticoagulation in the acute phase response

British Journal of Haematology — Thu, 11 Mar 2010 00:00:00 +0100

The anticoagulant effect of unfractionated heparin (UFH) is monitored using the activated partial thromboplastin time (APTT). An APTT of 1·5[ndash]2·5 times the control is usually taken as the therapeutic range and assumed to reflect an anti-activated factor X (anti-Xa) level of 0·35[ndash]0·7 u/ml. However, in some cases, despite administration of sufficient heparin to achieve a therapeutic anti-Xa assay level, the APTT remains sub-therapeutic. This 'apparent heparin resistance' is commonly due to high levels of factor VIII (FVIII). In these situations, the anti-Xa is usually preferred for monitoring in order to avoid, what might be, dangerously high levels of heparin. We hypothesized that at high FVIII levels, the heparin resistance encountered may be genuine rather than apparent and...

Advances in the understanding of myeloma bone disease and tumour growth

British Journal of Haematology — Thu, 11 Mar 2010 00:00:00 +0100

Advances in multiple myeloma support the notion that the associated bone disease, characterized by increased osteoclastogenesis and suppressed osteoblastogenesis, is both a consequence and necessity of tumour progression. Osteoblastogenesis is suppressed by secreted inhibitors and dysregulation of cell-surface 'coupling' factors on osteogenic cells. Osteoclastogenesis is increased as a consequence of osteoblast deactivation and of production of osteoclast-activating factors. Osteoclasts express soluble and cell-surface factors that stimulate myeloma growth, while osteoblasts produce bone-building factors that restrain growth of myeloma cells that are dependent on the microenvironment; detailed molecular mechanisms are discussed. Experimental and clinical findings indicate that pharmacologi...

Isoform-selective phosphoinositide 3-kinase inhibitors induce apoptosis in chronic lymphocytic leukaemia cells

British Journal of Haematology — Thu, 11 Mar 2010 00:00:00 +0100

(Source: British Journal of Haematology)

HCV genotype 2 as a risk factor for reactivation in patients with B-cell lymphoma undergoing rituximab combination chemotherapy

British Journal of Haematology — Tue, 09 Mar 2010 00:00:00 +0100

(Source: British Journal of Haematology)

Effect of eculizumab on haemolysis-associated nitric oxide depletion, dyspnoea, and measures of pulmonary hypertension in patients with paroxysmal nocturnal haemoglobinuria

British Journal of Haematology — Mon, 08 Mar 2010 00:00:00 +0100

Pulmonary hypertension (PH) is a common complication of haemolytic anaemia. Intravascular haemolysis leads to nitric oxide (NO) depletion, endothelial and smooth muscle dysregulation, and vasculopathy, characterized by progressive hypertension. PH has been reported in patients with paroxysmal nocturnal haemoglobinuria (PNH), a life-threatening haemolytic disease. We explored the relationship between haemolysis, systemic NO, arginine catabolism and measures of PH in 73 PNH patients enrolled in the placebo-controlled TRIUMPH (Transfusion Reduction Efficacy and Safety Clinical Investigation Using Eculizumab in Paroxysmal Nocturnal Haemoglobinuria) study. At baseline, intravascular haemolysis was associated with elevated NO consumption (P < 0·0001) and arginase-1 release (P < 0·0001). Almost...

CD66a (CEACAM1) is the only CD66 variant expressed on the surface of plasma cells in multiple myeloma: a refined target for radiotherapy trials?

British Journal of Haematology — Mon, 08 Mar 2010 00:00:00 +0100

(Source: British Journal of Haematology)

Lipid levels in sickle-cell disease associated with haemolytic severity, vascular dysfunction and pulmonary hypertension

British Journal of Haematology — Mon, 08 Mar 2010 00:00:00 +0100

Pulmonary hypertension (PH) in sickle cell disease (SCD) is an emerging and important clinical problem. In a single-institution adult cohort of 365 patients, we investigated lipid and lipoprotein levels and their relationship to markers of intravascular haemolysis, vascular dysfunction and PH. In agreement with prior studies, we confirm significantly decreased plasma levels of total cholesterol, high-density lipoprotein-cholesterol (HDL-C) and low-density lipoprotein-cholesterol (LDL-C) in SCD versus ethnically-matched healthy controls. Several cholesterol parameters correlated significantly with markers of anaemia, but not endothelial activation or PH. More importantly, serum triglyceride levels were significantly elevated in SCD compared to controls. Elevated triglyceride levels correlat...

Second malignancies in B-cell chronic lymphocytic leukaemia: possible association with human papilloma virus

British Journal of Haematology — Mon, 08 Mar 2010 00:00:00 +0100

This report describes preliminary evidence for the presence of HPV in secondary malignancies, in patients with CLL. (Source: British Journal of Haematology)

Mitochondrial D-loop variations in paediatric acute myeloid leukaemia: a potential prognostic marker

British Journal of Haematology — Mon, 08 Mar 2010 00:00:00 +0100

In conclusion, this is the largest study to show a high frequency of mtDNA variations in paediatric AML and their potential relevance as a prognostic marker in this disease. (Source: British Journal of Haematology)

Monoclonal gammopathy of undetermined significance: to screen or not to screen for multiple myeloma? – response

British Journal of Haematology — Mon, 08 Mar 2010 00:00:00 +0100

(Source: British Journal of Haematology)

Randomized trial of two schedules of low-dose gemtuzumab ozogamicin as induction monotherapy for newly diagnosed acute myeloid leukaemia in older patients not considered candidates for intensive chemotherapy. A phase II study of the EORTC and GIMEMA leukaemia groups (AML-19)

British Journal of Haematology — Mon, 08 Mar 2010 00:00:00 +0100

This study compared two schedules of low-dose gemtuzumab ozogamicin (GO) as induction monotherapy for untreated acute myeloid leukaemia in older patients unfit for intensive chemotherapy, to identify the more promising regimen for further study. Patients were randomized to receive either best supportive care or a course of GO according to one of two schedules: 3 mg/m2 on days 1, 3 and 5 (arm A), or GO 6 mg/m2 on day 1 and 3 mg/m2 on day 8 (arm B). Primary endpoint was the rate of disease non-progression (DnP), defined as the proportion of patients either achieving a response or maintaining a stable disease following GO induction in each arm. Fifty-six patients were randomized in the two GO arms (A, n = 29; B, n = 27). The rate of DnP was 38% [90% confidence interval (CI), 23[ndash]55] in a...

Favourable outcome of patients with childhood acute promyelocytic leukaemia after treatment with reduced cumulative anthracycline doses

British Journal of Haematology — Mon, 08 Mar 2010 00:00:00 +0100

Acute promyelocytic leukaemia (APL) treatment often includes high cumulative doses of anthracyclines, which can cause long-term cardiotoxicity. Here, we report the favourable outcome in 81 paediatric APL patients treated according to the consecutive acute myeloid leukaemia-Berlin/Frankfurt/Muenster (AML-BFM) trials -93/-98/-2004 with an anthracycline-cytarabine regimen in combination with all-trans-retinoid acid (ATRA). Outcomes achieved by treatment with a reduced cumulative anthracycline dose (350 mg/m2) were comparable to those reported for studies with higher doses. Five-year overall survival of the total cohort was 89 ± 4% and event-free survival (pEFS) was 73 ± 6%. Overall survival was similar when comparing AML-BFM trial periods (trial 93: 88 ± 8%, 98: 85 ± 7% and 2004: 94 ± 8%...

Multiple myeloma-associated polyarteritis nodosa

British Journal of Haematology — Thu, 04 Mar 2010 00:00:00 +0100

(Source: British Journal of Haematology)

Single nucleotide polymorphism-arrays provide new insights in the pathogenesis of post-transplant diffuse large B-cell lymphoma

British Journal of Haematology — Wed, 03 Mar 2010 00:00:00 +0100

In conclusion, PT-DLBCL presented unique features when compared with IC-DLBCL. Changes in PT-DLBCL were partially different to those in HIV-DLBCL, suggesting different pathogenetic mechanisms in the two conditions linked to immunodeficiency. (Source: British Journal of Haematology)

Reproductive history, hormone replacement, and incidence of venous thromboembolism: the Longitudinal Investigation of Thromboembolism Etiology

British Journal of Haematology — Wed, 03 Mar 2010 00:00:00 +0100

Numerous studies have established that hormone replacement therapy increases the risk of venous thromboembolism (VTE), but an association of endogenous oestrogen exposure with the incidence of VTE is not fully established. Using a prospective design combining the Atherosclerosis Risk in Communities and the Cardiovascular Health Study cohort, we studied the 12-year risk of VTE in relation to hormone replacement therapy use, age at menopause, parity number, and type of menopause in 8236 post-menopausal women. There were no significant associations of age at menopause, parity number, or type of menopause with incidence of VTE. Women currently using hormone replacement had a 1·6-times higher multivariate-adjusted rate ratio (RR) of VTE compared with those without hormone use in the time-depen...

Epidemiology of β-thalassaemia in Western India: mapping the frequencies and mutations in sub-regions of Maharashtra and Gujarat

British Journal of Haematology — Wed, 03 Mar 2010 00:00:00 +0100

Although the average frequency of [beta]-thalassaemia carriers in India is 3[ndash]4% and the prevalent mutations have been studied, no micromapping has been done. This is the first attempt to provide an accurate estimate of the frequencies of [beta]-thalassaemia and the expected annual births of homozygous children in different districts of Maharashtra and Gujarat in Western India as well as to determine the molecular heterogeneity in different sub-regions in these states. A total of 18 651 individuals were screened for haemo-globinopathies and mutations were characterized in 1334 [beta]-thalassaemia heterozygotes. There was an uneven distribution of the frequencies of [beta]-thalassaemia, varying from 1·0% to 6·0% and 0% to 9·5% in different districts of Maharasthra and Gujarat. The r...

A novel missense mutation c.470 A>C (p.D157A) in the SLC40A1 gene as a cause of ferroportin disease in a family with hyperferritinaemia

British Journal of Haematology — Wed, 03 Mar 2010 00:00:00 +0100

(Source: British Journal of Haematology)

Asparaginase-related venous thrombosis in UKALL 2003- re-exposure to asparaginase is feasible and safe

British Journal of Haematology — Mon, 01 Mar 2010 00:00:00 +0100

This report confirms a significant risk of thrombosis with such therapy, but demonstrates that re-exposure to Asparaginase is feasible and safe. (Source: British Journal of Haematology)

Stem cell transplantation after alemtuzumab in T-cell prolymphocytic leukaemia results in longer survival than after alemtuzumab alone: a multicentre retrospective study

British Journal of Haematology — Mon, 01 Mar 2010 00:00:00 +0100

(Source: British Journal of Haematology)

Reticulocytes and erythroid precursors in haemolysis vasculopathy

British Journal of Haematology — Mon, 01 Mar 2010 00:00:00 +0100

(Source: British Journal of Haematology)

Emergent T-helper 2 profile with high interleukin-6 levels correlates with the appearance of bortezomib-induced neuropathic pain

British Journal of Haematology — Mon, 01 Mar 2010 00:00:00 +0100

(Source: British Journal of Haematology)

The novel inhibitor of histone deacetylase resminostat (RAS2410) inhibits proliferation and induces apoptosis in multiple myeloma (MM) cells

British Journal of Haematology — Mon, 01 Mar 2010 00:00:00 +0100

In conclusion, we have identified potent anti-myeloma activity for this novel HDAC inhibitor. (Source: British Journal of Haematology)

Unexpected detection of monoclonal B-cell lymphocytosis in a HLA-matched sibling donor on the day of allogeneic stem cell transplantation for a patient with chronic lymphocytic leukaemia: clinical outcome

British Journal of Haematology — Mon, 01 Mar 2010 00:00:00 +0100

(Source: British Journal of Haematology)

Final analysis of the UKLG LY02 trial comparing 6–8 cycles of CHOP with 3 cycles of CHOP followed by a BEAM autograft in patients

British Journal of Haematology — Mon, 01 Mar 2010 00:00:00 +0100

In conclusion, no survival benefit was demonstrated for an early autograft in first response. (Source: British Journal of Haematology)

Advances in the understanding of haemoglobin switching

British Journal of Haematology — Mon, 01 Mar 2010 00:00:00 +0100

The study of haemoglobin switching has represented a focus in haematology due in large part to the clinical relevance of the fetal to adult haemoglobin switch for developing targeted approaches to ameliorate the severity of the [beta]-haemoglobinopathies. Additionally, the process by which this switch occurs represents an important paradigm for developmental gene regulation. In this review, we provide an overview of both the embryonic primitive to definitive switch in haemoglobin expression, as well as the fetal to adult switch that is unique to humans and old world monkeys. We discuss the nature of these switches and models of their regulation. The factors that have been suggested to regulate this process are then discussed. With the increased understanding and discovery of molecular regu...

Review of phenotypic markers used in flow cytometric analysis of MGUS and MM, and applicability of flow cytometry in other plasma cell disorders

British Journal of Haematology — Mon, 01 Mar 2010 00:00:00 +0100

The objective of this review is to update the malignant plasma cells phenotypic profile of MGUS and MM. The most comprehensive antigens, such as CD19, CD27, CD28, CD45, CD56 and CD117, play a significant role in the characterization of normal and malignant plasma cells. Several research groups described the putative phenotype of myeloma cell progenitors, but no remarkable suggestion could be made because of disparity. This review also focuses on the association of malignant phenotypic markers and chromosomal aberrations that identify the specific prognostic features in monoclonal gammopathies. (Source: British Journal of Haematology)

High immunohistochemical expression of p-AKT predicts inferior survival in patients with diffuse large B-cell lymphoma treated with immunochemotherapy

British Journal of Haematology — Mon, 01 Mar 2010 00:00:00 +0100

Chemotherapy and rituximab (R) is current standard therapy in diffuse large B-cell lymphoma (DLBCL), but a substantial proportion of patients still fail to reach sustained remission. In vitro studies have indicated that rituximab resistance could be accompanied by dysregulated apoptotic pathways, such as the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway, which can be constitutively activated in DLBCL. In this retrospective, immunohistochemical study on 106 patients treated with R-CHO(E)P (cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab [+etoposide]), we investigated the prognostic role of proteins involved in different apoptotic pathways; phosphorylated AKT (p-AKT), bcl-2, MCL1, bcl-xL, Bax and Bak. High p-AKT expression (>108 cells/mm2, highest quartile, n =...

Update on the hyper immunoglobulin M syndromes

British Journal of Haematology — Wed, 24 Feb 2010 00:00:00 +0100

The Hyper-immunoglobulin M syndromes (HIGM) are a heterogeneous group of genetic disorders resulting in defects of immunoglobulin class switch recombination (CSR), with or without defects of somatic hypermutation (SHM). They can be classified as defects of signalling through CD40 causing both a humoral immunodeficiency and a susceptibility to opportunistic infections, or intrinsic defects in B cells of the mechanism of CSR resulting in a pure humoral immunodeficiency. A HIGM picture can also be seen as part of generalized defects of DNA repair and in antibody deficiency syndromes, such as common variable immunodeficiency. CD40 signalling defects may require corrective therapy with bone marrow transplantation. Gene therapy, a potential curative approach in the future, currently remains a di...

Paraneoplastic pemphigus due to CD8-positive cytotoxic T-cell lymphoma

British Journal of Haematology — Sat, 20 Feb 2010 00:00:00 +0100

(Source: British Journal of Haematology)

Exercise capacity and haemodynamics in patients with sickle cell disease with pulmonary hypertension treated with bosentan: results of the ASSET studies

British Journal of Haematology — Thu, 18 Feb 2010 00:00:00 +0100

Doppler-defined pulmonary hypertension (PH) in sickle cell disease (SCD) is associated with 40% mortality at 40 months. To assess the effect of bosentan in SCD-PH, two randomized, double-blind, placebo-controlled, 16-week studies were initiated. Safety concerns are particularly relevant in SCD due to comorbid conditions. ASSET-1 and -2 enrolled patients with pulmonary arterial hypertension (PAH) and pulmonary venous hypertension (PH), respectively. Haemodynamics and 6-min walk distance (6MWD) were obtained at baseline and week 16. The studies were terminated due to slow site initiation and patient enrolment (n = 26). Bosentan appeared to be well tolerated. Although sample sizes were limited, in ASSET-1 at baseline, 6MWD correlated with cardiac output (CO; P = 0·006) with non-significant i...

Patients undergoing high dose chemotherapy for primary CNS lymphoma should receive prophylactic thiamine to prevent Wernike's encephalopathy

British Journal of Haematology — Fri, 12 Feb 2010 00:00:00 +0100

(Source: British Journal of Haematology)

Clinical utility of routine MPL exon 10 analysis in the diagnosis of essential thrombocythaemia and primary myelofibrosis

British Journal of Haematology — Thu, 11 Feb 2010 00:00:00 +0100

Approximately 50% of essential thrombocythaemia and primary myelo-fibrosis patients do not have a JAK2 V617F mutation. Up to 5% of these are reported to have a MPL exon 10 mutation but testing for MPL is not routine as there are multiple mutation types. The ability to routinely assess both JAK2 and MPL mutations would be beneficial in the differential diagnosis of unexplained thrombocytosis or myelofibrosis. We developed and applied a high resolution melt (HRM) assay, capable of detecting all known MPL mutations in a single analysis, for the detection of MPL exon 10 mutations. We assessed 175 ET and PMF patients, including 67 that were JAK2 V617F-negative by real time polymerase chain reaction (PCR). Overall, 19/175 (11%) patients had a MPL exon 10 mutation, of whom 16 were JAK2 V617F-nega...

The effect of rituximab on humoral and cell mediated immunity and infection in the treatment of autoimmune diseases

British Journal of Haematology — Thu, 11 Feb 2010 00:00:00 +0100

Depletion of B lymphocytes using the anti-CD20 monoclonal antibody rituximab has wide-spread use in the treatment of patients with autoimmune disorders. As haematopoietic progenitor cells and only a fraction of differentiated plasma express CD20, the effect of rituximab on immune function appears to be minimal. However, hypogammagobulinaemia can occur with repeated doses and emerging data from large studies suggest a subtle increase in the risk of infection. Reactivation of latent JC virus, resulting in progressive multifocal leucoencephalopathy, and hepatitis B virus, resulting in hepatoxicity, have been documented in patients receiving rituximab; although confounding effects of concomitant immunosuppressive therapies and immune dysregulation due to the underlying disease make causal asso...

Prospects for the manufacture of red cells for transfusion

British Journal of Haematology — Thu, 11 Feb 2010 00:00:00 +0100

Whilst red cell transfusion is a well established cellular therapy, the problems of insufficiency of supply, transfusion transmitted infections and the requirement for immunological matching persist. The possibility of generating large numbers of O Rh D negative red cells at Good Manufacturing Practice grade as a route to circumvent these issues is therefore an attractive proposition. Significant numbers of erythrocytes can be generated from somatic haematopoietic stem cells, but it seems unlikely that these can provide sufficient volumes for large scale manufacture. However, human embryonic stem cells (hESC) and, potentially, induced pluripotent stem cells (iPSC), may provide a route to this objective. Red cell transfusion is an attractive goal for pluripotent stem cell-derived therapeuti...

The management of pregnancy in paroxysmal nocturnal haemoglobinuria on long term eculizumab

British Journal of Haematology — Thu, 11 Feb 2010 00:00:00 +0100

We report on seven patients exposed to eculizumab at different stages of pregnancy including the first two patients to receive the drug from conception to delivery. There was no evidence of complement blockade from cord blood samples taken at delivery. Eculizumab appears safe to use in this setting and is likely to prevent many of the complications usually observed. (Source: British Journal of Haematology)

The role of haematopoietic growth factors granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor in the management of drug-induced agranulocytosis

British Journal of Haematology — Thu, 11 Feb 2010 00:00:00 +0100

Drug-induced agranulocytosis (neutrophil count (Source: British Journal of Haematology)

Targeting SYK kinase-dependent anti-apoptotic resistance pathway in B-lineage acute lymphoblastic leukaemia (ALL) cells with a potent SYK inhibitory pentapeptide mimic

British Journal of Haematology — Thu, 11 Feb 2010 00:00:00 +0100

The present study found that the pentapeptide mimic C-61, targeting the substrate binding P-site of SYK tyrosine kinase acted as a potent inducer of apoptosis in chemotherapy-resistant SYK-expressing primary leukemic B-cell precursors taken directly from relapsed B-precursor leukaemia (BPL) patients (but not SYK-deficient infant pro-B leukaemia cells), exhibited favourable pharmacokinetics in mice and non-human primates, and eradicated in vivo clonogenic leukaemia cells in severe combined immunodeficient mouse xenograft models of chemotherapy-resistant human BPL at dose levels non-toxic to mice and non-human primates. These in vitro and in vivo findings provide proof of principle for effective treatment of chemotherapy-resistant BPL by targeting SYK-dependent anti-apoptotic blast cell surv...

Influence of dietary vitamin K intake on subtherapeutic oral anticoagulant therapy

British Journal of Haematology — Thu, 11 Feb 2010 00:00:00 +0100

It is unclear what advice should be given to patients using vitamin K antagonists with respect to dietary vitamin K intake. We performed a nested case[ndash]control study in patients attending a Dutch anticoagulation clinic, to determine the association between vitamin K intake and subtherapeutic International Normalized Ratio (INR) values and the interaction between usual and recent vitamin K intake. Compared to patients with a normal usual vitamin K intake, those with a high vitamin K intake had a decreased risk of a subtherapeutic INR [Hazard Ratio (HR) 0·80, 95% confidence interval (CI): 0·56[ndash]1·16] and patients with a low vitamin K intake an increased risk (HR 1·33, 95% CI: 0·79[ndash]2·25). In patients with a low usual vitamin K intake, recent vitamin K intake was twice as...

Congestive heart failure as presentation of acute lymphoblastic leukaemia with eosinophilia

British Journal of Haematology — Wed, 10 Feb 2010 00:00:00 +0100

(Source: British Journal of Haematology)

The t(14;20)(q32;q12): a rare cytogenetic change in multiple myeloma associated with poor outcome

British Journal of Haematology — Tue, 09 Feb 2010 00:00:00 +0100

(Source: British Journal of Haematology)

Long-term, sub-clinical cardiac and renal complications in patients with multiple relapses of thrombotic thrombocytopenic purpura

British Journal of Haematology — Tue, 09 Feb 2010 00:00:00 +0100

(Source: British Journal of Haematology)

Monoclonal gammopathy of undertermined significance: to screen or not to screen for multiple myeloma?

British Journal of Haematology — Mon, 08 Feb 2010 00:00:00 +0100

(Source: British Journal of Haematology)

Restored platelet function after romiplostim treatment in a patient with immune thrombocytopenic purpura

British Journal of Haematology — Mon, 08 Feb 2010 00:00:00 +0100

(Source: British Journal of Haematology)

Managing anticoagulated patients during neuraxial anaesthesia

British Journal of Haematology — Mon, 08 Feb 2010 00:00:00 +0100

The widespread use of central neuraxial block (CNB) and the prevalence of anticoagulation for different indications have led to an inevitable overlap between the two. The most serious complication of CNB in anticoagulated patients is the risk of spinal/epidural haematoma. Performing CNB in these patients is a complex decision that should take into account the twin risks of bleeding and venous/arterial thrombosis if anticoagulation therapies were to be stopped. Various guidelines have been issued to achieve normal haemostasis and thus allow safe administration of CNB. However, the evidence base for many such recommendations is weak, relying mainly on case reports, small studies and pharmacokinetics of the drugs. Given these limitations it is crucial to fully assess individual risk factors a...

The genotype nucleophosmin mutated and FLT3-ITD negative is characterized by high bax/bcl-2 ratio and favourable outcome in acute myeloid leukaemia

British Journal of Haematology — Mon, 08 Feb 2010 00:00:00 +0100

Nucleophosmin gene (NPM1) mutations characterize acute myeloid leukaemia (AML) with normal karyotype and frequently co-exist with FLT3 internal tandem duplications (ITD). We evaluated bcl-2, bax, NPM1 and FLT3-ITD in 222 AML patients. Bax/bcl-2 ratio >0·35 and NPM1 without FLT3-ITD were significantly associated (P = 0·0001). NPM1-mutated (mt)/FLT3-ITD negative patients showed a higher complete remission (CR) rate (90%, P = 0·0002) and a longer overall survival (OS, P = 0·00007). NPM1-mt/FLT3-ITD negative plus bax/bcl-2 > 0·35 subset showed a very high CR rate (96%), very long OS (P = 0·00005) and disease-free survival (P = 0·004). The favourable prognosis of NPM1-mt/FLT3-ITD negative patients might be explained by a higher bax/bcl-2 ratio. (Source: British Journal of Haematology)

Acute lymphoblastic leukaemia in children – is there a role for MTHFR?

British Journal of Haematology — Mon, 08 Feb 2010 00:00:00 +0100

(Source: British Journal of Haematology)

Acute lymphoblastic leukaemia in children – is there a role for MTHFR? – response to Lightfoot et al

British Journal of Haematology — Mon, 08 Feb 2010 00:00:00 +0100

(Source: British Journal of Haematology)

Venous thrombosis prevention – more than just guidelines

British Journal of Haematology — Mon, 08 Feb 2010 00:00:00 +0100

Hospital-associated venous thromboembolism remains a major international cause of avoidable mortality and morbidity. Although the publication of national guidelines does increase the use of thromboprophylaxis, we present the results of a recent audit of thrombosis prevention in UK hospitals which, despite published guidelines, shows continuing significant variations in guideline implementation and practice. The results of this audit are paralleled with UK and international data on hospital-acquired thrombosis prevention and the potential solutions to these problems, particularly the lessons which can be learned from other areas of clinical practice, are discussed. (Source: British Journal of Haematology)

Actin filaments and microtubule dual-granule transport in human adhered platelets: the role of α-dystrobrevins

British Journal of Haematology — Mon, 08 Feb 2010 00:00:00 +0100

Upon activation with physiological stimuli, human platelets undergo morphological changes, centralizing their organelles and secreting effector molecules at the site of vascular injury. Previous studies have indicated that the actin filaments and microtubules of suspension-activated platelets play a critical role in granule movement and exocytosis; however, the participation of these cytoskeleton elements in adhered platelets remains unexplored. [alpha]- and [beta]-dystrobrevin members of the dystrophin-associated protein complex in muscle and non-muscle cells have been described as motor protein receptors that might participate in the transport of cellular components in neurons. Recently, we characterized the expression of dystrobrevins in platelets; however, their functional diversity wi...

Genetic susceptibility, smoking, obesity and risk of venous thromboembolism

British Journal of Haematology — Mon, 08 Feb 2010 00:00:00 +0100

The F5 G1691A (Factor V Leiden) and F2 G20210A (prothrombin) mutations are linked to an increase in the incidence rate of venous thromboembolism (VTE), but their effects are highly variable. We investigated whether the effects of smoking and obesity might explain this variability. In a case-cohort study including the participants of the Danish Diet, Cancer and Health study, we computed incidence rates and Cox proportional hazard ratios for VTE in individuals with and without the mutations, categorized by weight and tobacco consumption. The sole effect of heavy smoking was 128 extra VTE events per 100 000 person years in individuals with the F5 G1691A mutation versus 59 in individuals without. The sole effect of obesity was 222 extra VTE events per 100 000 person years in individuals with t...

Non-Homologous End-Joining Gene Profiling Reveals Distinct Expression Patterns Associated with Lymphoma and Multiple Myeloma

British Journal of Haematology — Mon, 08 Feb 2010 00:00:00 +0100

Repair of DNA strand breaks induced during lymphoid antigen receptor rearrangement involves non-homologous end-joining (NHEJ). We investigated NHEJ in the aetiology of lymphoproliferative disorders (LPDs) and the disease subtypes therein through real-time quantitative RT-PCR gene expression analysis. Lower expression of XRCC6 and MRE11A was observed in all tumours, with higher expression of both XRCC4 and RAD50 observed only in multiple myeloma (MM). Hierarchical clustering enabled tumours to be clearly distinguished from controls, and by morphological sub-type. We postulate this identifies targets worthy of investigation in the genetic predisposition, pathogenesis and prognosis of lymphoid malignancies. (Source: British Journal of Haematology)

Increased adhesive properties of platelets in sickle cell disease: roles for αIIbβ3-mediated ligand binding, diminished cAMP signalling and increased phosphodiesterase 3A activity

British Journal of Haematology — Sat, 06 Feb 2010 00:00:00 +0100

Whilst high pro-coagulant activity is reported in sickle cell disease (SCD), the precise role of platelets (PLTs) in SCD inflammatory and vaso-occlusive processes is unclear. Adhesion of PLTs from healthy controls (CON), SCD individuals (SCD) and SCD patients on hydroxycarbamide (SCDHC) to fibrinogen (FB) was compared using static adhesion assays. PLT adhesion molecules and intraplatelet cyclic adenosine monophosphate (icAMP) were observed by flow cytometry and enzyme-linked immunosorbent assay. SCD-PLTs demonstrated significantly greater adhesion than CON-PLTs to FB. Participation of the [alpha]IIb[beta]3-integrin in SCD-PLT adhesion was implicated by increased [alpha]IIb[beta]3 activation and data showing that an [alpha]IIb[beta]3-function-inhibiting antibody significantly diminished SCD...

Haematopoeitic cell transplantation for Fanconi anaemia – when and how?

British Journal of Haematology — Fri, 05 Feb 2010 00:00:00 +0100

Allogeneic haematopoietic cell transplantation (HCT) remains the only treatment that can correct the haematological manifestations in patients with Fanconi anaemia. Over the last two decades, sequential changes to the approach to HCT have resulted in reduced regimen-related toxicity, superior engraftment and less graft-versus-host disease (GVHD), resulting in improved survival. The two pivotal changes that most influenced these improvements were the addition of fludarabine to the preparative regimen to augment engraftment, and the use of T cell depletion to reduce GVHD. With these improved HCT outcomes, indications for HCT are quite consistent regardless of donor source. Emphasis is now being placed on developing HCT regimens that will improve quality of life by reducing late effects, part...

Prolonged survival with improved tolerability in higher-risk myelodysplastic syndromes: azacitidine compared with low dose ara-C

British Journal of Haematology — Fri, 05 Feb 2010 00:00:00 +0100

In the phase III AZA-001 trial, low-dose cytarabine (LDara-C), the most widely used low-dose chemotherapy in patients with higher-risk myelodysplastic syndrome (MDS) who are ineligible for intensive treatment, was found to be associated with poorer survival compared with azacitidine. This analysis further compared the efficacy and the toxicity of these two drug regimens. Before randomization, investigators preselected patients to receive a conventional care regimen, one of which was LDara-C. Of 94 patients preselected to LDara-C, 45 were randomized to azacitidine and 49 to LDara-C. Azacitidine patients had significantly more and longer haematologicalal responses and increased red blood cell transfusion independence. Azacitidine prolonged overall survival versus LDara-C in patients with poo...

Whole-body magnetic resonance imaging, including diffusion-weighted imaging, for diagnosing bone marrow involvement in malignant lymphoma

British Journal of Haematology — Fri, 29 Jan 2010 00:00:00 +0100

(Source: British Journal of Haematology)

Clinical guidelines for testing for heritable thrombophilia

British Journal of Haematology — Thu, 28 Jan 2010 00:00:00 +0100

(Source: British Journal of Haematology)

Venous thrombosis of the upper extremity: effect of blood group and coagulation factor levels on risk

British Journal of Haematology — Thu, 21 Jan 2010 00:00:00 +0100

Venous thrombosis of the upper extremity is a rare form of thrombosis, accounting for around 4% of all venous thromboses, and for which only a few risk factors are known. This case-control study investigated the effect of coagulation factors on risk of venous thrombosis of the upper extremity. Patients with venous thrombosis of the arm and partner controls were selected from the Multiple Environmental and Genetic Assessment study, a large population-based case-control study. Participants with a malignancy were excluded. Odds ratios (OR) were estimated for elevated levels of factor II, VII, VIII, IX, X, XI, von Willebrand Factor (VWF), and fibrinogen, low levels of protein C, protein S, and antithrombin, and for blood group non-O. Substantially increased risks of venous thrombosis of the up...

Epigallocatechin-3-gallate induces cell death in acute myeloid leukaemia cells and supports all-trans retinoic acid-induced neutrophil differentiation via death-associated protein kinase 2

British Journal of Haematology — Wed, 20 Jan 2010 00:00:00 +0100

Acute promyelocytic leukaemia (APL) patients are successfully treated with all-trans retinoic acid (ATRA). However, concurrent chemotherapy is still necessary and less toxic therapeutic approaches are needed. Earlier studies suggested that in haematopoietic neoplasms, the green tea polyphenol epigallocatechin-3-gallate (EGCG) induces cell death without adversely affecting healthy cells. We aimed at deciphering the molecular mechanism of EGCG-induced cell death in acute myeloid leukaemia (AML). A significant increase of death-associated protein kinase 2 (DAPK2) levels was found in AML cells upon EGCG treatment paralleled by increased cell death that was significantly reduced upon silencing of DAPK2. Moreover, combined ATRA and EGCG treatment resulted in cooperative DAPK2 induction and poten...

Comparison of intravenous immune globulin and high dose anti-D immune globulin as initial therapy for childhood immune thrombocytopenic purpura

British Journal of Haematology — Wed, 20 Jan 2010 00:00:00 +0100

This report documents our experience with intravenous immune globulin (IVIG) (1 g/kg, iv) and high-dose, anti-D immune globulin (anti-D) (75 [mu]g/kg) as initial treatment for childhood immune thrombocytopenic purpura (ITP). The medical records of children diagnosed with ITP at a single institution between January 2003 and May 2008 were retrospectively reviewed. Participants received either IVIG or high-dose anti-D immune globulin as their initial treatment for ITP. For the 53 patients included for analysis, there was no statistical difference in efficacy between each group; however, patients who received anti-D experienced a higher rate of adverse drug reactions (ADRs), particularly chills and rigours, and 2 of 24 patients in the anti-D group developed severe anaemia requiring medical int...

Aberrant expression of the neuronal transcription factor FOXP2 in neoplastic plasma cells

British Journal of Haematology — Wed, 20 Jan 2010 00:00:00 +0100

FOXP2 mutation causes a severe inherited speech and language defect, while the related transcription factors FOXP1, FOXP3 and FOXP4 are implicated in cancer. FOXP2 mRNA and protein expression were characterised in normal human tissues, haematological cell lines and multiple myeloma (MM) patients' samples. FOXP2 mRNA and protein were absent in mononuclear cells from different anatomical sites, lineages and stages of differentiation. However, FOXP2 mRNA and protein was detected in several lymphoma (8/20) and all MM-derived cell lines (n = 4). FOXP2 mRNA was expressed in bone marrow samples from 96% of MM patients (24/25), 66·7% of patients with the pre-neoplastic plasma cell proliferation monoclonal gammopathy of undetermined significance (MGUS) (6/9), but not in reactive plasma cells. The ...

CMV-related immune thrombocytopenic purpura or CMV-induced thrombocytopenia?

British Journal of Haematology — Wed, 20 Jan 2010 00:00:00 +0100

(Source: British Journal of Haematology)

Comparison between British and Japanese guidelines for the diagnosis and treatment of disseminated intravascular coagulation

British Journal of Haematology — Wed, 20 Jan 2010 00:00:00 +0100

(Source: British Journal of Haematology)

Advances in understanding the pathogenesis of primary familial and congenital polycythemia

British Journal of Haematology — Wed, 20 Jan 2010 00:00:00 +0100

Primary familial and congenital polycythemia (PFCP) is an autosomal-dominant proliferative disorder characterized by erythrocytosis and hypersensitivity of erythroid progenitors to erythropoietin (Epo). Several lines of evidence suggest a causal role of truncated erythropoietin receptor (EpoR) in this disease. In this review, we discuss PFCP in the context of erythrocytosis and EpoR signalling. We focus on recent studies describing mechanisms underlying Epo-dependent EpoR down-regulation. One mechanism depends on internalization mediated through the p85 regulatory subunit of the Phosphoinositide 3-Kinase, and the other utilizes ubiquitin-based proteasomal degradation. Truncated PFCP EpoRs are not properly down-regulated upon stimulation, underscoring the importance of these mechanisms in t...

Epidemiology of paediatric invasive fungal infections and a case-control study of risk factors in acute leukaemia or post stem cell transplant

British Journal of Haematology — Wed, 20 Jan 2010 00:00:00 +0100

Patients aged 0[ndash]18 years with confirmed or possible invasive fungal infection were identified by medical record and database searches. Cases with an underlying diagnosis of acute leukaemia or following stem cell transplantation were included in a case control study. Controls included all other children with acute leukaemia or stem cell transplant in the corresponding time period. Variables collected included demographics, underlying disease risk and status, organ impairment, admission to intensive care unit, fungal infection details and certain transplant variables. Risk factors for development of invasive fungal infection were examined using logistic regression. There were 106 cases of invasive fungal infection during the study. The incidence of invasive fungal infection was 21% in ...

WT1 expression levels at diagnosis could predict long-term time-to-progression in adult patients affected by acute myeloid leukaemia and myelodysplastic syndromes

British Journal of Haematology — Tue, 19 Jan 2010 00:00:00 +0100

(Source: British Journal of Haematology)

The endothelial cells downregulate the generation of factor VIIa through EPCR binding

British Journal of Haematology — Tue, 19 Jan 2010 00:00:00 +0100

Traces of activated factor VII (FVIIa) are required to maintain haemostasis. Activated factor X (FXa) is the main activator of FVII in the absence of tissue factor. However, little is known about how this mechanism is regulated. We and others reported the interaction between FVII and the endothelial cell protein C receptor (EPCR). We have analysed the role of EPCR in the FXa-dependent FVIIa generation. Activation was performed on the surface of human aortic endothelial cells in the presence or absence of a blocking anti-EPCR monoclonal antibody (mAb). Western-blot analyses revealed that FVII activation was increased twofold upon EPCR blocking. Kinetic analyses revealed that blocking doubled the catalytic efficiency for activation. Protein C was unable to mimic the effect of the anti-EPCR m...

Mimicking the haematopoietic niche microenvironment provides a novel strategy for expansion of haematopoietic and megakaryocyte-progenitor cells from cord blood

British Journal of Haematology — Mon, 18 Jan 2010 00:00:00 +0100

Severe neutropenia and protracted thrombocytopenia remain serious clinical problems following cord blood transplantation (CBT) due to the paucity of stem and progenitor cells in the grafts. Administration of ex-vivo expanded megakaryocyte progenitor cells may facilitate platelet production. We propose a novel strategy to expand these rare cells ex-vivo, from a small portion of the cord blood (CB) unit, using fibronectin (FN), a major component of hematopoietic niches, combined with cytokines, including thrombopoietin and the hematopoietic stress-associated acetylcholinesterase readthrough peptide (ARP). Application of multiple gates and high definition flow cytometry enabled clear resolution of expanded hematopoietic stem/precursor cells (HSPC) and megakaryocyte progenitors (Mk-p) and thei...

Glucose 6-phosphate dehydrogenase Palermo R257M: a novel variant associated with chronic non-spherocytic haemolytic anaemia

British Journal of Haematology — Mon, 18 Jan 2010 00:00:00 +0100

(Source: British Journal of Haematology)

High-dose chemo-radiotherapy for relapsed or refractory hodgkin lymphoma and the significance of pre-transplant functional imaging

British Journal of Haematology — Mon, 18 Jan 2010 00:00:00 +0100

We previously reported that three risk factors (RF): initial remission duration (Source: British Journal of Haematology)

Macrophage colony-stimulating factor produced by diffuse large B-cell lymphoma

British Journal of Haematology — Mon, 18 Jan 2010 00:00:00 +0100

(Source: British Journal of Haematology)

Acute leukaemias of ambiguous lineage in children: characterization, prognosis and therapy recommendations

British Journal of Haematology — Mon, 18 Jan 2010 00:00:00 +0100

This study retrospectively analyzed data from 92 children (biphenotypic n = 78, bilineal n = 6, lineage switch n = 8) with ALAL registered in the Berlin-Frankfürt-Münster (BFM) acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL) studies between 1998 and 2006 (2·4% of all cases with acute leukaemia). Our cohort of ALAL patients was characterized by comparatively high median age (8·9 years), high median white blood cell count (14·9 × 109/l), as well as frequent hyperleucocytosis (18·5%) and central nervous system involvement (24·1%). The most frequent cytogenetic abnormalities were ETV6/RUNX1 fusion (16%) and trisomy 8 (14·6%). Complete remission rate was significantly lower than in ALL-BFM patients (91·8% vs. 99·1%, P < 0·001), but comparable to AML-BFM patient...

Individual myeloma-specific T-cell clones eliminate tumour cells and correlate with clinical outcomes in patients with multiple myeloma

British Journal of Haematology — Wed, 13 Jan 2010 00:00:00 +0100

Despite novel treatment strategies, multiple myeloma (MM) remains an incurable disease with low immunogenicity and multiple immune defects. We developed an ex vivo strategy for inducing myeloma-specific cytotoxic T lymphocytes (CTLs) and demonstrate the possibility of identification and long-term in vivo monitoring of individual myeloma-specific T-cell clones using the most sensitive clonotypic assay that is able to detect low frequencies of T-cell clones (1 clonotypic cell in 106 cells). Ten patients with MM were examined for the presence of tumour-reactive T cells using dendritic cells loaded with autologous tumour cells. All patients had detectable myeloma-reactive T cells in vitro. Expanded myeloma-reactive T cells demonstrated specific cytotoxic effects against autologous tumour cells...

Long-term dual donor derived haematopoietic reconstitution following double unrelated cord blood transplantation – single unit dominance is not always the case

British Journal of Haematology — Wed, 13 Jan 2010 00:00:00 +0100

(Source: British Journal of Haematology)

The embryonic origins of lymphatic vessels: an historical review

British Journal of Haematology — Wed, 13 Jan 2010 00:00:00 +0100

Work on the lymphatic system began in the 17th century, and by the beginning of the 19th century the anatomy of most of the lymphatic system had been described. One of the most important questions in this field has been the determination of the embryological origin of the lymphatic endothelium. Two theories were proposed. The first suggested that lymphatic endothelium derived by sprouting from venous endothelium, the so-called centrifugal theory. The second, the so-called centripetal theory, suggested that lymphatic endothelium differentiates in situ from primitive mesenchyme, and secondarily acquires connection with the vascular system. More recent evidence has provided support for both hypotheses. (Source: British Journal of Haematology)

Significant haemoglobinopathies: guidelines for screening and diagnosis

British Journal of Haematology — Wed, 13 Jan 2010 00:00:00 +0100

(Source: British Journal of Haematology)

Combined bezafibrate and medroxyprogesterone acetate have efficacy without haematological toxicity in elderly and relapsed acute myeloid leukaemia (AML)

British Journal of Haematology — Wed, 13 Jan 2010 00:00:00 +0100

Acute myeloid leukaemia (AML) causes life-threatening deficits of functional blood cells that require management using red cell and platelet transfusion and aggressive treatment of neutropenic infections. Current cytotoxic chemotherapy further worsens the problem of reduced haemopoiesis and two-thirds of patients are too frail to tolerate intensive chemotherapy at all. Median survival amongst these patients remains at 4 weeks. One reverted from high risk myelodysplasia and remains transfusion independent after 201 weeks of therapy. Three AML patients gained major haematological improvements for 22[ndash]30 weeks; in one, marrow was available to document a partial AML response. Thus, this trial indicates that BaP therapy has potential for treatment of elderly and relapsed AML. (Source: Brit...

Prognostic relevance of dic(9;20)(p11;q13) in childhood B-cell precursor acute lymphoblastic leukaemia treated with Berlin-Frankfurt-Münster (BFM) protocols containing an intensive induction and post-induction consolidation therapy

British Journal of Haematology — Wed, 13 Jan 2010 00:00:00 +0100

In conclusion, in the context of ALL-BFM protocols dic(9;20)-positivity appeared to have a favourable prognosis, which could be due to a dose- and time-intensified induction and induction consolidation therapy. Given that in vitro studies have shown high cellular sensitivity of dic(9;20)-positive leukemic blasts to l-asparaginase and cytarabine, it is reasonable to speculate that both drugs, as given early during BFM-like induction and consolidation therapy, may have contributed to this good outcome. (Source: British Journal of Haematology)

The impact of donor type and ABO incompatibility on transfusion requirements after nonmyeloablative haematopoietic cell transplantation

British Journal of Haematology — Tue, 12 Jan 2010 00:00:00 +0100

In conclusion, nonmyeloablative recipients required fewer platelet and RBC transfusions and among them, both unrelated and major/bidirectionally ABO-mismatched recipients required more RBC transfusions. ABO incompatibility did not affect nonmyeloablative HCT outcomes. (Source: British Journal of Haematology)

Validation of follicular lymphoma international prognostic index 2 (FLIPI2) score in an independent series of follicular lymphoma patients

British Journal of Haematology — Mon, 11 Jan 2010 00:00:00 +0100

(Source: British Journal of Haematology)

Blasts in transient leukaemia in neonates with Down syndrome differentiate into basophil/mast-cell and megakaryocyte lineages in vitro in association with down-regulation of truncated form of GATA1

British Journal of Haematology — Mon, 11 Jan 2010 00:00:00 +0100

Mutations of GATA1, leading to aberrant expression of a truncated form of GATA1 (called GATA1s), are present in transient leukaemia (TL) in neonates with Down syndrome. Using these molecular markers of TL, we investigated the growth and differentiation potential of TL blasts in the presence of hematopoietic growth factors (HGFs). Interleukin-3, stem cell factor and granulocyte-macrophage colony-stimulating factor potently stimulated the growth of TL blast progenitors and induced differentiation towards basophil/mast cell lineages, whereas thrombopoietin induced differentiation towards megakaryocytes. GATA1s was expressed in TL blasts in all five patients examined but was down-regulated during differentiation induced by these HGFs, while full-length GATA1 was not expressed throughout the cu...

Molecular characterisation of a recurrent, semi-cryptic RUNX1 translocation t(7;21) in myelodysplastic syndrome and acute myeloid leukaemia

British Journal of Haematology — Mon, 11 Jan 2010 00:00:00 +0100

A proportion of cytogenetic abnormalities in myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) may escape detection by high-resolution genomic technologies, but can be identified by conventional cytogenetic and molecular analysis. Here, we report the detection of a reciprocal translocation t(7;21)(p22;q22) in the marrow of two adults with MDS and AML, using conventional cytogenetic analysis and fluorescence-in situ-hybridization (FISH). Reverse-transcription polymerase chain reaction (RT-PCR) and sequence analysis identified a fusion between RUNX1 and the gene encoding ubiquitin specific peptidase-42 (USP42), with splice-variants and variable break-points within RUNX1. Combined cytomorphology and FISH studies in MDS marrow revealed abnormal RUNX1 signals within megakaryocyt...

Recent advances in the understanding of iron overload in sideroblastic myelodysplastic syndrome

British Journal of Haematology — Mon, 11 Jan 2010 00:00:00 +0100

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal haematopoietic stem cell malignancies. A subgroup, the so-called sideroblastic MDS, shows ring sideroblasts in the bone marrow aspirate that represent mitochondrial iron accumulation. Patients with sideroblastic MDS also develop systemic iron overload and generally have a low-risk MDS. Therefore it is important to understand the mechanisms responsible for iron accumulation and the associated toxicity in these patients. Recently, low levels of the iron-regulatory peptide hepcidin were found to contribute to body iron overload in [beta]-thalassaemia patients. A similar mechanism may account for systemic iron accumulation in sideroblastic MDS. Mitochondrial iron accumulation is observed in several subtypes of MDS, and predomi...

Platelet von Willebrand factor – structure, function and biological importance

British Journal of Haematology — Mon, 11 Jan 2010 00:00:00 +0100

Besides circulating in normal plasma, von Willebrand factor (VWF) is also stored at relatively high concentration within the [alpha]-granules of platelets. This pool of platelet VWF exists distinct from plasma VWF, and is enriched in haemostatically-active high molecular weight multimers. Interestingly, the glycosylation profile of platelet VWF differs significantly from that of plasma VWF. Total sialic acid and galactose expression are reduced twofold on platelet VWF, and ABO blood group carbohydrate determinants are not present on the N-linked glycans of platelet VWF. Consequently, in view of the critical role played by VWF glycans in modulating its activity, it is not surprising that the functional properties of platelet VWF differ markedly compared to those of plasma VWF. Nevertheless,...

Rescue of genomic information in adult acute lymphoblastic leukaemia (ALL) with normal/failed cytogenetics: a GIMEMA centralized biological study

British Journal of Haematology — Mon, 11 Jan 2010 00:00:00 +0100

Metaphase (M-) and array (A-) Comparative Genomic Hybridization (CGH) were used to investigate 40 cases of T- and 32 of B-cell acute lymphoblastic leukaemia (ALL) with normal/failed cytogenetics. M-CGH was performed in all cases and A[ndash]CGH in 10/12 T-ALL cases with uncertain/normal M-CGH results. M-CGH was abnormal in 38/72 cases, with a total of 110 imbalances (60 gains, 50 losses). 25/40 patients with T-ALL (62·5%) showed 77 imbalances, with at least 1 genomic imbalance and a mean of 3 aberrations/patient (range 1[ndash]12). 13/32 patients with B-ALL (40·6%) presented 34 imbalances, with a mean of 2·6 imbalances (range 1[ndash]8). A-CGH detected 4 more T-ALL cases with genomic imbalances. A-CGH identified NF1/17q11·2 deletion and interphase fluorescence in situ hybridization pro...

BCR-ABL1 tyrosine kinase activity at diagnosis, as determined via the pCrkL/CrkL ratio, is predictive of clinical outcome in chronic myeloid leukaemia

British Journal of Haematology — Mon, 11 Jan 2010 00:00:00 +0100

(Source: British Journal of Haematology)

Rapid isolation of translocation breakpoints in chronic myeloid and acute promyelocytic leukaemia

British Journal of Haematology — Mon, 11 Jan 2010 00:00:00 +0100

Isolation and sequencing of the translocation breakpoint in chronic myeloid leukaemia-(CML) and acute promyelocytic leukaemia (APML) may help to elucidate the mechanism of translocation and provide a molecular marker for monitoring of minimal residual disease. Amplification across the translocation breakpoint was performed in samples from 91 patients with CML and 15 patients with APML using single-tube multiplex polymerase chain reaction (PCR) involving 308 primers for CML and 40 primers for APML. Nonspecific amplification was removed by a modification of PCR, termed sequential hybrid primer PCR (SHP-PCR), which involved two sequential rounds of PCR, each of which used a low concentration of a specially designed hybrid primer. The resultant amplified material was sequenced. The method as f...

Novel conjugates of single-chain Fv antibody fragments specific for stem cell antigen CD123 mediate potent death of acute myeloid leukaemia cells

British Journal of Haematology — Fri, 08 Jan 2010 00:00:00 +0100

Four new single-chain Fv antibody fragments (scFvs) specific for the human leucocyte surface antigen CD123 (interleukin-3 receptor [alpha]) were generated to achieve preferential targeting of leukaemia stem cells (LSCs) in acute myeloid leukaemia (AML). The scFvs were isolated from a phage display library generated with spleen RNA from mice, immunized with a fusion protein consisting of the extracellular domain of CD123 and the Fc domain of a human immunoglobulin G1. The scFvs displayed CD123-specific binding on tumour cells (binding constants (KD) 4·5[ndash]101 nmol/l). The scFv with the highest affinity was used to design two cell death-inducing molecules. First, an immunotoxin, a fusion protein with truncated Pseudomonas Exotoxin A, induced potent apoptosis of AML-derived MOLM-13 and S...

KIT mutations confer a distinct gene expression signature in core binding factor leukaemia

British Journal of Haematology — Fri, 08 Jan 2010 00:00:00 +0100

Core binding factor (CBF) leukaemias, characterized by either inv(16)(p13.1q22) or t(8;21)(q22;q22), constitute acute myeloid leukaemia (AML) subgroups with favourable prognosis. However, 40[ndash]50% of patients relapse, emphasizing the need for risk-adapted treatment approaches. In this regard, studying secondary genetic aberrations, such as mutations of the KIT gene, is of great interest, particularly as they can be targeted by receptor tyrosine kinase inhibitors (TKI). However, so far little is known about the biology underlying KIT-mutated CBF leukaemias. We analysed gene expression profiles of 83 CBF AML cases with known KIT mutation status in order to gain novel insights in KIT-mutated CBF pathogenesis. KIT-mutated cases were characterized by deregulation of genes belonging to the N...

Sustained pharmacological depletion of serum amyloid P component in patients with systemic amyloidosis

British Journal of Haematology — Fri, 08 Jan 2010 00:00:00 +0100

Serum amyloid P component (SAP) is a universal constituent of amyloid deposits and contributes to their formation and/or persistence. We therefore developed CPHPC ((R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexa-noyl]pyrrolidine-2 carboxylic acid), a novel bis(D-proline) drug, to specifically target SAP and report here a first, exploratory, open label proof of principle study in systemic amyloidosis. CPHPC produced sustained, >95% depletion of circulating SAP in all patients and c. 90% reduction in the SAP content of the two amyloidotic organs that became available. There were no significant adverse effects of either SAP depletion or CPHPC itself. No accumulation of amyloid was demonstrable by SAP scintigraphy in any patient on the drug. In hereditary fibrinogen amyloidosis, which is i...

CD23 expression in plasma cell myeloma is specific for abnormalities of chromosome 11, and is associated with primary plasma cell leukaemia in this cytogenetic sub-group

British Journal of Haematology — Fri, 08 Jan 2010 00:00:00 +0100

(Source: British Journal of Haematology)

The difficult distinction between antiphospholipid syndrome and thrombotic thrombocytopenic purpura

British Journal of Haematology — Fri, 08 Jan 2010 00:00:00 +0100

(Source: British Journal of Haematology)

Tissue inhibitor of matrix metalloproteinase-1 reduces phosphatidylserine exposure on activated and aged platelets

British Journal of Haematology — Fri, 08 Jan 2010 00:00:00 +0100

(Source: British Journal of Haematology)

IGHD3-3 fails to behave as unfavourable prognostic marker in chronic lymphocytic leukaemia

British Journal of Haematology — Thu, 07 Jan 2010 00:00:00 +0100

(Source: British Journal of Haematology)

Prolonged responses in patients with MDS and CMML treated with azacitidine and etanercept

British Journal of Haematology — Thu, 07 Jan 2010 00:00:00 +0100

Combination therapy with azacitidine and etanercept was hypothesized to lead to improved responses in myelodysplastic syndrome (MDS) patients. Thirty-two patients with MDS/chronic myelomonocytic leukaemia were treated with azacitidine + etanercept; 30 completed at least three therapy cycles. At 3 months, nine patients had achieved complete response (CR), two had partial response, 10 had marrow CRs, seven had stable disease, two patients had haematological improvement without marrow response and two patients had disease progression. The overall response rate was 72%; median duration of response was not reached at 2 years. Marrow response rates and duration were improved with azacitidine + etanercept compared to azacitidine alone. (Source: British Journal of Haematology)

Acute human parvovirus B19 infection and nephrotic syndrome in patients with sickle cell disease

British Journal of Haematology — Thu, 07 Jan 2010 00:00:00 +0100

We report three cases of patients who developed nephrotic syndrome (NS) with chronic sequelae after initially presenting with HPV B19-associated TRCA. There was no correlation between evidence of HPV B19 infection and impaired renal function in our cohort of adult sickle cell patients. This is consistent with a view that although NS is potentially a rare complication of symptomatic acute HPV B19 infection, exposure to HPV B19 is not associated with an increased risk of renal disease. (Source: British Journal of Haematology)

All-trans-retinoic acid therapy

British Journal of Haematology — Thu, 07 Jan 2010 00:00:00 +0100

(Source: British Journal of Haematology)

The 'Sandwich Sign' of Mesenteric Lymphoma

British Journal of Haematology — Thu, 07 Jan 2010 00:00:00 +0100

(Source: British Journal of Haematology)

Feto-maternal haemorrhage does not account for the differences in cord blood volume obtained from Black and Asian versus Caucasoid donors

British Journal of Haematology — Thu, 17 Dec 2009 00:00:00 +0100

(Source: British Journal of Haematology)

Dic(17;18)(p11.2;p11.2) is a recurring abnormality in chronic lymphocytic leukaemia associated with aggressive disease

British Journal of Haematology — Wed, 16 Dec 2009 00:00:00 +0100

Interphase cytogenetics are commonly used to identify clonal abnormalities in chronic lymphocytic leukemia (CLL) patients but fail to identify recurrent translocations that ultimately can direct more focused molecular characterization. Given the importance of del(17p13.1) in CLL outcome, we performed an extensive review of 1213 patients undergoing metaphase cytogenetics at our institution and identified 16 (1·3%) with a recurrent unbalanced translocation between the p arms of chromosomes 17 and 18 that results in a dicentric chromosome with loss of much of 17p and 18p. The dic(17;18)(p11.2;p11.2) was associated with a complex (three or more unrelated cytogenetic abnormalities) karyotype in 12 patients (75%) at the time that the abnormality was first identified, and eventually associated w...

Mixed phenotype acute leukaemia with giant inclusions

British Journal of Haematology — Wed, 09 Dec 2009 00:00:00 +0100

(Source: British Journal of Haematology)

Platelets release novel thiol isomerase enzymes which are recruited to the cell surface following activation

British Journal of Haematology — Tue, 08 Dec 2009 00:00:00 +0100

This study aimed to identify which other thiol isomerase enzymes are present in human platelets. Through the use of immunoblotting, flow cytometry, cell-surface biotinylation and gene array analysis, we report the presence of five additional thiol isomerases in human and mouse platelets and megakaryocytes, namely; ERp57, ERp72, ERp44, ERp29 and TMX3. ERp72, ERp57, ERp44 and ERp29 are released by platelets and relocate to the cell surface following platelet activation. The transmembrane thiol isomerase TMX3 was also detected on the platelet surface but does not increase following activation. Extracellular PDI is also implicated in the regulation of coagulation by the modulation of tissue factor activity. ERp57 was identified within platelet-derived microparticle fractions, suggesting that E...

Salvage treatment for children with refractory first or second relapse of acute myeloid leukaemia with gemtuzumab ozogamicin: results of a phase II study

British Journal of Haematology — Tue, 08 Dec 2009 00:00:00 +0100

This study showed a favourable safety/efficacy profile of single-agent GO in children with refractory first or second relapse of AML. (Source: British Journal of Haematology)

Increased levels of the inflammatory biomarker C-reactive protein at baseline are associated with childhood sickle cell vasocclusive crises

British Journal of Haematology — Tue, 08 Dec 2009 00:00:00 +0100

In this study of 70 children with SCD at steady state evaluated by a broad panel of biomarkers representing previously examined mechanisms of pathogenicity in SCD, high sensitivity C-reactive protein (hs-CRP), a marker of low-grade, systemic inflammation, emerged as the most significant laboratory correlate of hospitalizations for pain or vaso-occlusive (VOC) events. While markers of increased haemolytic status, endothelial activation and coagulation activation all correlated positively with VOC events by univariate analysis, baseline hs-CRP levels provided the most significant contribution to the association in multiple regression models (22%), and, hs-CRP, along with age, provided the best fit in negative binomial models. These data highlight the clinical relevance of the role of inflamm...

Activated protein C action in inflammation

British Journal of Haematology — Tue, 08 Dec 2009 00:00:00 +0100

Activated protein C (APC) is a natural anticoagulant that plays an important role in coagulation homeostasis by inactivating the procoagulation factor Va and VIIIa. In addition to its anticoagulation functions, APC also has cytoprotective effects such as anti-inflammatory, anti-apoptotic, and endothelial barrier protection. Recently, a recombinant form of human APC (rhAPC or drotrecogin alfa activated; known commercially as 'Xigris') was approved by the US Federal Drug Administration for treatment of severe sepsis associated with a high risk of mortality. Sepsis, also known as systemic inflammatory response syndrome (SIRS) resulting from infection, is a serious medical condition in critical care patients. In sepsis, hyperactive and dysregulated inflammatory responses lead to secretion of p...

Haemostasis and thrombosis in liver disease

British Journal of Haematology — Tue, 08 Dec 2009 00:00:00 +0100

Liver disease impacts on both primary and secondary haemostatic mechanisms and historically these changes were thought to underpin the bleeding diathesis. However, bleeding complications in patients with liver disease are unpredictable, with the majority of haemorrhagic episodes occurring as a result of porto-systemic varices. Thrombosis is an increasingly recognised complication and systemic hypercoagulability may contribute to the development of parenchymal extinction and accelerated hepatic fibrosis. Routine laboratory tests do not reliably predict the risk of haemorrhage and the optimal management strategy to avert potential bleeding complications is yet to be established. There may be a future role for global coagulation assays, such as thrombelastograpy and thrombin generation, in bo...

Bone marrow signal during PET imaging in Hodgkin lymphoma

British Journal of Haematology — Tue, 08 Dec 2009 00:00:00 +0100

(Source: British Journal of Haematology)

Graft-versus-lymphoma effect

British Journal of Haematology — Tue, 08 Dec 2009 00:00:00 +0100

(Source: British Journal of Haematology)

NOTCH2 links protein kinase C delta to the expression of CD23 in chronic lymphocytic leukaemia (CLL) cells

British Journal of Haematology — Tue, 08 Dec 2009 00:00:00 +0100

This study showed that peripheral CLL cells overexpressed transcriptionally active NOTCH2 (N2IC), irrespective of their prognostic marker profile. When placed in culture, NOTCH2 activity was spontaneously decreased in 25 out of 31 CLL cases (81%) within 24 h. DNA-bound N2IC complexes could be maintained by the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) or by [gamma]-interferon (IFN-[gamma]), two CLL characteristic inducers of CD23 expression. Inhibition of PKC-[delta] by RNA interference or by rottlerin antagonised PMA-induced NOTCH2 activation and also suppressed NOTCH2 activity in CLL cases with constitutively activated NOTCH2 signalling. In 23 out of 29 CLL cases tested (79%), DNA-bound N2IC complexes were found to be resistant to the [gamma]-secretase inhibi...

Temporal trends in the proportion cured among adults diagnosed with acute myeloid leukaemia in Sweden 1973–2001, a population-based study

British Journal of Haematology — Tue, 08 Dec 2009 00:00:00 +0100

Large age-dependant differences in temporal trends in 1- and 5-year relative survival have been observed in patients with acute myeloid leukaemia (AML) in Sweden. This investigation used an alternative approach to studying patient survival that simultaneously estimated the proportion of patients cured from their cancer and the survival of the 'uncured'. We conducted a population-based study including 6439 AML patients aged 19[ndash]80 years in Sweden between 1973 and 2001. Mixture cure models were estimated, with age at diagnosis categorised (19[ndash]40, 41[ndash]60, 61[ndash]70 and 71[ndash]80) and year of diagnosis modelled using splines. In 1975 the cure proportion was [le]6% in all age groups and the median survival time for 'uncured' patients was (Source: British Journal of Haematolo...

The oestrogen receptor GPER is expressed in human haematopoietic stem cells but not in mature megakaryocytes

British Journal of Haematology — Tue, 08 Dec 2009 00:00:00 +0100

(Source: British Journal of Haematology)

Induction of complete remission of acute myeloid leukaemia by pegylated interferon-α-2a in a patient with transformed primary myelofibrosis

British Journal of Haematology — Tue, 08 Dec 2009 00:00:00 +0100

(Source: British Journal of Haematology)

Prognostic relevance of in vitro response to cell stimulation via surface IgD in binet stage a CLL

British Journal of Haematology — Tue, 08 Dec 2009 00:00:00 +0100

(Source: British Journal of Haematology)

188Re anti-CD66 radioimmunotherapy combined with reduced-intensity conditioning and in-vivo T cell depletion in elderly patients undergoing allogeneic haematopoietic cell transplantation

British Journal of Haematology — Mon, 07 Dec 2009 00:00:00 +0100

The addition of radioimmunotherapy to conventional and reduced-intensity conditioning has been shown to be feasible and effective. Within an ongoing prospective phase II trial, 22 patients with advanced myeloid malignancies and a median age of 65 years (range 54[ndash]76) received anti-CD66 Rhenium radioimmunotherapy followed by fludarabine (150 mg/m2), busulfan (8 mg/kg) and alemtuzumab (75 mg) before allogeneic haematopoietic stem cell transplantation from matched sibling (n = 7) and unrelated donors (n = 15). The extramedullary toxicity in the first 100 d post-transplantation was limited and all patients engrafted with complete donor chimaerism. The incidence of non-relapse mortality at day 100 and after 2 years was 4·5% and 23%, respectively. The probability of overall survival at 2 y...

Alemtuzumab is safe and effective as immunosuppressive treatment for aplastic anaemia and single-lineage marrow failure: a pilot study and a survey from the EBMT WPSAA

British Journal of Haematology — Mon, 07 Dec 2009 00:00:00 +0100

An alemtuzumab-based experimental immunosuppressive treatment (IST) regimen was investigated in 35 patients with severe aplastic anaemia (SAA), pure red cell (PRCA) or pure white cell aplasia (PWCA). Alemtuzumab total dose was 73[ndash]103 mg s.c., followed by cyclosporine. No serious toxicity due to the regimen was observed. Adverse events were clinically irrelevant; infectious events were rare. The total response rate was 58%, 84% and 100% in SAA, PRCA and PWCA, respectively, with corresponding 6 months cumulative response probabilities of 84%, 84% and 100%. Subcutaneous alemtuzumab is a feasible and sufficiently safe IST regimen for patients suffering from immune-mediated marrow failures. (Source: British Journal of Haematology)

CD20-positive multiple myeloma – differential expression of cyclins D1 and D2 suggests a heterogeneous disease

British Journal of Haematology — Mon, 07 Dec 2009 00:00:00 +0100

(Source: British Journal of Haematology)

Von Willebrand disease, angiodysplasia and atorvastatin

British Journal of Haematology — Mon, 07 Dec 2009 00:00:00 +0100

(Source: British Journal of Haematology)

Advances in the understanding and management of angioimmunoblastic T-cell lymphoma

British Journal of Haematology — Sat, 05 Dec 2009 00:00:00 +0100

Angioimmunoblastic T-cell lymphoma (AITL) is a distinct peripheral T-cell lymphoma (PTCL) entity with peculiar clinical and pathological features. The recent identification of follicular helper T (TFH) cell as the cell of origin of this neoplasm represents a major step in our understanding of the pathobiological characteristics of the disease and should, in the future, clarify the diagnostic criteria for AITL and help to delineate its spectrum, especially from PTCL, not otherwise specified (PTCL, NOS). Deciphering the pathogenesis of the disease is needed to identify targets for new therapies that are expected to improve the poor outcome of AITL patients, when treated with conventional chemotherapy regimens. In this respect, efforts will be needed to evaluate promising innovative therapies...

Impact of dexamethasone responsiveness on long term outcome in patients with newly diagnosed multiple myeloma

British Journal of Haematology — Fri, 04 Dec 2009 00:00:00 +0100

Dexamethasone (Dex), alone or in combination, is commonly used for treating multiple myeloma. Dex as single agent for initial therapy of myeloma results in overall response rates of 50[ndash]60%. It is unclear whether steroid responsiveness reflects any biological characteristic that impacts long-term outcome. We studied a cohort of 182 patients with newly diagnosed myeloma seen between March 1998 and June 2007, initially treated with single-agent Dex for at least 4 weeks. The median age at diagnosis was 63 years (range, 39[ndash]81) and the median estimated survival was 55 months. At a median duration of therapy of 15 weeks, 91 (50%) patients had a partial response or better, 80 (44%) had less than partial response and the remaining (6%) patients were not evaluable. The median overall sur...

Perifosine plus nutlin-3 combination shows a synergistic anti-leukaemic activity

British Journal of Haematology — Wed, 02 Dec 2009 00:00:00 +0100

(Source: British Journal of Haematology)

Evidence of a colocalisation of osteoprotegerin (OPG) with von Willebrand factor (VWF) in platelets and megakaryocytes alpha granules. Studies from normal and grey platelets

British Journal of Haematology — Tue, 01 Dec 2009 00:00:00 +0100

(Source: British Journal of Haematology)

Pathogenesis of the erythroid failure in Diamond Blackfan anaemia

British Journal of Haematology — Tue, 01 Dec 2009 00:00:00 +0100

Diamond Blackfan anaemia (DBA) is a severe congenital failure of erythropoiesis. Despite mutations in one of several ribosome protein genes, including RPS19, the cause of the erythroid specificity is still a mystery. We hypothesized that, because the chromatin of late erythroid cells becomes condensed and transcriptionally inactive prior to enucleation, the rapidly proliferating immature cells require very high ribosome synthetic rates. RNA biogenesis was measured in primary mouse fetal liver erythroid progenitor cells; during the first 24 h, cell number increased three to fourfold while, remarkably, RNA content increased sixfold, suggesting an accumulation of an excess of ribosomes during early erythropoiesis. Retrovirus infected siRNA RPS19 knockdown cells showed reduced proliferation bu...

ITD- and FL-induced FLT3 signal transduction leads to increased C/EBPβ-LIP expression and LIP/LAP ratio by different signalling modules

British Journal of Haematology — Tue, 01 Dec 2009 00:00:00 +0100

FLT3 receptor-associated signalling plays a role in proliferation and leukaemia. The transcription factor C/EBP[beta] may be involved in malignancy with its alternative translation product C/EBP[beta]-LIP. We investigated a potential connection between FLT3 signalling and the C/EBP[beta] system in FLT3-internal tandem duplication (ITD)-positive leukaemia cells and FLT3-ITD- or FLT3-wild type (WT)-transfected 32D cells. In FLT3-ITD-positive cells or when ITD sequences were inserted into the FLT3-WT receptor, significant LIP levels, increased LIP/LAP ratios, and enhanced proliferation rates were detected, which were reduced by FLT3 inhibition. In FLT3-WT cells, incubation with FLT3 receptor ligand (FL) also elevated LIP, LIP/LAP, and proliferation, albeit to a lesser extent. CEBPB-directed s...

IKK inhibitor bay 11-7082 induces necroptotic cell death in precursor-B acute lymphoblastic leukaemic blasts

British Journal of Haematology — Tue, 01 Dec 2009 00:00:00 +0100

(Source: British Journal of Haematology)

Pleiotropic effects of intravascular haemolysis on vascular homeostasis

British Journal of Haematology — Tue, 01 Dec 2009 00:00:00 +0100

This article reviews the haemolytic disorders that have been reported to manifest vascular complications, and explores the speculative possibility that haemolysis mediates some of the vascular complications of inflammation and diabetes. (Source: British Journal of Haematology)

Co-morbidities and quality of life in elderly persons with haemophilia

British Journal of Haematology — Tue, 01 Dec 2009 00:00:00 +0100

The life expectancy and quality of life of persons with haemophilia has dramatically increased since the 1970s, with the exception of the increased rate of deaths observed during the 1980s and the 1990s due to blood-borne viral infections. Improvements of factor replacement therapy, treatment of infectious diseases and comprehensive health care provided by specialised haemophilia centres are the main determinants of the increasing age of the haemophilia population. As a consequence, a growing number of these patients develop age-related co-morbidities, such as cardiovascular disease and cancer. The care of these previously rare conditions is a new challenge for caregivers in haemophilia centres. This review focuses on co-morbidities in the ageing haemophilia patients, their impact on quali...

The proteasome inhibitor CEP-18770 enhances the anti-myeloma activity of bortezomib and melphalan

British Journal of Haematology — Tue, 01 Dec 2009 00:00:00 +0100

The anti-multiple myeloma (MM) efficacy of bortezomib has led to the development of other proteasome inhibitors (PI), including CEP-18770 which has shown anti-MM effects in preclinical studies. However, the efficacy of orally (PO) or intravenously (IV) administered CEP-18770 in multiple MM models and in combination with conventional anti-MM therapies has not been evaluated. Herein, we show that CEP-18770 combined with melphalan or bortezomib induces synergistic inhibition of MM cell viability in vitro. In MM xenograft models, the addition of CEP-18770 IV to melphalan completely prevented the growth of both melphalan-sensitive and melphalan-resistant tumours. The combination of CEP-18770 IV and bortezomib induced complete regression of bortezomib-sensitive tumours and markedly delayed progr...

The Haematological Malignancy Research Network (HMRN): a new information strategy for population based epidemiology and health service research

British Journal of Haematology — Tue, 01 Dec 2009 00:00:00 +0100

The Haematological Malignancy Research Network (HMRN) was established in 2004 to provide robust generalizable data to inform clinical practice and research. It comprises an ongoing population-based cohort of patients newly diagnosed by a single integrated haematopathology laboratory in two adjacent UK Cancer Networks (population 3·6 million). With an emphasis on primary-source data, prognostic factors, sequential treatment/response history, and socio-demographic details are recorded to clinical trial standards. Data on 8131 patients diagnosed over the 4 years 2004[ndash]08 are examined here using the latest World Health Organization classification. HMRN captures all diagnoses (adult and paediatric) and the diagnostic age ranged from 4 weeks to 99 years (median 70·4 years). In line with p...

Lenalidomide treatment of chronic lymphocytic leukaemia patients reduces regulatory T cells and induces Th17 T helper cells

British Journal of Haematology — Tue, 01 Dec 2009 00:00:00 +0100

(Source: British Journal of Haematology)

Multipotent adult progenitor cell isolation and proliferation in cytokine and serum-free medium conditioned by rat B104 cells

British Journal of Haematology — Mon, 30 Nov 2009 00:00:00 +0100

This report describes the isolation of rodent multipotent adult progenitor cells (MAPCs) and proliferation of these cells in both standard medium and medium without exogenous serum or growth factors conditioned by the rat cell line B104. MAPCs have exacting requirements for their proliferation in vitro but once established proliferate rapidly at low seeding density, requiring almost daily passage and media exchange. Previously published methods for growth of MAPCs in vitro all used media supplemented with serum and growth factors, which adds considerable expense. (Source: British Journal of Haematology)

VKORC1 mutations in patients with partial resistance to phenprocoumon

British Journal of Haematology — Wed, 25 Nov 2009 00:00:00 +0100

(Source: British Journal of Haematology)