Showing papers in "British Journal of Haematology in 2003"

Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group

Abstract: The monoclonal gammopathies are a group of disorders associated with monoclonal proliferation of plasma cells. The characterization of specific entities is an area of difficulty in clinical practice. The International Myeloma Working Group has reviewed the criteria for diagnosis and classification with the aim of producing simple, easily used definitions based on routinely available investigations. In monoclonal gammopathy of undetermined significance (MGUS) or monoclonal gammopathy, unattributed/unassociated (MG[u]), the monoclonal protein is < 30 g/l and the bone marrow clonal cells < 10% with no evidence of multiple myeloma, other B-cell proliferative disorders or amyloidosis. In asymptomatic (smouldering) myeloma the M-protein is greater than or equal to 30 g/l and/or bone marrow clonal cells greater than or equal to 10% but no related organ or tissue impairment (ROTI)(end-organ damage), which is typically manifested by increased calcium, renal insufficiency, anaemia, or bone lesions (CRAB) attributed to the plasma cell proliferative process. Symptomatic myeloma requires evidence of ROTI. Non-secretory myeloma is characterized by the absence of an M-protein in the serum and urine, bone marrow plasmacytosis and ROTI. Solitary plasmacytoma of bone, extramedullary plasmacytoma and multiple solitary plasmacytomas (+/- recurrent) are also defined as distinct entities. The use of these criteria will facilitate comparison of therapeutic trial data. Evaluation of currently available prognostic factors may allow better definition of prognosis in multiple myeloma.

Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy

Abstract: Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by persistent thrombocytopenia (peripheral blood platelet count < 150 · 10 ⁄ l) due to autoantibody binding to platelet antigen(s) causing their premature destruction by the reticuloendothelial system, and in particular the spleen (Woods et al, 1984a,b). Although the basic underlying pathophysiology of ITP has been known for 50 years (Harrington et al, 1951), the literature shows that the investigation and management of patients with thrombocytopenia vary widely, and is not evidence-based, due to a lack of clinical trials and quality research. Despite major advances in our understanding of the molecular basis of many blood disorders, the diagnosis of ITP remains one of exclusion; there are currently no robust clinical or laboratory parameters that are able to establish the diagnosis of ITP with accuracy. This guideline aims to assess available diagnostic tests and therapies, and attempts to provide a rational approach to the diagnosis and treatment in adults, children and in pregnancy. Although natural history data are becoming available (Cohen et al, 2000; Djulbegovic & Cohen, 2001; Portielje et al, 2001), there are few randomized trials in ITP and many of the recommendations, like those of the American Society of Hematology (ASH) Panel (George et al, 1996), are based on expert opinion.

Adult bone marrow is a rich source of human mesenchymal ‘stem’ cells but umbilical cord and mobilized adult blood are not

Abstract: Summary. In postnatal life, mesenchymal stem cells (MSC) self-replicate, proliferate and differentiate into mesenchymal tissues, including bone, fat, tendon, muscle and bone marrow (BM) stroma. Possible clinical applications for MSC in stem cell transplantation have been proposed. We have evaluated the frequency, phenotype and differentiation potential of MSC in adult BM, cord blood (CB) and peripheral blood stem cell collections (PBSC). During culture, BM MSC proliferated to confluence in 10–14 d, maintaining a stable non-haemopoietic phenotype, HLA class-1+, CD29+, CD44+, CD90+, CD45–, CD34– and CD14 through subsequent passages. Using the colony forming unit fibroblasts assay, the estimated frequency of MSC in the BM nucleated cell population was 1 in 3·4 × 104 cells. Both adipogenic and osteogenic differentiation of BM MSC was demonstrated. In contrast, CB and PBSC mononuclear cells cultured in MSC conditions for two passages produced a population of adherent, non-confluent fibroblast-like cells with a haemopoietic phenotype, CD45+, CD14+, CD34–, CD44–, CD90– and CD29–. In paired experiments, cultured BM MSC and mature BM stroma were seeded with CB cells enriched for CD34+. Similar numbers of colony-forming units of granulocytes–macrophages were produced by MSC-based and standard stroma cultures over 10 weeks. We conclude that adult BM is a reliable source of functional cultured MSC, but CB and PBSC are not.

Heparin-induced thrombocytopenia: pathogenesis and management.

Abstract: Heparin-induced thrombocytopenia (HIT) is a transient prothrombotic disorder initiated by heparin. Its central feature is thrombocytopenia caused by antibody-mediated platelet activation. HIT can be viewed as an acquired hypercoagulability disorder, with increased thrombin generation in vivo, and increased risk for arterial and, especially, venous thrombosis. The pathogenic HIT antibodies are directed against neoepitopes on a ‘self’ protein, platelet factor 4 (PF4), that are expressed when PF4 is bound to heparin or certain other polyanions. This review focuses on studies published since 1990, and summarizes the pathogenesis, laboratory testing, frequency and clinical picture of HIT. Two treatment situations are reviewed critically: management of thrombosis complicating HIT and treatment of ‘isolated HIT’ (HIT recognized because of thrombocytopenia alone). There is potential for medicolegal risk, particularly if inappropriate therapy contributes to patient harm.

Murine marrow-derived mesenchymal stem cell: isolation, in vitro expansion, and characterization.

Abstract: In spite of the attention given to the study of mesenchymal stem cells (MSCs) derived from the bone marrow (BM) of humans and other species, there is a lack of information about murine MSCs. We describe the establishment of conditions for the in vitro expansion of plastic-adherent cells from murine BM for over 50 passages, and provide their characterization regarding morphology, surface marker profile and growth kinetics. These cells were shown to differentiate along osteogenic and adipogenic pathways, and to support the growth and differentiation of haematopoietic stem cells, and were thus operationally defined as murine mesenchymal stem cells (mMSCs). mMSCs were positive for the surface markers CD44, CD49e, CD29 and Sca-1, and exhibited a homogeneous, distinctive morphology. Their frequency in the BM of adult BALB/c and C57Bl/6 mice, normal or knockout for the alpha-L-iduronidase (IDUA) gene, was preliminarily estimated to be 1 per 11,300-27,000 nucleated cells. The emergence of a defined methodology for the culture of mMSCs, as well as a comprehensive understanding of their biology, will make the development of cellular and genetic therapy protocols in murine models possible, and provide new perspectives in the field of adult stem cells research.

Acquired Haemophilia: Review and Meta‐Analysis Focused on Therapy and Prognostic Factors

Abstract: Acquired haemophilia (AH) is a rare disease that occurs at a rate of approximately 1 person per million each year. Antifactor VIII is the most commonly recognized autoantibody directed against a clotting factor, and is associated with bleeding complications that can be life threatening. These bleeding episodes, however, can be controlled when the correct diagnosis is made quickly and appropriate therapy is applied. Although the aetiology of this disorder remains obscure, about 40–50% of cases are associated with other conditions, mainly the post-partum period, underlying malignancies, drug administration or autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosus. This article provides a succinct review of the clinical features, laboratory diagnosis, prognostic factors and therapeutic management of patients with AH.

A validated decision model for treating the anaemia of myelodysplastic syndromes with erythropoietin + granulocyte colony-stimulating factor: significant effects on quality of life.

Abstract: We have published previously a prototype of a decision model for anaemic patients with myelodysplastic syndromes (MDS), in which transfusion need and serum erythropoietin (S-Epo) were used to define three groups with different probabilities of erythroid response to treatment with granulocyte colony-stimulating factor (G-CSF) + Epo. S-Epo 500 U/l and >/= 2 units/month for a poor response, whereas the presence of only one negative prognostic marker predicted an intermediate response. A total of 53 patients from a prospective study were included in our evaluation sample. Patients with good or intermediate probability of response were treated with G-CSF + Epo. The overall response rate was 42% with 28.3% achieving a complete and 13.2% a partial response to treatment. The response rates were 61% and 14% in the good and intermediate predictive groups respectively. The model retained a significant predictive value in the evaluation sample (P < 0.001). Median duration of response was 23 months. Scores for global health and quality of life (QOL) were significantly lower in MDS patients than in a reference population, and fatigue and dyspnoea was significantly more prominent. Global QOL improved in patients responding to treatment (P = 0.01). The validated decision model defined a subgroup of patients with a response rate of 61% (95% confidence interval 48-74%) to treatment with G-CSF + Epo. The majority of these patients have shown complete and durable responses.

Outcome in systemic AL amyloidosis in relation to changes in concentration of circulating free immunoglobulin light chains following chemotherapy.

Abstract: Monoclonal immunoglobulin light chains are deposited as amyloid fibrils in systemic AL (primary) amyloidosis, but the underlying plasma cell dyscrasias are often difficult to detect or unquantifiable. The relationships between circulating monoclonal light chains, amyloid load and clinical outcome, and the relative efficacies of chemotherapy regimens aimed at suppressing monoclonal immunoglobulin production, have not been determined. Circulating free immunoglobulin light chain (FLC) concentration was measured with a sensitive nephelometric immunoassay in 262 patients with AL amyloidosis, and followed serially in 137 patients who received either high-dose chemotherapy or one of two intermediate-dose cytotoxic regimens. Amyloid load was quantified by serum amyloid P component scintigraphy. A monoclonal excess of FLC was identified at diagnosis in 98% of patients. Among 86 patients whose abnormal FLC concentration fell by more than 50% following chemotherapy, 5-year survival was 88% compared with only 39% among those whose FLC did not fall by half (P < 0·0001). Amyloid deposits regressed in 58 patients. The magnitude and duration of the FLC responses to intermediate- and high-dose chemotherapy regimens were similar. The FLC assay enabled the circulating fibril precursor protein in AL amyloidosis to be quantified and monitored in most patients. Reduction of the amyloidogenic FLC by more than 50% was associated with substantial survival benefit, regardless of the type of chemotherapy used. Clinical improvement following chemotherapy in AL amyloidosis is delayed, but treatment strategies can be guided by their early effect on serum FLC concentration.

Guidelines on the diagnosis and management of the thrombotic microangiopathic haemolytic anaemias.

Abstract: Thrombotic thrombocytopenic purpura (TTP) was first described by Moschowitz (1924). The classic pentad of diagnostic features has been recognized for many years. However, several other syndromes are also characterized by similar features. These include haemolytic uraemic syndrome (HUS), eclampsia and the HELLP syndrome (haemolysis, elevated liver enzymes, low platelets). The concept has arisen that they might represent an overlapping spectrum of disease, although with varying pathophysiological features (see Table I). The recent characterization of a novel von Willebrand factor (VWF)-cleaving metalloprotease activity (Furlan et al, 1996; Tsai, 1996) and its deficiency or inhibition in some forms of microangiopathic haemolysis (Furlan et al, 1997, 1998; Tsai & Lian, 1998) has led to speculation that a pathogenic mechanism for individual patients can be defined more readily and appropriate treatment introduced more rapidly. However, there is still considerable confusion, a lack of properly conducted randomized clinical trials and poor co-ordination of clinical data. This is, in part, because these patients present to a range of specialists including haematologists, obstetricians, nephrologists and infectious disease physicians. These guidelines attempt to define the various clinical subtypes, specify the recognized diagnostic features and look critically at management options. It is acknowledged that there is a lack of evidence from well-conducted studies on which to support some of the recommendations made.

Incidence and prognosis of c-KIT and FLT3 mutations in core binding factor (CBF) acute myeloid leukaemias.

Abstract: DNA from 110 adult de novo acute myeloid leukaemia (AML) patients exhibiting either inv(16) (n = 63) or t(8;21) (n = 47) was screened for mutations in the c-KIT (exon 8 and Asp816) and FLT3 (ITD and Asp835) genes. c-KIT exon 8 mutations were found in 15/63 (23.8%) inv(16) patients and 1/47 (2.1%) t(8;21) patients. c-KIT Asp816 mutations were present in 5/63 (7.9%) inv(16) AML and 5/47 (10.6%) t(8;21) AML. FLT3 mutations were identified in five patients (7.9%) with inv(16) and three patients (5.6%) with t(8;21) AML. All mutations were mutually exclusive; 40% of inv(16) AML patients possessed either a c-KIT or FLT3 mutation. c-KIT exon 8 mutations were shown to be a significant factor adversely affecting relapse rate.

Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: a randomized, double-blind, placebo-controlled study

Abstract: This phase 3, randomized, double-blind, placebo-controlled study was designed to evaluate the efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies. Patients (n = 344) with lymphoma or myeloma received darbepoetin alfa 2.25 microg/kg or placebo s.c., once weekly for 12 weeks. The percentage of patients achieving a haemoglobin response was significantly higher in the darbepoetin alfa group (60%) than in the placebo group (18%) (P < 0.001), regardless of baseline endogenous erythropoietin level. However, increased responsiveness was observed in patients with lower baseline erythropoietin levels. Darbepoetin alfa also resulted in higher mean changes in haemoglobin than placebo from baseline to the last value during the treatment phase (1.80 g/dl vs 0.19 g/dl) and after 12 weeks of treatment (2.66 g/dl vs 0.69 g/dl). A significantly lower percentage of patients in the darbepoetin alfa group received red blood cell transfusions than in the placebo group (P < 0.001). The efficacy of darbepoetin alfa was consistent for patients with lymphoma or myeloma. Improvements in quality of life were also observed with darbepoetin alfa. The overall safety profile of darbepoetin alfa was consistent with that expected for this patient population. Darbepoetin alfa significantly increased haemoglobin and reduced red blood cell transfusions in patients with lymphoproliferative malignancies receiving chemotherapy.

Clinically significant newly presenting autoimmune thrombocytopenic purpura in adults: a prospective study of a population‐based cohort of 245 patients

Abstract: The true incidence and prognosis of autoimmune thrombocytopenic purpura (ITP) in adults is unknown. We present the results of a prospective study in a population-based cohort of newly presenting adults (> or = 16 years) with ITP and platelet count of 60 years. Thirty patients (12%) presented with frank bleeding, and 28% were asymptomatic. Forty-five patients (18%) received no treatment, and 135 (55%) received first-line treatment only. Thirty patients (12%) underwent splenectomy. There were four deaths (1.6%) from bleeding and/or the complications of therapy in this cohort, but only one was in the acute phase of the illness. The majority of patients (155 out of 245) achieved remission (platelet count > 100 x 109/l), with a further 59 (24%) in partial remission with no symptoms (platelet count 30-100 x 109/l). This population-based study suggests that the traditional view of adult ITP as being a predominantly chronic disease that preferentially affects females needs to be modified.

Causes of death in sickle cell disease: an autopsy study.

Abstract: More precise analysis of causes of death is needed to focus research efforts and improve morbidity and mortality in sickle cell disease. In this study, the morphological evidence of the cause of death was studied in 306 autopsies of sickle cell disease, which were accrued between 1929 and 1996. The most common cause of death for all sickle variants and for all age groups was infection (33-48%). The terminal infection was heralded by upper respiratory tract syndromes in 72.6% and by gastroenteritis in 13.7%. The most frequent portal of entry in children was the respiratory tract but, in adults, a site of severe chronic organ injury. Other causes of death included stroke 9.8%, therapy complications 7.0%, splenic sequestration 6.6%, pulmonary emboli/thrombi 4.9%, renal failure 4.1%, pulmonary hypertension 2.9%, hepatic failure 0.8%, massive haemolysis/red cell aplasia 0.4% and left ventricular failure 0.4%. Death was frequently sudden and unexpected (40.8%) or occurred within 24 h after presentation (28.4%), and was usually associated with acute events (63.3%). This study shows that the first 24 h after presentation for medical care is an especially perilous time for patients with sickle cell disease and an acute event. Close monitoring and prompt aggressive treatment are warranted.

Angioimmunoblastic T‐cell lymphoma

Abstract: Angioimmunoblastic T-cell lymphoma (AITL) is one of the most common types of T-cell lymphoma, representing about 15–20% of cases of peripheral T-cell lymphoma (PTCL). It is characterized by a unique clinical presentation and distinct pathologic and molecular features. Classes of drugs particularly active in AITL are emerging; however, treatment of relapsed and refractory disease remains a challenge. This chapter reviews the epidemiology, clinical presentation, pathogenesis, diagnosis, and treatment of AITL.

Guidelines for the diagnosis and therapy of adult myelodysplastic syndromes.

Abstract: The myelodysplastic syndromes (MDS) represent a heterogeneous group of haematopoietic disorders affecting predominantly elderly individuals (median age 69 years). The overall disease incidence is about 4 per 100 000 population but this rises to > 30 per 100 000 in the over 70 year age group. The pathological processes underlying the haematological abnormalities seen in MDS are: 1. augmented apoptosis, leading to ineffective haematopoiesis and peripheral cytopenias; 2. transformation to acute myeloid leukaemia (AML). The precise relationship between these pathological processes remains uncertain but has important implications for the design of new therapeutic strategies targeting one or the other or indeed both.

Guidelines on fibrinogen assays.

Abstract: Haematology departments in the UK have traditionally performed fibrinogen assays to detect decreased levels and abnormalities of fibrinogen, and to assess haemorrhagic risk. It has also been shown that elevated fibrinogen levels are a predictor of a variety of arterial cardiovascular events, and fibrinogen assays are sometimes recommended with this in mind. The Clauss fibrinogen assay (based on the thrombin clotting time) is the most popular technique in UK hospital laboratories, although many other methods are also in use. There appears to be great variability in both the source of reagents and the exact method used for the Clauss assay. Most laboratories are now equipped with automated coagulation analysers, and many of these perform a fibrinogen estimation derived from the degree of change of light scatter or optical density during the prothrombin time (PT-Fg). A number of problems have been described in the use of the PT-Fg method: it generally gives higher values than the Clauss technique, but the exact degree of discrepancy seems to depend on a number of different variables. International and National standards are available for fibrinogen, but do not appear to be universally used. These guidelines have been prepared against this background and recommend which methods should be used in various clinical settings, as well as highlighting a variety of problems with fibrinogen assays.

Guidelines for the management of the acute painful crisis in sickle cell disease

Abstract: Severe acute pain is the commonest manifestation of sickle cell disease (SCD) requiring hospital admission in Europe and the USA. Although the pain itself is not directly lifethreatening, inappropriate treatment leads to unnecessary suffering and potentially fatal complications, related both to the disease and the treatment, and repeated admissions with pain are associated with a higher mortality rate (Platt et al, 1994). There are thought to be more than 10 000 patients with SCD in the UK (Streetly et al, 1997), the majority of these live in London. Whereas some hospitals see large numbers of patients with SCD and have established protocols and experienced staff, most hospitals will see only a few patients each year. These guidelines aim to provide advice on a basic, minimum standard of care for patients with acute painful crises and SCD, and pay particular attention to adequate analgesia and monitoring for life-threatening complications.

Chromosome anomalies detected by interphase fluorescence in situ hybridization: correlation with significant biological features of B-cell chronic lymphocytic leukaemia

Abstract: Fluorescence in situ hybridization (FISH) was used to detect 6q-, 11q-, +12, 13q-, 17p- and translocations involving 14q32 in interphase nuclei from blood and/or bone marrow from 113 patients with B-cell chronic lymphocytic leukaemia (B-CLL). A total of 87 patients (77%) had a FISH anomaly: 13q- x 1 was most frequent (64%) followed by 13q- x 2 (28%), +12 (25%), 11q- (15%), 17p- (8%) and 6q- (0%). FISH results for blood and bone marrow cells in 38 patients were similar. Purified CD5+/CD19+ cells from blood were studied in eight patients and results indicate that in some patients not all B cells have FISH anomalies. We used a defined set of hierarchical FISH risk categories to compare FISH results by stable versus progressive disease, age, sex, Rai stage, CD38+ expression and IgVH mutational status. Significant differences in FISH risk distributions were associated with Rai stage, disease status and CD38+, but not by age, sex or IgVH mutational status. To look for baseline factors associated with high-risk disease, multivariate analysis of age, sex, Rai stage, CD38+ and disease status versus FISH risk category was performed. Importantly, only CD38+ was significantly associated with high-risk FISH categories (+12, 11q- and 17p-) after adjustment for the effects of other variables.

Role of the microenvironment in chronic lymphocytic leukaemia

Abstract: In several B-cell malignancies the microenvironment confers a growth advantage and extended survival to malignant B cells. In chronic lymphocytic leukaemia three issues need to be resolved. First, to determine whether the microenvironment favours the development of the disease, promotes its progression or is involved in both events. Secondly, to define the microenvironmental elements that influence the malignant clone and the relevant molecular pathways. Thirdly, to clarify how the microenvironment affects the relationships between proliferation and extended survival. A number of findings indirectly suggest that antigen stimulation within specific microenvironments may be involved in the genesis of the disease and indicate that critical malignant cell/microenvironment cross-talks may decisively influence the disease progression. T lymphocytes, mainly CD40Ligand, CD4 cells, as well as a variety of stromal cells, appear to have a central role in amplifying a microenvironment able to favour the proliferation within tissue pseudofollicles and to inhibit the apoptosis of malignant cells. B-cell chronic lymphocytic leukaemia (CLL) is the most common leukaemia in the western world, diagnosed with increasing frequency in industrialized countries (Rozman & Montserrat, 1995) and is the prototype of B-cell chronic lymphoid malignancies CLL cells, that accumulate in peripheral blood (PB), express all the membrane markers of mature B lymphocytes, such as CD19, CD20, CD21, CD24, CD40, co-express CD5 and CD23 (reviewed by Caligaris-Cappio & Hamblin, 1999) and have a gene expression profile consistent with memory B cells (Klein et al, 2001; Rosenwald et al, 2001). Most circulating CLL lymphocytes are long-lived and arrested in the G0/early G1 phase of the cell cycle. They share with anergic B cells low to almost absent levels of surface immunoglobulins (sIg) and unresponsiveness to the conventional stimuli that promote the cell cycle progression of normal B cells (Caligaris-Cappio, 1996). Notwithstanding their resting state, PB CLL cells express membrane markers of cellular activation (Damle et al, 2002), have the mRNA for virtually all the cytokines investigated (Pistoia, 1997) and secrete several of them as activated B cells do (Caligaris-Cappio & Hamblin, 1999). In essence, PB CLL cells tend to be kinetically resting, phenotypically activated and functionally anergic. Three main issues are intermingled in the natural history of CLL. The analysis of IgVH gene sequences has revealed that the detection of somatic mutations is associated with a significantly longer median survival (Damle et al, 1999; Hamblin et al, 1999). The implication is that at least two molecularly recognizable distinct clinical entities (mutated and unmutated) are grouped under the name of CLL. There is a genetic predisposition and a familial tendency to develop CLL (Houlston et al, 2002). The gene(s) sustaining this predisposition and the gene(s) that underlie the primary transforming event(s) are unknown, while detailed cytogenetic studies are mapping with great accuracy a number of secondary genetic abnormalities that gradually render CLL more malignant (Dohner et al, 2000). Accordingly, the natural history of the disease is frequently prolonged, sometimes measurable in decades at least in the mutated group. The salient biological feature of CLL is the relentless in vivo accumulation of monoclonal B cells characterized by an extended survival in peripheral lymphoid organs, bone marrow (BM) and PB. Numerous investigations on the intrinsic ability of CLL cells to elude apoptosis (reviewed by Caligaris-Cappio & Hamblin, 1999 and Wickremasinghe & Hoffbrand, 1999) and quantitative assessment of apoptosisassociated molecules (Korz et al, 2002) have led to the notion that, irrespective of the rarity of the t(14;18) translocation, the Bcl-2 protein is consistently overexpressed in CLL cells when compared with CD19 B-cell fractions purified from normal donors. In addition, and again in the absence of known specific genetic abnormalities, the overall pattern of the BCL-2 gene family expression is tuned to shield CLL cells from apoptosis (Caligaris-Cappio & Hamblin, 1999). These observations have turned the attention to extrinsic factors and suggested the possibility that an important role in favouring the extended survival of malignant cells might be played by the malignant cell capacity to respond to selected signals from the microenvironment (Ghia & Caligaris-Cappio, 2000) by upregulating Bcl-2 and other anti-apoptotic proteins such as Mcl-1 (Pedersen et al, 2002).

The eosinophilias, including the idiopathic hypereosinophilic syndrome.

Abstract: An elevated blood eosinophil count may be associated with a number of reactive conditions and with clonal disorders of the bone marrow. When the blood eosinophil count is persistently greater than 1Æ5 · 10 ⁄ l for a period of 6 months, and damage to end organs such as the heart, lungs, skin, joints and nervous system can be demonstrated then, in the absence of any clonal abnormality or reactive cause, the term idiopathic hypereosinophilic syndrome (HES) is used. There is evidence to suggest that, in some patients, clonal T-cell populations are present. Treatment of the idiopathic hypereosinophilic syndrome has been varied and has included steroids, hydroxyurea, interferon and Tcell agents, and chemotherapy. Recently, patients have been treated successfully with imatinib mesylate and a trial of its use in HES is planned.

Galactomannan detection in computerized tomography-based broncho-alveolar lavage fluid and serum in haematological patients at risk for invasive pulmonary aspergillosis.

Abstract: We determined the value of galactomannan (GM) detection in computerized tomography (CT)-based broncho-alveolar lavage (BAL) fluid and serum for the diagnosis of invasive pulmonary aspergillosis (IPA) in haemato-oncological patients with neutropenia. CT of the thorax and BAL were performed systematically at predefined clinical indications. GM was determined by sandwich enzyme-linked immunosorbent assay; the clinicians were unaware of the results. Of 160 patients, 17 patients (10.6%) presented with proven, probable or suspected IPA. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of GM detection in CT-based BAL fluid were all 100%. For GM detection in serially sampled serum, the sensitivity was 47%, the specificity 93%, the PPV 73% and the NPV 82%. A non-blinded follow-up study was performed to validate these results. In this study, 22 of 198 patients (11.1%) presented with IPA, and the sensitivity, specificity, PPV and NPV of GM detection in CT-based BAL fluid were 85%, 100%, 100% and 88% respectively. None of BAL fluids obtained after antifungal treatment of 3 d or more were positive. These results indicate that, when CT is used systematically and at an early stage, GM detection in CT-based BAL fluid has a high PPV for diagnosing IPA early in untreated patients.

Bone marrow biopsy morbidity and mortality.

Abstract: A postal survey of adverse events associated with bone marrow biopsy (aspiration biopsy with or without trephine biopsy) was carried out among British Society of Haematology members, between 1995 and 2001. A total of 26 adverse events, including one death directly attributable to the procedure, were reported among an estimated 54 890 biopsies. The most frequent and most serious adverse event was haemorrhage, reported in 14 patients, necessitating blood transfusion in six patients and leading to the single death. The potential risk factors most often associated with haemorrhage were a diagnosis of a myeloproliferative disorder, aspirin therapy or both. Other potential risk factors were warfarin therapy, disseminated intravascular coagulation and obesity.

Diagnosis and treatment of systemic mastocytosis: state of the art.

Abstract: Mast cells are tissue-fixed cells originating from uncommitted and mast cell-committed haematopoietic progenitors (Kitamura et al, 1981; Kirshenbaum et al, 1992; Agis et al, 1993; Rottem et al, 1994; Kempuraj et al, 1999). Mast cellcommitted progenitors co-express CD13 and KIT with CD34 (Kirshenbaum et al, 1999) and are detectable in the bone marrow as well as in the peripheral blood (Valent et al, 1992; Rottem et al, 1994; Valent, 1994). Homing, differentiation and maturation of mast cell progenitor cells are regulated by a complex network of growth factors, receptors and other antigens (Galli, 1990; Valent, 1994). The most important growth factor for human mast cells appears to be stem cell factor (SCF) (Irani et al, 1992; Kirshenbaum et al, 1992; Valent et al, 1992; Mitsui et al, 1993). This cytokine is a natural ligand for the c-kit proto-oncogene product, KIT, a tyrosine kinase receptor expressed on the surface of precommitted myelopoietic progenitor cells, mast cell-committed progenitor cells as well as mature mast cells (Galli et al, 1993; Simmons et al, 1994; Valent, 1994). Based on their unique phenotype and distinct functional properties, mast cells represent a distinct myeloid cell lineage within lympho-haematopoietic tissues. Likewise, mast cells express a unique composition of CD antigens and granular mediators when compared with other myeloid cells (Schwartz, 1985; Valent et al, 1989; Valent & Bettelheim, 1992; Agis et al, 1996) (Table I). Moreover, in contrast to blood basophils and other myeloid cells, mast cells exhibit an extremely long life span in vivo ranging from several months to years (Galli, 1990; Födinger et al, 1994). In contrast to other haematopoietic cells, mast cells produce substantial amounts of histamine and heparin and express the high-affinity IgE receptor on their surface (Ishizaka & Ishizaka, 1984; Schwartz, 1985; Galli, 1990). The concept that mast cells represent a unique myeloid lineage is in line with the notion that systemic mastocytosis (SM) is a distinct haematopoietic (myeloid) neoplasm with unique pathogenetic and clinical features (Lennert & Parwaresch, 1979; Parwaresch et al, 1985; Metcalfe, 1991a; Valent, 1996). The clonal nature of the disease has been reinforced by the association with the somatic c-kit mutation Asp-816-Val (Nagata et al, 1995; Longley et al, 1996, 1999; Buttner et al, 1998). This transforming mutation is detectable in the bone marrow (mast cells) in a majority of patients with SM but usually is not found in other myeloid neoplasms (Fritsche-Polanz et al, 2001). Remarkably, in a group of patients with (advanced) SM, the c-kit mutation Asp-816-Val is detectable not only in mast cells but also in other haematopoietic lineages, including blood monocytes (Akin et al, 2000a; Sotlar et al, 2000; Yavuz et al, 2002). Based on this notion and several clinical observations, SM can be regarded as a myeloproliferative disorder. In line with this concept, patients with SM are at a certain risk of acquiring a secondary myeloid leukaemia (Travis et al, 1988a,b; Horny et al, 1990a; Lawrence et al, 1991; Sperr et al, 2000). In the management of patients with SM, two major problems have to be faced. The first is mediator release from mast cells with respective clinical symptoms that can be observed frequently in these patients (Horan & Austen, 1991; Metcalfe, 1991a; Austen, 1992; Valent, 1996). In fact, mast cells store (in their granules) or generate a number of vasoactive mediators [histamine, tumour necrosis factor-a (TNFa), vascular endothelial growth factor (VEGF), leukotrienes, prostaglandin D2 (PGD2)] and other biologically active molecules (interleukins, proteases, heparin) (Roberts et al, 1980; Lewis & Austen, 1981; Serafin & Austen, 1987; Burd et al, 1989; Plaut et al, 1989; WodnarFilipowicz et al, 1989; Gordon et al, 1990; Gordon & Galli, 1990) (Table II). In response to activating stimuli, mast cells can generate and ⁄ or release their mediator substances (Lewis & Austen, 1981; Ishizaka & Ishizaka, 1984; Schwartz, 1985; Burd et al, 1989; Plaut et al, 1989; Wodnar-Filipowicz et al, 1989; Gordon et al, 1990). Resulting clinical symptoms include headache, flushing, pruritus, diarrhoea, vascular instability, hypotension and shock (Austen, 1992) (Table II). Such symptoms may be grave and life threatening, especially in patients with SM who also have a co-existing disease predisposing for mediator secretion (allergies). The second management problem in SM results from the uncontrolled (aggressive) growth and infiltration of mast cells in diverse organs with consecutive organopathy (Lennert & Parwaresch, 1979; Parwaresch et al, 1985; Metcalfe, 1991a; Valent, 1996). Such organopathies are seen in patients with aggressive systemic mastocytosis (ASM), mast cell leukaemia (MCL) and in a group of patients with an associated clonal haematological nonmast cell lineage disease (SM-AHNMD), but not in those with indolent systemic mastocytosis (ISM). The organ systems most frequently affected in patients with aggressive Correspondence: Peter Valent, Department of Internal Medicine I, Division of Haematology & Haemostaseology, University of Vienna, Währinger Gürtel 18–20, A-1090 Vienna, Austria. E-mail: peter.valent@akh-wien.ac.at British Journal of Haematology, 2003, 122, 695–717

Stem cell plasticity

Abstract: Developmental studies over the last few decades have provided us with an understanding of cell ancestries, i.e. how the major classes of cells in the body are generated. Until recently, the dogma has been that adult mammalian stem cells progress in one direction only along differentiation pathways, from totipotent, pluripotent or multipotent stem cells to more differentiated cells and, once committed to a somatic cell lineage, do not differentiate across different embryonic-derived somatic lineages. Even though most cells in adulthood are differentiated cells, ‘self-renewing’ stem cells are also maintained in many, if not all, tissues. Such adult stem cells serve multiple functions. Where there is a need to replenish mature cells constantly (e.g. blood and skin) or to replace the differentiated cells in the case of injury or stress to the tissue, stem cells will have an active role. Stem cells may also persist in tissues as the residue of embryonic development and may rarely contribute to tissue renewal in the adult. While embryonic stem (ES) cells are thought to have an unlimited life span, and to generate most cell lineages, adult stem cells generally appear to have a limited life span and, until recently, were thought to have a restricted potential to generate primarily the cell types present in the specific tissue in which they reside. The concept of tissueand organ-specific stem cells has been addressed in a number of studies published in recent years. Scientists have postulated that adult stem cells may be either more ‘plastic’ than previously thought or have extraordinary potentials that are regulated by the microenvironment they occupy. In a new or different environment, the adult stem cell would be able to respond to new cues and therefore reprogramme itself to generate unrelated lineages or cells that are appropriate components of the new environment. This plasticity or potentiality has been proposed to be a reflection of cellular differences in organisms, the ontogenic stage of the stem cell (i.e. embryonic, fetal, adult) or the environmental conditions to which the stem cell is exposed (Wells, 2002). Although many experimental situations, in which adult stem cell plasticity or potentiality has been reported, were carried out in mice (Ferrari et al, 1998; Bjornson et al, 1999; Brazelton et al, 2000; Clarke et al, 2000; Lagasse et al, 2000; Mezey et al, 2000; Krause et al, 2001), there are several examples in humans (Table I). Transplants have been carried out in patients who have received tissue from a donor of the opposite sex, therefore making it possible to trace the progeny of the engrafted cells. Liver cells, for example, that stain positive for the Y-chromosome, have been found in women who have received bone marrow or haematopoietic stem cells (HSC) from male donors (Alison et al, 2000). Likewise, XY cells were detected in female livers engrafted in male patients (Theise et al, 2000a,b). The results of these studies suggest that, in humans, both bloodand bone marrow-derived stem cells can generate hepatocytes and vice versa. Similar results have been found in the brain following human bone marrow transplants (Mezey et al, 2003). Is it plasticity, cell fusion or potentiality that makes a progenitor ⁄ stem cell or more mature cell change its fate? There is evidence that stem cells can be influenced by external cues to generate unrelated cell lineages (Kondo et al, 2000). Equally, several reports demonstrate that stem cells from haematopoietic tissues have the potential to generate multiple lineages (Krause et al, 2001). Both plasticity and potentiality are characteristics that may coexist in a stem cell and represent its hallmark. More recently, evidence that cells may fuse to take on the characteristics of their partners has also been reported (Terada et al, 2002; Ying et al, 2002; Vassilopoulos et al, 2003; Wang et al, 2003a). This review will focus on the concept of plasticity in murine and human adult haematopoietic stem cells, discussing some of the most recent examples reported to date. The rationale for not including embryonic stem cells is that, by definition, these cells are able to generate most tissue types of an organism. The review will also focus on the haematopoietic system as a model, as a large number of the experiments have been described in this system, and haematopoietic tissues, together with neuronal stem cells, seem to be particularly promiscuous in their lineage commitment. We will also discuss some of the questions that arise when testing plasticity in adult stem cells, and will examine the robustness of these experimental results. Finally, a brief overview of experimental outcomes required to test stem cell plasticity or potentiality will be presented.

Transient leukaemia--a benign form of leukaemia in newborn infants with trisomy 21.

Abstract: Transient Leukaemia (TL) occurs frequently in newborn infants with Down Syndrome. Because in most cases the disease disappears spontaneously, it has been difficult to accept it as leukaemia, and as a result it has been referred by a variety of names including Transient Myeloproliferative Disorder and Transient Abnormal Myelopoiesis, suggesting that it is not leukaemia. In this review I shall present evidence that the disease is leukaemia and that although in most cases the course of the disease is transient in others it is life threatening. Also, I shall explore the nature of the leukaemic cell, its association with trisomy 21 and its relationship to other forms of leukaemia frequently found in children with Down Syndrome.

Extracorporeal photochemotherapy for paediatric patients with graft‐versus‐host disease after haematopoietic stem cell transplantation

Abstract: This study aimed to ascertain whether extracorporeal photochemotherapy (ECP) is an effective treatment for paediatric patients with refractory graft-versus-host disease (GVHD). From January 1992 to December 2000, 77 children (median age 8.6 years) with either acute (n = 33) or chronic (n = 44) GVHD, resistant to conventional immunosuppressive therapy, were treated with ECP in four Italian paediatric hospitals. After ECP, acute GVHD involving skin, liver and gut responded completely in 76%, 60% and 75% of patients respectively. The 5-year overall survival was 69% for responding patients vs 12% for non-responders (P = 0.001). Among the 44 children with chronic GVHD, 15 (44%) showed a complete response and 10 (29%) a significant improvement after ECP. The 5-year overall survival was 96% for responders vs 58% for non-responders (P = 0.04). Our results suggest that ECP is an effective treatment that may be useful in paediatric patients with either acute or chronic GVHD who have failed to respond to standard immunosuppressive therapy.

Thalidomide and dexamethasone for resistant multiple myeloma

Abstract: Between November 1998 and April 2000, the combination of thalidomide and dexamethasone was evaluated in 47 consecutive patients with multiple myeloma that was resistant to prior high-dose dexamethasone-based therapies Remission was observed in 22 patients (47%), including six patients with complete remission Side-effects were frequent, mild and usually reversible, but deep vein thrombosis occurred in 8% of patients Survival and remission times were longer among patients treated for previous resistant disease rather than for resistant relapse This experience supports the use of thalidomide-dexamethasone in myeloma patients with resistant disease and justifies further trials in newly diagnosed patients

Burkitt's and Burkitt-like lymphoma in children and adolescents: a review of the Children's Cancer Group experience.

Abstract: Historically, the survival of children and adolescents with Burkitt's and Burkitt-like lymphoma had been poor. Recently, short and intensive chemotherapy appears to have improved disease outcome. We therefore reviewed the results of four successive Children's Cancer Group trials conducted on 470 children with disseminated Burkitt's and Burkitt-like lymphoma. Of the patients studied, the median age was 8 years (0-21 years), the male:female ratio was 4:1, 58% had lactate dehydrogenase (LDH) > or = 500 IU/l, 23% had M2 or M3 bone marrow (BM), and 12% demonstrated central nervous system involvement. In a multivariate analysis, the 4-year event-free survival (EFS) in patients > or = 15-years-old compared with or = 500 IU/l compared with LDH < 500 IU/l was 49 +/- 3 versus 71 +/- 4% (P < 0.001). Furthermore, patients treated on the most recent protocol, which was short and more intensive, had a significantly improved survival compared with those on previous trials (4-year EFS 80 +/- 6 versus 54 +/- 2%, P < 0.001). In summary, the outcome for childhood Burkitt's and Burkitt-like lymphoma has recently improved with the use of short and intensive B-cell non-Hodgkin's lymphoma-directed therapy.

Serum levels of macrophage inflammatory protein-1 alpha (MIP-1α) correlate with the extent of bone disease and survival in patients with multiple myeloma

Abstract: Summary. The role of serum macrophage inflammatory protein-1 alpha (MIP-1α) in bone disease and survival was evaluated in 85 newly diagnosed multiple myeloma (MM) patients. MIP-1α was elevated in MM patients and correlated with the extent of bone disease, bone resorption markers and levels of soluble receptor activator of nuclear factor-κB (RANK) ligand. MIP-1α was also associated with survival; the 3-year probability of survival was 85% and 44% for MIP-1α levels below and above 48 pg/ml respectively (P = 0·021). This suggests that MIP-1α contributes to the pathogenesis of bone disease in MM and possibly in tumour growth, as reflected by its impact on survival.

Outcome of autologous transplantation for mantle cell lymphoma: a study by the European Blood and Bone Marrow Transplant and Autologous Blood and Marrow Transplant Registries

Abstract: Summary. Mantle cell lymphoma (MCL) has an aggressive clinical course with a median survival < 3 years and is incurable with conventional chemotherapy. A large multicentre study with adequate follow-up may clarify the role of significant factors affecting outcome in autologous stem cell transplantation for MCL. Patients receiving an autologous transplant for MCL between 1988 and 1998, and reported to the European Blood and bone Marrow Transplant (EBMT) registry or Autologous Blood and Marrow Transplant Registry (ABMTR), were included. Expert haematopathology review was required on all identified patients. Disease and transplant details were requested from the transplant centres, and the final cohort of patients with verified pathology, adequate clinical information and follow-up was analysed. One hundred and ninety-five patients were included in the analyses (149 EBMT, 46 ABMTR) with a median follow-up of 3·9 years. The 2 year and 5 year overall survival were 76% and 50%, and progression free survival was 55% and 33% respectively. Disease status at transplant was the most significant factor affecting survival: patients with chemosensitive disease but not in first complete remission (CR1) were 2·99 times (95% CI: 1·66–5·38, P < 0·001) more likely to die than patients transplanted in CR1. Autologous transplantation probably improves survival in patients with MCL especially if performed in first CR.