Showing papers in "Haematologica in 1997"

The clinical course of deep-vein thrombosis. Prospective long-term follow-up of 528 symptomatic patients

Abstract: BACKGROUND AND OBJECTIVE: In contrast to the extensive documentation on the short-term outcome of patients with acute deep vein thrombosis (DVT) of the lower extremities, little is known about the long-term clinical course of this disease. To determine the clinical course of patients with a first episode of symptomatic DVTn over an 8-year follow-up period. The primary aims were to assess the long-term incidence of recurrent venous thromboembolism and that of the post-thrombotic syndrome. In addition, we determined mortality and evaluated potential risk factors for all these outcomes. METHODS: This was designed as a prospective cohort follow-up study. Consecutive symptomatic outpatients with a first episode of venography proven DVT were treated with an initial course of full-dose (low molecular weight) heparin, followed by at least three months of oral anticoagulants. After discharge, they were instructed to wear compression elastic stockings for at least two years. Follow-up assessments were scheduled at three and six months, and then every six months up to eight years. Diagnosis of recurrent venous thromboembolism was made according to standard criteria. The presence of post-thrombotic syndrome was evaluated using a standardized scale. RESULTS: A total of 528 consecutive patients with a first episode of venography confirmed DVT were included in the study. The cumulative incidence of recurrent venous thromboembolism after two, five and eight years was 17.2, 24.3 and 29.7%, respectively. Malignancy and impaired coagulation inhibition increased the risk of recurrent venous thromboembolism (RR = 1.48 and 2.0, respectively). In contrast, surgery and recent trauma or fracture were associated with a diminished risk of recurrent venous thromboembolism (RR = 0.65 and 0.39, respectively). The cumulative incidence of post-thrombotic syndrome after two, five and eight years was 24.5, 29.6 and 29.8%, respectively. The development of ipsilateral recurrent DVT was strongly associated with the risk for post-thrombotic syndrome (risk ratio, 2.4). Survival after eight years was 69%. The presence of malignancy increased the risk of death remarkably (risk ratio, 7.1). INTERPRETATION AND CONCLUSIONS: Symptomatic DVT carries a high risk for recurrent venous thromboembolism that persists for many years, especially in patients without transient risk factors for DVT. The post-thrombotic syndrome occurs in almost one-third of patients and is strongly related to recurrent ipsilateral DVT. Our findings challenge the widely adopted short course of anticoagulation in patients with symptomatic DVT.

Definition of acute biphenotypic leukemia

Abstract: BACKGROUND AND OBJECTIVE: A minority of acute leukemias have features characteristic of both the myeloid and lymphoid lineages and for this reason are designated mixed-lineage, hybrid or biphenotypic acute leukemias (BAL). There have been difficulties in establishing whether BAL represents a distinct clinico-biological entity due to a lack of objective criteria for distinguishing BAL from acute myeloid leukemias (AML) or acute lymphoblastic leukemias (ALL) with aberrant expression of a marker from another lineage. In this work we analyze diagnostic criteria for BAL. METHODS: We describe the features of 26 patients (19 adults and 7 children) with BAL diagnosed at the Royal Marsden Hospital. BAL was defined according to a scoring system devised by our group and the European Group for the Immunological Classification of Leukemia (EGIL). This system is based on the number and degree of specificity of the markers (lymphoid and myeloid) expressed by the blasts. RESULTS: According to the FAB criteria, BAL may present as "ALL" or as one of the "AML" subtypes, often M1. It is not infrequent to identify two distinct blast populations: one of small size resembling lymphoblasts and the other larger. The most common immunophenotype is coexpression of B-lymphoid and myeloid markers and less frequently, T-lymphoid and myeloid markers. Cases with a B and T lymphoid phenotype or with trilineage differentiation are rare. BAL has a high incidence of clonal chromosomal abnormalities, the most common being the t(9;22) (q34;q11) (Ph chromosome) and structural abnormalities involving 11q23. Data are emerging that BAL has a negative prognosis in both children and adults and this may be related to the underlying chromosome abnormalities. INTERPRETATION AND CONCLUSIONS: In summary, BAL is an uncommon type of leukemia which probably arises from a multipotent progenitor cell and carries a poor prognosis. Although there are no uniform criteria about whether to treat these patients as ALL or AML, it is likely that an intensive approach with high-dose therapy followed by bone marrow transplantation will be required to eradicate the disease permanently.

Primary intestinal lymphoma: clinical and therapeutic features of 32 patients.

Abstract: BACKGROUND AND OBJECTIVE: Lymphomas of the gastrointestinal tract are the most common type of primary extranodal lymphomas, accounting for 5 to 10% of all non-Hodgkin's lymphomas. In particular, primary intestinal lymphomas represent about 15-20% of gastrointestinal lymphomas. New multimodal therapeutic approaches have improved the prognosis of this once deadly disease: we report a retrospective analysis of our experience with 32 cases of primary western intestinal lymphomas, presenting clinical, therapeutical and prognostic data. PATIENTS AND METHODS: From March 1989 to November 1995, 32 patients with untreated primary western intestinal lymphomas were submitted to radical surgery plus polychemotherapy (early stages, I and II; 22 patients), or polychemotherapy alone (advanced stage, III and IV; 10 patients). The most frequent symptoms were abdominal pain, nausea, vomiting and weight loss. The tumor was located in the jejunum in 2 cases (6.2%), in the proximal small bowel in 15 cases (46.9%), in the distal and terminal ileum in 8 cases (25%), in the colon and rectum in 4 cases (12.5%), and multiple sites were found in 3 cases (9.4%). According to histology, 26 patients had high-grade and 6 low-grade non-Hodgkin's lymphoma. RESULTS: Stage I-II patients underwent radical resection of the tumor and chemotherapy; advanced (III-IV) stage patients were treated with chemotherapy alone as first-line approach. Of the 32 patients, 24 (75%) achieved a complete response (CR); according to stage, all stage I-II patients had CR, while only 2 of the 10 stage III-IV patients reached CR. The risk of a lower response rate was significantly correlated with the presence of advanced stage (III-IV) (p = 0.000001). The overall 5-year survival rate was 59%, with a relapse-free survival rate of 72% among the 24 complete responders. INTERPRETATION AND CONCLUSIONS: Intestinal lymphomas differ significantly from their gastric counterpart, not only in pathology, but also with regard to clinical features, management and prognosis. Our experience confirm the efficacy of the surgery-chemotherapy combination in obtaining a good remission rate for localized early primary intestinal lymphoma and indicates that this combination represents the only means for managing complications.

Antiplatelet agents in thrombotic thrombocytopenic purpura (TTP). Results of a randomized multicenter trial by the Italian Cooperative Group for TTP

Abstract: BACKGROUND AND OBJECTIVE: Antiplatelet agents are often included in plasma exchange-based regimens for thrombotic thrombocytopenic purpura (TTP) patients; however, the opportuneness of their use in TTP is still controversial. The italian Cooperative Group for TTP carried out a randomized trial to investigate their actual effectiveness, both in acute TTP and as maintenance treatment. METHODS: Seventy-two TTP patients were randomized to receive plasma exchange and steroids with (group B) or without (group A) aspirin and dipyridamole. Treatment efficacy was evaluated after 15 days and salvage treatments were also considered for non-responders. Upon disease remission, the patients already treated with antiplatelet agents received ticlopidine for one year. RESULTS: Regarding the treatment of acute phase TTP, similar overall response rates were observed in the two groups (91.4% in group B vs. 75.6% in group A), but lower mortality rates were observed at 15 days in the patients treated with antiplatelet agents; as a matter of fact, 5 patients from arm A died in the first 15 days (13.5%) versus only one in arm B (2.8%). These figures, while not statistically significant, seem to suggest that antiplatelet agents might be useful in preventing deaths in acute TTP; moreover, bleeding did not worsen in antiplatelet agent-treated patients. As for the role of maintenance treatment, our results support the efficacy and safety of one-year ticlopidine therapy since the current relapse rate is significantly higher in non-treated patients; as a matter of fact, 6 patients (21.4%) in the non-ticlopidine group and only 2 (6.25%) in the ticlopidine group relapsed (P = .0182 in favor of maintenance treatment). INTERPRETATION AND CONCLUSIONS: Our results suggest the usefulness of antiplatelet agents in the treatment of acute phase TTP patients. Moreover, one-year ticlopidine maintenance therapy appears to be beneficial in preventing TTP relapses; however, only the completion of an adequate follow-up for all patients will definitively confirm this observation.

Effects of recombinant human granulocyte colony-stimulating factor administration on neutrophil phenotype and functions

Abstract: BACKGROUND AND OBJECTIVE: Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is currently used for treatment of various types of neutropenia, treatment of aplastic anemia, mobilization of peripheral blood progenitor cells. However, rhG-CSF is not only a growth factor for the myeloid lineage, but it also acts as a modulator of neutrophil behavior. The aim of the present review article is to examine the following aspects of rhG-CSF therapy: 1) does rhG-CSF influence neutrophil functions, and in particular their microbicidal properties? 2) does rhG-CSF modify neutrophil phenotype? 3) If so, what are the mechanisms potentially involved? EVIDENCE AND INFORMATION SOURCES: The author of the present article has been working in the field of rhG-CSF effects on neutrophil function, contributing original papers in peer-reviewed journals. In addition, the present review critically examines articles and abstracts published in journals covered by the Science Citation Index and Medline. STATE OF ART AND PERSPECTIVES: Treatment with rhG-CSF causes enhancement of functions such as phagocytosis, superoxide anion generation, chemiluminescence, bacterial killing, and ADCC. Neutrophil phenotype changes after rhG-CSF administration: immediate effects cause direct activation of circulating neutrophils, but delayed effects are characterized by increased surface expression of important effector molecules directly involved in neutrophil functions, such as CD14, CD32, CD64. These effects may have useful clinical consequence in patients who show an increased risk of infections, such as cancer patients, subjects with hematologic diseases (myelodysplasia, aplastic anemia), congenital diseases characterized by neutropenia, and patients with AIDS. Other changes which characterize neutrophils after rhG-CSF administration are represented by significant impairment of CD16 expression, chemotaxis, and reduced in vivo migration of neutrophils to inflammatory sites. These effects may be explained by bone marrow modification due to rhG-CSF therapy. In fact, treatment with rhG-CSF causes a significant acceleration of transit time of cells belonging to the myeloid lineage, along with amplification of the mitotic pool and a relative decrease of elements of the post-mitotic pool. It is possible that, because of the accelerated bone marrow transit time of myeloid cells, rhG-CSF causes a relative immaturity of circulating neutrophils. It is known that both CD16 expression and chemotaxis properties are acquired by neutrophils in the late stages of maturation, but the time necessary to acquire full functional maturity seems to be shortened by rhG-CSF administration, and this kinetic aspect may play a non-negligible role in the modification of neutrophil behavior.

Anemia of chronic disorders in systemic autoimmune diseases

Abstract: BACKGROUND AND OBJECTIVE: Anemia of chronic disorders (ACD) is a mild to moderate anemia characterized by decreased serum iron, decreased total iron-binding capacity and increased iron stores that occurs in a wide variety of diseases including cancer, chronic infections and inflammatory disorders. The reason for this review is two-fold. First, systemic autoimmune diseases are frequently characterized by ACD. Second, advances in our knowledge of the pathophysiology of systemic autoimmune diseases as well as pathogenesis and treatment of ACD have so far been dealt with separately. Consequently, the approach to the evaluation of ACD in systemic autoimmune disorders has usually been either immunology- or hematology-oriented. The aim of this review is to integrate the pertinent information from both these fields in order to arrive at a more complete understanding of a problem common to hematologists and immunologists. INFORMATION SOURCES: The articles reviewed have been published in journals listed in the Science Citation Index and Medline. In addition, the authors have a vast experience in the field of hematology and are actively working in the field of systemic autoimmune disorders. STATE OF ART AND PERSPECTIVES: ACD is a parameter of disease activity in systemic autoimmune diseases. The severe inflammatory stimuli responsible for the pathophysiology of these disorders lead to several systemic changes (referred to as chronic active phase response) through which the organism tries to cope with chronic tissue injuries. These reactions are brought about by inflammation-associated cytokines, like IL-6, IL-1, TNF alpha, TGF beta that regulate hepatic synthesis of acute phase proteins. Many cytokines involved in chronic acute phase response, including IL-1, TNF alpha, TGF beta, have an inhibitory activity on erythroid colony formation in vitro. In addition, circulating TNF alpha is elevated in rheumatoid arthritis (RA), IL-1 beta serum levels are significantly increased in RA with ACD and RA patients treated in vivo with antibodies (Abs) to TNF alpha show disease improvement, including an increase in Hb values. Reduced erythropoietin (EPO) activity, usually the result of reduced production, plays a role in the pathogenesis of ACD observed in systemic autoimmune diseases. Both the production and the action of EPO may fall under the control of IL-1 and IFN-gamma. The most controversial and stimulating aspect of the pathogenesis of ACD in systemic autoimmune disorders is the role of iron metabolism and nitric oxide (NO), which contributes to the regulation of iron cellular metabolism. Both iron deficiency and iron overload may influence the proliferation of B and T lymphocytes and differentially affect T helper (TH)-1 and TH-2 lymphocytes. Furthermore, TH-1 cytokines stimulate and TH-2-type cytokines inhibit NO production. For these reasons, cell-mediated immunity may be expected to have influence on NO synthesis and on the mechanisms leading to iron accumulation in the reticuloendothelial system.

Expression of the stem cell factor receptor C-KIT (CD117) in acute leukemias

Abstract: BACKGROUND AND OBJECTIVE: The receptor for stem cell factor (CD117) is the gene product of the c-kit proto-ontogene. Together with its ligand, the stem cell factor (SCF), it plays an important role in hematopoiesis. In this study, we review the cellular distribution of CD117 in normal hematopoiesis and in hematopoietic malignancies focusing on the differential expression in subtypes of acute leukemias. EVIDENCE AND INFORMATION SOURCES: This review is based on a literature search in the Medline database, personal publications and results obtained as a reference laboratory of the German AML-BFM, AMLCG and ALL multi-center therapy studies. STATE OF THE ART AND PERSPECTIVES: Membrane expression of CD117 can be found on leukemic blasts from approximately 60% of adult and childhood AML patients, often associated with an immature immunophenotype (CD34). Moreover, AML with t(8;21) are frequently CD117 positive. Despite earlier reports, most recent studies have not been able to demonstrate any significant prognostic impact of CD117 expression in either childhood or adult AML. A small proportion of T-lineage ALL (9%), mainly consisting of immature pro-T/pre-T-ALL, is CD117 positive. CD117 expression is rare in B-cell-precursor-ALL and occurs in less than 3% of cases. CD117 in combination with other antigens might facilitate the immunologic characterization of acute leukemias, especially those of myeloid and early T-cell origin.

The Italian Registry of Antiphospholipid Antibodies

Abstract: BACKGROUND AND OBJECTIVE: The clinical importance of antiphospholipid antibodies (APA) derives from their association with a syndrome of venous and arterial thrombosis, recurrent fetal loss and thrombocytopenia known as the antiphospholipid syndrome (APS). The Italian Registry of Antiphospholipid Antibodies was set up in 1989 for the purpose of collecting a large number of patients with lupus anticoagulant (LA) or anticardiolipin antibodies (ACA) for clinical studies in order to obtain more information on the clinical features of APS. EVIDENCE AND INFORMATION SOURCES: The Italian Registry has completed two clinical studies and proposed an international trial on the treatment of APS patients. These activities of the Registry are reviewed herein. Additional information has been obtained from pertinent articles and abstracts published in journals covered by the Science Citation Index and Medline. STATE OF ART: The first study of the Registry was a retrospective analysis of enrolled patients which showed that: a) the prevalence of thrombosis and thrombocytopenia was similar in cases with idiopathic APA or APA secondary to systemic lupus erythematosus, and b) the rate of thrombosis was significantly reduced in patients with severe thrombocytopenia but not in those with only a mild reduction of the platelet count. The second study was a prospective survey of the natural history of the disease, showing that a) previous thrombosis and ACA titer > 40 units were independent predictors of subsequent vascular complications; b) a history of miscarriage or thrombosis is significantly associated with adverse pregnancy outcome; c) hematological malignancies can develop during follow-up and patients with APA should be considered at increased risk of developing NHL. Thus the possibility of a hematologic neoplastic disease should be borne in mind in the initial evaluation and during the follow-up of these patients. PERSPECTIVES: The latest initiative of the Registry was the proposal of an international, randomized clinical trial (WAPS study) aimed at assessing the efficacy and safety of high-dose warfarin in preventing recurrent thrombosis in patients with APA and vascular disease. The study is scheduled to start in March 1997.

Severe bleeding due to acquired hypoprothrombinemia-lupus anticoagulant syndrome. Case report and review of literature

Abstract: A 17-year-old girl was admitted to our department with a hemorrhagic syndrome due to a serious coagulopathy; prothrombin time (PT) INR was 2.46 and the activated partial thromboplastin time (aPTT) ratio 3.46. Coagulation tests with pooled normal fresh plasma did not correct aPTT because of a coagulation inhibitor, and only partially corrected PT. Factor II activity reached only 5%. Diluted Russell viper venom tests (dRVVT) and kaolin clotting time (KCT) of patient plasma (PP) and of a mixture of PP/normal plasma (NP) detected the lupus anticoagulant (LA). The level of factor II antigen was 10%. We diagnosed systemic lupus erythematosus (SLE) with a rare acquired hypoprothrombinemia-LA syndrome (HLAS). The patient was treated with corticosteroids and high-dose Ig and a normal PT value was re-established.

Risk of reactivation of a recent invasive fungal infection in patients with hematological malignancies undergoing further intensive chemo-radiotherapy. A single-center experience and review of the literature

Abstract: BACKGROUND: Patients with hematologic malignancies and a history of an invasive fungal infection are considered to be at high risk of suffering reactivation of the infection during subsequent intensive chemotherapy. PATIENTS AND METHODS: From January 1993 to September 1996, nine patients with a hematologic malignancy and previous invasive pulmonary aspergillosis (IPA) or Pseudallescheria boydii pneumonia and five with invasive candidiasis received further intensive chemotherapy (n = 3) or a bone marrow or peripheral blood stem cell transplant (n = 11) four days to 13 months (median three months) from the start of therapy for the fungal infection. Five patients with IPA and all five with invasive candidiasis showed complete or good partial radiologic resolution of the infection with the primary antifungal therapy given, which was continued before, during and after the period(s) of subsequent neutropenia. RESULTS: Twelve of the 14 patients showed no signs of progression or reactivation of the fungal infection during therapy, while two patients with active IPA died with progressive aspergillosis shortly after an allogeneic transplant. A review of the literature revealed that in both types of infections the risk of reactivation and dissemination appears low after achieving clinical and radiologic signs of response, which takes several weeks or months before proceeding to further antileukemic therapy. INTERPRETATION AND CONCLUSIONS: Despite lack of definite evidence, administration of an active antifungal drug before, during and after the period of neutropenia appears to be useful. In IPA, residual masses, nodules or cavities in the lung usually contain viable invasive fungal elements and should be resected whenever possible. On the other hand, the risk of reactivation and progression of an active fungal infection during intensive chemoradiotherapy is very high, and novel therapeutic strategies appear warranted in this setting.

The molecular basis of myelodysplastic syndromes

Abstract: BACKGROUND AND OBJECTIVE: The myelodysplastic syndromes comprise a heterogeneous group of neoplastic disorders characterized by ineffective hematopoiesis with an increased tendency to evolve to acute leukemia. Clinically, the common manifestations include peripheral blood cytopenias of one or more lineages and a normal to hyperplastic marrow. MDS has been defined on the basis of morphological criteria, namely the percentage of blast cells in the bone marrow, by the French-American-British study group. Scoring systems have been developed to include such factors as hemoglobin, leukocyte count and age in the evaluation of MDS prognosis. Although useful in the prediction of clinical course and design of therapy regimens, our understanding of the basis of MDS has come from recent advances in molecular analysis of these disorders. This review describes some of the established and recent contributions to our understanding of the molecular basis of the myelodysplastic syndromes. EVIDENCE AND INFORMATION SOURCES: The authors of the present review have been working in the field of myelodysplastic syndromes for several years and have contributed original papers on the molecular pathogenesis of these disorders. In addition, in the present review they have critically examined articles and abstracts published in journals covered by the Science Citation Index and Medline. STATE OF ART AND PERSPECTIVES: Cytogenetic anomalies and proto-oncogene abnormalities point to new understanding of the pathogenesis of MDS as a sequence of DNA lesions leading to the evolution of the pre-malignant clone. The prognostic significance of these factors in predicting leukemic transformation and survival remains controversial. Characterization of MDS cells in vitro in response to combinations of exogenous growth factors have not only provided valuable information regarding ineffective hematopoiesis in MDS but have provided a new insight into treatment of MDS. One major development in our understanding of MDS is the possible explanation for the apparent paradox of a cellular marrow in combination with peripheral cytopenias. Extensive premature programmed cell death or apoptosis has been reported to be at least partly responsible. It will remain to be seen whether this fundamental characteristic of myelodysplastic hematopoiesis will play a central role in the drug or genetic based therapy in the myelodysplastic syndromes.

Hepatitis C virus infection among cryoglobulinemic and non-cryoglobulinemic B-cell non-Hodgkin's lymphomas

Abstract: BACKGROUND AND OBJECTIVE: Since hepatitis C virus (HCV) infection has been associated with different histotypes of B-cell non-Hodgkin's lymphoma (NHL), with or without concomitant production of cryoglobulins (cryolg), we have investigated the prevalence of the infection among NHL with the aim of defining its relationship with the histotype and with the production of cryolg. METHODS: Four-hundred and seventy unselected, consecutive patients with a diagnosis of B-cell NHL were investigated. Anti-HCV antibodies (Ab) and cryolg were sought in all while HCV RNA and rheumatoid factor were detected on HCV-Ab positive samples. RESULTS: Overall, the prevalence of HCV infection was 8.9% (42/470). It was 95.4% (#21) among the 22 patients with, and 4.6% (#21) among the 448 without production of cryoIg. The most common histotype among the HCV-positive, cryoIg-producing cases, was the immunocytoma (16/21, 76%). Among the HCV-positive, non cryoIg-producing cases, the marginal zone and the follicle center lymphomas were the commonest. INTERPRETATION AND CONCLUSIONS: Close association between HCV infection and cryoIg production, already described in mixed cryoglobulinemia, is confirmed also among B-cell NHL. Nevertheless, 50% of HCV-related lymphomas are non-cryoIg producers. Low-grade lymphomas (in particular the immunocytoma) are the most frequent HCV-related lymphomas. Since new therapeutic strategies might be necessary if the virus is detected, screening for cryoIg and for HCV-Ab among B-cell NHL at diagnosis is mandatory.

The AML1 gene: a transcription factor involved in the pathogenesis of myeloid and lymphoid leukemias

Abstract: BACKGROUND AND OBJECTIVE: The AML1 gene was identified in 1991 by cloning the t(8;21) chromosome translocation associated with FAB M2 acute myeloid leukemia (AML). AML1 encodes a nuclear transcription factor (TF) which shows homology in its 5' part with the Drosophila melanogaster segmentation gene, runt, and contains a transactivation domain in the carboxyterminal portion. In the t(8;21), AML1 is fused to the ETO (MTG8) gene, resulting in a hybrid AML1/ETO mRNA, which in turn is translated into a chimeric protein. The objective of this article is to review here the main structural and biological features of AML1 and of its fusion products, with special focus on their clinical correlations and their potential usefulness for prognostic and monitoring studies in human leukemia. EVIDENCE AND INFORMATION SOURCES: The material examined in the present review includes articles and abstracts published in journals covered by the Science Citation Index and Medline. STATE OF ART: The normal AML-1 protein forms the alpha-subunit of the heterodimeric TF core binding factor (or CBF), whose beta-subunit is encoded by the CBF beta gene on chromosome 16q22. CBF beta is rearranged and fused to the MYH11 gene in the AML M4Eo-associated inv(16) aberration. Thus, the two most common chromosome abnormalities of AML, i.e. t(8;21) and inv(16), affect the two subunits of the same target protein. This suggests that the wild type CBF must exert an important role in the control of myeloid cell growth and/or differentiation. Evidence that AML1 is a pivotal regulator of definitive hematopoiesis has been recently provided by analyzing AML1 knockout mice. The chromosome region 21q22, where AML1 maps, is involved in several other karyotypic aberrations, such as the t(3;21) translocation associated with a subset of therapy-related myelodysplastic syndromes and AML, and the blast phase of chronic myelogenous leukemia. In this abnormality, three distinct genes: EVI1, EAP, MDS1, located on chromosome band 3q26, have been identified that may recombine with AML1. Finally, the recently cloned t(12;21) translocation has been found to involve the TEL gene (coding for a novel TF) on 12p13, and AML1 on 21q22. This alteration, which results in the production of a TEL/AML1 chimeric protein, is restricted to pediatric B-lineage acute lymphoid leukemia (ALL), where it represents the most frequent molecular defect known to date (up to 25% of cases). Strikingly, the same t(12;21) is identified in only 0.05% of pediatric B-lineage ALL cases analyzed by conventional karyotyping. Other relevant characteristics of TEL/AML1-positive ALL are frequent deletion of the other TEL allele and association with an excellent prognostic outcome. PERSPECTIVES: It is expected that future studies will provide more detailed information on the leukemogenic effect of AML1 alterations, and better define the prognostic relevance of detecting the hybrid proteins formed by this gene at diagnosis and during remission.

Localized orbital lymphoma

Abstract: BACKGROUND AND OBJECTIVE: Localized orbital non Hodgkin's lymphoma is a rare event which has not been reported much in the literature. The aim of this study was to evaluate the clinical features, histology, treatment and clinical outcome of patients with localized orbital lymphoma. METHODS AND RESULTS: Fifteen patients with stage I-E orbital lymphoma diagnosed between 1975 and 1992 were reviewed. Diagnosis was formulated from 3-84 (median 23) months after the appearance of symptoms. Eight patients were males and 7 were females; median age was 55 years. The lacrimal gland was involved in 8 cases, the orbit in 7. Bilateral orbital localization was observed in only one patient. All cases were diagnosed as low-grade MALT lymphoma. Chemotherapy was administered in 7 patients, radiotherapy was employed in 7 and surgical excision was performed in the remaining case. Almost all the patients (14/15; 93%) achieved a complete remission (CR). Local relapse (LR) was observed in 3 cases but disease spread was never recorded. INTERPRETATION AND CONCLUSIONS: Correct histological diagnosis and careful staging are very important for the treatment and outcome of localized low-grade orbital lymphoma. These patients show a very good prognosis and radiation therapy alone is very effective in the treatment of this malignancy.

Bacteremia in patients with hematological malignancies. Analysis of risk factors, etiological agents and prognostic indicators.

Abstract: BACKGROUND AND OBJECTIVE: Patients with hematological malignancies are at increased risk for developing bacteremia. No previous study has investigated the risk and prognostic indicators of bacteremia in such patients using a statistical approach. METHODS: A case-control study was performed in 106 patients with hematological malignancies (group A). Two hundred and twelve patients were included as controls and divided into two groups: 106 patients with hematological malignancy without bacteremia (group B) and 106 HIV-infected patients with bacteremia (group C). RESULTS: At univariate analysis, bacteremia risk factors in group A were: neutropenia for more than six days (p = 0.03 vs. group B), central venous catheter usage (p = 0.04) and absence of antibiotic prophylaxis (p = 0.03). At multivariate analysis, the use of CVC and neutropenia were independent bacteremia risk factors. The most frequent etiological agents were: Staphylococcus epidermidis and Pseudomonas aeruginosa. Comparing groups A and C, the distribution of Staphylococcus spp. was different, with S. epidermidis being prevalent in hematological patients only. As regards gram-negative organisms, it is of note that no episode of NT-Salmonella bacteremia was observed in group A, unlike group C, where they represent the second leading etiological agents. In group A, 14% of the patients died. Persistent neutropenia (p = 0.01) and the presence of relapsed neoplasm (p = 0.04) were prognostic indicators of bacteremia. INTERPRETATION AND CONCLUSIONS: Our findings suggest that bacteremia in patients with hematological malignancies strictly correlates with the intensity and length of neutropenia and CVC usage. Although we observed a low mortality rate, we stress that this clinical condition requires special attention from the physician, who must recognize and treat it promptly.

Acute hepatic toxicity during cyclic chemotherapy in non hodgkin's lymphoma

Abstract: BACKGROUND AND OBJECTIVE: Hepatic toxicity directly related to the drugs administered in cyclic chemotherapy (CT), although sometimes serious, does not limit the treatment of non-Hodgkin's lymphoma (NHL) Nevertheless, reports of reactivation of viral hepatitis in NHL patients with B virus (HBV) infection are becoming more frequent The recent observation of two cases of severe liver toxicity directly correlated to CT and a case of fatal hepatic failure due to HBV replication prompted us to evaluate the hepatic toxicity of CT in 98 consecutive B-cell NHL patients treated with relatively homogeneous cyclic CT METHODS: Acute hepatic toxicity was retrospectively evaluated in 98 consecutive B-cell NHL patients who received induction CT HBV and HCV markers were checked at presentation All patients were tested for ALT and bilirubin before every CT course, while tests for HBV-DNA and/or for HCV-RNA were performed with PCR only when hepatitis occurred RESULTS: At presentation 22 patients (224%) were positive for HBsAg, and 11 (159%) were positive for anti-HCV Acute hepatitis developed in 12 (122%) NHL patients: 8 (out of 22) in HBsAg-positive and anti-HCV-negative patients, 3 (out of 76) in HBsAg-negative patients, and 1 (out of 11) in anti-HCV-positive patients Hepatitis was attributed to reactivation of chronic B hepatitis in 3 patients and to drug toxicity in 3 others; hepatitis was undefined in 6 cases INTERPRETATION AND CONCLUSIONS: Drug-related liver toxicity is not a rare occurrence in NHL patients Reactivation of HBV replication is responsible for a relevant number of the hepatitis cases observed We did not detect acute hepatitis due to the reactivation of HCV replication (in chronic C hepatitis carriers)

New insights in biology and current therapeutic options for patients with chronic myelogenous leukemia

Abstract: BACKGROUND AND OBJECTIVE: From the discovery of the Ph-chromosome, there has been an extraordinary progress in our understanding of chronic myeloid leukemia (CML). During the last three decades, new findings arising from dissection of the genetic abnormalities at a molecular level have received the most attention, but there have also been important new observations arising from studies of the biologic behaviour of normal and leukemic stem cells and, more recently, from clinical investigations. In this review we first report the most important observations relevant to understanding the oncogenic potential of the BCR-ABL chimeric gene, and the behaviour and the relationships of normal and leukemic stem cells. From a clinical point of view, allogeneic stem cell transplantation is the only procedure able to cure CML. The main issues are: who can receive this procedure, and when and how it can be given. The situation is more complex in unrelated transplants. In patients without HLA compatible donors, many large trials in different countries have demonstrated that interferon alpha therapy is indicated and effective in the majority of patients. On the other hand, autologous stem cell transplantation is still an experimental procedure. These aspects will be analyzed in detail and, at the end, a therapeutic algorithm of a possible approach to the patients with untreated CML is provided. EVIDENCE AND INFORMATION SOURCES: The method used for preparing this review was an informal consensus development. All the authors of the present review have been working in the field of chronic myeloid leukemia, and have contributed original papers in peer-reviewed journals. In addition, the material examined in the present review includes articles and abstracts published in journals covered by the Science Citation Index and Medline. STATE OF ART AND PERSPECTIVES: The oncogenic potential of BCR-ABL has been demonstrated in a number of in vitro and in vivo model systems. Current research efforts are focused on defining the mechanism by which BCR-ABL transforms primary hematopoietic cells. The fact that BCR-ABL contains tyrosine residues, an SH2 domain, an SH3 domain, and proline-rich sequences raises the possibility of multiple protein-protein interactions. Indeed, BCR-ABL is reported to bind and/or phosphorylate more than 20 proteins. The insights into the signal transduction pathways activated by BCR-ABL will hopefully provide a new basis for the treatment of CML patients. Clinical evidence of the existence of a transplantable CML stem cell population has recently been extended to xenogeneic recipients of transplanted CML cells and by retroviral marking to autograft recipients. The potential of using immunodeficient mice as recipients of CML stem cells to create an in vivo model of chronic phase CML should be invaluable for testing novel therapies designed to eliminate residual disease in the patient. Current therapeutic options include conventional chemotherapy, IFN-a and allogeneic stem cell transplantation as established procedures, and autografting as an experimental procedure. While IFN-a as a first line therapy does not seem to jeopardize further treatments, autografting, according to the Genoa approach or other procedures, i.e. Ph-positive cells collected at diagnosis without mobilization therapy, raises the question of an ideal sequential strategy in the management of CML patients. There seems to be a general agreement that a patient less than 50 years old, with an HLA identical sibling, should receive an allogeneic stem cell transplant. This approach should be offered also to younger patients (< or = 40 years) who are able to find an unrelated matched donor. Since it seems that the normal hematopoietic reservoir declines with time, it may be desiderable to mobilize and collect peripheral stem cells in order to store Ph-negative progenitors as soon after diagnosis as possible when the WBC count has been controlled by hydroxyurea while searchin

Molecular heterogeneity of glucose-6-phosphate dehydrogenase (G6PD) variants in Italy.

Abstract: BACKGROUND: Glucose-6-phosphate dehydrogenase deficiency, one of the most common human enzymatic defects, is characterized by extreme molecular and biochemical heterogeneity. The molecular bases of almost all polymorphic italian variants have now been identified and the overall heterogeneity is lower than expected from biochemical data. METHODS: We examined 161 G6PD-deficient subjects (130 males and 31 females) originating from different parts of Italy. G6PD activity and molecular characterization were determined in all the subjects analyzed. RESULTS: We found the G6PD Mediterranean genotype in roughly 70%, G6PD Union and G6PD Seattle in about 6% and G6PD A- in 4% of the samples analyzed. G6PD S. Antioco and G6PD Cosenza were less frequent (1.2%), and single cases of G6PD Partenope and G6PD Tokyo were also detected. CONCLUSIONS: We report the frequency and distribution of the most common G6PD variants in Italy. Greater molecular heterogeneity than described by others was observed, especially in Sardinia. Among the severe deficient variants, G6PD Mediterranean has a higher prevalence in Sardinia (83%) than in continental Italy (61%), as does G6PD Union (10% and 4%, respectively). G6PD Seattle and A-, associated with mild G6PD deficiency, are by contrast more frequent in continental Italy.

Silent thalassemias: genotypes and phenotypes

Abstract: BACKGROUND AND OBJECTIVE: Current application of molecular biology techniques to the study of the DNA of globin genes has confirmed the existence of silent alpha and beta thalassemias; which had already been reported on the basis of red blood cell parameters and family studies. The present work was aimed at analyzing all the aspects of the phenotype of the most common varieties of silent thalassemia. MATERIALS AND METHODS: Groups of heterozygous carriers of these varieties were examined using established techniques that determined all hematologic, hemoglobin (electrophoresis and measurement of Hb A2 and Hb F levels), and globin synthesis (evaluation of the alpha/beta ratio) parameters. Furthermore, all subjects underwent a complete molecular study of the alpha and beta globin genes by means of the ARMS, SSCP, DGGE, PCR and Southern blotting techniques. RESULTS: 1) The -101 C-->T mutation of the promoter of the beta globin gene shows a normal hematological picture with the Hb A2 level often slightly raised and the alpha/beta globin synthesis ratio slightly greater than 1; 2) beta + thalassemia resulting from the IVS II 844 C-->G mutation has a phenotype that is even closer to normal; 3) -alpha 3.7 deletion type I usually has a totally silent phenotype; 4) the alpha Ncol mutation almost always gives rise to a sub-silent phenotype if it is located on gene alpha 2 and to a silent phenotype if it is found on gene alpha 1; 5) alpha + thalassemia due to the alpha 2 Hphl mutation displays a sub-silent phenotype in some cases and a silent one in others; 6) triplication of the alpha genes gives rise to a phenotype that is quite similar to that of the -101 C-->T mutation of the promoter of the beta globin gene, namely one that is very often silent. INTERPRETATION AND CONCLUSIONS: Many of these silent varieties (beta + thalassemia due to the -101 C-->T mutation; alpha + thalassemia from a deletion or point mutation of an alpha gene; alpha alpha alpha triplication) are quite frequent in the overall group of thalassemias. It is therefore important for the operators in the field of thalassemia diagnosis to possess exact knowledge of them especially in order to prevent thalassemia major.

Human leukemia k562 cells: induction to erythroid differentiation by guanine, guanosine and guanine nucleotides

Abstract: BACKGROUND AND OBJECTIVE: Human leukemic K562 cells are able to undergo erythroid differentiation in vitro when cultured with a variety of inducers, leading to increased expression of embryo-fetal globin genes such as the zita, epsilon and gamma-globin genes. Therefore the K562 cell line has been proposed as a very useful in vitro model system for determining the therapeutical potential of new differentiating compounds as well as for studying the molecular mechanism(s) that regulate changes in the expression of embryonic and fetal human globin genes. In this study we explored whether nucleoside triphosphates and related compounds are able to induce differentiation of K562 cells. METHODS: K562 cell differentiation was studied using the benzidine test; hemoglobins were characterized by cellulose acetate gel electrophoresis and mRNA accumulation was investigated by Northern blot analysis. RESULTS: The main conclusion of this paper is that guanine, guanosine and guanine ribonucleotides are effective inducers of K562 cell differentiation. Expression of both Hb Portland and Hb Gower 1 is increased in GTP-induced K562 cells. This increase is associated with greater gamma-globin mRNA accumulation. By contrast, ATP, CTP and UTP are not able to induce erythroid differentiation. INTERPRETATION AND CONCLUSIONS: These findings suggest that guanine, guanosine and guanine ribonucleotides are inducers of erythroid differentiation of K562 cells. This is of some relevance since differentiating compounds have been proposed as antitumor agents. In addition, inducers of erythroid differentiation that stimulate gamma-globin synthesis might be considered in the experimental therapy of hematological diseases associated with a failure in the expression of adult beta-globin genes.

Combined treatment with amphotericin-B and granulocyte transfusion from G-CSF-stimulated donors in an aplastic patient with invasive aspergillosis undergoing bone marrow transplantation

Abstract: Granulocyte transfusions from G-CSF stimulated donors were added to standard anti-infective treatment in preparation for and during allogeneic bone marrow transplantation in a young man affected by very severe acute aplastic anemia and invasive aspergillosis. Nine concentrates with a mean neutrophil content of 18.7 x 10(9)/L (2.6 x 10(8)/kg patient b.w.) were transfused before and after marrow infusion. An impressive clinical improvement was noticed after each granulocyte transfusion, although this was not always paralleled by a neutrophil increase in the peripheral blood. Engraftment (N > 0.5 x 10(9)/L and Plt > 25 x 10(9)/L) was verified at +16 and +40 days, respectively. The patient is currently in complete hematological and microbiological remission 14 months after transplantation. Granulocyte apheresis from G-CSF stimulated donors provides a high number of activated neutrophils. At the dose given (300 micrograms/day) donor tolerance to G-CSF was excellent. This new approach is indicated when life-threatening infections develop in patients exposed to prolonged severe neutropenia.

Hereditary hemochromatosis: recent advances in molecular genetics and clinical management

Abstract: BACKGROUND AND OBJECTIVE: Hereditary hemochromatosis (HC) is an inborn error of iron metabolism leading to increased intestinal iron absorption and progressive iron overload. There have been definite advances in our knowledge of the pathogenesis and management of idiopathic hemochromatosis in recent years, which prompted us to review this subject. INFORMATION SOURCES: The material examined in the present review includes articles and abstracts published in the journals covered by the Science Citation Index and Medline. In addition, both authors have been working in this field for several years and have contributed twelve of the papers cited in the references. STATE OF ART AND PERSPECTIVES: The disease is a late onset autosomic recessive condition, especially frequent in Caucasians. If unrecognized, severe clinical symptoms develop in mid-life related to organ failure. Early diagnosis prevents complications, since an intensive phlebotomy course removes excess iron and offers patients a normal life expectancy. Transferrin saturation is the first examination step, but liver biopsy is still essential for diagnosis and prognosis of HC. The biochemical defect is unknown. Positional cloning of the HC gene has led to the isolation of all the candidate region on the short arm of chromosome 6, telomeric to HLA-A. Recently a putative HC gene has been cloned from this region and found to be mutated in a large proportion of patients. The gene, known as HLA-H, is an atypical MHC class I gene. Although its biological function remains unknown, HLA-H is the first strong HC candidate gene. Molecular screening of patients and carriers is now possible in a significant portion of cases, thereby permitting better control of the disease. If it is unequivocally confirmed that the HLA-H gene is responsible for the disease, understanding of its biological function will provide information on the type and activity of the involved protein, revealing new insights into iron uptake and metabolism in humans.

Myelodysplastic syndromes with monocytic component: hematologic and cytogenetic characterization

Abstract: BACKGROUND AND OBJECTIVE: Patients with myelodysplastic syndromes (MDS) showing high numbers of abnormally localized immature precursors (ALIP) also display myelomonocytic antigens on immature cells, and it has been suggested that the presence of monocytosis could define a distinct subset of MDS characterized by poorer survival. The objective of this study was to analysis the incidence and significance of monocytosis among our series of patients with MDS and correlate the distributions of these elements with other hematologic features. METHODS: We evaluated the monocytic component in myelodysplastic syndromes in order to clarify the significance of monocytosis in MDS and its relationship with CMMoL and other MDS. Monocytosis was defined as a percentage of blood monocytes greater than 10%. RESULTS: Among a series of 139 consecutive MDS patients, we describe a group of 29 (20.8%) patients with monocytosis and dysplastic features involving multiple cell lineages which do not fulfill the criteria for diagnosis of CMMoL or aCML. These patients, who do not differ from MDS without monocytosis in the main clinical parameters, are characterized by relatively higher leukocyte (WBC 6.6 x 10(9)/L) and granulocyte counts (PMN 2.5 x 10(9)/L), hypercellular bone marrow and relatively poor prognosis. Among these patients, we observed a particularly high incidence of evolution to CMMoL (34.5%) and AML (17.2%) with monocytic component (FAB M4 and M5). Cytogenetic data demonstrated clonal chromosome changes in 11/13 patients with MDS and monocytosis, while only 19/41 patients without monocytosis showed clonal abnormalities. CONCLUSIONS AND PERSPECTIVES: The combination of hematologic and cytogenetic features in our study suggests that it is reasonable to consider myelodysplasia with monocytosis as a distinct disease subset of MDS, characterized by multilineage dysplasia along with a higher incidence of karyotype aberrations. The multi-step pathogenetic process in these patients may have reached a more advanced stage at which the relative or absolute increase in the number of monocytes may represent the first event in the subsequent progression of the disease towards acute leukemia.

The utility and cost-effectiveness of D-dimer measurements in the diagnosis of deep vein thrombosis

Abstract: BACKGROUND AND OBJECTIVE: The potential utility of D-dimer measurements for the diagnosis of deep vein thrombosis became evident soon after the development of reliable commercial assays. The purpose of this review is to outline some critical aspects affecting cost-effectiveness of D-dimer measurements in the diagnosis of deep vein thrombosis (DVT). METHODS: The authors have been working in this field contributing original papers whose data have been used for this study. In addition, the material analyzed in this article includes papers published in the journals covered by the Science Citation Index and Medline. RESULTS: D-dimer levels are very sensitive to the process of fibrin formation/dissolution occurring with ongoing thrombosis. However, they may not be highly specific for venous thromboembolism as they are influenced by the presence of comorbid conditions potentially elevating plasma D-dimer (cancer, surgery, infectious diseases). In addition, commercially available ELISA assays, although quantitative and reproducible, cannot be used under emergency conditions because they are time-consuming and suited for batch-processing of plasma samples. Recently, new assays have been introduced which permit fast and quantitative D-dimer estimations in individual patients. We have evaluated the utility of two new rapid assays (LPIA D-dimer. Mitsubishi, and VIDAS D-DIMER, bio-Merieux) in combination with compression real-time-B-mode ultrasonography for the detection of deep vein thrombosis in asymptomatic patients following elective hip replacement and in patients with clinically suspected deep vein thrombosis. In both settings, we identified cut-off values with optimal sensitivity which allow exclusion of deep vein thrombosis in a considerable percentage of patients, with substantial sparing of economic resources. In fact, based on a cost-effectiveness analysis, a diagnostic algorithm combining D-dimers measurement and compression ultrasonography would result in cost-savings ranging from 5% to 55% in patients with high or low clinical pretest probability respectively. However, the specificity of D-dimer measurements for deep vein thrombosis was much higher in symptomatic than in asymptomatic patients. Choice of the cut-off value proved to be dependent on the method as well as on the patient populations studied. CONCLUSIONS: The cost-effectiveness of D-dimers measurement in the diagnosis of asymptomatic DVT remains questionable. Conversely, our data strongly support the utility of D-dimers determinations in the diagnosis of symptomatic DVT. In terms of sparing economic resources, the introduction in the clinical laboratory of the rapid quantitative assays would be highly convenient, because they avoid a source of bias in the interpretation of D-dimers results, are easy to perform and do not require dedicated personnel or instrumentation. Prospective management studies validating the utility of D-dimer measurement in the diagnosis of deep vein thrombosis are urgently needed.

High incidence of chronic graft versus host disease after allogeneic peripheral blood progenitor cell transplantation. The Spanish Group of Allo-PBPCT

Abstract: BACKGROUND AND OBJECTIVE: The incidence of acute GVHD (aGVHD) in allogeneic peripheral blood progenitor cell transplantation (allo-PBPCT) seems to be similar to that seen in allogeneic bone marrow transplantation (allo-BMT). In contrast, some preliminary results suggest that the incidence of chronic GVHD (cGVHD) might be higher. The aim of the present study was to analyze the actuarial probability of developing cGVHD in allo-PBPCT, its clinical manifestations and response to treatment. METHODS: We have retrospectively analyzed clinical results from 21 allo-PBPCT recipients that had been transplanted at least 18 months before this study and that fulfilled the following criteria: HLA identical sibling donor, non T-cell depleted apheresis and more than 90 days of survival with sustained engraftment. The median follow-up was 12 months (range 4.5-22). RESULTS: Twelve out of the 21 (57%) patients presented cGVHD, 1 limited and 11 extensive. The actuarial probability of cGVHD was 72.7% (95% CI, 49-96%). The median interval from transplant to onset was 180 days (range 95-270). Nine of the 12 cases (75%) presented combined skin and liver involvement. Of the other three, the liver was involved in one case; skin, mouth, and nail cGVHD was observed in another case; and skin and mouth involvement together with an obstructive pulmonary disease was observed in the remaining case. Under therapy, a complete resolution of cGVHD manifestations was achieved in five cases, and a partial improvement was attained in three other cases. In two responsive patients, cGVHD reappeared after stopping treatment. Four patients were refractory to the treatment. INTERPRETATION AND CONCLUSIONS: It would appear from this retrospective and multicenter study that, after a median follow-up of 12 months, cGVHD after allo-PBPCT could be more frequent than after allo-BMT. A randomized trial with a large number of patients and a sufficient follow-up will be necessary to answer this question definitively.

Mobilization and collection of PBSC in healthy donors: a retrospective analysis of the Italian Bone Marrow Transplantation Group (GITMO).

Abstract: BACKGROUND AND OBJECTIVE: The number of allogeneic transplants of peripheral blood stem cells (PBSC) is rapidly increasing. Collection of PBSC in healthy subjects currently implies the administration of G-CSF or GM-CSF and, of course, the use of apheretic devices. These procedures involve potential risks, in particular the risk of leukemia secondary to growth-factor treatment. To evaluate the current practice of PBSC mobilization and collection, and initially assess the short-term side effects and efficiency of procedures, the GITMO (Gruppo Italiano Trapianti di Midollo Osseo) promoted a retrospective cooperative study among the Italian centers. METHODS: Seventy-six healthy individuals donating to their HLA-identical or partially matched sibling recipients in seven Italian centers form the basis of the present analysis. The data were retrospectively collected by proper forms, pooled and analyzed by means of a commercially available statistical soft package. RESULTS: All donors received G-CSF as mobilizing agent with different schedules according to each single center policy. A median of 2.5 (range 1-4) aphereses per donor were run. The most frequent side effect was bone pain. In no case did the medium term follow-up reveal subjective complaints or laboratory modifications. After G-CSF mobilization, WBC and lymphocytes counts increased to a maximum of (mean +/- SD) 48.1 +/- 15.6 x 10(9)/L and 4.2 +/- 1.5 x 10(9)/L, respectively. The peak was reached on day 5 in both cases. Platelets decreased after the apheretic procedures, reaching a minimum of (mean +/- SD) 77 +/- 26 x 10(9)/L on day 8 and returning to normal values on day 11. Overall, the apheretic collection yielded (mean +/- SD) 18.6 +/- 19.2 x 10(8)/kg donor body weight MNC; 10.4 +/- 5.7 x 10(6)/kg CD34+ cells; 90.6 +/- 75.9 x 10(4)/kg CFU-GM and 4.3 +/- 1.8 x 10(8)/kg CD3+ cells. The target dose of 4 x 10(6)/kg CD34+ cells was harvested in 51.3% donors after a single apheresis, in 85.5% after the second, and in nearly 100% after a maximum of 3 aphereses. INTERPRETATION AND CONCLUSIONS: These data demonstrate that collection of adequate numbers of circulating progenitors is feasible and well tolerated in healthy donors. However, only careful monitoring of donors and international cooperation will help to definitively assess the long-term safety of G-CSF for mobilization of PBSC.

Hyperhomocysteinemia and venous thromboembolic disease

Abstract: BACKGROUND AND OBJECTIVE: In spite of the large number of reports showing that hyperhomocysteinemia (HHcy) is an independent risk factor for atherosclerosis and arterial occlusive disease, this metabolite of the methionine pathway is measured in relatively few laboratories and its importance is not fully appreciated. Recent data strongly suggest that mild HHcy is also involved in the pathogenesis of venous thromboembolic disease. The aim of this paper is to analyze the most recent advances in this field. EVIDENCE AND INFORMATION SOURCES: The material examined in the present review includes articles and abstracts published in journals covered by the Science Citation Index and Medline. In addition the authors of the present article have been working in the field of mild HHcy as cause of venous thromboembolic disease. STATE OF ART AND PERSPECTIVES: The studies examined provide very strong evidence supporting the role of moderate HHcy in the development of premature and/or recurrent venous thromboembolic disease. High plasma homocysteine levels are also a risk factor for deep vein thrombosis in the general population. Folic acid fortification of food has been proposed as a major tool for reducing coronary artery disease mortality in the United States. Vitamin supplementation may also reduce recurrence of venous thromboembolic disease in patients with HHcy. At the present time, however, the clinical efficacy of this approach has not been tested. In addition, the bulk of evidence indicates that fasting total homocysteine determinations can identify up to 50% of the total population of hyperhomocysteinemic subjects. Patients with isolated methionine intolerance may benefit from vitamin B6 supplementation. Homocysteine-lowering vascular disease prevention trials are urgently needed. Such controlled studies, however, should not focus exclusively on fasting homocysteine determinations and folic acid monotherapy.

Factor V and protein S as cofactors to activated protein C

Abstract: BACKGROUND AND OBJECTIVE: Activated protein C (APC)-resistance, the most common risk factor for venous thrombosis described so far, is due to a single point mutation in the factor V gene. As a result, inactivation of factor-activated factor V by APC is impaired, which leads to a hypercoagulable state and a lifelong increased risk of thrombosis. The importance of protein S as an anticoagulant protein is illustrated by the association between protein S deficiency and venous thrombosis. The objective of this article is to examine the most recent advances on the role of factor V and protein S as cofactors to activated protein C. EVIDENCE AND INFORMATION SOURCES: The material examined in the present review includes several personal papers in this field, and articles and abstracts published in journals covered by the Science Citation Index. STATE OF ART: Factors V and VIII are homologous, high molecular weight glycoproteins with similar functional properties. Factors Va and VIIIa bind to negatively charged phospholipid and function as high affinity receptors/cofactors for factors Xa and IXa, respectively. Factors Va and VIIIa account for at least a 10(3) increase in the rate of activation of prothrombin and factor Xa, respectively. The potent anticoagulant activity of APC is mediated by the degradation of factors VIIIa and Va, resulting in inhibition of both Xase and prothrombinase activities. APC specifically degrades the membrane-bound activated forms of factors V and VIII, whereas the unactivated factors V and VIII are poor substrates for APC. Mature human protein S is a single chain glycoprotein composed of multiple domains, including a thrombin-sensitive region. Protein S acts as a cofactor to activated protein C. Thus function of protein S is lost upon thrombin cleavage, suggesting that the thrombin-sensitive region interacts with APC on the phospholid surface. PERSPECTIVES: Recent data suggest that factor V and protein S work in synergy as phospholipid-bound cofactors to APC in the degradation of factor VIIIa and that factor VIIIa is preferred over factor Va as APC-substrate. Thus complicated multimolecular complexes, which are the result of protein-protein as well as protein-phospholipid interactions, appear to form the basis for efficient cleavage and inhibition of factors VIIIa and Va.

Clonal karyotype abnormalities in EBV-associated hemophagocytic syndrome

Abstract: BACKGROUND AND OBJECTIVE: An EBV-associated hemophagocytic syndrome (HS) in previously healthy children or young adults has been documented in Taiwan. The exact nature of this syndrome, i.e., either an infectious process or a neoplastic disease, remains to be clarified. METHODS: Three patients diagnosed as having HS were studied retrospectively. Chromosomes from bone marrow were examined by a conventional trypsin-Giemsa banding technique and karyotyped at the beginning of diagnosis or during treatment. In situ hybridization studies for EBV using EBER1 were performed. RESULTS: All three patients presented the classic manifestations of HS including fever, splenomegaly, jaundice, pancytopenia and coagulopathy. Bone marrow aspiration revealed atypical lymphocyte and histiocyte infiltration with hemophagocytosis. EBV genomes were found in bone marrow in all patients. In addition to normal mitotic cells, clonally karyotypically abnormal cells were demonstrated in all three patients whose diseases were rapidly progressive and eventually refractory to etoposide-based therapy. The consistent karyotypical abnormality of add(9)(p24) was noted in two of them. INTERPRETATION AND CONCLUSIONS: Although HS is usually considered a reactive process, the emergence of clonal cytogenetic abnormalities should be considered a malignant entity and treated with more intensive chemotherapy. A large series of cytogenetic and molecular studies is needed to clarify the exact nature of this fatal disease.

The value of combination therapy in adult acute myeloid leukemia with central nervous system involvement

Abstract: BACKGROUND AND OBJECTIVE: In adult patients with acute myeloid leukemia (AML), central nervous system (CNS) involvement is a rare event and treatment has not yet been defined. Because there are no definitive data as to the most appropriate therapeutic approach to CNS leukemia in AML, we retrospectively analyzed a cohort of AML patients with meningeal leukemia in order to increase our knowledge on this particular matter. METHODS: Out of 410 patients with de novo AML observed at our Institute from 1986 to 1995, 9 (2.2%) showed CNS leukemia (CNSL) during the follow-up. CNSL was treated as follows: in a first group of 4 patients we combined systemic HD Ara-C 3 g/m2 (every 12 hours by 3-hour infusion, for 6 doses), cranial radiation therapy and intrathecal (IT) methotrexate (MTX); a second group of 4 patients was treated with HD Ara-C, IT MTX without cranial irradiation; HD Ara-C alone was administered in one patient. RESULTS: All patients of the first group and 2 patients of the second who achieved a complete remission (CR) had a median survival of 10 months (range 5-25+) after CNS involvement, while for the non-remitters it was 2 months (range 1-5). The only patient still living underwent allogeneic bone marrow transplantation. INTERPRETATION AND CONCLUSIONS: The combination treatment of HD Ara-C, IT MTX and cranial irradiation is well tolerated and seems to be an effective therapy for CNSL, presenting a high incidence of neurologic CR that correlates with a longer survival. As expected, the number of AML patients with CNSL was small, due to the fact that CNS in those patients is a rare complication. However, this study provides further information about the therapeutic possibilities in such restricted subsets of AML patients.