Waldenström's macroglobulinemia: clinical course and prognostic factors in 60 patients. Experience from a single hematology unit.

Waldenström's macroglobulinemia (WM) is a lymphoplasmacytic lymphoma characterized by the presence in patients' serum of an IgM monoclonal component. We report on our experience with 60 WM patients, focusing on their clinical findings, response to treatment, and the possible identification of prognostic factors. Of these patients, 70% presented with fatigue, and lymphadenopathy was observed in 22%, splenomegaly in 18%, hepatomegaly in 13%, and extranodal site of involvement in 6%. Bleeding tendency was seen in 17%, infections in 17%, hyperviscosity syndrome in 12%, and cardiac failure in 25% of the patients. The median of IgM levels was 30 g/l with hypoalbuminemia in 20% of cases, hypogammaglobulinemia in 27%, polyclonal hypergammaglobulinemia in 15%, kappa light-chain restriction in 78%, and Bence-Jones proteinuria in 54%. Anemia was frequent (85%), followed by leukocytosis (18%), lymphocytosis (12%), leukopenia (10%), and thrombocytopenia (10%). Cryoglobulinemia and autoimmune hemolytic anemia were encountered in 5%. In all cases but two, bone marrow was involved. Of 50 patients initially treated with intermittent oral chlorambucil, 46 (92%) responded. Median overall survival was 108 months. Factors associated with adverse prognosis were age > or =65 years (p=0.06), presence of lymphadenopathy (p=0.06), bone marrow infiltration > or =50% (p=0.007), international prognostic index (IPI) > or =3 (p=0.0001), and Morel's scoring system (p=0.04). Concluding, we found in this series of WM patients that chlorambucil is an effective treatment and that the parameters of age, lymphadenopathy, percentage of bone marrow infiltration, IPI, and Morel's scoring system carry prognostic significance.

HLA antigens and asthma in Greeks.

HLA-A and -B antigens were determined in a group of 76 Greek asthmatic patients: 35 children (1.5-15 years) and 41 adults (18-73 years). The results were compared to those of 400 healthy unrelated controls from the same population. The standard NIH lymphocytotoxicity test was applied. When all 76 patients were compared to the controls, a statistically significant lower frequency of HLA-B5 and -B35 antigens was noted. When adults were analysed alone, an increased frequency of HLA-B8 was found. On the other hand, in the asthmatic children sub-group, the HLA-A10 antigen was significantly higher and the HLA-B5 was significantly lower than in the controls. These data imply that different HLA antigens may be involved in the pathogenesis of several clinical forms of asthma and that, in order to study the role of immunogenetic factor(s) in the pathogenesis of this disease, more adequate grouping criteria are needed.

Low incidence of acute myocardial infarction in beta-thalassaemia trait carriers.

The frequency of beta-thalassaemia trait was estimated in 209 consecutive patients hospitalized for acute myocardial infarction in order to answer the question of the possible protective effect of heterozygosity for beta-thalassaemia on the incidence of the disease. 212 patients hospitalized during the same period for various accidental bone fractures served as controls. Diagnosis of both, acute myocardial infarction and beta-thalassaemia trait, was based on the standard clinical and laboratory criteria. We found that patients with acute myocardial infarction had low frequency of beta-thalassaemia trait (4.31%), as compared with the mean incidence of heterozygosity for beta-thalassaemia in the whole Greek population (7.61%) (p < 0.02). This finding was more clear in the older age groups of the patients studied. No statistically significant differences were found in the frequency of beta-thalassaemia trait between control subjects (8.49%) and the whole Greek population. We concluded that the heterozygosity for beta-thalassaemia may protect the carrier from acute myocardial infarction. This effect is probably related to low serum cholesterol levels, slight anaemia, and microcytosis lowering the blood viscosity. These changes are usually present in the beta-thalassaemia trait carriers.

Multiple myeloma associated with autoimmune hemolytic anemia.

A rare case of multiple myeloma associated with severe Coombs-positive hemolytic anemia is described. A 60-year-old woman was hospitalized for acute hemolysis due to an IgG warm autoantibody with pan-agglutinin specificity. Serum and urine electrophoresis revealed the presence of a monoclonal IgGk protein and a BJk protein, respectively. Bone marrow aspirates showed diffuse infiltration with plasma cells, and skeletal survey revealed lytic lesions in the skull and diffuse osteoporosis. Treatment with prednisone, and subsequently with melphalan, cyclophosphamide and vincristine resulted in hematological improvement within two weeks. A reduction of paraprotein below 50% of the initial levels was found after six months of therapy.

Molecular basis and haplotype analysis of delta, beta-thalassemic chromosomes in Greece.

The molecular defect was defined in 38 delta beta-thalassemic chromosomes from 30 unrelated heterozygous and 4 homozygous patients of Greek origin. Restriction fragment beta-gene cluster haplotypes were studies in 23 delta beta-thalassemic chromosomes. The molecular lesion was identical in all studied cases and corresponds to the 'Sicilian' type of delta beta-thalassemia. Restriction haplotypes analysis has shown that, with one exception only, all Greek delta beta-thalassemic chromosomes bear the polymorphic sites which characterize haplotypes I or VII, the former being probable by indirect evidence. The striking similarities of the molecular lesion and the underlying haplotypes are consistent with two theories: (1) The deletion occurred once on a chromosome and spread all over Greece and the Mediterranean area thereafter; (2) the 5' subhaplotype +----favors the deletional event in the delta-beta gene area.

Pseudoxanthoma elasticum-like skin lesions and angioid streaks in beta-thalassemia.

One hundred patients with homozygous or doubly heterozygous beta-thalassemia (62 with the major form and 38 with beta-thalassemia intermedia) were examined for signs of Pseudoxanthoma elasticum (PXE). Diagnostic skin lesions were found in 16 patients with either form of the basic disease. Twenty percent of all patients had angioid streaks (AS); both PXE skin lesions and AS were found in 10% of the patients; in all, 26% had either one or both of these manifestations. A positive correlation was found between the presence of one or both types of lesion and age of the patients (P = 0.032); there were no differences as regards ferritin and hematocrit levels, number of transfused units, chelation therapy, and splenic status between patients with PXE/AS findings and those without. The pathogenesis of these connective tissue manifestations at such a high frequency in beta-thalassemia is not clear; the possibilities of it's being acquired or inherited are discussed, the former being considered to be the more economical interpretation.

A case of spinal cord compression by extramedullary haemopoiesis in a thalassaemic patient: a putative role for hydroxyurea?

We report a case of homozygous beta thalassaemia who developed chronic paraparesis due to spinal cord compression by paravertebral extramedullary masses. Our patient was successfully treated with hypertransfusion and hydroxyurea. This drug in addition to its well-known cytostatic effects, may be a good alternative in conditions analogous to our case. This action of hydroxyurea can also be attributed to its favourable effect on foetal haemoglobin production.

Tuberculosis associated hemophagocytic syndrome complicated with severe bone marrow failure and disseminated intravascular coagulation.

Tuberculosis associated hemophagocytic syndrome (HPS) has recently been recognized as a benign reactive histiocytic proliferation with marrow hemophagocytosis. To our knowledge, only five autopsy documented cases have previously been reported. We present here a unique case of the disorder complicated by severe bone marrow failure and disseminated intravascular coagulation. The possible mechanisms of these complications are discussed and it is concluded that the immunological disturbances usually occurring in miliary tuberculosis could play a role in the pathogenesis of HPS.

Early plasmapheresis in patients with thrombotic thrombocytopenic purpura.

OBJECTIVES: To investigate the relationship of thrombotic thrombocytopenic purpura to adult respiratory distress syndrome (ARDS) and study the responses of thrombotic thrombocytopenic purpura patients to early plasmapheresis. DESIGN: Case series. SETTING: ICU of a university hospital. PATIENTS: Twenty-four consecutive patients with thrombotic thrombocytopenic purpura, with various periods of time (1 to 18 days) having elapsed since the onset of this condition. Patients ranged in age from 17 to 66 yrs. INTERVENTIONS: Plasmapheresis, using intermittent flow separators, was instituted soon after the patients' ICU admission. The retinoscopic findings on admission and the relationship of Pao2 to platelet counts before and after plasmapheresis therapy were recorded. Antiplatelet agents were given to the survivors to prevent relapses. MEASUREMENTS AND MAIN RESULTS: Eighteen patients survived and six died. Plasmapheresis was administered for a range of 1 to 5 days (mean 3) and 3 to 18 days (mean 9.8) in survivors and nonsurvivors, respectively (p less than .001). Four patients with confluent fundus hemorrhages died and seven without these fundoscopic findings had easily controlled disease. Increases in Pao2 paralleled increases in platelet counts after plasmapheresis (p less than .001) in this small series of patients. Three of 18 discharged survivors relapsed over a period of 3 to 56 months of follow-up. CONCLUSIONS: Early introduction of plasmapheresis in thrombotic thrombocytopenic purpura seems to increase the survival rate and to halt the development of ARDS. Fundus findings may be a prognostic factor in thrombotic thrombocytopenic purpura. The antiplatelet agents seem to be efficacious in the prevention of relapses.

The effect of recombinant alpha-interferon on natural killer cell activity and clinical course in patients with myelodysplastic syndrome.

Thirteen patients with myelodysplastic syndrome (MDS) were included in this study and consented to treatment with recombinant alpha-interferon (a-IFN). These patients were subclassified: six as RAEB, one as RAEB-T and six as CMML. T-cell subsets and natural killer cells were identified in the peripheral blood with the use of monoclonal antibodies and natural killer cell activity (NKa) was assayed before, during and after a-INF treatment. The treatment schedule consisted of 2.0 MU/m2 sc t.i.w. continuously for the three months. Prior to treatment, NKa was found decreased in 11 of 13 patients as compared to that of normal individuals. Following a-IFN administration, a rise of NKa was observed in eight of the eleven patients. In those who responded, a-IFN was continued for 1 to 21 months. Alpha-IFN treatment was myelosuppressive for most of the patients, but transient increase of the number of neutrophils and platelets was observed in 3 and of the reticulocytes in one patient. Disease progression was recorded in 9/13 patients (69%) at a median time of 17.3 months. The median overall survival was 30.5 months (range 7.5 to 65+ months). No evidence of a relationship was found between the rise in Nka and the limited clinical improvement observed. Two NKa responders under continuous a-IFN treatment are in stable clinical condition for 36+ and 65+ months. The study provides only limited evidence that a-IFN may improve the clinical course of patients with MDS.

The origin of the sickle mutation in Greece; evidence from beta S globin gene cluster polymorphisms.

Study of the Hpa I polymorphism 3' to the beta-globin gene in the Greek population revealed absence of the site in 238 beta S chromosomes, in contrast to a much larger sample of chromosomes carrying the beta A gene, where this site was consistently positive. Subsequent haplotype analysis of the beta-globin gene cluster in 82 beta S chromosomes demonstrated that 79 (96%) belonged to haplotype #19, while the three exceptions (all Hpa I negative) could be explained by a delta-beta recombination event. Haplotype #19 was never encountered in a parallel study of the 83 beta A chromosomes. Comparison of the above results with similar surveys in other parts of the world and consideration of various historical events suggest that the beta S mutation was introduced into Greece over the last few centuries by the Saracen raids and/or by settlements of North African slaves brought in by the Arabs, Franks, Venetians, or Ottoman Turks, who have occupied the country over the last millennium.

Recurrent attacks of hemolytic uremic syndrome.

In 1955 Gasser and his co-workers were the first to describe the so-called hemolytic uremic syndrome (HUS); since then, the number of reports has steadily increased. Some authors consider HUS as a unique syndrome, while others suggest that HUS is both heterogenic and heterogeneous. It is generally emphasized that HUS never recurs. However, this view should be reconsidered due to the numerous reports on a recurrent form of HUS, which is beginning to be recognized as an important subset or variant of this syndrome. This report describes a case, where three similar recurrent episodes of hemolytic anemia, thrombocytopenia and uremia had occurred during the past eight years.

Defective CSA-dependent granulopoiesis in patients with chronic drug-induced neutropenia.

Colony stimulating activity (CSA) and granulocyte-macrophage progenitor cells (GM-CFC) were assayed in the bone marrow and peripheral blood of 17 patients with drug-induced chronic neutropenia. Leukocyte-derived and monocyte/macrophage-derived CSA from the neutropenic patients was found to be significantly decreased compared to normal control. However, bone marrow and peripheral blood GM-CFC were within normal limits. These data suggest that in neutropenic patients monocyte/macrophages exhibit most likely a qualitative defect in CSA production, which may account at least in part, for the impaired granulopoiesis observed in drug-induced neutropenia.

Hemoglobin Köln occurring in association with a beta zero thalassemia: hematologic and functional consequences.

Hemoglobin (Hb) Köln-beta zero thalassemia compound heterozygosity was discovered in a young Greek patient. This gave us the unique opportunity for studying the functional properties of this unstable high-oxygen affinity hemoglobin variant in red cells containing almost pure Hb Köln. The red cells of the proposita exhibit morphological alterations and hematologic indices corresponding to the presence of an unstable Hb and beta thalassemia. Globin chain synthesis confirmed the association with a beta zero thalassemia gene. Oxygen-binding curves for these cells were biphasic, indicating the presence of both heme-saturated and of approximately 20% of non-cooperative Hb Köln. The major component exhibits an increased oxygen affinity, reduced cooperativeness, and normal alkaline Bohr effect. The 35-year-old proposita is active, has not been splenectomized, and has not been transfused in several years.

Lactate dehydrogenase isoenzyme pattern in sera of patients with malignant diseases.

Total lactate dehydrogenase (LDH; EC 1.1.1.27) activity and the percentage distribution of LDH isoenzymes were determined in 127 patients with malignant diseases. A shift in the isoenzyme patterns was observed toward the M-type, with an increase in the percentage of LDH-4 and LDH-5 isoenzymes and a slight increase in total LDH activity of all patients. Serum samples from 68 of the patients contained an abnormal isoenzyme of LDH, "LDH-1 ex," that, on agarose gel electrophoresis at pH 8.6, migrated between albumin and LDH-1 isoenzyme. Chemotherapy, radiotherapy, or surgical removal of the tumor was accompanied by disappearance of this abnormal isoenzyme. The heat stability of LDH-1 ex isoenzyme appears to be similar to that of LDH-1 but greater than that of the other LDH isoenzymes. Statistical analysis of these data demonstrated a significant correlation between malignancy and the appearance of LDH-1 ex isoenzyme (P less than 0.001). In contrast, the relationship between LDH-1 ex isoenzyme and metastasis or anatomical location of the malignancy is not statistically important (P less than 0.1).