Plasma histamine and serum pepsinogen I concentrations in chronic myelogenous leukaemia.

A male patient with multiple gastroduodenal ulcers and gastric hypersecretion due to hyperhistaminaemia associated with extreme basophilia occurring in chronic myelogenous leukaemia (CML) is described. In addition, plasma histamine levels and serum pepsinogen I concentrations, reflecting gastric acid secretion, were studied in 18 CML patients. As compared to controls, plasma histamine levels were clearly increased in CML patients and correlated well with the basophil count. Serum pepsinogen I concentrations were normal in 14 out of 17 cases and did not correlate with plasma histamine levels. This absence of a direct relation between plasma histamine concentrations and serum pepsinogen I levels suggests that a high concentration of circulating histamine does not inevitably lead to increased gastric acid secretion. This offers one explanation of the fact that, in spite of the frequent occurrence of basophilia and hyperhistaminaemia in CML, ulcerogenic diathesis is quite rare in this disease and complicates only cases with extreme basophilia.

Acquired pure red-cell aplasia: a consequence of increased natural killer cell activity?

A 19-year-old man with severe pure red-cell aplasia is described. An unusually high proportion of this patient's lymphocytes were large granular lymphocytes (LGL), both in the blood (40%) and in the bone marrow (50%). His blood leukocytes displayed a strongly elevated natural killer (NK) cell activity in vitro against the erythroblastic leukemia line K562. The patient's non-T blood lymphocytes inhibited in vitro erythroid colony formation (BFU-E and CFU-E) but not the granulocyte-monocyte colony growth (CFU-GM) from autologous and allogeneic bone marrow. Neither T-cell-mediated cytotoxicity nor circulating antibodies against erythroid precursors could be demonstrated. The patient's haemoglobin values returned to normal levels after three weeks of glucocorticoid treatment and have since then remained stable with continued prednisone administration. Attempts to reduce the prednisone dose to less than 10 mg/day have led to relapses. It is tempting to suggest that the patient's disease might be caused by hyperactivity of cytotoxic non-T (NK) cells specific for K562 cells and early erythroid precursors.

Erythroid blast crisis in chronic myelogenous leukemia.

Blood or bone marrow specimens from 22 patients with chronic myelogenous leukemia in blast crisis were studied for the surface expression of glycophorin-A, a marker for early erythroid differentiation. The leukemic blasts were stained with rabbit anti-glycophorin-A antiserum. The glycophorin-A molecules detected by the rabbit antiserum were identified by polyacrylamide slab gel electrophoresis of the immunoprecipitates from the membrane lysates of surface-labeled blasts. Blasts expressing surface glycophorin-A were found in 9 of the 22 patients. In 4 patients, almost all blasts were glycophorin-A positive, and in 5 patients, less than half of the blast population expressed glycophorin-A. The present study shows that when glycophorin-A is used as a marker for erythroid blasts, involvement of the erythroid lineage during blast crisis of chronic myelogenous leukemia seems to occur more frequently than previously recognized.

Chromosome 1q+ in erythroid and granulocyte-monocyte precursors in a patient with essential thrombocythemia.

A 55-year-old man with essential thrombocythemia had multiplication of bands q21 to q32 of chromosome 1 in all studied mitoses from bone marrow, from unstimulated blood, and from erythroid and granulocyte-monocyte colonies grown in vitro. The multiplication was in the form of triplication in 16 out of 20 mitoses from the marrow and in 4 of 6 mitoses from the blood; the rest showed a duplication of this region. All 20 mitoses from erythroid and granulocyte-monocyte colonies showed the abnormality in the form of duplication. These findings indicate most probably a clonal evolution, the triplication having arisen in the clone with the duplication. This may be associated with early leukemic transformation. The detection of the 1q+ aberration in two different types of hematopoietic colonies indicates the involvement of multipotent stem cells in at least this patient with essential thrombocythemia.

Haematopoietic progenitors in essential thrombocythaemia.

Colony formation by haematopoietic progenitors from the bone marrow and blood of 4 patients with essential thrombocythaemia was studied in vitro using the methyl cellulose assay. 3 patients had clearly elevated numbers of BFU-E in bone marrow. 1 patient also had markedly increased numbers of CFU-E and CFU-GM, whereas the other patients had only marginally increased or normal numbers of these progenitors in the marrow. 3 patients showed markedly increased numbers of all progenitors in peripheral blood. All 4 patients showed spontaneous erythroid colony formation by progenitors from the bone marrow and 2 had spontaneous colony formation by progenitors from the blood. We conclude that essential thrombocythaemia shows abnormal colony formation in line with other myeloproliferative syndromes.

Value of liver and spleen aspiration biopsy in malignant diseases when these organs show no signs of involvement in sonography.

To determine whether an aspiration biopsy of liver and/or spleen is likely to reveal a clinically silent malignant infiltration, fine-needle aspiration biopsies were carried out in 180 patients with a diagnosed malignancy in whom neither the liver nor the spleen gave signs of involvement in sonography. Few, if any, findings were positive in patients with cancer or Hodgkin's disease. In non-Hodgkin lymphoma, about 25% of the biopsies were positive for malignancy or aroused suspicion of malignancy. We conclude that fine-needle aspiration biopsies of the liver and spleen may be of value in the clinical follow-up of non-Hodgkin lymphoma.

Glucocorticoid receptors in hairy-cell leukemia.

Glucocorticoid receptors were measured from leukemic cells of five patients with hairy-cell leukemia as well as a cell line (JOK-1) derived from one of the patients studied and grown in continuous culture in vitro. Receptor analyses were accomplished using a whole-cell binding assay with [3H]dexamethasone as the ligand. Glucocorticoid receptor sites in the leukemic hairy cells ranged from 5,710 to 11,400 sites/cell, and the mean dissociation constant (KD) between the receptor sites and [3H]dexamethasone was 0.67 +/- 0.03 X 10(-8) M. The glucocorticoid receptor nature of the binding activity was verified by demonstration of an appropriate order of competing ability for a selected group of ligands. The cell line JOK-1 contained 9830 receptor sites/cell with a KD of 0.78 X 10(-8) M. The in vitro growth pattern of this cell line was characterized by an almost complete insensitivity to glucocorticoids. We conclude that the postulated general presence of glucocorticoid receptors in various types of normal and malignant leukocytes extends to hairy-cell leukemia, a disease often characterized by resistance to antileukemic drugs, including corticosteroids. The sole presence of the glucocorticoid receptor thus does not seem to signify steroid responsiveness.

Circulating haematopoietic progenitors in myelofibrosis.

We studied circulating erythroid and granulocyte-monocyte progenitors in 18 patients with idiopathic myelofibrosis and in healthy controls, using the methyl cellulose assay. 9 of the patients had been splenectomized prior to the study. The median number of circulating erythroid burst-forming units (BFU-E) was 8 times higher than that of the controls. 12 patients also had CFU-E (colony-forming unit, erythroid) in the blood. 10 patients had spontaneous BFU-E colony formation, and 8 patients had spontaneous CFU-E colony growth. Granulocyte-monocyte progenitors (CFU-GM) were increased 47 times compared to the controls. There were no differences in colony numbers between splenectomized and non-splenectomized patients. We conclude that in myelofibrosis, circulating erythroid and granulocyte-monocyte progenitors are usually markedly increased in number, but erythroid precursors to a lesser extent than granulocyte-monocyte precursors. Many patients, but not all, show spontaneous erythroid colony formation.

Acute erythroleukaemia with L3 morphology and the 14q+ chromosome.

L3 morphology according to the FAB classification and the 14q+ chromosome are usually ascribed to the Burkitt type of leukaemia or lymphoma with a B or pre-B cell phenotype. We report here a case of adult acute leukaemia with Burkitt morphology and the 14q+, which did not express lymphoid markers. Instead, the leukaemia was shown to be an acute erythroleukaemia. The erythrocyte marker glycophorin A was present on the surface of the leukemic blasts as shown by immunofluorescence and immunoprecipitation from membrane lysates of surface labeled cells with antiglycophorin A antiserum. Spectrin and fetal hemoglobin appeared after cultivation of the blasts in the presence of sodium butyrate. The present case shows that a short term cultivation is sometimes useful for further characterization of the commitment of acute leukaemias.

Haema synthesis during pyridoxine therapy in two families with different types of hereditary sideroblastic anaemia.

The activity of delta-aminolaevulinic acid synthase (ALA-S) as well as the concentrations of coproporphyrin and protoporphyrin in peripheral red blood cells were examined in 2 sisters and in 2 brothers with hereditary sideroblastic anaemias (HSA) of different types. The measurements were done before and during treatment by pyridoxal-5-phosphate (PLP) and/or pyridoxine chloride. Previous family studies indicated an X chromosome linked HSA in the 2 brothers, whereas the precise mode of inheritance in the 2 sisters has not been established. Previous and present studies have revealed no characteristic defect in haema synthesis in the 2 sisters and their treatment by PLP or pyridoxine produced no haematologic response although a slight stimulation of haema synthesis was observed. In contrast, the 2 brothers showed decreased activity of ALA-S and decreased protoporphyrin concentration in peripheral red blood cells. After treatment by PLP and/or pyridoxine the ALA-S activity was restored to normal. Corresponding to the stimulation of haema synthesis a partial haematological response was observed in both brothers. Stopping and restarting of pyridoxine therapy in one brother confirmed the above results. These observations indicate the presence of two genetically and biochemically different types of HSA and help us to understand the varying response to pyridoxine therapy in this rare disorder.

Splenectomy for myelofibrosis.

In 30 consecutive splenectomies for myelofibrosis (MF) with cytopenia(s) and/or massive splenomegaly the operative mortality was 6.7% (2 patients). Postoperative complications were observed in 11 (37%) patients. When surgery was undertaken within one year of the diagnosis of MF the postoperative morbidity rate was 13% (2/16), but significantly (p less than 0.01) higher at 64% (9/14) in patients operated on later. A similar significant difference was observed in the amount of intraoperative blood loss. Of the patients undergoing splenectomy for anaemia and/or thrombocytopenia, 79% gained definite benefit from the operation for 2 to 70 months (median 10 months). It is concluded that, although splenectomy probably does not prolong the life of patients with MF, it gives considerable symptomatic relief in cases with massive splenomegaly, and can improve the patient's haematological status and reduce blood transfusion requirements. To avoid the increased risks of postoperative complications surgery is best undertaken as soon as cytopenia is present.

Abnormalities of chromosome No. 17 in myeloproliferative disorders.

In routine analyses, abnormalities of chromosome No. 17 were found in the bone marrow cells of 28 patients with Ph1-positive and three patients with Ph1-negative chronic myeloid leukemia (CML), 4 patients with acute nonlymphocytic leukemia (ANLL), and 4 patients with preleukemia. With three exceptions, all patients were in the blastic (CML) or the terminal phase. In 28 patients, the aberrant chromosome No. 17 arose by clonal evolution from the karyotype found at diagnosis or before the terminal phase. The abnormalities encountered were an isochromosome for the long arm, i(17q), (26 cases), translocations involving No. 17 (12 cases), trisomy 17 (three cases), and ring 17 (one case). In 35 patients, there was an unbalanced structural aberration of at least one of the No. 17 chromosomes. In every case (35/35), detailed analysis of the structurally abnormal No. 17 revealed loss of the distal part of the short arm (or possibly most of the short arm). Gain of the long arm (or at least its proximal part) was also common, but not invariably present (26/35). It is suggested that loss of 17p is a highly nonrandom event related to blastic crisis in CML and the terminal phase in other myeloid leukemias.

The Finnish leukaemia group: levamisole in maintenance therapy of acute myeloid leukemia in adults.

The Finnish Leukaemia Group has carried out a randomized, multicenter trial to study the effect of levamisole on the remission maintained with 6-mercaptopurine and methotrexate in acute myeloid leukaemia in adults. Levamisole was given on 3 consecutive days every 2 weeks. Twenty-five patients received only chemotherapy, while 26 patients received levamisole as well. The patients receiving levamisole showed significantly better remission duration than those given only chemotherapy (P = 0.033, Mantel's summary chi 2-text). There are four long term survivors in the levamisole group versus none in the chemotherapy group. The remissions have lasted 48-75 months.

Defective neutrophil migration in monosomy-7.

The migration in vitro of neutrophils from six patients with monosomy-7 or partial deletion of the long arm of chromosome 7 was studied by two methods: the Millipore filter assay and the migration under agarose assay. Four of the patients had preleukemia, one had subacute myelomonocytic leukemia, and one polycythemia vera. In four patients, chemotaxis (migration towards a higher concentration of chemoattractant) and chemokinesis (stimulated migration without a gradient) were shown to be defective by both methods. In the remaining two patients, this defect could be demonstrated only by the Millipore filter assay or by the agarose assay. Under agarose, random locomotion (no chemoattractant present) of the patients' neutrophils was less than that of the control subjects in four patients, whereas no clear difference could be shown by the Millipore filter method. This study demonstrates that the previously described defect of neutrophil migration in monosomy-7 involves not only chemotaxis but all stimulated migration and, at least in some patients, random locomotion as well. Defective migration in two patients with an apparently terminal deletion of the long arm of one chromosome 7 indicates that the distal half of 7q carries genetic material important for neutrophil locomotion.

The 5q- chromosome in preleukaemia and acute leukaemia.

13 patients with the 5q- chromosome are described. In 6 patients the 5q- chromosome was the sole aberration. 10 patients had preleukaemia, 1 a preleukaemia-like syndrome after treatment of polycythaemia vera, a 2 acute myeloid leukaemia. The prognosis was especially poor in terms of survival in preleukaemic patients with 3 or more affected chromosomes: none of these 6 patients survived for more than 6 months. In 4 patients the haematological picture resembled 'the 5q- syndrome'. In the long arm of chromosome No 5 deletions of 3 different kinds were detected. They were named according to the size of the 5q- marker: the short type (10 patients), the intermediate type (1 patient) and the long type (2 patients). There was no clear correlation between the clinical picture and the type of deletion. While the break points cannot always be exactly defined, our data and those reviewed from the literature suggest that the loss of a segment of regions 5q2 or 5q3 is common to all or most deletions.

Chromosome changes in human chronic lymphocytic leukemia.

Karyotypes were studied in B- and T-lymphocyte cultures from 66 patients with B-cell CLL and two patients wtih T-cell CLL. Thirty-one of the B-cell cases had not been treated for their disease; 35 had received radiotherapy, corticosteroids, or cytostatic drugs. Only one of the untreated patients had a clone with an abnormal karyotype. This was present in all her mitotic cells found in cultures containing lipopolysaccharide B (LPS, a B-cell mitogen) and 10% of those in cultures with pokeweed mitogen (PWM, a T- and B-cell mitogen). The karyotype of this clone was 46,XX,t(6;7),t(7;13),t(11;14). Four of the treated patients had clones with specific chromosome changes. These were 47,XY,+12 in 10% of leukoagglutinin (LA, T-cell mitogen) and protein A (PA, T- and B-cell mitogen) cultures in one case; 47,XX,+12,del(14) in 80% of LPS cultures and in all spontaneously dividing cells in another case; 46,XY,t(6;20) in all LPS cultures in another; and 46,XX,t(1;8) in all PA cultures in another. Both structural and numerical nonclonal chromosome aberrations (9%) were found in 24% of the different cultures of cells from untreated patients, and in 15% of the cells in 20% of the different cultures in the patient who had received treatment. Both patients with T-cell CLL had receive) in all PA cultures in another. Both structural and numerical nonclonal chromosome aberrations (9%) were found in 24% of the different cultures of cells from untreated patients, and in 15% of the cells in 20% of the different cultures in the patient who had received treatment. Both patients with T-cell CLL had receive) in all PA cultures in another. Both structural and numerical nonclonal chromosome aberrations (9%) were found in 24% of the different cultures of cells from untreated patients, and in 15% of the cells in 20% of the different cultures in the patient who had received treatment. Both patients with T-cell CLL had received treatment for their disease, and had a normal karyotype in all cultures.

Haem biosynthesis in refractory sideroblastic anaemia associated with the preleukaemic syndrome.

The activities of 5 enzymes of the haem biosynthetic pathway and the protoporphyrin concentrations have been measured in peripheral red blood cells of 23 patients having a preleukaemic syndrome with refractory sideroblastic anaemia. A decreased delta-aminolaevulinic acid synthase (ALA-S) activity, an increased uroporphyrinogen I synthase activity and an increased red cell protoporphyrin concentration were consistent findings. Patients with abnormal leucocyte and/or platelet counts in the peripheral blood as well as patients with an excess of blast cells in the bone marrow had the lowest ALA-S activities. A further decrease in ALA-S activity was observed in 3 patients after leukaemic change in the disease. Patients having cytogenetic abnormalities showed no unique enzyme abnormalities. These results indicate that enzymatic disturbances of haem synthesis cannot be used as prognostic indicator of leukaemic transformation in refractory sideroblastic anaemia, but a very low ALA-S activity appears to accompany the development of a leukaemia in such patients.