bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular analysis of the bcr rearrangement in a case of Ph‘‐negative blastic crisis of Ph’‐positive chronic myelogenous leukemia
Authors: Melani Cecilia , Canepa Letizia , Sessarego Mario , Miglino Maurizio , Ferraris Anna Maria , Gaetani Gian Franco
Published: July 2010

We describe here a patient with Ph'‐positive chronic myelogenous leukemia (CML) who developed a Ph'‐negative blastic crisis. The blast DNA was analyzed on two different occasions, at the beginning of the blastic phase and at the end, shortly before the patient's death. Although cells from both samples had no Ph' chromosome marker (not even a masked one) we could detect a rearrangement of the bcr gene in the second DNA sample, using a ‘3′‐bcr’ probe. The same probe and a ‘5′‐bcr’ probe failed to detect any rearranged band in the first DNA sample. No rearrangement was identified at the c‐myc and N‐ras loci, while a slight c‐myc amplification was evident in both DNA samples tested.
Leucopoiesis versus concentration of cytokines in diffusion chamber cultures of mouse bone marrow cells: Clues to the physiological roles of growth factors
Authors: Benestad H. B. , Løvhaug D. , Strøm‐Gundersen I.
Published: July 2010

Physiological mechanisms that regulate formation of neutrophil granulocytes, macrophages and their precursor cells were studied with the diffusion chamber (DC) technique. DC inoculated with mouse bone marrow cells were implanted intraperitoneally into host mice. When these in vivo cultures had been established and their marrow populations were expanding (2‐day cultures), the DC were transferred to different environments: new, normal mice, lethally irradiated mice, or incubation flasks with optimal concentrations of growth factors. Culture development during the following final culture period was correlated to the concentration of some select candidate growth regulators in DC. After 3 d the cellularity of DC in irradiated hosts had increased significantly more than in the normal hosts. A difference was detectable already after 1–2 d when preculturing was omitted. The increased growth appeared to take place at several stages of cell maturation and not only at the progenitor cell level. Colony stimulating factor(s) for granulocyte and macrophage progenitors, as well as cytokines stimulating the bone marrow‐derived cell line, 14 M.1, were present in DC fluid (DCF) at higher concentrations in irradiated than in normal mice throughout the final culture period. On the other hand, DCF concentrations of tumour necrosis‐like factor (that may either induce CSF secretion or directly inhibit myelopoiesis), were not significantly different in irradiated compared with normal DC hosts. The cytokines detected in the DC may at least in part stem from inflammatory cells accumulating around the chambers. This animal model should be useful in further investigation of the highly complex regulatory network governing formation of white blood cells in the intact organism.
Immunological recovery and dose evaluation in IFN‐α treatment of hairy cell leukemia: Analysis of leukocyte differentiation antigens, NK and 2‘,5’‐oligoadenylate synthetase activity
Authors: Nielsen Bendt , Hokland Marianne , Justesen Just , Hasselbalch Hans , Ellegaard Jørgen , Hokland Peter
Published: July 2010

A low‐dose interferon (IFN)‐α regimen for the treatment of hairy cell leukemia (HCL) was evaluated by following changes in leukocyte differentiation antigens (LDA), natural killer cell (NK) and 2′,5′‐oligoadenylate (2‐5A) synthetase activities. Due to hairy cells' (HC) weak expression of several antigens positive for T cells, B cells, NK cells and monocytes, the use of a double marker specific for hairy cells was needed to distinguish the different subpopulations. Analysis of LDA in peripheral blood (PB) showed a total normalization of the T cell and monocyte numbers within 90 days, the number of NK cells normalized in 90 to 180 d, whereas normalization of B cell number was seen only after 180 to 360 d of treatment. Mean pretreatment 2‐5A synthetase activity was normal or low, but upon treatment the levels rose immediately to higher than normal values and remained high throughout the study. Pretreatment NK activity was low, but normalized after between 90 to 360 d, except in 2 patients with severe splenomegaly. In vitro incubation of peripheral blood mononuclear cells (PBMNC) with IFN‐α induced activation of the NK and 2‐5A synthetase activity in untreated patients, but with treatment these effects were gradually abolished, indicating an increasing effect of IFN‐α in vivo with time. These results shows that the different PBMNC subpopulations and important immunological functions normalize with treatment. This normalization is, however, not seen until at least after 1 year of treatment, indicating that the treatment schedule should be longer. As no exhaustion to the effect of IFN was seen, as measured by the 2‐5A synthetase activity, a continuing beneficial effect of treatment is anticipated. The increasing effect of IFN‐α after the first signs of clinical effect suggests that the doses used in the present study were higher than necessary.
Haem arginate treatment for hereditary sideroblastic anaemia
Authors: Volin Liisa
Published: July 2010

It has been shown that haem arginate treatment increases blood cell counts, improves the sideroblast status of the bone marrow and normalises decreased activities of haem synthesising enzymes in some patients with acquired sideroblastic anaemia, or with other types of myelodysplastic syndromes. 4 patients with hereditary sideroblastic anaemia (HSA), belonging to two families, were therefore treated with haem arginate infusions, 3 mg/kg, on 4 consecutive days, and thereafter weekly for 10 wk. No effect was observed on the mildly anaemic haemoglobin levels or on the red cell counts. However, the initially low or low‐normal myeloid to erythroid ratio in the marrow increased in all patients. A consistent decrease in the percentage of ring sideroblasts and other abnormal sideroblasts was seen in 1 patient (Family A), and a temporary decrease of abnormal sideroblasts took place during the most intensive treatment period in 2 other patients (Family B). Two of three initially abnormal haem synthesising enzyme activities became normal in Family A, whereas no clearly consistent effects on the haem synthesising enzymes were observed in Family B. The present study shows that haem arginate infusions can normalise the activities of haem synthesising enzymes in some patients with HSA. Further studies are needed to evaluate the impact of haem infusions on the iron balance of these patients.
Laboratory control of immunocytochemistry
Authors: Forrest M. J. , Barnett D.
Published: July 2010

Monoclonal antibody technology is now used in many haematology departments for the analysis and phenotyping of haematological malignancies. Immunocytochemical analysis, in particular the alkaline phosphatase anti‐alkaline phosphatase (APAAP) technique is increasing in popularity. This paper describes the findings from the 1st year of an external quality assurance scheme for immunocytochemistry. Initially, there was a wide variation amongst the results received. An improvement was seen over the year with subsequent concordance in the results. This variation could be due to a number of variables within the technique which this report highlights.
Trends in the incidence of multiple myeloma in Denmark 1943–1982: A study of 5500 patients
Authors: Hansen Niels Ebbe , Karle Hans , Olsen Jørgen H.
Published: July 2010

The incidence of multiple myeloma in Denmark during the period 1943‐82 was examined, based on the files of the Danish National Cancer Registry. A total of 5535 patients (3023 male and 2512 female) were registered. Over the period 1943‐62 the incidence increased 2‐ to 3‐fold for both men and women, but the increase in men was steeper and was seen several years before the increase in women in all 5‐yr age groups from 50 to 75 yr of age. This pattern would be compatible with an impact of environmental factors. The increase, also percentagewise, rose with increasing age. Since 1963 the incidence has been virtually stable with a possibly decreasing trend during the latest 5‐ to 10‐yr period.
Childhood transient erythroblastopenia complicated by thrombocytopenia and neutropenia
Authors: Hanada Takashi , Koike Kazutosi , Hirano Ciaki , Takeya Tosiki , Suzuki Tosiyuki , Matsunaga Yasuko , Takita Hitoshi
Published: July 2010

We report on 4 children with transient erythroblastopenia complicated by thrombocytopenia and/or neutropenia. Bone marrow examination revealed severe erythroid hypoplasia with normal granulopoiesis and thrombopoiesis. Human parvovirus B19 infection was confirmed serologically in 2 children. An in vitro study using autologous bone marrow cells after recovery demonstrated IgG‐mediated inhibition of erythropoiesis in 4 children. Additionally, antibodies directed against platelets and neutrophils were detected. These findings suggest that the IgG‐mediated mechanism may be pathogenetic for the transient pancytopenia of these children.
Cultured human basophils with ultrastructural and ultracytochemical features of mast cells
Authors: Eguchi Mitsuoki , Suda Junto , Sugita Kenichi , Suda Toshio , Furukawa Toshiharu
Published: July 2010

To clarify whether in vitro‐cultured basophils have features of mast cells, basophils grown in semisolid and liquid culture were studied ultrastructurally and cytochemically and were compared with freshly isolated basophils and mast cells. Ultrastructurally, the cultured basophils had pleomorphic cytoplasmic granules, some of which were similar to mast cell granules. However, scroll formation, characteristic of mast cell granules, was not observed in cells grown in semisolid and liquid culture. Cytochemially, the reactivity patterns of acidic glycoconjugates in the cultured cells more closely resembled those of the freshly isolated basophils than of the mast cells. In addition, the basophils grown in liquid culture showed a more matured form and had stronger reactivity to glycoconjugates, acid phosphatase and peroxidase than did the cells grown in semisolid culture, suggesting that the liquid culture system was better for the basophil.
Clinical manifestations and laboratory findings in patients with lupus anticoagulants
Authors: Kornberg Abraham , Silber Lili , Yona Rivka , Kaufman Susana
Published: July 2010

Clinical and laboratory features were evaluated in 48 patients with lupus anticoagulants and the efficiency of three different assays in the detection of lupus anticoagulants was compared. The diagnosis of lupus anticoagulants was based on a prolonged activated partial thromboplastin test not corrected in a mixture of 1:1 with normal plasma and lack of specific inhibitors against coagulation factors. Platelet neutralization procedure was positive for lupus anticoagulants in 98% of the patients, tissue thromboplastin inhibition ratio in 79%, and kaolin clotting time index in 77%. At least one of the assays was positive in 100% of the cases. The largest minority of the patients (31%) suffered from systemic lupus erythematosus. The others had a variety of non‐immunological disorders. In the 13 patients who had been operated on, only 1 with renal failure developed hemorrhagic complications after renal biopsy due to thrombocytopathy. The incidence of recurrent spontaneous miscarriage, immune thrombocytopenia and positive direct antiglobulin test, anti‐nuclear and anti‐DNA antibodies and VDRL was significantly higher in patients with lupus anticoagulants and systemic lupus erythematosus compared to patients with lupus anticoagulants but without systemic lupus erythematosus.
Development of polycythaemia vera in a patient with myelofibrosis
Authors: Dokal I. , Pagliuca A. , Deenmamode M. , Mufti G. J. , Lewis S. M.
Published: July 2010

In March 1981, a 53‐year‐old man presented with itching and was diagnosed as having myelofibrosis. There was gradual enlargement of the spleen over the following 5 yr. His spleen had to be removed in February 1986 because of physical discomfort. 3 months post‐splenectomy he became polycythaemic. Bone marrow examination was consistent with severe myelofibrosis. It was possible to demonstrate erythropoietin‐independent BFU‐E from peripheral blood, and ferrokinetic studies showed that erythropoiesis was localised to the liver with little bone marrow activity. Thus, despite severe marrow fibrosis, liver erythropoiesis was now polycythaemic, suggesting the coexistence of myelofibrosis and polycythaemia vera.
A myelokathexis‐like variant of myelodysplasia
Authors: Rassam Saad M. B. , Roderick Paul , Al‐Hakim Issam , Hoffbrand A. Victor
Published: July 2010

A 34‐year‐old woman presented with pancytopenia, profound neutropenia and repeated infections. A bone marrow specimen revealed hypercellularity with trilineage dysplasia and bizarre granulocytic morphology identical to that of the rarely reported myelokathexis. Investigations revealed defects in platelet and neutrophil functions and markedly reduced colony‐to‐cluster ratio in bone marrow culture. She required treatment with antibiotics, surgical intervention for a gangrenous abdominal wall, and eventually underwent a successful allogeneic bone marrow transplant from her sister. This case suggests that myelokathexis is an unusual form of myelodysplasia with a relatively benign course and presenting at a young age.
The radiation response and recovery of bone marrow stroma with particular reference to long‐term bone marrow cultures
Authors: Bierkens J. G. , Hendry J. H. , Testa N. G.
Published: July 2010

There is evidence for long‐term haematopoietic dysfunction in some patients treated with radiotherapy. Although the underlying mechanisms are unclear, both stem cell and environmental defects have been implicated. In the present article we review the evidence concerning the role of stromal cells. According to the endpoints used, a wide range of radiosensitivities for the stroma have been reported. Long‐term bone marrow cultures provide a system in which both functional and regenerative aspects of the stroma can be studied. A dose of 5 Gy applied prior to the establishment of long‐term bone marrow cultures decreases both the formation of a confluent adherent stromal layer and its capacity to support haematopoiesis. In contrast, in its fully established phase, the adherent layer displays a high radioresistance due to the low proliferative stress applied to its stromal populations. A dose of 10 Gy given to a fully established adherent layer does not prevent haematopoietic engraftment and sustained haematopoiesis. At doses above 100 Gy a macrophage‐like and epithelioid cell‐type become dominant, which preserve their ability of producing growth regulatory molecules at doses as high as 500 Gy. These data suggest that the main effect on the stroma is a delayed expression of irradiation damage due to the slow rate of turnover of stromal cells. So far, there is little evidence for persistent deficiencies in the functional roles of stromal cell populations.
An investigation into the effects of bacterial lipopolysaccharide on human platelets
Authors: Whitworth N. H. , Barradas M. A. , Mikhailidis D. P. , Dandona P.
Published: July 2010

The addition of lipopolysaccharide (LPS) from Gram‐negative bacteria to whole blood induced a consistent enhancement of platelet impedance aggregation (WB‐PIA) and an increase in median platelet volume (MPV). In contrast, the addition of LPS to platelet rich plasma (PRP) resulted in inconsistent changes in turbidometric platelet aggregation (TPA) and no significant change in MPV. The LPS‐induced increase of MPV in whole blood was inhibited by verapamil, a calcium channel blocker. We conclude that: (a) LPS consistently activates platelets in whole blood but not in PRP; (b) LPS‐induced activation of platelets is probably mediated by products released by leucocytes and/or erythrocytes; (c) the increase in MPV induced by LPS is probably dependent upon calcium influx; and (4) an increase in MPV may be a useful and sensitive model for the study of platelet activation by LPS, in vitro and in vivo.
Bone marrow morphology during alpha‐interferon treatment in hairy cell leukemia
Authors: Hassan Inaam Bashir , Sundström Christer , Hagberg Hans
Published: July 2010

14 patients with HCL were started on α‐interferon (IFN) treatment. Bone marrow changes were followed in trephine biopsies every 3rd month. Differential counting was performed according to the point counting method and fiber content was evaluated. At the start of treatment all patients had 80% or more of tumor cells in the bone marrow. The reduction of granulopoiesis was more pronounced than for erythropoie‐sis. During treatment cellularity decreased in 6/13 patients already after 3 months; later, cellularity was normalized in most patients. Only 1 patient showed a complete remission. 12/14 patients showed a significant but slow reduction of tumor cells. Also, between 12 and 18 months an improvement was seen in some patients. The megakaryocytes improved rapidly and the erythropoiesis was normalized before the granulopoiesis. Only 1 patient did not show a bone marrow response. 5/14 patients showed a reduction of bone marrow fibers, first seen after 6 months of treatment. IFN was discontinued in 9/14 patients. 7 of these relapsed during the observation period (18 months).
Hodgkin's disease and age*
Authors: Specht Lena , Nissen Nis I.
Published: July 2010

506 unselected, previously untreated patients with Hodgkin's disease were treated at the Finsen Institute between 1969 and 1983. The prognostic significance of age, sex, stage, systemic symptoms, histologic subtype, number of involved nodal regions, total tumour burden (peripheral + intrathoracic nodal tumour burden, intraabdominal nodal tumour burden, and number of involved extranodal sites), pretreatment ESR, lymphocytopenia, and treatment modality were examined in multivariate analyses. The only factors of independent prognostic significance for disease‐free survival proved to be treatment modality, stage, and total tumour burden, whereas age had no prognostic significance. With regard to death from Hodgkin's disease only age and total tumour burden had independent significance. The significance of age would seem to stem from the fact that some older patients could not be given adequate treatment for relapse. The present study indicates that Hodgkin's disease in older patients is not prognostically very different from Hodgkin's disease in younger patients.
Oral cyclosporin‐A is effective treatment for untreated and also for previously immunosuppressed patients with severe bone marrow failure*
Authors: Hinterberger‐Fischer Margareta , Höcker Paul , Lechner Klaus , Seewann Heinz , Hinterberger Wolfgang
Published: July 2010

16 patients with transfusion‐dependent, life‐threatening bone marrow failure (14 with severe aplastic anaemia, 1 with systemic lupus erythematosus and 1 with pure red cell aplasia) were treated with cyclosporin‐A (Cy‐A) after either lack of response to conventional immunosuppression with antithymocyte‐globulin/high‐dose methylpred‐nisolone for 95 to 1190 days (median 186.5) (group I, 8 patients) or as a primary treatment due to ineligibility for conventional immunosuppression (group II, 8 pat.). Cyclosporin‐A was given orally to maintain trough levels of 200 to 300 ng/ml (RIA). In group I, 6 out of 8 patients responded 30 to 480 d (median 53) and are currently alive 627 to 1482 d (median 731) after initiation of Cy‐A, respectively. In 3 of the responders Cy‐A has been withdrawn, without relapse. In group II, 5 of 8 patients responded 26 to 170 d (median 63) and are currently alive 142 to 697 (median 420) d following initiation of Cy‐A, respectively. These data indicate a place for cyclosporin‐A in the management of patients with life‐threatening bone marrow failure in whom a) immunosuppressive therapy with antithymocyte‐globulin and high‐dose methylprednisolone had failed and b) who are not candidates for vigorous immunosuppression or bone marrow transplantation, for medical or other reasons.
Expression of isoferritins in peripheral blood lymphocytes: Effect of phytohaemagglutinin and iron
Authors: Pattanapanyasat Kovit
Published: July 2010

This study shows that incubation of lymphocytes in phytohaemagglutinin medium together with iron supplementation leads to an increase of ferritin synthesis concomitant with increased intracellular ferritin concentration especially of heart‐type ferritin. Increasing levels of iron do not increase heart‐type ferritin concentration further; in contrast, spleen‐type ferritin is gradually increased with increasing iron levels. The preferential increase in spleen‐type ferritin on growth in iron‐enriched medium may be explained by two distinct roles in the metabolism of these two isoferritins. Heart‐type isoferritin appears to be involved in more active iron metabolism in lymphocytes whilst the spleen‐type isoferritin may function as an intracellular depot of excess iron that is not immediately utilised for metabolic activity.
The nonspecific esterases of human mononuclear leukocytes metabolize arylamine carcinogens and steroids esters
Authors: Lund‐Pero Margaretha , Pero Ronald W. , Miller Daniel G.
Published: July 2010

The presence of non‐specific esterases in various leukocyte subfractions of whole blood is well established, but no endogenous substrates or function for these esterases have been identified. Here we report on the metabolism of N‐acetoxy‐2‐acetylami‐nofluorene (NA‐AAF) and beclomethasone‐17–21‐dipropinate (BDP) in viable human mononuclear leukocytes (HML). Conversion of NA‐AAF to DNA binding intermediates and BDP to beclomethasone‐17‐monopropionate by a common esterase was demonstrated and then further characterized by a broad spectrum of effectors including well‐established inhibitors and substrates for the nonspecific esterases. Two esters, beta estradiol‐17‐propionate and alpha naphtyl propionate, competitively inhibited this esterase activity. Together, these data identify at least one isozyme of the A‐or B‐classes of HML nonspecific esterases as being responsible for the metabolism of NA‐AAF and BDP. That HML nonspecific esterases may be functionally involved in arylamine carcinogenesis (i.e. as it may relate to immune function) and in the endogenous production of steroids from their naturally occurring esters emphasizes the importance of continuing their characterization.
Acute lymphoblastic leukaemia in adults in Sweden 1977–84: A retrospective analysis
Authors: Smedmyr B. , Simonsson B. , Sundström C.
Published: July 2010

The present study is a retrospective analysis of the outcome in 210 patients diagnosed and treated as having acute lymphoblastic leukaemia (ALL) in Sweden during 1977–84. 131 patients were morphologically rediagnosed as ALL. For the ALL‐patients, nine different remission induction regimens were used. Remission frequency was 69%, without statistical difference according to induction treatment. However, the reasons for remission failure differed among therapy groups. The number of responders was significantly higher among patients who received a remission induction therapy with an anthracycline and/or L‐asparaginase. Maintenance therapy consisted in most cases of 6‐mercaptopurine and methotrexate with reinduction courses for 2–3 years. Median survival time was 13 months and median duration of first remission (MRD) 11 months. For a subgroup of patients (n = 29) treated with the most intense remission induction regimens, including at least 4 cytostatic drugs with both an anthracyclilne and L‐asparaginase, the MRD is not yet reached, the shortest follow up time is 43 + months, and the probability of remaining in complete remssion is 66%. We conclude that aggressive cytostatic therapy, with induction regimens including both an anthracycline and L‐asparaginase, may cure a considerable number of adult ALL‐patients.
Trisomy 11 in myelodysplastic syndrome‐derived acute myeloblasts leukaemias
Authors: Avanzi Gian Carlo , Giovinazzo Bruna , Rosso Arturo , Depaoli Lorella , Bertini Marilena , Resegotti Luigi , Pegoraro Luigi
Published: July 2010

Here we report 3 cases of trisomy 11 observed in 1 patient with secondary acute myeloblastic leukaemia and in 2 patients with spontaneous acute myeloblastic leukaemia. In all 3 patients, the picture of overt acute leukaemia arose following a clinically established myelodysplastic syndrome. These findings, together with the previously reported occurrence of trisomy 11 in myelodysplastic syndrome and in acute myeloblastic leukaemia, suggest that this abnormality can be considered specifically associated with myelodysplastic syndrome and with the subsequent and related acute myeloblastic leukaemia.
Simultaneous expression of cytoplasmic IgM and IgG in plasma cells in a patient with IgG paraproteinaemia
Authors: Veer M. B. Van't , Radl J. , Waltman F. L. , Moberts M. , Bolhuis R. L. H.
Published: July 2010

A dual expression of IgM and IgG was found in the cytoplasm of nearly all plasma cells in the bone marrow from a patient with an IgG, paraprotein in the serum. These cells were morphologically and immunologically mature plasma cells. They lacked the B‐cell markers surface Ig, CD19 and HLA‐Dr, and were positive for HAN‐PC, and CD38. The cells were weakly positive for anti‐J‐chain and did not bind secretory component, indicating that the IgM was monomeric or aberrant. These findings show that class switch by deletion of DNA regions in mature plasma cells is not obligatory for the secretion of immunoglobulin classes other than IgM.
Red cell aplasia due to host type isohemagglutinins with exuberant red cell progenitor production of donor type in an ABO‐mismatched allogeneic bone marrow transplant recipient
Authors: Cockerill Kevin J. , Lyding Judith , Zander Axel R.
Published: July 2010

ABO‐mismatched bone marrow transplants have resulted in delayed red cell production in patients who have persistently elevated anti‐ABO isohemagglutinin titers. We present a patient with chronic myelogenous leukemia who received an HLA‐matched, ABO‐incompatible bone marrow transplant from his sister. Post‐transplant, he developed pure red cell aplasia with exuberant production of donor red cell precursors by in vitro BFU‐E assay. Restriction fragment length polymorphism (RFLP) analysis of bone marrow, peripheral blood and BFU‐E colonies demonstrated only donor type DNA post‐transplant. However, the patient had persistently elevated isohemagglutinin titer and Ph' chromosome‐positive metaphases on chromosome analysis, indicating the presence of persistent host lymphocytes. With onset of acute graft vs. host disease (GVHD), the isohemagglutinin titer dropped, Ph1 chromosome‐positive metaphases disappeared, and full hematopoietic recovery ensued. Longitudinal analysis of RFLP's, isohemagglutinin titers and chromosomes may be helpful in understanding the immunological interplay following allogeneic bone marrow transplantation.
Erythropoietin/haemoglobin relationship in leukaemia and ulcerative colitis
Authors: Johannsen Hartmut , Jelkmann Wolfgang , Wiedemann Günther , Otte Michael , Wagner Thomas
Published: July 2010

The erythropoietin level was measured, by bioassay in polycythaemic mice, in the serum of anaemic patients suffering from different types of leukaemia. Comparative measurements were carried out in patients with ulcerative colitis. Serum erythropoietin was less well‐correlated with the haemoglobin concentration in leukaemia than in ulcerative colitis. While serum erythropoietin did no exceed 200 mU/ml in patients with ulcerative colitis (lowest blood haemoglobin concentration 56 g/l), several of the leukaemic patients had serum erythropoietin levels above 500 mU/ml at comparable degrees of anaemia. Bone marrow biopsy showed that erythropoiesis was severely impaired in the leukaemic patients whose erythropoietin values were relatively high. These findings are in accord with the hypothesis that the plasma level of erythropoietin depends not only on the haemoglobin concentration of the blood but also on the bone marrow responsiveness to the hormone.
Vascular endothelial cell function and ultrastructure in thrombotic microangiopathy following allogeneic bone marrow transplantation
Authors: Cohen H. , Bull H. A. , Seddon A. , Enayat M. S. , Hill F. G. H. , Woolf N. , Machin S. J.
Published: July 2010

We report studies on vascular endothelial function and ultrastructure in 2 cases of fatal cyclosporin (CS)‐associated thrombotic microangiography following allogeneic bone marrow transplantation (BMT). Spontaneous vascular release of prostacyclin (PGI2) from a vein sample ex vivo was absent, and scanning electron microscopy (SEM) showed surface changes indicative of vascular endothelial damage (case 1). PGI2 release from cultured human umbilical vein endothelial cells incubated with patients' serum in vitro was normal in both cases. Plasma von Willebrand factor (vWF) antigen and ristocetin cofactor activity levels were raised in both patients, 5.06 and 7.02 (case 1) and 3.60 and 2.01 (case 2) (normal ranges 0.59–1.57 and 0.42–1.74 U/ml), respectively, but multimer patterns were normal. The SEM appearances coupled with the absent PGI2 release and raised vWF levels suggest that vascular endothelial damage is central to the pathogenic process in thrombotic microangiopathy following allogeneic BMT but the mechanisms appear to be distinct from those in the haemolytic uraemic syndrome and de novo thrombotic thrombocytopenic purpura. The precise role of CS in this process remains to be identified.
Binding patterns of monoclonal anti‐B, anti‐H and anti‐(Leb+ Y) on erythrocytes, imaged in the scanning electron microscope
Authors: Heier Hans Erik , Namork Ellen
Published: July 2010

Binding patterns of monoclonal IgM anti‐B, anti‐H and anti‐(Leb + Y) antibodies on erythrocytes were visualized in the backscatter electron imaging (BEI) mode of a scanning electron microscope by indirect immunogold labelling. The results were independent of secretor status, supporting the view that type 2 oligosaccharides predominate on erythrocytes. There were considerable cell‐to‐cell variations of amounts of the antigens, presumably because of differences of antigen development. The amount of H antigens may have been overestimated in previous studies. B and H antigens seemed linked mostly to mobile structures, probably lipid, on the convex parts of the cells and to immobile structures, probably protein, on the concave parts. Y antigens appeared bound to mobile structures also on the concave part of the cell membrane. The results therefore confirm that B oligosaccharides on erythrocytes develop from both lipid‐ and protein‐bound H, but suggest that Y develops mainly from lipid‐bound H.
Hypocholesterolemia, an unfavorable feature of prognostic value in chronic myeloid leukemia
Authors: Muller Claude P. , Wagner Ansgar U. , Maucher Christa , Steinke Berthold
Published: July 2010

In chronic myeloid leukemia (CML) low serum cholesterol is not uncommon and has been linked to the activity of the disease. Despite these observations, most studies concerned with prognostic signs in CML have not included cholesterol. In our study, cholesterol correlated positively with survival (p = 0.0012) and with the duration of chronic phase (p = 0.0059) in a univariate analysis. The multivariate Cox regression model selected cholesterol as a parameter of additive prognostic value in addition to marrow myeloblasts plus promyelocytes, sex, eosinophilia and lactate dehydrogenase.
Effect in vivo of recombinant GM‐CSF on neutropenia and survival in mice treated by high‐dose melphalan
Authors: Sagi Orit , Witz Isaac P. , Snaked Nili , Ramot Bracha , Douer Dan
Published: July 2010

High doses of melphalan cause severe neutropenia and may irreversibly damage hematopoietic stem cells. Treatment of mice with recombinant murine GM‐CSF (GM‐CSF) for 5 days immediately after 400 μg of melphalan did not prevent the severe neutropenia. However, GM‐CSF accelerated the neutrophil recovery and reduced the mortality rate during the neutropenic period compared to melphalan‐only treated mice. CFU‐GM levels measured 6 d after melphalan treatment without GM‐CSF were markedly reduced in the bone marrow while being elevated in the spleen. In comparison, GM‐CSF further reduced the total CFU‐GM population in melphalan‐treated mice including the levels in the bone marrow and in the spleen. On d 14 after melphalan, the spleen regained its active CFU‐GM production. By d 90, the number of circulating neutrophils, the number of bone marrow CFU‐GM and splenic CFU‐GM were the same in GM‐CSF‐treated and ‐untreated mice. The results suggest that GM‐CSF could be used to shorten the neutropenic period and reduce mortality caused by a high dose of melphalan. Though this effect could be at the expense of a temporary reduction in CFU‐GM population, GM‐CSF did not induce more long‐term damage to myelopoiesis than that already caused by melphalan alone.
The mechanism of heparin‐induced platelet aggregation
Authors: Chong B. H. , Ismail F.
Published: July 2010

When heparin was added to platelet‐rich plasma, mild but irreversible platelet aggregation was demonstrated. This platelet response was not accompanied by release of α‐granules and dense body constituents, nor by prostaglandin biosynthesis. It did, however, require metabolic energy and divalent cations as metabolic inhibitors (anti‐mycin A and 6‐deoxyglucose) and EDTA blocked the reaction. Bernard‐Soulier syndrome platelets, which lack glycoprotein (GP) Ib, but not Glanzmann's Thrombasthenia platelets, which lack GP IIb/IIIa, were aggregated by heparin. Monoclonal antibody (mAb) against GP IIb/IIIa, but not mAb against GP Ib, strongly inhibited the reaction. These combined results suggest the participation of GP IIb/IIIa but not GP Ib in heparin‐induced platelet aggregation. Fibrinogen was a cofactor in the reaction as gel‐filtered platelets were unreactive to heparin but addition of fibrinogen restored their reactivity. Antithrombin III and fibronectin inhibited platelet response to heparin, suggesting that these proteins may protect platelets from aggregation by heparin.
Effects of recombinant tumor necrosis factor (rHuTNFα)on human neutrophils and monocytes: In vitro, ex vivo and in vivo
Authors: Schell‐Frederick E. , Tepass T. , Lorscheidt G. , Pfreundschuh M. , Schaadt M. , Diehl V.
Published: July 2010

In in vitro experiments, tumor necrosis factor (rHuTNFα) was found to inhibit spontaneous and directed migration of normal human neutrophils and monocytes. RHuTNFα showed no chemoattractant activity. In conjunction with a Phase‐2 clinical trial, we also studied in vivo rHuTNFα effects on neutrophil and monocyte number and function. At the time of maximal plasma TNF levels (30 min), marked neutropenia and monocytopenia were observed. Isolated neutrophils were activated for superoxide production but were unable to migrate. Monocyte migration was inhibited at later times. Neutrophil migratory function recovered between 4 and 8 h but was again depressed at 24 h. The data demonstrate the complexity of the response to TNF, comprising direct and indirect effects which are concentration‐, time‐ and place‐dependent. They further suggest that the only neutrophils and monocytes available for participation in an anti‐tumor activity of TNF in vivo are those present in the tumor at the outset.
2‘‐deocycoformycin after failure of alpha‐interferon in hairy cell leukemia
Authors: Durrleman Sylvain , Grem Jean L. , Cheson Bruce D.
Published: July 2010

Alpha‐interferon (IFN) and 2‘‐deoxycoformycin (dCF) both exhibit substantial activity in the treatment of hairy cell leukemia (HCL). Anecdotal reports have suggested that patients who failed IFN could achieve durable responses with dCF, although the frequency with which this was said to have occurred was unknown. We reviewed the available data on the responsiveness of HCL to dCF after IFN therapy by analyzing cases reported in the literature and those treated under the Special Exception mechanism of the National Cancer Institute, Division of Cancer Treatment. Of 60 such cases identified there were 22 (37%) “compete responses” and 22 (37%) “partial responses” for a total response rate of 74%. Responses appeared to be durable in many cases, lasting up to 2 years at the time of reporting. dCF is an active agent in HCL both as initial therapy and for the salvage of patints who have failed IFN. The relative activity of these two agents and the optimal strategies for their use are currently under investigation in ongoing clinical trials.
Role of autologous lymph node T cells in membrane expression of Mu‐ or Gamma‐ heavy chain isotype by malignant B NHL cells
Authors: Bonnefoix Thierry , Orfeuvre Hubert , Jacob Marie‐Christine , Piccinni Marie‐Pierre , Sotto Jean‐Jacques
Published: July 2010

We investigated the possibility that T cells observed in lymph nodes involved by B‐non‐Hodgkin's lymphomas (B‐NHL) may have a direct role in the expression of Mu‐ or Gamma‐ heavy chain isotype by autologous malignant B cells. T cells were separated from lymph nodes involved by B‐NHL cells expressing either surface IgM (19 cases) or surface IgG (4 cases) and compared to peripheral blood T lymphocytes of healthy subjects (19 cases) for their ability to promote both IgG and IgM secretion in Cowan‐activated normal B lymphocytes. The mean values of IgG/IgM ratios obtained under the influence of T cells associated with malignant B cells expressing either surface IgM or surface IgG were not statistically different to that obtained with the help of control T cells (0.60 and 0.62 versus 0.47, respectively). These results do not account for the hypothesis that autologous lymph node T cells may directly affect the expression of the heavy chain isotype by malignant B‐NHL cells.
Idarubicin in combination with intermediate‐dose cytarabine in the treatment of refractory or relapsed acute leukemias*
Authors: Carella Angelo M. , Pungolino Ester , Piatti Gabriella , Gaozza Eugenia , Nati Sandro , Spriano Mauro , Giordano Domenico , D'Amico Tiziana , Damasio Eugenio
Published: July 2010

13 patients with refractory or relapsed acute lymphoblastic leukemia (ALL) and 7 patients with acute myeloid leukemia (AML) were treated with a regimen that included idarubicin 12 mg/m2 intravenously daily for 3 d plus cytarabine 2 g/m2 by infusion over 3 hours daily for 3 d. There were 10 remissions (ALL:7; AML:3) in the 15 relapsed patients and 4 (ALL:3) in the 5 patients with primary refractory disease. Severe myelosuppression was observed in all patients. Toxicity of this regimen caused nausea and vomiting, stomatitis, infections and/or liver enzymes increase. Cardiac toxicity was not observed. 2 patients died in aplasia of Gram‐negative septicemia and brain hemorrhage. In conclusion, the combination of idarubicin and intermediate‐dose cytarabine (IDARA‐C) seems to be highly effective and sufficiently well‐tolerated for the treatment of refractory and relapsed acute leukemias.
A comparison between regimens containing chemotherapy alone (busulfan and cyclophosphamide) and chemotherapy (V. RAPID) plus total body irradiation on marrow engraftment following allogeneic bone marrow transplantation
Authors: Reynolds Maura , McCann S. R.
Published: July 2010

The effect of two conditioning regimens given prior to allogeneic bone marrow transplantation (BMT) on the kinetics of engraftment were compared. 5 patients received busulfan and cyclophosphamide: 7 patients received daunorubicin, vincristine, cytosine arabinoside, methylprednisone and VM‐26 plus total body irradiation (TBI). Bone marrow progenitors (BFU‐E, CFU‐E, CFU‐GM, CFU‐F) were assayed up to 3 months post‐BMT. All progenitors were severely depressed in spite of peripheral blood recovery. There was no stromal recovery in any adult patient post‐BMT. There was no significant difference in time to engraftment, or colony forming units, or between patients conditioned with chemotherapy alone or chemotherapy plus TBI. We were unable to detect effects of graft‐verus‐host disease or cytomegalic viral infection on bone marrow progenitors or peripheral blood recovery in this study.
Low molecular weight iron from guinea pig reticulocytes isolated by Sephadex G‐25 chromatography
Authors: Weaver Janet , Pollack Simeon , Zhan Hui
Published: July 2010

As part of a continuing study of the low MW iron pool, guinea pig reticulocytes were incubated with 59Fe‐labeled transferrin, and the reticulocyte hemolysate was chromatographed on Sephadex G‐25. 59Fe, in amounts corresponding to that which was in a low MW peak eluting from an Ultrogel column and to that not precipitated by ammonium sulfate, adsorbed to the Sephadex column. The adsorbing 59Fe, on elution from the Sephadex with dilute formic acid, coeluted with phosphate and pentose. When EDTA was added to disrupt the putative iron complex, neither iron nor P adsorbed to the column, supporting the argument that they exist as a compound in the cytosol and adsorb and elute together for that reason. These observations provide additional evidence that P‐containing compounds, probably originating as nucleotides, are important components of the low MW iron pool of cells.
Treatment of multiple myeloma in old patients
Authors:   Finnish Leukaemia Group, Palva I.P , Ahrenberg P. , Ala‐Harja K. , Almqvist A. , Hänninen A. , Ilvonen M. , Isomaa B. , Jouppila J. , Järvenpää E. , Kilpi H. , Koivunen E. , Kätkä K. , Kääriäinen M. , Lahtinen R. , Laitinen A. , Mäkelä H. , Nyländen P. , Oivanen T. , Pakkala S. , Pelliniemi T‐T. , Rajamäki A. , Soininen K. , Timonen T. , Wasastjerna C. , Vilpo J.
Published: July 2010

Patients aged 70 yr or older with multiple myeloma were treated, when suitable, according to concurrent trial protocols for younger patients, with the exception that the cytostatic regimen was not allocated at random. Intermittent melphalan and prednisone (MP) was given as the primary treatment to 42 patients and 5‐drug combination MOCCA to 68 patients. The groups were comparable with each other, and the distribution of the clinical stages of the patients was similar to the younger patients in concurrent trials. An at least 50% response was achieved in 33% (SE 7.3) with MP and in 75% (SE 5.3) with MOCCA. The median survival times were 39 and 32 months, the relative age‐adjusted survival times 45 and 41 months, respectively. Advanced age as such is thus no contraindication for active treatment of myeloma, and in suitable patients the results compare well with those achieved in younger patients.
In vitro drug testing in patients with acute leukemia with incubations mimicking in vivo intracellular drug concentrations
Authors: Tidefelt Ulf , Sundman‐Engberg Britt , Rhedin Ann‐Sofie , Paul Christer
Published: July 2010

The differential staining cytotoxicity (DiSC) assay was evaluated as a predictive test for response to therapy in patients with acute non‐lymphoblastic leukemia. Incubations were designed in such a way that the intracellular concentrations of cytostatic drugs in vitro parallelled those in vivo. Leukemic cells were isolated from 53 patients with acute non‐lymphocytic leukemia. 13 of these patients died early due to supportive care failure and were not evaluable for the predictive drug testing. Of the remaining 40 patients, 25 entered a complete remission (CR) and 15 had a resistant disease (RD). According to the patients randomization to therapy the cells were incubated with anthracyclines and Ara‐C separately and in combination. After 4 days of culturing in liquid medium the in vitro cytotoxicity was determined by dye exclusion according to Weisenthal. The cytotoxic effect in vitro was significantly higher on cells from patients who achieved a CR compared to patients with RD after incubations with anthracyclines 0.2 μmol/l (p ≤ 0.005), Ara‐C 0.5 μmol/l (p ≤ 0.05) and with the combination of anthracyclines with Ara‐C (p ≤ 0.0005). The best predictive value was achieved when incubations with 0.2 μmol/l anthracyclines and 0.5 μmol/l Ara‐C were analyzed together. With these incubations cells from 20 out of 21 patients who achieved CR showed either ≤ 60% surviving cells after the anthracycline incubation or ≤ 35% surviving cells after the Ara‐C incubation. Cells from 11 out of 13 patients with RD did not fulfill either of these criteria. In vitro drug sensitivity was signiñcantly correlated to a prolonged survival (p < 0.01). We conclude that, when performed with incubations that mimic in vivo tumor cell exposure to cytostatic drugs, the DiSC assay shows a high correlation to clinical outcome for patients with acute non‐lymphocytic leukemia.
Antibody to Mol abrogates the increase in neutrophil phagocytosis and degranulation induced by granulocyte‐macrophage colony‐stimulating factor
Authors: Kletter Y. , Bleiberg I. , Golde D. W. , Fabian I.
Published: July 2010

We studied the ability of the human hemopoietic growth factors, granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) and granulocyte colony‐stimulating factor (G‐CSF) to activate polymorphonuclear neutrophils (PMN) for increased phagocytosis of opsonized Candida albicans and enhanced degranulation. Exposure of neutrophils to these two growth factors resulted in an increased number of Candida phagocytosed. Pretreatment of the neutrophils with the monoclonal antibody anti‐Mol abrogated the enhanced phagocytosis associated with GM‐CSF priming but not that of G‐CSF primed PMN. In examining the effect of these two colony‐stimulating factors (CSFs) on neutrophil degranulation we found that GM‐CSF induced enhanced release of lysozyme from cytochalasin‐treated PMN in the presence of Candida; however, G‐CSF did not. The effect of GM‐CSF on lysozyme release was abrogated by anti‐Mol antibody. These data suggest that GM‐CSF and G‐CSF prime PMN for certain enhanced functional activities by distinct mechanisms. The differential effect of the CSFs on neutrophil degranulation may relate to the more common inflammatory symptoms seen when GM‐CSF is used clinically as compared to the experience with G‐CSF.
B‐cell chronic lymphocytic leukaemia: Clonal chromosome abnormalities and prognosis in 89 cases
Authors: Geisler Christian H. , Philip Preben , Hansen Mogens Mørk
Published: July 2010

The results of cytogenetic studies are reported in 89 patients with B‐cell CLL. LPS (E.coli lipopolysaccharide), PWM (pokeweed mitogen), PHA (phytohaemagglutinin), EBV (Epstein‐Barr virus), TPA (phorbol 12‐myristate 13‐acetate), and LA (leucoagglutinin) were used as mitogens. Mitoses were obtained from 78 cases. Clonal aberrations could be demonstrated in 26 cases. Trisomy 12 was the most frequent finding (8 cases) and was sole abnormality in 4 cases. Chromosomes # 14, # 17, and # 11 were involved in structural aberrations in 5, 7, and 7 cases respectively, but a t(11;14)(q13;q32) was the only structural aberration seen more than once. The median observation time was 47 months (range 1–87). The presence of clonal abnormalities did not influence survival significantly, either when calculated from diagnosis or from cytogenetic analysis. Patients with more than one aberration, however, had a significantly shorter survival than patients with normal mitoses only (p < 0.05). The survival of 8 patients with trisomy 12 (in 4 as sole abnormality) was not different from that of patients with normal mitoses only.