bluuebunny/crossref_metadata_2025 huggingface dataset:
Melphalan/prednisone versus drug combinations for plasma cell myeloma
Authors: Bergsagel Daniel E.
Published: July 2010

Reports of 13 prospective, randomized clinical trials comparing standard treatment with melphalan and prednisone (MP) versus various drug combinations in the treatment of myeloma patients are presented. These studies reveal that patients with Durie‐Salmon Stage III disease respond significantly more frequently to MP and drug combinations than those with Stage I and II. Drug combinations may be more effective in inducing objective responses. The response rates were significantly better for the drug combinations in 3 of the 13 comparisons. There was little evidence that either form of treatment was superior in prolonging survival, for in one study the patients treated with a drug combination lived significantly longer than those treated with MP, while in another the reverse was true, and there was no difference in the survival of the two groups in the remaining 11 studies. In the Vth MRC myelomatosis trial, patients treated with a combination of adriamycin, carmustine, cyclophosphamide and melphalan are living significantly longer than those treated with melphalan alone, and this survival advantage persists after correction for the most important prognostic factor, β2 microglobulin. Attempts to increase the intensity of treatment by using syngeneic, allogeneic or autologous marrow transplantation to rescue patients following otherwise lethal chemoradiotherapeutic treatments, have not yet demonstrated conclusively that the myeloma clone can be eliminated by this form of treatment.
Induction treatment with α‐interferon in multiple myeloma: An interim report from MGCS
Authors: Mellstedt H. , Österborg A. , Björkholm M. , Björeman M. , Brenning G. , Gahrton G. , Grimfors G. , Gyllenhammar H. , Hast R. , Johansson B. , Juliusson G. , Järnmark M. , Killander A. , Kimby E. , Lerner R. , Merk K. , Paul C. , Simonsson B. , Smedmyr B. , Stalfelt A‐M , Strander H. , Svedmyr E. , Udén A‐M , Wadman B. , Ösby E.
Published: July 2010

A randomized study comparing melphalan/prednisone (M/P) therapy with MP + natural α‐IFN in untreated patients with multiple myeloma stages II and III started April 1, 1986. By March 1989, 78 patients were evaluable in the MP group and 80 in the MP/IFN group. 48% of the MP patients achieved a response and 66% in the MP/IFN group (p = 0.04). Stage II patients responded better to MP/IFN (76%) than MP alone (47%) (p = 0.02), while no statistically significant difference was noted for stage III patients. 90% of the IgA myelomas responded to MP/IFN and 52% to MP (p = 0.02). Both for IgG and BJ myelomas the response rates of MP/IFN were higher than of MP, although the differences were not statistically significant. The observation period is still short. There was no difference in total survival between the two treatment groups. However, in patients ≤ 65 years a tendency to a longer survival was seen for those receiving the IFN combination (p = 0.12).
Treatment of painful bone lesions and hypercalcemia
Authors: Ascari Edoardo , Attardo‐Parrinello Giuseppe , Merlini Giampaolo
Published: July 2010

The control of myeloma bone disease has been an important therapeutic problem. Bisphosphonates are potentially active for the control of myeloma bone resorption. Athough several studies proved the efficacy of short‐term bisphosphonate treatment in inhibiting myeloma bone destruction, data on the long‐term efficacy are scanty. We present the results of a prospective pilot study for the evaluation of long‐term parenteral administration of dichloromethylene bisphosphonate (Clodronate) in 30 patients with active myeloma bone disease. Patients were treated with a mean of 4 courses (range 2–8) of Clodronate: 300 mg/d i.v. for 7 days followed by 100 mg/d i.m. for 10 d, administered at a mean interval of 4 months.

The median follow‐up was 24 months (range 8–36). Clodronate reduced bone pain rapidly and significantly, and reduced the mean values of the biochemical indices of bone resorption to within normal limits. The occurrence of skeletal morbidity in patients treated with Clodronate was compared with that observed in the control group of myeloma patients treated with chemotherapy only: Clodronate provided a significant (p < 0.001) reduction in severe bone pain as well as in the incidence of new osteolytic lesions and pathological fractures. The results of this prospective pilot trial indicate that supportive long‐term treatment with parenteral Clodronate can contribute significantly to controlling the progression of myeloma bone disease.
Chemotherapy for resistant and relapsing multiple myeloma
Authors: Alexanian Raymond , Barlogie Bart , Ventura Gerard
Published: July 2010

This report summarizes a broad experience in the treatment of patients with multiple myeloma resistant to standard chemotherapy. The VAD regimen has induced remissions in about 50% of relapsing patients but in only about 25% of previously unresponsive patients. In patients resistant to VAD, high‐dose therapies with intravenous melphalan, a CBV combination (cyclophosphamide‐BCNU‐VP‐16) or an EDAP regimen (VP‐16 ‐platinum) produced responses in about 40% of patients. However, these treatments usually required autologous bone marrow or blood stem cell support and the median duration of control was only 6 months. With an even more intensive program using high‐dose melphalan and total body irradiation supported by autologous bone marrow, all patients who survived the early treatment period responded for a median duration of about 1 year. Results indicated a dose‐response effect of chemoradiotherapy on VAD‐resistant myeloma with the potential that such intensive regimens will prolong disease‐free survival time.
Maintenance treatment of multiple myeloma
Authors: Baccarani Michele , Fanin Renato , Fasola Gianpiero , Gallizia Cristiana
Published: July 2010

In multiple myeloma (MM), low‐cost maintenance treatment has some attractions, since maintenance of a small tumor is usually compatible with a fairly healthy state. However, the great majority of the studies of maintenance treatment have failed to show any clinical benefit. Based on simple theoretical considerations, it is shown that in MM response duration and survival are affected primarily by the residual tumor mass after primary treatment, and by the kinetics of the tumor. Continuation of maintenance treatment is likely to have a moderate effect. The main cause of that is identified in the presence or in the development of a substantial proportion of drug‐resistant cells. Preliminary data suggest that only alpha‐interferon can be useful for maintenance, and that it can act by slowing down the kinetics of the tumor.
Autologous bone marrow transplantation therapy for multiple myeloma
Authors: Anderson Kenneth C. , Barut Bruce A. , Ritz Jerome , Freedman Arnold S. , Nadler Lee M.
Published: July 2010

We have begun an autologous bone marrow transplantation (ABMT) treatment protocol for patients with myeloma who achieve a minimal disease (< 10% marrow plasma cells) status. Sites of bony disease are irradiated before BMT. Melphalan 70 mg/m2 on days 1 and 2 is followed by 1200 rads total‐body irradiation administered in fractionated doses over 3 d. Autologous marrow which has been previously treated with anti‐CALLA, B1, and PCA‐1 monoclonal antibodies is then thawed and reinfused. 4 males and 2 females with median age of 46 yr (41–56) have been treated. Granulocytes > 500/mm3 and platelets > 20 000/mm3 were noted at 21 (12–46) and 23 (12–53) d post‐transplant (PT), respectively. Acute mucositis and dermatomal Herpes zoster developed in 3 patients each; all patients are clinically well at 233 (30–807) d PT. All patients achieved pathologically normal marrows, but monoclonal plasma cells and marrow myelofibrosis were each noted in a single patient at 486 and 272 d PT, respectively. A single patient has responded to α2 interferon therapy PT; all others have received no therapy. AMBT offers an exciting new treatment for myeloma; however, relapses post‐ABMT suggest that improved ablative regimens and/or marrow purging methods may be required.
Autologous bone marrow transplantation with immunotoxin‐purged marrow for advanced multiple myeloma
Authors: Gobbi Marco , Cavo Michele , Tazzari Pier Luigi , Dinota Angelo , Tassi Cristina , Bontadini Andrea , Albertazzi Livia , Miggiano Cristina , Rizzi Simonetta , Rosti Gianantonio , Bolognesi Andrea , Stirpe Fiorenzo , Tura Sante
Published: July 2010

A system to purge the bone marrow of myeloma cells has been developed in our laboratories with the aim of treating with myeloablative radiochemotherapy patients suffering from advanced multiple myeloma. This system is based on the ex vivo incubation of the marrow with an immunotoxin composed of the 8A monoclonal antibody — that recognizes plasma cells and B‐cell precursors — and the ribosome‐inactivating protein momordin. 8 patients have so far been treated. 4 are surviving from 4 to 18 months after ABMT, whereas 4 died after 1 to 6 months, 2 from infections, 1 from relapsing disease and 1 from veno‐occlusive disease. A marked tumour reduction was observed in all evaluable patients; however, none has achieved complete disappearance of the disease. The hæmopoietic reconstitution was significantly delayed in 3 patients. These preliminary results show the feasibility of this approach in advanced MM patients with heavily infiltrated marrow. The place of ABMT in the treatment of MM remains to be determined; the selection of patients with still responding and less advanced disease would probably produce better results.
Allogeneic bone marrow transplantation in patients with multiple myeloma
Authors: Gahrton G. , Tura S. , Belanger C. , Cavo M. , Chapvis B. , Ferrant A. , Flesch M. , Gore M. , Gratwohl A. , Gravett P. J. , Harrouseau J. L. , Lindeberg A. , Ljungman P. , Löwenberg B. , Lucarelli G. , Michallet M. , Reiffers J. , Ringdén O. , Van Lint M. T. , Vernant J. P. , Sallerfors B. , Simonsson B. , Toivanen A. , Troussard X. , Verdonck L. F. , Volin L. , Zwaan F. E.
Published: July 2010

50 patients with a median age of 41 years (range 29–54) underwent allogeneic bone marrow transplantation for multiple myeloma. 35 patients were on second‐line treatment, and 15 on first‐line treatment. 24 patients were considered refractory to previous treatment. 45 patients received marrow from HLA‐matched sibling donors (3 of these from twin donors), and 5 from unrelated or related non‐sibling donors. 21 patients entered complete remission, while 15 had persistent disease following repopulation of the marrow. 14 patients were not evaluable for remission status because of early transplantation‐related death. The overall median survival from bone marrow transplantation was 27 months, with a projected long‐term survival of 34%. Patients who were 40 yr of age or older had a survival that was not different from that of patients between 29 and 40 yr of age. The median disease‐free survival of patients who entered complete remissions was 41 months. These patients tended to have a longer survival than patients with persistent disease following repopulation of the marrow. Allogeneic bone marrow transplantation appears to be a promising method for treatment of certain patients with multiple myeloma.
Marrow transplantation for malignant plasma cell disorders: Summary of the Seattle experience*
Authors: Buckner C. D. , Fefer A. , Bensinger W. I. , Storb R. , Durie B. G. , Appelbaum F. R. , Petersen F. B. , Weiden P. , Clift R. A. , Sanders J. E. , Sullivan K. M. , Witherspoon R. P. , Hill R. , Martin P. , Thomas E. D.
Published: July 2010

28 patients with plasma cell malignancies received marrow transplants from identical twins (N = 8), HLA‐identical family members (N = 15), HLA partially‐matched relatives (N = 3) or cryopreserved autologous marrow (N = 2). Treatment regimens included cyclophosphamide (CY) and total body irradiation (TBI) for 15 patients and busulphan (BU) and CY for 13 patients. 3 of 8 twins are alive, 2 without disease at 24 and 34 months, and 1 is alive and well at 116 months without evidence of disease except for at small residual monoclonal protein spike. 12 of the 18 allografted patients died of transplant‐related causes and 2 died of progressive disease. 4 of 18 allograft receipients are alive; 2 are free of disease at 16 and 15 months, 1 is alive at 6 months without disease except for persistent monoclonal Kappa protein. 1 patient is alive with residual marrow involvement and a persistent IGA lambda monoclonal protein at 7 months. 1 of the 2 autograft recipients is alive 2 months after transplant and is not yet evaluable for tumor response and the other patient died early of transplant‐related complications. Both CY+TBI and BU + CY resulted in remissions in patients with advanced plasma cell malignancies. However, the optimal treatment regimen and timing of transplantation remain to be determined.
High‐dose chemoradiotherapy and allogeneic bone marrow transplantation in multiple myeloma
Authors: Tura Sante , Cavo Michele , Gobbi Marco , Rosti Gianantonio , Bandini Giuseppe , Miggiano Cristina , Albertazzi Livia , Grimaldi Maria , Visani Giuseppe
Published: July 2010

17 patients with multiple myeloma (MM) received marrow transplants from their HLA‐matched, MLC‐negative sibling donors. 9 patients had progressive disease not responding to conventional treatments, while the other 8 patients were rated as responders. The most frequently used conditioning regimen consisted of total body irradiation and high‐dose, multi‐agent chemotherapy with cyclophosphamide plus either oral melphalan (5 cases) or BCNU (1 case) on both these drugs (7 cases). 12 patients were evaluable for response to BTM: 7 of them (6 responders and 1 with advanced refractory MM) entered complete remission, while 5 had a sustained decrease in tumor mass that ranged between 72% and 93%. 11 patients died of transplant‐related causes, 1 of them with signs of progressive disease. The remaining 6 patients are alive and 5 of them maintain a complete remission status 4 to 67 (median 36) months after BMT. It is concluded that therapeutic benefits of transplantation in MM are still offset by the high mortality related to the procedure. A more accurate selection of patients who would most benefit from BMT and performing transplant at an earlier phase of the disease are warranted before major advances can be made in the cure of these patients.
Defensins
Authors: Ganz Tomas , Selsted Michael E. , Lehrer Robert I.
Published: July 2010

Abstract: Defensins are a family of small, variably cationic proteins which are highly abundant in the granules of mammalian phagocytes. Three defensins, HNP‐1, 2, and 3, comprise 30–50% of total protein in azurophil granules of human neutrophils. Some defensins are broadly antimicrobial, antiviral and cytotoxic, while others are chemotactic, opsonic, or may modulate hormonal responses. The defensin molecule typically consists of 29–34 amino acids with a conserved pattern of disulfide linkage among its 6 cysteines. The three‐dimensional fold of defensins forms a highly amphiphilic molecule. Microbicidal and cytotoxic properties of defensins are most likely a consequence of their ability to insert into biological membranes and to generate pores. Defensins are synthesized by phagocytes or their precursors as a 94–95 amino acid charge‐neutralized preprodefensin, an arrangement which may avoid cytotoxic injury to the phagocyte. Although defensins were recognized only recently, the existence of homologs in certain invertebrates suggests that they are ancestral components of the host defense system.
Characterization of a new malignant human T‐cell line (PFI‐285) sensitive to ascorbic acid
Authors: Helgestad Jon , Pettersen Rolf , Storm‐Mathisen Ingebørg , Schjerven Leif , Ulrich Kay , Smeland Erlend B. , Egeland Torstein , Sørskaard Dag , Brøgger Anton , Hovig Torstein , Degré Miklos , Lie Sverre O.
Published: July 2010

Abstract: A new malignant human T‐cell line‐labelled PFI‐285‐has been isolated from a boy with malignant lymphoma. Morphologically, the cells had characteristics of malignant lymphoid cells. The cells presented surface antigens as early cortical lymphocytes and proliferated non‐adherently as single cells, independent of T‐cell growth factor (IL‐2), in liquid culture. The cells had undetectable levels of receptors for IL‐2, were not clonogenic in soft agar, but did form tumors in nude mice. Their establishment and continuous growth in vitro was dependent on the number of cells inoculated and on the growth medium used. Cytogenetic alteration, HTLV‐1 or reverse transcriptase activity were not detected. The production of known T‐cell derived lymphokines such as IL‐2, B‐cell growth factor(s), α‐interferon or granulocyte/macrophage colony stimulating or inhibiting factor(s) was not detected. The cells had 5–8% natural killer (NK)‐cell activity against NK‐cell sensitive target cells (K562) and were not sensitive for NK cells. A most unusual characteristic was the pronounced sensitivity of the cells to ascorbic acid. Concentrations down to 50 μmol/l killed the cells within hours.
Autoimmune cytopenias in pernicious anemia: A report of four cases and review of the literature
Authors: Rabinowitz Arthur P. , Sacks Yale , Carmel Ralph
Published: July 2010

Abstract: Pernicious anemia appears to be autoimmune in origin and is associated with immune disorders of several organ systems. We report 4 patients with pernicious anemia and immune cytopenias, an association that may sometimes pose diagnostic problems unless specifically considered. Pernicious anemia coexisted with or was closely followed by idiopathic thrombocytopenic purpura in 3 patients and by autoimmune hemolytic anemia in a 4th patient. In addition to cobalamin therapy, all patients required corticosteroids (2 also received danazol), while 1 also required splenectomy. All 4 patients were women. The 3 patients with idiopathic thrombocytopenic purpura were also blood group O and were iron‐deficient. Autoimmune cytopenias may occur in patients with treated or untreated pernicious anemia and require specific therapy.
Flow cytometric analysis of membrane CD11b, CD11c and CD14 expression in acute myeloid leukaemia: relationships with monocytic subtypes and the concept of relative antigen expression
Authors: Scott Colin Stephen , Richards Stephen J. , Master Peter S. , Kendall Jane , Limbert Howard J. , Roberts Bryon E.
Published: July 2010

Abstract: Blast cells from 26 cases of acute myeloid leukaemia (AML) were examined, by single and “two‐colour” flow cytometry, for relationships between membrane CD11b (monoclonal antibody OKM1), CD11c (KB90) and CD14 (Leu‐M3). Increased expression of all three determinants was associated with myelomonocytic leukaemias, with their relative diagnostic value in discriminating monocytic (M4 and M5) from non‐monocytic (M1, M2 and M3) subtypes being CD14 > CD11c > CD11b. However, the results also indicated, because of the heterogenous expression of CD11c in particular, and to a lesser extent CD11b, that the patterns or histograms of fluorescent staining were potentially more informative than an empirical subdivision of blasts into positive and negative sub‐populations. In addition, analysis of phenotypic correlations by simultaneous two‐colour fluorescence showed that the expression of CD11b and CD11c determinants by leukaemic myeloid blasts was highly correlated, in contrast to the expression of CD14 and CD11c which were relatively independent. Consequently, CD11c + myeloid blasts almost always co‐expressed CD11b whereas CD14 + cases of AML often comprised CD14 + CD11c + and CD14 + CD11c‐ subpopulations. It is concluded from these observations that CD11c immunophenotyping is a useful supplementary investigation, particularly in CD14‐ cases of myelomonocytic leukaemia. However, it is also apparent that the presence of membrane CD11c per se is not lineage‐specific and that the level of expression is perhaps a more discriminatory factor.
Serum erythropoietin and erythropoiesis in patients with myelodysplastic syndromes
Authors: Bowen D. T. , Jacobs A. , Cotes P. Mary , Lewis T. C.
Published: July 2010

Abstract: Ineffective erythropoiesis is an early feature of the myelodysplastic syndromes (MDS), usually accompanying an hypercellular marrow. In a previous study, concentrations of serum erythropoietin (EPO) in MDS have been shown to correlate inversely both with haemoglobin concentration and with% bone marrow erythroblasts. We have measured erythroid production using a radioisotopic technique in 20 patients with MDS. Although haemoglobin concentration shows a weak inverse relationship with serum EPO concentration there is considerable variation in EPO concentration at a given haemoglobin level. There is no correlation between serum EPO and total erythroid production, though there is a weak correlation with effective erythropoiesis. The data suggests that control mechanisms of erythropoiesis in patients with MDS are complex.
Reversal of myelofibrosis by hydroxyurea
Authors: Löfvenberg Eva , Wahlin Anders , Roos Göran , Öst Åke
Published: July 2010

Abstract: Bone marrow morphology in 39 symptomatic patients with myeloproliferative disorders (polycythaemia vera 15, essential thrombocythaemia 14, idiopathic myelofibrosis 9, myeloproliferative syndrome 1) and elevated platelet counts was studied before and after a median of 18 months of continuous treatment with hydroxyurea. We found a significant reduction of bone marrow fibrosis, believed to be mediated by suppression of thrombopoiesis by hydroxyurea.
Prognostic significance of immune function parameters in patients with chronic lymphocytic leukaemia
Authors: Apostolopoulos Apostolos , Symeonidis Argiris , Zoumbos Nicholas
Published: July 2010

Abstract: We determined immune function parameters in 41 newly diagnosed patients with chronic lymphocytic leukaemia (CLL) and correlated these findings with the clinical data and the subsequent course of the disease. The ratio of helper to suppressor T cells (CD4/CD8), the proportion of circulating natural killer (NK) cells and the NK activity were significantly low in clinical stage B and C patients. Among patients presenting with advanced disease, those who subsequently had a more severe course, characterised mainly by frequent respiratory infections, were found to have at presentation a significantly lower CD4/CD8 ratio (× ± SEM = 0.95 ± 0.09, vs 1.28 ± 0.14), a very low proportion of NK cells (4.78 ± 0.85, vs 11.75 ± 2.1%) and decreased amount of γ‐globulins (0.66 ± 0.08, vs 0.97 ± 0.09 g/dl), in comparison with patients with a much milder later course. These simple parameters of immune function seem to have prognostic value for patients with CLL.
Platelet calmodulin correlates with platelet turnover
Authors: Endoh N. , Oh H. , Itoh K. , Asai T. , Yoshida S.
Published: July 2010

Abstract: We measured the calmodulin content in platelets in 13 normal persons and in 62 patients with hematological diseases. The level of platelet calmodulin was higher in patients with idiopathic thrombocytopenic purpura (ITP), systemic lupus erythematosus, myeloproliferative disorders, acute leukemia in a recovery phase, aplastic anemia, thrombosis and hyper‐splenism as compared to the controls. Among the patients with ITP, calmodulin was lower in responders than in nonresponders and those at the initial diagnosis. We also measured the volume, life‐span and aggregation of the platelets and demonstrated a significant relationship between the calmodulin level and the platelet volume, and a negative relationship between the calmodulin level and platelet life‐span, there was no correlation between the calmodulin level and platelet aggregation. We thus conclude that platelet calmodulin is inversely correlated with platelet turnover.
Hypoxia and deposition of iron in liver and spleen of mice given iron supplement
Authors: Borch‐Iohnsen Berit , Myhre Kjell , Norheim Gunnar
Published: July 2010

Abstract: Iron‐related changes in peripheral blood and variations in liver and spleen iron concentrations during alternating periods of hypoxia and normoxia have been investigated in iron‐supplemented mice by chemical and histological methods. During hypoxia, packed cell volume increased from 40 to 70%. The iron content of the liver increased during the first hypoxic and the following normoxic period, while an increase in spleen iron started after the first hypoxic period. Transferrin saturation fell from about 60 to about 20% during hypoxia and normalized during normoxia. Hypoxia together with iron supplementation led to increased erythropoiesis and parenchymal iron deposition in liver. The reduction in transferrin saturation may be attributed to the effective uptake of iron by hepatocytes simultaneously with the erythropoiesis. The spleen seemed to participate in the production of red cells during hypoxia. The increase in spleen iron during normoxia can be explained by the role of the spleen in the catabolism of excess erythrocytes.
Comparative study of immunocytochemical staining versus Giemsa stain for detecting dysmegakaryopoiesis in myelodysplastic syndromes (MDS)
Authors: Kawaguchi Masato , Nehashi Yoshio , Aizawa Shin , Toyama Keisuke
Published: July 2010

Abstract: 23 patients with myelodysplastic syndromes (MDS) and 8 normal controls were analyzed for dysmegakaryopoiesis (DMP) in the bone marrow by alkaline phosphatase anti‐alkaline phosphatase (APAAP) technique and by conventional May‐Giemsa staining. In the immunocytochemical study, monoclonal antibody (MoAb) against glycoprotein (GP) IIb/IIIa was utilized to demonstrate megakaryocyte cells. 91% (21/23) of MDS cases were detected as having DMP by APAAP method, while only 52% (12/23) were detectable by Giemsa stain. There were difficulties in recognizing small micromegakaryocytes (micro MKs), designated as type 1 atypical MKs, by Giemsa staining. Furthermore, megakaryoblasts (MKBs) were detectable only by APAAP technique. In 8 normal controls, no type 1 and type 3 atypical MKs (round shaped multinuclear MKs) were observed either by Giemsa staining or by the APAAP method, suggesting that they are a distinctive feature of MDS. These results indicate the necessity of immunocytochemical technique for accurate recognition of DMP in MDS.
Bone marrow histopathology in primary myelofibrosis: Clinical and haematologic correlations and prognostic evaluation
Authors: Pereira Arturo , Cervantes Francisco , Brugues Rosa , Rozman Ciril
Published: July 2010

Abstract:In 51 patients with primary myelofibrosis the initial bone marrow biopsy findings were evaluated by morphometric methods, correlated with the patients' main clinical and haematologic data and analysed for prognostic significance. The high variability of the marrow features was the most striking finding of the morphologic study. The only remarkable clinico‐pathological correlation was that found between the extent of stromal proliferation in the bone marrow and the number of WBC precursors in peripheral blood. Classical bone marrow histologic patterns did not correlate with the main clinical or haematologic data nor did they influence the patients' survival. Finally, collagen fibrosis and abnormal clusters of immature myeloid precursors were the only histologic features showing an unfavourable prognostic significance at the multivariate study.
Effect of N‐methionine‐free, bacterially synthesized recombinant human granulocyte‐macrophage colony‐stimulating Factor in a primate model
Authors: Akashi K. , Taniguchi S. , Teshima T. , Shibuya T. , Okamura T. , Harada M. , Niho Y.
Published: July 2010

Abstract: We demonstrate the in vivo effects of bacterially synthesized, N‐methionine‐free recombinant human granulocyte‐macrophage colony stimulating factor (rh GM‐CSF) using a crab‐eating monkey model. Monkeys were treated with cyclophosphamide (60 mg/kg) and administered with rh GM‐CSF (30 μg/kg/d) subcutaneously (s.c.) for 7 days. Within 12 h, a transient increase of neutrophils (> 15.0 × 109/l) was observed, and complete recovery of WBC counts was obtained by d 9 (d 16 in control monkeys). Neutrophils and eosinophils were absolutely increased (>8 × 109/l) on d 10. Readministration of rh GM‐CSF (30 μg/kg/d, s.c.) for 3 d (including control monkeys) revealed absolute increases of neutrophils, eosinophils, monocytes and platelets. A two‐fold increase of granulocyte/macrophage colony‐forming units was also seen in the bone marrow, while the number of burst‐forming units‐erythroid was not affected. These data indicate that rh GM‐CSF of this type stimulates granulopoiesis and thrombopoiesis in vivo.
Evaluation of microcytosis using serum ferritin and red blood cell distribution width
Authors: van Zeben Derkjen , Bieger Robert , van Wermeskerken Robert K. A. , Castel Ad , Hermans Jo
Published: July 2010

Abstract: Out of 104 patients with microcytosis (MCV < 80 fl), 69% had an iron deficiency, 21% a chronic disease and 10%, hemoglobinopathy or thalassemia trait. The absence of bone marrow iron stores or the response to iron supplementation were used to establish the diagnosis iron deficiency. On the basis of sensitivity (90%) and specificity (100%), the serum ferritin concentration is more suitable for assessment of iron deficiency than the serum iron concentration, the total iron‐binding capacity or the percentual saturation of transferrin. The red cell distribution width (RDW) is the parameter with the highest sensitivity for iron deficiency (94%). An RDW value within the reference interval can be used to exclude iron deficiency in those cases in which the serum ferritin concentration does not accurately reflect the iron stores owing to severe tissue damage, as in inflammation or malignancy.
α Thalassaemia in two Spanish families
Authors: Villegas A. , Calero F. , Vickers M. A. , Ayyub H. , Higgs D. R.
Published: July 2010

Abstract: Two Spanish families with α thalassaemia, including 4 individuals with Hb H disease, are described. DNA mapping shows that, in addition to the common α thalassaemia determinant (‐α3.7), a different and previously unreported allele is present in each family. In one, there is a deletion of 10.5–12 kb of DNA including both α genes (‐SPAN). in the other, a deletion of more than 100 kb has removed the entire α globin gene complex (‐BR).
Platelets of patients affected with essential thrombocythemia are abnormal in plasma membrane and adenine nucleotide content
Authors: Leoncini G. , Maresca M. , Buzzi E. , Piana A. , Armani U.
Published: July 2010

Abstract: The adenine nucleotides present in distinct cellular compartments of platelets of 27 patients affected with essential thrombocythemia have been measured. In order to quantify granule‐bound nucleotides and adenylic cytoplasmic pool, platelets have been stimulated with thrombin or treated with increasing digitonin concentrations, respectively. Among patients, we have identified two groups: 12 patients (Group 1) had normal platelet level of ATP and ADP both in dense granules as well as in cytoplasmic pool. The other patients (Group 2) had granule ATP and ADP significantly lower and ATP/ADP ratio significantly higher than controls. In these patients an increase in hypoxantine level, derived from metabolic ATP degradation occurring during stimulation, was observed. In addition, in the latter patients an increased resistance of plasma membrane to digitonin was shown, suggesting that membrane fluidity should be reduced owing to a modified cholesterol/phospholipid ratio.
Intensive chemotherapy with combinations containing anthracyclines for refractory and relapsing multiple myeloma
Authors: Palva I. P. , Ahrenberg P. , Harja K. Ala , Almqvist A. , Elonen E. , Hallman H. , Hänninen A. , Ilvonen M. , Isomaa B. , Jouppila J. , Järvenpää E. , Järventie G. , Kilpi H. , Koivunen E. , Kätkä K. , Kääriäinen M. , Lahtinen R. , Laitinen A. , Lehtinen M. , Mäkelä H. , Nyländen P. , Nyman D. , Oivanen T. , Pakkala S. , Pelliniemi T‐T. , Pulli T. , Rajamäki A. , Ruutu T. , Savola J. , Soininen K. , Timonen T. , Wasastjerna C. , Vilpo J.
Published: July 2010

Abstract: 94 patients with refractory multiple myeloma were treated in a multicentre trial with combinations of cytotoxic drugs including anthracyclines. All were refractory to a 5‐drug combination containing 3 alkylating agents, vincristine and methylprednisolone (MOCCA). With a combination of epirubicin and iphosphamide a 50% response was achieved in 9% of 22 patients. The response rate after schedule VAP (vincristine, doxorubicin and prednisolone) was 8% of 13 patients and that after schedule VAD (vincristine, doxorubicin and dexamethasone) 20% of 59 patients. The previous chemotherapy had lasted for less than 12 months in 13 cases from among all these patients, and 5 of these (38%) responded. In contrast, there were only 10 responders (12%) among the 81 patients with longer previous chemotherapy.
Iron bound to low MW ligands: Interactions with mitochondria and cytosolic proteins
Authors: Zhan Hui , Gupta Raj K. , Weaver Janet , Pollack Simeon
Published: July 2010

Abstract: The iron in the low MW pool of the cell is the precursor of iron in haem and is bound primarily to ATP. This precursor‐product relationship suggested that reticulocytes might accumulate ATP‐iron if their haem synthesis were blocked. However reticulocytes, treated with succinyl‐acetone or rotenone and taking up iron from transferrin, accumulated iron in nonhaem cytosolic proteins and in mitochondria and not in the low MW pool. This was demonstrated by NMR and also by disrupting the cell with shear stress, separating the cytosol and pellet and fractionating the cytosol with ammonium sulfate. This constancy of the low MW iron pool in the face of blocked haem synthesis could not be explained by saturation of cytosolic ATP or by sluggish exchange of the low MW pool with other compartments. Rather, nonhaem cytosolic proteins and mitochondria appeared to have a higher affinity for iron and to exchange it rapidly with that in the low MW pool.
Extramedullary plasmacytomas and solitary plasma cell tumours of bone
Authors: Brinch Lorentz , Hannisdal Einar , Abrahamsen Arne Foss , Kvatøy Stein , Langholm Ruth
Published: July 2010

Abstract: We describe clinical features and treatment results in 25 patients with solitary osseous (SOP) and 18 patients with solitary extramedullary plasmacytoma (EMP). 41 patients were treated with high‐voltage radiotherapy, median 40 Gy in 20 fractions. Surgery was part of the treatment in 21 and chemotherapy in 5 patients. The median age in both groups was 56 years, with a preponderance of males. Myelomatosis developed in 10 SOP and 2 EMP patients, and this development did not correlate with the presence or absence of an M‐component at the time of diagnosis of plasmacytoma. The estimated 5‐ and 10‐y survival was 87% and 76% without a statistical difference between SOP and EMP groups. The patients in the SOP group usually died from myelomatosis while EMP patients died from other causes.
Clinical value of a direct platelet suspension immunofluorescence test in adult idiopathic thrombocytopenic purpura
Authors: Nieminen U. K.
Published: July 2010

Abstract: 109 adult patients with ITP were tested with the direct platelet suspension immunofluorescence test (PSIFT) for platelet‐associated immunoglobulins (PAIg). 88 patients (81%) had a positive direct PSIFT. The mean platelet level at the time of the test was 45 × 2*109/1 (SD = 28.8) with no difference between PSIFT‐positive and ‐negative groups. The results of direct PSIFT were of limited value in predicting patient outcome. The overall better prognosis of patients with a negative direct PSIFT compared to those with a positive result was statistically significant. The PSIFT negatives achieved complete remission more often than PSIFT positives; and they also showed a tendency for a better response to splenectomy and therapy with high‐dose i.v.Ig. Moreover, all the 21 patients refractory to therapy with corticosteroids, splenectomy or i.v.Ig, were PAIg positives.
Comparison of bone marrow histology in early chronic granulocytic leukemia and in leukemoid reaction
Authors: Schmid C. , Frisch B. , Beham A. , Jäger K. , Kettner G.
Published: July 2010

Abstract: A retrospective study was performed on bone marrow biopsies of 50 untreated patients with leukemoid reactions (LR) and 50 untreated patients with early chronic granulocytic leukemia (CGL). A comparison was made between hematopoietic and adipose tissues, bone and its cells, as well as other stromal components in these two disorders. Histologic and histomorphometric analyses revealed significant differences in trabecular structure, in localization of fat cells, in numbers of sinusoids, capillaries and various stromal elements. No significant differences between LR and CGL were detected in the quantity of erythro‐ and granulocytopoiesis and of megakaryocytes, but these were smaller in CGL than in LR. This histologic and histomorphometric evaluation demonstrates that certain histologic features may serve as valuable aids in distinguishing LR from CGL.
Serum immunoreactive erythropoietin in children with acute leukaemia at various stages of disease — and the effects of treatment
Authors: Hellebostad Marit , Marstrander Jens , Slørdahl Sofie H. , Cotes P. Mary , Refsum Harald E.
Published: July 2010

Abstract: Most children with leukaemia are anaemic at diagnosis and at various times during treatment. Serum erythropoietin (EPO) was estimated in 27 children with acute leukaemia (n = 26) or lymphoma (n = 1) at diagnosis (n = 16), in relation to treatment with high‐dose methotrexate (MTX, n = 11) or cytosine arabinoside (Ara‐C, n = 8), and during oral maintenance therapy (n = 10). At diagnosis, in children with anaemia serum EPO was increased, and was inversely related to haemoglobin (Hb). After treatment with high‐dose MTX, in some children serum EPO increased where Hb was unchanged or increased. After treatment with high‐dose Ara‐C, Hb declined, and serum EPO increased markedly in everyone. During oral maintenance therapy without significant anaemia, serum EPO was slightly increased in some children. In conclusion, children with leukaemia respond to anaemia with increased serum EPO concentration, but in relation to treatment with high‐dose MTX and Ara‐C, additional mechanisms may influence the EPO concentration.
Late effects on pulmonary function of mantle‐field irradiation, chemotherapy or combined modality therapy for Hodgkin's disease
Authors: Jensen Benny V. , Carlsen Niels L. T. , Groth Steffen , Nissen Nis I.
Published: July 2010

Abstract: The aim of the present study was to assess late pulmonary sequelae after treatment for Hodgkin's disease with various treatment modalities. Pulmonary function was studied in 142 patients per median 8 years after treatment for Hodgkin's disease with mantle‐field irradiation (54 patients), chemotherapy (26 patients) or mantle‐field irradiation followed by chemotherapy (62 patients). Mantle‐field irradiation was associated with a primary obstructive and minor restrictive lung function impairment, whereas chemotherapy and combined modality therapy were associated with a restrictive lung function impairment. The number of patients with impaired lung function and the number of patients with complaints of dyspnea, however, were almost the same in the three treatment groups. 5% of the 142 patients had a pathologically low total lung capacity, i.e. values less than 2 standard deviations below predicted values. Pathologically low values of forced vital capacity and forced expiratory volume in 1 second were seen in 33% and 27% of the patients. 33% of the smokers (n = 80) had a pathologically low diffusion capacity in contrast to 8% of the non‐smokers (n = 62). Dyspnea on exertion was present in 24% of the 142 patients and was more frequent among patients with pulmonary functional abnormalities. In conclusion, late pulmonary sequelae after treatment for Hodgkin's disease do not provide a basis for choice between otherwise equally effective treatment regimes.
Prognostic factors in idiopathic myelofibrosis: A simple scoring system with prognostic significance
Authors: Hasselbalch Hans , Jensen Bjarne Anker
Published: July 2010

Abstract: In a prognostic univariate analysis of a series of 80 patients with idiopathic myelofibrosis the Hb‐concentration, the platelet count and osteomyelosclerosis emerged as factors with prognostic significance. A Hb‐concentration < 10 g/dl was associated with a significantly shorter survival than a Hb‐concentration ≥ 10 g/dl. A platelet count < 100 × 109/1 also implied a significantly shorter survival. Patients with osteomyelosclerosis on X‐ray of the skeleton had a significantly better prognosis as compared to those without osteomyelosclerosis. In a multivariate regression analysis the Hb‐concentration consistently emerged as an important prognostic parameter, whereas the platelet count was only of prognostic significance within the first 6 months from diagnosis and the presence of osteomyelosclerosis emerged as a favourable parameter at 3 and 5 years. Based upon the above parameters and spleen size, a prognostic scoring system was designed which categorized the patients into three prognostic groups with highly different survival times (low risk group = 69 months; intermediate risk group = 33 months; high risk group = 4 months).
Allo‐activated CD4+ and CD8+ lymphocyte subsets: New ultrastructural findings based on computer‐assisted image analysis
Authors: Balercia G. , Sbarbati A. , Franceschini F. , Bravo‐Cuellar A. , Osculati A. , Accordini C. , Orbach‐Arbouys S.
Published: July 2010

Abstract: Primary allo‐stimulation induces substantial and differentiated modifications in the development of cytoplasmic organelles of peripheral T‐lymphocyte subsets. The present computer‐assisted image analysis provides evidence that the CD4 + subset undergoes significant increase in organelle density after stimulation, while the CD8 + subset exhibits a post‐stimulation organelle development proportional to the cell size. Each immunological subset contains two distinct patterns of cytoplasmic organization, here defined as type I (containing a few cytoplasmic organelles) and type II (with well‐developed synthesis and storage organelles). On the basis of these findings cytologic parameters could be ascribed to a heterogeneous proliferation of functionally distinct T‐cell clones in CD4 + and CD8 + subsets.
Correlation between neopterin, interferon‐gamma and haemoglobin in patients with haematological disorders
Authors: Denz Hubert , Fuchs Dietmar , Huber Heinz , Nachbaur David , Reibnegger Gilbert , Thaler Josef , Werner Ernst R. , Wachter Helmut
Published: July 2010

Abstract: In this study, we further investigated a possible link between activation of cell‐mediated immunity and anaemia in patients with haematological neoplasias. We compared serum concentrations of interferon‐gamma and neopterin with haemoglobin levels. Significantly increased interferon‐gamma and neopterin concentrations indicated persistent activation of cell‐mediated immunity. Neopterin levels correlated significantly to interferon‐gamma concentrations and inversely to haemoglobin levels. The data indicate an association between activated macrophages and the development of anaemia in patients with haematological neoplasias.
Expression of cell‐surface transferrin receptor following in vitro stimulation of peripheral blood lymphocytes in patients with β‐thalassaemia and iron‐deficiency anaemia
Authors: Pattanapanyasat Kovit
Published: July 2010

Abstract: The ferritin concentration in peripheral blood lymphocyte extracts was measured in 10 normal subjects, 7 patients with homozygous β‐thalassaemia, and 5 patients with iron‐deficiency anaemia. The mean intracellular ferritin content was found increased in β‐thalassaemia and reduced in iron‐deficient patients. Incubation of mononuclear cells in phytohaemagglutinin medium led to an increase of DNA synthesis concomitant with an increased number of lymphocytes bearing transferrin receptor and interleukin‐2 receptor as measured by immunofluorescent technique. Although there was an immunological impairment of lymphocytes in patients with either iron depletion or iron loading compared to normal subjects, their ability to express transferrin receptor and interleukin‐2 receptor on their cell surface was normal.
The deoxyuridine suppression test in peripheral lymphocytes
Authors: Remacha A. , Barceló M. J. , Pastor M. , Ubeda J. , Espadaler M. , Gimferrer E.
Published: July 2010

Abstract: The effects of different deoxyuridine (dU) concentrations on lymphocytes stimulated with phytohemagglutinin (PHA) were studied for use in a lymphocyte dU suppression test (L‐dUST). High concentrations of dU were necessary to overcome the unspecific spontaneous pattern of folate deficiency, dU suppression tests with cells of bone marrow (BM‐dUST) and with lymphocytes were carried out in 15 patients with vitamin B‐12 deficiency, in 12 with folate deficiency, and in 10 with other pathological conditions. L‐dUST was also carried out in 15 healthy reference controls. The BM‐dUST was able to distinguish patients with vitamin B‐12 or folate acid deficiencies from those without, while the L‐dUST was unable to do so in most cases. L‐dUST does not, therefore, appear to be a reliable method for the diagnosis of megaloblastic changes.
Haematological response to supplements of riboflavin and ascorbic acid in Nigerian young adults
Authors: Ajayi Olufunmike Alalade , Okike Onuorah C. , Yusuf ‘Yinka
Published: July 2010

Abstract: The effect of supplementing a regular diet with riboflavin or a combination of riboflavin and ascorbic acid on haematological indices was studied in 27 young Nigerian adults. Vitamin supplementation produced a significant increase (p < 0.001) in haemoglobin concentration, haematocrit level and erythrocyte count. Both males and females responded similarly to the supplementation. The effect of riboflavin was similar to the combined effect of riboflavin and ascorbic acid. A significant association suggestive of enhanced erythropoiesis existed between Hb concentration and erythrocyte count in vitamin‐supplemented subjects (r = 0.9722, p < 0.002). The withdrawal of vitamin(s) supplements significantly diminished Hb concentration, haematocrit level and erythrocyte count to values similar to placebo. The data further showed that, even in malarial infection, Hb concentration, Hct level and erythrocyte count were maintained if high vitamin status was established through supplementation.
Aggressive polychemotherapy for acute myelofibrosis
Authors: Hertenstein B. , Kurrle E. , Frickhofen N. , Heil G. , Heimpel H.
Published: July 2010

Abstract: Acute myelofibrosis is a rare and still ill‐defined disease. Based on morphological observation, immunophenotyping and ultrastructural analysis, we support the assumption that acute myelofibrosis is a malignant disorder mainly of the megakaryocyte lineage and is closely related to acute megakaryocytic/blastic leukaemia. Consequently, the 11 patients reported here were treated with aggressive polychemotherapy with combinations including daunorubicin and cytosine arabinoside and 6‐thioguanin or VP16–213. 4 complete remissions, 2 partial remissions and 1 minor response were observed. Duration of aplasia was not significantly prolonged. These findings indicate that the use of aggressive polychemotherapy is feasible in acute myelofibrosis and results in a significant number of remissions.