bluuebunny/crossref_metadata_2025 huggingface dataset:
Mitoxantrone, etoposide and ara‐C vs doxorubicin‐DNA, ara‐C, thioguanine, vincristine and prednisolone in the treatment of patients with acute myelocytic leukaemia. A randomized comparison
Authors: Björkholm M. , Liliemark J. , Gahrton G. , Grimfors G. , Gruber A. , Hast R. , Juliusson G. , Jämmark M. , Killander A. , Kimby E. , Lerner R. , Ljungman P. , Lönnqvist B. , Palmblad J. , Paul C. , Petterson C. , Simonsson B. , Stalfelt A‐M. , Stenke L. , Sundström C. , Tidefelt U. , Udén A‐M. , Öberg G. , Öst Å. ,   (Leukemia Group of Middle Sweden;LGMS)
Published: July 2010

Abstract: Complex‐binding of anthracyclines to DNA may increase their therapeutic efficacy. In a previous randomized trial patients with acute myelocytic leukaemia (AML) receiving combination chemotherapy including a DNA‐bound doxorubicin preparation had a longer duration of first complete remission (CR) and survival than patients receiving free doxorubicin. In a parallel phase I/II study a combination of mitoxantrone, etoposide and ara‐C (MEA) was found to have a high antileukaemic activity. In this randomized study of AML patients (15–60 years) induction treatment with MEA was compared to a combination of doxorubicin/DNA conjugate ara‐C, thioguanine, vincristine and prednisolone (POCAL‐DNA). The study was closed after an interim analysis of 86 patients. Thirty‐five/42 (83%) and 20/44 (45%) patients entered CR in the MEA and POCAL‐DNA groups, respectively (p < 0.001). With rescue therapy the corresponding figures were 88 and 64% (p < 0.02). Median survival was 27.8 and 13.1 months for MEA and POCAL‐DNA patients, respectively (p < 0.03). In conclusion, the MEA regimen has a very high antileukaemic activity in good accordance with our previous experience. Since we could not reproduce our earlier clinical results using DNA‐bound anthracyclines, the source and preparation of DNA seem to be of major importance.
Influence of cytokines (IL‐1α, IL‐3, IL‐11, GM‐CSF) on megakaryocyte‐fibroblast interactions in normal human bone marrow
Authors: Schmitz Beate , Thiele Juergen , Witte Oliver , Kaufmann Regina , Wickenhauser Claudia , Fischer Robert
Published: July 2010

Abstract: The evolution of myelofibrosis accompanying chronic myeloproliferative disorders (CMPDs) is often linked with megakaryopoiesis. However, it is not known whether or to what extent megakaryocytes of normal human bone marrow are capable of stimulating fibroblast growth. For this reason, an in vitro study was performed to elucidate possible cytokine‐dependent interactions between megakaryocytes and fibroblasts derived from healthy volunteers. Fibroblast growth was significantly promoted by the presence of megakaryocytes and modulated by additional application of various cytokines. While recombinant human (rh) interleukin (IL)‐1α had no obvious effect on fibroblast proliferation, a slight increase was detected on adding granulocyte‐macrophage colony stimulating factor (rhGM‐CSF). Application of rhIL‐3 caused a significant increase in the number of fibroblasts. In contrast, administration of rhIL‐11 suppressed the megakaryocyte‐dependent growth‐promoting effect and co‐stimulation with rhIL‐3 led to a significant decrease of fibroblast number in comparison to rhIL‐3‐stimulated co‐cultures. Inhibition of cell‐cell contact in unstimulated, as well as in rhIL‐3‐stimulated co‐cultures led to a conspicuous impairment of fibroblast growth. A similar effect was observed when neutralizing antibodies directed against platelet‐derived growth factor (PDGF) and transforming growth factor (TGF)β1 were added to rhIL‐3‐stimulated cultures. Our findings are in keeping with the assumption that interactions between megakaryocytes and fibroblasts involve in cytokine‐mediated functional network regulated by factors such as spatial relationship, cytokine stimulation, and low concentrations of mediators, particularly PDGF and TGFβ. In this complex system rhIL‐3 seems to play a crucial role in the promotion of these various interrelationships.
Evidence for involvement of activated CD8+/HLA‐DR+cells in the pathogenesis of neutropenia in patients with B‐cell chronic lymphocytic leukaemia
Authors: Katrinakis George , Kyriakou Despina , Alexandrakis Michael , Sakellariou Dimitra , Foudoulakis Andreas , Eliopoulos George D.
Published: July 2010

Abstract: B‐cell chronic lymphocytic leukaemia (B‐CLL) is often associated with peripheral blood cytopenias resulting, in most cases, from bone marrow infiltration, hypersplenism, or circulating autoantibodies. The present study was undertaken to investigate the possible involvement of a cell‐mediated suppression of granulopoiesis in these patients. We studied two groups of patients, 8 neutropenic and 26 non‐neutropenic, defined by the arbitrarily taken cutoff count of 2000 neutrophils/μl. We found that neutropenic patients had higher numbers of peripheral blood CD3 +, CD8 +and CD57+cells, and higher numbers of activated CD8 +/HLA‐DR +cells than the non‐neutropenic ones. A negative correlation between CD8 +cells and circulating neutrophils, and a suggested negative correlation between CD8 +/HLA‐DR+cells and circulating neutrophils were noted in the patients studied. Furthermore, we investigated the capacity of immunomagnetically isolated CD8 +cells to inhibit in vitro colony formation by normal granulocyte/macrophage colony‐forming units (CFU‐GM) and we found that inhibition was more pronounced when CD8 +cells, added in the culture, were derived from neutropenic than from non‐neutropenic patients. The degree of colony inhibition correlated with the number of circulating neutrophils and the numbers of CD8+and CD8 +/HLA‐DR +cells in the patients studied. Since tumour necrosis factor‐α (TNF‐α) has been reported to be involved in myelosuppression, we also investigated the capacity of isolated CD8+cells to release this cytokine into the culture supernatant fluids, and we found that comparable amounts of TNF‐α were produced after stimulation in both neutropenic and non‐neutropenic patients. Elevated serum TNF‐α concentrations were noted only in a number of neutropenic and non‐neutropenic patients. All these data taken together provide strong evidence that a T‐cell subpopulation of activated CD8 +/HLA‐DR+cells may be involved in the pathogenesis of neutropenia, at least in a subset of B‐CLL patients, suppressing myelopoiesis by a TNF‐α‐unrelated mechanism. Efforts to isolate this cell subpopulation by flow cytometry for further analysis and a better understanding of its effect on myelopoiesis in patients with B‐CLL are in progress in our laboratory.
Immune‐mediated complications in patients with myelodysplastic syndromes – clinical and cytogenetic features
Authors: Billström Rolf , Johansson Heléne , Johansson Bertil , Mitelman Felix
Published: July 2010

Abstract: It has been recognized in recent years that some patients with myelodysplastic syndromes (MDS) develop immune‐mediated complications (IMC), but little is known about the correlations to MDS‐specific disease features. In a retrospective study of 82 MDS patients, we identified 10 (12%) with IMC (group A) and compared them to the remaining 72 cases (group B). Group A consisted of 5 patients with biopsy‐verified skin vasculitis and 1 case each with temporal arteritis/polymyalgia rheumatica, necrotising panniculitis, Hashimoto's thyroiditis, autoimmune thrombocytopenia, and Sweet's syndrome. Survival times, sex ratio and distribution of MDS subtypes were similar in the two groups. The patients in group A were younger than those in group B (median 66 vs. 76 years, p<0.01). Four patients (40%) in group A had a history of previous genotoxic therapy for malignant disorders. The bone marrow karyotype was evaluated in 62 patients. Clonal chromosomal abnormalities were found more frequently in Group A than in group B (8/9 vs. 26/53, p = 0.03), and complex karyotypes, i.e., three or more aberrations, were also observed to be more common in group A (3/9 vs. 8/53). The results indicate that IMC preferentially develop in patients with secondary MDS, in younger MDS cases, and in patients with cytogenetic abnormalities.
Significance of cytokines and CD68‐positive microparticles in immune thrombocytopenic purpura
Authors: Nomura Shosaku , Yanabu Mutsumasa , Kido Hirofumi , Lan Xie Gui , Ichiyoshi Hiroshi , Katsura Kaoruko , Miyake Tetsuya , Miyazaki Yasuhiko , Kagawa Hideo , Fukuhara Shirou
Published: July 2010

Abstract: We investigated the significance of cytokines (soluble interleukin‐2 receptor, granulocyte‐macrophage colony‐stimulating factor, interleukin‐6, and interferon‐gamma) and CD68‐positive microparticles in immune thrombocytopenic purpura. Cytokines were measured by enzyme‐linked immunosorbent assay and microparticles were detected by flow cytometry. CD68 expression by histiocytic U937 cells incubated with lipopolysaccharide or cytokines was also assessed in a control study. The level of CD68‐positive microparticles was significantly higher in the patients with thrombocytopenia than in normal controls (p<0.01). The soluble interleukin‐2 receptor level was also significantly higher in patients than in controls (p<0.01), but the other cytokines did not show a significant difference. However, patients with severe thrombocytopenia (platelet count >20000/μl) had significantly higher levels of granulocyte‐macrophage colony‐stimulating factor and interleukin‐6 than the controls (p<0.05). When opsonized platelets were incubated with activated U937 cells, lipopolysaccharide and granulocyte‐macrophage colony‐stimulating factor caused an increase of CD68‐positive microparticles in the supernatant. These results suggest that granulocyte‐macrophage colony‐stimulating factor is released by activated T cells in immune thrombocytopenic purpura and activates monocyte/macrophage phagocytosis, resulting in an increase of circulating CD68‐positive microparticles and enhanced platelet destruction.
Cell surface expression of lysosome‐associated membrane protein‐2 (lamp2) and CD63 as markers ofin vivoplatelet activation in malignancy
Authors: Kannan K. , Divers S. G. , Lurie A. A. , Chervenak R. , Fukuda M. , Holcombe R. F.
Published: July 2010

Abstract:Platelets may become activatedin vivoin a number of prethrombotic conditions including cancer. In the present study, cell surface expression of lysosome‐associated membrane protein‐2 (lamp2) and CD63 (lamp3) were examined by flow cytometry in 15 healthy volunteers and 5 patients with metastatic cancer to determine their utility as markers ofin vivoplatelet activation. Unstimulated platelets from controls had low levels of lamp2 expression, in contrast to cancer patients, who had significantly elevated levels (3.79 ± 1.48%vs33.9 ± 5.6%). Upon stimulation with collagen, a greater than two‐fold increase in the number of platelets expressing detectable levels of lamp2 was seen only among controls and not in cancer patients. Stimulation with collagen also resulted in a nearly two‐fold increase in the proportion of platelets expressing CD63 in the control group, and a less than 1.5‐fold increase in CD63 was seen in the patient group. The results suggest that cell surface lamp2 and CD63, like cell surface expression of GMP‐140, may be good indicators ofin vivoplatelet activation and may be potentially useful in identifying patients with prethrombotic disorders.
Effects of anti‐platelet glycoprotein Ib and /or IIb/IIIa autoantibodies on the size of megakaryocytes in patients with immune thrombocytopenia
Authors: Hasegawa Y. , Nagasawa T. , Kamoshita M. , Komeno T. , Itoh T. , Ninomiya H. , Abe T.
Published: July 2010

Abstract: To determine whether anti‐platelet autoantibodies react with megakaryocytes, as well as with platelets, in immune thrombocytopenia (ITP), 38 ITP patients were studied. They were classified into four groups; anti‐platelet glycoprotein lb‐positive (group A, n> = 5), anti‐platelet glycoprotein II/b/IIIa‐positive (group B, n = 2), positive to both antibodies (group C, n = 3), and negative to both antibodies (group D, n = 28). The number and size of megakaryocytes in each group were compared. The number of megakaryocytes in groups A, B, C, and D was 12.8 ± 8.9, 75.2, 29.1, and 17.0 ± 21.7/mm2, respectively. The mean cytoplasmic area of megakaryocytes in groups A, B, C, and D was 1001 ± 26.3, 1621, 1109, and 1311 ± 235.6/μm2, respectively. This finding indicated that, in the presence of anti‐platelet glycoprotein Ib, megakaryocytes were not increased in number and were small in size, whereas, in the presence of anti‐platelet glycoprotein Ilb/IIIa, megakaryocytes were increased in number and in cytoplasmic area. Our study suggested that anti‐platelet glycoprotein Ib may impair platelet production by megakaryocytes in ITP.
Treatment of chronic lymphocytic leukemia in early and stable phase of the disease: Long‐term results of a randomized trial
Authors: Brugiatelli M. , Jaksic B. , Planinc‐Peraica A. , Kusec R. , Ostojic S. , Callea V. , Lacopino P. , Morabito F. , Stelitano C. , Lutz D.
Published: July 2010

Abstract: In 1982 the IGCI CLL cooperative group decided to investigate the usefulness of treating, at diagnosis B‐cell chronic lymphocytic leukemia (CLL) in early and stable phase of the disease. From January 1982 to December 1986, 148 patients were randomized either to receive immediate treatment with chlorambucil (CLB) or to defer therapy to the time of progression. The early and stable phase of the disease was defined by a total tumor mass (TTM) score < 9, the absence of anemia or thrombocytopenia and a doubling time > 12 months. The main end‐point of the study was survival. At the last evaluation in April 1993, after a median follow‐up of 75 months, no significant difference was found in overall survival between early vs. deferred treatment patients from every cause of death as well as from death due to CLL‐related causes only. The same results were obtained when the patients in more favorable stages, such as Binet stage A and TTM < 4.5, were considered. Interestingly, the incidence of epithelial cancer was similar in the two groups. Early treatment was associated with a significantly better response and a lower progression rate. From this long‐term experience, it can be concluded that immediate chemotherapy with CLB is not beneficial for CLL patients in early and stable phase of the disease in terms of survival.
Mixed haematopoietic colony formation via immature blast cell clusters on foetal mesenchymal cell layers distinguishes stem cells from peripheral blood, cord blood, bone marrow and blood stem cells mobilized by granulocyte‐macrophage colony‐stimulating factor
Authors: Harms B. , Burdach S. , Goebel U. , Schneider E. M.
Published: July 2010

Abstract: Multilineage colony formation was evaluated from healthy donors' bone marrow (BM), peripheral blood (PB) and cord blood (CB) and compared with blood stem cell (BSC) harvests of sarcoma patients mobilized with granulocyte‐macrophage colony‐stimulating factor (GM‐CSF). The test was a modified CFU‐blast assay performed with and without an irradiated foetal mesenchymal cell layer (HFFF). These non‐transformed mesenchymal cells served as a good source of haematopoietically active stroma cells in that cytokine expression patterns (interleukin (IL)‐6, granulocyte (G)‐CSF, GM‐CSF) and adhesion molecules on HFFF cells were qualitatively identical to BM‐derived fibroblasts, but the expression density of adhesion receptors was significantly higher. This HFFF layer stimulated blood stem cells of GM‐CSF‐treated patients significantly more than a cocktail of exogenous growth factors with IL‐1, IL‐6, and stem cell factor (SCF). The reverse was true for multilineage colonies from healthy donors' PB, BM, and CB. According to these results, stem cells of GM‐CSF‐treated patients are functionally distinct due to their dependence on stroma‐derived factors and/or matrix‐adhesion interactions and can be reproducibly evaluated on these mesenchymal cells.
α‐Thalassaemia and globin gene rearrangements in French Polynesia
Authors: Philippon G. , Martinson J. J. , Rugless M. J. , Moulia‐Pelat J. P. , Plichart R. , Roux J.‐F. , Martin P. M. V. , Clegg J. B.
Published: July 2010

Abstract: The prevalence of α‐thalassaemia and various globin gene rearrangements was determined in 1992 individuals living on 11 islands in French Polynesia. The gene frequencies for α+ ‐thalassaemia (almost exclusively the ‐α3.7III deletion form) range from 5.3% to 19.2%. Haematological indices on 177 heterozygotes and 27 homozygotes for the ‐α3.7 III variant showed considerable overlap with indices of normal individuals; although there was a broad correlation of average indices with α‐globin genotype, individual values were a poor indication of genotype. A non‐deletion form of α+ ‐thalassaemia (ααTh), triplicated α genes (ααα) and single zeta gene (‐ζ) chromosomes were present at low frequencies (< 1%), whereas triplicated γ gene (γγγ) and triplicated ζ (ζζζ) arrangements were more common (1.1–16.3%). α0‐thalassaemia, probably introduced from Southeast Asia in the early part of this century, was observed in a number of individuals of Chinese and Chinese/Polynesian ancestry. Because of the high frequency of α+ ‐Thalassaemia on some islands, it therefore seems likely that haemoglobin H disease (resulting from the interaction between α0 and α+ ‐thalassaemia) must occur in parts of French Polynesia.
Expression of c‐myc and c‐ras oncogenes in the neoplastic and non‐neoplastic cells of Hodgkin's disease
Authors: Benharroch D. , Yermiahu T. , Geffen D. B. , Prinsloo I. , Gopas J. , Segal S. , Aboud M.
Published: July 2010

Abstract: The oncogenes c‐myc and c‐ras are known to elicit a cooperative tumorigenicity. In this study we investigated their role in the pathogenesis of Hodgkin's disease. The expression of these oncogenes was determined in Hodgkin's disease patients by avidin‐biotin peroxidase complex immunohistochemical staining and was compared to their expression in patients with non‐Hodgkin's lymphomas and inflammatory reactive lymph nodes. Of 29 examined patients with different histological types of Hodgkin's disease, 21 (72.4%) showed an elevated expression of c‐myc and 28 (96.5%) of c‐ras. Although this expression was marked especially in the neoplastic Reed‐Sternberg cells, it was also noted in the numerous reactive cells present in the involved lymph nodes. By contrast, a much lower frequency of increased expression of these oncogenes was recorded in 19 patients with different grades of non‐Hodgkin's lymphoma and in 29 patients with inflammatory reactive lymph nodes. The elevated expression of c‐myc and c‐ras in the neoplastic Reed‐Sternberg cells may reflect an oncogenic event that directly activates these genes. However, their increased expression in the surrounding non‐neoplastic cells probably results from signal transduction induced by certain growth‐promoting factors possibly released by the Reed‐Sternberg cells and that act paracrinally to stimulate the proliferation of the neighboring cells. Furthermore, the continuous c‐ras elevation may impair the normal cell cycle control and thereby promote mutagenesis and overt malignancy.
Interferon‐α plus low‐dose cytosine arabinoside in advanced phase chronic myelogenous leukaemia patients
Authors: Ferrajoli A. , Liberati A. M. , Caricchi P. , Donti E. , Morra E. , Lazzarino M. , Betti A. R. , Bernasconi P. , Saglio G.
Published: July 2010

Abstract: Twenty‐nine late chronic and accelerated phase chronic myelogenous leukaemia (CML) patients were entered in a pilot study designed to test the therapeutic efficacy of treatment with interferon‐α (IFN‐α) and low‐dose cytosine arabinoside (ARA‐C). IFN‐α was administered at a dose of 2–10 × 106 IU/day and ARA‐C at 15 mg/m2/day for 14 days each month. The treatment was well tolerated by 73% of the patients. Side effects were mainly asthenia, anorexia, anaemia and piastrinopenia. Haematological and cytogenetic responses were evaluated in the 19 patients who received more than 6 cycles. Four complete haematological response, 7 partial haematological response, 6 minor haematological response, 2 stable disease were obtained in this patient group. Two complete cytogenetic responses and 2 minor cytogenetic responses were detected in these patients. Suppression of secondary Ph' positive clones which appeared during the previous IFN‐α treatment was documented in 3 accelerated phase patients after ARA‐C was added to their IFN‐α treatment. It would therefore seem that late chronic and accelerated phase CML patients benefit from combined IFN‐α/ARA‐C treatment and achieve haematological and cytogenetic responses not obtained during previous treatment without being exposed to undue toxicity. However, we cannot judge whether it offers any advantage in terms of survival.
Constitutive and selective expression of basic fibroblast growth factor in human leukaemia cell lines
Authors: Gu Xue Fan , Bikfalvi Andréas , Chen Yuan Zhong , Caen Jacques P. , Han Zhong Chao
Published: July 2010

Abstract: We have previously shown that basic fibroblast growth factor (bFGF) stimulates megakaryocytopoiesis and granulopoiesis in vitro and that normal haematopoietic cells and several leukaemic cell lines express FGF receptors. In this paper, we demonstrate by reverse transcriptase‐mediated polymerase chain reaction (RT‐PCR) that bFGF mRNA is expressed in two leukaemia cell lines with megakaryocyte features (Meg‐01 and K562), in two lymphocytic cell lines (Hut 78 and CA) and in normal human peripheral blood mononuclear cells. In addition, the conditioned media of Meg‐01, but not Dami, contained a potent fibroblast‐stimulating activity which could be neutralized by bFGF antibodies. Furthermore, bFGF antibody significantly inhibited the autocrine growth of Meg‐01 cells in vitro. However, we could not detect cell‐associated 18 kDa bFGF or HMW bFGF by immunofluorescence, immunoprecipitation or Western blotting. These data indicate that bFGF is expressed by certain haematopoietic cells and support further a role of this FGF prototype in haematopoiesis.
Presenting features, natural history, and prognostic factors in localized non‐Hodgkin's lymphomas: analysis of 117 cases from a single institution
Authors: Esteve J. , López‐Guillermo A. , Martínez‐Francés A. , Bosch F. , Terol M.‐J. , Campo E. , Montserrat E. , Rozman C.
Published: July 2010

Abstract: Clinical features and prognostic factors were analyzed in a series of 117 patients with localized non‐Hodgkin's lymphoma (stage I‐II). Median age of the patients was 53 years and 52% were men; 22% had a lymphoma of low‐grade histology and one‐third presented with extranodal involvement. Eighty percent of the patients achieved a complete response (CR); stage of disease and histology were revealed as the most important factors for response. When analysis was restricted to intermediate/high‐grade cases, stage showed a predictive value for response. With a median follow‐up of 4.5 years, median overall survival was 12.0 years, with 73% and 62.5% of patients being alive at 5 and 10 years, respectively. Main initial parameters significantly related to a shorter survival were intermediate/high‐grade histology, stage II, poor performance status, bulky disease, high serum LDH levels, increased ESR, and advanced International Index. In the multivariate analysis, stage, histology and performance status (PS) were statistically significant. Among intermediate/high‐grade lymphoma patients, stage and PS provided prognostic value for survival. Twenty‐six patients relapsed after CR; median survival after relapse was 2.7 years. Stage (IvsII) was the only predictive variable for relapse in both the whole series and the intermediate/high‐grade subset.
Ifosfamide, mitoxantrone and etoposide (VIM) as salvage therapy of low toxicity in non‐Hodgkin's lymphoma
Authors: Hopfinger G. , Heinz R. , Koller E. , Schneider B. , Pittermann E.
Published: July 2010

Abstract:  Patients with non‐Hodgkin's lymphoma (NHL) who fail to respond to first‐line treatment or relapse after having shown complete or partial remission have a poor prognosis, especially in high‐grade NHL. Several salvage regimens show considerable toxicity and a poor long‐term outcome. In this retrospective study we analyzed data of 55 patients (34 men and 21 women) with a median age of 66 years (range: 18–89). The combination chemotherapy (VIM) consisted of VP‐16 (etoposide) 65 mg/m2, ifosfamide 650 mg/m2 and mitoxantrone 3 mg/m2 and was administered on 3 consecutive days along with mesna as uroprotection. Patients were treated for refractory disease or relapse and did not qualify for high‐dose chemotherapy and ABMT. Stages according to the An Arbor classification were: stage I/16, II/4, III/8 and IV/37 patients. Thirty‐three patients suffered from high‐grade and 22 from low‐grade NHL. Toxicity (WHO recommendations) was very mild. High‐grade NHL showed a better response rate (18/33, 46%) than low‐grade NHL (7/22, 36%). Overall response was 41% (12 CR and 11 PR) with a median duration of 36 months (range: 6–57 months). The combination therapy investigated exhibits mild toxicity even in extensively pretreated or elderly patients. The overall response rate of 41% might be improved by increased dosage and growth factor support.
The effect of mast cell growth factor on peripheral blood granulocyte‐macrophage colony‐forming cells in methylcellulose in myeloproliferative disorders
Authors: Siitonen T. , Zheng A. , Savolainen E.‐R. , Koistinen P.
Published: July 2010

Abstract:  Clonogenic cell culture assay was used to evaluate the effect of mast cell growth factor (MGF) on peripheral blood granulocyte‐macrophage (GM) progenitors in 26 patients with myeloproliferative disorders (MPDs). MGF alone had a statistically significant stimulatory effect on GM colony formation, as also did interleukin‐3 (IL‐3) and GM colony‐stimulating factor (GM‐CSF), although the progenitors could form colonies spontaneously as well. When MGF was combined with either IL‐3 or GM‐CSF the effect was additive and was as great as that achieved with a mixture of IL‐3, GM‐CSF, G‐CSF and IL‐6. The highest colony‐forming capacity of all was seen when MGF was added to the above mixture. Within the subgroups of MPDs, the stimulatory effect of MGF was significant in polycythemia vera (PV), essential thrombocythosis (ET) and chronic myelogenous leukemia (CML). MGF was the most potent single factor in PV, while GM‐CSF was most effective in idiopathic myelofibrosis and both IL‐3 and GM‐CSF in CML. The fact that the ability of MGF to induce colony growth varied between the subgroups of MPDs may mean that the target progenitors in these diseases are biologically different. In conclusion, MGF, either alone or with others, was a potent growth factor for GM progenitors in MPDs.
Treatment of 34 patients with myelodysplastic syndromes with 13‐CIS retinoic acid
Authors: Bourantas K. L. , Tsiara S. , Christou L.
Published: July 2010

Abstract:  Thirty‐four patients with myelodysplastic syndromes, 23 men and 11 women, aged between 47 and 80 years, with all types of myelodysplastic syndromes were treated with 13‐cis‐retinoic acid. The dose of retinoic acid ranged between 10 and 60 mg/m2/daily and was administered in combination with vitamin E to diminish side effects. The duration of treatment was 3 months to 5 years. Partial remission was achieved in 4 patients, 1 with RA type, 2 with RAEB and 1 with CMML. Survival ranged from 1 to 5 years. Patients who received retinoic acid developed mild side effects. In conclusion, the administration of 13‐cis‐retinoic acid improves the hematological picture in a small number of MDS patients (11.7%).
Virus‐associated haemophagocytic syndrome in previously healthy adults
Authors: Shirono Kenji , Tsuda Hiroyuki
Published: July 2010

Abstract:  The clinical characteristics of 15 adult patients with virus‐associated haemophagocytic syndrome (VAHS) were studied. The patients were 3 males and 12 females with a mean age of 39.5 years (range 20 to 67 years). Seven patients (mean age 48.6 years) were immunosuppressed by drugs or as a result of having malignant or autoimmune disease. Eight patients (mean age 31.6 years) had no underlying diseases. The prognosis of the patients with immunosuppression was poor, as previously reported, and 3 of them died. In younger adult patients with this syndrome who had no underlying immunosuppressive diseases, the prognosis was good even without therapy. The sera from the patients in both groups contained extremely high levels of macrophage colony‐stimulating factor (M‐CSF) and slightly elevated levels of tumour necrosis factor‐α (TNF‐α). These findings suggested that VAHS, can occur in presumably healthy adults and that VAHS can be a more benign condition than previously believed. M‐CSF and TNF‐α may play an important role in the development of the syndrome in both groups.
HIV‐related non‐Hodgkin's lymphoma among European AIDS patients
Authors: Pedersen C. , Barton S. E. , Chiesi A. , Skinhøj P. , Katlama C. , Johnson A. , van Lunzen J. , Hirschel B. , Maayan S. , Lundgren J. D. ,   AIDS in Europe Study Group
Published: July 2010

Abstract:  The epidemiology of HIV associated non‐Hodgkin's lymphoma (NHL) was investigated in 6550 European patients with AIDS. NHL was diagnosed in 3.5% of all patients at the time of the AIDS diagnosis. Although the probability of being diagnosed with NHL at AIDS diagnosis was significantly higher among intravenous drug users than among homosexual men, and was associated with increasing age, the observed incidences of NHL were more strikingly similar than any differences.

The rate of developing NHL after a previous AIDS diagnosis was 2.4 per 100 patient years of follow‐up, and remained constant during a 5‐year follow‐up period. While primary brain lymphomas comprised only 9% of NHL diagnosed at the time of AIDS, they comprised 38% of NHL diagnosed after AIDS (p<0.001).

The prognosis for patients with NHL at AIDS diagnosis was poor with a median survival of 5 months. A diagnosis of primary brain lymphoma was uniformly associated with a poor outcome.

It is concluded that the probability of developing NHL in late stage HIV infection is lower than previously anticipated from the results of small studies on patients receiving long‐term anti‐retroviral therapy.
Blunted erythropoietin response to anaemia in tuberculosis
Authors: Ebrahim O. , Folb P. I. , Robson S. C. , Jacobs P.
Published: July 2010

Abstract:  The precise cause of the anaemia that is commonly associated with severe pulmonary tuberculosis (PTB) has not been elucidated. The role of erythropoietin (Epo), the central hormone regulating red cell formation, still awaits clarification. We therefore determined serum Epo levels in patients with PTB; group 1, haemoglobin less than 110 g/L, group 2, haemoglobin greater than 110 g/L; group 3, controls, consisted of matched individuals with uncomplicated iron deficiency; group 4, healthy volunteers. Peripheral blood monocytes were obtained from patients with PTB and the controls, cultured, and the supernatant fluid (SNF) harvested. Tumour necrosis factor alpha (TNFα) levels were determined in the SNF, which were then added in various dilutions to a hepatocellular carcinoma cell line (HepG2) capable of regulated EPO synthesis in vitro. The influence of this cytokine was defined by the addition of specific neutralising anti‐TNFα antibodies in this assay system. Patients in group 1 had significantly lower Epo levels (54 ± 11 mU/mL) compared with those in group 3 (142 ± 41 mU/mL) (p<0.01). Monocyte supernatants from patients in the anaemic PTB group had markedly elevated TNFα levels and significantly suppressed Epo output by HepG2 cells in vitro (p<0.01). This inhibition was consistently abrogated by anti‐TNFα antibodies. Serum Epo levels were inappropriately low in untreated PTB patients when compared with corresponding haemoglobin levels in iron deficient controls. This blunted response could be ascribed to release of TNFα or other cytokines by activated monocytes.
Persistent growth impairment of bone marrow stroma after antilymphocyte globulin treatment for severe aplastic anaemia and its association with relapse
Authors: Nissen C. , Wodnar‐Filipowicz A. , Krieger M. Slanicka , Gratwohl A. , Tichelli A. , Speck B.
Published: July 2010

Abstract:  Bone marrow from 65 patients with aplastic anaemia (AA) was tested for stroma growth in short term cultures (2 weeks) and for colony formation by haemopoietic precursor cells during the course of their disease. In 18 untreated patients, mean stroma growth was 30% of normal and colony formation was virtually absent. After treatment with immunosuppression (IS), as estimated from 90 examinations in 54 patients, stroma growth was approximately 50% and colony growth approximately 10% of normal. Growth impairment of stroma and haemopoietic precursors persisted for 10 and more years after IS. Results of 2‐week stroma cultures were compared with results of long term bone marrow cultures in 10 AA patients and 4 controls. At 2 weeks, growth of aplastic marrow was delayed compared to normal, but this difference became less evident with prolonged incubation time. In vitro growth abnormalities were compared with the clinical evolution after IS. The development of late haematological complications (paroxysmal nocturnal haemoglobinuria (PNH)) and myelodysplastic syndrome (MDS), did not correlate with the degree of stroma growth impairment. However, relapse of aplasia was associated with poor stroma growth: 8/29 patients with stroma confluence of ≤30% during haematological remission versus 1/25 with stroma confluence of >30% relapsed. We conclude that (i) the haematopoietic microenvironment is frequently coinvolved in the disease process of AA, (ii) a defect is detected in short term rather than in long term stroma cultures and, (iii) relapse is more frequent in patients with poor stroma growth.
FMP regimen (fludarabine, mitoxantrone, prednisone) as therapy in recurrent low‐grade non‐Hodgkin's lymphoma
Authors: Zinzani P. L. , Bendandi M. , Tura S.
Published: July 2010

Abstract:  Fludarabine (FLU) is a new antimetabolite chemotherapeutic agent with promising therapeutic activity in the lymphoproliferative disorders and in particular in low‐grade non‐Hodgkin's lymphoma (LG‐NHL). In order to evaluate FLU in combination with other antincoplastic agents, we used a three‐drug combination of FLU, mitoxantrone and prednisone (FMP) to treat 18 patients with recurrent LG‐NHL. The FMP regimen was as follows: FLU, 25 mg/m2 i.v. on days 1 to 3; mitoxantrone, 10 mg/m2 i.v. on day 1; prednisone 40 mg i.v. on days 1 to 5. Of the 18 patients, 4 (22%) achieved complete response (CR), 9 (50%) partial response, and the remaining 5 showed no benefit from the treatment. The 4 CR patients are still in remission after 4, 6, 6, and 8 months, respectively. The median duration of overall survival of all patients was 9 months. The major toxic effects observed were neutropenia (50%) and infections and/or febrile episodes (17%); no fatalities due to drug side effects occurred. These results confirm the efficacy of the fludarabine‐mitoxantrone combination‐containing regimen in inducting a good remission rate with moderate side effects in recurrent LG‐NHL.
Methicillin‐resistant staphylococcus aureus: colonization and development of infection in patients with haematological disorders
Authors: Hagiwara S. , Miwa A. , Yoshida M. , Imagawa S. , Komatu N. , Muroi K. , Sasaki R. , Hatake K. , Sakamoto S. , Miura S.
Published: July 2010

A retrospective study of 53 patients with haematological disorders whose bacterial cultures were positive for methicillin‐resistant Staphylococcus aureus (MRSA), was performed to analyse the risk factors for MRSA infection, and the prognostic factors. Sixteen patients showed colonization by MRSA but never developed infection(C), 16 showed colonization and subsequent infection(C‐I), while 21 had MRSA infection at the time of first culture (I). Poor performance status, thrombocytopenia, increased serum urea nitrogen and decreased serum cholinesterase were more prominent in (I) than (C) + (C‐I). The risk factors associated with the development of infection from colonization were age and serum cholinesterase. In addition, lower respiratory tract infection as a type of infection, non‐remission status of the haematological malignancy and an inappropriate antibiotic therapy were associated with a poor prognosis for MRSA infection.
Evidence for a lymphotropic nature of circulating plasmacytoid monocytes: findings from a case of CD56+ chronic myelomonocytic leukemia
Authors: Horny H‐P. , Kaiserling E. , Handgretinger R. , Ruck P. , Frank D. , Weber R. , Jaschonek K‐G. , Waller H‐D.
Published: July 2010

Abstract: Because the cells previously designated plasmacytoid T cells share major immunophenotypic features with cells of the mononuclear‐phagocyte system, they have been re‐named and are now known as plasmacytoid monocytes (PM). We describe a unique case of chronic myelomonocytic leukemia with circulating PM. The patient, a 48‐year‐old man, presented initially with refractory anemia. Four years later his general condition deteriorated, accompanied by an increase in leukocytes to 200 000/μl blood. The bone marrow histology was interpreted as compatible with a diagnosis of chronic myelomonocytic leukemia. Two months before he died, the patient developed generalized lymphadenopathy clinically simulating malignant lymphoma. Histologic examination of an axillary lymph node revealed diffuse infiltration by PM. The PM in the lymph node and some circulating cells closely resembling PM expressed L‐selectin, a finding that could be interpreted as a morphologic correlate of their marked lymphotropism. The detection of large numbers of CD56/CD33 double‐positive circulating blast cells by FACS analysis strongly supported the diagnosis of a leukemia of myelogenous origin. The patient died of tumor cachexia. Autopsy revealed widespread leukemic infiltrates (always containing clusters of PM) in bone marrow, spleen, liver, lymph nodes, and mucosa‐associated lymphoid tissue of the oropharynx. The final diagnosis was one of chronic myelomonocytic leukemia with marked lymphotropism and partial differentiation towards PM. We consider that the rare instances of a hematologic tumor with differentiation towards PM should be classified amongst the myelogenous leukemias.
Hematologic effects of stem cell factor (SCF) and leukemia inhibitory factor (LIF) in vivo: LIF‐induced thrombocytosis in SCF‐primed mice
Authors: Ulich Thomas R. , del Castillo Juan , Shin Sung S. , Yin Songmei , Duryea Diane , Tarpley John , Samal Babru
Published: July 2010

Abstract: Stem cell factor (SCF) administered as daily bolus injections in dose‐response experiments in mice causes a progressive and dramatic dose‐dependent panleukocytosis characterized by neutrophilia, eosinophilia, monocytosis, and lymphocytosis. SCF causes circulating platelet numbers to be dose‐dependently increased after 2 weeks of daily injections. Leukemia inhibitory factor (LIF) administered as daily bolus injections in mice causes a peripheral leukopenia that is largely due to peripheral lymphopenia. LIF causes thrombocytosis peaking after approximately 1 w. Coinjection of SCF and LIF for 1 to 2 wk in mice does not cause a much greater thrombocytosis than the maximum thrombocytosis achievable with SCF or LIF alone. On the other hand, daily injection of SCF for 5 days followed by daily injection of LIF for 5 to 6 d in mice causes a very substantial increase in platelets that was lineage‐specific in terms of not being accompanied by a generalized leukocytosis. In contrast, only a very modest thrombocytosis was noted in SCF‐primed LIF‐treated rats. LIF causes a large increase in the cytoplasmic volume of splenic megakaryocytes in mice, but not in rats. In conclusion, SCF‐induced priming followed by LIF‐induced maturation of megakaryocytes causes a substantial selective increase in the numbers of circulating platelets in mice.
Monitoring of endotoxin, interleukin‐6 and C‐reactive protein serum concentrations in neutropenic patients with fever
Authors: Engervall Per , Granström Marta , Andersson Birger , Björkholm Magnus
Published: July 2010

Abstract: Serum endotoxin, interleukin‐6 (IL‐6) and C‐reactive protein (CRP) were serially determined in 26 patients with hematological malignancies and chemotherapy‐induced neutropenia who developed fever. Endotoxin in serum was detected in 69% of the patients, with the highest values being recorded in patients with gram‐negative (Gr‐) bacteremia. High levels of IL‐6 were found after start of fever, and in 6/9 patients with Gr‐ bacteremia levels exceeded 200 ng/l in samples drawn within the first 72 hours. However, only in 2/17 patients with gram‐positive bacteremias and blood culture‐negative fever episodes did IL‐6 exceed this concentration (p<0.05). High CRP values (exceeding 100 mg/l) did not discriminate between Gr‐ and non‐Gr‐ episodes (7/9 versus 10/17, respectively). In patients with fever at day 3–5 (n = 15), IL‐6 values > 100 ng/l were associated with fever continuing for more than 7 days after start of the episode; contrarily, CRP values did not indicate the persistence of fever. Determination of IL‐6 may be a better test than CRP in monitoring the acute response to infection in the neutropenic patient. A combination of high endotoxin and IL‐6 values may indicate a Gr‐ bacteremia. This could have therapeutic implications before results of blood cultures are obtained.
Refractory anemia with excess of blasts: A multivariate analysis of prognostic factors in 91 patients and a simplified scoring system for predicting survival
Authors: Guerci Agnès‐Paule , Feldmann Luc , Humbert Jean‐Claude , Guerci Olièro
Published: July 2010

Abstract: Prognosis in myelodysplastic syndromes is extremely variable. The prognostic value of the FAB classification has been demonstrated in many studies. However, within the same FAB subtype, some patients may experience prolonged survival, whereas others die in a few weeks. This prognostic heterogeneity makes the therapy decision difficult. In an attempt to identify significant prognostic factors for survival in refractory anemia with excess of blasts (RAEB), clinical and hematological characteristics were analyzed in 91 patients. Multivariate regression analysis showed that bone marrow total blast cells percentages, sex and hemoglobin level were the characteristics significantly associated with survival. A scoring index based upon these three characteristics may be proposed and had a great prognostic value (p < 0.00001). It allows us to separate patients into three groups with low, intermediate and high score with a median survival of 239, 133 and 45 days for each group respectively. This scoring index may be useful in the design of therapy and analysis of future clinical trials. However, its predictive value needs to be confirmed in other series.
The frequently low cobalamin levels in dementia usually signify treatable metabolic, neurologic and electrophysiologic abnormalities
Authors: Carmel Ralph , Gott Peggy S. , Waters Cheryl H. , Cairo Kathy , Green Ralph , Bondareff William , DeGiorgio Christopher M. , Cummings Jeffrey L. , Jacobsen Donald W. , Buckwalter Galen , Henderson Victor W.
Published: July 2010

Abstract: Cobalamin levels are frequently low in patients with dementia, but it is unclear if they represent definable deficiency and what the mechanisms are. Therefore, patients being evaluated for dementia who had low cobalamin levels but no obvious evidence of deficiency were studied hematologically, neurologically and with metabolic tests and were re‐evaluated after cobalamin treatment. Abnormalities suggestive of or diagnostic for deficiency were documented in most of the 16 demented and nondemented patients. Metabolic results: 50% of patients tested had abnormal deoxyuridine suppression and 44% had increased serum methylmalonic acid and/or homocysteine levels; these test results correlated with each other. Neurologic results: 73% of patients had clinical abnormalities, primarily mild neuropathies, not attributable to other causes, 75% had electroencephalographic abnormalities, 77% had abnormal visual evoked potentials and 33% had abnormal somatosensory potentials. Metabolic and neurologic dysfunction were present together or absent together in all but 2 cases. Cobalamin therapy improved 50–100% of the various types of abnormalities, although it did not improve cognitive function in the 13 demented patients. Food‐cobalamin malabsorption was found in 60% of the patients. Despite the absence of megaloblastic anemia and rarity of traditional malabsorption of free cobalamin, low cobalamin levels in demented patients frequently represent mild cobalamin deficiency and are often associated with food‐cobalamin malabsorption. Perhaps most importantly, this is accompanied not only by metabolic changes but by evidence of mild neurologic dysfunction. Their frequent reversibility by cobalamin confirms that these defects indeed arise from cobalamin deficiency. Although the long‐standing dementia does not improve, treating such patients with cobalamin has other concrete benefits.
Separate clones in concomitant multiple myeloma and a second B‐cell neoplasm demonstrated by molecular and immunophenotypic analysis
Authors: Novak Patricia M. , Mattson Joan C. , Crisan Domnita , Chen Jenn , Poulik M. Dave , Decker David
Published: July 2010

Abstract: The occurrence of multiple myeloma (MM) and a second B‐cell neoplasm in the same patient is a rare event. We present 2 such patients, and provide evidence to support the presence of separate clones in these coexisting neoplasms. In the first case, MM became evident 14 months after the diagnosis of chronic lymphocytic leukemia (CLL). In past reports, most occurrences of this association, when investigated, have been regarded to be biclonal disease processes; however, with few exceptions, most were documented by immunologic studies alone. To establish the clonality in our case of CLL with MM, we examined both immunophenotypic data obtained by standard two‐color flow cytometric analysis, and patterns of immunoglobulin gene rearrangement, using standard Southern analysis and hybridization with 32P‐labelled JH and JK probes. This provided evidence for the presence in this patient of two separate monoclonal populations of B cells, manifested as light chain restrictions and gene rearrangements which differed in blood (CLL) and bone marrow (MM) samples. In the second case, MM presented simultaneously with bone marrow lymphocytosis and abnormal peripheral lymphocytes. Clonality studies on blood were not done. Bone marrow B‐cell gene rearrangement studies, however, revealed the presence of three bands in the JK blot of significantly different intensities, suggestive of two monoclonal populations. A monoclonal population of small cells with surface B markers and surface IgM was demonstrated by flow cytometry, while a second population of larger cells with intracytoplasmic IgG matching the patient's serum monoclonal protein was detected by immunofluorescence microscopy. The results in these 2 cases expand previous findings of the rare association of MM with a second B‐cell neoplasm, and demonstrate the usefulness of molecular diagnostic investigation.
Stem‐cell factor in aplastic anemia: in vitro expression in bone marrow stroma and fibroblast cultures
Authors: Krieger M. Slanicka , Nissen C. , Wodnar‐Filipowicz A.
Published: July 2010

Abstract: In vitro expression of stem‐cell factor (SCF) by bone marrow (BM) cells of 30 patients with aplastic anemia (AA) has been analyzed at the mRNA and protein levels. While no deficiencies were found in SCF mRNA expression, low levels of soluble SCF protein were measured in poorly growing AA stroma cultures. The SCF protein concentration in the supernatant and the confluence of AA stroma growth were found to correlate (R = 0.70). Defective proliferation was observed in the majority (20/30) of AA stroma cultures and was paralleled by poor growth of homogeneous cultures of fibroblasts from the same marrow sample. AA stroma growth was enhanced by addition of exogenous SCF in combination with interleukin‐11 (IL‐11), leukemia inhibitory factor (LIF), and basic fibroblast growth factor (bFGF). Our results demonstrate that deficient growth of stroma cells results in decreased production of SCF. Therefore, SCF and other stroma‐derived cytokines may be of therapeutic value in AA patients with documented defects within the BM microenvironment.