bluuebunny/crossref_metadata_2025 huggingface dataset:
The proportion of reticulated platelets is higher in bone marrow than in peripheral blood in haematological patients
Authors: Stohlawetz Petra , Schulenburg Axel , Stiegler Gabriele , Panzer Simon , Höcker Paul , Kalhs Peter , Schwerzinger Use , Müllauer Leo , Simonitsch Ingrid , Geissler Klaus , Jilma Bernd
Published: July 2010

Abstract: Since the detection that platelets originate from megakaryocytes (MK), the site of megakaryocyte fragmentation has been disputed. Some authors have even postulated that platelets are solely produced in the lungs. Thus, we have directly measured platelet generation in the bone marrow (BM) by comparing the relative number of young RNA‐containing, so‐called reticulated platelets (%RP) in the BM and in the peripheral blood (PB). Two separate prospective, cross sectional trials have been conducted in patients routinely undergoing BM biopsies for diagnostic purposes. In the first part of the study 30 patients with stem cell or bone marrow transplantation were examined. The second part of the study was performed in 62 haematological patients visiting the outpatient's clinic. Median %RP were higher in BM than in PB (p < 0.001). In the second part of the study the difference averaged 133% (interquartile range: 30–383%). There was a moderate correlation between %RP in BM and in PB (r = 0.67; p < 0.001). The absolute number of RP in PB correlated weakly with the number of megakaryocytes (0.42; p = 0.001), which was due to a correlation between the platelet counts and the megakaryocyte counts (r = 0.55; p < 0.001 in biopsies). Two patients with autoimmune antibodies against GPIIb/IIIa exhibited 10% and 16% RP in PB, and had 29% and 59% RP in BM, respectively. It is concluded that the relative number of RP is significantly higher in BM than in blood. This supports the notion that platelets are at least in part released from MK in the bone marrow, particularly in patients suffering from immune thrombocytopenia.
Serum thrombopoietin levels in thrombocytopenic and non‐thrombocytopenic patients with human immunodeficiency virus (HIV‐1) infection
Authors: Español I. , Muñiz‐Diaz E. , Margall N. , Rabella N. , Sambeat M.‐A. , Hernández A. , Pujol‐Moix N.
Published: July 2010

Abstract: HIV‐1 seropositive patients often exhibit thrombocytopenia, considered of multifactorial aetiology. Thrombopoietin (TPO), a recently isolated cytokine, is the main regulator of megakaryocyte and platelet production. The objective of this study was to analyse serum TPO levels in thrombocytopenic and non‐thrombocytopenic HIV‐1 infected patients. Serum TPO levels were measured by ELISA in 43 healthy individuals and in 88 HIV‐1 infected patients: 68 thrombocytopenics and 20 non‐thrombocytopenics. Thrombocytopenic HIV‐1 infected patients showed higher TPO concentrations (263 ± 342 pg/ml) than non‐thrombocytopenics (191 ± 86 pg/ml); levels in both groups were significantly higher than those of healthy controls (121 ± 58 pg/ml). Two subgroups of thrombocytopenic patients, the autoimmune thrombocytopenic purpura (AITP) group and the mild thrombocytopenic group, presented TPO levels similar to those of non‐thrombocytopenics. Patients exhibiting pancytopenia showed the highest TPO concentrations. However, there was no correlation between TPO levels and platelet counts in any group of HIV‐1 infected patients. TPO levels in HIV‐1 seropositive patients were slightly increased and the differences in TPO levels between thrombocytopenic and non‐thrombocytopenic patients were generally small. The finding of mildly increased TPO levels along with the recently described recovery of thrombocytopenia following recombinant TPO administration confirms the implication of ineffective platelet production in the origin of HIV‐associated thrombocytopenia.
Natural effector cells in patients with acute myeloid leukemia treated with the immunomodulator Linomide after autologous bone marrow transplantation
Authors: Hokland M. , Jørgensen H. , Holm Mette Skov , Simonsson Bengt , Nilsson Bo , Bengtsson Mats , Hokland P.
Published: July 2010

Abstract: Roquinimex, Linomide, is a quinoline derivative with pleiotropic immunomodulatory activities which has been shown to enhance NK function. As part of a phase III placebo‐controlled multicenter study patients were randomized to receive Roquinimex, 0.2 mg/kg body weight, or a placebo twice weekly for a duration of 2 yr following autologous bone marrow transplantation for acute myeloid leukemia in remission. At Arhus University Hospital 7 patients were randomized to receive the active drug and 6 to receive the placebo. Surviving patients were followed for 2 yr with immunological monitoring of their natural immune effector cells (NK‐ and LAK cell activity). Peripheral heparinized blood samples were obtained twice before the onset of conditioning therapy and at several time points after ABMT, and whole blood samples were analyzed by flow cytometry for the detection of leukocyte differentiation antigens as well as by 4 h 51Cr release assays for cytotoxicity. In contrast to previous experience with Linomide, in the present study we found that at 36 wk or later time points Linomide patients exhibited a significant suppression of circulating natural effector cell number and activity when compared with the control group. These observations underline the need for further exploration into novel and manageable immunostimulators.
Clinical immunology of chronic cold agglutinin disease
Authors: Ulvestad Elling , Berentsen Sigbjørn , Bø Kristine , Shammas Fuad V.
Published: July 2010

We studied clinical and immunological characteristics of 15 patients with chronic cold agglutinin disease (CAD). Mean age at disease debut was 68 years for female and 67 years for male patients. The patients had no signs of other autoimmune diseases. All patients had VH4–34 encoded IgM kappa cold agglutinins (CA) in high titre. In five patients IgM increased significantly with advancing disease. Seven patients had reduced concentrations of lymphocytes, largely of CD4 and CD8 T cells. Percentages of NK cells (CD56) and B cells (CD19) were increased in seven and three patients, respectively. In six out of nine patients a clonal expansion of kappa positive B cells was found. Serum C3 was decreased in nine patients and C4 was decreased in 11 patients, six of whom had reduced CH50. Such data indicate that patients with CAD experience a continuous low‐grade complement consumption. Five patients had experienced increased haemolysis during infections. After addition of active complement to patient sera in vitro, six sera showed increased haemolytic activity. Our results indicate that some patients with CAD have a relative deficit of complement in their serum and that an increase of complement production occurs during an acute phase reaction which enhances haemolysis. Our data also indicate that both CA titre and thermal amplitude are important characteristics when predicting complement activation and clinical course in CAD.
Malaria parasite metabolism in sickle cells
Authors: Orjih A. U.
Published: July 2010

Abstract:  Intraerythrocytic malaria parasites meet part of their growth requirements by ingesting and digesting haemoglobin (Hb). To see whether this process is affected by Hb types, the growth and metabolism of Plasmodium falciparum in normal AA, heterozygous AS and homozygous SS erythrocytes were compared in this study. Parasites that have been adapted to continuous growth in AA and AS erythrocytes in vitro were used, and the cultures were incubated in an environment that contained 3% oxygen, 4% carbon dioxide and 93% nitrogen. It was found that exposure of the cultures to this gas mixture caused 5–10% of the AS and up to 90% of the SS erythrocytes to sickle. Parasite growth was essentially normal in the 3 cell types, although multiplication was significantly lower in SS than in AS and AA erythrocytes. Parasite metabolism was evaluated through measurement of haemozoin production. The mean quantity of haemozoin produced by the parasites in AA was comparable to that produced in AS, but significantly higher than that produced in SS erythrocytes. This finding suggests that P. falciparum metabolism is impaired in SS but not in AS erythrocytes. The impairment may be related to polymerization of Hb S.
Evaluation of purine and pyrimidine analogues in human tumor cells from patients with low‐grade lymphoproliferative disorders using the FMCA
Authors: Åleskog A. , Larsson R. , Höglund M. , Sundström C. , Kristensen J.
Published: July 2010

Abstract:  The purine analogues fludarabine and cladribine (CdA) have recently become established to be effective treatment for low‐grade non‐Hodgkin's lymphoma (NHL). The pyrimidine nucleoside analogue cytarabine (AraC) has an important place in the treatment of acute leukemia, and gemcitabine is a new pyrimidin antimetabolite which has shown clinical activity against solid tumors. We have used the semiautomated fluorometric microculture cytotoxicity assay (FMCA), based on the measurement of fluorescence generated from cellular hydrolysis of fluorescein diacetate (FDA), to study these drugs. Eighty samples from 60 patients with low‐grade NHL were studied. Fifty samples from patients with acute lymphoid leukemia (ALL) and 118 samples from patients with acute myeloid leukemia (AML) were included for comparison. The results indicate that the purine‐ and pyrimidine nucleoside analogues tested may be as active against low‐grade NHL as against acute leukemia. In low‐grade NHL, AraC seems to be even more active in comparison to CdA (p = <0.0001) and fludarabine (p=0.001). Untreated patients were more drug sensitive than previously treated patients. Gemcitabine showed the highest correlation with AraC (0.90) whereas CdA showed the highest correlation with fludarabine (0.84). Based on these results we propose that AraC and gemcitabine may have a role in the treatment of low‐grade NHL.
Evaluation of bone disease in multiple myeloma: a comparison between the resorption markers urinary deoxypyridinoline/creatinine (DPD) and serum ICTP, and an evaluation of the DPD/osteocalcin and ICTP/osteocalcin ratios
Authors: Carlson K. , Larsson A. , Simonsson B. , Turesson I. , Westin J. , Ljunghall S.
Published: July 2010

Abstract:  Markers of bone metabolism were measured in 73 newly diagnosed myeloma patients and in age‐matched controls. Correlations to bone disease on X‐rays and survival were performed. In urine deoxypyridinoline/creatinine (DPD) and in serum carboxyterminal pyridinoline cross‐linked telopeptide of type I collagen (ICTP), procollagen type I carboxy‐terminal extension peptide (PICP) and osteocalcin were analyzed. The ratios DPD/osteocalcin and ICTP/osteocalcin were calculated. Skeletal X‐ray findings were divided into no, limited and extensive bone involvement. DPD and ICTP levels were significantly elevated in patients compared to controls. Levels increased with advancing skeletal involvement. Serum osteocalcin was elevated in patients without visible bone disease. The level decreased with more advanced bone involvement. The finding of significantly elevated osteocalcin and ICTP levels in patients without bone involvement on X‐rays indicates that bone markers might reflect bone disease better than X‐rays in untreated myeloma patients. Ratios between bone resorption and bone formation markers added no further information on bone disease or survival. Only ICTP had prognostic value with an inverse correlation between serum levels and survival.
Bilirubin levels in the acute hemolytic crisis of G6PD deficiency are related to Gilbert's syndrome
Authors: Iolascon Achille , Faienza Maria Felicia , Giordani Lucia , Perrαtta Silverio , Ruggiu Giuseppina , Meloni Gian Franco , del Giudice Emanuele Miraglia
Published: July 2010

Abstract:  In this study we analyzed the effect of the (TA)7 polymorphism of the UGT1A gene associated with Gilbert's syndrome in G6PD‐deficient subjects during an acute hemolytic crisis (tabic crisis). DNA from 44 subjects originating from the same geographic area in Sardinia was analyzed for the UGT1A promoter polymorphism. The increase of unconjugated bilirubin level during fabic crisis and its relationship with UGT1A polymorphism was evaluated. The UGT1A (TA)7 TATA box variant was found in 9/44 (21%) of the G6PD deficient subjects examined. The median value for unit of increase of bilirubin (mg/dl)/unit of decrease of hemoglobin (g/dl) was higher in variant homozygous than in heterozygous and normal subjects. These findings imply a contribution of the UGT1A polymorphism associated to Gilbert's syndrome to development of the hyperbilirubinemia in G6PD deficient subjects during acute hemolytic anemia.
The antiplatelet activity of Escherichia coli lipopolysaccharide is mediated through a nitric oxide/cyclic GMP pathway
Authors: Sheu J. R. , Hung W. C. , Su C. H. , Lin C. H. , Lee L. W. , Lee Y. M. , Yen M. H.
Published: July 2010

Abstract:  In this study, Escherichia coli LPS dose‐dependently (100–500 μg/ml) and time‐dependently (10–60 min) inhibited platelet aggregation in human and rabbit platelets stimulated by agonists. LPS also dose‐dependently inhibited the intracellular Ca2+ mobilization in human platelets stimulated by collagen. In addition, LPS (200 and 500 μg/ml) significantly increased the formation of cyclic GMP but not cyclic AMP in platelets. LPS (200 μg/ml) significantly increased the production of nitrate within a 10‐min incubation period. Furthermore, LPS also dose‐dependently inhibited platelet aggregation induced by PDBu (30 nmol/l), a protein kinase C activator. These results indicate that the antiplatelet activity of E. coli LPS may be involved in the activation of a nitric oxide/cyclic GMP pathway in platelets, resulting in inhibition of platelet aggregation. Therefore, LPS‐mediated alteration of platelet function may contribute to bleeding diathesis in septicemic and endotoxemic patients.
Clinico‐haematological profile of isolated PF3 availability defect: therapeutic potential of soya bean — a pilot study
Authors: Saxena R. , Choudhry V. P. , Mishra D. K. , Kashyap R. , Mohanty S. , Mahapatra M. , Dwivedi S. N.
Published: July 2010

Abstract:  Isolated platelet factor 3 (PF3) availability defect has been observed to be a common platelet functional disorder (PFD) in the Department of Haematology, All India Institute of Medical Sciences, New Delhi, India. One hundred and thirty‐two patients were diagnosed to have this defect based on the presence of reduced PF3 availability, normal platelet aggregation with ADP, collagen, adrenaline, ristocetin, and arachidonic acid and normal PF3 content. PF3 availability was evaluated by measurement of Russel viper venom time (RVVT) on the patient's platelet‐rich plasma (PRP) after incubation with ADP for 20 min. An RVVT value > 19.0 s was considered diagnostic of reduced PF3 availability in patients with normal prothrombin and activated partial thromboplastin times. Isolated PF3 availability defect occurred in patients with ages between 2 and 65 yr and had a female preponderance (M:F=1:2). One fifth of the patients had a positive family history of similar mild bleeding diathesis, indicating an autosomal dominant pattern of inheritance. All patients presented with mild bleeding manifestations, the commonest symptom being appearance of recurrent ecchymotic spots. In females, menorrhagia was the commonest symptom. A pilot study was conducted on 45 patients to evaluate the therapeutic role of oral soya bean (50 g/d). The clinical response was evaluated after 3 months. Soya therapy resulted in disappearance of bleeding problems in 5 patients and reduction in frequency and severity of bleeding in 26 patients. A repeat PF3 availability test after 3 months of therapy showed complete correction in 4 and partial correction in 12 patients. It is evident from McNemer's test that both the clinical and the laboratory parameters (PF3 availability) showed a similar response to soya therapy (p >0.05). Pre‐soya therapy mean PF3 availability values differ significantly from those after soyatherapy (p <0.01). Thus, soya bean appears to have a therapeutic potential in isolated PF3 availability defect.
Kinetics of indium‐ 111‐labelled platelets in HIV‐infected patients with and without associated thrombocytopaenia
Authors: Van Wyk V. , Kotzé H. F. , Heyns A. du P.
Published: July 2010

Abstract:  Seven to 12% of HIV‐infected patients have thrombocytopaenia. The pathophysiology of the thrombocytopaenia is not clear. It has been variously suggested that it may be caused by an increased peripheral platelet destruction, a defect in platelet production, or by a combination of these. The aim of the study was to elucidate the pathogenesis of HIV‐associated thrombocytopaenia. We determined the mean platelet life span (MPLS) and calculated the turnover of autologous indium‐111‐labelled platelets in 17 HIV‐positive patients, seven with thrombocytopaenia. The sites of sequestration of labelled platelets were quantified. The thrombocytopaenic patients had a very short MPLS (3.0±3.8 h) and a marked increase in platelet production (18.2±12.6× 109/l/h). The majority of these patients (5 of 7) had excessive sequestration of platelets in the spleen. Five of the patients with a normal blood platelet count had a shortened MPLS (109±23 h) and increased platelet turnover (3.8±1.2×109/l/h), i.e. the increased peripheral platelet destruction was compensated for by increased platelet production. The other five patients with a normal platelet count had normal MPLS (195±11 h) and slightly increased platelet production (2.5±0.6× 109/l/h). We conclude that patients with HIV‐associated thrombocytopaenia have increased peripheral platelet destruction. Platelet production is elevated but is insufficient to maintain a normal peripheral platelet count. In these patients platelets are predominantly sequestrated in the spleen. Patients with HIV infection and a normal blood platelet count may also have increased platelet production. This may be an early subclinical phase in the development of full‐blown HIV‐associated thrombocytopaenia.
Megakaryocytic growth in patients with refractory anemia is suppressed by treatment with interferon alpha
Authors: Hofmann Wolf‐Karsten , Kalina Uwe , Seipelt Gernot , Hoffmann Kristina , Wagner Sandra , Hoelzer Dieter , Ottmann Oliver G.
Published: July 2010

Abstract:  IFNα alone or in combination with retinoids or haematopoietic growth factors has been used to treat patients with early MDS because of its properties as a differentiation inducing agent. We investigated whether treatment of patients with refractory anemia (RA) with IFNα (1.5×106 IU twice a week) and intermittent all‐trans retinoic acid (ATRA, 25 mg/m2/d) influences in‐vitro megakaryocytic (MK) proliferation and differentiation stimulated by PEG‐rHuMGDF. Lowdensity non‐adherent bone marrow (BM) cells from 8 patients with RA were assayed prior to any treatment other than supportive and after a period of 6 months of treatment. MK development was assayed in suspension cultures in the presence of PEG‐rHuMGDFand SCF for 7 d using morphological criteria and flowcytometric analysis of CD42b (GPIb) positive cells. BM‐cells from 10 healthy individuals served as control. Following stimulation with PEG‐rHuMGDF 23±7% and 16±4% of control cells were CD42b positive after 5 and 7 d of cultures, respectively. In cultures of cells from MDS patients prior to treatment 8±2% and 7±3% of cells were CD42b+ on days 5 and 7. In the course of IFNα treatment cultures of all BM samples from these MDS patients revealed a significant reduction of MK precursor cells (3±2% CD42b+, p = 0.03 and 0.04). In conclusion, treatment with IFNα and ATRA did not result in improved megakaryocytopoiesis as assessed by in‐vitro cultures. On the contrary, low‐dose IFNα appears to suppress cell proliferation as well as MK development.
Effects of neopterin and 7,8‐dihydroneopterin on hypoxia‐induced renal erythropoietin production
Authors: Pagel H. , Fandrey J. , Schobersberger W. , Fuchs D. , Jelkmann W.
Published: July 2010

Abstract: Activation of the human cellular immune system is associated with greatly increased formation of the pteridines neopterin and 7,8‐dihydroneopterin. It has been postulated that pteridines play a role in the pathogenesis of the anaemia of inflammation. Herein, we studied effects of pteridines on renal function, primarily on the synthesis of erythropoietin (Epo). The experiments were performed with isolated rat kidneys which were perfused hypoxically (pO226 mmHg) at constant pressure (100 mmHg) in a serum‐free recirculation system for 3 h. The results show that the rate of the production of Epo was significantly lowered when neopterin or 7,8‐dihydroneopterin were added to the perfusate. Neopterin (200 μM) also reduced the renal Epo mRNA level. Both pteridines increased renal vascular resistance. 7,8‐Dihydroneopterin lowered urine flow and glomerular filtration rate more potently than neopterin. Renal O2consumption and parameters of exocrine renal function (fractional reabsorption rates of sodium, glucose and water) were not altered by the pteridines, while the glomerular permeability was greatly increased. These results suggest that activated macrophages may not only inhibit the synthesis of Epo by generating cytokines and reactive O2species but also by the release of pteridines.In vivo, high concentrations of pteridines in renal tissue may aggravate the anaemia of inflammation.
Increased vascularization in myeloma
Authors: Laroche M. , Brousset P. , Ludot I. , Mazières B. , Thiechart M. , Attal M.
Published: July 2010

Abstract: Several studies have shown that the number of intratumoral vessels can predict the aggressiveness of a solid cancer, development of metastases and patient survival. Does angiogenesis play an important role in myeloma?

The aim of our study was to quantify bone marrow vascularity in various stages of proliferative plasma cell disorders (monoclonal gammopathies of undetermined significance (MGUS), stage I multiple myeloma (MM), stage III MM and Waldenström's macroglobulinemia (WM)) and to compare it with that of patients with osteoporosis.

The study included 15 MGUS patients, 15 patients with stage I MM, 15 patients with symptomatic stage III MM, 7 patients with WM, 10 patients with osteoporosis, and 10 patients with reactive bone marrow (RBM), matched for sex and age. After iliac crest biopsy, the various vessels (arterioles, capillaries and sinusoids) were labeled with monoclonal antibodies CD34 and counted, and a histomorphometric study was done. The number of arterioles and arterial capillaries was significantly increased in MGUS and myeloma compared with osteoporosis. The number of arterioles and arterial capillaries increased moderately according to the stage of gravity of myeloma. The number of arterioles is negatively correlated with the trabecular bone volume and positively correlated with the eroded surfaces.
Expression of HLA‐DR, CAM and co‐stimulatory molecules on cord blood monocytes
Authors: Varis I. , Deneys V. , Mazzon A.M. , De Bruyere M. , Cornu G. , Brichard B.
Published: July 2010

Abstract: Umbilical cord blood (CB) transplantations are associated with a lower risk of severe graft‐versus‐host disease (GVHD) compared to BMT. GVHD is an immune reaction that involves interaction between cell surface molecules resulting in cell activation and release of many cytokines. Monocytes are known to be an important source of cell adhesion (CAM) and co‐stimulatory molecules which play a crucial role in the efficient activation of T and B cells. We analyzed the phenotype of CB monocytes in the presence or absence of an inflammatory signal (rIFN‐γ) and compared them to adult blood (AB); the expression of HLA‐DR and 17 different markers (CD11a, CD11b, CD11c, CD18, CD29, CD40, CD44, CD49a, CD49d, CD49e, CD49f, CD54, CD58, CD62L, CD80, CD86 and CD102) was measured by flow cytometry. Statistical analysis showed that, compared to AB, CB monocytes did not express CD11b, CD11c, CD49d and after stimulation with rIFNγ, they lost the expression of CD58 and CD102, whereas CD80 and CD86 expression was induced. The analysis of fluorescence intensity (MFI) revealed that CB monocytes expressed some CAM (CD29, CD54, CD102) with a lower intensity than AB monocytes except CD44. In conclusion, absence and reduced expression of some markers argue for a different phenotypic profile of CB monocytes compared to AB monocytes, which might partly contribute to their impaired immune response and to the low incidence of GVHD observed after CB transplantations. However, CB monocytes expressed CD80 and CD86 co‐stimulatory molecules, but this expression did not prove a normal co‐stimulatory function.
Clinical and hematological features of codon 17, A‐T mutation of β‐thalassemia in Thai patients
Authors: Laosombat Vichai , Wongchanchailert Malai , Sattayasevana Benjamas , Wiriyasateinkul Aranya , Fucharoen Supan
Published: July 2010

Abstract: Forty‐one patients with codon 17, A‐T mutation of β‐thalassemia, which is commonly found in Thailand, were studied to determine whether it is possible to predict phenotypic severity from genetic factors. The clinical phenotype of homozygotes for codon 17, A‐T and compound heterozygotes for codon 17, A‐T and β+‐thalassemia may be used to predict a severe phenotype with TM. However, the clinical phenotype of compound heterozygotes for codon 17, A‐T and β+‐thalassemia or Hb E were variable and could not be accurately predicted. The association of α‐thalassemia2 and milder disease was and was not evident in patients with codon 17, A‐T and Hb E. The association between Hb CS gene or the presence of XmnI‐Gγ polymorphism and a mild clinical phenotype is not apparent, indicating the involvement of other ameliorating determinants or genetic modifications.
Flow cytometry using the monoclonal antibody CD10‐Pe/Cy5 is a useful tool to identify follicular lymphoma cells
Authors: Bellido M. , Rubiol E. , Ubeda J. , López O. , Estivill C. , Carnicer M. J. , Muñoz L. , Bordes R. , Sierra J. , Nomdedéu J.
Published: July 2010

Abstract: Follicular lymphoma (FL) is a specific entity defined by characteristic histology, phenotype and molecular rearrangements. Classically, reactivity for CD19, CD10, and strong positivity for the surface light chain immunoglobulin (SIg) are considered to be phenotypic signs typically expressed in FL. In practice, this pattern is difficult to identify since most neoplastic cells analysed by flow cytometry (FC) show weak intensity for CD19‐Pe/Cy5 and for SIg and negativity for CD10‐FITC. We used triple antigen combinations including two monoclonal antibodies (MoAbs) against CD10 (CD10‐FITC and CD10‐Pe/Cy5) and a long‐distance polymerase chain reaction (PCR) approach to establish the phenotypic pattern of neoplastic cells carrying t(14;18)(q32;q21). Neoplastic cells showed the following immunophenotype: stronger reactivity against CD20 than against CD19, positivity for CD22 and SIg and negativity for CD5, CD11c and CD10‐FITC. Characteristically, CD10‐Pe/Cy5 was expressed in all the samples with positive bcl‐2/JH rearrangements. In FL, there was a high correlation between histologic diagnosis and reactivity against CD10‐Pe/Cy5 (96% cases). In diffuse large cell lymphomas (DLCL), CD10‐Pe/Cy5 identified positive cases with t(14;18)(q32;q21) chromosomal translocation, whereas Burkitt lymphomas showed all cases reactivity against CD10‐Pe/Cy5. In conclusion, CD10‐Pe/Cy5 is a useful antibody for identifying neoplastic cells carrying t(14;18)(q32;q21) in FL and DLCL. In combination with other MoAbs, anti‐CD10 (HI10a, Cy‐Chrome) can be used to identify a characteristic phenotypic profile of FL against other lymphoproliferative disorders.
Serum levels of the angiogenic cytokines basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in multiple myeloma
Authors: Sezer Orhan , Jakob Christian , Eucker Jan , Niemöller Kathrin , Gatz Frauke , Wernecke Klaus‐Dieter , Possinger Kurt
Published: July 2010

Abstract: Angiogenesis is a crucial process in growth and progression of cancer and there is growing evidence that neovascularisation is important in hematological malignancies. Since an increased angiogenic potential has been identified in multiple myeloma, we simultaneously measured circulating serum levels of the cytokines bFGF, VEGF, HGF and IL‐6 by ELISA in 67 patients with multiple myeloma or monoclonal gammopathies of undetermined significance (MGUS) and in 20 controls. Median values of bFGF were 4.7 pg/ml in healthy volunteers, 6.2 in MGUS, 6.3 in myeloma stage I, 13.4 in stage II and 21.7 in stage III. Myeloma patients had significantly higher bFGF serum levels than controls (p<0.001). Pretreatment bFGF levels differed significantly in the Salmon and Durie stages I–III (p=0.02) and were significantly elevated in stage II–III compared to stage I myeloma (p=0.02). In patients responding to chemotherapy according to the CLMTF criteria, a significant decrease in serum bFGF, VEGF and HGF levels occurred (median pretreatment values for bFGF 23.9 pg/ml, post‐treatment 6.5 pg/ml; p<0.001, for VEGF 223 pg/ml versus 105 pg/ml; p=0.02 and for HGF 1429 pg/ml versus 1077 pg/ml; p=0.02, respectively). In 11 patients who did not achieve a remission, there was no significant decrease in bFGF, VEGF and HGF levels. These data show that myeloma in stages II and III is associated with an increase in serum bFGF concentrations and give the first report that effective chemo‐therapy is accompanied by a significant decrease in the angiogenic factors bFGF, VEGF and HGF, while no decrease of these factors could be found in nonresponders.
Allogeneic bone marrow transplantation with reduced conditioning (RC‐BMT)
Authors: Vindeløv Lars
Published: July 2010

Abstract: Allogeneic bone marrow transplantation with conventional conditioning (CC‐BMT) has the potential of curing various malignant and non‐malignant diseases. The curative mechanisms encompass 1) stem cell support for myeloablative radio‐chemotherapy, 2) the graft‐versus‐tumor (GVT) effect, 3) gene replacement for genetic diseases and 4) immunoablation for autoimmune diseases. CC‐BMT is characterized by high intensity conditioning, the requirement of prolonged and expensive hospital treatment and a treatment related mortality (TRM) of 10–50% depending on diagnosis, disease stage, patient age and donor type. Recent preclinical and clinical progress has resulted in the emergence of new concepts and procedures that allow replacement of patient bone marrow and immune system with that of the donor by a transplant procedure with markedly reduced conditioning (RC‐BMT). This type of transplant, sometimes referred to as mini‐BMT, activates curative mechanisms 2–4, which for a number of diseases seems sufficient for cure. It avoids the severe organ toxicity of myeloablative radio‐chemotherapy and the complications of profound neutropenia. Patients beyond the age limit of conventional BMT (50–60 yr) may therefore be candidates for this type of transplant as well as patients which because of other medical conditions or the type of disease for which the transplant is needed are poor candidates for CC‐BMT. The procedure can be performed in an outpatient setting. The resulting cost reduction should contribute to making allogenic BMT more readily available. This review describes basic concepts and procedures involved in RC‐BMT and summarizes preliminary results obtained with RC‐BMT in different transplant centers.
Identification of a new Leu354Pro mutation responsible for factor XIII deficiency
Authors: Anwar Rashida , Gallivan Louise , Trinh Chi H. , Hill Frank G.H. , Markham Alexander F.
Published: July 2010

Abstract: We report a new homozygous CTG→CCG (Leu→Pro) mutation at codon 354 in the factor XIIIA gene of a patient suffering from FXIII deficiency. Leu354 lies in a pocket within the core domain of the FXIIIA molecule, with its side chain pointing into the structure of the barrel 1 domain. Replacement of leucine with a proline residue gives rise to steric hindrance between the proline ring and the surrounding residues, and rearrangement of these residues would be necessary for proline to be accommodated at this position. Using PCR‐RFLP, we have demonstrated the absence of this mutation from 220 normal alleles. Together, these data suggest that Leu354Pro is likely to be the disease‐causing mutation in this factor XIII deficient family.
Treatment of T‐prolymphocytic leukemia with nonmyeloablative allogeneic stem cell transplantation
Authors: Garderet L. , Bittencourt H. , Kaliski A. , Daniel M. T. , Ribaud P. , Socié G. , Gluckman E.
Published: July 2010

Abstract: Aim: T‐prolymphocytic leukemia (T‐PLL) is a rare disease of the elderly characterized by a high white blood cell count and organomegaly, and is currently incurable. Our aim was to elicit graft‐versus‐leukemia reactions in a patient with T‐PLL. Methods: A 52‐yr‐old woman with refractory T‐PLL underwent a nonmyeloablative regimen followed by allogeneic peripheral blood stem cell transplantation (a “minitransplant”) from her HLA‐matched sibling. Results: There was no treatment related toxicity other than neutropenia. Engraftment was successful. The patient experienced no graft‐versus‐host disease (GVHD) at any time but, on day 84 after transplantation, had a relapse in the central nervous system. Despite infusion of donor lymphocytes and intralumbar chemotherapy, she died on day 157 of systemic disease. Conclusion: The reasons why treatment may have failed are discussed (nature of disease, disease progression, treatment schedule).
Overview of the Sixth International Symposium on Hodgkin's disease – recent advances in basic and clinical trials
Authors: Josting Andreas , Heidecke Cordula , Diehl Volker
Published: July 2010

Abstract:  The Sixth International Symposium on Hodgkin's disease was held in Cologne, Germany, between September 18 and 21, 2004, organized by the German Hodgkin Study Group (GHSG) and chaired by Volker Diehl. Since 1987 the international symposia were held at regular intervals in Cologne with the aim to facilitate international cooperation and to bring together new scientific and clinical results reached in the field of Hodgkin's disease. The expanding number of participants from about 300 attendees at the first symposium to almost 800 from 48 countries at the Sixth International Symposium indicates the increasing importance of this meeting. For the second time a patient seminar with more than 350 attendees has been organized. This sixth meeting was going to be unique, since the GHSG celebrated its 25th anniversary and honored Volker Diehl, the group's founder in recognition of his work during more than 25 yr. The symposium was held at the University of Cologne's main building, creating a special, scientific and familiar atmosphere. Throughout the symposia carried out by the GHSG, preclinical and clinical several topics have always been of basic interest and have provided a basis for discussion and scientific exchange.
Hodgkin lymphoma: a curable disease: what comes next?
Authors: Diehl Volker , Klimm Beate , Re Daniel
Published: July 2010

Bonadonna Lecture at the Sixth International Hodgkin Lymphoma Congress Cologne, 19 September 2004.
Twenty‐five years clinical trials of the German Hodgkin Study Group (GHSG)
Authors: Behringer K. , Diehl V.
Published: July 2010

Abstract:  This review presents a short overview of 25‐years of clinical trials by the GHSG for the treatment of primary Hodgkin's Lymphoma. The trials HD1‐HD12 that have been conducted between 1978–2002 are reviewed and major results are discussed. Furthermore, the development of the strategies concerning chemo‐ and radiotherapy for the treatment of Hodgkin's Lymphoma is characterized.
Pathogenesis of Hodgkin's lymphoma
Authors: Küppers Ralf , Schmitz Roland , Distler Verena , Renné Christoph , Bräuninger Andreas , Hansmann Martin‐Leo
Published: July 2010

Abstract:  In Hodgkin's lymphoma (HL), the B cell origin of the tumour cells, the Hodgkin and Reed‐Sternberg (HRS) cells, has been disclosed by molecular single cell analysis about 10 yr ago. This finding formed the basis for various studies aimed to better understand the pathogenesis of this peculiar malignancy and the pathophysiology of the HRS cells. Work of our groups in this regard was focussed recently on two main topics, namely the study of differential gene expression in HRS cells and the pathogenesis of composite lymphomas. Composite lymphomas are combinations of HL and B cell non‐Hodgkin lymphomas, that turned out to be often clonally related. By molecular analysis of several composite lymphomas for potential transforming events, we identified examples of both shared as well as distinct transforming events. Comparing gene expression profiles of HL‐derived cell lines with the corresponding profiles from other B cell lymphomas and normal B cell subsets revealed a global down‐regulation of the B cell‐specific gene expression signature in HRS cells. Moreover, we identifed aberrant expression and activity of multiple receptor tyrosine kinases in HRS cells of classical and to a lesser extend lymphocyte predominant HL, which appears to be a unique feature of HL, and may offer novel strategies for treatment.
Genetic susceptibility to Hodgkin's lymphoma associated with the human leukocyte antigen region
Authors: Diepstra A. , Niens M. , Te Meerman G. J. , Poppema S. , van den Berg A.
Published: July 2010

Abstract:  Based on the presence of an abundant inflammatory infiltrate, expression of a broad spectrum of cytokines and the professional antigen presenting phenotype of Hodgkin Reed‐Sternberg cells it can be anticipated that immunological mechanisms play a major role in the pathogenesis of Hodgkin's lymphoma (HL). Genetic susceptibility to HL probably relates to functionality of the immune system and the large number of associations with the human leukocyte antigen (HLA) region in family and population‐based studies supports this relation. In Epstein–Barr virus (EBV) positive HL cases, which usually demonstrate HLA class I expression, HRS cells should be able to present EBV derived antigenic peptides and trigger the immune system. This process depends on the affinity of the HLA binding groove for binding immunogenic peptides and thus on the HLA alleles. It can be anticipated that certain combinations of alleles predispose to or protect from the development of EBV positive HL. In EBV negative HL cases other antigenic peptides, related to malignant transformation, in combination with other HLA alleles may be involved. In addition, differential attraction and activation of inflammatory cells may influence HL subtype. In this article, possible roles of HLA in HL pathogenesis are explored and genetic associations of HLA with HL are reviewed and commented on.
Non‐mediastinal grey zone lymphomas and report from the workshop
Authors: Stein Harald , Jöhrens Korinna , Anagnostopoulos Ioannis
Published: July 2010

Abstract:  Grey zone lymphomas represent borderline lesions between classical Hodgkin lymphoma (cHL) and other morphologically and immunophenotypically related diseases and entities like nodular lymphocyte predominant HL, T‐cell rich B‐cell lymphoma, ALK‐negative anaplastic large cell lymphoma (ALCL), diffuse large B cell lymphoma (DLBCL) anaplastic variant and primary mediastinal LBCL. The sharp definition of morphological, immunophenotypical and molecular features of the ‘‘text‐book cases’’ of each disease and the comparison with grey zone cases has reduced most of the latter cases. Two reports in this workshop dealt with the problematic non‐mediastinal grey zone lymphomas, one with a cHL of T cell‐type presenting in the skin as a ALK‐negative ALCL and the other with the grey zone between cHL of B‐cell type and ALK‐negative ALCL.
Report: workshop on mediastinal grey zone lymphoma
Authors: Poppema Sibrand , Kluiver Joost L , Atayar Cigdem , van, den Berg Anke , Rosenwald Andreas , Hummel Michael , Lenze Dido , Lammert Hetty , Stein Harald , Joos Stephan , Barth Thomas , Dyer Martin , Lichter Peter , Klein Uwe , Cattoretti Giorgio , Gloghini Annunziata , Tu Yuhai , Stolovitzky Gustavo A , Califano Andrea , Carbone Antonino , Dalla‐Favera Ricardo , Melzner Ingo , Bucur Alexandra J , Brüderlein Silke , Dorsch Karola , Hasel Cornelia , Barth Thomas FE , Leithäuser Frank , Möller Peter
Published: July 2010

Abstract:  There are several indications that classical Hodgkin lymphoma (cHL) and at least a proportion of cases of Primary Mediastinal B cell Lymphoma (PMBL) are derived from B cells at similar stages of differentiation and share common pathogenic mechanisms. The first indication was the existence of mediastinal grey zone lymphomas as identified in the 4th International Symposium on HL, with clinical, histological and immunohistochemical features intermediate between cHL and PMBL. Second, both tumor types resemble a cell that is developmentally situated in‐between the germinal center reaction and a plasma cell. Third, cHL and PMBL were found to have similar gene expression profiles, including the lack of immunoglobulin expression and low levels of B cell receptor signalling molecules, and the secretion of molecules like the chemokine TARC and the prominent expression of IL‐13 receptors. Fourth, both entities were found to have common genomic aberrancies, notably in 2p15 and 9p24, the sites of the REL oncogene and the tyrosine kinase gene JAK2, respectively. Further comparison of both lymphoma types may provide further insight in the pathogenic mechanisms and allow the design of diagnostic algorithms to sort out the small number of so‐called mediastinal grey zone lymphomas, that appear to be intermediate between PMBL and cHL.
International harmonization of trial parameters in malignant lymphoma
Authors: Pfistner B. , Diehl V. , Greb A. , Cheson B.
Published: July 2010

Abstract:  Despite the publication of standardized response criteria for non‐Hodgkin's lymphomas by Cheson et al., an examination of current trial parameters in nine international lymphoma study groups by the working group for quality management (WG‐QM) of the Competence Network Malignant Lymphoma found differences or even missing definitions. This finding led V. Diehl, B. Cheson, and B. Pfistner to found an international project to harmonize trial parameters for malignant lymphoma. Committees of international experts on various aspects of clinical trials design and execution were formed with the charge of summarizing the current status of each aspect of trial conduct, developing a consensus as to the most current definitions, and publishing the report of those deliberations.
Special issues in pediatric Hodgkin's disease
Authors: Schwartz Cindy L.
Published: July 2010

Abstract:  Childhood Hodgkin's disease (HD) is not a biologically unique disease; it differs from adult HD primarily in the relative incidence of disease histology. Preadolescent children are more likely to have Mixed Cellularity and nodular lymphocyte predominant HD. Adolescent and young adult HD is indistinguishable, with a predominance of nodular sclerosing (NS) HD. Nonetheless, treatment paradigms have diverged over the years as pediatric oncologists responded first to developmental issues in the young child, and later to the long‐term treatment consequences in all young survivors. The latter concerns are of equal relevance to the young adult with HD. The increasing convergence of treatment approaches in the past decade is therefore most appropriate. Reproductive potential, risk of secondary malignancy and cardiopulmonary consequences of therapy have driven the pediatric treatment paradigm of care. Chemotherapy with low dose, limited field radiation is standard, with low‐stage patients often treated by chemotherapy alone. Algorithms tailor therapy to response. The prognostic importance of very early chemotherapy response rather than end‐of‐chemotherapy response has led the Children's Oncology Group to use early response (after 6 wk) to titrate individual therapy and dense regimens to maximize the early response rates. Although the dose dense regimens of adult groups are similar, the pediatric algorithms emphasize using the enhanced efficacy to limit cumulative therapy. This review intends to address the special issues of childhood HD, with the intent of further encouraging understanding that will foster convergence of pediatric and adult treatment paradigms.
An international approach to the treatment of Hodgkin's disease in the elderly: launch of the SHIELD study programme
Authors: Proctor Stephen J. , White Jo , Jones Gail L.
Published: July 2010

Abstract:  Utilising the Scotland and Newcastle Lymphoma Group population data for Hodgkin's disease (HD), collected over a 20‐year period, it is evident that 20% of patients are over the age of 60 yr at diagnosis. Data from 674 patients are available. This group comprised 346 men and 328 women. Median follow‐up was 9.5 yr. In total 361 patients had stage I/II disease. In this cohort overall response and complete response (CR) rates were 88% and 79%, respectively, for treated patients. Overall 308 patients had stage III/IV disease. Among treated patients in this cohort, overall and CR rates were 78% and 59%, respectively. Response data were missing for 26 patients with stage I/II disease and 43 patients with stage III/IV disease. The chlorambucil, vinblastine, procarbazine and prednisolone, mechlorethamine, vincristine, probarbazine and prednisolone and doxorubicin, bleomycin, vinblastine and decarbazine were the commonest chemotherapy regimens, in descending order of frequency, used to treat this cohort of patients. Outcome did not vary with these regimens. Thirty‐four other chemotherapy combinations were used, some curative others palliative. These data and all other published studies confirm the need for a prospective, age‐defined approach to HD in the elderly. Such an approach needs to be closely linked to issues of comorbidity, an assessment of frailness and the tailoring of specific protocols for the elderly to allow full dose delivery. The Study of Hodgkin Lymphoma In the Elderly/Lymphoma Database programme has now been launched and attempts to address these issues (http://www.shieldstudy.co.uk).
Report from the Rockefellar Foundation Sponsored International Workshop on reducing mortality and improving quality of life in long‐term survivors of Hodgkin's disease: July 9–16, 2003, Bellagio, Italy
Authors: Mauch Peter , Ng Andrea , Aleman Berthe , Carde Patrice , Constine Louis , Diehl Volker , Dinshaw Ketayun , Gospodarowicz Mary , Hancock Steve , Hodgson David , Hoppe Richard , Liang Raymond , Loeffler Markus , Specht Lena , Travis Lois B. , Wirth Andrew , Yahalom Joachim
Published: July 2010

Abstract:  A workshop, sponsored by the Rockefellar Foundation, was held between 9 to 16 July, 2003 to devise strategies to reduce mortality and improve quality of life of long‐term survivors of Hodgkin's disease. Participants were selected for their clinical and research background on late effects after Hodgkin's disease therapy. Experts from both developed and developing nations were represented in the workshop, and efforts were made to ensure that the proposed strategies would be globally applicable whenever possible. The types of late complications, magnitude of the problem, contributing risk factors, methodology to assess the risk, and challenges faced by developing countries were presented. The main areas of late effects of Hodgkin's disease discussed were as follows: second malignancy, cardiac disease, infection, pulmonary dysfunction, endocrine abnormalities, and quality of life. This report summarizes the findings of the workshop, recommendations, and proposed research priorities in each of the above areas.
Female fertility after cytotoxic therapy – protection of ovarian function during chemotherapy of malignant and non‐malignant diseases
Authors: Mattle Verena , Behringer Karolin , Engert Andreas , Wildt Ludwig
Published: July 2010

Abstract:  Due to the dramatic improvements in cure and survival of young patients of reproductive age suffering from malignant or systemic disease, the preservation of fertility and ovarian function during cytostatic treatment has become of increased importance during the last decade. Pharmacological therapy with GnRH analogues and the cryopreservation of ovarian tissue are discussed in this context. The value of these treatment procedures and their potential clinical applications are critically reviewed in this article.