bluuebunny/crossref_metadata_2025 huggingface dataset:
BEAM+autologous stem cell transplantation in malignant lymphoma: 100 consecutive transplants in a single centre. Efficacy, toxicity and engraftment in relation to stem‐cell source and previous treatment
Authors: Geisler C. H. , Hansen M. Mørk , Andersen N. S. , Brown P. , Christensen L. Dalh , Dickmeiss E. , Ersbøll J. , Myhre J. , Hansen M. , Juhl B. Ravn , Mortensen B. Thing , Pedersen‐Bjergaard J.
Published: July 2010

Abstract:One hundred consecutive patients with malignant lymphoma treated with high‐dose chemotherapy and autologous stem cell transplantation, followed at least 1 yr post‐transplant, are reported, 68 with non‐Hodgkin's lymphoma and 32 with Hodgkin's disease. At transplant, 23 patients were in first remission, 69 in later chemosensitive disease and 8 were chemotherapy resistant. Based on previous treatment and stem‐cell source, the patients were subdivided into 3 cohorts: BMT1: bone‐marrow harvest and transplant after ≥3 treatment regimens (38 patients); BMT2: bone marrow harvest and transplant after less than 3 treatment regimens (24 patients); PBSCT: peripheral‐blood stem cell transplant (38 patients, 5 of these with CD34+ cell selected PBSC). The 4‐yr survival and progression‐free survival of all patients was 45 and 40%, respectively. Forty‐one patients have died, 27 of lymphoma, evenly distributed in the cohorts. Fourteen treatment‐related deaths occurred, 13 of these in the BMT1cohort, significantly more than in the other cohorts (p=0.001). In univariate survival analysis cohort, age, disease status at transplant and number of previous treatment regimens were significant. In multivariate survival analysis cohort, age and sex were independently significant, women having a shorter survival. The patients transplanted with unselected PBSC had significantly shorter duration of pancytopenia and hospital stay than the otherwise comparable BMT2patients, but their progression‐free survival was identical. We confirm that high‐dose therapy with autologous stem cell transplant from blood or bone marrow in not‐too‐heavily pretreated patients is a safe procedure but will cure only half the patients.
Genetic polymorphism H131R of Fcγ receptor type IIA (FcγRIIA) in a healthy Finnish population and in patients with or without platelet‐associated IgG
Authors: Joutsi Lotta , Javela Kaija , Partanen Jukka , Kekomäki Riitta
Published: July 2010

Abstract: Patients (n = 113) with histories of thrombocytopenia and with different profiles for platelet‐associated IgG (PA‐IgG) were subdivided according to the genetic polymorphism H131R in the Fcγ receptor type IIA (FcγRIIA). PA‐IgG was measured by the direct platelet immunofluorescence test (PIFT), and GP IIbIIIa and/or GP Ib‐specific PA‐IgG was investigated by a modified version of the direct monoclonal antibody‐specific immobilization of platelet antigens (MAIPA) assay. As a control, the distribution of FcγRIIA polymorphism H131R was determined among 93 healthy Finnish blood donors. The frequencies for H131 and R131 were 0.56 and 0.44 (CI: 0.37–0.51), respectively, which did not differ significantly from those in other Caucasian populations. The distribution of the genotypes HH131, HR131 and RR131 in the patients and controls did not differ significantly. In the HH131 group, the PA‐IgG was higher than in the RR131 group (p = 0.082). Female patients with the genotype RR131 seemed to be younger than those with HH131 (p = 0.065). Among the female patients, a significantly greater number were under 40 yr old in the RR131 group than in the HH131 group (p = 0.0060). Within the RR131 group, the female patients were far younger than the male patients (median 29 vs. 61 yr; p = 0.0021). The results point to the heterogeneity of immune thrombocytopenia, which may partly explain the poor predictive value of PA‐IgG studies.
Signaling through interleukin‐6 receptor supports blast cell proliferation in acute myeloblastic leukemia
Authors: Säily Marjaana , Koistinen Pirjo , Zheng Aiping , Savolainen Eeva‐Riitta
Published: July 2010

Abstract: The role of the interleukin‐6/interleukin‐6 receptor (IL‐6/IL‐6R) system in regulating blast cell growth in 8 acute myeloblastic leukemia (AML) patient‐derived cell lines was investigated. As they all expressed IL‐ 6R and as none of them responded to exogenous IL‐6 under conventional serum‐supplemented culture conditions, we investigated whether signaling through IL‐6R plays any role in maintaining their spontaneous colony growth. This was done by treating the cells with monoclonal antibodies made against the ligand‐specific IL‐6R α‐chain or the signal transducer gp130. In serum‐supplemented cultures inhibition of gp 130 function did not affect the cell line growth, whereas anti‐IL‐6R α‐chain antibody reduced colony growth. While some of the cell lines also showed similar growth characteristics in a serum‐free environment, some others changed their growth pattern and stopped responding to anti‐IL‐6R α‐chain treatment. At the same time, these cell lines also began to respond to exogenously added IL‐6 and, interestingly, were stimulated by anti‐gp130 antibody. Hence, in some of the blast cells, clonogenic cell growth seemed to be also negatively controlled by an endogenously produced growth‐depressing cytokine or cytokines that utilize gp130. All the cell lines, whether cultured in the presence or absence of serum expressed IL‐6 both at mRNA and protein level. The current results indicate that AML cells can use IL‐6 as a growth stimulating factor, supplied either paracrinely or autocrinely. This could implicate the use of anti‐IL‐6R α‐chain antagonists in AML treatment, not IL‐6.
First line Fludarabine treatment of symptomatic chronic lymphoproliferative diseases: clinical results and molecular analysis of minimal residual disease
Authors: Clavio M. , Miglino M. , Spriano M. , Pietrasanta D. , Vallebella E. , Celesti L. , Canepa L. , Pierri I. , Cavaliere M. , Ballerini F. , Beltrami G. , Rossi E. , Vimercati R. , Bruni R. , Congiu M. , Nati S. , Damasio E. , Santini G. , Gobbi M.
Published: July 2010

Abstract: Fludarabine (25 mg/m2 for 5 d, every 4 wk, for 6 courses) was administered as first line therapy in 32 symptomatic chronic lymphoproliferative diseases. All CLL patients achieved at least partial response (5 CR, 2 nPR, 9 PR) but 44% of patients relapsed. In LG‐NHLs response and relapse rate were similar. Haematological toxicity was low. VDJ rearrangement PCR analysis was performed on marrow samples at diagnosis and at the time of response evaluation. In the 3 patients who underwent high dose therapy with peripheral blood progenitor cell rescue analysis was also performed on apheresis samples and on marrow samples at the end of the procedure. Clonal VDJ rearrangement was always evident after Fludarabine therapy even in those patients who achieved histological and immunophenotypic complete remission, whereas it disappeared in 2 of 3 patients who underwent HDT. Our data confirm that Fludarabine monotherapy can reduce the neoplastic mass to a subclinical level and suggest the possibility that high dose therapy might produce true complete remission.
Avascular osteonecrosis in patients treated for Hodgkin's disease
Authors: Enrici Riccardo Maurizi , Anselmo Anna Paola , Donate Vittorio , Santoro Mariaquila , Tombolini Vincenzo
Published: July 2010

Abstract: The aim of this study is to assess the risk of avascular osteonecrosis (AVN) of the femoral head in patients treated for Hodgkin's disease (HD), in relation to the type of treatment they have received. For this purpose, a cohort of 1391 patients treated for HD at University of Rome between 1972 and 1996 was divided into 2 groups according to their initial treatment. The first group contained 784 patients treated, at the onset of HD, either with chemotherapy (CT) containing steroids, combined in some cases with subdiaphragmatic radiotherapy (RT), or with subdiaphragmatic RT combined with CT without steroids. The second group was made up of 607 patients who had received, initially, supradiaphragmatic RT alone or supradiaphragmatic RT combined with CT without steroids. For the purpose of this study, only the 784 patients belonging to the first group were observed for the appearance of AVN, which occurred in 9 cases. The period of time which elapsed between the end of treatment and the radiological evidence of AVN ranged from 23 to 97 months, with an average of 35 months. Because the number of cases of AVN was so small, the pathogenesis of this complication could not be identified.
Elevated IL‐8 levels during sickle cell crisis
Authors: Duits A. J. , Schnog J. B. , Lard L. R. , Saleh A.W. , Rojer R. A.
Published: July 2010

Abstract: The vaso‐occlusive process (VOC) in sickle cell disease is of a complex nature. It involves intricate interactions between sickle red blood cells, endothelium and probably also leukocytes. As these interactions are regulated by cytokines, we analyzed the role of the potent neutrophil chemokine IL‐8 by measuring serum levels in sickle cell patients during sickle cell crisis. These results were compared to nonsymptomatics and healthy controls. In patients having a vaso‐occlusive crisis both HbSS and HbSC patients showed significantly enhanced serum IL‐8 levels compared to healthy controls. Several of these patients showed extremely elevated serum IL‐8 levels which were independent of the crisis inducing factor. Furthermore, a sickle cell patient with VOC as a complication of rhGM‐CSF treatment similarly showed high IL‐8 serum levels at crisis onset. Nonsymptomatic sickle cell patients serum IL‐8 levels were comparable to healthy controls. These results implicate a role for IL‐8 at or during (the initiation of) sickle cell crisis.
The use of intravenous intermediate dose melphalan and dexamethasone as induction treatment in the management of de novo multiple myeloma
Authors: Schey S. A. , Kazmi M. , Ireland R. , Lakhani A.
Published: July 2010

Abstract: The variable absorption of melphalan from the gastrointestinal tract results in response rates between 40 and 60%. High dose melphalan increases response rates but at the cost of increased morbidity and mortality. We have investigated intravenous intermediate dose melphalan and dexamethasone in the treatment of patients presenting with de novo multiple myeloma with the object of reducing toxicity while preserving an improved response rate compared to oral melphalan and prednisolone. The results show that this treatment can be delivered safely on an outpatient basis in patients up to the age of 78 yr; 82% of patients achieved an objective response and 30% a complete haematological and clinical remission. Median overall survival for the whole group is 37 months.
Serum levels of soluble vascular cell adhesion molecule‐1 (sVCAM‐1) are elevated in advanced stages of non‐Hodgkin's lymphomas
Authors: Christiansen Use , Sundström Christer , Kälkner Karl‐Mikael , Bring Johan , Tötterman Thomas H.
Published: July 2010

Abstract: The serum levels of soluble vascular cell adhesion molecule‐1 (sVCAM‐1) were measured in 116 patients with non‐Hodgkin's lymphomas (NHL) tested previously for soluble intercellular adhesion molecule‐1 (sICAM‐1). In contrast to Hodgkin's disease and chronic lymphocytic leukaemia, the sVCAM‐1 levels in NHL patients were not significantly different from the levels of healthy controls (n = 31). However, sVCAM‐1 was elevated in advanced stage disease, i.e. stages III + IV. Elevated serum levels of sVCAM‐1 were associated with significantly poorer disease‐free (p = 0.024) and overall (p = 0.02) survival. sVCAM‐1 correlated poorly with other known prognostic variables (LDH, sTK and β2m) and with sICAM‐1. None of the tested markers added prognostic information for disease‐free survival independently of Ann Arbor stage and B‐symptoms. The expression of VCAM‐1 and ICAM‐1 in tumour biopsies from 15 patients representing 7 different histologies were examined and compared with the serum levels of the soluble adhesion molecules. No correlation was found between the adhesion molecule expression by vascular endothelium and the corresponding serum levels.
Platelet membrane lipid fluidity and intraplatelet calcium mobilization in type 2 diabetes mellitus
Authors: Watala Cezary , Boncer Magdalena , Golański Jacek , Koziołkiewicz Wiktor , Trojanowski Zygmunt , Walkowiak Bogdan
Published: July 2010

Abstract:The aim of the present study was to relate the impairments in calcium mobilization and/or release to the altered membrane dynamics in platelets from patients with type 2 diabetes mellitus. Higher expression of P‐selectin (1.4‐fold, NS) and the reduction in GPIbα expression (by 27.8 ± 16.7%,p< 0.0002), as well as the increased fractions of platelet microparticles (p< 0.03), reflected more intensified platelet release reaction in diabetic platelets. Overall, diabetic platelets appeared more vulnerable to stimuli facilitating calcium mobilization (by 41%,p< 0.01) and less susceptible to preventive effects of the agents hampering calcium release from intraplatelet storage pools (by 38%,p< 0.01). Both the increased calcium mobilization from intraplatelet storage pools and higher levels of intracellular free calcium in the presence of procaine in diabetic platelets correlated with the reduced platelet membrane lipid fluidity (resp.pR< 0.03 andpR< 0.015). We conclude that the biophysical state of platelet membrane components in diabetes mellitus is the crucial determinant of platelet hyperfunction and probably contributes to the intensified calcium mobilization in diabetic platelets. The depressed preventive effects of procaine on platelet release reaction and calcium mobilization in diabetic platelets may result from the primary dislocations and/or distortions of membrane components caused by the diabetic state.
Acute promyelocytic leukaemia: epidemiology and risk factors. A report of the GIMEMA Italian archive of adult acute leukaemia
Authors: Pulsoni Lessandro , Stazi Antonia , Cotichini Rodolfo , Allione Bernardino , Cerri Raffaella , Di Bona Eros , Nosari Anna Maria , Pagano Livio , Recchia Anna , Ribersani Michela , Rocchi Lucilla , Veneri Dino , Visani Giuseppe , Mandelli Franco , Mele Alfonso ,   GIMEMA Cooperative Group
Published: July 2010

Abstract: Acute promyelocytic leukaemia (APL) exhibits peculiar epidemiological, clinical, cytogenetic and molecular features, compared to the other acute myeloid leukaemias (AML). Data on epidemiology and occupational risk factors for APL desumed from the GIMEMA archive are reported and compared with those of the other AML. An exploratory case‐case study was designed on AML patients from 56 haematology centres in Italy. Overall, 4296 patients older than 15 yr with a new diagnosis of acute leukaemia were recorded between July 1992 and July 1997. Of these, 335 were classified as APL, and 2894 as other AML. The median age of APL patients was 43 compared to 59 yr for the other AML (p< 0.00001). In order to identify peculiar risk factors for APL development, different parameters were compared in the 2 groups. After adjusting by age no significant differences were observed with regard to education, lifetime prevalence of cancer among siblings and previous diseases in the patient's history. Occupational exposure as a possible risk factor for APL showed no increased risk compared to other AML among farmers, builders and leather workers. A significant association was found in electricians (OR = 4.4, 95% CI = 2.0–9.7) and a weak association was found in wood workers (OR = 3.2, 95% CI = 0.8–10.8). The proportion of APL with respect to other AML was significantly higher in the north east of Italy compared to the rest of the country (OR = 1.7, 95% CI = 1.3–2.2). These data confirm the younger age of APL patients compared to the other AML. A possible role of electromagnetic fields is suggested by the higher risk of APL in electrical workers and in the more industrialized areas of the country.
Flow cytometric identification of myeloid disorders by asynchronous expression of the CD14 and CD66 antigens
Authors: Hansen Ib , Meyer Karin , Hokland Peter
Published: July 2010

Abstract: Using a multiparameter flow cytometry assay enumerating cells positive for CD13, CD14 and CD66 antigens, we determined the asynchronous CD14/CD66 co‐expression in unselected bone marrow and peripheral blood samples with suspected malignant blood disorders. CD14/CD66 co‐expression >5% were found in 131/691 bone marrow samples. Only 55 of these exhibited an identifiable population in 2‐parameter flow cytometry histograms. Of the 55 samples 43 (78%) came from patients with myeloid disorders; e.g. 11 with myelodysplastic syndromes, 15 with chronic myeloproliferative disorders and 17 with acute myeloid leukaemia. Only one of these 17 cases was a de novo case, while 8 were secondary to another malignant haematological disease and 8 were from the period after cytoreductive therapy. Notably, CD14/CD66 co‐expression patterns were related to disease categories; e.g. in chronic myelomonocytic leukaemia and acute myeloid leukaemia following a dysplastic phase the co‐expression displayed two subsets in peripheral blood, low‐avidity CD14 and low‐avidity CD66, respectively. The latter disease category also exhibited these 2 subsets in bone marrow. In all other cases, the CD14/CD66 co‐expression in bone marrow was heterogeneous. In conclusion, abnormal CD14/CD66 co‐expression might be a valuable parameter in defining asynchronous myelopoiesis in malignant myeloid disorders, especially myeloproliferative disorders and secondary acute myeloid leukemias.
Acute neurohumoral and cardiovascular effects of idarubicin in leukemia patients
Authors: Nousiainen T. , Jantunen E. , Vanninen E. , Remes J. , Puustinen J. , Rantala A. , Vuolteenaho O. , Hartikainen J.
Published: July 2010

Abstract: Idarubicin has been shown to have similar or superior antileukemic activity to daunorubicin with less cumulative cardiotoxicity. However, data of acute cardiovascular effects of idarubicin are scanty but may have clinical significance in predicting late cardiovascular complications. In the present study we evaluated prospectively acute neurohumoral and cardiovascular effects of idarubicin containing induction chemotherapy in 10 patients with newly diagnosed AML or MDS. Idarubicin was administered intravenously 12 mg/m2 on d 1, 3 and 5 as a part of the induction chemotherapy. Serial measurements of plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were performed at baseline and the day following each idarubicin infusion. Echocardiography was performed to assess cardiac systolic and diastolic function. Signal averaged electrocardiography (ECG) was recorded to observe myocardial late potentials associated with possible myocardial injury. In addition, ambulatory ECG recording was performed to assess arrhythmias. Plasma concentrations of ANP increased from 18.2 ± 1.5 pmol/l to 27.8 ± 3.5 pmol/l (p = 0.011), to 30.2 ± 3.0 pmol/l (p = 0.002) and to 40.8 ± 6.0 pmol/l (p = 0.006) after the first, second and third doses of idarubicin, respectively. Similarly, plasma concentration of BNP increased from 6.2 ± 1.9 to 9.0 ± 1.8 pmol/l (p = 0.049) and 17.5 ± 8.1 pmol/l (p = 0.203) after the first and third idarubicin infusion. Concomitantly, there was a trend towards an increase in left ventricular end diastolic diameter (LVEDD) (50.2 ± 1.8 to 54.4 ± 2.2 mm, p = 0.070). The increase in plasma BNP concentrations correlated significantly with the increase in LVEDD (r = 0.624; p = 0.002). No significant ECG changes or arrhythmias were associated with idarubicin infusions except in 1 patient who developed abnormal myocardial late potentials. Our results show that idarubicin causes acute neurohumoral activation associated with increased LVEDD indicating subclinical myocardial dysfunction. Whether these acute changes predict late clinical cardiomyopathy should be evaluated in prospective studies with larger number of patients and with higher cumulative anthracycline doses.
Early treatment with recombinant factor VIIa results in greater efficacy with less product
Authors: Lusher Jeanne M.
Published: July 2010

Abstract: Early treatment of bleeding episodes in haemophilia patients offers advantages over later treatment, including minimizing the damage caused by the haemorrhage and reducing the amount of product needed to control it. Self‐administration at home also offers greater convenience, and time and cost savings for both patient and physician. We compared the amount of recombinant activated factor VII (rFVIIa; NovoSeven®, Novo Nordisk, Bagsværd, Denmark) used in the treatment of peripheral intramuscular haemorrhages in people with haemophilia A and B with inhibitors and in those with acquired haemophilia, in the compassionate use, dose‐finding and US home treatment studies. We also compared the response rates in each of the 3 studies. In the compassionate use setting, in which the mean time from onset of bleeding to initiation of treatment with rFVIIa was 5 d, the mean number of doses given per bleeding episode was 13.6, with 63.1% of episodes without compartment syndrome and 73% with tense muscle/compartment syndrome having an excellent or effective response. In the dose‐finding study, average time from onset of bleeding to treatment with rFVIIa was 9 h. The average number of doses given was 3.55, and 72% in the high‐dose arm were judged to have an excellent or effective response. In the US home treatment study in which bleeding episodes were treated earlier (mean 1.2 h from onset of bleeding), the mean number of doses given was 2.3, and 92% had an effective response to treatment. These findings indicate that early treatment with rFVIIa has a greater success rate, with fewer doses being required. Home treatment results in cost savings, greater convenience, and less morbidity.
Approaches towards successful home treatment in patients with inhibitors
Authors: Ingerslev Jergen , Thykjær Hanne , Scheibel Elma
Published: July 2010

Abstract: Significant advances have been achieved in prevention of haemophilic disability through prophylactic administration of concentrates and early administration of coagulation factors to control new bleeding episodes, but there is only limited experience with home treatment in haemophilia patients with inhibitors. A home treatment programme using recombinant activated factor VII (rFVIIa; NovoSeven®, Novo Nordisk, Bagsværd, Denmark) in early intervention against minor bleeds in patients with high responding inhibitors was initiated in Denmark in June 1994. Following careful education and instruction, 2–3 doses each giving 90–100 μg/kg bodyweight of rFVIIa were stored in each patient's home. At the onset of a new bleeding episode patients were instructed to inject 1 dose of rFVIIa, and to call the Haemophilia Centre to discuss further management of the episode. If the drug was not completely effective after 1–2 h, a second dose was injected after 3 h. Patients were further instructed to contact us the following day for final efficacy reporting. In total, 7 patients have been enrolled into the study, and to date 114 bleeding episodes have been managed at home with a mean of 2.1 doses per bleed. On 4 occasions, recurrence of bleeding was noted within 24 h. Hospital admission was required in 9 cases, because of a serious injury, insufficient compliance or, in 2 cases, because bleeding required prolonged treatment. Management of these bleeding episodes required a mean of 18 doses. We propose and discuss key criteria for selection of patients for a home treatment programme. The results of this study demonstrate that early intervention in the home setting with rFVIIa is safe and effective in the management of minor bleeding episodes in haemophilia patients with inhibitors.
Optimal care of inhibitor patients during surgery
Authors: Vermylen Jos , Peerlinck Kathelijne
Published: July 2010

Abstract: The care of haemophilia patients with high titre inhibitors during surgery has always been a formidable challenge. The introduction of recombinant activated factor VII (rFVIIa; NovoSeven®, Novo Nordisk, Bagsværd, Denmark) appears to be a major breakthrough for the management of such patients. Administration of rFVIIa as a continuous infusion is a very attractive option and precludes the need for very frequent (2‐h) injections due to the very short half‐life of the product. Successful major surgery has been performed in patients with high titre inhibitors using continuous infusion of rFVIIa. Several questions remain, however, such as optimal therapeutic level, optimal monitoring, optimal prevention of thrombophlebitis at the injection site and the necessity for antifibrinolytic agents.
Immune tolerance induction: a role for recombinant activated factor VII (rFVIIa)?
Authors: Brackmann Hans‐Hermann , Effenberger Wolfgang , Hess Lothar , Schwaab Rainer , Oldenburg Johannes
Published: July 2010

Abstract: The development of factor VIII (FVIII) and FIX inhibitors is one of the most serious complications of repeated transfusions in patients with haemophilia. Management of patients with haemophilia with inhibitors must be separated into 2 concepts: the control of acute bleeding episodes and, in the long term, the treatment of the inhibitor itself. This paper will discuss both aspects of the management of these patients, focusing in particular on the therapeutic options available for the treatment of bleeding episodes during immune tolerance induction (ITI) therapy. The second part of the paper will review the management and outcomes of 10 patients with severe haemophilia in whom recombinant activated FVII (rFVIIa; NovoSeven®, Novo Nordisk, Bagsværd, Denmark) has been used to treat bleeding episodes in the Haemophilia Centre at Bonn University; 6 patients were treated with rFVIIa for bleeding episodes while undergoing ITI. The results obtained demonstrate that rFVIIa is a safe and effective treatment for bleeding episodes and haemostatic cover for surgical procedures in patients with inhibitors. Inhibitor titres were not boosted in patients with haemophilia and inhibitors on treatment with rFVIIa. Therefore, rFVIIa is also a suitable treatment for bleeding episodes or control of haemostasis during surgery in patients prior to initiation of ITI therapy.
Pharmaco‐economic aspects of inhibitor treatment
Authors: Goudemand Jenny
Published: July 2010

Abstract: The management of bleeding episodes and surgery in haemophilia patients who develop inhibitors is especially difficult. Haemostasis is typically achieved using high doses of factor VIII (FVIII) or FIX to overcome the inhibitor, or by using activated products, or by inhibitor eradication by immune tolerance induction. We assessed the costs of coagulation factors for non‐inhibitor haemophilia A and B patients (ACneg; n = 104), patients with low responding inhibitors (LR; n = 24) and patients with high responding inhibitors (HR; n = 17) in our centre between 1988 and 1995. In ACneg and LR patients, >90% of costs were attributed to home treatment, compared with 54% for HR patients. The costs of treatment were $US 36.8m total, $US; 41,000 mean per patient for ACneg patients; $US 10m total, $US; 46,000 mean per patient for LR patients; and $US; 7.6m total, $US; 59,000 mean per patient for HR patients. The mean cost of hospital treatment per HR patient was more than 10 times that for ACneg or LR patients and this was influenced by the occurrence of 4 very severe bleeding episodes in these patients. This analysis highlights the different costs and treatment patterns for inhibitor patients and should enable us to evaluate the impact of new treatments such as recombinant activated rFVII (rFVIIa; NovoSeven®, Novo Nordisk, Bagsværd, Denmark) on treatment at our centre in the future.
Plasma autoantibodies against platelet glycoprotein IIb/IIIa from patients with autoimmune thrombocytopenic purpura may recognize different antigenic determinants
Authors: Berchtold P. , Müller D. , Kouns W. C. , Riederer M. A. , Steiner B.
Published: July 2010

Abstract:  Autoantibodies against platelet glycoprotein (GP) GPIIb/IIIa have been demonstrated in patients with autoimmune thrombocytopenic purpura. Recently, it has been shown that plasma autoantibodies from some patients bind to the cytoplasmic domain of GPIIIa. Our aim was to evaluate further the binding specificity of these plasma autoantibodies. From 7 patients with detectable plasma antibodies against intact GPIIb/IIIa, 1 showed strong antibody binding to a synthetic C‐terminal peptide of GPIIIa. Ig class analysis of affinity purified anti‐GPIIb/IIIa autoantibodies from this patient revealed an IgM antibody that reacted with intact GPIIb/IIIa as well as with recombinant GPIIb/IIIa lacking the C‐terminal domains, and an IgG antibody that bound to intact GPIIb/IIIa but not to GPIIb/IIIa lacking the C‐terminal region. These data indicate that this patient has at least 2 autoantibodies, an IgG directed against the cytoplasmic domain of GPIIIa and an IgM reacting with the extracellular part of GPIIIa. This may support the hypothesis that plasma IgG antibodies directed against the C‐terminal domain of GPIIIa may be due to the exposition of cytoplasmic epitopes of GPIIIa as a result of increased cell lysis by IgM autoantibodies.
Comparison of rhG–CSF primed bone marrow and blood stem cell autografts: an analysis of engraftment in malignant lymphomas and solid tumours
Authors: Knudsen Lene Meldgaard , Hansen Steen Werner , Daugård Gedske , Jarlbæk Lene , Agerbæk Mads , Jensen Linda , Skovsgård Torben , Hansen Flemming , Johnsen Hans E.
Published: July 2010

Abstract:  Many studies have documented faster engraftment after transplantation with peripheral blood stem cells (PBSC) compared to bone marrow (BM) stem cells. Most comparisons, however, have been between unprimed BM and primed PBSC. We have collected engraftment data on 39 patients from 4 Danish centres and compared G–CSF primed BM with G–CSF primed PBSC in malignant lymphoma and solid tumours. In the lymphoma group 6 BM transplants were compared with 8 PBSC transplants, whereas in the testicular cancer group 16 BM transplants were compared with 9 PBSC transplants. In the lymphoma group, the time to platelet engraftment (platelets >20times109/l unsupported) was median 15 d in PBSC transplants and median 34 d in BM transplants (p=0.003). In the solid tumour patients the difference in time to platelet engraftment was 11 and 18 d in PBSC and BM transplants, respectively (p<0.0001). In an attempt to explain this difference we performed CD34+ subset analysis of BM and PBSC. This analysis revealed a higher content of lineage restricted cells (CD34+CD61+ and CD34+GlyA+) in PBSC compared to BM. In conclusion, G–CSF mobilized PBSC seems to result in faster engraftment than G–CSF primed BM, which could be explained by an increased number of lineage specific progenitors in PBSC compared to BM.
Efficient and persistent expression of β‐glucuronidase gene in CD34+ cells from human umbilical cord blood by retroviral vector
Authors: Ohashi T. , Iizuka S. , Sly W. S. , Machiki K. , Eto Y.
Published: July 2010

Abstract:  We succeeded in efficiently transferring the β‐glucuronidase gene in a retroviral vector to human hematopoietic progenitor cells using a centrifugation enhancement protocol. The transduction efficiency in CFU–GM was highly variable (23–100%) with an average of 66.8%. In the case of BFU–E, efficiency was 83% and 76% in 2 separate experiments. In LTCIC (long‐term culture‐initiating cell), transduction efficiency were 20% and 50% in 2 experiments. The enzymatic activity of β‐glucuronidase in transduced cells were increased above the control level up to 5 wk. Considering that correction of the enzyme deficiency in a small number of hematopoietic cells can be therapeutic for the Sly disease mouse, our data provide encouragement that human trials of gene therapy based on transferring β‐glucuronidase gene to hematopoietic cells may be efficacious.
Pirarubicin nuclear uptake does not correlate with its induced cell death effect during reversal of multidrug resistance by quinine in human K562 and CEM leukemic cells
Authors: Morjani H. , Belhoussine R. , Lahlil R. , Manfait M.
Published: July 2010

Abstract: A number of small and lipophilic cations are able to reversein vitrothe resistance to anthracyclines and other natural products through their interaction with P‐glycoprotein or P‐gp. However, some modulators do not interact with P‐gp. We have demonstrated in a previous a work, using confocal laser microspectrofluorometry, that quinine does not increase nuclear anthracycline uptake in multidrug‐resistant Chinese hamster ovary LR73 cells. In this case the LR73 cells were transfected with themdr1gene. Moreover, quinine induced in these cells an increase ofmdr1gene expression. In the present study, we investigated verapamil and quinine for their ability to increase nuclear pirarubicin uptake in multidrug‐resistant K562R and CEMR human leukemic cell lines. These two cell lines resist, respectively, to doxorubicin and vinblastine and both overexpress the P‐gp. Verapamil was able to restore nuclear pirarubicin in both cell lines. On the other hand, quinine was unable to significantly increase nuclear pirarubicin uptake. Both modulators were able to restore pirarubicin sensitivity in both resistant cell lines. After treatment with quinine,mdr1gene and P‐gp expression was not significantly altered as observed previously in the LR73 cells. This suggest that the effect of quinine onmdr1gene expression is dependent on the cell line studied. These data suggest that quinine could modify the molecular environment of anthracyclines and/or its binding to a possible cytoplasmic target, and that the mechanisms by which anthracyclines induce cell death, and ways by which chemotherapy fails in multidrug‐resistant leukemic cells remain complex and are related to more than one target.
Intestinal permeability in patients with acute myeloid leukemia
Authors: Sundström Gunnel M. , Wahlin Anders , Nordin‐Andersson Ingrid , Suhr Ole B.
Published: July 2010

Intestinal permeability was studied in patients with acute myeloid leukemia (AML) before, during and after chemotherapy. Intestinal permeability was determined by the lactulose (La)/mannitol (Ma) absorption test in 16 adult patients with de novo AML. The hydrogen breath test was used to disclose bacterial fermentation of the test substances in the small intestine. The permeability was found significantly increased (p<0.02) in the patients before induction chemotherapy treatment. During induction treatment and throughout the cytopenic period the intestinal permeability was constantly and significantly increased, compared with controls. In patients with abnormally increased permeability, no increase in hydrogen breath test result was noted. From our results it can be concluded that increased intestinal permeability is present in AML patients before commencing chemotherapy. Factors other than chemotherapy would seem to be more important regarding the occurrence of intestinal disturbances in these patients.
HIV influence on hematopoiesis at the initial stage of infection
Authors: Spada C. , Treitinger A. , Hoshikawa‐Fujimura A. Y.
Published: July 2010

Abstract:  Alterations in the parameters responsible for the characteristic anemic condition of AIDS patients who are at the final stage of infection have already been established. However, the development of these alterations at the initial stage of infection, where no opportunistic infections occur, needs further study. The goal of this study was to verify whether laboratory alterations observed on patients at the final stages of the disease could already be seen at the beginning of HIV infection, or were the result of opportunistic infections. To that end, HIV‐seropositive patients identified by the ELISA test and confirmed by immunofluorescence were screened by infectologist doctors and classified as per the Walter Reed Army Institute System. Results showed that thrombocytopenia occurred at an early stage during HIV infection. The number of leukocytes and erythrocytes diminished progressively as the disease advanced, and levels of hemoglobin, transferrin and serum iron were also diminished with the progression of the disease. These results indicate that the laboratory alterations observed in HIV‐seropositive patients during the initial stages were, probably, due to virus infection, because these patients did not present opportunistic infections.
VB‐CHEP chemotherapy regimen for aggressive non‐Hodgkin's lymphomas
Authors: Yalçin Şuayib , Kars Ayşe , Ozişik Yavuz , Tekuzman Gülten , Özyilkan Özgür , Çelik Ismail , Barişta Ibrahim , Güllü Ibrahim , Güler Nilüfer , Baltali Eşmen , Firat Dinçer
Published: July 2010

Abstract:  Despite intensive search for the optimal combination chemotherapy for aggressive non‐Hodgkin's lymphoma (NHL), the CHOP (cyclophosphamide, adriamycin, vincristine and prednisolone) regimen is still the standard therapy. We investigated the clinical efficacy of a new combination regimen consisting of vincristine, bleomycin–cyclophosphamide, adriamycin, etoposide and prednisolone (VB‐CHEP) in patients with aggressive NHL. A total of 29 patients with aggressive NHL was enrolled into the protocol. Eight patients were consolidated with cisplatin and cytarabine and 5 patients received radiotherapy for bulky disease. Objective response was achieved in 82.8% of the patients. Complete remission (CR) and partial remission rates were 72.4%, and 10.3%, respectively. CR rate was significantly lower in patients with advanced stage, extranodal disease and bone marrow involvement. Median follow‐up time is 34+ months; 17 patients are disease‐free while 12 died and only 2 patients with CR have relapsed so far. Median response duration is 29+ months and the median survival is 48+ months. The survival rate is 69% in the first year and 66% in the second year. A total of 152 cycles were evaluated for toxicity. Major hematological toxicity was myelosuppression and neutropenia, detected in 50.65%, was mostly grades 1–2. Neutropenic fever occurred in only 11 cycles. The side effects of the consolidation therapy were also acceptable. We conclude that the VB‐CHEP regimen with consolidation therapy for high‐risk patients may be an effective treatment for advanced stage aggressive NHL.
Enhanced neutrophil extravasation may be a contributing factor in the determination of neutropenia in patients with chronic idiopathic neutropenia of adults
Authors: Papadaki Helen A. , Eliopoulos George D.
Published: July 2010

Abstract:  To test the hypothesis that low numbers of circulating neutrophils may be due to enhanced neutrophil extravasation in patients with chronic idiopathic neutropenia of adults (CINA), serum levels of endothelial cell‐derived soluble cell adhesion molecules (sE‐selectin, sICAM and sVCAM) usually used as indicators of endothelial cell activation, serum levels of two potent endothelial cell activators (IL‐1β and TNF‐α), and serum levels of the chemokine interleukin‐8 (IL‐8) which is one of the main chemoattractant substances for neutrophils at sites of inflammation, were measured in 84 CINA patients and 30 healthy volunteers using the respective micro‐ELISA methods. We found that serum sE‐selectin, sICAM, sVCAM, IL‐1β and TNF‐α concentrations were all significantly increased in the group of patients compared to controls, and were correlated inversely with the number of circulating neutrophils. Serum levels of IL‐8 were also markedly increased in the patients compared to controls, and they were correlated positively with the levels of serum sE‐selectin, sICAM, sVCAM, IL‐1β and TNF‐α, and inversely with the number of circulating neutrophils. No significant differences were noted between patients and normal controls in the proportions of neutrophils carrying the cell adhesion molecules CD11a/CD18, CD15 and CD62L. These findings suggest strongly that CINA patients have activated endothelium to which circulating neutrophils may adhere by interacting with counter‐structures found on their surface. Subsequent diapedesis and subendothelial migration may be facilitated by IL‐8 and possibly other chemoattractant substances. We conclude that an enhanced neutrophil extravasation may be involved, at least in part, in the determination of neutropenia in CINA patients.
Transfusion‐transmitted diseases: risks, prevention and perspectives
Authors: Moor Anne C. E. , Dubbelman Tom M. A. R. , VanSteveninck John , Brand Anneke
Published: July 2010

Abstract: During the past decades major improvements in blood safety have been achieved, both in developed and developing countries. The introduction of donor counseling and screening for different pathogens has made blood a very safe product, especially in developed countries. However, even in these countries, there is still a residual risk for the transmission of several pathogens. For viruses such as the human immunodeficiency virus (HIV), and the hepatitis viruses B and C, this is due mainly to window‐period donations. Furthermore, the threat of newly emerging pathogens which can affect blood safety is always present. For example, the implications of the agent causing new variant Creutzfeld‐Jakob disease for transfusion practice are not yet clear. Finally, there are several pathogens, e.g. CMV and parvo B19, which are common in the general donor population, and might pose a serious threat in selected groups of immunosuppressed patients. In the future, further improvements in blood safety are expected from the introduction of polymerase chain reaction for testing and from the implementation of photochemical decontamination for cellular blood products. The situation in transfusion medicine in the developing world is much less favorable, due mainly to a higher incidence and prevalence of infectious diseases.
Extensive apoptosis of bone marrow cells as evaluated by the in situ end‐labelling (ISEL) technique may be the basis for ineffective haematopoiesis in patients with myelodysplastic syndromes
Authors: Parcharidou Agapi , Raza Azra , Economopoulos Theofanis , Papageorgiou Efstathios , Anagnostou Dimitra , Papadaki Theodora , Raptis Sotirios
Published: July 2010

Abstract: Apoptosis is a gene‐directed cellular self‐destruction which begins with internucleosomal cleavage of DNA and ends eventually with fragmentation of the nucleus. We have shown that the technique of ISEL of fragmented DNA appears to be an accurate and reliable measurement of the early stages of apoptosis. The present study was undertaken in order to define the incidence of programmed cell death in bone marrow (BM) haematopoietic and stromal cells of myelodysplastic syndromes (MDS). The ISEL technique was employed in 21 BM biopsies of MDS patients. The analysis showed that in 11/21 patients, >70% cells (high score) were undergoing programmed cell death while 5 patients showed up to 1/3 of the biopsy containing apoptotic cells and 2 patients had only few occasional ISEL positive cells. Stromal cells including fat cells, endothelial cells and fibroblasts were frequently in apoptosis in large clusters. Our results indicate that extensive apoptosis of haematopoietic cells documented in BM biopsies of MDS patients may be the explanation for the ineffective haematopoiesis which is the hallmark of these disorders.
The effect of interferon alpha on myeloproliferation and vascular complications in polycythemia vera
Authors: Heis N. , Rintelen C. , Gisslinger B. , Knöbl P. , Lechner K. , Gisslinger H.
Published: July 2010

Abstract: The effect of interferon alpha (IFN) on myeloproliferation and vascular complications was studied in 32 patients (17 female, 15 male; median age 60.5 yr) with polycythemia vera (PV). IFN therapy was initiated at a median time of 19 months after diagnosis. Ten patients were pretreated with chemotherapy in addition to phlebotomy. IFN dose was 12 megaU/wk during the first year, 9 megaU/wk during the second year and 12 megaU/wk thereafter. During IFN alpha treatment hematocrit level was 45.7% and remained at this level after the second year of treatment, compared to 46.5% before IFN. The frequency of phlebotomy before IFN was 0.49/month and dropped to 0.19/month (p<0.0005) during the first year of IFN treatment. IFN normalized high platelet and leukocyte counts in a majority of patients. The incidence of deep venous thromboses was 3.6%/yr before IFN alpha and 1.8%/yr during the first year of treatment. IFN‐induced side‐effects were mainly flu‐like symptoms, fever, fatigue and arthralgia. In conclusion, IFN allowed the reduction of the dose of chemotherapy and decreased the need of phlebotomy. Despite improvement of hematological parameters, it is still uncertain whether IFN alpha can improve clinical symptoms in PV.
Quality assurance of CFU‐GM assays: inter‐laboratory variation despite standard reagents
Authors: Lumley M. A. , Burton A. , Billingham L. J. , McDonald D. F. , Czarnecka H. M. , Milligan D.W.
Published: July 2010

Abstract: To investigate the hypothesis that commercial kits for CFU‐GM (colony forming unit granulocyte‐macrophage) assay will reduce the inter‐laboratory variation noted by many workers, we carried out a quality assurance exercise in 2 parts. There were 8 participants in the first study and each performed CFU‐GM assays using their in‐house method and a commercial kit (Stem Cell CFU Kit, Gibco) in parallel. In the second exercise there were 10 participants and each performed CFU‐GM with in‐house methods and with a different commercial medium (Methocult GF H4534, Stem Cell Technologies). Twelve samples of cryopreserved peripheral blood progenitor cells (PBPC) were analysed by each participant in each part of the study. A very wide range of results was found for the different in‐house methods, but standardizing the clonogenic assay with the commercial kits did not reduce the variation seen. To improve the reproducibility of CFU‐GM assays between laboratories, scrupulous attention should be paid to all the steps involved in the assays, as little progress will be made by using commercial medium in isolation from efforts to reduce other sources of variation.
Haematopoietic response and bcl‐2 expression in patients with acute myeloid leukaemia
Authors: Bincolettu Claudia , Saad Sara T. O. , da Silva Elizabeth Soares , Queiroz Mary L. S.
Published: July 2010

Abstract: Bcl‐2 expression, the number of apoptotic cells and the growth and differentiation of early bone marrow progenitor cells were studied in patients with confirmed diagnosis of acute myeloid leukaemia (AML). Bone marrow cells from normal individuals were used as controls. We observed an increased percentage of bcl‐2+ mononuclear bone marrow cells expression in AML patients in relation to controls (p = 0.002). Accordingly, the number of apoptotic cells was reduced (p = 0.001) and there was a negative correlation between bcl‐2 expression and the number of apoptotic cells (r=‐0.664, p< 0.001). In addition, bcl‐2 expression was significantly increased in the chemotherapy resistant group in relation to the responsive group (p = 0.03). Lower rate of survival was observed in the group of AML patients with autonomous proliferation (p = 0.01). These results suggest that a high bcl‐2 expression and the presence of autonomous proliferation are related to a poor prognosis in AML.