bluuebunny/crossref_metadata_2025 huggingface dataset:
Mobilization and collection of PBSC in healthy donors: comparison between two schemes of rhG‐CSF administration
Authors: Majolino I. , Scimé R. , Vasta S. , Cavallaro A. M. , Fiandaca T. , Indovina A. , Catania P. , Santoro A.
Published: July 2010

Abstract:  Procurement of a high number of progenitor cells is of primary interest in allogeneic PBSC transplantation. We have retrospectively compared toxicity, mobilization effect and progenitor cell yields of two different rhG‐CSF schedules in 11 consecutive healthy individuals donating their PBSC. Five of them received rhG‐CSF 16 μg/kg/d for 4 subsequent d in 2 divided subcutaneous injections (group A); similarly, 6 donors received rhG‐CSF 10 μg/kg/d for 5 d (group B). The aphereses were started the last day of rhG‐CSF treatment; 9 donors underwent 2 aphereses, one underwent 1 and another 3 procedures, always on subsequent days. Toxicity was mild, but moderate thrombocytopenia developed following apheretic collections, irrespective of rhG‐CSF schedule. In all the donors WBC, as well as circulating CD34+ cells, CFU‐GM, CFU‐GEMM and BFU‐E dramatically increased over the baseline values, peaking on d 5 or 6, with no statistical difference between the 2 groups for the height of the cell peaks. Also the peripheral lymphoid cell populations (CD3+, CD19+ and CD56+/CD3‐) increased following the rhG‐CSF administration. The number of MNC, CFU‐GM, BFU‐E, CFU‐GEMM, as well as CD34+, CD3+, CD19+ and CD56+/CD3 cells collected by apheresis showed no statistical difference in the 2 groups. Overall, 8 of the 11 donors collected the target number of CD34+ cells > 4times106/kg ideal recipient body weight with the first apheresis, with no difference between the 2 groups. Mobilization with rhG‐CSF in healthy donors enables the collection of large number of progenitor cells with modest side effects. A schedule of 10 μg/kg for 5 d is as effective as 16 μg/kg for 4 d. A single apheresis would be enough in 80% of cases.
Are different reference intervals for methylmalonic acid and total homocysteine necessary in elderly people?
Authors: Joosten Etienne , Lesaffre Emmanuel , Riezler Reiner
Published: July 2010

Abstract:  To determine whether age‐adjusted reference intervals for methymalonic acid (MMA) and total homocysteine (tHcy) are necessary, data from 2 previous studies were used. First, the reference intervals for serum vitamin B12, folate, methylmalonic acid and total homocysteine were determined in 2 reference sample groups: 99 healthy adults and 64 selected healthy elderly subjects living at home. Secondly, health‐related reference limits were estimated in 143 elderly subjects after supplementing the nutritional status with a combination of vitamin B12, vitamin B6 and folate during a 3‐wk period. In the latter group, the adjusted reference intervals for MMA (46–288 nmol/L) as well as for tHey (5–13.6 μmol/L) are different with considerably lower upper reference limits than that estimated with the original reference values (72–476 nmol/L for MMA; 6.8–21 μmol/L for tHcy) in the elderly subjects. Our data suggest that the MMA and tHcy levels increase with age. Moreover, the upper reference limit for MMA and tHcy, conventionally defined as the mean +2 SD in a healthy elderly reference sample group without supplementing the nutritional status, might result in falsely high values due to a high prevalence of an inadequate vitamin B12, vitamin B6 and folate status.
Megakaryocyte progenitors in paroxysmal nocturnal haemoglobinuria are sensitive to complement
Authors: Basara Nadezda , Antunovic Petar , Sefer Dijana , Radosevic Nina , Gotic Mirjana
Published: July 2010

Abstract:  We have investigated growth in vitro of bone marrow megakaryocytic progenitors (CFU‐Mk) in 7 patients with paroxysmal nocturnal haemoglobinuria (PNH) to determine the sensitivity of CFU‐Mk to complement. Bone marrow light density mononuclear cells were exposed to fresh or heat‐inactivated AB human serum in the presence of medium or isotonic sucrose solution. We found that the proliferative activity of bone marrow CFU‐Mk in PNH patients was significantly lower than in controls. In addition, the number of CFU‐Mk in PNH bone marrow cells exposed to isotonic sucrose and complement was reduced to 25% of that in PNH cells exposed to isotonic sucrose without complement. In conclusion, our finding showed an increased sensitivity of CFU‐Mk in PNH bone marrow cells to complement, supporting the hypothesis that the PNH defect is present at the level of CFU‐Mk.
Analysis of the p53 and MDM‐2 gene in acute myeloid leukemia
Authors: Seliger Barbara , Papadileris Stefan , Vogel Detlef , Hess Georg , Brendel Cornelia , Störkel Stephen , örtel Joachim , Kolbe Karin , Huber Christoph , Huhn Dieter , Neubauer Andreas
Published: July 2010

Abstract:  The MDM‐2 (murine double minute 2) gene codes for a cellular protein that can bind to the p53 tumor suppressor gene product, thereby functioning as a negative regulator of p53. In order to define the role of the MDM‐2 gene in the pathogenesis of human acute myeloid leukemia, the expression and the sequence of the MDM‐2 gene were examined in samples of bone marrow and/or peripheral mononuclear cells of 38 patients by using immunostaining, polymerase chain reaction (PCR), single strand conformation polymorphism, and sequencing. Immunohistochemical staining detected a weak accumulation of the MDM‐2 protein in AML patients of FAB classification M4 and M5. RT‐PCR analysis revealed a heterogeneous expression pattern of MDM‐2 mRNA in AML samples of different FAB classification. An increased level of MDM‐2 mRNA expression was observed in 17 of 38 AML patients when compared to normal controls. No structural changes in a 488 bp region extending from nucleotide 890 to 1378 of the MDM‐2 cDNA were detected using RT‐SSCP and sequence analysis. In addition, heterogeneous expression of p53 transcripts was found with the highest p53 mRNA levels in AML M4 and M5. Interestingly, there seems to be a correlation between the relative ratios of p53 and MDM‐2 mRNA levels in AML M4 and M5: in 15 of 23 cases high p53 mRNA expression was directly associated with high levels of MDM‐2 transcripts. An exclusively intranuclear p53 immunostaining pattern was found in 10 of 16 (58%) AML FAB M4 and M5, whereas the remaining AML samples tested were negative for p53 (0/10). Using RT‐SSCP analysis and direct sequencing of the RT‐PCR amplification products of p53 exon 5–8, we observed that only 1 of 38 AML patients showed a point mutation in the p53 gene. This missense mutation occurred in the evolutionary highly conserved region of p53 at codon 255 (Ile to Phe). These data indicated that structural alterations of the p53 gene do not play an important role in the initiation and progression of AML. However, abrogation of p53 tumor suppressor function due to MDM‐2 overexpression may be an alternative molecular mechanism by which a subset of AMLs may escape from p53‐regulated growth control.
Red blood cell permeability to thiol compounds following oxidative stress
Authors: Mazor D. , Golan E. , Philip V. , Katz M. , Jafe A. , Ben‐Zvi Z. , Meyerstein N.
Published: July 2010

Abstract:  The permeability of red blood cells (RBCs) to thiol containing compounds, reduced glutathione (GSH) and N‐acetyl cysteine (NAC), has been studied in control adult and neonatal cells and after oxidative stress. NAC penetrates the cell membrane easily while GSH hardly permeates. We measured their capacity to enhance intracellular non‐protein thiols (NPSH), after inducing damage to the membrane by formation of defects. Diamide, phenazine methosulfate (PMS) and t‐butyl hydroperoxide (BHP) were chosen as exogenous oxidants, each inducing damage by a different mechanism. Our data indicate that although neonatal cells are more sensitive to oxidative stress, only membrane damage induced by diamide, renders adult and neonatal cells permeable to GSH. NAC treatment enhances thiol levels in cells exposed to oxidizing agents, as well as in control cells.
Prognostic value of serum M‐protein doubling time at escape from plateau of multiple myeloma
Authors: Oivanen Tiina M. ,   Finnish Leukaemia Group
Published: July 2010

Abstract:  A long plateau phase is one of the strongest signs predicting long survival in multiple myeloma. The kinetics of escape from the plateau is, however, poorly known, and so is its influence on subsequent survival. During a 9‐yr follow‐up of 432 myeloma patients the serum M‐protein doubling time at first relapse was measured from serial observations in 137 cases. Univariate and multivariate analyses of pretreatment characteristics and of characteristics associated with chemotherapy were used to identify the predictors influencing on M‐protein doubling time. In 65 patients the M‐protein doubling time was 6 months or less and in 72 longer, with median remaining survival times of 17 and 45 months, respectively; 50% of the former group had any response to salvage chemotherapy, compared to 75% of the latter group. In univariate analysis stage and Hb were significant predictors for the M‐protein doubling time. An at least 75% response was associated with short doubling time. However, the multivariate analysis left only a long preceding plateau and use of several drug combinations during primary chemotherapy as significant predictors for a long M‐protein doubling time. A M‐protein doubling time of 6 months or less is associated with frequent resistance to salvage chemotherapy and short remaining survival. A short doubling of the M‐protein is preceded by a short plateau. The use of several drug combinations during primary chemotherapy does not jeopardize the later course of the disease. A short M‐protein doubling time seems not be a chemotherapy induced phenomenon.
“Benign erythrocytosis” and other familial and congenital polycythemias
Authors: Prchal Josef T. , Sokol Lubomir
Published: July 2010

Abstracts:  The term familial and congenital polycythemia encompasses a heterogeneous group of disorders with the common characteristic of an absolute increased red cell mass since birth and/or similar phenotype also present in relatives. In the last 2 decades the differential diagnosis between primary and secondary familial polycythemias became more physiologically relevant as new sensitive techniques, such as accurate measurements of serum erythropoietin (S‐EPO) concentration by radioimmunoassay (RIA) or ELISA, and assessment of growth of erythroid progenitor cells in vitro became available. Consequently, correct classification of many older previous reports of familial polycythemias is difficult. While familial secondary polycythemias due to high oxygen affinity hemoglobin mutants are not infrequent and have been well delineated in terms of molecular pathophysiology and phenotype during the last 3 decades, those secondary familial polycythemias due to 2,3 DPG deficiency are very rare. Familial and congenital polycythemias with increased EPO concentration and normal arterial oxygen saturation and oxygen dissociation kinetics represent an intriguing group of disorders wherein the molecular lesions remain obscure; however, in some instances a possibility of abnormal oxygen sensing pathway involving hypoxia inducible factor –1 (HIF‐1) open an intriguing yet unexplored area of hematology and biology. In contrast the primary familial and congenital polycythemia (PFCP) has been only recently recognized (the first report published in 1977). Various designations have been used in the past to describe PFCP, a rare clinical syndrome, including: benign familial erythrocytosis, polycythemia vera of childhood, primary polycythemia, pure erythrocytosis, etc. Some of these terms stressed the relatively benign, non‐progressive course of the disease with a normal lifespan of affected subjects; however, the apparent benignity of some of these disorders has been questioned. These disorders are familial and/or congenital, and the clinical and laboratory evidence of secondary polycythemias must be excluded. Only about 2 dozen familial and sporadic cases with PFCP have been reported. However, the mutations of erythropoietin receptor (EPOR) found in some of families with PFCP represent the only defined molecular defect of primary polycythemic phenotypes. All reported PFCP associated EPOR mutations result in truncation of its intracytoplasmic C‐terminal domain which negatively regulates the EPO/EPOR signal transduction pathway. Subjects with these mutations have decreased or normal S‐EPO and increased sensitivity of erythroid progenitor cells to low EPO concentrations in in vitro assays. Mutations of other genes involved in post EPOR signaling pathway such as JAK‐2, HCP and STAT 5 may also play a causative role in pathogenesis of some of PFCP families where mutation of EPOR was not found.
Peripheral blood progenitor cell (PBPC) transplantation with a single apheresis in patients with lymphoma, myeloma and solid tumors
Authors: Efremidis A. P. , Koumakis G. , Filis J. , Moraki M. , Vassilomanolakis M. , Hatzichristou H. , Barbounis V. , Stamatellou M. , Papanastasiou K. , Kritsioti M. , Plataniotis G. , Arseni P.
Published: July 2010

Abstract:  The aim of this study was to investigate if a single apheresis after peripheral blood progenitor cell (PBPC) mobilization can be used to rescue patients receiving high dose chemotherapy (HD.CHE) as treatment for an underlying malignancy. Eighteen consecutive patients who were admitted to the transplant unit for treatment were leukapheresed following mobilization with one of the following protocols: group I: rHuG–CSF alone, group II: conventional chemotherapy (C.CHE)+rHuG–CSF or rHuGM–CSF and group III: high dose Cytoxan (HD.CTX)+rHuG–CSF. The optimal day for leukapheresis was determined by following white blood cell counts (WBC), mononuclear cell counts (MNC) and CD34+ cell counts daily. Granulocyte – macrophage colony‐forming cells (GM–CFC) assay was performed at the leukapheresis product and prior to reinfusion. All patients proceeded directly to ablative therapy according to their underlying malignancy. PBPC from single apheresis were reinfused to all patients and cytokines started 24 h after infusion. Hematologic recovery after HD.CHE was the parameter used to ensure successful engraftment. We have been able to recover adequate number of PBPC for transplantation with a single apheresis in all patients. The number of infused cells were for groups I, II and III: (1) median number of MNC 4.7, 3.58 and 2.79 × 108/kg, respectively (2); median number of CD34+ cells 4.4, 2.8, 2.7 × 106/kg, respectively. The median apheresis day was 6, 16 and 16, respectively. Recovery times to granulocyte count >0.5 × 109/L was 9 d (range 9–12) and to platelets >20 × 109/L was 12 d (range 1–135); 17/18 patients have engrafted successfully independent of the mobilization method used.These data suggest that sufficient PBPC can be harvested at a single leukapheresis for hemopoietic rescue after myeloablative therapy. Rapid hematologic recovery occurs when cytokines alone after conventional or HD.CHE are used for mobilization. Results of collection products and hematopoietic recovery are independent of the mobilization technique used.
Gene transduction into murine primitive hematopoietic cells with 2‐gene retroviral vectors using a Transwell coculture system
Authors: Asami N. , Germeraad W. T. V. , Fujimoto S. , Nagai S. , Izumi T. , Katsura Y.
Published: July 2010

The present study aims at expressing a reporter gene in hematopoietic cells in vivo by introducing it into primitive hematopoietic cells with a 2‐gene retroviral vector. Various constructs of retroviral vectors containing the human IL‐2 receptor α chain gene (TAC) as the reporter and the neomycin phosphotransferase gene (neo) as a selectable marker were engineered, and the effectiveness of these vectors for expression of the reporter gene was evaluated after transfection into the packaging cell line GP+E86. It was found that the highest levels of reporter gene expression were attained with constructs ordered 5′ long terminal repeat (LTR)‐TAC‐internal promoterneo‐3′ LTR. In experiments investigating the expression of a reporter gene in hematopoietic cells, we used the Escherichia coli β‐galactosidase gene (lacZ) instead of TAC, because a very sensitive detection method was available for lacZ. For transduction of hematopoietic progenitors, packaging cell lines producing recombinant viruses were cultured in a Transwell hung into a Dexter‐type bone marrow (BM) culture. The BM cells were selected with G418, and transferred into irradiated recipient mice. LacZ enzyme activity was detectable in the peripheral blood lymphocytes (PBL) of recipients taken 8 wk after reconstitution.
An assessment of the clinicohematological criteria for the accelerated phase of chronic myeloid leukemia
Authors: Cervantes Francisco , López‐Guillermo Armando , Bosch Francesc , Terol María‐José , Rozman Ciril , Montserrat Emilio
Published: July 2010

In order to assess the relative importance of the clinicohematological features most commonly associated with the accelerated phase (AP) of chronic myeloid leukemia (CML) in 175 consecutive patients, 12 variables generally considered as indicating AP were analyzed for their predictive value for blast crisis (BC) appearance in less than 1 yr. At the time of analysis, 118 patients had died and 104 had developed BC. At univariate study, 6 features were associated with a significantly higher BC‐probability: poor performance status (ECOG score >2), unexplained fever/sweats, severe bone pain, progressive splenomegaly despite adequate therapy, blood basophils (>20%) and peripheral blasts (6–12%). At logistic regression, only bone pain and blood blasts (6–12%) retained their prognostic importance; the relative risk of unexplained fever/sweats and progressive splenomegaly was also clinically relevant. One‐year BC‐probability from the appearance of 1 or more of the above features was 77.3% (95% CI: 66–86.6) and 100% since all 4 were observed. Finally, at least 1 of the 4 features was present prior to death in 6 of 7 patients dying from CML‐related causes while not in BC. AP can be defined by the appearance along CML evolution of 1 or more of the 4 above‐mentioned clinicohematological features.
The bone‐marrow infiltration pattern in B‐cell chronic lymphocytic leukemia is not an important prognostic factor
Authors: Geisler C. H. , Hou‐Jensen K. , Jensen O. Myhre , Tinggaard‐Pedersen N. , Hansen M. Mørk , Hansen N. E. , Holm M. , Christensen B. Egelund , Drivsholm A. , Nielsen J. Boye , Thorling K. , Andersen E. , Larsen J. K. , Andersen P. Kragh ,   Danish CLL Study Group
Published: July 2010

Abstract: In a multicentre study of 635 consecutive newly diagnosed patients with B‐CLL, the histological bone marrow (BM) specimens were reviewed independently by each of 3 pathologists and found evaluable for BM infiltration pattern in 575 patients, 404 of whom had a CD5+, mainly FMC7–, faint surface‐membrane immunoglobulin (SIg) fluorescence‐intensity phenotype. In these 404 patients the following BM infiltration patterns were found: mixed nodular‐interstitial (30%), moderate interstitial (44%), heavy interstitial (20%) and diffuse packed (6%). In univariate survival analysis, significant differences were found according to BM pattern (p< 0.05), the presence of nodules being a favorable prognostic sign. In multivariate survival analysis in a model including age, clinical stage, BM pattern, BM lymphocytosis, WBC and sex, only age and stage but not BM pattern or BM lymphocytosis had independent prognostic significance. In stage A, progression‐free survival was significantly longer in patients with nodular than in patients with non‐nodular bone‐marrow pattern. The overall survival of these patients, however, did not differ, possibly owing to the prompt and prolonged treatment given to most patients at the time of progression to stage B or C. We conclude that in CD5+, SIgfaint, mainly FMC7–B‐CLL, bone‐marrow histology may predict unstable disease in early clinical stage but is not important for treatment decisions, when these are based on clinical stage.
All‐trans retinoic acid and in vitro cytokine production by acute promyelocytic eukemia cells
Authors: Visani G. , Tosi P. , Ottaviani E. , Zaccaria A. , Baccini C. , Manfroi S. , Pastano R. , Remiddi C. , Morelli A. , Molinari A. L. , Zanchini R. , Tura S.
Published: July 2010

Abstract:  Leukemic cells spontaneously secrete cytokines involved in the proliferation of the clone; in this study we evaluated the effects of all‐trans retinoic acid (ATRA) on the in vitro autocrine production of cytokines by acute myeloid leukemia cells. Thirty acute nonlymphoid leukemia cases (ANLL) (10 APL and 20 ANLL of other cytotypes than APL) were studied; the in vitro secretions of IL‐1α, IL‐3, IL‐4, IL‐6, IL‐10, G–CSF, GM–CSF, TNF‐α were tested with and without ATRA addition. After 5 d exposure to ATRA 10−6 m APL‐treated samples showed a significant reduction of IL‐6 (p = 0.008) and GM–CSF (p = 0.03) and a significant increase of IL‐1α (p = 0.01) production, if compared to untreated APL samples. No difference was seen in IL‐3, IL‐10 and IL‐4 productions; G–CSF production resulted absent in all but 3 APL cases, in which addition of ATRA determined increase in the production. Interestingly, the 3 G–CSF‐producing cases did not obtain clinical remission with ATRA; GM–CSF and IL‐6 were spontaneously produced by all the cases, and 7 of 10 APL patients subsequently obtained complete remission after induction. TNF‐α was produced only in 1 case. No statistical difference was seen in all the productions obtained from other than promyelocytic acute leukemic cells, both with and without ATRA addition. However, it is noteworthy that the production of IL‐6 was more than twice as high in ANLL non‐APL than in APL cases. In conclusion, these data could thus suggest possible complementary mechanisms of the exhaustion of the leukemic clone upon treatment with ATRA.
Transfusion of platelet concentrates – clinical evaluation of two preparations
Authors: Strindberg J. , Berlin G.
Published: July 2010

Abstract:  The aim of this study was to compare the clinical effect of transfusion of platelet concentrates (PC) prepared from pooled buffy coats (BC) and PCs collected from a single donor (SD) by an apheresis technique. The influence of storage time and various clinical conditions was also studied. Thirty‐two patients suffering from haematological malignancies were given a total of 326 platelet concentrates; 180 BC‐PCs and 146 SD‐PCs, median 7 transfusions per patient. BC‐PCs contained 312±52×109 and SD‐PCs 383 ± 133 × 109 platelets/unit (mean ± SD). The mean storage time of BC‐PC was 3 d and that of SD‐PC 1 d. The mean platelet count of the patients before transfusion was 11 ± 8 ×109/L. Regression analysis showed a significant decrease of the post‐transfusion platelet corrected count increment (CCI) during storage of PCs for 1–5 d (BC‐PC: p <0.01; SD‐PC: p <0.05). There was no difference in platelet increment between BC‐PC and SD‐PC. Human leukocyte antigen (HLA) alloimmunization was the major cause of clinical refractoriness to random donor platelet transfusions but splenomegaly also caused low CCI values.
Clinical implications of serum levels of soluble CD23 and tumor necrosis factor alpha in low‐grade non‐Hodgkin's lymphoma
Authors: Zinzani P. L. , Baccini C. , Zaccaria A. , Visani G. , Buzzi M. , Morelli A. , Molinari A. L. , Salvucci M. , Bendandi M. , Rubboli D. , Gherlinzoni F. , Zanchini R. , Tura S.
Published: July 2010

Abstract: In the last few years the research for new biological features in low‐grade non‐Hodgkin's lymphoma has provided important results. Several biological parameters are under evaluation and, in particular, cytokines and soluble receptors levels are showing their importance as prognostic parameters. In the present study, serum levels of tumor necrosis factor alpha (TNF‐α) and soluble CD23 (sCD23) were measured at the time of diagnosis and after induction polychemotherapy in 40 patients with newly diagnosed low‐grade non‐Hodgkin's lymphoma (LG‐NHL). The treaments were CIOP (cyclophosphamide, idarubicin, vincristine, prednisone) regimen for 28 patients and FMP (fludarabine, mitoxantrone, prednisone) scheme for 12 patients. Pretreatment levels of TNF‐α were highly elevated in patients with LG‐NHL compared with healthy controls (p=0.005) and were significantly correlated with the Ann Arbor stage (p=0.001). sCD23 was detected in 35 patients at diagnosis and were markedly increased in LG‐NHL patients when compared to healthy controls (p=0.005); patients with advanced stage presented higher values than those with early stage disease (p=0.002). All the complete responders (20/40, 50%) showed a decrease of TNF‐α and sCD23 levels. By contrast, the combination of high levels of TNF‐α and sCD23 correspond to a group of non‐responders. Our results suggest that TNF‐α and sCD23 are specific prognostic parameters for LG‐NHL, and that they could be used as tumor markers within a potential biological prognostic index.
Early diagnosis of low grade malignant lymphoma and chronic lymphocytic leukaemia. Verification of morphologically suspected malignancy in blood lymphocytes by flow cytometry
Authors: Schleiffenbaum B. E. , Rüegg R. , Zimmermann D. , Fehr J.
Published: July 2010

Abstract:  According to international recommendations, the diagnosis of chronic lymphocytic leukaemia (CLL) is made on the grounds of persistent peripheral lymphocytosis or lymphocytic infiltration of the bone marrow. The appearance of morphologically atypical lymphocytes in low‐grade malignant lymphoma (NHL) or CLL is easily overlooked, and is generally not regarded as a diagnostic criterion. We report 12 cases of CLL/NHL who were detected only by morphological screening of routine peripheral blood smears (83,400 blood smears). The diagnosis of CLL/NHL was not suggested by the patients' history, physical or other laboratory findings, and had not been contemplated by the physician in charge. Monoclonality of peripheral lymphocytes was confirmed by immunophenotyping and Southern blotting. The lymphoma was classified histologically according to the International Working Formulation (bone marrow biopsy). A monoclonal lymphatic population was not found by immunophenotyping in the blood of 11 patients whose lymphocytes were morphologically classified as activated‐abnormal. However, 3 patients suspected to have NHL/CLL on morphological screening of blood smears had to be classified as benign after immunophenotyping. We conclude that morphological screening of routine blood smears is an inexpensive and easy additional screening method for CLL and low grade malignant NHL.
Serum erythropoietin levels in patients with sepsis and septic shock
Authors: Abel Jörg , Spannbrucker Nestor , Fandrey Joachim , Jelkmann Wolfgang
Published: July 2010

Abstract:  The role of the immune system in the control of the production of erythropoietin is still poorly understood. Herein, the levels of circulating immunoreactive erythropoietin, tumour necrosis factor α, interleukin‐1β and interleukin‐6 were determined in 10 septic patients for up to 4 d following the admission to an internal intensive care unit. The data show that the production of erythropoietin was not suppressed despite an increase in the levels of proinflammatory cytokines. Circulating erythropoietin and interleukin‐6 greatly increased in the 6 nonsurviving patients. The pattern of the serum erythropoietin level in the nonsurvivors resembled that of acute phase proteins and was independent of the blood haemoglobin concentration. Similar to interleukin 6, abnormally high serum erythropoietin levels appear to be a negative prognostic indicator in patients suffering from septic shock.
Assessment of bone involvement in patients with multiple myeloma using bone densitometry
Authors: Abildgaard N. , Brixen K. , Kristensen J. E. , Vejlgaard T. , Charles P. , Nielsen J. L.
Published: July 2010

Abstract:  To evaluate the use of dual energy X‐ray absorptiometry (DXA) in multiple myeloma (MM) we performed a prospective study of 34 patients with newly diagnosed MM. Most patients had advanced disease and all but two patients had osteolytic bone destructions and/or pathological fractures. Bone mineral content (BMC) and bone mineral density (BMD) of the lumbar spine (L1–L4) and hip were measured using a Hologic QDR‐1000 scanner. Collapsed vertebrae were not excluded from analysis. Data from 289 healthy Danish volunteers aged 21–79 yr were used for calculation of Z‐scores. Lumbar spine BMC (Z‐score –0.46±0.23, p=0.05) and lumbar spine BMD (Z‐score –0.56±0.23, p=0.02) were significantly reduced in MM patients, whereas no reduction was seen in hip BMC or BMD. Collapsed vertebrae had marked reduced BMD (Z‐score –1.34±0.22, p<0.001), as had non‐fractured vertebrae in the same individuals (Z‐score –1.42±0.25, p<0.001). Lumbar spine BMD correlated with radiologically assessed bone morbidity (r –0.37, p=0.03) and stronger with the incidence of vertebral fractures (r –0.64, p<0.001). Thus, osteopenia of the back is common in multiple myeloma and correlates with an increased incidence of fractures. DXA may identify subjects with increased risk of vertebral fractures for more intensive chemotherapeutic or anti‐resorptive treatment.
CHOP vs. ProMACE‐CytaBOM in the treatment of aggressive non‐Hodgkin's lymphomas: long‐term results of a multicenter randomized trial
Authors: Montserrat E. , García‐Conde J. , Viñolas N. , López‐Guillermo A. , Hernández‐Nieto L. , Zubizarreta A. , Maldonado J. , Alcalá A. , Faura M.‐V. , Llorente A. , Bladé J. , Fontanillas M. ,   J. Estapé and (PETHEMA: Spanish Cooperative Group for the Study of Hematological Malignancies Treatment, Spanish Society of Hematology)
Published: July 2010

Abstract:  From May 1985 to May 1989, 175 patients with previously untreated aggressive non‐Hodgkin's lymphoma were randomized to receive CHOP or ProMACE‐CytaBOM. Eligibility criteria included follicular large‐cell, diffuse small cleaved‐cell, diffuse mixed, diffuse large‐cell and immunoblastic lymphoma with an Ann Arbor stage II, III or IV. One hundred and forty‐eight patients were evaluable. There were no significant differences between the 2 treatments in response rate (83.5% [57.5% CR] for CHOP vs. 88% [62% CR] for ProMACE‐CytaBOM), time to treatment failure (29% vs. 31% at 5 yr), or overall survival (42% in both groups at 5 yr). Furthermore, there were no significant differences between the 2 regimens when response rates and outcome were analyzed for different prognostic subgroups. Toxicity was not significantly different between the 2 regimens, although only 1 patient died as result of treatment‐related toxicity in the CHOP arm compared to 6 patients in the ProMACE‐CytaBOM group (p = 0.126). In conclusion, in this study ProMACE‐CytaBOM has not proved to be superior to CHOP in aggressive lymphomas. This trial gives support to the notion that CHOP still is the standard chemotherapy for aggressive lymphomas, and that new treatment approaches for these lymphomas should be compared to CHOP.
Changes in serum erythropoietin and the reticulocyte count during chemotherapy for leukemias
Authors: Sawabe Y. , Kikuno K. , Iseki T. , Iida S. , Tabata Y. , Yonemitsu H.
Published: July 2010

Abstract:  We serially determined serum erythropoietin (Epo) and the reticulocyte count in patients with various types of leukemia during chemotherapy. Serum Epo increased soon after the initiation of chemotherapy and decreased after the termination of therapy irrespective of the types of leukemia or treatment regimen. However, it did not stay at low level but fluctuated. The reticulocyte count, on the other hand, showed a transient rise while serum Epo level descended. The value of serum Epo when increased was higher than the value expected from hemoglobin concentration; this finding was similar to that in aplastic anemia. These results suggest that myelosuppression is a major factor for the increase in serum Epo level during leukemia chemotherapy.
When should the clinician suspect a drug‐induced blood dyscrasia, and how should he proceed?
Authors: Heimpel H.
Published: July 2010

Abstract:  Blood dyscrasias account for only a minor fraction of all adverse drug reactions (ADRs), but are relevant because of their relatively high morbidity and mortality. For the majority of drugs, the magnitude of risk is low enough to remain undetected until wider distribution of the drug takes place. Thus, only post‐marketing studies, carried out with appropriate methodology and sufficient statistical power, will allow the risk of serious haematological side‐effects of new drugs to be ascertained. Publication of carefully studied and thoroughly described single case studies and reports to registries are necessary to detect new associations between drugs and blood dyscrasias, while only large cohort or case‐control studies are suited to quantify the risks. Physicians managing a newly detected blood dyscrasia should be aware that it may be drug‐induced. They should assess the exact diagnosis, obtain and thoroughly document a detailed exposure history and follow the blood counts after withdrawal of all potentially relevant agents. The recognition and appropriate management of the problem in individual cases is the basis for both effective patient care and the quality of subsequent pharmaco‐epidemiological evaluation.
Drugs in the aetiology of agranulocytosis and aplastic anaemia
Authors: Kaufman David W. , Kelly Judith P. , Jurgelon Jan M. , Anderson Theresa , Issaragrisil Surapol , Wiholm Bengt‐Erik , Young Neal S. , Leaverton Paul , Levy Micha , Shapiro Samuel
Published: July 2010

Abstract:  Agranulocytosis and aplastic anaemia are rare but serious conditions known to be caused by numerous drugs. Most of what is known or suspected about the aetiology is based on case reports, with only a few formal epidemiological studies that provide quantitative estimates of risk. Updated results have been obtained from a combined analysis of data from 3 case‐control studies that used similar methods: the International Agranulocytosis and Aplastic Anemia Study (IAAAS), conducted in Israel and Europe; a study conducted in the northeast US; and a study conducted in Thailand. Totals of 362 cases of agranulocytosis, 454 cases of aplastic anaemia and 6458 controls were included in the analyses. The IAAAS and Thai study were population‐based, providing estimates of the incidence of the 2 dyscrasias. The overall annual incidence of agranulocytosis in the ambulatory population was 3.4/106 in the IAAAS and 0.8/106 in Thailand; by contrast the incidence of aplastic anaemia was 2.0/106 in the IAAAS and 4.1/106 in Thailand. A total of 21 compounds were significantly associated with an increased risk of agranulocytosis in the IAAAS and US studies. Excess risks ranged from 0.06 to 13 cases/106 users/wk; the most strongly associated drugs were procainamide, anti‐thyroid drugs and sulphasalazine. An association with drugs that had previously been suspected was also seen in Thailand. The overall aetiologic fractions of agranulocytosis due to drug use were 62% in the IAAAS, 72% in the US and 70% in Thailand. Eleven drugs were significantly associated with an increased risk of aplastic anaemia, with excess risks ranging from 1.4 to 60 cases/106 users in a 5‐month period. The most strongly associated drugs were penicillamine, gold and carbamazepine. Aetiologic fractions were 27% in the IAAAS, 17% in the US and 2% in Thailand, which paralleled the prevalence of use of associated drugs in the 3 populations. The present results confirm that agranulocytosis is largely a drug‐induced disease, with similar proportions accounted for in 3 disparate geographic regions. By contrast, although many of the expected associations were observed for aplastic anaemia, most of the aetiology is not explained by drugs. For all associated drugs, the excess risks are sufficiently low that blood dyscrasias should not figure prominently in the balancing of risks and benefits.
Incidence and non‐drug aetiologies of aplastic anaemia in Thailand
Authors: Issaragrisil Surapol , Kaufman David W. , Anderson Theresa ,   for the Thai Aplastic Anaemia Study Group
Published: July 2010

Abstract:  A population‐based, case‐control study of aplastic anaemia has been conducted in Thailand since 1989. Up to December 1994, the overall annual incidence was 3.9/106 in Bangkok, 5.0/106 in Khonkaen and 3.0/106 in Songkla. In Bangkok, the incidence peaked in 2 age groups (at 15–24 yr and ≥60 yr), whereas in Khonkaen and Songkla there was a consistent increase in incidence with increasing age. The results of case‐control analyses for non‐drug risk factors indicate a strong inverse association with socio‐economic status present in all 3 areas; a strong association with grain farming in the 2 rural areas that does not appear to be explained by pesticides; an association with occupational exposure to solvents in Bangkok; and a positive association with hepatitis A seropositivity.
Drug use and aplastic anaemia: the French experience
Authors: Mary Jean Yves , Guiguet Marguerite , Baumelou Elizabeth ,   French Cooperative Group for the Epidemiological Study of Aplastic Anaemia
Published: July 2010

Abstract:  The cause of the rare and severe condition of aplastic anaemia is largely unknown, although certain drugs have been implicated as possible aetiological factors, mostly through the evidence of case reports. A case‐control study was conducted in metropolitan France between 1985 and 1988 to investigate aetiological factors in aplastic anaemia. It was conducted in parallel with the establishment of a national register of the incidence of aplastic anaemia, which started in May 1984. The controls used in the study consisted of 2 hospitalized controls (i.e. patients admitted to hospital at the same time as the case) and a neighbour control named by the case. All three controls were matched for age and sex, and were interviewed by the same investigator as the case. A total of 147 cases, 287 hospitalized controls and 108 neighbour controls were interviewed. An association of varying degrees was noted between aplastic anaemia and the following conditions or treatments: clinical hepatitis during the past 6 months; history of chronic immune disorder (mainly rheumatoid arthritis); gold salts and d‐penicillamine; colchicine and allo‐thiopurinol; acetaminophen and salicylates. This survey confirmed the vanishing role of previously known toxic agents in the aetiology of aplastic anaemia. Some differences observed between the results of the present study and those published previously suggest that targeted studies on each category of drug according to specific disease areas should be initiated.
Drug‐related blood dyscrasias in a Swedish reporting system, 1985–1994
Authors: Wiholm Bengt‐Erik , Emanuelsson Staffan
Published: July 2010

Abstract:  Drug‐related blood dyscrasias as reported in Sweden during a 10‐yr period have been analysed in relation to sales and prescription data. The number of cases reported were as follows: agranulocytosis 390, thrombocytopenia 391, pancytopenia 50 and aplastic anaemia 36. The annual incidence rates per 106 inhabitants were: agranulocytosis 4.8, thrombocytopenia 5.6, pancytopenia 1.1 and aplastic anaemia 0.5. Incidences in the elderly were higher for all dyscrasias except aplastic anaemia. The most commonly reported drugs for all dyscrasias were sulphonamides and diuretics, but when related to sales data the risk of agranulocytosis was high for clozapine, dapsone, mianserin and sulphasalazine, while the risk did not seem to be increased for furosemide. For thrombocytopenia, furosemide, co‐trimoxazole and the measles, mumps and rubella vaccine were most commonly reported. The risk for pancytopenia and aplastic anaemia was increased for acetazolamide and co‐trimoxazole. As spontaneous reporting systems are primarily set up for signalling purposes, such data must always be interpreted with utmost care.
An epidemiological study of aplastic anaemia: relationship of drug exposures to clinical features and outcome
Authors: Kelly Judith Parsells , Jurgelon Jan M. , Issaragrisil Surapol , Keisu Marianne , Kaufman David W.
Published: July 2010

Abstract: Two hypotheses were examined in the combined data from 3 case‐control studies of aplastic anaemia, conducted in Thailand, Europe/Israel and the US: 1. Cases exposed to drugs associated with a significantly increased risk of aplastic anaemia are more likely to present with thrombocytopenia (e.g. petechiae, easy bruising); and 2. cases exposed to these drugs are more likely to recover quickly than non‐exposed cases. After excluding all cases who lacked information on timing of symptoms and those whose symptoms began ≥ 180 d before hospital admission, 392 cases remained for analysis. A total of 51 (13%) had been exposed to one of the significantly associated drugs; the remaining 341 (87%) had not. Among the former, 31% reported thrombocytopenia either before or at the same time as non‐bleeding symptoms (e.g. pallor, fatigue); the corresponding proportion among the non‐exposed was 53%. Data on time to recovery (return of the 3 blood cell lines to normal levels) were not available for the Thai cases; among the others, the median time to recovery for the non‐fatal cases was 7 and 6 months in the 29 exposed and the 83 non‐exposed cases, respectively. The data do not support either hypothesis: the two groups of aplastic anaemia cases appeared to be similar in both the presenting symptoms and the recovery time.
Immune pathophysiology of acquired aplastic anaemia
Authors: Young Neal S.
Published: July 2010

Abstract:  Clinical observations and laboratory studies have supported an immune basis for most acquired aplastic anaemias, with the majority of patients responding to immunosuppressive therapy. In vitro, interferon (IFN) and tumour necrosis factor (TNF) inhibit haematopoiesis, including colony formation by early and late progenitor cells and the generation of long‐term culture initiating cells (LTCIC). These lymphokines induce Fas antigen expression on CD34+ cells and apoptosis within the haematopoietic cell compartment. Local secretion of cytokines is far more potent than addition to long‐term bone marrow cultures. Activated cytotoxic lymphocytes, high levels of INFγ and TNFα, and increased Fas expression on CD34+ marrow cells are present in patients. Haematopoiesis is severely diminished in severe aplastic anaemia on presentation: CD34+ cell numbers, colony forming cells and LTCIC are all markedly decreased. LTCIC numbers do not predict recovery. Blood cell counts increase in some cases in the absence of changed numbers of LTCIC, but recovered patients have higher and sometimes normal LTCIC numbers. The mechanism by which chemical and biological agents incite altered immunity remains unclear. Drug associations have been inferred from case reports and formal epidemiological studies, but have remained refractory to systematic laboratory study. Whatever the initial events, immune system destruction of haematopoiesis plays a central role in the development of acquired aplastic anaemia.
Could aplastic anaemia be considered a pre‐pre‐leukaemic disorder?
Authors: Socié G.
Published: July 2010

Abstract:  Clinical evidence for a link between aplastic anaemia, paroxysmal nocturnal haemoglobinuria (PNH) and hypoplastic leukaemia is provided by studies of clonal disorders, which may be a complication of congenital or acquired aplastic anaemia. Fanconi's anaemia is the most common congenital disorder and leukaemia occurs in at least 10% of cases. In acquired aplastic anaemia, a high incidence of myelodysplastic syndrome (MDS) was noted in patients with aplastic anaemia, seemingly cured of their aplasia by antilymphocyte globulins (ALG). In a recent survey, the 10‐year cumulative incidence rates were 9.6% for MDS, 6.6% for acute leukaemia (115‐fold higher than in the general population). Biological evidence is provided by bone marrow morphology, as a certain degree of dysmyelopoiesis is not unusual in aplastic anaemia. Cytogenetic analyses in aplastic anaemia are scarce, but data have shown clonal cytogenetic abnormalities at diagnosis in otherwise typical aplastic anaemia. Recently, flow cytometry to assess the glycosyl‐phosphatidylinositol (GPI) molecule defect in PNH has demonstrated that a significant proportion of patients with otherwise typical aplastic anaemia have, in fact, a GPI defect due to alterations within the PIG‐A gene. Finally, aplastic anaemia patients were recently reported to have molecular evidence of clonal haematopoiesis; this must now be discussed in light of recent clonality studies in normal individuals. The clinical and biological evidence for a link between aplastic anaemia, PNH and hypoplastic leukaemia allows the generation of a model of aplastic anaemia as a possible pre‐pre‐leukaemic disorder.
Immune mechanisms leading to drug‐induced blood dyscrasias
Authors: Claas F. H. J.
Published: July 2010

Abstract:  Drug‐induced blood dyscrasias may be due to toxicity of the drug, inborn errors of metabolism or immunological reactions. In the latter case, drug‐induced antibodies are directed to specific target cells, such as platelets (thrombocytopenia) or granulocytes (agranulocytosis). Some of these immune mechanisms are based on the physical interaction between drug, antibody and target cells. A particular drug may bind to the surface of the blood cell which, as a carrier of the drug, will be destroyed as part of the immune reaction to the drug (hapten mechanism). Other drugs will form immune complexes with drug‐specific antibodies. These immune complexes will bind to certain blood cells and destroy them as innocent bystanders (immune complex mechanism). In vitro assays are described which enable the offending drug to be detected by mimicking these immune mechanisms using patient serum, platelets or granulocytes, and the suspected drug. The diagnostic value of these in vitro assays is discussed.
The role of cytokines in haematopoiesis
Authors: Schwarzmeier Josef D.
Published: July 2010

Abstract:  Cytokines, by definition, exert an effect on haematopoiesis. Diseases characterized by haematopoietic insufficiency, such as aplastic anaemia, should therefore be investigated for abnormal expression of these regulatory proteins. In studies on hairy cell leukaemia, a severe deficiency was found in the production of interleukin‐3 (IL‐3), granulocyte‐macrophage colony stimulating factor (GM‐CSF), granulocyte CSF, IL‐6 and tumour necrosis factor α (TNFα). Further studies on IL‐6 at the mRNA and protein levels revealed that peripheral blood mononuclear cells and even hairy cells could be stimulated by interferon α (IFNα) to produce IL‐6. It is interesting to speculate on the beneficial effects of IFNα therapy on the expansion of normal haematopoiesis and suppression or even elimination of malignant cells. Studies on a patient with angio‐immunoblastic lymphadenopathy, another disease showing haematopoietic insufficiency, who developed severe aplastic anaemia, showed massive increases in IFNγ and TNFα levels in serum; IL‐6 and GM‐CSF levels were below the limit of detection. These results correlated with an abnormal distribution of CD4+ and CD8+ T lymphocytes in the patient's blood and were compatible with the suppressive effects of IFNγ and TNFα on haematopoiesis.