ILL# 161499334
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`Trans. # 2409470
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`1111111 1111111111 IIIII 111111111111111 IIIII 1111111111111
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`I IIIII I IIIII IIIII 111111111111111 IIIII 1111 1111
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`Odyssey
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`Processed: 11/23/15
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`HSRS
`* Haematologica - RESEND
`
`Journal Title: Haematologica.
`
`Volume: 84
`Issue: 8
`Month/Year: August 1999
`
`Pages: 767-8+ TOC+cvr w/acq
`datestamp
`
`Article Author: Carrasco et al.,
`
`Article Title: Acute megaloblastic
`anemia: homocysteine levels are useful
`for diagnosis and follow-up.+ TOC+acq
`date stamp on cover
`
`Imprint: Roma : II Pensiero Scientifico,
`[1974]-
`
`ISSN: 0390-6078
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`Lender String:
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`Notes ***RESEND, However we are
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`NEPTUNE GENERICS 1038- 00001
`
`APOTEX 1038-0001
`
`

`
`Scientific correspondence
`
`767
`
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`
`References
`
`1. Caballero MD, Gonzalez M, Canizo MC, Orfao A,
`Nieto MJ, San-Miguel JF. Concomitant chronic lym(cid:173)
`phocytic leukemia (CLL) and acute myeloid leukemia.
`Complete remission of CLL achieved with high-dose
`cytosine arabinoside. Leukemia 1992; 6:856-8.
`2. Conlan MG, Mosher OF. Concomitant chronic lym(cid:173)
`phocytic leukemia, acute myeloid leukemia, and
`thrombosis with protein C deficiency. Case report and
`review of the literature. Cancer 1989; 63:1398-401.
`3. Rai KR, Patel DV. Chronic lymphocytic leukemia. In
`Hoffman R, Benz EJ. Jr, Shattil SJ, Furie B, Cohen HJ,
`Silberstein LE (eds): Hematology: Basic Principles and
`Clinical Practice. 2nd ed. Curchill Livingstone, New
`York, 1995, p 1308.
`4. Lima M, Porto B, Rodrigues M, et al. Cytogenetic find(cid:173)
`ings in a patient presenting simultaneously with chron(cid:173)
`ic lymphocytic leukemia and acute myeloid leukemia.
`Cancer·Genet Cytogenet 1996; 87:38-40.
`5. Mateu R, Bellido M, Sureda A, et al. Concomitant
`chronic lymphocytic leukemia and acute myeloid
`leukemia with an uncommon immunophenotype. Am
`J Hematol 1997; 56:281.
`6. Tamul KR, Meyers DC, Bentley SA, FoldsJO. Two col(cid:173)
`or flow cytometric analysis of concomitant acute
`myeloid leukemia and chronic lymphocytic leukemia.
`Cytometry 1994; 18:30-4.
`
`Acute megaloblastic anemia: homocysteine
`levels are useful for diagnosis and follow-up
`
`Sir,
`Vitamin B12 (cobalamin) and folic acid deficiencies
`lead to megaloblastic anemia ( MA), and induce
`accumulation of methylmalonic acid (MMA) and
`homocysteine (HCY). 1 The most common presenta(cid:173)
`tion ofMA is classical macrocytic anemia. Other pre(cid:173)
`sentations are acute megaloblastosis (AM) and
`masked megaloblastosis. 2•3 1n this report, we present
`a case of AM diagnosed and followed up by evalua(cid:173)
`tion of HCY levels.
`A 45-year old male was diagnosed as having
`Philadelphia-positive chronic myelogenous leukemia.
`Three years after diagnosis the patient developed a
`lymphoid blast crisis and was started on a chemo(cid:173)
`therapy protocol. The first consolidation treatment
`consisted of6-mercaptopurine, methotrexate (MTX),
`VM-26 and cytarabine. MTX rescue with folinic acid
`was performed following standard guidelines. On day
`+14 a platelet count of9x 1 0 9/L was found. Hb was
`99 giL, mean corpuscular volume (MCV) 92 fL and
`leukocyte count was 7.06x 10 9 /L with 84% of neu(cid:173)
`trophils with hypersegmentation. Reticulocyte count
`was 0.053x1 0 12/L (1.66%). Vitamin B12 levels and
`red cell folate were 322 pmol /L (normal 150-1200)
`and 938 nmoljl (normal 441-1285), respectively. A
`BM aspirate revealed 30% of erythroid precursors
`with megaloblastic features and a 55% of myeloid
`precursors with increased size and no blast cells.
`Serum HCYievels were 38 ~moi/L (normal< 16). The
`
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`1.51
`
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`
`Figure 1. Light scatter properties Clf analyzed cells (top).
`The flow cytometric dot plots clearly show that virtually all
`CD19• cells are positive for CDS antigen and there are two
`cell populations with different HLA·DR antigen expressiGn
`pattern. CD33 antigen Is found to be the only antigen that
`expressed more than 50% of the bells and most of them are
`negative for HLA.OR antigen.
`
`nosis but we do not have any doubts about the diag(cid:173)
`nosis because more then 10x10 9/L cells expressed
`CDS, CD19, CD20 and CD22 (Figure 1 ).
`The concomitant presentation of AML and CLL is
`extremely rare and the use of two-color flow cytom(cid:173)
`etry to differentiate the cell populations demon(cid:173)
`strates the utility of this technology in the diagnosis
`of unusual hematologic malignancies.
`
`Mustafa Nuri Yenerel, • Ibrahim Hatemi, o Huseyin Keskin •
`
`*Istanbul University, Istanbul Medical School, Department of Inter·
`nat Medicine, Division of Hematology, (:apa, Istanbul; 0 Haseki
`State Hospital, Haseki, Istanbul, Turkey
`
`Key words
`CCL, AML, flowcytometry.
`Correspondence
`Mustafa Nuri Yenerel, MD, Istanbul University, Istanbul
`Medical School, Department of internal Medicine, Division
`of Hematoloyy, c;apa, Istanbul, Turkey. Fax: international
`+90.212.6311263.
`
`~·"''··c.·,·=·~··•d··=='"''···•.•~><·z·!·.···-·""~·<•ffi#eh .. •,&~.--•·'·-"''"'·'-~··-'"·'· ==~~1
`
`NEPTUNE GENERICS 1038-00002
`
`Haell)atologica vol. 84(8):August 1999
`
`APOTEX 1 038 - 0002
`
`

`
`768
`
`Scientific correspondence
`
`Table :t. Evolution of analytical parameters during folinic
`acid and vitamin B" treatment.
`
`Pre-treatment Onset
`Day -9
`Day 0
`
`Post-treatment
`Day +9
`
`Platelets (x109/L)
`Leukocytes (x109/L)
`Hemoglobin (giL)
`MCV (fl)
`Reticulocytes (x10 12/L)
`Homocysteine (~moljl)
`
`134
`6.76
`91
`93
`0.037
`
`9
`7.06
`99
`92
`0.053
`38
`
`112
`5.72
`95
`95.3
`0.163
`9
`
`AM, acute megaloblastosls; MCV, mean corpuscular volume.
`
`patient was diagnosed as having AM and began
`treatment with folinic acid 12 mg iv in one single dose
`and folic acid 5 mg/day po for 14 days and par(cid:173)
`enteral vitamin B12 2 mg!day for 4 consecutive days.
`After 10 days of treatment the platelet count
`increased to 112x109/L and reticulocyte count to
`0.163x10 12/L (5A1%). Vitamin B12 level was 716
`pmoi/L, red cell folate level 1,506 nmoi/L and serum
`HCY level decreased to normal value (9 IJmoi/L)
`(Table 1 )-
`Four different clinical forms of megaloblastosis
`have been described. 3 ·4 The classical form has an
`insidious onset with frequent neurologic symptoms
`and macrocytic anemia_ Vitamin B·2 and( or red cell
`folate levels are decreased. The second form is the
`subtle MA anemia with ill-defined clinical symptoms
`and decreased or borderline vitamin B12 and folic acid
`levels with other abnormalities (dUST, HCY, MMA). 2
`Masked megaloblastosis coexists with other defi(cid:173)
`ciencies; MCV is normal or decreased. 5·6 MA of acute
`onset is the rarest form_' There are two clinical pre(cid:173)
`sentations; the masked undiagnosed classical MA
`with cytopenias of abrupt onset and the so-called
`AM. 3 7 In AM severe thrombocytopenia develops in 1
`to 3 weeks, MCV is normal or only moderately
`increased_ This presentation is more frequent in
`patients with risk factors: parenteral nutrition, infec(cid:173)
`tion, dialysis or treatment with some antifolate drugs.
`Mortality is high. 1 The reticulocyte count is low. Vit(cid:173)
`amin B12 and red cell folate levels are normal. BM
`aspirate shows megaloblastic changes_ Classically,
`dUST is used as a diagnostic test. Nevertheless, HCY
`serum assays provide a sensitive test for the diagno(cid:173)
`sis of AM, especially in its early stages 8 In vitamin B12
`deficiences both HCY and MMA levels are high. In
`
`is
`folate deficiencies only HCY concentration
`10 HCY levels are also useful for AM follow(cid:173)
`increased. 9
`•
`up of AM; levels return to normal after starting treat(cid:173)
`ment with vitamin B12 or folic acid. The evaluation of
`serum HCY levels is an easy and non-invasive test for
`the diagnosis and follow-up of AM.
`
`Marina Carrasco, Angel Remacha, Anna Sureda,
`Pilar Sarda, Rodrigo Martino, Jorge Sierra
`
`Department of Hematology, Hospital de Ia Santa Creu i Sant Pau,
`Barcelona, Spain
`
`Keywords
`Acute megaloblastosis, folic acid, cobalamin, homocysteine
`
`Correspondence
`Angel Remacha Sevilla, MD, Laboratorio de Hematologfa,
`Hosprtal de Ia Santa Creu i Sant Pau, Antoni Maria i Claret,
`167, 08025 Barcelona, Spain_ Phone: international + 34-
`93-2919290- Fax· international +34-93-2919192- E(cid:173)
`mail.- 2107@hsp.santpau.es
`
`References
`
`1. Green R. Metabolite assay in cobalamin and folate
`deficiency. Bailliere Clin Haematol1995; 8:533-66_
`2. Carmel R. Subtle cobalamin deficiency. Ann Intern
`Med 1996; 124:338-40_
`3. Remacha A, Gimferrer E_ Las megaloblastosis agudas·
`revision y reconsideraci6n conceptual de las distintas
`formas de presentaci6n de las megaloblastosis_ Bioi
`Clin Hematol1984; 6:167-82_
`4_ Carmel R_ Pernicious anemia_ The expected findings of
`very low serum cobalam1n levels, anemia, and macro(cid:173)
`cytosis are often lacking_ Arch Intern Med 1988;
`148:1712-4.
`5_ Spivakjl. Masked megaloblastic anemia. Arch Intern
`Med 1982; 142:2111-4.
`6. Bennett M, Koren A, Ludacer E. B12 deficiency in a(cid:173)
`thalassemia. N Englj Med 1984; 310:1058-9_
`7. Martinez E, Remacha A, Roca-Cusachs A. Acute exac(cid:173)
`erbation offolate-dependent chronic megaloblastosis.
`Bioi Clin Hematol. 1992; 14:223-9.
`~- Vester t:l, H.asmussen K. H1gh performance llqu1d chro(cid:173)
`matography method for rapid and accurate determi(cid:173)
`nation of homocysteine in plasma and serum. Eur J
`Clin Chem Clin Biocherm. 1991; 29:549-54_
`9_ Allen RH, Stabler SP, Savage DG, Lindenbaum J- Diag(cid:173)
`nOSIS of cobalamin deficiency: 1: usefulness of serum
`methylmalonic acid and total homocysteine concen(cid:173)
`trations_ Am J Hematol 1990; 34: 90-8
`10. Lindenbaumj, Savage DG, Stabler SP, Allen RH. Diag(cid:173)
`nosis of cobalamin deficiency: II: relative sensitivities
`of serum cobalamin, methylmalonic acid and total
`homocysteine concentrations. Am J Hematol 1990;
`34:99-107.
`
`Haell)atologica vol. 84(8):August 1999
`
`NEPTUNE GENERICS 1038-00003
`
`APOTEX 1 038 - 0003
`
`

`
`Haell)atolo~ica 1999; val. 84, no. s
`
`Contents
`(indexed by Current Contents/Life Sciences and in Faxon Finder and Faxon XPRESS, also available on diskette with abstracts)
`
`editorial, comments and views
`
`How safe is hydroxyurea in the treatment
`of polycythemia vera? ................. 673-674
`
`Autologous bone marrow transplantation
`for chronic myeloid leukemia ............... 67 4
`
`original papers
`
`Short-term, serum-free, static culture of cord blood(cid:173)
`derived CD34• cells: effects of FL T3-L and MIP-1a
`on In vitro expansion of hematopoietic progenitor cells
`Gemma Capmany, Sergi Querol, Jose Antonio Cancelas,
`Joan Garcia ......................... 675-682
`
`Peripheral T lymphocyte cytokine profile (IFN-y, IL-2,
`IL-4) and CD30 expression/release during measles
`infection
`Fabrizio Vinante, Mauro Krampera, Lore/fa Morosato,
`Antone/la Riga, Sergio Romagnani,
`Giovanni Pizzolo ...................... 683-689
`
`3q21 and 3q26 cytogenetic abnormalities in acute
`myeloblastic leukemia: biological and clinical features
`Nicoletta Testoni, Gabriela Borsaru, Giovanni Martinelli,
`Cristina Carboni, Deborah Ruggeri, Emanue/a Ottaviani,
`Susanna Pelliconi, Paolo Ricci, Rocco Pastano, Giuseppe
`Visani, Alfonso Zaccaria, Sante Tura ........ 690-694
`
`Cleavage of the ALL1 gene in acute lymphoid
`leukemia before treatment disappears in relapse
`Eduardo Anguita, Ana Villegas, Anna Serra,
`Fernando Ataulfo Gonzalez, Paloma Ropero,
`Trinidad Contra, Giuseppe Sag/io . ......... 695-698
`
`Outcome of biphenotypic acute leukemia
`Sally Killick, Estella Matutes, Ray L. Powles,
`Mike Hamblin, John Swansbwy, Jennifer G. Tre/eaven,
`Athanasios Zomas, Ayad Atra, Daniel Catovsky . 699-706
`
`A prospective study of a-interferon and autologous
`bone marrow transplantation in chronic myeloid
`leukemia
`The Italian Cooperative Study Group on Chronic Myeloid
`Leukemia. Writing committee: Giovanna Meloni,
`Domenico Russo, Michele Baccarani, Nicoletta Testoni,
`Giovanni Martinelli, Renata Fanin, Eliana Zuffa,
`Gianantonio Rosti, Giuliana Alimena, Giuseppe Saglio,
`Franco Mandelli, Sante Tura . ............ 707-715
`
`Favorable impact of low-<lose fludarabine plus
`epirubicin and cyclophosphamide regimen {FLEC) as
`treatment for low-grade non-Hodgkin's lymphomas
`Monica Bocchia, Catia Bigazzi, Silvia Marconcini,
`Francesco Forconi, Giuseppe Marotta, Renata Algeri,
`Francesco Lauria ..................... 716-720
`
`Effect of adenosine derivatives on thrombus formation
`in vitro induced by shear stress
`Marzia Menegatti, Gloria Cristalli, Luciana Gallo,
`Pier Mannuccio Mannucci, Francesco I. Pareti . 721-725
`
`Lipoprotein( a) concentration is not associated with
`venous thromboembolism in a case control study
`Giuseppe Lippi, Antone/la Bassi, Giorgio Brocco,
`Franco Manzato, Maddalena Marini,
`Giancesare Guidi ..................... 726-729
`
`decision making and problem solving
`
`Long-term cost-effectiveness of low molecular weight
`heparin versus unfractionated heparin for
`the prophylaxis of venous thromboembolism
`in elective hip replacement
`Mania Marchetti, Nicola Lucio Liberato, Nicola Ruperta,
`Giovanni Barosi ...................... 730-737
`
`trends in hematology
`
`Placental/umbilical cord blood transplantation
`Girolamo Sirchia, Paolo Rebuf/a . .......... 738-747
`
`the irreplaceable image
`
`Homozygous form of the Pelger-Huet anomaly
`Jesus Gastearena Erice, Jose Marfa Arguifiano Perez,
`Francisco Sa/a Pericas .................... 748
`
`Bilobulated circulating lymphocytes in persistent
`polyclonal B-cell lymphocytosis
`Soledad Woessner, Lourdes Florensa,
`Blanca Espinet . ......................... 749
`
`Atypical clinical presentation of visceral leishmaniasis
`Jose-Angel Hernandez, Maria Alba Bosch,
`Goretti Sauca ........................... 750
`
`NEPTUNE GENERICS 1038-00004
`
`APOTEX 1 038 - 0004
`
`

`
`scientific correspondence
`
`Immunosuppression due to MACOP-B does not seem
`to cure the antiphospholipid syndrome
`Piero Maria Stefani, Francesco Pietrogrande,
`Roberto Sartori, Antomo Giro/ami . ......... 751-752
`
`New technology and changing parameters
`of leukapheresis for blood cell transplantation
`Katharina Granzow, Roberta Schiavo, lnna Timofeeva,
`Gianalessandro Moroni, Armando Santoro,
`Salvatore Siena . ......................... 752
`
`INR variability in anticoagulation with acenocoumarol:
`is it useful for identifying patients at risk of bleeding
`and thrombosis?
`Patricia Casais, Anal/a Sanchez Luceros,Susana
`Meschengieser, Emilse Bermejo,
`Maria Angela Lazzari . .................. 753-754
`
`The frequency of aii~Je ex"", a low expression allele of
`the gene encoding erythroid spectrin a-chain, in the
`Greek population
`lssidora Papassideri, Marianna Antonelou,
`Fotini Karababa, Afroditi Loutradi-Anagnostou,
`Jean Delaunay, Lukas H. Margaritis . ....... 754-755
`
`Acute myeloid leukemia occurring in a patient with
`polycythemia vera in treatment with hydroxyurea
`Emma Cacciola, Rosse/la Rosaria Cacciola,
`Patrizia Guglielmo, Fabio Stagna,
`Rosario Giustolisi . .................... 755-756
`
`Absence of p53 mutation in 15 cases of myeloid
`malignancies with structural rearrangements of 3q
`Luz Munoz, Camino Estivi/1, Anna Aventin,
`Conxa Boque, Olga Lopez, Josep F. Nomdedeu 757-758
`
`Invasive cerebral aspergillosis in a patient
`with aplastic anemia.
`Response to liposomal amphotericin and surgery
`Dolores Lopez Rodriguez. Carmen Alba Lopez,
`Esmeralda Benitez Cobos, Aida Jimenez Blanco,
`Angeles Fernandez Fernandez,
`LuiL Franr.;isco Araujo . .................. 758-759
`
`Transient response of myeloma clone
`to pamidronate therapy
`Alessandro Corso, Cesare Astori, Ester Orlandi,
`Patrizia Zappasodi, Luca Arcaini,
`Carlo Bernasconi ..................... 759-760
`
`A paradoxical side-effect of antiaggregating treatment
`with ticlopidine: the Moschowitz syndrome
`Fabrizio Fabris. Guido Luzzatto, MariaTeresa Sartori.
`Ilia Zanella, Antonio Giro/ami ............. 760-762
`
`Flow cytometry of cell suspensions from lymph nodes:
`immunophenotype, DNA content and proliferative rate
`are strongly correlated with histopathology diagnosis
`Joaquin Sanchez, _iosefina Serrano, Jose Manuel
`Garcia, Jose Romar., Javier Casaiio,
`Antonio Torres ....................... 762-763
`
`Previous occurrence of life-threatening abdominal
`infection is not a contraindication to bone marrow
`transplantation
`Marco Picardi, Carmine Se/leri, Gennaro De Rosa,
`Catello Califano, Andrea Camera, Bruno Rotoli . 764-765
`
`Splenic inflammatory pseudotumor mimicking
`primary splenic malignancy
`Yeouda Edoute, Ariel Roguin. Zahava Gallimidi,
`Ofer Ben-lzhak, Pradeep Nagachandran,
`Haim Ben-Ami ....................... 765-766
`
`Concomitant chronic lymphocytic leukemia and
`acute myeloid leukemia diagnosed by two color flow
`cytometric analysis
`Mustafa Nuri Yenerel, Ibrahim Hatemi,
`Huseyin Keskin ...................... 76fr767
`
`Acute megaloblastic anemia: homocysteine levels are
`useful for diagnosis and follow-up
`Marina Carrasco, Angel Remacha, Anna Sureda,
`Pilar Sarda, Rodrigo Martino, Jorge Sierra ... 767-768
`
`announcements
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`
`Haell)atologica
`is a Latin adjective, neuter and plural,
`used in this context as a noun:
`it means "hematological subjects".
`The appropriate English translation is therefore
`Journal of Hematology.
`
`On the cover.
`
`Bone marrow aspirate smear. Leishmania sp within reticulo(cid:173)
`endothelial macrophages. Note the platelet clump to
`compare with the sharper and stronger staining of
`Leishmania sp). (see p. 750).
`
`NEPTUNE GENERICS 1038-00005
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`NEPTUNE GENERICS 1038-00006
`NEPTUNE GENERICS 1038 - 00006
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