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National Cancer Institute®
Ultima Vez Modificado: 1 de enero del 2002
UI - 10669443
AU - Regan FA; Hewitt P; Barbara JA; Contreras M
TI - Prospective investigation of transfusion transmitted infection in recipients of over 20 000 units of blood. TTI Study Group.
SO - BMJ 2000 Feb 12;320(7232):403-6
AD - National Blood Service, London and South East Zone, North London Centre, London NW9 5BG.
OBJECTIVES: To follow up recipients of 20 000 units of blood to identify any transmissions of infections through blood transfusion. DESIGN: Follow up study of recipients of transfusion. SETTING: 22 hospitals in north London. PARTICIPANT: Adult patients who had recently been transfused. MAIN OUTCOME MEASURES: Patients had further blood samples taken at 9 months that were tested for markers of hepatitis B and C and HIV and human T cell leukaemia/lymphoma virus type I or II (HTLV) infections. Recent infections were distinguished from pre-existing infections by comparison with blood samples taken before transfusion. RESULTS: 9220 patients were recruited, and 5579 recipients of 21 923 units of blood were followed up. No transfusion transmitted infections were identified. The incidence of transfusion transmitted infections was 0 in 21 043 units (95% confidence interval for risk 0 to 1 in 5706 recipients) for hepatitis B; 0 in 21 800 units (0 to 1 in 5911 recipients) for hepatitis C; 0 in 21 923 units (0 to 1 in 5944 recipients) for HIV; and 0 in 21 902 units (0 to 1 in 5939 recipients) for human T cell leukaemia/lymphoma virus. Three patients acquired hepatitis B during or after hospital admission but not through transfusion; 176 (3%) had pre-existing hepatitis B infection. Sixteen (0.29%) patients had hepatitis C, and five (0.09%) had human T cell leukaemia/lymphoma virus. CONCLUSIONS: The current risk of transfusion transmitted infections in the United Kingdom is very small, though hospital acquired infections may arise from sources other than transfusion. A considerable proportion of patients have pre-existing infections.
UI - 11474564
AU - Schaison G; Auclerc MF; Baruchel A; Leblanc T; Leverger G
TI - [Prognosis of acute lymphoblastic leukemia in children. Results of the French protocol FRALLE 93]
SO - Bull Acad Natl Med 2001;185(1):149-60; discussion 160-2
AD - Service de Pediatrie a Orientation Hematologique-Hopital Saint-Louis, 1 avenue Claude Vellefaux-75475 Paris.
1,120 children were included in protocol FRALLE 93 from june 1993 to september 1998. Disease Free Survival for the all protocol is 78% +/- 3 and overall survival 83% +/- 3. Various clinical and laboratory features at the time of diagnosis have been correlated with prognosis. They provide a potential mean to stratify patients into treatment subgroups according their relative risk of treatment failure. The identification of these prognostic factors has been an essential element in the design of current therapeutic trials. Prognostic characteristics of childhood ALL include: age, white blood cell count, tumor burden, cytogenetics (chromosome count and chromosomal translocation), immunophenotype and early response to treatment. Molecular biology has been the revolution of the last two decades permitting the cloning of the genes involved in the leukemic process. Finally the new molecular techniques allow a sensitive diagnostic approach to minimal residual disease (MRD). The better detection of MRD must allow a more rational basis for therapeutic intensification for a subset of poor responder patients. A decrease in therapy of very good responders can also be envisaged.
UI - 11410424
AU - Nomdedeu JF; Badell I; Estivill C; Carnicer MJ; Sierra J; Baiget M
TI - TEL rearrangements in acute lymphoblastic leukemia: association with p16 deletions in relapsed cases.
SO - Haematologica 2001 May;86(5):547-8
UI - 11432614
AU - de Haas V; van der Schoot CE; van den Berg H
TI - Risk assessment in ALL in children: a focus on PCR-based techniques for MRD detection.
SO - Ann Oncol 2001 May;12(5):587-92
AD - Department of Paediatric Oncology, Emma Kinderziekenhuis/Academic Medical Centre, Amsterdam, The Netherlands.
UI - 11509123
AU - Beck JF; Brugger D; Brischwein K; Liu C; Bader P; Niethammer D; Gekeler
TI - V Anticancer drug-mediated induction of multidrug resistance-associated genes and protein kinase C isozymes in the T-lymphoblastoid cell line CCRF-CEM and in blasts from patients with acute lymphoblastic leukemias.
SO - Jpn J Cancer Res 2001 Aug;92(8):896-903
AD - Department of Pediatric Haematology/Oncology, University of Greifswald, Soldmannstr. 15, D-17487 Greifswald, Germany. email@example.com
The major determinants mediating drug resistance in acute lymphoblastic leukemias (ALL) unresponsive to chemotherapy, are still unclear. For example, it is still unknown whether selection or induction processes are responsible for drug resistance here or whether protein kinase C (PKC) isozymes contribute to the resistant phenotype. Therefore, inducibility of resistance factors or PKC isozymes genes was examined in CCRF-CEM cells treated with diverse anticancer drugs--adriamycin, camptothecin, etoposide or vincristine--at sublethal concentrations for 24 h. MDR1, MRP1, LRP and PKC isozyme alpha, beta(1), beta(2), epsilon, iota, eta, theta, zeta gene expression was determined by cDNA-PCR. We found significant dose-dependent, mostly combined, induction of the MDR1, MRP1 and LRP genes. Significantly enhanced gene expression of the majority of PKC isozyme genes was found after treatment with camptothecin. PKCzeta was upregulated throughout by each anticancer drug applied in this setting. A series of selected CCRF-CEM-derived multidrug resistance (MDR) sublines also showed enhanced expression of the PKC isozymes compared to the parental cell line. MDR1 and PKCeta gene expression levels were correlated highly significantly. Blasts from two patients with ALL during the first week of monotherapy with steroids revealed combined induction of the MDR1, multidrug resistance-associated protein 1 (MRP1), lung cancer resistance-related protein (LRP) and most PKC isozymes, predominantly PKCzeta. Another patient with T-ALL, who failed to respond to four months of intensive chemotherapy, showed an enhanced MRP1 gene expression combined with markedly overexpression of PKCeta and PKCtheta. Furthermore, the camptothecin and etoposide-mediated induction of resistance factors in the CCRF-CEM cell line could be suppressed by staurosporine, a rather unspecific inhibitor of protein kinases. However, selective inhibitors of PKC isozymes (bisindolylmaleimide GO 6850, indolocarbazole GO 6976) produced no significant effects here. Therefore, the PKC isozymes eta, theta and zeta are of interest as potential targets to overcome drug resistance in ALL.
UI - 11561155
AU - Hiebert SW; Lutterbach B; Amann J
TI - Role of co-repressors in transcriptional repression mediated by the t(8;21), t(16;21), t(12;21), and inv(16) fusion proteins.
SO - Curr Opin Hematol 2001 Jul;8(4):197-200
AD - Department of Biochemistry, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, 23rd and Pierce Avenue, Nashville, TN 37232, USA. firstname.lastname@example.org
The t(8;21), t(16;21), inv(16), and t(12;21) are some of the most frequent chromosomal translocations found in acute myeloid and acute lymphoblastic leukemia. The fusion proteins created by these chromosomal translocations are transcriptional repressors. A full understanding of the types of proteins that these fusion proteins recruit to repress transcription will not only clarify understanding of the molecular mechanism of action of these fusion proteins but also provide further targets for therapeutic intervention.
UI - 11550288
AU - Mathew S; Shurtleff SA; Raimondi SC
TI - Novel cryptic, complex rearrangements involving ETV6-CBFA2 (TEL-AML1) genes identified by fluorescence in situ hybridization in pediatric patients with acute lymphoblastic leukemia.
SO - Genes Chromosomes Cancer 2001 Oct;32(2):188-93
AD - Department of Pathology, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105-2794. email@example.com
In childhood B-lineage acute lymphoblastic leukemia (ALL), the most common genetic change, the ETV6-CBFA2 (TEL-AML1) fusion resulting from the cryptic t(12;21)(p13;q22) is associated with a favorable outcome. Therefore, it is important to identify patients with this translocation so that they can receive appropriate treatment. To identify new partner breakpoints for ETV6 and CBFA2, we selected 30 patients with childhood ALL in whose leukemic cells a t(12;21) had been detected by RT-PCR. Conventional cytogenetics revealed that 12p abnormalities were present in 10 patients and that other random abnormalities were present in another 15, including 9 with a numerical or structural abnormality of chromosome 21. Normal karyotypes were observed in the leukemic blasts of five patients. Interphase fluorescence in situ hybridization (FISH) confirmed the RT-PCR finding of the t(12;21) in each patient and detected the loss of the wild-type ETV6 allele in 14 (47%) patients. Metaphase cells from only 20 patients were available for additional FISH analysis. In 13 patients, the expected fusion signal of t(12;21) was observed on der(21)t(12;21), and the reciprocal CBFA2 signal was observed on der(12)t(12;21). However, in six patients with the ETV6-CBFA2 fusion on chromosome 21, the reciprocal CBFA2 signal was observed not on 12p13 but on 4q21, 4q27, 8q24, 11q24, 14q11.2, or 16p13.1. In four of these six patients, we found interstitial insertions of part of CBFA2. In another patient, the ETV6-CBFA2 fusion was observed on 4q21 rather than on 21q. Thus, seven (35%) of the 20 patients with a t(12;21) revealed complex rearrangements. Our findings also indicate the importance of analyzing metaphase chromosomes in identifying cryptic and complex rearrangements involving ETV6 and CBFA2. Copyright 2001 Wiley-Liss, Inc.
UI - 11564065
AU - Muller HJ; Beier R; Loning L; Blutters-Sawatzki R; Dorffel W; Maass E;
TI - Muller-Weihrich S; Scheel-Walter HG; Scherer F; Stahnke K; Schrappe M; Horn A; Lumkemann K; Boos J Pharmacokinetics of native Escherichia coli asparaginase (Asparaginase medac) and hypersensitivity reactions in ALL-BFM 95 reinduction treatment.
SO - Br J Haematol 2001 Sep;114(4):794-9
AD - Department of Paediatric Haematology/Oncology, University of Munster, Germany. firstname.lastname@example.org
Repeated asparaginase treatment has been associated with hypersensitivity reactions against the bacterial macromolecule in a considerable number of patients. Immunological reactions may range from anaphylaxis without impairment of serum asparaginase activity to a very fast decline in enzyme activity without any clinical symptoms. Previous investigations on a limited number of patients have shown high interindividual variability of asparaginase activity time courses and hypersensitivity reactions in about 30% of patients during reinduction treatment. Therefore, monitoring of reinduction treatment was performed prospectively in 76 children with newly diagnosed acute lymphoblastic leukaemia (ALL). According to the ALL-Berlin-Frankfurt-Munster (BFM) 95 protocol, 10 000 U/m2 body surface area of native Escherichia coli asparaginase (Asparaginase medac) was given on d 8, 11, 15 and 18. In 45/76 children, trough and peak activities were determined with every dose, and also on d 4 and d 11 after the last administration. Data on asparaginase activity were not available from the remaining 31 patients, but information with regard to hypersensitivity reactions only was given. Eighteen out of 76 patients (24%) suffered a clinical hypersensitivity reaction; however, no silent inactivation was observed. Activity in the therapeutic range of greater than 100 U/l for at least 14 d was determined in 43 of the 45 patients who were analysed for enzyme activity.
UI - 11568017
AU - Fasching K; Panzer S; Haas OA; Borkhardt A; Marschalek R; Griesinger F;
TI - Panzer-Grumayer ER Presence of N regions in the clonotypic DJ rearrangements of the immunoglobulin heavy-chain genes indicates an exquisitely short latency in t(4;11)-positive infant acute lymphoblastic leukemia.
SO - Blood 2001 Oct 1;98(7):2272-4
AD - Children's Cancer Research Institute, St Anna Kinderspital, and Clinic for Blood Group Serology, University of Vienna, Austria.
Childhood acute lymphoblastic leukemia (ALL) is frequently initiated in utero at a time of developmentally regulated insertion of N regions into the DJ(H) rearrangements of immunoglobulin heavy-chain (Ig(H)) genes. Here it is shown that N regions are present in the clonotypic DJ(H) rearrangements in 11 of 12 infant ALLs with t(4;11). These data are compared with the 122 previously published DJ(H) sequences and were found to have a pattern similar to that of ALL in children older than 3 years at diagnosis but were unlike that in children younger than 3 years who predominantly lack N regions. These findings, therefore, indicate that t(4;11)-positive infant ALL is initiated later in fetal development than most B-cell precursor ALL from children younger than 3 years and that they have a shorter latency period already in utero.
UI - 11568909
AU - Pajor L; Lacza A; Jakso P; Kajtar B
TI - Characteristics of TEL/AML-1 positive acute lymphoblastic leukemia in Hungarian children.
SO - Med Pediatr Oncol 2001 Oct;37(4):409-11
AD - Pecs University, Faculty of Medicine, Department of Pathology, 12 Szigeti Str., H-7643 Pecs, Hungary. email@example.com
UI - 11568911
AU - Alessandri AJ; Knezevich SR; Mathers JA; Schultz KR; Sorensen PH
TI - Absence of t(12;15) associated ETV6-NTRK3 fusion transcripts in pediatric acute leukemias.
SO - Med Pediatr Oncol 2001 Oct;37(4):415-6
AD - Department of Pediatrics, Division of Hematology/Oncology/Bone Marrow Transplantation, University of British Columbia and Children's and Women's Hospital, Vancouver, BC, Canada V5Z 4H4.
UI - 11598799
AU - Bernhard D; Skvortsov S; Tinhofer I; Hubl H; Greil R; Csordas A; Kofler
TI - R Inhibition of histone deacetylase activity enhances Fas receptor-mediated apoptosis in leukemic lymphoblasts.
SO - Cell Death Differ 2001 Oct;8(10):1014-21
AD - Tyrolean Cancer Research Institute, Innrain 66, A-6020 Innsbruck, Austria. David_Bernhard@yahoo.com
We recently reported that butyrate, an inhibitor of histone deacetylases, is capable of inducing Fas-independent apoptosis in the acute lymphoblastic leukemia cell line CCRF-CEM. Here we demonstrate that butyrate enhances Fas-induced apoptosis in this cell line. The application of different histone deacetylase inhibitors revealed that tetra-acetylated histone H4 is associated with the amplifying effect of butyrate on Fas-induced cell death. FasL, Fas, FADD, RIP, caspase-8, caspase-3, Bid, FLIP(S+L), FLASH and FAP-1, proteins known to act within the Fas-apoptosis cascade, showed no changes in their expression levels in cells treated with butyrate compared with untreated cells. Analyses of Fas-oligomerization and Western blotting as well as enzyme activity assays of caspase-2, caspase-3 and caspase-8 suggest that butyrate enhances Fas-induced apoptosis downstream of Fas but upstream of caspase-8 activation. In immunoprecipitation experiments a 37 kD butyrate-regulated protein was detected which specifically interacts with caspase-8.
UI - 11601199
AU - Niu C; Huang W; Su X
TI - [Study of TEL-AML1 fusion gene in childhood B-lineage acute lymphoblastic leukemia]
SO - Zhonghua Xue Ye Xue Za Zhi 1999 Feb;20(2):61-4
AD - Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Second Medical University, Shanghai 200025.
OBJECTIVE: To determine the incidence of TEL-AML1 fusion gene and its role in clinical diagnosis and prognosis of childhood B-lineage acute lymphoblastic leukemia (B-ALL), and to compare the two techniques: nested RT-PCR and dual-color fluorescence in situ hybridization (FISH). METHODS: Nested RT-PCR and dual-color FISH techniques were used to detect TEL-AML1 fusion gene. RESULTS AND CONCLUSION: TEL-AML1 fusion transcript was found in 22.5%(9/40) of patients with B-ALL by RT-PCR. The prognosis of these TEL-AML1 positive patients was relatively good and the complete remission rate was 100%. Both RT-PCR and FISH techniques were proved to be useful for detecting TEL-AML1 fusion gene and suitable for clinical diagnosis and prognosis evaluation.
UI - 11601202
AU - Hu J; Lu L; Chen Y
TI - [Clinical and experimental study of 9 cases of adult T cell leukemia]
SO - Zhonghua Xue Ye Xue Za Zhi 1999 Feb;20(2):73-5
AD - Union Hospital of Fujian Medical University, Fujian Institute of Hematology, Fuzhou 350001.
OBJECTIVE: In order to clarify the clinical and laboratory features of adult T cell leukemia (ATL): morphology, immunology, cytogenetics, serology and molecular biology. METHODS: Indirect immunofluorescence assay and ELISA were used to detect serum HTLV-I antibody. The HTLV-I provirus sequence were amplified by PCR and confirmed by liquid hybridization. RESULTS AND CONCLUSION: Nine cases of ATL were diagnosed. The major clinical manifestation was lymph node enlargement found in all patients. Skin involvement and osteolysis were not frequent. The characteristic finding was leukemic cells with highly indented or lobulated flower-like nuclei in peripheral blood and bone marrow. ATL cells were CD2, CD3, CD4, CD25 positive and CD8 negative. No specific chromosome abnormality or HLA type was found. Seven of 8 patients examined had HTLV-I antibody. The HTLV-I provirus genome sequence integrated into host cell DNA was amplified by PCR and confirmed by liquid hybridization. All of these results showed that HTLV-I was also the etiological agent of ATL in China. One of the 9 cases of ATL was classified as lymphoma type, one as chronic-type, and the rest as acute type.
UI - 11601203
AU - Mi Y; Bian S; Chen G
TI - [Study on the expression of myeloid markers and CD34 antigen in adult acute lymphoblastic leukemia]
SO - Zhonghua Xue Ye Xue Za Zhi 1999 Feb;20(2):76-8
AD - Institute of Hematology and Blood Diseases Hospital, CAMS and PUMC, Tianjin 300020.
OBJECTIVE: To analyse the expression of myeloid markers and CD34 antigen on lymphoblasts in adult ALL and its relationship with prognosis. METHOD: Immunophenotypes were examined using indirect immunofluorescence method in 102 de novo ALL. RESULTS: The incidence of myeloid antigen expression in adult ALL was 21.6% and the commonest one was CD33 (15.7%). There was a higher incidence of myeloid antigens expression in ALL-L2 than in ALL-L1 (25.6% vs 5.3%, P = 0.05). CD34 was expressed in lymphoblasts from 30 of 56 patients (53.6%). Incidence of CD34 expression in B-ALL was higher than that in T-ALL (61.7% vs 11.1%, P < 0.01). No relationship between CD34, myeloid antigens and cell maturity was found within B-ALL. There was no relation between expression of myeloid antigens and CD34. The CR rate in My(+)-ALL was lower than that in My(-)-ALL (52.6% vs 80.0%, P < 0.025), and was no relation with CD34 expression. In addition, Ph chromosome and/or bcr/abl fusion gene was positive in 35.9% of the patients, and CR rate of Ph positive patients was higher than that in Ph negative patients. CONCLUSION: Expression of myeloid antigens was related to FAB subtype and cell maturity in adult ALL. There was no relationship between myeloid antigen expression and CR rate. A higher incidence of CD34 expression was found in Pro-B-ALL than in common-ALL and Pre-B-ALL. Expression of CD34 had no relation with CR rate.
UI - 11595704
AU - Ohno N; Tani A; Chen ZS; Uozumi K; Hanada S; Akiba S; Ren XQ; Furukawa
TI - T; Sumizawa T; Arima T; Akiyama SI Prognostic significance of multidrug resistance protein in adult T-cell leukemia.
SO - Clin Cancer Res 2001 Oct;7(10):3120-6
AD - Department of Cancer Chemotherapy, Second Department of Internal Medicine, Kagoshima University, Sakura-gaoka 8-35-1, Kagoshima 890-8520, Japan.
The response of adult T-cell leukemia (ATL) to chemotherapy is poor, and a major obstacle to successful treatment is intrinsic or acquired drug resistance. To determine the clinical significance of multidrug resistance protein (MRP) 1 in ATL, we studied MRP1 expression and its association with clinical outcome. The expression of MRP1 mRNA in leukemia cells from 48 ATL patients was studied by slot blot analysis. The expression level of MRP1 mRNA in chronic-type ATL was significantly higher than that in lymphoma-type ATL (P = 0.033). There was no correlation between MRP1 expression and age, gender, WBC count, LDH, hypercalcemia, blood urea nitrogen, or performance status. However, the expression of MRP1 mRNA correlated only with peripheral blood abnormal lymphocyte counts (P = 0.008). The transporting activity of MRP1 was assessed using membrane vesicles. Membrane vesicles prepared from ATL cells with high expression of MRP1 mRNA showed a higher ATP-dependent leukotriene C(4) uptake than did those with low expression of MRP1 mRNA. This uptake was almost completely inhibited by LTD(4) antagonists ONO-1078 and MK571. In acute- and lymphoma-type ATL, high expression of MRP1 mRNA at diagnosis correlated with shorter survival, and Cox regression analysis revealed that MRP1 expression was an independent prognostic factor. These findings suggest that functionally active MRP1 is expressed in some ATL cells and that it is involved in drug resistance and has a possible causal relationship with poor prognosis in ATL. Multidrug resistance-reversing agents, such as ONO-1078 and MK571, that directly interact and inhibit the transporting activity of MRP1 may be useful for treating ATL patients.
UI - 11597739
AU - Yoshida Y
TI - Life and death of ALL cells in the milieu of bone marrow stroma.
SO - Leuk Res 2001 Nov;25(11):1025-6
AD - Division of Hematology, Department of Medicine, Takeda General Hospital, Fushimi-ku, 601-1495, Kyoto, Japan. firstname.lastname@example.org
UI - 11669298
AU - Ko BS; Tang JL; Tsai W; Chen YC; Wang CH; Sheng MC; Lin DT; Lin KH; Tien
TI - HF Philadelphia chromosome-positive acute lymphoblastic leukemia in Taiwan.
SO - Ann Hematol 2001 Sep;80(9):510-5
AD - Department of Internal Medicine, National Taiwan University Hospital, Taipei. leukemia (ALL) patients older than 15 years were found to have Philadelphia (Ph) chromosome. They accounted for 28% (26 of 94) of the patients with B-lineage ALL. Compared with the other 88 ALL patients, the leukemic cells from all but one Ph-positive ALL patients were early pre-B cells with a higher rate of CD34 expression (92% vs 50%, P<0.05). At presentation, the Ph-positive adult ALL patients had higher circulating blasts (mean 21.4 vs 3.66x10(4)/microl, P<0.05) and lower initial platelet counts (mean 4.47 vs 7.34x10(4)/microl, P<0.01) and showed a trend toward higher frequency of initial central nerve system (CNS) involvement (25% vs 11%, P=0.098) than the others. Among patients with adequate chemotherapy, 16 (64%) of the 25 Ph-positive ALL patients achieved complete remission (CR), an incidence marginally lower than that of Ph-negative ALL (62 of 76, 82%, P=0.06) and significantly lower than that of Ph-negative B-lineage ALL (50 of 58, 86%, P=0.0037). However, all patients relapsed except for those who received allogeneic hemopoietic stem cell transplantation (allo-HSCT). The probabilities of 5-year continuous CR and 5-year survival for Ph-positive adult ALL patients were significantly inferior to those for Ph-negative adult ALL patients (0% vs 12%, P=0.0001, and 7% vs 19%, P=0.047, respectively), and those for Ph-negative B-lineage ALL (0% vs 14%, P<0.0001, and 7% vs 23%, P=0.002, respectively). Prognostic factors were analyzed among the Ph-positive ALL patients including the 26 adults mentioned above and an additional 11 children. No clinical or biological characteristics such as age, sex, initial circulating blast count, extramedullary involvement, or CD34 expression had an impact on the disease outcome. Allo-HSCT in first CR may improve the probability of 5-year continuous CR (100% vs. 0% for those without allo-HSCT, P=0.0091) although only three patients received it in this study. In conclusion, Ph-positive ALL patients tended to have a poor prognosis, regardless of whether other possible risk factors were present or not. Aggressive treatment, such as high-dose chemotherapy with allo-HSCT, should be considered for these patients to improve survival.
UI - 11640871
AU - Harrison CJ
TI - Acute lymphoblastic leukaemia.
SO - Best Pract Res Clin Haematol 2001 Sep;14(3):593-607
AD - Leukaemia Research Fund/UK Cancer Cytogenetics Group Karyotype Database in Acute Lymphoblastic Leukaemia, Department of Haematology, Royal Free and University College School of Medicine, Rowland Hill Street, London, NW3 2PF, UK.
In acute lymphoblastic leukaemia (ALL) the karyotype provides important prognostic information which is beginning to have an impact on treatment. The most significant structural chromosomal changes include: the poor-risk abnormalities; t(9;22)(q34;q11), giving rise to the BCR/ABL fusion and rearrangements of the MLL gene; abnormalities previously designated as poor-risk; t(1;19)(q23;p13), producing the E2A/PBX1 and rearrangements of MYC with the immunoglobulin genes; and the probable good risk translocation t(12;21)(p13;q22), which results in the ETV6/AML1 fusion. These abnormalities occur most frequently in B-lineage leukaemias, while rearrangements of the T cell receptor genes are associated with T-lineage ALL. Abnormalities of the short arm of chromosome 9, in particular homozygous deletions involving the tumour suppressor gene (TSG) p16(INK4A), are associated with a poor outcome. Numerical chromosomal abnormalities are of particular importance in relation to prognosis. High hyperdiploidy (51-65 chromosomes) is associated with a good risk, whereas the outlook for patients with near haploidy (23-29 chromosomes) is extremely poor. In view of the introduction of risk-adjusted therapy into the UK childhood ALL treatment trials, an interphase FISH screening programme has been developed to reveal chromosomal abnormalities with prognostic significance in childhood ALL. Novel techniques in molecular cytogenetics are identifying new, cryptic abnormalities in small groups of patients which may lead to further improvements in future treatment protocols. Copyright 2001 Harcourt Publishers Ltd.
UI - 11681411
AU - Dervieux T; Medard Y; Verpillat P; Guigonis V; Duval M; Lescoeur B;
TI - Suciu S; Vilmer E; Jacqz-Aigrain E Possible implication of thiopurine S-methyltransferase in occurrence of infectious episodes during maintenance therapy for childhood lymphoblastic leukemia with mercaptopurine.
SO - Leukemia 2001 Nov;15(11):1706-12
AD - Service de Pharmacologie Pediatrique et Pharmacogenetique, Hjpital Robert Debre, Paris, France.
6-Mercaptopurine (6-MP) is metabolized by thiopurine S-methyltransferase (TPMT), an enzyme subject to genetic polymorphism. We investigated the relationships between the TPMT locus (TPMT activity and genotype) and the pharmacological response to 6-MP during maintenance therapy of 78 children with acute lymphoblastic leukemia (ALL). For each patient, 6-MP dosage, leukocyte counts and occurrence of infectious episodes were monitored on an 8 week basis. Higher 6-MP dosage was associated with higher TPMT activity (P = 0.03) and higher average leukocyte counts (P < 0.01). Eight patients (10%) carrying a TPMT mutant genotype (one homozygous and seven heterozygous) received lower 6-MP doses (average: 48 vs 65 mg/m2/day; P = 0.02) and had on average lower leukocyte counts (2834 vs 3398 cells/mm3; P = 0.003) than patients carrying the wild-type TPMT genotype. Higher occurrence of infectious episodes graded 2 or 3 was correlated with higher 6-MP dosage (P < 0.01) but no difference was observed between TPMT mutants and TPMT wild-type patients. Patients who received 6-MP dosage above the group median (62 mg/m2/day) or having a TPMT activity above the group median (21.5 nmol/h/ml) had a higher percentage of 8 week periods with infectious episodes requiring treatment (34% vs 17% and 33% vs 19%, respectively) than those with 6-MP dose or TPMT activity below the group median (P < 0.01). In the last 25 patients enrolled in the study, steady-state erythrocyte thioguanine nucleotide (TGN) concentrations were associated with lower leukocyte counts (P= 0.01) but not with a higher occurrence of infectious episodes. In contrast, higher steady-state erythrocyte methylmercaptopurine nucleotide (MeMPN) concentrations were associated with higher 6-MP dosage (P< 0.01) and higher occurrence of infectious episodes (P < 0.001). In conclusion, during maintenance therapy of ALL, children with higher TPMT activity receive a higher 6-MP dosage and may have infectious episodes caused by metabolism of 6-MP into methylmercaptopurine nucleotides.
UI - 11681428
AU - Brisco MJ; Sykes PJ; Hughes E; Story CJ; Rice MS; Schwarer AP; Morley AA
TI - Molecular relapse can be detected in blood in a sensitive and timely fashion in B-lineage acute lymphoblastic leukemia.
SO - Leukemia 2001 Nov;15(11):1801-2
UI - 11684274
AU - Li AH; Rosenquist R; Forestier E; Lindh J; Roos G
TI - Detailed clonality analysis of relapsing precursor B acute lymphoblastic leukemia: implications for minimal residual disease detection.
SO - Leuk Res 2001 Dec;25(12):1033-45
AD - Department of Medical Biosciences, Pathology, Umea University, 90187 Umea, Sweden.
Genetic instability has important implications for detection of minimal residual disease (MRD) when the target is a clonal genetic marker revealed at diagnosis. A successful MRD detection approach requires a stable marker and for lymphoid leukemias clonal rearrangements of immunoglobulin (Ig) and T cell receptor (TCR) genes are commonly used. In the present study, Ig heavy chain (IgH) and TCR (gamma and delta) genes were studied in 18 consecutive, relapsing precursor-B ALL patients. At least one clonal rearrangement was found in all cases at presentation (IgH 94%, TCRgamma 39% and TCRdelta 28%). An altered rearrangement pattern between diagnosis and relapse was demonstrated in 14 patients (78%). At least one stable molecular target was found in 13 out of 18 cases (72%). Clonal differences between diagnostic and relapse samples were explained by: (1) loss of original rearrangements; (2) V(H) to DJ(H) joining; (3) V(H) gene replacement; (4) appearance of new rearrangements. In two cases with apparently new IgH gene rearrangements at relapse extended sequencing of the diagnostic samples revealed minor clonal rearrangements identical to the relapse clones. Interestingly, one patient displayed instability on both the IgH and TCR gene loci, whereas a stable Igkappa rearrangement was found at presentation and relapse. These data show that clonal diversity is common in precursor-B ALL and strongly suggest that MRD detection should include multiple gene targets to minimize false-negative samples. Even so, five of our 18 relapse cases (28%) lacked stable clonal markers and should have been unsuitable for MRD detection.
UI - 11703363
AU - Consolini R; Pala S; Legitimo A; Crimaldi G; Ferrari S; Ferrari S
TI - Effects of vitamin D on the growth of normal and malignant B-cell progenitors.
SO - Clin Exp Immunol 2001 Nov;126(2):214-9
AD - Dipartimento di Medicina della Procreazione e dell'Eta Evolutiva, Istituto di Clinica Paediatrica, Universita di Pisa, Italy. email@example.com
As the effects of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25-(OH)2-D3) (VD, calcitriol) on the proliferation and differentiation potential of normal and leukaemic cells in vitro of myeloid lineage are known, we investigated the response to VD on the growth of both normal and malignant lymphoid progenitors. Effects of vitamin D on normal human lymphoid progenitors and B lineage acute lymphoblastic leukaemia (ALL) progenitors were assessed by using an in vitro cell colony assay specific for either B or T cell lineages. The expression of VDR on B untreated malignant progenitors at diagnosis was investigated by RT-PCR analysis. VD induced a significant inhibition of normal lymphoid cell progenitors growth of both T and B lineage. VD inhibited significantly also the growth of malignant B cell lineage lymphoid progenitors, without inducing cytotoxic effect. As it has been reported that VD effects on activated lymphocytes are mediated by 1,25-(OH)2-D3 nuclear receptor (VDR), we investigated VDR expression on malignant B cell progenitors. We did not detect VDR expression on these cells examined at diagnosis. We demonstrated that VD inhibited in vitro the clonogenic growth of both normal and malignant lymphoid B cell progenitors and that this inhibitory effect on malignant B cell progenitors was not related to VDR. Our work contributes to understanding of the mechanism of action of this hormone in promoting cellular inhibition of clonal growth of malignant lymphoid B cell progenito
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