National Cancer Institute®
Last Modified: July 1, 2002
UI - 11865290
AU - Gozdasoglu S; Uysal Z; Tacyildiz N; Yavuz G; Unal E; Kurekci E
TI - Is it possible to perform contrast venography during neutropenic period or infection?
SO - J Pediatr 2002 Feb;140(2):277-8
UI - 11972513
AU - Peham M; Panzer S; Fasching K; Haas OA; Fischer S; Marschalek R; Gadner
TI - H; Panzer-Grumayer ER Low frequency of clonotypic Ig and T-cell receptor gene rearrangements in t(4;11) infant acute lymphoblastic leukaemia and its implication for the detection of minimal residual disease.
SO - Br J Haematol 2002 May;117(2):315-21
AD - Children's Cancer Research Institute, St. Anna Kinderspital, Kinderspitalgasse 6, A-1090 Vienna, Austria.
Infant t(4;11) acute lymphoblastic leukaemia (ALL) is a rare but cytogenetically well defined subgroup of immature B-cell precursor (BCP) ALL. To date, the configuration of their antigen receptor genes has not been studied in a large group of patients so far. In this study on 27 t(4;11) infant ALL, we have used standardized primer sets for the detection of all incomplete and complete immunoglobulin (Ig) heavy chain (IGH) rearrangements, as well as for the Ig light chain kappa (IGK), T-cell receptor delta (TCRD) and gamma (TCRG) rearrangements that are most common in childhood BCP ALL. Only 52% of cases displayed clonotypic antigen receptor gene rearrangements (IGH in 48%, IGK, TCRD and TCRG in 12%, 41% and 6% respectively). This low frequency suggests, together with the findings of predominantly incomplete DJh joins and monoallelic IGH rearrangements, that they are derived from an immature progenitor cell. As 48% of the t(4;11) infant ALL cases had no detectable antigen receptor gene rearrangements that could be used for minimal residual disease (MRD) analysis, we established an expression-independent, leukaemia-specific polymerase chain reaction (PCR) using the genomic sequence of the MLL-AF4 fusion genes. This method had high sensitivity and specificity and resulted in identical estimations of tumour loads when compared with IGH targets. Thus, genomic MLL-AF4 fusion genes are a good alternative target for the analysis of MRD in patients with t(4;11) leukaemias.
UI - 11879691
AU - Dehee A; Cesaire R; Desire N; Lezin A; Bourdonne O; Bera O; Plumelle Y;
TI - Smadja D; Nicolas JC Quantitation of HTLV-I proviral load by a TaqMan real-time PCR assay.
SO - J Virol Methods 2002 Apr;102(1-2):37-51
AD - Laboratoire de Microbiologie, Hopital Rothschild, Paris, France.
A quantitative real-time PCR assay was developed to measure the proviral load of human T-lymphotropic virus type I (HTLV-I) in peripheral blood mononuclear cells (PBMCs). The HTLV-I copy number was referred to the actual amount of cellular DNA by means of the quantitation of the albumin gene. Ten copies of HTLV-I DNA could be detected with 100% sensitivity, and the assay had a wide range of at least 5 log(10). Intra- and inter-assay reproducibility was evaluated using independent extractions of PBMCs from an HTLV-I-infected patient (coefficients of variation, 24 and 7% respectively). The performance of this TaqMan PCR assay, coupled with its high throughput, thus allows reliable routine follow-up of HTLV-I proviral load in infected patients. Preliminary results using clinical samples indicate a higher proviral load in patients with HTLV-I-associated myelopathy/tropical spastic paraparesis than in asymptomatic carriers, and also suggest the usefulness of this quantitative measurement to assess the etiological link between HTLV-I and adult T-cell leukaemia/lymphoma-like syndromes.
UI - 12090419
AU - Onciu M; Bueso-Ramos C; Medeiros LJ; Ball G; Smith T; Lai R
TI - Acute lymphoblastic leukemia in elderly patients the Philadelphia chromosome may not be a significant adverse prognostic factor.
SO - Am J Clin Pathol 2002 May;117(5):716-20
AD - Department of Hematopathology, University of Taxas M. D. Anderson Cancer Center, Houston 77030, USA.
Acute lymphoblastic leukemia (ALL) in elderly patients (59 years or older) carries a poor prognosis, and this finding may be attributed to the relatively high frequency of the Philadelphia chromosome (Ph). To test this hypothesis, we reviewed the clinicopathologic features of 23 consecutive, newly diagnosed elderly patients with ALL (14 men, 9 women, aged 59-92 years) uniformly treated at our institution and compared the Ph+ and Ph- groups. Conventional cytogenetic data were available for 21 of 23 cases; 7 (33%) were Ph+. All Ph+ cases were of precursor B-cell type. The remaining 16 tumors were of precursor B-cell (10), mature B-cell (2), precursor T-cell (3), and mixed precursor T-cell/B-cell (1) type. Ph+ and Ph- groups did not differ significantly in median survival (13.4 months vs 19.0 months) or other variables studied. The Ph may not be a significant adverse prognostic factor in ALL in elderly patients.
UI - 11804271
AU - Brenner TL; Pui CH; Evan WE
TI - Pharmacogenomics of childhood acute lymphoblastic leukemia.
SO - Curr Opin Mol Ther 2001 Dec;3(6):567-78
AD - Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Approximately 80% of children with acute lymphoblastic leukemia (ALL) can be cured with modern therapy. Despite this success, the number of cases of relapsed ALL remains greater than the number of new cases of most childhood cancers. New strategies are needed to develop curative therapy for the 20% of patients who are not being cured today, and to develop less toxic and less onerous treatment for ALL patients. Molecular genetics has already provided important insights to the mechanisms of leukemogenesis and is now routinely used to define the prognosis and guide treatment intensity for childhood ALL. Pharmacogenomics is a burgeoning field that aims to elucidate inherited differences in drug disposition and treatment response, toward individualizing therapy to enhance efficacy and reduce toxicity. Herein, we review recent progress in thesefields as they relate to childhood ALL, and discuss the promise they hold to further enhance treatment of the most common cancer in children.
UI - 11996453
AU - Kulkarni AG
TI - Acute lymphoblastic leukemia presenting as breast mass.
SO - J Assoc Physicians India 2001 Dec;49():1213-4
UI - 12036851
AU - Bhatia S; Sather HN; Pabustan OB; Trigg ME; Gaynon PS; Robison LL
TI - Low incidence of second neoplasms among children diagnosed with acute lymphoblastic leukemia after 1983.
SO - Blood 2002 Jun 15;99(12):4257-64
AD - City of Hope National Medical Center, Duarte, CA, USA. smason@childrensoncology group.org
Second malignant neoplasms are a serious complication after successful treatment of childhood acute lymphoblastic leukemia (ALL). With improvement in survival, it is important to assess the impact of contemporary risk-based therapies on second neoplasms in ALL survivors. A cohort of 8831 children diagnosed with ALL and enrolled on Children's Cancer Group therapeutic protocols between 1983 and 1995 were observed to determine the incidence of second neoplasms and associated risk factors. The median age at diagnosis of ALL was 4.7 years. The cohort had accrued 54 883 person-years of follow-up. Sixty-three patients developed second neoplasms, including solid, nonhematopoietic tumors (n = 39: brain tumors n = 19, other solid tumors n = 20), myeloid leukemia or myelodysplasia (n = 16), and lymphoma (n = 8). The cumulative incidence of any second neoplasm was 1.18% at 10 years (95% confidence interval, 0.8%-1.5%), representing a 7.2-fold increased risk compared with the general population. The risk was increased significantly for acute myeloid leukemia (standardized incidence ratio [SIR] 52.3), non-Hodgkin lymphoma (SIR 8.3), parotid gland tumors (SIR 33.4), thyroid cancer (SIR 13.3), brain tumors (SIR 10.1), and soft tissue sarcoma (SIR 9.1). Multivariate analysis revealed female sex (relative risk [RR] 1.8), radiation to the craniospinal axis (RR 1.6), and relapse of primary disease (RR 3.5) to be independently associated with increased risk of all second neoplasms. Risk of second neoplasms increased with radiation dose (1800 cGy RR 1.5; 2400 cGy RR 3.9). Actuarial survival at 10 years from diagnosis of second neoplasms was 39%. Follow-up of this large cohort that was treated with contemporary risk-based therapy showed that the incidence of second neoplasms remains low after diagnosis of childhood ALL.
UI - 12036898
AU - Graf Einsiedel H; Taube T; Hartmann R; Wellmann S; Seifert G; Henze G;
TI - Seeger K Deletion analysis of p16(INKa) and p15(INKb) in relapsed childhood acute lymphoblastic leukemia.
SO - Blood 2002 Jun 15;99(12):4629-31
AD - Department of Pediatric Oncology/Hematology, Charite Medical Center, Campus Virchow-Klinikum, Humboldt University of Berlin, Germany. hagenve@@charite.de
This study aimed at determining the prevalence of INK4 deletions and their impact on outcome in 125 children with acute lymphoblastic leukemia (ALL) at first relapse using real-time quantitative polymerase chain reaction. Patients were enrolled into relapse trials ALL-REZ BFM (ALL-Relapse Berlin-Frankfurt-Munster) 90 and 96. The prevalence of p16(INK4a) and p15(INK4b) homozygous deletions was 35% (44 of 125) and 30% (38 of 125), respectively. A highly significant association of both gene deletions was found with the 2 major adverse prognostic factors known for relapsed childhood ALL: T-cell immunophenotype and first remission duration. There was no correlation between INK4 deletions and probability of event-free survival. These findings argue against an independent prognostic role of INK4 deletions in relapsed childhood ALL.
UI - 12066788
AU - Hayette S; Tigaud I; Maguer-Satta V; Bartholin L; Thomas X; Charrin C;
TI - Gadoux M; Magaud JP; Rimokh R Recurrent involvement of the MLL gene in adult T-lineage acute lymphoblastic leukemia.
SO - Blood 2002 Jun 15;99(12):4647-9
UI - 12028018
AU - Takanashi M; Yagi T; Imamura T; Tabata Y; Morimoto A; Hibi S; Ishii E;
TI - Imashuku S Expression of the Ikaros gene family in childhood acute lymphoblastic leukaemia.
SO - Br J Haematol 2002 Jun;117(3):525-30
AD - Department of Pediatrics, Kyoto Prefectural University of Medicine, Kajiicho 465 Hirokoji, Kamigyoku, Kyoto 602-8566, Japan. firstname.lastname@example.org
The Ikaros (Ik) gene family, which includes Ik, Aiolos (Ai), and Helios (He), is a primary regulator of lymphocyte differentiation, and is involved in the development of acute lymphoblastic leukaemia (ALL). We analysed the expression of the Ik gene family isoforms in 97 ALL cases, consisting of 64 childhood and 33 infant ALL cases, using reverse transcription-polymerase chain reaction (RT-PCR). Expression of Ik was detected in all cases, 87 of which expressed either Ik1 or Ik2, or both, five of which expressed Ik1/Ik2 and Ik6, and another five of which expressed only Ik6. Therefore, the dominant negative isoform of Ik6 was expressed in 10 of the 38 cases of childhood precursor B ALL, but was absent in other types of childhood ALL (26.3%, chi2-test, P = 0.0001). In terms of Aiolos and Helios expression, 49 (65.3%) out of the 75 and 40 (50%) out of the 80 ALL cases tested showed non-spliced Ai1 and He1 respectively. Only one case of T lineage ALL expressed a small-sized isoform of Helios (designated as He6). It was also found that the expression of Ai1 and He1 was low in Ik6-positive patients (Fisher's exact test; Ai1 P = 0.005, Hel P = 0.035).
UI - 12028019
AU - Hoshino K; Asou N; Okubo T; Suzushima H; Kiyokawa T; Kawano F; Mitsuya H
TI - The absence of the p15INK4B gene alterations in adult patients with precursor B-cell acute lymphoblastic leukaemia is a favourable prognostic factor.
SO - Br J Haematol 2002 Jun;117(3):531-40
AD - Department of Internal Medicine II, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
We examined deletion and methylation of the p15INK4B (p15) and p16INK4A (p16) genes, using Southern blotting and methylation-specific polymerase chain reaction (PCR), in 70 untreated adult patients with precursor B-cell acute lymphoblastic leukaemia (PBC-ALL) and analysed the relationship between their genetic changes and clinical outcome. Methylation and homozygous deletion of the p15 gene were detected in 30 (43%) and 18 (26%) patients, while those of the p16 gene were found in 16 (23%) and 11 (16%) patients respectively. Thirteen out of 17 patients with wild-type p15 gene showed expression of p15 mRNA, whereas 31 out of 39 patients with alteration (deletion and methylation) of the p15 gene showed no p15 mRNA expression by reverse transcription-PCR, suggesting that alterations of the p15 gene are highly associated with loss of p15 mRNA expression. Disease-free survival (DFS) at 4 years in patients with wild-type p15 gene is 33%, compared with 4% of those with p15 gene alterations (P = 0.049). Multivariate analysis showed that the absence of p15 gene alterations was an independent significant favourable prognostic factor for longer DFS (P = 0.0001). These results suggest that alterations in the p15 but not p16 gene can be used as a genetic prognostic indicator in PBC-ALL.
UI - 11938792
AU - Wang D; Xiao Y; Luo M; Zhang X
TI - [Examination of human herpesvirus-6 antibody in blood patients serum]
SO - Hunan Yi Ke Da Xue Xue Bao 1999;24(2):198-200
AD - Department of Transplantation Blood, Xiangya Hospital, Hunan Medical University, Changsha 410008.
To know the infection state of human herpesvirus-6(HHV-6) in leukemia, lymphoma, myeloproliferative disorder syndrome, and multiple myeloma, indirect fluoroimmunoassay was taken to examine the rate of HHV-6's antibody. The results were that: the patient's rate of HHV-6 antibody was 75.6% (149/197), the blood donor's rate was 45.6% (115/252), there was a significant difference between them (P < 0.01). The results show that the examined patients are infected by HHV-6, which has a good relationship with leukemia, lymphoma, myeloproliferative disorder syndrome, and multiple myeloma.
UI - 12057109
AU - Siegel RS; Gartenhaus RB; Kuzel TM
TI - Human T-cell lymphotropic-I-associated leukemia/lymphoma.
SO - Curr Treat Options Oncol 2001 Aug;2(4):291-300
AD - Division of Hematology/Oncology, Department of Medicine, Northwestern University Medical School, and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, 676 N. St. Clair, Suite 850, Chicago, IL 60611, USA.
Human T-cell lymphotropic virus-I (HTLV-I)-related adult T-cell leukemia/lymphoma (ATL) is a model disease for proof of viral oncogenesis. HTLV-I infection is endemic in southern Japan and the Caribbean basin, and occurs sporadically in Africa, Central and South America, the Middle East, and the southeastern United States. ATL occurs in only 2% to 4% of HTLV-I-infected people [1-3]. When it does occur, it is usually aggressive and difficult to treat; most people survive for less than 1 year [1-3]. Combination chemotherapy with cytotoxic agents has yielded complete response rates of 20% to 45%, but responses usually last only a few months . Recently, novel treatments, such as monoclonal antibodies directed at the interleukin-2 receptor and the combination of interferon alfa and zidovudine, have been shown to be active in the treatment of patients with ATL. A small percentage of patients achieve long-lasting remissions [2,3].
UI - 12060313
AU - Chan LC; Lam TH; Li CK; Lau YL; Li CK; Yuen HL; Lee CW; Ha SY; Yuen PM;
TI - Leung NK; Patheal SL; Greaves MF; Alexander FE Is the timing of exposure to infection a major determinant of acute lymphoblastic leukaemia in Hong Kong?
SO - Paediatr Perinat Epidemiol 2002 Apr;16(2):154-65
AD - Haematology Section, Department of Pathology, University of Hong Kong, Hong Kong. email@example.com
The hypothesis that protection of infants from exposure to infectious agents with delayed first exposure to one or more specific agents together contribute to the aetiology of childhood leukaemia, especially common acute lymphoblastic leukaemia (cALL), has substantial indirect support from descriptive epidemiology and case-control studies in developed Western countries. A case-control study of childhood leukaemia diagnosed at ages 2-14 years has now been conducted in Hong Kong. Cases (n=98) formed a consecutive series of Chinese children diagnosed with acute leukaemia; controls (n=228) were identified following a survey using random digit dialling and required to attend for medical examination by a paediatrician. Interviews with mothers were conducted in hospital by one trained interviewer using a structured questionnaire. Odds ratios (OR) and 95% confidence intervals (CI) are reported for exposure variables capable of serving as proxies for exposure to infection in two critical time periods: first year of life, year before reference date (diagnosis for cases, corresponding date for controls). Analyses used logistic regression with adjustment for appropriate confounders. Change of area of residence reduced risk if during the first time period (OR = 0.47 [95% CI 0.23, 0.98]) and increased risk if during the second (OR=3.92, [95% CI 1.47, 10.46]). Reported roseola and/or fever and rash in the first year of life reduced risk (OR=0.33 [95% CI 0.16, 0.68]) whereas tonsillitis in the period 3-12 months before reference date increased risk (OR=2.56 [95% CI 1.22, 5.38]). Some other proxies for exposure to infection at the critical times were associated with predicted patterns of risk but day-care attendance failed to show predicted associations. These results provide support for the delayed exposure hypothesis in an affluent geographical setting in which population exposure to infectious agents is quite distinct from the settings of previous case-control studies.
UI - 12094263
AU - van der Velden VH; Wijkhuijs JM; Jacobs DC; van Wering ER; van Dongen JJ
TI - T cell receptor gamma gene rearrangements as targets for detection of minimal residual disease in acute lymphoblastic leukemia by real-time quantitative PCR analysis.
SO - Leukemia 2002 Jul;16(7):1372-80
AD - Department of Immunology, Erasmus MC, Rotterdam, The Netherlands.
Several studies have shown that quantitative detection of minimal residual disease (MRD) predicts clinical outcome in childhood acute lymphoblastic leukemia (ALL). In this report we investigated the applicablility of T cell receptor gamma (TCRG) gene rearrangements as targets for MRD detection by real-time quantitative PCR analysis. Seventeen children with precursor-B-ALL and 15 children with T-ALL were included in this study. Using an allele-specific (ASO) forward primer in combination with germline Jgamma reverse primers and Jgamma TaqMan probes, a reproducible sensitivity of < or =10(-4) (defined by strict criteria) was obtained in only four out of 19 (21%) TCRG gene rearrangements in precursor-B-ALL patients and in 10 out of 15 (67%) TCRG gene rearrangements in T-ALL patients. The main reason for not obtaining a reproducible sensitivity of < or =10(-4) in approximately 60% of cases was the non-specific amplification of TCRG gene rearrangements in normal T-lymphocytes. A maximal sensitivity of < or =10(-4) (defined by less strict criteria) was obtained in 42% of TCRG gene rearrangements in precursor-B-ALL patients. The number of inserted nucleotides was significantly higher in T-ALL (mean: 8.5) as compared to precursor-B-ALL (mean: 6.8) and appeared to be the most important predictor for reaching a reproducible sensitivity < or =10(-4). The usage of a touchdown PCR or the usage of an ASO reverse primer in combination with Vgamma member forward primers and TaqMan probes did not clearly improve the overall results. Nevertheless, RQ-PCR analysis of TCRG gene rearrangements in follow-up samples obtained from 12 ALL patients showed the applicability of this method for MRD detection. We conclude that RQ-PCR analysis of TCRG gene rearrangements can be used for the detection of MRD, but that sensitivities might be limited due to non-specific amplification. This method is applicable in the majority of T-ALL patients and in almost half of precursor-B-ALL patients, particularly when used as second-choice target for confirmation of the MRD results obtained via the first-choice target.
UI - 12055050
AU - Infante-Rivard C; Amre D; Sinnett D
TI - GSTT1 and CYP2E1 polymorphisms and trihalomethanes in drinking water: effect on childhood leukemia.
SO - Environ Health Perspect 2002 Jun;110(6):591-3
AD - Joint Department of Epidemiology and Biostatistics, Faculty of Medicine, McGill University Montreal, Quebec, Canada. cirivard@epid.Ian.mcgill.ca
The purpose of the study was to determine whether the risk of childhood acute lymphoblastic leukemia (ALL) associated with drinking water disinfection by-products was modified in the presence of variants in genes involved in the metabolism of trihalomethanes (THMs). We included a subset of cases from a population-based case-control study in a case-only study to estimate the interaction odds ratios (IORs) between prenatal and postnatal exposure to THMs and polymorphisms in the GSTT1 and CYP2E1 genes. We compared cases with and without a given variant regarding their exposure to THMs using unconditional logistic regression. The IOR for a postnatal average of total THM above the 95th percentile with GSTT1 null genotype was 9.1 [95% confidence interval (95% CI), 1.4-57.8]. With CYP2E1 (variant G-1259C, known as the allele CYP2E1*5), the effect of exposure during pregnancy for an average exposure to total THM at or above the 75th percentile was 9.7 (95% CI, 1.1-86.0). These results contrast strongly with those from our case-control analysis, in which we considered the exposure to THMs only in relation with ALL, and observed no increase in risk or very moderate ones. The present preliminary study shows suggestive but imprecise results. We found no similar results in the literature, underscoring the need for other studies as well as the potential usefulness of combining exposure and relevant genetic information in such studies.
UI - 11325820
AU - Varon R; Reis A; Henze G; von Einsiedel HG; Sperling K; Seeger K
TI - Mutations in the Nijmegen Breakage Syndrome gene (NBS1) in childhood acute lymphoblastic leukemia (ALL).
SO - Cancer Res 2001 May 1;61(9):3570-2
AD - Institute of Human Genetics, Charite, Humboldt-University, 13353 Berlin, Germany.
The Nijmegen Breakage Syndrome (NBS) is a rare autosomal recessive disorder associated with immune deficiency, chromosome fragility, and increased susceptibility to lymphoid malignancies. The aim of the present study was to elucidate the potential role of the gene mutated in NBS (NBS1) in the pathogenesis and disease progression of childhood acute lymphoblastic leukemia (ALL). Samples from 47 children with first relapse of ALL were analyzed for mutations in all 16 exons of the NBS1 gene, and in 7 of them (14.9%), four novel amino acid substitutions were identified. Mutations S93L, D95N, and I171V occur in the two known domains of nibrin that are probably involved in protein-protein interactions. Germ-line origin of the I171V mutation was confirmed in three patients, whereas the D95N exchange was present only in leukemic cells. The R215W mutation was observed in one ALL but also in a population-based study and probably represents a rare sequence variant. No additional mutations were found on the second allele in any of these seven patients. The observed NBS1 gene mutations in ALL patients points to its possible involvement in the pathogenesis of this disease.
UI - 12085192
AU - Asumendi A; Morales MC; Alvarez A; Arechaga J; Perez-Yarza G
TI - Implication of mitochondria-derived ROS and cardiolipin peroxidation in N-(4-hydroxyphenyl)retinamide-induced apoptosis.
SO - Br J Cancer 2002 Jun 17;86(12):1951-6
AD - Department of Cell Biology and Histology, School of Medicine and Dentistry, University of The Basque Country, Leioa- 48940, Bizkaia, Spain. firstname.lastname@example.org
We have studied the effect of N-(4-hydroxyphenyl)retinamide on either malignant human leukaemia cells or normal cells and investigated its mechanism of action. We demonstrate that 4HPR induces reactive oxygen species increase on mitochondria at a target between mitochondrial respiratory chain complex I and II. Such oxidative stress causes cardiolipin peroxidation which in turn allows cytochrome c release to cytosol, caspase-3 activation and therefore apoptotic consumption. Moreover, this apoptotic pathway seems to be bcl-2/bax independent and count only on malignant cells but not normal nor activated lymphocytes. Copyright 2002 Cancer Research UK
UI - 12058344
AU - Labuda D; Krajinovic M; Sabbagh A; Infante-Rivard C; Sinnett D
TI - Parental genotypes in the risk of a complex disease.
SO - Am J Hum Genet 2002 Jul;71(1):193-7
AD - Centre de recherche, Hopital Sainte Justine, Universite de Montreal, Quebec, H3T 1C5 Canada. email@example.com
Our understanding of the genetic etiology of complex disorders is still elusive. According to the common-variant/common-disease hypothesis, frequent functional polymorphisms are the best candidates for disease-susceptibility alleles. Implicitly, we also assume that disease-susceptibility alleles are preferentially transmitted from parents to the affected offspring and that this effect can be captured by the transmission/disequilibrium test (TDT). However, our study of genetic predisposition to childhood acute lymphoblastic leukemia suggests that a focus on the patient's genotype might, in certain instances, be misleading. Our results indicate that, at least at some loci, parental genetics might be of primary importance in predicting the risk of cancer in this pediatric model of a complex disease. Consequently, in addition to TDT, other complementary strategies will need to be simultaneously applied to dissect genetic predisposition to complex disorders.
UI - 12070006
AU - Sandlund JT; Harrison PL; Rivera G; Behm FG; Head D; Boyett J; Rubnitz
TI - JE; Gajjar A; Raimondi S; Ribeiro R; Hudson M; Relling M; Evans W; Pui CH Persistence of lymphoblasts in bone marrow on day 15 and days 22 to 25 of remission induction predicts a dismal treatment outcome in children with acute lymphoblastic leukemia.
SO - Blood 2002 Jul 1;100(1):43-7
AD - Department of Hematology-Oncology, St Jude Children's Research Hospital, and the University of Tennessee, College of Medicine, Memphis, TN 38105, USA. firstname.lastname@example.org
We determined the prognostic importance of morphologically identifiable persistent disease at day 15 and days 22 to 25 of remission induction in childhood acute lymphoblastic leukemia (ALL). Among 546 patients entered on 2 consecutive protocols, 397 patients had evaluable bone marrow (BM) examinations on day 15 (+/- 1 day) and 218 on days 22 to 25 (+/- 1 day). Fifty-seven patients (14%) had persistent lymphoblasts (> or = 1%) in the BM on day 15 and 27 patients (5.5%) had persistent lymphoblasts on days 22 to 25. The 5-year event-free survival (EFS) was significantly worse for patients with lymphoblasts on day 15 (40% +/- 6%) or on days 22 to 25 (4% +/- 3%) as compared to those without lymphoblasts on these dates (78% +/- 2% and 76% +/- 2%, respectively, P <.001 for both comparisons). A worse prognosis was observed even for patients with a low percentage of lymphoblasts (ie, 1%-4%) at either day 15 (5-year EFS = 56% +/- 8%) or days 22 to 25 (5-year EFS = 0%) compared to those without morphologically identifiable persistent lymphoblasts at these times (P <.001 for both comparisons). The prognostic impact of persistent lymphoblasts on both dates remained significant after adjusting for other known risk factors, including treatment protocol, age, white blood cell count, DNA index, cell lineage, and central nervous system status, and National Cancer Institute/Rome criteria simultaneously. Hence, persistence of lymphoblasts (even 1%-4%) on day 15 of remission induction was associated with a poor prognosis and on days 22 to 25 signified a particularly dismal outcome; these very high-risk patients require novel or more intensive therapy to improve outcome.
UI - 12070008
AU - Coustan-Smith E; Sancho J; Behm FG; Hancock ML; Razzouk BI; Ribeiro RC;
TI - Rivera GK; Rubnitz JE; Sandlund JT; Pui CH; Campana D Prognostic importance of measuring early clearance of leukemic cells by flow cytometry in childhood acute lymphoblastic leukemia.
SO - Blood 2002 Jul 1;100(1):52-8
AD - Department of Hematology-Oncology, St Jude Children's Research Hospital and the University of Tennessee, Memphis, TN 38105, USA.
Early clearance of leukemic cells is a favorable prognostic indicator in childhood acute lymphoblastic leukemia (ALL). However, identification of residual leukemic cells by their morphologic features is subjective and lacks sensitivity. To improve estimates of leukemia clearance, we applied flow cytometric techniques capable of detecting 1 leukemic cell in 10,000 or more normal cells and prospectively measured residual leukemia in bone marrow samples collected on day 19 of remission-induction chemotherapy from 248 children with newly diagnosed ALL. In 134 samples (54.0%), we identified at least 0.01% leukemic cells (0.01%-< 0.1% in 51 samples [20.6%], 0.1%-< 1% in 36 [14.5%], and > or = 1% in 47 [19.0%]). Among 110 children treated within a single chemotherapy program, the 5-year mean +/- SE cumulative incidence of relapse or failure to achieve remission was 32.2% +/- 6.5% for the 59 patients with 0.01% residual leukemic cells or greater on day 19 and 6.0% +/- 3.4% for the 51 patients with less than 0.01% leukemic cells (P <.001). The prognostic value of day-19 bone marrow status defined by flow cytometry was superior to that defined by morphologic studies and remained significant after adjustment for other clinical and biologic variables. Lack of detectable leukemic cells on day 19 was more closely associated with relapse-free survival than was lack of detectable residual disease at the end of remission induction (day 46). Thus, approximately half of the children with ALL achieve profound clearance of leukemic cells after 2 to 3 weeks of remission-induction chemotherapy, and these patients have an excellent treatment outcome.
UI - 12070010
AU - Davies SM; Bhatia S; Ross JA; Kiffmeyer WR; Gaynon PS; Radloff GA;
TI - Robison LL; Perentesis JP Glutathione S-transferase genotypes, genetic susceptibility, and outcome of therapy in childhood acute lymphoblastic leukemia.
SO - Blood 2002 Jul 1;100(1):67-71
AD - Children's Oncology Group, Arcadia, CA 91066-6012, USA. email@example.com
The glutathione S-transferase (GST) genes are involved in the metabolism of environmental carcinogens and of some classes of chemotherapy drugs. GSTM1 and GSTT1 genotypes are polymorphic in humans, and the phenotypic absence of enzyme activity is caused by a homozygous inherited deletion of the gene. Previous, smaller studies of childhood acute lymphoblastic leukemia (ALL) provided contrasting data on the role of the GST genotype in susceptibility and treatment outcomes. We analyzed GST genotypes in 710 children with ALL treated by the Children's Cancer Group. Frequencies were compared with those of normal controls, and outcomes were analyzed according to genotype. Comparisons of gene frequencies in ALL case and control patients showed similar frequencies (54% vs 53% GSTM1 null in whites, P =.9; 40% versus 32% in blacks, P =.45; 16% versus 15% GSTT1 null in whites, P =.8; 17% versus 28% in blacks, P =.3). ALL was not associated with the GSTM1-null genotype or the double-null genotype in blacks or whites, in contrast to previous reports. Stratification of cases by age at diagnosis, sex, white blood cell count at diagnosis, B or T lineage, or cytogenetics revealed no differences in genotype frequencies. Analysis of treatment outcomes showed no differences in outcome according to GST genotype; in particular, there were no differences in frequencies of relapse at any site. These data, representing a larger series than any reported previously, suggest that GST genotype does not affect etiology or outcome of childhood ALL.
UI - 12007502
AU - Kanerva J; Vettenranta K; Autio K; Knuutila S; Saarinen-Pihkala UM
TI - Minimal residual disease by metaphase FISH in children with ALL: clonal cells during or after chemotherapy may not predict relapse.
SO - Leuk Res 2002 Jun;26(6):545-50
AD - Hospital for Children and Adolescents, Helsinki University Central Hospital, P.O.B. 281, FIN-00029 Helsinki, Finland. firstname.lastname@example.org
The evaluation of minimal residual disease (MRD) is increasingly gaining ground in the prognostic assessment of childhood acute lymphoblastic leukemia (ALL). We studied MRD by metaphase-fluorescent in situ hybridization (FISH) in 41 children with ALL. At diagnosis, all patients were karyotyped by standard G-banding and studied with comparative genomic hybridization (CGH). Standard cytogenetic preparations were used for FISH. Eleven children were FISH-positive at some point post-induction. One of the eleven had a bone marrow (BM) relapse, and another a central nervous system (CNS)-relapse at the end of maintenance therapy, while the others remain in continuous complete remission (CCR). Five of the eleven FISH-positive were positive also after cessation of therapy, but none have relapsed. Of the 30 children with no FISH-detectable MRD post-induction, 2 have relapsed. We show that despite the presence of mitotically active blasts from the original leukemic clone during or after treatment, most of the children in our series remain in CCR although no action is taken to intensify or prolong the treatment.
UI - 12087466
AU - Cutrona G; Tasso P; Dono M; Roncella S; Ulivi M; Carpaneto EM; Fontana
TI - V; Comis M; Morabito F; Spinelli M; Frascella E; Boffa LC; Basso G; Pistoia V; Ferrarini M CD10 is a marker for cycling cells with propensity to apoptosis in childhood ALL.
SO - Br J Cancer 2002 Jun 5;86(11):1776-85
AD - Servizi di Immunologia Clinica, Istituto Nazionale per la Ricerca sul Cancro, IST, Genoa, Italy, and Dipartimento di Oncologia, Biologia e Genetica, Universita di Genova, Genoa, Italy. email@example.com
CD10 constitutes a favourable prognostic marker for childhood acute lymphoblastic leukaemia. Since correlations between CD10, cell cycle and apoptotic abilities were demonstrated in various cell types, we investigated whether differences existed in the cycling/apoptotic abilities of CD10-positive and CD10-negative B acute lymphoblastic leukaemia cells. Twenty-eight cases of childhood acute lymphoblastic leukaemia (mean age of 6.8 years) were subdivided into two groups according to high (17 cases, 93.2+/-4.5%, MRFI 211+/-82 CD10-positive cells) or low (11 cases, 11.5+/-6.2%, MRFI 10+/-7 CD10-negative cells) expression of CD10. CD10-positive acute lymphoblastic leukaemia cells were cycling cells with elevated c-myc levels and propensity to apoptosis, whereas CD10-negative acute lymphoblastic leukaemia cells had lower cycling capacities and c-myc levels, and were resistant to apoptosis in vitro. A close correlation between all these properties was demonstrated by the observations that the few CD10-positive cells found in the CD10-negative acute lymphoblastic leukaemia group displayed elevated c-myc and cycling capacities and were apoptosis prone. Moreover, exposure of CD10-positive acute lymphoblastic leukaemia B cells to a peptide nucleic acid anti-gene specific for the second exon of c-myc caused inhibition of c-myc expression and reduced cell cycling and apoptotic abilities as well as decreased CD10 expression. Copyright 2002 Cancer Research UK
UI - 12116070
AU - Luczynski W; Krawczuk-Rybak M; Muszynska-Roslan K; Stasiak-Barmuta A;
TI - Zak J Immunosuppression in childhood acute lymphoblastic leukemia after remission induction therapy concerns B not T lymphocytes.
SO - Med Pediatr Oncol 2002 Aug;39(2):147-8
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