Table of Contents
1
UI - 11960347
AU - Mikhail FM; Serry KA; Hatem N; Mourad ZI; Farawela HM; El Kaffash DM;
TI -
Coignet L; Nucifora G
AML1 gene over-expression in childhood acute lymphoblastic leukemia.
SO - Leukemia 2002 Apr;16(4):658-68
AD - Department of Clinical Pathology, Faculty of Medicine, University of
Alexandria, Alexandria, Egypt.
The present study was conducted on a series of 41 Egyptian children with
newly diagnosed acute lymphoblastic leukemia (ALL) to investigate TEL
and AML1 abnormalities. The TEL-AML1 fusion was observed in six patients
both by RT-PCR and FISH analyses, with a frequency of 22.2% among the
B-lineage group, whereas TEL deletion was seen by FISH analysis in seven
patients (17.1%). By FISH analysis, nine patients (22%) showed evidence
of extra AML1 copies. In five of these patients the extra copies were
due to non-constitutional trisomy 21, whereas in the remaining four
cases they were due to tandem AML1 copies on der(21), as evidenced by
metaphase FISH. Unexpectedly however, enhanced AML1 expression levels
were seen by real-time quantitative RT-PCR in 18 out of the 41 ALL
patients (43.9%). This high level of AML1 expression could be an
important factor contributing to the pathogenesis and progression of
childhood ALL. One key mechanism for over-expression seems to be the
extra copies of AML1, but other mechanisms may involve an alteration of
the activity of the AML1 promoter. Here, we also report two novel
findings. The first is an intragenic deletion of TEL exon 7 in a case of
T cell ALL. This deletion creates a frame-shift and results in a
truncated protein lacking the C-terminus that includes the ETS domain.
This shorter TEL is presumably unable to bind DNA. The second finding is
a rearrangement of AML1 in a case of T cell ALL due to t(4;21)(q31;q22).
This is the first reported chromosomal translocation where AML1is
rearranged in childhood T cell ALL.
2
UI - 11960348
AU - Jabber Al-Obaidi MS; Martineau M; Bennett CF; Franklin IM; Goldstone AH;
TI -
Harewood L; Jalali GR; Prentice HG; Richards SM; Roberts K; Harrison CJ;
Medical Research Council Adult Leukaemia Working Party
ETV6/AML1 fusion by FISH in adult acute lymphoblastic leukemia.
SO - Leukemia 2002 Apr;16(4):669-74
AD - LRF/UKCCG Karyotype Database in ALL, Department of Haematology, The
Royal Free and University College Medical School, London, UK.
Dual-color interphase fluorescence in situ hybridization (FISH) with
ETV6 and AML1 probes was used for the first time on a series of 159
adult patients with acute lymphoblastic leukemia (ALL), for detection of
the t(12;21)(p13;q22) translocation. Seven patients (4.4%) were found,
with 50-100% of positive cells, of whom one of two tested, proved
negative for the fusion product by RT-PCR. Two of them, aged 43 and 50
years, are the oldest patients so far confirmed to have the
translocation. Three who relapsed at 10, 11 and 24 months, suggest that
adults may not enjoy the good short-term prognosis reported for
t(12;21)-positive children. Thirty-one-negative cases had signal numbers
differing from the two expected for each gene. In 15 cases these results
were consistent with the karyotype. In nine cases with uninformative
cytogenetics, the numbers were consistent with those for centromeres and
indicated a hidden aneuploidy. Loss of ETV6 genes in two cases and AML1
amplification in three others were not suspected from the cytogenetics.
In conclusion, FISH proved to be reliable in defining ETV6/AML1
positivity in this group of patients as well as providing valuable
insights into negative cases.
3
UI - 11960354
AU - Salonen MJ; Siimes MA; Salonen EM; Vaheri A; Koskiniemi M
TI -
Antibody status to HHV-6 in children with leukaemia.
SO - Leukemia 2002 Apr;16(4):716-9
AD - Haartman Institute, Department of Virology, University of Helsinki,
Helsinki, Finland.
Forty children with acute lymphoblastic (33) or myeloid leukaemia
(seven) were studied for IgG and IgM antibodies and IgG avidity against
human herpesvirus 6 (HHV-6) at the time of diagnosis, and compared with
age-, sex- and season-matched children with various neurological
diseases of suspected viral origin. Of the children with leukaemia,
97.5% had IgG antibodies and 40% IgM antibodies to HHV-6 compared with
92.3% and 7.7% of reference subjects (P = 0.005). A seronegative child
with leukaemia seroconverted 3 weeks after the diagnosis. The avidity of
IgG antibodies (based on the resistance to urea treatment) was high in
all children with leukaemia. One reference child had HHV-6-specific IgG
antibodies with low avidity, which together with his positive IgM
indicated an acute infection. The presence of specific IgM antibodies in
40% of children with leukaemia and the high avidity of IgG suggest a
reactivation or an inaproppriate primary response to HHV-6 infection.
The results support the conclusion of the role of the HHV-6 infection at
the onset of childhood leukaemia.
4
UI - 11960355
AU - Hrusak O; Trka J; Zuna J; Polouckova A; Kalina T; Stary J; Czech
TI -
Pediatric Hematology Working Group
Acute lymphoblastic leukemia incidence during socioeconomic transition:
selective increase in children from 1 to 4 years.
SO - Leukemia 2002 Apr;16(4):720-5
AD - Institute of Immunology, 2nd Medical School, Charles University, Prague,
Czech Republic.
Pre-school acute lymphoblastic leukemia (ALL) peak is consistent in
developed but not in developing countries and its magnitude apparently
correlates with the socioeconomic status. A population-based study
describing ALL incidence during socioeconomic transition has been
lacking. Central European post-communist countries (with very low
foreign migration and centralized statistics) offer reliable data for
the period before and during major socioeconomic changes.
Population-based data on Czech ALL patients younger than 18 years were
taken from two independent Czech national registries partially
overlapping in time (1980-1998, n = 1236 and 1991-1999, n = 570). During
the 1980s and 1990s, ALL incidence among children 1-4 years increased
1.5 times (P = 0.01). This increase was more prominent in females than
in males (slopes 0.13 and 0.09, P values 0.03 and >0.05, respectively).
No significant change was observed in other age groups (0, 5-9, 10-14,
15-17 years or all others combined). We discuss possible underlying
socioeconomic factors including infant care and breast-feeding, hygiene,
birth order, industry and pollution. Moreover, we try to pinpoint the
immunophenotypic/molecular-genetic subsets of ALL that might be
socioeconomically affected. Selective increase of ALL in children 1-4
years old provides epidemiological evidence that etiology and/or trigger
mechanisms are different for a considerable proportion of these children
and that these mechanisms are exogenous.
5
UI - 11960364
AU - van der Burg M; Smit B; Brinkhof B; Barendregt BH; Verschuren MC; Dib M;
TI -
Beverloo HB; van Dongen JJ; Langerak AW
A single split-signal FISH probe set allows detection of TAL1
translocations as well as SIL-TAL1 fusion genes in a single test.
SO - Leukemia 2002 Apr;16(4):755-61
AD - Dept of Immunology, Erasmus University Rotterdam/University Hospital
Rotterdam, The Netherlands.
About 30% of T cell acute lymphoblastic leukemias (T-ALL) carry TAL1
gene aberrations. In the majority of cases (approximately 25%), this
concerns a submicroscopic deletion of approximately 90 kb in chromosome
region 1p32, which deletes the coding regions of the SIL gene and the
untranslated region of the TAL1 gene, thereby placing the TAL1 gene
under control of the SIL promoter region. Translocation (1;14)(p32;q11)
involving the TAL1 gene occurs at a much lower frequency (3%), whereas
some other rare variant translocations have been described as well. In
this study we developed a set of TAL1 FISH probes based on the
split-signal FISH principle that enables detection of both types of TAL1
gene aberrations in single test. For this purpose, one probe was
designed downstream of the TAL1 gene (TAL1-D) and the second probe in
the region upstream of the TAL1 gene, partly covering the SIL gene
(SIL-U). We show that this split-signal FISH probe set allows reliable
detection of the unaffected SIL-TAL1 gene region with a fusion signal,
SIL-TAL1 fusion genes with loss of the SIL-U signal, and TAL1 gene
translocations with a split-signal, independent of the involved partner
gene.
6
UI - 11960365
AU - Guidal C; Vilmer E; Grandchamp B; Cave H
TI -
A competitive PCR-based method using TCRD, TCRG and IGH rearrangements
for rapid detection of patients with high levels of minimal residual
disease in acute lymphoblastic leukemia.
SO - Leukemia 2002 Apr;16(4):762-4
7
UI - 11960366
AU - Taub JW; Matherly LH; Ravindranath Y; Kaspers GJ; Rots MG; Zantwijk CH
TI -
Polymorphisms in methylenetetrahydrofolate reductase and methotrexate
sensitivity in childhood acute lymphoblastic leukemia.
SO - Leukemia 2002 Apr;16(4):764-5
8
UI - 11902549
AU - Pui C H; Campana D; Evans W E
TI -
Childhood acute lymphoblastic leukaemia--current status and future
perspectives.
SO - Lancet Oncol 2001 Oct;2(10):597-607
AD - Leukaemia/Lymphoma Division, Fahad Nassar Al-Rashid Chair of Leukaemia
Research at St Jude Children's Research Hospital, Memphis, TN 38105,
USA. ching-hon.pui@stjude.org
The current cure rate of 80% in childhood acute lymphoblastic leukaemia
attests to the effectiveness of risk-directed therapy developed through
well-designed clinical trials. In the past decade there have been
remarkable advances in the definition of the molecular abnormalities
involved in leukaemogenesis and drug resistance. These advances have led
to the development of promising new therapeutic strategies, including
agents targeted to the molecular lesions that cause leukaemia. The
importance of host pharmacogenetics has also been recognised. Thus,
genetic polymorphisms of certain enzymes have been linked with host
susceptibility to the development of de novo leukaemia or
therapy-related second cancers. Furthermore, recognition of inherited
differences in the metabolism of antileukaemic agents has provided
rational selection criteria for optimal drug dosages and scheduling.
Treatment response assessed by measurements of submicroscopic leukaemia
(minimal residual disease) has emerged as a powerful and independent
prognostic indicator for gauging the intensity of therapy. Ultimately,
treatment based on biological features of leukaemic cells, host
genetics, and the amount of residual disease should improve cure rates
further.
9
UI - 11699206
AU - Betts DR; Riesch M; Grotzer MA; Niggli FK
TI -
The investigation of karyotypic instability in the high-hyperdiploidy
subgroup of acute lymphoblastic leukemia.
SO - Leuk Lymphoma 2001 Jun;42(1-2):187-93
AD - Department of Oncology, University Children's Hospital, Steinwiesstrasse
75, CH-8032 Zurich, Switzerland. David.Betts@kispi.unizh.ch
Acute lymphoblastic leukemia (ALL) of childhood has been cytogenetically
well characterized, and approximately 25% of cases will have a
high-hyperdiploid (51-68) chromosome complement. In a 5 year period a
consecutive series of 152 presentation ALL's were karyotyped. In all
cases a result was obtained and 138 (91%) had a detectable abnormal
clone of which 44 (29%) were high-hyperdiploid. Within the
high-hyperdiploidy group karyotypic cell to cell variation was observed
in many cases. To provide further evidence of this phenomenon a
dual-color fluorescence in-situ hybridization (FISH) experiment was
performed on stored fixed suspension from 14 ALL's with such a
karyotype. In each case 4-6 probes were investigated, employing probes
to centromeres of chromosomes X, 4, 6, 8, and 10 and a locus specific
probe to chromosome 21q22. It was found that the FISH produced results
that were generally in good agreement with the G-banding findings and
supported the notion of karyotypic cell to cell variation. FISH further
showed that most of cases would have two extra copies of chromosome 21
in the majority of leukemic cells and a single extra copy in the
minority. A further finding was that fewer cells contained extra copies
of chromosomes 6, 8 and 10 than was expected based on the comparison of
the signal number of the other probes investigated. In contrast
chromosomes X, 4, and 21 seldom displayed this feature. We have
demonstrated that karyotypic instability as defined by karyotypic cell
to cell variation is a feature of the high-hyperdiploid subgroup in
childhood ALL. It is questioned whether the underlying defect resulting
in the observed karyotypic instability of this subgroup is one of the
primary causative events in the formation of the leukemia.
10
UI - 11699220
AU - Uckun FM; Pallisgaard N; Hokland P; Navara C; Narla R; Gaynon PS; Sather
TI -
H; Heerema N
Expression of TEL-AML1 fusion transcripts and response to induction
therapy in standard risk acute lymphoblastic leukemia.
SO - Leuk Lymphoma 2001 Jun;42(1-2):41-56
AD - Children's Cancer Group ALL Biology Reference Laboratory, Parker Hughes
Institute, 2665 Long Lake Road, Suite 300, St. Paul, MN 55113, USA.
We prospectively examined the frequency of the t(12;21)TEL-AML1 fusion
in 504 children with newly diagnosed standard risk ALL using RT-PCR
assays. Cells from 95 patients (18.8%) were TEL-AML1+. There was a
significantly higher frequency of pseudodiploidy among the TEL-AML1+
cases (39.4% versus 14.1%, P = 0.001), primarily because structural
abnormalities involving 12p and del(6q) occurred more frequently in the
TEL-AML1+ group. TEL-AML1+ ALL was more sensitive to the induction
chemotherapy than TEL-AML1- ALL. The percentage of "rapid early
responders", i.e., patients who achieved an M1 (< 5% blasts) or M2
(5-25% blasts) marrow status on day 7 of induction chemotherapy, was
significantly higher among TEL-AML1+ cases. The quality of remission of
RT-PCR positive cases was excellent, as evidenced by the very low to
absent MRD burden of their end-of-induction bone marrow specimens.
TEL-AML1+ patients also had an excellent early EFS outcome. The
probability of EFS at 30 months from study entry were 98.9 +/- 1.0% for
the TEL-AML1+ group and 92.1 +/- 1.5% for the TEL-AML1- group (P =
0.0001). This prospective study significantly expands the knowledge
gained from previous studies regarding the prognostic significance of
t(12;21)TEL-AML1 fusion in pediatric ALL.
11
UI - 11699224
AU - Firat H; Favier R; Adam M; Leverger G; Landman-Parker J; Cayre Y; Douay
TI -
L
Determination of myeloid antigen expression on childhood acute
lymphoblastic leukaemia cells: discrepancies using different monoclonal
antibody clones.
SO - Leuk Lymphoma 2001 Jun;42(1-2):75-82
AD - Service d'Hematologie Biologique, Hopital d'enfants Armand Trousseau, 26
Avenue du Docteur Arnold Netter, 75571 Paris, France.
Prospective clinical studies including large numbers of patients have
led to the conclusion that co-expression of myeloid antigens in
childhood acute lymphoblastic leukaemia (My+ ALL) does not have
prognostic significance. However, reports of the frequency of My+ ALL in
children vary widely across laboratories using different mAb clones and
staining and analysing procedures. Taking two commonly accepted
thresholds of positivity for myeloid antigens (20 and 30%), we analysed
the immunoreactivity of the most widely employed mAb clones against CD13
(SJ1D1, L138 and My7) and CD33 (My9, P67.6 and D3HL60) and compared the
proportions of My+ ALL detected by these clones in childhood ALL. The
correlation between myeloid antigen expression and the presence of the
t(12;21) translocation was analysed concomitantly in the same samples.
The percentage of ALL cases positive for myeloid markers varied
significantly depending on the mAb clone and the positive threshold.
Among patients with B-ALL, the proportion of CD13+ ALL was significantly
lower using SJ1D1 than using L138 or My7, while the proportion of CD33+
ALL was significantly higher for My9 than for P67.6 or D3HL60. Analysis
of the co-expression of CD13 and CD33 on B-ALL cells using combinations
of mAb clones showed that this frequency was either underestimated by
the SJ1D1/D3HL60 or overestimated by the L138/P67.6 and My7/My9
combinations. A correlation between CD13/CD33 positivity and the
t(12;21) translocation was uniformly observed in B-ALL patients for a
positive threshold of 30%, whereas SJ1D1/D3HL60 detected no correlation
between t(12;21) and CD13/CD33 positivity when the threshold was lowered
to 20%. These data show that the mAb clones commonly used to detect the
CD13 and CD33 surface antigens have variable immunoreactivity against
childhood ALL cells, which may partly explain the conflicting reports
concerning the prognostic significance of myeloid antigen expression in
paediatric ALL and its association with different translocations. The
present findings may also be of clinical importance for therapeutic
choices.
12
UI - 11861265
AU - Gleissner B; Gokbuget N; Bartram CR; Janssen B; Rieder H; Janssen JW;
TI -
Fonatsch C; Heyll A; Voliotis D; Beck J; Lipp T; Munzert G; Maurer J;
Hoelzer D; Thiel E; German Multicenter Trials of Adult Acute
Lymphoblastic Leukemia Study Group
Leading prognostic relevance of the BCR-ABL translocation in adult acute
B-lineage lymphoblastic leukemia: a prospective study of the German
Multicenter Trial Group and confirmed polymerase chain reaction
analysis.
SO - Blood 2002 Mar 1;99(5):1536-43
AD - Department of Hematology, Oncology, and Transfusion Medicine, University
Hospital Benjamin Franklin, Free University of Berlin, Germany.
gleisner@zedat.fu-berlin.de
The BCR-ABL fusion, the molecular equivalent of the Philadelphia
translocation, gains importance for treatment stratification in adult
acute lymphoblastic leukemia (ALL). In this prospective study, samples
from 478 patients with CD10(+) B-cell precursor ALL (c-ALL and pre-B
ALL) underwent BCR-ABL reverse transcription-polymerase chain reaction
(RT-PCR) analysis with double testing of positive samples. Patients were
stratified according to the PCR result and treated in 2 German
Multicenter Trials of Adult ALL. The outcome was followed and the
prognostic impact of BCR-ABL was compared to clinical risk features. Of
the 478 samples, 432 had an evaluable BCR-ABL result. Thirty-seven
percent of the c-ALL and pre-B ALL patients were BCR-ABL(+) (p190, 77%;
p210, 20%; simultaneous p190/p210, 3%). BCR-ABL positivity was
associated with the high-risk features of older age (45 years versus 30
years median age; P =.0001) and higher white blood cell counts (23
500/microL versus 11 550/microL; P =.0001). Univariate and multivariate
analyses revealed BCR-ABL as the leading factor for a poor prognosis (P
=.0001) in comparison to clinical risk criteria. Irrespective of the
breakpoint, presence of any BCR-ABL transcript predicted a lower chance
of initial treatment response (68.4% versus 84.6%; P =.001) and a lower
probability of disease-free survival at 3 years (0.13 versus 0.47; P
=.0001). This bad outcome was not influenced by postinduction high-dose
treatment stratifications. The results show a high prevalence of BCR-ABL
fusion transcripts with predominance of p190. BCR-ABL RT-PCR is
confirmed as a sensitive, rapid method to diagnose t(9;22), and p190 and
p210 are unequivocally demonstrated as the most important predictors of
poor long-term survival despite intensified chemotherapy.
13
UI - 11916514
AU - Scrideli CA; Kashima S; Cipolloti R; Defavery R; Bernardes JE; Tone LG
TI -
Minimal residual disease in Brazilian children with acute lymphoid
leukemia: comparison of three detection methods by PCR.
SO - Leuk Res 2002 May;26(5):431-8
AD - Departamento de Pediatria and Puericultura, Faculdade de Medicina de
Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil.
The minimal residual disease (MRD) detection by the polymerase chain
reaction (PCR) in children with acute lymphoblastic leukemia has been
pointed to be an adverse prognostic factor. Detection methods based on
this technique using clone-specific primers are cumbersome and time
consuming. The detection of monoclonal gene rearrangements of gamma
T-cell receptors (TCRgamma) is a simpler although less sensitive method.
In the present study, we analyzed the presence of MRD during four
different phases of treatment (week 4; 3-6, 12-24 months, and end of
treatment) in 34 Brazilian children with lymphoid leukemia by three
detection methods based on the PCR technique: (1) using consensus
primers for the detection of a clonal population for TCRgamma; (2)
clone-specific primers for the junctional region of TCRgamma; and (3) a
semi-nested reaction with an initial cycle with consensus primers
followed by a second cycle with clone-specific primers. MRD presence was
associated with a shorter event-free survival and was the major
independent prognostic factor in most of the phases analyzed. The use of
consensus primers for the detection of TCRgamma clonality, although less
sensitive, proved to be a simpler, faster and less costly method whose
positivity was associated with more than 90% relapse rates during all
phases analyzed.
14
UI - 11846198
AU - Myoken Y; Sugata T; Kyo T; Fujihara M; Mikami Y
TI -
Itraconazole prophylaxis for invasive gingival aspergillosis in
neutropenic patients with acute leukemia.
SO - J Periodontol 2002 Jan;73(1):33-8
AD - Department of Oral Surgery, Hiroshima Red Cross and Atomic Bomb
Survivors Hospital, Japan. myoken@do5.enjoy.ne.jp
BACKGROUND: Due to an increasing number of leukemic patients with
invasive gingival aspergillosis during neutropenia (neutrophils <500
cells/microl for >10 days), we evaluated the efficacy of oral
itraconazole prophylaxis for preventing this invasive infection at our
hospital. METHODS: This was a retrospective, non-randomized study to
analyze the onset of identified invasive gingival aspergillosis among
536 patients with acute leukemia at risk due to the presence of
neutropenia from 1991 to 1998. Patients received itraconazole capsules
levels at day 10 were measured in some patients. RESULTS: In the 39
invasive gingival aspergillosis were detected in 192 high risk patients
with 469 episodes of neutropenia (7.8% of the high risk patients).
100 mg/day, there was a dramatic decrease in the infections resulting in
3 of 198 high risk patients with 511 episodes of neutropenia (1.5% of
1998, using itraconazole prophylaxis at 200 mg/day, no cases of the
infection were observed in the 146 high risk patients with 380 episodes
of neutropenia. The incidence of invasive gingival aspergillosis was
significantly lower among patients administered itraconazole than among
those without itraconazole (100 mg/day; P = 0.006 and 200 mg/day; P =
0.001). The mean itraconazole serum level in 20 patients receiving 100
mg/day was 71.78 ng/mL and in 16 patients receiving 200 mg/day was
202.67 ng/ml. CONCLUSIONS: These findings suggest that oral itraconazole
could be effective for preventing invasive gingival aspergillosis in
neutropenic patients with acute leukemia and warrants further randomized
investigation.
15
UI - 11808713
AU - Perrillat F; Clavel J; Jaussent I; Baruchel A; Leverger G; Nelken B;
TI -
Philippe N; Schaison G; Sommelet D; Vilmer E; Bonaiti-Pellie C; Hemon D
Family cancer history and risk of childhood acute leukemia (France).
SO - Cancer Causes Control 2001 Dec;12(10):935-41
AD - Institut National de la Sante et de la Recherche Medicale, INSERM U170,
Villejuif, France.
OBJECTIVE: A case-control study was carried out to investigate the role
of a family history of solid tumor or hematologic neoplasm in the
etiology of childhood acute leukemia. METHODS: Family cancer history in
first- and second-degree relatives was compared in 279 incident cases
(242 cases of acute lymphocytic leukemia and 37 of acute myeloid
leukemia) and 285 controls. Recruitment was stratified by age, gender,
hospital, area of residence, and ethnic origin. Odds ratios (OR) were
estimated using an unconditional regression model taking into account
the stratification variables, socioeconomic status, and familial
structure. RESULTS: A significant association between childhood acute
leukemia and a family history of hematologic neoplasm (OR = 2.7,
confidence interval (CI) = 1.1-6.9) was found. This association was
particularly clear-cut when the cases were restricted to acute myeloid
leukemia (OR = 13.3, CI = 2.5-70.9). Childhood acute leukemia was
associated with a family history of solid tumor (OR = 1.5, CI =
1.0-2.2), and elevated odds ratios were observed for family history of
gastrointestinal cancer and melanoma. Those results are most unlikely to
be explained by socioeconomic status and familial structure, which were
very similar for the cases and controls. Differential misclassification
is also unlikely for the first-degree relatives, even though it is
difficult to rule it out for the second-degree relatives' history.
CONCLUSION: The present study supports the hypothesis that a family
history of cancer may be a risk factor for childhood acute leukemia.
16
UI - 11877265
AU - Dworzak MN; Froschl G; Printz D; Mann G; Potschger U; Muhlegger N;
TI -
Fritsch G; Gadner H; Austrian Berlin-Frankfurt-Munster Study Group
Prognostic significance and modalities of flow cytometric minimal
residual disease detection in childhood acute lymphoblastic leukemia.
SO - Blood 2002 Mar 15;99(6):1952-8
AD - Children's Cancer Research Institute, St Anna Kinderspital,
Kinderspitalgasse 6, A-1090 Vienna, Austria. dworzak@ccri.univie.ac.at
Detection of minimal residual disease (MRD) in acute lymphoblastic
leukemia (ALL) predicts outcome. Previous studies were invariably based
on relative quantification and did not investigate sample-inherent
parameters that influence test accuracy, which makes comparisons and
clinical conclusions cumbersome. Hence, we conducted a prospective,
population-based MRD study in 108 sequentially recruited children with
ALL uniformly treated with the ALL-Berlin-Frankfurt-Munster (ALL-BFM) 95
protocol in Austria (median follow-up of 40 months). Using sensitive,
limited antibody panel flow cytometry applicable to 97% of patients, we
investigated 329 bone marrow samples from 4 treatment time points. MRD
was quantified by blast percentages among nucleated cells (NCs) and by
absolute counts (per microliter). Covariables such as NC count, normal B
cells, and an estimate of the test sensitivity were also recorded.
Presence and distinct levels of MRD correlated with a high probability
of early relapse at each of the time points studied. Sequential
monitoring at day 33 and week 12 was most useful for predicting outcome
independently from clinical risk groups: patients with persistent
disease (> or =1 blast/microL) had a 100% probability of relapse,
compared to 6% in all others. Absolute MRD quantification was more
appropriate than relative, due to considerable variations in total NC
counts between samples. Regeneration of normal immature B cells after
periods of rest from treatment limited the test sensitivity. In
conclusion, MRD detection by flow cytometry is a strong and independent
outcome indicator in childhood ALL. Standardization regarding absolute
quantification on the basis of NCs and assessment during periods of
continuous treatment promise to increase the accuracy, simplicity, and
cost efficiency of the approach.
17
UI - 11902139
AU - Reid AG; Huntly BJ; Hennig E; Niederwieser D; Campbell LJ; Bown N;
TI -
Telford N; Walker H; Grace CD; Deininger MW; Green AR; Nacheva EP
Deletions of the derivative chromosome 9 do not account for the poor
prognosis associated with Philadelphia-positive acute lymphoblastic
leukemia.
SO - Blood 2002 Mar 15;99(6):2274-5
18
UI - 11964928
AU - Infante-Rivard C; Krajinovic M; Labuda D; Sinnett D
TI -
Childhood acute lymphoblastic leukemia associated with parental alcohol
consumption and polymorphisms of carcinogen-metabolizing genes.
SO - Epidemiology 2002 May;13(3):277-81
AD - Joint Department of Epidemiology and Biostatistics, Faculty of Medicine,
McGill University, Montreal, Quebec, Canada. cirivard@epid.lan.mcgill.ca
BACKGROUND: Limited information is available on the association of
parental consumption of alcohol prior to and during pregnancy with the
risk of childhood leukemia, as well as for the potentially modifying
role of genetic polymorphisms. METHODS: We conducted a population-based,
case-control study of 491 incident cases of acute lymphoblastic leukemia
age 0-9 years and matched on age and sex to 491 healthy controls. Cases
were identified at tertiary care centers in the Province of Quebec
between 1980 and 1993. Each parent was interviewed separately about
alcohol consumption habits. We also used a case-only design with 186
cases to estimate interaction odds ratios between prenatal exposure and
child DNA variants in the GSTM1 and CYP2E1 genes. RESULTS: The adjusted
odds ratio for any maternal consumption during pregnancy was 0.7 (95%
confidence interval = 0.5-0.9). The interaction odds ratios for the
GSTM1 null genotype during third pregnancy trimester was 2.4 (95%
confidence interval = 1.1-5.4); the interaction odds ratio for CYP2E1
variant G-1295C (or allele *5) during the nursing period was 4.9 (95%
confidence interval = 1.5-16.7). CONCLUSIONS: The observed association
with maternal alcohol consumption during pregnancy could be due to the
potential chemopreventive effects of flavonoids found in wine and beer.
These possible effects of alcohol may be at least partially genetically
determined, although data are preliminary.
19
UI - 11954028
AU - Dahmoush L; Hijazi Y; Barnes E; Stetler-Stevenson M; Abati A
TI -
Adult T-cell leukemia/lymphoma: a cytopathologic, immunocytochemical,
and flow cytometric study.
SO - Cancer 2002 Apr 25;96(2):110-6
AD - National Institutes of Health/National Cancer Institute, Section of
Cytopathology, Bethesda, Maryland 20892, USA.
BACKGROUND: Adult T-cell leukemia/lymphoma (ATLL) is a postthymic
lymphoproliferative neoplasm of T cells caused by human T-cell
lymphotropic virus (HTLV-1). Most cases are found in Japan, the
Caribbean basin, and West Africa. DESIGN: To identify diagnostic
parameters for cytology in this neoplasm, the authors undertook a
retrospective review of all ATLL samples from 1990 to 2000. RESULTS: One
hundred fourteen samples from 34 patients with the diagnosis of ATLL
were reviewed: 80 cerebrospinal fluids, 7 pleural effusions, 4
bronchoalveolar lavages, 2 peritoneal effusions as well as fine-needle
aspirations of 15 lymph nodes, 4 subcutaneous lesions, and 2 breast
nodules. Twenty-one patients were women and 13 were men, with an age
range of 30 to 71 years. Morphologically, all specimens were
characterized by the presence of a polymorphous population of
lymphocytes ranging from small bland-appearing lymphocytes to large
atypical ones with bizarre, multilobulated nuclei (flower-like or clover
leaf cells) with coarse chromatin and prominent nucleoli. The cytoplasm
was deeply basophilic with occasional vacuoles. Immunocytochemistry was
performed on 17 specimens from 14 patients. In all cases tested, tumor
cells were immunoreactive for CD3, CD4, CD5, and CD25 and were
nonimmunoreactive for CD7 and CD8. Flow cytometry was performed on 12
specimens from 9 patients. The tumor cells in all cases tested were
positive for CD2, CD3, CD4, CD5, and CD25 and were negative for CD7.
CONCLUSIONS: Despite the polymorphous nature of ATLL, diagnosis can be
established by close attention to nuclear cytologic features in
conjunction with ancillary studies such as immunocytochemistry and/or
flow cytometry. Copyright 2002 American Cancer Society.
20
UI - 11952819
AU - Nordgren A; Heyman M; Sahlen S; Schoumans J; Soderhall S; Nordenskjold
TI -
M; Blennow E
Spectral karyotyping and interphase FISH reveal abnormalities not
detected by conventional G-banding. Implications for treatment
stratification of childhood acute lymphoblastic leukaemia: detailed
analysis of 70 cases.
SO - Eur J Haematol 2002 Jan;68(1):31-41
AD - Department of Molecular Medicine, Karolinska Institutet, L8-02
Karolinska Hospital, SE-17176 Stockholm, Sweden. ann.nordgren@cmm.ki.se
Seventy uniformly treated children with acute lymphoblastic leukemia
were analysed for chromosomal abnormalities with conventional G-banding,
spectral karyotyping (SKY) and interphase fluorescent in situ
hybridisation (FISH) using probes to detect MLL, BCR/ABL, TEL/AML1
rearrangements and INK4 locus deletions. Numerical and/or structural
changes could be identified in 80% of the patients by the use of
molecular cytogenetic techniques, whereas abnormalities could be
detected in 60% of the patients using G-banding alone. Altogether, 106
structural aberrations were defined by FISH compared to 34 using
G-banding. Seventy-four percent of the patients had numerical
aberrations, 54% structural aberrations and 20% had no identified
aberrations. Twelve cases had prognostically unfavourable chromosomal
aberrations that had not been detected in the G-banded analysis. We
identified three novel TEL partner breakpoints on 1q41, 8q24 and 21p12,
and a recurrent translocation t(1;12)(p32;p13) was found. In addition,
two cases displayed amplification (7-15 copies) of AML1. Our results
demonstrate the usefulness of SKY and interphase FISH for the
identification of novel chromosome aberrations and cytogenetic
abnormalities that provide prognostically important information in
childhood ALL.
21
UI - 11878571
AU - Pui CH
TI -
Risk assessment in acute lymphoblastic leukemia: beyond leukemia cell
characteristics.
SO - J Pediatr Hematol Oncol 2001 Oct;23(7):405-8
AD - St. Jude Children's Research Hospital, and University of Tennessee,
Memphis, USA.
22
UI - 11878574
AU - Gump J; McGavran L; Wei Q; Hunger SP
TI -
Analysis of TP53 mutations in relapsed childhood acute lymphoblastic
leukemia.
SO - J Pediatr Hematol Oncol 2001 Oct;23(7):416-9
AD - Department of Pediatrics, University of Colorado School of Medicine,
Denver, USA.
TP53 is the most commonly mutated gene in human cancer, but TP53
mutations are present in less than 5% of children with acute
lymphoblastic leukemia (ALL) at initial presentation. Mutations are
detected more frequently in children with relapsed T-cell ALL, but the
potential role of TP53 mutations in relapsed B-lineage childhood ALL is
not understood as well. The authors determined the nucleotide sequence
of amplified DNA from exons 5 to 8 of the TP53 gene in leukemic cells
obtained from 17 children with ALL at the time of first bone marrow
relapse. All 17 contained only germline TP53 sequences. Review of the
published literature disclosed that TP53 mutations have been found in
22% of cases of relapsed ALL. To understand the role of p53
abnormalities in this clinical setting, it will be important for future
studies to analyze cases of relapsed ALL with assays capable of
interrogating the functional integrity of the p53 pathway.
23
UI - 11918540
AU - Lee S; Kim DW; Kim YJ; Park YH; Min CK; Lee JW; Min WS; Kim CC
TI -
Influence of karyotype on outcome of allogeneic bone marrow
transplantation for adults with precursor B-lineage acute lymphoblastic
leukaemia in first or second remission.
SO - Br J Haematol 2002 Apr;117(1):109-18
AD - Catholic Hemopoietic Stem Cell Transplantation Center, College of
Medicine, The Catholic University of Korea, Seoul, Korea.
The prognostic relevance of karyotype has been established in adult
acute lymphoblastic leukaemia (ALL) patients treated with chemotherapy
but not definitively evaluated in an allogeneic bone marrow
transplantation (BMT) setting. To determine the factors affecting the
outcome of allogeneic BMT for adults with precursor B-lineage ALL in
first or second complete remission (CR), a total of 41 consecutive
patients with a successful karyotype were enrolled in this study. There
were 21 men and 20 women with a median age of 27 (15-43) years. The
distribution of French-American-British (FAB) subtypes was as follows:
L1 (n = 26), L2 (n = 15). Unfavourable karyotypes (n = 12) were defined
as Ph+ or t(4;11). Disease status at the time of transplant was first CR
(n = 35) or second CR (n = 6). With a median follow-up of 36 months, the
3-year probabilities of relapse and disease-free survival (DFS) were
36.3 +/- 8.4% and 57.3 +/- 8.4% respectively. Potential variables
predicting worse relapse and DFS were FAB subtype (L2), extramedullary
involvement, pre-BMT status (second CR), unfavourable karyotype and type
of graft-versus-host disease (GVHD). Further multivariate analysis
showed that karyotype and pre-BMT status were independently associated
with relapse and DFS. In addition, chronic GVHD was found to be
significantly associated with a lower relapse rate.
24
UI - 11996453
AU - Kulkarni AG
TI -
Acute lymphoblastic leukemia presenting as breast mass.
SO - J Assoc Physicians India 2001 Dec;49():1213-4
25
UI - 12015077
AU - Wan S; Gong W; Sun X; Xu J; Tian D
TI -
[Immunophenotyping of eighty six children with acute lymphoblastic
leukemia by three-color flow cytometry]
SO - Zhonghua Xue Ye Xue Za Zhi 2002 Feb;23(2):83-6
AD - Department of Hematology, Xuanwu Hospital, CUMS, Beijing 100053, China.
OBJECTIVES: To evaluate the specificity of three-color flow cytometry in
childhood acute lymphoblastic leukemia (ALL) immunophenotyping. METHODS:
Immunophenotyping was performed by three-color flow cytometry analysis
using CD(45)/SSC gating. RESULTS: The percentage of blasts was
correlated better with leukemic cell count compared with that of
FSC/SSC, and the false positive results were low. Among eighty six cases
of ALL, 95.3% was B-ALL, in which common-ALL and Pro-B-ALL were 76.8%
and 6.1%, respectively, and 2.3% was T-ALL. CD(34)(+) and
myeloid-associated antigen expression were observed in 57.0% and 34.9%
of the cases, respectively, among which Pro-B-ALL was the commonest.
CD(33) was more commonly expressed than CD(13) in Pro-B-ALL cases, but
no difference in the expression between these two antigens in other
subtypes. CONCLUSION: Gating of CD(45)/SSC eliminated effection of
normal cells to blasts in bone marrow, with which the immunophenotyping
results were more reliable.
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