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NCI CANCERLIT® Search: Diagnosis-Histopathology-Pathogenesis of All - January 2002
National Cancer Institute®
Last Modified: January 1, 2002
Table of Contents
1
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.
2
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.
3
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
4
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.
5
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.
beck@mail.uni-greifswald.de
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.
6
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. scott.hiebert@mcmail.vanderbilt.edu
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.
7
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. susan.mathew@stjude.org
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.
8
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. hmuller@uni-muenster.de
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.
9
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.
10
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. pajor@pathology.pote.hu
11
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.
12
UI - 11568912
AU - Eguchi M; Eguchi-Ishimae M
TI -
Absence of t(12;15) associated ETV6-NTRK3 fusion transcripts in
pediatric acute leukemias.
SO - Med Pediatr Oncol 2001 Oct;37(4):417
13
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.
14
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.
15
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.
16
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.
17
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.
18
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. yyoshida@cseas.kyoto-u.ac.jp
19
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.
20
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.
21
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.
22
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
23
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.
24
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.
rita.consolini@dp.med.unipi.it
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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