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Blood, Vol. 93 No. 9 (May 1), 1999:
pp. 3074-3080
Prognostic Implication of FLT3 and N-RAS Gene
Mutations in Acute Myeloid Leukemia
By
Hitoshi Kiyoi,
Tomoki Naoe,
Yasuyuki Nakano,
Shohei Yokota,
Saburo Minami,
Shuichi Miyawaki,
Norio Asou,
Kazutaka Kuriyama,
Itsuro Jinnai,
Chihiro Shimazaki,
Hideki Akiyama,
Kenji Saito,
Hakumei Oh,
Toshiko Motoji,
Eijiro Omoto,
Hidehiko Saito,
Ryuzo Ohno, and
Ryuzo Ueda
From the Department of Infectious Diseases, Nagoya University School
of Medicine, Nagoya; the Third Department of Medicine and the Second
Department of Medicine Kyoto Prefectural University of Medicine, Kyoto;
the Department of Medicine, Japanese Red Cross Nagoya First Hospital,
Nagoya; the Department of Medicine, Saiseikai Maebashi Hospital,
Maebashi; the Second Department of Internal Medicine, Kumamoto
University School of Medicine, Kumamoto; the Department of Hematology,
Atomic Disease Institute Nagasaki University School of Medicine; the
First Department of Internal Medicine, Saitama Medical School, Saitama;
the Department of Hematology, Tokyo Metropolitan Komagome Hospital,
Tokyo; the Third Department of Internal Medicine, Dokkyo University
School of Medicine, Tochigi; the Second Department of Internal
Medicine, Chiba University School of Medicine, Chiba; the Department of
Hematology, Tokyo Women's Medical College, Tokyo; the Department of
Medicine, Okayama University Medical School, Okayama; the Department of
Medicine III, Hamamatsu University School of Medicine, Hamamatsu; and
the Second Department of Internal Medicine, Nagoya City University
School of Medicine, Nagoya, Japan.
 |
ABSTRACT |
Internal tandem duplication of the FLT3 gene and point
mutations of the N-RAS gene are the most frequent somatic
mutations causing aberrant signal-transduction in acute myeloid
leukemia (AML). However, their prognostic importance is unclear. In
this study, their prognostic significance was analyzed in 201 newly diagnosed patients with de novo AML except acute promyelocytic leukemia. Three patients had mutations in both genes, 43 had only the
FLT3 gene mutation, 25 had only the N-RAS gene
mutation, and 130 had neither. These mutations seemed to occur
independently. Both mutations were related to high peripheral white
blood cell counts, and the FLT3 gene mutation was infrequently
observed in the French-American-British (FAB)-M2 type. AML cases with
wild FLT3/mutant N-RAS had a lower complete remission
(CR) rate than those with wild FLT3/wild N-RAS, whereas
the presence of mutant FLT3 did not affect the CR rate.
Univariate analysis showed that unfavorable prognostic factors for
overall survival were age 60 years or older (P = .0002),
cytogenetic data (P = .002), FAB types other than M2
(P = .002), leukocytosis over 100 ± 109/L
(P = .003), and the FLT3 gene mutation
(P = .004). However, the N-RAS gene mutation was
only a marginal prognostic factor (P = .06). For the
subjects under 60 years old, multivariate analysis showed that the
FLT3 gene mutation was the strongest prognostic factor
(P = .008) for overall survival. The FLT3 gene
mutation, whose presence is detectable only by genomic polymerase chain reaction amplification and gel electrophoresis, might serve as an
important molecular marker to predict the prognosis of patients with AML.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
OUR UNDERSTANDING of the pathophysiology
of acute myeloid leukemia (AML) has rapidly advanced over the past two
decades. Cytogenetic studies have clarified the molecular mechanism of leukemogenesis. Chromosomal translocations, which are found in half of
all AML cases and correlate with the French-American-British (FAB)
types, target and deregulate the gene-coding transcriptional factors
that are important to hematopoiesis.1-3
Nonrandom chromosomal loss or deletion suggests that anti-oncogenes are
also involved in AML.1,2 Mutations and/or deletion of the
P53 gene were observed in AML,4 although the
incidence of these events is far lower than that in solid
tumors.5 Transfection studies using NIH/3T3 cells showed
that activated RAS genes are associated with the pathogenesis
of AML.6 RAS gene mutations, the majority of which
involve the N-RAS gene, are found in up to 30% of AML cases.7-9 These genetic alterations have been molecularly
detectable and used for diagnosis, detection of minimal residual
disease, and prediction of prognosis. For routine assessment, however, the following factors are required: clinical incidence and
significance, time- and cost-saving measures, and specificity and
sensitivity of the examination.
Recently an internal tandem duplication of the juxtamembrane (JM)
domain-coding sequence of the FLT3 gene was found in 20% of
AML.10,11 FLT3 is a class III receptor tyrosine kinase
(RTK), along with KIT, FMS, and PDGFR.12,13 Since FLT3
preferentially expressed on hematopoietic stem cells and its ligand
(FL) on bone marrow stroma cells,13-15 FLT3-FL interaction
plays an important role in primitive hematopoiesis. Furthermore, most
clinical samples from AML express functional FLT3, and the FLT3-FL
interaction might also be associated with the proliferation of leukemia
cells.16 The duplicated sequences of the mutant
FLT3 consisted of exon 11, but sometimes involved intron 11 and
exon 12.10,11 Although their location and length varied
from sample to sample, the portion of tandem duplication was always
readable in frame. Actually the transcripts with a long JM domain did
not disrupt the downstream regions. The mutant FLT3 was
ligand-independently phosphorylated when expressed in Cos 7 cells,17 indicating dominant positive mutation.
Interleukin-3 (IL-3)-dependent myeloid progenitor cell lines, FDC/P1
and 32D, exhibited IL-3-independent growth when transfected with
mutant FLT3 (H. Kiyoi, T. Naoe, unpublished data, 1998). The FLT3 gene mutation was found in all types of the FAB classification and in 3% of myelodysplastic syndrome, but never in
chronic myeloid leukemia or in lymphoid malignancies.11 In acute promyelocytic leukemia (FAB-M3), the presence of the FLT3 gene mutation was related to high peripheral white blood cell (WBC)
counts, high peripheral leukemia cell counts, and high lactate dehydrogenase (LDH) level.18 These findings suggest that
the FLT3 gene mutation plays an important role in leukemia
progression rather than initiation.
Since the detection of the FLT3 gene mutation requires only
polymerase chain reaction (PCR) amplification using genomic DNA followed by gel electrophoresis, we studied whether it could be used as
a standard molecular marker for the prognosis of AML. Here we analyzed
the prognostic significance of the FLT3 gene mutation together
with the N-RAS gene mutations in a large number of patients
with AML.
| |
PATIENTS AND METHODS |
Patients and treatments.
Two hundred one newly diagnosed patients with AML except for M3, who
were treated with three protocols of the Japan Adult Leukemia Study
Group, and whose leukemia cells were preserved with informed consent at
initial diagnosis, were eligible for this study. Twenty-eight, 40, and
133 patients were treated by the AML-87,19
AML-89,20 and AML-9221 protocols, respectively. AML was diagnosed according to the FAB classification, which was evaluated by the central review committee.
In the AML-87 study,19 the induction therapy consisted of
daily behenoyl cytarabine (BHAC) 200 mg/m2, daily
6-mercaptopurine (6-MP) 70 mg/m2, daily prednisolone 40 mg/m2, and daunorubicin (DNR) 40 mg/m2 on days
1 to 3, and if necessary on days 7, 8, and 11. The therapy was
continued for 10 to 12 days until the bone marrow became severely hypoplastic with less than 5% blasts. In the AML-89
study,20 patients were randomized to receive induction
therapy that included BHAC (200 mg/m2 by 3-hour infusion)
or cytarabine (AraC, 80 mg/m2 by continuous infusion). BHAC
or AraC, and 6-MP 70 mg/m2 were administered for 10 to 12 days, and DNR 40 mg/m2 was administered on days 1 to 4, and
if necessary, on days 10 to 12 in addition to the above schedule for
AML-87. In the AML-92 study,21 patients were randomized to
receive BHAC-DM similar to the AML-87 protocol with or without
etoposide (ETP, 100 mg/m2 for 5 days). After achieving
complete remission (CR), three courses of consolidation chemotherapy
and six courses of intensification chemotherapy were administered.
Patients 60 years or older received about two thirds of the dosage of
each drug throughout the study period.
CR was determined when there were less than 5% blasts in
normo-cellular bone marrow with normal levels of peripheral neutrophil and platelet counts. Overall survival (OS) was calculated from the
first day of therapy to death. Disease-free survival (DFS) for patients
who had achieved CR was measured from the date of CR to relapse or
death. Patients who underwent bone marrow transplantation (BMT) were
censored at the date of BMT.
Analysis of the internal tandem duplication of the FLT3
gene.
High molecular weight DNA was extracted from AML cells as previously
described.9 Because previous studies showed that the location of internal tandem duplication of the FLT3 gene was
restricted to exons 11 and 12,11,18 genomic PCR
amplification was performed using the primers 11F,
5'-GCAATTTAGGTATGAAAGCCAGC, and 12R, 5'-CTTTCAGCATTTTGACGGCAACC-3'. The
PCR mixture contained 500 ng of genomic DNA, 50 pmol of 11F and 12R
primers, 0.2 mmol/L of each deoxynucleotide triphosphate, 10 mmol/L
Tris-HCl (pH 8.3), 50 mmol/L KCl, 1.5 mmol/L MgCl2, 0.001%
gelatin (wt/vol), 50 mmol/L tetramethylammonium chloride and 2.5 U of
Taq polymerase (Amplitaq; Perkin Elmer, Norwalk, CT).
Denaturing, annealing, and extension steps were performed at 94°C for
30 seconds, 56°C for 1 minute and 72°C for 2 minutes, respectively,
for 35 cycles on a GeneAmp PCR system 9600 (Perkin Elmer) including an
initial 3 minutes denaturation step at 94°C and a final extension
step at 72°C for 10 minutes. The amplified product was cut out from
an agarose gel, purified with a Qiaex gel extraction kit (Qiagen Inc,
Chatsworth, CA), and cloned into the pMOSBlue T-vector
(Amersham, Buckinghamshire, UK) according to the manufacturer's
recommendation. Ten recombinant colonies were chosen and cultured in
LB medium. Plasmid DNA was prepared using a QIAprep spin
plasmid miniprep kit (Qiagen Inc), and both strands were sequenced
using fluorescein-conjugated  21M13 and T7 primers on a DNA sequencer
(377; Applied Biosystems, Foster City, CA).
N-RAS gene amplification and dot-blot hybridization.
To amplify the sequences spanning codons 12 and 13, and codon 61, the
oligonucleotide primers were prepared as follows; 5'primer for codons
12, 13 (named NA12): 5'-GACTGAGTACAAACTGGTGG-3', 3'primer for codons
12, 13 (NB12): 5'-CTCTATGGTGGGATCATATT-3', 5'primer of codon 61 (NA61):
5'-GGTGAAACCTGTTTGTTGGA-3', and 3'primer of codon 61 (NB61):
5'-ATACACAGAGGAAGCCTTCG-3'. The PCR was performed as described
previously.9 Genomic DNA was subjected to 35 cycles of PCR
amplification (denaturation for 60 seconds at 92°C, annealing for 60 seconds at 55°C, and elongation for 60 seconds at 72°C). The
efficiency of amplification was evaluated by agarose gel
electrophoresis, and only the reactions resulting in the appropriately
sized band were further analyzed. Dot-blot and oligonucleotide probe
hybridization were performed as previously described.9
Briefly, either 100 ng DNA amplified by PCR was transferred to nylon
filter membranes (Hybond-N+; Amersham) with a 96-well filtration
manifold. Blotted DNA was crosslinked by UV illumination and the
membranes were hybridized with [ -32P] labeled
oligonucleotide probes. The oligonucleotide panel included probes
specific for the wild-type allele and all possible amino acid
substitutions at codons 12, 13, and 61 of the N-RAS gene. The
prehybridization, hybridization, and washing of membranes were
performed under standard conditions.9 The membranes were exposed to Kodak XAR5 films (Eastman Kodak, Rochester, NY)
at 70°C using intensifying screens.
Statistical methods.
The following clinical characteristics at diagnosis were analyzed: age,
sex, FAB classification, peripheral WBC count, percentage of blasts in
bone marrow, platelet count, serum LDH concentration, the presence of
hepato-splenomegaly or extramedullary involvement, and cytogenetic
findings. Analysis of frequencies was performed using the Fisher's
exact test for 2 × 2 tables or the Pearson's  2 test
for larger tables. Differences in median variables in age, peripheral
WBC counts, platelet counts, percentage of blasts in bone marrow, and
LDH were also analyzed with the Wilcoxon rank-sum test. CR rates in the
two groups were compared using the Fisher's exact test. The logistic
progression model was used for multivariate analysis.
Survival probabilities were estimated by the Kaplan-Meier method, and
differences in the survival distributions between the mutation-positive
and -negative groups were evaluated by the log-rank test. The
prognostic significance of the clinical variables was assessed using
the Cox proportional hazards model. These statistic analyses were
performed with StatView software (Abacus Concepts Inc, Berkeley, CA) or
SAS programs (SAS Institute Inc, Cary, NC). Because CR rates, OS, and
DFS according to induction therapies (the AML-87, -89, and -92 studies)
did not show any difference, the data of the three studies were
combined and analyzed. For all analyses, the P values were
two-tailed, and a P value of less than .05 was considered
statistically significant.
| |
RESULTS |
A total of 201 newly diagnosed patients with AML were studied for the
FLT3 and N-RAS gene mutations. FLT3 gene
mutations were identified in 46 of the 201 patients. Translated into
amino acids, the tandem duplications frequently involved a Y-rich
stretch from codon 589 to 599 (data not shown), the same position as in
previous studies.11,18 N-RAS gene mutations were
detected in 28 of the 201 patients. The mutations at codons 12, 13, and
61 were observed in 12, 13, and 7 patients, respectively. Three of the
28 patients had multiple mutations at codon 12, one at codon 61, and
three at codons 12 and 13. Of a total of 37 N-RAS gene point
mutations, G to A transition was the most frequent (16/37).
In a total of 201 patients, 3 patients (1.5%) had mutations in both
genes (mutant FLT3/mutant N-RAS), 43 (21.4%) had
only mutant FLT3 gene (mutant FLT3/wild
N-RAS), 25 (12.4%) had only mutant N-RAS gene (wild
FLT3/mutant N-RAS), and 130 (64.7%) had neither
(wild FLT3/wild N-RAS). Clinical characteristics were analyzed comparing these four groups (Table
1). The presence of mutant FLT3 or
mutant N-RAS was not related to age and sex (data not shown).
WBC counts in the wild FLT3/wild N-RAS group were
significantly lower than in other groups (P = .03 v
mutant FLT3/mutant N-RAS, P < .0001
v mutant FLT3/wild N-RAS, P = .002 v wild FLT3/mutant N-RAS) (Table
1). Serum LDH level in the wild FLT3/wild N-RAS group
tended to be lower than that in the other groups. The occurrence of
hepato-splenomegaly or extramedullary involvement was not
significantly affected by these mutations. The incidence of the
FLT3 gene mutation according to FAB classification was ranked
as follows: M4/5 (22/62) > M1 (14/48) > M2 (8/83). Additionally,
the FLT3 gene mutation was infrequently observed in
the leukemia with t(8;21) (P = .02). The incidence of the
N-RAS gene mutation was similarly ordered: M4/5 (11/62) > M1
(6/48) > M2 (10/83).
WBC counts were further analyzed in each FAB group. In M1 and M2, WBC
counts in the wild FLT3/wild N-RAS group were lower than the mutant groups (P = .004 v mutant
FLT3/wild N-RAS, P = .09 v wild
FLT3/mutant N-RAS). In M2, those in the mutant
FLT3/wild N-RAS group tended to be lower than other
groups (P = .2 v mutant FLT3/wild
N-RAS, P = .1 v wild FLT3/mutant
N-RAS). In M4/5, however, there was no difference of WBC counts.
The CR rates by initial induction therapy were significantly different
between the wild FLT3/mutant N-RAS group and the wild FLT3/wild N-RAS group (52.0% v 79.7%,
P = .005). However, the presence of mutant FLT3 did
not affect the CR rate. Chi-squared analysis showed that FAB types
other than M2, the presence of N-RAS gene mutation, and
leukocytosis (over 100 × 109/L) were unfavorable
factors for achieving CR (P = .001, P = .04, and
P = .07, respectively). Multivariate analysis using the
logistic progression model showed that FAB types other than M2
(P = .001) and N-RAS gene mutation
(P = .05) were independent unfavorable factors for achieving
CR, whereas leukocytosis was not significant.
At a median follow-up time of 50 months (range, 3 to 118 months), 68 of
201 patients (33.8%) were alive. The predicted OS rates at 60 months
were 14.0%, 16.0%, and 44.6% in the mutant FLT3/wild
N-RAS, wild FLT3/mutant N-RAS, and wild
FLT3/wild N-RAS groups, respectively (Fig
1). Mutant FLT3/wild N-RAS
and wild FLT3/mutant N-RAS groups had worse prognosis
than the wild FLT3/wild N-RAS group
(P = .0006 and P = .008, respectively).
View larger version (18K):
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| Fig 1.
Kaplan-Meier curves according to the FLT3 and
N-RAS gene mutations. (A) OS of 198 patients. (B) DFS of 145 patients who achieved CR. Three patients with both FLT3 and
N-RAS gene mutations were excluded from the analysis because
the number was small. Statistic difference was evaluated by the
log-rank test.
|
|
The prognosis of AML depends on factors such as age, initial leukocyte
count, FAB classification, karyotype, immune phenotype, and response to
remission-induction therapy.19-23 Among them, cytogenetic data is thought to be the most important prognostic factor for AML.1 Based on cytogenetic findings, the 201 patients were segregated into four groups: a good-risk group (n = 34) was defined by karyotype, t(8;21) or inv(16); a poor-risk group (n = 14) by t(9;22), 11q23 alterations, del(5) or del(7); a standard-risk group
(n = 123) by normal or other karyotypes; and a karyotype-unknown group (n = 30). The predicted OS rates at 60 months were 57.1%, 33.6%, 13.3%, and 20.7% in the good-risk, standard-risk, poor-risk, and karyotype-unknown groups, respectively. In the good-risk and standard-risk groups, the FLT3 and N-RAS gene mutations
were associated with unfavorable prognosis (Fig
2). In the poor-risk and karyotype-unknown groups, however, there was no significant association between these
mutations and prognosis.
View larger version (28K):
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| Fig 2.
OS according to the FLT3 and N-RAS gene
mutations in each karyotype-risk group. In good-risk patients, the
mutant FLT3/wild N-RAS group had worse prognosis than
the wild FLT3/wild N-RAS group (P = .05).
In standard-risk patients, the mutant FLT3/wild N-RAS
group and wild FLT3/mutant N-RAS group had worse
prognosis than the wild FLT3/wild N-RAS group
(P = .02).(), Mutant
FLT3/mutant N-RAS; ( ), mutant FLT3/wild
N-RAS;
(···),
wild FLT3/mutant N-RAS;
(····): wild FLT3/wild N-RAS.
|
|
Univariate analysis showed that unfavorable prognostic factors for OS
were age 60 years or older (P = .0002), cytogenetic data
(P = .002), leukocytosis over 100 × 109/L
(P = .003), the FLT3 gene mutation
(P = .004) (Table
2). However, the N-RAS
gene mutation was only a marginal prognostic factor (P = .06). Multivariate analysis showed that age (60 years or older) was the strongest unfavorable factor (relative risk [RR], 1.9;
P = .002), followed by cytogenetics (P = .004). FAB
types, leukocytosis, and the FLT3 gene mutation were less
important. It might be partly associated with the poor prognosis that
the dosage of chemotherapy to the patients 60 years or older was
reduced. If the subjects were limited to under 60 years old, the
FLT3 gene mutation became the strongest prognostic factor (RR,
2.1; P = .008), with a second factor being cytogenetics
(P = .07) and N-RAS gene mutation (RR, 1.7;
P = .09) (Table 3).
DFS was further analyzed in 147 patients who achieved CR. The predicted
DFS rates at 60 months were 20.0%, 23.1%, and 53.9% in the mutant
FLT3/wild N-RAS, wild FLT3/mutant
N-RAS, and wild FLT3/wild N-RAS groups,
respectively (Fig 1). According to univariate analysis, the following
pretreatment variables showed statistical significance for DFS: age
(P = .002), cytogenetic data (P = .004), leukocytosis (P = .004), the FLT3 gene mutation
(P = .006) (Table 4).
Multivariate analysis showed that age was the most unfavorable factor
(RR, 2.0; P = .003), followed by cytogenetic data
(P = .001), and leukocytosis (P = .04). For the
subjects under 60 years old, leukocytosis was the sole important factor
(RR, 2.6; P = .01) (Table 5).
| |
DISCUSSION |
In this study, we showed that the FLT3 gene mutation is
significantly associated with clinical feature and prognosis of AML. In
our previous analysis on M3,18 the FLT3 gene
mutation closely correlated to leukocytosis but not significantly to
prognosis. The reasons for the discrepancy between M3 and the others
are the sample size and that the prognosis for M3 was favorable
compared with other types of AML, especially after the clinical
introduction of differentiation therapy with all-trans retinoic
acid.24 The present study showed that the FLT3 gene
mutation was significantly associated with leukocytosis in M1 and M2
but not in M4/5. However, the FLT3 gene mutation was associated
with an unfavorable prognosis regardless of FAB type. Mutant
FLT3 might not be simply associated with cell proliferation but
also with inhibition of apoptosis.25 The relevance of
mutant FLT3 may be dependent on intracellular conditions, which
are determined by cell lineage and gene alterations. Importantly, the
difference of prognosis between mutant and wild FLT3 was more
remarkable in the good- and standard-risk groups than in the poor-risk
and karyotype-unknown groups. Furthermore, the FLT3 gene
mutation was the strongest prognostic factor for subjects under 60 years old. Thus the FLT3 gene mutation is a useful molecular
marker to identify high-risk patients who could not be characterized by
conventional criteria.
The prognostic significance of the N-RAS gene mutation is a
matter of controversy. Generally RAS gene mutation is
associated with tumor progression and was reported to be associated
with poor prognosis in solid tumors and acute lymphoblastic leukemia (ALL).26,27 In AML, however, there was no difference in
survival between RAS mutation-positive and -negative
patients.7,8 In this study, the presence of N-RAS
gene mutation was related to low CR rate and was marginally associated
with unfavorable prognosis. One reason for the discrepancy between our
data and previous reports is that we could exclude the influence of
FLT3 gene mutation in this study. When the cases with mutant
N-RAS were compared with those with wild N-RAS, the
prognostic difference was limited (OS, P = .06; DFS,
P = .2). Because no ALL cases have mutant FLT3, their
prognosis might be directly influenced by the presence of mutant
N-RAS.27
It is particularly interesting to investigate the multiplicity of gene
alterations associated with leukemia. Our results suggest that the
mutations of FLT3 and N-RAS genes occurred
independently (P = .07 by the Fisher's exact test), although
we could not entirely rule out the possibility that a weak adverse
interaction exists between mutant FLT3 and mutant
N-RAS. Because both gene alterations are associated with
aberrant signal-transduction, these mutations may be additively or
synergistically associated with leukemia progression. Our serial
studies indicated that no leukemia cases carry both
t(9;22)/BCR-ABL and mutant FLT3.11 Because
p115CBL, which is activated by BCR-ABL,28 is one of the
downstream proteins for FLT3,29 FLT3 gene
mutation may bring no growth advantage to leukemia clone with
BCR-ABL. Aberrant signal-transduction through mutant
FLT3 should be clarified to further characterize the functional significance of mutant FLT3.
Gain-of-function mutation of the FLT3 gene suggests that new
strategies would be applicable for the treatment of AML. Inhibitors of
FLT3-pathway may selectively inhibit leukemia cell proliferation. It
has been reported that inhibition of Jak-2 activity by a specific tyrosine kinase blocker blocks leukemic cell growth in vitro and induces programmed cell death in vivo.30 In the future, the best choice of therapy may be established depending on an individual set of molecular alterations in each patient with leukemia.
| |
ACKNOWLEDGMENT |
We are grateful to Drs Akihisa Kanamaru, Junko Ohyashiki, Ritsuro
Suzuki, and Masatomo Takahashi for sending patients' samples.
| |
FOOTNOTES |
Submitted September 18, 1998; accepted January 5, 1999.
Supported by a Grant-in-Aid from the Japanese Ministry of Health and Welfare.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Tomoki Naoe, MD, Department of Infectious
Diseases, Nagoya University School of Medicine, Nagoya 466-8560, Japan.
| |
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TOP
ABSTRACT
INTRODUCTION