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Blood, Vol. 92 No. 3 (August 1), 1998:
pp. 795-801
Expression of Myeloid Markers Lacks Prognostic Impact in Children
Treated for Acute Lymphoblastic Leukemia: Italian
Experience in AIEOP-ALL 88-91 Studies
By
Maria Caterina Putti,
Roberto Rondelli,
Maria Grazia Cocito,
Maurizio Aricó,
Laura Sainati,
Valentino Conter,
Cesare Guglielmi,
Angelo Cantú-Rajnoldi,
Rita Consolini,
Andrea Pession,
Luigi Zanesco,
Giuseppe Masera,
Andrea Biondi, and
Giuseppe Basso
From the Dipartimento di Pediatria, Universitá di Padova,
Padova; III Clinica Pediatrica, Universitá di Bologna, Bologna;
Clinica Pediatrica, Universitá di Pavia, Pavia; Clinica
Pediatrica Universitá di Milano-Ospedale San Gerardo, Monza;
Cattedra di Ematologia, Universitá La Sapienza,
Roma; Clinica Pediatrica, Universitá di Pisa, Pisa;
Dipartimento di Pediatria, Universitá di Torino, for the Italian
Association for Pediatric Hematology and Oncology (AIEOP).
 |
ABSTRACT |
The importance of coexpression of myeloid antigens in childhood
acute lymphoblastic leukemia (ALL) has long been debated; results are
conflicting. We studied children with ALL treated at Italian
Association for Pediatric Hematology-Oncology (AIEOP) institutions over
6 years with Berlin-Frankfurt-Muenster (BFM)-based protocols and have analyzed the incidence of coexpression of six MyAg (CD11b, CD13, CD14, CD15, CD33, CD65w) to determine
its prognostic impact. Criteria for MyAg coexpression
(MyAg+ALL) included positivity to one or more MyAg on at
least 20% of blasts and confirmation of coexpression at
double-fluorescence analysis. A total of 291 of 908 cases were
MyAg+ALL (32%). Incidence was similar in B-ALL and
T-ALL; among common, pre-B, and pre-pre-B-ALL. CD13 and CD33 were most
common. Patients with MyAg+ALL had presenting features
similar to MyAg ALL. They entered standard or
intermediate risk protocols more frequently and had better prednisone
response, but similar complete remission rates. Six-year event-free
survival (EFS) was 69.0% in 291 MyAg+ALL
cases and 65.3% in 617 MyAgALL cases, without
significant difference. Cases expressing two or more MyAg presented
similar clinical features and treatment response.
MyAg+ALL had worse EFS only in infants (0% v
47%) (P = .01). Therefore, in this series of homogeneously
diagnosed and treated ALL, coexpression of MyAg was not associated with
prognostic significance, without relevance for clinical purposes or for
patient stratification, except for infants.
© 1998 by The American Society of Hematology.
| |
INTRODUCTION |
RECOGNIZABLE IMMUNOLOGIC patterns usually
allow to attribute childhood acute lymphoblastic leukemia (ALL) to T or
B lineages.1,2 Based on experience of a large series of
patients homogeneously treated, such information has been associated
with some clinical and biologic features and with different prognosis
in some cases.3-5
Abnormal expression of antigens of different lineages on leukemic cells
has driven much interest because it suggests aberrant hematopoietic
differentiation.6 Moreover, its correlation with leukemias
with peculiar clinical and biological features [eg, ALL with Ph1
chromosome or translocation t(4;11)] has long been studied as a sign
of neoplastic involvement of very immature progenitors. In fact, these
leukemias often present "hybrid" features as the rearrangement of
different genes or the response to various growth factors. Some of them
often present an aggressive clinical course, with poor response to
standard therapy.7-9 The above observations have suggested
we should consider the expression of myeloid antigens (MyAg) in ALL as
a possible indicator of abnormal biological behavior and possibly of
different prognosis.6,10 However, results have been
controversial in different series and prognostic data are still
awaiting a conclusive confirmation. In fact, while many adult series
have shown poorer outcome for ALL with myeloid
markers,10-17 this significance has not yet been firmly
established for pediatric patients, about whom opinions in the
literature are rather conflicting.16-25 However,
differences may be due to the consistency of series, as well as to
technical details about recognition of coexpression. The current
widespread use of monoclonal antibodies (MoAbs) and of fluorescence
activated cytometry has extended the possibility of precise
immunophenotyping, thereby allowing easy confirmation of the
coexpression of different markers on the surface of blasts by
multiparametric analysis.
In this study, we have analyzed the pattern of expression of the most
common MyAg in a large group of childhood ALL (908 cases), all
homogeneously diagnosed and treated according to two cooperative studies of the Italian Association for Pediatric Hematology-Oncology (AIEOP). Three myeloid markers (CD13, CD33, and CDw65) have been analyzed as part of an obligatory panel, according to the
Italian-Berlin-Frankfurt-Muenster Study Group (I-BFM-SG)
recommendations.26 Three additional markers (CD11b, CD14,
and CD15) have also been evaluated to extend the analysis on the most
widely studied antigens in the literature. The association with the
most important clinical parameters and the prognostic significance of
the coexpression of MyAg are also analyzed and discussed in this
report.
| |
MATERIALS AND METHODS |
Patients.
A total of 1,811 children with newly diagnosed ALL have been reported
by the AIEOP institutions from January 1988 to April 1995. Of them,
1,612 (89%) were eligible for the two subsequent trials, AIEOP ALL 88 and 91, respectively. For this study, a group of 908 patients (56.3%)
was analyzed, of whom the main prognostic indices and a complete
immunophenotype were known. The remaining patients were not used for
analysis because a full set of their records was not available.
Treatment schedule.
Patient stratification was based on tumor burden estimated as BFM Risk
Factor (RF).3 They were treated using three different risk-directed regimens according to the criteria of BFM and AIEOP groups.27-29 Details of the treatment schedule have been
provided elsewhere for both the AIEOP-ALL 8828 and the
AIEOP-ALL 91 study.29 Treatment consisted of a classical BFM backbone3 with minor modifications. Patients in the
high-risk (HR) group of the study 91 received a block-type
chemotherapy, derived from the BFM experience in relapsed
ALL.30 Cranial irradiation was only given to HR patients
older than 1 year of age or with central nervous system
(CNS) involvement. The remaining patients had extended
intrathecal chemotherapy for CNS prophylaxis.
Diagnostic criteria and immunophenotype.
All cases were diagnosed as ALL according to the
French-American-British (FAB) morphological and cytochemical
criteria.31 Immunophenotypic studies were performed on bone
marrow samples at diagnosis by indirect immunofluorescence on flow
cytometry.32 Analyses were centrally performed using
shipped samples at the reference Laboratory for Hemato-Oncology
(Department of Pediatrics, University of Padova, Padova, Italy). All
results were carefully revised and accepted by standard procedures. A
base-line panel of leukocyte antigens was used in all cases, comprising
B-cell antigens (CD19, CD10, CD20; CD24; surface [SIg] and
cytoplasmic [CyIg] immunoglobulins), T-cell antigens (CD2, CD7, CD1a,
surface and cytoplasmic CD3, CD5), myeloid antigens (CD13, CD14, CD33, CD65w, CD11b, CD15), and lineage-nonspecific markers (CD34, HLA-DR, TdT). Surface markers were considered positive when present on more
than 20% of the blast cells. Antigen coexpression was always confirmed
by double fluorescence tests using directly conjugated reagents
(fluorescein isothiocyanate [FITC] and phycoerythrin [PE]) (Fig 1). Analyses were performed on an Epics XL
(Coulter, Miami, FL) cytometer. Isotypic controls were
always added. Nonspecific binding was prevented by incubation with
AB human serum.
Different immunological groups were identified by positivity to
different markers, and the criteria recommended by the I-BFM-SG Biological Cooperative Group were used for classification, thus recognizing the following categories26: pre-pre-B, common
ALL, pre-B ALL, T ALL. Mature B-ALL were not eligible for these
studies. We defined MyAg+ALLs as the cases coexpressing at
least one MyAg among all six evaluated markers in any immunophenotypic
group. Hybrid leukemias26,33 were the cases with
coexpression of at least two MyAg (of CD13, CD33, CD65w) in
common-ALL, pre-B-ALL, T-ALL, and of at least one MyAg in
pre-pre-B-ALL.
Statistical methods.
Data were collected on protocol-specific forms. The information was
stored, controlled, and analyzed by VENUS, an integrated system of
software facilities manufactured by the North-East Italian Interuniversities Computing Center (CINECA, Bologna, Italy), running on
an IBM mainframe. The following presenting features were
evaluated34: age (cut-offs >1, 1-9, >9 years), sex,
hepatomegaly, splenomegaly (below the umbilical line); CNS involvement,
leukocyte count (cut-off point at 50,000/µL),
hemoglobin (cut-off 8.0 g/dL), platelets (cut-off 50,000/µL), FAB
morphology (L1 or L2), prednisone response (good for less than 1,000 blasts/µL after 7 days of steroid therapy)27 could be
investigated only in the 816 cases (98.6%) for whom information was
available. Cytogenetics and DNA index were excluded from analysis because they have become mandatory since 1995.
Difference in the distribution of single or multiple MyAg+
coexpression among immunophenotypic subgroups was tested by
 2 test for heterogeneity.35 Event-free
survival (EFS) was estimated by the Kaplan-Meyer method.36
Time on study or time to terminal event was calculated from the day of
diagnosis. Failure to achieve remission, relapse, or death from any
cause were considered events, whichever occurred first. The follow-up
was updated on May 31, 1996. The log-rank test37 was
adopted to assess differences in univariate analysis. The Cox model was
used to draw a multivariate regression.38
| |
RESULTS |
Clinical features.
The present study included 908 patients (56.3%) for whom a complete
set of clinical and immunophenotypic information was available. Their
presenting features are summarized in Table
1. They were compared with the remaining 704 eligible patients for whom
significant differences in presenting features were not found by Fisher
and 2 tests. However, cases in study had high white
blood cell (WBC) counts more often than other patients (22% v
19%) P = .05.
Immunophenotype.
A total of 572 cases (63%) were diagnosed as common ALL, 185 (20.7%)
were pre-B ALL, 29 (3.2%) were pre-pre-B ALL, and 122 (13.5%) were
T-ALL. In 291 cases (32%), one or more myeloid antigens (MyAg+ALL) were coexpressed; most of them (n = 256) were of
B lineage and 35 were of T lineage; their frequency was similar in the
two groups (32.5% and 28.7%, respectively, P = .3). Frequency
among the three B-lineage subtypes was also similar; in particular, the
pattern of myeloid positivity in the immature pre-pre-B type (38%)
was comparable to that of C-ALL (31%) and pre-B ALL (36.2%) (Table 2). T-ALL expressing MyAg were
present in all stages of cell maturation; intermediate stage T-ALL was
more frequently associated with expression of MyAg (19 MyAg+ of the 43 intermediate T-ALL; 7 MyAg+ of
the 24 early T-ALL; 9 MyAg+ of the 55 mature T-ALL;
P = .005). Ninety-four cases (10.3%) were "hybrid"
according to the above-mentioned definition26; 84 were
B-lineage and 10 were T-ALL, without any difference in incidence either
between these two lineages (10.6% B-ALL v 8% T-ALL) or for
common-ALL versus pre-B ALL.
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Table 2.
Distribution of Immunophenotype Among 908 Cases of
Childhood ALL Studied for MyAg Coexpression and Reactivity to Each
MyAg
|
|
The distribution of positivity to each MyAg in the four different
immunological subtypes is also shown in Table 2. An example of a
CD13, CD33, CD15+
common ALL is shown in Fig 1. Of the
analyzed MyAg, CD13 and CD33 were most frequently found: 142 cases were
CD13+ and 130 were CD33+. They were mostly
found in B precursor ALL positive to CD10 (common and pre-B) and in
T-ALL (P, not significant). Eleven pre-pre-B ALL expressed
MyAg; CD15 and CD65w were the most common ones (6 positive cases each),
being the association of pre-pre-B phenotype with both antigens
statistically significant (P = .003 and P = .008, respectively). Seven of 23 infant patients were MyAg+ALL:
all markers were equally present twice in these cases. Among 291 MyAg+ALL, 158 cases (54.2%) showed positivity to one
single MyAg. CD13 and CD33 were the most frequent (53 and 35 times,
respectively). However, 44 ALL were only positive either to CD11b,
CD14, or CD15. In 75 cases, two MyAg were positive and in 58 cases,
three or more MyAg were present. The most common association was
CD13+, CD33+ (28 cases). Three cases were
positive to all six MyAg: their phenotypes were the following: one
pre-B, one pre-pre-B, one T-ALL. Three more cases were positive only
to "minor" MyAg (CD11b, CD14, and CD15) in various combinations.
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| Fig 1.
Fluorescence-activated cell sorting
(FACS) multigraph images of double-fluorescence analysis
in a case of MYA+ALL. The patient had a B-lineage ALL
with common phenotype. Blast cells showed positivity to CD19, CD11b,
CD65w, and CD15 and negativity to CD13 and CD33. Fluorochrome used are
FITC (for CD19) and PE (for MyAg).
|
|
Association with presenting features.
There were no significant associations between MyAg+ALL and
the clinical presenting features; in particular, the distribution of
age, initial WBC counts, T or B phenotype, and CD10 reactivity was more
similar than in all other ALL. However, MyAg+ALL were more
frequently assigned to standard or intermediate risk protocols (78%)
than MyAg cases (65%; P = .001). They were
also frequently prednisone responders (93% v 88%; P = .03), although this did not result in different rate of achievement of
complete remission (Table 1). When hybrid cases26 were
considered separately, these patterns of results did not change.
Response to treatment.
Six-year EFS of the cohort of studied patients was 66.4% (standard
deviation [SD], 1.6) with median follow-up of 48 months; this was not
significantly different from EFS of the 704 nonstudied patients
(71.2%; SD, 1.9) (P = .23). The only pretreatment factors found to correlate favorably with EFS, also by multivariate analysis, were: age (1 to 9 years) (P = .0001), good prednisone response (P = .0002), and lower WBC count (P = .0033).
Both univariate and multivariate analyses suggest that the EFS of
childhood ALL is not affected by MyAg coexpression. The 6-year EFS for
MyAg+ALL was 69.0% (SD, 3.6). This was not significantly
different from that of the 617 patients with MyAgALL
who had a 6-year EFS of 65.3% (SD, 2.3) (P = .47)
(Fig 2). Cases of hybrid ALL by BFM
criteria did not have a poorer outcome either: their EFS (78.6%, SD,
4.4) was not different from that of nonhybrid cases (61.8%; SD, 3.1)
(P = .15). The only exception was represented by the infant
group: in fact, the 23 children younger than 12 months of age had a
significantly worse outcome if they were MyAg+ (EFS, 0%)
than if they were MyAg (EFS, 43.7%; SD, 12.4)
(P = .01). In the other age groups, MyAg coexpression was not
associated with any difference in EFS: 69.5% (SD, 2.5) for
MyAg ALL versus 73.9% (SD, 3.7) for
MyAg+ALL in children aged 1 to 9 years; 50.6% (SD, 5.3)
for MyAgALL versus 54.9% (SD, 9.8) for
MyAg+ALL in children older than 9 years. This pattern was
not modified when hybrid cases were considered separately. Moreover,
none of the six analyzed myeloid markers was independently associated with a different outcome.
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| Fig 2.
Comparison of EFS in MyAg+ALL and
MyAgALL. EFS in MyAg+ALL is not
significantly different than in MyAgALL. Follow-up time
is 72 months and median follow-up is 48 months. ev, events; MYA, My
Ag.
|
|
MyAg coexpression was not associated with a different outcome within
the different immunophenotypic subgroups. Among the 122 patients with
T-lineage ALL, the 35 MyAg+ cases had a 6-year EFS of
46.7% (SD, 8.7), which was comparable to that of the 87 patients with
MyAg ALL (EFS 47.1%; SD, 5.5). The 256 MyAg+ cases of B-lineage ALL had a EFS of 72.1% (SD, 3.9),
which was comparable to that of the 530 patients with
MyAgALL (EFS, 68.1%; SD, 2.5).
All other evaluated parameters, in particular, WBC count, organomegaly,
FAB morphology, risk-directed therapy, response to steroids, CD10
expression in B-lineage ALL, B-lineage subgroups, could not demonstrate
any statistically significant difference for EFS in MyAg+
versus MyAgALLs.
| |
DISCUSSION |
MyAg coexpression is not a rare event in childhood ALL. In our
experience, it occurs in about one third of all cases. This frequency
is higher than in previous studies, which reported a range between 4%
and 22%3,16-24 (Table 3).
However, it is comparable to the 10% to 54% range reported for adult
patients.10-15 The sensitivity of the most recent methods
used in our study could possibly explain the different percentages
reported by most investigators. In a recent report, Uckun et
al25 found a 16.6% incidence of MyAg coexpression among 1,557 patients enrolled in the Childrens Cancer Group
(CCG) protocols. Such apparently lower incidence may be
explained by their choice to include only two MyAg, CD13 and CD33, in
the panel of the MoAbs used for central investigation of
immmunophenotype. The investigators suggest that the reported incidence
of CD13 and CD33 coexpression in childhood ALL should be representative
of overall MyAg expression. Although we may confirm that CD13 and CD33,
alone or in combination, are the most frequently observed MyAg, in our
series they might account for about one half of all cases coexpressing
at least one MyAg. Actually, in our study, four more antigens were
evaluated to analyze a wider panel of myeloid antigenic
molecules.19,39 Using the "minor" ones (CD11b, CD14,
and CD15), 47 additional cases (16%) were identified. False positive
results may be easily ruled out in our setting, based on our study
design: immunonophenotyping was performed centrally by flow cytometry,
using highly specific MoAbs for all cases; thus even weak antigen
expression might be detected. It is to be noted that limit for
positivity in single fluorescence analysis was 20%, while it was 30%
in the study by Uckun et al.25 Double fluorescence analysis
was always performed to confirm all cases, including those that showed
low percentages of positive cells as having coexpressing blasts. This
should avoid the main difficulties in interpreting data on
MyAg+ALL. In fact, results could be altered by using the
overlapping of percentages to identify coexpression, because of the
presence of residual normal myeloid cells in the
samples.19,25 In our series, cases coexpressing CD13
and/or CD33 on more than 30% of blasts were 152 (16% of all
cases), the same percentage found by Uckun et al.25
The frequency of myeloid coexpression was comparable in T- and in
B-ALL, as well as in all subgroups of B-lineage ALL. In particular,
CD10, B-lineage ALL (pre-pre-B ALL) had the same
incidence of MyAg coexpression than other more mature types, while
Ludwig et al16 suggested a particularly high frequency
(50%). Moreover, CD13 and CD33 were not typical of this group, while
the most frequent MyAg was CD15, in agreement with previous
reports.22,40 The presence of CD15 in infant ALL has
already been found in a larger group of our patients,32
even if it could not be confirmed in this limited subset of infants.
The correlation of MyAg coexpression, the peculiar chromosomal
translocation t(4;11), and poor prognosis in infant and pre-pre-B ALL
has often been suggested.41 T-ALL of intermediate
maturational stage showed a particularly high number of
MyAg+ cases. This difference with previous
observations19,22 may be due to the small numbers of T-ALL
MyAg+ cases analyzed therein.
Coexpression of MyAg+ALL was not associated with any of the
presenting features, in particular previous reports34
prompted us to explore any association with those
presenting features known to bear an adverse prognostic value, such as
infant or older age and higher leukocyte count. Interestingly, poor
steroid response on day 7, indeed a powerful independent adverse
prognostic factor in the BFM-chemotherapy setting,3,42 was
not associated with MyAg coexpression. On the contrary,
MyAg+ cases were more frequently good steroid responders.
Accordingly, they were more frequently eligible for the non-high
(standard and intermediate) risk groups. This also agrees with a recent report from our group, describing a higher incidence of MyAg
coexpression in the ALL subset identified by the prospective molecular
screening of the t(12; 21) translocation,43 which is
associated with favorable prognosis.44,45 Thus, our data
confirm that MyAg coexpression is usually associated with a
constellation of favorable presenting features. For this reason, the
MyAg+ cases have a nonrandom distribution toward the lower
risk groups. Finally, myeloid antigen coexpression is not associated
with a different outcome in childhood ALL. Because only infant patients with MyAg+ALL have shown a worse prognosis, their presence
could affect statistical analysis in small series. This conclusion on
our large series of unselected, newly diagnosed childhood ALL cases is
in agreement with the recent report from the CCG25 for
patients who are treated with a BFM-based chemotherapy.
In conclusion, our large, prospective study of coexpression of six
different MyAg in childhood ALL confirms it is not associated either
with immunophenotype, response to therapy, or long-term outcome and
thus has no prognostic value, as far as aggressive treatment is
used.46,47 Therefore, it should not be used for any
therapeutic choice, including patient stratification or indication for
bone marrow transplantation, with the exception of infant leukemia.
Nevertheless, continuous use of a wide panel, including many different
MyAg (up to six in our experience), is justified by the possibility of
identifying cases of undifferentiated leukemia and FAB type Mo
AML48 and also to define in the majority of cases a
leukemia-associated immunophenotype for individual
patients.48-51 This information, jointly with molecular
studies, might be highly valuable when drawing prospective studies of
minimal residual disease aimed to tailor treatment.
We also suggest that the term "hybrid" leukemia for
MyAg+ALL is not supported by any clinical evidence of
heterogeneity. On the contrary, it could induce incorrect impressions
of "myeloid" or "atypical" characteristics and might be
misleading.
| |
FOOTNOTES |
Submitted November 24, 1997;
accepted April 1, 1998.
Supported by AIRC (Associazione Italiana per la Ricerca sul Cancro); by
AIL (Associazione Italiana Leucemie), Progetto "30 Ore per la
Vita".
Presented in part at the XXIX Congress of SIOP, held in Instanbul,
September 23-27, 1997.
Address reprint requests to Maria Caterina Putti, MD, Dipartimento di
Pediatria, Via Giustiniani, 3, 35128 Padova, Italy.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
The authors thank all investigators from AIEOP Institutions: L. Felici
(Cl. Pediatrica, Ancona); N. Santoro (Cl. Pediatrica I, Bari); T. Santostasi (Cl. Pediatrica II, Bari); P. Cornelli (O. Riuniti,
Bergamo); A. Pession (Cl. Pediatrica III, Bologna); A. Arrighini (Cl.
Pediatrica, Brescia); G. M. Fiori (Div. Oncoematologia Pediatrica,
Cagliari); R. Galanello (Cl. Pediatrica II; Cagliari); A. Sciotto (Div.
Oncoematologia Pediatrica, Catania); S. Magro (Div. Ematologia,
Catanzaro); A. Lippi (O. Meyer, Firenze); M. Cominetti (O. Galliera,
Genova); C. Rosanda (O. Gaslini, Genova); F. Massolo, (Cl. Pediatrica
II, Modena); A. Murano (Cl. Pediatrica I, Napoli); M.F. Pinta (O. Pausillipon, Napoli); S. Auricchio, (Cl. Pediatrica II, Napoli); A. Correra (O. SS. Annunziata, Napoli); L. Zanesco (Cl. Pediatrica II,
Padova), G. Fugardi (Cl. Pediatrica I, Palermo); G. Izzi (Div.
Ematologia Pediatrica, Parma); M. Aricò (Cl. Pediatrica, Pavia);
A. Amici (Cl. Pediatrica, Perugia); R. Di Lorenzo (Div. Ematologia,
Pescara); C. Favre (Cl. Pediatrica III, Pisa); F. Nobile (Div.
Ematologia, Reggio Calabria); A.M. Testi (Cattedra di Ematologia, La
Sapienza, Roma); G. De Rossi (O. Bambino Gesù, Roma); B. Werner
(Cl. Pediatrica, La Sapienza, Roma); D. Gallisai (Cl. Pediatrica,
Sassari); C. D'Ambrosio (Cl. Pediatrica, Siena); E. Barisone (Cl. Pediatrica, Torino); P. Tamaro (Cl. Pediatrica, Trieste);
L. Nespoli (Cl. Pediatrica, Varese); G. Marradi (Cl. Pediatrica,
Verona). We also wish to thank Dr Lucia Masiero for statistical
assistance and Dr M. Spinelli, G. Giacometti and B. Michielotto for
technical work.
| |
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Abstract
Introduction
Abstract