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Blood, Vol. 91 No. 8 (April 15), 1998:
pp. 2955-2960
The Clinical Significance of Molecular Response in Indolent
Follicular Lymphomas
By
Armando López-Guillermo,
Fernando Cabanillas,
Peter McLaughlin,
Terry Smith,
Fredrick Hagemeister,
María A. Rodríguez,
Jorge E. Romaguera,
Anas Younes,
Andreas H. Sarris,
H. Alejandro Preti,
William Pugh, and
Ming-Seng Lee
From the Departments of Lymphoma, Biomathematics, Pathology, and
Laboratory Medicine, University of Texas, M.D. Anderson Cancer Center,
Houston, TX.
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ABSTRACT |
Most patients with follicular lymphoma (FL) achieve a
complete response (CR) after treatment, but eventually most of them, particularly those with stage IV, relapse due to minimal residual disease (MRD). The t(14;18) gives rise to a rearrangement of the bcl-2
oncogene that constitutes an excellent target for detection of MRD by
polymerase chain reaction (PCR). One hundred ninety-four previously
untreated patients with indolent FL and detectable bcl-2 rearrangement
were studied. The PCR assay was used to detect bcl-2-rearranged cells
in blood and marrow before and after treatment. Molecular response rate
was 37%, 53%, 56%, and 66% at 3 to 5, 6 to 8, 9 to 14, and 15 to 18 months from the start of therapy, respectively. Although molecular
response was higher among clinical CRs, one third of partial responders
at 3 to 5 months also achieved a molecular response. Patients who
achieved a molecular response during the first year of treatment had a
significantly longer failure-free survival (FFS) than those who did not
(4-year FFS: 76% v 38%, respectively; P < .001).
Similar results were also observed in the subset of patients in
clinical CR 1 year after treatment. By multivariate analysis,
 2-microglobulin (2-M; P < .01), and molecular response
(P < .001) were the most important variables associated with
outcome. When we combined 2-M and molecular response, three
prognostic groups emerged: (1) low 2-M and molecular responders, (2)
low 2-M and nonresponders or high 2-M and responders, and (3)
high 2-M and nonresponders. The 4-year FFS of these 3 groups were
86%, 65%, and 23%, respectively. Finally, patients who achieved
molecular response and sustained it had better FFS than those who
either reverted back to PCR-positive or who never achieved molecular
response. Serial PCR analysis to determine the molecular response in FL
correlates well with outcome especially when combined with pretreatment
2-M.
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INTRODUCTION |
ALTHOUGH PATIENTS with
follicular lymphoma (FL) often achieve a clinical complete response
(CR), the majority of them, in particular those with advanced
presentations, eventually develop relapse.1,2 This probably
happens because residual lymphoma persists below the detection
threshold of standard procedures. FL are characterized by the t(14;18)
translocation, present in up to 85% of the cases, resulting in
rearrangement of the bcl-2 oncogene.3-5 The translocation
occurs most frequently in one of two molecular sites: the major
breakpoint cluster region or MBR (~70% of the
cases)6,7 and the minor cluster region or mcr (10%
to 15% of the cases).8 Potentially, the most important practical application is the use of bcl-2/IgH rearrangement as a marker
to detect minimal residual disease (MRD).9 In 1987, we
developed a polymerase chain reaction (PCR) assay to detect as little
as one cell carrying the bcl-2 rearrangement among several hundred
thousand normal cells and postulated that this could be used to detect
MRD.9 Using this method, we and others were able to
demonstrate persistent t(14;18) cells after therapy.9-14 To
better understand the meaning of a molecular response and also to
evaluate the significance of such response at various time points
during therapy, we decided to analyze serial post-therapy PCR results
in a large cohort of patients. A similar study has been published on
patients with relapsed FL submitted to high-dose chemotherapy and bone
marrow transplantation15,16 but not in previously untreated
patients receiving conventional dose regimens.
Using the PCR assay, we serially tested during and after treatment the
peripheral blood and, when possible, the bone marrow of 194 patients
who had either MBR or mcr bcl-2 rearrangements at
diagnosis. The major aim was to correlate the presence of minimal residual disease with failure-free survival (FFS) in de novo indolent FL treated with conventional dose therapy.
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PATIENTS AND METHODS |
Patients.
We analyzed by means of the PCR assay the pretreatment peripheral blood
of 236 patients with FL for the presence of bcl-2 gene rearrangements.
A total of 194 cases (82.2%) had a bcl-2/IgH rearrangement detectable:
167 (70.8%) had the rearrangement within the major breakpoint region
(MBR) and other 27 patients (11.4%) in the minor cluster
region (mcr), whereas the remaining 42 cases (17.8%) were
germline for both MBR and mcr. The 194 cases with assessable bcl-2 rearrangement were the patients included for the
longitudinal follow-up in the present study.
Staging evaluation included physical examination, measurement of serum
lactate dehydrogenase (LDH) and 2-microglobulin
(2-M) levels, chest x-ray, computer tomography (CT)
scans of abdomen and pelvis, and bilateral bone marrow
biopsies. The median age was 52 years (range, 18 to 84 years); 92 (47%) were men and 102 (53%) were women. The histologic
distribution was follicular center cell lymphoma grade I (follicular
small cleaved cell; Working Formulation) in 126 cases (65%),
follicular center cell lymphoma grade II (mixed small and large cell)
in 62 cases (32%), and follicular center cell grade III (large cell)
in 6 cases (3%). Only 6 patients whose tumor predominantly contained
cleaved cells were considered indolent and admitted into the study as
grade III histology. Forty-three patients (22%) presented with stage
I-II, 28 (14.5%) with stage III, and 123 (63.5%) with stage IV.
All patients were informed of the investigational nature of this study
and informed consent was obtained from each patient in accordance with
institutional guidelines.
Treatment regimens and evaluation of clinical response.
Patients with stage IV were treated with the investigational
anthracycline containing protocols available at the time of their presentation. Therapy was alternating triple therapy
(ATT)17 in 87 cases, Fludarabine, Mitoxantrone
(Novantrone), and Dexamethasone (FND) in 24, and CHOP in 12 patients
who refused investigational treatments. Interferon maintenance was used
after completion of chemotherapy in all those cases. Patients with
stage III were treated with ATT in 13 cases or with CHOP plus
radiotherapy in 15. Patients with early stages (I or II) received
radiotherapy (6 cases) or COP-bleo plus involved field radiotherapy (35 cases).
Follow-up consisted of physical examination, routine blood tests, and
CT scans. If positive at diagnosis, bilateral bone marrow biopsies were
repeated after every 3 to 4 cycles during the first year and every 4 to
6 months thereafter.
CR was defined as the disappearance of all signs and symptoms of
disease as determined by clinical, radiographic, and laboratory parameters. Partial remission (PR) was defined as a reduction of 50%
or more in measurable disease for at least 1 month. Any other
responses, including mixed response, stable disease, progressive disease, early death, or death from toxicity, were considered treatment
failures.
PCR methods for detecting bcl-2 rearrangements.
Samples from both peripheral blood and/or bone marrow aspirates
were collected before starting treatment and, whenever possible, every
3 to 4 months for the first 2 years after starting therapy, and then
every 6 months until relapse or progression of the lymphoma.
DNA was isolated from blood and/or bone marrow using
conventional methods. PCR amplification was used to detect both MBR
and mcr breakpoints by subjecting one microgram of genomic
DNA to 45 cycles of amplification.9,18 The primers
MBR(+), mcr(+), and JH( ) have been previously
described.8,9,18 Twenty percent of PCR products were
size-fractionated in a 2% NuSieve gel and then transferred to a nylon
membrane. Membranes were hybridized with 5 end radiolabeled
oligonucleotide probes MBR and mcr at 63°C
(MBR) or 42°C (mcr) overnight. Washing was performed in 2 SSPE/0.1% sodium dodecyl sulfate at 55°C (MBR) or at room
temperature (mcr) for 1 hour. Autoradiography was performed
against a double intensifying screen at 70°C for 72 hours.9
To ensure the reliability of the PCR assay, we routinely included a
weak positive control (100 pg of positive DNA), a negative control from
normal DNA, a reagent control, and an internal control. These controls
helped to detect contamination, avoid false negativity due to
suboptimal PCR efficiency, and standardize the variation in PCR
efficiency. The sensitivity of the PCR technique was estimated by a
dilutional method in 1/105 to 1/106.
Molecular response.
Molecular response was defined as the disappearance of t(14;18)
amplicons in peripheral blood at any given point during or after
therapy in a patient with a known baseline bcl-2 rearrangement. Molecular response during the first year was considered as achievement of a PCR-negative status at any point during the first year of treatment. In analyses involving the molecular response during the
first year, patients were omitted who did not have at least two of the
first three PCR determinations or who were censored before 1 year.
Statistical analysis.
FFS was measured from the start of therapy until relapse or toxic
death. Patients not relapsing were censored at the last follow-up.
Actuarial probability of FFS was estimated according to the method of
Kaplan-Meier,19 and curves compared using the log-rank
test.20 Categorical data were compared using
 2 or Fisher's exact tests.
Although the intent was to obtain peripheral blood and bone marrow
samples for PCR analysis every 3 to 4 months during the first 2 years,
this was not possible for every patient. Because the exact timing of
specimens was determined by clinic visits, the first posttreatment PCR
determination may have occurred within 3 to 5 months after the start of
treatment, the second determination within 6 to 8 months posttreatment
start, and the third determination within 9 to 14 months. In tabulating
molecular response status within these time intervals, all patients
with PCR determinations within that time were included.
The association of molecular response to FFS was evaluated by two
approaches: (1) the landmark method, comparing the FFS subsequent to 1 year according to molecular response at that time,21 and (2) the use of a proportional hazards regression model.22
In the landmark method, patients who failed or were censored before 12 months were excluded, and molecular response was determined based on
samples taken before 12 months. In the proportional hazards model, an
indicator variable took the value zero for each patient until the time
a molecular response was detected and a value of one for each patient
thereafter. A test for statistical significance of the coefficient for
this term was, therefore, a test for whether conversion to PCR
negativity was associated with subsequent risk of treatment failure.
| |
RESULTS |
Patients and clinical response.
Patients were seen between July 1988 and August 1995. The median
follow-up is 29 months (range, 6 to 91 months). Clinical CR was
attained in 173 patients (90.6%), PR was attained in 17 (8.9%), and 1 (0.5%) did not respond (in 3 cases the response was not evaluable).
Forty patients have so far developed relapse, with an actuarial FFS of
89.1% (95% confidence interval [CI], 83.8% to 94%)
and 62.5% (95% CI, 51.5% to 73.5%) at 2 and 5 years from diagnosis,
respectively (Fig 1).
Correlation of clinical and molecular response.
Clinical and molecular response assessed in blood at different
time-points are detailed in Table 1. The
clinical response refers to that observed in all sites where there was
disease present at baseline. The molecular response rates progressively
increased from 37% at 3 to 5 months to 66% at 15 to 19 months. On the
other hand, the proportion of patients in clinical PR that presented with molecular response, as assessed in blood, was 37% (31/84), 31%
(10/32), and 35% (5/14) at 3 to 5, 6 to 8, and 9 to 14 months, respectively. At the same times, the proportion of patients in CR who
achieved molecular response were 38%, 67%, and 60%, respectively. Although molecular CRs were more frequent in patients with clinical CR,
the molecular response was not completely dependent on the clinical
response. Of note, all the patients that were in clinical PR but in
molecular CR at 3 to 5 months, and with follow-up greater than 1 year,
eventually reached clinical CR.
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Table 1.
Clinical and Molecular Response Assessed in Peripheral
Blood in 194 Patients With FL at Different Time Points From the
Beginning of Treatment
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Pretreatment variables and molecular response.
Pretreatment variables, including histology, Ann Arbor stage, bulky
disease, bone marrow infiltration, and serum levels of LDH and 2-M,
did not predict the achievement of a molecular response within the
first year of follow-up. No correlation was observed between treatment
regimen and molecular response. Although stage IV patients receiving
the FND fludarabine combination presented a higher molecular response
rate at 6 to 8 months than those treated with ATT (82% v 49%,
respectively; P = .024), such difference disappeared at later
time points.
Molecular response and FFS.
FFS results correlated with achievement of molecular response at each
of the first three PCR determinations (3 to 5, 6 to 8, and 9 to 14 months; Fig 2). In each set of curves,
patients observed for less than the landmark time were omitted.
Patients who were PCR negative at the respective intervals tended to
have longer FFS than nonresponders (PCR positive) at the same times. The differences in FFS were more pronounced at the later time points.
These results suggest that determination of molecular response may be
more clinically meaningful after the first 5 months of therapy.
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| Fig 2.
FFS of patients with FL according to molecular response
(Responders: PCR-negative status; Nonresponders: PCR-positive status), assessed in peripheral blood at different time points from the onset of
therapy: (A) 3 to 5 months (P = .1), (B) 6 to 8 months (P < .02), and (C) 9 to 14 months (P < .005). In
each time point, patients observed for less than that time or who
relapsed before were omitted.
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In Fig 3, FFS is compared from 1 year after
the start of therapy according to molecular response status during the
first year. Only patients who achieved a molecular response at any
point during the first year were considered as molecular responders.
There was a substantial failure-free advantage for patients with
evidence of molecular response within the first year of therapy (4-year FFS: 76% v 38%; P < .001). Moreover, late failures
occurred more frequently in the molecular nonresponders.
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| Fig 3.
FFS from 1 year after the start of treatment according to
the molecular response status within the 1st year (Responders:
PCR-negative; Nonresponders: PCR-positive status). Landmark: 12 months:
P < .001. Only 116 patients with two or more PCR
determinations during the first year were included; in addition, 4 patients who failed and 8 censored before 1 year were omitted.
According to the landmark rules, patients who achieved a late molecular
response (ie, after 1 year) were included in the nonresponders group.
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The same landmark analysis was performed only on patients who achieved
clinical CR during the first year and whose follow-up exceeded 1 year
(88 of 116 cases). The substantial difference in FFS between molecular
responders and nonresponders was preserved (P < .02),
suggesting a further prognostic role for molecular response beyond that
of clinical response.
In a separate analysis of the association between pretreatment patient
characteristics and FFS (including age, sex, histologic subtype,
performance status, B-symptoms, bulky disease, extranodal involvement,
bone marrow infiltration, Ann Arbor stage, serum LDH, serum 2-M, and
treatment; results not presented), it was determined that serum LDH and
2-M values were the two factors most closely associated with FFS
outcomes. The second approach to analyzing the association between
molecular response and FFS involved fitting a proportional hazards
model with a time-dependent covariate indicating whether a molecular
response had been achieved. Terms identifying abnormal levels for
pretreatment values of LDH and 2-M were also included because of
their recognized prognostic importance. Results indicated a highly
statistically significant association between attaining a molecular
response and risk of failure, with the direction of effect for the
reduced risk of failure when molecular response was achieved (P < .001). In addition, 2-M retained independent prognostic value
(P < .01).
As a further demonstration of the independent association of 2-M and
molecular response with FFS, the landmark analysis of Fig 3 was
repeated with patients in the molecular responder and nonresponder
groups divided according to whether their pretreatment levels of 2-M
were abnormal. Figure 4 depicts the FFS
curves according to the various combinations of serum 2-M levels and molecular response within the first year. By combining patients into
these categories, they can be divided into three groups: normal 2-M
and molecular CR (45% of all cases), either normal 2-M with no
molecular CR or high 2-M with molecular CR (40%), and high 2-M
without molecular CR during the first year (15%). The 4-year FFS for
these three groups were 86%, 65%, and 23%, respectively (P < .001).
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| Fig 4.
FFS from 1 year after the onset of treatment according to
the different combinations of 2-M at presentation (normal v
high) and molecular response within the first year (Responders
v Nonresponders). Patients included were the same as in Fig 3.
Three possible combinations were plotted: (A) normal 2-M and
molecular responders, (B) either high 2-M and molecular responders
or normal 2-M and molecular nonresponders, and (C) high 2-M and
molecular nonresponders. Landmark: 12 months; P < .0001.
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Molecular response pattern and FFS.
Because not only the achievement of a molecular response, but also the
maintenance of such response could be important for outcome, we
analyzed the molecular response pattern for the first four
determinations (up to 18 months). Patients were excluded if they
developed clinical relapse before 18 months (4 cases), if there was
less than 18 months of follow-up (19 cases), or if fewer than 3 PCR
determinations were made during that time (18 cases). In the remaining
75 patients, three patterns of PCR response could be distinguished: (1)
35 achieved molecular response during the first year of therapy and
sustained it at least for the 18 months period; (2) 25 achieved
molecular response but reverted back to PCR-positive status; and (3) 15 never achieved molecular response or did so after 1 year. Median FFS
has not been reached yet for the sustained response group; for the
mixed responders and for the nonresponder groups, estimated medians
were 50 and 31 months, respectively (P < .05;
Fig 5).
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| Fig 5.
FFS survival from 18 months after the onset of treatment
according to the pattern of molecular response. Seventy-five patients with at least three PCR determinations in this period were included. Three patterns could be distinguished: (A) 35 patients achieved molecular response and sustained it at least for 18 months, (B) 25 patients achieved molecular response but reverted back to PCR-positive status, and (C) 15 patients did not achieve molecular response. Patients who relapsed before 18 months were omitted from the analysis. Landmark: 18 months; P < .05.
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In the overall series, 43 patients that had previously achieved
molecular response reverted back to positive during the follow-up. The
risk of clinical relapse was of 41% (95% CI, 23% to 59%) and 52%
(95% CI, 32% to 72%) at 2 and 3 years from the first PCR-positive status, respectively.
PCR results before and after clinical relapse.
Finally, we studied the subset of 40 patients who developed relapse at
any point during or after treatment. Four molecular response patterns
in peripheral blood emerged in this group: 15 patients (37.5%) were
always PCR positive; 13 (32.5%) had achieved a PCR negative state but
had reverted back to a positive PCR before or at clinical relapse; 9 (22.5%) attained a molecular CR, reverted back to a positive PCR, and
then fluctuated between positive and negative; and 3 (7.5%) had been
always PCR negative during the follow-up after achieving a molecular
CR.
Molecular response assessed in bone marrow samples.
The degree of agreement between the molecular response assessed in bone
marrow and in peripheral blood analyzed for each time point is detailed
in Table 2. In addition to the correlation observed between peripheral blood PCR results and FFS, there was also a
similar trend for a correlation between bone marrow molecular response
and FFS at each time point considered, but the number of samples was
not large enough to allow in-depth statistical analysis (data not
shown).
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Table 2.
Agreement Between the Molecular Response Assessed in
Peripheral Blood or in Bone Marrow at Different Time Points
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DISCUSSION |
The t(14;18) translocation provides an excellent target that can be
applied to the detection of minimal residual disease in peripheral
blood and bone marrow. Using the PCR technique, we detected the
t(14;18) in blood and/or bone marrow of more than 80% of these
cases. We have also shown that (1) molecular remissions can be achieved
with standard-dose chemotherapy and (2) molecular remissions correlate
with durable clinical remissions.
During the first year of treatment, more than 60% of patients became
PCR negative in blood and bone marrow. Agreement in the molecular
response rate assessed in simultaneous blood and marrow specimens was
observed in 70% of cases (Table 2). In the 30% of cases in which the
results were different, the marrow aspirate tended to be positive more
frequently than blood, but in a substantial number of cases the blood
was positive when the marrow was negative. Good concordance between
blood and bone marrow PCR results at diagnosis has been previously
observed by different groups.23-25 Gribben et
al26,27 were able to detect bcl-2-positive cells in both
blood and marrow before and after high-dose chemotherapy and bone
marrow transplantation, although in their experience bone marrow biopsy
samples were more predictive of outcome.26 In our
experience, peripheral blood PCR seems to be almost as sensitive as
bone marrow for detecting minimal residual disease; and from the
practical standpoint, it is easier to obtain.
The achievement of molecular response in peripheral blood was to a
certain extent independent of the clinical response. At 6 months from
the beginning of treatment, the proportion of molecular responders was
higher in clinical CRs than in PRs. Approximately one third of clinical
CRs failed to attain a molecular response at that point; on the other
hand, one third of PRs achieved a molecular response. Patients in
clinical CR with positive PCR probably represent those with MRD not
assessable by conventional methods. Conversely, the patients in PR with
a negative PCR in peripheral blood likely are those with residual
fibrotic masses or with nonmalignant marrow lymphocytic aggregates. In
fact, all the clinical PRs whose molecular response was a CR eventually reached clinical CR with longer follow-up.
The most important conclusion of this study was that the molecular
response at different time-points during the first year of therapy
strongly correlates with FFS (Figs 2 and 3). More than three fourths of
the patients who achieved a PCR-negative state at any of the tested
time points (3 to 5, 6 to 8, and 9 to 14 months) were expected to be
alive and in clinical CR 5 years after starting therapy. An interesting
observation is that, irrespective of the PCR results, there was very
little difference in the FFS during the first 2 years of follow-up.
Thus, PCR only seems to predict the outcome several years after therapy
(Figs 2 and 3). Although our patient population differs from that of
Gribben et al13,15,27 in various aspects, the results
resemble those reported by them.
We also found that both the molecular response within the first year
and the pretreatment serum 2-M were independent and important
prognostic factors for FFS. With the combination of 2-M and
molecular response within 1 year it is possible to identify those cases
whose prognosis is excellent, with more than 80% of them projected to
be alive and in CR 5 years later (Fig 4). This group with excellent
prognosis represents approximately one half of all the FL cases in this
study. Longer follow-up will be necessary to determine if a significant
proportion of those patients are cured. On the other hand, a small
subset of patients consisting of approximately 15% of the population
are at high risk of early relapse. These cases could in the future be
considered candidates for investigational therapy.
The serial pattern of the PCR results is also important in its
correlation with clinical outcome. Those who never became PCR negative
showed a high risk of relapse, in contrast with those that were
persistently negative after treatment. Patients who attained a
molecular response but later on experienced a molecular relapse also
had a higher risk of clinical relapse (Fig 5).
One potential criticism of these data is that the bcl-2-rearranged
cells we detected might not represent malignant cells. Healthy donors
can show evidence of bcl-2-rearranged cells in the peripheral
blood.28-30 However, when only 1 µg of DNA is loaded for
the PCR assay, the proportion of normal individuals who had detectable
bcl-2-rearranged cells by PCR was only 6.6%.28 Moreover, when unsorted peripheral blood white blood cells are
examined, as in the present study, the proportion would be expected to
be much lower. Therefore, although we cannot discard the possibility that circulating bcl-2-rearranged cells in a small proportion of our
patients represent instances of nonmalignant cells, this is expected to
be unusual. Furthermore, if the bcl-2-rearranged cells we detected in
this study do not represent the malignant clone, it would be unlikely
that the clinical outcome would correlate so well with the molecular
response.
In conclusion, the use of serial PCR analysis to determine the
molecular response is a very useful tool, especially when combined with
other prognostic factors such as 2-M.
| |
FOOTNOTES |
Submitted June 3, 1997;
accepted November 24, 1997.
Supported in part by National Cancer Institute Grant No. CA62518 and by
the Herschel and Hilda Rich Fund for Lymphoma Research. A.L.-G. was
supported by the Hospital Clínic of Barcelona and the Spanish
Ministry of Education (EX-43390399/95).
Address reprint requests to Fernando Cabanillas, MD, Lymphoma
Department, MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX
77030.
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.
| |
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Abstract
Introduction
Abstract
