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Endocrine Care |
Dipartimento di Endocrinologia e Metabolismo, Ortopedia e Traumatologia, Medicina del Lavoro (C.M., M.L.T., L.M., E.D.U., R.R., G.B., B.M., A.P.), Dipartimento di Neuroscienze (M.P.B., P.L., M.N.) e Dipartimento di Oncologia (F.C.), University of Pisa, 56124 Pisa, Italy; and Cattedra di Endocrinologia, University of Insubria (L.B.), Varese 21100, Italy
Address all correspondence and requests for reprints to: Claudio Marcocci, M.D., Dipartimento di Endocrinologia e Metabolismo, Ortopedia e Traumatologia, Medicina del Lavoro, Università di Pisa, Via Paradisa 2, 56124 Pisa, Italy. E-mail: c.marcocci{at}endoc.med.unipi.it
Abstract
Eighty-two consecutive patients with moderate-to-severe and active Graves’ ophthalmopathy were randomly treated with orbital radiotherapy combined with either oral (prednisone; starting dose, 100 mg/d; withdrawal after 5 months) or iv (methylprednisolone; 15 mg/kg for four cycles and then 7.5 mg/kg for four cycles; each cycle consisted of two infusions on alternate days at 2-wk intervals) glucocorticoids. The two groups did not differ for age, gender, duration of hyperthyroidism and ophthalmopathy, prevalence of smokers, thyroid volume, and pretreatment ocular conditions. Both groups of patients received radioiodine therapy shortly before treatment for Graves’ ophthalmopathy. Follow-up lasted for 12 months.
A significant reduction in proptosis (from 23.2 ± 3.0 to 21.6 ± 1.2 mm in the iv glucocorticoid group, P < 0.0001; and from 23 ± 1.8 to 21.7 ± 1.8 mm in oral glucocorticoid group, P < 0.0001) and in lid width (from 13.3 ± 2.5 to 11.8 ± 2.2 mm, and from 13.6 ± 2.0 to 11.5 ± 1.9 mm, respectively; P < 0.001 in both cases) occurred, with no difference between the two groups. Diplopia significantly improved in both groups: it disappeared in 13 of 27 (48.1%) iv glucocorticoid patients (P < 0.005) and in 12 of 33 (36.4%) oral glucocorticoid patients (P < 0.03). The degree of amelioration of diplopia did not significantly differ between the two groups (P = 0.82). Optic neuropathy improved in 11 of 14 iv glucocorticoid (P < 0.01) and only in 3 of 9 oral glucocorticoid (P = 0.57) patients, with no significant difference in these outcomes. The Clinical Activity Score decreased from 4.5 ± 1.2 to 1.7 ± 1.0 (P < 0.0001) in the iv glucocorticoid group and from 4.2 ± 1.1 to 2.2 ± 1.2 (P < 0.0001) in the oral glucocorticoid group; final Clinical Activity Score was significantly lower in iv glucocorticoid than in oral glucocorticoid patients (P < 0.01). By self-assessment evaluation, 35 (85.3%) iv glucocorticoid and 30 (73.2%) oral glucocorticoid patients reported an improvement of ocular conditions (P = 0.27). Overall, both treatments produced favorable effects in most patients, but responders in the iv glucocorticoid group (36 of 41, 87.8%) were more than in the oral glucocorticoid group (26 of 41, 63.4%) (P < 0.02). Moreover, iv glucocorticoid treatment was better tolerated than oral glucocorticoid treatment. Side effects occurred in 23 (56.1%) iv glucocorticoid and 35 (85.4%) oral glucocorticoid patients (P < 0.01); in particular, cushingoid features developed in 5 of the former and 35 of the latter patients. One iv glucocorticoid patient had severe hepatitis of undetermined origin at the end of glucocorticoid treatment, followed by spontaneous recovery.
In conclusion, high-dose iv glucocorticoid and oral glucocorticoid (associated with orbital radiotherapy) are effective in the management of severe Graves’ ophthalmopathy, but the iv route seems to be more effective and better tolerated than the oral route and associated with a lower rate of side effects.
GRAVES’ OPHTHALMOPATHY (GO), THE most frequent extrathyroidal manifestation of Graves’ disease, is a disorder of autoimmune origin, the pathogenesis of which is, however, incompletely understood (1, 2, 3). Only a minority of patients develop severe expressions of the disease, requiring aggressive treatments (1). Together with orbital radiotherapy and decompressive orbital surgery, glucocorticoids (GC) represent a mainstay and a well established treatment for severe and active ophthalmopathy (4, 5). They are used in view of their anti-inflammatory and immunosuppressive actions (6). Most commonly, GC have been used through the oral or local (retrobulbar or subconjunctival) routes (6), but locally administered GC are not as effective as systemic GC (7). On the other hand, oral GC (ORGC) therapy requires the use of high doses of the drug (prednisone, 60–100 mg/d, or equivalent) for prolonged periods of time (several months) (5). Side effects are a major drawback of ORGC, although their precise prevalence is unknown (1, 8). In addition, recurrence of active ophthalmopathy is not infrequent when GC is tapered down or withdrawn (1). The use of radiotherapy at the same time of glucocorticoid administration has been shown to prevent the rebound of the inflammatory manifestations that are often seen after GC alone in GO as well as in other autoimmune diseases (1).
In the last 13 yr, several studies documented the effectiveness of iv GC (IVGC) pulse therapy (9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19). The rationale for the use of pulse therapy is the observation that GO, at difference with other chronic autoimmune diseases, is most often characterized by a single flare of activity of the autoimmune process. In this view, a short-term of high-dose GC may be effective in smoldering the progression and eventually improving the final outcome of the disease. An overview of the published studies showed a higher percentage of favorable results with the iv route than with the oral route (1). However, in most studies ORGC were also given in the interpulse period, or azathioprine or orbital radiotherapy were associated with GC, making it difficult to ascertain the precise role of iv pulse therapy (1). In addition, no randomized study directly compared the iv and oral routes of GC administration.
Aim of the present study was to compare, in a prospective, single-blind, randomized study, the effectiveness and tolerability of the IVGC and ORGC routes in a large series of patients with GO. In both groups GC therapy was associated with orbital radiotherapy. Our results showed that both treatment modalities are associated with favorable effects in the majority of patients, but the iv route seems to be more effective and better tolerated than the oral route.
Materials and Methods
Patients
The study included 82 consecutive patients with hyperthyroidism
due to Graves’ disease and moderate-to-severe and active
ophthalmopathy (see below) (Table 1
).
Three patients, two with very severe optic neuropathy and one with a
previous episode of eye subluxation, were discarded from enrollment.
These patients were submitted to immediate treatment, including
high-dose GC and orbital decompression. Two patients with
contraindications to the use of high-dose systemic GC (active peptic
ulcer and insulin-dependent diabetes) were excluded from the study. In
addition to ophthalmopathy, other inclusion criteria were a thyroid
volume smaller than 60 ml or the presence of contraindications to
thyroidectomy. All but one patient (who had euthyroid GO) were
hyperthyroid when enrolled in the study and were treated with
methimazole for 3–4 months before radioiodine therapy. Methimazole was
discontinued 5 d before the administration of radioiodine [given
at a dose of 120–150 Ci (4.4–5.6 MBq) per gram of thyroid
tissue].
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Six patients had been previously treated with partial thyroidectomy, and two had persistent hyperthyroidism after radioiodine therapy. Twelve patients had received previous treatment for ophthalmopathy (nine oral or retrobulbar GC, one cyclosporin, one octreotide, and one orbital decompression).
Following radioiodine therapy patients were randomly assigned by computer-generated random numbers to treatment with either iv methylprednisolone acetate (IVGC) or oral prednisone (ORGC), starting 1 wk after radioiodine administration. All patients were also treated by orbital radiotherapy (see below). Before GC therapy patients were submitted to the following diagnostic procedures: oral glucose tolerance test, serum aminostransferases and immunoglobulins, serologic markers of viral hepatitis, tuberculin test, fecal occult blood test, urinalysis, chest x-rays; bone density was measured in a subgroup of patients.
Patients were seen, and their thyroid function as well as ocular conditions were checked within 1 month after radioiodine therapy and then every 1–2 months for 12 months. Hypothyroidism or persistent hyperthyroidism after radioiodine treatment were corrected within 2–3 wk by the administration of T4 or methimazole, respectively. Treatment was adjusted to maintain serum TSH concentration between 0.4 and 1.0 mU/liter. A second dose of radioiodine was administered at the end of the follow-up to patients who had persistent hyperthyroidism.
Patients gave their informed consent to this study, and the protocol was approved by the institutional review committee. The treatment plan for ophthalmopathy was extensively discussed with patients, who were informed about alternative treatments including orbital decompression. No patient was lost to follow-up.
GC therapy
IVGC. Methylprednisolone acetate was given iv in 250 ml saline over a period of 60–90 min. The dose was 15 mg/kg body weight for four cycles and then 7.5 mg/kg body weight for four cycles; each cycle consisted of two infusions on alternate day at 2-wk intervals. The duration of treatment was 14 weeks. The total dose of methylprednisolone ranged between 9 and 12 g. Serum glucose, aminotransferases, gammaglutamyltranspeptidase, immunoglobulins, markers of viral hepatitis, urinalysis, fecal occult blood test, and blood pressure were analyzed before each cycle of methylprednisolone.
ORGC. The initial daily dose was 100 mg prednisone for 7 d, followed by gradual weekly reduction until a dose of 25 mg was reached; the dose was then tapered by 5 mg every 2 wk. The duration of treatment was about 22 wk. The total dose of prednisone was about 6 g. Serum glucose, blood pressure, and fecal occult blood test were monitored at 2-wk intervals.
Radiotherapy procedure
Orbital irradiation was performed using a 4 MeV linear accelerator, as described previously (20). A computer-assisted tomography of the orbit was performed in all patients before treatment to define the radiation field. The field (4 x 4 cm) had the anterior border located just behind the lateral canthus and the posterior border located just anterior to the sella turcica. The floor and the roof of the orbit represented the lower and the upper limit of the radiation area. The field was angled 10 degrees posteriorly to avoid the irradiation of the contralateral lens and cornea. The head of the patient was stabilized with a head holder. All patients were treated bilaterally. A total of 20 Gy was delivered to each eye in 10 fractionated doses over a period of 2 wk.
Ocular evaluation
Ocular evaluation was carried out every 2 months by the same
examiner (M.P.B.), who was blind to the treatment given to the patient.
The examination included evaluation of soft tissue changes, measurement
of proptosis (Inami exophthalmometer), lid width, eye muscle function
(Hess chart), computerized perimetry, visual evoked potentials, color
test, and visual acuity. The activity of the ophthalmopathy was scored
according to Mourits et al. (21), and the
subsequent revision of an ad hoc international Committee
(22) using the Clinical Activity Score (CAS), which
takes into account seven manifestations (spontaneous retrobulbar pain,
pain with eye movement, eyelid erythema, eyelid edema, conjunctival
injection, chemosis and swelling of the caruncle); 1 point is given for
any manifestation, and the score may range from 0 (no activity) to 7
(very high activity). The severity of the ophthalmopathy was graded as
indicated in Table 2. At least one marked
manifestation, or two moderate manifestations, or one moderate and two
mild manifestations, or four mild manifestations of the disease had to
be present. In addition, a CAS score of 4 or higher was required.
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Progression or improvement of ophthalmopathy was defined by changes in at least two major criteria (variations in proptosis and lid width of 2 mm or greater, appearance, disappearance, or change in the degree of diplopia, changes in the activity score 2 points or more, and changes on one tenth or more in visual acuity) and one minor criterion (soft tissue changes, self-assessment evaluation) (23).
Evaluation of thyroid function
Thyroid function was assessed by measuring serum free T4 (FT4) and free T3 (FT3) (Lisophase kits; Laboratory Bouty, Sesto S. Giovanni, Italy; normal range, 8.4–23.2 pmol/liter for FT4 and 3.8–8.5 pmol/liter for FT3) and TSH (Auto-DELFIA; Wallac, Inc. Gaithersburg, MD; normal range, 0.4–3.7 mU/liter). Serum TSH-receptor antibodies were measured by radio receptor assay (TRAK assay; BRAHMS Diagnostica, Berlin Germany; normal values, <5 U/liter).
Bone density measurement
Bone density was measured at the lumbar spine and femoral neck in a subgroup of patients (nine treated by IVGC and seven by ORGC) before therapy and at the end of follow-up using x-ray absorptiometry (Lunar Corp., Madison, WI) (24).
Statistical analysis
Baseline and posttreatment (at 12 months after radioiodine)
values of the two groups were compared using the two-tailed unpaired
Student’s t test, the Mann-Whitney test (CAS), and
2 test (diplopia and optic neuropathy).
Differences between pretreatment and posttreatment values were analyzed
by two-tailed paired Student’s t test for exophthalmometer
readings and lid width, the Wilcoxon test for clinical activity score,
and 2 test for diplopia and optic neuropathy.
Differences between groups with respect to overall clinical response,
self-assessment evaluation, and side effects were evaluated by
2 or Fischer’s exact test, as
appropriate.
Results
There was no significant differences in the baseline clinical and
biochemical features of the patients in the two treatment groups (Table 1
).
Proptosis
Proptosis significantly decreased from 23.2 ± 3.0 mm to
21.6 ± 1.2 mm (P < 0.0001) in the IVGC group,
and from 23.0 ± 1.8 mm to 21.7 ± 1.8 mm (P
< 0.0001) in the ORGC group (Table 3).
The final exophthalmometer readings in the two groups did not
significantly differ (P = 0.41). Nineteen of the 40
patients (47.5%) with proptosis in the IVGC group and 16 of the 40
patients (40.0%) in the ORGC group had a decrease in proptosis of 2 mm
or more. However, abnormal exophthalmometer readings (i.e.
values of 19 mm or more) persisted at the end of follow-up in the
majority of patients (35 in the IVGC group and 37 in the ORGC
group).
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Lid width values decreased from 13.6 ± 1.2 mm to 11.5
± 1.9 mm in the IVGC group (P < 0.0001) and from
13.3 ± 2.5 mm to 11.8 ± 1.2 mm (P <
0.0005) in the ORGC group (Table 3). Final values did not differ in the
two groups (P = 0.65). Among patients with a baseline
lid width of 13 mm or more, 10 of 19 (52.6%) in the IVGC group and 6
of 12 patients (50.0%) had a decrease in lid width of at least 3
mm.
Diplopia
In the IVGC group diplopia disappeared in 13 (10 with inconstant
and 3 with intermittent) of 27 patients (48.1%), improved in 1 (from
constant to inconstant) (3.8%), and did not change in 13 (3
with constant and 10 with inconstant diplopia) (48.1%) (Table 3).
Changes in the degree of diplopia were significant
(2 = 7.02, P < 0.01). In the
ORGC group, diplopia disappeared in 12 (9 with inconstant and 3 with
intermittent diplopia) of 33 patients (36.4%), improved in 5 (from
constant to inconstant in 4, and from inconstant to intermittent in 1)
(15.2%), and did not change in 16 (3 with constant, 11 with
inconstant, and 2 with intermittent diplopia) (48.4%); diplopia newly
appeared in 2 patients. The changes in the degree of diplopia were
significant also in this group (2 = 4.56,
P = 0.05). The degree of amelioration of diplopia did
not significantly differ between the two groups
(2 = 0.06, P = 0.82).
Optic neuropathy
In the IVGC group, optic neuropathy improved in eight of nine
patients with subclinical involvement and in three of five patients
with decreased visual acuity (Table 3). Thus, an improvement of optic
nerve involvement was observed in 11 of 14 patients (78.6%) (Fisher’s
exact test, P < 0.01). In the ORGC group, optic
neuropathy improved in two of eight patients with subclinical
involvement and in the only patient with clinical involvement. Thus, an
improvement occurred in three of nine patients (33.3%)
(2 = 0.33, P = 0.57) (Table 3). These outcomes did not reach statistical significance (Fisher’s
exact test, P = 0.08)
CAS
CAS decreased from 4.5 ± 1.2 (median, 5) to 1.7 ± 1.0 (median, 2) (P < 0.0001) in the IVGC group and from 4.2 ± 1.1 (median, 4) to 2.2 ± 1.2 (median, 2) (P < 0.0001) in the ORGC group. The final CAS values in the two groups were significantly different (P < 0.01), and the mean decrease in the IVGC group was significantly greater than that in the ORGC group (P < 0.005). Twenty-six patients in the IVGC group (63.4%) and 11 patients in the ORGC group (26.8%) had a CAS decrease of at least 3 points (P < 0.002). Two patients in the ORGC group had an increase in the CAS value.
Overall clinical response
A favorable clinical response to treatment, based on the criteria
described in Materials and Methods, was observed in 36
patients in the IVGC group (87.8%) and 26 patients in the ORGC group
(63.4%) (Fisher’s exact test, P < 0.02) (Fig. 1). Complete regression of eye disease
occurred in three patients in the IVGC group and one patient in the
ORGC group. Later in the follow-up, further treatment for
ophthalmopathy was needed for nine patients in the ORGC group (two
orbital decompression, three orbital decompression and eye muscle
surgery, and four eye muscle surgery) and for three patients in the
IVGC group (eye muscle surgery in all cases). All surgical procedures
were performed after completion of the study, to correct residual
disabling diplopia and/or disfiguring proptosis.
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)
The majority of patients were satisfied with the effects of
treatment. In the IVGC group, 35 patients
(85.3%) reported an improvement of ocular conditions, 4 (9.8%) did
not notice substantial changes, and 2 (4.9%) had the impression of a
progression of eye signs and symptoms. In the ORGC group, 30 patients
(73.2%) felt that their eye disease had improved, 8 (19.5%) reported
no changes, and 3 (7.3%) had a progression of the ophthalmopathy.
Differences between the two groups did not reach statistical
significance when comparing patients with improved vs. not
improved (no change or progression) ocular conditions
(2 = 1.19, P = 0.28).
In both groups, self-assessment evaluation was in good agreement with the overall clinical evaluation, although few patients in both groups (categorized as nonresponders) considered their ocular conditions to be improved.
Thyroid status
Following radioiodine administration in the IVCG group, 23 (56.1%) patients became hypothyroid, 7 (17.1%) became euthyroid, and 11 (26.8%) remained thyrotoxic. In the ORGC group 33 (80.5%) became hypothyroid, 2 (4.9%) became euthyroid, and 6 (14.6%) showed persistent hyperthyroidism.
Side effects
Despite the need of iv administration, the IVGC procedure was
better tolerated than the ORGC procedure. Minor side effects or
complications occurred in 23 patients (56.1%) of the IVGC group (Table 4). In most cases, they consisted of
urinary tract infections or glucose intolerance. One patient treated
with IVGC had a marked, asymptomatic increase in serum
aminotransferases levels (with no serologic evidence of viral
hepatitis) at the end of GC treatment, with a recovery after 2 months.
Cushingoid features were present only in five cases. A few patients
complained of hot flashes on the day after treatment. Bone
density measurement in nine patients at the end of the follow-up period
showed a mean percentage increase over basal value of 3.0 ± 1.8%
(±SE).
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The occurrence of side effects was more frequent in ORGC patients compared with the IVGC patients (Fisher’s exact test, P < 0.005).
Discussion
Management of severe GO remains a difficult task, and many patients are not satisfied with the effects of treatment (25). GC therapy is one of the established and most commonly used treatments for the ophthalmopathy, but the treatment seems to be more effective in association with orbital radiotherapy (8, 26). Indeed, a favorable response has been reported by us in about two thirds of patients treated by high-dose ORGC associated with orbital radiotherapy (1).
High-dose IVGC have been used therapeutically in several immune-mediated disorders to avoid the complications and side effects of long-term GC therapy. In addition, there is evidence that in rapidly progressive autoimmune disorders high-dose iv methylprednisolone may achieve a more rapid and effective immune suppression.
The present randomized study addressed the question of whether the iv scheme of GC administration might increase the effectiveness of treatment compared with the oral route. Several treatment modalities have been used in the use of IVGC. In the present study, we compared the ORGC treatment we used in the last 25 yr with an iv pulse therapy schedule not associated with ORGC in the interpulse period. Our results indicate that both treatment modalities (associated with orbital radiotherapy) are effective in the majority of patients, thus confirming the data of the literature (1). As expected, GC showed the greatest effectiveness on optic nerve involvement and soft tissue changes (incorporated in the CAS), whereas proptosis was less responsive. An improvement of diplopia occurred in approximately one half of patients. Comparison of the iv and the oral routes showed an overall greater effectiveness of the former, because 83% of patients treated iv had a favorable outcome of therapy compared with 63% of those treated orally. These results, obtained in a randomized study, are in agreement with the data of the literature (1). In a recent analysis of published studies, all nonrandomized, the mean percentage of responders was 77% in patients treated iv and 63% in patients treated orally (1).
Optic neuropathy and inflammatory changes were the ocular manifestations in which the greater effectiveness of IVGC were more evident, although there was a trend toward a greater efficacy also for diplopia. Interestingly, self-assessment of ocular changes by the patients was in good agreement with the clinical response, pointing to a more favorable outcome of the iv treatment.
Side effects and complications of GC treatment were rather frequent in both groups, as expected. Prummel et al. (8) reported that among 28 patients receiving oral prednisone treatment for GO, 2 patients had severe untoward effects (severe depression, recurrent herpes zooster infection) and 18 had minor side effects. In our series, the most frequent side effects were urinary tract infections and reduced glucose tolerance. The large majority of patients treated orally developed iatrogenic Cushing’s syndrome (likely associated with suppression of the hypothalamic-pituitary-adrenal axis), which, on the other hand, was present in only a few patients treated iv. In addition, although no definite conclusion can be drawn due to the small subgroups of patients, ORGC seemed to affect bone mineral density to a larger extent than IVGC. One patient of the IVGC group developed an asymptomatic, marked increase in serum aminotransferases levels (with no serologic evidence of viral hepatitis) at the end of GC treatment with spontaneous recovery in the following 2 months. One similar case of severe lever toxicity over several hundreds of patients with GO treated with IVGC has been observed after completion of the present study. Weissel and Hauff (27) have recently reported a patient who died from hepatic failure following IVGC pulse therapy for GO (28). We have also observed several years ago a case of fatal liver failure at the end of IVGC treatment for severe GO, at doses higher than those used in the present study (unpublished data). In the last 10 yr we further reduced the dose of IVGC up to a cumulative highest dose of 8 g, and no additional cases of liver dysfunction have been observed. Despite these occasional observations, the relationship between GC therapy and liver damage remains to be established. It is worth noting that iv pulse GC therapy has been widely used in several conditions other than GO (28), and, to our knowledge, no cases of severe liver damage have been reported.
Admittedly, the difference in efficacy may be related to the different cumulative doses of GC in the two groups. However, our study was designed to compare the efficacy and safety of two different protocols of treatment independently of their absolute pharmacologic potency. Undoubtedly, patients treated orally received a cumulative dose of GC that was lower than that of patients treated iv. Still, patients who received ORGC showed a higher rate of side effects, possibly because a continuous and more prolonged administration of GC may have stronger untoward metabolic effects. It seems, therefore, that the iv route allows the administration of a higher cumulative dose of GC with fewer side effects.
In conclusion, this prospective and randomized study confirms the effectiveness of GC, in association with orbital radiotherapy, in patients with severe and active GO. Our study represents the first randomized study comparing the oral and iv procedures. The latter seems to have a greater effectiveness and to be better tolerated than the oral route. Liver function tests should be included among parameters to be checked in patients receiving high doses of GC.
Footnotes
This work was supported in part by grants from the University of Pisa (Fondi d’Ateneo), from the Ministero dell’Università e della Ricerca Scientifica e Tecnologica (MURST), Rome (project "New Models for the Diagnosis and Management of Graves’ Ophthalmopathy; to M.N. and L.B.), and from European Community [project "Screening Program for the Assessment of the Prevalence of Clinical and Subclinical Thyroid Autoimmunity and Insulin-Dependent Diabetes Mellitus (IDDM) in Contaminated Territories of CIS Countries and Western Europe"; to A. P.].
Abbreviations: CAS, Clinical Activity Score; FT3, free T3; FT4, free T4; GC, glucocorticoid(s); GO, Grave’s ophthalmopathy; IVGC, iv GC; ORGC, oral GC.
Received December 27, 2000.
Accepted March 27, 2001.
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