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Suppressive therapy of nontoxic goiter
Suppressive Therapy of Nontoxic Goiter
KATSUTARO JOSEPH
SHIMAOKA.
E. SOKAL,
In a double-blind study, 114 patients with clinically benign nontoxic goiter were treated either with liothyronine (T3), 50 pg/day, or thyroxine (T4), 200 pg/day. After 12 weeks of therapy, patients whose goiters decreased in size were continued on the same therapy for an additional 16 weeks. Those who did not respond were randomly divided into two groups: in one group the same dose of the same medication was continued, and in the other twice the dose of their original medication was gfven. By the end of 26 weeks, 40 of 54 patients treated with T3 and 29 of 59 patients treated with T4 showed a significant decrease in goiter size. The difference in effectiveness of the two agents was statistically significant (p <0.025). Both T3 and T4 were effective in reducing small goiters, but T4 was relatively ineffective in shrinking large goiters. Duration of treatment, rather than dose of thyroid hormone, was the major determinant of goiter shrinkage. T3 produced a uniform and consistent depression of radioiodine uptake and circulating hormonal iodine levels, and was effective in shrinking both small and large thyroid nodules, whether or not radioiodine uptake was reduced to hypothyroid levels. T4 uniformly increased circulating hormonal iodine levels. However, in T4-treated patients who responded with regression of thyroid nodules, suppression of radioiodine uptake was substantially greater than in those who did not respond.
M.D
M.D.
Buffalo, New York
From the Department Memorial Institute, of Health, Buffalo, for reprints should ro
Shimaoka,
of Medicine,
Roswell
Park
New York State Department New York 14203. Requests be addressed to Dr. Katsuta-
Department
of
Medicine
B,
Roswell Buffalo,
Park Memorial Institute, 666 Elm Street, New York 14203. Manuscript accepted
January
31, 1974.
576
October
1974
The American
Therapeutic administration of thyroactive substances to patients with nontoxic goiter is quite old, antedating most of our knowledge of thyroid physiology. Despite gratifying results obtained in many cases, this form of treatment was largely abandoned several decades ago. As the concept of a thyropituitary axis became generally accepted, and the role of thyrotropic hormone (TSH) in the genesis of nontoxic goiter recognized, the interest in suppressive therapy revived. In 1953, Greer and Astwood [l] reviewed the earlier experience and reported their results in treatment of nontoxic goiter with thyroid preparations. They found that 38 of 50 patients with nontoxic goiter showed partial or complete regression of goiter during administration of desiccated thyroid, whereas only 6 of 40 control subjects showed spontaneous regression of their goiters. This study was subsequently expanded to 230 patients, with 68 per cent showing a response [ 21. Similar results were reported by Lamberg et al. [3]. Although material prepared from animal thyroid was used exclusively in the earlier studies, availability of synthetic thyroactive preparations has made it possible to evaluate the effectiveness of sodium l-thyroxine (T4) [4-71, sodium liothyronine (T3) [5-l I] and triiodothyroacetic acid (triac) [ 51. These agents induced significant reduction of goiter size in 39 to 100 per cent of treated patients. Although various groups have reported favorable results, others have
Journal of Medicine
Volume
57
SUPPRESSIVE
Suppressive
TABLE I
Therapy
of Goiter-Results
of Phase
THERAPY
OF NONTOXIC
GOITER-SHIMAOKA,
SOKAL
I (12 weeks) and Two Phases Combined (28 weeks)
Decrease 111Goiter Size Phase Medication
(no.)
I
No. - .
%
No.
%
(no.)
55 39
40 29 _.~
73 49
6 7
47
69
T3 T4
55 59
30 24
Total
114
54
_
~~~ ~~~
been pessimistic [ 12-151. Some believed quite strongly that medical treatment of nodular goiter is useless [ 151. Because of these conflicting views. we undertook a double-blind study in which the action of T3 was compared to that of a placebo [lo]. We found that a moderate dose of T3 for 12 weeks produced a measurable decrease in the size of goiter in about half of the patients. Although a spontaneous decrease in the size of goiter was observed in some of the patients treated with placebos, the difference in responses to T3 and to placebo was highly signifi-
_
increases erage
nodules
complete
ters were deemed were
examined
to be benign
geon and an internist. per measurements sible,
two
to the
sectional base
Each recorded
sets of base institution
area
Then,
T3 (50 pglday)
the location
of identifiable
of the gland.
nodules
were
The was
were
and T4 (200 pg/day)
and cali-
thyroid
Whenever
line measurements
patients
a sur-
recorded
significantly in one
randomly
treatment
groups.
other
group
pg/day
of T3,
phase vided
(phase
ratory
reports
third physician tored
the
pertinent (KS.),
study
closely
might require modification the study for thyroidectomy. al area
of thyroid
to thyroid
function.
who had access
nodules
and
examined
of therapy Changes were
However,
to all records, all patients
a
moniwho
or withdrawal from in the cross section-
expressed
II) lasted
into two equal
the other py,
or 400
as percentage
was
pglday
failed
to palas a
of the
same
into two groups:
continued, was
and
doubled
respectively.
All medications
one given
offered
in the
(i.e.,
to patients
100 This
were
in the morning
At the end of 28 weeks
was
sup-
had not decreased
of T4,
16 weeks.
in the evening.
thyroidectomy
dose
dose
doses,
diand
of thera-
whose
goiter
size had not regressed. However, patients whose goiters were clinically nonmalignant, and who were reluctant to undergo study
surgery,
were
of suppressive
termine
how frequently whose
accepted
therapy
goiter
suppressive were
withdrawn
supplementary herein)
might occur.
in size continued
therapy.
significant
a
response
regressed
showed
for
(not reported
delayed
Patients
growth
from
the
whose and
Pa-
to receive
during
study
to de-
thyroid
suppressive urged
to un-
dergo thyroidectomy. Twenty-four by column study
hour
thyroidal
determinations
and repeated
radioiodine
uptakes
and T4
at entry
into this
4, 12, 20 and 28 weeks
of sup-
were
after
at least once
tients were reexamined by the same physicians at 4 week intervals. The examining physicians did not have access to the records of their previous examinations or to the labo-
than
as a near-
recorded
randomly
dose
the suppressive
repeated
Pa-
on more
it was
goiters
divided
the same
pos-
to
20
When
to one examiner,
examiners
same
whose
in size were
group
therapy.
as the
assigned
both
the
Patients
pressive
cross
significant.
it was classified
observation,
to receive agent.
nod-
obtained
average
When
under
If the av-
exceeded
response.
pressive
They
physicians,
of treatment.
of thyroid
line size.
by two
(in two axes)
ules on a card with a diagram prior
on initial evaluation.
independently
considered
became.impalpable
response.
continued
therapy whose goi-
line size.
At the end of 12 weeks (phase I), patients who showed a significant reduction in the size of their thyroid masses
MATERIALS
patients
were
examinations,
the nodule
complete
the base
by two examiners
to one or both examiners
two consecutive pate
13 (11%)
from
obtained
or unmeasurable
long-term
to euthyroid
61
the changes
the thyroid
nodules
This study was restricted
-__-__.
or decreases
per cent,
tients
METHODS
-
of changes
cant (p
Complete and Near Complete Responders
Phases I & II
Thyroid
scan
during
obtained
was obtained suppressive
at entry
therapy
and
if there
was sufficient radioiodine uptake for scanning. There were 114 patients (106 female and 8 male) in this study
who
therapy. clinical
completed
Of these, evaluation),
fuse goiters
at least
71 patients
12 weeks
of suppressive
had uninodular
38 had multinodular
and one had a substernal
goiters
goiters, goiter.
(by
4 had dif-
As has been
found by others [ 171, single nodules were more frequent in the right lobe of the thyroid. Nineteen patients (17 per cent) current
had previously goiter.
undergone
Family
history
thyroidectomy regarding
and had re-
thyroid
disease
was positive in 24 cases (21 per cent). The mean age of these patients was 48.1 f 15.3 years with a range of 13 to
76 years.
Mean
duration
of goiter
was
6.2
f
11.1
years.
October 1974
The American Journal of Medicine
Volume 57
577
SUPPRESSIVE THERAPY OF NONTOXIC GOITER-SHIMAOKA,
TABLE
TABLE III
Suppressive Therapy of Goiter-Results During Phase II (16 weeks), Among Patients Who Did Not Respond in Phase I
II
Same T3 T4
(no.)
Double 13 T4
Not Available
Cold
Warm
Hot
Responders Nonresponders
5 4
19 6
3 0
7 2
6 3
Responders Nonresponders Corn bined
4 6
15 7
1 2
5 9
5 5
Responders Nonresponders ___
9 10
34 13
4 2
12 11
11 8
Total
19
47
6
23
19
T4
14 10
7 1
24
S (33%)
8 15
3 4
23
J (30%)
dose
I
Indeterminate*
Scan and
T3
0-Q
dose
Total
Correlation of Findings on Thyroid Response to Suppressive Therapy
Medication and Response
Decrease in Goiter Size
Patients Medrcatron
Tota
SOKAL
*The scans presented mottled areas creased function. Clinically observed identified in these scans.
of increased and denodules could not be
RESULTS
Of these 114 patients, 54 showed a significant decrease in the size of their thyroid nodules at the end of 12 weeks of suppressive therapy (Table I). The difference in response rate between the TS-treated and T4-treated groups was not statistically significant at this point. Among those who showed no response, six in the T3-treated group and five in the T6treated group showed an increase in goiter size. Nine of these patients (including the only patient in this study so far found to have thyroid cancer) accepted our recommendation and underwent thyroidectomy; in the remaining two patients suppressive therapy was continued and they subsequently showed significant shrinkage of their goiter. The combined results for both phases of suppressive therapy show that a decrease in goiter size was recorded among 73 per cent of the patients treated with T3 and 49 per cent of those treated with T4, during a half year of thyroid hormone administration. This difference in response rate is statistically TABLE IV
Correlation Between Goiter Size and Response to Suppressive Therapy Onginal Srze of Nodules 8.0 cm” or Less *
More Than 8.0 cm2
Responders Nonresponders
21 4
20 10
Responders Nonresponders Combined Responders Nonresponders
19 6
10 24
40 10
30 34
Medrcatron and Resporrse T3
T4
* Product
579
of two diameters,
October 1974
at right angles
to each
other.
The American Journal of Medicine
significant (p cO.025). In only one fifth of the patients who responded, however, did the thyroid nodules become unmeasurable during this time period. This is consistent with our previous experience [IO], which indicated that it is unrealistic to expect the thyroid nodules to disappear during a few months of suppressive therapy. Table II shows the results during phase II among patients whose goiters did not decrease during the first 12 weeks of suppressive therapy. One third of the patients in whom suppressive therapy was continued showed a significant shrinkage in the size of their goiter during this phase. Responses among the patients who continued to receive their original doses of thyroid hormone were just as frequent as among those whose dose was doubled. Thus, it appears that the duration of suppressive therapy is more important than the dose. Among those who did not respond to therapy, four patients showed a significant increase in goiter size. There was no difference in response to suppressive therapy, according to number and location of thyroid nodules, base line radioactive iodine uptake or base line serum hormonal iodine levels. Although the response rate was relatively poor among those who had had their goiters for more than 10 years (37 per cent), there was no consistent correlation between the duration of goiter and the response to suppressive therapy. “Cold” nodules responded somewhat less well than those which concentrated radioiodine (Table Ill); this difference was not statistically significant. All six patients with hot nodules showed more than 50 per cent suppression of radioiodine uptake during the study period. Patients with small goiters responded more frequently than those with large ones (Table IV). In pa-
Volume 57
SUPPRESSIVE THERAPY OF NONTOXIC GOITER-SHIMAOKA,
TABLE V
T4 by Column Determinations in Patients Receiving Suppressive Therapy
Medicationand Response
SerumHormonalIodine &g/100 BaseLine
PhaseI
TABLE VI
ml)
PhaseI I
Responders Nonresponders Combined
5.28i.0.27 5.88zt: 0.53 5.44&.0.25
2.91zt0.19 3.321 0.33 3.02AzO.17
2.21+0.14 2.78f 0.25 2.36+ 0.13
~~_~ T3 Responders Nonresponders Combined 14 Responders Nonresponders Combined -__ __ _.
Responders Nonresponders Combined
5.20+ 5.49A. 5.34+
7.1010.19 7.60% 0.23 7.35kO.15
7.79* 0.30 7.73i 0.21 7.761t0.19
T4
NOTE:
Values
given
0.27 0.18 0.16
are the mean
& standard
error.
NOTE:
tients with multinodular goiters in whom two or more nodules were measured, the respective cross sectional “areas” (product of two diameters, at right angles) were calculated and the sum of these was used as the size. When combined results for T3 and T4 therapy are analyzed, the patients whose goiters were smaller than 8.0 cm* responded more often than those whose goiters were larger than 8.0 cm* (p
TABLE VII
T4 By Column Determinations ~.__ ~~ ~_~
in Patients
24-Hour Radioiodine Uptake in Patients Receiving Suppressive Therapy Radioiodine Uptake (%)
Medication and Response
T3
Base Line
-... _
Valuesgiven
Phase
Phase II
I
31.1+ 26.5% 29.9 t
1.7 1.5 1.3
9.3 t 1.0 10.9 .i- 1.5 9.7 !- 0.8
27.0% 31.9+ 29.34:
2.2 2.2 1.6
6.5 l-O.7 14.9 im 1.5 10.8 t 1.0
~.
are the mean
I standard
9.3* 9.7+ 9.4xt
1.1 1.8 1.0
6.5& 0.9 11.1:+x 1.3 8.5+ 0.8 error.
tients treated with T4 (both responders and nonresponders) had a highly significant elevation in T4 by column values in phase I (p
Receiving Suppressive
Therapy
Serum Hormonal Base Line
Data
SOKAL
Iodine &g/100
Phase
ml)
I
Phase II
T3 Phase I nonresponders Same dose in phase II Double dose in phase II
5.41 ! 0.35 4.97 m!- 0.98
3.18 3.17
IZ 0.19 1: 0.46
2.86 2.27
+ 0.18 I: 0.36
Phase I nonresponders Same dose in phase II Double close in phase II
5.56 XI= 0.31 5.61-k 0.35
7.62 f 0.27 7.39 -t 0.24
7.74 8.17
!- 0.31 i_ 0.35
T4
NOTE:
Values
given
are the mean
:t standard
error.
October 1974
The American Journal of Medicine
Volume 57
579
SUPPRESSIVE THERAPY OF NONTOXIC GOITER-SHIMAOKA,
24-Hour Radioactive
TABLE VIII
SOKAL
Iodine Uptakes in Patients
Receiving Suppressive
Therapy
Radioiodine Uptake (%)
T3 Phase
28.6 i 27.0 t
1.7 2.9
10.0 f 9.8 f
1.4 2.4
30.2 f 30.8 f
3.1 3.5
13.6 f 2.3 13.3 + 2.2
12.5 f 2.1 4.8 f. 1.1
I nonresponders
Same dose in phase II Double dose in phase II NOTE: Values given are the mean *
standard
dose of T3 (p <0.025). Table IX shows the patterns
of suppression
of ra-
dioiodine uptake among responders and nonresponders. There was a significant correlation between the degree of suppression of radioiodine uptake and the decrease in goiter size (p
Correlation Between Suppression of Radioiodine Uptake and Clinical Response
Medication and Response T3 Responders Nonresponders T4 Responders Nonresponders Combined Responders Nonresponders Total
-
October 1974
Consistently 10% or more .____
Variable
12.1 f 9.0 f
2.4 1.5
error.
among the patients who took double doses. However, the only individual difference which was statistically significant was in the suppression of radioiodine uptake among the patients who received the double
580
Phase II
I nonresponders
Same dose in phase II Double dose in phase II T4 Phase
Phase I
Base Line
Data ~____~~~
Consistently below 10%
complete responses have been observed among patients who continued to receive suppressive therapy after completing phase II.) In six cases reduction of goiter size was recorded in phase I and regrowth of goiter was observed at a later date. In three of these patients, increase in nodule size was associated with softened consistency, and this was thought to be due to hemorrhage into the nodule or cystic degeneration. In two patients, regrowth of the nodule was associated with signs and symptoms highly suggestive of subacute thyroiditis. All these patients, however, showed shrinkage of their goiter again, during continued suppressive therapy. So far, 28 patients have undergone thyroidectomy (Table X). These were mostly nonresponders, but there were six responders. Two of the latter were symptomatic from their goiters; the other four had goiter of relatively short duration, were reluctant to commit themselves to a long-range program and expressed a preference for thyroidectomy. There was one case each of follicular carcinoma, subacute thyroiditis and Hashimoto’s disease. The patient with chronic thyroiditis showed a progressive increase in goiter size during 3 months of suppressive therapy. The remaining 25 patients had other benign lesions, including adenomas and nontoxic nodular goiters. Nine of these had associated cystic changes (36 per cent). In two patients an urticarial rash developed a few days after starting suppressive therapy. In both cases, the drug was T4, and the rash subsided promptly on discontinuing medication. One of these patients dropped out of the study, and the other was placed on a regimen of T3, without incident. All other patients were able to tolerate their assigned medication throughout the study period.
10 6
12 5
18 3
3 13
7 6
18 9
13 19
19 11
36 12
COMMENTS
32 (29%)
30 (27%)
48 (44%)
This study confirms therapy in reducing
The American Journal of Medicine
Volume 57
the effectiveness of suppressive the size of nontoxic goiters. Dur-
SUPPRESSIVE
TABLE X
Thyroid
Histology
Among Patients
Who Underwent
No. Patients
Cancer
THERAPY OF NONTOXIC GOITER-SHIMAOKA.
SOKAL
Thyroidectomy Iksociated
Medication
and Response
Thyroidltis
Other Lesions
Cystic
Changes
.
.--. _~_.. -.___ l
Responders T3 T4 Nonresponders T3 T4 Total _.-.-
-
Eight adenomas
ing the first
-.
_ --...
0 0
0
4
?
1
1
1
10 12
1 0
0 1
9 11
4 2
1
2
25*
9
- -____. ~. _._
28
..~. ~~__~______
and 17 “nontoxic
12 weeks
4 2
of therapy
nodular
_~~~~
goiters.”
54 (47 per cent) of
114 patients responded; after an additional 16 weeks of therapy 15 more responded, for a total of 69 patients (61 per cent) with a significant decrease in goiter size. In other reported studies also, patients who received longer treatment [2,3,7] appeared to do better than those who were treated for shorter periods [4,5]. It is clear that thyroid nodules cannot be expected to disappear during a brief trial of suppressive therapy; we saw only one complete response during the first 12 weeks. Our study indicates that suppressive therapy is more effective in shrinking smaller goiters than larger ones (Table IV), but this was principally due to resistance of the latter to T4 administration. Other investigators have stated that large diffuse goiters often fail to respond, but that this is not so in the case of nodular goiter [ 2,131. T3 therapy was significantly more effective than T4 therapy in inducing goiter regression in this study (p <0.025). The two thyroid hormones differ considerably in their metabolic behavior. Also, T3 is almost completely absorbed from the intestine whereas only one half of T4 is absorbed [ 181. We do not think that this would account for the difference in their effectiveness in this study. The initial doses arbitrarily chosen were 50 pglday for T3 and 200 yglday for T4. This dose difference is enough to compensate for the differences in molecular weight and absorption. Furthermore, randomization of the nonresponders during phase I was designed to examine the possibility of a dose-dependent response. During phase II, the decrease in goiter size among those who did not respond during phase I showed no correlation with the dose (TabI, II). As already stated, these results indicate that duration of treatment is more important than the dose of thyroid hormone; however, the kind of thyroid hormone administered may be important. Some of the differences between the action of T3 and T4 recorded in this study were quite unexpected. For example, T4 was considerably less effective in
October
patien?s with larger goiters than II; patients with smaller ones, whereas the response to T3 appeared to be virtually independent of goiter size (Table IV). Also, response to T4 clearly correlated with major suppression of thyroidal radioiodine uptake, whereas this seemed to be significantly less important for the action of T3 (Tables V and VI). These findings suggest a qualitative difference between the action of the two hormones. In addition, there appears to be a difference among patients in the action of T4. Responders and nonresponders to this agent had similar serum T4 levels (Table V) but widely divergent radioiodine uptakes (Table VI). Suppression of radioiodine uptake was greater in the responders to T4 than in the responders to T3 (Table VI). The nonresponders who received the double dose of T4 during phase II, and who had the highest serum T4 levels of any group in this study, showed less suppression of radioiodine uptake than the responders who received the lower dose, but this was not statistically significant. These differences cannot be due to failure to take medication or to impaired absorption of T4, since these would be reflected in lower serum T4 values. Others [2,13] have also commented on the poorer suppression of radioiodine uptake among nonresponders to desiccated thyroid. Such inconsistencies were not encountered among patients receiving T3. Responders and nonresponders who received the same dose of this drug had similar radioiodine uptake values (Table VI), and doubling the dose resulted in a substantial further decrease in radioiodine uptake. Circulating TSH levels of patients with nontoxic goiter are well within the normal range in the absence of severe iodine deficiency [ 19-2 11. TSH response to TRH administration is similar among normal subjects and patients with nontoxic goiter [ 221. However, TSH is believed to play an important role in the genesis and growth of such goiters [ 14,21,231. Administration of exogenous thyroid hormone can block TSH production and suppress its secretion
1974
The American
Journal of Medicine
Volume 57
581
SUPPRESSIVE THERAPY OF NONTOXIC GOITER-SHIMAOKA,
SOKAL
[ 24-271. There appear to be selective localization of T4 and T3, and active monodeiodination of T4 to T3 in the pituitary gland [ 28-3 11. Furthermore, the demonstration of specific T3-binding sites and the failure to find such binding sites for T4 in the pituitary of the rat are very interesting [32]. Various investigators have shown that significant conversion of T4 to T3 at the periphery takes place both in experimental animals and in man [33-381. It is tempting to speculate that conversion of T4 to T3 is somewhat impaired in some patients with nontoxic goiter. This would explain the difference in response to the two thyroid hormones. However, no evidence is presently available on this point. Our data provide indirect evidence that there might be some difference in TSH suppression by T4 among different patients (Table VI). However, even the nonresponders had substantial sup-
pression of radioiodine uptake. It is also possible that T3 or T4 might act directly on the goiter itself. However, this appears unlikely in the light of our current concepts of thyroid-pituitary relationships and the genesis of nontoxic goiter. Since T3 appears to be more uniformly effective in suppressing TSH secretion than T4, as is suggested by our data, it should be the agent of choice for suppressive therapy. ACKNOWLEDGMENT We gratefully acknowledge assistance given to this study by Drs. T. Chang, E. Ezdinli, H. Feliciano, P. Friedman, D. Holyoke, H. Karna, G. Koepf, F. Marchetta, J. Park, M. Razack, K. Sako, N. Silva, B. Thumasathit and S. Young.
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Volume 57
Harper & Row, 1971. Psarras A, Papadopoulos SN, Livadas D, Pharmakiotis AD, Koutras DA: The single thyroid nodule. Br J Surg 59: 545, 1972. Hays MD: Absorption of triiodothyronine in man. J Clin Endocrinol Metab 30: 675, 1970. Pisarev MA, Utiger RD. Salvaneschi JP, Altschuler N, DeGroot LJ: Serum TSH and thyroxine in goitrous subjects in Argentina. J Clin Endocrinol Metab 30: 680, 1970. Cole YD Jr, Kohler PO: Plasma TSH levels in endemic goiter subjects. J Clin Endocrinol Metab 31: 220, 1970. Beckers C, Cornette C: TSH production rate in nontoxic goiter. J Clin Endocrinol Metab 32: 852, 1971. Beckers C, Maskens A, Cornette C: Thyrotropin response to synthetic thyrotropin releasing hormone in normal subjects and in patients with nontoxic goiter. Europ J Clin Invest 2: 220, 1972. Taylor S: Physiologic considerations in the genesis and management of nodular goiter. Am J Med 20: 698, 1956. Snyder PJ, Utiger RD: Inhibition of thyrotropin response to thyrotropin releasing hormone by small quantities of thyroid hormones. J Clin Invest 51: 2077, 1972. Vigneri R, Papalia D, Pezzino V, Squatrito S, Motta L, Polosa P: Triiodothyronine and thyrotropin releasing hormone interaction on TSH release in man. Hormones 3: 250, 1972. Bakke JL, Kammer H, Lawrence N: Effect of thyroid hormone on human pituitary thyroid stimulating hormone content. J Clin Endocrinol Metab 24: 28 1, 1964. Cotton GE, Gorman CA, Mayberry WE: Suppression of thyrotropin (h-TSH) in serums of patients with myxedema of varying etiology treated with thyroid hormones. N Engl J Med 285: 529, 1971. Ford DH. Gross J: The metabolism of l’3’-labeled thyroid hormones in the hypophysis and brain of the rabbit. Endocrinology 62: 416, 1958. Grinberg R, Volpert EM, Werner SC: In vivo deiodination of labeled l-thyroxine to 1-3:5:3’-triiodothyronine in mouse and human pituitaries. J Clin Endocrinol Metab 23: 140, 1963. Ford D, Kantounis S, Lawrence R: The localization of 1 i3’labeled triiodothyronine in the pituitary and brain of normal and thyroidectomized male rats. Endocrinology 64: 977, 1958.
SUPPRESSIVE THERAPY OF NONTOXIC GOITER-
31.
32.
33.
34.
35.
Reichlin S, Volpert EM, Werner SC: Hypothalamic influence on thyroxine monodeiodination by rat anterior pituitary gland. Endocrinology 78: 302, 1966. Schadlow AR, Surks MI, Schwartz HL, Oppenheimer JH: Specific triiodothyronine binding sites in the anterior pituitary of rat. Science 176: 1252, 1972. Braverman LE, lngbar SH, Sterling K: Conversion of thyroxine (T4) to triiodothyronine (T3) in athyreotic human subjects. J Clin Invest 49: 855, 1970. Sterling K, Brenner MA, Neuman ES: Conversion of thyroxine to triiodothyronine in normal human subjects. Science 169: 1099, 1970. Schwartz HL. Surks MI. Oppenheimer JH: Quantitation of
36.
37.
38.
October 1974
SHIMAOKA,
SOKAL
extrathyroidal conversion of l-thyroxine to 3,5.3’-triiodoI-thyronine in the rat. J Clin Invest 50: 1124, 197 1. Pittman CS, Chambers JB Jr, Read VH: The extrathyroidal conversion rate of thyroxine to triiodothyronine in normal man. J Clin Invest 50: 1187. 1971. Refetoff S, Matalon R, Bigazzi M: Metabolism of I-thyroxine (T4) and I-triiodothyronine(T3) by human fibroblasts in tissue culture. Evidence for cellular binding proteins and conversion of T4 to T3. Endocrinology 91: 934, 1972. Fisher DA, Chopra IJ, Dussault JH: Extrathyroidal conversion of thyroxine to triiodothyronine in sheep. Endocrinology 91: 1141, 1972.
The American Journal of Medicine
Volume 57
583
KATSUTARO JOSEPH
SHIMAOKA.
E. SOKAL,
In a double-blind study, 114 patients with clinically benign nontoxic goiter were treated either with liothyronine (T3), 50 pg/day, or thyroxine (T4), 200 pg/day. After 12 weeks of therapy, patients whose goiters decreased in size were continued on the same therapy for an additional 16 weeks. Those who did not respond were randomly divided into two groups: in one group the same dose of the same medication was continued, and in the other twice the dose of their original medication was gfven. By the end of 26 weeks, 40 of 54 patients treated with T3 and 29 of 59 patients treated with T4 showed a significant decrease in goiter size. The difference in effectiveness of the two agents was statistically significant (p <0.025). Both T3 and T4 were effective in reducing small goiters, but T4 was relatively ineffective in shrinking large goiters. Duration of treatment, rather than dose of thyroid hormone, was the major determinant of goiter shrinkage. T3 produced a uniform and consistent depression of radioiodine uptake and circulating hormonal iodine levels, and was effective in shrinking both small and large thyroid nodules, whether or not radioiodine uptake was reduced to hypothyroid levels. T4 uniformly increased circulating hormonal iodine levels. However, in T4-treated patients who responded with regression of thyroid nodules, suppression of radioiodine uptake was substantially greater than in those who did not respond.
M.D
M.D.
Buffalo, New York
From the Department Memorial Institute, of Health, Buffalo, for reprints should ro
Shimaoka,
of Medicine,
Roswell
Park
New York State Department New York 14203. Requests be addressed to Dr. Katsuta-
Department
of
Medicine
B,
Roswell Buffalo,
Park Memorial Institute, 666 Elm Street, New York 14203. Manuscript accepted
January
31, 1974.
576
October
1974
The American
Therapeutic administration of thyroactive substances to patients with nontoxic goiter is quite old, antedating most of our knowledge of thyroid physiology. Despite gratifying results obtained in many cases, this form of treatment was largely abandoned several decades ago. As the concept of a thyropituitary axis became generally accepted, and the role of thyrotropic hormone (TSH) in the genesis of nontoxic goiter recognized, the interest in suppressive therapy revived. In 1953, Greer and Astwood [l] reviewed the earlier experience and reported their results in treatment of nontoxic goiter with thyroid preparations. They found that 38 of 50 patients with nontoxic goiter showed partial or complete regression of goiter during administration of desiccated thyroid, whereas only 6 of 40 control subjects showed spontaneous regression of their goiters. This study was subsequently expanded to 230 patients, with 68 per cent showing a response [ 21. Similar results were reported by Lamberg et al. [3]. Although material prepared from animal thyroid was used exclusively in the earlier studies, availability of synthetic thyroactive preparations has made it possible to evaluate the effectiveness of sodium l-thyroxine (T4) [4-71, sodium liothyronine (T3) [5-l I] and triiodothyroacetic acid (triac) [ 51. These agents induced significant reduction of goiter size in 39 to 100 per cent of treated patients. Although various groups have reported favorable results, others have
Journal of Medicine
Volume
57
SUPPRESSIVE
Suppressive
TABLE I
Therapy
of Goiter-Results
of Phase
THERAPY
OF NONTOXIC
GOITER-SHIMAOKA,
SOKAL
I (12 weeks) and Two Phases Combined (28 weeks)
Decrease 111Goiter Size Phase Medication
(no.)
I
No. - .
%
No.
%
(no.)
55 39
40 29 _.~
73 49
6 7
47
69
T3 T4
55 59
30 24
Total
114
54
_
~~~ ~~~
been pessimistic [ 12-151. Some believed quite strongly that medical treatment of nodular goiter is useless [ 151. Because of these conflicting views. we undertook a double-blind study in which the action of T3 was compared to that of a placebo [lo]. We found that a moderate dose of T3 for 12 weeks produced a measurable decrease in the size of goiter in about half of the patients. Although a spontaneous decrease in the size of goiter was observed in some of the patients treated with placebos, the difference in responses to T3 and to placebo was highly signifi-
_
increases erage
nodules
complete
ters were deemed were
examined
to be benign
geon and an internist. per measurements sible,
two
to the
sectional base
Each recorded
sets of base institution
area
Then,
T3 (50 pglday)
the location
of identifiable
of the gland.
nodules
were
The was
were
and T4 (200 pg/day)
and cali-
thyroid
Whenever
line measurements
patients
a sur-
recorded
significantly in one
randomly
treatment
groups.
other
group
pg/day
of T3,
phase vided
(phase
ratory
reports
third physician tored
the
pertinent (KS.),
study
closely
might require modification the study for thyroidectomy. al area
of thyroid
to thyroid
function.
who had access
nodules
and
examined
of therapy Changes were
However,
to all records, all patients
a
moniwho
or withdrawal from in the cross section-
expressed
II) lasted
into two equal
the other py,
or 400
as percentage
was
pglday
failed
to palas a
of the
same
into two groups:
continued, was
and
doubled
respectively.
All medications
one given
offered
in the
(i.e.,
to patients
100 This
were
in the morning
At the end of 28 weeks
was
sup-
had not decreased
of T4,
16 weeks.
in the evening.
thyroidectomy
dose
dose
doses,
diand
of thera-
whose
goiter
size had not regressed. However, patients whose goiters were clinically nonmalignant, and who were reluctant to undergo study
surgery,
were
of suppressive
termine
how frequently whose
accepted
therapy
goiter
suppressive were
withdrawn
supplementary herein)
might occur.
in size continued
therapy.
significant
a
response
regressed
showed
for
(not reported
delayed
Patients
growth
from
the
whose and
Pa-
to receive
during
study
to de-
thyroid
suppressive urged
to un-
dergo thyroidectomy. Twenty-four by column study
hour
thyroidal
determinations
and repeated
radioiodine
uptakes
and T4
at entry
into this
4, 12, 20 and 28 weeks
of sup-
were
after
at least once
tients were reexamined by the same physicians at 4 week intervals. The examining physicians did not have access to the records of their previous examinations or to the labo-
than
as a near-
recorded
randomly
dose
the suppressive
repeated
Pa-
on more
it was
goiters
divided
the same
pos-
to
20
When
to one examiner,
examiners
same
whose
in size were
group
therapy.
as the
assigned
both
the
Patients
pressive
cross
significant.
it was classified
observation,
to receive agent.
nod-
obtained
average
When
under
If the av-
exceeded
response.
pressive
They
physicians,
of treatment.
of thyroid
line size.
by two
(in two axes)
ules on a card with a diagram prior
on initial evaluation.
independently
considered
became.impalpable
response.
continued
therapy whose goi-
line size.
At the end of 12 weeks (phase I), patients who showed a significant reduction in the size of their thyroid masses
MATERIALS
patients
were
examinations,
the nodule
complete
the base
by two examiners
to one or both examiners
two consecutive pate
13 (11%)
from
obtained
or unmeasurable
long-term
to euthyroid
61
the changes
the thyroid
nodules
This study was restricted
-__-__.
or decreases
per cent,
tients
METHODS
-
of changes
cant (p
Complete and Near Complete Responders
Phases I & II
Thyroid
scan
during
obtained
was obtained suppressive
at entry
therapy
and
if there
was sufficient radioiodine uptake for scanning. There were 114 patients (106 female and 8 male) in this study
who
therapy. clinical
completed
Of these, evaluation),
fuse goiters
at least
71 patients
12 weeks
of suppressive
had uninodular
38 had multinodular
and one had a substernal
goiters
goiters, goiter.
(by
4 had dif-
As has been
found by others [ 171, single nodules were more frequent in the right lobe of the thyroid. Nineteen patients (17 per cent) current
had previously goiter.
undergone
Family
history
thyroidectomy regarding
and had re-
thyroid
disease
was positive in 24 cases (21 per cent). The mean age of these patients was 48.1 f 15.3 years with a range of 13 to
76 years.
Mean
duration
of goiter
was
6.2
f
11.1
years.
October 1974
The American Journal of Medicine
Volume 57
577
SUPPRESSIVE THERAPY OF NONTOXIC GOITER-SHIMAOKA,
TABLE
TABLE III
Suppressive Therapy of Goiter-Results During Phase II (16 weeks), Among Patients Who Did Not Respond in Phase I
II
Same T3 T4
(no.)
Double 13 T4
Not Available
Cold
Warm
Hot
Responders Nonresponders
5 4
19 6
3 0
7 2
6 3
Responders Nonresponders Corn bined
4 6
15 7
1 2
5 9
5 5
Responders Nonresponders ___
9 10
34 13
4 2
12 11
11 8
Total
19
47
6
23
19
T4
14 10
7 1
24
S (33%)
8 15
3 4
23
J (30%)
dose
I
Indeterminate*
Scan and
T3
0-Q
dose
Total
Correlation of Findings on Thyroid Response to Suppressive Therapy
Medication and Response
Decrease in Goiter Size
Patients Medrcatron
Tota
SOKAL
*The scans presented mottled areas creased function. Clinically observed identified in these scans.
of increased and denodules could not be
RESULTS
Of these 114 patients, 54 showed a significant decrease in the size of their thyroid nodules at the end of 12 weeks of suppressive therapy (Table I). The difference in response rate between the TS-treated and T4-treated groups was not statistically significant at this point. Among those who showed no response, six in the T3-treated group and five in the T6treated group showed an increase in goiter size. Nine of these patients (including the only patient in this study so far found to have thyroid cancer) accepted our recommendation and underwent thyroidectomy; in the remaining two patients suppressive therapy was continued and they subsequently showed significant shrinkage of their goiter. The combined results for both phases of suppressive therapy show that a decrease in goiter size was recorded among 73 per cent of the patients treated with T3 and 49 per cent of those treated with T4, during a half year of thyroid hormone administration. This difference in response rate is statistically TABLE IV
Correlation Between Goiter Size and Response to Suppressive Therapy Onginal Srze of Nodules 8.0 cm” or Less *
More Than 8.0 cm2
Responders Nonresponders
21 4
20 10
Responders Nonresponders Combined Responders Nonresponders
19 6
10 24
40 10
30 34
Medrcatron and Resporrse T3
T4
* Product
579
of two diameters,
October 1974
at right angles
to each
other.
The American Journal of Medicine
significant (p cO.025). In only one fifth of the patients who responded, however, did the thyroid nodules become unmeasurable during this time period. This is consistent with our previous experience [IO], which indicated that it is unrealistic to expect the thyroid nodules to disappear during a few months of suppressive therapy. Table II shows the results during phase II among patients whose goiters did not decrease during the first 12 weeks of suppressive therapy. One third of the patients in whom suppressive therapy was continued showed a significant shrinkage in the size of their goiter during this phase. Responses among the patients who continued to receive their original doses of thyroid hormone were just as frequent as among those whose dose was doubled. Thus, it appears that the duration of suppressive therapy is more important than the dose. Among those who did not respond to therapy, four patients showed a significant increase in goiter size. There was no difference in response to suppressive therapy, according to number and location of thyroid nodules, base line radioactive iodine uptake or base line serum hormonal iodine levels. Although the response rate was relatively poor among those who had had their goiters for more than 10 years (37 per cent), there was no consistent correlation between the duration of goiter and the response to suppressive therapy. “Cold” nodules responded somewhat less well than those which concentrated radioiodine (Table Ill); this difference was not statistically significant. All six patients with hot nodules showed more than 50 per cent suppression of radioiodine uptake during the study period. Patients with small goiters responded more frequently than those with large ones (Table IV). In pa-
Volume 57
SUPPRESSIVE THERAPY OF NONTOXIC GOITER-SHIMAOKA,
TABLE V
T4 by Column Determinations in Patients Receiving Suppressive Therapy
Medicationand Response
SerumHormonalIodine &g/100 BaseLine
PhaseI
TABLE VI
ml)
PhaseI I
Responders Nonresponders Combined
5.28i.0.27 5.88zt: 0.53 5.44&.0.25
2.91zt0.19 3.321 0.33 3.02AzO.17
2.21+0.14 2.78f 0.25 2.36+ 0.13
~~_~ T3 Responders Nonresponders Combined 14 Responders Nonresponders Combined -__ __ _.
Responders Nonresponders Combined
5.20+ 5.49A. 5.34+
7.1010.19 7.60% 0.23 7.35kO.15
7.79* 0.30 7.73i 0.21 7.761t0.19
T4
NOTE:
Values
given
0.27 0.18 0.16
are the mean
& standard
error.
NOTE:
tients with multinodular goiters in whom two or more nodules were measured, the respective cross sectional “areas” (product of two diameters, at right angles) were calculated and the sum of these was used as the size. When combined results for T3 and T4 therapy are analyzed, the patients whose goiters were smaller than 8.0 cm* responded more often than those whose goiters were larger than 8.0 cm* (p
TABLE VII
T4 By Column Determinations ~.__ ~~ ~_~
in Patients
24-Hour Radioiodine Uptake in Patients Receiving Suppressive Therapy Radioiodine Uptake (%)
Medication and Response
T3
Base Line
-... _
Valuesgiven
Phase
Phase II
I
31.1+ 26.5% 29.9 t
1.7 1.5 1.3
9.3 t 1.0 10.9 .i- 1.5 9.7 !- 0.8
27.0% 31.9+ 29.34:
2.2 2.2 1.6
6.5 l-O.7 14.9 im 1.5 10.8 t 1.0
~.
are the mean
I standard
9.3* 9.7+ 9.4xt
1.1 1.8 1.0
6.5& 0.9 11.1:+x 1.3 8.5+ 0.8 error.
tients treated with T4 (both responders and nonresponders) had a highly significant elevation in T4 by column values in phase I (p
Receiving Suppressive
Therapy
Serum Hormonal Base Line
Data
SOKAL
Iodine &g/100
Phase
ml)
I
Phase II
T3 Phase I nonresponders Same dose in phase II Double dose in phase II
5.41 ! 0.35 4.97 m!- 0.98
3.18 3.17
IZ 0.19 1: 0.46
2.86 2.27
+ 0.18 I: 0.36
Phase I nonresponders Same dose in phase II Double close in phase II
5.56 XI= 0.31 5.61-k 0.35
7.62 f 0.27 7.39 -t 0.24
7.74 8.17
!- 0.31 i_ 0.35
T4
NOTE:
Values
given
are the mean
:t standard
error.
October 1974
The American Journal of Medicine
Volume 57
579
SUPPRESSIVE THERAPY OF NONTOXIC GOITER-SHIMAOKA,
24-Hour Radioactive
TABLE VIII
SOKAL
Iodine Uptakes in Patients
Receiving Suppressive
Therapy
Radioiodine Uptake (%)
T3 Phase
28.6 i 27.0 t
1.7 2.9
10.0 f 9.8 f
1.4 2.4
30.2 f 30.8 f
3.1 3.5
13.6 f 2.3 13.3 + 2.2
12.5 f 2.1 4.8 f. 1.1
I nonresponders
Same dose in phase II Double dose in phase II NOTE: Values given are the mean *
standard
dose of T3 (p <0.025). Table IX shows the patterns
of suppression
of ra-
dioiodine uptake among responders and nonresponders. There was a significant correlation between the degree of suppression of radioiodine uptake and the decrease in goiter size (p
Correlation Between Suppression of Radioiodine Uptake and Clinical Response
Medication and Response T3 Responders Nonresponders T4 Responders Nonresponders Combined Responders Nonresponders Total
-
October 1974
Consistently 10% or more .____
Variable
12.1 f 9.0 f
2.4 1.5
error.
among the patients who took double doses. However, the only individual difference which was statistically significant was in the suppression of radioiodine uptake among the patients who received the double
580
Phase II
I nonresponders
Same dose in phase II Double dose in phase II T4 Phase
Phase I
Base Line
Data ~____~~~
Consistently below 10%
complete responses have been observed among patients who continued to receive suppressive therapy after completing phase II.) In six cases reduction of goiter size was recorded in phase I and regrowth of goiter was observed at a later date. In three of these patients, increase in nodule size was associated with softened consistency, and this was thought to be due to hemorrhage into the nodule or cystic degeneration. In two patients, regrowth of the nodule was associated with signs and symptoms highly suggestive of subacute thyroiditis. All these patients, however, showed shrinkage of their goiter again, during continued suppressive therapy. So far, 28 patients have undergone thyroidectomy (Table X). These were mostly nonresponders, but there were six responders. Two of the latter were symptomatic from their goiters; the other four had goiter of relatively short duration, were reluctant to commit themselves to a long-range program and expressed a preference for thyroidectomy. There was one case each of follicular carcinoma, subacute thyroiditis and Hashimoto’s disease. The patient with chronic thyroiditis showed a progressive increase in goiter size during 3 months of suppressive therapy. The remaining 25 patients had other benign lesions, including adenomas and nontoxic nodular goiters. Nine of these had associated cystic changes (36 per cent). In two patients an urticarial rash developed a few days after starting suppressive therapy. In both cases, the drug was T4, and the rash subsided promptly on discontinuing medication. One of these patients dropped out of the study, and the other was placed on a regimen of T3, without incident. All other patients were able to tolerate their assigned medication throughout the study period.
10 6
12 5
18 3
3 13
7 6
18 9
13 19
19 11
36 12
COMMENTS
32 (29%)
30 (27%)
48 (44%)
This study confirms therapy in reducing
The American Journal of Medicine
Volume 57
the effectiveness of suppressive the size of nontoxic goiters. Dur-
SUPPRESSIVE
TABLE X
Thyroid
Histology
Among Patients
Who Underwent
No. Patients
Cancer
THERAPY OF NONTOXIC GOITER-SHIMAOKA.
SOKAL
Thyroidectomy Iksociated
Medication
and Response
Thyroidltis
Other Lesions
Cystic
Changes
.
.--. _~_.. -.___ l
Responders T3 T4 Nonresponders T3 T4 Total _.-.-
-
Eight adenomas
ing the first
-.
_ --...
0 0
0
4
?
1
1
1
10 12
1 0
0 1
9 11
4 2
1
2
25*
9
- -____. ~. _._
28
..~. ~~__~______
and 17 “nontoxic
12 weeks
4 2
of therapy
nodular
_~~~~
goiters.”
54 (47 per cent) of
114 patients responded; after an additional 16 weeks of therapy 15 more responded, for a total of 69 patients (61 per cent) with a significant decrease in goiter size. In other reported studies also, patients who received longer treatment [2,3,7] appeared to do better than those who were treated for shorter periods [4,5]. It is clear that thyroid nodules cannot be expected to disappear during a brief trial of suppressive therapy; we saw only one complete response during the first 12 weeks. Our study indicates that suppressive therapy is more effective in shrinking smaller goiters than larger ones (Table IV), but this was principally due to resistance of the latter to T4 administration. Other investigators have stated that large diffuse goiters often fail to respond, but that this is not so in the case of nodular goiter [ 2,131. T3 therapy was significantly more effective than T4 therapy in inducing goiter regression in this study (p <0.025). The two thyroid hormones differ considerably in their metabolic behavior. Also, T3 is almost completely absorbed from the intestine whereas only one half of T4 is absorbed [ 181. We do not think that this would account for the difference in their effectiveness in this study. The initial doses arbitrarily chosen were 50 pglday for T3 and 200 yglday for T4. This dose difference is enough to compensate for the differences in molecular weight and absorption. Furthermore, randomization of the nonresponders during phase I was designed to examine the possibility of a dose-dependent response. During phase II, the decrease in goiter size among those who did not respond during phase I showed no correlation with the dose (TabI, II). As already stated, these results indicate that duration of treatment is more important than the dose of thyroid hormone; however, the kind of thyroid hormone administered may be important. Some of the differences between the action of T3 and T4 recorded in this study were quite unexpected. For example, T4 was considerably less effective in
October
patien?s with larger goiters than II; patients with smaller ones, whereas the response to T3 appeared to be virtually independent of goiter size (Table IV). Also, response to T4 clearly correlated with major suppression of thyroidal radioiodine uptake, whereas this seemed to be significantly less important for the action of T3 (Tables V and VI). These findings suggest a qualitative difference between the action of the two hormones. In addition, there appears to be a difference among patients in the action of T4. Responders and nonresponders to this agent had similar serum T4 levels (Table V) but widely divergent radioiodine uptakes (Table VI). Suppression of radioiodine uptake was greater in the responders to T4 than in the responders to T3 (Table VI). The nonresponders who received the double dose of T4 during phase II, and who had the highest serum T4 levels of any group in this study, showed less suppression of radioiodine uptake than the responders who received the lower dose, but this was not statistically significant. These differences cannot be due to failure to take medication or to impaired absorption of T4, since these would be reflected in lower serum T4 values. Others [2,13] have also commented on the poorer suppression of radioiodine uptake among nonresponders to desiccated thyroid. Such inconsistencies were not encountered among patients receiving T3. Responders and nonresponders who received the same dose of this drug had similar radioiodine uptake values (Table VI), and doubling the dose resulted in a substantial further decrease in radioiodine uptake. Circulating TSH levels of patients with nontoxic goiter are well within the normal range in the absence of severe iodine deficiency [ 19-2 11. TSH response to TRH administration is similar among normal subjects and patients with nontoxic goiter [ 221. However, TSH is believed to play an important role in the genesis and growth of such goiters [ 14,21,231. Administration of exogenous thyroid hormone can block TSH production and suppress its secretion
1974
The American
Journal of Medicine
Volume 57
581
SUPPRESSIVE THERAPY OF NONTOXIC GOITER-SHIMAOKA,
SOKAL
[ 24-271. There appear to be selective localization of T4 and T3, and active monodeiodination of T4 to T3 in the pituitary gland [ 28-3 11. Furthermore, the demonstration of specific T3-binding sites and the failure to find such binding sites for T4 in the pituitary of the rat are very interesting [32]. Various investigators have shown that significant conversion of T4 to T3 at the periphery takes place both in experimental animals and in man [33-381. It is tempting to speculate that conversion of T4 to T3 is somewhat impaired in some patients with nontoxic goiter. This would explain the difference in response to the two thyroid hormones. However, no evidence is presently available on this point. Our data provide indirect evidence that there might be some difference in TSH suppression by T4 among different patients (Table VI). However, even the nonresponders had substantial sup-
pression of radioiodine uptake. It is also possible that T3 or T4 might act directly on the goiter itself. However, this appears unlikely in the light of our current concepts of thyroid-pituitary relationships and the genesis of nontoxic goiter. Since T3 appears to be more uniformly effective in suppressing TSH secretion than T4, as is suggested by our data, it should be the agent of choice for suppressive therapy. ACKNOWLEDGMENT We gratefully acknowledge assistance given to this study by Drs. T. Chang, E. Ezdinli, H. Feliciano, P. Friedman, D. Holyoke, H. Karna, G. Koepf, F. Marchetta, J. Park, M. Razack, K. Sako, N. Silva, B. Thumasathit and S. Young.
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10.
11
12. 13.
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