Quantitative thyroglobulin response to radioactive iodine treatment in predicting radioactive iodine-refractory thyroid cancer with pulmonary metastasis
Quantitative thyroglobulin response to radioactive iodine treatment in predicting radioactive iodine-refractory thyroid cancer with pulmonary metastasis
Chen Wang 0
Xin Zhang 0
Hui Li 0
Yansong Lin 0
☯ These authors contributed equally to this work.
Abhijit De, Advanced Centre for Treatment
Research and Education in Cancer, INDIA
0 Department of Nuclear Medicine, Peking Union Medical College Hospital , Beijing , China , 2 Department of Nuclear Medicine, Zhejiang Cancer Hospital , Hangzhou, Zhejiang , China
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
Funding: This work was supported by National
Natural Science Foundation of China (Grant No
81571714). The funders had no role in study
design, data collection and analysis, decision to
publish, or preparation of the manuscript.
Competing interests: The authors have declared
that no competing interests exist.
Current diagnosis of radioactive iodine (RAI)-refractory (RAIR) differentiated thyroid cancer
(DTC) is based on the imaging technique, which is of a high cost. Serum thyroglobulin (Tg)
is a sensitive and easily obtained biomarker. Hence, we aimed to assess the predicting
value of quantitative response of Tg in earlier identifying the RAIR-DTC with pulmonary
Patients and methods
Pulmonary metastatic DTC patients who underwent total or near-total thyroidectomy and at
least two times of RAI therapy were included in this study. The pre-ablative stimulated Tg at
the first and second RAI therapy were defined as pstim-Tg1 and pstim-Tg2, while the
suppressed Tg before and after the second RAI therapy were designated sup-Tg1 and
Tg2. The predicted value of pstim-Tg2/Tg1 and sup-Tg2/Tg1 ratio were detected using the receiver operating characteristic (ROC) curve and logistic regression analyses.
Totally 115 patients were involved in this study. ROC curves showed a cut-off value of 0.544
for pstim-Tg2/ pstim-Tg1 in detecting RAIR, with a sensitivity of 0.9 and specificity of 0.477,
and an area under the curve (AUC) of 0.744. Similarly, the cut-off of sup-Tg2/ sup-Tg1 was
0.972, with a sensitivity of 0.733 and specificity of 0.935, and AUC of 0.898. Univariate
analysis illustrated that age, tumor size, pstim-Tg2/Tg1, sup-Tg2/ sup-Tg1 and BRAFV600E
mutation were eligible to predict RAIR. While from multivariate analysis, only age,
Tg2/Tg1, sup-Tg2/ sup-Tg1 and BRAFV600E mutation were verified to be the independent
The quantitative Tg response was encouraging in identifying RAIR-DTC with pulmonary
metastasis. Age, BRAFV600E mutation and Tg response were independent predictors in
These years, with a rapidly rising incidence, thyroid cancer has gained globlal concern.
Differentiated thyroid carcinoma (DTC) originates from aberrant follicular cells, accounting for
nearly 95% of all thyroid tumors [
]. In general, most DTCs can achieve peculiarly good
prognosis under surgery, radioactive iodine (RAI) and thyroxine therapy [
]. Unfortunately, up to
10% of DTC patients develop distant metastases, the most frequent cause of cancer-related
death, and 30% of whom become radioiodine-refractory DTC (RAIR-DTC) [
]. With a
10-year survival rate less than 10%, RAIR-DTC has received wide attention [
]. RAI therapy
is an effective way for DTC patients with metastasis. However, patients would benefit little
from RAI therapy if they do not respond or become refractory to 131I. Hence, recognizing the
RAIR-DTC in time is imperative for such patients, with an aim to avoid unnecessary RAI
therapy and gain more time to the effective treating regimen like tyrosine kinase inhibitor. Till
now, 18F-fluorodeoxyglucose positron emission tomography / computed tomography
(18FDG-PET/CT) is the only recommendation for identifying RAIR-DTC in guidelines, in
combination with whole body scan (WBS), CT after multiple RAI therapy and serum
thyroglobulin (Tg) [
]. Though convincing, these methods sometimes may be high-cost and
timeconsuming to prevent those patients from the unbenefited RAI treatment. As a sensitive
biomarker, Tg tests are indispensable for DTC patients, due to the usefulness during the
followup as well as in predicting distant metastasis [
]. Our previous studies have demonstrated
the impressing value of Tg in decision-making and prognosis estimation [
of Tg after RAI implies the potential benefit from the therapy, while the increasing or
stabilizing of Tg reflects the unsatisfied efficacy, which may be latent to be RAIR-DTC [
]. In 2015
American Thyroid Association (ATA) guideline on the management of thyroid nodule and
thyroid cancer, the change of Tg to therapy has been adopted as one of the essential parts in
response to therapy system[
], while little study has focused on predictive performance of
quantitative Tg response in RAIR-DTC so far. Easily obtained and low-cost, as well as a
routine test during the follow-up, is it feasible to use Tg response alone to forecast RAIR as early
as just after the second RAI therapy?
In this research, we aim to assess the predictive value of Tg response in identifying RAIR in
DTC patients with pulmonary metastasis.
This study was deemed to be exempt from the requirement for review by the ethics committee
of Peking Union Medical College Hospital. Informed consent was obtained from all individual
participants included in the study. All procedures performed in studies involving human
participants were in accordance with the ethical standards of the Peking Union Medical College
Hospital and with the 1964 Helsinki declaration and its later amendments or comparable
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This was a retrospective analysis for including DTC patients who underwent total or near-total
thyroidectomy and RAI therapy at our hospital from Jan. 2008 to Dec. 2015. Inclusion criteria
were as follows: (1) aged 18 years or older, (2) underwent total or near-total thyroidectomy of
DTC, (3) present of pulmonary metastasis, (4) underwent at least two times of RAI therapy,
(5) data were eligible for analysis, (6) negative thyroglobulin antibody (TgAb). Patients would
be defined as pulmonary metastasis with any of the following: (1) pulmonary metastatic lesions
confirmed by pathology, (2) focal or diffuse uptake in pulmonary metastatic lesions on whole
body scan (WBS) after excluding the contamination and physiological RAI uptake, with or
without positive findings on other complementary imaging modalities (chest CT, x-rays, MRI,
bone scintigraphy or 18F-FDG PET/CT) or elevated Tg levels; (3) positive findings on
18F-FDG PET/CT after excluding other malignancies and benign diseases, with a rising Tg
level, despite of the negative WBS results; (4) negative findings on functional imaging, but
structural lesions suggested by other imaging instruments with a rising Tg level after excluding
other malignancies and benign diseases.
Postoperative RAI therapy and follow-up strategy
A serum thyroid stimulating hormone (TSH) more than 30 mU/L was achieved by thyroid
hormone withdrawal (THW) before RAI therapy. All patients were instructed with a low iodine
diet from the beginning of THW to 3 weeks after RAI therapy. Patients were administrated with
a radioactive iodine dose of 3.7±7.4GBq (100-200mCi) according to the physicians. The second
RAI therapy was usually performed after 6 to 12 months after first therapy. A serum stimulated
or suppressed thyroglobulin, TSH, thyroglobulin antibody (TgAb) were usually followed 1 day
before and 2±3 months after RAI therapy. Stimulated Tg was defined as Tg measured after
THW or rhTSH with TSH level >30 mU/L. Post-therapeutic whole-body scan (Rx-WBS) was
performed 5±7 days after RAI therapy. High resolution computed tomography (CT) without
contrast was carried out according to the patients`situation. All patients were under TSH
suppressive therapy by using sodium levothyroxine with TSH < 0.1 μIU/mL. The presence of RAIR
was defined as the end-point event, and the non-RAIR duration (survival time) was defined as
the time period from the initial diagnosis of thyroid cancer to the end-point event occurrence.
Measurement of Tg, TgAb and TSH
Tg and TgAb levels were determined by electrochemiluminescence immunoassay (provide by
Roche Diagnostics GmbH, Mannheim, Germany) with a functional sensitivity of 0.100 ng/mL
and 10 IU/mL, respectively. TSH was determined by chemiluminescence immunoassay
(provided by Siemens Healthcare Diagnostics Inc, New York, New York, USA), with a measuring
range from 0.004 to 150 μIU/mL. TgAb values >100 IU/mL were considered positive. WBS
was obtained in the anterior and posterior projections using dual-head gamma cameras
(Infinia Hawkeye; GE, Fairfield, Connecticut, USA) equipped with high-energy parallel-hole
collimators, and a 20% energy window was centered at 364 keV, at a table speed of 20 cm/min for a
total time of 15 min (256×1024 matrix).
Radioactive iodine-refractory and radioactive iodine-avid assessment
Till the last time of follow-up, RAIR-DTC was defined if the patient meets either of the
followings: (1) patients with distant metastatic disease that does not take up radioactive iodine
according to the 131I-WBS, (2) had one measurable lesion that had progressed within the past
12 months even it could uptake radioiodine (3) received cumulative activity of 131I over 600
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mCi. Pulmonary metastases were divided into 131I-avid and non-131I-avid according to the
results of 131I-WBS.
Tg assessment profile
A series of Tg were available during the therapy and follow-up. In this research, we conducted
the quantitative analysis of stimulated Tg and suppressed Tg, respectively. The stimulated Tg
and TSH at the day of first (pstim-Tg1, TSH1) and second (pstim-Tg2, TSH2) time of RAI
therapy, and the suppressed Tg at 1 to 3 months before (sup-Tg1) and 3 months after
(supTg2) the second RAI therapy were further analyzed to detect the prediction value.
BRAFV600E mutation analysis
Genomic DNA was extracted from four 5μm-thick slices of formalin-fixed paraffin-embedded
primary tumor samples, using a commercial DNA extraction kit (GeneRead DNA
formalinfixed paraffin-embedded kit, Qiagen, Catalog No. 180134, Germany). Exon 15 of the BRAF
gene containing the site for the T1799A (V600E) mutation was PCR amplified using primers
5’-TGCTTGCTCTGATAGGAAAATG-3’ (sense) and 5’-AGCCTCAATTCTTACCATCCA-3’
(antisense). PCR protocol comprised an initial denaturation of 3 min at 95ÊC, 40 amplification
cycles (denaturation for 30 s at 95ÊC, annealing for 30 s at 60ÊC and extension for 30 s at 72ÊC)
and final extension for 10 min at 72ÊC. After quality confirmation by agarose gel
electrophoresis, the PCR products were subjected to Sanger sequencing performed using an ABI Prism
3730 DNA Analyzer (Applied Biosystems, Villebon sur Yvette, France).
For univariate analysis, the Mann-Whitney test was used for quantitative and qualitative
variables. The Chi-square test and Fisher exact test were used to compare the categorical data.
Logistic regression was used in multivariate analysis. A P value less than 0.05 was considered
significant. Receiver operating characteristic (ROC) curve analysis was used to determine the
cut-off level of Tg for predicting the radioactive iodine-refractory. Time to RAIR duration
analyses was estimated using the Kaplan-Meier method. The log-rank test was used for
comparisons between groups. The multiple Cox model was used to calculate the hazard ratio (HR)
between groups. Statistical analysis was carried out using SPSS (version 19.0; SPSS Inc,
Chicago, Illinois, USA) and Prism 6 (GraphPad Software, San Diego, CA, USA).
Characteristics of the patients
A total of 115 patients were involved in this study for further analysis, 4 of whom were
follicular thyroid carcinoma (FTC), 111 of papillary thyroid carcinoma (PTC). The mean age of the
involved patients was 43.04 years at the time the first RAI therapy. The ratio of female to male
was 2.1:1. The mean follow-up time was 55.17±22.77 months. The mean pre-ablative TSH
level was 81.6 and 91.0 μIU/mL at the first and the second RAI therapy, respectively. A total of
50 patients were considered to be RAIR (S1 File), among which, 41 were of non-131I-avid WBS
after the successful thyroid-ablation, 3 of accumulated RAI dose more than 600 mCi, and 6 of
progression disease after high-dose RAI therapy within 12 months. Most patients (92/115)
were American Joint Committee on Cancer (AJCC) stage T3 or T4. All 115 patients were all
eligible for further stimulated Tg analysis. Besides, 76 patients were available for suppressed Tg
analysis. Totally 71 patients meet all the parameters were involved in the logistic regression
analysis. The details of the included patients were shown in Table 1.
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Tg level in RAIR and non-RAIR patients
The Tg level presented disparity between non-RAIR and RAIR group.The mean pstim-Tg1
level in non-RAIR and RAIR group was 346.1±44.71 and 362.3±49.37, respectively(P = 0.56).
And mean pstim-Tg2 level of 258.2±42.3 and 415.7±54.18, respectively (P = 0.003).
Furthermore, the mean sup-Tg1 was 70.74±25.59 and 118.8±48.66 in non-RAIR and RAIR group,
respectively (P = 0.056). While the mean sup-Tg2 was 33.18±10.65 and 88.76±29.24,
respectively (P<0.001) (Fig 1). Totally 12.3% (8/65) patients presented increasing pstim-Tg level
after the first RAI therapy in non-RAIR group, compared to 30% (15/50) in RAIR group.
Similarly, only 2.2% (1/46) cases showed increasing sup-Tg after the second RAI therapy in
nonRAIR group, and 63.3% (19/30) in RAIR group.
ROC curve analysis and diagnostic performances
We further used ROC curve to detect diagnostic performances and the cut-off value of Tg2/
Tg1 in predicting the RAIR. ROC curves showed a fairly good performance of quantitative Tg
in detecting RAIR. For stimulated Tg (pstim-Tg), a cut-off value of pstim-Tg2/ pstim-Tg1 at
0.544 was achieved in detecting patients with RAIR, with a sensitivity of 0.9 and specificity of
0.477, and an area under the curve (AUC) of 0.747. To minimize the influence of TSH,
(pstimTg2/TSH2)/(pstim-Tg1/TSH1) was also performed in the analyses. A cut-off value of
(pstimTg2/TSH2)/(pstim-Tg1/TSH1) at 0.564 was attained with sensitivity of 0.84, specificity of
0.477, and AUC of 0.734, respectively (Fig 2), indicating a non-superior value of pstim-Tg/
TSH than pstim-Tg alone. Then, only pstim-Tg was used for further analysis. Moreover,
suppressed Tg showed a higher specificity. Regarding suppressed Tg, a cut-off value of sup-Tg2/
sup-Tg1 at 0.972 was obtained, with a sensitivity of 0.733 and specificity of 0.935, and AUC of
0.898, respectively (Fig 3). The higher Tg2/Tg1 ratio above the cut-off value, the more likely to
be RAIR-DTC. Combined test represented a sensitivity of 0.9 and specificity of 0.609 in
parallel, and 0.733 and 0.935 in series, respectively, which showed no improvement.
Influence factors and logistic regression analyses
Factors including gender (male or female), age ( 45 years or <45 years), tumor size, tumor
type (unifocality or multifocality), extra-thyroidal extension, AJCC T stage, N stage,
pstimTg2/pstim-Tg1 ( 0.544 or <0.544), sTg2/sTg1 ( 0.972 or <0.972) and BRAFV600E mutation,
were analyzed using the univariate and multivariate logistic regression. In univariate logistic
regression analyses, the age (odds ratio (OR): 3.65, 95% confidence interval (CI): 1.349±9.876,
P = 0.011), tumor size (OR:1.439, 95%CI: 1.042±1.988, P = 0.027), pstim-Tg2/pstim-Tg1 (OR:
12.745, 95%CI: 3.322±48.897, P<0.001), sup-Tg2/sup-Tg1 (OR: 34.125, 95%CI: 8.174±
142.458, P<0.001)) and BRAFV600E mutation (OR: 4.091, 95%CI: 1.497±11.18, P = 0.006) were
eligible to predict the RAIR. In multivariate logistic regression analyses, only the age (OR:
10.484, 95%CI: 1.009±108.942, P = 0.049), pstim-Tg2/pstim-Tg1 (OR: 10.829, 95%CI: 1.098±
106.789, P = 0.041), sTg2/sTg1 (OR: 54.232, 95%CI: 3.614±813.853, P = 0.004) and BRAFV600E
mutation (OR: 10.887, 95%CI: 1.483±79.923, P = 0.019) were verified to be the independent
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Fig 1. The relevant Tg level of radioactive iodine-refractory (RAIR) and non-RAIR group. A, B: pstim-Tg level at the first and
second RAI therapy; C, D: sup-Tg level before and after the second RAI therapy.
predictive factors in detecting RAIR (Table 2). In summary, the age, tumor size, pstim-Tg2/
pstim-Tg1, sup-Tg2/sup-Tg1, and BRAFV600E mutation could predict the RAIR. Meanwhile,
only the age, pstim-Tg2/pstim-Tg1, sup-Tg2/sup-Tg1, and BRAFV600E mutation were
identified as independent predictive factors in detecting RAIR. This showed the peculiarly important
value of quantitative Tg from a different angle.
Non-RAIR duration according to the Tg2/Tg1 ratio
To further evaluate the merits of quantitative Tg in evaluating the long-term prognosis, a time
to RAIR analysis was performed. Patients with positive Tg2/Tg1 were more likely refractory to
RAI therapy. In this section, the presence of RAIR was defined as the end-point event, and the
survival time (non-RAIR duration) was defined as the time period from the initial diagnosis of
thyroid cancer to the end-point event occurrence. Patients were divided into two groups
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Fig 2. Receiver operating characteristic (ROC) curves of pstim-Tg2/pstim-Tg1 for detecting the radioactive iodine refractory.
Area under the ROC curve (AUC): 0.747(95%CI: 0.658±0.836), cut-off value: 0.544, sensitivity: 0.9, specificity: 0.477, negative predict
value: 0.861, positive predict value: 0.570.
according to the pstim-Tg2/pstim-Tg1 0.544 (Fig 4) and sup-Tg2/sup-Tg1 0.972 (Fig 5).
The Tg2/Tg1 ratio greater than the cut-off value (0.544 and 0.972, respectively)was deemed as
positive, the opposite as negative. The medium non-RAIR survival was 20.1 months for
pstimTg positive group and 42.6 months for negative group (P<0.001) with a hazard ratio (HR) of
5.390 (95% CI 2.137±13.594, P<0.001) (Fig 4). The medium non-RAIR duration was 8.2
months for sup-Tg positive group and 39.9 months for negative (P<0.001), with HR of 9.531
(95%CI 4.184±21.709, P<0.001) (Fig 5).
RAI is the mainstay for the management of distant metastatic DTC, especially for patients with
pulmonary metastasis, while its efficacy peculiarly depends on the ability of radioiodine uptake
in their metastatic lesions. The non-avidity in these lesions usually indicates more tendency of
RAIR and less favorable outcome. Owing to the low survival rate, many researchers focused on
the RAIR-DTC these years and gained impressive achievements [
]. The diagnosis
and treatments of RAIR-DTC have been hotspots worldwide [
]. Till now, the diagnosis of
RAIR-DTC mainly relies on WBS and trend of Tg after multiple times of RAI therapy,
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Fig 3. Receiver operating characteristic (ROC) curves of sup-Tg2/sup-Tg1 for detecting the radioactive iodine refractory. Area
under the ROC curve (AUC): 0.898(95%CI: 0.823±0.974), cut-off value: 0.972, sensitivity: 0.733, specificity: 0.935, negative predict
value: 0.843, positive predict value: 0.88.
combining with the findings of CT, 18FDG-PET/CT, which is high-cost and time-consuming.
As the increasing risk of adverse effect from repeated high-dose RAI and limited benefit from
RAI, predictive markers regarding an earlier identification of RAIR and timely preventing
such patients from unnecessary RAI therapy are highly desired. It may not only reduce the risk
of progression during the thyroid hormone withdraw (THW) in some countries like China,
but also gains more time for other effective therapy.
Tg, as a specific biomarker produced by the thyroid tissue and DTC lesions, has been
reported to be both sensitive and convenient means in the surveillance of patients with DTC
during follow-up. Furthermore, it has been confirmed as a predictor of distant metastasis,
recurrence, and prognosis [
]. Due to easily obtained and low-cost, Tg has been
advocated during the RAI therapy and follow-up [
]. Song et al. reported the decreasing Tg from
683 to 311 ng/mL after the RAI therapy in 131I-avid patients [
], suggesting the connection
between the efficacy of RAI therapy and the variation of Tg level. In the 2015 ATA guideline,
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Abbreviations: ps-Tg: pre-ablative stimulated thyroglobulin at the first (pstim-Tg1) or second (pstim-Tg2) radioactive iodine (RAI) therapy, sup-Tg:
suppressed Tg before (sup-Tg1) or after (sup-Tg2) the second RAI therapy.
the Tg plays a great part in the response system predicting the clinical outcome. However, little
has been reported on the relationship between the quantitative Tg analysis and RAIR-DTC.
Hence, in this research, we tend to use quantitative Tg, a handy biomarker, to early and easily
detect the occurrence of RAIR.
In our research, the Tg level presented its significance in two aspects. Firstly, as the Fig 1
showed, the Tg level and trend were fairly different between the RAIR and non-RAIR DTC
group. This might shed light on the aggressive tumor burden reflected by the persistent high
Tg level being the pejorative factor. If the Tg level does not decrease appreciably after RAI
therapy, the patients may benefit little. Owing to reflecting the tumor burden [
], our results
suggested that the change of Tg reflected by quantitative Tg would give evidence to the tumor
response to the RAI therapy. Secondly, the response of Tg might be a good indicator in
predicting the RAIR-DTC. The pstim-Tg response showed a higher sensitivity than sup-Tg (0.9
VS 0.733), whereas, the sup-Tg response possessed a higher specificity than pstim-Tg (0.935
VS 0.477). This is consistent with the higher sensitivity of pstim-Tg as previous studies
]. Though limited by specificity, pstim-Tg seems to be an easy tool to screen the
RAIR-DTC. We also attempted to use pstim-Tg/TSH to minimize the effect of TSH level,
nevertheless, the pstim-Tg showed non-inferior diagnostic performance to pstim-Tg/TSH. So for
the practicability of clinical use, we only take pstim-Tg for further analysis. On the other hand,
the sup-Tg, considering its high specificity, is a wonderful biomarker in determining the
RAIR-DTC. Consequently, we explored the predicting value of quantitative Tg response in
refractory to RAI.
Furthermore, in the univariate and multivariate analysis, the age, Tg response and
BRAFV600E mutation were correlated to the resistance to RAI therapy. According to the AJCC
TNM Stage [
], the age older than 45 was relevant to the higher death risk. Here comes to a
deduction that older age presents a greater possibility to RAIR, resulting in an increased risk of
mortality. In our study, BRAFV600E mutation was also detected in the primary focus. It is well
known that the BRAFV600E mutation is related to the recurrence and poor prognosis
]. Furthermore, our previous study demonstrated that the BRAFV600E mutation was
correlated to the non-131I-avid of DTC lesions in distant metastasis [
]. Our research comes
to a similar conclusion that the BRAFV600E mutation was a predictor to RAIR. In the RAIR
duration analysis, the non-RAIR durations were significantly different between the positive
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Fig 4. The non-radioactive iodine-refractory (RAIR) duration between groups by classification of pre-ablative stimulated Tg
(pstim-Tg). The positive was defined as pstim-Tg2/pstim-Tg1 0.544, the opposite negative.
and negative groups (Fig 3). This may suggest the efficacy of Tg2/Tg1 level in predicting the
occurrence of RAIR on the other side. Patient with higher Tg2/Tg1 ratio than the cut-off values
will have a greater risk to be refractory to the RAI with HRs of 5.390 and 9.531 in pstim-Tg
and sup-Tg, respectively. Furthermore, less non-RAIR durations may also be revealed by the
Tg response, which needs more caution.
To our knowledge, though retrospective, our study might be the first and largest work in
exploring the prognosis value of quantitative Tg in RAIR. Further work with larger samples
and more factors is in the process.
In conclusion, our study indicated the predicting value of quantitative Tg response in early
detecting the refractory to RAI in DTC patients with pulmonary metastasis. Both quantitative
pstim-Tg and sup-Tg responses were useful in forecasting the performance of RAIR-DTC.
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Fig 5. The non- radioactive iodine-refractory (RAIR) duration between groups by classification of suppressed Tg (sup-Tg). The
positive was defined as sup-Tg2/sup-Tg1 0.972, the opposite negative.
Age, BRAFV600E mutation, and quantitative Tg response were independent predictors in
S1 File. The supporting data is the originally data of included patients in our study. In the
RAIR row, 0 refers to the patients with non-radioactive iodine-refractory thyroid cancer; while
1 refers to radioactive iodine-refractory thyroid cancer. In the stimu-Tg2/Tg1 and sup-Tg2/
Tg1 rows, the values refer to the Tg2/Tg1 ratio.
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Conceptualization: Chen Wang, Yansong Lin.
Data curation: Chen Wang, Xin Zhang.
Formal analysis: Chen Wang, Xin Zhang.
Funding acquisition: Yansong Lin.
Methodology: Xin Zhang, Hui Li, Xin Li.
Project administration: Hui Li, Xin Li.
Resources: Chen Wang, Xin Li.
Software: Hui Li, Xin Li.
Supervision: Xin Li.
Validation: Xin Zhang, Hui Li.
Visualization: Chen Wang, Hui Li.
Writing ± original draft: Chen Wang, Xin Zhang.
Writing ± review & editing: Chen Wang, Yansong Lin.
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