Predictive factor analysis and scoring system for radioiodine-refractory differentiated thyroid cancer: a retrospective study.

DOI: https://doi.org/10.21203/rs.3.rs-1413588/v1

Abstract

Background

The incidence of thyroid cancer has been rising worldwide. Differentiated thyroid carcinoma (DTC) originates from abnormal follicular cells and accounts for about 90–95% of thyroid malignancies. The diagnosis of radioiodine-refractory DTC (RR-DTC) is based on clinical evolution and iodine-intake characteristics rather than pathological characteristics, so it takes a long time to become apparent, and the definition of RR-DTC covers multiple aspects. The purpose of this study was to analyze the clinical and molecular imaging characteristics of patients with RR-DTC and identify independent predictors to develop an RR-DTC scoring system. We reviewed data on 404 patients with metastatic DTC who underwent both radioactive iodine therapy scanning and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography. Data on the clinical features and molecular characteristics of RR-DTC and non-RR-DTC were obtained from the medical records. We screened for predictors using univariate analyses, obtained independent predictors through multivariate analyses, then established a scoring system for predicting RR-DTC according to the corresponding odds ratio (OR) values.

Results

Diagnosis at age ≥ 48 years (OR, 1.037; 95% confidence interval [CI], 1.007–1.069), recurrence between the operation and iodine-131 treatment (OR, 7.362; 95% CI, 2.388–22.698), uptake of 18F-FDG (OR, 39.534; 95% CI, 18.590–84.076), and the site of metastasis (OR, 4.365; 95% CI, 1.593–11.965) were highly independently associated with RR-DTC. We established a scoring system for predicting RR-DTC, showing that the area under the receiver operating characteristic curve (AUC) with a cut-off value of 10 points (AUC = 0.898) had a higher discernibility than any other single independent predictor.

Conclusions

This study demonstrated that a predictive model based on four factors has a good ability to predict RR-DTC. An index score ≥ 10 was found to be the optimal index point for predicting RR-DTC. This model may help to establish an active surveillance or appropriate treatment strategy for cases of RR-DTC.

Background

The incidence of thyroid cancer has been rising worldwide. According to Surveillance and Epidemiology and End Results data, there are going to be 44,280 new cases and 2,200 deaths from thyroid cancer in 2021. Differentiated thyroid carcinoma (DTC) originates from abnormal follicular cells and accounts for about 90–95% of thyroid malignancies [1]. Multimodal treatment including surgery, selective radioactive iodine (RAI) therapy, and thyroid stimulating hormone (TSH) suppression therapy can achieve good outcomes with excellent 10-year overall survival exceeding 90% and lead to survival times of more than 40 years [2, 3]. Unfortunately, the rates of local recurrence and distant metastasis are 30% and 10%, respectively [4]. There are multiple treatments, such as surgery and RAI therapy for these patients [5]. RAI therapy is an effective treatment for DTC patients with metastasis. With this treatments, only one-third of patients achieve a complete response; the remaining two-thirds of patients will be classified as having radioiodine-refractory differentiated thyroid cancer (RR-DTC), and their overall prognosis is poor [6–8] with a median overall survival of 2.5–3.5 years [9]. The diagnosis of RR-DTC is based on clinical evolution and iodine-intake characteristics rather than pathological characteristics, so it takes a long time to become apparent, and the definition of RR-DTC covers multiple aspects. Therefore, early identification of RR-DTC is important to optimize treatment strategies during long-term follow-up [10]. Early identification of malignant/metastatic tissue with non-radioiodine avidity can avoid unnecessary radioiodine therapy. RR-DTC cases with concentrated RAI can be managed with multiple therapeutic options including local and systemic therapy.

Most studies of RR-DTC are conducted on the prognostic factors of DTC at the time of initial diagnosis, including the patient’s age, sex, tumor characteristics, extrathyroidal spread, and clinical staging [11]. There are few predictive factor models, particularly for RR-DTC. The prediction of RAI-related factors not only helps to understand the natural course of RR-DTC, but also helps to optimize patient management. Li et al. [12] studied a multivariate prediction model for postoperative RR-DTC, but the factors in the study were limited and did not include predictions at the molecular imaging level. In recent years, the roles of nuclear medicine and molecular imaging methods have attracted widespread attention in the determination of RR-DTC.

Methods

This study aimed to analyze the clinical and molecular imaging characteristics of RR-DTC patients and to identify independent predictors, to establish an effective multivariable prediction model for RR-DTC.

Patients and data collection

Following study approval by the Ethics Review Board of Shanxi Bethune Hospital (approval number: YXLL-KY-2021-005), we reviewed clinical records to identify 404 postoperative DTC patients who had metastatic lesions which were detected on various imaging examinations including cervical ultrasound, roentgenography, computed tomography (CT), and magnetic resonance imaging and had undergone both RAI therapy and 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG PET/CT) scans between January 2014 and January 2021. The Ethics Committee waived the requirement for informed consent due to the retrospective study design. The patients had been referred for at least two courses of RAI after total or near-total thyroidectomy. Patients met the requirements for inclusion in the study when the time interval between baseline 18F-FDG PET/CT and the initiation of treatment was less than one week. The end-point event was defined as the presence of RR-DTC or non-RR-DTC. The Discovery Elite (General Electric Healthcare, Boston, MA, USA) was used for PET/CT examination and the Discovery 670 Elite (General Electric Healthcare, Boston, MA, USA) was used for whole body iodine imaging examination. RR-DTC was diagnosed when patients had the following conditions according to the 2015 guidelines of the American Thyroid Association (ATA) [2, 7]: “(i) the foci never concentrate RAI; (ii) despite previous evidence of RAI concentration, the foci lose the ability to be RAI-avid; (iii) despite the significant concentration of RAI, concentration is presented in some foci but not in others; or (iv) metastasis progression within one year after RAI therapy.” In addition, “patients receiving RAI doses of more than 600 mCi may be considered to have RR-DTC based on the benefits (longer progression-free survival and overall survival) and risks (higher incidence of adverse effects)” [7, 8]. Follow-up ranged between 6 and 90 months (median, 20 months), and to date, no patient in the cohort has died of thyroid carcinoma. The data on the RR-DTC and non-RR-DTC clinical features, such as sex, age, operation frequency, histological subtype, recurrence risk group, extrathyroidal extension, autoimmune thyroid disease, tumor diameter, multifocality, lymph node involvement (including numbers and proportion of lymph node metastasis in the central or lateral neck region), locally advanced disease, clinical stage, recurrence between the operation and iodine-131 treatment, the time from the first operation to the first iodine-131 treatment, the site of metastasis, and molecular characteristics such as the uptake of iodine-131 and the uptake of 18F-FDG in the first iodine-131 treatment (maximum standardized uptake values [SUVmax] ≥ 2.5 were considered positive, and values < 2.5 were considered negative), were acquired from the medical records.

Statistical analysis

The factors related to RR-DTC were screened through univariate analyses. Significant variables selected in the univariate analyses were included in multivariate logistic regression. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to determine the correlation of all potential predictors. Through multi-factor logistic regression analysis, the characteristics of independent factors were assigned different scores according to the ORs, and a scoring system was established. We evaluated the optimal cut-off values by using receiver operating characteristic (ROC) curves for predicting the presence of RR-DTC. Box and scatter plots were used to compare mean scores and show the distribution of scores. We then identified the best points with high sensitivity and low false negative rates (1-specificity). P values < 0.05 were considered statistically significant, and the analyses were performed using SPSS software (version 26.0; IBM Corp., Armonk, NY, USA).

Results

Characteristics of the patients

Between January 2014 and January 2021, of the 1,403 postoperative DTC patients treated for RAI therapy, 788 patients were diagnosed with metastatic lesions; of these, 404 patients underwent 18F-FDG PET/CT examination less than one week before or after initial iodine treatment and underwent at least two courses of radioiodine therapy. Therefore, 404 patients were enrolled in the present study. The end-point event was defined as the presence of RR-DTC or non-RR-DTC. Follow-up was performed until RR-DTC or non-RR-DTC was evident. The time to determine the presence of RR-DTC ranged from 4 months to 72 months (median, 6 months). We categorized patients into RR-DTC and non-RR-DTC groups. Of the total 404 patients (mean age = 46 ± 13 years, age range = 11–77 years, M:F = 1:2.4), 223 patients (55.2%) had confirmed RR-DTC, while 181 patients (44.8%) had non-RR-DTC. The sites of metastasis involved the lymph nodes, lung, bone, larynx, trachea, pleura, liver, kidney, adrenal gland, and bone marrow (Fig. 1).

Univariate analysis of the impact of RR-DTC

The clinical, histopathological, and tumor characteristics of the two groups are summarized and compared in Table 1. We found that the age at diagnosis, primary tumor diameter, and the time from the first operation to the first iodine-131 treatment were significantly different between the RR-DTC and non-RR-DTC groups. Therefore, we used the ROC curve to determine the optimal cut-off value to predict RR-DTC in terms of age at diagnosis, primary tumor diameter, and the time from the first operation to the first iodine-131 treatment, which were 48 (area under the curve [AUC] = 0.613), 18.5 mm (AUC = 0.591) and 16 months (AUC = 0.572), respectively (Fig. 2a–c). In univariate analysis, the following nine factors were found to significantly increase the risk of RR-DTC by comparing RR-DTC with non-RR-DTC patients: age at diagnosis ≥ 48 years (P = 0.000), operation frequency (P = 0.000), autoimmune thyroid disease (P = 0.011), primary tumor diameter > 18.5 mm (P = 0.007), clinical stage (P = 0.000), recurrence between the operation and iodine-131 treatment (P = 0.000), the time from the first operation to the first iodine-131 treatment (P = 0.001), the uptake of 18F-FDG (P = 0.000), and the site of metastasis (P = 0.000).

Table 1

Patient demographics, tumor histology, and laboratory results
 

RR-DTC

Non-RR-DTC

P

223

181

value

Sex (male/female)

70/153

50/131

0.410

Age (mean ± SD, years)

48.79 ± 13.93

43.49 ± 11.88

0.000*

≥ 48/<48

129/94

67/114

0.000*

Operation frequency (once/ two or more)

162/61

159/22

0.000*

Histological subtype (PTC/FTC/Mixed)

208/6/8

179/2/0

0.722

Recurrence risk group

(low, medium/high risk)

26/197

24/157

0.627

Extrathyroidal extension

(no/pathological/intraoperative/both)

117/39/40/27

113/28/26/14

0.203

Autoimmune thyroid disease (no/yes)

187/36

133/48

0.011*

Tumor diameter (mean ± SD, mm)

2.08 ± 1.58

1.68 ± 1.26

0.007*

≥18.5/<18.5

114/109

57/124

0.000*

Multifocality (no/yes)

95/128

79/102

0.833

Site of lymph node metastasis

(no/central/lateral neck region /both)

22/42/23/136

13/49/16/103

0.230

Numbers of lymph node metastasis (mean ± SD, number)

9.20 ± 8.16

9.02 ± 8.33

0.832

Proportion of lymph node metastasis (mean ± SD, %)

37.07 ± 0.27

40.05 ± 0.27

0.265

Locally advanced (no/yes)

190/33

164/17

0.103

Clinical stage (I/II/III/IVA/IVB)

110/63/7/0/43

135/31/10/2/3

0.000*

Recurrence between the operation and iodine-131 treatment (no/yes)

167/56

161/20

0.000*

Time from the first operation to the first iodine-131 treatment (mean ± SD, month)

25.93 ± 56.64

8.90 ± 22.66

0.001*

≥16/<16

52/171

16/165

0.000*

Site of metastasis

      

(single-site/ multi-partial metastases)

143/80

170/11

0.000*

(local/distant metastases)

133/90

155/26

0.000*

Uptake of 131I (negative/positive)

123/100

92/89

0.386

Uptake of 18F-FDG (negative/positive)

61/162

170/11

0.000*
*Statistically significant difference
RR-DTC, radioiodine-refractory differentiated thyroid carcinoma; SD, standard deviation; 18F-FDG, 18F-fluorodeoxyglucose; PTC, papillary thyroid carcinoma; FTC, follicular thyroid cancer

Independent predictors related to RR-DTC in multivariate analysis

The ORs associated with RR-DTC were determined by 9 single factors included in the logistic regression model. Of the nine variables, there were no significant differences in operation frequency (OR, 0.284; 95% CI, 0.079–1.016), autoimmune thyroid disease (OR, 0.631; 95% CI, 0.308–1.294), primary tumor diameter ≥ 18.5 mm (OR, 1.002; 95% CI, 0.788–1.274), clinical stage (OR, 0.803; 95% CI, 0.340–1.894), or the time from the first operation to the first iodine-131 treatment (OR, 1.005; 95% CI, 0.996–1.014). However, age at diagnosis ≥ 48 years (OR, 1.037; 95% CI, 1.007–1.069), recurrence between the operation and iodine-131 treatment (OR, 7.362; 95% CI, 2.388–22.698), the uptake of 18F-FDG (OR, 39.534; 95% CI, 18.590–84.076), and the site of metastasis (OR, 4.365; 95% CI, 1.593–11.965) displayed highly independent associations with RR-DTC. These results are shown in Table 2.

Table 2

Multivariate analyses of factors related to radioiodine-refractory differentiated thyroid cancer

Variable

Odds ratio

95% CI

P value

Age ≥ 48 years

1.037

1.007–1.069

0.015*

Operation frequency

0.284

0.079–1.016

0.053

Autoimmune thyroid disease

0.631

0.308–1.294

0.209

Tumor diameter ≥ 18.5 mm

1.002

0.788–1.274

0.988

Clinical stage

0.803

0.340–1.894

0.616

Recurrence between the operation and iodine-131 treatment

7.362

2.388–22.698

0.001*

Time from the first operation to the first iodine-131 treatment ≥ 16 months

1.005

0.996–1.014

0.290

Site of metastasis

4.365

1.593–11.965

0.004*

Uptake of 18F-FDG

39.534

18.590-84.076

0.000*
*Statistically significant difference.

CI, confidence interval; 18F-FDG, 18F-fluorodeoxyglucose

Scoring system for predicting RR-DTC

According to the OR values of the multivariate logistic regression, different score values were obtained for the characteristics related to RR-DTC. The evaluated cut-off points for each predictor are shown in Table 3. The sum of RR-DTC and non-RR-DTC points was calculated. The scatter diagram of the fractional distribution is shown in Fig. 3a. The number of high scores in the non-RR-DTC group decreased, and the number of high scores in the RR-DTC group increased. The average scores were significantly different: 33.96 ± 18.80 in the RR-DTC group and 3.82 ± 10.09 in the non-RR-DTC group, as shown in Fig. 3b. Finally, we used the ROC curve to determine the optimal score for predicting RR-DTC and found that 10 was the optimal score with an AUC of 0.898 (Fig. 4). Compared with other independent predictors, as shown in Table 4, the scoring system has higher predictive value, and its sensitivity, specificity, and Youden index values were 76.0%, 93.0%, and 0.69, respectively. In addition, as shown in Fig. 5, the AUC for the scoring system had a higher discernibility than any other single independent predictor.

Table 3

Scoring system for predicting the radioiodine-refractory differentiated thyroid cancer

Variable

Odds ratio

Score

Age at diagnosis (≥ 48/<48 years)

1.037

1

Recurrence between the operation and iodine-131 treatment

7.362

7

Site of metastasis

4.365

4

Uptake of 18F-FDG

39.534

40
   

Total: 52
18F-FDG, 18F-fluorodeoxyglucose

Table 4

Predictive value for the scoring system and independent risk factors

Variable

Sensitivity

(%)

Specificity (%)

Youden index

AUC

Age

58.0

63.0

0.21

0.613

Recurrence between the operation and iodine-131 treatment

41.0

89.0

0.30

0.651

Site of metastasis

36.0

94.0

0.30

0.649

Uptake of 18F-FDG

73.0

94.0

0.67

0.833

Scoring system

76.0

93.0

0.69

0.898
AUC, area under the curve; 18F-FDG, 18F-fluorodeoxyglucose

Discussion

In the present study, we used a moderately large sample size to investigate the clinical and molecular imaging characteristics of RR-DTC patients and the ability of these characteristics to predict RR-DTC, with the overall aim of establishing an effective multivariable prediction model for RR-DTC; such a model may prove valuable in further optimizing the treatment strategy in the early stages of metastatic DTC. Our study found that nine predictors were significantly related to RR-DTC based on univariate analyses. In addition, four independent predictors of RR-DTC were confirmed in multivariate logistic regression analysis: age at diagnosis ≥ 48 years, recurrence between the operation and iodine-131 treatment, the uptake of 18F-FDG, and the site of metastasis. According to the ORs, different scores were assigned to predictors that were positively correlated with RR-DTC, and we then established a 52-point scoring system. Finally, we determined that 10 was the optimal score for predicting RR-DTC, and the associated AUC was 0.898. The scoring system has higher predictive value than any other single independent predictor; its sensitivity, specificity, and Youten index were 76.0%, 93.0%, and 0.69, respectively.

There have been many studies on the prognostic factors associated with RR-DTC; however, the identification of predictors of RR-DTC rather than pure prognostic factors may be helpful in changing prognostic strategies and outcomes [13]. In a previous study, Li et al. explored RR-DTC predictors and found that certain factors were highly correlated with RR-DTC, including smoking, tumor type, extrathyroid extension, pN stage, and number and rate of lymph node metastasis [12]. However, in view of the latest advances in genetic analysis of thyroid tumors, including molecular methods, we have incorporated molecular imaging characteristics into our prediction model for RR-DTC.

In our study, 55.2% (223/404) of patients developed RR-DTC, and 28.7% (116/404) had distant metastasis, which is consistent with the literature reporting that 7–23% DTC have distant metastasis [14]. However, 77.6% (90/116) of patients with distant metastases developed RR-DTC in our study, which is higher than previous work showing 25–50% of patients with distant metastases developing RR-DTC [15]. One explanation is that our study only comprised patients with metastatic DTC who had undergone PET/CT imaging, the use of which depends on the judgment of their physician; meanwhile, patient decisions were also an important factor, which may not fully reflect the true clinical features of metastatic DTC.

Using univariate analysis, our study found age to be a predicting factor. Prior studies have shown that the adverse effect of age on prognosis gradually increases with each decade, especially after 40–45 years [16, 17]. Different studies use different cut-off values; in this study, the cut-off age was 48 years. In the Union for International Cancer Control/American Joint Committee on Cancer (UICC/AJCC) staging system, an age threshold of 45 years is one of the main criteria [13]. It is inferred from this that the older the age, the greater the possibility of RR-DTC, leading to an increased risk of death [18]. The cut-off point value of diagnostic age was changed from 45 years to 55 years in the 8th edition of the AJCC TNM staging system. Wassermann et al. showed that age ≥ 60 years old significantly affected a patient's cancer-specific survival after the detection of RR-DTC [19]. Studies have shown that some elderly men have more advanced disease, lower disease-free survival, and higher mortality than female patients [20, 21]. However, whether sex can predict the occurrence of RR-DTC is unknown; our results showed that sex was not a statistically significant factor. Operation frequency was another predictive factor. Cervical scar adhesion, unclear anatomical level, recurrent external invasion of residual cancer after the initial operation, and the incidence of complications reduce the possibility of complete resection of the tumor, thus increasing the risk of RR-DTC. Some studies have suggested that some pathological subtypes of thyroid cancer are more likely to develop into RR-DTC, such as follicular thyroid cancer, Hürthle cell carcinoma, and poorly differentiated thyroid cancer (PDTC) [22, 23]. One meta-analysis also confirmed that the pathological subtype was a predictor of RR-DTC [6]. However, our results showed that histological subtype was not a statistically significant factor, although there were a relatively low proportion of adverse pathological subtypes in our study, which may explain this finding.

Next, we discuss the conclusions of the molecular imaging in RR-DTC. In our study, 18F-FDG uptake was a predictor for RR-DTC, whereas iodine uptake was not. This is consistent with a study of Kang et al., who showed that RAI uptake of metastasis was not correlated with RR-DTC, but FDG uptake was negatively correlated with RR-DTC [10]. Previous studies have shown that despite repeated RAI treatment, more than 50% of patients eventually show disease progression and are ultimately considered refractory to RAI [24]. Moreover, more courses of prior TSH stimulation before iodine-131 administration, as well as more administration of probably overused iodine-131, possibly lead to a higher tumor burden [25–27]. Therefore, they may be of great value in the early identification of RR-DTC patients and combination with other therapeutic modalities [27, 28]. Early 18F-FDG imaging can not only predict the occurrence of RR-DTC but also predict the prognosis because RR-DTC is closely related to iodine treatment response. When FDG PET is used in conjunction with RAI whole body scan (WBS), we can obtain the metabolic information of the two radioactive tracers and infer the differentiation status of thyroid carcinoma at the same time. Many studies have shown that regardless of the affinity of iodine-131, FDG uptake is an adverse prognostic factor [10, 29, 30]. Incidentally, thyroglobulin response can also predict RR-DTC [18], but it lags behind molecular imaging, so it was not included in our prediction model. However, the advantage of 18F-FDG PET/CT lies in its ability to identify and locate tumor lesions.

In univariate analysis, some variables could not be used as independent factors of the disease. Therefore, multivariate analysis was conducted, and several scoring systems for predicting disease-specific mortality based on clinical and pathological prognostic factors were developed [13]. This research may help establish a predictive scoring system for RR-DTC that incorporates molecular imaging.

Currently, the diagnosis of RR-DTC takes a long time because it relies on the trend of thyroglobulin (Tg) and WBS after multiple RAI treatments, combined with relevant imaging examination results. If the development of RR-DTC is determined according to the normal procedures, it required 4–77 months in our study, with a median of 6 months. However, using our scoring system, the prediction can be made at the first appointment of RAI therapy, and the time is significantly shorter than 6 months. The disadvantage is that patients with metastatic DTC need to undergo whole body PET/CT examination at the first RAI therapy, which has a high cost. However, our research is worthwhile because it proves that FDG PET/CT is a powerful early predictor. If FDG PET/CT is examined early after treatment initiation, it can avoid adverse reactions and costly treatment for patients who are unlikely to benefit from it.

There are some limitations to this study. Given that this study used a retrospective design, it is inherent to selection bias. Second, due to clinical limitations, few metastases could be confirmed pathologically. This is a problem that we need to solve when we study tumor metastasis. Third, we did not validate the scoring system in the current study. Many prospective cohorts need to be further validated. Lastly, genetic status was not included at the very beginning of the research. Some studies have shown that molecular markers provide useful insight into the role of predicting the occurrence of RR-DTC, and this is an area for future research efforts.

Conclusions

It remains a challenge for clinicians to identify the radioiodine-refractory status of DTC early enough to initiate follow-up treatment at the individual level. This study indicated that age, recurrence between the operation and iodine-131 treatment, the uptake of 18F-FDG, and the site of metastasis were independent predictors in predicting RR-DTC. The predictive model based on the four factors demonstrated good identification ability of RR-DTC cases. An index score ≥ 10 was found to be the best score for predicting RR-DTC and helps to establish an active surveillance or appropriate treatment strategy for postoperative cases of RR-DTC undergoing follow-up treatment.

Abbreviations

18F-FDG, 18F-fluorodeoxyglucose

AJCC, American Joint Committee on Cancer

ATA, American Thyroid Association

AUC, area under the curve

CI, confidence interval

DTC, differentiated thyroid carcinoma

OR, odds ratio

PDTC, poorly differentiated thyroid cancer

PET-CT, positron emission tomography/computed tomography

RAI, selective radioactive iodine

RR-DTC, radioiodine-refractory differentiated thyroid carcinoma

 SD, standard deviation

SUV, standardized uptake values

TSH, thyroid stimulating hormone

UICC, Union for International Cancer Control

WBS, whole body scan

Declarations

Ethics approval and consent to participate: All methods were carried out in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments. The study was approved by the Ethics Review Board of Shanxi Bethune Hospital (approval number: YXLL-KY-2021-005), and the requirement for informed consent was waived by the Ethics Committee due to the retrospective study design.

Consent for publication

Not applicable

Availability of data and materials

The datasets generated and/or analyzed during the current study are not publicly available due to data security restrictions but are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

This research received no external funding.

Authors' contributions

YL and WZ conceived and designed the study. YL was responsible for data collection and analysis and was the main author of the manuscript. YW and WZ were responsible for the PET/CT image analysis. All authors read and approved the final manuscript.

Acknowledgements

We thank all the doctors, nurses, and technicians in the Nuclear Medicine Department of Shanxi Bethune Hospital for their contributions in patient management and PET/CT examinations. We would like to thank Editage (www.editage.cn) for English language editing.

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