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Investigative Surgery ADVANCES IN SURGICAL RESEARCH TECHNIQUES AND EDUCATION
Volume 35 + Number 5 May 2022
The Official Journal of the Academy of Surgirul Kewarch
Nomograms for Individualized Evaluation of Prognosis in Adrenocortical Carcinomas for the Elderly: A Population-Based Analysis
Weixi Wang, Guilin Chang, Yan Sun, Ran Zhuo, Huiting Li, Yu Hu & Cong Ye
To cite this article: Weixi Wang, Guilin Chang, Yan Sun, Ran Zhuo, Huiting Li, Yu Hu & Cong Ye (2022) Nomograms for Individualized Evaluation of Prognosis in Adrenocortical Carcinomas for the Elderly: A Population-Based Analysis, Journal of Investigative Surgery, 35:5, 1153-1160, DOI: 10.1080/08941939.2021.1968981
To link to this article: https://doi.org/10.1080/08941939.2021.1968981
Published online: 25 Aug 2021.
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Nomograms for Individualized Evaluation of Prognosis in Adrenocortical Carcinomas for the Elderly: A Population-Based Analysis
Weixi Wanga,*, Guilin Changa,*, Yan Suna, Ran Zhuob, Huiting Lic, Yu Hua and Cong Yed
aDepartment of Geriatrics, Zhongshan Hospital, Fudan University, Shanghai, Xuhui District, China; bDepartment of Urology, Zhongshan Hospital, Fudan University, Shanghai, Xuhui District, China; “Department of Respiratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China; dDepartment of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
ABSTRACT
Background: Adrenocortical carcinoma (ACC) is extremely rare in elderly patients. Thus, this study aimed to identify the incidence rate and develop nomogram models for predicting survival in elderly ACC patients.
Methods: Data of ACC patients aged >60 years from 1975 to 2016 were obtained from the Surveillance, Epidemiology, and End Results dataset. The national incidence rate was estimated, and survival was subjected to Kaplan-Meier analysis. A multivariate Cox regression model was used to identify predictors of survival. Nomograms were generated to predict survival, calibrated and internally validated.
Results: We identified 583 cases. Univariate analysis showed that patients with younger age (≤67 years), female sex, lower tumor grade, surgical treatment performed, and earlier European Network for the Study of Adrenal Tumors (ENSAT) stage had a better survival (P<0.05). In the Cox regression analysis, no surgery performed (hazard ratio [HR]: 3.544, 95% CI: 1.142-10.995, P=0.029 for overall survival [OS]; HR: 3.230, 95% CI: 1.040-10.034, P=0.043 for disease-specific survival [DSS]) and advanced ENSAT stage (HR: 3.328, 95% CI: 1.628-6.801, P=0.001 for OS; HR: 3.701, 95% CI: 1.682-8.141, P=0.001 for DSS) were associated with worse outcomes. Age, sex, histologic grade, surgical resection, radiotherapy, and ENSAT stage were included in the nomograms, with a C-index of 0.692 for OS and 0.694 for DSS, demonstrating a good accuracy in predicting survival.
Conclusions: This study is the largest review of ACC in elderly patients. We present nomograms to predict survival in elderly ACC patients using clinicopathologic data, which could aid in accurate clinical decision-making.
ARTICLE HISTORY Received 5 May 2021 Accepted 10 August 2021
KEYWORDS
Nomogram; adrenocortical carcinoma; elderly; survival; SEER
Introduction
Adrenocortical carcinoma (ACC) is a rare and rapidly pro- gressive endocrine malignant tumor, with an incidence of 0.7-2.0/1,000,000 people per year, and leads to approximately 0.2% of deaths due to cancers in the US [1, 2]. However, ACC is characterized by a conspicuous heterogeneity, with the 5-year overall survival (OS) ranging from 20% to 59% [2, 3], and the clinical outcome varying greatly for different age groups and tumor stages [4]. Furthermore, ACC is more likely to occur before the age of 10 and at the age of 40-50 [5], exhibiting a bimodal age distribution. In addition, ACC is highly aggressive in adults, while the outcome in children is better than that in adults. However, tumor behavior in elderly patients is much more difficult to predict [6, 7].
The highest incidence of ACC has been found in children in southern Brazil, with an estimated annual incidence of 10-15 times as that in the US [8]. The germline mutation of TP53 is thought to be related to this observation, occur- ring in 78%-97% of these pediatric populations [9, 10].
Therefore, most of the literature on ACC epidemiology comes from this Brazilian population. However, most ACCs are sporadic, and it is unclear whether the findings of this unique population are applicable to other age groups or regions, especially to the elderly.
Elderly patients are more vulnerable to multiple medical comorbidities, as well as treatment-related morbidities and mortalities; thus, special studies need to be carefully designed to assess clinical outcomes in this specific population. Therefore, we formulated nomogram models to make an accurate prediction of survival in elderly patients with ACC using a large, multi-regional database to determine import- ant prognostic indicators of survival.
Materials and methods
Data sources and study population
The publicly available Surveillance, Epidemiology, and End Results (SEER) database covers approximately one-third of
Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, No. 507
Department of Geriatrics, Zhongshan Hospital, Fudan University,
the population in the US, and it collects medical record data from 18 regional population-based cancer registries. The information reviewed included patient demographics, tumor characteristics, treatment modalities, and cause of death [11]. The dataset for the present study was extracted using the SEER*Stat software (version 8.3.8) on January 7, 2021. Data of patients with ACC were acquired from 1975 to 2016 to extract demographic, clinical, pathologic, and survival information. According to the International Classification of Diseases for Oncology, third edition (ICD-O-3), the primary site of ACC was identified as C74.0 and C74.9, all accompanied by a histologic subtype code of 8370. The available inclusion criteria were as follows: first and only primary tumor and confirmed histological or cyto- logical diagnosis of ACC. Patients with bilateral tumors were excluded from the study. A total of 583 records were iden- tified based on these criteria (Figure 1).
ACC in SEER (1975-2016) ICD-O-3: 2179 cases
Patients with age ≥60 years: 859 cases
Diagnosed with ACC as its first and only malignancy: 632 cases;
Exclude patients with bilateral ACC: 605 cases;
Diagnostic Confirmation: positive histology or cytology: 583 cases
Study variables
Pertinent information on sex, age at diagnosis, race, tumor size, tumor laterality, histologic grade, lymph node (LN) status, distant metastasis, surgery, radiotherapy, and survival information were retrieved. The tumor stage was based on the European Network for the Study of Adrenal Tumors (ENSAT) staging system and consistent with the 8th American Joint Committee on Cancer staging system, which was adapted by the Union for International Cancer Control (UICC) and World Health Organization (WHO) for its supe- riority over other staging systems [12]. The incidence rate was adjusted by age and normalized according to the 2000 American standard population. OS and DSS were the pri- mary endpoint outcomes of this study, which were defined as the time interval from diagnosis to death from any cause and the time interval between diagnosis and death caused by ACC, respectively.
Statistical analysis
Simple statistical methods were used to describe the socio- logical, clinical, and pathological features of these subjects. Pearson’s chi-squared (x2) test was used to analyze categor- ical variables. Survival rate was calculated through Kaplan- Meier analysis, and predictors of prognosis were identified using the multivariate Cox proportional hazard model, adjusting variables with P<0.1 in the univariate analysis.
Nomograms of 1-, 3-, and 5-year OS and DSS were estab- lished to visualize the manually predicted values. Discriminative ability was assessed using Harrell’s concor- dance index (C-index), and internal validation was per- formed by bootstrap resampling of 200 iterations to estimate predictive accuracy. In addition, calibration curves for 3-year OS and DSS were provided to compare the consistency of bias adjusted for the predicted survival and observed sur- vival. All computations were performed using SPSS version 25.0 and R version 4.0.0. Statistical significance was set at P<0.05 (two-tailed).
Results
Baseline information
A total of 583 reports of ACC in patients aged >60 years were included in the SEER registry. The overall incidence rate was 0.88/1,000,000 person-years and was highest in patients aged 60-70 years at 1.8/1,000,000 person-years. The demographic and clinicopathological features are listed in Table 1. Caucasians (86.8%) were predominant in the study, and females outnumbered males with a ratio of 1.5:1. The median age at diagnosis among patients included in the present study was 67 years, and it was used as the cutoff point in the following study. More lesions were located on the left (n=322, 55.3%) than on the right (n=260, 44.7%). Most patients also presented with ENSAT stage IV disease (n=229, 39.3%). Furthermore, treatment modalities include surgery, radiotherapy, and chemotherapy. Most patients
| Variables | Number (% total, effective %) |
|---|---|
| Median age at diagnosis (range, years) | 67 (60-92) |
| Age (years) | |
| >67 | 284 (48.7, 48.7) |
| 60-67 | 299 (51.3, 51.3) |
| Sex | |
| Male | 235 (40.3, 40.3) |
| Female | 348 (59.7, 59.7) |
| Ethnicity | |
| Caucasian | 506 (86.8, 87.1) |
| Non-Caucasian | 75 (12.9, 12.9) |
| Unknown | 2 (0.3) |
| Tumor grade | |
| I | 16 (2.7, 12.5) |
| II | 14 (2.4, 10.9) |
| III | 58 (9.9, 45.3) |
| IV | 40 (6.9, 31.3) |
| Unknown | 455 (78.0) |
| Laterality | |
| Right | 260 (44.6, 44.7) |
| Left | 322 (55.2, 55.3) |
| One-side but unspecified | 1 (0.2) |
| Surgery performed | |
| Yes | 412 (70.7, 71.4) |
| No | 165 (28.3, 28.6) |
| Unknown | 6 (1.0) |
| Radiotherapy | |
| Yes | 68 (11.7, 15.6) |
| No | 369 (63.3, 84.4) |
| Unknown | 146 (25.0) |
| Chemotherapy | |
| Yes | 161 (27.6) |
| No/Unknown | 422 (72.4) |
| Treatment modality | |
| Surgery with radiotherapy | 43 (7.4, 9.9) |
| Surgery only | 369 (63.3, 84.8) |
| Radiotherapy only | 23 (3.9, 5.3) |
| Unknown | 148 (25.4) |
| ENSAT stage | |
| I | 8 (1.4, 2.0) |
| II | 88 (15.1, 21.9) |
| III | 77 (13.2, 19.2) |
| IV | 229 (39.3, 57.0) |
| Unknown | 181 (31.0) |
| Tumor size, mean (SD) [median], cm | 10.5 (4.6) [9.8] |
| AJCC T, 8th edition | |
| I | 8 (1.4, 2.0) |
| II | 88 (15.1, 21.9) |
| III | 77 (13.2, 19.2) |
| IV | 229 (39.3, 57.0) |
| Tx | 181 (31.0) |
| Lymph node involvement | |
| Yes | 65 (11.1, 15.5) |
| No | 355 (60.9, 84.5) |
| Unknown | 163 (28.0) |
| Distant metastasis | |
| Yes | 229 (39.3) |
| No | 194 (33.3) |
| Unknown | 160 (27.4) |
| Metastasis at bone | |
| Yes | 23 (3.9, 10.8) |
| No | 189 (32.4, 89.2) |
| Unknown | 371 (63.6) |
| Metastasis at brain | |
| Yes | 2 (0.3, 1.0) |
| No | 208 (35.7, 99.0) |
| Unknown | 373 (64.0) |
| Metastasis at liver | |
| Yes | 44 (7.5, 21.1) |
| No | 165 (28.3, 78.9) |
| Unknown | 374 (64.2) |
| Metastasis at lung | |
| Yes | 45 (7.7, 21.5) |
| No | 164 (28.1,78.5) |
| Unknown | 374 (64.2) |
(n=412, 70.7%) underwent surgery, while fewer patients (n=68, 11.7%) received radiotherapy. Information on che- motherapy was incomplete in 422 (72.4%) cases, which were recorded as “no or unknown,” making it impossible to ana- lyze the role of chemotherapy. Moreover, elderly patients with ACC were vulnerable to distant metastasis (n=229, 39.3%), while LN involvement was found in only 65 (11.1%) cases. The top four metastatic sites were the lung, liver, bone, and brain.
Survival analysis
The univariate analysis of survival is presented in Table 2. The 5-year OS was 21.6% in patients aged >60 years and did not differ significantly by ethnicity. There were statistical differences in survival among different age groups, and the most significant drop in survival was noted in patients aged >80 years. Patients with younger age (P=0.024 for OS; P=0.015 for DSS), female sex (P<0.001 for both OS and DSS), lower histologic grade (I-II) (P<0.001 for OS; P=0.009 for DSS), surgery performed (P<0.001 for both OS and DSS), and earlier ENSAT stage (I-II) (P<0.001 for both OS and DSS) had a significantly superior outcome. Interestingly, patients receiving radiotherapy tend to have better prognosis (5-year OS in patients with radiotherapy vs. without radiotherapy: 20.0 months vs. 28.4 months) with the P=0.074 for OS and P=0.059 for DSS. The survival curves of the different subgroups are illustrated in Figure 2.
Multivariate analysis of OS and DSS
Further multivariate analysis using the Cox proportional hazard model was performed to control for potential con- founding factors (Table 3). This model indicated that patients without surgical performance (hazard ratio [HR]: 3.544, 95% confidence interval [CI]: 1.142-10.995, P=0.029 for OS; HR: 3.230, 95% CI: 1.040-10.034, P=0.043 for DSS) and higher ENSAT stage (HR: 3.328, 95% CI: 1.628-6.801, P=0.001 for OS; HR: 3.701, 95% CI: 1.682-8.141, P=0.001 for DSS) were associated with worse outcomes. Conversely, age at diagnosis, sex, tumor grade, and radiation treatment were not significantly associated with OS or DSS.
Development of prognostic nomograms for survival
The present study established nomograms to predict the 1-, 3-, and 5-year OS and DSS by incorporating the significant prognostic factors (Figure 3). Because age at diagnosis, sex, histologic grade, radiotherapy, surgery performance, and ENSAT stage were closely related to OS and DSS, we included these factors in the nomogram models. Based on these clinical characteristics, the total scores of 1-, 3-, and 5-year OS and DSS were calculated. For example, a 68-year- old man with an ACC of histologic grade III and ENSAT stage IV who received surgical resection and radiotherapy, would have a total score of 156 points for OS and 134.75
| Variables | 5-year OS (%) | P value | 5-year DSS(%) | P value |
|---|---|---|---|---|
| Age at diagnosis | 0.024 | 0.015 | ||
| (years) | ||||
| >67 | 18.8 | 15.7 | ||
| ≤67 | 24.0 | 22.1 | ||
| Sex | <0.001 | <0.001 | ||
| Male | 16.5 | 11.5 | ||
| Female | 25.1 | 23.9 | ||
| Ethnicity | 0.408 | 0.419 | ||
| Caucasian | 21.3 | 18.8 | ||
| Non-Caucasian | 24.4 | 23.0 | ||
| Histologic grade | 0.006 | 0.028 | ||
| I-II | 43.1 | 33.3 | ||
| III-IV | 16.8 | 16.7 | ||
| Laterality | 0.266 | 0.199 | ||
| Right | 20.0 | 17.6 | ||
| Left | 23.1 | 20.7 | ||
| Radiotherapy | 0.074 | 0.059 | ||
| Yes | 20.0 | 17.0 | ||
| No | 28.4 | 26.2 | ||
| Surgery | <0.001 | <0.001 | ||
| performed | ||||
| Yes | 28.7 | 26.4 | ||
| No | 3.2 | 2.2 | ||
| Treatment | <0.001 | <0.001 | ||
| modality | ||||
| Surgery with | 31.6 | 26.5 | ||
| radiotherapy | ||||
| Surgery only | 28.4 | 26.2 | ||
| Radiotherapy | 0.0 | 0.0 | ||
| only | ||||
| ENSAT stage | <0.001 | <0.001 | ||
| I-II | 39.5 | 44.8 | ||
| III-IV | 7.2 | 7.7 | ||
| Distant met | <0.001 | <0.001 | ||
| Yes | 1.1 | 1.2 | ||
| No | 32.5 | 37.0 | ||
| LN status | <0.001 | <0.001 | ||
| Positive | 2.0 | 2.3 | ||
| Negative | 27.8 | 27.3 | ||
| Met at bone | 0.001 | 0.002 | ||
| Yes | 0.0 | 0.0 | ||
| No | 27.5 | 32.3 | ||
| Met at brain | <0.001 | <0.001 | ||
| Yes | 0.0 | 0.0 | ||
| No | 30.8 | 29.5 | ||
| Met at liver | <0.001 | <0.001 | ||
| Yes | 9.1 | 0.0 | ||
| No | 43.1 | 36.5 | ||
| Met at lung | <0.001 | <0.001 | ||
| Yes | 0.0 | 0.0 | ||
| No | 31.4 | 37.2 |
Note: LN, lymph node; met, metastasis; OS, overall survival; DSS, disease-specific survival.
points for DSS. Therefore, the predicted 1-year OS and DSS would be approximately 27% and 30%, respectively.
Internal validation of the nomograms
The nomograms were validated internally by evaluating both the calibration and discrimination. Figure 4 illustrates the calibration curves of the 3-year OS and DSS, which demon- strated a good correlation between the nomogram prediction and actual observation. The C-index was calculated to eval- uate discrimination, with a value of 0.692 (95% CI: 0.667- 0.717) for OS and 0.694 (95% CI: 0.669-0.719) for DSS in the prediction model. These results indicate that the vali- dated nomograms are reliable for predicting the survival probability.
Discussion
ACC is extremely rare in the elderly and is typically aggres- sive and has a poor prognosis. Currently, few studies have explored the clinical stage criteria and prognosis of ACC in the elderly. Recently, Li et al. revealed that the survival of elderly patients aged 60-89 years was worse than that in younger patients [13]. Therefore, our objective was to estab- lish nomograms for the individualized prediction of ACC prognosis in the elderly. The present nomogram models were based on the following factors: age at diagnosis, sex, histologic grade, surgical resection, radiotherapy, and ENSAT stage.
Similar to previous studies, our present research demon- strated a predominance of female and Caucasian patients among those with ACC [6, 13-15]. The proportion of ACC on the left side is higher than that on the right side, and this peculiar laterality difference has also been found in previous studies [13, 16-18]. However, the exact mechanisms behind this phenomenon remain unclear [3]. Furthermore, most of the ACCs were at high histological grade and advanced ENSAT stage. One possible explanation is that limited by the relatively low specificity of current diagnostic tools, ACCs at a lower histologic grade and earlier ENSAT stage might initially be mistakenly classified as benign tumors, and ACC was only diagnosed when the tumors developed to a higher grade and advanced stage [19, 20].
Another important point for discussion is the multiple treatment paradigms of ACC in elderly patients. In the pres- ent study, surgical resection of the primary tumor remains as the main treatment. Previous studies have shown that complete tumor resection and LN dissection are of great importance for survival and control of recurrence [21]. Consistently, our multivariate Cox-regression model demon- strated that surgical resection was independently associated with superior survival, reaching statistical significance (P<0.001). The rationale may be that ACC is highly malig- nant and progresses aggressively; therefore, surgical resection tends to be the only choice for the control of local diseases. In addition, surgical treatment might also benefit the survival of advanced diseases [1, 3, 22-25]. However, the role of radiotherapy in ACC is much more controversial. Although radiotherapy exerts certain effects on locoregional control of ACC in adults, its role in senile diseases remains unclear [13, 26]. ACC is generally considered to be insensitive to radiotherapy, a treatment that increases the risk of secondary malignancies [27]. Only 68 (11.7%) patients in our study received radiation. The survival of patients receiving radio- therapy was poorer (P<0.005 for both OS and DSS) in the univariate analysis; however, no significant difference was found in the multivariate Cox proportional hazard model. Furthermore, our study could not evaluate the application of chemotherapy owing to the limitations of the SEER data- set. Although some cases seem to be sensitive to chemo- therapy, its role in elderly ACC patients remains unclear [28].
Previous studies have reported some nomogram models for predicting the prognosis of ACC [13, 29, 30]. However, these models mainly focused on ACCs in adults but not in the elderly. Li et al. and Laurent et al. developed nomograms
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| Characteristic | OS, HR (95% CI) | P value | DSS, HR (95% CI) | P value |
|---|---|---|---|---|
| Age (years) | 0.578 | 0.406 | ||
| ≤67 | 1 | 1 | ||
| >67 | 1.190 (0.645-2.196) | 1.322 (0.684-2.554) | ||
| Sex | 0.347 | 0.228 | ||
| Male | 1 | 1 | ||
| Female | 0.756 (0.422-1.354) | 0.682 (0.367-1.270) | ||
| Histologic grade | 0.131 | 0.185 | ||
| I-II | 1 | 1 | ||
| III-IV | 1.763 (0.845-3.675) | 1.709 (0.774-3.773) | ||
| Surgery | 0.029 | 0.043 | ||
| Yes | 1 | 1 | ||
| No | 3.544 (1.142-10.995) | 3.230 (1.040-10.034) | ||
| Radiotherapy | 0.215 | 0.244 | ||
| Yes | 1 | 1 | ||
| No | 1.777 (0.716-4.411) | 1.730 (0.688-4.355) | ||
| ENSAT stage | 0.001 | 0.001 | ||
| Early stage (I-II) | 1 | 1 | ||
| Advance stage (III-IV) | 3.328 (1.628-6.801) | 3.701 (1.682-8.141) |
Note: OS, overall survival; HR, hazard ratio; CI, confidence interval; DSS, disease-specific survival.
predicting OS and DSS in patients managed either with or without surgery for ACC, using the older SEER data, and they focused on ACC patients of all ages (adults and pedi- atrics) [13, 29]. Kong et al. also developed a nomogram to predict the OS probability in adult patients with ACC after surgery, incorporating age at diagnosis and TNM stage [30]. Compared with these prediction models, our research has the following advantages. First, we extracted data on ACC in the elderly from the SEER database from 1975 to 2016, which is the latest version of the database. Second, the indi- cators included in the present nomograms were more com- prehensive. Variables such as age at diagnosis, sex, histological grade, ENSAT stage, surgical resection, and radiation therapy
were included in our model; to our knowledge, this is the first study to include the ENSAT staging system into nomo- grams based on the SEER registry. The ENSAT stage seems to be superior to other stage systems and is adapted by the UICC and WHO; thus, it is recommended by the ESMO-EURACAN Clinical Practice Guidelines in the assess- ment of ACC [12, 31]. Third, we also explored univariate analysis and multivariate Cox regression model in the sur- vival analysis; combined with nomogram models, we made a comprehensive assessment of survival in the elderly with ACC. Lastly, the prediction accuracy of nomograms in this study could also be evaluated by nomograms of other urinary system tumors, such as malignancies of the bladder, kidney,
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Predicted 3-year DSS
and prostate, with a C-index ranging from 0.620 to 0.774, and the trend of the calibration curve in our models is consistent with that of urinary system tumor models [32-34].
The present study has several limitations. First, the study was retrospective and observational in nature, which inev- itably led to selective bias. Second, the SEER database does not include some potential prognostic parameters, such as information on chemotherapy, virilization, and hormonal status; thus, it may be unavailable to evaluate some cor- relations for certain factors. Third, the size of the tumor was only encoded after 1983, making the data of ENSAT staging partially missing; thus, the sample size of regression analysis using the variable of ENSAT stage was smaller than that of the whole cohort. Fourth, the relatively small sample size of patients with ACC made it difficult to uncover subtle correlations. Therefore, it is necessary to establish international multi-centers to carry out large-scale observational studies and prospective trials to address the
current defects. Lastly, further external validation of our nomogram is needed to confirm its predictive effect on the prognosis of ACC in the elderly and to expand the utility of our models.
In conclusion, our research revealed the importance of surgery and the ENSAT stage in the prognosis of elderly ACC. Additionally, we developed and validated nomograms that can individually provide the predictors of OS and DSS in the ACC. Although our nomograms have some limitations, they may be helpful in assisting individualized clinical decision-making. Concurrently, we are looking forward to future prospective studies to establish more accurate prog- nostic models.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Ethics approval
None. This study was exempted from institutional review board approval because it was based on a publicly available database.
Funding
This work was funded by the Youth Foundation of Zhongshan Hospital Affiliated to Fudan University (2019ZSQN48) and National Natural Science Foundation of China (82002828).
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