Body mass index-defined overweight (but not obese) correlates with better postoperative prognosis in colorectal cancer

Introduction

Colorectal cancer (CRC) is one of the most common malignancies globally, with an increasing incidence rate year by year (1,2). Similar to the trend in CRC incidence, rates of overweight and obesity increased worldwide. In China, the mean adult body mass index (BMI) increased from 22.7 kg/m² in 2004 to 24.4 kg/m² in 2018 (3,4). BMI is a commonly used and convenient indicator for assessing obesity, nutritional condition, and metabolic status. There may be a close relationship between BMI and CRC, with previous literature suggesting that a higher BMI can promote the occurrence and development of CRC (5-7), while the impact of BMI on the prognosis of CRC remains controversial (8-11). Currently, the principle of CRC treatment is to use a comprehensive treatment approach, including surgery, chemotherapy, radiotherapy, and immunotherapy, according to different stages. Radical surgery remains the cornerstone of CRC treatment (2,12,13). However, surgery is a double-edged sword; it treats the disease but also brings trauma to the body, and the healing relies on good nutritional status. A large number of prospective and retrospective studies have proven that poor nutritional status is an independent risk factor for postoperative infectious complications, impaired immune function, increased mortality, and prolonged hospital stay (14,15). BMI can reflect the nutritional status to a certain extent, and the importance of nutrition for surgical outcomes and tumor prognosis is self-evident. Moreover, changes in BMI can simultaneously reprogramme the body’s entire metabolic network; metabolic status not only determines the energy supply of tumor cells, but also exerts an independent influence on the prognosis of multiple solid tumors by reshaping the immune micro-environment and altering genomic stability (16,17).

In view of the ongoing controversy over the impact of BMI on CRC prognosis, this study aims to investigate the prognostic significance of different BMI levels in CRC patients undergoing surgical treatment. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-351/rc).

Methods

Patients collection

The retrospective study was approved by the Ethics Committee of The First Affiliated Hospital of Chongqing Medical University (No. 2020-444). Informed consent was waived after review by the Ethics Committee as it did not involve patient interests nor privacy. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. From January 2019 to June 2019, a total of 428 patients underwent CRC surgery at the Department of Gastrointestinal Surgery of The First Affiliated Hospital of Chongqing Medical University. The inclusion and exclusion criteria were shown in Figure 1. Cases with any of the following conditions were excluded: (I) incomplete clinicopathological data (104 cases); (II) received neoadjuvant therapy before surgery (39 cases); (III) personal history of cancer or family history of CRC (24 cases); (IV) secondary surgery or palliative surgery (18 cases); (V) postoperative pathology confirmed as intraepithelial neoplasia or Tis (12 cases); and (VI) lost to follow-up after surgery (27 cases). Ultimately, 204 eligible patients were included in this study.

Figure 1 Flowchart of patient selection in this study.

Clinicopathological characteristics

Information from the perioperative period was collected from the hospitalization system. These information included BMI, age, gender, tumor location, tumor-node-metastasis (TNM) staging, degree of differentiation, adjuvant therapy, alcohol consumption, smoking, underlying metabolic diseases (hypertension/diabetes/hyperlipidemia), Ki-67, NAS and BRAF mutation status, mismatch repair (MMR) and microsatellite stable (MSS) status, complete blood counts, liver and kidney function and electrolytes, peripheral blood immune cells, tumor antigens carbohydrate antigen 199 (CA199) and carcinoembryonic antigen (CEA), etc.

Peripheral blood immune cell counts are part of our institutional routine work-up and are performed by multicolor flow cytometry in five sequential steps:

• Venous blood (2–4 mL) was collected into vacuum tubes containing heparin or ethylenediaminetetraacetic acid (EDTA) and processed within 4 h at room temperature.
• Fluorochrome-conjugated monoclonal antibodies were added according to the pre-defined antibody panel; the sample is incubated for 15–30 min at room temperature in the dark.
• Erythrocyte-lysing solution was added, mixed gently, and left at room temperature for 10 min, followed by centrifugation at 300 g for 5 min; the supernatant was discarded.
• The pellet was washed once or twice with phosphate-buffered saline (PBS) and finally resuspended in 0.5 mL PBS to remove unbound antibodies and minimize non-specific fluorescence.
• ≥30,000 leukocytes were acquired on a flow cytometer. Lymphocytes are first gated as CD45⁺ events, then sub-classified into CD3⁺CD4⁺, CD3⁺CD8⁺, CD19⁺, and CD16⁺CD56⁺ populations.

Detailed follow-up information, including recurrence/progression-free survival (RPFS) and overall survival (OS), was collected from the outpatient system and telephone interviews. RPFS referred to the time from surgery to recurrence, progression, or the last follow-up, while OS referred to the time from surgery to death or the last follow-up.

Follow-up monitoring

CRC surgery conformed to clinical guidelines. Complete mesocolic excision or complete mesorectal excision was performed, and R0 resection was pathologically confirmed. Patients were followed up every 3 months for the first 3 years and every 6 months for the next 2 years. Follow-up items included chest/abdominal/pelvic computed tomography (CT), magnetic resonance imaging (MRI), CEA, or colonoscopy.

Statistical analysis

Patients were stratified according to the Chinese criteria for adult overweight and obesity into three groups (18): low/normal weight (BMI <24 kg/m²), overweight (24 kg/m² ≤ BMI <28 kg/m²), and obese (BMI ≥28 kg/m²) groups.

Continuous variables were expressed as median [interquartile range (IQR)], and differences between the two groups were compared using the Kruskal-Wallis test. Categorical variables were presented as counts (%) and compared with the Chi-squared test or Fisher’s exact test. Cox proportional hazards model was performed for factor analysis. A P value <0.05 was considered statistically significant. Kaplan-Meier method was used to analyze RPFS and OS. All statistical analyses were performed using SPSS version 25.0.

Results

Clinicopathological characteristics

A total of 204 patients with CRC were enrolled: 52 had right-sided colon cancer, 54 had left-sided colon cancer, and 98 had rectal cancer. TNM staging showed stage I in 51, stage II in 91, stage III in 55, and stage IV in 7 patients. There were 120 males and 84 females. The median BMI at diagnosis was 23.28 (range, 14.79–36.11) kg/m², and the median age was 64 (range, 32–90) years.

Histopathologically, 17 tumors were poorly differentiated, 182 moderately differentiated, and 5 well differentiated. The median Ki-67 proliferation index was 70% (range, 20–90%). BRAF mutations were detected in 18.14% of cases, and 14.22% of tumors exhibited deficient MMR (dMMR). Only 68 and 82 patients underwent RAS mutation analysis and microsatellite instability (MSI) testing, respectively. Among the tested cases, RAS mutations were present in 50%, and MSS tumors accounted for 85.37%.

The enrolled patients were divided into three groups based on BMI: low/normal weight (BMI <24 kg/m²), overweight (24 kg/m² ≤ BMI <28 kg/m²), and obese (28 kg/m² ≤ BMI). The median BMI of these groups was 21.83, 25.26, and 28.69 kg/m², respectively. Significant differences among the groups were observed for RPFS (P=0.02) and OS (P=0.003).

However, the prevalence of hypertension (P=0.03) and diabetes (P=0.02) also differed significantly across BMI groups. Therefore, we further used Cox proportional hazards models to determine whether these prognostic disparities were attributable to BMI itself or to confounding factors such as hypertension and diabetes. Other detailed baseline clinicopathological characteristics are provided in Table 1.

Prognostic factors

As of June 2024, a total of 231 postoperative patients were followed up; 27 patients were lost, yielding a follow-up rate of 88.31%. The median follow-up times for RPFS and OS were 60 and 60.5 months, respectively. Among all 204 patients, 55 (26.96%) and 44 (21.57%) patients experienced recurrence and death, respectively.

Univariate Cox regression analysis showed that age, BMI, tumor stage, chemotherapy and immunotherapy were associated with recurrence or progression, while age, BMI, and tumor stage were associated with survival. Subsequent multivariate Cox regression analysis identified age, BMI and tumor stage as independent prognostic factors for both recurrence/progression and survival. Notably, overweight BMI was an independent protective factor against tumor recurrence or progression [hazard ratio (HR) =0.367; 95% confidence interval (CI): 0.175–0.769] and cancer-related death (HR =0.273; 95% CI: 0.105–0.714). See Tables 2,3 for details.

Similarly, the survival curves drawn according to the Kaplan-Meier method showed significant differences in RPFS (P=0.02) and OS (P=0.004) across BMI groups. Specifically, the overweight group exhibited significantly better RPFS (P=0.009 vs. low/normal weight; P=0.09 vs. obesity) and OS (P=0.009 vs. low/normal weight; P<0.001 vs. obesity) than both the low/normal weight and obese groups. With further BMI increase, no significant differences were observed between the obese and low/normal weight groups for either RPFS (P=0.10) or OS (P=0.82). Details are shown in Figures 2,3.

Figure 2 RPFS among different BMI groups. BMI, body mass index; CI, confidence interval; HR, hazard ratio; RPFS, recurrence/progression-free survival.

Figure 3 OS among different BMI groups. BMI, body mass index; CI, confidence interval; HR, hazard ratio; OS, overall survival.

Laboratory examinations

Immune cell profiling of peripheral blood from the enrolled cases showed a median lymphocyte count of 1,476 (range, 351–3,516) cells/µL, and median CD3⁺ T cells (total T lymphocytes), CD4⁺ T cells (helper/inducer T cells), and CD8⁺ T cells (suppressor/cytotoxic T cells) were 1,001 (range, 153–2,024), 567.5 (range, 84–1,521), and 330.5 (range, 45–1,029) cells/µL, respectively. The median CD3⁺CD4⁺CD8⁺ T (double-positive) and CD3⁺CD4⁻CD8⁻ T (double-negative) T cells were 6 (range, 0–87) and 54 (range, 2–406) cells/µL, respectively. Other immune cells such as B lymphocytes (CD19⁺), natural killer (NK) cells (CD3⁻CD16/56⁺), and NK T (NKT) (CD3⁺CD16/56⁺) cells had median counts of 145 (range, 12–966), 230 (range, 31–1,164), and 49.5 (range, 3–455) cells/µL, respectively. Notably, the counts of CD8⁺ T cells (P=0.043) and CD3⁺CD4⁻CD8⁻ T cells (P=0.03) differed significantly among the BMI groups, with both populations markedly reduced in the peripheral blood of overweight patients. No statistically significant differences were observed for any other immune-cell subsets; see Table 4 for details.

Serum biochemistry revealed significant differences across BMI groups in alanine aminotransferase (ALT; P<0.001), γ-glutamyl transferase (GGT; P=0.004), bicarbonate (HCO₃⁻; P=0.004), and glucose (P<0.001). ALT and glucose levels were modestly elevated in the overweight group but remained lower than in the obese group. Notably, GGT showed the most pronounced increase, whereas HCO₃⁻ exhibited the greatest decline, in the overweight group. Complete data on blood counts, hepatic and renal function, electrolytes, glucose, and tumor markers CA199 and CEA are provided in Table 5.

Postoperative courses

Among the 204 enrolled patients, 30 experienced postoperative complications: 18 developed infections, 5 had anastomotic leakage, 4 had lymphatic fistula or chylous leakage, 4 experienced early intestinal obstruction, and 2 suffered postoperative bleeding. The median length of hospital stay was 14 (range, 7–82) days. Neither the incidence of postoperative complications nor the length of hospital stay differed significantly among BMI groups (P=0.70 for both), as detailed in Table 6.

Discussion

In this study, the overall 5-year RPFS rate for all included patients was 73.04%, and the overall OS rate was 78.43%. A multicenter study involving 1,524 patients reported that the overall disease-free survival (DFS) for CRC ranged from 62.6% to 76.6% (19). In a report by Kong et al., which included 1,054 CRC patients followed for up to 20 years, the overall recurrence or metastasis rate was 23.5% (20). In a single-center retrospective cohort study by Hong et al. involving 1,126 patients, the OS across all stages was 79.5% (21). These studies show outcomes similar to those in our study; slight differences may be attributed to heterogeneity in study populations, variations in follow-up duration, and differences in the definitions of recurrence and progression.

It is widely acknowledged that BMI is closely associated with hypertension, diabetes, and dyslipidemia, showing a significant and progressively increasing risk relationship (22-26). Consistent with this, the incidence of hypertension and diabetes was markedly higher in overweight and obese individuals than in those with low or normal weight. Dyslipidemia was also more common in the overweight and obese groups, though the difference did not reach statistical significance.

BMI was closely associated with the prognosis of CRC, yet its specific impact on RPFS and OS varied across studies (27-30). In the present study, prognosis differed significantly among BMI groups: compared with low/normal weight and obese patients, those who were overweight had superior RPFS and OS, a finding consistent with previous Asian reports on the prognostic role of BMI in CRC (31,32).

However, due to inconsistent baseline data on comorbid hypertension and/or diabetes across the study groups, we conducted additional Cox proportional hazards analyses to adjust for these and other confounders, which confirmed that an overweight BMI is an independent protective factor against CRC recurrence/progression and death. Notably, further increases in BMI to the obese range conferred an adverse prognosis, indicating that the relationship between BMI and CRC outcome was not simply linear, an observation corroborated by the survival curves. Moreover, advanced age and higher tumor grade emerged as independent risk factors for poor prognosis, in line with earlier reports (33,34).

Why can differences in BMI drive the same tumor type toward divergent prognoses? A paper published in Cell by Ringel et al. showed that in obesity hypertrophic and hypoxic adipocytes released tumor necrosis factor (TNF)-α, interleukin (IL)-6, and C-reactive protein (CRP), which recruited myeloid-derived suppressor cells and regulatory T (Treg) cells while paralyzing CD8⁺ T cell function. Conversely, overweight individuals maintained an adequate basal metabolic rate that supplied immune cells with sufficient adenosine triphosphate (ATP) and glutamine, preserved CD8⁺ T cell mechanistic target of rapamycin (mTOR) activity and interferon (IFN)-γ secretion and thereby created a “metabolic buffer” and moderate immune activation (35). Moreover, a study in an Asian cohort revealed that among patients with a BMI of 24–27 kg/m², circulating adiponectin levels positively correlate with the CD8⁺/Treg ratio; adiponectin activated the AMPK-mTOR axis, enhanced CD8⁺ T cell glucose uptake, mitochondrial oxidative phosphorylation and INF-γ production, while simultaneously down-regulating STAT3 signaling to curtail Treg expansion and dampen the immunosuppressive microenvironment (36). When BMI was low, mTOR signaling was suppressed and mitochondrial dysfunction ensues, leading to inadequate glucose uptake by CD4⁺ T cells and exhaustion of memory T cells, resulting in nutritional depletion and immune suppression (37). In summary, different BMI levels might exert systemic effects through the metabolic, immune, and nutritional dimensions, reshaped the host immune-metabolic state via the “adipose-immune-metabolism” axis and thereby influenced tumor progression and prognosis. Therefore, we shifted our focus from macroscopic clinical outcomes to microscopic systems biology. Peripheral blood was the most accessible “liquid biopsy” window that mirrored whole-body status in real time. By flow cytometry, we simultaneously quantified T, B, and NK cell subsets, while tumor markers (CEA, CA199) reflected tumor burden, routine hematology reveals anemia or inflammation, and liver renal function plus electrolytes mapped the metabolic-detoxification axis. Integrating these multi-dimensional data with BMI was expected to resolve the paradox whereby overweight conferred a “metabolic buffer” yet obesity triggers an “inflammatory storm”.

The tumor microenvironment (TME) was considered the “nursery” for tumors, with T cell subsets being key members (38). CD3⁺, CD4⁺, and CD8⁺ T lymphocytes were T cell subtypes related to malignant tumor immunity. CD3⁺ T lymphocytes were mature T lymphocytes, and their number directly reflected the state of cellular immune function. CD4⁺ T lymphocytes were helper T lymphocytes that secreted a variety of cytokines to assist other immune cells and enhance the body’s immune tolerance. CD8⁺ T cells, also known as cytotoxic T cells, could directly kill target cells, but their activation required the assistance of CD4⁺ T cells and were an extremely important part of the body’s anti-tumor mechanism. The CD4⁺/CD8⁺ ratio was related to the body’s cellular immune homeostasis; a ratio above the normal level suggested an overactive immune function, while a value below indicated a weakened immune function. CD8⁺ T cells were at the forefront of the interaction between the body’s immune system and tumor cells in local anti-tumor immunity, and their functional characteristics reflected the nature, intensity, and overall level of the body’s anti-tumor response to a certain extent (39,40). CD3⁺CD4⁺CD8⁺ T cells, termed double-positive T (DPT) cells, were normally located in the thymic cortex and represent an immature stage of T cell development. Peripheral DPT cells, in contrast, were “unconventional mature T cells”; they were scarce in healthy individuals but expanded markedly in autoimmunity, infection, transplant rejection, or malignancy, where they exerted both helper and cytotoxic functions (41). CD3⁺CD4⁻CD8⁻ T cells, known as double-negative T (DNT) cells, included TCRαβ⁺ DNT cells as the predominant subset in peripheral blood; these possessed immunosuppressive capacity and inhibited autoimmune responses by secreting IL-10 or TGF-β (42). In this study, significant differences in peripheral blood immune cell counts across BMI groups were observed only for CD8⁺ T cells and DNT cells, both of which were lower in overweight patients than in the other two BMI groups. We posited that the reduction in circulating CD8⁺ T cells did not reflect a “loss of function”, but rather their egress to the tumor bed and subsequent conversion into tissue-resident memory or exhausted phenotypes (PD-1⁺LAG-3⁺TIM-3⁺). Although these cells were depleted in the periphery, they might retain appreciable antitumor activity within the TME, consistent with the findings of Alden et al. (43). Moreover, the more favorable nutritional status associated with overweight could improve, to some extent, the competition for tryptophan, arginine, and oxygen between immune and tumor cells, thereby enhancing CD8⁺ T cell efficacy and reducing the body’s reliance on ineffective CD8⁺ T cells. As a result, the level of peripheral blood CD8⁺ T cells was significantly reduced (44). The decrease in DNT cells, on the other hand, might mirror a waning systemic inflammatory or immunosuppressive milieu. DNT cells could exert regulatory or suppressive functions in certain cancers, so their reduction could relieve inhibition and permit effector T cell reinvigoration. Indeed, in melanoma patients who received immune-checkpoint inhibitors, responders exhibited a marked drop in peripheral DNTs alongside augmented CD4⁺ and CD8⁺ T cell functionality, which suggested that DNT depletion served as a biomarker of restored antitumor immunity (45). Overweight individuals often harbored low-grade systemic inflammation; visceral adipose tissue secreted IL-6, TNF-α, and other mediators that suppressed DNT proliferation and promoted apoptosis. Additionally, obesity-driven expansion of M1 macrophages further amplified inflammatory signaling and contributed to DNT attrition (46,47).

ALT was one of the most commonly used and sensitive indicators for liver function testing. Under normal conditions, the concentration of ALT in the human bloodstream was very low, and it only increases when liver cells were damaged or the permeability of the hepatocyte membrane increases. GGT was mainly distributed in solid organs such as the kidney, liver, and pancreas. In the liver, GGT was mainly localized in the microsomes of the bile canaliculi and hepatocytes, which was used for the diagnosis of space-occupying liver diseases and liver parenchymal damage (such as chronic hepatitis) (48,49). Previous studies have shown that an increase in BMI can lead to liver dysfunction and even non-alcoholic fatty liver disease (50,51). However, this study found that although ALT and GGT levels differed significantly between the overweight group and the low/normal weight group, the ranges in the former were 7–58 U/L for ALT and 7–164 U/L for GGT. These elevations were only mild (all <3× upper limit of normal) and had not reached the threshold for clinically significant hepatic dysfunction. In contrast, serological markers reflecting renal function showed no significant differences across BMI groups.

Further serum biochemical analyses revealed metabolic differences across BMI groups: HCO₃⁻ levels were modestly lower, whereas glucose levels were slightly elevated in the overweight group, and these subtle changes nonetheless produced significant inter-group differences. This might be due to the fact that patients with high BMI were in a state of chronic, mild inflammation, with elevated levels of pro-inflammatory cytokines, especially TNF, which were negatively correlated with insulin sensitivity (52,53). Moreover, the increase in fat mass could lead to elevated levels of free fatty acids in the blood, affecting the recovery of blood vessels. Progressive microvascular dysfunction could lead to insulin resistance, which in turn caused abnormally increased blood sugar. On the other hand, the uncontrolled growth of fat cells could lead to hypoxia and dysregulation of glycolipid metabolism, which in turn exacerbated the acidosis of the microenvironment, leading to the consumption of HCO₃⁻ by hydrogen (54,55). Although elevated blood glucose provided a relatively abundant nutritional supply, an acidic milieu promoted the expression of HIF-1α and VEGF, enhancing tumor invasion and angiogenesis, whereas elevated glucose stimulated tumor-cell proliferation and inhibited apoptosis via the PI3K/AKT, MAPK, and NF-κB pathways (56,57). Taken together, these metabolic alterations portended a worse prognosis. Therefore, we must emphasize the importance of modest perioperative weight gain, as being merely overweight—rather than obese—was more likely to confer a more favorable outcome.

Weight gain was reported to be closely associated with an increased risk of various postoperative complications in CRC patients: postoperative weight gain was significantly linked to a higher incidence of postoperative ileus, and patients with visceral obesity (VO) showed significantly higher rates of postoperative complications—anastomotic leakage, ileus, intra-abdominal abscess, and wound infection—than non-VO patients (58,59). Therefore, this study also focused on postoperative complications and length of hospital stay, but found no significant differences in either the incidence of complications or the duration of hospitalization among different BMI groups; modest weight gain did not worsen the postoperative course in CRC patients.

There were some limitations in this study: (I) its single-center, retrospective design was prone to selection bias. (II) Extensive clinical data collection combined with strict inclusion and exclusion criteria resulted in a relatively small sample size. (III) The long follow-up period inevitably led to a non-negligible loss-to-follow-up rate (11.69%); future studies should enroll a larger cohort to reduce this proportion. (IV) Only BRAF mutation and MMR status were routinely assessed; RAS mutation and MSI testing were not performed in all patients, and the absence of these established prognostic factors may introduce confounding. (V) Patients were stratified solely by BMI, without incorporating central adiposity measures such as waist-to-hip ratio or waist circumference, which previous studies have shown to be superior to BMI in predicting CRC incidence, progression, and prognosis (60,61). (VI) Although our findings indicated that an overweight BMI was an independent protective factor against recurrence/progression and death, with significantly better RPFS and OS in overweight patients, the proposed mechanism—reprogramming of the immune-metabolic milieu via the “fat-immune-metabolic axis”—remained speculative, having been inferred only from routine blood parameters and prior literature. Experimental validation through basic and translational research was warranted.

In summary, the most important finding of this study was that overweight CRC patients had significantly better RPFS and OS, without evident impairment of hepatic or renal function, electrolyte disturbances, or adverse postoperative courses. Therefore, we believed that modest perioperative weight gain could help patients achieve superior outcomes. Moreover, by integrating multiple routine peripheral blood parameters for the first time, we proposed that this phenomenon might stem from an appropriately activated immune response and adequate nutritional reserves. Although robust experimental evidence was still lacking, the present study—grounded in previous literature and comprehensive hematological data—offered a plausible mechanistic hypothesis and provided a conceptual framework for future in-depth investigations.

Conclusions

Overweight patients with CRC exhibited significantly better RPFS and OS, possibly owing to a mild systemic inflammatory milieu, an appropriately primed immune status, and a favorable nutritional condition. Moreover, modest perioperative weight gain did not increase postoperative complications or length of stay. Therefore, CRC patients might benefit from controlled weight gain during the perioperative period, and clinicians should devise individualized weight-management strategies based on each patient’s profile to optimally balance potential benefits and risks.

Acknowledgments

The authors appreciate all of the staff involved in the preparation of the study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-351/rc

Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-351/dss

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-351/prf

Funding: This work was supported by the National Natural Science Foundation of China (No. 82273125), the Natural Science Foundation of Chongqing, China (No. CSTB2022NSCQ-MSX0803), and the High-level Medical Reserved Personnel Training Project of Chongqing (No. 2023GDRC009).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-351/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was reviewed and approved by Ethics Committee of The First Affiliated Hospital of Chongqing Medical University (No. 2020-444). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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