Complications of microwave ablation in patients with persistent/recurrent hyperparathyroidism after surgical or ablative treatment

Abstract

Objective

To evaluate the complications associated with microwave ablation (MWA) in treating persistent/recurrent hyperparathyroidism (HPT) post-surgical or ablative treatments.

Materials and methods

From January 2015 to December 2022, 87 persistent/recurrent HPT patients (primary HPT [PHPT]: secondary HPT [SHPT] = 13:74) who underwent MWA after surgical or ablative treatment were studied. Grouping was based on ablation order (initial vs. re-MWA), prior treatment (parathyroidectomy [PTX] vs. MWA), and etiology (PHPT vs. SHPT). The study focused on documenting and comparing treatment complications and analyzing major complication risk factors.

Result

Among the 87 patients, the overall complication rate was 17.6% (15/87), with major complications at 13.8% (12/87) and minor complications at 3.4% (3/87). Major complications included recurrent laryngeal nerve (RLN) palsy (12.6%) and Horner syndrome (1.1%), while minor complications were limited to hematoma (3.4%). Severe hypocalcemia noted in 21.6% of SHPT patients. No significant differences in major complication rates were observed between initial and re-MWA groups (10.7% vs. 13.8%, p = 0.455), PTX and MWA groups (12.5% vs. 15.4%, p = 0.770), or PHPT and SHPT groups (15.4% vs. 13.5%, p > 0.999). Risk factors for RLN palsy included ablation of superior and large parathyroid glands (>1.7 cm). All patients recovered spontaneously except for one with permanent RLN palsy in the PTX group (2.1%).

Conclusion

Complication rates for MWA post-surgical or ablative treatments were comparable to initial MWA rates. Most complications were transient, indicating MWA as a viable and safe treatment option for persistent/recurrent HPT patients.

Keywords:

• Microwave ablation
• complication
• hyperparathyroidism
• recurrent laryngeal nerve

Introduction

Hyperparathyroidism (HPT) leads to elevated levels of parathyroid hormone (PTH), disrupting normal calcium and phosphorus metabolism. This imbalance can cause extensive damage to various body systems, significantly impacting patients’ quality of life and survival duration [1]. Traitionally, parathyroidectomy (PTX) has been adopted as a standard therapy for drug-resistance HPT [2,3]. In recent years, US-guided microwave ablation (MWA) has emerged as a promising alternative, demonstrating encouraging results in HPT management [4–7].

However, the occurrence of persistent or recurrent HPT is notably higher following both PTX and MWA. Contributing factors to this issue include the presence of ectopic HPT lesions, inaccurate preoperative localization, omission of small lesions, and operator inexperience. Research indicates that the rate of persistent or recurrent primary HPT (PHPT) post-PTX is approximately 14.8% [8], and post-MWA, it reaches 19.7% [9,10]. Similarly, for secondary HPT (SHPT), these rates are about 20% following PTX [11] and escalate to 35.9% after MWA [6,12,13]. Persistent or recurrent HPT affects patient quality of life and long-term survival. When conservative medical therapies are ineffective, re-PTX becomes a necessary intervention [14].

Nevertheless, re-PTX presents greater technical challenge than the initial procedure, mainly due to missed diagnose, ectopic gland locations and intricate surgical difficulties like complex neck adhesion. These factors contribute to an elevated risk of complications, including recurrent laryngeal nerve (RLN) injuries. Consequently, some guideline recommends avoiding re-PTX when possible [15].

MWA offers a novel approach to managing persistent or recurrent HPT [16]. However, there is a notable gap in research regarding the complications associated with MWA in patients who have previously undergone surgical or ablative treatments for persistent/recurrent HPT. This study aims to address this gap by compiling and analyzing clinical data from patients who received MWA post-surgical or ablative treatments. Our primary focus is to assess the complications arising from MWA and screening out any potential risk factors associated with these outcomes.

Materials and methods

Patients

This retrospective study, approved by the Human Ethics Review Committee of China-Japan Friendship Hospital (2015-GZR-77), analyzed the medical records of 528 HPT patients treated with MWA from January 2015 to December 2022. The focus was on patients who underwent MWA for persistent/recurrent HPT following surgical or ablative treatments. Participants were categorized into groups based on the order of ablation (initial vs. re-MWA), previous treatments (parathyroidectomy [PTX] vs. MWA), and etiology (PHPT vs. SHPT). All patients provided written informed consent before MWA, and the requirement to obtain informed consent for study inclusion was waived because the personal details were kept confidential.

Inclusion and exclusion criteria

The inclusion criteria were as follows: (1) persistent/recurrent HPT after surgical or ablative treatment; (2) enlarged parathyroid gland detected by preoperative imaging (ultrasound and positive technetium 99-m-labeled sestamibi single-photon emission computed tomography [99mTc-sestamibi SPECT] results); (3) refusal or ineligibility for PTX; and (4) follow-up time more than 6 months [3,17].

The exclusion criteria were as follows: (1) abnormal results of coagulation function (prothrombin time < 18 s, prothrombin activity > 60%, and platelet count < 60 × 10⁹ cells/L); (2) severe cardiopulmonary dysfunction; or (3) more than one prior HPT operation (Figure 1).

Figure 1. Patient flowchart. Note: MWA: microwave ablation; PTX: parathyroidectomy; HPT: hyperparathyroidism; PHPT: primary hyperparathyroidism; SHPT: secondary hyperparathyroidism; RLN: recurrent laryngeal nerve.

MWA procedures

The same procedure was used for the initial and re-MWA. Patients were placed in a supine position with the neck extended. Contrast-enhanced US (CEUS) was performed to evaluate the enhancement pattern of HPT lesions. The ablation site was sterilized and draped with sterile towels. First, an 18-gauge PTC needle (Hakko Medical) was inserted into the area around the HPT lesion to provide hydrodissection (a slow continuous infusion of saline was administered between the parathyroid and adjacent critical structures to maintain a safe distance of at least 0.5 cm). Then, a lidocaine and NS mixture (1:3) was administered near the parathyroid capsule as topical anesthesia. A 17 G cooled MWA antenna with a 3-mm active tip (Intelligent Basic Type Microwave Tumor Ablation System, Nanjing ECO Microwave System) was used for ablation. A multipoint ablation technique was adopted. The power was 30 W, and the radiation time was 15–20 s at each point. The therapy was terminated when the hyperechoic zone covered the entire HPT lesion. CEUS was performed 3–5 min later to assess the efficacy of MWA. Complete ablation was achieved if a nonenhanced zone covered the whole ablated HPT lesion on CEUS; if there was enhancement inside the ablation zone, additional ablation was performed immediately. For patients with bilateral HPT lesions, contralateral side ablation was performed only if vocal cord movement was normal on US and no RLN palsy was noted after ablation on one side.

Follow-up

Follow-up included US examination and blood biochemistry assessments, specifically measuring serum intact PTH [iPTH], calcium and phosphate levels, at intervals of 1 day, 1 month, 3 months and 6 months after ablation and then at the end of follow-up. CEUS was conducted only when US indicated suspicious local recurrence or new HPT lesions. All complications encountered during the treatment and throughout the follow-up were meticulously documented.

Definition of complications and effectiveness

The definitions of complications were consistent with the standardization of terminology and reporting criteria for image-guided tumor ablation [18,19]. A major complication was defined as one that might threaten the patient’s life, lead to substantial morbidity or disability, require an increased level of care, or result in hospital admission or substantially delayed hospital discharge. All other complications were considered minor [20]. Persistent hoarseness was defined as any RLN palsy at 6 months postoperation [21,22]. Severe hypocalcemia was defined as a serum calcium value less than 1.875 mmol/L [23,24].

In PHPT patients, cure was defined as reestablishment of normal values of serum calcium and iPTH within 6 months [3]. In SHPT patients, effectiveness was defined as achieving postoperative iPTH levels in the target range of less than 300 pg/mL [2,25].

Definition of persistent and recurrent HPT

Persistent PHPT referred to a failure to achieve normal serum calcium or iPTH within 6 months, and recurrent PHPT referred to the recurrence of hypercalcemia and/or an elevated iPTH level after 6 months [3]. Persistent SHPT referred to the lowest iPTH level remaining higher than 300 pg/mL after the operation, and recurrent SHPT referred to the iPTH level being lower than 300 pg/mL within 6 months after the operation and becoming elevated again 6 months later [26].

Outcomes

The primary outcome of the study was to (i) assess and compare the incidence of complications during MWA across different patient groups, and (ii) identify risk factors contributing to major complications, specifically RLN palsy. The secondary outcome was evaluating the effectiveness of MWA in the treatment of HPT.

Statistical analysis

Statistical analyses were performed using SPSS version 20.0 (IBM, Armonk) and Stata version 15.0 (StataCorp LLC). Descriptive statistics are presented as either the mean ± standard deviation or the median for continuous variables and as the frequency and percentage for categorical variables. Student’s t-tests and independent Mann–Whitney U tests were used to compare continuous variables, and the Chi-square test was used for categorical variables. Logistic stepwise regression with the forward selection of variables was adopted to screen out the risk factors for RLN palsy. All tests were two sided, with p < 0.05 considered to indicate a statistically significant difference.

Results

Baseline characteristics

Eighty-seven patients with persistent/recurrent HPT (PHPT: SHPT = 13:74) who underwent MWA from January 2015 to December 2022 were enrolled. There were 40 males and 47 females. The mean age was 51.9 ± 12.5 years (range, 26–76 years). A total of 55.2% of patients (48/87) had undergone prior PTX and 44.8% (39/87) had previous MWA treatment. A total of 119 HPT lesions were ablated in 87 patients, which included 100 in regular locations and 19 in ectopic locations. The median maximum diameter of the HPT lesions was 1.4 cm ((interquartile range [IQR], 0.6–2.8 cm).

MWA was successfully performed in all 87 patients at a median time of 12.9 months (range, 2.5–96 months) after the initial treatment. The median ablation time per lesion was 159 s (range, 49–428 s). The median follow-up duration was 16.7 months (IQR, 11.6–38.6 months). In the SHPT group, the effectiveness rate was 74.3% (55/74). In the PHPT group, the cure rate was 84.6% (11/13). For the two cases where HPT persisted post-MWA, subsequent follow-up using US and MIBI scans did not detect any new HPT lesions.

Overall complications

No ablation-related deaths occurred during the perioperative period. The incidence of complications across different groups is detailed in Table 1. According to different grouping, the overall complication rate was 12.0% (53/441) in the initial MWA group and 17.2% (15/87) in the re-MWA group (p = 0.219), 14.6% (7/48) in the PTX group and 20.5% (8/39) in the MWA group (p = 0.572), 15.4% (2/13) in the PHPT group and 17.6% (13/74) in the SHPT group (p > 0.999) (Table 2). There was no significant difference regarding the overall complication rates among the various groups.

Table 1. Complications and side effects in 87 HPT patients who underwent re-MWA.

Complication or side effect	Number (%)					Time of detection (D)	Time to recovery (D)
	Total (87)	PHPT (13)	SHPT (74)	PTX (48)	MWA (39)
Major	12 (13.8)	2 (15.4)	10 (13.5)	6 (12.5)	6 (15.4)	1–3	30–180
RLN palsy	11 (12.6)	2 (15.4)	9 (12.2)	5 (10.4)	6 (15.4)	1–2	30–180
Horner syndrome	1 (1.1)	–	1 (1.4)	1 (2.1)	–	3	180
Minor	3 (3.4)	–	3 (4.1)	1 (2.1)	2 (5.1)	1	1–7
Hematoma	3 (3.4)	–	3 (4.1)	1 (2.1)	2 (5.1)	1	1–7
Side effect	16 (18.4)	6 (46.2)	10 (13.5)	9 (18.7)	7 (18.4)	1–7	1–30
Pain	3 (3.4)	–	3 (4.1)	1 (2.1)	2 (5.2)	1	1–3
Numbness	8 (9.2)	8 (61.5)	–	3 (6.3)	5 (12.8)	1–3	1–30
Hypoparathyroidism	5 (5.7)	1 (7.7)	4 (5.4)	3 (6.3)	2 (5.2)_	1–7	3–14
Severe hypocalcemia	16 (18.4)	–	16 (21.6)	11 (22.9)	5 (12.8)	1–7	3–180

Note: PTX: parathyroidectomy; MWA: microwave ablation; SHPT: secondary hyperparathyroidism; PHPT: primary hyperparathyroidism; RLN: recurrent laryngeal nerve.

Table 2. Comparison of complications between different groups.

Complications	Number (%)		p	Number (%)		p	Number (%)		p
	PHPT (13) vs. SHPT (74)			PTX (48) vs. MWA (39)			Initial MWA (441) vs. Re-MWA (87)
Overall	2 (15.4)	13 (17.6)	>.999	7 (14.6)	8 (20.5)	.572	53 (12.0)	15 (17.2)	.219
Major	2 (15.4)	10 (13.5)	>.999	6 (12.5)	6 (15.4)	.770	47 (10.7)	12 (13.8)	.455
Minor	0 (0)	3 (4.1)	>.999	1 (2.1)	2 (5.1)	.585	6 (1.4)	3 (3.4)	.172

Note: PTX: parathyroidectomy; MWA: microwave ablation; SHPT: secondary hyperparathyroidism; PHPT: primary hyperparathyroidism.

Major complications

The incidence of major complications following subsequent MWA was 13.8% (12/87). By group, the major complication rate was 12.5% (6/48) in the PTX group,15.4% (6/39) in the MWA group (p = 0.770), 15.4% (2/13) in the PHPT group and 13.5% (10/74) in the SHPT group (p > 0.999) (Table 2).

Of these 12 patients (13.8%,12/87) with major complications, 11 (12.6%, 11/87) experienced RLN palsy, comprising 10 cases of temporary RLN palsy (11.5%, 10/87) and one case of permanent RLN palsy (1.1%, 1/87). Additionally, one patient (1.1%) developed slightly Horner syndrome. Significantly, 72.7% (8/11) of the patients with RLN palsy had superior parathyroid glands located close to the RLN. Among the SHPT patients with RLN palsy, two had a history of PTX, and for them, hydrodissection during MWA was difficult to perform due to postoperative adhesions (Figure 2). All patients’ symptoms recovered completely 1–6 months after MWA except one patient who developed permanent hoarseness, dysphonia and abnormal tonality during the follow-up period.

Figure 2. Postoperative adhesion during hydrodissection. A 39-year-old patient with SHPT and a previous PTX history underwent hydrodissection using a 18G PTC needle (white arrowhead). Within the echoless isolation fluid, several cord-like hyperechoic bands (yellow arrows) were observed, pulling the SHPT lesion (white arrows) and the surrounding structures. Note: SHPT: secondary hyperparathyroidism; PTX: parathyroidectomy; CCA: common carotid artery; IJV: internal jugular vein.

Minor complications and side effects

Hematomas as the exclusive minor complication occurred in 3 SHPT patients (3/87, 3.4%), 1 in the PTX group (1/48, 2.1%) and 2 in the MWA group (2/39, 5.1%). There was no significant difference in minor complications between the PTX group and MWA group (p = 0.585) (Table 2). All patients recovered without management within 2 weeks.

Severe hypocalcemia

Severe hypocalcemia occurred in 16 cases (16/74, 21.6%) in the SHPT group but did not occur in the PHPT group. Among these cases of severe hypocalcemia, 11 (11/48, 22.9%) were in the PTX group, and 5 (5/39, 12.8%) were in the MWA group. There was no significant difference in severe hypocalcemia between the PTX and MWA groups (p = 0.274). After receiving oral calcium supplementation, intravenous calcium gluconate and high calcium dialysis fluids, all patients recovered within 6 months.

Risk factors for RLN palsy

A comparison of variables between patients with and without RLN palsy is summarized in Table 3. RLN palsy was more prevalent in HPT patients who underwent ablation of superior parathyroid glands (p = 0.007) and those with larger parathyroid glands (p = 0.03) (Table 4). Receiver Operating Characteristic (ROC) analysis revealed that a maximum diameter greater than 1.7 cm significantly increases the risk of RLN palsy, offering the highest Youden index values. The time interval between operations (p = 0.093) and the type of previous operations (p = 0.531) was not significantly associated with RLN palsy after MWA (Table 3). Consequently, the risk factors for RLN palsy were ablation of superior and large parathyroid glands. The cutoff value of the maximum parathyroid diameter is 1.7 cm.

Table 3. Comparison of relevant clinical parameters between patients with and without RLN palsy.

Variables	With RLN palsy (11)	Without RLN palsy (76)	p
Baseline
Female (n)	5	42	0.748
Age (years)	52.8 ± 12.6	45.9 ± 11.3	0.087
History of operation (PTX/MWA)	5/6	43/33	0.531
PHPT/SHPT	2/10	11/64	>0.999
Time interval (months) second operation	23.7 (2.9–84.0)	12.7 (2.3–99.6)	0.093
Laboratory examination
Pre-MWA iPTH (pg/mL)	1014.0 (116.2–2907.6)	766.0 (103.2–3273.1)	0.609
Serum calcium (mmol/L)	2.4 ± 0.3	2.5 ± 0.3	0.314
Serum phosphorus (mmol/L)	1.9 ± 0.6	1.6 ± 0.7	0.160
ALP (U/L) regenerative growth	163 (35–1639)	126 (54–973)	0.964
Parathyroid glands
No. of glands (n)	1 (1–3)	1 (1–3)	0.183
Bilateral (n)	3	12	0.394
Superior glands (n)	8	24	0.016
Max diameter (cm)	2.0 ± 0.5	1.6 ± 0.7	0.081
Ablation time per gland (s)	179 (71–426)	159 (47–424)	0.471

Note: PTX: parathyroidectomy; MWA: microwave ablation; iPTH: intact parathyroid hormone. ALP: alkaline phosphatase; RLN: recurrent laryngeal nerve.

Table 4. The factors influencing the development of RLN palsy.

Variables	OR	SE	p	95% CI
Female (n)	0.433	0.418	0.386	(0.065–2.875)
Age (years)	0.948	0.043	0.238	(0.867–1.036)
History of operation (PTX/MWA)	1.628	1.469	0.589	(0.278–9.545)
Time interval (months)	1.006	0.012	0.637	(0.982–1.030)
Pre-MWA iPTH (pg/mL)	0.999	0.001	0.109	(0.997–1.000)
Serum calcium (mmol/L)	0.107	0.177	0.178	(0.004–2.767)
Serum phosphorus (mmol/L)	3.580	3.050	0.134	(0.674–19.016)
ALP (U/L)	1.002	0.002	0.278	(0.998–1.006)
No. of glands (n)	0.196	0.229	0.164	(0.020–1.939)
Bilateral (n)	6.350	12.126	0.333	(0.150–267.990)
Superior glands (n)	23.696	27.700	0.007	(2.397–234.256)
Max diameter (cm)	5.662	4.520	0.030	(1.184–27.071)
Ablation time per gland (s)	0.999	0.004	0.725	(0.991–1.006)

Note: PTX: parathyroidectomy; MWA: microwave ablation; iPTH: intact parathyroid hormone; ALP: alkaline phosphatase; RLN: recurrent laryngeal nerve.

Discussion

Reoperation on patients with persistent/recurrent HPT after the initial operation presents significant challenges, including difficulties in precise preoperative localization, distorted anatomy, scarring and adhesions. Common complications after reoperation for HPT include RLN palsy, permanent hypoparathyroidism, hypocalcemia, bleeding and even death, with a 30-day mortality rate of 3.1% [27]. Therefore, the decision to perform reoperation must carefully weigh these risks against the severity of the disease. Given these challenges, there is an urgent need for new treatment strategies for persistent/recurrent HPT.

Over the past decade, thermal ablation techniques such as MWA and radiofrequency ablation have been increasingly utilized in the management of HPT [7,12]. MWA, as an alternative treatment option, offers several advantages including minimally invasiveness, effectiveness and safety [5,28]. Yu et al. in 2016, reported promising outcomes from using MWA in treating persistent/recurrent HPT in a small sample [16]. Similarly, radiofrequency ablation for persistent and recurrent SHPT has demonstrated encouraging outcomes in a small cohort with a mean follow-up of 49.6 ± 34.5 months [29]. However, to date, a comprehensive study focusing on the complications associated with MWA in patients with persistent or recurrent HPT following surgical or other ablative treatments has not been conducted.

In this retrospective study, MWA was successfully performed in all 87 HPT patients at a median of 12.9 months after the initial operation. In patients with SHPT, the effectiveness rate of treatment was 74.3%. This rate is somewhat less compared to the 89% effectiveness observed following re-PTX [30,31]. Similarly, in PHPT patients, the cure rate was recorded at 84.6%, marginally lower than the 95% cure rate achieved after re-PTX. MWA is a minimally invasive and safe treatment, effectiveness can be achieved through fractionated treatments.

RLN palsy is the common major complication of concern in the treatment of HPT. Transient RLN palsy occurs in approximately 12.6% of cases following MWA in the present study, a rate comparable to the 11% observed in repeat minimally invasive PTX. Notably, permanent RLN palsy is less common after MWA, with an incidence of just 1.1%, which is significantly lower than the 6.8% rate reported in patients receiving subsequent re-PTX treatments [32,33]. Additionally, in the present study, there was no ablation-related death. All these results indicated that MWA is safe in patients with persistent/recurrent HPT after surgical or ablative treatment.

Generally, the operative risks are generally higher in SHPT compared to PHPT, mainly due to the long-term dialysis, multiple comorbidities, poor general health, and multiple lesions typically present in SHPT patients. The complication risk is even more pronounced in reoperations for persistent/recurrent SHPT than that in initial operation. Nevertheless, the results of the subgroup analysis revealed no significant differences in the incidence of overall, major, or minor complications between the PHPT and SHPT groups post-MWA treatment. This finding suggests that MWA, even for SHPT patients who are in a weakened state following surgical or ablative treatments, is a viable and safe treatment option for managing persistent/recurrent HPT.

Reoperations for persistent/recurrent HPT present unique challenges compared to initial PTX, particularly due to complex neck adhesions in some patients. In the present study, two patients with previous PTX histories experienced difficulties with hydrodissection due to postoperative adhesions. Despite these challenge, MWA was still successfully and safely performed in these two cases. Further subgroup analyses revealed no significant differences in the incidence of overall, major or minor complications between patients previously treated with PTX and those who underwent MWA. This outcome underscores MWA’s minimally invasive and repeatable nature, affirming its role as a viable alternative therapy for persistent/recurrent HPT, unaffected by previous surgical interventions.

The results of this study indicate that complications from MWA in treating persistent/recurrent HPT are relatively low, predominantly transient, and within acceptable limits. In thermal ablation, major complications typically arise from thermal injury. Based on our experience, several strategies can enhance the safety of ablation treatment. Firstly, implementing hydrodissection to distance the parathyroid gland from surrounding critical structures can significantly reduce the risk of thermal damage to nerves. Secondly, employing a multiple-point technique is advisable over the moving-shot method, especially given the typically small size of HPT glands. Finally, utilizing repeated ablation cycles with a lower power setting of 30 W and shorter radiation durations of 15–20 s can help prevent thermal injury to surrounding vital structures.

As one of the major complications after MWA, RLN palsy was encountered in 12.6% patients [15]. Multifactor analysis identified two primary risk factors for RLN palsy: ablation of superior parathyroid glands and the treatment of larger parathyroid glands (with a maximum diameter greater than 1.7 cm). Typically, the RLN is positioned behind the inferior parathyroid glands and in front of the superior glands. When ablated superior parathyroid glands, the establishment of hydrodissection tends to push both the HPT lesion and the RLN forwards and laterally. Given that the ablation antenna is usually inserted anteriorly from the central or lateral neck, there is an increased risk of RLN stimulation from the energy directed posteriorly. Consequently, ablations of superior glands carry more risk [15,34]. For larger parathyroid glands, the extended ablation time and cumulative higher energy used may heighten the chances of thermal stimulation to the RLN.

There are a few limitations in the present study. First, this was a retrospective study, and observational studies cannot escape selection bias. Second, the number of MWA procedures was relatively small, and future studies with large sample sizes might help to provide more definitive results.

Conclusion

The complication rate associated with MWA after either surgical or ablative treatments for HPT was comparable to that observed in initial MWA procedures. Notably, the majority of these complications were transient in nature. This finding underscores MWA's viability as a treatment option for patients with persistent or recurrent HPT, highlighting its favorable safety profile.

Ethical approval

Our retrospective study was approved by the institutional review board of our hospital. Written informed consent was obtained from each patient before the ablation procedure. The patients consented to publishing their examination results and radiological images anonymously and the written informed consent for publication of their data was waived by ethics committee of China-Japan Friendship Hospital.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

Additional information

Funding

This work was funded by National High Level Hospital Clinical Research Funding, Elite Medical Professionals Project of China-Japan Friendship Hospital [NO. ZRJY2023-GG19], National High Level Hospital Clinical Research Funding [grant 2023-NHLHCRF-YYPP-TS-01], National High-Level Hospital Clinical Research Funding [2022-NHLHCRF-PY-07], Beijing Research Ward Project [2022-YJXBF-04-04], and The National Natural Science Foundation of China [62176268].