Abstract
Background
Preoperative CT-guided percutaneous localization of pulmonary nodules is widely used in clinical practice but is often associated with localization-related complications. Intraoperative titanium clip localization may provide a safer localization strategy. This study aimed to compare the effectiveness and safety of these two approaches.
Methods
This single-center prospective cohort study included 189 patients who underwent pulmonary nodule resection after localization between October 2023 and November 2025. Patients were divided into an intraoperative titanium clip localization group (n = 123) and a preoperative medical glue localization group (n = 66) based on the localization method. Localization success rate, localization-related complications, and perioperative outcomes were analyzed.
Results
A total of 252 pulmonary nodules were localized. The intraoperative group demonstrated a significantly higher localization success rate than the preoperative group (99.4% vs. 89.0%; OR, 18.07; 95% CI, 2.18–149.84; P = 0.007), along with a lower incidence of localization-related complications (0% vs. 30.3%; OR, 0.004). However, the duration of general anesthesia was longer in the intraoperative group (196.34 ± 54.46 vs. 162.76 ± 57.19 min; P = 0.001). There were no significant differences in postoperative drainage volume, postoperative complication rates, or length of hospital stay between the two groups.
Conclusions
Intraoperative titanium clip localization demonstrated a higher localization success rate and a lower incidence of localization-related complications. It may have potential value for simultaneous localization of multiple pulmonary nodules. However, this approach was associated with a longer duration of general anesthesia.
Introduction
Lung cancer is one of the major malignancies threatening human health. According to the latest data released by the National Cancer Center of China in 2024, the incidence and mortality rates of lung cancer rank first among malignant tumors [1]. In recent years, the promotion of low-dose spiral CT lung cancer screening programs has significantly improved the early diagnosis rate of lung cancer, and early surgical intervention has effectively improved the prognosis of patients with early-stage lung cancer [2–5]. Studies have shown that the 5-year disease-specific survival rate after complete resection of adenocarcinoma in situ and minimally invasive adenocarcinoma can reach 100% [6]. However, early-stage lung cancers are usually small in size, making intraoperative identification of pulmonary nodules challenging. When pulmonary nodules are located more than 15 mm from the pleural surface, nearly 60% of nodules cannot be located by visual inspection or finger palpation during surgery. In such cases, auxiliary localization techniques are required to facilitate successful resection of the pulmonary nodules [7]. Therefore, accurate localization of these lesions is crucial to ensure precise surgical resection.
The main localization methods for pulmonary nodules include CT-guided percutaneous localization techniques, such as hookwire localization, coil localization, and injection of liquid materials; bronchoscopic localization techniques; and CT-based virtual three-dimensional localization techniques [8]. Among these methods, CT-guided percutaneous localization is the most widely used. Based on the timing of localization, these techniques can be categorized into preoperative localization and intraoperative localization. Preoperative localization is usually performed in the CT suite, where patients undergo percutaneous localization under local anesthesia before being transferred to the operating room for pulmonary nodule resection. The interval between completion of localization and skin incision ranges from several minutes to one or two days. This period, known as the “risk time”, is when complications such as pneumothorax and hemorrhage are most likely to occur, and there is also a risk of marker dislodgement [9, 10]. Intraoperative localization was first proposed by Gill et al. in 2015 [11]. Its core concept is to complete both localization and resection of pulmonary nodules sequentially in a hybrid operating room, thereby avoiding patient transfer, significantly shortening the risk time, and reducing the occurrence of complications.
The Department of Thoracic Surgery at Beijing Hospital performs both preoperative and intraoperative localization techniques. Preoperative localization utilizes percutaneous liquid material injection, with medical glue being the chosen liquid material. Although this technique has been widely applied in clinical practice, it still carries risks of complications such as pneumothorax and pulmonary parenchymal hemorrhage [12–18]. To address this issue, our department introduced an intraoperative titanium clip localization technique that avoids percutaneous puncture-related complications. This localization method is pioneered by our department, and currently only our own research data and a small number of similar studies are available [19]. Preliminary clinical practice has shown that intraoperative titanium clip localization achieves a high localization success rate with a low incidence of complications [20]. This study systematically compares the clinical performance of intraoperative titanium clip localization and preoperative medical glue localization in pulmonary nodule surgery, aiming to evaluate differences in the efficacy and safety of the two localization methods and to provide a more optimized localization strategy for clinical practice.
Methods
This study was a single-center prospective cohort study that included 189 patients who underwent pulmonary nodule resection after localization between October 2023 and November 2025. According to the localization method used, patients were divided into an intraoperative titanium clip localization group (n = 123) and a preoperative medical glue localization group (n = 66). The choice of localization technique was primarily determined by the availability of the hybrid operating room. As the hybrid operating room was available to the Department of Thoracic Surgery only on Tuesdays, patients whose clinical condition allowed their surgery to be appropriately rescheduled to Tuesday underwent intraoperative titanium clip localization, whereas those scheduled at other times underwent preoperative medical glue localization.
The main inclusion criterion was the need for pulmonary nodule localization before surgical resection based on imaging evaluation. The main exclusion criterion was severe organ dysfunction that precluded tolerance of surgery. The imaging criteria for pulmonary nodules requiring localization were as follows: pure ground-glass nodules; part-solid nodules with a solid component of < 50%; part-solid nodules with a solid component of > 50% but a diameter of < 1 cm; and solid nodules with a diameter of < 1 cm. The imaging exclusion criteria were as follows: nodules with obvious pleural traction signs or nodules located in the inner one-third of the lung field. The main study workflow is shown in the figure below (Fig. 1).
Fig. 1.
Main study flowchart
The primary outcomes of this study were the effectiveness and safety of localization.
Localization effectiveness was assessed by the localization success rate at the nodule level. Successful localization was defined as meeting the following criteria:
the localization marker could be identified intraoperatively, and both the pulmonary nodule and the localization marker were successfully resected according to the marker position, with nodule resection confirmed by postoperative pathology;
the localization marker did not migrate or dislodge from the completion of localization to the end of surgery.
The localization success rate=Number of nodules localized successfully / Number of nodules requiring localization.
Safety was evaluated by comparing localization-related complications at the patient level. These complications included pneumothorax, pulmonary parenchymal hemorrhage, air embolism, and other unexpected events.
Pneumothorax was defined as abnormal accumulation of air between the visceral and parietal pleura during or after localization.
Pulmonary parenchymal hemorrhage was defined as blood extravasation into the lung parenchyma during or after localization. It should be noted that tissue injury and minor bleeding are unavoidable during puncture. On CT images, both medical glue and hemorrhage appear as high-density shadows and are difficult to distinguish. Moreover, medical glue has a hemostatic effect. Typically, injection of 0.3 mL of medical glue produces a high-density area with a diameter of 1–2 cm. Therefore, a high-density shadow larger than 2 cm was defined as pulmonary parenchymal hemorrhage.
Air embolism was defined as air entering the blood vessels through the puncture tract during or after localization, resulting in circulatory disturbance.
Complications were counted on a per-patient basis. If a single patient experienced multiple complications, it was counted as one event, while the specific complications were documented in detail. The complication incidence rate = Number of complication events / Number of patients.
Preoperative medical glue localization was performed by the same physician in the CT room. After localization, the physician reported to the surgical team whether localization-related complications, such as pneumothorax or pulmonary parenchymal hemorrhage, had occurred based on the post-localization CT images and the patient’s clinical manifestations. Meanwhile, another physician independently reviewed the post-localization CT images of all patients who underwent medical glue localization and assessed the presence of complications according to predefined imaging criteria. If either the localization operator or the independent image reviewer suggested a possible complication, the surgical team jointly reviewed the patient’s CT images and made a comprehensive judgment in combination with the patient’s clinical manifestations.
Secondary evaluation outcomes included risk time, operation time, anesthesia time, drainage volume, postoperative hospital stay and postoperative complications. Postoperative complications were defined as complications occurring from the end of surgery until hospital discharge and were assessed at the patient level. These mainly included:
Postoperative hemorrhage: bleeding from the surgical wound after surgery, diagnosed based on the color and volume of pleural drainage. Minor oozing was not counted as a complication; only cases requiring clinical intervention such as hemostatic medication or reoperation for hemostasis, were included in the statistics.
Prolonged air leak: continuous leakage of alveolar air into the pleural cavity lasting longer than five days after surgery.
Subcutaneous emphysema: abnormal accumulation of air in the subcutaneous tissue.
Atelectasis: persistent collapse of lung tissue on the operated side after surgery.
Arrhythmia: mainly including atrial fibrillation, premature atrial contractions, and premature ventricular contractions.
This study was funded by the National High Level Hospital Clinical Research Funding (BJ-2023-177), approved by the Ethics Committee of Beijing Hospital (2023BJYYEC-261-01), and registered with the Chinese Clinical Trial Registry (ChiCTR2400082662). Written informed consent was obtained from all patients for data collection.
Localization Procedure
Preoperative localization
On the day of surgery, patients were transferred to the CT suite. According to the location of the pulmonary nodule, an appropriate position (supine, lateral, or prone) was selected. A CT positioning grid was placed on the body surface, and CT scanning was performed to determine the puncture pathway. After routine skin disinfection and sterile draping, local anesthesia was administered. A suction biopsy needle (manufactured by CareFusion; model: CHI2020) was used for puncture. During the puncture procedure, repeated CT scans were performed to adjust the position and angle of the needle until the needle tip reached the vicinity of the nodule. After confirming the absence of blood upon aspiration, 0.3 mL of medical glue (manufactured by Beijing Compont Medical Devices Co., Ltd.; main component: n-butyl-2-cyanoacrylate) was injected, and the puncture needle was removed. A repeat CT scan was then performed to confirm the relative position of the medical glue and the nodule. Subsequently, the patient was either returned to the ward to wait for surgery or transferred directly to the operating room for the surgical procedure (Fig. 2).
Fig. 2.
Preoperative localization procedure. (A) The patient was placed in an appropriate position, and a CT-guided positioning grid was placed on the body surface. (B) A CT scan was performed to determine the puncture pathway; the blue line indicated the planned puncture path. (C) Puncture was performed along the predetermined pathway, and CT scans were conducted to adjust the direction and depth of the needle. (D) Medical glue was injected. (E) A repeat CT scan was performed to confirm the relative position between the glue and the pulmonary nodule. (F) Under thoracoscopic view, the medical glue caused a localized pleural bulge which appeared firm on palpation. (G) The pulmonary nodule was resected based on the medical glue localization
The red arrow indicates the medical glue, and the yellow arrow indicates the pulmonary nodule.
Intraoperative localization
Patients were directly transferred to the hybrid operating room. According to the location of the pulmonary nodule, patients were placed in either the left or right lateral decubitus position. After general anesthesia and tracheal intubation, a baseline CT scan was performed at end-inspiration. The pulmonary nodule requiring localization was identified by correlating with the preoperative CT images. Following routine sterilization and draping, one surgical titanium clip (manufactured by Ethicon Endo-Surgery; model: Ligaclip LT 300) was applied on the visceral pleura at the point closest to the pulmonary nodule under thoracoscopic guidance. The lung on the operative side was then ventilated, and the clip was observed to check whether displacement or detachment had occurred. Typically, the titanium clip remained securely attached to the lung surface. When the lung was fully inflated, a repeat CT scan was performed to confirm the relative position of the titanium clip and the nodule. The ideal position was defined as the point on the lung surface with the shortest linear distance to the nodule. If the distance between the clip and the ideal position was less than 1 cm, the localization was considered appropriate. If the position was unsatisfactory, the previously placed clip was removed and a new clip was applied for localization. This process was repeated until an appropriate position was achieved (Fig. 3).
Fig. 3.
Intraoperative localization procedure. (A) A baseline CT scan was performed to identify the pulmonary nodule requiring localization. (B) Under thoracoscopic guidance, a titanium clip was placed on the visceral pleura closest to the nodule. (C) A repeat CT scan was performed to confirm the relative position between the pulmonary nodule and the titanium clip. (D) The pulmonary nodule was resected according to the titanium clip position
The red arrow indicates the titanium clip, and the yellow arrow indicates the pulmonary nodule.
Surgical method
The surgical methods included wedge resection, segmentectomy, and lobectomy. If the nodule was located in the outer one-third of the lung and the solid component accounted for less than 50%, wedge resection was performed. If the nodule was located deeper in the lung parenchyma or the solid component accounted for ≥ 50%, segmentectomy was performed. If localization failed or the surgical margin was insufficient, extended resection or lobectomy was performed. If the intraoperative frozen section pathology indicated malignancy, hilar and mediastinal lymph node dissection or sampling was usually performed concurrently.
All surgical procedures were performed by the same thoracic surgery team, with two chief surgeons, each having more than 10 years of experience in thoracic surgery, serving as the primary operators. Intraoperative titanium clip localization was also performed by these two surgeons. Since the introduction and clinical application of this technique, both surgeons have continuously participated in its implementation, thereby ensuring relatively stable and consistent operative experience.
Statistical analysis
This study involved two units of analysis: the patient level, with one record per patient, and the nodule level, with one record per nodule. For nodule-level data, because some patients had multiple pulmonary nodules, observations from nodules within the same patient may have been correlated. Therefore, all nodule-level comparisons and models accounted for clustering by patient ID using generalized estimating equations (GEE) with an exchangeable working correlation structure and robust standard errors.
For patient-level analyses, information from all nodules in each patient was aggregated into a single record. The aggregation was performed as follows: the number of nodules was summarized as the total number of nodules per patient, and the presence of multiple nodules was defined as two or more nodules; nodule size and depth were summarized using both mean and maximum values; nodule composition was summarized as the proportion of ground-glass nodules and the presence of any solid or part-solid component; nodule location was represented by the mode; malignancy status was defined according to the highest malignant category; and the surgical procedure was categorized based on the greatest extent of resection performed (lobectomy > segmentectomy > wedge resection). In addition, the proportion of patients who underwent two or more types of procedures, defined as mixed procedures, was reported as n (%).
Baseline patient characteristics were summarized at the patient level. Continuous variables were first assessed for normality using the Shapiro-Wilk test. Normally distributed variables were presented as the mean ± standard deviation and compared between groups using the independent-samples t-test. Non-normally distributed variables were presented as the median and interquartile range and compared using the Mann-Whitney U test. Categorical variables were presented as counts and percentages, n (%), and compared between groups using Pearson’s chi-square test or Fisher’s exact test, as appropriate.
Baseline nodule level characteristics were compared using GEE. For continuous variables, a Gaussian distribution was assumed, and mean differences were reported. For binary variables, a binomial distribution was assumed, and odds ratios (ORs) were reported. For multicategorical variables, dummy variables were entered into separate GEE models, and a joint Wald test was performed to assess overall significance.
Localization success was analyzed at the nodule level. Because localization success was determined for each individual nodule and patients could have more than one nodule, localization outcomes within the same patient were not independent. Therefore, GEE was used with patient ID as the clustering variable. Age, sex, nodule size, and nodule depth were included as covariates to adjust for potential confounding [12, 21, 22]. Given that the localization success rate in the intraoperative group was as high as 99.4%, suggesting possible near-complete separation, a sensitivity analysis was further performed using Firth’s penalized likelihood logistic regression with adjustment for the same covariates to confirm the robustness of the findings.
Localization-related complications were analyzed at the patient level. Each patient contributed only one outcome (presence or absence of complications), so no clustering was present and the patient was the unit of analysis. Since no localization-related complications occurred in the intraoperative group, conventional logistic regression may have been affected by complete separation. Therefore, Firth’s penalized likelihood logistic regression was used for confounder adjustment. The adjusted covariates included age, sex, multiple nodules, mean nodule size, and mean nodule depth. Owing to complete separation, only point estimates of ORs were reported, supplemented by the results of univariable Fisher’s exact tests.
Secondary outcomes were analyzed at the patient level. These outcomes were recorded at the individual patient level (one value per patient), with no multilevel structure. Accordingly, the patient was the unit of analysis, and clustering was not considered. Multivariable regression models were used to adjust for potential confounders. Multivariable linear regression was used for continuous outcomes, with regression coefficients (β) reported as the effect estimates, whereas multivariable logistic regression was used for binary outcomes, with ORs reported as the effect estimates. All patient-level multivariable models were adjusted for age, sex, multiple nodules, mean nodule size, and mean nodule depth. Notably, the variable “number of nodules requiring localization per patient” was highly correlated with “multiple nodules,” with a variance inflation factor greater than 10. To avoid multicollinearity, the former variable was excluded from the models, while the latter was retained because of its greater clinical interpretability.
All statistical analyses were performed using Python 3.12 with the statsmodels, scipy, and firthlogist libraries. All hypothesis tests were two-sided, and a P value < 0.05 was considered statistically significant.
Results
A total of 189 patients were included, with 123 patients in the intraoperative localization group and 66 patients in the preoperative localization group. The clinical characteristics of the two groups are shown in Table 1.
Table 1.
Clinical characteristics of patients
| Variable | Intraoperative localization | Preoperative localization | P value |
|---|---|---|---|
| Number of patients, n | 123 | 66 | |
| Age, years | 58.00 (50.00–66.00) | 61.50 (52.25–67.75) | 0.124 |
| Sex, n (%) | 0.745 | ||
| Male | 38 (30.9%) | 22 (33.3%) | |
| Female | 85 (69.1%) | 44 (66.7%) | |
| Height, cm | 164.00 (159.50–170.00) | 164.00 (158.25–170.00) | 0.929 |
| Weight, kg | 66.00 (58.25–71.00) | 65.00 (60.00–73.88) | 0.705 |
| Smoking status, n (%) | 13 (10.6%) | 12 (18.2%) | 0.177 |
| Patients undergoing localization of multiple nodules, n (%) | 43 (35.0%) | 7 (10.6%) | < 0.001 |
| Number of nodules requiring localization per patient, n | 1 (1–2) | 1 (1–2) | < 0.001 |
| Mean size of nodules requiring localization per patient, cm | 0.80 (0.62–0.90) | 0.88 (0.70–1.10) | 0.039 |
| Maximum nodule size, cm | 0.80 (0.70–1.00) | 0.90 (0.70–1.10) | 0.259 |
| Mean depth of nodules requiring localization per patient, cm | 0.80 (0.30–1.50) | 1.12 (0.40–2.00) | 0.068 |
| Maximum nodule depth, cm | 0.90 (0.40–1.85) | 1.25 (0.40–2.00) | 0.305 |
| Patients with at least one solid or part-solid nodule, n (%) | 32 (26.0%) | 10 (15.2%) | 0.100 |
| Proportion of ground-glass nodules, % | 100 (62–100) | 100 (100–100) | 0.148 |
| Most common nodule location, n (%) | 0.723 | ||
| Right upper lobe | 45 (36.6%) | 27 (40.9%) | |
| Right lower lobe | 18 (14.6%) | 12 (18.2%) | |
| Right middle lobe | 3 (2.4%) | 1 (1.5%) | |
| Left upper lobe | 37 (30.1%) | 14 (21.2%) | |
| Left lower lobe | 20 (16.3%) | 12 (18.2%) | |
| Surgical procedure, greatest extent of resection, n (%) | 0.372 | ||
| Wedge resection | 90 (73.2%) | 42 (63.6%) | |
| Segmentectomy | 26 (21.1%) | 18 (27.3%) | |
| Lobectomy | 7 (5.7%) | 6 (9.1%) | |
| Mixed procedures, ≥ 2 types, n (%) | 8 (6.5%) | 3 (4.5%) | 0.750 |
| At least one malignant nodule, n (%) | 117 (95.1%) | 61 (92.4%) | 0.520 |
Compared with the preoperative localization group, the intraoperative localization group had a significantly higher proportion of patients undergoing simultaneous localization of multiple nodules (35.0% vs. 10.6%, P < 0.001). The mean nodule size per patient was smaller in the intraoperative localization group than in the preoperative localization group [0.80 (0.62–0.90) cm vs. 0.88 (0.70–1.10) cm, P = 0.039]. The mean nodule depth per patient also tended to be shallower in the intraoperative localization group [0.80 (0.30–1.50) cm vs. 1.12 (0.40–2.00) cm, P = 0.068], although the difference was not statistically significant. No significant differences were observed between the two groups in maximum nodule size or maximum nodule depth.
A total of 252 pulmonary nodules were localized, including 179 nodules in the intraoperative localization group and 73 nodules in the preoperative localization group. The clinical characteristics of the nodules are shown in Table 2. Nodules in the intraoperative localization group were smaller than those in the preoperative localization group (0.83 ± 0.33 cm vs. 0.92 ± 0.35 cm, P = 0.048). Nodule depth also tended to be shallower in the intraoperative localization group, although the difference was not statistically significant (1.02 ± 1.04 cm vs. 1.30 ± 1.06 cm, P = 0.057). Most nodules were pure ground-glass nodules, and wedge resection was the predominant surgical procedure.
Table 2.
Clinical characteristics of pulmonary nodules
| Variable | Intraoperative localization | Preoperative localization | P value |
|---|---|---|---|
| Number of localized nodules, n | 179 | 73 | |
| Nodule size, cm | 0.83 ± 0.33 | 0.92 ± 0.35 | 0.048 |
| Nodule depth, cm | 1.02 ± 1.04 | 1.30 ± 1.06 | 0.057 |
| Nodule composition, n (%) | 0.449 | ||
| Pure ground-glass nodule | 144 (80.4%) | 63 (86.3%) | |
| Part-solid nodule | 27 (15.1%) | 9 (12.3%) | |
| Solid nodule | 8 (4.5%) | 1 (1.4%) | |
| Surgical procedure, n (%) | 0.399 | ||
| Wedge resection | 144 (80.4%) | 50 (68.5%) | |
| Segmentectomy | 28 (15.6%) | 18 (24.7%) | |
| Lobectomy | 7 (3.9%) | 5 (6.8%) | |
| Extended resection due to localization-related reasons, n | 2 | 5 | 0.154 |
| Malignant nodules, n (%) | 157 (87.7%) | 66 (90.4%) | 0.393 |
In the intraoperative localization group, extended resection was performed for two nodules due to localization-related reasons. In one patient, the pleural cavity was obliterated by severe adhesions. After adhesiolysis, the titanium clip could not be successfully applied to the pleural surface, and lobectomy was therefore performed. In another patient, although frozen-section pathology suggested a benign lesion, malignancy was still suspected based on CT findings and gross inspection. Considering possible localization failure, lobectomy was performed; final pathology revealed fibrous tissue hyperplasia of the target nodule.
In the preoperative localization group, extended resection was performed for five nodules due to localization-related reasons. Among them, three nodules could not be identified in the surgical specimens, and extended resection was subsequently performed. In one patient, the medical adhesive was inadvertently injected into the bronchus, causing severe coughing. Bronchoscopy was performed to remove the adhesive, after which the patient’s symptoms improved markedly. Lobectomy was subsequently performed, resulting in extended resection of two pulmonary nodules in the affected lobe.
The clinical outcomes of the localization procedures are summarized in Table 3. The success rate of localization was significantly higher in the intraoperative group than in the preoperative group (99.4% vs. 89.0%, P = 0.007). In the intraoperative localization group, localization failed in one nodule. T The patient had an obliterated pleural cavity due to severe adhesions, after adhesiolysis, the titanium clip could not be applied at an appropriate location. Therefore, lobectomy was performed instead. In the preoperative localization group, localization failed in eight nodules. In three cases, the medical glue was not injected into the lung parenchyma but adhered between the visceral and parietal pleura; however, the nodules were successfully resected intraoperatively based on the medical glue’s location. In another three cases, no nodules were identified near the medical glue in the resected specimens. Among these, two nodules were successfully removed after extending the resection range, while one nodule could not be identified. In one patient, the medical adhesive was injected into the bronchus during localization, and lobectomy was subsequently performed; both nodules in this lobe were considered localization failures.
Table 3.
Localization success rate and localization-related complications
| Variable | Intraoperative localization | Preoperative localization | Odds ratio (95% CI) | P value |
|---|---|---|---|---|
| Successful localization, nodule level, n (%) | 178 (99.4%) | 65 (89.0%) | 18.07 (2.18–149.84)† | 0.007† |
| Localization-related complications, patient level, n (%) | 0 (0%) | 20 (30.3%) | 0.004‡ | - |
† GEE was used, with adjustment for age, sex, nodule size, and nodule depth
‡ Firth’s penalized likelihood logistic regression was used, with adjustment for age, sex, multiple nodules, mean nodule size, and mean nodule depth. Owing to complete separation, only the point estimate was reported. The P value from the univariable Fisher’s exact test was < 0.001
The incidence of localization-related complications was lower in the intraoperative localization group than in the preoperative localization group (0% vs. 30.3%; OR = 0.004; univariable Fisher’s exact test, P < 0.001). The severity of complications and the corresponding clinical management are shown in Table 4. No patient experienced more than one type of complication.
Table 4.
Severity and management of localization-related complications
| Localization-related Complication | Severity (Clavien–Dindo) | Management | Cases |
|---|---|---|---|
| Pneumothorax | Grade I | Observation | 15 |
| Pneumothorax | Grade III | Thoracentesis | 1 |
| Pulmonary hemorrhage | Grade I | Observation | 3 |
| Medical glue injected into the bronchus | Grade III | Medical glue removed by bronchoscopy | 1 |
Perioperative outcomes are shown in Table 5. Intraoperative localization did not require patient transfer, and the risk time was therefore significantly shortened. Because intraoperative localization was performed after the induction of general anesthesia and the localization time was included in the operative time, both operative time and anesthesia time were longer in the intraoperative localization group than in the preoperative localization group (118.80 vs. 96.11 min, P = 0.007; 196.34 vs. 162.76 min, P = 0.001, respectively). The mean localization time in the preoperative localization group was 15.82 ± 7.78 min. No significant difference was observed between the two groups in total procedural time [β = 2.96 (95% CI: -12.61 to 18.53), P = 0.708].
Table 5.
Perioperative outcomes
| Variable | Intraoperative localization | Preoperative localization | Adjusted effect estimate (95% CI) | P value |
|---|---|---|---|---|
| Number of patients, n | 123 | 66 | ||
| Risk time, min | 0 | 298.47 ± 181.24 | β=-297.87 (-332.17, -263.57) | < 0.001 |
| Operative time, min | 118.80 ± 47.65 | 96.11 ± 46.88 | β = 20.63 (5.81, 35.45) | 0.007 |
| Anesthesia time, min | 196.34 ± 54.47 | 162.76 ± 57.19 | β = 30.61 (13.29, 47.94) | 0.001 |
| Postoperative chest tube duration, days | 2.50 ± 0.78 | 3.09 ± 1.57 | β=-0.60 (-0.96, -0.24) | 0.004 |
| Drainage volume from the operative day to postoperative day 3, mL | 475.93 ± 242.55 | 541.59 ± 353.69 | β=-53.44 (-144.60, 37.73) | 0.249 |
| Postoperative complications, n (%) | 9 (7.3%) | 8 (12.1%) | OR = 0.63 (0.21, 1.88) | 0.412 |
| Postoperative hospital stay, days | 3.93 ± 1.13 | 4.33 ± 1.64 | β=-0.42 (-0.85, 0.00) | 0.050 |
The duration of postoperative chest tube drainage was shorter in the intraoperative localization group, whereas the drainage volume during the first three postoperative days was comparable between the two groups. In general, patients were discharged on the day after chest tube removal. Accordingly, the shorter chest tube duration in the intraoperative localization group was associated with a shorter postoperative hospital stay [3.93 ± 1.13 vs. 4.33 ± 1.64 days; β=-0.42 (95% CI: -0.85 to 0.00), P = 0.050]. There was no significant difference in the incidence of postoperative complications between the two groups.
In the intraoperative localization group, five patients developed atrial fibrillation, three patients developed postoperative hemorrhage which improved after hemostatic medication, and one patient had a prolonged air leak more than five days. In the preoperative localization group, three patients developed atrial fibrillation, two patients developed postoperative hemorrhage which improved after hemostatic medication, one patient had a prolonged air leak lasting more than five days, one developed subcutaneous emphysema, and one developed atelectasis. All patients recovered after treatment and were safely discharged.
Discussion
This study systematically compared the clinical application of intraoperative titanium clip localization and preoperative medical glue localization for pulmonary nodules. The results showed that intraoperative localization was associated with a higher localization success rate and a significantly lower incidence of localization-related complications.
The high effectiveness of intraoperative titanium clip localization may be attributed to several factors. First, the clip is applied directly to the visceral pleura under thoracoscopic visualization, and its position can be continuously monitored during lung re-expansion, allowing timely detection of clip dislodgement. If there is concern regarding clip stability, additional clips can be applied; if the clip position is unsatisfactory, adjustments can be made multiple times until an optimal position is achieved. Second, intraoperative localization eliminates the need for patient transfer and therefore significantly shortens the risk time, reducing the occurrence of marker displacement or dislodgement during this period. Finally, titanium clip localization avoids excessive changes in body position. After localization is completed, the surgical procedure can be initiated without further repositioning, which reduces the risk of marker displacement or dislodgement caused by positional changes [9, 10, 23].
In terms of safety, intraoperative titanium clip localization also demonstrated notable advantages. CT-guided percutaneous localization inevitably causes injury to tissues along the puncture pathway, which may lead to complications such as pneumothorax and bleeding, with reported incidence rates ranging from 16% to 47% [12–16]. In contrast, intraoperative titanium clip localization is confined to the pleural surface and theoretically avoids injury to the lung parenchyma. Moreover, titanium clips cause minimal damage to the pleura. Even when repeated adjustments are required due to an unsatisfactory position, the integrity of the pleura is generally preserved. Therefore, the risks of pneumothorax, bleeding, and air embolism are extremely low. In addition, the opportunity for multiple attempts provides beginners with more room for trial and error, which may facilitate the rapid accumulation of experience.
Intraoperative titanium clip localization also provides a unique opportunity for intraoperative reassessment, which may reduce unnecessary invasive procedures. In this study, five patients initially scheduled for intraoperative localization were found to have visibly identifiable or palpable pulmonary nodules after thoracic exploration, thus localization was abandoned, and direct nodule resection was performed. Previous studies have reported that approximately 28% (15/53) of preoperative localization procedures may be unnecessary [7]. However, the most widely used CT-guided percutaneous localization techniques are invasive and irreversible once performed. Even if the nodule is easily identifiable during intraoperative exploration, patients still bear the risk of puncture. In contrast, intraoperative titanium clip localization allows surgeons to reassess the need for localization under thoracoscopic visualization, thereby minimizing unnecessary trauma.
Intraoperative titanium clip localization also showed potential advantages in the management of multiple pulmonary nodules. In this study, 43 patients (35.0%) in the intraoperative localization group underwent simultaneous localization and resection of multiple nodules, including two cases with bilateral pulmonary nodules. All 97 nodules requiring localization were successfully localized, and no localization-related complications occurred. In comparison, only 7 patients (10.6%) in the preoperative localization group underwent localization for multiple nodules. Among the 14 nodules requiring localization, four localization failures occurred, and two patients developed pneumothorax, while one developed pulmonary parenchymal hemorrhage. In scenarios involving simultaneous localization of multiple nodules, the technical advantages of intraoperative titanium clip localization become more pronounced. Simultaneous percutaneous localization of multiple nodules is associated with a higher incidence of complications [24], and these complications could further increase the difficulty of subsequent nodule localization. For example, pulmonary hemorrhage may produce high-density shadows on CT images that interfere with accurate identification of nodules. Similarly, pneumothorax may cause lung collapse, altering the depth of the nodules and their spatial relationship with the chest wall, thereby invalidating the originally planned puncture pathway and increasing the difficulty and risk of subsequent localization. In contrast, intraoperative titanium clip localization is performed under direct thoracoscopic visualization, and multiple clips do not interfere with each other. In this study, no cases were observed in which complications affected subsequent titanium clip localization procedures. Furthermore, for bilateral pulmonary nodules, localization markers with extracorporeal components such as hookwires may be susceptible to displacement due to friction with surrounding objects when positioning the contralateral lung. Intraoperative titanium clip localization allows bilateral procedures to be completed sequentially without mutual interference, effectively avoiding these risks.
Limitations
This study has several limitations. First, it was a single-center study with a relatively limited sample size and no randomized grouping. Group allocation was influenced by the availability of the hybrid operating room, which may introduce selection bias. Second, intraoperative titanium clip localization relies on hybrid operating room facilities, which require specialized equipment and may limit its widespread adoption. Third, percutaneous localization allows markers to be placed near the nodule, which may help estimate nodule depth intraoperatively, whereas titanium clip localization is limited to the pleural surface and provides less information regarding nodule depth. Fourth, both medical glue and hemorrhage appear as high-density shadows on CT imaging. Although a predefined criterion (high-density shadows larger than 2 cm) was used to define hemorrhage, potential assessment bias may still exist. Finally, the localization success rate in the preoperative medical glue localization group in this study was relatively low (89%) compared with similar studies [16–18], and larger sample sizes are needed in future studies to reduce potential random error.
Conclusion
In our center, intraoperative titanium clip localization appears to be a safe and effective method for pulmonary nodule localization compared with preoperative medical glue localization. This technique also showed potential advantages in the simultaneous localization of multiple pulmonary nodules, although it was associated with a longer anesthesia time.
Acknowledgements
Not applicable.
Authors’ contributions
WJY, JP, GHL and TWX contributed to the conception and design of the study, data acquisition, and drafting of the manuscript. YHB, LDH and TY contributed to data acquisition. All authors reviewed and revised the manuscript.
Funding
This study was funded by the National High Level Hospital Clinical Research Funding (BJ-2023-177).
Data availability
The datasets used and analysed during the current study are available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
The study was approved by the Ethics Committee of Beijing Hospital (2023BJYYEC-261-01). Written informed consent was obtained from all participants prior to participation.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
- 1.Zheng R, Chen R, Han B, Wang S, Li L, Sun K et al. Cancer incidence and mortality in China, 2022. Zhonghua zhong liu za zhi [Chinese journal of oncology]. 2024;46:221–31. [DOI] [PubMed]
- 2.Li N, Tan F, Chen W, Dai M, Wang F, Shen S, et al. One-off low-dose CT for lung cancer screening in China: a multicentre, population-based, prospective cohort study. Lancet Respiratory Med. 2022;10(4):378–91. [DOI] [PubMed] [Google Scholar]
- 3.He J, Li N, Chen W, Wu N, Shen H, Jiang Y, et al. China guideline for the screening and early detection of lung cancer (2021, Beijing). Zhonghua zhong liu za zhi. [Chinese J Oncology]. 2021;43(3):243–68. [DOI] [PubMed] [Google Scholar]
- 4.Group CLO. China national lung cancer screening guideline with low-dose computed tomography (2023 version). Chin J Lung Cancer. 2023;26(1):1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Society CT, Association CM, Group CAALCE. Chinese expert consensus on diagnosis and treatment of pulmonary nodules (2024). Zhonghua jie he he hu xi za zhi= Zhonghua jiehe he huxi zazhi=. Chin J tuberculosis respiratory Dis. 2024;47(8):716–29. [DOI] [PubMed] [Google Scholar]
- 6.Society CT. Chinese expert consensus on diagnosis of early lung cancer (2023 Edition). Zhonghua jie he he hu xi za zhi= Zhonghua jiehe he huxi zazhi= Chinese journal of tuberculosis and respiratory diseases. 2023;46(1):1–18. [DOI] [PubMed]
- 7.Ciriaco P, Negri G, Puglisi A, Nicoletti R, Del Maschio A, Zannini P. Video-assisted thoracoscopic surgery for pulmonary nodules: rationale for preoperative computed tomography-guided hookwire localization. Eur J Cardiothorac Surg. 2004;25(3):429–33. [DOI] [PubMed] [Google Scholar]
- 8.Gu C, Liu B, Chinese Medical Education Association Lung Cancer Committee, Cross-Strait Medical and Health Exchange Association Thoracic Surgery Committee. Preoperative localization techniques for small pulmonary nodules: Chinese expert consensus (2025 edition). Chin J Clin Thorac Cardiovasc Surg. 2025;32(8):1047–55. 10.7507/1007-4848.202505036. [DOI] [Google Scholar]
- 9.Thistlethwaite PA, Gower JR, Hernandez M, Zhang Y, Picel AC, Roberts AC. Needle localization of small pulmonary nodules: Lessons learned. J Thorac Cardiovasc Surg. 2018;155(5):2140–7. [DOI] [PubMed] [Google Scholar]
- 10.Wang G, Lin Y, Zheng L, Liang Y, Zhao L, Wen Y, et al. A new method for accurately localizing and resecting pulmonary nodules. J Thorac Disease. 2020;12(9):4973. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Gill RR, Zheng Y, Barlow JS, Jayender J, Girard EE, Hartigan PM, et al. Image-guided video assisted thoracoscopic surgery (iVATS)‐phase I‐II clinical trial. J Surg Oncol. 2015;112(1):18–25. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Hu L, Gao J, Hong N, Liu H, Zhi X, Zhou J. CT-guided microcoil localization of pulmonary nodules before VATS: clinical experience in 1059 patients. Eur Radiol. 2024;34(3):1587–96. [DOI] [PubMed] [Google Scholar]
- 13.Guo H, Ouyang Z, Li X, Han Y, Tao F, Liu M, et al. Robotic-assisted CT-guided percutaneous pulmonary nodules localization by hook-wire needles: a retrospective observational study. J Thorac Disease. 2024;16(7):4263–74. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Wang R, Chen Y, Wang C, Li Z, Zhong Y, Liang Y, et al. A better option for localization of multiple pulmonary nodules in the ipsilateral lung: electromagnetic navigation bronchoscopy-guided preoperative localization. Translational Lung Cancer Res. 2025;14(3):775–84. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Sowe B, Wan J, Yang F, Wu C, Wang S, Tong S. Comparison of electromagnetic navigation bronchoscopic localization and computed tomographic imaging-guided methylene blue localization in the resection of pulmonary nodules: a retrospective cohort study. PeerJ. 2025;13:e19224. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Zhang H, Li Y, Chen X, He Z. Comparison of hook-wire and medical glue for CT-guided preoperative localization of pulmonary nodules. Front Oncol. 2022;12:922573. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Zhang H, Zhang X, Li Y, Huang Z, Liu H, Chen X. The efficacy and safety of CT-guided localization of pulmonary nodules by medical adhesives containing methylene blue before surgery. Heliyon. 2024;10(11). [DOI] [PMC free article] [PubMed]
- 18.Fu L, Wu W, Oblokulov A, Zhu T, Ma Z, Wang H, et al. Noninvasive 3D-CT simulation versus glue injection to localize small pulmonary nodules prior to anatomical segmentectomy: a randomized controlled trial. Interdisciplinary Cardiovasc Thorac Surg. 2024;38(1):ivad156. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Kaiho T, Suzuki H, Hata A, Ito T, Tanaka K, Sakairi Y, et al. Efficacy and safety of intraoperative cone-beam CT-guided localization of small pulmonary nodules. Interact Cardiovasc Thorac Surg. 2022;35(4):ivac236. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Yu H, Tian W, Sun Y, Wu Q, Ma C, Jiao P, et al. Localization of small peripheral pulmonary nodules for surgical resection: a new intraoperative technique in hybrid operating room. J Cardiothorac Surg. 2022;17(1):241. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.He C, Zhao L, Yu H-L, Zhao W, Li D, Li G-D, et al. Pneumothorax after percutaneous CT-guided lung nodule biopsy: a prospective, multicenter study. Quant Imaging Med Surg. 2024;14(1):208–18. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Huang JY, Tsai SCS, Wu TC, Lin FCF. Puncture frequency predicts pneumothorax in preoperative computed tomography-guided lung nodule localization for video‐assisted thoracoscopic surgery. Thorac Cancer. 2022;13(13):1925–32. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Wang Z, Li B, Hu Z, Zhao Q, Zhang X, Zhao H, et al. Comparison of different localization needles and postures in localization of pulmonary nodules. J Cardiothorac Surg. 2024;19(1):668. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Xu Y, Ma L, Sun H, Huang Z, Zhang Z, Xiao F, et al. The utility of simultaneous CT-guided localization for multiple pulmonary nodules using microcoil before video-assisted thoracic surgery. BMC Pulm Med. 2021;21(1):39. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets used and analysed during the current study are available from the corresponding author on reasonable request.