Precise localization techniques for small pulmonary nodules: what is next?

Introduction

Lung cancer is one of the most common cancers and the leading cause of cancer-related deaths worldwide (1,2). The advanced stage at diagnosis is the main contributor to the high mortality of lung cancer (3). Therefore, it is critical to detect early lung cancer in a timely manner. Low-dose computed tomography (LDCT) screening is currently the most effective method for early diagnosis of lung cancer, which has been demonstrated to reduce lung cancer-related mortality by 20% (4). As LDCT screening becomes more widespread, a greater number of small lung nodules are being discovered, becoming a common issue. Pathological diagnosis is necessary when the nodule persists for a long time and the solid component ≥5 mm, or when the nodule progressively enlarges (5). Advances in technology have led to an evolution of approaches from endobronchial biopsy (EBB) to computed tomography (CT) guided biopsy and video-assisted thoracoscopic surgery (VATS) biopsy. VATS is considered the gold standard for diagnosing and treating pulmonary nodules (6,7). However, there remains a huge challenge for thoracic surgeons, because it is difficult to localize small or deeply situated target nodules merely through palpation during VATS. It has been reported that the most common reason (46%) for conversion to thoracotomy was the failure to localize nodules (8). Therefore, precise localization of small pulmonary nodules during the preoperative or intraoperative period is a key step to avoid expanding the scope of unnecessary resection.

Several localization techniques for small pulmonary nodules have been developed over the last decade to address this issue. These techniques are categorized into intraoperative localization methods (e.g., ultrasound, endo-finger, finger palpation, and wait-and-watch) and preoperative localization methods (e.g., CT-guided transthoracic needle biopsy or bronchoscopic techniques) (9-11). Image-guided CT involves percutaneous placement of a metallic marker (i.e., hook wires, microcoils and fiducial markers) or injection of a liquid material through a fine needle [i.e., methylene blue (MB), indocyanine green (ICG), radionuclides, barium, lipiodol and agar marking] (12-16). Bronchoscopy also includes flexible bronchoscope (FB), electromagnetic navigation bronchoscopy (ENB) and radial endobronchial ultrasound (EBUS). Currently, the most commonly used localization technique by clinicians is preoperative localization (17,18). Despite technical advancements, several limitations remain, including procedure-related complications and operator dependency. However, the accuracy of CT-guided puncture localization is often limited by factors such as insertion angle, respiratory movements, patient position changes, and soft tissue shifts (19). Therefore, precise positioning largely depends on the experience and level of the operators. Young chest physicians face a steep learning curve in acquiring positioning skills, and this may also be limited in some institutions. Moreover, inaccurate placement can lead to prolonged operation time, unnecessary radiation exposure or adverse events (20). Additionally, due to limited access to the lung periphery and the lack of fine motor control of instruments in this area, no single conventional bronchoscopic approach has consistently shown high yields (21-23). Fortunately, a robotic-assisted navigation localization system has been developed to potentially free surgeons from the limitations of traditional positioning methods. The system includes a robotic-assisted CT-guided navigation localization system and robotic bronchoscopy (RB). CT imaging to guide robotic-assisted localization has been reported in a large number of studies, from providing guidance for manual punctures to achieving completely automated puncture and positioning. It has the advantages of stable guidance and precise localization (24). Meanwhile, RB has the potential to not only improve the diagnostic sensitivity of peripheral pulmonary nodules but also navigation and visualization (25).

In consideration of the advancement in localization techniques for pulmonary nodules, we now pose the question: what is the future of localization techniques? In this article, we review the history of pulmonary nodule localization techniques, discuss the details of these technologies, and propose potential future directions.

Invasive preoperative techniques (CT-guided)

The injection of a liquid material through a fine needle

Injection of contrast medium

The injection-based localization with contrast agents refers to the use of CT guidance to inject substances such as dyes, medical biological glue, iodized oil, barium, and radioactive tracers around the pulmonary nodule, enabling the surgeon to accurately locate the target nodule during surgery.

MB and ICG are the most frequently used dyes in localization procedures. Lin et al. reviewed 388 cases and found CT-guided MB localization for pulmonary nodules to be safe and effective, with high success rates of single nodules and multiple nodules (26). MB has the disadvantage of rapid diffusion and poor visualization in the lungs of patients with severe anthracosis. Additionally, it fails to reveal the depth of lesions beneath the surface of the visceral pleura, preventing its use in assessing safety margins before histopathological examination (26).

ICG, an economical and relatively non-toxic near-infrared dye, has been used in several studies for preoperative localization via CT-guided transthoracic injection, achieving a success rate exceeding 98% (27,28). These studies consistently confirm the efficacy and safety of ICG in localizing both small and multiple pulmonary nodules. Compared to MB, the near-infrared light emitted by ICG is imperceptible, avoiding interference with the surgical field, while MB may obstruct visibility. However, the ICG solution tends to permeate adjacent healthy lung tissue, and high doses may pose certain risks (29).

α-cyanoacrylate is a fast-acting medical adhesive that is non-toxic and biosafe. Cyanoacrylate helps localize nodules by rapidly solidifying after injection, forming a palpable marker that can be identified during surgery. When exposed to blood, tissue fluids, organic amines, and other trace chemicals at room temperature, it polymerizes rapidly. In clinical practice, CT-guided cyanoacrylate injection has been used effectively for the localization and resection of pulmonary nodules, achieving a high success rate in localization without severe complications (30). However, when dealing with multiple nodules in the same lung, the localization process tends to take longer and is more likely to be associated with a higher incidence of emphysema (31). Cyanoacrylate may cause localized emphysema due to chemical irritation of the airway, inflammatory reactions, or parenchymal necrosis leading to alveolar rupture and air trapping. Additionally, there is a risk of complications, such as the development of iatrogenic airway foreign bodies, during the preoperative localization of pulmonary nodules using cyanoacrylate glue (32).

Lipiodol

Lipiodol is a cost-effective, non-absorbable radiopaque substance that, when injected into lung parenchyma, creates a lasting marking area. After administering local anesthesia at the puncture site, the physician inserts the needle near the target nodule and manually injects iodinated oil (33).

A study involving 56 small pulmonary nodules has demonstrated the efficacy of CT-guided lipiodol labeling. The procedure achieved a 100% localization success rate, and any surgical complications were effectively managed (34). These findings suggest that Lipiodol labeling is a safe and practical approach for localizing pulmonary nodules.

Metallic markers

Metallic markers play a pivotal role in the precise localization of pulmonary nodules, enabling minimally invasive surgical approaches. Among these, techniques such as hook wire implantation, microcoil placement, and the four-hook anchor device have demonstrated varying degrees of success and limitations, shaping their utility in clinical practice.

Hook wire

Percutaneous hook wire implantation is a simple technique for localizing pulmonary nodules, requiring minimal specialized equipment or expertise. Yao et al. conducted a retrospective analysis of 95 patients undergoing CT-guided hook wire localization, achieving successful localization of all nodes (35). Even with hook wire displacement, VATS resection is still feasible as the puncture site on the pleural surface stays visible. Multiple studies indicate that decoupling can be significantly minimized at insertion depths exceeding 1 cm (35-37). The phenomenon of decoupling—defined as the dislodgement or migration of the hookwire from its initial position prior to resection—must not be overlooked. This complication can prolong the surgical procedure, increase the risk of pulmonary hemorrhage, and result in significantly higher pain scores when compared to ICG-based localization.

Microcoils

Microcoil placement is guided by CT imaging, with the coil inserted into lung tissue using a puncture needle. Factors such as chest wall thickness and lesion depth are carefully considered. The coil is wrapped around the nodule, and the excess segment is secured to ensure that its end remains external to the pleura (38). Microcoil can be fully embedded in lung parenchyma without an external segment protruding beyond the pleura. Microcoil utilization is more complex and time-consuming than hook wire application. However, microcoil placement is associated with a lower incidence of complications such as chest discomfort, pneumothorax, and pulmonary hemorrhage compared to hook wires (39). Unlike the hook wire, which requires an externalized segment extending beyond the pleura, microcoils can be entirely embedded within the lung parenchyma. This reduces the risk of dislodgement and allows for greater flexibility during surgery.

Hookwire and microcoil techniques typically require intraoperative fluoroscopic confirmation to verify the marker’s position prior to wedge resection. In contrast, dye or cyanoacrylate localization does not require fluoroscopy, as these markers are visually detectable during thoracoscopic exploration.

Four-hook

The four-hook anchor device is a superior approach relative to hook wire, demonstrating a higher success rate in operational localization, reduced localization-related problems, and decreased VATS operative duration. The four-hook localization needle is an innovative technology that has steadily demonstrated its major advantages in the field of lung nodule localization. In comparison to the conventional hook-and-wire, Zhang et al. showed that the quadruple-hook localization needle significantly improved localization success and complication rates. They emphasized that the stability of the four anchors in its design increases the physician’s operation’s dependability, reducing the patient’s discomfort and risk associated with repeated attempts (40).

Robotic-assisted puncture localization

In robotic-assisted puncture localization, the patient’s preoperative CT scan is imported into the surgical planning system to generate a three-dimensional (3D) model of the pulmonary nodules, vessels, bronchi, bones, and skin. This model is aligned with the patient’s positional data obtained from the photoelectric navigation system. Based on the nodule’s location, the system defines the puncture path, which is then registered within the surgical space. The robotic arm accurately positions the puncture site, needle direction, and depth, followed by manual insertion of the puncture needle to place the marker for intraoperative localization (41). Figure 1 shows navigation planning and robotic-assisted positioning for puncture procedures.

Figure 1 Demonstration of real-time non-invasive localization technique and imaging display.

Robot-assisted CT-guided percutaneous localization of lung nodules has a high success rate when combined with hook-and-line localization (42). In practice, the patient’s respiratory motion is the primary factor influencing localization success; the pulmonary nodule’s position relative to the chest wall may vary with diaphragmatic movement during respiration, and the selection of localization material is contingent upon the pulmonary nodule’s location and the lung’s condition. The benefit of automated puncture lies in a marked decrease in the incidence of puncture-related problems, attributable to the diminished frequency and duration of aided modifications (42-44). Simultaneously, robot-assisted puncture offers clinicians a more straightforward positioning technique with a reduced learning curve, owing to the placement of a robotic arm.

Bronchoscopy-guided localization procedures

The diagnosis and treatment of pulmonary nodules, particularly the localization of tiny and deep nodules, increasingly depend on bronchoscopy-guided localization procedures. The ability to precisely locate nodules has greatly increased with the development of technologies like robotic-assisted bronchoscopy (RAB), EBUS, augmented fluorescence bronchoscopy (AFB), and ENB, which also lower radiation exposure and surgical risk.

ENB

ENB is a pivotal tool in lung nodule localization, offering a significant advantage with its electromagnetic field localization, which overcomes the limitations of traditional methods. ENB enhances the accuracy of localization and the safety of minimally invasive lung nodule surgery, leading to growing interest in recent years. This technology has attracted considerable attention due to its potential benefits.

The ENB technique requires a preoperative high-resolution CT scan of the patient, followed by the generation of an individualized bronchial tree map after lung reconstruction. During the operation, the electromagnetic device at the tip of the bronchoscope monitors the coordinates of the flexible endoscope. The operator observes the real-time position of the bronchoscope on the reconstructed navigation screen, allowing for precise adjustments to the probe position as needed. The planned path is displayed on both real and virtual images (45,46). ENB is gaining traction in the minimally invasive management of lung nodules. offering notable benefits in terms of operational flexibility and adaptability, particularly for accessing challenging locations that are less accessible through conventional CT-guided puncture (47). When combined with dyes such as MB and indole turnip green, ENB demonstrates a high success rate and minimal complications (48).

In terms of surgical safety, ENB has been shown to reduce postoperative complications, including pneumothorax and pulmonary hemorrhage. Xia et al. reported a pneumothorax incidence of 2.1% in the ENB group, compared to 6.4% in the CT-guided technique group (49). The ability to minimize complications is attributed to the electromagnetic localization of ENB and the reduced radiation dose, resulting in a patient radiation exposure decrease of approximately 40% during ENB (3).

The integration of ENB with additional innovative materials enhances the accuracy in lung nodule localization. Fang et al. utilized a positioning material called H-marker, which is a disposable, specialized pulmonary surgical marker intended for application in navigational bronchoscopy. The H-marker provides radial support to prevent off-target movement during the anchoring process (50). Another technique, virtual navigational bronchoscopy (VNB), is also based on lung reconstruction by CT for bronchial construction. However, VNB is less costly, offering some advantages in clinical use (51,52). VNB has been used primarily for preoperative planning and intraoperative navigation of peripheral pulmonary nodules, particularly when ENB is unavailable. It is also combined with dye or contrast agent injection to assist in thoracoscopic localization (52).

Bronchoscopic approaches, including ENB, VNB, and RB, generally do not require intraoperative fluoroscopy, as they provide real-time endoluminal navigation and dye or marker deposition.

EBUS

The radial microprobe of the ultrasound bronchoscope, with a diameter of 1.4 mm, produces circumferential radial ultrasound images as it navigates through the working channel of the FB into the lung’s periphery. When the radial probe is situated within the lesion and entirely encircled by it, the radial EBUS visualization of the surrounding lesion is described as ‘concentric’ (22). Lung nodules were localized using the integration of various localization agents, including MB, alongside ultrafine bronchoscopy and frozen biopsy, leading to improved rates of ultrasound localization and diagnosis (53,54). Nonetheless, the overall outcomes of using ultrasound bronchoscopy for lung nodule localization remain suboptimal.

AFB

AFB is a localization technique used in conjunction with the C-arm cone-beam computed tomography (CBCT) system. Following CBCT scanning, the system displays the marked contours based on the 3D location of the pulmonary nodule on the two-dimensional fluoroscopic live screen, enhancing the functionality of the augmented fluoroscopy system (55). AFB can localize lung nodules in combination with materials such as dyes or microcoils (56). However, since ABF is used in conjunction with CBCT, the radiation dose to both the patient and physician is a critical factor that must be carefully addressed.

RAB

RAB, an emerging diagnostic tool for lung nodules, offers significant advantages in achieving accurate biopsies. Shape-sensing robotic-assisted bronchoscopy (ssRAB) creates the navigation path from the patient’s CT images towards the virtual target.

RAB is particularly suitable for small and deep nodules, which localization is crucial for lung cancer early diagnosis. It is also less traumatic for the surrounding tissues during the procedure than traditional bronchoscopy (57). With a high diagnostic yield and minimal risk of complications, RAB has been proven effective in clinical practice to diagnose nodules of various sizes, especially ground-glass nodules with a solid component smaller than 6 mm (58). To enhance safety and accuracy, clinicians should prioritize the safety of robotic-assisted devices in clinical practice and explore new techniques that integrate ssRAB, r-EBUS, and CBCT (59).

Use of hybrid operating theatres

The integration of hybrid operating theatres, equipped with intraoperative CT and real-time navigation systems, enables accurate confirmation of marker positioning and reduces the “at-risk” interval between localization and resection. This is particularly beneficial for difficult-to-palpate or subsolid pulmonary nodules. The hybrid theatre setup supports the use of ENB, RB, hookwire, and microcoil techniques, facilitating real-time adjustments during surgery (60,61). However, limitations include significant financial investment, increased intraoperative radiation exposure, and the need for specialized staff and scheduling coordination. These considerations have also been reflected in recent European guidelines, which emphasize the importance of individualized localization strategies based on institutional resources and nodule characteristics (62).

Noninvasive intraoperative techniques

Traditional non-invasive positioning techniques

Intraoperative localization of pulmonary nodules during VATS involves both traditional palpation and image-guided techniques, such as intraoperative ultrasound guidance.

Thoracoscopic palpation is widely recognized as the most straightforward and direct technique for nodule identification. Using the index finger or a metal suction tube for thoracoscopic probing is particularly useful for detecting tumors located in the outer third of the lung (63).

Intraoperative ultrasound-guided localization involves identifying pulmonary nodules during single-lung ventilation, followed by their surgical resection. This method was first reported by Yuan et al. in 1992 for peripheral pulmonary nodules (64).

With advancements in technology, numerous studies have demonstrated the efficacy of ultrasound localization for pulmonary nodules. However, this technique requires considerable operator proficiency and is not suitable for patients with asthma, alveolar diseases, diffuse emphysema or fibrosis.

Emerging technologies

Technological advancements are revolutionizing medicine by improving accuracy, efficiency, and safety. Innovations such as 3D printing, augmented reality (AR), and virtual reality enhance surgical precision while reducing operating time and risks. These breakthroughs mark the beginning of a new era in minimally invasive and highly effective medical care.

3D printing technology

In recent years, 3D printing technology has been increasingly applied in pre-operative planning, intra-operative supervision, and medical education, showcasing significant potential in the medical field. Currently, there are three primary methods for utilizing 3D printing in positioning, with the most common being 3D printing navigation-assisted subcutaneous placement puncture technology. This technique uses a patient’s high-resolution thin-layer CT scans as a reconstruction template, followed by the planning of the navigational pathway and the application of customized positioning guidance through 3D printing. The 3D-printed templates showed no significant difference in positioning outcomes compared to the CT-guided group in terms of positioning deviation, while markedly reducing positioning time and radiation exposure for the patient (65).

The second approach involves reconstructing and 3D printing the lungs. Medical professionals use 3D reconstruction software, such as 3D Slicer or Mimics, to process CT data. CT scans are imported into these applications to generate an accurate 3D model of the patient’s lung lobes for subsequent printing. This labeling method clearly illustrates the anatomical structure of the lungs and lung nodules while accurately depicting the relative positions of the reconstructed lung lobes and nodules, enabling precise nodule localization (66).

The third method, similar to the first, uses thermoplastic polyurethane (TPU) as the flexible printing material for the navigation template. It is distinct in its ability to be performed intraoperatively without requiring a puncture, thus significantly reducing complications associated with the puncture procedure and enhancing safety (67).

Virtual reality

AR is a rapidly evolving technology characterized by its ability to superimpose data and virtual objects onto the user’s natural vision through sensors and receivers. In surgical procedures, AR enables surgeons to view the actual operative field while simultaneously displaying an enhanced field of vision. This capability significantly reduces the time surgeons spend away from the surgical field and improves surgical efficiency. One of the primary advantages of AR in clinical practice is its facilitation of small nodule localization in the lungs, leading to increased time efficiency and reduced radiation exposure (68).

Real-time non-invasive localization technique

In the field of pulmonary nodule identification and surgical interventions, advancements in 3D technology have facilitated the integration of various virtual reality approaches. However, the majority of current 3D applications still require surgeons to wear 3D glasses to view stereoscopic images on a screen during procedures. This approach has several drawbacks. First, 3D glasses lack universal compatibility, posing challenges related to portability and storage. Second, they compromise the sterile surgical environment and demand higher levels of technical skill and expertise from surgeons.

Against this backdrop, virtual imaging technology capable of rendering 3D images without the need for 3D glasses has become highly sought after. A real-time, non-invasive localization technique introduces an advanced, multi-layered, multi-perspective naked-eye 3D positioning system that combines virtual reality and AR technologies. This technology is based on capturing and storing multiple sets of stereoscopic images of the target scene using a naked-eye 3D camera. A complementary metal-oxide-semiconductor (CMOS) image sensor, positioned in the central and lower sections of the display panel, is specifically designed for multi-view, naked-eye, high-definition visualization. Its primary function is to determine the real-time position of the viewer’s eyes. By comparing the detected eye position with the distribution of independent viewing zones, the system accurately identifies the corresponding viewing zone for the eyes. Based on the identified viewing zone, the pixels of the stereo-pair images are precisely reconfigured and displayed.

This innovative display system allows viewers to observe positional and angular changes in the images from various angles within the independent viewing zone. Moreover, the system can instantaneously switch video images between the left and right eye sub-screens, dynamically aligning them with the viewer’s position in the independent viewing zone, thereby enhancing the viewing experience.

The real-time non-invasive localization technique (Figure 1) provides precise visualization of lung anatomy and lesions through naked-eye 3D imaging, enabling automatic lung lobe segmentation, accurate lesion localization, and detailed resection range planning. This approach maps the 3D spatial relationships between lesions, bronchi, and blood vessels, reducing the risk of damage to anatomical variations and enhancing surgical safety. By eliminating the need for preoperative punctures or bronchial localization, surgeons can intuitively identify lesion positions in real time, efficiently plan surgical scopes, and preserve functional lung tissue. Even anatomically complex lesions can be accurately resected without extensive lung lobe removal, minimizing trauma while maintaining surgical efficacy.

Molecular imaging and targeted fluorophores

Molecular imaging and targeted fluorophores represent promising emerging techniques for intraoperative localization of pulmonary nodules. These approaches rely on tumor-specific probes—such as fluorescently labeled antibodies, peptides, or small molecules—that bind selectively to surface markers overexpressed on tumor cells, such as folate receptor alpha, EGFR, or fibroblast activation protein (FAP). Upon binding, these agents can be visualized using real-time near-infrared fluorescence imaging systems, enabling precise lesion identification without the need for mechanical markers (69,70). ICG, folate-linked fluorophores, and FAP-targeted tracers have been explored in clinical trials and preclinical models (71). While further validation is needed, these technologies offer the potential for high specificity, reduced invasiveness, and enhanced surgical precision.

Alternative marker-guided localization techniques

In recent years, several novel localization techniques have been developed to enhance intraoperative accuracy and reduce complications. Among them, radiofrequency identification (RFID)-guided localization involves the placement of a micro-RFID tag near the pulmonary lesion under CT guidance. During surgery, the RFID signal is detected using a probe, offering precise, radiation-free localization (72). Radioguided occult lesion localization (ROLL) uses technetium-99m-labeled radiotracers injected around the nodule preoperatively. The radiotracer is then detected intraoperatively using a gamma probe, which enables accurate localization with minimal invasiveness. This technique has been adapted from breast tumor localization and has shown promising results in thoracic surgery (73). Magnetic-guided occult lesion localization (M-GOLL) employs magnetized markers detectable with a magnetic sensing probe (74). This approach eliminates radiation and offers a stable, retrievable marker for localization, although it requires specialized instrumentation and experience. While these techniques are still in the early stages of adoption, they represent important variations that expand the surgical toolbox for small and deeply seated pulmonary nodules.

Anatomical landmark-based localization

Another approach to noninvasive intraoperative localization involves anatomical landmark-based strategies, where the location of the pulmonary nodule is estimated by measuring distances from visible anatomical structures on preoperative CT scans, such as pulmonary fissures, pleural surfaces, or vascular landmarks. These measurements are then translated intraoperatively to guide wedge resections, often aided by surface markers or MB staining. The advantages of this approach include its simplicity, low cost, and avoidance of radiation exposure or puncture-related complications. However, two major limitations exist. First, the absence of depth perception increases the risk of insufficient deep margins. Second, discrepancies between preoperative CT images (obtained under normal lung inflation) and intraoperative lung conditions (deflated or overinflated due to anesthesia and ventilation) may lead to localization errors. Some studies may have also overestimated the efficacy of this approach by including nodules that were visible or palpable without localization, or those that would require larger resections regardless (75,76).

Conclusions

With the increasing detection of small pulmonary nodules, accurate localization has become essential in thoracic surgery. This review outlines a broad spectrum of localization techniques—from traditional CT-guided methods to bronchoscopy-assisted approaches and emerging noninvasive intraoperative strategies. Each modality offers unique advantages and limitations in terms of safety, accuracy, invasiveness, and technological requirements (Table 1). Notably, recent innovations such as hybrid operating rooms, RFID and magnetic localization, anatomical landmark-based methods, and molecular imaging using targeted fluorophores provide a glimpse into the future of precision localization. Moving forward, clinical integration of real-time multimodal imaging, artificial intelligence, and patient-specific localization strategies will be key to optimizing surgical outcomes while minimizing procedural risks.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-330/prf

Funding: This work was supported by the National Key Research and Development Program of China (No. 2022YFB4702600).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-330/coif). H.L. serves as an unpaid editorial board member of Journal of Thoracic Disease. The other 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.

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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