Pulsed electric field ablation safety and characterization near sensitive structures in lung: a preclinical and clinical case series study

Introduction

Lung cancer remains the leading cause of cancer deaths despite substantial advancements in treatment for the disease (1). Nonsurgical focal therapies in the treatment of cancer, such as radiation and thermal modalities, must balance tumor destruction with safety to surrounding structures, and must contend with unpredictable heat sink effects near vessels (2). Nonetheless, local thermal ablative modalities like microwave ablation (MWA) and cryotherapy have evolved in the treatment of certain tumors, especially in the liver (3,4). However, treatment is often limited to sensitive structures. Indeed, recent safety concerns around the bronchoscopic use of MWA in the lungs highlight the need for new technologies to enable treatment while preserving patient safety (5).

Pulsed electric field (PEF) technologies do not primarily rely on thermal mechanisms and have shown the ability to ablate tissue while preserving stromal matrix in the zone of injury (6-11). However, the heterogeneous environment for solid tumor masses embedded within aerated lung can influence the electric field distribution and resulting ablation zone, particularly for bipolar PEF, where multiple needles are placed that may span both aerated parenchyma and tumor tissue (12,13). This may have contributed to challenges with some of these technologies in past clinical trials (14). Alternately, the Aliya PEF system (Galvanize Therapeutics, Redwood City, CA, USA), uses a single needle placed within the tumor and a biphasic waveform, which collectively reduces arrhythmia risk (15,16) and is less susceptible to tissue variability outside the tumor.

This safety study of Aliya PEF in a porcine model evaluates the radiological and histological characteristics in normal lung parenchyma and the safety of delivery intentionally adjacent to critical anatomical structures. Finally, clinical case examples in patients with mediastinal tumors where the needle was positioned 1 cm of various mediastinal structures are presented to support the preclinical findings. We present this article in accordance with the ARRIVE and AME Case Series reporting checklists (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-1976/rc).

Methods

PEF system

Aliya PEF has one fixed dose with brief 3,000 V biphasic pulses delivered to target tissues through a single monopolar needle with a dispersive electrode serving as the return (Figure S1). Two end-effectors, a 19-gauge percutaneous needle (20 cm in length with a 1cm non-insulated distal tip) and a 21-gauge bronchoscopic needle (1,150 mm length flexible needle with a 5-mm non-insulated distal tip and a 3 cm throw length), were used.

Study methods

Percutaneous and bronchoscopic end-effectors were evaluated in separate studies that were both approved by the Institutional Animal Care and Use Committees of both laboratories [Synchrony Labs, LLC, NC (approval No. 373-07-22) and NAMSA, Coons Rapids, MN (approval No. JOL005-IS75)], and were performed in compliance with Good Laboratory Practices (GLP) standards and institutional guidelines for the care and use of animals. A protocol was prepared before the study without registration. Animals were anesthetized to reduce procedural pain, and pain medication was administered as necessary during the survival period. Humane endpoints were established, but adverse events were noted that required early termination. Each study enrolled six female Yorkshire cross pigs, with three followed for four days and three followed for 28 days. Animals were sourced by each laboratory and consent for research use was obtained. These timepoints enabled assessment of both the short-term impact on the tissue and neighboring structures and the long-term response and injury kinetics. Table 1 summarizes the treatments for each study. No control group was included, but non-ablated tissue was evaluated for comparison. Three animals were included in each group to facilitate comparison and to reduce the overall number of animals needed for the study per the FDA’s “replace, reduce, refine” objectives. No animals were excluded in this study. Animals were not randomized to groups because percutaneous and endoluminal procedures had to be completed in different ORs due to the different equipment needs for each procedure type.

Ablations were intentionally delivered near a variety of critical structures in the right lung (e.g., pericardium, pleura, the pulmonary arteries, including both the main trunks and the lobar vessels, airways, both central and conducting, as well as the IVC and the diaphragm (Figure S2). To accomplish placement within ~5 mm or less of each structure, both the rigid and flexible needles were placed using either standard computed tomography (CT) or cone-beam computed tomography (CBCT) guidance.

ECG monitoring was performed intraprocedurally and during recovery using the included cardiac gating device (Ivy 7600, Ivy Biomedical, Branford, CT, USA) and traditional anesthetic cardiac and respiratory monitoring, and any anomalies were captured per protocol. Each ablation site received at least one activation, with some receiving a second dose at the same position to understand any risk posed by completely overlapped ablations. Following PEF procedures, pigs were recovered until their prescribed survival timepoints. During the in-life phase, physical examinations, clinical observations, weight checks, and clinical pathology on blood samples were conducted to evaluate animal health.

Radiographic image analysis

Multidetector CT scanning was conducted at termination in the 4-day cohorts and weekly post treatment in the 28-day cohorts to evaluate the radiographic characteristics of the treatments over time. Both unenhanced and contrast enhanced imaging from the arterial phase to a late parenchymal phase (3–4 minutes after injection) were performed. Images were reviewed by a board-certified radiologist, and the dimensions of each lesion and general comments about individual lesion appearance were documented. The shortest distance to nearby critical structures was measured radiographically.

Pathologic examination

A complete necropsy was performed by a board-certified veterinary pathologist to inspect the treated tissues and collateral structures for ablation lesions, macroscopically evaluate downstream organs, perform gross treatment zone measurements, and collect samples for histopathologic analysis. Detailed pathology methods are available in the Appendix 1. Briefly, all identified ablation zones, grossly impacted adjacent structures, and prespecified nontarget organs were trimmed and processed for histopathologic evaluation with hematoxylin and eosin (H&E) and Masson’s Trichrome (MT).

Clinical case series

The Aliya PEF system is currently commercially available with a percutaneous needle for clinical use. In that context, the system has been used to treat lesions in challenging locations, including in and around the mediastinum. Herein, a clinical case series of six patients from a single institution (Duke University School of Medicine, Durham, NC, USA) is presented that required placement of the needle within 1 cm of mediastinal structures to deliver the ablation. All procedures performed in this study were in accordance with the Helsinki Declaration and its subsequent amendments. The clinical cases are part of a retrospective study approved by the Duke University Health System Institutional Review Board (protocol number: PRO00109757) and a waiver of informed consent was obtained from patients receiving ablation from September 2023 through January 2024. The waiver of consent was granted per the strict standards of the Duke University IRB. Patients were followed for 30 days postablation to assess safety. Patients were eligible because they presented with lesions adjacent to sensitive structures that were not considered candidates for traditional ablative modalities. The relevant characteristics of the participants are presented in Table 2.

Statistical analysis

Summary statistics are presented for observational data as applicable, presented as mean ± standard deviation. Histomorphology data are presented in tabular format and/or qualitative description. Student’s t-test was used to compare ablation zone sizes between different timepoints and different organs using Graphpad Prism v 9.5.0 (GraphPad Software LLC, San Diego, USA).

Results

There were no complications reaching any target location and no procedure-related complications noted. No cardiac rhythm disturbances were noted intraprocedurally in any treatments, even when energy was delivered near the mediastinum.

General in life, gross, and histopathological results

There were no adverse effects of the treatments on the animals. Laboratory data were unremarkable, with only occasional insignificant excursions from the reference ranges that occurred on an individual basis, including mildly elevated gamma-glutamyl transferase (GGT), mild monocytosis, mild hypercalcemia, mild neutrophilia, etc. For a complete list of parameters measured, refer to Tables S1,S2.

Representative gross images of ablation sites and average short-axis measurements are shown in Figure S3. No safety concerns were noted in the lungs. At the short-term timepoint, the 18 ablations typically appeared dark red due to the hemorrhage and hyperemia of the lesions within the zone of necrosis. Three of the lesions appeared tan, as histologically they exhibited much less hemorrhage and hyperemia within the zone of necrosis. In the long-term cohort, 6 out of 9 total treatment sites were identified grossly at necropsy for the endobronchial group and 5 out of 11 for the percutaneous group, despite serial sectioning of the entire lung. Treated sites were moderately-to-well demarcated foci of firmness and tan discoloration of the parenchyma. Grossly, each potential treatment site lesion was minimally to mildly discernible, slightly firm, and tan. At 4 and 28 days, the ablated zones measured 8.2±2.6 and 6.4±1.5 mm, respectively.

Figure S4, top shows a 4-day lesion with discernible zones of hemorrhage, fibrin, and necrosis in the central region, along with atelectasis and early fibroplasia at the periphery. The alveoli contained erythrocytes and fibrin. Connective tissue elements were unaffected. Blood vessels in the lesion exhibited disorganized thrombi. Interlobular septa were expanded due to edema and fibrin. The outer part of the lesion showed hypercellularity and minimal inflammation. Fibrin extended into alveoli briefly.

At 28 days, lung ablation zones showed well-demarcated parenchymal fibrosis (Figure S4, bottom). Minimal mononuclear inflammatory cells, including macrophages and lymphocytes, were present within the fibrotic zone. Hemosiderin, an iron-containing pigment, was observed in macrophages. The presence of hemosiderin was expected due to chronic resolution of hemorrhage. Some samples had small foci of mineralization with multinucleated giant cells. Necrosis, hemorrhage, edema, fibrin/thrombus, intravascular thrombi, and peribronchiolar lymphoid hyperplasia were absent in the 28-day treatment site lesions.

Radiographical findings and proximity to critical structures

For all ablation sites, the ablation size observed by Day 7 gradually decreased over the 28-day period. Representative images of the CT scans over time are presented in Figure 1A. The average short-axis radiographic ablation size for each treatment over time is presented in Figure 1B.

Figure 1 Radiographic treatment resolution. The area targeted with the needle placement is circled (A, left). Treatment zones are indicated by red arrows. Treatment sites appeared as focal hypoechoic regions (A). Ablation zones generally decreased in size radiographically (B), nearly resolving by 28 days.

Intraprocedural CT or CBCT showed proximity to the targeted critical structures, with some less than 1 mm away. A complete list of sensitive structures and their distances from each treatment site is provided in Table 3.

Critical structure safety

There were no safety concerns noted in sensitive structures across all 12 animals in both studies, despite the close positioning of the treatments to the numerous structures. Of the 42 treatments, there were two instances of collateral findings. In one instance, the needle was inadvertently advanced through the diaphragm and into the liver, resulting in a lesion on the liver (Figure 2A-2C).

Figure 2 Collateral findings in liver and IVC. (A) Needle placement near the diaphragm. Purple and blue lines intersect at the needle tip location. (B) Resulting lesion (yellow arrow) on the liver. (C) The radiographic pulmonary ablation zone at 5 days. (D) Axial CT scans at the time of treatment when the needle was positioned 3.8 mm from the IVC. Yellow and blue lines intersect at the needle tip location. (E) The gross lesion in the lung parenchyma (yellow arrow indicates lesion location). (F) Collateral lesion on the IVC was visible grossly (yellow arrow indicates lesion location). (G) Histological characterization with hematoxylin and eosin staining at 2× magnification of the collateral lesion shows a zone of expanded adventitia due to edema, low numbers of neutrophils and macrophages, early fibroplasia, and capillary hyperplasia that bordered a zone of native adventitia. The stars denote the border of the affected adventitia and the tunica media. The tunica media and intima are unaffected. (H) At the 5-day termination timepoint axial CT showed a lesion abutting the IVC. CT, computed tomography; IVC, inferior vena cava.

Inferior vena cava (IVC)

In the second instance (Figure 2D-2H), the PEF needle tip was 3.8 mm from the IVC (see Figure 2D). At day 5, the lesion clearly included the IVC on CT imaging (Figure 2H), and gross lesions were evident in the lung parenchyma (Figure 2E) and on the adventitial layer of the IVC (Figure 2F). Histology confirmed that the IVC injury did not alter the structural integrity of the IVC nor its thickness (Figure 2G). Expansion of the adventitial layer due to fibroplasia, capillary proliferation, inflammatory cells, and edema was present, but there were no alterations to the tunica media or tunica intima. Other treatments were located near the IVC in both short-term (5 mm) and long-term cohorts (<1 mm) of animals with no gross or histological findings.

Pulmonary artery & mainstem bronchus

An ablation was located less than 1 mm from the right main pulmonary artery and approximately 2.7 mm from the proximal right mainstem bronchus (Figure 3A,3B). The day 5 CT showed a well-defined lesion that included both structures (Figure 3C). A clearly visible parenchymal lesion was identified grossly (Figure 3D), but no collateral injury was noted to either the bronchus or the pulmonary artery.

Figure 3 Ablation near the right mainstem bronchus and pulmonary artery. (A) Coronal CT. Yellow and purple lines intersect at the needle tip location. (B) Axial CT scans at the time of treatment. Yellow and blue lines intersect at the needle tip location. Both coronal and axial images show proximity to both the right mainstem bronchus and the right main pulmonary artery. (C) Day 5 CT image showing how the lesion abutted both the artery and bronchus. (D) A gross lesion was evident in the pulmonary parenchyma, but none were noted on either the bronchus or the pulmonary artery. CT, computed tomography.

Lastly, an example of a mediastinal pleural ablation is shown in Figure 4. This treatment was delivered endobronchially, and the ablation lesion could be easily visualized on CT 5 days post-treatment (Figure 4A). Proximity to the pleural surface was evident both grossly and histologically (Figure 4B-4E), but no clinically significant alterations to the pleura were observed.

Figure 4 Endobronchial pleural ablation. Needle location with the intersection of the colored lines indicating needle tip location (A) was close to the mediastinum and a mediastinal ablation zone was visible on CT (B). Gross image (C) and histological images with hematoxylin and eosin staining (D) and Masson’s Trichrome (E) showing involvement of the mediastinal pleural surface. The micrographs show the treatment site lesion which is characterized by a well demarcated focus of necrosis and hemorrhage which extends to the pleural surface. There is a narrow zone of hypercellularity due mostly to atelectasis circumferentially peripheral to the necrosis and hemorrhage. CT, computed tomography.

Clinical cases

A total of six patients were selected for inclusion in this study. Patient demographics and clinical characteristics are summarized in Table 2. There were a variety of tumor histologies treated (see Table 4). The 19 G needle was deployed under CT guidance. The average distance from the needle to the various structures in the chest was ~5.8 mm (Table 5).

Two of the six patients had prior treatment with radiation in the area of ablation. Representative intraprocedural CT images for two of the cases from Table 5 are shown in Figure 5, demonstrating ablation needle placement near the descending thoracic aorta (5.7 mm) and the left atrium (7 mm). In those patients, the procedure was well tolerated and without significant complications. No additional clinical issues were noted in the treatment-related time window out to 30 days.

Figure 5 Needle location adjacent to sensitive vascular and nonvascular intrathoracic structures. Sensitive intrathoracic structures adjacent to the needle are shaded in red. (A) Descending thoracic aorta and (B) left atrium.

Discussion

This porcine study evaluated the delivery of Aliya PEF ablation in healthy lung tissue via percutaneous and endobronchial needles, and explicitly targeted critical structures within the chest that contraindicate other focal approaches, such as surgery, ionizing radiation, and thermal ablation (17). All animals recovered uneventfully and survived for the designated periods with no untoward observations or pathology variances related to ablation throughout the in-life period, despite multiple ablations near various sensitive structures.

At 4 and 28 days, the ablated zones measured 8.2±2.6 mm and 6.4±1.5 mm, respectively, consistent with the partial resolution observed radiographically (Figure 1). This is smaller than the largest zones achievable with MWA, but those systems create variable-sized zones depending on parameter settings (5). Similarly, IRE systems have many possible settings, but can create larger zones at the highest settings (18). Sensitive structures within the ablation zone for this study included major venous and arterial vasculature, diaphragm, mainstem bronchi, and the mediastinum. Despite proximity of the needle within 2 mm of some structures, there was no histological impact on the structural integrity of neighboring structures. In one ablation, a collateral lesion on the liver was identified when the needle was positioned 1.3 mm from the diaphragm. No observable injury was noted on the diaphragm. In a case near the IVC, injury was noted to the adventitial surface of the IVC, but it did not extend to inner layers of the IVC and the IVC structure was preserved. Microscopic changes observed in this IVC were consistent with the healing process, and there were no concerning observations of exuberant fibrosis, hemorrhage external to the treatment site, or thermal-induced injury. Overall, there were no pathology-based safety concerns associated with the inflammatory injury response at the treatment sites over 28 days.

The results of this study are in considerable contrast to published data on flexible MWA, a commonly employed thermal ablation modality that has been used previously for pulmonary metastases (19). While broad adoption of percutaneous MWA has been limited due to complication rates and complicated dose management near heat sinks (e.g., vessels and airways), a clinical feasibility study for transbronchial MWA delivery has not indicated a favorable safety profile in this environment (5). Namely, on 30-day CT, a sizable area of heterogeneous density, including hypodense zones consistent with cavitation that raises significant safety concerns. Further, in the same study, one patient died as a result of the treatments (5). This suggests that PEF may be a clinically feasible ablation modality in the lung. This finding may be explained in the context of prior studies of pulsed field effects which have shown that the relative lack of thermal effects in the ablation zone imparts a superior safety profile and sparing of structural tissue elements (6-11). In the lung, the sparing of stromal proteins is particularly important due to the thin planes of tissue that are present.

Time-dependent healing was found in all lesions radiographically and pathologically, with complete resolution of several lesions by 28 days. In fact, several ablation zones could not be identified at the 28-day timepoint due to the complete resolution of the injury. This aligns with previously published progression of PEF treatments in solid organs, which result in visible lesions at three days that rapidly resolve into small foci of fibrosis or even completely replaced tissue in liver, including one study of the same system (20,21). Both devices evaluated here yielded equivalent ablation zone dimensions (1.0 cm diameter) when evaluated in liver, a more homogeneous tissue that better represents the impedance and density of tumors (Figure S5). The radiographic results also yielded similar measurements at the 4±1 day timepoint (Figure 1, 10.2±2.4 mm).

Outside of delivery near the diaphragm, where occasional paralytic dosing mitigated movement, little muscle stimulation was noted. The mild contractions are likely due to the use of biphasic waveforms, which have been shown to reduce muscle contraction (22). This also contributes to the lack of cardiac interference (15) observed, despite treatments being delivered near the mediastinum in contrast to other PEF modalities (23).

The limitations of this study include the use of a healthy porcine model, which may not represent the pathological and physiological response of human tissues, particularly solid tumor masses in healthy lung parenchyma. To that end, a cohort of clinical cases is also presented where the needle was placed within 1cm of the mediastinal structures and the procedure was well tolerated and without substantive complications. However, it should be noted that the influence of disease on these structures, such as tumor infiltration into a major blood vessel, may alter the associated safety profile observed here. Additionally, this study did not evaluate the functional outcomes of the ablation treatment, such as the explicit impact on organ function. However, there were no animal health concerns noted, and organ function clinically would likely be more a function of the pre-existing disease burden than the effect of PEF, since tissue structure was largely preserved. No cardiac abnormalities were noted in any animals, but continuous ECG recording with post hoc review was not conducted, though no issues are anticipated given the previous study of similar waveforms (15).

Conclusions

Collectively, these preclinical and clinical findings suggest that the Aliya system offers a viable ablation method with a superior safety profile to surgery, irradiative ablation, or thermal ablation for the treatment of targeted regions in the lung. Future studies enrolling larger numbers of patients should be completed to corroborate these findings and to establish efficacy in addition to safety.

Acknowledgments

We would like to thank Dr. Blair Andrew for reviewing CT images.

Footnote

Reporting Checklist: The authors have completed the ARRIVE and AME Case Series reporting checklists. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-1976/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-1976/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-1976/prf

Funding: This work was funded by Galvanize Therapeutics.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-1976/coif). All authors report this study received funding from Galvanize Therapeutics. D.W.H., W.K., and R.K. are employees of Galvanize Therapeutics and consequently have stock options. D.W.H. and W.K. had co-inventorship on patents owned by Galvanize Therapeutics, and are reimbursed for conferences and travel from Galvanize Therapeutics. R.K. received travel support from Galvanize Therapeutics. J.G.M. and W.C.S. are consultants of Galvanize Therapeutics. J.R. had a grant from Intuitive Surgical; received consulting payment from Elucent, Noah, MaunaKea, and Vergent; and received payment/honoraria from Chest. The authors have no other 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. The animal study was approved a priori by the Institutional Animal Care and Use Committees at NAMSA (approval No. JOL005-IS75) and Synchrony Labs (approval No. 373-07-22), and was performed in compliance with Good Laboratory Practices (GLP) standards and institutional guidelines for the care and use of animals. All procedures performed in this study were in accordance with the Helsinki Declaration and its subsequent amendments. The clinical cases are part of a retrospective study approved by the Duke University Health System Institutional Review Board (protocol number: PRO00109757) and a waiver of informed consent obtained with patients receiving ablation from September 2023 through January 2024. The waiver of consent was granted per the strict standards of the Duke University IRB.

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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