Anatomic evaluation of Pancoast tumors using three-dimensional models for surgical strategy development.

OBJECTIVE: Pancoast tumor resection planning requires precise interpretation of 2-dimensional images. We hypothesized that patient-specific 3-dimensional reconstructions, providing intuitive views of anatomy, would enable superior anatomic assessment. METHODS: Cross-sectional images from 9 patients with representative Pancoast tumors, selected from an institutional database, were randomly assigned to presentation as 2-dimensional images, 3-dimensional virtual reconstruction, or 3-dimensional physical reconstruction. Thoracic surgeons (n = 15) completed questionnaires on the tumor extent and a zone-based algorithmic surgical approach for each patient. Responses were compared with surgical pathology, documented surgical approach, and the optimal "zone-specific" approach. A 5-point Likert scale assessed participants' opinions regarding data presentation and potential benefits of patient-specific 3-dimensional models. RESULTS: Identification of tumor invasion of segmented neurovascular structures was more accurate with 3-dimensional physical reconstruction (2-dimensional 65.56%, 3-dimensional virtual reconstruction 58.52%, 3-dimensional physical reconstruction 87.50%, P < .001); there was no difference for unsegmented structures. Classification of assessed zonal invasion was better with 3-dimensional physical reconstruction (2-dimensional 67.41%, 3-dimensional virtual reconstruction 77.04%, 3-dimensional physical reconstruction 86.67%; P = .001). However, selected surgical approaches were often discordant from documented (2-dimensional 23.81%, 3-dimensional virtual reconstruction 42.86%, 3-dimensional physical reconstruction 45.24%, P = .084) and "zone-specific" approaches (2-dimensional 33.33%, 3-dimensional virtual reconstruction 42.86%, 3-dimensional physical reconstruction 45.24%, P = .501). All surgeons agreed that 3-dimensional virtual reconstruction and 3-dimensional physical reconstruction benefit surgical planning. Most surgeons (14/15) agreed that 3-dimensional virtual reconstruction and 3-dimensional physical reconstruction would facilitate patient and interdisciplinary communication. Finally, most surgeons (14/15) agreed that 3-dimensional virtual reconstruction and 3-dimensional physical reconstruction's benefits outweighed potential delays in care for model construction. CONCLUSIONS: Although a consistent effect on surgical strategy was not identified, patient-specific 3-dimensional Pancoast tumor models provided accurate and user-friendly overviews of critical thoracic structures with perceived benefits for surgeons' clinical practices.

Preclinical evaluation of thin convex probe endobronchial ultrasound-guided transbronchial needle aspiration for intrapulmonary lesions.

Background: Conventional flexible bronchoscopy has not achieved the high diagnostic yield for intrapulmonary lesions as seen with image-guided transthoracic biopsy. A thin convex probe endobronchial ultrasound bronchoscope (TCP-EBUS) with a 5.9-mm tip was designed to improve peripheral access over conventional EBUS bronchoscopes to facilitate real-time sampling of intrapulmonary lesions under ultrasound guidance. Methods: TCP-EBUS was inserted into the distal airways of ex-vivo human lungs to assess bronchial accessibility relative to clinically available bronchoscopes. The short- (≤1 h) and medium-term (≤10 d) safety of TCP-EBUS insertion and EBUS-guided transbronchial needle aspiration (TBNA) using a 25-gauge needle were evaluated physiologically and radiologically in live pigs. TCP-EBUS-guided TBNA feasibility was assessed in-vivo with pig intrapulmonary pseudo-tumors and ex-vivo with resected human lung cancer specimens. Results: For bronchial accessibility, TCP-EBUS demonstrated greater reach than the 6.6-mm convex probe endobronchial ultrasound (CP-EBUS) in all bronchi, as well as surpassed a 5.5-mm conventional bronchoscope in 63% (131/209) and a 4.8-mm conventional bronchoscope in 27% (57/209) of assessed bronchi. The median bronchial generation and the mean diameter of bronchi TCP-EBUS reached was 4 (range, 3-7) and 3.3±0.7 mm, respectively. No major complications related to TCP-EBUS-guided TBNA in distal airways were observed in the live pigs. Scattered mucosal erythema of the bronchial walls was observed immediately after TCP-EBUS insertion; this self-resolved by day 10. TCP-EBUS could successfully reach and visualize intrapulmonary targets via ultrasound, with no difficulty in needle deployment or sampling. Conclusions: TCP-EBUS has the potential to facilitate safe real-time transbronchial sampling of intrapulmonary lesions in the central and middle lung fields.

Endobronchial ultrasound-guided bipolar radiofrequency ablation for lung cancer: A first-in-human clinical trial.

OBJECTIVE: Percutaneous radiofrequency ablation (RFA) is a therapeutic option for lung tumors. However, percutaneous approaches have limited access to central lung regions and a relatively high complication rate. To overcome these limitations, a needle-type bipolar RFA device compatible with an endobronchial ultrasound (EBUS) bronchoscope was developed. The aim of this pilot study was to evaluate the immediate-term safety and ablation zone of lung tumor EBUS-guided RFA. METHODS: This was an ablate-and-resect study in patients scheduled for surgical resection of clinical stage I or II lung cancer or metastatic lung lesions ≥1 cm that were accessible using an EBUS bronchoscope. The RFA electrodes were placed within the lung nodule using EBUS guidance followed by ablation. Bronchoscopy and contrast-enhanced computed tomography were performed to evaluate for post-RFA complications. The resected lung underwent pathological assessment to characterize the ablation zone. RESULTS: A total of 5 primary lung cancers were ablated in 5 separate patients; no patients with metastatic lesions were recruited. For a total energy of 4 kJ (n = 3), 6 kJ (n = 1), and 8 kJ (n = 1) delivered, the ablation time was a mean of 13.8 (range, 10.3-16.0) minutes, 8.4 minutes, and 15.6 minutes, respectively, and the maximum ablation diameter was a mean of 1.8 (range, 1.3-2.1) cm, 2.7 cm, and 2.6 cm, respectively. No immediate post-RFA complications were observed. CONCLUSIONS: EBUS-guided bipolar RFA can ablate lung tumors using real-time ultrasound guidance. EBUS-guided RFA might ultimately represent a minimally invasive therapy for lung cancer in patients unable to tolerate surgery. Longer-term safety will need to be evaluated.

Development of a minimally invasive pulmonary porcine embolism model via endobronchial ultrasound.

Background: Current massive pulmonary embolism (PE) animal models use central venous access to deliver blood clots, which have features of random clot distribution and potentially fatal hemodynamic compromise. A clinically relevant preclinical model for generating pulmonary emboli in a more controlled fashion would be of value for a variety of research studies, including initial evaluation of novel therapeutic approaches. Endobronchial ultrasound-guided transbronchial needle injection (EBUS-TBNI) is a newly established approach for peri-tracheal/bronchial targets. The purpose of the present work was to establish a minimally invasive PE model in swine via a transbronchial approach. Methods: In anesthetized Yorkshire pigs, a 21-G EBUS-guided transbronchial needle aspiration (EBUS-TBNA) needle was introduced into the pulmonary artery under EBUS guidance. Autologous blood clots were administered into the right and left lower pulmonary arteries sequentially (PE1 and PE2, respectively). Hemodynamic and biochemical responses were evaluated. Results: Ten pigs were evaluated; all 20 blood clots (6.3±1.9 mL) were successfully injected. After injection, mean pulmonary artery pressure (mPAP; mmHg) increased (baseline: 16.6±5.6 vs. PE1: 24.5±7.6, P<0.0001 vs. PE2: 26.9±6.7, P<0.0001), and a positive correlation was observed between clot volume and change in mPAP (PE1: r=0.69, P=0.025; PE1 + PE2: r=0.60, P=0.063). Mean arterial pressure (MAP; mmHg) (baseline: 57.5±5.1 vs. PE1: 59.0±9.1, P=0.918 vs. PE2: 60.9±9.6, P=0.664) remained stable. No complications were observed. Conclusions: EBUS allows minimally invasive, precise, and reliable generation of pulmonary emboli in pigs. This model may serve as an important tool for new PE-related diagnostic and therapeutic research.

Pilot study using virtual 4-D tracking electromagnetic navigation bronchoscopy in the diagnosis of pulmonary nodules: a single center prospective study.

BACKGROUND: Electromagnetic navigation bronchoscopy (ENB) is a navigation technology intended to improve the diagnostic yield of pulmonary nodules. However, nodule displacement due to respiratory motion may compromise the accuracy of the navigation guidance. The Veran SPiNDrive ENB system employs respiratory-gating (4D-tracking) to compensate for this motion. The aim of the present study was to evaluate the diagnostic performance and safety of the Veran SPiNDrive system for biopsy of pulmonary nodules. METHODS: Adult patients with pulmonary nodules of ≥1 cm were enrolled at a single center. Both conventional bronchoscopy and 4D-tracking ENB were performed in one procedure session under general anesthesia, with the procedure order being randomly assigned. Radial probe endobronchial ultrasound and fluoroscopy were used in both groups. The diagnostic performance, safety, total procedure time, and total fluoroscopy time of the ENB phase were compared to the corresponding conventional bronchoscopy phase. RESULTS: The study was terminated due to poor accrual; a total of eleven patients were enrolled. The mean size of pulmonary nodules was 2.1 cm. The sensitivity for malignancy was 67% (6/9) and 56% (5/9) with conventional bronchoscopy and with 4D-tracking ENB, respectively. Two cases developed minor bleeding after conventional bronchoscopy, while no complications were observed after 4D-tracking ENB. The mean procedure time was 16.1 and 21.7 min (P=0.090), and the mean duration time for fluoroscopy use was 77 and 44 sec (P=0.056) for the conventional bronchoscopy and the 4D-tracking ENB phases, respectively. CONCLUSIONS: The diagnostic performance of the Veran SPiNDrive 4D-tracking ENB did not exceed that of conventional bronchoscopy for pulmonary nodules. No complications were seen during 4D-tracking ENB. A study with a larger number of participants is required for further assessment.

Thrombolysis of Pulmonary Emboli via Endobronchial Ultrasound-Guided Transbronchial Needle Injection.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle injection (EBUS-TBNI) is a novel technique for treating peribronchial targets. The aim of this study was to evaluate preliminary feasibility of thrombolysis of pulmonary emboli via EBUS-TBNI. METHODS: Yorkshire pigs (30-48 kg) were anesthetized and mechanically ventilated. Pre-formed autologous clots were injected sequentially into bilateral lower pulmonary arteries in bilateral models (PE1 and PE2, respectively) or into 1 side in unilateral models using a 21-gauge EBUS-TBNA needle under EBUS guidance. In the bilateral model, 2 hours after clot injection either 25 mL of tissue-plasminogen activator (t-PA; 1mg/mL) or distilled water were administered into each embolus via 25-gauge EBUS-TBNA needle. In the unilateral model, 25 mg t-PA was administered intravenously. Hemodynamic parameters were monitored continuously, and clot dissolved volume was evaluated by EBUS 30 minutes post-treatment administration. RESULTS: All clots (6.1 ± 1.7 mL) were successfully injected as documented by EBUS Doppler imaging. Clot injection in the bilateral model (n = 6) increased pulmonary arterial pressure (mm Hg: Baseline 19.2 ± 5.9 vs PE1: 26.7 ± 9.1, P = .005 vs PE2 29.9 ± 7.1, P = .0007). After t-PA TBNI in the bilateral model (n = 6), pulmonary arterial pressure at 30 minutes post-injection showed improvement (mm Hg: PE2 29.9 ± 7.1 vs post-t-PA 24.4 ± 3.9, P = .0283). Treatment with t-PA TBNI demonstrated superior clot dissolution at 30 minutes post-treatment (dissolved mm3: t-PA TBNI 625.4 ± 156.6 vs t-PA intravenously: 181.6 ± 94.3, P = .0003 vs distilled water TBNI 42.5 ± 33.0, P < .0001). There were no complications. CONCLUSIONS: EBUS-guided transbronchial thrombolysis may be a feasible approach for treating central pulmonary emboli.

A preclinical research platform to evaluate photosensitizers for transbronchial localization and phototherapy of lung cancer using an orthotopic mouse model.

BACKGROUND: Establishing the efficacy of novel photosensitizers (PSs) for phototherapy of lung cancer requires in vivo study prior to clinical evaluation. However, previously described animal models are not ideal for assessing transbronchial approaches with such PSs. METHODS: An ultra-small parallel-type composite optical fiberscope (COF) with a 0.97 mm outer diameter tip. The integration of illumination and laser irradiation fibers inside the COF allows simultaneous white-light and fluorescence imaging, as well as real-time monitoring of tip position during laser phototherapy. An orthotopic lung cancer mouse model was created with three human lung cancer cell lines transbronchially inoculated into athymic nude mice. The COF was inserted transbronchially into a total of 15 mice for tumor observation. For in vivo fluorescence imaging, an organic nanoparticle, porphysome, was used as a PS. Laser excitation through the COF was performed at 50 mW using a 671 nm source. RESULTS: The overall success rate for creating orthotopic lung tumors was 71%. Transbronchial white light images were successfully captured by COF. Access to the left main bronchus was successful in 87% of mice (13/15), the right main bronchus to the cranial lobe bronchus level in 100% (15/15), and to the right basal trifurcation of the middle lobe, caudal lobe and accessory lobe in 93% (14/15). For transbronchial tumor localization of orthotopic lung cancer tumors, PS-laden tumor with the strong signal was clearly contrasted from the normal bronchial wall. CONCLUSIONS: The ultra-small COF enabled reliable transbronchial access to orthotopic human lung cancer xenografts in vivo. This method could serve as a versatile preclinical research platform for PS evaluation in lung cancer, enabling transbronchial approaches in in vivo survival models inoculated with human lung cancer cells.

Repeated porphyrin lipoprotein-based photodynamic therapy controls distant disease in mouse mesothelioma via the abscopal effect.

While photodynamic therapy (PDT) can induce acute inflammation in the irradiated tumor site, a sustained systemic, adaptive immune response is desirable, as it may control the growth of nonirradiated distant disease. Previously, we developed porphyrin lipoprotein (PLP), a ∼20 nm nanoparticle photosensitizer, and observed that it not only efficiently eradicated irradiated primary VX2 buccal carcinomas in rabbits, but also induced regression of nonirradiated metastases in a draining lymph node. We hypothesized that PLP-mediated PDT can induce an abscopal effect and we sought to investigate the immune mechanism underlying such a response in a highly aggressive, dual subcutaneous AE17-OVA+ mesothelioma model in C57BL/6 mice. Four cycles of PLP-mediated PDT was sufficient to delay the growth of a distal, nonirradiated tumor four-fold relative to controls. Serum cytokine analysis revealed high interleukin-6 levels, showing a 30-fold increase relative to phosphate-buffered solution (PBS) treated mice. Flow cytometry revealed an increase in CD4+ T cells and effector memory CD8+ T cells in non-irradiated tumors. Notably, PDT in combination with PD-1 antibody therapy prolonged survival compared to monotherapy and PBS. PLP-mediated PDT shows promise in generating a systemic immune response that can complement other treatments, improving prognoses for patients with metastatic cancers.

Rabbit VX2 lung tumor models can form early nodal metastases.

BACKGROUND: The rabbit squamous cell cancer line, VX2, has been used to generate various tumor models in rabbits. It is notable for its ability to generate nodal metastases. However, the timing and extent of nodal metastases vary by primary inoculation site and methodology. The development of metastases specifically in lung cancer models has not been well-described. We sought to characterize the generation of nodal metastases in rabbit transbronchial VX2 lung tumor models. METHODS: Rabbit VX2 lung tumor models were created in the right lung via transbronchial injection and serially imaged by computed tomography. Rabbits (n = 15) were sacrificed from between 5 and 24 days post-inoculation for collection of the ipsilateral and contralateral paratracheal lymph nodes. These underwent histopathological evaluation for metastases using hematoxylin and eosin as well as cytokeratin AE1/AE3 immunohistochemical staining. RESULTS: Nodal metastases were detectable as early as 1 week after inoculation but were more prevalent with longer inoculation; all rabbits at > 2 weeks post-inoculation had nodal metastases. Contralateral metastases were in general seen later than ipsilateral metastases. Lymph node volume did not predict the likelihood of nodal metastases (p = 0.4 and p = 0.07 for ipsilateral and contralateral nodal metastases, respectively), but primary tumor volume was significantly associated with the likelihood of nodal metastases (p = 0.001 and p = 0.005 for ipsilateral and contralateral nodal metastases, respectively). Ipsilateral metastases were detectable at a tumor diameter of 1 cm; contralateral metastases were more variable but in general required a tumor diameter of 2 cm. CONCLUSIONS: Rabbit transbronchial VX2 lung tumor models generate nodal metastases relatively early after inoculation. These results suggest such models may be valuable tools in the investigation of novel therapeutic modalities relevant for the treatment of both early-stage and locally advanced lung cancer.