Investigating the effects of a temperature dependent photodynamic dose: A numerical study.

SIGNIFICANCE: Photodynamic therapy (PDT) and photothermal therapy (PTT) show promise as cancer treatments, but challenges in generating large ablative volumes for deep-seated tumours persist. Using simulations, this study investigates combined PDT and PTT to increase treatment volumes, including the impact of a temperature-dependent PDT dose on the treatment volume radius. APPROACH: A finite-element model, using the open-source SfePy package, was developed to simulate combined interstitial photothermal and photodynamic treatments. Results compared an additive dose model to a temperature-dependent dose model with enhanced PDT dosimetry and examined typical clinical scenarios for possible synergistic effects. RESULTS: Findings revealed that the temperature-dependent dose model could significantly expand the damage radius compared to the additive model, depending on the tissue and drug properties. CONCLUSIONS: Characterizing synergistic effects of PDT and PTT could enhance treatment planning. Future work is ongoing to implement additional variables, such as photosensitizer photobleaching, and spatial and temporally varying oxygenation.

Laser interstitial thermal therapy of lung lesions near large vessels: a numerical study.

Objective.Laser interstitial thermal therapy (LITT) is an evolving hyperthermia-based technology that may offer a minimally invasive alternative to inoperable lung cancer. LITT of perivascular targets is challenged by higher risk of disease recurrence due to vascular heat sinks, as well as risk of damage to these vascular structures. The objective of this work is to examine the impact of multiple vessel parameters on the efficacy of the treatment and the integrity of the vessel wall in perivascular LITT.Approach.A finite element model is used to examine the role of vessel proximity, flow rate, and wall thickness on the outcome of the treatment. Main result. The simulated work indicates that vessel proximity is the major factor in driving the magnitude of the heat sink effect. Vessels situated near the target volume may act as a protective measure for reducing healthy tissue damage. Vessels with thicker walls are more at risk of damage during treatment. Interventions to reduce the flow rate may reduce the vessel's heat sink effect but may also result in increased risk of vascular wall damage. Lastly, even at reduced blood flow rates, the volume of blood reaching the threshold of irreversible damage (>43 °C) is negligible compared to the volume of blood flow throughout the treatment duration.Significance.This investigative simulation yields results that may help guide clinicians on treatment planning near large vessels.

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.

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.

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.

A Novel Laser Fiberscope for Simultaneous Imaging and Phototherapy of Peripheral Lung Cancer.

BACKGROUND: Phototherapy is an alternative treatment for patients with localized non-small cell lung cancer who are unable to undergo surgical resection. However, phototherapy is currently limited to treatment of centrally located lung cancer, with the much larger proportion of peripheral lesions remaining inaccessible. There are also concerns over the accuracy of targeted laser treatment because of the need to exchange visualization and irradiation fibers during therapy, preventing the operator from confirming the final location of the irradiation fiber. METHODS: A newly developed parallel-type ultrasmall composite optical fiberscope (Laser-eYe Ultrathin fiberscope [LYU]), which enables simultaneous white-light imaging and phototherapy, was evaluated in preclinical lung cancer models. Three models were used: human lung cancer xenografts (A549) in mice, orthotopic VX2 lung tumors in rabbits, and ex vivo pig lungs into which A549 tumor tissue was transplanted. A multifunctional porphyrin-phospholipid nanoparticle (porphysome) was used as a photosensitizer to evaluate fluorescence-guided photothermal therapy. RESULTS: The LYU's 0.97 mm diameter and hydrophilic coating allowed easy passage through the working channel of all types of bronchoscopes and controlled guidance of the LYU tip in any desired direction. The LYU could visualize the peripheral bronchus and porphysome-laden peripheral tumors. The LYU could also perform photothermal therapy with simultaneous imaging. CONCLUSIONS: The LYU enables simultaneous imaging and phototherapy that allows accurate irradiation of peripheral lung cancers. This new laser device may enable ultraminimally invasive transbronchial treatment of peripheral lung cancer.

Evaluation of Novel Imaging Devices for Nanoparticle-Mediated Fluorescence-Guided Lung Tumor Therapy.

BACKGROUND: Nonsurgical and minimally invasive approaches for early-stage peripheral lung cancer are needed to avoid the known morbidity of surgical resection, particularly in high-risk patients. We previously demonstrated the utility of multifunctional porphyrin-phospholipid nanoparticles (porphysomes) for fluorescence imaging and phototherapy after preferential accumulation into tumors. The objective of this study was to demonstrate the feasibility of porphysome-mediated imaging and photothermal therapy using a newly developed fiberscope and thoracoscope. METHODS: To prepare this technology for clinical translation, we developed a porphysome-specific fiberscope (scanning fiber endoscope and porphysome-specific thoracoscope), both capable of detecting porphysome fluorescence, for image-guided transbronchial and transpleural photothermal therapy to treat endobronchial/peribronchial and subpleural tumors, respectively. These were tested in three animal models: human lung cancer xenografts (A549) in mice, orthotopic VX2 lung tumors in rabbits, and ex vivo pig lung into which A549 tumor tissue was transplanted. RESULTS: The scanning fiber endoscope, with a 1.2-mm diameter, is small enough to pass through the working channel of a conventional bronchoscope and could visualize porphysome-laden tumors located inside or close to the peripheral bronchial wall. The porphysome-specific thoracoscope system had high sensitivity for porphysome fluorescence and enabled image-guided thoracoscopic resection of porphysome-accumulating tumors close to the pleura. Porphysomes also enhanced the efficacy of scanning fiber endoscope-guided transbronchial photothermal therapy and porphysome-specific thoracoscope-guided transpleural photothermal therapy, resulting in selective and efficient tumor tissue ablation in the rabbit and pig models. CONCLUSIONS: These results support the potential for clinical translation of this novel platform to affect nonsurgical and minimally invasive treatment options for early-stage peripheral lung cancer.

Image-guided thoracic surgery in the hybrid operation room.

There has been an increase in the use of image-guided technology to facilitate minimally invasive therapy. The next generation of minimally invasive therapy is focused on advancement and translation of novel image-guided technologies in therapeutic interventions, including surgery, interventional pulmonology, radiation therapy, and interventional laser therapy. To establish the efficacy of different minimally invasive therapies, we have developed a hybrid operating room, known as the guided therapeutics operating room (GTx OR) at the Toronto General Hospital. The GTx OR is equipped with multi-modality image-guidance systems, which features a dual source-dual energy computed tomography (CT) scanner, a robotic cone-beam CT (CBCT)/fluoroscopy, high-performance endobronchial ultrasound system, endoscopic surgery system, near-infrared (NIR) fluorescence imaging system, and navigation tracking systems. The novel multimodality image-guidance systems allow physicians to quickly, and accurately image patients while they are on the operating table. This yield improved outcomes since physicians are able to use image guidance during their procedures, and carry out innovative multi-modality therapeutics. Multiple preclinical translational studies pertaining to innovative minimally invasive technology is being developed in our guided therapeutics laboratory (GTx Lab). The GTx Lab is equipped with similar technology, and multimodality image-guidance systems as the GTx OR, and acts as an appropriate platform for translation of research into human clinical trials. Through the GTx Lab, we are able to perform basic research, such as the development of image-guided technologies, preclinical model testing, as well as preclinical imaging, and then translate that research into the GTx OR. This OR allows for the utilization of new technologies in cancer therapy, including molecular imaging, and other innovative imaging modalities, and therefore enables a better quality of life for patients, both during and after the procedure. In this article, we describe capabilities of the GTx systems, and discuss the first-in-human technologies used, and evaluated in GTx OR.