Bronchoscopic lung volume reduction for Emphysema: physiological and radiological correlations

Introduction: Patient selection in lung volume reduction (LVR) plays a pivotal role in achieving meaningful clinical outcomes. Currently, LVR patients are selected based on three established criteria: heterogeneity index, percentage of low attenuation area (%LAA), and fissure integrity score. Quantitative computed tomography (QCT) has been developed to quantify lung physiological indices at the lobar level and could potentially revolutionise patient selection in LVR procedures. We developed an in-house QCT software, LungSeg, and used its radiological indices for the purposes of this thesis. The aim of this thesis is to discover potential physiological and radiological indices that could serve as predictors for superior LVR outcomes for better patient selection. Methods: This thesis took two studies and analysed them using LungSeg. The first study was the long-term coil study, a randomised controlled study that had the control group crossing over to the treatment arm at 12 months. At 12 months post-procedure the baseline measurements were assessed against the 12-months post-procedural measurements. The second study was the short-term valve study which was another randomised controlled study that compared the primary and secondary endpoints between the control and the valve-treated group at three months post-procedure. Results: In the long-term coil study, we found that the best statistically significant combination of predictors for change in target lobar volume at inspiration was found to be the combination of baseline target LV at inspiration, -950HU EI at inspiration, and TLCabs with a model adjusted R2 of 0.407 (p = 0.0001). In a subsequent multivariate analysis using ≥45% LAA on the -950HU at Inspiration, the R2 of the same prediction model did improve to 0.493 (P-value = 0.002). Meanwhile, the best statistically significant combination of predictors for change in target lobar volume at inspiration following valve treatment was found to be the combination of baseline target LV at inspiration, target lobar fissure integrity and baseline FEV1abs with a model adjusted R2 of 0.193 (p = 0.105). Conclusion: Using QCT, we have improved the proposed patient selection algorithm for LVR procedures based on the best QCT and lung function predictors.Open Acces

Open-source virtual bronchoscopy for image guided navigation

This thesis describes the development of an open-source system for virtual bronchoscopy used in combination with electromagnetic instrument tracking. The end application is virtual navigation of the lung for biopsy of early stage cancer nodules. The open-source platform 3D Slicer was used for creating freely available algorithms for virtual bronchscopy. Firstly, the development of an open-source semi-automatic algorithm for prediction of solitary pulmonary nodule malignancy is presented. This approach may help the physician decide whether to proceed with biopsy of the nodule. The user-selected nodule is segmented in order to extract radiological characteristics (i.e., size, location, edge smoothness, calcification presence, cavity wall thickness) which are combined with patient information to calculate likelihood of malignancy. The overall accuracy of the algorithm is shown to be high compared to independent experts' assessment of malignancy. The algorithm is also compared with two different predictors, and our approach is shown to provide the best overall prediction accuracy. The development of an airway segmentation algorithm which extracts the airway tree from surrounding structures on chest Computed Tomography (CT) images is then described. This represents the first fundamental step toward the creation of a virtual bronchoscopy system. Clinical and ex-vivo images are used to evaluate performance of the algorithm. Different CT scan parameters are investigated and parameters for successful airway segmentation are optimized. Slice thickness is the most affecting parameter, while variation of reconstruction kernel and radiation dose is shown to be less critical. Airway segmentation is used to create a 3D rendered model of the airway tree for virtual navigation. Finally, the first open-source virtual bronchoscopy system was combined with electromagnetic tracking of the bronchoscope for the development of a GPS-like system for navigating within the lungs. Tools for pre-procedural planning and for helping with navigation are provided. Registration between the lungs of the patient and the virtually reconstructed airway tree is achieved using a landmark-based approach. In an attempt to reduce difficulties with registration errors, we also implemented a landmark-free registration method based on a balanced airway survey. In-vitro and in-vivo testing showed good accuracy for this registration approach. The centreline of the 3D airway model is extracted and used to compensate for possible registration errors. Tools are provided to select a target for biopsy on the patient CT image, and pathways from the trachea towards the selected targets are automatically created. The pathways guide the physician during navigation, while distance to target information is updated in real-time and presented to the user. During navigation, video from the bronchoscope is streamed and presented to the physician next to the 3D rendered image. The electromagnetic tracking is implemented with 5 DOF sensing that does not provide roll rotation information. An intensity-based image registration approach is implemented to rotate the virtual image according to the bronchoscope's rotations. The virtual bronchoscopy system is shown to be easy to use and accurate in replicating the clinical setting, as demonstrated in the pre-clinical environment of a breathing lung method. Animal studies were performed to evaluate the overall system performance

Quantitative lung CT analysis for the study and diagnosis of Chronic Obstructive Pulmonary Disease

The importance of medical imaging in the research of Chronic Obstructive Pulmonary Dis- ease (COPD) has risen over the last decades. COPD affects the pulmonary system through two competing mechanisms; emphysema and small airways disease. The relative contribu- tion of each component varies widely across patients whilst they can also evolve regionally in the lung. Patients can also be susceptible to exacerbations, which can dramatically ac- celerate lung function decline. Diagnosis of COPD is based on lung function tests, which measure airflow limitation. There is a growing consensus that this is inadequate in view of the complexities of COPD. Computed Tomography (CT) facilitates direct quantification of the pathological changes that lead to airflow limitation and can add to our understanding of the disease progression of COPD. There is a need to better capture lung pathophysiology whilst understanding regional aspects of disease progression. This has motivated the work presented in this thesis. Two novel methods are proposed to quantify the severity of COPD from CT by analysing the global distribution of features sampled locally in the lung. They can be exploited in the classification of lung CT images or to uncover potential trajectories of disease progression. A novel lobe segmentation algorithm is presented that is based on a probabilistic segmen- tation of the fissures whilst also constructing a groupwise fissure prior. In combination with the local sampling methods, a pipeline of analysis was developed that permits a re- gional analysis of lung disease. This was applied to study exacerbation susceptible COPD. Lastly, the applicability of performing disease progression modelling to study COPD has been shown. Two main subgroups of COPD were found, which are consistent with current clinical knowledge of COPD subtypes. This research may facilitate precise phenotypic characterisation of COPD from CT, which will increase our understanding of its natural history and associated heterogeneities. This will be instrumental in the precision medicine of COPD

Interventional Bronchoscopy:State-of-the-Art Review

For over 150 years, bronchoscopy, especially flexible bronchoscopy, has been a mainstay for airway inspection, the diagnosis of airway lesions, therapeutic aspiration of airway secretions, and transbronchial biopsy to diagnose parenchymal lung disorders. Its utility for the diagnosis of peripheral pulmonary nodules and therapeutic treatments besides aspiration of airway secretions, however, has been limited. Challenges to the wider use of flexible bronchoscopy have included difficulty in navigating to the lung periphery, the avoidance of vasculature structures when performing diagnostic biopsies, and the ability to biopsy a lesion under direct visualization. The last 10-15 years have seen major advances in thoracic imaging, navigational platforms to direct the bronchoscopist to lung lesions, and the ability to visualize lesions during biopsy. Moreover, multiple new techniques have either become recently available or are currently being investigated to treat a broad range of airway and lung parenchymal diseases, such as asthma, emphysema, and chronic bronchitis, or to alleviate recurrent exacerbations. New bronchoscopic therapies are also being investigated to not only diagnose, but possibly treat, malignant peripheral lung nodules. As a result, flexible bronchoscopy is now able to provide a new and expanding armamentarium of diagnostic and therapeutic tools to treat patients with a variety of lung diseases. This State-of-the-Art review succinctly reviews these techniques and provides clinicians an organized approach to their role in the diagnosis and treatment of a range of lung diseases

Segmentation, tracking, and kinematics of lung parenchyma and lung tumors from 4D CT with application to radiation treatment planning.

This thesis is concerned with development of techniques for efficient computerized analysis of 4-D CT data. The goal is to have a highly automated approach to segmentation of the lung boundary and lung nodules inside the lung. The determination of exact lung tumor location over space and time by image segmentation is an essential step to track thoracic malignancies. Accurate image segmentation helps clinical experts examine the anatomy and structure and determine the disease progress. Since 4-D CT provides structural and anatomical information during tidal breathing, we use the same data to also measure mechanical properties related to deformation of the lung tissue including Jacobian and strain at high resolutions and as a function of time. Radiation Treatment of patients with lung cancer can benefit from knowledge of these measures of regional ventilation. Graph-cuts techniques have been popular for image segmentation since they are able to treat highly textured data via robust global optimization, avoiding local minima in graph based optimization. The graph-cuts methods have been used to extract globally optimal boundaries from images by s/t cut, with energy function based on model-specific visual cues, and useful topological constraints. The method makes N-dimensional globally optimal segmentation possible with good computational efficiency. Even though the graph-cuts method can extract objects where there is a clear intensity difference, segmentation of organs or tumors pose a challenge. For organ segmentation, many segmentation methods using a shape prior have been proposed. However, in the case of lung tumors, the shape varies from patient to patient, and with location. In this thesis, we use a shape prior for tumors through a training step and PCA analysis based on the Active Shape Model (ASM). The method has been tested on real patient data from the Brown Cancer Center at the University of Louisville. We performed temporal B-spline deformable registration of the 4-D CT data - this yielded 3-D deformation fields between successive respiratory phases from which measures of regional lung function were determined. During the respiratory cycle, the lung volume changes and five different lobes of the lung (two in the left and three in the right lung) show different deformation yielding different strain and Jacobian maps. In this thesis, we determine the regional lung mechanics in the Lagrangian frame of reference through different respiratory phases, for example, Phase10 to 20, Phase10 to 30, Phase10 to 40, and Phase10 to 50. Single photon emission computed tomography (SPECT) lung imaging using radioactive tracers with SPECT ventilation and SPECT perfusion imaging also provides functional information. As part of an IRB-approved study therefore, we registered the max-inhale CT volume to both VSPECT and QSPECT data sets using the Demon\u27s non-rigid registration algorithm in patient subjects. Subsequently, statistical correlation between CT ventilation images (Jacobian and strain values), with both VSPECT and QSPECT was undertaken. Through statistical analysis with the Spearman\u27s rank correlation coefficient, we found that Jacobian values have the highest correlation with both VSPECT and QSPECT

Personalised Procedures for Thoracic Radiotherapy

This thesis presents the investigation, development, and estimation of two personalised procedures for thoracic cancer therapy in Shenzhen, China and two projects were carried out: (1) respiratory motion management of a lung tumour, and (2) the application of a three-dimensional (3D) printing technique for postmastectomy irradiation. For the first project, all subjects attended sessions of free-breathing (FB) and personalised vocal coaching (VC) for respiratory regulation. Thoracic and abdominal breathing signals were extracted from the subjects’ surface area then estimated as kernel density estimation (KDE) for motion visualisation. The mutual information (MI) and correlation coefficient (CC) calculated from KDEs indicate the variation in the relationship between the two signals. From the 1D signal, through VC, the variation of cycle time and the signal value of end-of-exhale/inhale increased in the patient group but decreased in volunteers. Mixed results were presented on KDE and MI. Compared with FB, VC improves movement consistency between the two signals in eight of eleven subjects by increasing MI. The fixed instruction method showed no improvement for day-to-day variation, while the daily generated instruction enhanced the respiratory regularity in three of five volunteers. VC addresses the variation of the single signal, while the outcome of the two signals, thoracic and abdominal signals, requires further interpretation. The second project aims to address both the enhancement of the skin dose and avoidance of hotspots of critical organs, focusing on improving irradiative treatment for post-mastectomy patients. A 3D-printed bolus was presented as a solution for the air gap between the bolus and skin. The results showed no evidence of significant skin dose enhancement with the printed bolus. Additionally, an air gap larger than 5 mm was evident in all patients. Until a solution for complete bolus adhesion is found, this customised bolus is not suitable for clinical use