Validating and improving CT ventilation imaging by correlating with ventilation 4D-PET/CT using 68Ga-labeled nanoparticles.

PURPOSE: CT ventilation imaging is a novel functional lung imaging modality based on deformable image registration. The authors present the first validation study of CT ventilation using positron emission tomography with (68)Ga-labeled nanoparticles (PET-Galligas). The authors quantify this agreement for different CT ventilation metrics and PET reconstruction parameters. METHODS: PET-Galligas ventilation scans were acquired for 12 lung cancer patients using a four-dimensional (4D) PET/CT scanner. CT ventilation images were then produced by applying B-spline deformable image registration between the respiratory correlated phases of the 4D-CT. The authors test four ventilation metrics, two existing and two modified. The two existing metrics model mechanical ventilation (alveolar air-flow) based on Hounsfield unit (HU) change (VHU) or Jacobian determinant of deformation (VJac). The two modified metrics incorporate a voxel-wise tissue-density scaling (ρVHU and ρVJac) and were hypothesized to better model the physiological ventilation. In order to assess the impact of PET image quality, comparisons were performed using both standard and respiratory-gated PET images with the former exhibiting better signal. Different median filtering kernels (σm = 0 or 3 mm) were also applied to all images. As in previous studies, similarity metrics included the Spearman correlation coefficient r within the segmented lung volumes, and Dice coefficient d20 for the (0 - 20)th functional percentile volumes. RESULTS: The best agreement between CT and PET ventilation was obtained comparing standard PET images to the density-scaled HU metric (ρVHU) with σm = 3 mm. This leads to correlation values in the ranges 0.22 ≤ r ≤ 0.76 and 0.38 ≤ d20 ≤ 0.68, with r = 0.42 ± 0.16 and d20 = 0.52 ± 0.09 averaged over the 12 patients. Compared to Jacobian-based metrics, HU-based metrics lead to statistically significant improvements in r and d20 (p < 0.05), with density scaled metrics also showing higher r than for unscaled versions (p < 0.02). r and d20 were also sensitive to image quality, with statistically significant improvements using standard (as opposed to gated) PET images and with application of median filtering. CONCLUSIONS: The use of modified CT ventilation metrics, in conjunction with PET-Galligas and careful application of image filtering has resulted in improved correlation compared to earlier studies using nuclear medicine ventilation. However, CT ventilation and PET-Galligas do not always provide the same functional information. The authors have demonstrated that the agreement can improve for CT ventilation metrics incorporating a tissue density scaling, and also with increasing PET image quality. CT ventilation imaging has clear potential for imaging regional air volume change in the lung, and further development is warranted

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

Time-series hyperpolarized xenon-129 MRI of lobar lung ventilation of COPD in comparison to V/Q-SPECT/CT and CT

Purpose To derive lobar ventilation in patients with chronic obstructive pulmonary disease (COPD) using a rapid time-series hyperpolarized xenon-129 (HPX) magnetic resonance imaging (MRI) technique and compare this to ventilation/perfusion singlephoton emission computed tomography (V/Q-SPECT), correlating the results with high-resolution computed tomography (CT) and pulmonary function tests (PFTs).Materials and methods Twelve COPD subjects (GOLD stages I–IV) participated in this study and underwent HPX-MRI, V/QSPECT/CT, high-resolution CT, and PFTs. HPX-MRI was performed using a novel time-series spiral k-space sampling approach. Relative percentage ventilations were calculated for individual lobe for comparison to the relative SPECT lobar ventilation and perfusion. The absolute HPX-MRI percentage ventilation in each lobe was compared to the absolute CT percentage emphysema score calculated using a signal threshold method. Pearson’s correlation and linear regression tests were performed to compare each imaging modality.Results Strong correlations were found between the relative lobar percentage ventilation with HPX-MRI and percentage ventilation SPECT (r = 0.644; p Conclusion Lobar ventilation with HPX-MRI showed a strong correlation with lobar ventilation and perfusion measurements derived from SPECT/CT, and is better than the emphysema score obtained with high-resolution CT.</div

3-D lung deformation and function from respiratory-gated 4-D x-ray CT images : application to radiation treatment planning.

Many lung diseases or injuries can cause biomechanical or material property changes that can alter lung function. While the mechanical changes associated with the change of the material properties originate at a regional level, they remain largely asymptomatic and are invisible to global measures of lung function until they have advanced significantly and have aggregated. In the realm of external beam radiation therapy of patients suffering from lung cancer, determination of patterns of pre- and post-treatment motion, and measures of regional and global lung elasticity and function are clinically relevant. In this dissertation, we demonstrate that 4-D CT derived ventilation images, including mechanical strain, provide an accurate and physiologically relevant assessment of regional pulmonary function which may be incorporated into the treatment planning process. Our contributions are as follows: (i) A new volumetric deformable image registration technique based on 3-D optical flow (MOFID) has been designed and implemented which permits the possibility of enforcing physical constraints on the numerical solutions for computing motion field from respiratory-gated 4-D CT thoracic images. The proposed optical flow framework is an accurate motion model for the thoracic CT registration problem. (ii) A large displacement landmark-base elastic registration method has been devised for thoracic CT volumetric image sets containing large deformations or changes, as encountered for example in registration of pre-treatment and post-treatment images or multi-modality registration. (iii) Based on deformation maps from MOFIO, a novel framework for regional quantification of mechanical strain as an index of lung functionality has been formulated for measurement of regional pulmonary function. (iv) In a cohort consisting of seven patients with non-small cell lung cancer, validation of physiologic accuracy of the 4-0 CT derived quantitative images including Jacobian metric of ventilation, Vjac, and principal strains, (V?1, V?2, V?3, has been performed through correlation of the derived measures with SPECT ventilation and perfusion scans. The statistical correlations with SPECT have shown that the maximum principal strain pulmonary function map derived from MOFIO, outperforms all previously established ventilation metrics from 40-CT. It is hypothesized that use of CT -derived ventilation images in the treatment planning process will help predict and prevent pulmonary toxicity due to radiation treatment. It is also hypothesized that measures of regional and global lung elasticity and function obtained during the course of treatment may be used to adapt radiation treatment. Having objective methods with which to assess pre-treatment global and regional lung function and biomechanical properties, the radiation treatment dose can potentially be escalated to improve tumor response and local control

Identifying the heterogeneity of COPD by V/P SPECT : a new tool for improving the diagnosis of parenchymal defects and grading the severity of small airways disease

Introduction: Airway obstruction and possible concomitant pulmonary diseases in COPD cannot be identified conventionally with any single diagnostic tool. We aimed to diagnose and grade COPD severity and identify pulmonary comorbidities associated with COPD with ventilation/perfusion single-photon emission computed tomography (V/P SPECT) using Technegas as the functional ventilation imaging agent. Methods: 94 COPD patients (aged 43-86 years, Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages I-IV) were examined with V/P SPECT and spirometry. Ventilation and perfusion defects were analyzed blindly according to the European guidelines. Penetration grade of Technegas in V SPECT measured the degree of obstructive small airways disease. Total preserved lung function and penetration grade of Technegas in V SPECT were assessed by V/P SPECT and compared to GOLD stages and spirometry. Results: Signs of small airway obstruction in the ventilation SPECT images were found in 92 patients. Emphysema was identified in 81 patients. Two patients had no signs of COPD, but both of them had a pulmonary embolism, and in one of them we also suspected a lung tumor. The penetration grade of Technegas in V SPECT and total preserved lung function correlated significantly to GOLD stages (r=0.63 and -0.60, respectively, P <0.0001). V/P SPECT identified pulmonary embolism in 30 patients (32%). A pattern typical for heart failure was present in 26 patients (28%). Parenchymal changes typical for pneumonia or lung tumor were present in several cases. Conclusion: V/P SPECT, using Technegas as the functional ventilation imaging agent, is a new tool to diagnose COPD and to grade its severity. Additionally, it revealed heterogeneity of COPD caused by pulmonary comorbidities. The characteristics of these comorbidities suggest their significant impact in clarifying symptoms, and also their influence on the prognosis.Peer reviewe

Comparison of CT ventilation imaging and hyperpolarised gas MRI: effects of breathing manoeuvre.

Image registration of lung CT images acquired at different inflation levels has been proposed as a surrogate method to map lung 'ventilation'. Prior to clinical use, it is important to understand how this technique compares with direct ventilation imaging modalities such as hyperpolarised gas MRI. However, variations in lung inflation level have been shown to affect regional ventilation distributions. Therefore, the aim of this study was to evaluate the impact of lung inflation levels when comparing CT ventilation imaging to ventilation from 3He-MRI.&#13; &#13; 7 asthma patients underwent breath-hold CT at total lung capacity (TLC) and functional residual capacity (FRC). 3He-MRI and a same-breath 1H-MRI were acquired at FRC+1L and TLC. Percentage ventilated volumes (%VVs) were calculated for FRC+1L and TLC 3He-MRI. TLC-CT and registered FRC-CT were used to compute a surrogate ventilation map from voxel-wise intensity differences in Hounsfield unit values, which was thresholded at the 10th and 20th percentiles. For direct comparison of CT and 3He-MRI ventilation, FRC+1L and TLC 3He-MRI were registered to TLC-CT indirectly via the corresponding same-breath 1H-MRI data. For 3He-MRI and CT ventilation comparison, Dice similarity coefficients (DSCs) between the binary segmentations were computed.&#13; &#13; The median (range) of %VVs for FRC+1L and TLC 3He-MRI were 90.5 (54.9-93.6) and 91.8 (67.8-96.2), respectively (p=0.018). For MRI versus CT ventilation comparison, statistically significant improvements in DSCs were observed for TLC 3He MRI when compared with FRC+1L, with median (range) values of 0.93 (0.86-0.93) and 0.86 (0.68-0.92), respectively (p=0.017), for the 10-100th percentile and 0.87 (0.83-0.88) and 0.81 (0.66-0.87), respectively (p=0.027), for the 20-100th percentile.&#13; &#13; Correlation of CT ventilation imaging and hyperpolarised gas MRI is sensitive to lung inflation level. For ventilation maps derived from CT acquired at FRC and TLC, a higher correlation with gas ventilation MRI can be achieved if the MRI is acquired at TLC. &#13

Quantifying the reproducibility of lung ventilation images between 4-Dimensional Cone Beam CT and 4-Dimensional CT.

PURPOSE: Computed tomography ventilation imaging derived from four-dimensional cone beam CT (CTVI4DCBCT ) can complement existing 4DCT-based methods (CTVI4DCT ) to track lung function changes over a course of lung cancer radiation therapy. However, the accuracy of CTVI4DCBCT needs to be assessed since anatomic 4DCBCT has demonstrably poor image quality and small field of view (FOV) compared to treatment planning 4DCT. We perform a direct comparison between short interval CTVI4DCBCT and CTVI4DCT pairs to understand the patient specific image quality factors affecting the intermodality CTVI reproducibility in the clinic. METHODS AND MATERIALS: We analysed 51 pairs of 4DCBCT and 4DCT scans acquired within 1 day of each other for nine lung cancer patients. To assess the impact of image quality, CTVIs were derived from 4DCBCT scans reconstructed using both standard Feldkamp-Davis-Kress backprojection (CTVIFDK4DCBCT) and an iterative McKinnon-Bates Simultaneous Algebraic Reconstruction Technique (CTVIMKBSART4DCBCT). Also, the influence of FOV was assessed by deriving CTVIs from 4DCT scans that were cropped to a similar FOV as the 4DCBCT scans (CTVIcrop4DCT), or uncropped (CTVIuncrop4DCT). All CTVIs were derived by performing deformable image registration (DIR) between the exhale and inhale phases and evaluating the Jacobian determinant of deformation. Reproducibility between corresponding CTVI4DCBCT and CTVI4DCT pairs was quantified using the voxel-wise Spearman rank correlation and the Dice similarity coefficient (DSC) for ventilation defect regions (identified as the lower quartile of ventilation values). Mann-Whitney U-tests were applied to determine statistical significance of each reconstruction and cropping condition. RESULTS: The (mean ± SD) Spearman correlation between CTVIFDK4DCBCT and CTVIuncrop4DCT was 0.60 ± 0.23 (range -0.03-0.88) and the DSC was 0.64 ± 0.12 (0.34-0.83). By comparison, correlations between CTVIMKBSART4DCBCT and CTVIuncrop4DCT showed a small but statistically significant improvement with = 0.64 ± 0.20 (range 0.06-0.90, P = 0.03) and DSC = 0.66 ± 0.13 (0.31-0.87, P = 0.02). Intermodal correlations were noted to decrease with an increasing fraction of lung truncation in 4DCBCT relative to 4DCT, albeit not significantly (Pearson correlation R = 0.58, P = 0.002). CONCLUSIONS: This study demonstrates that DIR based CTVIs derived from 4DCBCT can exhibit reasonable to good voxel-level agreement with CTVIs derived from 4DCT. These correlations outperform previous cross-modality comparisons between 4DCT-based ventilation and nuclear medicine. The use of 4DCBCT scans with iterative reconstruction and minimal lung truncation is recommended to ensure better reproducibility between 4DCBCT- and 4DCT-based CTVIs

Changes in Regional Ventilation During Treatment and Dosimetric Advantages of CT Ventilation Image Guided Radiation Therapy for Locally Advanced Lung Cancer

PURPOSE: Lung functional image guided radiation therapy (RT) that avoids irradiating highly functional regions has potential to reduce pulmonary toxicity following RT. Tumor regression during RT is common, leading to recovery of lung function. We hypothesized that computed tomography (CT) ventilation image-guided treatment planning reduces the functional lung dose compared to standard anatomic image-guided planning in 2 different scenarios with or without plan adaptation. METHODS AND MATERIALS: CT scans were acquired before RT and during RT at 2 time points (16-20 Gy and 30-34 Gy) for 14 patients with locally advanced lung cancer. Ventilation images were calculated by deformable image registration of four-dimensional CT image data sets and image analysis. We created 4 treatment plans at each time point for each patient: functional adapted, anatomic adapted, functional unadapted, and anatomic unadapted plans. Adaptation was performed at 2 time points. Deformable image registration was used for accumulating dose and calculating a composite of dose-weighted ventilation used to quantify the lung accumulated dose-function metrics. The functional plans were compared with the anatomic plans for each scenario separately to investigate the hypothesis at a significance level of 0.05. RESULTS: Tumor volume was significantly reduced by 20% after 16 to 20 Gy (P = .02) and by 32% after 30 to 34 Gy (P < .01) on average. In both scenarios, the lung accumulated dose-function metrics were significantly lower in the functional plans than in the anatomic plans without compromising target volume coverage and adherence to constraints to critical structures. For example, functional planning significantly reduced the functional mean lung dose by 5.0% (P < .01) compared to anatomic planning in the adapted scenario and by 3.6% (P = .03) in the unadapted scenario. CONCLUSIONS: This study demonstrated significant reductions in the accumulated dose to the functional lung with CT ventilation image-guided planning compared to anatomic image-guided planning for patients showing tumor regression and changes in regional ventilation during RT

Tomographic ventilation-perfusion lung scintigraphy in cardiopulmonary disease

Respiration relies, among other things, on the balance between regional ventilation and perfusion in the lungs. There are many cardiopulmonary diseases, such as pulmonary embolism (PE), chronic obstructive pulmonary disease (COPD) and left heart failure (LHF), which can affect respiration negatively. The diagnosis of PE, COPD and LHF follows separate diagnostic pathways. However, the symptoms that cause the patient to seek medical care are overlapping. This results in a diagnostic dilemma that is complicated by the fact that cardiopulmonary diseases often coexist. Ventilation and perfusion can be imaged with lung scintigraphy. Lung scintigraphy is primarily used to diagnose PE. The introduction of 3-dimensional tomographic lung scintigraphy (V/P SPECT) has resulted in an improved accuracy in the diagnosis of PE. Follow-up with V/P SPECT may lead to better individualization of PE treatment, but has not yet been evaluated. Changes in ventilation and perfusion are also found in COPD and LHF. V/P SPECT may have a clinical role in the diagnosis and characterization of COPD and LHF, but this has been insufficiently studied. Therefore, this thesis focuses on the potential role for V/P SPECT in the follow-up of PE and in the diagnosis and classification of LHF and COPD. In study I, we found that V/P SPECT can be used to diagnose LHF with a high positive predictive value. We developed an algorithm to objectively calculate perfusion gradients and found that an inverted gravitational gradient in the lungs is indicative of LHF. It was also shown that LHF was common among patients with suspected PE. In study II we compared ventilation studies performed with 99mTc-DTPA and 99mTc-Technegas, in patients with and without COPD. This study showed that 99mTc-Technegas, due to a more homogeneous distribution with less focal deposition and better peripheral penetration, should be regarded as the preferred radioaerosol in V/P SPECT studies. Study III indicated an additional value of V/P SPECT in the diagnosis of COPD. V/P SPECT could also be used to characterize the severity of COPD. In study IV, we found that restoration of regional perfusion after acute PE occurred during the first 3 months of treatment, but not thereafter. Follow-up after an episode of PE, using V/P SPECT, seems important since about 20% of the patients in the study had remaining perfusion defects at 3 months after diagnosis, although all were free from symptoms