EVALUATION OF RADIATION DOSE EFFECT ON LUNG FUNCTION USING IODINE MAPS DERIVED FROM DUAL-ENERGY COMPUTED TOMOGRAPHY.

PURPOSE: There is interest in using dual-energy computed tomography (DECT) to evaluate organ function before and after radiotherapy. The purpose of this study (trial identifier: XXXX) is to assess longitudinal changes in lung perfusion using iodine maps derived from DECT in lung cancer patients treated with conventional or stereotactic radiotherapy (RT). METHODS: For 48 prospectively enrolled lung cancer patients, a contrast-enhanced DECT using a dual-source CT simulator was acquired pre-treatment and at 6 and 12 months post-treatment. Pulmonary functions tests (PFT) were obtained at baseline and at 6 and 12 months post-treatment. Iodine maps were extracted from the DECT images using a previously described 2-material decomposition framework. Longitudinal iodine maps were normalized using a reference region defined as all voxels with perfusion in the top 10% outside of the 5 Gy isodose volume. Normalized functional responses (NFR) were calculated for three dose ranges: <5 Gy, 5-20 Gy and >20 Gy. Mixed model analysis was used to assess the correlation between dose metrics and NFR. Pearson correlation was used to assess if NFR are correlated with PFT changes. RESULTS: Out of the 48 patients, 21 (44%) were treated with stereotactic body radiation therapy (SBRT) and 27 (56%) were treated with conventionally fractionated IMRT. 31 out of these 48 patients were ultimately included in data analysis. It was found that NFR is linearly correlated with dose (p < 0.001) for both groups. The number of months elapsed post-RT is also found to correlate with NFR (p = 0.029), although this correlation was not observed for the SBRT subgroup. The NFR is not found to correlate with PFT changes. CONCLUSION: DECT derived iodine maps are a promising method for detailed anatomic evaluation of radiation effect on lung function, including potentially subclinical changes.

The potential of photon-counting CT for quantitative contrast-enhanced imaging in radiotherapy.

The aim of this study is to use a simulation environment to evaluate the potential of using photon-counting CT (PCCT) against dual-energy CT (DECT) in the context of quantitative contrast-enhanced CT for radiotherapy. An adaptation of Bayesian eigentissue decomposition by Lalonde et al (2017 Med. Phys. 44 5293-302) that incorporates the estimation of contrast agent fractions and virtual non-contrast (VNC) parameters is proposed, and its performance is validated against conventional maximum likelihood material decomposition methods for single and multiple contrast agents. PCCT and DECT are compared using two simulation frameworks: one including ideal CT numbers with image-based Gaussian noise and another defined as a virtual patient with projection-based Poisson noise and beam hardening artifacts, with both scenarios considering spectral distortion for PCCT. The modalities are compared for their accuracy in estimating four key physical parameters: (1) the contrast agent fraction, as well as VNC parameters relevant to radiotherapy such as the (2) electron density, (3) proton stopping power and (4) photon linear attenuation coefficient. Considering both simulation frameworks, a reduction of root mean square (RMS) errors with PCCT is noted for all physical parameters evaluated, with the exception of the error on the contrast agent fraction being about constant through modalities in the virtual patient. Notably, for the virtual patient, RMS errors on VNC electron density and stopping power are respectively reduced from 2.0% to 1.4% and 2.7% to 1.4% when going from DECT to PCCT with four energy bins. The increase in accuracy is comparable to the differences between contrast-enhanced and non-contrast DECT. This study suggests that in a realistic simulation environment, the overall accuracy of radiotherapy-related parameters can be increased when using PCCT with four energy bins instead of DECT. This confirms the potential of PCCT to provide robust and quantitative tissue parameters for contrast-enhanced CT required in radiotherapy applications.

Dual-energy computed tomography for prediction of loco-regional recurrence after radiotherapy in larynx and hypopharynx squamous cell carcinoma.

PURPOSE: To investigate the role of quantitative pre-treatment dual-energy computed tomography (DECT) for prediction of loco-regional recurrence (LRR) in patients with larynx/hypopharynx squamous cell cancer (L/H SCC). METHODS: Patients with L/H SCC treated with curative intent loco-regional radiotherapy and that underwent treatment planning with contrast-enhanced DECT of the neck were included. Primary and nodal gross tumor volumes (GTVp and GTVn) were contoured and transferred into a Matlab® workspace. Using a two-material decomposition, GTV iodine concentration (IC) maps were obtained. Quantitative histogram statistics (maximum, mean, standard deviation, kurtosis and skewness) were retrieved from the IC maps. Cox regression analysis was conducted to determine potential predictive factors of LRR. RESULTS: Twenty-five patients, including 20 supraglottic and 5 pyriform sinus tumors were analysed. Stage I, II, III, IVa and IVb constituted 4% (1 patient), 24%, 36%, 28% and 8% of patients, respectively; 44% had concurrent chemo-radiotherapy and 28% had neodjuvant chemotherapy. Median follow-up was 21 months. Locoregional control at 1 and 2 years were 75% and 69%, respectively. For the entire cohort, GTVn volume (HR 1.177 [1.001-1.392], p = 0.05), voxel-based maximum IC of GTVp (HR 1.099 [95% CI: 1.001-1.209], p = 0.05) and IC standard deviation of GTVn (HR 9.300 [95% CI: 1.113-77.725] p = 0.04) were predictive of LRR. On subgroup analysis of patients treated with upfront radiotherapy +/- chemotherapy, both voxel-based maximum IC of GTVp (HR 1.127 [95% CI: 1.010-1.258], p = 0.05) and IC kurtosis of GTVp (HR 1.088 [95% CI: 1.014-1.166], p = 0.02) were predictive of LRR. CONCLUSION: This exploratory study suggests that pre-radiotherapy DECT-derived IC quantitative analysis of tumoral volume may help predict LRR in L/H SCC.

Robust quantitative contrast-enhanced dual-energy CT for radiotherapy applications.

PURPOSE: The purpose of this study was to develop and validate accurate methods for determining iodine content and virtual noncontrast maps of physical parameters, such as electron density, in the context of radiotherapy. METHODS: A simulation environment is developed to compare three methods allowing extracting iodine content and virtual noncontrast composition: (a) two-material decomposition, (b) three-material decomposition with the conservation of volume constraint, and (c) eigentissue decomposition. The simulation allows comparing the performance of the methods using iodine-based contrast agent contents in tissues from a reference dataset with variable density and elemental composition. The comparison is performed in two ways: (a) with a priori knowledge on the composition of the targeted tissue, and (b) without a priori knowledge on the base tissue. The three methods are tested with patient images scanned with dual-energy CT and iodine-based contrast agent. An experimental calibration adapted to the presence of iodine is performed by imaging tissue equivalent materials and diluted contrast agent solutions with known atomic composition. RESULTS: Results show that in the case of known a priori on the composition of the targeted tissue, the two-material decomposition is robust to variable densities and atomic compositions without biasing the results. In the absence of a priori knowledge on the target tissue composition, the eigentissue decomposition method yields minimal bias and higher robustness to variations. Results from the experimental calibration and the images of two patients show that the extracted quantities are accurate and the bias is negligible for both methods with respect to clinical applications in their respective scope of use. For the patient imaged with a contrast agent, virtual noncontrast electron densities are found in good agreement with values extracted from the scan without contrast agent. CONCLUSION: This study identifies two accurate methods to quantify iodine-based contrast agents and virtual noncontrast composition images with dual-energy CT. One is the two-material decomposition with a priori knowledge of the constituent components focused on organ-specific applications, such as kidney or lung function assessment. The other method is the eigentissue decomposition and is useful for general radiotherapy applications, such as treatment planning where accurate dose calculations are needed in the absence of contrast agent.

Phase 1-2 Study of Dual-Energy Computed Tomography for Assessment of Pulmonary Function in Radiation Therapy Planning.

PURPOSE: To quantify lung function according to a dual-energy computed tomography (DECT)-derived iodine map in patients treated with radiation therapy for lung cancer, and to assess the dosimetric impact of its integration in radiation therapy planning. METHODS AND MATERIALS: Patients treated with stereotactic ablative radiation therapy for early-stage or intensity modulated radiation therapy for locally advanced lung cancer were prospectively enrolled in this study. A DECT in treatment position was obtained at time of treatment planning. The relative contribution of each voxel to the total lung function was based on iodine distribution. The composition of each voxel was determined on the basis of a 2-material decomposition. The DECT-derived lobar function was compared with single photon emission computed tomography/computed tomography (SPECT/CT). A functional map was integrated in the treatment planning system using 6 subvolumes of increasing iodine distribution levels. Percent lung volume receiving 5 Gy (V5), V20, and mean dose (MLD) to whole lungs (anatomic) versus functional lungs were compared. RESULTS: Twenty-five patients with lung cancer, including 18 patients treated with stereotactic ablative radiation therapy and 7 patients with intensity modulated radiation therapy (locally advanced), were included. Eighty-four percent had chronic obstructive pulmonary disease. Median (range) forced expiratory volume in 1 second was 62% of predicted (29%-113%), and median diffusing capacity of the lung for carbon monoxide was 56% (39%-91%). There was a strong linear correlation between DECT- and SPECT/CT-derived lobar function (Pearson coefficient correlation r=0.89, P<.00001). Mean (range) differences in V5, V20, and MLD between anatomic and functional lung volumes were 16% (0%-48%, P=.03), 5% (1%-15%, P=.12), and 15% (1%-43%, P=.047), respectively. CONCLUSIONS: Lobar function derived from a DECT iodine map correlates well with SPECT/CT, and its integration in lung treatment planning is associated with significant differences in V5 and MLD to functional lungs. Future work will involve integration of the weighted functional volume in the treatment planning system, along with integration of an iodine map for functional lung-sparing IMRT.

Assessing lung function using contrast-enhanced dual-energy computed tomography for potential applications in radiation therapy.

PURPOSE: There is an increasing interest in the evaluation of lung function from physiological images in radiation therapy treatment planning to reduce the extent of postradiation toxicities. The purpose of this work was to retrieve reliable functional information from contrast-enhanced dual-energy computed tomography (DECT) for new applications in radiation therapy. The functional information obtained by DECT is also compared with other methods using single-energy CT (SECT) and single-photon emission computed tomography (SPECT) with CT. The differential function between left and right lung, as well as between lobes is computed for all methods. METHODS: Five lung cancer patients were retrospectively selected for this study; each underwent a SPECT/CT scan and a contrast-injected DECT scan, using 100 and 140 Sn kVp. The DECT images are postprocessed into iodine concentration maps, which are further used to determine the perfused blood volume. These maps are calculated in two steps: (a) a DECT stoichiometric calibration adapted to the presence of iodine and followed by (b) a two-material decomposition technique. The functional information from SECT is assumed proportional to the HU numbers from a mixed CT image. The functional data from SPECT/CT are considered proportional to the number of counts. A radiation oncologist segmented the entire lung volume into five lobes on both mixed CT images and low-dose CT images from SPECT/CT to allow a regional comparison. The differential function for each subvolume is computed relative to the entire lung volume. RESULTS: The differential function per lobe derived from SPECT/CT correlates strongly with DECT (Pearson's coefficient r = 0.91) and moderately with SECT (r = 0.46). The differential function for the left lung shows a mean difference of 7% between SPECT/CT and DECT; and 17% between SPECT/CT and SECT. The presence of nonfunctional areas, such as localized emphysema or a lung tumor, is reflected by an intensity drop in the iodine concentration maps. Functional dose volume histograms (fDVH) are also generated for two patients as a proof of concept. CONCLUSION: The extraction of iodine concentration maps from a contrast-enhanced DECT scan is achieved to compute the differential function for each lung subvolume and good agreement is found in respect to SPECT/CT. One promising avenue in radiation therapy is to include such functional information during treatment planning dose optimization to spare functional lung tissues.

Genome-wide stochastic adaptive DNA amplification at direct and inverted DNA repeats in the parasite Leishmania.

Gene amplification of specific loci has been described in all kingdoms of life. In the protozoan parasite Leishmania, the product of amplification is usually part of extrachromosomal circular or linear amplicons that are formed at the level of direct or inverted repeated sequences. A bioinformatics screen revealed that repeated sequences are widely distributed in the Leishmania genome and the repeats are chromosome-specific, conserved among species, and generally present in low copy number. Using sensitive PCR assays, we provide evidence that the Leishmania genome is continuously being rearranged at the level of these repeated sequences, which serve as a functional platform for constitutive and stochastic amplification (and deletion) of genomic segments in the population. This process is adaptive as the copy number of advantageous extrachromosomal circular or linear elements increases upon selective pressure and is reversible when selection is removed. We also provide mechanistic insights on the formation of circular and linear amplicons through RAD51 recombinase-dependent and -independent mechanisms, respectively. The whole genome of Leishmania is thus stochastically rearranged at the level of repeated sequences, and the selection of parasite subpopulations with changes in the copy number of specific loci is used as a strategy to respond to a changing environment.