Polymorphism in glutathione S-transferase P1 is associated with susceptibility to chemotherapyinduced leukemia

Glutathione S-transferases (GSTs) detoxify potentially mutagenic and toxic DNA-reactive electrophiles, including metabolites of several chemotherapeutic agents, some of which are suspected human carcinogens. Functional polymorphisms exist in at least three genes that encode GSTs, including GSTM1, GSTT1, and GSTP1. We hypothesize, therefore, that polymorphisms in genes that encode GSTs alter susceptibility to chemotherapy-induced carcinogenesis, specifically to therapy-related acute myeloid leukemia (t-AML), a devastating complication of long-term cancer survival. Elucidation of genetic determinants may help to identify individuals at increased risk of developing t-AML. To this end, we have examined 89 cases of t-AML, 420 cases of de novo AML, and 1,022 controls for polymorphisms in GSTM1, GSTT1, and GSTP1. Gene deletion of GSTM1 or GSTT1 was not specifically associated with susceptibility to t-AML. Individuals with at least one GSTP1 codon 105 Val allele were significantly over-represented in t-AML cases compared with de novo AML cases [odds ratio (OR), 1.81; 95% confidence interval (CI), 1.11–2.94]. Moreover, relative to de novo AML, the GSTP1 codon 105 Val allele occurred more often among t-AML patients with prior exposure to chemotherapy (OR, 2.66; 95% CI, 1.39–5.09), particularly among those with prior exposure to known GSTP1 substrates (OR, 4.34; 95% CI, 1.43–13.20), and not among those t-AML patients with prior exposure to radiotherapy alone (OR,1.01; 95% CI, 0.50–2.07). These data suggest that inheritance of at least one Val allele at GSTP1 codon 105 confers a significantly increased risk of developing t-AML after cytotoxic chemotherapy, but not after radiotherapy

Whole lung morphometry with 3D multiple b-value hyperpolarized gas MRI and compressed sensing.

PURPOSE: To demonstrate three-dimensional (3D) multiple b-value diffusion-weighted (DW) MRI of hyperpolarized (3) He gas for whole lung morphometry with compressed sensing (CS). METHODS: A fully-sampled, two b-value, 3D hyperpolarized (3) He DW-MRI dataset was acquired from the lungs of a healthy volunteer and retrospectively undersampled in the ky and kz phase-encoding directions for CS simulations. Optimal k-space undersampling patterns were determined by minimizing the mean absolute error between reconstructed and fully-sampled (3) He apparent diffusion coefficient (ADC) maps. Prospective three-fold, undersampled, 3D multiple b-value (3) He DW-MRI datasets were acquired from five healthy volunteers and one chronic obstructive pulmonary disease (COPD) patient, and the mean values of maps of ADC and mean alveolar dimension (LmD ) were validated against two-dimensional (2D) and 3D fully-sampled (3) He DW-MRI experiments. RESULTS: Reconstructed undersampled datasets showed no visual artifacts and good preservation of the main image features and quantitative information. A good agreement between fully-sampled and prospective undersampled datasets was found, with a mean difference of +3.4% and +5.1% observed in mean global ADC and LmD values, respectively. These differences were within the standard deviation range and consistent with values reported from healthy and COPD lungs. CONCLUSIONS: Accelerated CS acquisition has facilitated 3D multiple b-value (3) He DW-MRI scans in a single breath-hold, enabling whole lung morphometry mapping. Magn Reson Med, 2016. © 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited

Spectral graph theory efficiently characterizes ventilation heterogeneity in lung airway networks

This paper introduces a linear operator for the purposes of quantifying the spectral properties of transport within resistive trees, such as airflow in lung airway networks. The operator, which we call the Maury matrix, acts only on the terminal nodes of the tree and is equivalent to the adjacency matrix of a complete graph summarizing the relationships between all pairs of terminal nodes. We show that the eigenmodes of the Maury operator have a direct physical interpretation as the relaxation, or resistive, modes of the network. We apply these findings to both idealized and image-based models of ventilation in lung airway trees and show that the spectral properties of the Maury matrix characterize the flow asymmetry in these networks more concisely than the Laplacian modes, and that eigenvector centrality in the Maury spectrum is closely related to the phenomenon of ventilation heterogeneity caused by airway narrowing or obstruction. This method has applications in dimensionality reduction in simulations of lung mechanics, as well as for characterization of models of the airway tree derived from medical images

Reproducibility of quantitative indices of lung function and microstructure from 129Xe chemical shift saturation recovery (CSSR) MR spectroscopy

Purpose To evaluate the reproducibility of indices of lung microstructure and function derived from 129Xe chemical shift saturation recovery (CSSR) spectroscopy in healthy volunteers and patients with chronic obstructive pulmonary disease (COPD), and to study the sensitivity of CSSR-derived parameters to pulse sequence design and lung inflation level. Methods Preliminary data were collected from five volunteers on three occasions, using two implementations of the CSSR sequence. Separately, three volunteers each underwent CSSR at three different lung inflation levels. After analysis of these preliminary data, five COPD patients were scanned on three separate days, and nine age-matched volunteers were scanned three times on one day, to assess reproducibility. Results CSSR-derived alveolar septal thickness (ST) and surface-area-to-volume (S/V) ratio values decreased with lung inflation level (P < 0.001; P = 0.057, respectively). Intra-subject standard deviations of ST were lower than the previously measured differences between volunteers and subjects with interstitial lung disease. The mean coefficient of variation (CV) values of ST were 3.9 ± 1.9% and 6.0 ± 4.5% in volunteers and COPD patients, respectively, similar to CV values for whole-lung carbon monoxide diffusing capacity. The mean CV of S/V in volunteers and patients was 14.1 ± 8.0% and 18.0 ± 19.3%, respectively. Conclusion 129Xe CSSR presents a reproducible method for estimation of alveolar septal thickness

Regional ventilation changes in the lung: Treatment response mapping by using hyperpolarized gas MR imaging as a quantitative biomarker

Purpose: To assess the magnitude of regional response to respiratory therapeutics in the lungs using Treatment Response Mapping (TRM) with hyperpolarized gas MRI. TRM is used to quantify regional physiological response in asthmatic adults using a bronchodilator challenge. Methods: The study was approved by the national research ethics committee and performed with informed consent. Imaging was performed in 20 adult asthmatic patients using hyperpolarized 3He ventilation MRI. Two sets of baseline images were acquired before inhalation of a bronchodilator (Inhaled Salbutamol 400 mcg) and one set was acquired after. All images were registered for voxelwise comparison. Regional treatment response, ΔR(r), is calculated as the difference in regional gas distribution (R(r) = ratio of inhaled gas to total volume of a voxel when normalized for lung inflation volume) before and after intervention. A voxelwise activation threshold from the variability of the baseline images was applied to ΔR(r) maps. The summed global TRM (ΔRnet) was then used as global lung index for comparison with metrics of bronchodilator response measured using spirometry and the global imaging metric, percentage ventilated volume (%VV). Results: ΔRnet showed significant correlation (p<0.01) with changes in FEV1 (r=0.70), FVC (r=0.84) and %VV (r=0.56). A significant (p<0.01) positive treatment effect was detected by all metrics, however ΔRnet showed a lower inter-subject coefficient of variation (CV=64%) than all of the other tests (CV≥99%). Conclusions: TRM provides regional quantitative information on changes in inhaled gas ventilation in response to therapy. This method could be used as sensitive regional outcome metric of novel respiratory interventions. Online supplemental material is available for this article

Patterns of regional lung physiology in cystic fibrosis using ventilation magnetic resonance imaging and multiple-breath washout

Hyperpolarised helium-3 (3He) ventilation magnetic resonance imaging (MRI) and multiple-breath washout (MBW) are sensitive methods for detecting lung disease in cystic fibrosis (CF). We aimed to explore their relationship across a broad range of CF disease severity and patient age, as well as assess the effect of inhaled lung volume on ventilation distribution.32 children and adults with CF underwent MBW and 3He-MRI at a lung volume of end-inspiratory tidal volume (EIVT). In addition, 28 patients performed 3He-MRI at total lung capacity. 3He-MRI scans were quantitatively analysed for ventilation defect percentage (VDP), ventilation heterogeneity index (VHI) and the number and size of individual contiguous ventilation defects. From MBW, the lung clearance index, convection-dependent ventilation heterogeneity (Scond) and convection-diffusion-dependent ventilation heterogeneity (Sacin) were calculated.VDP and VHI at EIVT strongly correlated with lung clearance index (r=0.89 and r=0.88, respectively), Sacin (r=0.84 and r=0.82, respectively) and forced expiratory volume in 1 s (FEV1) (r=-0.79 and r=-0.78, respectively). Two distinct 3He-MRI patterns were highlighted: patients with abnormal FEV1 had significantly (p<0.001) larger, but fewer, contiguous defects than those with normal FEV1, who tended to have numerous small volume defects. These two MRI patterns were delineated by a VDP of ∼10%. At total lung capacity, when compared to EIVT, VDP and VHI reduced in all subjects (p<0.001), demonstrating improved ventilation distribution and regions of volume-reversible and nonreversible ventilation abnormalities

Imaging gas-exchange lung function and brain tissue uptake of hyperpolarized 129Xe using sampling density-weighted MRSI

PURPOSE: Imaging of the different resonances of hyperpolarized 129 Xe in the brain and lungs was performed using a 3D sampling density-weighted MRSI technique in healthy volunteers. METHODS: Four volunteers underwent dissolved-phase hyperpolarized 129 Xe imaging in the lung with the MRSI technique, which was designed to improve the point-spread function while preserving SNR (1799 phase-encoding steps, 14-s breath hold, 2.1-cm isotropic resolution). A frequency-tailored RF excitation pulse was implemented to reliably excite both the 129 Xe gas and dissolved phase (tissue/blood signal) with 0.1° and 10° flip angles, respectively. Images of xenon gas in the lung airspaces and xenon dissolved in lung tissue/blood were used to generate quantitative signal ratio maps. The method was also optimized and used for imaging dissolved resonances of 129 Xe in the brain in 2 additional volunteers. RESULTS: High-quality regional spectra of hyperpolarized 129 Xe were achieved in both the lung and the brain. Ratio maps of the different xenon resonances were obtained in the lung with sufficient SNR (> 10) at both 1.5 T and 3 T, making a triple Lorentzian fit possible and enabling the measurement of relaxation times and xenon frequency shifts on a voxel-wise basis. The imaging technique was successfully adapted for brain imaging, resulting in the first demonstration of 3D xenon brain images with a 2-cm isotropic resolution. CONCLUSION: Density-weighted MRSI is an SNR and encoding-efficient way to image 129 Xe resonances in the lung and the brain, providing a valuable tool to quantify regional spectroscopic information

Standalone portable xenon-129 hyperpolariser for multicentre clinical magnetic resonance imaging of the lungs

Objectives Design and build a portable xenon-129 (129Xe) hyperpolariser for clinically accessible 129Xe lung MRI. Methods The polariser system consists of six main functional components: (i) a laser diode array and optics; (ii) a B0 coil assembly; (iii) an oven containing an optical cell; (iv) NMR and optical spectrometers; (v) a gas-handling manifold; and (vi) a cryostat within a permanent magnet. All components run without external utilities such as compressed air or three-phase electricity, and require just three mains sockets for operation. The system can be manually transported in a lightweight van and rapidly installed on a small estates footprint in a hospital setting. Results The polariser routinely provides polarised 129Xe for routine clinical lung MRI. To test the concept of portability and rapid deployment, it was transported 200 km, installed at a hospital with no previous experience with the technology and 129Xe MR images of a diagnostic quality were acquired the day after system transport and installation. Conclusion This portable 129Xe hyperpolariser system could form the basis of a cost-effective platform for wider clinical dissemination and multicentre evaluation of 129Xe lung MR imaging

Compressed sensing reconstruction for high-SNR, rapid dissolved 129Xe gas exchange MRI

Purpose Three-dimensional hyperpolarized 129Xe gas exchange imaging suffers from low SNR and long breath-holds, which could be improved using compressed sensing (CS). The purpose of this work was to assess whether gas exchange ratio maps are quantitatively preserved in CS-accelerated dissolved-phase 129Xe imaging and to investigate the feasibility of CS-dissolved 129Xe imaging with reduced-cost natural abundance (NA) xenon. Methods 129Xe gas exchange imaging was performed at 1.5 T with a multi-echo spectroscopic imaging sequence. A CS reconstruction with an acceleration factor of 2 was compared retrospectively with conventional gridding reconstruction in a cohort of 16 healthy volunteers, 5 chronic obstructive pulmonary disease patients, and 23 patients who were hospitalized following COVID-19 infection. Metrics of comparison included normalized mean absolute error, mean gas exchange ratio, and red blood cell (RBC) image SNR. Dissolved 129Xe CS imaging with NA xenon was assessed in 4 healthy volunteers. Results CS reconstruction enabled acquisition time to be halved, and it reduced background noise. Median RBC SNR increased from 6 (2–18) to 11 (2–100) with CS, and there was strong agreement between CS and gridding mean ratio map values (R2 = 0.99). Image fidelity was maintained for gridding RBC SNR > 5, but below this, normalized mean absolute error increased nonlinearly with decreasing SNR. CS increased the mean SNR of NA 129Xe images 3-fold. Conclusion CS reconstruction of dissolved 129Xe imaging improved image quality with decreased scan time, while preserving key gas exchange metrics. This will benefit patients with breathlessness and/or low gas transfer and shows promise for NA-dissolved 129Xe imaging

Spectral graph theory efficiently characterises ventilation heterogeneity in lung airway networks

This paper introduces a linear operator for the purposes of quantifying the spectral properties of transport within resistive trees, such as airflow in lung airway networks. The operator, which we call the Maury matrix, acts only on the terminal nodes of the tree and is equivalent to the adjacency matrix of a complete graph summarising the relationships between all pairs of terminal nodes. We show that the eigenmodes of the Maury operator have a direct physical interpretation as the relaxation, or resistive, modes of the network. We apply these findings to both idealised and image-based models of ventilation in lung airway trees and show that the spectral properties of the Maury matrix characterise the flow asymmetry in these networks more concisely than the Laplacian modes, and that eigenvector centrality in the Maury spectrum is closely related to the phenomenon of ventilation heterogeneity caused by airway narrowing or obstruction. This method has applications in dimensionality reduction in simulations of lung mechanics, as well as for characterisation of models of the airway tree derived from medical images