Automatic planning for functional lung avoidance radiotherapy based on function-guided beam angle selection and plan optimization.

Objective.This study aims to develop a fully automatic planning framework for functional lung avoidance radiotherapy (AP-FLART).Approach.The AP-FLART integrates a dosimetric score-based beam angle selection method and a meta-optimization-based plan optimization method, both of which incorporate lung function information to guide dose redirection from high functional lung (HFL) to low functional lung (LFL). It is applicable to both contour-based FLART (cFLART) and voxel-based FLART (vFLART) optimization options. A cohort of 18 lung cancer patient cases underwent planning-CT and SPECT perfusion scans were collected. AP-FLART was applied to generate conventional RT (ConvRT), cFLART, and vFLART plans for all cases. We compared automatic against manual ConvRT plans as well as automatic ConvRT against FLART plans, to evaluate the effectiveness of AP-FLART. Ablation studies were performed to evaluate the contribution of function-guided beam angle selection and plan optimization to dose redirection.Main results.Automatic ConvRT plans generated by AP-FLART exhibited similar quality compared to manual counterparts. Furthermore, compared to automatic ConvRT plans, HFL mean dose,V20, andV5were significantly reduced by 1.13 Gy (p< .001), 2.01% (p< .001), and 6.66% (p< .001) respectively for cFLART plans. Besides, vFLART plans showed a decrease in lung functionally weighted mean dose by 0.64 Gy (p< .01),fV20by 0.90% (p= 0.099), andfV5by 5.07% (p< .01) respectively. Though inferior conformity was observed, all dose constraints were well satisfied. The ablation study results indicated that both function-guided beam angle selection and plan optimization significantly contributed to dose redirection.Significance.AP-FLART can effectively redirect doses from HFL to LFL without severely degrading conventional dose metrics, producing high-quality FLART plans. It has the potential to advance the research and clinical application of FLART by providing labor-free, consistent, and high-quality plans.

Phase-Resolved Functional Lung (PREFUL) MRI May Reveal Distinct Pulmonary Perfusion Defects in Postacute COVID-19 Syndrome: Sex, Hospitalization, and Dyspnea Heterogeneity.

BACKGROUND: Pulmonary perfusion defects have been observed in patients with coronavirus disease 2019 (COVID-19). Currently, there is a need for further data on non-contrast-enhanced MRI in COVID patients. The early identification of heterogeneity in pulmonary perfusion defects among COVID-19 patients is beneficial for their timely clinical intervention and management. PURPOSE: To investigate the utility of phase-resolved functional lung (PREFUL) MRI in detecting pulmonary perfusion disturbances in individuals with postacute COVID-19 syndrome (PACS). STUDY TYPE: Prospective. SUBJECTS: Forty-four participants (19 females, mean age 64.1 years) with PACS and 44 healthy subjects (19 females, mean age 59.5 years). Moreover, among the 44 patients, there were 19 inpatients and 25 outpatients; 19 were female and 25 were male; 18 with non-dyspnea and 26 with dyspnea. FIELD STRENGTH/SEQUENCE: 3-T, two-dimensional (2D) spoiled gradient-echo sequence. ASSESSMENT: Ventilation and perfusion-weighted maps were extracted from five coronal slices using PREFUL analysis. Subsequently, perfusion defect percentage (QDP), ventilation defect percentage (VDP), and ventilation-perfusion match healthy (VQM) were calculated based on segmented lung parenchyma ventilation and perfusion-weighted maps. Additionally, clinical features, including demographic data (such as sex and age) and serum biomarkers (such as D-dimer levels), were evaluated. STATISTICAL TESTS: Spearman correlation coefficients to explore relationships between clinical features and QDP, VDP, and VQM. Propensity score matching analysis to reduce the confounding bias between patients with PACS and healthy controls. The Mann-Whitney U tests and Chi-squared tests to detect differences between groups. Multivariable linear regression analyses to identify factors related to QDP, VDP, and VQM. A P-value <0.05 was considered statistically significant. RESULTS: QDP significantly exceeded that of healthy controls in individuals with PACS (39.8% ± 15.0% vs. 11.0% ± 4.9%) and was significantly higher in inpatients than in outpatients (46.8% ± 17.0% vs. 34.5% ± 10.8%). Moreover, males exhibited pulmonary perfusion defects significantly more frequently than females (43.9% ± 16.8% vs. 34.4% ± 10.2%), and dyspneic participants displayed significantly higher perfusion defects than non-dyspneic patients (44.8% ± 15.8% vs. 32.6% ± 10.3%). QDP showed a significant positive relationship with age (ß = 0.50) and D-dimer level (ß = 0.72). DATA CONCLUSION: PREFUL MRI may show pulmonary perfusion defects in patients with PACS. Furthermore, perfusion impairments may be more pronounced in males, inpatients, and dyspneic patients. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Integrating local and distant radiation-induced lung injury: Development and validation of a predictive model for ventilation loss.

BACKGROUND: Investigations on radiation-induced lung injury (RILI) have predominantly focused on local effects, primarily those associated with radiation damage to lung parenchyma. However, recent studies from our group and others have revealed that radiation-induced damage to branching serial structures such as airways and vessels may also have a substantial impact on post-radiotherapy (RT) lung function. Furthermore, recent results from multiple functional lung avoidance RT trials, although promising, have demonstrated only modest toxicity reduction, likely because they were primarily focused on dose avoidance to lung parenchyma. These observations emphasize the critical need for predictive dose-response models that effectively incorporate both local and distant RILI effects. PURPOSE: We develop and validate a predictive model for ventilation loss after lung RT. This model, referred to as P+A, integrates local (parenchyma [P]) and distant (central and peripheral airways [A]) radiation-induced damage, modeling partial (narrowing) and complete (collapse) obstruction of airways. METHODS: In an IRB-approved prospective study, pre-RT breath-hold CTs (BHCTs) and pre- and one-year post-RT 4DCTs were acquired from lung cancer patients treated with definitive RT. Up to 13 generations of airways were automatically segmented on the BHCTs using a research virtual bronchoscopy software. Ventilation maps derived from the 4DCT scans were utilized to quantify pre- and post-RT ventilation, serving, respectively, as input data and reference standard (RS) in model validation. To predict ventilation loss solely due to parenchymal damage (referred to as P model), we used a normal tissue complication probability (NTCP) model. Our model used this NTCP-based estimate and predicted additional loss due radiation-induced partial or complete occlusion of individual airways, applying fluid dynamics principles and a refined version of our previously developed airway radiosensitivity model. Predictions of post-RT ventilation were estimated in the sublobar volumes (SLVs) connected to the terminal airways. To validate the model, we conducted a k-fold cross-validation. Model parameters were optimized as the values that provided the lowest root mean square error (RMSE) between predicted post-RT ventilation and the RS for all SLVs in the training data. The performance of the P+A and the P models was evaluated by comparing their respective post-RT ventilation values with the RS predictions. Additional evaluation using various receiver operating characteristic (ROC) metrics was also performed. RESULTS: We extracted a dataset of 560 SLVs from four enrolled patients. Our results demonstrated that the P+A model consistently outperformed the P model, exhibiting RMSEs that were nearly half as low across all patients (13 ± 3 percentile for the P+A model vs. 24 ± 3 percentile for the P model on average). Notably, the P+A model aligned closely with the RS in ventilation loss distributions per lobe, particularly in regions exposed to doses ≥13.5 Gy. The ROC analysis further supported the superior performance of the P+A model compared to the P model in sensitivity (0.98 vs. 0.07), accuracy (0.87 vs. 0.25), and balanced predictions. CONCLUSIONS: These early findings indicate that airway damage is a crucial factor in RILI that should be included in dose-response modeling to enhance predictions of post-RT lung function.

Functional gas exchange measures on 129Xe MRI and spectroscopy are associated with age, sex, and BMI in healthy subjects.

Introduction: Hyperpolarized 129Xe MRI and spectroscopy is a rapidly growing technique for assessing lung function, with applications in a wide range of obstructive, restrictive, and pulmonary vascular disease. However, normal variations in 129Xe measures of gas exchange across healthy subjects are not well characterized, presenting an obstacle to differentiating disease processes from the consequences of expected physiological heterogeneity. Here, we use multivariate models to evaluate the role of age, sex, and BMI in a range of commonly used 129Xe measures of gas exchange. Materials and methods: Healthy subjects (N = 40, 16F, age 44.3 ± 17.8 yrs., min-max 22-87 years) with no history of cardiopulmonary disease underwent 129Xe gas exchange MRI and spectroscopy. We used multivariate linear models to assess the associations of age, sex, and body mass index (BMI) with the RBC:Membrane (RBC:M), membrane to gas (Mem:Gas), and red blood cell to gas (RBC:Gas) ratios, as well as measurements of RBC oscillation amplitude and RBC chemical shift. Results: Age, sex, and BMI were all significant covariates in the RBC:M model. Each additional 10 years of age was associated with a 0.05 decrease in RBC:M (p < 0.001), each additional 10 points of BMI was associated with a decrease of 0.07 (p = 0.02), and males were associated with a 0.17 higher RBC:M than females (p < 0.001). For Mem:Gas, male sex was associated with a decrease and BMI was associated with an increase. For RBC:Gas, age was associated with a decrease and male sex was associated with an increase. RBC oscillation amplitude increased with age and RBC chemical shift was not associated with any of the three covariates. Discussion: 129Xe MRI and spectroscopy measurements in healthy subjects, particularly the widely used RBC:M measurement, exhibit heterogeneity associated in part with variations in subject age, sex, and BMI. Elucidating the contributions of these and other factors to 129Xe gas exchange measurements is a critical component for differentiating disease processes from expected variation in healthy subjects. Notably, the Mem:Gas and RBC chemical shift appear to be stable with aging, suggesting that unexplained deviations in these metrics may be signs of underlying abnormalities.

Evaluation of Dynamic Contrast-Enhanced and Oxygen-Enhanced Functional Lung Magnetic Resonance Imaging in Chronic Obstructive Pulmonary Disease Patients.

Chronic obstructive pulmonary disease (COPD) is a chronic respiratory condition characterized by obstruction of airways and emphysematous lung tissue damage, with associated hypoxic vasoconstriction in the affected lung parenchyma. In our study, we evaluate the role of oxygen-enhanced (OE) MRI and dynamic contrast enhanced (DCE)-MRI in COPD patients for assessment of ventilation and perfusion defects and compared their severity with clinical severity. A total of 60 patients with COPD (diagnosed based on clinical and spirometry findings) and 2 controls with normal spirometry and no history of COPD were enrolled. All patients underwent MRI within 1 month of spirometry. OE-MRI was performed by administering oxygen at 12 L/min for 4 min to look for ventilation defects. DCE-MRI was performed by injecting intravenous gadolinium contrast, and perfusion abnormalities were detected by subtracting the non-enhanced areas from the first pass perfusion contrast images. A total of 87% of the subjects demonstrated ventilation and perfusion abnormalities on MRI independently. The lobe-wise distribution of ventilation and perfusion abnormalities correlated well with each other and was statistically significant in all lobes (p < 0.05). The severity of ventilation-perfusion defects also correlated well with clinical severity, as their median value (calculated using a Likert rating scale) was significantly lower in patients in the Global initiative for chronic Obstructive Lung Disease (GOLD) I/II group (3.25) compared to the GOLD III/IV group (7.25). OE- and DCE-MRI provide functional information about ventilation-perfusion defects and their regional distribution, which correlates well with clinical severity in patients with COPD.

Relationship between pulmonary blood flow and volume following lung resection using dynamic perfusion digital radiography.

Background: Surgical intervention for lung resection can cause ventilation-perfusion mismatches and affect gas exchange; however, minimally invasive assessment of blood flow is difficult. This study aimed to evaluate changes in pulmonary blood flow after radical lung cancer surgery using a minimally invasive dynamic digital chest radiography system. Methods: We evaluated 64 patients who underwent radical lobectomies. Postoperative changes in pulmonary blood flow, assessed using dynamic chest radiography-based blood flow ratios (BFRs), were compared with the temporal evolution of both functional lung volumes (FLVs) and estimated lung weight (ELW) derived from computed tomography (CT) volumetry. Results: FLVs on the affected side gradually recovered over time from the lowest value observed 3 months after surgery in all procedures. BFRs on the affected side also showed a gradual recovery from the lowest value 1 month after surgery, except for left upper lobectomies (LULs). In LULs, FLVs and ELWs increased proportionally up to 3 months after surgery, with lung volumes continuing to increase thereafter. The recovery of BFRs differed depending on the resected lobe. Conclusions: A relationship between pulmonary blood flow and FLV was observed in the postoperative period. Despite varying compensatory responses depending on the surgical procedure, FLV recovery coincided with increased pulmonary blood flow.

Diagnostic accuracy of perfusion-weighted phase-resolved functional lung magnetic resonance imaging in patients with chronic pulmonary embolism.

Purpose: This study aimed to evaluate the diagnostic performance of perfusion-weighted phase-resolved functional lung (PW-PREFUL) magnetic resonance imaging (MRI) in patients with chronic pulmonary embolism (CPE). Materials and methods: This study included 86 patients with suspected chronic thromboembolic pulmonary hypertension (CTEPH), who underwent PREFUL MRI and ventilation/perfusion (V/Q) single-photon emission computed tomography/computed tomography (SPECT/CT). PREFUL MRI was performed at 1.5 T using a balanced steady-state free precession sequence during free breathing. Color-coded PW images and quantitative parameters were obtained by postprocessing. Meanwhile, V/Q SPECT/CT imaging was performed as a reference standard. Hypoperfused areas in the lungs were scored for each lobe and segment using V/Q SPECT/CT images and PW-PREFUL MR images, respectively. Normalized perfusion (QN) and perfusion defect percentage (QDP) were calculated for all slices. For intra- and interobserver variability, the MRI images were analyzed 2 months after the first analysis by the same radiologist and another radiologist (11 years of lung MRI experience) blinded to the results of the first reader. Results: Of the 86 enrolled patients, 77 met the inclusion criteria (36 diagnosed with CPE using V/Q SPECT/CT and 41 diagnosed with non-CPE etiology). For the PW-PREFUL MRI, the sensitivity, specificity, accuracy, and positive and negative predictive values for the diagnosis of CPE were 97, 95, 96, 95, and 98% at the patient level; 91, 94, 93, 91, and 94% at the lobe level, and 85, 94, 92, 88, and 94% at the segment level, respectively. The detection of segmental and subsegmental hypoperfusion using PW-PREFUL MRI revealed a moderate agreement with V/Q SPECT/CT (κ = 0.65; 95% confidence interval: 0.61-0.68). The quantitative results indicated that the QN was lower in the CPE group than in the non-CPE group [median score (interquartile range, IQR) 6.3 (2.8-9.2) vs. 13.0 (8.8-16.7), p < 0.001], and the QDP was higher [median score (IQR) 33.8 (15.7-51.7) vs. 2.2 (1.4-2.9), p < 0.001]. Conclusion: PREFUL MRI could be an alternative test to detect CPE without requiring breath-hold, contrast agents, or ionizing radiation.

Quantifying ventilation by X-ray velocimetry in healthy adults.

RATIONALE: X-ray velocimetry (XV) has been utilized in preclinical models to assess lung motion and regional ventilation, though no studies have compared XV-derived physiologic parameters to measures derived through conventional means. OBJECTIVES: To assess agreement between XV-analysis of fluoroscopic lung images and pitot tube flowmeter measures of ventilation. METHODS: XV- and pitot tube-derived ventilatory parameters were compared during tidal breathing and with bilevel-assisted breathing. Levels of agreement were assessed using the Bland-Altman analysis. Mixed models were used to characterize the association between XV- and pitot tube-derived values and optimize XV-derived values for higher ventilatory volumes. MEASUREMENTS AND MAIN RESULTS: Twenty-four healthy volunteers were assessed during tidal breathing and 11 were reassessed with increased minute ventilation with bilevel-assisted breathing. No clinically significant differences were observed between the two methods for respiratory rate (average Δ: 0.58; 95% limits of agreement: -1.55, 2.71) or duty cycle (average Δ: 0.02; 95% limits of agreement: 0.01, 0.03). Tidal volumes and flow rates measured using XV were lower than those measured using the pitot tube flowmeter, particularly at the higher volume ranges with bilevel-assisted breathing. Under these conditions, a mixed-model based adjustment was applied to the XV-derived values of tidal volume and flow rate to obtain closer agreement with the pitot tube-derived values. CONCLUSION: Radiographically obtained measures of ventilation with XV demonstrate a high degree of correlation with parameters of ventilation. If the accuracy of XV were also confirmed for assessing the regional distribution of ventilation, it would provide information that goes beyond the scope of conventional pulmonary function tests or static radiographic assessments.

Functional imaging for assessing regional lung ventilation in preclinical and clinical research.

Dynamic heterogeneity in lung ventilation is an important measure of pulmonary function and may be characteristic of early pulmonary disease. While standard indices like spirometry, body plethysmography, and blood gases have been utilized to assess lung function, they do not provide adequate information on regional ventilatory distribution nor function assessments of ventilation during the respiratory cycle. Emerging technologies such as xenon CT, volumetric CT, functional MRI and X-ray velocimetry can assess regional ventilation using non-invasive radiographic methods that may complement current methods of assessing lung function. As a supplement to current modalities of pulmonary function assessment, functional lung imaging has the potential to identify respiratory disease phenotypes with distinct natural histories. Moreover, these novel technologies may offer an optimal strategy to evaluate the effectiveness of novel therapies and therapies targeting localized small airways disease in preclinical and clinical research. In this review, we aim to discuss the features of functional lung imaging, as well as its potential application and limitations to adoption in research.

Deep learning-based combination of [18F]-FDG PET and CT images for producing pulmonary perfusion image.

BACKGROUND: The main application of [18F] FDG-PET (18 FDG-PET) and CT images in oncology is tumor identification and quantification. Combining PET and CT images to mine pulmonary perfusion information for functional lung avoidance radiation therapy (FLART) is desirable but remains challenging. PURPOSE: To develop a deep-learning-based (DL) method to combine 18 FDG-PET and CT images for producing pulmonary perfusion images (PPI). METHODS: Pulmonary technetium-99 m-labeled macroaggregated albumin SPECT (PPISPECT ), 18 FDG-PET, and CT images obtained from 53 patients were enrolled. CT and PPISPECT images were rigidly registered, and registration displacement was subsequently used to align 18 FDG-PET and PPISPECT images. The left/right lung was separated and rigidly registered again to improve the registration accuracy. A DL model based on 3D Unet architecture was constructed to directly combine multi-modality 18 FDG-PET and CT images for producing PPI (PPIDLM ). 3D Unet architecture was used as the basic architecture, and the input was expanded from a single-channel to a dual-channel to combine multi-modality images. For comparative evaluation, 18 FDG-PET images were also used alone to generate PPIDLPET . Sixty-seven samples were randomly selected for training and cross-validation, and 36 were used for testing. The Spearman correlation coefficient (rs ) and multi-scale structural similarity index measure (MS-SSIM) between PPIDLM /PPIDLPET and PPISPECT were computed to assess the statistical and perceptual image similarities. The Dice similarity coefficient (DSC) was calculated to determine the similarity between high-/low- functional lung (HFL/LFL) volumes. RESULTS: The voxel-wise rs and MS-SSIM of PPIDLM /PPIDLPET were 0.78 ± 0.04/0.57 ± 0.03, 0.93 ± 0.01/0.89 ± 0.01 for cross-validation and 0.78 ± 0.11/0.55 ± 0.18, 0.93 ± 0.03/0.90 ± 0.04 for testing. PPIDLM /PPIDLPET achieved averaged DSC values of 0.78 ± 0.03/0.64 ± 0.02 for HFL and 0.83 ± 0.01/0.72 ± 0.03 for LFL in the training dataset and 0.77 ± 0.11/0.64 ± 0.12, 0.82 ± 0.05/0.72 ± 0.06 in the testing dataset. PPIDLM yielded a stronger correlation and higher MS-SSIM with PPISPECT than PPIDLPET (p < 0.001). CONCLUSIONS: The DL-based method integrates lung metabolic and anatomy information for producing PPI and significantly improved the accuracy over methods based on metabolic information alone. The generated PPIDLM can be applied for pulmonary perfusion volume segmentation, which is potentially beneficial for FLART treatment plan optimization.

Functional lung imaging using novel and emerging MRI techniques.

Respiratory diseases are leading causes of death and disability in the world. While early diagnosis is key, this has proven difficult due to the lack of sensitive and non-invasive tools. Computed tomography is regarded as the gold standard for structural lung imaging but lacks functional information and involves significant radiation exposure. Lung magnetic resonance imaging (MRI) has historically been challenging due to its short T2 and low proton density. Hyperpolarised gas MRI is an emerging technique that is able to overcome these difficulties, permitting the functional and microstructural evaluation of the lung. Other novel imaging techniques such as fluorinated gas MRI, oxygen-enhanced MRI, Fourier decomposition MRI and phase-resolved functional lung imaging can also be used to interrogate lung function though they are currently at varying stages of development. This article provides a clinically focused review of these contrast and non-contrast MR imaging techniques and their current applications in lung disease.

Comparison of ventilation defects quantified by Technegas SPECT and hyperpolarized 129Xe MRI.

Introduction: The ideal contrast agents for ventilation SPECT and MRI are Technegas and 129Xe gas, respectively. Despite increasing interest in the clinical utility of ventilation imaging, these modalities have not been directly compared. Therefore, our objective was to compare the ventilation defect percent (VDP) assessed by Technegas SPECT and hyperpolarized 129Xe MRI in patients scheduled to undergo lung cancer resection with and without pre-existing obstructive lung disease. Methods: Forty-one adults scheduled to undergo lung cancer resection performed same-day Technegas SPECT, hyperpolarized 129Xe MRI, spirometry, and diffusing capacity of the lung for carbon monoxide (DLCO). Ventilation abnormalities were quantified as the VDP using two different methods: adaptive thresholding (VDPT) and k-means clustering (VDPK). Correlation and agreement between VDP quantified by Technegas SPECT and 129Xe MRI were determined by Spearman correlation and Bland-Altman analysis, respectively. Results: VDP measured by Technegas SPECT and 129Xe MRI were correlated (VDPT: r = 0.48, p = 0.001; VDPK: r = 0.63, p < 0.0001). A 2.0% and 1.6% bias towards higher Technegas SPECT VDP was measured using the adaptive threshold method (VDPT: 23.0% ± 14.0% vs. 21.0% ± 5.2%, p = 0.81) and k-means method (VDPK: 9.4% ± 9.4% vs. 7.8% ± 10.0%, p = 0.02), respectively. For both modalities, higher VDP was correlated with lower FEV1/FVC (SPECT VDPT: r = -0.38, p = 0.01; MRI VDPK: r = -0.46, p = 0.002) and DLCO (SPECT VDPT: r = -0.61, p < 0.0001; MRI VDPK: r = -0.68, p < 0.0001). Subgroup analysis revealed that VDP measured by both modalities was significantly higher for participants with COPD (n = 13) than those with asthma (n = 6; SPECT VDPT: p = 0.007, MRI VDPK: p = 0.006) and those with no history of obstructive lung disease (n = 21; SPECT VDPT: p = 0.0003, MRI VDPK: p = 0.0003). Discussion: The burden of ventilation defects quantified by Technegas SPECT and 129Xe MRI VDP was correlated and greater in participants with COPD when compared to those without. Our observations indicate that, despite substantial differences between the imaging modalities, quantitative assessment of ventilation defects by Technegas SPECT and 129Xe MRI is comparable.

Ventilation and perfusion MRI at a 0.35 T MR-Linac: feasibility and reproducibility study.

BACKGROUND: Hybrid devices that combine radiation therapy and MR-imaging have been introduced in the clinical routine for the treatment of lung cancer. This opened up not only possibilities in terms of accurate tumor tracking, dose delivery and adapted treatment planning, but also functional lung imaging. The aim of this study was to show the feasibility of Non-uniform Fourier Decomposition (NuFD) MRI at a 0.35 T MR-Linac as a potential treatment response assessment tool, and propose two signal normalization strategies for enhancing the reproducibility of the results. METHODS: Ten healthy volunteers (median age 28 ± 8 years, five female, five male) were repeatedly scanned at a 0.35 T MR-Linac using an optimized 2D+t balanced steady-state free precession (bSSFP) sequence for two coronal slice positions. Image series were acquired in normal free breathing with breaks inside and outside the scanner as well as deep and shallow breathing. Ventilation- and perfusion-weighted maps were generated for each image series using NuFD. For intra-volunteer ventilation map reproducibility, a normalization factor was defined based on the linear correlation of the ventilation signal and diaphragm position of each scan as well as the diaphragm motion amplitude of a reference scan. This allowed for the correction of signal dependency on the diaphragm motion amplitude, which varies with breathing patterns. The second strategy, which can be used for ventilation and perfusion, eliminates the dependency on the signal amplitude by normalizing the ventilation/perfusion maps with the average ventilation/perfusion signal within a selected region-of-interest (ROI). The position and size dependency of this ROI was analyzed. To evaluate the performance of both approaches, the normalized ventilation/perfusion-weighted maps were compared and the deviation of the mean ventilation/perfusion signal from the reference was calculated for each scan. Wilcoxon signed-rank tests were performed to test whether the normalization methods can significantly improve the reproducibility of the ventilation/perfusion maps. RESULTS: The ventilation- and perfusion-weighted maps generated with the NuFD algorithm demonstrated a mostly homogenous distribution of signal intensity as expected for healthy volunteers regardless of the breathing maneuver and slice position. Evaluation of the ROI's size and position dependency showed small differences in the performance. Applying both normalization strategies improved the reproducibility of the ventilation by reducing the median deviation of all scans to 9.1%, 5.7% and 8.6% for the diaphragm-based, the best and worst performing ROI-based normalization, respectively, compared to 29.5% for the non-normalized scans. The significance of this improvement was confirmed by the Wilcoxon signed rank test with [Formula: see text] at [Formula: see text]. A comparison of the techniques against each other revealed a significant difference in the performance between best ROI-based normalization and worst ROI ([Formula: see text]) and between best ROI-based normalization and scaling factor ([Formula: see text]), but not between scaling factor and worst ROI ([Formula: see text]). Using the ROI-based approach for the perfusion-maps, the uncorrected deviation of 10.2% was reduced to 5.3%, which was shown to be significant ([Formula: see text]). CONCLUSIONS: Using NuFD for non-contrast enhanced functional lung MRI at a 0.35 T MR-Linac is feasible and produces plausible ventilation- and perfusion-weighted maps for volunteers without history of chronic pulmonary diseases utilizing different breathing patterns. The reproducibility of the results in repeated scans significantly benefits from the introduction of the two normalization strategies, making NuFD a potential candidate for fast and robust early treatment response assessment of lung cancer patients during MR-guided radiotherapy.

The spatial-temporal dynamics of pulmonary blood flow are altered in pulmonary arterial hypertension.

Global fluctuation dispersion (FDglobal), a spatial-temporal metric derived from serial images of the pulmonary perfusion obtained with MRI-arterial spin labeling, describes temporal fluctuations in the spatial distribution of perfusion. In healthy subjects, FDglobal is increased by hyperoxia, hypoxia, and inhaled nitric oxide. We evaluated patients with pulmonary arterial hypertension (PAH, 4F, aged 47 ± 15, mean pulmonary artery pressure 48 ± 7 mmHg) and healthy controls (CON, 7F, aged 47 ± 12) to test the hypothesis that FDglobal is increased in PAH. Images were acquired at ∼4-5 s intervals during voluntary respiratory gating, inspected for quality, registered using a deformable registration algorithm, and normalized. Spatial relative dispersion (RD = SD/mean) and the percent of the lung image with no measurable perfusion signal (%NMP) were also assessed. FDglobal was significantly increased in PAH (PAH = 0.40 ± 0.17, CON = 0.17 ± 0.02, P = 0.006, a 135% increase) with no overlap in values between the two groups, consistent with altered vascular regulation. Both spatial RD and %NMP were also markedly greater in PAH vs. CON (PAH RD = 1.46 ± 0.24, CON = 0.90 ± 0.10, P = 0.0004; PAH NMP = 13.4 ± 6.1%; CON = 2.3 ± 1.4%, P = 0.001 respectively) consistent with vascular remodeling resulting in poorly perfused regions of lung and increased spatial heterogeneity. The difference in FDglobal between normal subjects and patients with PAH in this small cohort suggests that spatial-temporal imaging of perfusion may be useful in the evaluation of patients with PAH. Since this MR imaging technique uses no injected contrast agents and has no ionizing radiation it may be suitable for use in diverse patient populations.NEW & NOTEWORTHY Using proton MRI-arterial spin labeling to obtain serial images of pulmonary perfusion, we show that global fluctuation dispersion (FDglobal), a metric of temporal fluctuations in the spatial distribution of perfusion, was significantly increased in female patients with pulmonary arterial hypertension (PAH) compared with healthy controls. This potentially indicates pulmonary vascular dysregulation. Dynamic measures using proton MRI may provide new tools for evaluating individuals at risk of PAH or for monitoring therapy in patients with PAH.

A hybrid model- and deep learning-based framework for functional lung image synthesis from multi-inflation CT and hyperpolarized gas MRI.

BACKGROUND: Hyperpolarized gas MRI is a functional lung imaging modality capable of visualizing regional lung ventilation with exceptional detail within a single breath. However, this modality requires specialized equipment and exogenous contrast, which limits widespread clinical adoption. CT ventilation imaging employs various metrics to model regional ventilation from non-contrast CT scans acquired at multiple inflation levels and has demonstrated moderate spatial correlation with hyperpolarized gas MRI. Recently, deep learning (DL)-based methods, utilizing convolutional neural networks (CNNs), have been leveraged for image synthesis applications. Hybrid approaches integrating computational modeling and data-driven methods have been utilized in cases where datasets are limited with the added benefit of maintaining physiological plausibility. PURPOSE: To develop and evaluate a multi-channel DL-based method that combines modeling and data-driven approaches to synthesize hyperpolarized gas MRI lung ventilation scans from multi-inflation, non-contrast CT and quantitatively compare these synthetic ventilation scans to conventional CT ventilation modeling. METHODS: In this study, we propose a hybrid DL configuration that integrates model- and data-driven methods to synthesize hyperpolarized gas MRI lung ventilation scans from a combination of non-contrast, multi-inflation CT and CT ventilation modeling. We used a diverse dataset comprising paired inspiratory and expiratory CT and helium-3 hyperpolarized gas MRI for 47 participants with a range of pulmonary pathologies. We performed six-fold cross-validation on the dataset and evaluated the spatial correlation between the synthetic ventilation and real hyperpolarized gas MRI scans; the proposed hybrid framework was compared to conventional CT ventilation modeling and other non-hybrid DL configurations. Synthetic ventilation scans were evaluated using voxel-wise evaluation metrics such as Spearman's correlation and mean square error (MSE), in addition to clinical biomarkers of lung function such as the ventilated lung percentage (VLP). Furthermore, regional localization of ventilated and defect lung regions was assessed via the Dice similarity coefficient (DSC). RESULTS: We showed that the proposed hybrid framework is capable of accurately replicating ventilation defects seen in the real hyperpolarized gas MRI scans, achieving a voxel-wise Spearman's correlation of 0.57 ± 0.17 and an MSE of 0.017 ± 0.01. The hybrid framework significantly outperformed CT ventilation modeling alone and all other DL configurations using Spearman's correlation. The proposed framework was capable of generating clinically relevant metrics such as the VLP without manual intervention, resulting in a Bland-Altman bias of 3.04%, significantly outperforming CT ventilation modeling. Relative to CT ventilation modeling, the hybrid framework yielded significantly more accurate delineations of ventilated and defect lung regions, achieving a DSC of 0.95 and 0.48 for ventilated and defect regions, respectively. CONCLUSION: The ability to generate realistic synthetic ventilation scans from CT has implications for several clinical applications, including functional lung avoidance radiotherapy and treatment response mapping. CT is an integral part of almost every clinical lung imaging workflow and hence is readily available for most patients; therefore, synthetic ventilation from non-contrast CT can provide patients with wider access to ventilation imaging worldwide.

Metrics of dose to highly ventilated lung are predictive of radiation-induced pneumonitis in lung cancer patients.

PURPOSE: To identify metrics of radiation dose delivered to highly ventilated lung that are predictive of radiation-induced pneumonitis. METHODS AND MATERIALS: A cohort of 90 patients with locally advanced non-small cell lung cancer treated with standard fractionated radiation therapy (RT) (60-66 Gy in 30-33 fractions) were evaluated. Regional lung ventilation was determined from pre-RT 4-dimensional computed tomography (4DCT) using the Jacobian determinant of a B-spline deformable image registration to estimate lung tissue expansion during respiration. Multiple voxel-wise population- and individual-based thresholds for defining high functioning lung were considered. Mean dose and volumes receiving dose ≥ 5-60 Gy were analyzed for both total lung-ITV (MLD,V5-V60) and highly ventilated functional lung-ITV (fMLD,fV5-fV60). The primary endpoint was symptomatic grade 2+ (G2+) pneumonitis. Receiver operator curve (ROC) analyses were used to identify predictors of pneumonitis. RESULTS: G2+ pneumonitis occurred in 22.2% of patients, with no differences between stage, smoking status, COPD, or chemo/immunotherapy use between G<2 and G2+ patients (P≥ 0.18). Highly ventilated lung was defined as voxels exceeding the population-wide median of 18% voxel-level expansion. All total and functional metrics were significantly different between patients with and without pneumonitis (P≤ 0.039). Optimal ROC points predicting pneumonitis from functional lung dose were fMLD ≤ 12.3 Gy, fV5 ≤ 54% and fV20 ≤ 19 %. Patients with fMLD ≤ 12.3 Gy had a 14% risk of developing G2+ pneumonitis whereas risk significantly increased to 35% for those with fMLD > 12.3 Gy (P = 0.035). CONCLUSIONS: Dose to highly ventilated lung is associated with symptomatic pneumonitis and treatment planning strategies should focus on limiting dose to functional regions. These findings provide important metrics to be used in functional lung avoidance RT planning and designing clinical trials.

Assessment of lung ventilation of premature infants with bronchopulmonary dysplasia at 1.5 Tesla using phase-resolved functional lung magnetic resonance imaging.

BACKGROUND: The most common chronic complication of preterm birth is bronchopulmonary dysplasia (BPD), widely referred to as chronic lung disease of prematurity. All current definitions rely on characterizing the disease based on respiratory support level and do not provide full understanding of the underlying cardiopulmonary pathophysiology. OBJECTIVE: To evaluate a rapid functional lung imaging technique in premature infants and to quantitate pulmonary ventilation using 1.5 Tesla magnetic resonance imaging (MRI). MATERIALS AND METHODS: We conducted a prospective MRI study of 12 premature infants in the neonatal intensive care unit (NICU) using the phase resolved functional lung MRI technique to calculate pulmonary ventilation parameters in preterm infants with and without BPD grade 0/1 (n = 6) and grade 2/3 (n = 6). RESULTS: The total ventilation defect percentage showed a significant difference between groups (16.0% IQR (11.0%,18%) BPD grade 2/3 vs. 8.0% IQR (4.5%,9.0%) BPD grade 0/1, p = 0.01). CONCLUSION: Phase-resolved functional lung MRI is feasible for assessment of ventilation defect percentages in preterm infants and shows regional variation in localized lung function in this population.

Effects of elexacaftor/tezacaftor/ivacaftor therapy in children with cystic fibrosis - a comprehensive assessment using lung clearance index, spirometry, and functional and structural lung MRI.

BACKGROUND: With improvement in supportive therapies and the introduction of cystic fibrosis transmembrane conductance regulator (CFTR)-modulator treatment in patients with cystic fibrosis (CF), milder disease courses are expected. Therefore, sensitive parameters are needed to monitor disease course and effects of CFTR-modulators. Functional lung MRI using matrix-pencil decomposition (MP-MRI) is a promising tool for assessing ventilation and perfusion quantitatively. This study aimed to assess the treatment effect of elexacaftor/tezacaftor/ivacaftor combination regimen (ELX/TEZ/IVA) on measures of structural and functional lung abnormalities. METHODS: 24 children with CF underwent lung function tests (multiple breath washout, spirometry), functional and structural MRI twice (one year apart) before and once after at least two weeks (mean 4.7 ± 2.6 months) on ELX/TEZ/IVA. Main outcomes were changes (Δ) upon ELX/TEZ/IVA in lung function, defect percentage of ventilation (VDP) and perfusion (QDP), defect distribution index of ventilation and perfusion (DDIV, DDIQ), and Eichinger score. Statistical analyses were performed using paired t-tests and multilevel regression models with bootstrapping. RESULTS: We observed a significant improvement in lung function, structural and functional MRI parameters upon ELX/TEZ/IVA treatment (mean; 95%-CI): ΔLCI2.5 (TO) -0.84 (-1.62 to -0.06); ΔFEV1 (z-score) 1.05 (0.56 to 1.55); ΔVDP (% of impairment) -6.00 (-8.44 to -3.55); ΔQDP (% of impairment) -3.90 (-5.90 to -1.90); ΔDDIV -1.38 (-2.22 to -0.53); ΔDDIQ -0.31 (-0.73 to 0.12); ΔEichinger score -3.89 (-5.05 to -2.72). CONCLUSIONS: Besides lung function tests, functional and structural MRI is a suitable tool to monitor treatment response of ELX/TEZ/IVA therapy, and seems promising as outcome marker in the future.

Reproducibility of non-contrast enhanced multi breath-hold ultrashort echo time functional lung MRI.

PURPOSE: To evaluate the intraindividual reproducibility of functional lung imaging using non-contrast enhanced multi breath-hold 3D-UTE MRI. METHODS: Ten healthy volunteers underwent non-contrast enhanced 3D-UTE MRI at three time points for same-day and different-day measurements employing a stack-of-spirals trajectory at 3 T. At each time point, inspiratory and expiratory breathing states were acquired for tidal and deep breathing, each within a single breath-hold. For functional image analysis, fractional ventilation (FV) was calculated pixelwise after image registration from the MR signal change. To decouple FV from breathing depth, the individual lung volume was used for volume adjustment (rFV). Reproducibility evaluation was performed in eight lung segments. Statistical analyses included two way mixed intraclass correlation (ICC), sign-test, Friedman-test and modified Bland-Altman analyses. RESULTS: FV from tidal breathing showed an ICC of 0.81, a bias of 1.3% and an interval of confidence (CI) ranging from -67.1 to 69.6%. FV from deep breathing was higher reproducible with an ICC of 0.92 (bias, -0.2%; CI, -34.2 to 33.7%). Following volume adjustment, reproducibility of rFV for tidal breathing improved (ICC, 0,86; bias, 2.0%; CI, -34.3 to 38.3%), whereas it did not bear significant benefits for deep breathing (ICC, 0.89; bias, 2.8%; CI, -24.9 to 30.5%). Reproducibility was independent from the examination day. CONCLUSION: Non-contrast-enhanced multi breath-hold 3D-UTE MRI allows for highly reproducible ventilation imaging.

Comparison between functional lung volume measurement and segment counting for predicting postoperative pulmonary function after pulmonary resection in lung cancer patients.

BACKGROUND: Functional lung volume (FLV) obtained from computed tomography images was a breakthrough for lung imaging and functional assessment. We compared the accuracy of the FLV measurement method and the segment-counting (SC) method in predicting postoperative pulmonary function. METHODS: A total of 113 patients who underwent two thoracoscopic surgeries were enrolled in our study. We predicted postoperative pulmonary function by the FLV measurement method and the SC method. Novel formulas based on the FLV measurement method were established using linear regression equations between the factors affecting pulmonary function and the measured values. RESULTS: The predicted postoperative forced vital capacity (ppoFVC) and forced expiratory volume in 1 s (ppoFEV1) measured by the 2 methods showed high concordance between the actual postoperative forced vital capacity (postFVC) and the forced expiratory volume in 1 s (postFEV1) [r = 0.762, P < 0.001 (FLV method) and r = 0.759, P < 0.001 (SC method) for FVC; r = 0.790, P < 0.001 (FLV method) and r = 0.795, P < 0.001 (SC method) for FEV1]. Regression analysis showed that the measured preoperative pulmonary function parameters (FVC, FEV1) and the ratio of reduced FLV to preoperative FLV were significantly associated with the actual postoperative values and could predict these parameters (all P < 0.001). The feasibility of using these equations [postFVC = 0.8 × FVC - 0.784 × ΔFLV/FLV + 0.283 (R2 = 0.677, RSD = 0.338), postFEV1 = 0.766 × FEV1 - 0.694 × ΔFLV/FLV + 0.22 (R2 = 0.743, RSD = 0.265)] to predict the pulmonary function parameters after wedge resection was also verified. CONCLUSIONS: The new FLV measurement method is valuable for predicting postoperative pulmonary function in patients undergoing lung resection surgery, with accuracy and consistency similar to those of the conventional SC method.