In the treatment of lung cancer, the best outcome is achieved when the lesion is detected and localized in the pre-invasive stage. To date, conventional white-light bronchoscopy has been inadequate for the identification and localization of many early bronchogenic carcinomas, carcinomas in situ (CIS), and pre-cancerous dysplasias because these lesions may exhibit little visual difference from normal tissue when examined with white light.

Recently, the light imaging fluorescence endoscope (LIFE, Xillix Technology, Vancouver, BC) has been approved by the Food and Drug Administration and is now in routine use worldwide at 35 centers. The LIFE system has been developed based on the principle of autofluorescence, that is, abnormal tissues have the natural ability to fluoresce when exposed to a specific wavelength of light. The LIFE system utilizes a blue laser light transmitted through a flexible fiberoptic bronchoscope to elicit autofluorescence, which is then projected on to a video screen. Real-time differentiation of normal bronchial mucosa from dysplastic or carcinomatous mucosa guides the bronchoscopist's biopsies. Clinical studies have shown that autofluorescence bronchoscopy, when used in conjunction with standard white-light bronchoscopy, increases the detection rate of CIS and moderate to severe dysplasias by 50 %, as compared to white-light bronchoscopy alone.

In a prospective, multi-center, comparative, single-arm trial, Edell et al (2009) evaluated the benefit of using a new fluorescence-reflectance imaging system, Onco-LIFE, for the detection and localization of intra-epitheal neoplasia and early invasive squamous cell carcinoma. A secondary objective was to evaluate the potential use of quantitative image analysis with this device for objective classification of abnormal sites. Subjects for this study were aged 45 to 75 years and either current or past smokers of more than 20 pack-years with airflow obstruction, forced expiratory volume in 1 second/forced vital capacity less than 75 %, suspected to have lung cancer based on either sputum atypia, abnormal chest roentgenogram/chest computed tomography, or patients with previous curatively treated lung or head and neck cancer within 2 years. The primary endpoint of the study was to determine the relative sensitivity of white light bronchoscopy (WLB) plus autofluorescence-reflectance bronchoscopy compared with WLB alone. Bronchoscopy with Onco-LIFE was carried out in 2 stages. The first stage was performed under white light and mucosal lesions were visually classified. Mucosal lesions were classified using the same scheme in the second stage when viewed with Onco-LIFE in the fluorescence-reflectance mode. All regions classified as suspicious for moderate dysplasia or worse were biopsied, plus at least 1 non-suspicious region for control. Specimens were evaluated by the site pathologist and then sent to a reference pathologist, each blinded to the endoscopic findings. Positive lesions were defined as those with moderate/severe dysplasia, CIS, or invasive carcinoma. A positive patient was defined as having at least 1 lesion of moderate/severe dysplasia, CIS, or invasive carcinoma. Onco-LIFE was also used to quantify the fluorescence-reflectance response (based on the proportion of reflected red light to green fluorescence) for each suspected lesion before biopsy. There were 115 men and 55 women with median age of 62 years. A total of 776 biopsy specimens were included; 76 were classified as positive (moderate dysplasia or worse) by pathology. The relative sensitivity on a per-lesion basis of WLB + FLB versus WLB was 1.50 (95 % confidence interval [CI]: 1.26 to 1.89). The relative sensitivity on a per-patient basis was 1.33 (95 % CI: 1.13 to 1.70). The relative sensitivity to detect intra-epithelial neoplasia (moderate/severe dysplasia or CIS) was 4.29 (95 % CI: 2.00 to 16.00) and 3.50 (95 % CI: 1.63 to 12.00) on a per-lesion and per-patient basis, respectively. For a quantified fluorescence reflectance response value of more than or equal to 0.40, a sensitivity and specificity of 51 % and 80 %, respectively, could be achieved for detection of moderate/severe dsyplasia, CIS, and micro-invasive cancer. The authors concluded that using autofluorescence-reflectance bronchoscopy as an adjunct to WLB with the Onco-LIFE system improves the detection and localization of intra-epitheal neoplasia and invasive carcinoma compared with WLB alone. The use of quantitative image analysis to minimize inter-observer variation in grading of abnormal sites should be explored further in future prospective clinical trial.

According to available literature, LIFE is considered medically inappropriate for any of the following groups:

Persons in whom white light bronchoscopic examination is contraindicated including:

Persons in whom fluorescence examination is contraindicated including:

Short and colleagues (2011) stated that pre-neoplastic lesions of the bronchial tree have a high probability of developing into malignant tumors. Currently, the best method for localizing them for further treatment is a combined WLB and autofluorescence bronchoscopy (AFB) (WLB + AFB). The average specificity from large clinical trials for this combined detection method is approximately 60 %, leading to many false-positives. In a pilot study, these researchers examined if adding point laser Raman spectroscopy (LRS) to a WLB + AFB has the potential to improve the specificity of pre-neoplastic lesion detection and what the implication is to the detection sensitivity. An LRS system was developed to collect real-time, in-vivo lung spectra with a fiber optic catheter passed down the instrument channel of a bronchoscope. WLB + AFB imaging modalities were used to identify lesions from 26 subjects, from which 129 Raman spectra were measured. Multi-variate statistical analyses were performed on the spectra with a leave-one-out cross-validation. Clear in-vivo Raman spectra were obtained in 1 second. The location of individual Raman peaks in the spectra correlated well with the known positions of Raman peaks generated by lipids, proteins, and water molecules. Pre-neoplastic lesions were detected with a sensitivity of 96 % and a specificity of 91 %. The authors concluded that adding point LRS analysis to WLB + AFB imaging has the ability to detect pre-neoplastic lesions in real time with high sensitivity and specificity. They stated that the use of LRS has great potential for substantially reducing the number of false-positive biopsies associated with WLB + AFB with very little reduction in the detection sensitivity. These preliminary findings need to be validated by well-designed studies.

An UpToDate review on "Screening for lung cancer" (Deffebach and Humphrey, 2014) states that "Non-radiographic technologies, including identification of molecular and protein-based tumor biomarkers, may also contribute to the early detection of lung cancer. Detection and treatment of small lung tumors (prior to radiographic visualization) may produce superior outcomes, though the possibility of lead-time and other types of bias influencing the assessment of these technologies is great. Outcome benefits must be thoroughly investigated prior to their widespread use …. Technologies under investigation include fluorescence bronchoscopy". Furthermore, an UpToDate review on "Fluorescence bronchoscopy" (Banerjee, 2014) states that "An important limitation of autofluorescence bronchoscopy is that false positive results are common. The impact of autofluorescence bronchoscopy on clinical outcomes, such as mortality, is unknown because it has not been well studied".

Xenon Xe-129 Hyper-Polarized Gas for the Evaluation of Lung Ventilation

In December 2022, the Food and Drug Administration (FDA) approved Xenon-129 gas (Xe-129) for the evaluation of lung ventilation in patients aged 12 years or older. Several disease states are being examined for potential use of this novel technique. The most common uses appear to be cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). The advantages include the lack of radiation exposure and the stability of Xenon Xe-129, which is a non-radioactive isotope. This FDA-approved pulmonary ventilation modality does not correlate with lung function testing and additional measurements are needed to obtain any useful data. Furthermore, there are several disadvantages to this technique. It requires specialized equipment to process the inhaled gas mixture, gas must be inhaled within 5 mins of being hyper-polarized and the magnetic resonance imaging (MRI) must start immediately following a single-breath hold. Available evidence suggests that the information obtained from these scans might provide more useful insight into disease states. This technique may allow earlier detection of disease progression and response to therapy compared to current typical evaluations using chest CT, pulmonary function tests (PFTs) and 6-minute walk tests.

Mata et al (2021) noted that IPF, a pattern of interstitial lung disease (ILD), is often clinically unpredictable in its progression. These researchers presented hyper-polarized Xenon-129 chemical shift imaging as a non-invasive, non-radioactive method of probing lung physiology as well as anatomy to monitor subtle changes in subjects with IPF. A total of 20 subjects (9 healthy controls and 11 IPF) underwent HP Xe-129 ventilation MRI and three-dimensional single-breath chemical shift imaging (3D-SBCSI). Spirometry was carried out on all subjects before imaging, and diffusing capacity of the lung for carbon monoxide (DLCO) and hematocrit (Hct) were measured in IPF subjects after imaging. Images were post-processed in MATLAB and segmented using ANTs. IPF subjects exhibited, on average, higher tissue/gas ratios and lower red blood cell (RBC)/gas ratios compared with healthy subjects, and quantitative maps were more heterogeneous in IPF subjects. The higher ratios were likely due to fibrosis and thickening of the pulmonary interstitium. T2* relaxation was longer in IPF subjects and corresponded with Hct scores, although the mechanism is not well-understood. A lower chemical shift in the RBC spectroscopic peak correlated well with a higher tissue/RBC ratio and may be explained by reduced blood oxygenation. Tissue/RBC also correlated well, spatially, with areas of fibrosis in HRCT images. The authors concluded that these findings may aid in understanding the underlying mechanism behind gas exchange impairment and disease progression. Moreover, these researchers stated that future work is needed to attain a better understanding of the physiological implications of these parameters. Longitudinal studies with a larger population of subjects with different types of IPF are also needed to validate the findings of this study. Nevertheless, having this novel regional physiological information from 3D-SBCSI in addition to high-resolution computed tomography (HRCT) could allow for a potentially earlier diagnosis of IPF and the stratification of IPF patient types leading to improved treatments and clinical outcomes.

The authors stated that this study had 2 main drawbacks. First, the total number of subjects that underwent HP Xe-129 MR imaging in this study was relatively small and may not be representative of the larger population of subjects with IPF. Second, the IPF and healthy subjects were not age-matched, and some of the differences observed may be confounded by age.

Mummy et al (2021) noted that recent studies showed that anti-fibrotic drugs previously reserved for IPF may slow progression in other interstitial lung diseases (ILDs), creating an urgent need for tools that can sensitively evaluate disease activity, progression, and therapy response across ILDs. Hyper-polarized 129Xe MRI and spectroscopy have provided non-invasive measurements of regional gas-exchange abnormalities in IPF. In a prospective study, these researchers examined gas exchange function using 129Xe MRI in a group of subjects with non-specific interstitial pneumonia (NSIP) compared with healthy controls (HCs). Participants with NSIP and HCs were enrolled between November 2017 and February 2020 and underwent 129Xe MRI and spectroscopy. Quantitative imaging provided 3D maps of ventilation, interstitial barrier uptake, and transfer into the red blood cell (RBC) compartment. Spectroscopy provided parameters of the static RBC and barrier uptake compartments, as well as cardiogenic oscillations in RBC signal amplitude and chemical shift. Differences between NSIP and HCs were assessed using the Wilcoxon rank-sum test. A total of 36 participants with NSIP (mean age of 57 years ± 11 [standard deviation]; 27 women) and 15 HCs (mean age of 39 years ± 18; 2 women) were evaluated. Participants with NSIP had no difference in ventilation compared with HCs (median, 4.4 % [1st quartile, 1.5 %; 3rd quartile, 8.7 %] versus 6.0 % [1st quartile, 2.8 %; 3rd quartile, 6.9 %]; p = 0.91); however, they had a higher barrier uptake (median of 6.2 % [1st quartile, 1.8 %; 3rd quartile, 23.9 %] versus 0.53 % [1st quartile, 0.33 %; 3rd quartile, 2.9 %]; p = 0.003) and an increased RBC transfer defect (median of 20.6 % [1st quartile, 11.6 %; 3rd quartile, 27.8 %] versus 2.8 % [1st quartile, 2.3 %; 3rd quartile, 4.9 %]; p < 0.001). NSIP participants also had a reduced ratio of RBC-to-barrier peaks (median of 0.24 [1st quartile, 0.19; 3rd quartile, 0.31] versus 0.57 [1st quartile, 0.52; 3rd quartile, 0.67]; p < 0.001) and a reduced RBC chemical shift (median of 217.5 ppm [1st quartile, 217.0 ppm; 3rd quartile, 218.0 ppm] versus 218.2 ppm [1st quartile, 217.9 ppm; 3rd quartile, 218.6 ppm]; p = 0.001). The authors concluded that these preliminary results suggested that hyper-polarized 129Xe MRI and spectroscopy may illuminate the fundamental abnormalities and regional severity of gas exchange that occur in patients with non-specific interstitial pneumonia and in those with potentially other non-IPF interstitial lung diseases. These researchers stated that future studies focused on 129Xe MRI characteristics early in the disease course and in response to therapies will advance this work and will further examine its potential clinical impact. This new modality may serve to identify “treatable traits”, monitor therapy response, and personalize treatment in this disorder.

The authors stated that this study had several drawbacks. First, the confounding effect of therapy. Given the availability of effective treatment for patients with NSIP, it was not possible to recruit a treatment-naive population. Although participants with NSIP who were above the 95th-percentile value in HCs (H95%) for both the high barrier uptake percentage and RBC defect percentage (RDP) were uniformly receiving advanced therapy, some participants below one or both of these H95% values were also undergoing advanced therapy. Although this was consistent with the hypothesis that effective treatment may reduce abnormalities detected using 129Xe MRI, these investigators could not assess any causal relationship between therapy and 129Xe MRI findings. Second, the group of HCs was younger than the group with NSIP and was predominantly composed of men. Because more women show NSIP patterns and are known to have an altered immune response, and age is a factor in lung function decline, these researchers acknowledged that an age- and sex-matched control population would result in a more specific comparison. However, this did not affect the variation in measurements between individual ILD patients. Furthermore, the observed differences in gas-exchange function between HCs and participants with NSIP were far starker in pattern and degree than would be expected of ordinary age and/or sex differences. Third, although preliminary studies have shown that dissolved-phase MRI has good repeatability in a cohort of healthy patients, neither the repeatability nor the minimal clinically important difference of these measurements in fibrotic lung disease have been characterized. Fourth, the average time between the screening CT examination and the 129Xe MRI examination was almost 2 years. To ensure the availability of contemporaneous clinical findings, it would be preferable to recruit patients immediately after they undergo clinical CT and are examined by a pulmonologist. Fifth, this study did not attempt to establish correlations between 129Xe MRI and other aspects of a multi-disciplinary ILD diagnosis such as pathologic findings and CT. Nonetheless, these findings were a necessary 1st step for characterizing the presentation of patients with NSIP assessed with 129Xe gas-exchange MRI and for determining possible markers of therapy response in patients with ILD in a broader way.

Guan et al (2022) stated that 3D-SBCSI is a hybrid MR-spectroscopic imaging modality that uses hyper-polarized Xe-129 to differentiate lung diseases by probing functional characteristics. These researchers tested the effectiveness of 3D-SBCSI in differentiating physiology among pulmonary diseases. A total of 45 subjects -- 16 healthy, 11 IPF, 13 CF, and 5 COPD -- were given 1/3 forced vital capacity (FVC) of hyper-polarized Xe-129, inhaled for approximately 7 s MRI acquisition. Proton, Xe-129 ventilation, and 3D-SBCSI images were acquired with separate breath-holds using a radiofrequency (RF) chest coil tuned to Xe-129. The Xe-129 spectrum was analyzed in each lung voxel for ratios of spectroscopic peaks, chemical shifts, and T2* relaxation. CF and COPD subjects had significantly more ventilation defects than IPF and healthy subjects, which correlated with FEV1 predicted (r = -0.74). FEV1 predicted correlated well with RBC/Gas ratio (r = 0.67). COPD and IPF had significantly higher tissue/RBC ratios than other subjects, longer RBC T2* relaxation times, and greater RBC chemical shifts. CF subjects had more ventilation defects than healthy subjects, elevated tissue/RBC ratio, shorter Tissue T2* relaxation, and greater RBC chemical shift. The authors concluded that findings of this study indicated that 3D-SBCSI was sensitive to the physiology of lung diseases and could therefore be used to help differentiate among healthy, IPF, CF, and COPD lung disease types. This method also provides additional MRI based markers that may reflect the underlying lung physiology, like voxel based full Xe-129 gas spectra, multiple lung compartment T2*, and chemical shift, which no other current techniques can offer. These researchers stated that all this regional information combined may be useful for monitoring disease progression on a regional level as well as for characterizing disease phenotypes and co-morbidities in the future.

The authors stated that drawbacks of this study included small sample size and no differentiation by severity within IPF and COPD subjects. The healthy volunteers tended to be closer to the age range of CF participants. While a limitation, this was also consistent with previous xenon MRI literature. Healthy and CF subjects were much younger than IPF and COPD subjects due to the differing disease populations which for CF tends to be a pediatric disease while COPD and IPF only manifests later in life.

Matheson et al (2022) noted that in patients with post-acute COVID-19 syndrome (PACS), abnormal gas-transfer and pulmonary vascular density have been reported; however, such findings have not been related to each other or to symptoms and exercise limitation. The pathophysiologic drivers of PACS in patients previously infected with COVID-19 who were admitted to in-patient treatment in hospital (or ever-hospitalized patients) and never-hospitalized patients are not well-understood. In a prospective study, these researchers examined the relationship of persistent symptoms and exercise limitation with 129Xe MRI and CT pulmonary vascular measurements in individuals with PACS. This trial included patients with PACS aged 18 to 80 years with a positive polymerase chain reaction COVID-19 test; they were recruited from a quaternary-care COVID-19 clinic between April and October 2021. Subjects with PACS underwent spirometry, DLCO, 129Xe MRI, and chest CT. Healthy controls had no history of COVID-19 and underwent spirometry, DLCO, and 129Xe MRI. The 129Xe MRI RBC to alveolar-barrier signal ratio, RBC area under the receiver operating characteristic curve (AUC), CT volume of pulmonary vessels with cross-sectional area of 5 mm2 or smaller (BV5), and total blood volume were quantified. St George’s Respiratory Questionnaire, International Physical Activity Questionnaire, and modified Borg Dyspnea Scale measured quality of life (QOL), exercise limitation, and dyspnea. Differences between groups were compared with Welch t-tests or Welch analysis of variance. Relationships were evaluated with use of Pearson (r) and Spearman (ρ) correlations. A total of 40 subjects were evaluated, including 6 controls (mean age ± SD, 35 ± 15 years, 3 women) and 34 subjects with PACS (mean age, 53 ± 13 years, 18 women), of whom 22 were never hospitalized. The 129Xe MRI RBC:barrier ratio was lower in ever-hospitalized participants (p = 0.04) compared to controls. BV5 correlated with RBC AUC (ρ = 0.44, p = 0.03). The 129Xe MRI RBC:barrier ratio was related to DLCO (r = 0.57, p = 0.002) and forced expiratory volume in 1 second (FEV1; ρ = 0.35, p = 0.03); RBC AUC was related to dyspnea (ρ = -0.35, p = 0.04) and International Physical Activity Questionnaire score (ρ = 0.45, p = 0.02). The authors concluded that Xenon 129 (129Xe) MRI measurements were lower in subjects previously infected with COVID-19 who were admitted to in-patient treatment in hospital with post-acute COVID-19 syndrome, 34 ± 25 weeks after infection compared to controls. The 129Xe MRI measures were associated with CT pulmonary vascular density, diffusing capacity of the lung for carbon monoxide, exercise capacity, and dyspnea.

The authors stated that this study had several drawbacks. First, the relatively small sample size of the control and PACS subgroups certainly limited the generalizability of these findings. This trial was not powered based on 129Xe MRI spectroscopy measurements; thus, these findings must be considered exploratory and hypothesis-generating. To provide a transparent snapshot of these results with the COVID-19 research community, these researchers provided data without statistical tests so that other centers may use their results to help generate sample sizes for long-term follow-up studies. Second, CT was not carried out in the control subgroup, which prevented CT comparisons across all 3 subgroups. Third, all subjects were referred from a COVID-19 clinic focusing on long-haul symptoms; thus, recruitment was likely biased toward symptomatic individuals seeking some form of explanation or intervention. Fourth, subjects with PACS were older than the controls (53 years ± 13 versus 35 years ± 15). To the authors’ knowledge, the effect of age on 129Xe gas-exchange biomarkers has not been reported. However, it is possible that similar to age-related changes observed for DLCO, age may also influence MRI gas-transfer measurements. Fifth, COVID-19 antibody testing was not carried out to verify COVID-19 infection status in the never–COVID-19 volunteers, so while unlikely, it was possible that some may have previously experienced an asymptomatic infection before the study. sixth, the mean RBC:barrier ratio estimated for the control subgroup was lower than previous reports, and this meant that the differences detected for patients with COVID-19 may be conservative under-estimates. Sixth, 129Xe gas-exchange MRI scan was conducted on either Visit 1, 2, or 3, which broadened the time after COVID-19 infection to 35 ± 25 weeks. Seventh, MRI scan heterogeneity was not evaluated quantitatively in this trial, and these researchers noted that previous 129Xe MRI COVID-19 investigations also reported the RBC:barrier ratio, which made comparisons with this study possible. Unfortunately, gas-exchange imaging was not technically implemented at the authors’ center until their COVID-19 study was already underway for 1 year, and in these subjects, MR spectroscopy was implemented first for this study.

Hahn et al (2022) noted that IPF is a temporally and spatially heterogeneous lung disease. Identifying whether IPF in a patient is progressive or stable is crucial for therapeutic regimens. In a prospective study, these investigators examined the role of hyper-polarized (HP) 129Xe MRI measures of ventilation and gas transfer in IPF generally and as an early signature of future IPF progression. Healthy volunteers and patients with IPF were consecutively recruited between December 2015 and August 2019 and underwent baseline HP 129Xe MRI and chest CT. Patients with IPF were followed-up with forced vital capacity percent predicted (FVC%p), DLCO percent predicted (DLCO%p), and clinical outcome at 1 year. IPF progression was defined as reduction in FVC%p by at least 10 %, reduction in DLCO%p by at least 15 %, or admission to hospice care. CT and MRI were spatially co-registered and a measure of pulmonary gas transfer (RBC-to-barrier ratio) and high-ventilation percentage of lung volume were compared across groups and across fibrotic versus normal-appearing regions at CT by using Wilcoxon signed rank tests. A total of 16 healthy volunteers (mean age of 57 years ± 14 [SD]; 10 women) and 22 patients with IPF (mean age of 71 years ± 9; 15 men) were evaluated, as follows: 9 IPF progressors (mean age of 72 years ± 7; 5 women) and 13 non-progressors (mean age of 70 years ± 10; 11 men). Reduction of high-ventilation percent (13 % ± 6.1 versus 8.2 % ± 5.9; p = 0.03) and RBC-to-barrier ratio (0.26 ± 0.06 versus 0.20 ± 0.06; p = 0.03) at baseline were associated with progression of IPF. Patients with progressive disease had reduced RBC-to-barrier ratio in structurally normal-appearing lung at CT (0.21 ± 0.07 versus 0.28 ± 0.05; p = 0.01) but not in fibrotic regions of the lung (0.15 ± 0.09 versus 0.14 ± 0.04; p = 0.62) relative to the non-progressive group. The authors concluded that in this preliminary study, functional measures of gas transfer and ventilation measured with 129Xe MRI and the extent of fibrotic structure at CT were associated with IPF disease progression. Differences in gas transfer were found in regions of nonfibrotic lung.

Xenon Xe-129 is a novel imaging technique that may have a future role in several pulmonary disease states and may provide new or additional information concerning disease progress and effectiveness of therapy. However, this technology is still awaiting definitive clinical research to prove its benefit. There are at least 45 clinical trials that are either recruiting, enrolling or active at this time on ClinicalTrials.gov.

XV LVAS Pulmonary Tissue Ventilation Analysis

XV LVAS pulmonary tissue ventilation analysis software is used for quantification of pulmonary tissue ventilation. However, there is insufficient evidence regarding its clinical value.

Yamashiro et al (2019) examined the accuracy of four-dimensional (4D) dynamic-ventilation computed tomography (CT) scanning coupled with their novel image analysis software to diagnose parietal pleural invasion/adhesion of peripheral (subpleural) lung cancer. A total of 18 patients with subpleural lung cancer underwent both 4D dynamic-ventilation CT during free breathing and conventional (static) chest CT during pre-operative assessment. The absence of parietal pleural invasion/adhesion was surgically confirmed in 13 patients, while the presence of parietal pleural invasion/adhesion was confirmed in 5 patients. Two chest radiologists, who were blinded to patient status, cooperatively examined the presence of pleural invasion/adhesion using 2 different imaging modalities: conventional high-resolution CT images, reconstructed in the axial, coronal, and sagittal directions, as well as 4D dynamic-ventilation CT images combined with a color map created by image analysis software to visualize movement differences between the lung surface and chest wall. Parameters of diagnostic accuracy were assessed, including a receiver operating characteristic (ROC) analysis. Software-assisted 4D dynamic-ventilation CT images achieved perfect diagnostic accuracy for pleural invasion/adhesion (sensitivity, 100 %; specificity, 100 %; area under the curve [AUC], 1.000) compared to conventional chest CT (sensitivity, 60 %; specificity, 77 %; AUC, 0.846). The authors concluded that software-assisted 4D dynamic-ventilation CT could be considered as a novel imaging approach for accurate pre-operative analysis of pleural invasion/adhesion of peripheral lung cancer. Moreover, these researchers stated that future studies with a larger number of enrolled patients are needed to verify the clinical utility of this imaging technique.

The authors stated that this study had several drawbacks. First, the study included a small number of patients (n = 18). Since this study was considered technical development of the methodology, these researchers prioritized promptness of the publication. More detailed studies, with an increased number of patients enrolled, and including different affected lung areas, are needed to confirm the reproducibility of these findings. Second, the conventional CT scans were only viewed in 2D. Third, extra-radiation exposure was needed, especially at a tube current setting of 40 mA. Therefore, these investigators used a 20-mA setting for some patients and confirmed that the 20-mA setting was more appropriate for future use (3.0 mSv for 6.5 s). However, an even greater reduction in radiation exposure, such as a 10-mA setting, may be tried in the future to increase the clinical utility of the 4D CT evaluation, especially with a combination of novel iterative reconstruction techniques. Fourth, since it has been reported that the lung surface around the lung apex or in patients with severe obstructive diseases does not reveal much movement during ventilation, their approach should be re-evaluated in a larger population including cancers in the apex and patients with obstructive diseases. Finally, this trial included only 2 radiologists.

In a preliminary study, Nagatani et al (2020) examined the usefulness of software analysis using dynamic-ventilation CT for localized pleural adhesion (LPA). A total of 51 patients scheduled to undergo surgery underwent both dynamic-ventilation CT and static chest CT as pre-operative assessments. A total of 5 observers independently examined the presence and severity of LPA on a 3-point scale (non, mild, and severe LPA) for 9 pleural regions (upper, middle, and lower pleural aspects on ventral, lateral, and dorsal areas) on the chest CT by 3 different methods by observing images from: static high-resolution CT (static image); dynamic-ventilation CT (movie image), and dynamic-ventilation CT while referring to the adhesion map (movie image with color map), which was created using research software to visualize movement differences between the lung surface and chest wall. The presence and severity of LPA was confirmed by intra-operative thoracoscopic findings. Parameters of diagnostic accuracy for LPA presence and severity were assessed among the 3 methods using Wilcoxon signed rank test in total and for each of the 3 pleural aspects. Mild and severe LPA were confirmed in 14 and 8 patients. Movie image with color map had higher sensitivity (56.9 ± 10.7 %) and negative predictive value (NPV) (91.4 ± 1.7 %) in LPA detection than both movie image and static image. Furthermore, for severe LPA, detection sensitivity was the highest with movie image with color map (82.5 ± 6.1 %), followed by movie image (58.8 ± 17.0 %) and static image (38.8 ± 13.9 %). For LPA severity, movie image with color map was similar to movie image and superior to static image in accuracy as well as under-estimation and over-estimation, with a mean value of 80.2 %. The authors concluded that software-assisted dynamic-ventilation CT may be a useful novel imaging approach to improve the detection performance of LPA.

The authors stated that this study had several drawbacks. First, because this study was carried out as a preliminary study to examine the usefulness of dedicated software analysis for LPA on dynamic-ventilation CT, the total number of enrolled patients was small (n = 51). The presence of lung tumors might have affected the movement of the lung periphery. Therefore, the findings of this study should be evaluated further in a larger study population without lung tumors. Second, the scanning area did not include the whole thorax on dynamic-ventilation CT. Pleural regions demonstrated at end inspiration were not always included in the scanning area with 16 cm coverage in the cranio-caudal direction in the remaining phases during respiration. Thus, it may make visual assessment of the movie image difficult and reduce LPA detectability using the 3D color map, especially for the lower pleural aspects. Furthermore, if dynamic ventilation CT data were obtained with the whole thorax contained in the scan in more cases in the future, motion vector from inside to outside lung field at specific respiratory phase from end inspiration such as 1.05 s later might be standardized and used for prediction of LPA presence and severity. Third, a relatively high radiation exposure for dynamic-ventilation CT may lead to concerns regarding the use of dynamic-ventilation CT in routine clinical series for LPA detection. In combination with iterative reconstruction, static-conventional CT at a considerably reduced dose (less than 0.3 mSv) has recently demonstrated similar pulmonary nodule detectability and equivalent quantification in larger sub-solid nodules to CT at reduced dose (0.92 to 1.74 mSv). Thus, the tube current was fixed at 7 mAs in this study, which was theoretically thought to correspond to less than 0.3 mSv for a single rotation during DVCT. However, a reduced tube current, such as 3.5 mAs, which is as low as achievable at this stage for this scanner, may be feasible in the future, especially in combination with full iterative reconstruction techniques or deep learning-based reconstruction technique. Fourth, the most advanced area-detector CT with the rotation time of 0.275 s/rotation, which is theoretically less susceptible to faster lung motion, was not employed in this study. If this latest scanner is adopted in the future study, improvement in image quality at time phases in mid-inspiration or mid-expiration as well as further dose reduction can be realized on dynamic-ventilation CT. Fifth, pleural aspects were assigned to upper, middle and lower lung fields at thoracoscopy based on rib locations. On the other hand, they were assigned to the 3 lung fields with the pre-defined 2 trans-axial planes at end-inspiration passing to the bronchial bifurcation and the superior edge of the diaphragm. Therefore, both of them could not correspond to each other in some cases. Sixth, subjective judgments of LPA by using CT images depend on individual observer’s experience and recognition, which may partly impair concordance in severe judgment for LPA between CT and VATS.

Scope of Policy

This Clinical Policy Bulletin addresses selected techniques for lung imaging.

Medical Necessity

Aetna considers lung imaging fluorescence endoscopy (LIFE) medically necessary to enhance the physician's ability to detect and biopsy abnormal bronchial tissue suspicious for pre-cancerous lesions, carcinomas in-situ, and early bronchogenic carcinomas in

of the following groups:

Experimental and Investigational

Aetna considers the following lung imaging modalities experimental and investigational because the effectiveness of these approaches has not been established: