Multiomics Analysis Reveals Distinct Immunogenomic Features of Lung Cancer with Ground-Glass Opacity.

Rationale: Ground-glass opacity (GGO)-associated lung cancers are common and radiologically distinct clinical entities known to have an indolent clinical course and superior survival, implying a unique underlying biology. However, the molecular and immune characteristics of GGO-associated lung nodules have not been systemically studied. Objectives: To provide mechanistic insights for the treatment of these radiologically distinct clinical entities. Methods: We initiated a prospective cohort study to collect and characterize pulmonary nodules with GGO components (nonsolid and part-solid nodules) or without GGO components, as precisely quantified by using three-dimensional image reconstruction to delineate the molecular and immune features associated with GGO. Multiomics assessment conducted by using targeted gene panel sequencing, RNA sequencing, TCR (T-cell receptor) sequencing, and circulating tumor DNA detection was performed. Measurements and Main Results: GGO-associated lung cancers exhibited a lower tumor mutation burden than solid nodules. Transcriptomic analysis revealed a less active immune environment in GGO components and immune pathways, decreased expression of immune activation markers, and less infiltration of most immune-cell subsets, which was confirmed by using multiplex immunofluorescence. Furthermore, T-cell repertoire sequencing revealed lower T-cell expansion in GGO-associated lung cancers. HLA loss of heterozygosity was significantly less common in lung adenocarcinomas with GGO components than in those without. Circulating tumor DNA analysis suggested that the release of tumor DNA to the peripheral blood was correlated with the tumor size of non-GGO components. Conclusions: Compared with lung cancers presenting with solid lung nodules, GGO-associated lung cancers are characterized by a less active metabolism and a less active immune microenvironment, which may be the mechanisms underlying their indolent clinical course. Clinical trial registered with www.clinicaltrials.gov (NCT03320044).

Fractionated deep-inspiration breath-hold ZTE Compared with Free-breathing four-dimensional ZTE for detecting pulmonary nodules in oncological patients underwent PET/MRI.

The zero echo time (ZTE) technique has improved the detection of lung nodules in PET/MRI but respiratory motion remains a challenge in lung scan. We investigated the feasibility and performance of fractionated deep-inspiration breath-hold (FDIBH) three-dimensional (3D) ZTE FDG PET/MRI for assessing lung nodules in patients with proved malignancy. Sixty patients who had undergone ZTE FDG PET/MRI and chest CT within a three-day interval were retrospectively included. Lung nodules less than 2 mm were excluded for analysis. Two physicians checked the adequacy of FDIBH ZTE and compared the lung nodule detection rates of FDIBH 3D ZTE and free-breathing (FB) four-dimensional (4D) ZTE, with chest CT as the reference standard. FDIBH resolved the effect of respiratory motion in 49 patients. The mean number and size of the pulmonary nodules identified in CT were 15 ± 31.3 per patient and 5.9 ± 4.6 mm in diameter. The overall nodule detection rate was 71% for FDIBH 3D ZTE and 70% for FB 4D ZTE (p = 0.73). FDIBH 3D ZTE significantly outperformed FB 4DZTE in detecting lung base nodules (72% and 68%; p = 0.03), especially for detecting those less than 6 mm (61% and 55%; p = 0.03). High inter-rater reliability for FDIBH 3D ZTE and FB 4D ZTE (k = 0.9 and 0.92) was noted. In conclusion, the capability of FDIBH 3D ZTE in respiratory motion resolution was limited with a technical failure rate of 18%. However, it could provide full expansion of the lung in a shorter scan time which enabled better detection of nodules (< 6 mm) in basal lungs, compared to FB 4D ZTE.

Electromagnetic Navigation Bronchoscopy Combined Endobronchial Ultrasound in the Diagnosis of Lung Nodules.

ABSTRACT: Electromagnetic navigational bronchoscopy (ENB) combined with a radial endobronchial ultrasound probe realizes a combination of magnetic navigation and ultrasound imaging, allowing for the accurate navigation of peripheral lung lesions in real time during surgery. ENB has been evaluated in many studies. However, a comparative report on the feasibility of ENB combined radial endobronchial ultrasound diagnosis in different density lung nodules was small, and few of these studies have reported long-term follow-up results to exclude false negative results. The aim of this study is to explore the applicability of ENB combined radial endobronchial ultrasound in the diagnosis of lung nodules with different densities.Patients underwent biopsy in our medical center from 2016-09 to 2019-03 were divided into 2 groups: the solid nodule group and the subsolid pulmonary nodule group. We collected and analyzed the diagnostic accuracy, the diagnostic yield, the false negative rate and the incidence of complications between these 2 groups.A total of 37 lesions in 25 patients were biopsied, 14 lesions were subsolid pulmonary nodules and 23 were solid nodules. The diagnostic accuracy (success rate to obtain meaningful pathology tissues) was 34/37 (91.8%). Lost to follow-up in 1 case and three cases were undiagnosed. After at least 12 months of follow-up, the total diagnostic yield (true positive rate+ true negative rate) was 27/36 (75%) (P = .006). The false negative rate was 9/19 (47.3%) (P = .26). Complications occurred in 1/36 (2.7%) lesions. For the subsolid pulmonary nodule group, the diagnostic accuracy was 13/14 (92.8%) and the diagnostic yield was 7/14 (50%). For the solid nodule group, the diagnostic accuracy was 21/23 (91.3%), and the diagnostic yield was 20/22 (90.9%).Electromagnetic navigational bronchoscopy combined with radial endobronchial ultrasound in peripheral lung nodule biopsies is safe and effective, especially for solid nodules, but the diagnostic yield in subsolid nodule biopsies remains to be improved.

Free-breathing radial volumetric interpolated breath-hold examination sequence and dynamic contrast-enhanced MRI combined with diffusion-weighted imaging for assessment of solitary pulmonary nodules.

OBJECTIVE: To test the performance of free-breathing Dynamic Contrast-Enhanced MRI (DCE-MRI) using a radial volumetric interpolated breath-hold examination (VIBE) sequence combined with diffusion-weighted imaging (DWI) for quantitative solitary pulmonary nodule (SPN) assessment. METHODS: A total of 67 SPN cases receiving routine MRI routine scans, DWI, and dynamic-enhanced MRI in our hospital from May 2017 to November 2018 were collected. These cases were divided into a malignant group and a benign group according to the characteristics of the SPNs. The quantitative DCE-MRI parameters (Ktrans, Kep, Ve) and apparent diffusion coefficient (ADC) values of the nodules were measured. RESULTS: The Ktrans and Kep values in the malignant group were higher than those in the benign group, while the ADC values in the malignant group were lower than those in the benign group. Furthermore, the Ktrans value of adenocarcinoma was higher than that of squamous cell carcinoma and small cell carcinoma (P < 0.05). The Ve value was significantly different between non-small cell carcinoma and small cell carcinoma (P < 0.05). With an ADC value of 0.98 × 10-3 mm2/s as the threshold, the specificity and sensitivity to diagnose benign and malignant nodules was 90.6% and 80%, respectively. CONCLUSION: High-temporal-resolution DCE-MRI using the r-VIBE technique in combination with DWI could contribute to pulmonary nodule analysis and possibly serve as a potential alternative to distinguish malignant from benign nodules as well as differentiate different types of malignancies.

A novel application of pulmonary transit time to differentiate between benign and malignant pulmonary nodules using myocardial contrast echocardiography.

Malignant pulmonary nodules (PNs) are often accompanied by vascular dilatation and structural abnormalities. Pulmonary transit time (PTT) measurement by contrast echocardiograghy has used to assess the cardiopulmonary function and pulmonary vascular status, such as hepatopulmonary syndrome and pulmonary arteriovenous fistula, but has not yet been attempted in the diagnosis and differential diagnosis of PNs. The aim of this work was to evaluate the feasibility and performance of myocardial contrast echocardiography (MCE) for differentiating malignant PNs from benign ones. The study population consisted of 201 participant: 66 healthy participants, 65 patients with benign PNs and 70 patients with malignant PNs. Their clinical and conventional echocardiographic characteristics were collected. MCE with measurements of PTT were performed. There was no difference in age, sex, heart rate, blood pressure, smoking rate, background lung disease, pulmonary function, ECG, myocardial enzymes, cardiac size and function among the healthy participant, patients with benign and malignant PNs (P > 0.05). PTT did not differ significantly in patients with PNs of different sizes, nor did they differ in patients with PNs of different enhancement patterns (P > 0.05). However, the PTT were far shorter (about one half) in patients with malignant PNs than in patients with benign ones (1.88 ± 0.37 vs. 3.73 ± 0.35, P < 0.001). There was no significantly different between patients with benign PNs and healthy participant (3.73 ± 0.35 vs.3.89 ± 0.36, P > 0.05). The area under the receiver operating characteristics curve (AUC) of PTT was 0.99(0.978-1.009) in discriminating between benign and malignant PNs. The optimal cutoff value was 2.78 s, with a sensitivity of 98.52%, a specificity of 97.34%, and a accuracy of 97.69%. MCE had a powerful performance in differentiating between benign and malignant PNs, and a pulmonary circulation time of < 2.78 s indicated malignant PNs.

Skin marking with computed tomography at functional residual capacity to predict lung nodule site.

Various marking techniques for lung nodules may be complex and can cause serious complications. In this study, we aimed to describe and evaluate the feasibility of CTFRC marking, a novel preoperative skin marking technique guided by computed tomography (CT) at functional residual capacity (FRC). This simple and non-invasive marking technique only requires a preoperative CT scan without any anaesthesia. We retrospectively reviewed CTFRC markings performed for 109 lung nodules in 108 patients. The mean nodule size was 11.4 ± 5.0 mm. The mean distance from the nodule to the lung marking point was 3.8 ± 7.3 mm. We found no procedure-associated complications. CTFRC marking is a simple, safe and non-invasive method to predict the precise location of lung nodules during thoracoscopic surgery.

Will That Pulmonary Nodule Become Cancerous? A Risk Prediction Model for Incident Lung Cancer.

This prospective investigation derived a prediction model for identifying risk of incident lung cancer among patients with visible lung nodules identified on computed tomography (CT). Among 2,924 eligible patients referred for evaluation of a pulmonary nodule to the Stony Brook Lung Cancer Evaluation Center between January 1, 2002 and December 31, 2015, 171 developed incident lung cancer during the observation period. Cox proportional hazard models were used to model time until disease onset. The sample was randomly divided into discovery (n = 1,469) and replication (n = 1,455) samples. In the replication sample, concordance was computed to indicate predictive accuracy and risk scores were calculated using the linear predictions. Youden index was used to identify high-risk versus low-risk patients and cumulative lung cancer incidence was examined for high-risk and low-risk groups. Multivariable analyses identified a combination of clinical and radiologic predictors for incident lung cancer including ln-age, ln-pack-years smoking, a history of cancer, chronic obstructive pulmonary disease, and several radiologic markers including spiculation, ground glass opacity, and nodule size. The final model reliably detected patients who developed lung cancer in the replication sample (C = 0.86, sensitivity/specificity = 0.73/0.81). Cumulative incidence of lung cancer was elevated in high-risk versus low-risk groups [HR = 14.34; 95% confidence interval (CI), 8.17-25.18]. Quantification of reliable risk scores has high clinical utility, enabling physicians to better stratify treatment protocols to manage patient care. The final model is among the first tools developed to predict incident lung cancer in patients presenting with a concerning pulmonary nodule.

Comparison of Various Parameters of DWI in Distinguishing Solitary Pulmonary Nodules.

In order to prospectively assess various parameters of diffusion weighted imaging (DWI) in differential diagnosis of benign and malignant solitary pulmonary nodules (SPNs), 58 patients (40 men and 18 women, and mean age of 48.1±10.4 years old) with SPNs undergoing conventional MR, DWI using b=500 s/mm2 on a 1.5T MR scanner, were studied. Various DWI parameters [apparent diffusion coefficient (ADC), lesion-tospinal cord signal intensity ratio (LSR), signal intensity (SI) score] were calculated and compared between malignant and benign SPNs groups. A receiver operating characteristic (ROC) curve analysis was employed to compare the diagnostic capabilities of all the parameters for discrimination between benign and malignant SPNs. The results showed that there were 42 malignant and 16 benign SPNs. The ADC was significantly lower in malignant SPNs (1.40±0.44)×10-3 mm2/s than in benign SPNs (1.81±0.58)×10-3 mm2/s. The LSR and SI scores were significantly increased in malignant SPNs (0.90±0.37 and 2.8±1.2) as compared with those in benign SPNs (0.68±0.39 and 2.2±1.2). The area under the ROC curves (AUC) of all parameters was not significantly different between malignant SPNs and benign SPNs. It was suggested that as three reported parameters for DWI, ADC, LSR and SI scores are all feasible for discrimination of malignant and benign SPNs. The three parameters have equal diagnostic performance.

Comparing Pulmonary Nodule Location During Electromagnetic Bronchoscopy With Predicted Location on the Basis of Two Virtual Airway Maps at Different Phases of Respiration.

BACKGROUND: Electromagnetic navigational bronchoscopy (ENB) is guided bronchoscopy to pulmonary nodules (PN) that relies on a preprocedural chest CT to create a three-dimensional (3D) virtual airway map. The CT is traditionally done at a full inspiratory breath hold (INSP), but the procedure is performed while the patient tidal breaths, when lung volumes are closer to functional residual capacity. Movement of a PN from INSP to expiration (EXP) has been shown to average 17.6 mm. Therefore, the hypothesis of this study is that preprocedural virtual maps built off a CT closer to physiological lung volumes during bronchoscopy may better represent the actual 3D location of a PN. METHODS: Consecutive patients with a PN needing a histological diagnosis were enrolled. A preprocedure INSP and EXP CT scan were obtained to create two virtual maps. During the airway inspection, the system tracked the sensor probe to collect 3D points that were reconstructed into the lumen registration map. This map is thought to best represent the patient's airways during bronchoscopy. Predicted PN location on an EXP and INSP map was compared with lumen registration. RESULTS: Twenty consecutive PN underwent ENB. The predicted PN location, compared with lumen registration, was significantly closer on EXP vs INSP (4.5 mm ± 3.3 mm vs 14.8 mm ± 9.7 mm; p < 0.0001). CONCLUSIONS: Predicted 3D nodule location using an EXP scan for ENB is significantly closer to actual nodule location when compared with an INSP scan, but whether this leads to increased yields needs to be determined.

[Analysis of Growth Curve Type in Pulmonary Nodules with
Different Characteristics].

BACKGROUND: Background and objective Follow up by computed tomography (CT) and growth evaluation are routine methods for the differential diagnosis of indeterminate pulmonary nodules in clinical practice. Pulmonary nodules with diverse biological behaviors may show different growth patterns and velocities. The aim of this study is to identify the volume growth curve of both benign and malignant pulmonary nodules. This work also intends to determine these nodules' growth patterns and provide evidence for the establishment of a follow-up strategy. METHODS: The CT data of 111 pulmonary nodules (54 solid, 57 subsolid) were retrospectively evaluated using 3D volumetric software. All of these nodules have been followed up at least twice. Of these nodules, 35 were confirmed as lung cancers, whereas 5 were confirmed as benign by pathology or histology. Moreover, 71 nodules showed no growth in more than 2 years. Stable nodules were defined as low-risk nodules, as confirmed by reevaluation from experts. On the basis of their densities and diameters, the nodules were classified into four types: benign/low-risk solid nodules, malignant solid nodules (diameter ≤1 cm and >1 cm), benign/low-risk subsolid nodules, and malignant subsolid nodules (diameter ≤1 cm and >1 cm). The follow-up interval time (d) were plotted on the x-axis, and the nodules' volume (mm3) and logarithmic volume were plotted on the y-axis. Two radiologists subjectively determined the type of growth curve. Chi-square test was performed to compare the growth curves of benign/low-risk and malignant nodules. RESULTS: Of 18 solid cancers, 12 cases (66%) were found with steep ascendant growth curves. Those of 3 cases (16.7%) were flat ascendant, 2 cases (11.1%) slowly ascendant, and 1 (5.56%) case flat. Of 17 subsolid cancers, 8 cases (47.1%) manifested steep ascendant growth curves. Those of 4 cases (23.5%) were slowly ascendant, 3 (17.6%) flat, and 2 (11.8%) descendant-ascendant. Of 36 benign/low-risk solid nodules, 5 cases (13.9%) manifested descendant growth curves, 17 cases (47.2%) flat, 8 cases (21.6%) slowly ascendant, and 6 cases (16.7%) undulate. Of 40 benign/low-risk subsolid nodules, 4 cases (10%) manifested descendant growth curves, 21 cases (52.5%) flat, 9 cases (22.5%) slowly ascendant, and 6 cases (15%) undulate. The distribution of growth curve types significantly differed between benign/low-risk and malignant nodules (χ2=42.4, P<0.01). CONCLUSIONS: The growth curves of lung cancers are heterogeneous. A steep ascendant curve is the main type for lung cancer, with the exception of flat, slowly ascendant, or even descendant curve. A slowly ascendant curve cannot exclude the diagnosis of lung cancer, especially for subsolid nodules.
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Statistical tools for the temporal analysis and classification of lung lesions.

BACKGROUND AND OBJECTIVE: Lung cancer remains one of the most common cancers globally. Temporal evaluation is an important tool for analyzing the malignant behavior of lesions during treatment, or of indeterminate lesions that may be benign. This work proposes a methodology for the analysis, quantification, and visualization of small (local) and large (global) changes in lung lesions. In addition, we extract textural features for the classification of lesions as benign or malignant. METHODS: We employ the statistical concept of uncertainty to associate each voxel of a lesion to a probability that changes occur in the lesion over time. We employ the Jensen divergence and hypothesis test locally to verify voxel-to-voxel changes, and globally to capture changes in lesion volumes. RESULTS: For the local hypothesis test, we determine that the change in density varies by between 3.84 and 40.01% of the lesion volume in a public database of malignant lesions under treatment, and by between 5.76 and 35.43% in a private database of benign lung nodules. From the texture analysis of regions in which the density changes occur, we are able to discriminate lung lesions with an accuracy of 98.41%, which shows that these changes can indicate the true nature of the lesion. CONCLUSION: In addition to the visual aspects of the density changes occurring in the lesions over time, we quantify these changes and analyze the entire set using volumetry. In the case of malignant lesions, large b-divergence values are associated with major changes in lesion volume. In addition, this occurs when the change in volume is small but is associated with significant changes in density, as indicated by the histogram divergence. For benign lesions, the methodology shows that even in cases where the change in volume is small, a change of density occurs. This proves that even in lesions that appear stable, a change in density occurs.

Effect of tomographic operator inaccuracies and respiratory motion on PET/CT lung nodule images smearing.

BACKGROUND: In thoracic PET/computed tomography (CT) imaging, uptake foci usually appear smeared because of postreconstruction smoothing and respiratory motion. OBJECTIVE: The aim of the present study was to assess the respective contributions of the reconstruction process and respiratory motion on PET/CT images. MATERIALS AND METHODS: Thirty-one pulmonary lesions were studied. Free-breathing PET/CT acquisitions were followed by a 10-min respiratory-gated PET/CT acquisition. Four different reconstructions were performed by combining two different tomographic operators (TOs) (i.e. the geometric clinical system matrix or a system matrix including the detector response) and taking account (or not) of respiratory motion using a previously developed 'CT-based' technique. For each reconstruction method, lesion segmentation was performed with an adaptive threshold. Next, we computed the volume differences between each reconstruction. Finally, we applied a multiple linear model to compute the relative contributions of TO-based and CT-based respiratory compensation to lesion volume. RESULTS: The three groups, combining the reconstruction methods and the respiratory compensation (or not), differed significantly in terms of the volume differences. For all lesions, the full linear model yielded a regression coefficient R of 76.10%. The partial R values were 65.58 and 10.52% for the detector response operator and the CT-based method, respectively. For lesions in the upper/middle lobes, blurring was mainly because of TO (partial R=78.53%), whereas, for lower lobe lesions, smearing was mainly because of respiratory motion (partial R=56.76%). CONCLUSION: Our results showed that image reconstruction, by TO accuracy, was the main explanatory factor for lesion smearing when considering the chest as a whole. Respiration had a major impact on the lower lobes.

Follow-up of CT-derived airway wall thickness: Correcting for changes in inspiration level improves reliability.

OBJECTIVES: Airway wall thickness (AWT) is affected by changes in lung volume. This study evaluated whether correcting AWT on computed tomography (CT) for differences in inspiration level improves measurement agreement, reliability, and power to detect changes over time. METHODS: Participants of the Dutch-Belgian lung cancer screening trial who underwent 3-month repeat CT for an indeterminate pulmonary nodule were included. AWT on CT was calculated by the square root of the wall area at a theoretical airway with an internal perimeter of 10mm (Pi10). The scan with the highest lung volume was labelled as the reference scan and the scan with the lowest lung volume was labelled as the comparison scan. Pi10 derived from the comparison scan was corrected by multiplying it with the ratio of CT lung volume of the comparison scan to CT lung volume on the reference scan. Agreement of uncorrected and corrected Pi10 was studied with the Bland-Altman method, reliability with intra-class correlation coefficients (ICC), and power to detect changes over time was calculated. RESULTS: 315 male participants were included. Limit of agreement and reliability for Pi10 was -0.61 to 0.57mm (ICC=0.87), which improved to -0.38 to 0.37mm (ICC=0.94) after correction for inspiration level. To detect a 15% change over 3 months, 71 subjects are needed for Pi10 and 26 subjects for Pi10 adjusted for inspiration level. CONCLUSIONS: Correcting Pi10 for differences in inspiration level improves reliability, agreement, and power to detect changes over time.

Pulmonary nodule on x-ray: An algorithmic approach.

The best way to manage a pulmonary nodule depends on the patient's history, risk factors for cancer, and nodule characteristics. This review can guide you.

Evaluation of the Solitary Pulmonary Nodule.

A solitary pulmonary nodule is a common radiologic finding that is often discovered incidentally and may require significant workup to establish a definitive diagnosis. A solitary pulmonary nodule is a well-circumscribed round lesion measuring up to 3 cm in diameter and surrounded by aerated lung. Once a nodule is discovered, clinical and radiologic features and quantitative models can be used to determine the likelihood of malignancy. Evaluation is guided by nodule size and assessment of probability of malignancy. Surgical resection or nonsurgical biopsy should be performed in patients with solid or subsolid solitary pulmonary nodules that show clear growth on serial imaging. Solid solitary pulmonary nodules that have been stable for at least two years typically do not need further evaluation. The workup for patients with solid solitary pulmonary nodules measuring 8 mm or greater in diameter, nodules measuring less than 8 mm in diameter, and subsolid nodules should be guided by the probability of malignancy, imaging results, and the risks and benefits of different management strategies. Management should be individualized according to patient values and preferences. Medicare now covers lung cancer screening with low-dose computed tomography for high-risk patients 55 to 77 years of age at institutions that can provide a comprehensive approach to the management of solitary pulmonary nodules.

The effects of computed tomography with iterative reconstruction on solid pulmonary nodule volume quantification.

BACKGROUND: The objectives of this study were to evaluate the influence of iterative reconstruction (IR) on pulmonary nodule volumetry with chest computed tomography (CT). METHODS: Twenty patients (12 women and 8 men, mean age 61.9, range 32-87) underwent evaluation of pulmonary nodules with a 64-slice CT-scanner. Data were reconstructed using filtered back projection (FBP) and IR (Philips Healthcare, iDose(4)-levels 2, 4 and 6) at similar radiation dose. Volumetric nodule measurements were performed with semi-automatic software on thin slice reconstructions. Only solid pulmonary nodules were measured, no additional selection criteria were used for the nature of nodules. For intra-observer and inter-observer variability, measurements were performed once by one observer and twice by another observer. Algorithms were compared using the concordance correlation-coefficient (pc) and Friedman-test, and post-hoc analysis with the Wilcoxon-signed ranks-test with Bonferroni-correction (significance-level p<0.017). RESULTS: Seventy-eight nodules were present including 56 small nodules (volume<200 mm(3), diameter<8 mm) and 22 large nodules (volume≥200 mm(3), diameter≥8 mm). No significant differences in measured pulmonary nodule volumes between FBP, iDose(4)-levels 2, 4 and 6 were found in both small nodules and large nodules. FBP and iDose(4)-levels 2, 4 and 6 were correlated with pc-values of 0.98 or higher for both small and large nodules. Pc-values of intra-observer and inter-observer variability were 0.98 or higher. CONCLUSIONS: Measurements of solid pulmonary nodule volume measured with standard-FBP were comparable with IR, regardless of the IR-level and no significant differences between measured volumes of both small and large solid nodules were found.