Incidence and Risk Factors for Pneumonitis Associated With Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer: A Single Center Experience.

INTRODUCTION: Immune checkpoint inhibitor (ICI) pneumonitis causes substantial morbidity and mortality. Estimates of real-world incidence and reported risk factors vary substantially. METHODS: We conducted a retrospective review of 419 patients with advanced non-small cell lung cancer (NSCLC) who were treated with anti-PD-(L)1 with or without anti-CTLA-4 therapy. Clinical, imaging, and microbiological data were evaluated by multidisciplinary adjudication teams. The primary outcome of interest was grade ≥2 (CTCAEv5) pneumonitis. Clinicopathologic variables, tobacco use, cancer therapies, and preexisting lung disease were assessed for univariate effects using Cox proportional hazards models. We created multivariate Cox proportional hazards models to assess risk factors for pneumonitis and mortality. Pneumonitis, pneumonia, and progression were modeled as time-dependent variables in mortality models. RESULTS: We evaluated 419 patients between 2013 and 2021. The cumulative incidence of pneumonitis was 9.5% (40/419). In a multivariate model, pneumonitis increased the risk for mortality (HR 1.6, 95% CI, 1.0-2.5), after adjustment for disease progression (HR 1.6, 95% CI, 1.4-1.8) and baseline shortness of breath (HR 1.5, 95% CI, 1.2-2.0). Incomplete resolution was more common with more severe pneumonitis. Interstitial lung disease was associated with higher risk for pneumonitis (HR 5.4, 95% CI, 1.1-26.6), particularly in never smokers (HR 26.9, 95% CI, 2.8-259.0). CONCLUSION: Pneumonitis occurred at a high rate and significantly increased mortality. Interstitial lung disease, particularly in never smokers, increased the risk for pneumonitis.

Pneumonitis after immune checkpoint inhibitor therapies in patients with acute myeloid leukemia: A retrospective cohort study.

BACKGROUND: Immune checkpoint inhibitors (ICI), combined with hypomethylating agents, can be used to treat acute myeloid leukemia (AML), but this strategy results in a high rate of pneumonitis. The authors sought to determine risk factors for pneumonitis development and whether pneumonitis increased mortality. METHODS: The authors conducted a retrospective review of 258 AML patients who received ICI-containing regimens from 2016 to 2018. A multidisciplinary adjudication committee diagnosed pneumonia and pneumonitis by reviewing symptoms, imaging, microbiology, and response to therapies. To measure risk factors for pneumonitis and mortality, multivariate Cox proportional hazards models were constructed. Pneumonia, pneumonitis, and disease progression were modeled as a time-dependent variable and incorporated a standard risk set modifying variables into the models. RESULTS: Thirty patients developed pneumonitis (12%). Of these, 17 had partial or complete resolution, whereas 13 patients died from pneumonitis. Increasing age (hazard ratio [HR], 1.04 per year; 95% confidence interval [CI], 1.00-1.08), and baseline shortness of breath increased pneumonitis risk (HR, 2.51; 95% CI, 1.13-5.55). Female sex (HR, 0.33; 95% CI, 0.15-0.70) and increasing platelet count (HR, 0.52 per log-unit increase; 95% CI, 0.30-0.92) decreased pneumonitis risk. In adjusted models, ICI-related pneumonitis significantly increased mortality (HR, 2.84; 95% CI, 1.84-4.37). CONCLUSIONS: ICI-related pneumonitis occurs at a high rate in AML patients and increases mortality. LAY SUMMARY: Immune checkpoint inhibitors (ICIs) remove inhibitory signals that reduce T-cell function and allow T-cells to better attack cancer cells. In acute myeloid leukemia (AML), the effectiveness of ICIs is limited in part by inflammation of the lung, called pneumonitis. This study reviewed 258 patients with AML who received ICIs and identified 30 patients who developed pneumonitis, nearly half of whom died. Older age and baseline shortness of breath increased pneumonitis risk, whereas female sex and higher baseline platelet counts decreased pneumonitis risk. Pneumonitis increased mortality by nearly 3-fold. This work highlights the significant harm imposed by pneumonitis after ICI therapies.

Imaging of Lung Cancer Staging.

Lung cancer is a leading cause of cancer-related mortality worldwide. Imaging is integral in accurate clinical staging to stratify patients into groups to predict survival and determine treatment. The eighth edition of the tumor, node, and metastasis (TNM-8) staging system proposed by the International Association for the Study of Lung Cancer in 2016, accepted by both the Union for International Cancer Control and the American Joint Committee on Cancer, is the current standard method of staging lung cancer. This single TNM staging is used for all histologic subtypes of lung cancer, including nonsmall cell lung cancer, small cell lung cancer, and bronchopulmonary carcinoid tumor, and it addresses both clinical and pathologic staging. Familiarity with the strengths and limitations of imaging modalities used in staging, the nuances of TNM-8, its correct nomenclature, and potential pitfalls are important to optimize patient care. In this article, we discuss the role of computed tomography (CT) and positron emission tomography/CT in lung cancer staging, as well as current imaging recommendations pertaining to TNM-8.

18F-fluorodeoxyglucose positron emission tomography correlates with tumor immunometabolic phenotypes in resected lung cancer.

Enhanced tumor glycolytic activity is a mechanism by which tumors induce an immunosuppressive environment to resist adoptive T cell therapy; therefore, methods of assessing intratumoral glycolytic activity are of considerable clinical interest. In this study, we characterized the relationships among tumor 18F-fluorodeoxyglucose (FDG) retention, tumor metabolic and immune phenotypes, and survival in patients with resected non-small cell lung cancer (NSCLC). We retrospectively analyzed tumor preoperative positron emission tomography (PET) 18F-FDG uptake in 59 resected NSCLCs and investigated correlations between PET parameters (SUVMax, SUVTotal, SUVMean, TLG), tumor expression of glycolysis- and immune-related genes, and tumor-associated immune cell densities that were quantified by immunohistochemistry. Tumor glycolysis-associated immune gene signatures were analyzed for associations with survival outcomes. We found that each 18F-FDG PET parameter was positively correlated with tumor expression of glycolysis-related genes. Elevated 18F-FDG SUVMax was more discriminatory of glycolysis-associated changes in tumor immune phenotypes than other 18F-FDG PET parameters. Increased SUVMax was associated with multiple immune factors characteristic of an immunosuppressive and poorly immune infiltrated tumor microenvironment, including elevated PD-L1 expression, reduced CD57+ cell density, and increased T cell exhaustion gene signature. Elevated SUVMax identified immune-related transcriptomic signatures that were associated with enhanced tumor glycolytic gene expression and poor clinical outcomes. Our results suggest that 18F-FDG SUVMax has potential value as a noninvasive, clinical indicator of tumor immunometabolic phenotypes in patients with resectable NSCLC and warrants investigation as a potential predictor of therapeutic response to immune-based treatment strategies.

Pulmonary Legionellosis in Oncologic Patients: Findings on Chest CT.

OBJECTIVE: The purpose of this study was to report the computed tomography (CT) findings of non-pneumophila Legionella pneumonia and to compare these CT findings to those caused by Legionella pneumophila in oncologic patients. METHODS: Chest CT scans of 34 oncologic patients with culture-proven Legionella infection (16 L. pneumophila and 18 non-pneumophila Legionella) were retrospectively reviewed. Radiologic checkpoints included consolidation, ground-glass opacities, cavitation, nodules, tree-in-bud opacities, septal thickening, pleural effusions, and adenopathy, as well as the halo, reversed halo, and bulging fissure signs. RESULTS: The most common imaging feature of Legionella pneumonia was consolidation, seen in 94% of patients. Ground-glass opacities were the next most common abnormality. The halo sign was present in 26% of patients, in both immunocompetent and immunosuppressed hosts. Most features occurred with similar frequency between L. pneumophila and non-pneumophila Legionella. CONCLUSIONS: Findings in L. pneumophila pneumonia and non-pneumophila Legionella pneumonia are similar but nonspecific. Airspace consolidation is almost always present; the halo sign is not uncommon.

Tuberous Sclerosis Complex: State-of-the-Art Review with a Focus on Pulmonary Involvement.

Tuberous sclerosis complex (TSC) is an autosomal-dominant neurocutaneous disease with high phenotypic variability. The incidence is approximately one in 5000-10,000 births. TSC is characterized by widespread hamartomas and benign or rarely malignant neoplasms affecting various organs, most commonly the brain, skin, retinas, kidneys, heart, and lungs. The wide range of organs affected reflects the roles of TSC1 and TSC2 genes in the regulation of cell proliferation and differentiation. Clinical diagnostic criteria are important because genetic testing does not identify the mutation in up to 25% of patients. Imaging is pivotal, as it allows a presumptive diagnosis of TSC and definition of the extent of the disease. Common manifestations of TSC include cortical tubers, subependymal nodules, white matter abnormalities, retinal abnormalities, cardiac rhabdomyoma, lymphangioleiomyomatosis (LAM), renal angiomyolipoma, and skin lesions. Pulmonary involvement consists of LAM and, less commonly, multifocal micronodular pneumocyte hyperplasia (MMPH), which causes cystic and nodular diseases, respectively. Recent reports indicate that pulmonary LAM is found by computed tomography in up to 35% of the female patients with TSC. MMPH is rare and may be associated with LAM or, less frequently, occurs as an isolated pulmonary manifestation in women with TSC. Dyspnea and pneumothorax are common clinical presentations of LAM, whereas MMPH is usually asymptomatic. The aim of this review is to describe the main clinical, imaging, and pathological aspects of TSC, with a focus on pulmonary involvement.

Multidetector CT evaluation of airway stents: what the radiologist should know.

Airway stents are increasingly used to treat symptomatic patients with obstructive tracheobronchial diseases who are not amenable to surgical resection or who have poor performance status, precluding them from resection. The most common conditions that are treated with tracheobronchial stents are primary lung cancer and metastatic disease. However, stents have also been used to treat patients with airway stenosis related to a variety of benign conditions, such as tracheobronchomalacia, relapsing polychondritis, postintubation tracheal stenosis, postoperative anastomotic stenosis, and granulomatous diseases. Additionally, airway stents can be used as a barrier method in the management of esophagorespiratory fistulas. Many types of stents are available from different manufacturers. Principally, they are classified as silicone; covered and uncovered metal; or hybrid, which are made of silicone and reinforced by metal rings. The advantages and disadvantages of each type of airway stent are carefully considered when choosing the most appropriate stent for each patient. Multidetector computed tomography plays an important role in determining the cause and assessing the location and extent of airway obstruction. Moreover, it is very accurate in its depiction of complications after airway stent placement.

Differentiating pericardial recesses from mediastinal adenopathy: potential pitfalls in oncological imaging.

In oncological imaging, staging with computed tomography (CT) is widely used to determine treatment. Misinterpretation of fluid in pericardial recesses as mediastinal adenopathy can lead to inaccurate clinical staging and inappropriate management. In this review, we describe normal pericardial anatomy and illustrate imaging features to differentiate fluid in pericardial sinuses and recesses from mediastinal adenopathy.

Lung cancer imaging.

Lung cancer remains the leading cause of cancer-related deaths in the US. Imaging plays an important role in the diagnosis, staging, and follow-up evaluation of patients with lung cancer. With recent advances in technology, it is important to update and standardize the radiological practices in lung cancer evaluation. In this article, the authors review the main clinical applications of different imaging modalities and the most common radiological presentations of lung cancer.

Functional imaging with diffusion-weighted MRI for lung biopsy planning: initial experience.

BACKGROUND: The purpose of this study was to evaluate the usefulness of diffusion-weighted magnetic resonance imaging (DW-MRI) and positron emission tomography/computed tomography (PET/CT) in planning transthoracic CT-guided biopsies of lung lesions. METHODS: Thirteen patients with lung lesions suspicious for malignancy underwent CT-guided biopsy. Chest DW-MRI and apparent diffusion coefficient (ADC) calculation were performed to aid biopsy planning with fused images. MRI was indicated due to large heterogeneous masses, association with lung atelectasis/consolidation/necrosis, and/or divergent results of other biopsy type and histopathology versus clinical/radiological suspicion. Eight patients underwent PET/CT to identify appropriate areas for biopsy. RESULTS: Mean patient (n = 9 males) age was 59 (range, 30 to 78) years. Based on DW-MRI results, biopsies targeted the most suspicious areas within lesions. All biopsied areas showed higher DW signal intensity and lower ADCs (mean, 0.79 (range, 0.54 to 1.2) × 10(-3) mm2/s), suggesting high cellularity. In patients who underwent PET/CT, areas with higher 18-fluorodeoxyglucose concentrations (standard uptake value mean, 7.7 (range, 3.6 to 13.7)) corresponded to areas of higher DW signal intensity and lower ADCs. All biopsies yielded adequate material for histopathological diagnosis. CONCLUSIONS: Functional imaging is useful for lung biopsy planning. DW-MRI and PET/CT increase overall performance and enable the collection of adequate material for specific diagnosis.

Synthetic PET from CT improves diagnosis and prognosis for lung cancer: Proof of concept.

[18F]Fluorodeoxyglucose positron emission tomography (FDG-PET) and computed tomography (CT) are indispensable components in modern medicine. Although PET can provide additional diagnostic value, it is costly and not universally accessible, particularly in low-income countries. To bridge this gap, we have developed a conditional generative adversarial network pipeline that can produce FDG-PET from diagnostic CT scans based on multi-center multi-modal lung cancer datasets (n = 1,478). Synthetic PET images are validated across imaging, biological, and clinical aspects. Radiologists confirm comparable imaging quality and tumor contrast between synthetic and actual PET scans. Radiogenomics analysis further proves that the dysregulated cancer hallmark pathways of synthetic PET are consistent with actual PET. We also demonstrate the clinical values of synthetic PET in improving lung cancer diagnosis, staging, risk prediction, and prognosis. Taken together, this proof-of-concept study testifies to the feasibility of applying deep learning to obtain high-fidelity PET translated from CT.

Enhancing NSCLC recurrence prediction with PET/CT habitat imaging, ctDNA, and integrative radiogenomics-blood insights.

While we recognize the prognostic importance of clinicopathological measures and circulating tumor DNA (ctDNA), the independent contribution of quantitative image markers to prognosis in non-small cell lung cancer (NSCLC) remains underexplored. In our multi-institutional study of 394 NSCLC patients, we utilize pre-treatment computed tomography (CT) and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) to establish a habitat imaging framework for assessing regional heterogeneity within individual tumors. This framework identifies three PET/CT subtypes, which maintain prognostic value after adjusting for clinicopathologic risk factors including tumor volume. Additionally, these subtypes complement ctDNA in predicting disease recurrence. Radiogenomics analysis unveil the molecular underpinnings of these imaging subtypes, highlighting downregulation in interferon alpha and gamma pathways in the high-risk subtype. In summary, our study demonstrates that these habitat imaging subtypes effectively stratify NSCLC patients based on their risk levels for disease recurrence after initial curative surgery or radiotherapy, providing valuable insights for personalized treatment approaches.

Lung cancer screening: state of the art.

Results from the National Lung Screening Trial have confirmed that lung cancer mortality is reduced using low-dose CT screening. Opening a lung cancer screening program requires a multidisciplinary approach. While the fundamental aspects of a screening program are similar, such as scheduling, performing, and managing follow-up, there are aspects of a lung cancer screening program that are unique. This article will discuss factors important in establishing a state of the art lung cancer screening program.

Benefit of computer-aided detection analysis for the detection of subsolid and solid lung nodules on thin- and thick-section CT.

OBJECTIVE: The objective of our study was to evaluate the impact of computer-aided detection (CAD) on the identification of subsolid and solid lung nodules on thin- and thick-section CT. MATERIALS AND METHODS: For 46 chest CT examinations with ground-glass opacity (GGO) nodules, CAD marks computed using thin data were evaluated in two phases. First, four chest radiologists reviewed thin sections (reader(thin)) for nodules and subsequently CAD marks (reader(thin) + CAD(thin)). After 4 months, the same cases were reviewed on thick sections (reader(thick)) and subsequently with CAD marks (reader(thick) + CAD(thick)). Sensitivities were evaluated. Additionally, reader(thick) sensitivity with assessment of CAD marks on thin sections was estimated (reader(thick) + CAD(thin)). RESULTS: For 155 nodules (mean, 5.5 mm; range, 4.0-27.5 mm)-74 solid nodules, 22 part-solid (part-solid nodules), and 59 GGO nodules-CAD stand-alone sensitivity was 80%, 95%, and 71%, respectively, with three false-positives on average (0-12) per CT study. Reader(thin) + CAD(thin) sensitivities were higher than reader(thin) for solid nodules (82% vs 57%, p < 0.001), part-solid nodules (97% vs 81%, p = 0.0027), and GGO nodules (82% vs 69%, p < 0.001) for all readers (p < 0.001). Respective sensitivities for reader(thick), reader(thick) + CAD(thick), reader(thick) + CAD(thin) were 40%, 58% (p < 0.001), and 77% (p < 0.001) for solid nodules; 72%, 73% (p = 0.322), and 94% (p < 0.001) for part-solid nodules; and 53%, 58% (p = 0.008), and 79% (p < 0.001) for GGO nodules. For reader(thin), false-positives increased from 0.64 per case to 0.90 with CAD(thin) (p < 0.001) but not for reader(thick); false-positive rates were 1.17, 1.19, and 1.26 per case for reader(thick), reader(thick) + CAD(thick), and reader(thick) + CAD(thin), respectively. CONCLUSION: Detection of GGO nodules and solid nodules is significantly improved with CAD. When interpretation is performed on thick sections, the benefit is greater when CAD marks are reviewed on thin rather than thick sections.

Multimodality imaging evaluation of esophageal cancer: staging, therapy assessment, and complications.

Esophageal cancer is among the leading causes of cancer-related deaths worldwide. The management of patients with esophageal cancer is determined to a large extent by patient performance status, location of the primary cancer, and stage of disease at presentation. Multimodality regimens combining neoadjuvant chemotherapy and/or radiotherapy followed by surgery have been increasingly used in suitable candidates with locally advanced cancer. There is substantial morbidity and mortality associated with this treatment strategy, which makes appropriate patient selection important. Endoscopic esophageal ultrasound is the optimal modality to evaluate the local extent of the primary tumor and diagnose locoregional nodal metastasis. Computed tomography is more useful in detecting distant nodal and systemic metastasis. Positron emission tomography/CT is increasingly being used in patient management and improves the accuracy of staging, particularly in the detection of distant nodal and systemic metastatic disease. In this article, we review the role of imaging in the staging, assessment of therapeutic response, and detection of recurrent disease, as well as the evaluation of therapeutic complications in patients with esophageal cancer.

Heterogenous lung inflammation CT patterns distinguish pneumonia and immune checkpoint inhibitor pneumonitis and complement blood biomarkers in acute myeloid leukemia: proof of concept.

Background: Immune checkpoint inhibitors (ICI) may cause pneumonitis, resulting in potentially fatal lung inflammation. However, distinguishing pneumonitis from pneumonia is time-consuming and challenging. To fill this gap, we build an image-based tool, and further evaluate it clinically alongside relevant blood biomarkers. Materials and methods: We studied CT images from 97 patients with pneumonia and 29 patients with pneumonitis from acute myeloid leukemia treated with ICIs. We developed a CT-derived signature using a habitat imaging algorithm, whereby infected lungs are segregated into clusters ("habitats"). We validated the model and compared it with a clinical-blood model to determine whether imaging can add diagnostic value. Results: Habitat imaging revealed intrinsic lung inflammation patterns by identifying 5 distinct subregions, correlating to lung parenchyma, consolidation, heterogenous ground-glass opacity (GGO), and GGO-consolidation transition. Consequently, our proposed habitat model (accuracy of 79%, sensitivity of 48%, and specificity of 88%) outperformed the clinical-blood model (accuracy of 68%, sensitivity of 14%, and specificity of 85%) for classifying pneumonia versus pneumonitis. Integrating imaging and blood achieved the optimal performance (accuracy of 81%, sensitivity of 52% and specificity of 90%). Using this imaging-blood composite model, the post-test probability for detecting pneumonitis increased from 23% to 61%, significantly (p = 1.5E - 9) higher than the clinical and blood model (post-test probability of 22%). Conclusion: Habitat imaging represents a step forward in the image-based detection of pneumonia and pneumonitis, which can complement known blood biomarkers. Further work is needed to validate and fine tune this imaging-blood composite model and further improve its sensitivity to detect pneumonitis.

Neoadjuvant chemotherapy plus nivolumab with or without ipilimumab in operable non-small cell lung cancer: the phase 2 platform NEOSTAR trial.

Neoadjuvant ipilimumab + nivolumab (Ipi+Nivo) and nivolumab + chemotherapy (Nivo+CT) induce greater pathologic response rates than CT alone in patients with operable non-small cell lung cancer (NSCLC). The impact of adding ipilimumab to neoadjuvant Nivo+CT is unknown. Here we report the results and correlates of two arms of the phase 2 platform NEOSTAR trial testing neoadjuvant Nivo+CT and Ipi+Nivo+CT with major pathologic response (MPR) as the primary endpoint. MPR rates were 32.1% (7/22, 80% confidence interval (CI) 18.7-43.1%) in the Nivo+CT arm and 50% (11/22, 80% CI 34.6-61.1%) in the Ipi+Nivo+CT arm; the primary endpoint was met in both arms. In patients without known tumor EGFR/ALK alterations, MPR rates were 41.2% (7/17) and 62.5% (10/16) in the Nivo+CT and Ipi+Nivo+CT groups, respectively. No new safety signals were observed in either arm. Single-cell sequencing and multi-platform immune profiling (exploratory endpoints) underscored immune cell populations and phenotypes, including effector memory CD8+ T, B and myeloid cells and markers of tertiary lymphoid structures, that were preferentially increased in the Ipi+Nivo+CT cohort. Baseline fecal microbiota in patients with MPR were enriched with beneficial taxa, such as Akkermansia, and displayed reduced abundance of pro-inflammatory and pathogenic microbes. Neoadjuvant Ipi+Nivo+CT enhances pathologic responses and warrants further study in operable NSCLC. (ClinicalTrials.gov registration: NCT03158129 .).

Subsolid pulmonary nodules: imaging evaluation and strategic management.

PURPOSE OF REVIEW: Given the higher rate of malignancy of subsolid pulmonary nodules and the considerably lower growth rate of ground-glass nodules (GGNs), dedicated standardized guidelines for management of these nodules have been proposed, including long-term low-dose computed tomography (CT) follow-up (≥3 years). Physicians must be familiar with the strategic management of subsolid pulmonary nodules, and should be able to identify imaging features that suggest invasive adenocarcinoma requiring a more aggressive management. RECENT FINDINGS: Low-dose CT screening studies for early detection of lung cancer have increased our knowledge of pulmonary nodules, and in particular our understanding of the strong although imperfect correlation of the subsolid pulmonary nodules, including pure GGNs and part-solid nodules, with the spectrum of preinvasive to invasive lung adenocarcinoma. Serial CT imaging has shown stepwise progression in a subset of these nodules, characterized by increase in size and density of pure GGNs and development of a solid component, the latter usually indicating invasive adenocarcinoma. SUMMARY: There is close correlation between the CT features of subsolid nodules (SSNs) and the spectrum of lung adenocarcinoma. Standardized guidelines are suggested for management of SSNs.

Chest radiography in the ICU: Part 1, Evaluation of airway, enteric, and pleural tubes.

OBJECTIVE: In this pictorial essay, we discuss and illustrate normal and aberrant positioning of nonvascular support and monitoring devices frequently used in critically ill patients, including endotracheal and tracheostomy tubes, chest tubes, and nasogastric and nasoenteric tubes, as well as their inherent complications. CONCLUSION: The radiographic evaluation of the support and monitoring devices used in patients in the ICU is important because the potentially serious complications arising from their introduction and use are often not clinically apparent. Familiarity with normal and abnormal radiographic findings is critical for the detection of these complications.