Imaging Primer on Chimeric Antigen Receptor T-Cell Therapy for Radiologists.

Chimeric antigen receptor (CAR) T-cell therapy is a recently approved breakthrough treatment that has become a new paradigm in treatment of recurrent or refractory B-cell lymphomas and pediatric or adult acute lymphoid leukemia. CAR T cells are a type of cellular immunotherapy that artificially enhances T cells to boost eradication of malignancy through activation of the native immune system. The CAR construct is a synthetically created functional cell receptor grafted onto previously harvested patient T cells, which bind to preselected tumor-associated antigens and thereby activate host immune signaling cascades to attack tumor cells. Advantages include a single treatment episode of 2-3 weeks and durable disease elimination, with remission rates of over 80%. Responses to therapy are more rapid than with conventional chemotherapy or immunotherapy, with intervening short-interval edema. CAR T-cell administration is associated with therapy-related toxic effects in a large percentage of patients, notably cytokine release syndrome, immune effect cell-associated neurotoxicity syndrome, and infections related to immunosuppression. Knowledge of the expected evolution of therapy response and potential adverse events in CAR T-cell therapy and correlation with the timeline of treatment are important to optimize patient care. Some toxic effects are radiologically evident, and familiarity with their imaging spectrum is key to avoiding misinterpretation. Other clinical toxic effects may be occult at imaging and are diagnosed on the basis of clinical assessment. Future directions for CAR T-cell therapy include new indications and expanded tumor targets, along with novel ways to capture T-cell activation with imaging. An invited commentary by Ramaiya and Smith is available online. Online supplemental material is available for this article. ©RSNA, 2022.

Habitat Imaging Biomarkers for Diagnosis and Prognosis in Cancer Patients Infected with COVID-19.

OBJECTIVES: Cancer patients have worse outcomes from the COVID-19 infection and greater need for ventilator support and elevated mortality rates than the general population. However, previous artificial intelligence (AI) studies focused on patients without cancer to develop diagnosis and severity prediction models. Little is known about how the AI models perform in cancer patients. In this study, we aim to develop a computational framework for COVID-19 diagnosis and severity prediction particularly in a cancer population and further compare it head-to-head to a general population. METHODS: We have enrolled multi-center international cohorts with 531 CT scans from 502 general patients and 420 CT scans from 414 cancer patients. In particular, the habitat imaging pipeline was developed to quantify the complex infection patterns by partitioning the whole lung regions into phenotypically different subregions. Subsequently, various machine learning models nested with feature selection were built for COVID-19 detection and severity prediction. RESULTS: These models showed almost perfect performance in COVID-19 infection diagnosis and predicting its severity during cross validation. Our analysis revealed that models built separately on the cancer population performed significantly better than those built on the general population and locked to test on the cancer population. This may be because of the significant difference among the habitat features across the two different cohorts. CONCLUSIONS: Taken together, our habitat imaging analysis as a proof-of-concept study has highlighted the unique radiologic features of cancer patients and demonstrated effectiveness of CT-based machine learning model in informing COVID-19 management in the cancer population.

Pembrolizumab with or without radiotherapy for metastatic non-small-cell lung cancer: a pooled analysis of two randomised trials.

BACKGROUND: Radiotherapy might augment systemic antitumoral responses to immunotherapy. In the PEMBRO-RT (phase 2) and MDACC (phase 1/2) trials, patients with metastatic non-small-cell lung cancer were randomly allocated immunotherapy (pembrolizumab) with or without radiotherapy. When the trials were analysed individually, a potential benefit was noted in the combination treatment arm. However, owing to the small sample size of each trial, differences in response rates and outcomes were not statistically significant but remained clinically notable. We therefore did a pooled analysis to infer whether radiotherapy improves responses to immunotherapy in patients with metastatic non-small-cell lung cancer. METHODS: Inclusion criteria for the PEMBRO-RT and MDACC trials were patients (aged ≥18 years) with metastatic non-small-cell lung cancer and at least one unirradiated lesion to monitor for out-of-field response. In the PEMBRO-RT trial, patients had previously received chemotherapy, whereas in the MDACC trial, patients could be either previously treated or newly diagnosed. Patients in both trials were immunotherapy-naive. In the PEMBRO-RT trial, patients were randomly assigned (1:1) and stratified by smoking status (<10 vs ≥10 pack-years). In the MDACC trial, patients were entered into one of two cohorts based on radiotherapy schedule feasibility and randomly assigned (1:1). Because of the nature of the intervention in the combination treatment arm, blinding to radiotherapy was not feasible in either trial. Pembrolizumab was administered intravenously (200 mg every 3 weeks) with or without radiotherapy in both trials. In the PEMBRO-RT trial, the first dose of pembrolizumab was given sequentially less than 1 week after the last dose of radiotherapy (24 Gy in three fractions), whereas in the MDACC trial, pembrolizumab was given concurrently with the first dose of radiotherapy (50 Gy in four fractions or 45 Gy in 15 fractions). Only unirradiated lesions were measured for response. The endpoints for this pooled analysis were best out-of-field (abscopal) response rate (ARR), best abscopal disease control rate (ACR), ARR at 12 weeks, ACR at 12 weeks, progression-free survival, and overall survival. The intention-to-treat populations from both trials were included in analyses. The PEMBRO-RT trial (NCT02492568) and the MDACC trial (NCT02444741) are registered with ClinicalTrials.gov. FINDINGS: Overall, 148 patients were included in the pooled analysis, 76 of whom had been assigned pembrolizumab and 72 who had been assigned pembrolizumab plus radiotherapy. Median follow-up for all patients was 33 months (IQR 32·4-33·6). 124 (84%) of 148 patients had non-squamous histological features and 111 (75%) had previously received chemotherapy. Baseline variables did not differ between treatment groups, including PD-L1 status and metastatic disease volume. The most frequently irradiated sites were lung metastases (28 of 72 [39%]), intrathoracic lymph nodes (15 of 72 [21%]), and lung primary disease (12 of 72 [17%]). Best ARR was 19·7% (15 of 76) with pembrolizumab versus 41·7% (30 of 72) with pembrolizumab plus radiotherapy (odds ratio [OR] 2·96, 95% CI 1·42-6·20; p=0·0039), and best ACR was 43·4% (33 of 76) with pembrolizumab versus 65·3% (47 of 72) with pembrolizumab plus radiotherapy (2·51, 1·28-4·91; p=0·0071). Median progression-free survival was 4·4 months (IQR 2·9-5·9) with pembrolizumab alone versus 9·0 months (6·8-11·2) with pembrolizumab plus radiotherapy (hazard ratio [HR] 0·67, 95% CI 0·45-0·99; p=0·045), and median overall survival was 8·7 months (6·4-11·0) with pembrolizumab versus 19·2 months (14·6-23·8) with pembrolizumab plus radiotherapy (0·67, 0·54-0·84; p=0·0004). No new safety concerns were noted in the pooled analysis. INTERPRETATION: Adding radiotherapy to pembrolizumab immunotherapy significantly increased responses and outcomes in patients with metastatic non-small-cell lung cancer. These results warrant validation in a randomised phase 3 trial. FUNDING: Merck Sharp & Dohme.

ACR Appropriateness Criteria® Occupational Lung Diseases.

Ordering the appropriate diagnostic imaging for occupational lung disease requires a firm understanding of the relationship between occupational exposure and expected lower respiratory track manifestation. Where particular inorganic dust exposures typically lead to nodular and interstitial lung disease, other occupational exposures may lead to isolated small airway obstruction. Certain workplace exposures, like asbestos, increase the risk of malignancy, but also produce pulmonary findings that mimic malignancy. This publication aims to delineate the common and special considerations associated with occupational lung disease to assist the ordering physician in selecting the most appropriate imaging study, while still stressing the importance of a multidisciplinary approach. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

ACR Appropriateness Criteria® Acute Respiratory Illness in Immunocompromised Patients.

The immunocompromised patient with an acute respiratory illness (ARI) may present with fever, chills, weight loss, cough, shortness of breath, or chest pain. The number of immunocompromised patients continues to rise with medical advances including solid organ and stem cell transplantation, chemotherapy, and immunomodulatory therapy, along with the continued presence of human immunodeficiency virus and acquired immunodeficiency syndrome. Given the myriad of pathogens that can infect immunocompromised individuals, identifying the specific organism or organisms causing the lung disease can be elusive. Moreover, immunocompromised patients often receive prophylactic or empiric antimicrobial therapy, further complicating diagnostic evaluation. Noninfectious causes for ARI should also be considered, including pulmonary edema, drug-induced lung disease, atelectasis, malignancy, radiation-induced lung disease, pulmonary hemorrhage, diffuse alveolar damage, organizing pneumonia, lung transplant rejection, and pulmonary thromboembolic disease. As many immunocompromised patients with ARI progress along a rapid and potentially fatal course, timely selection of appropriate imaging is of great importance in this setting. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking, or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

ACR Appropriateness Criteria® Noninvasive Clinical Staging of Primary Lung Cancer.

Lung cancer is the leading cause of cancer-related deaths in both men and women. The major risk factor for lung cancer is personal tobacco smoking, particularly for small-cell lung cancer (SCLC) and squamous cell lung cancers, but other significant risk factors include exposure to secondhand smoke, environmental radon, occupational exposures, and air pollution. Education and socioeconomic status affect both incidence and outcomes. Non-small-cell lung cancer (NSCLC), including adenocarcinoma, squamous cell carcinoma, and large cell carcinoma, comprises about 85% of lung cancers. SCLC accounts for approximately 13% to 15% of cases. Prognosis is directly related to stage at presentation. NSCLC is staged using the eighth edition of the tumor-node-metastasis (TNM) criteria of the American Joint Committee on Cancer. For SCLC the eighth edition of TNM staging is recommended to be used in conjunction with the modified Veterans Administration Lung Study Group classification system distinguishing limited stage from extensive stage SCLC. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

ACR Appropriateness Criteria® Acute Respiratory Illness in Immunocompetent Patients.

Acute respiratory illness, defined as cough, sputum production, chest pain, and/or dyspnea (with or without fever), is a major public health issue, accounting for millions of doctor office and emergency department visits every year. While most cases are due to self-limited viral infections, a significant number of cases are due to more serious respiratory infections where delay in diagnosis can lead to morbidity and mortality. Imaging plays a key role in the initial diagnosis and management of acute respiratory illness. This study reviews the current literature concerning the appropriate role of imaging in the diagnosis and management of the immunocompetent adult patient initially presenting with acute respiratory illness. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

ACR Appropriateness Criteria® Chronic Dyspnea-Noncardiovascular Origin.

Chronic dyspnea may result from a variety of disorders of cardiovascular, pulmonary, gastrointestinal, neuromuscular, systemic, and psychogenic etiology. This article discusses guidelines for the initial imaging of six variants for chronic dyspnea of noncardiovascular origin: (1) Chronic dyspnea of unclear etiology; (2) Chronic dyspnea with suspected chronic obstructive pulmonary disease; (3) Chronic dyspnea with suspected central airways disease; (4) Chronic dyspnea with suspected interstitial lung disease; (5) Chronic dyspnea with suspected disease of the pleura or chest wall; and (6) Chronic dyspnea with suspected diaphragm dysfunction. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

The epidemiology of lung cancer.

The incidence and mortality from lung cancer is decreasing in the US due to decades of public education and tobacco control policies, but are increasing elsewhere in the world related to the commencement of the tobacco epidemic in various countries and populations in the developing world. Individual cigarette smoking is by far the most common risk factor for lung carcinoma; other risks include passive smoke inhalation, residential radon, occupational exposures, infection and genetic susceptibility. The predominant disease burden currently falls on minority populations and socioeconomically disadvantaged people. In the US, the recent legalization of marijuana for recreational use in many states and the rapid growth of commercially available electronic nicotine delivery systems (ENDS) present challenges to public health for which little short term and no long term safety data is available.

Role of Dual-Energy Computed Tomography in Thoracic Oncology.

Dual-energy CT (DECT) is an emerging technology that has potential to enhance diagnostic performance and radiologists' confidence in the evaluation of thoracic malignancies. DECT clinical applications include characterization of solitary pulmonary nodule, lung masses and mediastinal tumors. DECT-derived iodine uptake quantification may assist in characterization of tumor differentiation and gene expression. The use DECT in oncology has potential to improve lung cancer staging, therapy planning, and assessment of response to therapy as well as detection of incidental pulmonary embolism.

Implications for high-precision dose radiation therapy planning or limited surgical resection after percutaneous computed tomography-guided lung nodule biopsy using a tract sealant.

PURPOSE: Precision radiation therapy such as stereotactic body radiation therapy and limited resection are being used more frequently to treat intrathoracic malignancies. Effective local control requires precise radiation target delineation or complete resection. Lung biopsy tracts (LBT) on computed tomography (CT) scans after the use of tract sealants can mimic malignant tract seeding (MTS) and it is unclear whether these LBTs should be included in the calculated tumor volume or resected. This study evaluates the incidence, appearance, evolution, and malignant seeding of LBTs. METHODS AND MATERIALS: A total of 406 lung biopsies were performed in oncology patients using a tract sealant over 19 months. Of these patients, 326 had follow-up CT scans and were included in the study group. Four thoracic radiologists retrospectively analyzed the imaging, and a pathologist examined 10 resected LBTs. RESULTS: A total of 234 of 326 biopsies (72%, including primary lung cancer [n = 98]; metastases [n = 81]; benign [n = 50]; and nondiagnostic [n = 5]) showed an LBT on CT. LBTs were identified on imaging 0 to 3 months after biopsy. LBTs were typically straight or serpiginous with a thickness of 2 to 5 mm. Most LBTs were unchanged (92%) or decreased (6.3%) over time. An increase in LBT thickness/nodularity that was suspicious for MTS occurred in 4 of 234 biopsies (1.7%). MTS only occurred after biopsy of metastases from extrathoracic malignancies, and none occurred in patients with lung cancer. CONCLUSIONS: LBTs are common on CT after lung biopsy using a tract sealant. MTS is uncommon and only occurred in patients with extrathoracic malignancies. No MTS was found in patients with primary lung cancer. Accordingly, potential alteration in planned therapy should be considered only in patients with LBTs and extrathoracic malignancies being considered for stereotactic body radiation therapy or wedge resection.

Postoperative Imaging and Complications in Resection of Lung Cancer.

Surgical resection offers the best hope of cure for patients with operable early-stage lung cancer. Wedge resection, segmentectomy, lobectomy, or pneumonectomy may be performed depending on the size and location of the tumor. Radiologists must be familiar with the types of surgical resection utilized in the treatment of lung carcinoma and with their normal and abnormal postsurgical appearance on imaging studies. Prompt identification of postoperative complications on imaging is essential to appropriate patient management and helps to determine when additional intervention is warranted.

Imaging on Lung Cancer and Treatment with Targeted Therapy.

The identification of genetic mutations known as oncogenic driver mutations that lead to the growth and survival of cancer cells has been an important advance in the field of oncology. Treatment in advanced non-small-cell lung cancer (NSCLC) has transitioned from a more general approach to a more personalized approach based on genetic mutations of the cancer itself. Common mutations detected in patients with advanced NSCLC include mutations of epidermal growth factor receptor and anaplastic lymphoma kinase (ALK). Targeted therapies are aimed at the products of these gene mutations and include erlotinib (used in epidermal growth factor receptor mutant NSCLC) and crizotinib (used in anaplastic lymphoma kinase positive NSCLC). In this review, we discuss common genetic mutations in advanced NSCLC, the role of targeted therapies, and imaging findings that can be associated with various genetic mutations.

Pulmonary Nodule Management in Lung Cancer Screening: A Pictorial Review of Lung-RADS Version 1.0.

The number of screening-detected lung nodules is expected to increase as low-dose computed tomography screening is implemented nationally. Standardized guidelines for image acquisition, interpretation, and screen-detected nodule workup are essential to ensure a high standard of medical care and that lung cancer screening is implemented safely and cost effectively. In this article, we review the current guidelines for pulmonary nodule management in the lung cancer screening setting.

Missed Lung Cancer.

The chest radiograph is one of the most commonly used imaging studies and is the modality of choice for initial evaluation of many common clinical scenarios. Over the last two decades, chest computed tomography has been increasingly used for a wide variety of indications, including respiratory illnesses, trauma, oncologic staging, and more recently lung cancer screening. Diagnostic radiologists should be familiar with the common causes of missed lung cancers on imaging studies in order to avoid detection and interpretation errors. Failure to detect these lesions can potentially have serious implications for both patients as well as the interpreting radiologist.

Targeted Therapy and Immunotherapy in the Treatment of Non-Small Cell Lung Cancer.

The treatment strategy in advanced non-small cell lung cancer (NSCLC) has evolved from empirical chemotherapy to a personalized approach based on histology and molecular markers of primary tumors. Targeted therapies are directed at the products of oncogenic driver mutations. Immunotherapy facilitates the recognition of cancer as foreign by the host immune system, stimulates the immune system, and alleviates the inhibition that allows the growth and spread of cancer cells. The authors describes the role of targeted therapy and immunotherapy in the treatment of NSCLC, patterns of disease present on imaging studies, and immune-related adverse events encountered with immunotherapy.

Revisions to the TNM Staging of Lung Cancer: Rationale, Significance, and Clinical Application.

Lung cancer remains the leading cause of cancer-related mortality worldwide. To formulate effective treatment strategies and optimize patient outcomes, accurate staging is essential. Lung cancer staging has traditionally relied on a TNM staging system, for which the International Association for the Study of Lung Cancer (IASLC) has recently proposed changes. The revised classification for this eighth edition of the TNM staging system (TNM-8) is based on detailed analysis of a new large international database of lung cancer cases assembled by the IASLC for the purposes of this project. Fundamental changes incorporated into TNM-8 include (a) modifications to the T classification on the basis of 1-cm increments in tumor size; (b) grouping of lung cancers that result in partial or complete lung atelectasis or pneumonitis; (c) grouping of tumors with involvement of a main bronchus irrespective of distance from the carina; (d) reassignment of diaphragmatic invasion in terms of T classification; (e) elimination of mediastinal pleural invasion from the T classification; and (f) subdivision of the M classification into different descriptors on the basis of the number and site of extrathoracic metastases. In response to these revisions, established stage groups have been modified, and others have been created. In addition, recommendations for classifying patterns of disease that result in multiple sites of pulmonary involvement, including multiple primary lung cancers, lung cancers with separate tumor nodules, multiple ground-glass/lepidic lesions, and consolidation, as well as recommendations for lesion measurement, are addressed. Understanding the key revisions introduced in TNM-8 allows radiologists to accurately stage patients with lung cancer and optimize therapy. ©RSNA, 2018.

Imaging of Metastases in the Chest: Mechanisms of Spread and Potential Pitfalls.

Pulmonary and pleural metastases are routinely identified on thoracic computed tomography. Pulmonary metastases are the most common pulmonary neoplasms and commonly originate from primary malignancies of the lung, breast, colon, pancreas, stomach, skin (ie, melanoma), head and neck, and kidney. Metastatic disease to the lungs may occur via 3 routes of spread: hematogenous, lymphatic, and endobronchial. Pleural metastases most commonly originate from primary malignancies of the lung and breast. Mechanisms of pleural metastatic involvement include hematogenous spread, direct invasion from a neighboring tumor, and retrograde lymphatic spread from the mediastinum. Awareness of the spectrum of appearances of metatastic disease in the chest is important in avoiding misinterpretation.

Immunotherapy in Non-Small Cell Lung Cancer Treatment: Current Status and the Role of Imaging.

Lung cancer remains the leading cause of cancer-related mortality and is responsible for more deaths than breast, prostate, and colon cancer combined. Most patients are diagnosed with advanced disease at the time of presentation, and treatment options have traditionally included surgery, chemotherapy, and/or radiation. However, significant advances in the molecular characterization of lung cancer have led to the creation of effective immunotherapies that assist in the recognition of cancer as foreign by the host immune system, stimulate the immune system, and relieve the inhibition that allows tumor growth and spread. Extensive experience with the immunomodulatory monoclonal antibody ipilimumab has demonstrated that unique responses may be seen with immunotherapies that are not adequately captured by traditional response criteria such as the World Health Organization criteria and Response Evaluation Criteria in Solid Tumors (RECIST). Consequently, several modified criteria have been developed to evaluate patients treated with immunotherapy, including immune-related response criteria, immune-related RECIST, and immune RECIST. Finally, patients undergoing immunotherapy may develop a wide variety of immune-related adverse events with which the radiologist must be familiar. In this article, we present the fundamental concepts behind immunotherapy, specific agents currently approved for the treatment of lung cancer, and immune-related adverse events. The role of imaging in the evaluation of these patients will also be discussed, including the general principles of treatment response evaluation, specific response criteria adopted with these agents, including immune-related response criteria, immune-related RECIST, and immune RECIST, and the imaging of immune-related adverse events.