CTLA4 blockade abrogates KEAP1/STK11-related resistance to PD-(L)1 inhibitors.

For patients with advanced non-small-cell lung cancer (NSCLC), dual immune checkpoint blockade (ICB) with CTLA4 inhibitors and PD-1 or PD-L1 inhibitors (hereafter, PD-(L)1 inhibitors) is associated with higher rates of anti-tumour activity and immune-related toxicities, when compared with treatment with PD-(L)1 inhibitors alone. However, there are currently no validated biomarkers to identify which patients will benefit from dual ICB1,2. Here we show that patients with NSCLC who have mutations in the STK11 and/or KEAP1 tumour suppressor genes derived clinical benefit from dual ICB with the PD-L1 inhibitor durvalumab and the CTLA4 inhibitor tremelimumab, but not from durvalumab alone, when added to chemotherapy in the randomized phase III POSEIDON trial3. Unbiased genetic screens identified loss of both of these tumour suppressor genes as independent drivers of resistance to PD-(L)1 inhibition, and showed that loss of Keap1 was the strongest genomic predictor of dual ICB efficacy-a finding that was confirmed in several mouse models of Kras-driven NSCLC. In both mouse models and patients, KEAP1 and STK11 alterations were associated with an adverse tumour microenvironment, which was characterized by a preponderance of suppressive myeloid cells and the depletion of CD8+ cytotoxic T cells, but relative sparing of CD4+ effector subsets. Dual ICB potently engaged CD4+ effector cells and reprogrammed the tumour myeloid cell compartment towards inducible nitric oxide synthase (iNOS)-expressing tumoricidal phenotypes that-together with CD4+ and CD8+ T cells-contributed to anti-tumour efficacy. These data support the use of chemo-immunotherapy with dual ICB to mitigate resistance to PD-(L)1 inhibition in patients with NSCLC who have STK11 and/or KEAP1 alterations.

Arsenic exposure is associated with elevated sweat chloride concentration and airflow obstruction among adults in Bangladesh: a cross sectional study.

Arsenic is associated with lung disease and experimental models suggest that arsenic-induced degradation of the chloride channel CFTR (cystic fibrosis transmembrane conductance regulator) is a mechanism of arsenic toxicity. We examined associations between arsenic exposure, sweat chloride concentration (measure of CFTR function), and pulmonary function among 285 adults in Bangladesh. Participants with sweat chloride ≥ 60 mmol/L had higher arsenic exposures than those with sweat chloride < 60 mmol/L (water: median 77.5 µg/L versus 34.0 µg/L, p = 0.025; toenails: median 4.8 µg/g versus 3.7 µg/g, p = 0.024). In linear regression models, a one-unit µg/g increment in toenail arsenic was associated with a 0.59 mmol/L higher sweat chloride concentration, p < 0.001. We found that toenail arsenic concentration was associated with increased odds of airway obstruction (OR: 1.97, 95%: 1.06, 3.67, p = 0.03); however, sweat chloride concentration did not mediate this association. Our findings suggest that sweat chloride concentration may be a novel biomarker for arsenic exposure and also that arsenic likely acts on the lung through mechanisms other than CFTR dysfunction.

The Potential Clinical Utility of an Artificial Intelligence Model for Identification of Vertebral Compression Fractures in Chest Radiographs.

PURPOSE: To assess the ability of the Annalise Enterprise CXR Triage Trauma (Annalise AI Pty Ltd, Sydney, NSW, Australia) artificial intelligence model to identify vertebral compression fractures on chest radiographs and its potential to address undiagnosed osteoporosis and its treatment. MATERIALS AND METHODS: This retrospective study used a consecutive cohort of 596 chest radiographs from four US hospitals between 2015 and 2021. Each radiograph included both frontal (anteroposterior or posteroanterior) and lateral projections. These radiographs were assessed for the presence of vertebral compression fracture in a consensus manner by up to three thoracic radiologists. The model then performed inference on the cases. A chart review was also performed for the presence of osteoporosis-related International Classification of Diseases, 10th revision diagnostic codes and medication use for the study period and an additional year of follow-up. RESULTS: The model successfully completed inference on 595 cases (99.8%); these cases included 272 positive cases and 323 negative cases. The model performed with area under the receiver operating characteristic curve of 0.955 (95% confidence interval [CI]: 0.939-0.968), sensitivity 89.3% (95% CI: 85.7%-92.7%) and specificity 89.2% (95% CI: 85.4%-92.3%). Out of the 236 true-positive cases (ie, correctly identified vertebral compression fractures by the model) with available chart information, only 86 (36.4%) had a diagnosis of vertebral compression fracture and 140 (59.3%) had a diagnosis of either osteoporosis or osteopenia; only 78 (33.1%) were receiving a disease-modifying medication for osteoporosis. CONCLUSION: The model identified vertebral compression fracture accurately with a sensitivity 89.3% (95% CI: 85.7%-92.7%) and specificity of 89.2% (95% CI: 85.4%-92.3%). Its automated use could help identify patients who have undiagnosed osteoporosis and who may benefit from taking disease-modifying medications.

Early Detection of Heart Failure with Autonomous AI-Based Model Using Chest Radiographs: A Multicenter Study.

The opportunistic use of radiological examinations for disease detection can potentially enable timely management. We assessed if an index created by an AI software to quantify chest radiography (CXR) findings associated with heart failure (HF) could distinguish between patients who would develop HF or not within a year of the examination. Our multicenter retrospective study included patients who underwent CXR without an HF diagnosis. We included 1117 patients (age 67.6 ± 13 years; m:f 487:630) that underwent CXR. A total of 413 patients had the CXR image taken within one year of their HF diagnosis. The rest (n = 704) were patients without an HF diagnosis after the examination date. All CXR images were processed with the model (qXR-HF, Qure.AI) to obtain information on cardiac silhouette, pleural effusion, and the index. We calculated the accuracy, sensitivity, specificity, and area under the curve (AUC) of the index to distinguish patients who developed HF within a year of the CXR and those who did not. We report an AUC of 0.798 (95%CI 0.77-0.82), accuracy of 0.73, sensitivity of 0.81, and specificity of 0.68 for the overall AI performance. AI AUCs by lead time to diagnosis (<3 months: 0.85; 4-6 months: 0.82; 7-9 months: 0.75; 10-12 months: 0.71), accuracy (0.68-0.72), and specificity (0.68) remained stable. Our results support the ongoing investigation efforts for opportunistic screening in radiology.

Clinical Intricacies and Advances in Neuroendocrine Tumors: An Organ-Based Multidisciplinary Approach.

ABSTRACT: Neuroendocrine neoplasms (NENs) are rare neoplasms originating from neuroendocrine cells, with increasing incidence due to enhanced detection methods. These tumors display considerable heterogeneity, necessitating diverse management strategies based on factors like organ of origin and tumor size. This article provides a comprehensive overview of therapeutic approaches for NENs, emphasizing the role of imaging in treatment decisions. It categorizes tumors based on their locations: gastric, duodenal, pancreatic, small bowel, colonic, rectal, appendiceal, gallbladder, prostate, lung, gynecological, and others. The piece also elucidates the challenges in managing metastatic disease and controversies surrounding MEN1-neuroendocrine tumor management. The article underscores the significance of individualized treatment plans, underscoring the need for a multidisciplinary approach to ensure optimal patient outcomes.

Efficacy and Safety of Dose-Escalated Alectinib in Patients With Metastatic ALK-Positive NSCLC and Central Nervous System Relapse on Standard-Dose Alectinib.

Introduction: Central nervous system (CNS) metastases remain a common challenge in patients with ALK-positive NSCLC. We previously reported reinduction of CNS responses using dose-intensified alectinib in two patients with CNS progression on standard-dose alectinib. Nevertheless, this strategy has not been assessed in larger cohorts. Methods: Patients were eligible for this retrospective study if they had metastatic ALK-positive NSCLC with CNS relapse on alectinib 600 mg twice daily dosing and subsequently received escalated dosing (900 mg twice daily) of alectinib. CNS efficacy was assessed per the modified Response Evaluation Criteria in Solid Tumors version 1.1. Results: Among 27 patients, median duration of dose-escalated alectinib was 7.7 months (95% confidence interval [CI]: 4.8-10.9), with median overall time-to-progression (TTP) of 7.1 months (95% CI: 4.4-9.6). Among 25 CNS response-assessable patients, CNS objective response rate was 12.0% (95% CI: 2.5-31.2) and CNS disease control rate was 92.0% (95% CI: 74.0-99.0), with median CNS duration of disease control of 5.3 months (95% CI: 3.4-8.3) and median CNS TTP of 7.1 months (95% CI: 4.4-9.6). Among four patients with measurable CNS disease at baseline, three experienced a best intracranial response of stable disease and one experienced intracranial partial response with CNS TTP ranging from 4.1 to 7.7 months. No patient required drug discontinuation due to treatment-related adverse event or experienced grade 3 or higher treatment-related adverse events. Conclusions: Dose-intensified alectinib was found to have tolerability and activity in patients with ALK-positive NSCLC who experienced CNS relapse on standard-dose alectinib and represents one clinically viable strategy for this population.

Correlation of Radiomics with Treatment Response in Liver Metastases.

RATIONALE AND OBJECTIVES: To assess differences in radiomics derived from semi-automatic segmentation of liver metastases for stable disease (SD), partial response (PR), and progressive disease (PD) based on RECIST1.1 and to assess if radiomics alone at baseline can predict response. MATERIALS AND METHODS: Our IRB-approved study included 203 women (mean age 54 ± 11 years) with metastatic liver disease from breast cancer. All patients underwent contrast abdomen-pelvis CT in the portal venous phase at two points: baseline (pre-treatment) and follow-up (between 3 and 12 months following treatment). Patients were subcategorized into three subgroups based on RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumors version 1.1): 66 with SD, 69 with PR, and 68 with PD on follow-up CT. The deidentified baseline and follow-up CT images were exported to the radiomics prototype. The prototype enabled semi-automatic segmentation of the target liver lesions for the extraction of first and high order radiomics. Statistical analyses with logistic regression and random forest classifiers were performed to differentiate SD from PD and PR. RESULTS: There was no significant difference between the radiomics on the baseline and follow-up CT images of patients with SD (area under the curve (AUC): 0.3). Random forest classifier differentiated patients with PR with an AUC of 0.845. The most relevant feature was the large dependence emphasis's high and low pass wavelet filter (derived gray level dependence matrix features). Random forest classifier differentiated PD with an AUC of 0.731, with the most relevant feature being the surface-to-volume ratio. There was no difference in radiomics among the three groups at baseline; therefore, a response could not be predicted. CONCLUSION: Radiomics of liver metastases with semi-automatic segmentation demonstrate differences between SD from PR and PD. SUMMARY STATEMENT: Semiautomatic segmentation and radiomics of metastatic liver disease demonstrate differences in SD from the PR and progressive metastatic on the baseline and follow-up CT. Despite substantial variations in the scanners, acquisition, and reconstruction parameters, radiomics had an AUC of 0.84-0.89 for differentiating stable hepatic metastases from decreasing and increasing metastatic disease.

Surgical Resection of Benign Nodules in Lung Cancer Screening: Incidence and Features.

Introduction: Interventions and surgical procedures are common for nonmalignant lung lesions detected on lung cancer screening (LCS). Inadvertent surgical resection of benign nodules with a clinical suspicion of lung cancer can occur, can be associated with complications, and adds to the cost of screening. The objective of this study is to assess the characteristics of surgically resected benign nodules detected on LCS computed tomography which were presumed to be lung cancers. Methods: This retrospective study included 4798 patients who underwent LCS between June 2014 and January 2021. The benign lung nodules, surgically resected with a presumed cancer diagnosis, were identified from the LCS registry. Patient demographics, imaging characteristics, and pathologic diagnoses of benign nodules were analyzed. Results: Of the 4798 patients who underwent LCS, 148 (3.1%) underwent surgical resection of a lung nodule, and of those who had a resection, 19 of 148 (12.8%) had a benign diagnosis (median age = 64 y, range: 56-77 y; F = 12 of 19, 63.2%; M = seven of 19, 36.8%). The median nodule size was 10 mm (range: 6-31 mm). Most nodules were solid (15 of 19, 78.9%), located in the upper lobes (11 of 19; 57.9%), and were peripheral (17 of 19, 89.5%). Most nodules (13 of 17; 76.5%) had interval growth, and four of 17 (23.5%) had increased fluorodeoxyglucose uptake. Of the 19 patients, 17 (89.5%) underwent sublobar resection (16 wedge resection and one segmentectomy), whereas two central nodules (10.5%) had lobectomies. Pathologies identified included focal areas of fibrosis or scarring (n = 8), necrotizing granulomatous inflammation (n = 3), other nonspecific inflammatory focus (n = 3), benign tumors (n = 3), reactive lymphoid hyperplasia (n = 1), and organizing pneumonia (n = 1). Conclusions: Surgical resections of benign nodules that were presumed malignant are infrequent and may be unavoidable given overlapping imaging features of benign and malignant nodules. Knowledge of benign pathologies that can mimic malignancy may help reduce the incidence of unnecessary surgeries.

Lorlatinib and capmatinib in a ROS1-rearranged NSCLC with MET-driven resistance: tumor response and evolution.

Acquired drug resistance remains a major problem across oncogene-addicted cancers. Elucidation of mechanisms of resistance can inform rational treatment strategies for patients relapsing on targeted therapies while offering insights into tumor evolution. Here, we report acquired MET amplification as a resistance driver in a ROS1-rearranged lung adenocarcinoma after sequential treatment with ROS1 inhibitors. Subsequent combination therapy with lorlatinib plus capmatinib, a MET-selective inhibitor, induced intracranial and extracranial tumor response. At relapse, sequencing of the resistant tumor revealed a MET D1246N mutation and loss of MET amplification. We performed integrated molecular analyses of serial tumor and plasma samples, unveiling dynamic alterations in the ROS1 fusion driver and MET bypass axis at genomic and protein levels and the emergence of polyclonal resistance. This case illustrates the complexity of longitudinal tumor evolution with sequential targeted therapies, highlighting challenges embedded in the current precision oncology paradigm and the importance of developing approaches that prevent resistance.

Dual-Energy Computed Tomography Applications in Lung Cancer.

This article examines the intrathoracic applications for dual-energy computed tomography (DECT), focusing on lung cancer. The topics covered include the image data sets, methods for iodine quantification, and clinical applications. The applications of DECT are to differentiate benign and malignant lung nodules, determining the grade of lung cancer and expression of ki-67 expression. Iodine quantification has role in assessment of treatment response in both the primary tumor and nodal metastases.

Impact of Baseline Interstitial Lung Abnormalities on Pneumonitis Risk in Patients Receiving Immune Checkpoint Inhibitors for Non-Small-Cell Lung Cancer.

INTRODUCTION/BACKGROUND: Immune-related pneumonitis is a potentially fatal complication of treatment with immune checkpoint inhibitors (ICIs). Interstitial lung disease (ILD) is associated with increased risk for pneumonitis, but the impact of interstitial abnormalities (ILA) in the absence of ILD has not been extensively assessed. We examined the relationship between ILA on pretreatment chest computed tomography (CT) scans and risk of pneumonitis in patients with non-small-cell lung cancer (NSCLC). METHODS: This retrospective cohort study included consecutive adult patients who received ICI for NSCLC between January 2013 and January 2020 at our institution. Two thoracic radiologists blinded to clinical outcomes independently reviewed pre-ICI chest CTs to identify and categorize ILA using previously published definitions. We used uni- and multivariable analysis adjusted for age, radiation, and smoking status to assess for associations between ILA, clinicopathologic characteristics, and symptomatic (CTCAE grade ≥2) pneumonitis. RESULTS: Of 475 patients who received ICI treatment and met inclusion criteria, baseline ILA were present in 78 (16.4%) patients, most commonly as a subpleural nonfibrotic pattern. In total, 43 (9.1%) of 475 patients developed symptomatic pneumonitis. Pneumonitis occurred in 16.7% of patients with ILA compared to 7.6% patients without ILA (P < .05). Presence of ground glass and extent of lung parenchymal involvement were associated with an increased risk of pneumonitis. On multivariable analysis, baseline ILA remained associated with increased risk of symptomatic pneumonitis (OR 2.2, 95% CI, 1.0-4.5). CONCLUSIONS: Baseline ILAs are associated with the development of symptomatic pneumonitis in patients with NSCLC treated with ICI. Additional studies are needed to validate these observations.

Extrathoracic Metastases in Pleural Mesothelioma.

Introduction: Guidelines recommend obtaining a computed tomography scan of the chest for the staging of pleural mesothelioma and for assessing response to treatment. Consensus is lacking regarding the necessity of serial imaging of distant extrathoracic sites. In this study, we determined the prevalence of extrathoracic metastases in patients with pleural mesothelioma. Methods: We conducted a retrospective review of patients with pleural mesothelioma treated at Massachusetts General Hospital between 1999 and 2022 who were referred for extrathoracic imaging during their disease course. Imaging reports were reviewed to determine sites of metastasis and calculate the time to development of extrathoracic metastasis. Overall survival and prevalence of extrathoracic metastasis were compared for patients with epithelioid versus nonepithelioid mesothelioma. Results: The study included 148 patients, 69 (47%) of whom had undergone cytoreductive surgery. Histologic types included epithelioid (n = 82, 55%), biphasic (n = 49, 33%), and sarcomatoid (n = 10, 7%) mesothelioma. The median overall survival for the cohort was 24.0 months, specifically 34.7 months and 16.7 months for patients with epithelioid and nonepithelioid tumors, respectively (p < 0.001). There were 65 (44%) patients who developed extrathoracic metastases, with a median time to extrathoracic metastasis of 11.5 months. The most common sites of involvement were extrathoracic nodes (22%), peritoneum (20%), bone (11%), and liver (11%). Of the 76 patients referred for brain imaging, seven (9%) had brain metastases. The frequency of extrathoracic metastasis was identical for epithelioid and nonepithelioid mesothelioma (44%). Overall survival was shorter for patients who developed extrathoracic metastases (hazard ratio 5.9, p < 0.001). Conclusions: Patients with pleural mesothelioma often develop extrathoracic metastases, providing a rationale for routinely obtaining imaging that encompasses sites outside of the thoracic cavity.

Efficacy and Tolerability of ALK/MET Combinations in Patients With ALK-Rearranged Lung Cancer With Acquired MET Amplification: A Retrospective Analysis.

Introduction: MET amplification is a potentially actionable resistance mechanism in ALK-rearranged (ALK+) lung cancer. Studies describing treatment outcomes of this molecular subgroup are lacking. Methods: We assembled a cohort of patients with ALK+ lung cancer and acquired MET amplification (identified by tissue or plasma) who received regimens targeting both ALK and MET. Efficacy and safety were assessed using the Response Evaluation Criteria in Solid Tumors version 1.1 and Common Terminology Criteria for Adverse Events version 4.03, respectively. Results: A total of 12 patients were included in the series. MET amplification was detected after a median of 1.5 (range 1-5) lines of therapy. Four distinct regimens were implemented to address MET amplification: crizotinib (n = 2), lorlatinib plus crizotinib (n = 6), alectinib plus capmatinib (n = 3), and alectinib plus crizotinib (n = 1). Partial responses were observed in five (42%) of 12 patients, including patients who received crizotinib (n = one of two), lorlatinib plus crizotinib (n = three of six), and alectinib plus capmatinib (n = one of three). Primary progression was observed in four patients (33%). Grades 1 to 2 peripheral edema, occurring in seven (58%) patients, was found with both crizotinib and capmatinib. One patient required dose reduction of capmatinib plus alectinib for persistent grade 2 edema. Across the regimens, one patient discontinued therapy for toxicity, specifically neurocognitive toxicity from lorlatinib plus crizotinib. At progression on ALK+ MET therapy, potential resistance mechanisms included MET copy number changes and ALK kinase domain mutations. Conclusions: Combined ALK and MET inhibition is associated with moderate antitumor activity in patients with ALK+ NSCLC with concurrent MET amplification. Prospective studies are indicated to confirm activity and identify individuals most likely to benefit from the treatment.

Integrated Radiology, Pathology, and Pharmacy Program to Accelerate Access to Osimertinib.

PURPOSE: Targeted therapy yields superior outcomes relative to genotype-agnostic therapy for patients with epidermal growth factor receptor (EGFR)-mutant lung cancer. Workflows that facilitate timely detection of EGFR mutations and early dispensation of osimertinib can improve management of this disease. METHODS: We developed an Integrated Radiology, Pathology, and Pharmacy Program to minimize delays in initiating osimertinib. The intervention consisted of parallel workflows coupling interventional radiology, surgical pathology, and analysis of nucleic acids from frozen tissue with early pharmacy engagement. We compared time to EGFR testing results and time to treatment for participating patients with those of historical cohorts. RESULTS: Between January 2020 and December 2021, 222 patients participated in the intervention. The median turnaround time from biopsy to EGFR results was 1 workday. Forty-nine (22%) tumors harbored EGFR exon 19 deletions or EGFR L858R. Thirty-one (63%) patients were prescribed osimertinib via the intervention. The median interval between osimertinib prescription and osimertinib dispensation was 3 days; dispensation occurred within 48 hours for 42% of patients. The median interval between biopsy and osimertinib dispensation was 5 days. Three patients received osimertinib within 24 hours of EGFR results. Compared with patients with EGFR-mutant non-small-cell lung cancer who were diagnosed through routine workflows, the intervention led to a significant reduction in median time between biopsy and EGFR results (1 v 7 days; P < .01) and median time to treatment initiation (5 v 23 days; P < .01). CONCLUSION: Combining radiology and pathology workflows with early parallel pharmacy engagement leads to a significant reduction in time to initiating osimertinib. Multidisciplinary integration programs are essential to maximize clinical utility of rapid testing.

Imaging in Lung Transplantation: Surgical Techniques and Complications.

Lung transplant is an established treatment for patients with end-stage lung disease. As a result, there is increased demand for transplants. Despite improvements in pretransplant evaluation, surgical techniques, and postsurgical care, the average posttransplant life expectancy is only around 6.5 years. Early recognition of complications on imaging and treatment can improve survival. Knowledge of surgical techniques and imaging findings of surgical and nonsurgical complications is essential. This review covers surgical techniques and imaging appearance of postsurgical and nonsurgical complications, including allograft dysfunction, infections, neoplasms, and recurrence of primary lung disease.

Low Contrast Volume Protocol in Routine Chest CT Amid the Global Contrast Shortage: A Single Institution Experience.

OBJECTIVE: To assess the effectiveness of low contrast volume (LCV) chest CT performed with multiple contrast agents on multivendor CT with varying scanning techniques. METHODS: The study included 361 patients (65 ± 15 years; M: F 173:188) who underwent LCV chest CT on one of the six 64-256 detector-row CT scanners using single-energy (SECT) or dual-energy (DECT) modes. All patients were scanned with either a fixed-LCV (LCVf, n = 103) or weight-based LCV (LCVw, n = 258) protocol. Two thoracic radiologists independently assessed all LCV CT and patients' prior standard contrast volume (SCV, n = 263) chest CT for optimality of contrast enhancement in thoracic vasculature, cardiac chambers, and in pleuro-parenchymal and mediastinal abnormalities. CT attenuations were recorded in the main pulmonary trunk, ascending, and descending thoracic aorta. To assess the interobserver agreement, pulmonary arterial enhancement was divided into two groups: optimal or suboptimal. RESULTS: There was no significant difference among patients' BMI (p = 0.883) in the three groups. DECT had a significantly higher aortic arterial enhancement (250 ± 99HU vs 228 ± 76 HU for SECT, p < 0.001). Optimal enhancement was present in 558 of 624 chest CT (89.4%), whereas 66 of 624 chest CT with suboptimal enhancement was noted in 48 of 258 LCVw (18.6%) and 14 of 103 LCVf (13.6%). Most patients with suboptimal enhancement with LCVw injection protocol were overweight/obese (30/48; 62.5%), (p < 0.001). CONCLUSION: LCV chest CT can be performed across complex multivendor, multicontrast media, multiscanner, and multiprotocol CT practices. However, LCV chest CT examinations can result in suboptimal contrast enhancement in patients with larger body habitus.

Radiologist-Trained AI Model for Identifying Suboptimal Chest-Radiographs.

RATIONALE AND OBJECTIVES: Suboptimal chest radiographs (CXR) can limit interpretation of critical findings. Radiologist-trained AI models were evaluated for differentiating suboptimal(sCXR) and optimal(oCXR) chest radiographs. MATERIALS AND METHODS: Our IRB-approved study included 3278 CXRs from adult patients (mean age 55 ± 20 years) identified from a retrospective search of CXR in radiology reports from 5 sites. A chest radiologist reviewed all CXRs for the cause of suboptimality. The de-identified CXRs were uploaded into an AI server application for training and testing 5 AI models. The training set consisted of 2202 CXRs (n = 807 oCXR; n = 1395 sCXR) while 1076 CXRs (n = 729 sCXR; n = 347 oCXR) were used for testing. Data were analyzed with the Area under the curve (AUC) for the model's ability to classify oCXR and sCXR correctly. RESULTS: For the two-class classification into sCXR or oCXR from all sites, for CXR with missing anatomy, AI had sensitivity, specificity, accuracy, and AUC of 78%, 95%, 91%, 0.87(95% CI 0.82-0.92), respectively. AI identified obscured thoracic anatomy with 91% sensitivity, 97% specificity, 95% accuracy, and 0.94 AUC (95% CI 0.90-0.97). Inadequate exposure with 90% sensitivity, 93% specificity, 92% accuracy, and AUC of 0.91 (95% CI 0.88-0.95). The presence of low lung volume was identified with 96% sensitivity, 92% specificity, 93% accuracy, and 0.94 AUC (95% CI 0.92-0.96). The sensitivity, specificity, accuracy, and AUC of AI in identifying patient rotation were 92%, 96%, 95%, and 0.94 (95% CI 0.91-0.98), respectively. CONCLUSION: The radiologist-trained AI models can accurately classify optimal and suboptimal CXRs. Such AI models at the front end of radiographic equipment can enable radiographers to repeat sCXRs when necessary.

Genomic and transcriptomic analysis of checkpoint blockade response in advanced non-small cell lung cancer.

Anti-PD-1/PD-L1 agents have transformed the treatment landscape of advanced non-small cell lung cancer (NSCLC). To expand our understanding of the molecular features underlying response to checkpoint inhibitors in NSCLC, we describe here the first joint analysis of the Stand Up To Cancer-Mark Foundation cohort, a resource of whole exome and/or RNA sequencing from 393 patients with NSCLC treated with anti-PD-(L)1 therapy, along with matched clinical response annotation. We identify a number of associations between molecular features and outcome, including (1) favorable (for example, ATM altered) and unfavorable (for example, TERT amplified) genomic subgroups, (2) a prominent association between expression of inducible components of the immunoproteasome and response and (3) a dedifferentiated tumor-intrinsic subtype with enhanced response to checkpoint blockade. Taken together, results from this cohort demonstrate the complexity of biological determinants underlying immunotherapy outcomes and reinforce the discovery potential of integrative analysis within large, well-curated, cancer-specific cohorts.

Comutations and KRASG12C Inhibitor Efficacy in Advanced NSCLC.

Molecular modifiers of KRASG12C inhibitor (KRASG12Ci) efficacy in advanced KRASG12C-mutant NSCLC are poorly defined. In a large unbiased clinicogenomic analysis of 424 patients with non-small cell lung cancer (NSCLC), we identified and validated coalterations in KEAP1, SMARCA4, and CDKN2A as major independent determinants of inferior clinical outcomes with KRASG12Ci monotherapy. Collectively, comutations in these three tumor suppressor genes segregated patients into distinct prognostic subgroups and captured ∼50% of those with early disease progression (progression-free survival ≤3 months) with KRASG12Ci. Pathway-level integration of less prevalent coalterations in functionally related genes nominated PI3K/AKT/MTOR pathway and additional baseline RAS gene alterations, including amplifications, as candidate drivers of inferior outcomes with KRASG12Ci, and revealed a possible association between defective DNA damage response/repair and improved KRASG12Ci efficacy. Our findings propose a framework for patient stratification and clinical outcome prediction in KRASG12C-mutant NSCLC that can inform rational selection and appropriate tailoring of emerging combination therapies. SIGNIFICANCE: In this work, we identify co-occurring genomic alterations in KEAP1, SMARCA4, and CDKN2A as independent determinants of poor clinical outcomes with KRASG12Ci monotherapy in advanced NSCLC, and we propose a framework for patient stratification and treatment personalization based on the comutational status of individual tumors. See related commentary by Heng et al., p. 1513. This article is highlighted in the In This Issue feature, p. 1501.