We conducted a cross-sectional, multicenter study to compare the demographics, clinical characteristics, and lung cancer screening results among individuals eligible for lung cancer screening per 2013 vs 2021 US Preventive Services Task Force recommendations. Statistical tests are 2 sided, with P less than  .05 considered statistically significant. Among 17 702 screened individuals (85.2% 2013 eligible, 14.8% 2021 newly eligible), a higher proportion of individuals screened per 2021 vs 2013 criteria were female (56.1% vs 48.1%, P < .001) and non-Hispanic Black (19.3% vs 13.4%, P < .001). The risk of developing and dying from lung cancer per 1000 people was statistically significantly higher among individuals eligible per 2013 vs 2021 criteria. A higher proportion of lung cancer screening exams had an increased suspicion of lung cancer in the 2013 vs 2021 criteria groups. Our data suggest that, as intended, updated 2021 US Preventive Services Task Force recommendations are leading to a higher proportion of lung cancer screening exams among non-Hispanic Black individuals and women.

PURPOSE: Increasing use of chest computed tomography has increased detection rates of small lung nodules.Minimally invasive thoracic surgery (MITS, including video-and robotic assisted thoracic surgery; VATS and RATS), allows surgeons to provide curative surgery with less morbidity than open thoracotomy.Despite this, the use of MITS in the resection of small nodules remains a challenge due to an inability to localize nodule targets, particularly those that are sub-solid and/or deep to the visceral pleura.This inability to localize target lesions for resection can lead to unplanned lobar resections or conversion to open thoracotomy.Perioperative nodule dye localization can help address these limitations, allowing for surgeons to resect nodules with less reliance on tactile feedback.We report nodule, patient, and surgical characteristics of localized versus non-localized resection targets during MITS in a single academic medical center.METHODS: A retrospective chart review was performed on all MITS cases from May 2016 to December 2021 at a single center.A total of 192 cases met study inclusion criteria.Patients with perioperative nodule localization all underwent electromagnetic guided transthoracic needle localization (Veran Medical Technologies, St. Louis, MO) with injection of a 1:1 ratio combination of methylene blue and the patient's own blood.Data was extracted based on patient imaging, test results, and physician documentation, including operative notes. RESULTS:Of the 192 cases identified, 71 were localized (21 VATS, 39 RATS) and 121 were not (79 VATS and 45 RATS).There was no statistical difference in overall nodule size in localized or non-localized cases (13.1 vs 14.1mm respectively, p¼0.26), though for RATS, localization was associated with significantly smaller nodules (14.1mm vs 16.8, p¼0.03).Localized nodules were more likely to be non-solid in both RATS and VATS cases (34% vs 12%, p¼0.0004) and have a longer distance from pleura to proximal edge of nodule (mean of 11.4mm vs 8.2mm respectively, p¼0.03).All other outcomes, including length of inpatient stay, volume of tissue resected, rate of conversion to thoracotomy and failure of localization, did now show statistical difference between localized and non-localized groups.CONCLUSIONS: Localized nodules were deeper in the parenchyma and less likely to be solid.Despite these limitations, outcomes were similar between groups, even for RATS where haptic feedback is particularly impaired.CLINICAL IMPLICATIONS: MITS resection for deeper and less solid nodules may be facilitated with dye localization.Prospective randomized studies are needed to confirm this association and the utility of localization for sub-lobar resection.

Study Design. A laboratory study comparing polyether ether ketone (PEEK)-zeolite and PEEK spinal implants in an ovine model. Objective. This study challenges a conventional spinal implant material, PEEK, to PEEK-zeolite using a nonplated cervical ovine model. Summary of Background Data. Although widely used for spinal implants due to its material properties, PEEK is hydrophobic, resulting in poor osseointegration, and elicits a mild nonspecific foreign body response. Zeolites are negatively charged aluminosilicate materials that are hypothesized to reduce this pro-inflammatory response when used as a compounding material with PEEK. Materials and Methods. Fourteen skeletally mature sheep were, each, implanted with one PEEK-zeolite interbody device and one PEEK interbody device. Both devices were packed with autograft and allograft material and randomly assigned to one of 2 cervical disc levels. The study involved 2 survival time points (12 and 26 weeks) and biomechanical, radiographic, and immunologic endpoints. One sheep expired from complications not related to the device or procedure. A biomechanical evaluation was based on measures of segmental flexibility, using 6 degrees of freedom pneumatic spine tester. Radiographic evaluation was performed using microcomputed tomography scans in a blinded manner by 3 physicians. Levels of the pro-inflammatory cytokines, interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha at the implant, were quantified using immunohistochemistry. Results. PEEK-zeolite and PEEK exhibited an equivalent range of motion in flexion extension, lateral bending, and axial torsion. A motion was significantly reduced for implanted devices at both time points as compared with native segments. Radiographic assessments of fusion and bone formation were similar for both devices. PEEK-zeolite exhibited lower levels of IL-1β (P = 0.0003) and IL-6 (P = 0.03). Conclusion. PEEK-zeolite interbody fusion devices provide initial fixation substantially equivalent to PEEK implants but exhibit a reduced pro-inflammatory response. PEEK-zeolite devices may reduce the chronic inflammation and fibrosis previously observed with PEEK devices.

Background: Esophageal perforation (EP) is a life-threatening emergency requiring emergent surgical intervention. Little is known about potential racial-ethnic disparities among patients with EP.Methods: Hospitalizations of adult (>= 18 years old) patients admitted with a diagnosis of EP were identified in the 2000-2017 National Inpatient Sample (NIS). Multivariable Cox proportional hazards regression was used to estimate the association between race-ethnicity and inpatient mortality. Inpatient complications were assessed using multivariable logistic regression.Results: There were an estimated 36,531 EP hospitalizations from 2000-2017. One quarter of hospitalizations were racial or ethnic minorities. Non-Hispanic (NH) White patients were, on average, older (median age 58 vs. 41 and 47 years, respectively, P<0.0001). The rate of EP admissions, per 1,000,000 the United States (US) adults, significantly increased among all groups over time. In-hospital mortality decreased for both NH White and NH Black patients (10.2% to 4.6% and 8.3% to 4.9%, respectively, P<0.0001) but increased for Hispanic patients and patients of other races (2.9% to 4.7% and 3.4% to 6.9%, P<0.0001). NH Black patients were more likely to have sepsis during their hospital course [odds ratio (OR) =1.34; 95% confidence interval (CI): 1.08 to 1.66], and patients of other races (OR =1.44; 95% CI: 1.01 to 2.07) were more likely to have pneumonia. Similar rates of surgical intervention were seen among all racialethic groups. After adjustment, inpatient mortality did not differ among racial-ethnic groups.Conclusions: Rates of EP admissions have increased for all racial-ethnic groups since 2000. Despite similar incidences of inpatient mortality across groups, NH Black and other race patients were more likely to experience postoperative complications, suggesting potential racial-ethnic disparities in quality or access to care.

Supplemental Figure 4. Prognostic value of STK11 status relative to transcriptional subtype.

This cohort study evaluates associations of communication methods and content of positive lung cancer screening findings with receipt of recommended follow-up care.

Supplementary methods, supplementary figures and tables

Supplemental Figure 1. Subtype identification in early/advanced LUAD.

Abstract Exon 20 genomic insertions of both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) are oncogenic drivers and are most commonly found in non-small cell lung cancer (NSCLC). NSCLC patients with exon 20 insertions have a worse prognosis compared to those with other activating EGFR mutations. Moreover, approximately one-third of patients with exon 20 insertion mutations develop central nervous system (CNS) metastases over the course of their disease. Unfortunately, current therapeutics lack sufficient brain exposure for treating this patient population. ORIC-114 is a brain penetrant, orally bioavailable, irreversible small molecule inhibitor designed to target exon 20 insertions in EGFR and HER2. Notably, ORIC-114 is highly selective for the EGFR family of receptors, with excellent kinome selectivity compared to other reported exon 20 inhibitors, reducing the risk of off-target kinase liabilities. The superior brain penetration and free unbound exposure of ORIC-114 in preclinical studies also differentiates it from comparator EGFR and HER2 exon 20 targeted agents. To further characterize ORIC-114, in vivo studies were undertaken to assess activity in both subcutaneous and intracranial NSCLC tumor patient-derived xenograft (PDX) models. Consistent with in vitro potency and selectivity, once daily oral administration of 3 mg/kg ORIC-114 induced robust tumor regressions with greater than 100% tumor growth inhibition in the absence of significant body weight loss in an EGFR exon 20 insertion H773_V774insNPH NSCLC PDX model. In this subcutaneous model, ORIC-114 was superior to CLN-081 in efficacy and tolerability, and superior to BDTX-189 in efficacy. To investigate whether the brain-penetrant attributes of ORIC-114 translated into antitumor activity in the CNS, we utilized an intracranial PC-9 luciferase-labeled EGFR del 19 mutant cell line model. Once daily oral administration of ORIC-114 significantly regressed established intracranial NSCLC tumors and demonstrated greater efficacy than TAK-788, commensurate with the superior brain exposure of ORIC-114. We further explored dosing regimens in this intracranial model and found that ORIC-114 demonstrated equivalent regressions at 1.5 mg/kg twice daily and 3 mg/kg once daily, and strong efficacy with 1.5 mg/kg once daily dosing. Taken together, these data confirm ORIC-114 as a potent, selective, irreversible, brain penetrant exon 20 inhibitor, and a promising therapeutic candidate, including for patients with CNS metastases. Based upon these data, ORIC-114 is entering a Phase 1/1b clinical trial in genetically defined cancers. Citation Format: Jason E. Long, Soochan Kim, Ha Yeong Kim, Dong Guk Shin, Dong Hyun Park, Robert Warne, Akash Das, Ganapati Hegde, Padmini Narayanan, Lidia Sambucetti, Brenda Chan, Xi Chen, Jae H. Chang, Paul Gibbons, Jessica Sun, Matthew Panuwat, Lori S. Friedman, Melissa R. Junttila. ORIC-114, an orally bioavailable, irreversible kinase inhibitor, has superior brain penetration and antitumor activity in subcutaneous and intracranial NSCLC models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3335.

FOR RELATED ARTICLE, SEE PAGE 475Aside from tobacco prevention and cessation, lung cancer screening (LCS) has the potential to be the single most important intervention to reduce lung cancer deaths due to shifting the stage at diagnosis to earlier, curable stages.1Aberle D.R. Adams A.M. et al.National Lung Screening Trial Research TeamReduced lung-cancer mortality with low-dose computed tomographic screening.N Engl J Med. 2011; 365: 395-409Crossref PubMed Scopus (6735) Google Scholar However, because clinical trials generally suffer from a healthy volunteer bias, questions remain regarding the generalizability of LCS in a real-world setting. The general population currently eligible for LCS is older, less educated, less racially diverse, and has more comorbidities than the National Lung Screening Trial (NLST) population.1Aberle D.R. Adams A.M. et al.National Lung Screening Trial Research TeamReduced lung-cancer mortality with low-dose computed tomographic screening.N Engl J Med. 2011; 365: 395-409Crossref PubMed Scopus (6735) Google Scholar,2Howard D.H. Richards T.B. Bach P.B. Kegler M.C. Berg C.J. Comorbidities, smoking status, and life expectancy among individuals eligible for lung cancer screening.Cancer. 2015; 121: 4341-4347Crossref PubMed Scopus (49) Google Scholar Furthermore, most patients were treated in tertiary hospitals with expertise in lung cancer care. An equally important concern centers on the potential risk of procedural complications, particularly in individuals with underlying comorbidities.2Howard D.H. Richards T.B. Bach P.B. Kegler M.C. Berg C.J. Comorbidities, smoking status, and life expectancy among individuals eligible for lung cancer screening.Cancer. 2015; 121: 4341-4347Crossref PubMed Scopus (49) Google Scholar In this issue of CHEST, Nuñez et al3Nuñez E.R. Caverly T.J. Zhang S. et al.Invasive procedures and associated complications following initial lung cancer screening in a national cohort of veterans.Chest. 2022; 162: 475-484Abstract Full Text Full Text PDF Scopus (1) Google Scholar report on major and intermediate complications within 10 days of an invasive procedure in a retrospective analysis of 82,641 veterans who underwent LCS from 2013 to 2019. Invasive procedures included transthoracic needle biopsy, bronchoscopy, thoracic surgery, and mediastinoscopy. The patients studied were more medically complex than those in the NLST, with higher rates of COPD (33.2% vs 17.5%), heart disease (16.6% vs 12.9%), stroke (4.1% vs 2.8%), and interstitial lung disease (1.6% vs 0.3%).3Nuñez E.R. Caverly T.J. Zhang S. et al.Invasive procedures and associated complications following initial lung cancer screening in a national cohort of veterans.Chest. 2022; 162: 475-484Abstract Full Text Full Text PDF Scopus (1) Google Scholar,4Aberle D.R. Adams A.M. et al.National Lung Screening Trial Research TeamBaseline characteristics of participants in the randomized National Lung Screening Trial.J Natl Cancer Inst. 2010; 102: 1771-1779Crossref PubMed Scopus (239) Google Scholar Although the procedural rate was one-half that of the NLST (2.1% vs 4.2%), the overall major or intermediate complication rate per number of patients who underwent a procedure was similar (19.1% vs 18.9%, respectively). The authors implied that the lower procedure rates in their study suggest that comorbid diseases may play a role in patient selection for downstream interventions following LCS, noting a lack of association between COPD and complication rate (OR, 1.17). This is in contrast to a subset analysis of the NLST showing that at the individual patient level, patients with self-reported COPD had nearly twice the rate of invasive procedures and complications compared with those without self-reported COPD (6% vs 3.8% and 1.5% vs 0.7%), while also having a significantly higher incidence of lung cancer (6.3% vs 3.6%).5Iaccarino J.M. Silvestri G.A. Wiener R.S. Patient-level trajectories and outcomes after low-dose CT screening in the National Lung Screening Trial.Chest. 2019; 156: 965-971Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar The lower procedural rate is also in contrast to a retrospective study of 11,520 commercially insured individuals undergoing diagnostic procedures for screen-detected nodules. Although the population was similarly more medically complex than the NLST cohort (54.8% vs 29.5% with two or more comorbidities), the rate of procedures (biopsy, bronchoscopy, and thoracoscopy) was 58% to 210% higher than in the NLST.1Aberle D.R. Adams A.M. et al.National Lung Screening Trial Research TeamReduced lung-cancer mortality with low-dose computed tomographic screening.N Engl J Med. 2011; 365: 395-409Crossref PubMed Scopus (6735) Google Scholar,6Nishi S.P.E. Zhou J. Okereke I. Kuo Y.F. Goodwin J. Use of imaging and diagnostic procedures after low-dose CT screening for lung cancer.Chest. 2020; 157: 427-434Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar Interpreting the findings of lower procedure rates reported by Nuñez et al3Nuñez E.R. Caverly T.J. Zhang S. et al.Invasive procedures and associated complications following initial lung cancer screening in a national cohort of veterans.Chest. 2022; 162: 475-484Abstract Full Text Full Text PDF Scopus (1) Google Scholar is challenging without knowing the rate of positive LCS examinations in their study. Lower procedure rates raise the possibility that some patients are not being offered appropriate diagnostic procedures for screen-detected nodules. Alternatively, clinicians may be more comfortable with managing screen-detected nodules in the decade since the publication of the NLST and offering noninvasive imaging follow-up for less concerning nodules. Nuñez et al3Nuñez E.R. Caverly T.J. Zhang S. et al.Invasive procedures and associated complications following initial lung cancer screening in a national cohort of veterans.Chest. 2022; 162: 475-484Abstract Full Text Full Text PDF Scopus (1) Google Scholar point out that thoracic surgery had the highest frequency of major and intermediate complications (11.1% and 28.1%, respectively, compared with 11.9% and 14% in the NLST) with an OR of 7.7 for any complication on multivariate analysis. The overall complication rate of 39.2% is higher than for either video-assisted thoracoscopic surgery (VATS) or thoracotomy reported in a previous meta-analysis showing overall complication rates of 16.4% and 31.2%, respectively.7Whitson B.A. Groth S.S. Duval S.J. Swanson S.J. Maddaus M.A. Surgery for early-stage non-small cell lung cancer: a systematic review of the video-assisted thoracoscopic surgery versus thoracotomy approaches to lobectomy.Ann Thorac Surg. 2008; 86: 2008-2016Abstract Full Text Full Text PDF PubMed Scopus (501) Google Scholar Furthermore, the rate of major complications from mediastinoscopy was much higher (9.1%)3Nuñez E.R. Caverly T.J. Zhang S. et al.Invasive procedures and associated complications following initial lung cancer screening in a national cohort of veterans.Chest. 2022; 162: 475-484Abstract Full Text Full Text PDF Scopus (1) Google Scholar than the 0.4% rate previously reported.8Verdial F.C. Berfield K.S. Wood D.E. et al.Safety and costs of endobronchial ultrasound-guided nodal aspiration and mediastinoscopy.Chest. 2020; 157: 686-693Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar Although it is difficult to generalize to the entire Veterans Integrated Health System, higher complication rates for lung cancer surgery have previously been reported among veterans. Comparing lobectomy by muscle-sparing thoracotomy performed at an academic medical center vs a Veterans Affairs Medical Center by the same surgeon revealed a complication rate of 30.9% vs 44.4%, respectively.9Geraci T. Baratta V. Young J. et al.Lobectomy for lung cancer at Veterans Administration Medical Center versus academic medical center.Ann Thorac Surg. 2017; 103: 1715-1722Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar The difference was attributed to differences in perioperative care and rates of postoperative pneumonia. It is also challenging to interpret the higher surgical complication rates reported by Nuñez et al3Nuñez E.R. Caverly T.J. Zhang S. et al.Invasive procedures and associated complications following initial lung cancer screening in a national cohort of veterans.Chest. 2022; 162: 475-484Abstract Full Text Full Text PDF Scopus (1) Google Scholar without knowing which surgical procedures were performed. In a retrospective Surveillance, Epidemiology, and End Results (SEER) registry of > 9,000 patients aged > 65 years undergoing surgery for stage I to II lung cancer between 2000 and 2009, VATS was associated with a reduced risk of cardiovascular (OR, 0.68) and thromboembolic (OR, 0.60) complications, transfusion requirements (OR, 0.57), extrapulmonary infections (OR, 0.71), and shorter length of hospital stay (OR, 0.49). These associations held for VATS when adjusted for both surgeon volume and surgeon subspecialty training.10Ezer N. Kale M. Sigel K. et al.Outcomes after video-assisted thoracoscopic lobectomy versus open lobectomy for early-stage lung cancer in older adults.Ann Am Thorac Soc. 2018; 15: 76-82Crossref PubMed Scopus (24) Google Scholar In addition, benefit for VATS in patients with more severe COPD has been reported, with pulmonary complication rates of VATS progressively decreasing in patients with the lowest ranges of predicted FEV1 (50%-60%, 40%-50%, and 20%-40%) compared with thoracotomy.11Ceppa D.P. Kosinski A.S. Berry M.F. et al.Thoracoscopic lobectomy has increasing benefit in patients with poor pulmonary function: a Society of Thoracic Surgeons database analysis.Ann Surg. 2012; 256: 487-493Crossref PubMed Scopus (190) Google Scholar Given the lower complication rate, minimally invasive surgery for lung cancer is the recommended approach.12Rocco G. Allen M.S. Altorki N.K. et al.Clinical statement on the role of the surgeon and surgical issues relating to computed tomography screening programs for lung cancer.Ann Thorac Surg. 2013; 96: 357-360Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar However, in a study of patients in the Veterans Integrated Service Networks who underwent thoracic surgery, only 50.6% of lung resections were performed by using VATS, with a wide variation in uptake from 0% to 81.7%, based mainly on volume per center.13Maiga A.W. Deppen S.A. Denton J. et al.Uptake of video-assisted thoracoscopic lung resections within the Veterans Affairs for known or suspected lung cancer.JAMA Surg. 2019; 154: 524-529Crossref PubMed Scopus (8) Google Scholar This rate compares to national rates for minimally invasive procedures but is lower than the 80% to 90% rate among Society of Thoracic Surgeons members.14Mehta H. Osasona A. Shan Y. Goodwin J.S. Okereke I.C. Trends and outcomes of thoracoscopic lobectomy or segmentectomy: a National Surgical Quality Improvement Project Analysis.Semin Thorac Cardiovasc Surg. 2018; 30: 350-359Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar The study by Nuñez et al3Nuñez E.R. Caverly T.J. Zhang S. et al.Invasive procedures and associated complications following initial lung cancer screening in a national cohort of veterans.Chest. 2022; 162: 475-484Abstract Full Text Full Text PDF Scopus (1) Google Scholar reiterates potential harms from screening, lending further support for research to develop tools to identify high-risk, high-benefit LCS individuals and assess the balance of life-years gained from LCS against risks of competing mortality from underlying comorbidities.15Rivera M.P. Tanner N.T. Silvestri G.A. et al.Incorporating coexisting chronic illness into decisions about patient selection for lung cancer screening. An Official American Thoracic Society Research Statement.Am J Respir Crit Care Med. 2018; 198: e3-e13Crossref PubMed Scopus (44) Google Scholar Moreover, the study supports that older and racially diverse individuals with more medical comorbidities cared for in real-world LCS settings are at risk for procedural complications following screening. Questions regarding adherence rates to guideline-recommended follow-up care after positive LCS, both in terms of who is offered invasive testing and which procedure is performed outside of a trial setting, are not fully answered. The difficulty still lies in achieving a balance between preventing a lung cancer death against the risk of procedural complications or competing causes of death due to underlying comorbidities. In the absence of validated risk assessment and balancing tools, we must rely on tailored management within systems with expertise across the continuum of lung cancer care, adherence to guideline-recommended care via multidisciplinary care teams, and pursuing the least invasive/risk-intense method of managing screen-detected nodules.15Rivera M.P. Tanner N.T. Silvestri G.A. et al.Incorporating coexisting chronic illness into decisions about patient selection for lung cancer screening. An Official American Thoracic Society Research Statement.Am J Respir Crit Care Med. 2018; 198: e3-e13Crossref PubMed Scopus (44) Google Scholar Financial/nonfinancial disclosures: None declared. Invasive Procedures and Associated Complications After Initial Lung Cancer Screening in a National Cohort of VeteransCHESTVol. 162Issue 2PreviewThese findings may reflect a higher threshold to perform procedures in veteran populations with multiple comorbidities and higher risks of complications. Future work should focus on optimizing the identification of patients whose chance of benefit likely outweighs the complication risks. Full-Text PDF

KRAS, which is mutated in ∼30% of all cancers, activates the RAF-MEK-ERK signaling cascade. CRAF is required for growth of KRAS mutant lung tumors, but the requirement for CRAF kinase activity is unknown. Here, we show that subsets of KRAS mutant tumors are dependent on CRAF for growth. Kinase-dead but not dimer-defective CRAF rescues growth inhibition, suggesting that dimerization but not kinase activity is required. Quantitative proteomics demonstrates increased levels of CRAF:ARAF dimers in KRAS mutant cells, and depletion of both CRAF and ARAF rescues the CRAF-loss phenotype. Mechanistically, CRAF depletion causes sustained ERK activation and induction of cell-cycle arrest, while treatment with low-dose MEK or ERK inhibitor rescues the CRAF-loss phenotype. Our studies highlight the role of CRAF in regulating MAPK signal intensity to promote tumorigenesis downstream of mutant KRAS and suggest that disrupting CRAF dimerization or degrading CRAF may have therapeutic benefit.

Here, we have developed an automated image processing algorithm for segmenting lungs and individual lung tumors in in vivo micro-computed tomography (micro-CT) scans of mouse models of non-small cell lung cancer and lung fibrosis. Over 3000 scans acquired across multiple studies were used to train/validate a 3D U-net lung segmentation model and a Support Vector Machine (SVM) classifier to segment individual lung tumors. The U-net lung segmentation algorithm can be used to estimate changes in soft tissue volume within lungs (primarily tumors and blood vessels), whereas the trained SVM is able to discriminate between tumors and blood vessels and identify individual tumors. The trained segmentation algorithms (1) significantly reduce time required for lung and tumor segmentation, (2) reduce bias and error associated with manual image segmentation, and (3) facilitate identification of individual lung tumors and objective assessment of changes in lung and individual tumor volumes under different experimental conditions.

Amplification and copy number alterations of the 17q23 amplicon are common in breast cancer and neuroblastoma and have been associated with early relapse and poor prognosis. Recent work identified a key vulnerability associated with amplicon-driven overexpression of TRIM37 in these tumor types (Meitinger et al. 2020; Yeow et al. 2020). High levels of TRIM37 prevent acentrosomal spindle assembly and render cells mitotically vulnerable to inhibition of polo-like kinase 4 (PLK4), a serine/threonine protein kinase that controls centrosome duplication. We have discovered potent small molecule inhibitors of PLK4 that are highly selective against the kinome, including against the closely related aurora kinases and PLK1-3. Self-regulation of PLK4 protein levels occurs through proteasomal degradation induced by PLK4 trans-autophosphorylation. ORIC PLK4 inhibitors blocked trans-autophosphorylation leading to stabilization of PLK4, thus directly demonstrating target inhibition in cells. Importantly, PLK4 inhibitor induced PLK4 protein stabilization correlated with cell viability, providing a quantifiable pharmacodynamic (PD) association with antitumor activity. Cell viability assessment across a cancer cell line panel revealed that the highly selective ORIC PLK4 inhibitors showed greater potency in TRIM37 high cancer cell lines as compared to TRIM37 low cell lines. In contrast, less selective compounds, including from the clinical literature, did not display differential potency in TRIM37 high versus low cancer cell lines. Importantly, cell potency in TRIM37 high cancer cells was rescued with knockdown of TRIM37, illustrating that selective PLK4 inhibitors are synthetic lethal with TRIM37 amplification. Oral administration of ORIC PLK4 inhibitors resulted in regressions of TRIM37 high xenograft tumors, with corresponding PD effects and no body weight loss. In summary, we have discovered novel, potent, highly selective small molecule inhibitors of PLK4 that are orally bioavailable and confirmed the potential for this new target in treating tumors with high levels of TRIM37. Citation Format: Kyle A. Edgar, Amy Young, Jared Moore, Xi Chen, Wei Fang, Jae H. Chang, Wayne Kong, Jason E. Long, Aleksandr Pankov, Anneleen Daemen, Daniel G. Shore, Robert Warne, Paul Gibbons, Chudi O. Ndubaku, Melissa R. Junttila, Lori S. Friedman. Discovery of novel, highly selective inhibitors of PLK4 that demonstrate in vivo regressions in TRIM37 high xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2633.

The increased use of chest computed tomography (CT) has led to an increased detection of pulmonary nodules requiring diagnostic evaluation and/or excision. Many of these nodules are identified and excised via minimally invasive thoracic surgery; however, subcentimeter and subsolid nodules are frequently difficult to identify intra-operatively. This can be mitigated by the use of electromagnetic transthoracic needle localization. This protocol delineates the step-by-step process of electromagnetic localization from the pre-operative period to the postoperative period and is an adaptation of the electromagnetically guided percutaneous biopsy previously described by Arias et al. Pre-operative steps include obtaining a same day CT followed by the generation of a three-dimensional virtual map of the lung. From this map, the target lesion(s) and an entry site are chosen. In the operating room, the virtual reconstruction of the lung is then calibrated with the patient and the electromagnetic navigation platform. The patient is then sedated, intubated, and placed in the lateral decubitus position. Using a sterile technique and visualization from multiple views, the needle is inserted into the chest wall at the prechosen skin entry site and driven down to the target lesion. Dye is then injected into the lesion and, then, continuously during needle withdrawal, creating a tract for visualization intra-operatively. This method has many potential benefits when compared to the CTguided localization, including a decreased radiation exposure and decreased time between the dye injection and the surgery. Dye diffusion from the pathway occurs over time, thereby limiting intra-operative nodule identification. By decreasing the time to surgery, there is a decrease in wait time for the patient, and less time for dye diffusion to occur, resulting in an improvement in nodule localization. When compared to electromagnetic bronchoscopy, airway architecture is no longer a limitation as the target nodule is accessed via a transparenchymal approach. Details of this procedure are described in a step-by-step fashion.

SESSION TITLE: Lung Nodule Biopsy: Yield and AccuracySESSION TYPE: Original InvestigationsPRESENTED ON: 10/16/2022 10:30 am - 11:30 amPURPOSE: Advances in CT imaging have enabled physicians to identify small, solitary pulmonary nodules (SPN) that represent early, curable lung cancer. Advances in thoracic surgery from open thoracotomy to minimally invasive thoracic surgery (MITS) have made resection of these nodules realistic for even frail candidates, but MITS limits the surgeon’s ability to palpate these progressively smaller nodules. Perioperative nodule localization with a dye inserted via an electromagnetic-guided transthoracic needle can provide guidance to surgeons to make up for these absent tactile cues. We report the nodule, patient and procedure characteristics of our localization experience.METHODS: A retrospective chart review of all perioperative localization cases prior to video-assisted thoracoscopic surgery (VATS) or robotic-assisted thoracoscopic surgery (RATS) at our institution was performed. Between May 2016 and September 2019, 74 patients were identified and data was extracted. All patients underwent localization in the operating room with an electromagnetic navigational (EMN) bronchoscopy system (Veran Medical Technologies, St. Louis, MO) for registration of anatomy, and marking was done with transthoracic needle insertion of a combination of methylene blue, indocyanine green, and the patient’s own blood.RESULTS: 74 patients who underwent MITS for lung nodule resection with perioperative EMNLN were identified. The mean nodule size was 13.1mm +- 5.8mm, and the mean distance from pleural to superficial and deep margins were 12.2mm +- 11.7mm and 23.2mm +- 12.3mm, respectively. The mean patient age was 64 years +- 10.5 years, 41% were female, 72% were active or former smokers. On CT scan, 35% had emphysema, 3% had ILD, and 1% had bronchiectasis. Only 7% had had prior thoracic radiation, and 14% had undergone prior thoracic surgery. The consistency of the identified nodules were 66% solid, 22% semisolid, and 11% ground glass. In order of prevalence, nodules were localized in the right upper lobe (38%), left upper lobe (27%), right lower lobe (22%), left lower lobe (12%), and right middle lobe (1%). Mean marking time was 39 minutes and the mean incision to closing time was 2.5 hours. 55% of patients underwent RATS. The rate of conversion to open thoracotomy was 10.4%, with a marking failure rate of 5.4% and benign resection rate of 18.9%.CONCLUSIONS: Perioperative marking successfully localized 95% of nodules with a mean size of 13mm at the time cost of only 40 minutes. One in ten patients still required open thoracotomy for resection, and one in five resections was benign. These data should inform patients and surgeons considering MITS for small SPN.CLINICAL IMPLICATIONS: Small SPN can effectively be localized with a perioperative EMN system.Localization added 40 minutes to OR time.One in ten patients needed conversion from MITS to open thoracotomy.DISCLOSURES: No relevant relationships by Jason AkulianNo relevant relationships by Maxwell DiddamsNo relevant relationships by Jason Long SESSION TITLE: Lung Nodule Biopsy: Yield and Accuracy SESSION TYPE: Original Investigations PRESENTED ON: 10/16/2022 10:30 am - 11:30 am PURPOSE: Advances in CT imaging have enabled physicians to identify small, solitary pulmonary nodules (SPN) that represent early, curable lung cancer. Advances in thoracic surgery from open thoracotomy to minimally invasive thoracic surgery (MITS) have made resection of these nodules realistic for even frail candidates, but MITS limits the surgeon’s ability to palpate these progressively smaller nodules. Perioperative nodule localization with a dye inserted via an electromagnetic-guided transthoracic needle can provide guidance to surgeons to make up for these absent tactile cues. We report the nodule, patient and procedure characteristics of our localization experience. METHODS: A retrospective chart review of all perioperative localization cases prior to video-assisted thoracoscopic surgery (VATS) or robotic-assisted thoracoscopic surgery (RATS) at our institution was performed. Between May 2016 and September 2019, 74 patients were identified and data was extracted. All patients underwent localization in the operating room with an electromagnetic navigational (EMN) bronchoscopy system (Veran Medical Technologies, St. Louis, MO) for registration of anatomy, and marking was done with transthoracic needle insertion of a combination of methylene blue, indocyanine green, and the patient’s own blood. RESULTS: 74 patients who underwent MITS for lung nodule resection with perioperative EMNLN were identified. The mean nodule size was 13.1mm +- 5.8mm, and the mean distance from pleural to superficial and deep margins were 12.2mm +- 11.7mm and 23.2mm +- 12.3mm, respectively. The mean patient age was 64 years +- 10.5 years, 41% were female, 72% were active or former smokers. On CT scan, 35% had emphysema, 3% had ILD, and 1% had bronchiectasis. Only 7% had had prior thoracic radiation, and 14% had undergone prior thoracic surgery. The consistency of the identified nodules were 66% solid, 22% semisolid, and 11% ground glass. In order of prevalence, nodules were localized in the right upper lobe (38%), left upper lobe (27%), right lower lobe (22%), left lower lobe (12%), and right middle lobe (1%). Mean marking time was 39 minutes and the mean incision to closing time was 2.5 hours. 55% of patients underwent RATS. The rate of conversion to open thoracotomy was 10.4%, with a marking failure rate of 5.4% and benign resection rate of 18.9%. CONCLUSIONS: Perioperative marking successfully localized 95% of nodules with a mean size of 13mm at the time cost of only 40 minutes. One in ten patients still required open thoracotomy for resection, and one in five resections was benign. These data should inform patients and surgeons considering MITS for small SPN. CLINICAL IMPLICATIONS: Small SPN can effectively be localized with a perioperative EMN system. Localization added 40 minutes to OR time. One in ten patients needed conversion from MITS to open thoracotomy. DISCLOSURES: No relevant relationships by Jason Akulian No relevant relationships by Maxwell Diddams No relevant relationships by Jason Long

The utilization of suitable mouse models is a critical step in the drug discovery oncology workflow as their generation and use are important for target identification and validation as well as toxicity and efficacy assessments. Current murine models have been instrumental in furthering insights into the mode of action of drugs before transitioning into the clinic. Recent advancements in genome editing with the development of the CRISPR/Cas9 system and the possibility of applying such technology directly in vivo have expanded the toolkit of preclinical models available. In this review, a brief presentation of the current models used in drug discovery will be provided with a particular emphasis on the novel CRISPR/Cas9 models.

Background: In the era of lung cancer screening with low-dose computed tomography, there is concern that high false-positive rates may lead to an increase in nontherapeutic lung resection. The aim of this study is to determine the current rate of major pulmonary resection for ultimately benign pathology. Materials and Methods: A single-institution, retrospective analysis of all patients > 18 y who underwent major pulmonary resection between 2013 and 2018 for suspected malignancy and had benign final pathology was performed. Results: Of 394 major pulmonary resections performed for known or presumed malignancy, 10 (2.5%) were benign. Of these 10, the mean age was 61.1 y (SD 14.6). Most were current or former smokers (60%). Ninety percent underwent a fluorodeoxyglucose positron emission tomography scan. Median nodule size was 27 mm (IQR 21-35) and most were in the right middle lobe (50%). Preoperative biopsy was performed in four (40%) but were nondiagnostic. Video-assisted thoracoscopic lobectomy (70%) was the most common surgical approach. Final pathology revealed three (30%) infectious, three (30%) inflammatory, two (20%) fibrotic, and two (20%) benign neoplastic nodules. Two (20%) patients had perioperative complications, both of which were prolonged air leaks, one (10%) patient was readmitted within 30 d, and there was no mortality. Conclusions: A small percentage of patients (2.5% in our series) may undergo major pulmonary resection for unexpectedly benign pathology. Knowledge of this rate is useful to inform shared decision-making models between surgeons and patients and evaluation of thoracic surgery program performance. (C) 2021 Elsevier Inc. All rights reserved.