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Kay See Tan,1 Takashi Eguchi,2 Prasad S Adusumilli21Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10017, USA; 2Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USACorrespondence: Kay See TanDepartment of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, 485 Lexington Avenue, New York, NY 10017, USATel +1 646 888 8257Email tank@mskcc.orgBackground: Net survival is commonly quantified as relative survival (observed survival among lung cancer patients versus expected survival among the general population) and cause-specific survival (lung cancer–specific survival among lung cancer patients). These approaches have drastically different assumptions; hence, failure to distinguish between them results in significant implications for study findings. We quantified the differences between relative and cause-specific survival when reporting net survival of patients with non-small cell lung cancer (NSCLC).Methods: Cases of NSCLC diagnosed between 2004 and 2014 were extracted from the Surveillance, Epidemiology, and End Results database. The net survival of each stage-by-age stratum was expressed as cause-specific survival (Kaplan-Meier approach) and relative survival (Ederer II approach); percentage-point (pp) differences between the survival estimates were quantified up to 10 years postdiagnosis.Results: Analyses included 263,894 cases. Cause-specific survival estimates were higher than relative survival estimates across all strata. Although the differences were negligible at 1 year postdiagnosis, they increased with increasing years of follow-up, up to 9.3 pp at 10 years (eg, aged 60–74 with stage I disease: 53.0% vs 43.7%). Differences in survival estimates between the methods also increased by increasing age groups (eg, at 10 years postdiagnosis: 5.1 pp for ages 18–44, 8.8 pp for ages 45–59, and 9.3 pp for ages 60–74) but decreased drastically for those aged ≥75 (3.1 pp).Conclusion: Relative survival and cause-specific survival are not interchangeable. The type of survival estimate used in cancer studies should be specified, particularly for long-term survival.Keywords: biostatistics, cancer epidemiology, epidemiological methods, mortality, lung cancer

Approximately 50% of patients with surgically resected early-stage lung cancer develop distant metastasis. At present, there is no in vivo metastasis model to investigate the biology of human lung cancer metastases. Using well-characterized lung adenocarcinoma (LUAD) patient-derived organoids (PDOs), we establish an in vivo metastasis model that preserves the biologic features of human metastases. Results of whole-genome and RNA sequencing establish that our in vivo PDO metastasis model can be used to study clonality and tumor evolution and to identify biomarkers related to organotropism. Investigation of the response of KRAS G12C PDOs to sotorasib demonstrates that the model can examine the efficacy of treatments to suppress metastasis and identify mechanisms of drug resistance. Finally, our PDO model cocultured with autologous peripheral blood mononuclear cells can potentially be used to determine the optimal immune-priming strategy for individual patients with LUAD., Competing Interests: Declaration of interests G.R. has financial relationships with Scanlan, AstraZeneca, and Medtronic. S.S. is a member of the AstraZeneca Advisory Board. J.M.I. has stock ownership in LumaCyte and is a consultant/advisory board member for Roche Genentech. M.J.B. is a consultant for AstraZeneca, Iovance Biotherapeutics, and Intuitive Surgical and receives research support from Obsidian Therapeutics. B.T.L. has served as an uncompensated advisor and consultant to Amgen, AstraZeneca, Boehringer Ingelheim, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, and Lilly; has received research grants (institutional) from Amgen, AstraZeneca, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, Hengrui USA, and Lilly; has received academic travel support from Amgen, Jiangsu Hengrui Medicine, and MORE Health; and has intellectual property rights as a book author at Karger Publishers and Shanghai Jiao Tong University Press. M.H.B. receives royalties from Globus Medical and DePuy Synthes. P.S.A. declares research funding from Atara Biotherapeutics; is a scientific advisory board member and consultant for ATARA Biotherapeutics, Bayer, Bio4T2, Carisma Therapeutics, Imugene, ImmPACT Bio, Johnson & Johnson, Orion, and Outpace Bio; has patents, royalties, and intellectual property on mesothelin-targeted chimeric antigen receptor and other T cell therapies, which have been licensed to Atara Biotherapeutics; and has an issued patent method for detection of cancer cells using virus and pending patent applications on PD-1 dominant negative receptor, a wireless pulse-oximetry device, and an ex vivo malignant pleural effusion culture system. MSK has licensed intellectual property related to mesothelin-targeted chimeric antigen receptors and T cell therapies to Atara Biotherapeutics and has associated financial interests. D.R.J. serves on a clinical trial steering committee for AstraZeneca and has research grant support from Merck., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Competing Interests: The authors report no conflicts of interest.

Objective: To generate a prediction model for selection of treatment modality for early-stage non-small cell lung cancer (NSCLC)., Summary Background Data: Stereotactic body radiotherapy (SBRT) and minimally invasive surgery (MIS) are used in the local treatment of early-stage NSCLC. However, selection of patients for either SBRT or MIS remains challenging, due to the multitude of factors influencing the decision-making process., Methods: We analyzed 1291 patients with clinical stage I NSCLC treated with intended MIS or SBRT from January 2020 to July 2023. A prediction model for selection for SBRT was created based on multivariable logistic regression analysis. The receiver operating characteristic curve analysis stratified the cohort into 3 treatment-related risk categories. Post-procedural outcomes, recurrence and overall survival (OS) were investigated to assess the performance of the model., Results: In total, 1116 patients underwent MIS and 175 SBRT. The prediction model included age, performance status, previous pulmonary resection, MSK-Frailty score, FEV1 and DLCO, and demonstrated an area-under-the-curve of 0.908 (95%CI, 0.876-0.938). Based on the probability scores (n=1197), patients were stratified into a low-risk (MIS, n=970 and SBRT, n=28), intermediate-risk (MIS, n=96 and SBRT, n=53) and high-risk category (MIS, n=10 and SBRT, n=40). Treatment modality was not associated with OS (HR of SBRT, 1.67 [95%CI: 0.80-3.48]; P=0.20)., Conclusion: Clinical expertise can be translated into a robust predictive model, guiding the selection of stage I NSCLC patients for MIS versus SBRT and effectively categorizing them into three distinct risk groups. Patients in the intermediate category could benefit most from multidisciplinary evaluation., Competing Interests: Disclosures: Prasad S. Adusumilli declares research funding from ATARA Biotherapeutics, is a scientific advisory board member and consultant for ATARA Biotherapeutics, Bayer, Bio4T2, Carisma Therapeutics, Imugene, ImmPactBio, Johnson & Johnson, Orion, Outpace Bio, has patents, royalties, and intellectual property on mesothelin-targeted chimeric antigen receptor and other T-cell therapies, which have been licensed to ATARA Biotherapeutics, and has an issued patent method for detection of cancer cells using virus and pending patent applications on PD-1 dominant negative receptor, a wireless pulse-oximetry device, and an ex vivo malignant pleural effusion culture system. Daniel Gomez receives research funding from AstraZeneca and Varian. He has received personal fees from Varian, AstraZeneca, GRAIL, Johnson & Johnson, Medtronic, Physicians Education Resource, and Regeneron. Daniela Molena serves on a steering committee for AstraZeneca, as a consultant for Johnson & Johnson, Bristol-Myers Squibb, AstraZeneca, and Boston Scientific, and has been an invited speaker for Merck and Genentech. Bernard J. Park serves as a consultant for Intuitive Surgical, CEEVRA, Medtronic, and Becton Dickinson. Matthew J. Bott is a consultant for AstraZeneca Pharmaceuticals, Iovance Biotherapeutics, and Intuitive Surgical and receives research support from Obsidian Therapeutics. Andreas Rimner served on a steering committee for Merck, served as a consultant for AstraZeneca and Merck, and received grant support (institutional) from Varian Medical Systems, Boehringer Ingelheim, AstraZeneca, Merck, and Pfizer, payments from NIH/Coordinating Center for Clinical Trials. Valerie W. Rusch reports grant support (institutional) from Genelux and Genentech, travel support from Intuitive Surgical, and travel support and payments from NIH/Coordinating Center for Clinical Trials. Smita Sihag is a member of the AstraZeneca Advisory Board. James M. Isbell has served as an advisory board member for AstraZeneca and Merck, as an uncompensated steering board member for Genentech, has received institutional research support from ArcherDx/Invitae, Guardant Health, GRAIL, and Intuitive Surgical and travel support from Intuitive Surgical, and has equity/ownership interest in LumaCyte. David R. Jones is a member of the Advisory Council for AstraZeneca and receives research grant support from Merck. Gaetano Rocco has financial relationships with Scanlan International, Medtronic, and Merck. The other authors have no conflict of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The newest Commission on Cancer standards recommend sampling 3 mediastinal and 1 hilar lymph node stations, 3 (N2) 1 (N1), for lung cancer resections. However, the relationship between the Commission on Cancer standards and outcomes has not been thoroughly investigated., Methods: A prospective institutional database was queried for clinical stage I-III lung resections before the implementation of the new standards. The relationship between the 3 (N2) 1 (N1) standard ("guideline concordant") and outcomes (upstaging, complications, receipt of adjuvant therapy, locoregional/distant recurrence, and survival) was assessed with multivariable models and stratified by stage., Results: Of 9289 pulmonary resections, 3048 (33%) were guideline concordant and 6241 (67%) were not. Compared with nonconcordant, those that were guideline concordant had higher rates of nodal upstaging (21% vs 13%; odds ratio [OR], 1.32 [95% CI, 1.14-1.51]; P < .001) and in-hospital complications (34% vs 27%; OR, 1.17 [95% CI, 1.05-1.30]; P = .004) but similar adjuvant systemic therapy administration (19% vs 13%; OR, 1.09 [95% CI, 0.95-1.24]; P = .2; 98% chemotherapy). Locoregional and distant recurrences were not significantly improved with guideline concordance across clinical stage I, II, and III subsets. Overall survival was similar in clinical stages I and II, but improved survival was observed for guideline concordant clinical stage III patients (hazard ratio, 0.85 [95% CI, 0.74-0.97]; P = .02)., Conclusions: Sampling 3 (N2) 1 (N1) was associated with increased upstaging and complications but not with decreased recurrence or mortality in clinical stage I or II patients. Survival was improved for concordant, clinical stage III patients. Further study is indicated to determine the ideal lymph node sampling strategy across heterogeneous lung cancer patients., Competing Interests: Disclosures James Isbell reports a relationship with LumaCyte that includes: equity or stocks; with Roche that includes: board membership; and with Genetech Biotech Co Ltd that includes: board membership and funding grants. Daniela Molena reports a relationship with Genetech Biotech Co Ltd that includes: board membership and funding grants; with AstraZeneca Pharmaceuticals LP that includes: board membership and consulting or advisory; with Johnson and Johnson Ltd that includes: consulting or advisory; with Bristol Myers Squibb Co that includes: consulting or advisory; and with Merck & Co Inc that includes: consulting or advisory. David Jones reports a relationship with Merck & Co Inc that includes: consulting or advisory; and with AstraZeneca Pharmaceuticals LP that includes: board membership and consulting or advisory. Matthew Bott reports a relationship with AstraZeneca Pharmaceuticals LP that includes: board membership and consulting or advisory. Prasad Adusumilli reports a relationship with Johnson and Johnson Ltd that includes: consulting or advisory; with Atara Biotherapeutics that includes: consulting or advisory; with Bayer Corporation that includes: consulting or advisory; with Carisma Therapeutics Inc that includes: consulting or advisory; with Imugene that includes: consulting or advisory; and with ImmPactBio that includes: consulting or advisory. Bernard Park reports a relationship with Intuitive Surgical Inc that includes: consulting or advisory; and with COTA, Inc that includes: consulting or advisory. Valerie Rusch reports a relationship with Genetech Biotech Co Ltd that includes: board membership and funding grants; with Intuitive Surgical Inc that includes: consulting or advisory; and with Genelux that includes: funding grants. Gaetano Rocco reports a relationship with AstraZeneca Pharmaceuticals LP that includes: board membership and consulting or advisory; with Scanlan International Inc that includes: consulting or advisory; and with Medtronic that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background and Objective: Robotic-assisted bronchoscopy (RAB) is an emerging modality to sample pulmonary lesions. Cone-beam computed tomography (CBCT) can be incorporated into RAB. We investigated the magnitude and predictors of patient and staff radiation exposure during mobile CBCT-guided shape-sensing RAB., Methods: Patient radiation dose was estimated by cumulative dose area product (cDAP) and cumulative reference air kerma (cRAK). Staff equivalent dose was calculated based on isokerma maps and a phantom simulation. Patient, lesion and procedure-related factors associated with higher radiation doses were identified by logistic regression models., Results: A total of 198 RAB cases were included in the analysis. The median patient cDAP and cRAK were 10.86 Gy cm 2 (IQR: 4.62-20.84) and 76.20 mGy (IQR: 38.96-148.38), respectively. Among staff members, the bronchoscopist was exposed to the highest median equivalent dose of 1.48 μSv (IQR: 0.85-2.69). Both patient and staff radiation doses increased with the number of CBCT spins and targeted lesions (p < 0.001 for all comparisons). Patient obesity, negative bronchus sign, lesion size <2.0 cm and inadequate sampling by on-site evaluation were associated with a higher patient dose, while patient obesity and inadequate sampling by on-site evaluation were associated with a higher bronchoscopist equivalent dose., Conclusion: The magnitude of patient and staff radiation exposure during CBCT-RAB is aligned with safety thresholds recommended by regulatory authorities. Factors associated with a higher radiation exposure during CBCT-RAB can be identified pre-operatively and solicit procedural optimization by reinforcing radiation protective measures. Future studies are needed to confirm these findings across multiple institutions and practices., (© 2024 Asian Pacific Society of Respirology.)

Introduction: Electronic nose (E-nose) technology has reported excellent sensitivity and specificity in the setting of lung cancer screening. However, the performance of E-nose specifically for early-stage tumors remains unclear. Therefore, the aim of our study was to assess the diagnostic performance of E-nose technology in clinical stage I lung cancer., Methods: This phase IIc trial (NCT04734145) included patients diagnosed with a single greater than or equal to 50% solid stage I nodule. Exhalates were prospectively collected from January 2020 to August 2023. Blinded bioengineers analyzed the exhalates, using E-nose technology to determine the probability of malignancy. Patients were stratified into three risk groups (low-risk, [<0.2]; moderate-risk, [≥0.2-0.7]; high-risk, [≥0.7]). The primary outcome was the diagnostic performance of E-nose versus histopathology (accuracy and F1 score). The secondary outcome was the clinical performance of the E-nose versus clinicoradiological prediction models., Results: Based on the predefined cutoff (<0.20), E-nose agreed with histopathologic results in 86% of cases, achieving an F1 score of 92.5%, based on 86 true positives, two false negatives, and 12 false positives (n = 100). E-nose would refer fewer patients with malignant nodules to observation (low-risk: 2 versus 9 and 11, respectively; p = 0.028 and p = 0.011) than would the Swensen and Brock models and more patients with malignant nodules to treatment without biopsy (high-risk: 27 versus 19 and 6, respectively; p = 0.057 and p < 0.001)., Conclusions: In the setting of clinical stage I lung cancer, E-nose agrees well with histopathology. Accordingly, E-nose technology can be used in addition to imaging or as part of a "multiomics" platform., Competing Interests: Disclosure Dr. Rocco has a financial relationship with Scanlan, Merck, and Medtronic. Dr. Prasad S. Adusumilli serves as consultant for ATARA Biotherapeutics, Bayer, Carisma Therapeutics, Imugene, ImmPactBio, and Johnson & Johnson. Dr. Park has received honoraria from Intuitive Surgical, AstraZeneca, and Medtronic, serves as a consultant to Ceevra, and has received institutional research support from Intuitive Surgical. Dr. Bott is a consultant for AstraZeneca Pharmaceuticals, Iovance Biotherapeutics, and Intuitive Surgical and receives research support from Obsidian Therapeutics. Dr. Molena serves on a steering committee for AstraZeneca and as a consultant for Johnson & Johnson, Bristol-Myers Squibb, AstraZeneca, and Boston Scientific, and has been an invited speaker for Merck and Genentech. Dr. Isbell has served as an advisory board member for AstraZeneca and Merck and as an uncompensated steering board member for Genentech, has received institutional research support from ArcherDx/Invitae, Guardant Health, GRAIL, and Intuitive Surgical and travel support from Intuitive Surgical, and has equity or ownership interest in LumaCyte. Dr. Rusch receives grant support (institutional) from Genelux and Genentech, travel support from Intuitive Surgical, and travel support and payments from the National Institutes of Health/Coordinating Center for Clinical Trials. Dr. Solomon serves as a consultant for GE Healthcare and Merck and on the data monitoring committee for Candel Therapeutics and Impact Biotech. Dr. Jones is a member of the Advisory Council for AstraZeneca and Advisory Committee for More Health, has been a speaker for DAVA Oncology, and receives research grant support from Merck. The remaining authors declare no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Results of recent clinical trials suggest that segmentectomy may be an acceptable alternative to lobectomy for selected patients with early-stage non-small cell lung cancer (NSCLC). Increased use of segmentectomy may result in a concomitant increase in occult node-positive (N+) disease on surgical pathology examination. The optimal management for such patients remains unknown., Methods: Clinicopathologic data were abstracted from a prospective institutional database to identify patients with pathologic N+ disease after segmentectomy for cT1 N0 M0 NSCLC. Propensity score matching identified a comparable lobectomy cohort for assessment of cumulative incidence of recurrence and overall survival (OS)., Results: Of 759 included patients, 27 (4%) had nodal upstaging on the final pathology report. Of these 27 patients, 4 (15%) had skip metastasis to N2 stations, and 20 (74%) received adjuvant therapy; no completion lobectomies were performed. Ten patients (37%) had disease recurrence: 3 isolated locoregional (11%) and 7 distant (26%). The median time to recurrence among patients with recurrence was 1.8 years; OS after recurrence was 3.4 years. After 5:1 matching with 109 patients who underwent lobectomy, all variables were balanced between the groups, except pathologic N2 stage and open surgical approach. The 5-year cumulative incidence of recurrence was not significantly different between segmentectomy and lobectomy (42% vs 52%, respectively; Gray's P = .1). The 5-year OS (63% and 50%) and rate of locoregional recurrence (12% vs 13%) were not statistically different between the groups., Conclusions: Patients with occult N+ disease after segmentectomy for cT1 N0 M0 NSCLC had limited isolated locoregional recurrences and outcomes similar to those in patients who underwent lobectomy. Lobectomy may not provide an advantage in these patients., Competing Interests: Disclosures James M. Isbell has served as an advisory board member for AstraZeneca and Merck; has served as an uncompensated steering board member for Genentech; has received travel support from Intuitive Surgical; and has equity or ownership interest in LumaCyte. Daniela Molena has served on a steering committee for AstraZeneca; has served as a consultant for Johnson & Johnson, Bristol Myers Squibb, AstraZeneca, and Boston Scientific; and has been an invited speaker for Merck and Genentech. Bernard J. Park has received honoraria from Intuitive Surgical, AstraZeneca, and Medtronic; and has served as a consultant for Ceevra. Gaetano Rocco has a financial relationship with Scanlan, Merck, and Medtronic. Valerie W. Rusch has received other support from DaVinci Surgery; has received nonfinancial support from Bristol Myers Squibb; and has received personal fees from the NIH Coordinating Center for Clinical Trials. Smita Sihag has served as a member of the AstraZeneca advisory board. David R. Jones has served as a member of the advisory council for AstraZeneca and the Advisory Committee for More Health; and has been a speaker for DAVA Oncology. Matthew J. Bott has served as a consultant for AstraZeneca Pharmaceuticals, Iovance Biotherapeutics, and Intuitive Surgical., (Copyright © 2024 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: To assess the performance of a lower predicted postoperative (ppo) forced expiratory volume in 1 second (FEV 1 ) or diffusion capacity of the lung for carbon monoxide (DLCO) (ppoFEV 1 /ppoDLCO) threshold to predict cardiopulmonary complications after minimally invasive surgery (MIS) lobectomy., Background: Although MIS is associated with better postoperative outcomes than open surgery, MIS uses risk-assessment algorithms developed for open surgery. Moreover, several different definitions of cardiopulmonary complications are used for assessment., Methods: All patients who underwent MIS lobectomy for clinical stage I to II lung cancer from 2018 to 2022 at our institution were considered. The performance of a ppoFEV 1 /ppoDLCO threshold of <45% was compared against that of the current guideline threshold of <60%. Three different definitions of cardiopulmonary complications were compared: Society of Thoracic Surgeons (STS), European Society of Thoracic Surgeons (ESTS), and Berry and colleagues' study., Results: In 946 patients, the ppoFEV 1 /ppoDLCO threshold of <45% was associated with a higher proportion correctly classified [79% (95% CI, 76%-81%) vs 65% (95% CI, 62%-68%); P <0.001]. The complication with the biggest difference in incidence between ppoFEV 1 /ppoDLCO of 45% to 60% and >60% was prolonged air leak [33 (13%) vs 34 (6%); P <0.001]. The predicted probability curves for cardiopulmonary complications were higher for the STS definition than for the ESTS or Berry definitions across ppoFEV 1 and ppoDLCO values., Conclusions: The ppoFEV 1 /ppoDLCO threshold of <45% more accurately classified patients for cardiopulmonary complications after MIS lobectomy, emphasizing the need for updated risk-assessment guidelines for MIS lobectomy to optimize additional cardiopulmonary function evaluation., Competing Interests: P.S.A. declares research funding from ATARA Biotherapeutics, is a scientific advisory board member and consultant for ATARA Biotherapeutics, Bayer, Bio4T2, Carisma Therapeutics, Imugene, ImmPactBio, Johnson & Johnson, Orion, Outpace Bio, has patents, royalties, and intellectual property on mesothelin-targeted chimeric antigen receptor and other T-cell therapies, which have been licensed to ATARA Biotherapeutics, and has an issued patent method for detection of cancer cells using virus and pending patent applications on PD-1 dominant negative receptor, a wireless pulse-oximetry device, and an ex vivo malignant pleural effusion culture system. D.M. serves on a steering committee for AstraZeneca, as a consultant for Johnson & Johnson, Bristol-Myers Squibb, AstraZeneca, and Boston Scientific, and has been an invited speaker for Merck and Genentech. B.J.P. has received honoraria from Intuitive Surgical, AstraZeneca, and Medtronic, serves as a consultant to CEEVRA, and has received institutional research support from Intuitive Surgical. M.J.B. is a consultant for AstraZeneca Pharmaceuticals, Iovance Biotherapeutics, and Intuitive Surgical and receives research support from Obsidian Therapeutics. V.W.R. reports grant support (institutional) from Genelux and Genentech, travel support from Intuitive Surgical, and travel support and payments from NIH/Coordinating Center for Clinical Trials. S.S. is a member of the AstraZeneca Advisory Board. J.M.I. has served as an advisory board member for AstraZeneca and Merck, as an uncompensated steering board member for Genentech, has received institutional research support from ArcherDx/Invitae, Guardant Health, GRAIL, and Intuitive Surgical and travel support from Intuitive Surgical, and has equity/ownership interest in LumaCyte. D.R.J. is a member of the Advisory Council for AstraZeneca and Advisory Committee for More Health, has been a speaker for DAVA Oncology, and receives research grant support from Merck. G.R. has financial relationships with Scanlan International, Medtronic, and Merck. The remaining authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Minimally invasive surgery (MIS) (video-assisted thoracoscopic surgery and robot-assisted thoracoscopic surgery) for pulmonary resection is standard in early-stage non-small cell lung cancer because it is associated with better perioperative outcomes than thoracotomy. MIS for resection of more advanced non-small cell lung cancer (Stages IB-IIIB) treated with neoadjuvant therapy has been utilized. However, the determinants of success are not well defined., Methods: A single institution retrospective review of a prospectively maintained database was conducted, querying for patients with clinical Stage IB through IIIB non-small cell lung cancer who had resection after neoadjuvant systemic therapy without radiation from 2013 to 2022. Patients were grouped by surgical approach; that is, open versus MIS. Successful MIS was defined by no conversion, R0 resection, and no major (grade 3 or greater) morbidity. Analyses by intent-to-treat assessed outcomes by Wilcoxon rank-sum test and Fisher exact test. (Multivariable regression analysis identified variables that contributed to successful MIS resection.) RESULTS: Of 627 eligible patients, 360 (57%) had open and 267 (43%) had MIS procedures. Most patients (79.1%) received neoadjuvant platinum-based chemotherapy, and 21.9% were treated with immunotherapy or targeted therapy alone or combined with chemotherapy. Among MIS resections, 179 (67%) were performed by video-assisted thoracoscopic surgery and 88 (33%) by robot-assisted thoracoscopic surgery. The conversion rate was 16% (n = 43). Successful MIS resection was achieved in 77% of patients. Multivariable regression analysis showed that pretreatment clinical N stage was a significant determinant of success, but not pretreatment clinical T stage or type of neoadjuvant therapy., Conclusions: Following neoadjuvant systemic therapy for clinical stage IB or IIIB non-small cell lung cancer, MIS resection can be successfully accomplished and should be considered in appropriate patients. Presence of pretreatment nodal disease is associated with higher odds of conversion, major morbidity, and incomplete resection., Competing Interests: Conflict of Interest Statement Dr Adusumilli declares research funding from ATARA Biotherapeutics; is a Scientific Advisory Board Member and consultant for ATARA Biotherapeutics, Bayer, Bio4T2, Carisma Therapeutics, Imugene, ImmPactBio, Johnston & Johnston, Orion Pharma, and Outpace Bio; and holds patents, royalties, and intellectual property on mesothelin-targeted CAR and other T-cell therapies that have been licensed to ATARA Biotherapeutics, issued a patent method for detection of cancer cells using virus, and has pending patent applications on PD-1 dominant negative receptor, wireless pulse-oximetry device, and on an ex vivo malignant pleural effusion culture system. Memorial Sloan Kettering Cancer Center has licensed intellectual property related to mesothelin-targeted CARs and T-cell therapies to ATARA Biotherapeutics and has associated financial interests. Dr Bott is a consultant for AstraZeneca Pharmaceuticals, Iovance Biotherapeutics, and Intuitive Surgical and receives research support from Obsidian Therapeutics. Dr Isbell has served as an advisory board member for AstraZeneca and Merck, as an uncompensated steering board member for Genentech, has received institutional research support from ArcherDx/Invitae, Guardant Health, GRAIL, and Intuitive Surgical and travel support from Intuitive Surgical, and has equity/ownership interest in LumaCyte. Dr Molena serves on a steering committee for AstraZeneca, as a consultant for Johnson & Johnson, Bristol-Myers Squibb, AstraZeneca, and Boston Scientific, and has been an invited speaker for Merck and Genentech. Dr Sihag is a member of the AstraZeneca Advisory Board. Dr Rocco has received royalties from Scanlan International, has served as an uncompensated advisor for AstraZeneca, and has served as a consultant for Medtronic. Dr Jones is a member of the advisory council for AstraZeneca and receives research grant support from Merck. Dr Park has received honoraria from Intuitive Surgical, AstraZeneca, Medtronic, serves as a consultant to CEEVRA, and has received institutional research support from Intuitive Surgical. Dr Rusch reports unreimbursed participation in Data Safety and Monitoring Committees for Cancer Research UK MARS II and RAMONA trials. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: The current clinical staging of pleural mesothelioma (PM) is often discordant with the pathologic staging. This study aimed to identify clinical and radiological features that could help predict unresectability in PM., Methods: Twenty-two descriptive radiologic features were retrospectively evaluated on preoperative computed tomography (CT) and/or positron emission tomography/CT (PET/CT) performed in patients with presumably resectable PM who underwent surgery. Measurements of maximum and sum pleural thickness at three levels of the thorax (upper, middle, and lower) were taken and stratified based on the cutpoints provided by the International Association for the Study of Lung Cancer (IASLC). Clinical and radiological features, including clinical-stage, were compared between resectable and unresectable tumors by univariate analysis and logistic regression modeling., Results: Of 133 patients, 69/133 (52%) had resectable and 64/133 (48%) had unresectable PM. Asbestos exposure (p = 0.005), neoadjuvant treatment (p = 0.001), clinical T-stage (p < 0.0001), all pleural thickness measurements (p < 0.05), pleural thickness pattern (p < 0.0001) and degree (p = 0.033), lung invasion (p = 0.004), extrapleural space obliteration (p < 0.0001), extension to subphrenic space (p = 0.0004), and two combination variables representing extensive diaphragmatic contact and/or chest wall involvement (p = 0.002) and mediastinal invasion (p < 0.0001) were significant predictors at univariate analysis. At multivariable analysis, all models achieved a strong diagnostic performance (area under the curve (AUC) > 0.8). The two best-performing models were one that included the upper-level maximum pleural thickness, extrapleural space obliteration, and mediastinal infiltration (AUC = 0.876), and another that integrated clinical variables and radiological assessment through the clinical T-stage (AUC = 0.879)., Conclusion: Selected clinical and radiologic features, including pleural thickness measurements, appear to be strong predictors of unresectability in PM., Clinical Relevance Statement: A more accurate prediction of unresectability in the preoperative assessment of patients with pleural mesothelioma may avoid unnecessary surgery and prompt initiation of nonsurgical treatments., Key Points: About half of pleural mesothelioma patients are reported to receive an incorrect disease stage preoperatively. Eleven features identified as predictors of unresectability were included in strongly performing predictive models. More accurate preoperative staging will help clinicians and patients choose the most appropriate treatments., (© 2024. The Author(s), under exclusive licence to European Society of Radiology.)

Objectives: The study objectives were to assess the outcomes of lung resection in patients with non-small cell lung cancer previously treated with nonoperative treatment and to identify prognostic factors associated with survival., Methods: Patients who underwent surgery (2010-2022) after initial nonoperative treatment at a single institution were identified from a prospectively maintained database. Exclusion criteria included metachronous cancer, planned neoadjuvant therapy, and surgery for diagnostic or palliative indications. Cox models were constructed for overall survival and event-free survival. Survival of patients with stage IV disease was compared with survival of a nonstudy cohort who did not undergo surgery., Results: In total, 120 patients met the inclusion criteria. Initial clinical stage was early stage in 16%, locoregionally advanced in 25%, and metastatic in 59% of patients. The indication for surgery was recurrence in 18%, local persistent disease in 23%, oligoprogression in 22%, and local control of oligometastatic disease in 38% of patients. Grade 3 or greater complications occurred in 5% of patients; 90-day mortality was 3%. Three-year event-free survival and overall survival were 39% and 73%, respectively. Male sex and lymphovascular invasion were associated with shorter event-free survival and overall survival; younger age and prior radiation therapy were associated with shorter overall survival. Patients with stage IV disease who received salvage lung resection had better overall survival than similar patients who received subsequent systemic therapy and no surgery., Conclusions: In this selected, heterogeneous population, lung resection after initial nonoperative treatment for non-small cell lung cancer was safe. Surgery as local consolidative therapy was associated with encouraging outcomes and should be considered for these patients., Competing Interests: Conflict of Interest Statement Dr Adusumilli declares research funding from ATARA Biotherapeutics; is a scientific advisory board member and consultant for ATARA Biotherapeutics, Bayer, Bio4T2, Carisma Therapeutics, Imugene, ImmPactBio, Johnson & Johnson, Orion, and Outpace Bio; has patents, royalties, and intellectual property on mesothelin-targeted chimeric antigen receptor and other T-cell therapies, which have been licensed to ATARA Biotherapeutics; and has an issued patent method for detection of cancer cells using virus and pending patent applications on PD-1 dominant negative receptor, a wireless pulse-oximetry device, and an ex vivo malignant pleural effusion culture system. MSK Cancer Center has licensed intellectual property related to mesothelin-targeted chimeric antigen receptors and T-cell therapies to ATARA Biotherapeutics and has associated financial interests. Dr Rocco has financial relationships with Scanlan International, Medtronic, and Merck. Dr Molena serves on a steering committee for AstraZeneca and as a consultant for Johnson & Johnson, Bristol Myers Squibb, Merck, and Genentech. Dr Park is a consultant for Intuitive Surgical, Medtronic, AstraZeneca, and CEEVRA. Dr Bott is a consultant for AstraZeneca. Dr Rusch reports grant support (institutional) from Genelux and Genentech, travel support from Intuitive Surgical, and travel support and payments from National Institutes of Health/Coordinating Center for Clinical Trials. Dr Sihag is a member of the AstraZeneca Advisory Board. Dr Isbell has stock ownership in LumaCyte and is a consultant/advisory board member for Roche Genentech. Dr Chaft serves as a consultant for AstraZeneca, Bristol Myers Squibb, Flame Biosciences, Regeneron-Sanofi, Guardant Health, and Arcus Biosciences and receives institutional research funding from AztraZeneca, Bristol Myers Squibb, Merck, and Novartis. Dr Li has served as an uncompensated advisor and consultant to Amgen, AstraZeneca, Boehringer Ingelheim, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, and Lilly; has received research grants to his institution from Amgen, AstraZeneca, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, Hengrui USA, and Lilly; has received academic travel support from Amgen, Jiangsu Hengrui Medicine, and MORE Health; and has intellectual property rights as a book author at Karger Publishers and Shanghai Jiao Tong University Press. Dr Gomez reports research funding from Merck, AstraZeneca, Varian, and Bristol Myers Squibb and serves on the advisory boards of MedLearning Group, Medtronic, GRAIL, Johnson & Johnson, AstraZeneca, and Varian. Dr Rimner is a consultant for AstraZeneca, Merck, and MoreHealth, serves as an advisory board member for Merck, and reports institutional grant support from Varian Medical Systems, AstraZeneca, Merck, Pfizer, and Boehringer Ingelheim. Dr Jones serves as a consultant for Merck, AstraZeneca, Genentech, and DAVA Oncology. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2023 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Introduction: This study aims to answer the question of whether adding mobile cone-beam computed tomography (mCBCT) imaging to shape-sensing robotic-assisted bronchoscopy (ssRAB) translates into a quantifiable improvement in the tool-lesion relationship., Methods: Data from 102 peripheral lung lesions with ≥2 sequential mCBCT orbital spins and from 436 lesions with 0-1 spins were prospectively captured and retrospectively analysed. The primary outcome was the tool-lesion relationship status across the first and the last mCBCT spins. Secondary outcomes included 1) the change in distance between the tip of the sampling tool and the centre of the lesion between the first and the last spins and 2) the per-lesion diagnostic yield., Results: Compared to lesions requiring 0-1 spins, lesions requiring ≥2 spins were smaller and had unfavourable bronchus sign and intra-operative sonographic view. On the first spin, 54 lesions (53%) were designated as non-tool-in-lesion (non-TIL) while 48 lesions (47%) were designated as TIL. Of the 54 initially non-TIL cases, 49 (90%) were converted to TIL status by the last spin. Overall, on the last spin, 96 out of 102 lesions (94%) were defined as TIL and six out of 102 lesions (6%) were defined as non-TIL (p<0.0001). The mean distance between the tool and the centre of the lesion decreased from 10.4 to 6.6 mm between the first and last spins (p<0.0001). The overall diagnostic yield was 77%., Conclusion: Targeting traditionally challenging lung lesions, intra-operative volumetric imaging allowed for the conversion of 90% of non-TIL status to TIL. Guidance with mCBCT resulted in a significant decrease in the distance between the tip of the needle to lesion centre., Competing Interests: Conflict of interest: B.C. Husta has received speaker honoraria from Intuitive Surgical and Siemens Healthineers. B.C. Husta is national co-principal investigator for a study sponsored by Intuitive Surgical. P.S. Adusumilli declares research funding from ATARA Biotherapeutics; has served as a Scientific Advisory Board Member and Consultant for ATARA Biotherapeutics, Bayer, Bio4T2, Carisma Therapeutics, Imugene, ImmPactBio, Johnston & Johnston, Orion Pharma and Outpace Bio; and has patents, royalties and intellectual property on mesothelin-targeted CAR and other T-cell therapies, which have been licensed to ATARA Biotherapeutics (issued patent for a method for detection of cancer cells using virus, and pending patent applications on PD-1 dominant negative receptor, a wireless pulse-oximetry device, and an ex vivo malignant pleural effusion culture system); Memorial Sloan Kettering Cancer Center has licensed intellectual property related to mesothelin-targeted CARs and T-cell therapies to ATARA Biotherapeutics and has associated financial interests. R.P. Lee has received speaker honoraria from Intuitive Surgical. B.J. Park has received speaker honoraria from CEEVRA, AstraZeneca, Medtronic and Intuitive Surgical. G. Rocco has financial relationships with Medtronic, Merck, AstraZeneca, CEEVRA and Scanlan International. M.J. Bott has received speaker honoraria from Intuitive Surgical, and serves as a consultant for AstraZeneca and Iovance Biotherapeutics. M. Chawla serves on an advisory board for Intuitive Surgical. O. Kalchiem-Dekel is an associate editor of this journal. All other authors have no conflicts to disclose., (Copyright ©The authors 2024.)

Background: Despite surgical resection, long-term survival of patients with resectable non-small cell lung cancer (NSCLC) remains poor. Adjuvant chemotherapy, the standard of care for locally advanced NSCLC, provides a marginal 5.4% benefit in survival. Immune checkpoint inhibitors (ICIs) have shown a significant survival benefit in some patients with advanced NSCLC and are being evaluated for perioperative use in resectable NSCLC., Methods: We conducted a literature search using the PubMed online database to identify clinical trials of immunotherapy in resectable NSCLC and studies analyzing biomarkers and immune priming strategies., Results: Building on previous phase I and II trials, randomized phase III trials have shown efficacy of neoadjuvant nivolumab, perioperative pembrolizumab, adjuvant atezolizumab, and adjuvant pembrolizumab in the treatment of NSCLC with improvement of event-free/disease-free survival of 24% to 42%, leading to United States Food and Drug Administration approval of these drugs in the treatment of resectable NSCLC. Three additional phase III trials have also recently reported the use of immunotherapy both before and after surgery, with pathologic complete response rates of 17% to 25%, significantly better than chemotherapy alone. Perioperative ICI therapy has comparable perioperative morbidity to chemotherapy alone and does not impair surgical outcomes., Conclusions: Perioperative immunotherapy, in combination with chemotherapy, is safe and improves outcomes in patients with resectable NSCLC. Questions regarding patient selection, the need for adjuvant ICI therapy after neoadjuvant chemoimmunotherapy, and the duration of perioperative immunotherapy remain to be answered by future trials., (Copyright © 2024 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

The new grading system for lung adenocarcinoma proposed by the International Association for the Study of Lung Cancer (IASLC) defines prognostic subgroups on the basis of histologic patterns observed on surgical specimens. This study sought to provide novel insights into the IASLC grading system, with particular focus on recurrence-specific survival (RSS) and lung cancer-specific survival among patients with stage I adenocarcinoma. Under the IASLC grading system, tumors were classified as grade 1 (lepidic predominant with <20% high-grade patterns [micropapillary, solid, and complex glandular]), grade 2 (acinar or papillary predominant with <20% high-grade patterns), or grade 3 (≥20% high-grade patterns). Kaplan-Meier survival estimates, pathologic features, and genomic profiles were investigated for patients whose disease was reclassified into a higher grade under the IASLC grading system on the basis of the hypothesis that they would strongly resemble patients with predominant high-grade tumors. Overall, 423 (29%) of 1443 patients with grade 1 or 2 tumors classified based on the predominant pattern-based grading system had their tumors upgraded to grade 3 based on the IASLC grading system. The RSS curves for patients with upgraded tumors were significantly different from those for patients with grade 1 or 2 tumors (log-rank P < .001) but not from those for patients with predominant high-grade patterns (P = .3). Patients with upgraded tumors had a similar incidence of visceral pleural invasion and spread of tumor through air spaces as patients with predominant high-grade patterns. In multivariable models, the IASLC grading system remained significantly associated with RSS and lung cancer-specific survival after adjustment for aggressive pathologic features such as visceral pleural invasion and spread of tumor through air spaces. The IASLC grading system outperforms the predominant pattern-based grading system and appropriately reclassifies tumors into higher grades with worse prognosis, even after other pathologic features of aggressiveness are considered., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Research into the risk factors associated with late recurrence (>2 years after surgery) of lung adenocarcinoma is limited. We investigated the incidence of and clinicopathologic and genomic features associated with late recurrence of resected stage I-IIIA lung adenocarcinoma., Methods: We performed a retrospective analysis of patients with completely resected pathologic stage I-IIIA lung adenocarcinoma (2010-2019). Patients with a history of lung cancer, neoadjuvant therapy, or mucinous or noninvasive lung adenocarcinoma, or with follow-up of less than 2 years were excluded. Cox and logistic regression modeling were used to compare clinicopathologic variables among patients with no, early (≤2 years), and late recurrence. Comparisons of genomic mutations were corrected for multiple testing., Results: Of the 2349 patients included, 537 developed a recurrence during follow-up. Most recurrences (55% [297/537]) occurred early; 45% (240/537) occurred late. A larger proportion of late recurrences than early recurrences were locoregional (37% vs 29%; P = .047). Patients with late recurrence had more aggressive pathologic features (International Association for the Study of Lung Cancer grade 2 and 3, lymphovascular invasion, visceral pleural invasion) and higher stage than patients without recurrence. Pathologic features were similar between patients with early and late recurrence, except stage IIIA disease was more common in the early cohort. No genomic mutations were associated with late recurrence., Conclusions: Late recurrence of lung adenocarcinoma after resection is more common than previously reported. Patients without disease more than 2 years after surgery who had aggressive pathologic features at the time of resection have an elevated risk of recurrence and may benefit from more aggressive follow-up., Competing Interests: Conflict of Interest Statement B.J.P. has received honoraria from Intuitive Surgical, AstraZeneca, Medtronic, consultants for CEEVRA, and has received research support from Intuitive Surgical. P.S.A. declares research funding from ATARA Biotherapeutics, is a scientific advisory board member/consultant for ATARA Biotherapeutics, Bayer, Bio4T2, Carisma Therapeutics, Imugene, ImmPactBio, Johnson & Johnson, Orion, and Outpace Bio, has patents, royalties, and intellectual property on T-cell therapies, licensed to ATARA Biotherapeutics, and has an issued patent method for detection of cancer cells using virus and pending patent applications on PD-1 dominant negative receptor, a wireless pulse-oximetry device, and an ex vivo malignant pleural effusion culture system. M.S.K. has licensed intellectual property related to mesothelin-targeted chimeric antigen receptors and T-cell therapies to ATARA Biotherapeutics. D.M. serves on a steering committee for AstraZeneca, consults for Johnson & Johnson, Bristol-Myers Squibb, AstraZeneca, and Boston Scientific, and has been an invited speaker for Merck and Genentech. S.S. serves on the AstraZeneca Advisory Board. M.J.B. consults for AstraZeneca Pharmaceuticals, Iovance Biotherapeutics, and Intuitive Surgical and receives research support from Obsidian Therapeutics. G.R. has financial relationships with Scanlan International, AstraZeneca, and Medtronic. J.M.I. has served on advisory boards for AstraZeneca and Merck, as an uncompensated steering board member for Genentech, has received research support from ArcherDx/Invitae, Guardant Health, GRAIL, and Intuitive Surgical and travel support from Intuitive Surgical, and has equity/ownership interest in LumaCyte. D.R.J. serves on the Advisory Council for AstraZeneca and receives research grant support from Merck. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2024 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: Shape-sensing robotic-assisted bronchoscopy is an emerging technology for the sampling of pulmonary lesions. We seek to characterize the shape-sensing robotic-assisted bronchoscopy learning curve at an academic center., Methods: Shape-sensing robotic-assisted bronchoscopy procedures performed by 9 proceduralists at a single institution were analyzed. Cumulative sum analyses were performed to examine diagnostic sampling and procedure time over each operator's first 50 cases, with the acceptable yield threshold set to 73%., Results: During the study period, 442 patients underwent sampling of 551 lesions. Each operator sampled 61 lesions (interquartile range, 60-63 lesions). Lesion size was 1.90 cm (interquartile range, 1.33-2.80 cm). The median procedure time for single-target cases decreased from 62 minutes during the first 10 cases to 39 minutes after case 40 (P < .001). The overall diagnostic yield was 72% (range, 58%-83%). Six of 9 operators achieved proficiency over the study period. An aggregated cumulative sum analysis of those who achieved competency demonstrated a steep improvement between lesions 1 and 21 and crossing of the competency threshold by lesion 25. Temporal analysis of yield-related lesion characteristics demonstrated that at approximately lesion 20, more challenging lesions were increasingly targeted, as evidenced by smaller target size, higher rates of unfavorable radial endobronchial ultrasound views, and a negative bronchus sign., Conclusions: Skills acquisition in shape-sensing robotic-assisted bronchoscopy is variable. Approximately half of proceduralists become facile with the technology within 25 lesions. After the initial learning phase, operators increasingly target lesions with more challenging features. Overall, these findings can inform certification and competency standards and provide new users with expectations related to performance over time., Competing Interests: Conflict of Interest Statement Dr Boot has received consulting fees from Astra-Zeneca and Intuitive Surgical, speaker honoraria from Intuitive Surgical, and research funding from Obsidian Biotherapeutics. Dr Husta has received speaker fees from Intuitive Surgical and Siemens Healthineers. Dr Adusumilli received research funding from ATARA Biotherapeutics, is a Scientific Advisory Board member and consultant for ATARA Biotherapeutics, Bayer, Bio4T2, Carisma Therapeutics, Imugene, ImmPactBio, Johnston & Johnston, Orion Pharma, and Outpace Bio, and holds patents, royalties and intellectual property on mesothelin-targeted CAR and other T-cell therapies that have been licensed to ATARA Biotherapeutics, issued patent method for detection of cancer cells using virus, and pending patent applications on PD-1 dominant negative receptor, wireless pulse-oximetry device, and on an ex vivo malignant pleural effusion culture system. Dr Beattie has received consultant and speaker fees from Intuitive Surgical. Dr Park has received speaker honoraria from Intuitive Surgical and Medtronic and is a stockholder with CEEVRA. Dr Jones is a member of the Advisory Council for AstraZeneca and receives research grant support from Merck. Dr Chawla is a member of the Ion Medical Advisory Board for Intuitive Surgical. Dr Rocco has financial relationships with Medtronic, Merck, and Scanlan International. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2024 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Most patients with pleural mesothelioma (PM) present with symptomatic pleural effusion. In some patients, PM is only detectable on the pleural surfaces, providing a strong rationale for intrapleural anticancer therapy. In modern prospective studies involving expert radiological staging and specialist multidisciplinary teams, the population incidence of stage I PM (an approximate surrogate of pleura-only PM) is higher than in historical retrospective series. In this Viewpoint, we advocate for the expansion of intrapleural trials to serve these patients, given the paucity of data supporting licensed systemic therapies in this setting and the uncertainties involved in surgical therapy. We begin by reviewing the unique anatomical and physiological features of the PM-bearing pleural space, before critically appraising the evidence for systemic therapies in stage I PM and previous intrapleural PM trials. We conclude with a summary of key challenges and potential solutions, including optimal trial designs, repurposing of indwelling pleural catheters, and new technologies., Competing Interests: Declaration of interests KGB declares institutional grant funding from Rocket Medical and RS Oncology; lecture honoraria from Bristol-Myers Squibb; and the role of chief investigator of the PREDICT-Meso International Accelerator Network. PSA declares research funding from ATARA Biotherapeutics; patents, royalties, and intellectual property on therapies licensed to ATARA Biotherapeutics; and scientific advisory board membership and consulting fees from ATARA Biotherapeutics, Bayer, Bio4T2, Carisma Therapeutics, Imugene, ImmPactBio, Johnson & Johnson, Orion Pharma, and Outpace Bio. PA declares equipment loans for courses from Novatech, Wolf, and Olympus. LD declares lecture honoraria from Bristol-Myers Squibb. YCGL declares receipt of equipment from Rocket Medical for use in clinical trials. ASM declares institutional grant funding from Novartis and Verily; consulting fees from Rising Tide and TRIPTYCH Health Partners; institutional payments or honoraria from Janssen, BeiGene, Chugai Pharmaceutical (Roche), Ideology Health (formerly Health Media), Antoni van Leeuwenhoek Kanker Instituut, AXIS Medical Education, Johnson & Johnson Global Services, Intellisphere, Answers in CME, University of Miami International Mesothelioma Symposium, and Immunocore; support for attending meetings from Shanghai Roche; membership of scientific advisory boards for AbbVie, AstraZeneca, Bristol-Myers Squibb, Genentech/Roche, Takeda Oncology, and Sanofi Genzyme; and study funding from Bristol-Myers Squibb. SJM is co-principal investigator of the Engineering and Physical Sciences Research Council Interdisciplinary Research Collaboration in Targeted Delivery for Hard-to-Treat Cancers; he declares consulting fees from DefiniGEN, and support for attending meetings from Alpha-1 Foundation, Federation of American Societies for Experimental Biology, and Mesothelioma UK. NM declares consulting fees from Rocket Medical UK, Cook Medical UK, and Becton Dickinson. VP declares grant funding from the Danish Comprehensive Cancer Center and no conflicts of interest within the scope of this Viewpoint. NMR declares consulting fees from Rocket Medical UK, Cook Medical UK, and LTI USA. MGZ declares institutional grant funding from Medimmune, Precog, GSK, Epizyme, Polaris, Sellas Life Sciences, Bristol-Myers Squibb, Millenium, Curis, and Atara; consulting fees from Curis, Ikena, Takeda, GSK, and Novocure; and honoraria from PER and Medscape. DS declares support including research funding and consulting fees from AstraZeneca, Boehringer Ingelheim, Exigo Management, Flame Biosciences, HitchBio, Intuitive Surgical, Janssen, Johnson & Johnson, Medscape, Olympus Corporation of the Americas (also known as Spiration), Sensei Biotherapeutics, Trizell, Trustees of the University of Pennsylvania, Verismo, and Wolters Kluwer Health. DAF declares institutional grants from Aldeyra, Astex Therapeutics, Bayer Oncology, Bergen Bio, Boehringer Ingelheim, Clovis Oncology, Eli Lilly, Lovance, MSD, Owkin, Roche Oncology, and RS Oncology; consulting fees from Cambridge Clinical Laboratories and RS Oncology; honoraria from MSD and Bristol-Myers Squibb; support for attending meetings from RS Oncology; and participation on data monitoring or advisory boards for AstraZeneca and RS Oncology. TP declares no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Objective: There is a lack of knowledge regarding the use of prognostic features in stage I lung adenocarcinoma (LUAD). Thus, we investigated clinicopathologic features associated with recurrence after complete resection for stage I LUAD., Methods: We performed a retrospective analysis of patients with pathologic stage I LUAD who underwent R0 resection from 2010 to 2020. Exclusion criteria included history of lung cancer, induction or adjuvant therapy, noninvasive or mucinous LUAD, and death within 90 days of surgery. Fine and Gray competing-risk regression assessed associations between clinicopathologic features and disease recurrence., Results: In total, 1912 patients met inclusion criteria. Most patients (1565 [82%]) had stage IA LUAD, and 250 developed recurrence: 141 (56%) distant and 109 (44%) locoregional only. The 5-year cumulative incidence of recurrence was 12% (95% CI, 11%-14%). Higher maximum standardized uptake value of the primary tumor (hazard ratio [HR], 1.04), sublobar resection (HR, 2.04), higher International Association for the Study of Lung Cancer grade (HR, 5.32 [grade 2]; HR, 7.93 [grade 3]), lymphovascular invasion (HR, 1.70), visceral pleural invasion (HR, 1.54), and tumor size (HR, 1.30) were independently associated with a hazard of recurrence. Tumors with 3 to 4 high-risk features had a higher cumulative incidence of recurrence at 5 years than tumors without these features (30% vs 4%; P < .001)., Conclusions: Recurrence after resection for stage I LUAD remains an issue for select patients. Commonly reported clinicopathologic features can be used to define patients at high risk of recurrence and should be considered when assessing the prognosis of patients with stage I disease., Competing Interests: Conflict of Interest Statement Dr Rocco has financial relationships with Scanlan International, AstraZeneca, and Medtronic. Dr Molena serves on a steering committee for AstraZeneca, consults for Johnson & Johnson, Bristol-Myers Squibb, AstraZeneca, Boston Scientific, and has been an invited speaker for Merck and Genentech. Dr Park has received honoraria from Intuitive Surgical, AstraZeneca, Medtronic, consults for CEEVRA, and has received research support from Intuitive Surgical. Dr Chaft consults for AstraZeneca, Bristol-Myers Squibb, Merck, Regeneron-Sanofi, Guardant Health, and Lily and receives research funding from AztraZeneca, Bristol-Myers Squibb, Merck, and Beigene. Dr Bott consults for AstraZeneca, Iovance Biotherapeutics, Intuitive Surgical, and receives research support from Obsidian Therapeutics. Dr Rusch reports grant support from Genelux and Genentech, and travel support from Intuitive Surgical and National Institutes of Health/Coordinating Center for Clinical Trials. Dr Adusumilli declares research funding from ATARA Biotherapeutics; is a scientific advisory board member and consultant for ATARA Biotherapeutics, Bayer, Bio4T2, Carisma Therapeutics, Imugene, ImmPactBio, Johnson & Johnson, Orion, and Outpace Bio; has patents, royalties, and intellectual property on T-cell therapies licensed to ATARA Biotherapeutics; and has an issued patent method for detection of cancer cells using virus and pending patent applications on PD-1 dominant negative receptor, a wireless pulse-oximetry device, and an ex vivo malignant pleural effusion culture system. Dr Sihag serves on the AstraZeneca advisory board. Dr Isbell has served on advisory boards for AstraZeneca and Merck; as an uncompensated steering board member for Genentech; has received research support from ArcherDx/Invitae, Guardant Health, GRAIL, Intuitive Surgical; has received travel support from Intuitive Surgical; and has equity/ownership interest in LumaCyte. Dr Jones serves on the advisory council for AstraZeneca and receives research grant support from Merck. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2024 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

9p21 deletions involving MTAP/CDKN2A genes are detected in diffuse pleural mesotheliomas (DPM) but are absent in benign mesothelial proliferations. Loss of MTAP expression by immunohistochemistry (IHC) is well accepted as a surrogate for 9p21 deletion to support a diagnosis of DPM. Accurate interpretation can be critical in the diagnosis of DPM, but variations in antibody performance may impact interpretation. The objectives of this study were to compare the performance of MTAP monoclonal antibodies (mAbs) EPR6893 and 1813 and to compare MTAP expression by IHC with 9p21 copy number status in DPM. Cytoplasmic expression of MTAP IHC with mAbs EPR6893 (ab126770; Abcam) and 1813 (NBP2-75730, Novus Biologicals) was evaluated in 56 DPM (47 epithelioid, 7 biphasic, and 2 sarcomatoid) profiled by targeted next-generation sequencing. 9p21 Copy number status was assessed by Fraction and Allele-Specific Copy Number Estimates from Tumor Sequencing (FACETS) analysis and also by CDKN2A fluorescence in situ hybridization in discrepant cases when material was available. MTAP mAb 1813 showed stronger immunoreactivity, more specific staining, and no equivocal interpretations compared to mAb EPR6893 which showed equivocal staining in 19 (34%) of cases due to weak or heterogenous immunoreactivity, lack of definitive internal positive control, and/or nonspecific background staining. MTAP expression with mAb 1813 showed near perfect agreement with 9p21 copy number by combined FACETS/fluorescence in situ hybridization calls (κ = 0.85; 95% CI, 0.71-0.99; P < .001). MTAP IHC with mAb 1813 was 96% sensitive, 86% specific, and 93% accurate for 9p21 homozygous deletion. The findings of this study suggest that interpretation of MTAP IHC is improved with mAb 1813 because mAb EPR6893 was often limited by equivocal interpretations. We show that MTAP IHC and molecular assays are complementary in detecting 9p21 homozygous deletion. MTAP IHC may be particularly useful for low tumor purity samples and in low-resource settings., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The objective of this study is to determine the outcomes and toxicities of patients with malignant pleural mesothelioma (MPM) treated with stereotactic body radiotherapy (SBRT)., Materials and Methods: Data were extracted from an institutional tumor registry for patients diagnosed with mesothelioma and treated with SBRT. Kaplan-Meier and Cox regression analyses were employed to determine local control (LC) and overall survival (OS)., Results: Forty-four patients with 59 total treated tumors from December 2006 to April 2022 were identified. Fifty-one (86.4 %) cases had oligoprogressive disease (five sites or less). The median prescription dose delivered was 3000 cGy in 5 fractions (range: 2700-6000 cGy in 3-8 fractions). Fifty-one (86.4 %) tumors were in the pleura, 4 (6.8 %) spine, 2 (3.4 %) bone, 1 (1.7 %) brain, and 1 (1.7 %) pancreas. The median follow-up from SBRT completion for those alive at last follow-up was 28 months (range: 14-52 months). The most common toxicities were fatigue (50.8 %), nausea (22.0 %), pain flare (15.3 %), esophagitis (6.8 %), dermatitis (6.8 %), and pneumonitis (5.1 %). There were no grade ≥ 3 acute or late toxicities. There were 2 (3.4 %) local failures, one of the pleura and another of the spine. One-year LC was 92.9 % (95 % CI: 74.6-98.2 %) for all lesions and 96.3 % (95 % CI: 76.5-99.5 %) for pleural tumors. One-year LC was 90.9 % (95 % CI: 68.1-97.6 %) for epithelioid tumors and 92.1 % (95 % CI: 72.1-98.0 %) for oligoprogressive tumors. One-year OS from time of SBRT completion was 36.4 % (95 % CI: 22.6-50.3 %). On multivariable analysis, KPS was the lone significant predictor for OS (p = 0.029)., Conclusions: Our single-institutional experience on patients with MPM suggests that SBRT is safe with a low toxicity profile and potentially achieve good local control., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jacob Y. Shin-No conflicts of interest to disclose. Michael Offin-Dr. Offin has consulted regarding oncology drug development with Novartis, Jazz, and PharmaMar; and has received honorarium from Targeted Oncology, OncLive, and the American Society for Radiation Oncology. Charles B. Simone II-Dr. Simone II reported receiving honoraria from Varian Medical Systems outside the submitted work. Zhigang Zhang-No conflicts of interest to disclose. Annemarie F. Shepherd-Dr. Shepherd reported having stock or stock options in Doximity and ArcellX. Abraham J. Wu-Dr. Wu reported receiving grants from CivaTech Oncology; receiving personal fees from MoreHealth, AstraZeneca, and Nanovi; receiving travel expenses from AlphaTau; and serving on the scientific advisory board of Simphotek outside the submitted work. Narek Shaverdian-Dr. Shaverdian reported receiving research funding from Novartis outside the submitted work. Daphna Y. Gelblum-No conflicts of interest to disclose. Daniel R. Gomez-Dr. Gomez reported receiving grants from Merck, AstraZeneca, Varian Medical Systems, and Bristol Myers Squibb during the conduct of the study and receiving personal fees from Bristol Myers Squibb, Reflexsion, Merck, Medscape, Vindico, US Oncology, MedLearning Group, AstraZeneca, GRAIL, Medtronic, Johnson & Johnson, and Varian Medical Systems outside the submitted work. Jennifer L. Sauter-Dr. Sauter reported having stock or stock options in Chemed Corporation, Merck & Co., Inc., Pfizer, Inc., and Thermo Fisher Scientific. Michelle S. Ginsberg-No conflicts of interest to disclose. Prasad S. Adusumilli-Dr. Adusumilli is a scientific advisory board member and consultant for ATARA Biotherapeutics, Bayer, Carisma Therapeutics, Imugene, ImmPACT Bio, Johnson & Johnson, and Outpace Bio; declares having patents, royalties, and intellectual property on mesothelin-targeted CAR and other T-cell therapies, which have been licensed to ATARA Biotherapeutics, issued patent method for detection of cancer cells using virus, and pending patent applications on PD-1–dominant negative receptor, wireless pulse oximetry device, and on an exvivo malignant pleural effusion culture system. Memorial Sloan Kettering Cancer Center (MSK) has licensed intellectual property related to mesothelin-targeted CARs and T-cell therapies to ATARA Biotherapeutics and has associated financial interests. Valerie W. Rusch-Dr. Rusch reported receiving grants from the National Institutes of Health (NIH)/National Cancer Institute, during the conduct of the study; grants from Genelux, Inc.; grants from Genentech, other from DaVinci Surgery; nonfinancial support from Bristol Myers Squibb; and personal fees from the NIH/Coordinating Center For Clinical Trials, outside the submitted work. Marjorie G. Zauderer-In the last 3 years, Dr. Zauderer has received consulting fees from Curis, Ikena, Takeda, GlaxoSmithKline, and Novocure and honoraria for CME content from PER, Medscape, and Research to Practice. Memorial Sloan Kettering receives research funding from the Department of Defense, the National Institutes of Health, MedImmune, Precog, GlaxoSmithKline, Epizyme, Polaris, Sellas Life Sciences, Bristol Myers Squibb, Millenium/Takeda, Curis, and Atara for research conducted by Dr. Zauderer. Dr. Zauderer serves as Chair of the Board of Directors of the Mesothelioma Applied Research Foundation, uncompensated. Andreas Rimner-Dr. Rimner has consulted regarding oncology drug development with AstraZeneca, Merck, Boehringer Ingelheim, and Cybrexa; has received honorarium from MoreHealth and ResearchToPractice; has served on a scientific advisory board of Merck; and has received grants from Varian Medical Systems, Boehringer Ingelheim, Pfizer, AstraZeneca, and Merck., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: This study compared outcomes in patients with solid tumor treated for pericardial effusion with surgical drainage versus interventional radiology (IR) percutaneous drainage and compared incidence of paradoxical hemodynamic instability (PHI) between cohorts., Background: Patients with advanced-stage solid malignancies may develop large pericardial effusions requiring intervention. PHI is a fatal and underreported complication that occurs following pericardial effusion drainage., Methods: Clinical characteristics and outcomes were compared between patients with solid tumors who underwent s urgical drainage or IR percutaneous drainage for pericardial effusion from 2010 to 2020., Results: Among 447 patients, 243 were treated with surgical drainage, of which 27 (11%) developed PHI, compared with 7 of 204 patients (3%) who were treated with IR percutaneous drainage ( P =0.002); overall incidence of PHI decreased during the study period. Rates of reintervention (30-day: 1% vs 4%; 90-day: 4% vs 6%, P =0.7) and mortality (30-day: 21% vs 17%, P =0.3; 90-day: 39% vs 37%, P =0.7) were not different between patients treated with surgical drainage and IR percutaneous drainage. For both interventions, OS was shorter among patients with PHI than among patients without PHI (surgical drainage, median [95% confidence interval] OS, 0.89 mo [0.33-2.1] vs 6.5 mo [5.0-8.9], P <0.001; IR percutaneous drainage, 3.7 mo [0.23-6.8] vs 5.0 mo [4.0-8.1], P =0.044)., Conclusions: With a coordinated multidisciplinary approach focusing on prompt clinical and echocardiographic evaluation, triage with bias toward IR percutaneous drainage than surgical drainage and postintervention intensive care resulted in lower incidence of PHI and improved outcomes., Competing Interests: J.E.L. serves as a consultant for Caption Health and on the Data and Safety Monitoring Board of Caelum Biosciences. Her research is supported by Johnson and Johnson. H.Y. serves as an advisory board member for AstraZeneca and Guerbet LLC, and he receives grant support from Guerbet LLC and the Thompson Family Foundation. E.Z. has research grants from AACR, NETRF, NANETS, Druckenmiller, MSK, SIR, RSNA, Ethicon, and Novartis. S.B.S. serves as a consultant to GE Healthcare and XACT Robotics. B.J.P. has served as a proctor for Intuitive Surgical and a consultant for COTA. D.R.J. serves as a consultant for AstraZeneca and on a Clinical Trial Steering Committee for Merck. P.S.A. declares research funding from ATARA Biotherapeutics; Scientific Advisory Board Member and Consultant for ATARA Biotherapeutics, Bayer, Bio4T2, Carisma Therapeutics, Imugene, ImmPactBio, Johnston & Johnston, Orion pharma, Outpace Bio; Patents, royalties and intellectual property on mesothelin-targeted CAR and other T-cell therapies, which have been licensed to ATARA Biotherapeutics, issued patent method for detection of cancer cells using virus, and pending patent applications on PD-1 dominant negative receptor, wireless pulse-oximetry device, and on an ex vivo malignant pleural effusion culture system. Memorial Sloan Kettering Cancer Center has licensed intellectual property related to mesothelin-targeted CARs and T-cell therapies to ATARA Biotherapeutics and has associated financial interests. The remaining authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Cohen's kappa is often used to quantify the agreement between two pathologists. Nevertheless, a high prevalence of the feature of interest can lead to seemingly paradoxical results, such as low Cohen's kappa values despite high "observed agreement." Here, we investigate Cohen's kappa using data from histologic subtyping assessment of lung adenocarcinomas and introduce alternative measures that can overcome this "kappa paradox.", Methods: A total of 50 frozen sections from stage I lung adenocarcinomas less than or equal to 3 cm in size were independently reviewed by two pathologists to determine the absence or presence of five histologic patterns (lepidic, papillary, acinar, micropapillary, solid). For each pattern, observed agreement (proportion of cases with concordant "absent" or "present" ratings) and Cohen's kappa were calculated, along with Gwet's AC1., Results: The prevalence of any amount of the histologic patterns ranged from 42% (solid) to 97% (acinar). On the basis of Cohen's kappa, there was substantial agreement for four of the five patterns (lepidic, 0.65; papillary, 0.67; micropapillary, 0.64; solid, 0.61). Acinar had the lowest Cohen's kappa (0.43, moderate agreement), despite having the highest observed agreement (88%). In contrast, Gwet's AC1 values were close to or higher than Cohen's kappa across patterns (lepidic, 0.64; papillary, 0.69; micropapillary, 0.71; solid, 0.73; acinar, 0.85). The proportion of positive versus negative agreement was 93% versus 50% for acinar., Conclusions: Given the dependence of Cohen's kappa on feature prevalence, interrater agreement studies should include complementary indices such as Gwet's AC1 and proportions of specific agreement, especially in settings with a high prevalence of the feature of interest., (© 2024 The Authors.)

Objectives: The aim of this study was to compare postoperative outcomes between biologic and synthetic reconstructions after chest wall resection in a matched cohort., Methods: All patients who underwent reconstruction after full-thickness chest wall resection from 2000 to 2022 were reviewed and stratified by prosthesis type (biologic or synthetic). Biologic prostheses were of biologic origin or were fully absorbable and incorporable. Integer matching was performed to reduce confounding. The study end point was surgical site complications requiring reoperation. Multivariable analysis was performed to identify associated risk factors., Results: In total, 438 patients underwent prosthetic chest wall reconstruction (unmatched: biologic, n = 49; synthetic, n = 389; matched: biologic, n = 46; synthetic, n = 46). After matching, the median (interquartile range) defect size was 83 cm2 (50-142) for the biologic group and 90 cm2 (48-146) for the synthetic group (P = 0.97). Myocutaneous flaps were used in 33% of biologic reconstructions (n = 15) and 33% of synthetic reconstructions (n = 15) in the matched cohort (P = 0.99). The incidence of surgical site complications requiring reoperation was not significantly different between biologic and synthetic reconstructions in the unmatched (3 [6%] vs 29 [7%]; P = 0.99) and matched (2 [4%] vs 4 [9%]; P = 0.68) cohorts. On the multivariable analysis, operative time [adjusted odds ratio (aOR) = 1.01, 95% confidence interval (CI), 1.00-1.01; P = 0.006] and operative blood loss (aOR = 1.00, 95% CI, 1.00-1.00]; P = 0.012) were associated with higher rates of surgical site complications requiring reoperation; microvascular free flaps (aOR = 0.03, 95% CI, 0.00-0.42; P = 0.024) were associated with lower rates., Conclusions: The incidence of surgical site complications requiring reoperation was not significantly different between biologic and synthetic prostheses in chest wall reconstructions., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objective: To investigate the association between operative time and postoperative outcomes., Background: The association between operative time and morbidity after pulmonary lobectomy has not been characterized fully., Methods: Patients who underwent pulmonary lobectomy for primary lung cancer at our institution from 2010 to 2018 were reviewed. Exclusion criteria included clinical stage ≥IIb disease, conversion to thoracotomy, and previous ipsilateral lung treatment. Operative time was measured from incision to closure. Relationships between operative time and outcomes were quantified using multivariable mixed-effects models with surgeon-level random effects., Results: In total, 1651 patients were included. The median age was 68 years (interquartile range, 61-74), and 63% of patients were women. Median operative time was 3.2 hours (interquartile range, 2.7-3.8) for all cases, 3.0 hours for open procedures, 3.3 hours for video-assisted thoracoscopies, and 3.3 hours for robotic procedures ( P =0.0002). Overall, 488 patients (30%) experienced a complication; 77 patients (5%) had a major complication (grade ≥3), and 5 patients (0.3%) died within 30 days of discharge. On multivariable analysis, operative time was associated with higher odds of any complication [odds ratio per hour, 1.37; 95% confidence interval (CI), 1.20-1.57; P <0.0001] and major complication (odds ratio per hour, 1.41; 95% CI, 1.21-1.64; P <0.0001). Operative time was also associated with longer hospital length of stay (β, 1.09; 95% CI, 1.04-1.14; P =0.001)., Conclusions: Longer operative time was associated with worse outcomes in patients who underwent lobectomy. Operative time is a potential risk factor to consider in the perioperative phase., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Current in vitro and in vivo assays used to study immunotherapeutic interventions lack human immune components that mimic the tumor microenvironment to investigate drug potency and limitations of efficacy. Herein, we describe an ex vivo pleural effusion culture (ePEC) assay, using malignant pleural-effusion-derived soluble and cellular factors that differentially affected the cytotoxicity of chimeric antigen receptor (CAR) T cells. Following identification of CAR T cell-suppressive factors, blocking of individual factors reveals their contribution to compromising T cell efficacy. ePEC is a human component assay that can be utilized for developing next-generation cell and antibody therapies that counteract immunosuppression., Competing Interests: Declaration of interests P.S.A. declares research funding from ATARA Biotherapeutics; is a scientific advisory board member and consultant for ATARA Biotherapeutics, Bayer, Carisma Therapeutics, Imugene, ImmPactBio, and Johnston & Johnston; has patents, royalties, and intellectual property on MSLN-targeted CAR and other T cell therapies, which have been licensed to ATARA Biotherapeutics; issued a patent method for detection of cancer cells using virus; and has pending patent applications on PD-1 dominant negative receptor, a wireless pulse-oximetry device, and an ex vivo MPE culture system (US20210190760). The Memorial Sloan Kettering Cancer Center (MSK) has licensed intellectual property related to MSLN-targeted CARs and T cell therapies to ATARA Biotherapeutics and has associated financial interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Lung adenocarcinoma (ADC) is the most common non-small cell lung cancer. Surgical resection is the primary treatment for early-stage lung ADC while lung-sparing surgery is an alternative for non-aggressive cases. Identifying histopathologic subtypes before surgery helps determine the optimal surgical approach. Predominantly solid or micropapillary (MIP) subtypes are aggressive and associated with a higher likelihood of recurrence and metastasis and lower survival rates. This study aims to non-invasively identify these aggressive subtypes using preoperative 18 F-FDG PET/CT and diagnostic CT radiomics analysis. We retrospectively studied 119 patients with stage I lung ADC and tumors ≤ 2 cm, where 23 had aggressive subtypes (18 solid and 5 MIPs). Out of 214 radiomic features from the PET/CT and CT scans and 14 clinical parameters, 78 significant features (3 CT and 75 PET features) were identified through univariate analysis and hierarchical clustering with minimized feature collinearity. A combination of Support Vector Machine classifier and Least Absolute Shrinkage and Selection Operator built predictive models. Ten iterations of 10-fold cross-validation (10 ×10-fold CV) evaluated the model. A pair of texture feature (PET GLCM Correlation) and shape feature (CT Sphericity) emerged as the best predictor. The radiomics model significantly outperformed the conventional predictor SUV max (accuracy: 83.5% vs. 74.7%, p = 9e-9) and identified aggressive subtypes by evaluating FDG uptake in the tumor and tumor shape. It also demonstrated a high negative predictive value of 95.6% compared to SUV max (88.2%, p = 2e-10). The proposed radiomics approach could reduce unnecessary extensive surgeries for non-aggressive subtype patients, improving surgical decision-making for early-stage lung ADC patients., Competing Interests: This work was supported in part by the NIH/NCI Grant No. R01 CA172638 and the NIH/NCI Cancer Center Support Grant P30 CA008748 and 5P30 CA056036. The authors have no relevant conflicts of interest to disclose., (© 2023 The Authors.)

Objective: To investigate the utility of serum soluble mesothelin-related peptide (SMRP) and tumor mesothelin expression in the management of esophageal adenocarcinoma (ADC)., Background: Clinical management of esophageal ADC is limited by a lack of accurate evaluation of tumor burden, treatment response, and disease recurrence. Our retrospective data showed that tumor mesothelin and its serum correlate, SMRP, are overexpressed and associated with poor outcomes in patients with esophageal ADC., Methods: Serum SMRP and tumoral mesothelin expression from 101 patients with locally advanced esophageal ADC were analyzed before induction chemoradiation (pretreatment) and at the time of resection (posttreatment), as a biomarker for treatment response, disease recurrence, and overall survival (OS)., Results: Pre and posttreatment serum SMRP was ≥1 nM in 49% and 53%, and pre and post-treatment tumor mesothelin expression was >25% in 35% and 46% of patients, respectively. Pretreatment serum SMRP was not significantly associated with tumor stage ( P = 0.9), treatment response (radiologic response, P = 0.4; pathologic response, P = 0.7), or recurrence ( P =0.229). Pretreatment tumor mesothelin expression was associated with OS (hazard ratio: 2.08; 95% CI: 1.14-3.79; P = 0.017) but had no statistically significant association with recurrence ( P = 0.9). Three-year OS of patients with pretreatment tumor mesothelin expression of ≤25% was 78% (95% CI: 68%-89%), compared with 49% (95% CI: 35%-70%) among those with >25%., Conclusions: Pretreatment tumor mesothelin expression is prognostic of OS for patients with locally advanced esophageal ADC, whereas serum SMRP is not a reliable biomarker for monitoring treatment response or recurrence., Competing Interests: P.S.A. declares research funding from ATARA Biotherapeutics; Scientific Advisory Board Member and Consultant for ATARA Biotherapeutics, Abound Bio, Adjuvant Genomics, Bayer, Carisma Therapeutics, Imugene, ImmPactBio, Johnston and Johnston, Orion pharma, OutpaceBio; Patents, royalties and intellectual property on mesothelin-targeted CAR and other T-cell therapies, which have been licensed to ATARA Biotherapeutics, issued patent method for detection of cancer cells using virus, and pending patent applications on PD-1 dominant negative receptor, wireless pulse-oximetry device, and on an ex vivo malignant pleural effusion culture system. His laboratory work is supported by grants from the National Institutes of Health (P30 CA008748, R01 CA236615-01, R01 CA235667, and U01 CA214195), the U.S. Department of Defense (BC132124, LC160212, CA170630, CA180889, and CA200437), the Batishwa Fellowship, the Cycle for Survival fund, the Comedy versus Cancer Award, the DallePezze Foundation, the Derfner Foundation, the Esophageal Cancer Education Fund, the Geoffrey Beene Foundation, the Memorial Sloan Kettering Technology Development Fund, the Miner Fund for Mesothelioma Research, the Mr. William H. Goodwin and Alice Goodwin, the Commonwealth Foundation for Cancer Research, and the Experimental Therapeutics Center of Memorial Sloan Kettering Cancer Center. Memorial Sloan Kettering Cancer Center has licensed intellectual property related to mesothelin-targeted CARs and T-cell therapies to ATARA Biotherapeutics and has associated financial interests. David Restle and Jennie K. Choe are supported, in part, by the National Institutes of Health (T32CA009501-33). The remaining authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Infiltration of tumor by T cells is a prerequisite for successful immunotherapy of solid tumors. In this study, we investigate the influence of tumor-targeted radiation on chimeric antigen receptor (CAR) T-cell therapy tumor infiltration, accumulation, and efficacy in clinically relevant models of pleural mesothelioma and non-small cell lung cancers. We use a nonablative dose of tumor-targeted radiation prior to systemic administration of mesothelin-targeted CAR T cells to assess infiltration, proliferation, antitumor efficacy, and functional persistence of CAR T cells at primary and distant sites of tumor. A tumor-targeted, nonablative dose of radiation promotes early and high infiltration, proliferation, and functional persistence of CAR T cells. Tumor-targeted radiation promotes tumor-chemokine expression and chemokine-receptor expression in infiltrating T cells and results in a subpopulation of higher-intensity CAR-expressing T cells with high coexpression of chemokine receptors that further infiltrate distant sites of disease, enhancing CAR T-cell antitumor efficacy. Enhanced CAR T-cell efficacy is evident in models of both high-mesothelin-expressing mesothelioma and mixed-mesothelin-expressing lung cancer-two thoracic cancers for which radiotherapy is part of the standard of care. Our results strongly suggest that the use of tumor-targeted radiation prior to systemic administration of CAR T cells may substantially improve CAR T-cell therapy efficacy for solid tumors. Building on our observations, we describe a translational strategy of "sandwich" cell therapy for solid tumors that combines sequential metastatic site-targeted radiation and CAR T cells-a regional solution to overcome barriers to systemic delivery of CAR T cells., (©2023 American Association for Cancer Research.)

Objective: Pedicled flaps (PFs) have historically served as the preferred option for reconstruction of large chest wall defects. More recently, the indications for microvascular-free flaps (MVFFs) have increased, particularly for defects in which PFs are inadequate or unavailable. We sought to compare oncologic and surgical outcomes between MVFFs and PFs in reconstructions of full-thickness chest wall defects., Methods: We retrospectively identified all patients who underwent chest wall resection at our institution from 2000 to 2022. Patients were stratified by flap reconstruction. End points were defect size, rate of complete resection, rate of local recurrence, and postoperative outcomes. Multivariable analysis was performed to identify factors associated with complications at 30 days., Results: In total, 536 patients underwent chest wall resection, of whom 133 had flap reconstruction (MVFF, n = 28; PF, n = 105). The median (interquartile range) covered defect size was 172 cm 2 (100-216 cm 2 ) for patients receiving MVFF versus 109 cm 2 (75-148 cm 2 ) for patients receiving PF (P = .004). The rate of R0 resection was high in both groups (MVFF, 93% [n = 26]; PF, 86% [n = 90]; P = .5). The rate of local recurrence was 4% in MVFF patients (n = 1) versus 12% in PF patients (n = 13, P = .3). Postoperative complications were not statistically different between groups (odds ratio for PF, 1.37; 95% confidence interval, 0.39-5.14]; P = .6). Operative time >400 minutes was associated with 30-day complications (odds ratio, 3.22; 95% confidence interval, 1.10-9.93; P = .033)., Conclusions: Patients with MVFFs had larger defects, a high rate of complete resection, and a low rate of local recurrence. MVFFs are a valid option for chest wall reconstructions., (Copyright © 2023 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: To determine the safety and efficacy of adding the anti-PD-L1 antibody durvalumab to induction FOLFOX and preoperative chemotherapy in locally advanced esophageal adenocarcinoma., Background: Neoadjuvant induction FOLFOX followed by positron emission tomography (PET) directed chemoradiation has demonstrated improved survival for esophageal adenocarcinoma. There is clear benefit now for the addition of immune checkpoint inhibitors both in early and advanced stage disease. Given these results we investigated the safety and efficacy of adding durvalumab to induction FOLFOX and preoperative chemoradiotherapy., Methods: Patients with locally advanced resectable esophageal/gastroesophageal junction adenocarcinoma received PET-directed chemoradiation with durvalumab before esophagectomy. Patients who had R0 resections received adjuvant durvalumab 1500 mg every 4 weeks for 6 treatments. The primary endpoint of the study was pathologic complete response., Results: We enrolled 36 patients, 33 of whom completed all preoperative treatment and underwent surgery. Preoperative treatment was well tolerated, with no delays to surgery nor new safety signals. Pathologic complete response was identified in 8 [22% (1-sided 90% lower bound: 13.3%)] patients with major pathologic response in 22 [61% (1-sided 90% lower bound: 50%)] patients. Twelve and 24-month overall survival was 92% and 85%, respectively., Conclusions: The addition of durvalumab to induction FOLFOX and PET-directed chemoradiotherapy before surgery is safe, with a high rate of pathologic response, as well as encouraging survival data., Competing Interests: G.Y.K. reports grant and personal fees from Astra Zeneca, Bristol-Myers Squibb, and Merck. AJC. A.J.-C.W. reports grant fees from CivaTech Oncology and personal fees from Nanovi A/S and Simphotek Inc. D.R.J. reports personal fees from Astra Zeneca and Merck. S.B.M. reports personal fees from Natera, Bicara, Novartis, Basilea and Daiichi-Sankyo. P.S.A. reports grant and personal fees from ATARA Biotherapeutics, and personal fees from Bayer, Carisma Therapeutics, Imugene, ImmPactBio, Johnson & Johnson, and OutpaceBio. D.H.I. reports personal fees from Astra Zeneca, Bristol-Myers Squibb, Taiho, Merck, Macrogenics, Amgen, Daiichi-Sankyo, Astellas and Adaptimmune. Y.Y.J. reports research funding from Bayer, Bristol-Myers Squibb, Cycle for Survival, Department of Defense, Eli Lilly, Fred’s Team, Genentech/Roche, Merck, NCI, RGENIX and personal fees from Amerisource Bergen, Arcus Biosciences, Astra Zeneca, Basilea Pharmaceutica, Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, Geneos Therapeutics, GlaxoSmithKline, Imedex, Imugene, Lynx Health, Merck, Merck Serono, Michael J. Hennessy Associates, Paradigm Medical Communications, PeerView Institute, Pfizer, Research to Practice, RGENIX, Seagen, Silverback Therapeutics, Zymeworks Inc. D.M. reports personal fees from Astra Zeneca, Bristol-Myers Squibb, Johnson & Johnson, Merck and Boston Scientific. The remaining authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The World Health Organization incorporates morphologic features with prognostic significance in the 2021 classification of epithelioid diffuse pleural mesothelioma (E-DPM). Although cytology specimens are often the first and occasionally the only specimen available for patients with DPM, these features have not yet been investigated in cytology., Methods: Nuclear atypia, pleomorphic features, necrosis, and architectural patterns were retrospectively assessed in 35 paired cytology and concurrent/consecutive surgical pathology specimens of E-DPM. Agreement between pairs was determined via unweighted κ scores. Discordant cases were re-reviewed to determine the reasons for disagreement., Results: Interpretation of nuclear atypia in cytology was concordant with histology in all cases (κ = 1.000; p < .001). The presence of pleomorphic features and necrosis was concordant in 97.1% (κ = 0.842; p < .001) and 85.7% (κ = 0.481; p = .001) of paired cases, respectively. Assessment of architectural patterns in cytology showed only slight agreement with histology (κ = 0.127; p = .037). In cytology cases (n = 23) with cell block material available, assessment of nuclear atypia and the presence of pleomorphic features showed perfect agreement (κ = 1.000; p < .001, each), the presence of necrosis showed moderate agreement (κ = 0.465; p = .008), and assessment of architectural patterns showed slight agreement (κ = 0.162; p = .15) in paired specimens. Most disagreements were due to sampling differences between cytology and histology specimens., Conclusions: Although complete nuclear grading of E-DPM is not possible given the unreliability of mitotic counts in cytology, assessment of nuclear atypia in cytology specimens is shown to be reliable. Identification of pleomorphic features and necrosis is also reliable despite occasional sampling issues. Assessment of architectural patterns is more limited in cytology., (© 2023 American Cancer Society.)

Objective: The objective is to determine how the COVID-19 pandemic affected care for patients undergoing thoracic surgery for cancer., Background: The COVID-19 pandemic accelerated the adoption of telemedicine., Methods: Characteristics and outcomes of new patients seen between March 1 and June 30, 2019, and the same period in 2020 were compared. Patients who did not undergo surgery were excluded. Patients who had a telemedicine visit (new and established) in the 2020 period were asked to complete a survey., Results: In total, 624 new patients were seen in 2019 versus 299 in 2020 (52% reduction); 45% of patients (n=136) in 2020 were seen via telemedicine. There was no statistically significant difference in time to surgery, pathological upstaging, or postsurgical complications between 2019 and 2020. In total, 1085 patients (new and established) had a telemedicine visit in 2020; 239 (22%) completed the survey. A majority replied that telemedicine was equivalent to in-person care (77%), did not impair care quality (84%), resulted in less stress (69%) and shorter waits (86%), was more convenient (92%), saved money and commuting time (93%), and expanded who could attend visits (91%). Some patients regretted the loss of human interaction (71%). Most would opt for telemedicine after the pandemic (60%), although some would prefer in-person format for initial visits (55%) and visits with complex discussions (49%). Only 21% were uncomfortable with the telemedicine technology., Conclusions: Telemedicine enabled cancer care to continue during the COVID-19 pandemic without delays in surgery, cancer progression, or worsened postoperative morbidity and was generally well received., Competing Interests: M.J.B. is a consultant for AstraZeneca. J.M.I. has stock ownership in LumaCyte and is a consultant/advisory board member for Roche Genentech. B.J.P. has served as a proctor for Intuitive Surgical and a consultant for COTA. V.W.R. reports grant support (institutional) from Genelux and Genentech, travel support from Intuitive Surgical, and travel support and payments from NIH/Coordinating Center for Clinical Trials. D.R.J. serves as a consultant for AstraZeneca and on a Clinical Trial Steering Committee for Merck. G.R. has a financial relationship with Scanlan. D.M. serves on a steering committee for AstraZeneca and as a consultant for Johnson & Johnson, Bristol Myers Squibb, Merck, and Genentech. The remaining authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

The limited efficacy of chimeric antigen receptor (CAR) T cell therapy for solid tumors necessitates engineering strategies that promote functional persistence in an immunosuppressive environment. Herein, we use c-Kit signaling, a physiological pathway associated with stemness in hematopoietic progenitor cells (T cells lose expression of c-Kit during differentiation). CAR T cells with intracellular expression, but no cell-surface receptor expression, of the c-Kit D816V mutation (KITv) have upregulated STAT phosphorylation, antigen activation-dependent proliferation and CD28- and interleukin-2-independent and interferon-γ-mediated co-stimulation, augmenting the cytotoxicity of first-generation CAR T cells. This translates to enhanced survival, including in transforming growth factor-β-rich and low-antigen-expressing solid tumor models. KITv CAR T cells have equivalent or better in vivo efficacy than second-generation CAR T cells and are susceptible to tyrosine kinase inhibitors (safety switch). When combined with CD28 co-stimulation, KITv co-stimulation functions as a third signal, enhancing efficacy and providing a potent approach to treat solid tumors., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: Molecular diagnostic assays require samples with high nucleic acid content to generate reliable data. Similarly, programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) requires samples with adequate tumor content. We investigated whether shape-sensing robotic-assisted bronchoscopy (ssRAB) provides adequate samples for molecular and predictive testing., Methods: We retrospectively identified diagnostic samples from a prospectively collected database. Pathologic reports were reviewed to assess adequacy of samples for molecular testing and feasibility of PD-L1 IHC. Tumor cellularity was quantified by an independent pathologist using paraffin-embedded sections. Univariable and multivariable linear regression models were constructed to assess associations between lesion- and procedure-related variables and tumor cellularity., Results: In total, 128 samples were analyzed: 104 primary lung cancers and 24 metastatic lesions. On initial pathologic assessment, ssRAB samples were deemed to be adequate for molecular testing in 84% of cases; on independent review of cellular blocks, median tumor cellularity was 60% (interquartile range, 25%-80%). Hybrid capture-based next-generation sequencing was successful for 25 of 26 samples (96%), polymerase chain reaction-based molecular testing (Idylla; Biocartis) was successful for 49 of 52 samples (94%), and PD-L1 IHC was successful for 61 of 67 samples (91%). Carcinoid and small cell carcinoma histologic subtype and adequacy on rapid on-site evaluation were associated with higher tumor cellularity., Conclusions: The ssRAB platform provided adequate tissue for next-generation sequencing, polymerase chain reaction-based molecular testing, and PD-L1 IHC in >80% of cases. Tumor histology and adequacy on intraoperative cytologic assessment might be associated with sample quality and suitability for downstream assays., (Copyright © 2022 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Tumor immune microenvironment (TIME) and cancer antigen expression, key factors for the development of immunotherapies, are usually based on the data from primary tumors due to availability of tissue for analysis; data from metastatic sites and their concordance with primary tumor are lacking. Although of the same origin from primary tumor, organ-specific differences in the TIME in metastases may contribute to discordant responses to immune checkpoint inhibitor agents. In immunologically 'cold' tumors, cancer antigen-targeted chimeric antigen receptor (CAR) T-cell therapy can promote tumor-infiltrating lymphocytes; however, data on distribution and intensity of cancer antigen expression in primary tumor and matched metastases are unavailable., Methods: We performed a retrospective review of a prospectively maintained database of patients who had undergone curative resection of pathological stage I-III primary lung adenocarcinoma from January 1995 to December 2012 followed by metastatic recurrence and resection of metastatic tumor (n=87). We investigated the relationship between the primary tumor and metastasis TIME (ie, tumor-infiltrating lymphocytes, tumor-associated macrophages, and programmed death-ligand 1 (PD-L1)) and cancer antigen expression (ie, mesothelin, CA125, and CEACAM6) using multiplex immunofluorescence., Results: Brain metastases (n=36) were observed to have fewer tumor-infiltrating lymphocytes and greater PD-L1-negative tumor-associated macrophages compared with the primary tumor (p<0.0001); this relatively inhibitory TIME was not observed in other metastatic sites. In one in three patients, expression of PD-L1 is discordant between primary and metastases. Effector-to-suppressor (E:S) cell ratio, median effector cells (CD20+ and CD3+) to suppressor cells (CD68/CD163+) ratio, in metastases was not significantly different between patients with varying E:S ratios in primary tumors. Cancer antigen distribution was comparable between primary and metastases; among patients with mesothelin, cancer antigen 125, or carcinoembryonic antigen adhesion molecule 6 expression in the primary tumor, the majority (51%-75%) had antigen expression in the metastases; however, antigen-expression intensity was heterogenous., Conclusions: In patients with lung adenocarcinoma, brain metastases, but not other sites of metastases, exhibited a relatively immune-suppressive TIME; this should be considered in the context of differential response to immunotherapy in brain metastases. Among patients with cancer antigen expression in the primary tumor, the majority had antigen expression in metastases; these data can inform the selection of antigen-targeted CARs to treat patients with metastatic lung adenocarcinoma., Competing Interests: Competing interests: PSA declares research funding from ATARA Biotherapeutics; Scientific Advisory Board Member and Consultant for ATARA Biotherapeutics, Bayer, Bio4T2, Carisma Therapeutics, Imugene, ImmPactBio, Johnston & Johnston, Orion Pharma, Outpace Bio; Patents, royalties and intellectual property on mesothelin-targeted CAR and other T-cell therapies, which have been licensed to ATARA Biotherapeutics, issued patent method for detection of cancer cells using virus, and pending patent applications on PD-1-dominant negative receptor, wireless pulse oximetry device, and on an ex vivo malignant pleural effusion culture system. Memorial Sloan Kettering Cancer Center has licensed intellectual property related to mesothelin-targeted CARs and T-cell therapies to ATARA Biotherapeutics and has associated financial interests., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We analyzed 2,532 lung adenocarcinomas (LUAD) to identify the clinicopathological and genomic features associated with metastasis, metastatic burden, organotropism, and metastasis-free survival. Patients who develop metastasis are younger and male, with primary tumors enriched in micropapillary or solid histological subtypes and with a higher mutational burden, chromosomal instability, and fraction of genome doublings. Inactivation of TP53, SMARCA4, and CDKN2A are correlated with a site-specific shorter time to metastasis. The APOBEC mutational signature is more prevalent among metastases, particularly liver lesions. Analyses of matched specimens show that oncogenic and actionable alterations are frequently shared between primary tumors and metastases, whereas copy number alterations of unknown significance are more often private to metastases. Only 4% of metastases harbor therapeutically actionable alterations undetected in their matched primaries. Key clinicopathological and genomic alterations in our cohort were externally validated. In summary, our analysis highlights the complexity of clinicopathological features and tumor genomics in LUAD organotropism., Competing Interests: Declaration of interests C.M.R. has consulted regarding oncology drug development with AbbVie, Amgen, Astra Zeneca, Epizyme, Genentech/Roche, Ipsen, Jazz, Lilly, and Syros and serves on the scientific advisory boards of Bridge Medicines, Earli, and Harpoon Therapeutics. G.J.R. has institutional research funding from Mirait, Takeda, Merck, Roche, Novartis, and Pfizer. D.B.S. has consulted for and received honoraria from Pfizer, Lilly/Loxo Oncology, Vividion Therapeutics, Scorpion Therapeutics, and BridgeBio. M.F.B. has consulted for Eli Lilly and PetDx and has received research funding from Grail, not related to the work presented. D.R.J. is a member of the Advisory Council for Astra Zeneca and a member of the Clinical Trial Steering Committee for Merck. All other authors have no relevant competing interests to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)