Lung cancer remains the leading cause of cancer-related mortality worldwide, and tumor recurrence following treatment with curative intent poses significant clinical challenges. Surveillance imaging with chest CT is essential for early detection of potentially curable recurrent disease. Recurrence may manifest locally, regionally, or distantly, depending on the mode of spread, and generally shares histologic and imaging characteristics with the primary tumor. The risk of recurrence varies on the basis of tumor histologic features and the treatment modality used. For example, adenocarcinoma with lepidic growth has a low risk of recurrence and a favorable prognosis, whereas adverse pathologic features, such as spread through airspaces, are associated with poor recurrence-free survival. Following curative lung resection, surveillance CT is used to assess the stability of surgical changes and detect new nodules at the surgical site that may indicate local recurrence. The type and method of delivery of radiation therapy influence the subsequent temporal and spatial posttreatment changes seen at CT, which can complicate detection of recurrent disease. Disseminated patterns of pulmonary tumor recurrence may manifest as aerogenous metastases, miliary metastases, pleural metastases, or lymphangitic carcinomatosis. Although posttherapy surveillance can be limited by image interpretation pitfalls, use of appropriate strategies can help overcome these challenges. Radiologists should recognize the imaging patterns of lung cancer recurrence to facilitate improved diagnostic accuracy and timely patient care. ©RSNA, 2026 Supplemental material is available for this article. See the invited commentary by Vlahos and Shroff in this issue.

KM curvces for recurrence based on stage and RVT

Immune checkpoint blockade (ICB) is standard of care in advanced diffuse pleural mesothelioma (DPM), but its role in the perioperative management of DPM is unclear. In tandem, circulating tumor DNA (ctDNA) ultra-sensitive residual disease detection has shown promise in providing a molecular readout of ICB efficacy across resectable cancers. This phase 2 trial investigated neoadjuvant nivolumab and nivolumab/ipilimumab in resectable DPM along with tumor-informed liquid biopsy residual disease assessments. Patients with resectable epithelioid/biphasic DPM enrolled sequentially to nivolumab 240 mg every 2 weeks (q2w) for three cycles (Arm A, n = 16) or nivolumab 3 mg kg-1 q2w for three cycles plus ipilimumab 1 mg kg-1 on cycle 1 (Arm B, n = 14), followed by surgery, optional chemotherapy and/or radiotherapy, and nivolumab 480 mg q4w for 1 year. Co-primary endpoints included safety and feasibility; key exploratory endpoints included progression-free survival (PFS), overall survival (OS) and ctDNA analyses. The trial met its primary endpoints, and, in Arms A and B, 81.3% and 85.7% of patients proceeded to surgery, respectively. Treatment was safe, with a single dose-limiting toxicity in each arm. In Arm A, median PFS and OS were 9.6 months (95% confidence interval (CI): 2.5-27.7) and 19.3 months (95% CI: 14.9-34.7), respectively. In Arm B, median PFS and OS were 19.8 months (7.1-not reached) and 28.6 months (20.4-not reached), respectively. Persistent ctDNA was detected during neoadjuvant therapy in patients who did not undergo complete surgical resection due to disease progression (Fisher's exact test, P = 0.00013). Patients with detectable ctDNA on cycle 3 and pre-surgery had shorter PFS (log-rank test, P = 0.027 and P = 0.0059, respectively); this association was more pronounced when quantitative ctDNA changes were considered (log-rank test, P = 1.8 × 10-6). Our findings support the feasibility of neoadjuvant ICB and the clinical utility of ctDNA analyses to capture residual disease in resectable DPM. ClinicalTrials.gov identifier: NCT03918252 .

In CheckMate 816, lower %RVT in primary tumor (PT) and lymph node (LN) after neoadjuvant (neoadj) NIVO + chemo correlated with improved EFS in patients (pts) with resectable NSCLC. To further evaluate %RVT as a surrogate for EFS, we report an exploratory analysis of efficacy with adjuvant (adj) NIVO after neoadj treatment (tx) by LN involvement, nodal (N) status, and %RVT in PT and LN in CheckMate 77T. Pts with resectable stage IIA-IIIB NSCLC were randomized to neoadj NIVO + chemo Q3W (up to 4 cycles [cyc]) followed by adj NIVO Q4W (up to 13 cyc) or neoadj placebo (PBO) + chemo Q3W (up to 4 cyc) followed by adj PBO Q4W (up to 13 cyc). Primary endpoint: EFS per BICR. This analysis, which included pts with pathologically evaluable samples who had definitive surgery and ≥ 1 adj tx dose, assessed EFS by LN involvement, N status, %RVT in PT and LN, and associations between %RVT and EFS per time-dependent ROC curve analysis. BL characteristics were similar between tx arms (NIVO, 123; PBO, 134; median f/u, 33.3 mo). NIVO improved EFS v PBO regardless of LN involvement or N status (Table). A higher proportion of pts treated with NIVO had 0% RVT in PT and/or LN v PBO (52% v 20%). In pts with LN involvement, 2-y EFS rates with NIVO were higher in pts with 0% RVT in both PT and LN (90%) or 0% RVT in PT or LN (85%) v > 0% RVT in both PT and LN (76%). Area under the ROC curve for %RVT-PT in pts with PT-only disease was 0.83. 2-y EFS rates with NIVO were 94%, 77%, and 50% in pts with 0-5%, > 5-80%, and > 80% RVT-PT, respectively; similar results were seen in all pts with pathologically evaluable samples whether they received adj tx or not. In this exploratory analysis, NIVO improved EFS v PBO, particularly in pts with LN involvement and regardless of N status. %RVT also associated with EFS in a continuous manner, supporting %RVT as a surrogate for EFS and highlighting its prognostic value in pts who receive perioperative NIVO. Julie Stein Deutsch, Ashley Cimino-Mathews, Elizabeth Thompson, Edward Gabrielson, Peter Illei, Jaroslaw Jedrych, Ezra Baraban, Alex S. Baras, Mariano Provencio Pulla, Tina Cascone, Jonathan D. Spicer, Mark M. Awad, Fumihiro Tanaka, Jie He, Shun Lu, Cinthya Coronado Erdmann, Vipul Devas, Sumeena Bhatia, Janis M. Taube. Associations between percent residual viable tumor (%RVT) and efficacy with perioperative nivolumab (NIVO) for resectable NSCLC in CheckMate 77T [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT097.

BACKGROUND:Endobronchial ultrasound-guided transbronchial aspiration (EBUS-TBNA) has become the standard for initial lung cancer diagnosis and staging. Previous guidelines have generally focused on the "when" and "how" of EBUS-TBNA; however, little guidance is available on handling and processing specimens during and after acquisition to help optimize both diagnostic yield and tissue integrity for ancillary studies. This document examines the available literature on EBUS-TBNA specimen processing and handling. STUDY DESIGN AND METHODS:Rigorous methodology was applied to provide a trustworthy evidence-based guideline and expert panel report. Panelists developed key clinical questions using the Population, Intervention, Comparator, and Outcome format, addressing specific topics in EBUS-TBNA specimen processing. MEDLINE (via PubMed) and the Cochrane Library were systematically searched to identify relevant literature, supplemented by manual searches. References were screened for inclusion with document evaluation tools to assess the quality of included studies, extract meaningful data, and grade the level of evidence to support each recommendation or suggestion. RESULTS:Our systematic review and critical analysis of the literature of the nine Population, Intervention, Comparator, and Outcome questions related to handling and processing EBUS-TBNA specimens resulted in nine evidence-based statements. INTERPRETATION:Evidence of the handling and processing of EBUS-TBNA specimens varies in strength but is satisfactory in some areas to guide clinicians in certain aspects of specimen handling. Additional research in many aspects of specimen handling and processing is needed to help improve our knowledge base.

AbstractPurpose: Although immunotherapy is the mainstay of therapy for advanced non–small cell lung cancer (NSCLC), robust biomarkers of clinical response are lacking. The heterogeneity of clinical responses together with the limited value of radiographic response assessments to timely and accurately predict therapeutic effect—especially in the setting of stable disease—calls for the development of molecularly informed real-time minimally invasive approaches. In addition to capturing tumor regression, liquid biopsies may be informative in capturing immune-related adverse events (irAE). Experimental Design: We investigated longitudinal changes in circulating tumor DNA (ctDNA) in patients with metastatic NSCLC who received immunotherapy-based regimens. Using ctDNA targeted error-correction sequencing together with matched sequencing of white blood cells and tumor tissue, we tracked serial changes in cell-free tumor load (cfTL) and determined molecular response. Peripheral T-cell repertoire dynamics were serially assessed and evaluated together with plasma protein expression profiles. Results: Molecular response, defined as complete clearance of cfTL, was significantly associated with progression-free (log-rank P = 0.0003) and overall survival (log-rank P = 0.01) and was particularly informative in capturing differential survival outcomes among patients with radiographically stable disease. For patients who developed irAEs, on-treatment peripheral blood T-cell repertoire reshaping, assessed by significant T-cell receptor (TCR) clonotypic expansions and regressions, was identified on average 5 months prior to clinical diagnosis of an irAE. Conclusions: Molecular responses assist with the interpretation of heterogeneous clinical responses, especially for patients with stable disease. Our complementary assessment of the peripheral tumor and immune compartments provides an approach for monitoring of clinical benefits and irAEs during immunotherapy.

Die neoadjuvante und perioperative Therapie des nicht kleinzelligen Lungenkarzinoms (NSCLC) hat sich durch bedeutende Fortschritte und die Einbeziehung von zielgerichteten Therapien und Immuncheckpoint-Inhibitoren allein oder in Kombination mit einer konventionellen Chemotherapie radikal verändert. Besonders bemerkenswert ist diese Entwicklung bei der Aufnahme von Immuntherapien und zielgerichteten Therapien in die Behandlung des resektablen NSCLC, wo die jüngsten FDA-Zulassungen von Medikamenten wie Nivolumab und Pembrolizumab in Kombination mit einer Platin-Doubletten-Chemotherapie zu erheblichen Verbesserungen bei den Raten des pathologischen Komplettansprechens und beim Potenzial für verbesserte Ergebnisse in Bezug auf das langfristige Überleben geführt haben. Diese Übersichtsarbeit beleuchtet die zunehmende Bedeutung von Biomarkern bei der Optimierung der Behandlungswahl und untersucht die Auswirkungen neuer Studien, die bestehende Behandlungsparadigmen infrage stellen und neuartige therapeutische Kombinationen untersuchen, die die Standardbehandlung neu definieren könnten. Darüber hinaus wird der ungedeckte Bedarf im Bereich der perioperativen Therapiebeurteilung und -prognose diskutiert und der zukünftige Wert von Biomarkern bei der Beurteilung von Therapieansprechen und -prognose hervorgehoben.

Supplementary Table S3. Summary of TEC-Seq characteristics for plasma and matched WBC samples analyzed.

Supplementary Fig.S5 Associations between ctDNA molecular responses and tumor PD-L1 expression levels. (A) Association between PD-L1 expression and ctDNA molecular response in 24 patients with detectable ctDNA and evaluable PD-L1 expression, the subset of 8 patients who received chemo-immunotherapy combination treatments and (C) in 16 patients who received immune checkpoint monotherapy. P values were assessed using the Fisher’s exact test. (D-E) Survival analyses following the stratification of molecular response groups according to PD-L1 expression levels. Four molecular responders with cfTL clearance across any sampled timepoint and low/negative (<50%) PD-L1 expression had superior PFS compared to molecular responders with high (>50%) PD-L1 expression and molecular progressors (log-rank p = 0.006). Of these 4 patients, 3 received first line pembro-chemotherapy combination regimens and 1 patient received first line pembrolizumab monotherapy. Differences in OS were not significant between molecular response/PD-L1 expression groups (log-rank p = 0.135).

Supplementary Fig.S9 Comparison between plasma proteomic profiles across treatment timepoints and toxicity. Heatmaps showing normalized protein expression (NPX) scores for 92 proteins evaluated using Olink analyses across all (A) baseline (n=19) and (B) on-therapy (n=47) plasma samples from 28 patients. Panels indicating treatment timepoint and the presence or absence of immunotherapy-related toxicity are displayed below the heatmaps.

Supplementary Fig.S2 Overview of variants detected in plasma cell-free DNA. (A) The percentage of all classified plasma variants that were assigned an origin of germline, tumor-derived or clonal haematopoiesis (CH)-derived. (B) The maximum mutant allele fraction (MAF) of tumor-derived circulating tumor DNA (ctDNA) variants at baseline sampling, stratified by treatment (immunotherapy (IO) or chemo-immunotherapy (chemo-IO)) and clinical benefit (durable clinical benefit (DCB) or non-durable clinical benefit (NDB)). P values were calculated using the Mann-Whitney U test. (C-F) Associations between baseline ctDNA maximal MAFs and survival outcomes according to progression-free (PFS) and overall survival (OS) in patients treated with (C-D) immune checkpoint monotherapy and (E-F) chemo-immunotherapy combination regimens. *, P < 0.05

Supplementary Table S10. Summary of TCR sequencing characteristics for the cohort

Supplementary Table S13. Summary of GLIPH2 TCR clustering analyses across patients analyzed.

Background: Advanced diagnostic bronchoscopy targeting the lung periphery has developed at an accelerated pace over the last two decades, whereas evidence to support introduction of innovative technologies has been variable and deficient. A major gap relates to variable reporting of diagnostic yield, in addition to limited comparative studies. Objectives: To develop a research framework to standardize the evaluation of advanced diagnostic bronchoscopy techniques for peripheral lung lesions. Specifically, we aimed for consensus on a robust definition of diagnostic yield, and we propose potential study designs at various stages of technology development. Methods: Panel members were selected for their diverse expertise. Workgroup meetings were conducted in virtual or hybrid format. The cochairs subsequently developed summary statements, with voting proceeding according to a modified Delphi process. The statement was cosponsored by the American Thoracic Society and the American College of Chest Physicians. Results: Consensus was reached on 15 statements on the definition of diagnostic outcomes and study designs. A strict definition of diagnostic yield should be used, and studies should be reported according to the STARD (Standards for Reporting Diagnostic Accuracy Studies) guidelines. Clinical or radiographic follow-up may be incorporated into the reference standard definition but should not be used to calculate diagnostic yield from the procedural encounter. Methodologically robust comparative studies, with incorporation of patient-reported outcomes, are needed to adequately assess and validate minimally invasive diagnostic technologies targeting the lung periphery. Conclusions: This American Thoracic Society/American College of Chest Physicians statement aims to provide a research framework that allows greater standardization of device validation efforts through clearly defined diagnostic outcomes and robust study designs. High-quality studies, both industry and publicly funded, can support subsequent health economic analyses and guide implementation decisions in various healthcare settings.

Purpose/Objective(s) DECT scans measure intratumoral iodine concentration, which provides valuable insights into the tumor environment including blood supply and metabolic activity. The purpose of this study is to examine the short-term changes in DECT parameters patients with stage I non-small cell lung cancer (NSCLC) after SABR therapy. Materials/Methods Patients ≥18 years with stage I NSCLC were consented and enrolled in an IRB-approved prospective study. Patients received SABR (48Gy/4 fractions or 50Gy/5 fractions) and had chest DECT scans before and 5-7 days following SABR. Color iodine maps and atomic number maps were generated utilizing a post-processing algorithm (Siemens Syngo.via). Two blinded radiologists reviewed scans and quantified DECT parameters (iodine concentration (IC) and atomic numbers (Zeff)). Normalized iodine concentration (NIC) was calculated to decrease hemodynamic impact by dividing the IC of the tumor by the IC of the aorta. Descriptive statistical analysis compared the parameters before and after SABR. The difference between values was calculated as the post-SABR value minus the pre-SABR value. Results Six patients enrolled, with a median age of 75 years (66 - 83) and a median tumor size of 1.9 cm (0.84 - 3.0). Adenocarcinoma was the predominant histopathology (n = 4). At a median follow-up of 40 months, 83% (5/6) patients had tumor control after SABR alone. One patient experienced locoregional recurrence 13 months post-SABR. In comparing IC from color iodine maps pre- and post-SABR, the mean IC was 1.95 and 2.37, respectively. Four patients showed increase in IC, with the patient who later developed recurrence displaying the largest increase (pre-SABR 2.5 ng/ml, post-SABR 3.6 ng/ml, difference 1.1 ng/ml). NIC analysis followed a similar pattern of increase in mean values post-SABR (pre-SABR: 0.35, post-SABR: 0.39). In atomic number maps, the mean Zeff was 8.60 pre-SABR and 8.56 post-SABR. Half the patients showed an increase in Zeff after SABR, and the patient with recurrence displayed the highest Zeff value after SABR (9.23). Conclusion These data provide evidence that SABR induces acute macroscopic changes within stage I NSCLC tumors, affecting their composition and vascularity. Our data show the greatest changes in IC, NIC and Zeff values in the patient who clinically recurred over a year following the SABR. This suggests DECT parameters may provide a noninvasive assessment of immediate clinical response to SABR and provide a foundation from which additional studies may be built to assess the extent to which DECT can be used a as marker of post-SABR clinical response or recurrence

Supplementary Table S12. Summary of global TCR clusters identified in at least 3 distinct patients using GLIPH2.

Supplementary Table S1. Clinical characteristics of the patients included in ctDNA analyses.