The efficacy and potential limitations of molecular residual disease (MRD) detection urgently need to be fully elucidated in a larger population of non–small cell lung cancer (NSCLC). We enrolled 261 patients with stages I to III NSCLC who underwent definitive surgery, and 913 peripheral blood samples were successfully detected by MRD assay. Within the population, only six patients (3.2%) with longitudinal undetectable MRD recurred, resulting in a negative predictive value of 96.8%. Longitudinal undetectable MRD may define the patients who were cured. The peak risk of developing detectable MRD was approximately 18 months after landmark detection. Correspondingly, the positive predictive value of longitudinal detectable MRD was 89.1%, with a median lead time of 3.4 months. However, brain-only recurrence was less commonly detected by MRD (n = 1/5, 20%). Further subgroup analyses revealed that patients with undetectable MRD might not benefit from adjuvant therapy. Together, these results expound the value of MRD in NSCLC. Significance: This study confirms the prognostic value of MRD detection in patients with NSCLC after definitive surgery, especially in those with longitudinal undetectable MRD, which might represent the potentially cured population regardless of stage and adjuvant therapy. Moreover, the risk of developing detectable MRD decreased stepwise after 18 months since landmark detection. This article is highlighted in the In This Issue feature, p. 1599

Circulating tumor DNA (ctDNA) has potential as a promising biomarker for molecular residual disease (MRD) detection in lung cancer. As the next‐generation sequencing standardized panel for ctDNA detection emerges, its clinical utility needs to be validated. We prospectively recruited 184 resectable lung cancer patients from four medical centers. Serial postoperative ctDNAs were analyzed by a standardized panel. A total of 427 postoperative plasma samples from 177 eligible patients were enrolled. ctDNA positivity after surgery was an independent predictor for disease recurrence and preceded radiological recurrence by a median of 6.6 months (range, 0.7–27.0 months). ctDNA‐positive or ‐negative patients with tumors of any stage had similar disease‐free survival (DFS). Patients who received targeted therapy had significantly improved DFS than those not receiving adjuvant therapy or receiving chemotherapy, regardless of baseline/preadjuvant ctDNA status. According to whether the ctDNA variants were detected in its matched tissue, they were classified into tissue derived and non‐tissue derived. Patients with detectable postoperative ctDNA with tissue‐derived mutations had comparable DFS with those with non‐tissue‐derived mutations. Collectively, we demonstrated that postoperative ctDNA has the potential to stratify prognosis and optimize tumor stage in resectable lung cancer. ctDNA variants not identified in tissue samples should be considered in MRD test.

Localizing non-palpable pulmonary nodules is challenging for thoracic surgeons. Here, we investigated the accuracy of three-dimensional (3D) printing technology combined with mixed reality (MR) for localizing ground glass opacity-dominant pulmonary nodules. In this single-arm study, we prospectively enrolled patients with small pulmonary nodules (<2 cm) that required accurate localization. A 3D-printing physical navigational template was designed based on the reconstruction of computed tomography images, and a 3D model was generated through the MR glasses. We set the deviation distance as the primary end point for efficacy evaluation. Clinicopathological and surgical data were obtained for further analysis. Sixteen patients with 17 non-palpable pulmonary nodules were enrolled in this study. Sixteen nodules were localized successfully (16/17; 94.1%) using this novel approach with a median deviation of 9 mm. The mean time required for localization was 25 ± 5.2 min. For the nodules in the upper/middle and lower lobes, the median deviation was 6 mm (range, 0–12.0) and 16 mm (range, 15.0–20.0), respectively. The deviation difference between the groups was significant (Z = −2.957, P = 0.003). The pathological evaluation of resection margins was negative. The 3D printing navigational template combined with MR can be a feasible approach for localizing pulmonary nodules.