Melatonin enhances radiofrequency-induced NK antitumor immunity, causing cancer metabolism reprogramming and inhibition of multiple pulmonary tumor development

Surgery is the common treatment for early lung cancer with multiple pulmonary nodules, but it is often accompanied by the problem of significant malignancy of other nodules in non-therapeutic areas. In this study, we found that a combined treatment of local radiofrequency ablation (RFA) and melatonin (MLT) greatly improved clinical outcomes for early lung cancer patients with multiple pulmonary nodules by minimizing lung function injury and reducing the probability of malignant transformation or enlargement of nodules in non-ablated areas. Mechanically, as demonstrated in an associated mouse lung tumor model, RFA not only effectively remove treated tumors but also stimulate antitumor immunity, which could inhibit tumor growth in non-ablated areas. MLT enhanced RFA-stimulated NK activity and exerted synergistic antitumor effects with RFA. Transcriptomics and proteomics analyses of residual tumor tissues revealed enhanced oxidative phosphorylation and reduced acidification as well as hypoxia in the tumor microenvironment, which suggests reprogrammed tumor metabolism after combined treatment with RFA and MLT. Analysis of residual tumor further revealed the depressed activity of MAPK, NF-kappa B, Wnt, and Hedgehog pathways and upregulated P53 pathway in tumors, which was in line with the inhibited tumor growth. Combined RFA and MLT treatment also reversed the Warburg effect and decreased tumor malignancy. These findings thus demonstrated that combined treatment of RFA and MLT effectively inhibited the malignancy of non-ablated nodules and provided an innovative non-invasive strategy for treating early lung tumors with multiple pulmonary nodules. Trial registration: www.chictr.org.cn, identifier ChiCTR2100042695, http://www.chictr.org.cn/showproj.aspx?proj=120931.

Comprehensive characterization of genomic and radiologic features reveals distinct driver patterns of RTK/RAS pathway in pulmonary nodules presenting as ground-glass opacity.

e20516 Background: GGO-associated pulmonary nodule has been known as radiological appearances of early stage and exhibit more indolent biological behavior. The correlation of different driver gene and radiological features remain poorly understood. Methods: We performed high-depth sequencing of 334 resected pulmonary nodules presenting as GGO from 262 Chinese patients with a custom 1021-gene panel. 130 were multiple pulmonary nodules from 58 patients (2-4 samples per patient). Clinical-pathologic and radiologic parameters of these pulmonary nodules were collected. Immunohistochemistry and multiplex immunofluorescent staining were applied to analyze proliferation and immune cell markers of GGO-associated pulmonary nodules. Results: Mixed GGO enriched in the pathology of invasive LUAD comparing to pure GGO (182/216 vs 73/118, p < 0.001). 88.0% (294/334) of GGO-associated nodules carried at least one gene mutation in EGFR/ERBB2/BRAF/KRAS/MAP2K1 of the RTK/RAS signaling pathway and these driver genes were mutual exclusive to each other. T790M mutation was detected in one patient who had a nodule with CTR > 0.5 and was pathologically defined as MIA. 96.4% (54/56) multiple pulmonary nodules from the same patients showed distinct oncogenic alterations, but 72.4% (42/58) patients carried at least one mutant gene in RTK/RAS pathway across each pulmonary nodule. Nodules with ERBB2/ BRAF/ MAP2K1 mutations tended to be more indolent than those with EGFR and KRAS mutations, showing fewer mutations in radiology status of mGGO or pathology of invasive LUAD. KRAS-mutant subgroup possessed the highest expression of Ki-67 and PD-L1, more infiltration of CD4+ T cell and CD8+T cell. The second highest Ki67-expression was in EGFR-mutant subgroup, together with more CD8+T cell. For EGFR-mutant nodules, co-mutations with TP53 or RBM10 enriched in nodules with CTR > 0.5 and showing higher values of mean CT attenuation and TMB, which may relate to GGO evolution or invasiveness progression. Conclusions: This study elucidated a comprehensive genomic landscape of Chinese radiologically detected GGO-associated pulmonary nodules and highlighted different driver patterns of RTK/RAS pathway corresponding to radiologic features. Our findings provided valuable insight for further research on driver event of RTK/RAS pathway and cancer interception of GGO-associated pulmonary nodules.

A Case of Granulomatosis With Polyangiitis With Pulmonary Nodules and Masses

Background: Granulomatosis with polyangiitis (GPA) is autoimmune-mediated, necrotizing granulomatous vasculitis, primarily involving the upper and lower respiratory tract and kidneys. Pulmonary parenchymal necrosis, vasculitis, and granulomatous inflammation are the main pathological features. Pulmonary imaging visualizes various manifestations, like lung consolidation, ground-glass shadow, speckle shadow, nodules and mass shadows, cavitation, pulmonary interstitial change, pleural effusion, and multiple mediastinal lymph nodes enlargements, and stenosis or occlusion of a lobe or bronchus segment. Case presentation: We report a 53-year-old patient diagnosed with Granulomatous polyangiitis with multiple pulmonary nodules and masses, by ultrasound-guided lung mass puncture biopsy. After treatment with methylprednisolone, Mycophenolate Mofetil, compound sulfamethoxazole and cyclophosphamide, the patient's condition improved and the pulmonary lesions were better than before.Conclusions: In addition to specific infections and tumors, immunological diseases, especially granulomatous polyangiitis, should be considered when treating patients in a clinical setting with multiple pulmonary nodules and weights. Through close multidisciplinary cooperation and communication, the disease will be hopefully received timely diagnosis and early treatment, relieving pain for more patients.

Computed Tomography-Guided Methylene Blue Localization: Single vs. Multiple Lung Nodules

Background: Preoperative localization for small invisible and impalpable pulmonary nodules is important in single-port video-assisted thoracoscopic surgery (VATS). Localization of multiple pulmonary nodules during VATS resection remains challenging. The aim of our study is to elucidate the efficacy of preoperative CT-guided methylene blue localization of both single and multiple pulmonary nodules.Methods: Consecutive patients undergoing preoperative CT-guided methylene blue dye localization for lung nodules, followed by VATS resection, were retrospectively analyzed between January 2014 and November 2019. Chi-square tests, Fisher's exact test and independent T-test were used to compare variables between the groups. Logistic regression was used to identify risk factors for procedure-related complications.Results: A total of 388 patients, including 337 with single nodule and 51 with multiple nodules, were analyzed. The success rate of preoperative CT-guided methylene blue localization for both single and multiple pulmonary nodules were comparable as 98.8% (333/337) vs. 100% (108/108). The procedure time was longer (23.2 ± 9.4 vs. 7.6 ± 4.8 min, p &lt; 0.001) and risk of pneumothorax was higher (47.1 vs. 25.5%, p = 0.002) in the multiple nodule group. The procedure time (OR 1.079; 95% CI = 1.041–1.118; p &lt; 0.001) was an independent risk factor for pneumothorax. Nodule depth (OR 2.829; 95% CI = 1.259–6.356; p = 0.011) was an independent risk factor for pulmonary hemorrhage.Conclusions: Preoperative CT-guided methylene blue localization for both single and multiple pulmonary nodules is safe, feasible, and effective.