Abstract
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.
Highlights
Lung cancer is the leading cause of cancer-related deaths worldwide; timely diagnosis and improved treatments are keys to improve the survival rate for this disease.[1,2] With recent rapid advances in medical technology including computerized tomography (CT) screening, detection of early lung cancers has been greatly improved
Combined treatment with radiofrequency ablation (RFA) and MLT improves clinical outcome of early lung cancer patients with ground-glass nodules (GGNs) comparing to standard care From Jan 2018 to Jun 2018, a total of 42 early lung cancer patients with multiple GGNs who met the inclusion criteria were recruited into the study to evaluate the combined treatment with RFA and MLT
In terms of pathology, such as atypical adenomatous hyperplasia (AAH) and adenocarcinoma in situ (AIS), cases AAH and cases AIS were recruited in both the RFA + MLT and Control groups
Summary
Lung cancer is the leading cause of cancer-related deaths worldwide; timely diagnosis and improved treatments are keys to improve the survival rate for this disease.[1,2] With recent rapid advances in medical technology including computerized tomography (CT) screening, detection of early lung cancers has been greatly improved. Patients with early lung cancer often were associated with pulmonary ground-glass nodules (GGNs).[3,4,5] For early lung cancer with multiple GGNs, the current standard protocol is recommended as following: if the main nodule diameter is ≥8 mm, it is suggested to remove the main lesion and follow-up for the other lesions. A common challenge for patients with multiple GGNs is the development or malignant transformation of remaining nodules after surgery. In Asia, it was reported that about 21% of patients would experience enlarged GGNs or malignant transformation 2 years after their initial GGN surgery. It was quite often that, due to reduced lung function and other complications, patients with initial surgery were not compatible with an additional one.[7,8] a new innovative strategy for treating multiple GGNs is urgently needed
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