Translational lung cancer research最新文献

Background: Circulating tumor cells (CTCs) provide a unique resource to decipher cell molecular properties of lung cancer. However, the clinicopathologic and radiological features associated with CTCs in different lung cancer subtypes remain poorly characterized. The aim of this study was to explore the clinicopathological and radiological features of CTCs in different lung cancer subtypes.

Methods: The CTC data were obtained using the CellSearch Circulating Tumor Cell Kit. CTCs were detected in 5,128 surgical patients with lung adenocarcinoma (LUAD), 2,226 with lung squamous cell carcinoma (LUSC), 248 with small cell lung cancer (SCLC), 99 with large cell carcinoma, and 70 with metastatic carcinomas. A Pearson correlation analysis was conducted to analyze the patients' clinical information, radiological features, and molecular characteristics, and logistic regression was used to examine the correlations between these factors and CTCs.

Results: For LUAD, the presence of tumor lobation, air bronchogram, and the epidermal growth factor receptor (EGFR) mutation were significantly associated with CTC levels. While the multivariable logistic regression analysis indicated that CD68 and P40 expression were independent factors associated with CTCs. For LUSC, tumor size, tumor spiculation, pleural indentation, air bronchogram, the expression levels of CK8/18, GPA33, and leucocyte common antigen (LCA) were significantly associated with CTC levels. The multivariable logistic regression analysis indicated that tumor size, pleural indentation, and air bronchogram were independent factors affecting CTCs. For SCLC, no factors were found to be significantly associated with CTC levels. For large cell carcinoma, tumor lobation and spiculation were significantly associated with CTC levels. For metastatic lung cancers, the presence of the positive lymphoid node was the only factor significantly associated with CTC levels.

Conclusions: We conducted a comprehensive analysis of the tumor properties, radiological features, and genomic characteristics that are significantly associated with CTCs in different lung cancer subtypes. This study helps elucidate the formation mechanism and relevant major regulation molecules of CTCs.

Background: Non-small cell lung cancer (NSCLC) is a significant health concern. The prognostic value of oxidative stress (OS)-related genes in NSCLC remains unclear. The study aimed to explore the prognostic significance of OS-genes in NSCLC using extensive datasets from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO).

Methods: The research used the expression data and clinical information of NSCLC patients to develop a risk-score model. A total of 74 OS-related differentially expressed genes (DEGs) were identified by comparing NSCLC and control samples. Univariate Cox and least absolute shrinkage and selection operator (LASSO) regression analyses were employed to identify the prognostic biomarkers. A risk-score model was constructed and validated with receiver operating characteristic (ROC) curves in TCGA and GSE72094 datasets. The model's accuracy was further verified by univariate and multivariate Cox regression.

Results: The identified biomarkers, including lactate dehydrogenase A (LDHA), protein tyrosine phosphatase receptor type N (PTPRN), and transient receptor potential cation channel subfamily A (TRPA1) demonstrated prognostic significance in NSCLC. The risk-score model showed good predictive accuracy, with 1-year area under the curves (AUC) of 0.661, 3-year AUC of 0.648, and 5-year AUC of 0.634 in the TCGA dataset, and 1-year AUC of 0.643, 3-year AUC of 0.648, and 5-year AUC of 0.662 in the GSE72094 dataset. A nomogram integrating risk score and tumor node metastasis (TNM) stage was developed. The signature effectively distinguished between patient responses to immunotherapy. High-risk groups were characterized by an immunosuppressive microenvironment and an increased tumor mutational burden (TMB), marked by a higher incidence of mutations in genes such as TP53, DCP1B, ELN, and MAGI2. Organoid drug sensitivity testing revealed that NSCLC patients with a low-risk score responded better to chemotherapy.

Conclusions: This study successfully developed a robust model for predicting patient prognosis in NSCLC, highlighting the critical prognostic value of OS-genes. These findings hold significant potential to refine treatment strategies, and enhance survival outcomes for NSCLC patients. By enabling a personalized therapeutic approach tailored to individual risk scores, this model may facilitate more precise decisions concerning immunotherapy and chemotherapy, thereby optimizing patient management and treatment efficacy.

Background: Cachexia is observed in around 60% of patients with extensive-stage small cell lung cancer (ES-SCLC) and may play an important role in the development of resistance to immunotherapy. This study aims to evaluate the influence of cachexia on the effectiveness of immunotherapy, develop and assess a deep learning (DL)-based prediction model for cachexia, as well as its prognostic value.

Methods: The analysis encompassed ES-SCLC patients who received the combination of first-line immunotherapy and chemotherapy from Shandong Cancer Hospital and Institute, Qilu Hospital, and Jining First People's Hospital. Survival analysis was conducted to examine the correlation between cachexia and the efficacy of immunotherapy. Medical records and computed tomography (CT) images of the third lumbar vertebra (L3) level were collected to construct the clinical model, radiomics, and DL models. The receiver operating characteristic (ROC) curve analysis was conducted to assess and analyze the efficacy of various models in detecting and evaluating the risk of cachexia.

Results: A total of 231 ES-SCLC patients were enrolled in the study. Cachexia was related to inferior progression-free survival (PFS) and overall survival (OS). In internal and external validation cohorts, the area under the curve (AUC) of the DL model were 0.73 and 0.71. Conversely, the radiomics model in external validation cohort recorded an AUC of 0.67, highlighting the superior performance of the DL model and its demonstrated capability for effective generalization in external validation. All patients were categorized into two groups, namely high risk and low risk using the DL model. It was shown that patients with low-risk cachexia were associated with significantly prolonged PFS and OS.

Conclusions: The DL model not only had better performance in predicting cachexia but also correlated with survival outcomes of ES-SCLC patients who receiving initial immunotherapy.

Background: Radiation-induced lung injury (RILI) is one of the serious adverse reactions of thoracic radiotherapy, which largely limits the dose and therapeutic effect of radiotherapy. The underlying mechanism has not been elucidated. RILI is characterized by an acute inflammatory response, and stimulator of interferon genes (STING) has been reported to play an important role in regulating inflammation and innate immune activation. However, its role in RLLI, remains unclear. Here, we reported the potential therapeutic effect of STING inhibitor H-151 on RILI.

Methods: C57BL/6J mice were exposed to 20 Gy whole-thorax irradiation and H-151 was injected intraperitoneally from the day of irradiation for 4 weeks. The degree of RILI was then assessed. To further explore the mechanism of STING in RILI, the supernatant of irradiated lung epithelial cell MLE-12 was co-cultured with embryonic fibroblast cell NIH/3T3.

Results: The cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-STING pathway is abnormally activated in irradiated mouse lung tissues. The early application of STING inhibitor significantly alleviated radiation-induced inflammatory cell infiltration and pro-inflammatory cytokine release in lung tissue, as well as the degree of fibrosis in the late stage. The amount of double-stranded DNA (dsDNA) in the supernatant of irradiated MLE-12 cells was abnormally increased, and the epithelial-derived dsDNA could promote the transformation of fibroblasts into myofibroblasts. Mechanistically, STING could mediate the activation of fibroblasts to myofibroblasts via the PKR-like endoplasmic reticulum kinase (PERK)-eukaryotic initiation factor 2α (eIF2α) pathway.

Conclusions: Our study focused on the activation of cGAS-STING signaling pathway in RILI, and inhibition of STING significantly ameliorated RILI in mice. STING mediated the effect of radiation-induced dsDNA release to stimulate the activation of inflammatory response, and STING restriction significantly delayed the fibrosis process through the PERK-eIF2α pathway, suggesting that STING intervention may pave a new avenue for the treatment of RILI.

Background: Bone metastasis (BoM) is a prevalent occurrence in patients with non-small cell lung cancer (NSCLC), significantly impacting prognosis and diminishing both survival rates and patients' quality of life. More and more studies have demonstrated that immunotherapy can improve the prognosis of NSCLC patients with bone metastases. Previous investigations pertaining to BoM in NSCLC have generally suffered from small sample sizes, absence of propensity score matching (PSM) to equate baseline characteristics, and an omission of the examination of patterns of treatment failure. This study aims to evaluate the prognostic significance of BoM and potential clinical value of bone radiation in metastatic NSCLC patients receiving immunotherapy.

Methods: Metastatic NSCLC patients receiving programmed cell death protein 1/programmed cell death-ligand 1 (PD-1/PD-L1) inhibitors from three academic centers were enrolled in a prospective, observational trial (https://clinicaltrials.gov/study/NCT04766515) and those with measurable disease and adequate follow-up were retrospectively reviewed. Propensity score matched (PSM) patients with and without BoM were included in this study. Treatment efficacy, pattern of failure and clinical value of bone radiotherapy were extensively evaluated.

Results: A total of 544 out of 1,451 immunotherapy-treated NSCLC patients were included after PSM, including 272 with BoM and 272 without. Patients with baseline BoM had a median progression-free survival (PFS) of 7.8 months [95% confidence interval (CI): 7.0-8.7], lower than those without it (9.5 months; 95% CI: 8.9-10.0) (P<0.001). Patients with baseline BoM had a median overall survival (OS) of 14.5 months (95% CI: 12.6-16.4), lower than those without 27.6 months (95% CI: 25.1-30.1) (P<0.001). Patients with BoM also had lower objective response rate than those without it (11.1% vs. 15.8%, P<0.001). Initial disease progression in the bone was more common in those with BoM (56.5%) compared to those without it (31.7%) (P<0.001). Meanwhile, among patients with BoM, no significant difference of PFS was found between those receiving bone radiation or not, possibly due to a dominant use of palliative radiotherapy.

Conclusions: Baseline BoM correlated with worse prognosis and palliative bone radiation did not improve PFS in metastatic NSCLC patients receiving PD-1/PD-L1 inhibitors.

Background: Electromagnetic navigation bronchoscopy (ENB) has been widely used to mark small peripheral pulmonary nodules (PPNs) in video-assisted thoracic surgery (VATS) resection. This technique offers the advantages of a high accuracy and fewer complications. However, few studies have analyzed the learning curve of ENB-guided preoperative localization. We aimed to describe the learning curve and factors influencing ENB-guided thoracoscopic pulmonary nodule resection.

Methods: This study included 300 consecutive patients with PPNs who underwent ENB-guided localization by the same endoscopist in our department between November 2019 and December 2021. The cumulative sum (CUSUM) method was used to analyze the learning curve of ENB-guided localization and the learning curve in different lobes, while logistic regression was used to analyze the risk factors affecting ENB operative time (OT).

Results: In 184 patients with 300 nodules, three learning phases were identified through turning points of the learning curve: Phase I (the 16^th nodule), Phase II (the 17^th to the 107^th nodule), and Phase III (the 107^th to the 300^th nodule). No significant difference was found in the success rate of ENB-guided localization in each phase of the learning curve (100%, 96.7%, and 97.9%, P=0.78). The distance from the localization to the pleura in Phase I was statistically significantly shorter than that in Phase II and Phase III (0.6±0.4 vs. 1.1±0.6 vs. 1.0±0.5 cm, P=0.001 and P=0.003). Furthermore, the learning curves for nodules in different lobes were different. The learning curve for the upper lobe nodules was divided into two phases; the learning curve for the middle lobe disclosed more negative values; and the learning curve for the lower lobe nodules displayed no obvious pattern. Significant differences were found in nodule location, distance from the localization to the pleura and learning curve phase (P=0.003, P<0.001, P=0.02). The independent factors for OT included gender, smoking history, nodule type, distance from localization to the pleura, and learning curve phase.

Conclusions: ENB OT at the 107^th nodule leveled off and showed a downward trend. Different lobes have different learning curves, the middle lobe is the easiest lobe to learn with ENB and can be used as the first lobe of choice for beginners. The learning curve can objectively evaluate the accuracy of ENB location and help endoscopists identify areas for improvement.

Background: The prognosis of patients with lung cancer and malignant pleural effusion (MPE) caused by carcinomatous pleurisy is poor. Chemical pleurodesis is commonly performed clinically, however, often has a high failure rate. Furthermore, prolonged sustained drainage and delayed introduction of systemic chemotherapy could increase the risk of worsening the Eastern Cooperative Oncology Group Performance Status (ECOG PS) in the treatment of patients with non-small cell lung cancer (NSCLC). Therefore, both systemic and local treatments are crucial to control MPE. Ramucirumab, an antibody targeting vascular endothelial growth factor receptor 2, is expected to be effective for treatment of MPE. However, there are no data supporting this hypothesis. Herein, we performed a prospective phase II study to evaluate the efficacy and safety of ramucirumab plus docetaxel in NSCLC patients with MPE.

Methods: A single-arm phase II study was conducted to elucidate the efficacy and safety of ramucirumab plus docetaxel as a combined treatment for patients NSCLC and MPE previously treated with platinum-based chemotherapy. The primary endpoint was the MPE control proportion at eight weeks after protocol treatment initiation. The secondary endpoints of the study were objective response rate (ORR), progression-free survival (PFS), one-year survival rate, overall survival (OS), and toxicity profile.

Results: Between September 2019 and March 2022, 15 patients were enrolled. The pleural effusion control proportion at eight weeks was 100% [90% confidence interval (CI): 84.0-100%, and 95% CI: 78.4-100%], and the primary endpoint of this study was met. The ORR was 6.7% (95% CI: 0.2-32.0%), the median PFS was 6.3 months (95% CI: 1.9-6.9), and the median OS was 10.4 months (95% CI: 3.2-16.5). No Grade 5 or unexpected adverse events were observed.

Conclusions: Ramucirumab plus docetaxel is a promising and safe treatment option for previously treated patients with NSCLC and MPE, showing a high pleural effusion control rate.

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of non-small cell lung cancer (NSCLC). TQB2450 (benmelstobart) is a novel humanized immunoglobulin G1 monoclonal antibody against programmed death-ligand 1 (PD-L1). Anlotinib, an oral multitargeted anti-angiogenic agent with potential synergy with ICIs, has shown efficacy in relapsed and advanced NSCLC. Accumulating preclinical data suggest a synergism between immunological and anti-angiogenic therapies through the improvement of the immune microenvironment of the tumor. In this study, we hypothesized that the combination of TQB2450 and anlotinib as maintenance treatment would enable further improvements in the outcomes of patients with locally advanced/unresectable NSCLC without driver mutations that have not progressed after definitive chemoradiotherapy.

Methods: The Radiotherapy and Anlotinib Let PD-L1 Superb (R-ALPS) study is a randomized, double-blind, placebo-controlled, multicenter phase III study (Clinicaltrials.gov identifier, NCT04325763). A total of 534 eligible participants will be randomized to receive TQB2450 (1,200 mg) plus anlotinib (8 mg), or TQB2450 (1,200 mg) plus placebo, or placebo as maintenance therapy. Progression-free survival (PFS), assessed by the independent review committee is the primary endpoint. The secondary endpoints include additional measures of efficacy, safety, and biomarkers. An interim analysis of the effectiveness will be conducted when 70% (286 cases) of the total PFS events have been reached.

Discussion: The development of the R-ALPS study will contribute to a deeper insight into the interplay between immunotherapy and anti-angiogenic therapy and thus might expand the treatment options available to patients with locally advanced or unresectable NSCLC.

Trial registration: Clinicaltrials.gov identifier: NCT04325763. Date of registration: May 27, 2020. Protocol version: Version 4.0, Sep 16, 2022 (https://classic.clinicaltrials.gov/ct2/show/NCT04325763).

[This corrects the article DOI: 10.21037/tlcr-23-98.].