Translational lung cancer research最新文献

Background: The B-Raf proto-oncogene, serine/threonine kinase (BRAF) V600E mutation is responsible for approximately 3% of acquired resistance mechanisms to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in advanced EGFR-mutant non-small cell lung cancer (NSCLC). This study investigated the efficacy and safety of a triple-targeted therapy combining EGFR/BRAF/mitogen-activated protein kinase kinase (MEK) inhibitors of dabrafenib, trametinib, and osimertinib in NSCLC patients with acquired BRAF V600E mutation after EGFR-TKI treatment.

Methods: A multi-center retrospective review of medical records was performed to analyze EGFR-mutated advanced Chinese NSCLC patients who acquired the BRAF V600E mutation following EGFR-TKI treatment. All patients subsequently received dabrafenib, trametinib, and osimertinib. The clinical characteristics, progression-free survival (PFS), and adverse events (AEs) were documented. The in-vivo drug response of patient-derived organoids (PDOs) was observed. Next-generation sequencing (NGS) was performed upon progression to triple-targeted therapy.

Results: Thirteen patients with BRAF V600E mutations were included. Following triple-targeted therapy, the corresponding objective response rate and disease control rate were 61.5% and 92.3%, respectively. The median PFS was 13.5 months (95% confidence interval: 6.6-20.4). PDOs derived from one patient's tumor sample were established, revealing that the triple-targeted therapy had a significantly lower half-maximal inhibitory concentration (IC₅₀) value compared to other regimens. The tumor growth inhibitory rate was 99.36% for dabrafenib, trametinib, and osimertinib; 99.25% for osimertinib plus vemurafenib; 98.92% for osimertinib, encorafenib, and cetuximab; and 62.83% for pemetrexed plus carboplatin. NGS analysis identified major resistance mechanisms following the triple-targeted therapy, including the EGFR-dependent pathway, EGFR and BRAF V600E-dependent pathway, and an off-target mechanism.

Conclusions: EGFR/BRAF/MEK triple-targeted therapy is an effective and safe approach for treating EGFR-mutated NSCLC patients resistant to EGFR-TKIs with acquired BRAF V600E mutations.

Background: Lung adenocarcinoma (LUAD) is one of the most prevalent types of lung cancer (LC), accounting for 50% of all LC cases. Despite therapeutic advancements, patients suffer from adverse drug reactions. Furthermore, the prognosis of LC patients remains poor. Necroptosis is a novel mode of cell death and is critically involved in regulating immunotherapy in patients. However, the correlation between the necroptosis-related long non-coding RNA (lncRNA) (necro-related lnc) signature (NecroLncSig) and the response of patients with LUAD to immunotherapy is unclear. This study developed a model using lncRNAs to predict the prognosis of patients with LUAD.

Methods: We obtained the transcriptomic and clinical data of LUAD patients from The Cancer Genome Atlas (TCGA) database. Next, we conducted a co-expression analysis to identify the necro-related lnc. In addition, we constructed the NecroLncSig using univariate and least absolute shrinkage and selection operator (LASSO) Cox regression analyses. Then we evaluated and validated the NecroLncSig using a Kaplan-Meier (KM) survival analysis, receiver operating characteristic (ROC) curves, principal component analysis (PCA), Gene Ontology (GO) enrichment analysis, a nomogram, and calibration curves. Finally, we used the NecroLncSig to predict the responses of patients to immunotherapy.

Results: We constructed the NecroLncSig based on seven necro-related lnc. The patients were classified into a high-risk group (HRG) and a low-risk group (LRG). The overall survival (OS) of patients in the HRG was significantly poorer in the training, testing, and entire sets (P<0.05) than that of the patients in the LRG. Univariate and multivariate Cox regression analyses demonstrated that the risk score could predict the OS of patients in an independent manner (P<0.001). Time-dependent ROC analysis demonstrated that the area under the curve values of the NecroLncSig for 1-, 2-, and 3-year OS were 0.689, 0.700, and 0.685, respectively, for the entire set. Furthermore, the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm showed that the response of patients in the HRG to immunotherapy was better than that of patients in the LRG.

Conclusions: Necro-related lnc can affect disease progression and patient prognosis. In addition, these lncRNAs can be used to design therapeutic strategies, such as immunotherapy, to treat patients with LUAD.

Background: The appreciation of sex differences is substantial for precise cancer management. Surgery is the main treatment for non-small cell lung cancer (NSCLC). We aimed to identify sex differences on perioperative outcomes in NSCLC patients and to uncover the origins of sex effect in outcomes using a Chinese cohort.

Methods: We retrospectively enrolled patients undergoing NSCLC surgery in the Western China Lung Cancer Database from January 2014 to April 2021. We compared baseline characteristics and perioperative outcomes between male and female. Multivariable analyses were performed. We conducted causal mediation analysis to identify drivers to sex differences in perioperative outcomes.

Results: Altogether, data of 10,181 patients (5,738 women and 4,443 men) were analyzed. Women had lower incidence of complications (5.05% vs. 12.15%), shorter postoperative length of stays (4.92 vs. 6.41 days), and less hospitalization cost (50,713.69 vs. 54,580.85, Chinese Yuan). Multivariable regression analysis identified sex as an independent factor of perioperative complications [odds ratio (OR), 1.843, 95% confidence interval (CI): 1.476-2.294], as well as of postoperative length of hospital stays (beta 0.123, 95% CI: 0.099-0.148), and hospitalization cost (beta 0.026, 95% CI: 0.026-0.026). Mediation analysis revealed that age, body mass index, prevalence of chronic obstructive pulmonary disease, predicted diffusion capacity for carbon monoxide, tumor size, pleural adhesion, and surgery duration were identified as mediators for sex differences in outcomes, while smoking status, surgery type, and resection extent were not.

Conclusions: Female NSCLC patients demonstrated lower incidence of complications, shorter postoperative length of stays, and less hospitalization cost after surgery. Those differences between men and women could be explained by their inherent biological differences and baseline health status. Perioperative management strategies for NSCLC should prioritize recognizing the potentially poorer outcomes among male patients and implementing tailored precautions accordingly.

Background: Chronic obstructive pulmonary disease (COPD) is associated with frequent complications after transthoracic biopsy. Radial probe endobronchial ultrasound-guided transbronchial lung biopsy (RP-EBUS-TBLB) is widely used to diagnose peripheral pulmonary lesions (PPLs). However, the efficacy and safety of this procedure for the diagnosis of PPLs in patients with COPD remain poorly understood. We investigated the usefulness of RP-EBUS-TBLB for diagnosing PPLs in patients with COPD.

Methods: This retrospective observational study aimed to identify clinical outcomes of RP-EBUS-TBLB in patients with COPD. A total of 175 patients with COPD and 439 patients without COPD were included in this study. RP-EBUS-TBLB was performed without fluoroscopy using a guide sheath.

Results: The overall diagnostic accuracies in patients with COPD and without COPD were 80.6% (141/175) and 78.8% (346/439), respectively. There was no significant difference in the diagnostic yield based on the severity of airflow limitation (80.0%, 81.4%, and 79.2% for mild, moderate, and severe to very airflow limitations, respectively; P=0.97). In patients with COPD, diagnostic yields for malignant and benign lesions were 85.6% (95/111) and 71.9% (46/64). In multivariable analyses, larger lesion size [≥30 mm; odds ratio (OR), 2.86; 95% confidence interval (CI): 1.10-7.45; P=0.03] and within the lesion on EBUS image (OR 9.29; 95% CI: 3.79-22.79; P<0.001) were associated with diagnostic success in patients with COPD, whereas lesion location of upper lobe (OR, 0.36; 95% CI: 0.14-0.92; P=0.03) were associated with diagnostic failure. The overall complication rate in our study was 7.4% (13/175) in patients with COPD. Pneumothorax occurred in 4.6% (8/175), and chest tube insertion was needed in 1.7% (3/175) of the patients.

Conclusions: RP-EBUS-TBLB can be used as an appropriate method to diagnose PPLs in patients with COPD. The size of the lesion (≥30 mm) and having the probe within the lesion were important for successful diagnosis. The location of the lesion in the upper lobe is associated with diagnostic failure. No difference was observed in the diagnostic yield based on the severity of airflow limitation. The complication rates were acceptable.

Background: Few studies have examined the safety and efficacy of docetaxel/ramucirumab (DOC/RAM) therapy in advanced non-small cell lung cancer (NSCLC) complicated by interstitial lung disease (ILD). Given the potential of vascular endothelial growth factor inhibitors to prevent drug-induced pneumonia, we aimed to clarify the role of this therapy in NSCLC with ILD.

Methods: This retrospective observational study evaluated the incidence of ILD in stage IV NSCLC patients receiving DOC/RAM therapy at our institution, stratified by ILD status. We also assessed the efficacy of this treatment. The primary objective was to investigate the incidence of ILD, while secondary objectives included evaluating the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS), stratified by ILD status.

Results: Among patients with pre-existing ILD, 7 out of 28 (25%) developed DOC/RAM-induced interstitial pneumonia, while none of the 40 patients without pre-existing ILD developed this condition (P<0.001). Comparing historical controls (DOC only) with the DOC/RAM group, RAM did not significantly alter the incidence of interstitial pneumonia (P=0.33). There were no significant differences in ORR, PFS, or OS between patients with and without ILD. Subgroup analysis of smokers showed a non-significant trend toward worse survival in those with pre-existing ILD (P=0.20).

Conclusions: DOC/RAM therapy significantly increased the incidence of interstitial pneumonia in NSCLC patients with pre-existing ILD but did not significantly affect efficacy outcomes such as ORR, PFS, or OS.

Background: The time to surgery (TTS) after the completion of the final cycle of neoadjuvant chemoimmunotherapy in patients with non-small cell lung cancer (NSCLC) is inconsistent. Pathological complete response (pCR) and major pathological response (MPR) are associated with enhanced survival in those with NSCLC. The optimal TTS interval remains to be determined, some studies indicated that TTS ≤6 weeks has a vital role in NSCLC prognosis. Therefore, this study aimed to determine whether TTS is correlated with pathological outcomes and to identify the factors associated with TTS.

Methods: We retrospectively analyzed 82 individuals who had surgery after neoadjuvant chemoimmunotherapy for NSCLC between January 2020 and December 2023. Fifty participants were included in this study after inclusion and exclusion criteria. Participants were categorized into two groups: TTS ≤4 weeks and TTS >4 to 6 weeks. Univariate and multivariate regression analyses were employed to determine the impact of TTS on pathological response and to identify the variables associated with TTS. Variables that showed their P value <0.2 in univariate analyses were included in the multivariate analysis. Kaplan-Meier analysis was used to analyze disease-free survival (DFS).

Results: Our study evaluating 50 patients revealed that patients in the TTS ≤4 weeks group achieved pCR or MPR compared to patients in the >4 to 6 weeks group (P=0.01). In univariate analyses, TTS ≤4 weeks was more correlated with achieving pCR or MPR than TTS >4 to 6 weeks [odds ratio (OR) =0.211; 95% confidence interval (CI): 0.062-0.711; P=0.01] The multivariate analysis showed that cT1 stage (compared to cT4), and cN1 stage (compared to cN0) showed statistical correlation with achieving pCR or MPR. cN1 stage was independent predictor of achieving pCR or MPR (OR =27.817; 95% CI: 1.536-503.88; P=0.02). Concerning to the DFS, TTS ≤4 weeks group and TTS >4 to 6 weeks group showed no statistical differences (2-year DFS rate were 70.6% and 72.6%, respectively). Regarding the tendency of being patients' TTS ≤4 weeks, patients with ventilatory impairment (OR =0.203; 95% CI: 0.04-0.98; P=0.047) were more tending to prolong the TTS to >4 to 6 weeks.

Conclusions: TTS ≤4 weeks was associated with a significant improvement of pathological response. Therefore, patients with NSCLC should undergo surgery within 4 weeks after the last cycle of neoadjuvant chemoimmunotherapy.

Background: The rise of low-dose computed tomography (LDCT) has increased the detection of small pulmonary nodules, demanding more effective localization techniques for their resection. Minimally invasive resection utilizing video-assisted thoracoscopic surgery (VATS) is a critical method for treating these nodules. However, traditional computed tomography (CT)-guided localization has limitations such as invasiveness and patient discomfort. The current gap in knowledge relates to the potential advantages of electromagnetic navigation bronchoscopy (ENB) in reducing complications and improving procedural efficiency. The NOVEL trial evaluates the non-inferiority of ENB-guided labeling against CT-guided puncture for lung nodule localization.

Methods: This multicenter, randomized, controlled, non-inferiority phase III trial includes 156 participants across four Chinese hospitals, randomized to undergo either ENB-guided or CT-guided localization prior to VATS sub-lobar resection. Randomization is performed using sealed opaque envelopes to ensure allocation concealment. Primary outcomes are the procedural success rates and complication rates of both techniques, with secondary outcomes including procedure times and lesion margins.

Discussion: The NOVEL trial aims to provide a detailed comparison of ENB-guided versus CT-guided localization for small pulmonary nodules. Establishing the safety and efficacy of the ENB method could significantly influence clinical practices and improve patient outcomes.

Trial registration: This trial was registered with the Medical Research Registration Platform (https://www.medicalresearch.org.cn), registration number MR-31-24-018575.

Background: Lung cancer is one of the most common malignant tumors worldwide. Despite advances in lung cancer treatment, patients still face challenges related to drug resistance and recurrence. Current methods for evaluating anti-cancer drug activity are insufficient, as they rely on two-dimensional (2D) cell culture and animal models. Therefore, the development of an in vitro drug evaluation model capable of predicting individual sensitivity to anti-cancer drugs would greatly enhance the success rate of drug treatments for lung cancer patients. The purpose of this research is to utilise conditional reprogramming technology to cultivate patient-derived lung cancer cells and to construct an in vitro 3D culture model using sodium alginate (SA) and gelatin. The aim is to study the biological characteristics of cells in the 3D culture model and to further investigate the sensitivity of anti-cancer drugs based on the alginate-gelatin 3D culture model. This approach provides new means and insights for personalized precision anti-cancer therapy and the development of new anti-cancer drugs.

Methods: Conditional reprogramming technology was used to generate conditionally reprogrammed lung adenocarcinoma cells (CRLCs). Alginate-gelatin hydrogel micro-beads were created to explore their potential use in the assessment of anti-cancer drugs. Cell proliferation was also examined using the MTS assay method. Live/dead staining was performed to estimate cell distribution and viability using calcein acetoxymethyl ester/propidium iodide (calcein-AM/PI) double staining. Protein expression was assessed by Western blot.

Results: The cells grown in the three-dimensional (3D) culture were in a state of continuous proliferation, and there was an obvious phenomenon of cell mass growth. The drug sensitivity assay results demonstrated that compared with the 2D-grown cells, the CRLCs grown in the alginate-gelatin hydrogel micro-beads exhibited more resistance to anti-cancer drugs. The results also showed that the 3D-cultured CRLCs showed greater protein expression levels of stem cell hallmarks, such as Nanog Homeobox (NANOG), SRY-Box Transcription Factor 2 (SOX-2), and aldehyde dehydrogenase 1 family member A1 (ALDH1A1), than the 2D-grown cells.

Conclusions: These findings suggest that the 3D hydrogel cell culture models more closely mimicked the in vivo biological and clinical behavior of cells, and demonstrated higher innate resistance to anti-cancer drugs than the 2D cell culture models, and thus could serve as valuable tools for diagnosis, drug screening, and personalized medicine.

Background: Neoadjuvant chemo-immunotherapy has increased the number of patients with advanced lung cancer eligible for surgery. However, only a small number of such patients respond to this approach. Intensive research is being conducted to identify biomarkers to predict the efficacy of neoadjuvant chemo-immunotherapy. Among these, blood predictive biomarkers are particularly promising, and have the advantages of being both non-invasive and cost effective. This study aims to evaluate the predictive value of blood biomarkers in determining the efficacy of neoadjuvant chemo-immunotherapy for patients with non-small cell lung cancer (NSCLC), addressing a critical need for more personalized treatment strategies in clinical practice.

Methods: We retrospectively collected the data of 199 NSCLC patients who received neoadjuvant chemo-immunotherapy from January 1, 2021 to December 31, 2023, at Zhejiang Cancer Hospital. We then analyzed the performance of blood biomarkers in predicting the efficacy of neoadjuvant chemo-immunotherapy.

Results: The patients in the major pathological response (MPR) group had significantly higher pre-treatment squamous cell carcinoma antigen (SCCA) levels, and a significantly lower post-treatment platelet-lymphocyte ratio (PLR) than those in the non-MPR group. For patients with higher pre-treatment SCCA levels, the 1- and 2-year event-free survival (EFS) rates were 97.87% [95% confidence interval (CI): 94.99-100.00%] and 93.21% (95% CI: 84.32-100.00%), respectively. In those with lower pre-treatment SCCA levels, the 1- and 2-year EFS rates were 91.39% (95% CI: 84.93-98.35%) and 82.24% (95% CI: 72.42-93.39%), respectively. The survival analysis showed that higher pre-treatment SCCA levels were correlated with improved EFS (P=0.02) in patients receiving neoadjuvant chemo-immunotherapy. Conversely, for patients undergoing surgery alone, high pre-treatment SCCA levels were correlated with a poorer prognosis [disease-free survival (DFS), P=0.001]. These findings confirm the value of SCCA levels in predicting which patients will have a more favorable response to neoadjuvant chemo-immunotherapy. In patients receiving neoadjuvant chemo-immunotherapy, a high post-treatment PLR indicated a poorer prognosis (P=0.02). The Cox regression analysis indicated that the pre-treatment SCCA level (P=0.04) and post-treatment PLR (P=0.04) were independent predictive factors of EFS.

Conclusions: In patients receiving neoadjuvant chemo-immunotherapy, high pre-treatment SCCA levels and low post-treatment PLRs were significantly associated with better efficacy and survival. Thus, these biomarkers could be used to guide the choice of treatment modalities.

Background: Recently, the impact of solar radiation (RAD) on diseases worldwide has garnered growing attention. However, the association between RAD and lung cancer remains largely unknow and no consensus has been reached. The aim of this study was to investigate the lag exposure-response of RAD on lung cancer and provide robust scientific evidence for updating prevention and treatment strategies of lung cancer.

Methods: Data of RAD were obtained from Google Earth Engine, which was post-processed by European Centre for Medium-Range Weather Forecasts (ECMWF). Lung cancer incidence, smoking prevalence and socio-demographic index (SDI) were obtained from Global Burden of Disease (GBD). Spearman's rank correlation tests and linear regression analyses were performed to investigate the relationship between RAD and lung cancer incidence. Additionally, a distributed lag non-linear model (DLNM) was utilized to reveal the lag effects of RAD on lung cancer incidence.

Results: There were 204 countries and territories and selected subnational locations with information recorded in GBD and radiation exposure was calculated in 272 countries and territories. After excluding missing and abnormal data, as well as Kashmir and Western Sahara which were two disputed districts, this study included 186 countries from 1992 to 2019. After adjusted for smoking and SDI, the Spearman's correlation coefficient ranged from -0.630 to -0.581. In the DLNM for lung cancer adjusted for smoking and SDI, the maximum relative risk (RR) was 1.013 [95% confidence interval (CI): 1.011-1.014], at RAD exposure of 12,760,000 with 5.8 lag years, while the minimum RR was 0.973 (95% CI: 0.947-0.992) at RAD exposure of 12,845,000 with 8.0 lag years.

Conclusions: The global rise in lung cancer incidence has been notably associated with low exposure to RAD, whereas the defensive influence of sunlight against lung cancer demonstrated hysteresis. This study shows that properly exposure to sunlight is a possible strategy for lung cancer prevention, which provides scientific support for the formulation of future health strategies. It is also crucial in epidemiological research as it offers a novel pattern for identifying additional potential risk factors for diseases.