Translational lung cancer research最新文献

Background: A positive correlation has been observed between computed tomography (CT) value and the invasiveness of neoplastic ground-glass nodules (GGNs). However, the traditional mean CT value cannot reflect the density heterogeneity of nodules. This study aimed to explore the value of artificial intelligence (AI)-based density proportion analysis in predicting the invasiveness of neoplastic GGNs.

Methods: Between January 2019 and May 2023, a total of 996 (687 in the training cohort and 309 in the validation cohort) neoplastic GGNs [352 adenocarcinomas in situ (AISs), 334 minimally invasive adenocarcinomas (MIAs), and 310 invasive adenocarcinomas (IACs)] in 963 patients were retrospectively analyzed. AI software was used to obtain the density histograms of the nodules, and the proportions of the components in lesions with higher density at different density thresholds were subsequently recorded. The optimal density threshold and the corresponding proportion cutoff value for determining invasive lesions (ILs) (MIAs and IACs) and IACs were respectively explored and validated. Comparison of diagnostic efficacy between AI density parameters and radiological features of GGNs for predicting ILs and IACs was also conducted respectively.

Results: For determining the ILs and IACs, the optimal density thresholds and the cutoff values for the proportion of components with density higher than the threshold were ≥-350 Hounsfield units (HU) and 17.22% [area under the curve (AUC): 0.801; 95% confidence interval (CI): 0.769-0.830; sensitivity: 51.59%; specificity: 93.52%; P<0.001] and ≥-250 HU and 5.64% (AUC: 0.882; 95% CI: 0.855-0.905; sensitivity: 85.65%; specificity: 76.15%; P<0.001) in the training cohort, respectively. Compared with other radiological features, the predictive performance of density proportion (AUC: 0.801 for ILs, 0.882 for IACs) was comparable to that of nodule size (AUC: 0.820 for ILs, 0.869 for IACs) but significantly higher than that of the remaining features. In the validation cohort, the AUCs of these parameters for determining ILs and IACs were 0.814 and 0.885 (each P<0.001), respectively. In combination with these indicators, the AUCs of the morphological features in predicting ILs and IACs increased from 0.794 to 0.849 and from 0.843 to 0.902 (each P<0.001) in the training cohort, respectively.

Conclusions: AI-based density analysis has a potential role in determining the invasiveness of neoplastic GGNs.

Background: The combination of an anti-programmed death-ligand 1 (PD-L1) antibody with etoposide and either carboplatin or cisplatin (platinum-etoposide) has become the first-line treatment for patients with extensive-stage small-cell lung cancer (ES-SCLC). Although previous studies have examined the relationship between geriatric assessments and treatment efficacy, the association with treatment tolerability in elderly patients with ES-SCLC remains insufficiently understood. We aimed to evaluate the association between low body mass index (BMI)-a component of geriatric assessment-and treatment tolerability.

Methods: We conducted a retrospective analysis of patients aged ≥65 years with ES-SCLC who received anti-PD-L1 antibody plus platinum-etoposide at a single center between August 2019 and April 2024. Tolerability was defined as the completion of four cycles of anti-PD-L1 antibody combined with platinum-etoposide. We also assessed treatment efficacy and safety profiles.

Results: A total of 71 patients were included, with a median age of 73 years (range: 65-91 years). Of these, 51 patients (72%) were male, and 54 (76%) had an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0 or 1. Sixteen patients (23%) showed a low BMI (<19 kg/m2), whereas 55 (77%) showed a non-low BMI. Tolerability was achieved in 8 patients (50%) with low BMI compared with 44 patients (80%) with non-low BMI. There were no significant differences in overall survival, progression-free survival, or the incidence of grade ≥3 adverse events among the two groups. In multivariate analysis, low BMI and ECOG-PS ≥2 were independently associated with reduced treatment tolerability [odds ratio (OR): 0.24, 95% confidence interval (CI): 0.06-0.88, P=0.03; OR: 0.13, 95% CI: 0.04-0.48, P<0.01, respectively].

Conclusions: Low BMI and poor performance status were independently associated with decreased tolerability to anti-PD-L1 antibody combined with platinum-etoposide in elderly patients with ES-SCLC. These findings underscore the importance of incorporating geriatric assessments into treatment decision-making for this population.

Background: Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors improve outcomes in EGFR T790M-positive non-small cell lung cancer (NSCLC), but the prognostic value of plasma-detected T790M remains uncertain. We evaluated the clinical significance of baseline plasma T790M in patients treated with lazertinib, accounting for metastatic distribution and coexisting genomic alterations.

Methods: In this prospective multicenter cohort, we analyzed 117 patients with EGFR-mutant NSCLC who received lazertinib after T790M confirmation in tissue or plasma. Plasma EGFR mutations were profiled using next-generation sequencing before treatment. Progression-free survival (PFS) and overall survival (OS) were compared by plasma T790M status, metastatic sites, and co-alterations.

Results: Of 117 patients, 92 were plasma T790M-positive and 25 were plasma T790M-negative. Plasma T790M positivity was associated with shorter PFS (10.0 vs. 23.0 months, P=0.03) and OS (20.0 months vs. not reached, P=0.006). All patients with liver or adrenal metastases were plasma T790M-positive, and involvement of either site predicted poorer outcomes than in patients without these metastases. Bone metastasis also portended a worse prognosis, irrespective of plasma T790M status. Among co-alterations, EGFR C797S or MYC alterations correlated with shorter PFS.

Conclusions: Baseline plasma T790M, interpreted alongside metastatic distribution, provided prognostic information in EGFR-mutant NSCLC treated with lazertinib. Liver and adrenal metastases occurred exclusively in plasma T790M-positive patients and were associated with markedly worse outcomes, consistent with a ctDNA-shedding phenotype. Bone metastasis was an adverse prognostic factor independent of plasma T790M, underscoring the combined prognostic impact of molecular and metastatic features.

Background: Pleural mesothelioma (PM) represents an uncommon and exceptionally lethal malignancy. The sarcomatoid subtype constitutes the rarest histological variant, traditionally linked to the worst prognosis, while the advantages of operative intervention remain inadequately established. In this study, we present findings from a cohort of 34 sequential cases with sarcomatoid mesothelioma managed at a specialized high-volume center employing pleurectomy decortication (PD) within a comprehensive therapeutic strategy. We aim to identify patients in this cohort who may benefit from a multimodality approach.

Methods: All patients diagnosed with sarcomatoid mesothelioma between 2007 and 2019 who received PD at our facility were enrolled, and relevant medical, histopathological, and operative data collected. Survival curves generated through Kaplan-Meier methodology alongside log-rank testing enabled comparison of longevity outcomes, while Cox proportional hazards modeling facilitated examination of predictive variables.

Results: The cohort included 31 male subjects (91.2%), 24 procedures performed on the right side (70.6%), with a median patient age of 71.5 years (range, 51-85 years). Preoperative treatment was administered to 8 individuals (24.2%), while 23 participants (67.7%) underwent intraoperative heated chemotherapy (IOHC). Macroscopic complete resection (MCR) was accomplished in 22 cases (64.7%). Mortality at 30 and 90 days post-surgery stood at 2.9% and 14.7%, respectively. The median overall survival for the entire cohort reached 7.4 months, extending to 20.1 months among those with forced expiratory volume in 1 second (FEV1) at or above 80% predicted. In multivariate analysis, preoperative FEV1 ≥80% was associated with prolonged overall survival [P=0.01; hazard ratio (HR) =0.54].

Conclusions: As expected, the median survival for most patients with sarcomatoid histology who undergo surgery is under one year. However, a small subset of patients with FEV1 ≥80% do quite well using the multimodality approach.

Background: The optimal volume for pleural lavage during lung cancer surgery remains controversial, despite its recognized importance in thoracic cavity decontamination, tumor cell clearance, and prevention of postoperative complications. This study assessed the impact of varying lavage volumes on perioperative outcomes in non-small cell lung cancer (NSCLC) patients, with the objective of establishing evidence-based procedural guidelines.

Methods: Participants underwent lobectomy for NSCLC were randomly assigned to receive either 1,000 or 250 mL of pleural lavage before chest closure. The primary outcome was overall fever rates, and secondary outcomes included complication rates, drainage parameters, and length of hospital stay.

Results: A total of 415 patients were screened, and 406 were randomized to either the 1,000 mL (n=206) or 250 mL (n=200) groups. Postoperative fever (≥37.3 ℃) occurred in 23.08% of the 1,000 mL group and 17.01% of the 250 mL group (P=0.17). The fever rates at ≥38 ℃ were similar between groups (5.13% vs. 4.12%, P=0.82). A temporal difference in fever progression was observed, with the 1,000 mL group peaking 24 hours earlier on postoperative day 1 (POD1) evening, while the 250 mL group peaked on POD2 evening. Postoperative pneumonias were comparable (1.54% vs. 1.55%, P>0.99) between groups. Surgery duration, drainage volume, and cost were slightly more favorable in the 250 mL group, though not statistically significant.

Conclusions: A volume of 250 mL pleural lavage demonstrated comparable efficacy to 1,000 mL in controlling postoperative fever and complications, while showing trends toward reduced resource utilization (shorter surgery duration, lower drainage volume and cost).

Trial registration: The trial protocol was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR1900021950) before patient enrollment.

Background: Synchronous multiple primary lung cancers are rare. The field cancerization model posits that carcinogen exposure leads to molecular damage and epigenetic reprogramming in the bronchial epithelium, predisposing individuals to multiple tumors. However, genetic factors may explain why only some individuals develop synchronous primaries. Whole genome sequencing (WGS) offers comprehensive insights into somatic mutations, structural variants, and DNA repair defects, surpassing the limitations of histology or exome sequencing.

Case description: An 80-year-old male underwent left upper lobectomy. The initial biopsy suggested adenocarcinoma, but the final specimen revealed two distinct invasive carcinomas: a 2.1 cm × 1.9 cm acinar- and papillary-predominant adenocarcinoma and a 1.1 cm × 0.7 cm non-keratinizing squamous cell carcinoma. WGS identified 564 variants across both tumors, with only six shared (Jaccard index 0.022). Tumor mutational burden was moderate (6.04 mutations/Mb in adenocarcinoma; 5.24 in squamous carcinoma). Clonal relatedness metrics, including variant allele frequency and cancer cell fraction correlations, were weak, supporting independent origins. Genomic analysis revealed a truncating PMS2 alteration in the adenocarcinoma and a missense ERCC2 variant of uncertain significance in the squamous carcinoma, implicating functional compromise of mismatch repair (PMS2) and nucleotide excision repair (ERCC2) pathways, both pivotal in tobacco-related mutagenic resistance. Oncogenic pathway analysis showed distinct alterations: adenocarcinoma was enriched in MET pathway alterations, while the squamous carcinoma exhibited alterations in alternative pathways.

Conclusions: This case demonstrates that synchronous lung cancers may result from the combined effects of carcinogen-induced field cancerization and DNA repair deficiencies. The identification of PMS2 and ERCC2 alterations provides mechanistic evidence of genetic vulnerability, highlighting the importance of counseling, surveillance, and potential DNA repair-targeted strategies.

Background: At initial lung cancer diagnosis, intrapulmonary metastasis (IPM) usually reflects more advanced intrathoracic disease than single primary lung cancer (SPLC). However, the clinical and pathological characteristics associated with presenting as IPM rather than SPLC, and with more extensive IPM patterns, are not well described. This study aimed to characterise how sociodemographic and tumor features at diagnosis are associated with IPM compared with SPLC and with different intrapulmonary metastatic patterns in a large population-based registry.

Methods: We conducted a cross-sectional analysis of patients with non-small cell lung cancer in the Surveillance, Epidemiology, and End Results database from 2000 to 2019. IPM and SPLC were defined using the "Separate Tumor Nodules Ipsilateral Lung" recode. Bayesian network modeling and structural equation modeling were used to describe conditional association structures among sociodemographic variables, tumor characteristics, and lung cancer type. Simulated interventions in the Bayesian network yielded model-based risk ratios (RRs) with 95% confidence intervals (CIs) for IPM versus SPLC. Logistic regression was used in an exploratory subgroup analysis of IPM patterns comparing disease confined to the same lobe, disease in different lobes, and disease in both the same and different lobes.

Results: Among 45,194 patients, 9,302 had IPM and 35,892 had SPLC. In the Bayesian network, tumor grade and laterality showed the strongest direct associations with lung cancer type, and the model discriminated IPM from SPLC with an area under the curve of 0.919. Sociodemographic variables showed weaker and less consistent associations with lung cancer type after adjustment for tumor characteristics. Simulated interventions suggested progressively higher model-based risk of IPM with poorer differentiation (RR of well-differentiated to poorly differentiated grade: 1.664, 95% CI: 1.571-1.772) and with right-sided disease (RR of right-sided to left-sided disease: 1.136, 95% CI: 1.093-1.178). In subgroup analyses, higher grade and lower and middle lobe location were associated with IPM patterns involving multiple lobes.

Conclusions: In this large registry-based study, intrapulmonary metastatic disease at first lung cancer diagnosis was more strongly associated with tumor differentiation, laterality, and anatomical distribution than with measured sociodemographic factors. These observational associations may help characterise patients who present with more extensive intrapulmonary disease.

Background: Precision oncology in non-small cell lung cancer (NSCLC) requires comprehensive genomic characterization to inform therapeutic decisions. However, the spectrum of genomic alterations and their co-mutation patterns, particularly in relation to immunotherapy biomarkers, remains incompletely understood. This study investigated the associations between driver gene alterations and clinicopathological characteristics, and characterized co-mutation patterns in relation to programmed cell death ligand 1 (PD-L1) expression and tumor mutational burden (TMB) levels.

Methods: We conducted a retrospective analysis of 431 NSCLC patients, utilizing a comprehensive pan-solid tumor next-generation sequencing (NGS) panel covering 654 genes to characterize genomic alterations. Clinicopathological characteristics were systematically collected and analyzed to identify significant differences across various mutational profiles. Systematic assessments were performed to evaluate interactions between co-mutations and PD-L1 expression as well as TMB.

Results: Genomic profiling revealed EGFR as the most frequently mutated driver gene (59.1%), followed by TP53 (39.7%), RBM10 (14.6%), MUC16 (12.7%), and KRAS (10.0%). EGFR mutations showed a strong female predominance (P<0.001), whereas MUC16 (P=0.004) and KRAS (P<0.001) alterations were more common in males. TP53 (P=0.005) and KRAS (P<0.001) alterations were more frequently found in smokers. Patients with advanced disease stages exhibited higher frequencies of TP53 mutations (P<0.001), contrasting with the predominance of EGFR (P<0.001) and RBM10 (P=0.04) mutations in early-stage tumors. TP53 co-mutations were the most common types, especially TP53-EGFR and TP53-KRAS co-mutations. TP53-EGFR co-mutations had higher PD-L1 expression (P=0.03) and TMB level (P=0.03) than EGFR-only mutations. Patients with TP53-KRAS co-mutations showed significantly higher PD-L1 expression (P=0.01) and TMB level (P=0.01) than KRAS-only mutations.

Conclusions: This study underscores the diverse genetic mutations occurring in NSCLC patients with varying risk factors. The identification of TP53 co-mutations provides critical insights for personalized immunotherapeutic strategies and optimizing treatment outcomes.

Background: The clinical management of lung adenocarcinoma (LUAD) is compromised by post-surgical recurrence and therapeutic resistance, underscoring the urgent need to uncover actionable therapeutic vulnerabilities. By integrating human genetics with multi-omics profiling and experimental validation, this study aims to systematically uncover critical molecular mediators of LUAD and delineate their therapeutic potential.

Methods: We implemented a multi-modal framework to identify and characterize causal LUAD therapeutic targets. We used two-sample Mendelian randomization (2SMR) to identify plasma proteins that are causally linked to LUAD risk. The lead candidate was then investigated using multi-omics to delineate its clinical relevance, cellular drivers, and tumor microenvironment. Oncogenic mechanisms were subsequently interrogated through functional experiments in LUAD models.

Results: Our unbiased genetic screen identified Rac GTPase-activating protein 1 (RACGAP1) as a high-confidence causal risk factor for LUAD. Clinically, elevated RACGAP1 expression served as a robust, independent prognostic biomarker associated with poor survival across multiple cohorts. Single-cell profiling revealed that RACGAP1 defines a specific expanding epithelial subpopulation characterized by chromosomal instability (CIN) and apoptosis resistance. Spatially, these cells organize into "malignant proliferative niches" that drive tumor expansion. Mechanistically, RACGAP1 transcends its canonical role in cytokinesis to function as a pivotal oncogenic hub. It disables p53-mediated tumor suppression by upregulating MDM2, while concurrently activating the pro-survival PI3K/AKT and MEK/ERK signaling cascades. Crucially, pharmacological inhibition of these pathways abrogated the RACGAP1-driven malignant phenotypes, confirming the functional dependence of the tumor on this rewired signaling architecture.

Conclusions: This study presents genetic evidence supportive of a causal contribution of RACGAP1 to LUAD, highlighting it as a promising prognostic biomarker and candidate therapeutic target. By delineating a RACGAP1-driven axis that coordinates survival signaling and suppresses tumor surveillance, our findings highlight RACGAP1 as a promising therapeutic target for novel adjuvant strategies.