Nomograms for intraoperative prediction of lymph node metastasis in clinical stage IA lung adenocarcinoma.

BACKGROUND: Accurate prediction of lymph node metastasis (LNM) is critical for selecting optimal surgical procedures in early-stage lung adenocarcinoma (LUAD). This study aimed to develop nomograms for intraoperative prediction of LNM in clinical stage IA LUAD. METHODS: A total of 1227 patients with clinical stage IA LUADs on computed tomography (CT) were enrolled to construct and validate nomograms for predicting LNM (LNM nomogram) and mediastinal LNM (LNM-N2 nomogram). Recurrence-free survival (RFS) and overall survival (OS) were compared between limited mediastinal lymphadenectomy (LML) and systematic mediastinal lymphadenectomy (SML) in the high- and low-risk groups for LNM-N2, respectively. RESULTS: Three variables were incorporated into the LNM nomogram and the LNM-N2 nomogram, including preoperative serum carcinoembryonic antigen (CEA) level, CT appearance, and tumor size. The LNM nomogram showed good discriminatory performance, with C-indexes of 0.879 (95% CI, 0.847-0.911) and 0.880 (95% CI, 0.834-0.926) in the development and validation cohorts, respectively. The C-indexes of the LNM-N2 nomogram were 0.812 (95% CI, 0.766-0.858) and 0.822 (95% CI, 0.762-0.882) in the development and validation cohorts, respectively. LML and SML had similar survival outcomes among patients with low risk of LNM-N2 (5-year RFS, 88.1% vs. 89.5%, Pp = 0.790; 5-year OS, 96.0% vs. 93.0%, p = 0.370). However, for patients with high risk of LNM-N2, LML was associated with worse survival (5-year RFS, 64.0% vs. 77.4%, p = 0.036; 5-year OS, 66.0% vs. 85.9%, p = 0.038). CONCLUSIONS: We developed and validated nomograms to predict LNM and LNM-N2 intraoperatively in patients with clinical stage IA LUAD on CT. These nomograms may help surgeons to select optimal surgical procedures.

Multi-omics analysis unravels the underlying mechanisms of poor prognosis and differential therapeutic responses of solid predominant lung adenocarcinoma.

Background: Solid predominant adenocarcinoma (SPA) has been reported to be a subtype with poor prognosis and unsatisfactory response to chemotherapy and targeted therapy in lung adenocarcinoma (LUAD). However, the underlying mechanisms remain largely unknown and the suitability of immunotherapy for SPA has not been investigated. Methods: We conducted a multi-omics analysis of 1078 untreated LUAD patients with clinicopathologic, genomic, transcriptomic, and proteomic data from both public and internal cohorts to determine the underlying mechanisms of poor prognosis and differential therapeutic responses of SPA and to investigate the potential of immunotherapy for SPA. The suitability of immunotherapy for SPA was further confirmed in a cohort of LUAD patients who received neoadjuvant immunotherapy in our center. Results: Along with its aggressive clinicopathologic behaviors, SPA had significantly higher tumor mutation burden (TMB) and number of pathways altered, lower TTF-1 and Napsin-A expression, higher proliferation score and a more immunoresistant microenvironment than non-solid predominant adenocarcinoma (Non-SPA), accounting for its worse prognosis. Additionally, SPA had significantly lower frequency of therapeutically targetable driver mutations and higher frequency of EGFR/TP53 co-mutation which was related to resistance to EGFR tyrosine kinase inhibitors, indicating a lower potential for targeted therapy. Meanwhile, SPA was enriched for molecular features associated with poor response to chemotherapy (higher chemoresistence signature score, lower chemotherapy response signature score, hypoxic microenvironment, and higher frequency of TP53 mutation). Instead, muti-omics profiling revealed that SPA had stronger immunogenicity and was enriched for positive biomarkers for immunotherapy (higher TMB and T cell receptor diversity; higher PD-L1 expression and more immune cell infiltration; higher frequency of gene mutations predicting efficacious immunotherapy, and elevated expression of immunotherapy-related gene signatures). Furthermore, in the cohort of LUAD patients who received neoadjuvant immunotherapy, SPA had higher pathological regression rates than Non-SPA and patients with major pathological response were enriched in SPA, confirming that SPA was more prone to respond to immunotherapy. Conclusions: Compared with Non-SPA, SPA was enriched for molecular features associated with poor prognosis, unsatisfactory response to chemotherapy and targeted therapy, and good response to immunotherapy, indicating more suitability for immunotherapy while less suitability for chemotherapy and targeted therapy.

Effect of histology on the efficacy of immune checkpoint inhibitors in advanced non-small cell lung cancer: A systematic review and meta-analysis.

Background: Little is known about the effect of histology on the efficacy of immune checkpoint inhibitors (ICI) in non-small-cell lung cancer (NSCLC). We conducted a systematic review and meta-analysis to assess the potential differences in the efficacy of ICIs between squamous NSCLC (SQ-NSCLC) and non-squamous NSCLC (non-SQ-NSCLC). Methods: Systematic searches of PubMed, Embase, Scopus, and Cochrane Library databases were conducted. All randomized clinical trials of ICIs with available hazard ratios (HR) for progression-free survival (PFS) or overall survival (OS) according to histology were included. The primary endpoint was to assess the difference in the efficacy of ICIs between SQ-NSCLC and non-SQ-NSCLC, measured by the ratio of the HR in SQ-NSCLC to the HR in non-SQ-NSCLC (RHR). Results: A total of 40 trials were included in the meta-analysis. ICI monotherapy could improve OS in both SQ-NSCLC (OS-HR 0.71, 95% CI 0.65-0.77) and non-SQ-NSCLC (OS-HR 0.80, 95% CI 0.73-0.87) while OS benefit was larger in SQ-NSCLC (OS-RHR 0.89, 95% CI 0.80-0.99). In terms of PFS, ICI monotherapy could reduce the risk of progression by 35% (PFS-HR 0.65, 95% CI 0.56-0.77) in SQ-NSCLC while the PFS benefit was smaller (10%) and not statistically significant in non-SQ-NSCLC (PFS-HR 0.90, 95% CI 0.76-1.07). Similarly, ICI-based combination treatments could reduce the risk of both progression and death in SQ-NSCLC (OS-HR 0.70, 95% CI 0.61-0.80; PFS-HR 0.56, 95% CI 0.48-0.65) and non-SQ-NSCLC (OS-HR 0.78, 95% CI 0.74-0.83; PFS-HR 0.63, 95% CI 0.57-0.69) while the survival benefits were larger in SQ-NSCLC (OS-RHR 0.83, 95% CI 0.70-0.99; PFS-RHR 0.82, 95% CI 0.70-0.96). Conclusions: ICIs could deliver survival benefits in both SQ-NSCLC and non-SQ-NSCLC while the magnitude of survival benefits was histology-dependent. Future researches should consider the effect of histology on the efficacy of ICIs. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier [CRD42022299603].