Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare, aggressive lung tumor marked by significant molecular heterogeneity. In a study of 590 patients across two independent cohorts, we observe comparable overall survival across treatment regimens (chemotherapy, chemoimmunotherapy, immunotherapy) without unexpected adverse events. Genomic analysis identifies distinct non-small cell lung cancer-like (NSCLC-like, KEAP1, KRAS, STK11 mutations) and SCLC-like (RB1, TP53 mutations) LCNEC subtypes, with 80% aligning with SCLC transcriptional profiles. Serial sampling reveals stable mutational but shifting transcriptomic landscapes over time. Here we show, elevated FGL-1 (a LAG-3 ligand) and SPINK1 expression in NSCLC-like LCNECs, and higher levels of DLL3 in SCLC-like LCNECs. Immunofluorescence confirms FGL-1 expression in NSCLC-like LCNECs, and H&E slide analyses indicates fewer tumor-infiltrating lymphocytes in LCNECs versus other lung cancers. These findings highlight LCNEC’s distinct immunogenomic profile, supporting future investigations into LAG-3, SPINK1, and DLL3-targeted therapies.

Targeted next-generation sequencing (NGS) is recommended to screen actionable genomic alterations (GAs) in patients with non-small-cell lung cancer (NSCLC). We determined the feasibility to detect actionable GAs using TruSight™ Oncology 500 (TSO500) in 200 consecutive patients with NSCLC. DNA and RNA were sequenced on an Illumina® NextSeq 550 instrument and processed using the TSO500 Docker pipeline. Clinical actionability was defined within the molecular tumour board following European Society for Medical Oncology (ESMO) guidelines for oncogene-addicted NSCLC. Overall survival (OS) was estimated as per the presence of druggable GAs and treatment with targeted therapy. Most patients were males (69.5%) and former or current smokers (86.5%). Median age was 64 years. The most common histological type and tumour stage were lung adenocarcinoma (81%) and stage IV (64%), respectively. Sequencing was feasible in most patients (93.5%) and actionable GAs were found in 26.5% of patients. A high concordance was observed between single-gene testing and TSO500 NGS panel. Patients harbouring druggable GAs and receiving targeted therapy achieved longer OS compared to patients without druggable GAs. Conversely, patients with druggable GAs not receiving targeted therapy had a trend toward shorter OS compared with driver-negative patients. Hybrid capture sequencing using TSO500 panel is feasible to analyse clinical samples from patients with NSCLC and is an efficient tool for screening actionable GAs.

Background: Neoadjuvant therapy, particularly the combination of chemotherapy and immunotherapy, has become standard in treating locally advanced non-small cell lung cancer (NSCLC). While this approach improves pathologic responses, its effect on postoperative outcomes following robotic-assisted thoracic surgery (RATS) is not fully characterized. Objective: This study aimed to evaluate the impact of neoadjuvant therapy on postoperative outcomes in patients undergoing RATS for NSCLC, focusing on operative time, conversion rates to open surgery, and postoperative complications. Methods: A retrospective cohort analysis was performed on patients who underwent RATS for NSCLC between February 2019 and August 2024. Propensity score matching was utilized to balance preoperative characteristics between the groups. The primary outcomes compared were operative time, conversion rates to open surgery, and postoperative complications, with statistical significance defined as p < 0.05. Results: A total of 253 patients were included in the analysis, of whom 23 received neoadjuvant therapy (either chemotherapy or chemoimmunotherapy) and 230 did not. The neoadjuvant group had significantly longer operative times (250 min vs. 221 min, p = 0.001) but there were no significant differences in conversion rates to open surgery (8.7% vs. 3.9%, p = 0.5). However, the neoadjuvant group showed a higher incidence of prolonged air leaks (>5 days) (39.13% vs. 35.21%, p < 0.001). Other parameters, such as hospital stay and chest drainage duration, showed no statistically significant differences between the groups (p = 0.860 and p = 0.760, respectively). Conclusions: These findings support the feasibility of robotic-assisted thoracic surgery following neoadjuvant therapy in NSCLC, suggesting that this approach may be safely integrated into clinical practice for selected patients. Further studies are needed to define patient selection criteria and optimize postoperative management, potentially guiding personalized treatment strategies in complex cases.

Cancer cachexia is a frequent complication of patients diagnosed with non-small cell lung cancer (NSCLC) that affects their quality of life and their prognosis. A detailed, multidimensional characterization of patients with cancer cachexia is lacking. We conducted a prospective study of 52 patients diagnosed with locally advanced unresectable NSCLC who underwent concurrent chemoradiotherapy followed by immunotherapy. At baseline, 53% of patients met the Fearon’s criteria for cachexia. Cachexia was significantly associated with tumor stage (p < 0.001), performance status (p = 0.027), lower skeletal muscle index (p = 9e-4) and total adipose tissue index (p = 0.004), elevated C-Reactive Protein blood levels (p = 0.004), moderate to severe malnutrition (p < 0.001), reduced caloric intake (p = 0.007) and diminished physical strength (p = 0.001). Proteomic profiling using the O-link platform revealed known and novel biomarkers of cachexia, including inflammatory cytokines. Cachexia was significantly associated with elevated serum levels of CCL23, IL-6, CSF1, complement factor C1QA, motilin, agouti-related protein (AGRP) and soluble CD4 and CD276, and with lower RANKL, CKAP4, LRRN1, FLT3LG or Persephin, among others. These proteins showed varying degrees of correlation with caloric intake. GDF-15 was associated with weight loss (p = 0.00014), but not with cachexia (p=0.08), calorie intake or body composition. This prospective study demonstrates that cancer cachexia is highly prevalent in patients with unresectable locally advanced NSCLC and is associated with specific, understudied cytokines. These findings provide further insight into the biological characterization cachexia and may help identify novel targets for therapeutic interventions.