Lung cancer is a leading cause of cancer-related deaths worldwide. Early detection using low-dose CT (LDCT) has shown promise in reducing mortality rates. Nevertheless, LDCT screening poses challenges, including a high false-positive rate and the risk of overdiagnosis. AI and biomarkers are crucial directions for the future of lung cancer screening. This study investigates the potential of multi-omics fusion, combining liquid biopsy biomarkers and computed tomography (CT) features, to enhance lung cancer differential diagnosis. A total of 146 participants were enrolled, including 111 early-stage lung adenocarcinoma patients and 35 controls. High throughput extracellular vesicle long RNA (evlRNA) sequencing were performed using serum samples obtained before lung surgery. A fusion model was developed to combine image-based features and evlRNA features. Our findings suggest that evlRNA and image-based features complement each other, achieving improved performance when evlRNA features are fused with radiological features from AI, CTR, or human experts. Our methods achieve notable differential diagnosis performance; for example, combining evlRNA and radiological AI yields a 4-class AUC of 0.919 and a benign-malignant AUC of 0.948 (sensitivity: 89.1%, specificity: 94.3%). Integrating multi-omics analysis with human experts further enhances diagnostic accuracy. Additionally, we provide post-hoc explanations using Shapley values to understand feature importance in the multi-omics modeling.Table: 1268PMethod4-Class Analysis(IA, MIA, AIS) vs Benign(IA, MIA) vs (AIS, Benign)AUCAUCSensSpecAUCSensSpecevlRNA79.286.483.985.775.873.378.9CTR77.675.759.594.362.977.359.2vCTR84.085.171.097.175.968.080.3Rad89.092.279.294.382.976.085.8Junior expert//83.751.4/76.066.2Senior expert//91.980.0/85.377.4evlRNA + CTR88.090.587.488.684.072.090.0evlRNA + vCTR89.191.084.691.482.768.091.4evlRNA + Rad91.994.889.194.387.280.087.1evlRNA + Junior expert83.489.986.488.682.873.384.5evlRNA + Senior expert89.395.186.597.187.886.780.2evlRNA + Rad + Junior expert92.496.095.591.487.378.788.6evlRNA + Rad + Senior expert93.497.991.8100.088.992.080.1 Open table in a new tab In summary, our study demonstrated that the combination of evlRNA-based and image-based features can complement each other and that the collaborative approach between multi-omics and human analysis can further enhance the performance. These findings highlight the importance of integrating multiple modalities including effective biomarkers and CT analysis with AI algorithms, into LDCT screening through multi-omics fusion.

KRAS mutation accounts the one of the most frequent alterations in non-small cell lung cancer (NSCLC). The biochemical and biological properties of KRAS mutation have been studied extensively over the past decades. However, the therapeutic strategy for the most KRAS mutation subtypes (including KRASG12F, KRASG12D, KRASQ61H, KRASG12V and KRASG12A) is still elusive.

Circulating tumour DNA (ctDNA)-based sequencing might provide a simple test for the genomic profile of non-small cell lung cancer (NSCLC) without the necessity of tissue biopsy. We aimed to assess the ctDNA sequencing-based tumour mutation index (TMI) model for screening responders (from non-responders) who received monotherapy with docetaxel or atezolizumab.

Platinum-based chemotherapy is still the standard of care for Epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) patients after developing EGFR-TKI resistance. However, no study focusing on the role of PD-1 inhibitor based treatments for EGFR mutated NSCLC patients who carried PD-L1 TPS ≥ 50% progressed after EGFR-TKI therapy. Thus, we aimed to investigate the outcomes of PD-1 inhibitor based treatments for these patients and to explore the population that may benefited from PD-1 inhibitor based therapies.

Angiogenic placental growth factor (PLGF) plays a role in hypoxia-induced angiogenesis. Here, we aimed to investigate the biological roles of PLGF in cell proliferation and glycolysis of lung adenocarcinoma (LUAD) and the underlying molecular mechanisms.

Anlotinib has been proven to prolong the progression-free survival (PFS) and overall survival (OS) as a third line or further therapy compared with placebo for non-small cell lung cancer (NSCLC). Herein we evaluate the effects and prognosis in patients with liver metastasis (LM) treated with anlotinib/placebo.

Anlotinib has been demonstrated to be effective in advanced non-small cell lung cancer (NSCLC) patients. DNA-seq- and RNA-seq-based anlotinib molecular mechanism and biomarker screening have been introduced in previous studies. The underlying value of proteomics for anlotinib study is still unclear.

Background: Racial differences in characteristics and prognosis of Asiatic and White patients receiving immunotherapy have not been well described. Methods: We studied 390 patients from the POPLAR and OAK studies who received atezolizumab with evaluable biomarker parameters retrieved from a subsequent blood-based study. The differences of Asians versus Whites in baseline characteristics, outcomes and genetic mutations of atezolizumab therapy were assessed. Results: Asiatic and White patients differed in characteristics including smoking history, baseline sum of the longest diameters (BLSLD), EGFR mutation frequency, programmed death-ligand 1 (PD-L1) expression and blood-based tumor mutational burden (bTMB) level. Overall survival (OS) was longer in Asians compared with Whites before (median OS: 18.7 vs. 11.1 mo; P = 0.005) and after (median OS: 20.9 vs. 12.6 mo; P = 0.005) propensity score matching (PSM). Race was an independent prognostic factor for OS (Asian vs White: HR 0.647, 95% CI 0.447-0.936, P = 0.021) in addition to performance status (PS), histology, BLSLD, and number of metastatic sites. The objective response rate (ORR) for Asians and Whites was 8.2% and 17.1%, respectively and disease control rate (DCR) was 51.2% and 47.7%, respectively. The blood-based mutational landscape differentiated between Asians and Whites. In the overall population, mutations of STK11, EGFR, KEAP1, POLE, GRM3, ATM and STAG2 were associated with treatment response while mutations of TP53, KEAP1, APC, RB1, CREBBP, EPHA5 and STAG2 were associated with OS. Comparing the frequency of efficacy- or prognosis- related mutations, Asians had more EGFR mutations and less TP53 and STK11 mutations than Whites. Conclusions: Asians and Whites differed in the clinicopathological features and mutational landscape which may explain the superior efficacy of atezolizumab in Asiatic patients with NSCLC. This study conveys implications for further studies on racial disparity in the treatment of immunotherapy. Legal entity responsible for the study: The authors. Funding: Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Support (No. 20161434). Disclosure: All authors have declared no conflicts of interest.

Resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI) is often acquired in non-small cell lung cancer (NSCLC) patients during treatment. We previously demonstrated that combined treatment with EGFR-TKI gefitinib plus chemotherapy improved progression-free survival (PFS) in NSCLC patients carrying sensitive EGFR mutations. Pharmacological interaction between gefitinib and pemetrexed was evaluated in NSCLC cell line PC-9 using MTT assay. The influence of combined treatment with gefitinib plus pemetrexed on gene expression profiles and signaling pathways has been investigated using microarray and Ingenuity Pathway Analysis (IPA). Synergistic inhibitory effect between gefitinib and pemetrexed was observed in NSCLC cell line PC-9. Figure 1A suggested representative proliferation inhibitory effects of gefitinib, pemetrexed and combined treatment for 48 hours. Figure 1B showed CI values of concurrent gefitinib-pemetrexed treatment in PC-9 NSCLC cell line. CI values at ED50, ED75 and ED90 were shown. Furthermore, widespread gene expression changes and critical signaling pathways were induced significantly by combined treatment in PC-9 cells. Figure 2A was heatmap of gene expression prolifes in human NSCLC PC-9 cell line treated with gefitinib (blue), pemetrexed (purple) or gefitinib-pemetrexed combination (orange) with the criteria P<0.05 and ▏fold change ▏>1.5. Genes and samples were listed in rows and columns, respectively. A colour standard for data normalization was shown at the bottom with green representing downregulated genes while red representing upregulated genes. In Figure 2B, pathway enrichment of differential expressed genes was analysed using Ingenuity Pathway Analysis (IPA). Signaling pathways shown here were based on a P<0.0001. Figure 2C showed heatmap of critical pathways affected by combined treatment as compared to gefitinib single treatment. Heatmap colour represented the Z-score of signalling pathways. Z-score>0 meant the signalling pathway was stimulated by related treatment while Z-score<0 meant the signalling pathway was inhibited by related treatment.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Gene expression profiles revealed potential signaling pathways contributing to the synergism.

Background: Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) have been demonstrated to be effective in ALK-rearranged, advanced lung adenocarcinoma patients. However, data from a real-world setting is very limited. The aim of the study was to: a) determine long-term survival in these patients and investigate factors associated with their prognosis; and b) analyze the clinical outcomes of patients who were sequentially treated with next-generation ALK-TKIs. Methods: ALK-rearranged, advanced lung adenocarcinoma patients who were treated with crizotinib were included between January 2013 and December 2016. Progression-free survival (PFS) and overall survival (OS) were calculated by the Kaplan-Meier method. The hazard ratio (HR) for the risk of progression or death was calculated using multivariate Cox regression model. Results: A total of 5286 patients were screened and 176 eligible patients were included. Median PFS and OS were 12.4 months (95% CI, 10.3-14.6 months) and 45.6 months (95% CI, 37.6-53.7 months), respectively. 36.3% of patients were 5-year survivors. Extrathoracic metastasis before crizotinib treatment was independently associated with worse PFS (HR, 1.77, 95% CI, 1.24-2.53, P < 0.01) and OS (HR, 1.61, 95% CI, 1.02-2.54, p = 0.04). 45 patients were sequentially treated with newer-generation ALK-TKIs, obtaining a statistically longer OS (54.8 months, 95% CI, not calculable) than patients who were solely treated with crizotinib during clinical management (36.6 months, 95% CI, 29.2-43.9 months, P < 0.01). Conclusions: Our study provides useful information about ALK-rearranged, advanced lung adenocarcinoma patients treated with ALK-TKIs in a real-world setting. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

Centromere protein U (CENPU), a centromere protein mediating kinetochore-microtubule interaction, is critical for proper cell cycle and mitosis. It has been implicated that CENPU promotes tumorigenesis in variant malignancies. However, roles of CENPU in lung adenocarcinoma progression and underlying mechanisms remain to be elucidated. CENPU expression in 90 pair lung adenocarcinoma/adjacent normal lung samples was examined with immunohistochemistry (IHC). Then CENPU expression was inhibited with lentiviral-mediated shRNA strategy in human lung adenocarcinoma cell line H1299 to examine the impact of CENPU knockdown for lung adenocarcinoma progression and metastasis. Cell proliferation, colony formation, cell cycle and cell survival were analyzed by Cellomics cell counting method, colonogenesis assay, PI and Annexin V-APC staining respectively while cellular migration and invasion were determined by cell scratch and transwell test. Furthermore, expression of critical factors involved in epithelial-to-mesenchymal transition (EMT) were determined with western blot. CENPU expression was significantly increased in lung adenocarcinomas as compared to adjacent normal lung tissues (fold change=8.54, P<0.0001) (Fig. 1A). Functionl analysis revealed that in human lung adenocarcinoma cell line H1299, CENPU knockdown impaired cell proliferation (Fig. 1B), inhibited colony formation ability (Fig. 1C) and induced cell cycle arrest (Fig. 1D). Additionally, cellular migration and invasion was also inhibited by CENPU knockdown (Fig. 1E-F). It is further shown that E-Cadherin was induced while N-Cadherin and vimentin were inhibited by CENPU knockdown (Fig. 1G), indicating that CENPU was important for EMT process and cancer metastasis. It showed that CENPU expression is significantly upregulated lung adenocarcinoma tissue. Functional analysis indicated that CENPU is critical for cell proliferation, survival, migration and metastasis in lung adenocarcinoma cell line H1299. CENPU represents a promising target for lung adenocarcinoma therapy.