Inflammation-scores as prognostic markers of overall survival in lung cancer: a register-based study of 6,210 Danish lung cancer patients

Background Inflammation-scores based on general inflammation markers are suggested as prognostic markers of overall survival (OS) in lung cancer. However, whether these inflammation-scores improves the prognostication performed by well-established prognostic markers is unsettled. In a large register-based lung cancer patient cohort, nine different inflammation-scores were compared, and their ability to optimize the prognostication of OS was evaluated. Methods Lung cancer patients diagnosed from 2009–2018 in The Central Denmark Region were identified in the Danish Lung Cancer Registry. Pre-treatment inflammation markers were extracted from the clinical laboratory information system. Prognostication of OS was evaluated by Cox proportional hazard models. Comparison of the inflammation-scores and their added value to established prognostic markers were assessed by Akaike's information criteria and Harrel's C-index. Results In total, 5,320 patients with non-small cell lung cancer (NSCLC) and 890 patients with small cell lung cancer (SCLC) were identified. In NSCLC, the Aarhus composite biomarker score (ACBS), including albumin, C-reactive protein, neutrophil count, lymphocyte count and haemoglobin, and the neutrophil-lymphocyte-ratio (NLR) were superior. Furthermore, they improved the prognostication of OS significantly (p <0.0001) (ACBS: HR: 2.24 (95%CI: 1.97–2.54); NLR: HR: 1.58 (95%CI: 1.47 – 1.69)). In SCLC, three scores were equally superior and improved the prognostication of OS p < 0.0001): neutrophil–lymphocyte-ratio (HR:1.62 (95%CI: 1.38–1.90)), modified Glasgow Prognostic Score (mGPS) (HR:1.70 (95%CI: 1.55–1.86) and the Combined NLR and GPS (CNG) (HR:2.10 (95%CI: 1.77–2.49). Conclusions The ACBS was the optimal score in NSCLC, whereas neutrophil–lymphocyte-ratio, mGPS and CNG were equally superior in SCLC. Additionally, these inflammation-scores all optimised the prognostication of OS and added value to well-established prognostic markers.

Targeting HSP90 Inhibits Proliferation and Induces Apoptosis Through AKT1/ERK Pathway in Lung Cancer

Lung cancer is one of the most common malignant cancers worldwide. Searching for specific cancer targets and developing efficient therapies with lower toxicity is urgently needed. HPS90 is a key chaperon protein that has multiple client proteins involved in the development of cancer. In this study, we investigated the transcriptional levels of HSP90 isoforms in cancerous and normal tissues of lung cancer patients in multiple datasets. The higher expression of HSP90AA1 in cancer tissues correlated with poorer overall survival was observed. The higher levels of transcription and expression of HSP90AA1 and the activity of AKT1/ERK pathways were confirmed in lung cancer patient tissues. In both human and mouse lung cancer cell lines, knocking down HSP90AA1 promoted cell apoptosis through the inhibition of the pro-survival effect of AKT1 by decreasing the phosphorylation of itself and its downstream factors of mTOR and BAD, as well as downregulating Mcl1, Bcl-xl, and Survivin. The knockdown also suppressed lung cancer cell proliferation by inhibiting ERK activation and downregulating CyclinD1 expression. The treatment of 17-DMAG, an HSP90 inhibitor, recaptured these effects in vitro and inhibited tumor cell growth, and induced apoptosis without obvious side effects in lung tumor xenograft mouse models. This study suggests that targeting HSP90 by 17-DMAG could be a potential therapy for the treatment of lung cancer.

Comprehensive Comparative Molecular Characterization of Young and Old Lung Cancer Patients

BackgroundYoung lung cancer as a small subgroup of lung cancer has not been fully studied. Most of the previous studies focused on the clinicopathological features, but studies of molecular characteristics are still few and limited. Here, we explore the characteristics of prognosis and variation in young lung cancer patients with NSCLC.MethodsA total of 5639 young lung cancer samples (NSCLC, age ≤40) were screened from the SEER and the same number of the old (NSCLC, age ≥60) were screened by propensity score matching to evaluate the prognosis of two groups. 165 treatment-naïve patients diagnosed with NSCLC were enrolled to explore the molecular feature difference between two age-varying groups. CCLE cell line expression data was used to verify the finding from the cohort of 165 patients.ResultsThe overall survival of the young lung cancer group was significantly better than the old. Germline analysis showed a trend that the young group contained a higher incidence of germline alterations. The TMB of the young group was lower. Meanwhile, the heterogeneity and evolutionary degrees of the young lung cancer group were also lower than the old. The mutation spectrums of two groups exhibited variance with LRP1B, SMARCA4, STK11, FAT2, RBM10, FANCM mutations, EGFR L858R more recurrent in the old group and EML4-ALK fusions, BCL2L11 deletion polymorphism, EGFR 19DEL, 20IN more recurrent in the young group. For the base substitution, the young showed a lower fraction of transversion. Further, we performed a pathway analysis and found the EGFR tyrosine kinase inhibitor resistance pathway enriched in the young lung cancer group, which was validated in gene expression data later.ConclusionsThere were significantly different molecular features of the young lung cancer group. The young lung cancer group had a more simple alteration structure. Alteration spectrums and base substitution types varied between two groups, implying the different pathogenesis. The young lung cancer group had more potential treatment choices. Although young lung patients had better outcomes, there were still adverse factors of them, suggesting that the young group still needs more caution for treatment choice and monitoring after the treatment to further improve the prognosis.

Serum Cytokine Levels for Predicting Immune-Related Adverse Events and the Clinical Response in Lung Cancer Treated with Immunotherapy

Analyses of the composition of peripheral cytokines hold promise for providing a basis for determining the prognosis of lung cancer treated with immunotherapy. In this study, we assessed correlations between interleukins in peripheral blood and the disease prognosis in patients with lung cancer. We retrospectively collected eligible adult patients with histologically confirmed lung cancer. Patients with immune-related adverse events (AE) from immunotherapy had higher pretreatment levels of IL-2 (p=0.002), IL-17 (p=0.01), and IFN-α (p=0.02) than patients with nonimmune-related adverse events (NAE). Univariate analysis showed that changes in IL-2 (p=0.04), IL-5 (p=0.007), IFN-α (p=0.003), IFN-γ (p=0.012) and TNF-α (p=0.049) levels were significantly increased in patients with AE compared with those with NAE before the second cycle of therapy. Patients with a clinical benefit had higher levels of IL-17 before the third cycle than patients without a clinical benefit. No significant cytokine differences were observed between patients with and without a clinical benefit undergoing ICI pretreatment or in the first two cycles of therapy. Plasma cytokines are related to immune-related adverse events and clinical responses, which are potential predictive markers for anti-PD-1/PD-L1 therapy in lung cancer patients and may play an important role in selecting patients who would benefit from PD-1/PD-L1 inhibitors.