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Summary The objective of this study was to analyze the clinical and pathological characteristics of patients with small cell lung cancer (SCLC) after curative surgery and to explore prognostic factors for disease-free survival (DFS) and overall survival (OS). Clinical data of 247 patients were collected, and clinicopathological features were retrieved, including gender, age, smoking history, tumor location, and distant metastasis. Histopathological features were also reviewed by three pathologists, including primary tumor (T), lymph node metastasis (N), pleural invasion, bronchial invasion, nerve invasion, spread through air spaces (STAS), tumor thrombosis, major cell shape (round Vs. spindle), tumor necrosis, stromal fibrosis, and tumor-infiltrating lymphocytes (TILs). Immunohistochemical staining of neuroendocrine markers (CD56, synapsin, chromogranin A) was also reviewed. All patients were followed up for recurrence, distant metastasis, and survival. Kaplan-Meier curves and log-rank tests were applied for survival analysis. The median DFS was 98 months, and the 1-year, 3-year, and 5-year DFS rates were 70.9%, 54.4%, and 52.2%, respectively. The median OS was not reached, and the 1-year, 3-year, and 5-year survival rates were 94.2%, 72.3%, and 65.4%, respectively. Univariate analysis revealed clinicopathological features with DFS (gender, smoking history, primary tumor, regional lymph node metastasis, major cell shape, and TILs) and OS (age, primary tumor, regional lymph node metastasis, distant metastasis, nerve invasion, major cell shape, and TILs). Multivariate analysis revealed DFS-related factors (smoking history, regional lymph node metastasis and major cell shape) and OS-related factors (age, primary tumor, distant metastasis in the brain, liver, bone, nerve invasion, and TILs). Age more than 65 years, smoking, advanced stage (T and N), distant metastasis, nerve invasion, major cell shape as spindle and TILs >30% were negatively correlated with survival. Neuroendocrine immunostaining markers showed no correlation with survival. Of interest, spindle cell type and TILs >30% are revealed as independent negative prognostic factors, and further molecular mechanisms need to be explored.

Background Small cell lung cancer (SCLC) is one of the most aggressive lung cancers. Treatment of SCLC has remained unchanged during the past decades. Preclinical studies have revealed ASCL1 as a transcription regulator in the neuroendocrine (NE) differentiation and carcinogenesis of SCLC. However, there are few studies on correlation of ASCL1 expression and clinicopathological factors in resected SCLCs. Here, we aimed to analyze the ASCL1 expression of SCLC and investigate its associations with clinicopathological factors and survival. Methods A total of 247 surgically resected pure SCLC specimens were included in this retrospective study, all of which were processed using tissue microarrays for immunohistochemistry analysis of ASCL1. A total of 48 of 247 cases were tested by NanoString for mRNA expression analysis on 50 SCLC related genes. Statistical analysis was performed using R studio and SPSS software. Results NE scores of 48 pure SCLC specimens were calculated by analyzing 50 preselected genes. A significant correlation between NE score with both ASCL1 mRNA expression and ASCL1 protein expression were observed. For the entire cohort of 247 patients, ASCL1 was highly expressed in 42.5% of pure SCLC patients according to IHC results. Significant differences were observed between ASCL1 high and low expression groups in variables including staging, lymph node metastasis, nerve invasion and overall survival. Conclusions In limited staged pure SCLC, ASCL1 expression was positively correlated with NE signature, pTNM stage, nerve invasion and OS. ASCL1 may therefore serve as a potential biomarker to predict prognosis as well as in the selection of patients for therapies targeting ASCL1‐regulated downstream molecules., ASCL1 expression is positively correlated with neuroendocrine signatures, pTNM stage, nerve invasion and OS. ASCL1 may serve as a potential biomarker to predict prognosis as well as to select patients for therapies targeting ASCL1‐regulated downstream molecules.

The roles of cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT) in solid tumors are well established. However, the interaction between CSCs and EMT in pulmonary large cell neuroendocrine carcinoma (LCNEC) remains unknown. The aim of this study was to investigate the expression and clinical significance of a CSC marker (ALDH1A1) and its correlation with Epithelial-like phenotype marker (E-cadherin) and Mesenchymal-like phenotype marker (N-cadherin) in LCNEC patients.Immunohistochemistry (IHC) for ALDH1A1, E-cadherin and N-cadherin expression was conducted on tissue microarrays made from 79 resected LCNEC patient samples. ALDH1A1 protein expression was evaluated by the IHC score, and its correlations with the expression of E-cadherin, N-cadherin and clinicopathological features were determined based on IHC data. Survival analyses were also performed.ALDH1A1 was positively expressed in 75.9% (60/79 cases) of LCNEC patients. No significant difference in clinicopathological variables was observed between the ALDH1A1-negative and ALDH1A1-positive groups. However, ALDH1A1 expression was positively correlated with E-cadherin (Spearman's rho = 0.229, p-value = 0.007), which represents the epithelial-like phenotype, but not with N-cadherin. Patients with expression of ALDH1A1 had significantly longer disease-free survival (DFS) and overall survival (OS) than those who were ALDH1A1 negative (median DFS: 52 vs 12 months, p = 0.028; median OS: not reached; p = 0.027). Multivariate analysis showed that ALDH1A1 was an independent favorable prognostic factor for DFS (p = 0.032, HR: 0.438, 95% CI: 0.206-0.932) and OS (p = 0.025, HR: 0.279, 95% CI: 0.091-0.852) in LCNEC patients.This study suggests that ALDH1A1 can act as a favorable independent prognostic factor for LCNEC, which related to the epithelioid phenotype in EMT, and its internal mechanism needs further study.

Background Recently, expression of YAP1, a nuclear effector of an inactivated HIPPO pathway, has been identified as one of four molecular subtypes of SCLC. However, the clinicopathological relevance and prognostic significance of YAP1 expression in SCLC stratified by histological subtypes has not been systematically reported to date. Methods Tumor sections and corresponding formalin-fixed paraffin-embedded (FFPE) samples of 297 SCLC patients were retrieved from the pathological specimen repository and were subsequently reviewed by pathologists. Forty-six C-SCLCs (combined SCLCs) (15.5%) and 251P-SCLCs (pure SCLCs) (84.5%) were identified respectively. YAP1 expression was examined by immunohistochemistry (IHC) and assessed semi-quantitatively on tumor tissue array (TMA). Propensity score was used to match C-SCLCs and P-SCLCs in a ratio of 1 to 2 to balance age, gender, tumor stage and treatment methods. Finally, 46C-SCLCs and 92P-SCLCs were included for prognostic analysis. Results The positive rate of YAP1 expression was significantly higher in C-SCLCs than P-SCLCs before matching (52.2% vs 29.1%, P = 0.004). After matching by propensity score, the prescribed clinical parameters were well balanced between P-SCLCs and C-SCLCs. Expression of YAP1 was associated worse overall survival (OS) (5- year OS%, 39.0% vs. 74.9%, P = 0.013) and was an independent risk factor for OS (HR = 2.93, 95% CI: 1.01–8.51; P = 0.048) exclusively in C-SCLC. Univariate survival analysis in subgroups of different clinical variables also confirmed the prognostic impact of YAP1 was most significant in C-SCLC. But for P-SCLCs, expression of YAP1 showed no prognostic impact. Conclusions Expression of YAP1 in small cell components of C-SCLC was significantly higher than that in P-SCLC. Besides, it served as an unfavorable predictor for OS in C-SCLC but not in P-SCLC, which suggested different entities of small cell components with variant YAP1 expression and potential different targetable oncogenic pathway between C-SCLC and P-SCLC.

Purpose: Yes-associated protein 1 (YAP1), a nuclear effector of an inactivated HIPPO pathway, has been identified as one of four molecular subtypes of SCLC defined by the transcriptional regulatory mechanism. We aimed to explore the clinicopathological relevance and prognostic significance of YAP1 expression in SCLC stratified by histological subtypes. Methods: Tumor sections and corresponding formalin-fixed paraffin-embedded (FFPE) samples of 297 SCLC patients were retrieved from the pathological specimen repository and were subsequently reviewed by pathologists. Forty-six C-SCLCs (15.5%) and 251 P-SCLCs (84.5%) were identified respectively. YAP1 expression was examined by immunohistochemistry (IHC) and assessed semi-quantitatively on tumor tissue array (TMA). Propensity score was used to match C-SCLCs and P-SCLCs in a ratio of 1 to 2 to balance age, gender, tumor stage and treatment methods. Finally, 46 C-SCLCs and 92 P-SCLCs were included for prognostic analysis.Results: The positive rate of YAP1 expression was significantly higher in C-SCLCs than P-SCLCs before matching (52.2% vs 29.1%, P = 0.004). After matching by propensity score, the prescribed clinical parameters were well balanced between P-SCLCs and C-SCLCs. Expression of YAP1 was associated worse overall survival (OS) (5- year OS%, 39.0% vs. 74.9%, P = 0.013) and was an independent risk factor for OS (HR = 2.93, 95% CI: 1.01-8.51; P=0.048) exclusively in C-SCLC. Univariate survival analysis in subgroups of different clinical variables also confirmed the prognostic impact of YAP1 was most significant in C-SCLC. But for P-SCLCs, expression of YAP1 showed no prognostic impact. Conclusions: Expression of YAP1 in small cell components of C-SCLC was significantly higher than that in P-SCLC. Besides, it served as an unfavorable predictor for OS in C-SCLC but not in P-SCLC, which suggested different entities of small cell components with variant YAP1 expression and potential different targetable oncogenic pathway between C-SCLC and P-SCLC.

Background The incidence of lung cancer is growing fast in China, however, the prognosis remains dismal due to the limited therapeutic approaches. The “ret proto-oncogene mutation” (RET) fusions have been proven to be the driver gene in lung cancer development and the therapeutic target of several multi-target tyrosine kinase inhibitors. Methods We applied formalin-fixed, paraffin-embedded (FFPE) samples of 39 patients with non-small cell lung cancer (NSCLC) using the Lung Plasma panel covering 168 cancer-associated genes and performed capture-based targeted deep sequencing to identify the RET fusion partners and concurrent gene mutation with Miseq. The log-rank test was used to compare the survival difference of patients according to treatment strategies. Statistical analyses and graphs were performed using R language and GraphPad Prism. Results Most of the samples were advanced (stage IIIb and IV) lung adenocarcinomas (80.77%). KIF5B-RET fusions were identified in 52% of the samples and K15-E12 was the most common variant. 6 (15%) samples harbored concurrent TP53 mutation and 3 samples were positive with EGFR mutation including a mutation in exon 19. Of these patients included, ten received cabozantinib, two received anlotinib, and one received crizotinib. Two (20%; 0–45) samples achieved stable disease and two were progressed in the cabozantinib treated group. Median progression-free survival (PFS) was 4 months (95% CI: 3.2–4.8) and median overall survival (OS) was 25 months (95% CI: 1.5–48.5). Three (11.54%; 0–24) samples achieved partial response in patients without RET inhibitor treatment and 4 (15.38%; 2–29) were stable disease. The median PFS was 11 months (95% CI: 1.2–20.8). There was no significant difference in PFS and OS between groups with or without RET inhibitors treatment. Conclusion This study provided insight into the RET fusions patients treatment. The survival benefit of current RET inhibitors was limited. More precise and potent RET inhibitors should be developed in the near future.

Background Deciphering the correlation between immune-related adverse events (irAEs) categorized by organ system class and clinical benefit of immunotherapy is critical for clinical practice. The aim of this study is to investigate the incidence rates of irAEs and their correlations with objective response rate (ORR) in patients with advanced solid tumours treated with nivolumab (NIVO) or nivolumab plus ipilimumab (NIVO+IPI). Methods PubMed, Embase and Cochrane library were searched for eligible studies from January 1st, 2000 to May 1st 2019. Published clinical trials on NIVO or NIVO+IPI with reported irAEs were included. Logit transformation of the irAE incidences was applied for the generation of pooled estimate and Pearson correlation coefficient was calculated to evaluate the correlation between irAE and ORR. Results 48 clinical trials involving 7936 patients treated with NIVO or NIVO+IPI were included. Compared to NIVO, NIVO+IPI led to more all-grade and grade 3 or higher irAEs categorized by system organ class (P

Additional file 1: Method. Search strategy. Table S1. Characteristics of the included studies. Table S2. Incidences of Categorical irAEs according to system organ class. Table S3. Sensitivity analysis of the correlation between irAEs and ORR in NIVO. Table S4. Sensitivity analysis of the correlation between irAEs and ORR in NIVO+IPI. Figure S1. Correlation between irAEs and ORR of chemotherapy-contained regimen. References (DOCX 276 kb)

Although evidence indicates that drug target genes share some common evolutionary features, there have been few studies analyzing evolutionary features of drug targets from an overall level. Therefore, we conducted an analysis which aimed to investigate the evolutionary characteristics of drug target genes. We compared the evolutionary conservation between human drug target genes and non-target genes by combining both the evolutionary features and network topological properties in human protein-protein interaction network. The evolution rate, conservation score and the percentage of orthologous genes of 21 species were included in our study. Meanwhile, four topological features including the average shortest path length, betweenness centrality, clustering coefficient and degree were considered for comparison analysis. Then we got four results as following: compared with non-drug target genes, 1) drug target genes had lower evolutionary rates; 2) drug target genes had higher conservation scores; 3) drug target genes had higher percentages of orthologous genes and 4) drug target genes had a tighter network structure including higher degrees, betweenness centrality, clustering coefficients and lower average shortest path lengths. These results demonstrate that drug target genes are more evolutionarily conserved than non-drug target genes. We hope that our study will provide valuable information for other researchers who are interested in evolutionary conservation of drug targets.