bluuebunny/crossref_metadata_2025_split huggingface dataset:
Economic evaluations of adjunctive osimertinib treatment in surgically resected epidermal growth factor receptor-positive (EGFR+) non-small cell lung cancer (NSCLC): Analysis for stage 2 disease.
Authors: Choi Briana M , Aqel Osama , Abraham Rachel B , Obeng-Kusi Mavis , Calamia Matthias , Halawah Hala , Alamer Ahmad , McBride Ali , Abraham Ivo , Tugay Deniz 
Published: June 2022

e20506 Background: Following surgical resection, patients with NSCLC require monitoring due to the risk of recurrence. Studies have demonstrated the clinical benefit of osimertinib, a tyrosine kinase inhibitor, as adjunctive therapy in surgically resected EGFR+ NSCLC, including in stage 2 disease. We performed a cost effectiveness/utility analysis of adjunctive osimertinib therapy in stage 2 disease following surgical resection. Methods: A two state partitioned survival model differentiating disease free survival (DFS) from disease recurrence and death was specified (US payer perspective). Parametric functions were fit to digitized overall survival (OS) and DFS curves. A 5 year time horizon was specified, with a 3% discount rate applied to costs and utilities beyond year 1. Costs of treatment (wholesale acquisition cost), adverse events (grade 3/4 except all grades for immunotherapy related AEs), and monitoring were sourced from, respectively, Redbook, literature, and Physician Fee Schedules (US $2021). DFS life years (DFSLY) and quality adjusted life years (DFSQALY), incremental cost effectiveness/utility ratios (ICER/ICUR) in terms of DFSLY and DFSQALY gained (g) were estimated in base case analyses (BSA) and probabilistic sensitivity analyses (PSA). Results: Exponential regression was used to extrapolate osimertinib and placebo Kaplan-Meier curves. As detailed below, in BCA (PSA) the incremental cost of osimertinib over placebo was $778,315 ($778,202). The incremental DFSLY was 1.740 (1.738), which yielded ICER of $447,349/DFSLYg ($447,768/DFSLYg). The incremental DFS QALY was 1.234 (1.232), yielding ICUR of $630,910/DFSQALYg ($631,498/DFSQALYg). Conclusions: As to disease recurrence in stage 2 surgically resected EGFR+ NSCLC, our model associated adjunctive osimertinib therapy with incremental clinical gains of 1.740 (1.738) DFSLY and 1.234 (1.232) DFSQALY compared to placebo, however at marked incremental cost. As adjunctive osimertinib treatment is indicated in EGFR+ NSCLC disease stages 1B and 3A, the present stage 2 cost effectiveness/utility results should be compared to those for stages 1B and 3A.[Table: see text]
Desmocollin 3 (DSC 3) expression in different subtypes of non-small cell lung cancer.
Authors: Ulianova Elena P. , Stateshny Oleg N. , Sagakyants Aleksandr B. , Kharagezov Dmitry A. , Leyman Igor A. , Milakin Anton G. , Gappoeva Madina A. , Iozefi Kristian D. , Chernyak Maksim N. , Shulgina Oksana G. , Lazutin Yuriy N. , Dzhenkova Elena A. , Novikova Inna A. , Popova Natalia N. , Rozenko Lyudmila Ya 
Published: June 2022

e20513 Background: Currently, an active search is underway for additional markers that predict the risk of tumor progression based on the epithelial-mesenchymal transition (EMT). Desmocollin 3 (DSC 3), a member of the Cadherin superfamily and a cell adhesion marker, is one of the markers for this transition. The aim of our study was to evaluate the expression of DSC 3 as a prognostic factor in different subtypes of non-small cell lung cancer. Methods: The study included 12 patients with squamous cell lung cancer and 8 patients with lung adenocarcinoma, aged 49 to 76 years. Immunohistochemical study was performed on sections from paraffin blocks of tumors using polyclonal rabbit antibodies to Desmocollin 3 (Invitrogen) at a dilution of 1:300 and the UltraVision Quanto Detection System HRP DAB. The expression of DSC 3 was semiquantitatively analyzed according to the percentage of cells and the intensity of staining: 0; 1+ (weak); 2+ (moderate); 3+ (high). Expression was considered positive if the score was ≥2. The Mann-Whitney U-test, Pearson's χ² distribution, and Spearman's correlation coefficient were used for statistical analysis of the results. Results: The predominance of patients with DSC3+ tumors was noted in the group with squamous cell carcinoma (64%), while the majority of patients with adenocarcinoma had DSC3- tumors (71%). However, Pearson's χ² was not statistically significant. Differences in DSC 3 expression values by 1.3 times were insignificant (p = 0.082): Me = 40 [0-80] in squamous cell carcinoma, Me = 30 [0-65] in adenocarcinoma. The correlation analysis between the expression of this marker and the survival rate of patients also had no statistical significance (rs = 0.061 for squamous cell carcinoma and rs = 0.196 for adenocarcinoma, p > 0.05). Conclusions: The immunohistochemical study revealed some specific features in the expression of DSC 3 in different subtypes of non-small cell lung cancer.
Dissecting transcriptional heterogeneity in multiple primary lung cancer by single cell RNA sequencing.
Authors: Guo Wei , Tan Fengwei , Xue Qi , Gao Shugeng , He Jie 
Published: June 2022

e20516 Background: The progression of multiple primary lung cancer has been involved in complex cell changes in composition and metabolic function. However, the role of immune related cells proliferation and epithelial cells differentiation during the synchronous multiple primary lung cancer development is still understudied. Methods: In this study, we performed scRNA sequencing of 167,397 cells from six patients with multiple primary lung cancer, combined with bulk RNAseq and whole exome sequencing. Results: We firstly revealed that both naïve and memory T cells participated in the differentiation of CD8+ T cells. One end state of CD8+ T cells is exhausted T cells and they response to stimulus and positive regulated the cell death. The Other end state is cytotoxic T cells which mainly implicated in regulation of cytokine production included positive regulation of myeloid leukocyte cytokine production involved in immune response, immune effector process, macrophage cytokine production and positive regulation of cytokine production involved in immune response. Multiple functional Treg cells and naïve T cells contributed to the CD4+ T cells origin. In addition, B cells with two main kinds of function also plays an important role in immune response. One is that the regulation and activation of innate immune response have been highly activated. The other were enriched in pathways that antigen binding, processing and presentation including MHC class II Antigen Presentation. We also revealed the cellular metabolic functions during the tumor invasion. The positive regulation of blood vessel diameter has been observed in endothelial cells, while angiogenesis has not been found in early glandular neoplasia of the lung. The development of epithelial cells mainly consists of two function states. One is that some cells response to the stress from immune, and the other is that some will die programmatically and begin to cell circle due to selective pressure with the development of tumor in multiple primary lung cancer. Conclusions: Our study showed a complete landscape of different dynamic cellular changes which might pinpoint the key cellular mechanisms of synchronous multiple primary lung cancer and therefore provided new clues for pathogenesis of tumors.
Clonal hematopoiesis in lung cancer and its impact on liquid biopsy based on targeted deep sequencing.
Authors: Yang Xue , Wang Youyu , Li Yingmei , Liu Danni , Shao Mengqi , Liu Lei , Liao Yida , Huang Tanxiao , Zhang Jing , Mu Tianhao , Chen Shifu , Feng Gang , Jia Kegang 
Published: June 2022

e20532 Background: Blood-based liquid biopsy has proved its potential in enormous clinical applications, such as cancer screening, diagnosis, treatment guidance, disease tracking and monitoring. In certain scenarios (e.g., molecular residual disease), it requires the technique to be able to detect mutation with very low frequency (0.001% ̃ 1%). The major hurdle of ultra-sensitive circulating tumor DNA sequencing is the high background noise of plasma cell-free DNA (cfDNA) and clonal hematopoiesis (CH). Here in this study, we investigated the prevalence of CH in lung cancer patients and its interference with liquid biopsy. Methods: We retrospectively analyzed cfDNA and blood cell genomic DNA (gDNA) sequencing data sets (n = 1,261) from a group of Chinese lung cancer patients. Threshold (1%) and subthreshold (0.2%) for variant allele frequency were set and compared. We focused on 23 clonal hematopoiesis genes that were selected based on previous publications. Results: CH mutations were detected in 27.68% of all the patients at the threshold and 62.01% at the subthreshold, and the detection rate increased with age. DNMT3A was the most frequently mutated CH gene, accounting for more than half of the CH mutations. The CH mutations had a higher detection rate in smokers (72%) than non-smokers (59.4%) at subthreshold. VAFs of CH mutations in cell-free DNA strongly correlated with their VAFs in gDNA (Pearson’s R = 0.92, p < 2.2x10-16), while tumor-derived somatic mutations didn’t have such correlation. Conclusions: Our study showed that clonal hematopoiesis is very common in lung cancer patients, especially when examining low-frequency mutations. Sequencing of gDNA at equivalent depth is very important to filter out CH mutation in cancer liquid biopsy.
ZFHX4 mutation as a novel predictive biomarker for immune checkpoint blockade in non-small cell lung cancer.
Authors: Shen Peng , Zeng Di , Lin Zhenzi , Lin Pei , Luo Mingyang , Zhao Lele , Chai Huizi , Huang Lingli , Xiao Mingzhe 
Published: June 2022

e20535 Background: ZFHX4 mutation as a novel predictive biomarker for immune checkpoint blockade in non-small cell lung cancer. Methods: 165 NSCLC patients treated with ICIs from independent public cohorts(Rizvi2015; Hellmann2018; Miao 2018) were included to assess immunotherapeutic predictive performance of ZFHX4 mutation. The genomic, mRNA profile and its corresponding survival data were retrieved from The Cancer Genome Atlas (TCGA) database for prognostic analysis. Results: In public cohorts 43 (26.06%) NSCLC patients harbored ZFHX4 mutations. Longer PFS was detected in NSCLC patients with ZFHX4 mutation (ZFHX4-mut) compared with those with wildtype ZFHX4 (ZFHX4-wt) (median PFS 22.1 months vs 4.2 months, HR 0.37; 95% CI 0.22 to 0.61; p < 0.001). Higher ORR and DCR were also observed in patients with ZFHX4-mut compared with ZFHX4-wt (ORR: 62.8% vs 21.3%, p＜0.001; DCR: 86.0% vs 60.7%, p＜0.001, respectively). In the multivariable Cox proportional hazards regression model adjusted by PD- L1 expression and tumor mutational burden (TMB) and other confounding factors, ZFHX4-mut remained an independent predictor (HR 0.43; 95% CI 0.22 to 0.83; p = 0.01). ZFHX4-mut was associated with significantly higher TMB compared to ZFHX4-wt (P＜0.001). According to ZFHX4 status and TMB level, we stratified patients into four subgroups: ZFHX4mut-TMB high, ZFHX4mut-TMB low, ZFHX4wt-TMB high, and ZFHX4wt-TMB low. As expected, ZFHX4mut-TMB high patients achieved the longest PFS 23 months (HR 0.21 95% CI 0.10 to 0.43; p < 0.01) among all groups. The combination of ZFHX4 mutation and TMB-H had a better predictive effect. Conclusions: Our results suggested that ZFHX4 mutation might be a potential predictor for ICIs therapy in NSCLC. Prospective studies to further understand the mechanism are warranted.
Co-occurring mutations in the DDR pathway and tumor-associated genes for predicting immunotherapeutic efficacy in non-small cell lung cancer patients.
Authors: Zhang Louqian , Fu Zhichao 
Published: June 2022

e20539 Background: In recent years, the advent of immunotherapy had provided a new approach for non-small cell lung cancer (NSCLC) patients. However, only a small subset of patients can benefit from immune checkpoint inhibitors (ICIs) and the majority of patients still show poorly durable responses. Although some biomarker for predicting clinical efficacy of immunotherapy has been reported, the more proper predictive biomarker is required to screen dominant populations for ICI efficacy. Methods: A total of three publicly available datasets of NSCLC patients treated with immunotherapy were collected for analysis. The discovery contained 57 NSCLC patients sequenced by WES from Miao et al. and another cohort of 75 patients with clinical data and WES data download from Hellman et al. studies. We collected two MSK-IMPACT cohorts including 240 and 350 NSCLC immunotherapy patients used as validation set from cBioPortal(www.cbioportal.org). Results: We detected 79 mutation genes (mutation frequency > 5% cases) associated with a better progressive free survival PFS (HR < 1, P value < 0.05) by univariate Cox regression analysis in the discovery cohort. The survival analysis results indicated that patients who carried co-occurring mutations of GRIN2A, FAT1, FLT1, ASXL2, PTPRS , and DDR pathway showed a longer PFS (p = 0.004, HR = 0.37, 95% Cl 0.235-0.644). Notably, comparing with the non-co-mutation group, the higher tumor mutation burden (TMB)(P < 0.01) and more durable clinical benefit(P < 0.05) have been detected in the co-mutations group. Next, we validated our findings using two independent validation cohorts who received ICI therapies from MSKCC, the results showed that PFS was significantly prolonged in the co-mutation group (p = 0.036, HR = 0.67, 95%CI 0.47-0.97), and with no significant difference in overall survival. Additionally, the TMB was significantly higher in the co-mutation group than that harbored non-co-mutation in two validation cohorts(p < 0.01). Conclusions: In this study, we found that co-occurring mutations in five genes and DDR pathways can predict a better immunotherapy efficacy of NSCLC. Therefore, the co-mutation signature may have great potential as a biomarker for guiding immunotherapy of NSCLC.
S100A7 as a founder of immunosuppressive tumor microenvironment shed light on immunotherapy in lung squamous cell carcinoma.
Authors: Liu Chengming , Zheng Sufei , Lu Zhiliang , Sun Nan , He Jie 
Published: June 2022

e20541 Background: The application of immune checkpoint inhibitors (ICIs) has revolutionarily improved the prognosis of patients with lung squamous cell carcinoma (LUSC) with limited treatment options, yet only certain patients can benefit from ICIs. S100A7 has been reported to accelerate tumor progression by activating oncogenic pathway in LUSC. Here, we aimed to deepen in the role played by S100A7 in the tumor immune microenvironment (TIME) and immunotherapeutic efficacy. Methods: Immunohistochemical analysis of PD-L1 expression and CD8+ tumor infiltrating lymphocytes (TILs) was applied to investigate the correlation between S100A7 expression and TIME. The mechanism of S100A7 regulating PD-L1 expression and infiltration of CD8+ TILs was then explored. Based on a mouse model and a clinical cohort, the association between S100A7 expression and the efficacy of ICIs was also analyzed. Results: Immunohistochemical analysis of 102 LUSC specimens revealed that S100A7 expression negatively corelated with PD-L1 expression and the infiltration of CD8+ TILs. The in vitro studies showed that S100A7 deregulated PD-L1 expression by activating the p-AKT pathway. Notably, a negative correlation between S100A7 expression and CXCL9 expression in tumor cell and CD68+ macrophage was observed in LUSC samples, which may lead to a decrease in CD8+ TILs. Results of murine models of LUSC revealed that dysregulation of S100A7 exerted an impact on anti-tumor response of immunotherapy. Further analysis showed that targeting S100A7 may enhance the efficacy of immunotherapy by yielding an inflammatory phenotype. In addition, baseline plasma level of S100A7 was higher in patients with progressive disease ( p = 0.0393) based on our cohort of LUSC patients treated with ICIs. The potential predictive value of baseline plasma level of S100A7 for immunotherapy response was then confirmed with area under curve up to 0.869. Multivariate Cox regression analyses revealed that baseline S100A7 level in plasma samples was an independent prognostic factor. Conclusions: This study deepened in the understanding of the role played by S100A7 in the TIME, offering a novel insight of its mechanism of action on immunotherapy resistance. Our results indicated that S100A7 may emerge as a powerful predictive tool for immunotherapy and the treatment targeting S100A7 may be beneficial for immunotherapy in LUSC.
Effects of high-fat and low-carbohydrate diet combined with radiation therapy on tumor microenvironment in LLC tumor-bearing mice.
Authors: Xiao Ling , Li Tao 
Published: June 2022

e20543 Background: Metabolic reprogramming of tumor immune cells can regulate immune function. To add a sentence linking tumor metabolism with radioimmunity. In this study, the high heterogeneity and reprogramming of tumor cell metabolism were utilized to explore the effects of high fat and low carbohydrate diet combined with radiotherapy on tumor immune microenvironment of tumor mice bearing LLC from the perspective of tumor microenvironment. Methods: Lewis lung cancer (LLC) model was established in female C57BL/6J mice aged 6 to 8 weeks and around 18g, and they were given a high fat and low carbohydrate diet (45F, fat 45.00% of energy) combined with radiotherapy. The body weight, tumor growth, blood glucose and blood ketone (βHB) values, survival time, median survival time and treatment safety of tumor-bearing mice were observed. Immunohistochemistry, multiple immunofluorescence and flow cytometry were used to detect the expression of tumor-associated microangiogenesis molecules (CD34), lymphatic microvessels (LYVE-1), collagen fibers and immune cell phenotypes (CD3, CD4, CD8, Treg and PD1). Results: High fat and low carbohydrate diet combined with radiotherapy (45F+RT) group had the best tumor control, and the tumor volume was significantly smaller than the control group (p < 0.001), and tumor weight in the combined treatment group (45F+RT) was significantly lower than that in the normal diet (PT, fat 12.11% of energy) and 45F group (p < 0.001); The blood glucose in 45F group was lower than that in PT group, but there was no statistical difference (p < 0.05); It was found that the βHB value in the high-fat and low-carbohydrate diet group was higher than that in the normal diet group. There were statistically significant differences in the second and third weeks (1.00±0.20mmol/L vs 0.63±0.06mmol/L, 0.90±0.17mmol/L vs 0.70±0.10mmol/L, p < 0.05). The median survival time of mice in each group was 38 days in the PT group, 55 days in the PT+RT group and 41 days in the 45F group, but not in the 45F+RT group. Immunohistochemistry and Multiple immunofluorescence showed that CD8 expression was up-regulated and PD1, CD34, LYVE-1 and collagen fiber expression were down-regulated in 45F+RT group. Flow cytometry showed that the proportion of CD8+T cells in 45F+RT group was higher than that in PT group and PT+RT group (p < 0.05) and higher than 45F group, but the difference was not statistically significant (p < 0.05); The proportion of CD4+T cells in PT+RT and 45F+RT groups was higher than that in PT and 45F groups (p < 0.05); The proportion of Treg in T cells in 45F+RT group was lower than that in PT+RT group, but the difference was not statistically significant (p < 0.05). Conclusions: High fat and low carbohydrate diet combined with radiotherapy can enhance the recruitment and function of immune effector cells in tumor microenvironment and inhibit tumor microangiogenesis, thereby inhibiting tumor growth.
Better tumor immune microenvironment in patients with older lung adenocarcinoma.
Authors: Wang Yongjie , Yang Ronghua , Wang Dong , Xuan Yunpeng , Yu Yi , Qi Yingxue , Ge Minghui , Luo Ningning , Zhu Xiaofeng , Li Mengmeng 
Published: June 2022

e20544 Background: Lung adenocarcinomas (LUAD) is the most common histological subtype of lung cancers. Immunotherapies (ICIs) have been confirmed to improve the clinical outcomes of LUAD patients. Efficacies of ICIs are considered strongly associated with tumor immune microenvironments (TIME). Age-related immune dysfunction might induce difference on the efficacy of ICIs between younger and older patients. However, the potential effect of age on TIME remains little known and controversial. Herein, we aimed to analysis the association between age and TIME based on The Cancer Genome Atlas (TCGA) database. Methods: We screened out 582 LUAD patients with complete information, whose tumors underwent next-generation sequencing (NGS) detection in TCGA. All patients were divided into two groups according to age, the younger group (age < 50-year old) and the older group (age≥50-year old). The differences of immune-related signatures between the two groups were calculated according to previous reports. We also analyzed the differences in immune-related signature between different clinical stages. P-values were calculated via the T.Test. Results: In total 582 patients with LUAD in our study, 115 (19.76%) patients in younger group and 467 (80.24%) patients in older group were found. Many immune-related signatures were found significantly higher in older group than in younger group, including cytolytic activity (CYT) (p = 0.0352), expanded immune signature (p = 0.0065), T cell inflamed gene expression profile (GEP) (p = 0.0048), IFN-γ-related response genes (p = 0.0346), immune signature (p = 0.0022), immunosuppression (p = 0.0065), major histocompatibility complex class I (MHC class I) (p = 0.0319), T-cell survival (p = 0.0235), tertiary lymphoid structures (TLS) signature (p = 0.0001) and total_TILs_scores (p = 0.0020). In addition, tertiary lymphoid structure (p = 0.0355) and TLS_signature (p = 0.0243) were found significantly difference in different clinical staging, which decreased as the staging get later. On the contrary, cell cycle score (p = 0.0001) increased as the staging get later. Conclusions: Our study evaluated the impact of age and clinical stage on the TIME in patients with LUAD using a threshold of 50 years old for the first time. We founded that LUAD patients in older group had better TIME than in younger group and some immune-related signatures were significantly related with clinical staging.
Prevalence and clinical significance of pathogenic germline mutations in homologous recombination repair genes in Chinese lung cancer patients.
Authors: Jiang Yanxia , Han Liying , Wang Yan , Wu Nuoting , Peisu Suo , Huang Tanxiao 
Published: June 2022

e20547 Background: There is accumulating evidence indicating that pathogenic germline mutations may contribute to lung cancer susceptibility besides environmental factors. The prevalence and clinical significance of pathogenic germline mutations in homologous recombination repair genes on lung cancer susceptibility has not been systematically investigated. Methods: We used real-world HaploX genomic data from patients (pts) with lung cancer to determine the prevalence of pathogenic germline mutations in homologous recombination repair genes from July 2020 to January 2022. Results: Out of the 766 patients screened, 5.5% (42/766) of the patients harbored the pathogenic germline mutations：12 with ATM, 12 with FANCA, 8 with ATR, 7 with BRCA1, and 3 with BRCA2. Conclusions: A proportion of 5.5% of patients carrying germline mutations in homologous recombination repair genes may be potentially linked to increased susceptibility to lung cancer. Our study has demonstrated that pathogenic germline mutations in homologous recombination repair genes are a risk factor for lung cancer.