bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical and genomic features of high tumor mutation burden in patients with non-small cell lung cancer.
Authors: Qiu Yuan , Yang Haihong , Chen Hanzhang , Deng Qiuhua , Liu Liping , Xiao Dakai , Shao Di , Li Weiwei , Jiang Wenxi , Zhu Changbin , Lin Yongping , He Jianxing 
Published: May 2020

e21023 Background: TMB is associated with mono-immunotherapy efficacy for patients with advanced or metastatic non-small-cell lung cancer (NSCLC). For early-stage NSCLC or EGFR mutated non-resectable NSCLC, TMB-H predicted better prognosis or poor response to TKIs. This research might develop potential predictive parameters for distinguishing NSCLC with high or low TMB. Methods: Samples of surgically resected, cancer tissues were collected from 499 patients with NSCLC: 29 (5.8%) lung squamous cell carcinoma (LUSC) and 468 (94.2%) lung adenocarcinoma (LUAD). The mutations and TMB were confirmed by target region capture sequencing (Oseq™-508). Results: According to the median value (3.08), TMB is divided into high (N = 244) and low (N = 255). Interactions between TMB and sex, age, location, histology, pathological subtype, lymph node, parabronchial lymph node, LVI, neuro-invasive, stage and mutation status were evaluated. The distribution of TMB-H was significantly (p < 0.001) correlated with sex, age, histology, pathological subtype, stage (TN stage) and partial mutations. Among all mutations, 6 genes (TP53 / FAT3 / KMT2D / TSHZ3 / NAV3 / EPHA3) were confirmed to be significantly related to TMB-H in NSCLC. We also found that TMB-H was significantly affected by mutation status of KRAS gene (P. G12X, p < 0.001) and missense mutations in FAT3 (p < 0.001). The Kruskal–Wallis H test results showed that the mutation types of FAT3, KRAS, TP53 and PIK3CA were closely related to TMB-H. Lasso linear regression analysis was applied and resulted the better predictors of TMB status including TSHZ3, KMT2D, TP53, gender and T stage. Conclusions: Instead of comprehensive genomic profiling to evaluate TMB, clinical characteristics and special mutation types may help to effectively screen and predicate patients with TMB-H status. [Table: see text]
Characterization of the tumor microenvironment landscape and deep learning-guided prediction of prognosis in lung adenocarcinoma with bulk RNA sequencing data.
Authors: Gui Philippe , Wu Wei , Yu Elizabeth , McCoach Caroline Elizabeth , Doebele Robert Charles , Bivona Trever G. 
Published: May 2020

e21025 Background: The tumor microenvironment (TME) plays an important role in tumor progression and treatment response, therefore profoundly affecting patient outcomes. Efforts to characterize the TME in lung adenocarcinoma are emerging but have been limited by the sample size and lack of treatment timepoints. Methods: We characterized changes in lung TME using the xCell algorithm to distinguish 64 immune and stroma cell types from bulk RNA sequencing data. The correlation between subtype cell population in lung TME and various clinical and biological characteristics was analyzed from over 500 lung adenocarcinoma (LUAD) samples from The Cancer Genome Atlas and an independent cohort of 48 advanced LUAD patients with treatment annotations (treatment-naive, residual disease, and progressive disease). In addition, we used key features in lung TME to predict prognosis using deep learning algorithms. Results: We found significant changes in both immune and stroma cell populations according to various clinical parameters such as smoking history, cancer stage, and treatment status. Specific sub-populations within lung TME correlate with survival outcomes based on Kaplan-Meier survival analyses. CD4- and CD8-positive T-cells are enriched in early stage disease and depleted in late stage disease, suggesting evolution of the TME during cancer progression. Consistent with previous reports, scores of immune cell populations associated with worse survival, such as T helper type 2 cells, are increased in late stage disease. Smoking history also reshapes the lung TME as populations correlated with better survival are decreased in smokers. We also found variations in sub-populations according to the driver oncogenes, with a less abundant lymphoid compartment in EGFR mutant samples compared to KRAS driven samples. Interestingly, we found higher scores of macrophage populations in residual disease following targeted-therapy treatment compared to pre-treatment. Finally, using machine and deep learning methods we identified a panel of 12 key features within the lung TME which could be used to predict prognosis. Conclusions: We comprehensively characterized immune and stroma cell type changes in the lung TME utilizing bulk RNA-seq data, and evaluated the association of sub-type cell populations with different clinical and biological features. Key features in lung TME could be used to predict prognosis.
The effect of different dose and sites of irradiation on lymphocyte subsets in peripheral blood of patients with lung cancer.
Authors: Duan Xiaotong , Zhu Xiaoxia 
Published: May 2020

e21032 Background: To explore the effect of different radiation doses and sites on systemic immunity in patients with lung cancer by detecting the changes in the percentage of lymphocyte subsets in peripheral blood before and after radiotherapy. Methods: Peripheral blood in 48 patients with lung cancer receiving radiotherapy were collected (before, during and after radiation), and the lymphocyte subsets as follow were examined: total T cell (CD3+), CD4+T cell, CD8+T cell, CD3+CD4+/CD3+CD8+, NK cell, memory T-helper cell subpopulation (CD4+ CD45RO+), CD4+ naïve T-cell subset (CD4+CD45RA+), cytotoxic T cell (CD8+CD28+), IL-2 receptor α(CD25+), B cells (CD3-CD19+), regulatory T cells (CD4+CD25+). The results were statistically analyzed with unpaired Student's t-test using GraphPrism6 software. Results: Among non-small cell lung cancer (NSCLC) patients treated with thoracic radiation (n = 21), B cells in patients receiving 20Gy/10F (P = 0.0072), 40Gy/ 20F (P = 0.0001), 60Gy/30F (P = 0.0002) irradiation were significantly lower than that before radiotherapy. However, CD4+ naïve T-cells decreased significantly at each dose point compared with that before radiotherapy, P values were 0.0394, 0.0081 and 0.0007, respectively. NK cells after completion of 60Gy/30F irradiation were distinctly lower than those after receiving 20Gy/10F of radiotherapy (P = 0.0278), and no significant difference was found in other immune cell subsets. Patients with small cell lung cancer (n = 6) who underwent thoracic radiation showed a similar trend of changes in B cells. However, the CD4+CD45RA+ subset decreased evidently after completing radiation compared with that after 10 fractions of irradiation (P = 0.0390). The NSCLC patients (n = 4) who received radiation for bone metastases (regimen: 36Gy/12F) had evidently lower B cells (CD3-CD19+) at the end of radiotherapy than that at the start of radiotherapy (P = 0.0286). Patients with NSCLC (n = 10) who received brain radiation (regimen: 40Gy/20F for whole brain, 54-56Gy/20F for multiple brain metastases) had a significantly reduced CD4+CD45RA+ subsets after finishing radiation (20F) compared with those after 10 fraction of radiation (P = 0.0497). The changes of other subsets were not statistically significant. Conclusions: The effect of radiation in different sites and doses on peripheral blood lymphocyte subsets is not identical.It is urgent to expand the sample size to explore the law for the optimization of radiation combined with immunotherapy.Funding: 81972853, 81572279, 2016J004, LC2019ZD009, 2018CR033
Prognostic value of the TGFß1 rs4803455 single nucleotide polymorphism and its association with prophylactic cranial irradiation in small cell lung cancer.
Authors: Ayala de Miguel Pablo , Enguix-Riego María Valle , Cacicedo Jon , Delgado Blas David , Pérez Marco , Praena-Fernández Juan Manuel , Quintana Cortés Laura , Borrega Pablo , Rivin del Campo Eleonor , Lopez Guerra Jose 
Published: May 2020

e21038 Background: Small cell lung cancer (SCLC) is one of the greatest therapeutic challenges of oncology. Potential associations between single-nucleotide polymorphisms (SNP) in Heat shock protein beta- 1 (HSPB1) and Transforming growth factor (TGFß1) and survival have been investigated. Methods: A prospective multicenter study of 94 SCLC patients treated between 2013 and 2016 was conducted. Several variables clinical, tumour-related, therapeutic, and genetic (9 SNPs of TGFß1 gene and 5 of HSPB1 gene) variables were analyzed. Results: The cohort included 77 men and 17 women with a median age of 61 years. Eighty percent presented with limited stage at diagnosis and received thoracic radiation with a median dose of 45 Gy (BID in 42%). Forty-seven percent received concomitant platinum-based chemotherapy and 57% received prophylactic cranial irradiation (PCI). Overall survival (OS) was 34% at 2 years and 16% at 3 years. In multivariate analysis PCI and the TGFß1 SNP rs4803455 showed a statistically significant association with OS and local control. Patients with the CA genotype of the TGFß1 SNP rs4803455 showed worse OS (HR 2.53; IC 1.22-5.21; p = 0.012) and higher local recurrence (HR 2.26; IC 1.01-5.08;p = 0.048). A combined analysis showed that those patients receiving PCI and carrying the rs4803455:CA genotype had a statistically significant lower OS (p < 0.001) and disease-free survival (p < 0.001) than patients receiving PCI and carrying the rs4803455:AA genotype. Conclusions: Genetic analysis showed that the CA genotype of TGFß1 SNP rs4803455 was associated with worse prognosis in SCLC patients and could be considered as a potential biomarker for OS.
Association of higher EGFR mutation in the primary lesions with lymph node metastasis in early lung adenocarcinoma.
Authors: Zhang Yi , Wang Jinjin , Yuan Yuwei 
Published: May 2020

e21039 Background: Prognosis of early stage lung adenocarcinoma after surgery are usually affected by whether the patients had lymph node metastasis along with the primary lesions. The pathological stage of operable lung adenocarcinoma without or with lymph node metastasis were ⅠA/B or ⅡB/ⅢA, respectively, which related to different clinical outcomes, especially 5 years survivors (90% vs 50%). Due to the high tumor heterogeneity, it is difficult to trace which genes lead to tumor metastasis. We hypothesis that the genetic mutations in the smaller tumor might discover the key genetic changes associated with metastasis. Methods: 47 NSCLC patients with the primary lesion diameter less than or equal to 3cm were enrolled for genotyping with multiple cancer-related genes. Among them, 20 were lymph node metastasis and 27 were non-metastasis. Fisher test was used to analyze the difference between the two primary tumors. Results: EGFR amplification in all patients with lymph node metastasis is higher than the non-metastasis group (0.250 vs 0.037, P = 0.043), shown in the following table. This tendency was also found when the tumor diameter thresholds were configurated as < 2.5cm and < 2cm, even more prominently in the latter, (0.400 vs 0, P = 0.020). The CNV value of EGFR increased while the tumor diameter threshold value decreased. The difference of EGFR VAF between the two groups showed the same pattern. The metastatic patients had higher VAF values than the non-metastatic patients (each P-value was lower than 0.05). Conclusions: Based on the above results, it is speculated that EGFR mutations plays an important role in tumor early metastasis, and the genetic mutations in the smaller tumor might discover the key genetic changes associated with metastasis more notably. [Table: see text]
Identification of a prognostic immune-related signature for small cell lung cancer.
Authors: WANG JUN , Zhang Bicheng , Sun Jianguo , Liang Jing , Liu Xiaolin , Li Yan , Wang Baocheng 
Published: May 2020

e21041 Background: As a subgroup of lung cancer, small cell lung cancer (SCLC) is characterized by a short tumor doubling time, high rates of early occurred distant cancer spread, and poor outcome. Despite its exquisite sensitivity to chemotherapy and radiotherapy, acquired drug resistance and tumor progression was impossibly avoided. This study aimed to develop a robust signature based on immune-related genes to predict the outcome of patients with SCLC. Methods: The expression data of 77 SCLC patients from George’s cohort were divided into training and testing set, and 1,534 immune-related genes from ImmPort database were used to generate and validate the signature. The Cox proportional hazards model was developed to determine the best gene model and construct the signature. The Kaplan-Meier survival analysis and Cox proportional hazards were used to test the prognostic significance of the signature. Results: A 10-genes model comprising NR3C1, NR1D2, TANK, ARAF, HDGF, INHBE, LRSAM1, PLXNA1, PML and SP1 with the highest frequency after 1,000 interactions, was chosen to construct an immune-related signature. This signature showed robust predictive value for SCLC patients’ survival in both training and testing set. This signature was closely associated with the activation of immune signal pathways, but not TNM stage. Furthermore, patients with high immune risk score presented with poor survival, whereas had high specific tumor-infiltrating immune cells such as NK CD56 bright cells. Conclusions: The present developed immune-related signature could predict the prognosis of SCLC patients, which to some extent reflect individual immune microenvironment phenotype in this highly lethal cancer type.
Stereotactic body radiotherapy for early-stage non-small cell lung cancer in patients with subclinical interstitial lung disease.
Authors: Hu Min , Sun Xiaojiang , Liu Yuanjun , Zhu Yaoyao , Xu Qinghua , Li Fangjuan , Liu Hui , Xu Yaping , Weng Denghu , Lin Qingren 
Published: May 2020

e21050 Background: Stereotactic body radiotherapy (SBRT) is a highly focused radiation treatment, which is now recommended to treat non-small cell lung cancer (NSCLC) patients with early stage disease. The purpose of this study is to evaluate the efficacy and toxicity of SBRT for early stage NSCLC patients with subclinical interstitial lung disease (ILD). Methods: One hundred and nine patients with early stage NSCLC were treated with SBRT between December 2011 and August 2016 in our institution; patients with subclinical (untreated and oxygen-free) ILD were treated with SBRT, while those with clinical ILD (post- or under treatment) were not. The median SBRT dose was 50 Gy in 5 fractions and the median biologically effective dose (BED; α/β = 10) was 100 Gy (range:72-119 Gy). The presence of subclinical ILD in the pre-SBRT CT findings was reviewed by two chest radiologists. The relationships among the efficacy, radiation pneumonitis (RP) and clinical factors were investigated. Results: Subclinical ILD was recognized in 38 (35%) of 109 patients. Grade 2–4 RP was recognized in 48 (44%) of 109 patients, no Grade 5 RP was happened. Grade 2–4 RP was observed in 17 (45%) of 38 patients with subclinical ILD. Subclinical ILD was not found to be a significant factor influencing Grade 2–4 RP; however, extensive RP beyond the irradiated field, including the contralateral lung, was recognized in only two patients who were both suffering from subclinical ILD, and the rate of extensive RP was significantly high in the patients with subclinical ILD. Dosimetric factors of the lungs (V5, V10, V20, MLD, V12.5, V13.5) were significantly associated with Grade 2–4 RP. The three-year overall survival and progression-free survival rates of all patients were 82.8% and 62.5%, respectively. No significant differences were seen in either overall survival or progression-free survival rates among the patients with ILD and those without ILD, or with RP and those without RP. Conclusions: Subclinical ILD was not found to be a significant factor for Grade 2–5 RP or clinical outcomes in early stage NSCLC treated with SBRT; however, uncommon extensive RP can occur in patients with subclinical ILD.
Thermal ablation versus stereotactic body radiotherapy for stage I non-small cell lung cancer: A cost-effectiveness analysis.
Authors: Wu Xiao , Uhlig Johannes , Blasberg Justin , Gettinger Scott N. , Suh Robert , Solomon Stephen Barnett , Kim Kevin 
Published: May 2020

e21061 Background: Stereotactic body radiotherapy (SBRT) and thermal ablation are increasingly used to treat medically inoperable patients with non-small cell lung cancer (NSCLC). The purpose of this study is to assess the cost-effectiveness of microwave (MWA) and stereotactic body radiotherapy (SBRT) for patients with stage I NSCLC. Methods: A decision-analysis model was constructed over a 5-year of Medicare billing data from a health care sector’s perspective using TreeAge Pro Suite 2019 (TreeAge Software LLC, Cambridge, MA). The two evaluated strategies were SBRT and MWA. All clinical, cost and health utility parameters were derived from the literature with preference to long-term prospective trials and assigned appropriate statistical distributions. Costs and health utilities (quantified by quality-adjusted life years (QALY)) associated with procedure, short-term complications, long-term surveillance and disease progression were incorporated. A willingness-to-pay (WTP) threshold of $100,000/QALY was used. One QALY is equivalent to 1 year of life in perfect health. Strategies were compared using incremental cost-effectiveness ratio (ICER). Base case calculations, Monte Carlo Simulations with 10,000 iterations drawing parameters from their respective distributions, and multiple sensitivity analyses were performed. Results: Literature review and interpolation showed that average annual recurrence risk of SBRT and MWA were 4.64% and 10.4% respectively. SBRT yielded 2.33 QALY and MWA yielded 2.31 QALY. The difference in health benefit is equivalent to 1 week of life in perfect health. The overall costs were $225,271 and $195,331. The ICER of MWA in reference to SBRT was $1,480,597/QALY, which is more than 10 times of the WTP threshold currently used in the US, indicating that MWA is the more cost-effective strategy. MWA was the optimal strategy in 99.84% of the Monte Carlo simulations. One-way sensitivity analyses showed that MWA is more cost-effective than SBRT if recurrence risk of MWA is < 18.4% per year or recurrence risk of SBRT is > 1.44% per year, or cost of MWA is lower than or at most $7,500 more than SBRT. One-way sensitivity analysis showed that MWA would achieve a higher health benefit than SBRT if the overall survival after MWA was > 76.9% per year or after SBRT was < 75.6% per year. Conclusions: Our study showed that MWA is more cost-effective than SBRT for medically inoperable stage I NSCLC patients with comparable health benefits based on multiple robust probabilistic and deterministic sensitivity analyses.
Targeted sequencing analysis of predominant histological subtypes in resected stage I invasive lung adenocarcinoma.
Authors: Li Chong , Li Yan , Tan Yan , Yan Zhantao , Xie Jun , Zhang Xian , Hu Song , Zong Yun , Li Qing , Ye Junyi , Li Xi , Han-Zhang Han 
Published: May 2020

e21067 Background: Lung adenocarcinoma (LADC) is classified into 5 main histological subtypes with distinct clinicopathologic characteristics: lepidic-predominant adenocarcinoma (LPA), acinar-predominant adenocarcinoma (APA), papillary-predominant adenocarcinoma (PPA), micropapillary component (MPC) and solid-predominant adenocarcinoma (SPA). However, the mutational profiles of predominant histological subtypes have not been well defined. In this study, we aimed to reveal the genomic landscape of the 5 main histological subtypes. Methods: Surgically resected tumor samples were obtained from 86 patients with pathological stage I invasive lung adenocarcinoma who underwent surgery between January 2015 and December 2018. No patient had received preoperative chemotherapy or radiotherapy. Capture-based targeted sequencing was performed in a cohort of 86 stage I invasive adenocarcinoma (IAC) patients spanning 5 subtypes using a panel consisting of 168 lung cancer-related genes. Results: Our analysis identified a total of 302 genomic alterations. Five subtypes showed distinct mutation profiles with LPA, APA, PPA, MPC and SPA had an average mutation rate of 1.95 (range: 0–5), 2.56 (range: 1–6), 3.5 (range: 1–7), 3.75 (range: 1-8) and 6.05 (range: 2-12), respectively (p = 4.17e-06). In this cohort, 96.55% (83/86) of all patients had mutations in classic lung cancer drivers with EGFR (73.3%), KRAS (9.3%), ALK (4.7%) and MET (4.7%) being the most commonly mutated drivers. TP53 is the top mutated tumor suppressor gene. It has been reported that SPA and MPC have unfavorable prognosis comparing to the rest subtypes. Interestingly, LRP1B mutations, which has been reported to be associated with high tumor mutation burden and better response to immunotherapy, were only detected from 5 SPA patients (p = 0.001). No MPC patients from this cohort harbored LRP1B mutations. Conclusions: We revealed distinctive mutation landscape of the 5 major histological subtypes of LADC, evident by distinctive average mutation rate with SPA and PLA having the highest and lowest average mutation rate, respectively. Furthermore, we also showed that SPA patients harboring LRP1B mutations may benefit from immunotherapy.
An exploratory study of PD-1 inhibitor for high-risk multiple ground-glass nodules (mGGNs) in synchronous stage I non-small cell lung cancer patients.
Authors: Xu Lin , Shi Meiqi , Li Ming , Xia Wenjia , Shen Wenrong , Zhang Jingyuan , Zhu Jun , Shao Yang , Yin Rong 
Published: May 2020

e21068 Background: Surgical resection is recommended for the stage I NSCLC patients. However it is lack of standard therapies for synchronous mGGNs. This study aims to explore the feasibility of a PD-1 inhibitor (sintilimab) in high-risk residual mGGNs in post-surgery synchronous stage I NSCLC patients. Methods: This is a single arm phase I trial intending to recruit 20 subjects. Eligible patients contained at least one high-risk residual mGGN (confirmed by MDT discussion) after surgical resection of stage I NSCLC. Patients received sintilimab (200mg i.v., Q3W) for 10 cycles since 6 weeks post-surgery. Radiological evaluations were performed at every 3 cycles in treatment period and every 3 months during follow-up. Whether re-operation is needed depends on MDT evaluation. The primary endpoints were safety and ORR. The secondary endpoints included DOR, MPR of re-operated GGNs, and the one-year PFS. Results: As data cutoff (23 Jan 2020), 20 patients (9 males and 11 females) were enrolled. The pathological results revealed that all were lung adenocarcinoma. The median treatment cycles was 6 (range 3 to 10). All lesions were evaluated as stable disease by RECIST 1.1. Six patients underwent re-operation safely and12 GGNs were resected. Pathology showed that 1 had no tumor cells residue, 4 had 20-35%, and 7 had over 80% residues. Whole-exome sequencing of 12 GGNs showed 6 harboring EGFR and 2 harboring KRAS mutations. Interestingly, 3 out of 6 with EGFR-mut showed less tumor cells residues (23.3%, 30%, and 80%). The highest TMB (15.7 mut/Mb) was observed in the complete response GGN. 65% patients experienced treatment-related 1-2 grade AEs. Conclusions: The PD-1 inhibitor showed well tolerability and a certain degree anti-tumor activity was seen from the pathologic results of re-operated GGNs. Radiological evaluation using RECIST 1.1 might be unsuitable for mGGNs. Further studies are needed to demonstrate the clinical benefits. ChiCTR: 1900022159 Clinical trial information: 1900022159 .