bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification and validation for biological characteristics and prognosis of tumor microenvironment subtypes in patients with lung adenocarcinoma.
Authors: Yao Yi , Zhou Jin , Zhang Haohan , Wu Jie , Zhao Yaqi , Liu Zheming , Xu Bin , Song Qibin 
Published: June 2022

e21006 Background: Immunotherapy has brought a great revolution to treatment of patients with lung adenocarcinoma (LUAD). However, the infiltrating cells in the tumor microenvironment (TME) could influence immunotherapy outcomes. This study aimed to investigate the TME subtypes based on 50 immune, stromal, and stem cell types in TME. Methods: The xCell algorithm was used to infer the enrichment scores in TME. We performed the k-mean consensus clustering to identify TME subtypes for LUAD patients. The ESTIMATE, ABSOLUTE, LUMP, and CPE algorithms were used to compare tumor purity and immune infiltration of TME subtypes. The genomic mutations and copy number variants were also calculated by “maftools” R package and GISTIC 2.0. We established a neural network model, based on the TCGA dataset and verified it in GEO datasets by the Kaplan-Meier curve and Cox regression analyses, to prove the stability of TME subtypes. Using prophetic algorithm, ridge regression model was established to predict the sensitivity of drugs in all datasets. In addition, TIDE score and submap analyses were used to speculate the potential response of patients in immunotherapy. Results: In our study, 50 types of cells, including immune (including lymphocyte and myeloid cells), stem, and stromal cells in TME, were included for analysis. Based on cell scores, 504 LUAD patients were divided into four different subtypes (C1, C2, C3 and C4). In univariable Cox regression, the hazard ratio (HR) value of C2 vs. C1 was 2.066 (95%CI: 1.313 - 3.250), the HR value of C3 vs. C1 was 1.821 (95%CI: 1.067- 3.108), and that of C4 vs. C1 was 2.313 (95%CI: 1.461 - 3.662). Then, a neural network model was established (the area under the curves in the testing cohort: 0.911) to validate our conclusions in external sets and similar results were observed. Through pseudotime trajectory, we discovered there were potential connections among clusters from C1 to C4. The C2 and C3 were the intermediate forms of C1 and C4, and thus, the survival, immunological, and metabolic status of C2 and C3 may be intermediate between C1 and C4. By comparing the cell infiltration and immune gene expression of the four clusters, we found that C1 and C3 may have a similar immune phenotype which was opposed to that of C2 and C4. Meanwhile, the enrichment scores of cell proliferation-related pathways were progressively increased in the four clusters, which may be related to survival outcomes of them. We noticed that C1 harbored a unique EGFR mutation compared to other clusters, which may be sensitive to erlotinib. Patients of C4 had lower TIDE scores, which indicated that these patients may get higher benefits from immunotherapy. Conclusions: In conclusion, we identified four TME subtypes with distinct clinical outcomes and biological features, including tumor immunity, TME status, tumor mutations, and responses to chemotherapy and immunotherapy.
Use of next-generation sequencing (NGS) to study the impact of demographic variables on prevalence of driver mutations in non-small cell lung cancer (NSCLC).
Authors: Choi WonSeok William , Haroun Faysal 
Published: June 2022

e21030 Background: The management of NSCLC is rapidly evolving with the discovery of new driver mutations and the introduction of targeted therapies (TT). The list of targets with FDA-approved TT is estimated to cover over half of the cases of non-squamous NSCLC. The prevalence of driver mutations varies significantly depending on several demographic variables such as smoking status, race, and sex. This abstract presents data obtained from a unique, racially diverse cohort of patients in the Washington, DC metropolitan area. Methods: Retrospective review of circulating tumor DNA NGS data from 2 commercial testing companies (Guardant and Tempus) and demographic data from our health records on 66 patients with NSCLC treated at the George Washington University Medical Faculty Associates between October 2017 and November 2021 was performed. Demographic information including age, sex, race, and smoking history, as well as histology, stage at diagnosis, and driver mutations were collected. Only patients with non-squamous NSCLC and identifiable mutations were included. Results: Mean age was 67. Most patients in this cohort were female (56.1%, male 43.9%), African-American (62.1%, Caucasian 25.8%, African 9.1%, Asian 3.0%), had smoking history (former smoker 48.5%, current smoker 25.8%, never smoker 25.8%), had adenocarcinoma (78.8%, other NSCLC (not squamous cell carcinoma or adenocarcinoma) 21.2%) with advanced stage (stage 4 62.1%, stage 3 28.8%, stage 1 3.0%, unknown 6.1%). Mutations are listed as follows: KRAS 28.8% (G12C accounted for 58% of all KRAS mutations), EGFR 19.7% (exons 19 and 21 mutations such as del19 and L858R accounted for 69%), MET 9.1% (MET amplification made up 83%), Her2 3.0% (2/66), ALK 3.0% (2/66), RET 1.5% (1/66), non-targetable mutations 34.8% (23/66). A table at the end of this abstract shows the frequency of three most prevalent mutations in this cohort distinguished by race, sex, and smoking status. Conclusions: KRAS was the most prevalent driver mutation in this cohort, followed by EGFR and MET. In concordance with the existing literature, EGFR was more prevalent in non-smokers and females, while KRAS was more common among smokers. Interestingly, a larger percentage of Africans had EGFR mutations compared to African-Americans. Given the small sample size, however, a larger scale study is needed to investigate this further. These findings show that demographic factors influence the prevalence of driver mutations which can have therapeutic implications in patients with NSCLC.[Table: see text]
Genetic mutations-based criteria to distinguish multiple primary lung cancers from intrapulmonary metastasis in patients with lung tumors.
Authors: Li Zhenhua , Lv Huilai , Zhang Fan , Zhu Ziming , Guo Qiang , Wang Mingbo , Huang Chao , Guo Lijie , Meng Fanfei , Yuan Shaohua , Shi Xiaoliang , Tian Ziqiang , Pang Fei 
Published: June 2022

e21038 Background: Patients with multiple primary lung cancers (MPLC) and intrapulmonary metastasis (IPM) are considered as different clinical stages and require different treatment strategies. At present, the molecular identification criteria employed for distinguishing MPLC and IPM still need to be improved. Therefore, there is an unmet medical need in regards to a diagnostic standard that could effectively distinguish MPLC from IPM. Methods: Between December 2014 and April 2020, a total of 35 patients, with more than two lung lesions, were selected and divided into a training cohort (N = 22) and a validation cohort (N = 13). Imaging, anatomical evidence, pathological results, and histological examinations of the primary tumor, as well as histological subtypes, were used to differentiate MPLC from IPM. Genomic profiles obtained using a targeted sequencing with 450 cancer-related genes panel were analyzed. Modified diagnostic criteria for MPLC and IPM were established based on Martini and Melamed criteria, as well as molecular profiles. Results: We developed interpretation criteria using a flowchart that distinguishes MPLC from IPM, as follows: 1) MPLC can be determined using the following aspects: no common mutations are present; one lesion has no mutations (tumor = 2); two common high frequency driver gene mutations are present, or one driver gene mutation and one rare mutation comprising the p53 mutation are present; and only one common mutation is present. 2) IPM can be determined using the following aspects: one driver gene mutation and one rare mutation comprising the p53 mutation (concordance rare ≥ 50%) are present; two driver gene mutations (concordance rare ≥ 60%) are present; all mutations are common; and more than three common mutations are present. 3) Undetermined results are based on the following aspects: no mutations in one tumor are present (tumor > 2); no mutations are identified in all tumors; or two rare mutations are present. Undetermined patients were identified by combining histological identifications. Subsequently, to verify the criteria, 13 patients were recruited as a validation cohort. Eight MPLC and 5 IPM patients were identified, and the results were 100% consistent with independent imaging and pathological diagnoses. Conclusions: In this work, we proposed more comprehensive and detailed molecular identification criteria for MPLC and IPM, and it suggested that genetic alterations may be an effective method for diagnosing MPLC and IPM. We also determined that NGS may be a useful tool for assisting with differential diagnoses. Key words: Multiple lung cancer, Multiple primary lung cancer, Intrapulmonary metastasis, Next-generation sequencing, molecular classification.
Low-dose selenite synergizes with KRAS inhibitor as a dual apoptotic and ferroptotic agent in lung adenocarcinoma.
Authors: Chan Lok Seng , Liu Johnson , Li Lili , Tao Qian , Mok Tony S. K. 
Published: June 2022

e21039 Background: Selenium, an essential trace element, has long been investigated as a pro-apoptotic and DNA demethylation agent. It sensitizes the response to chemotherapy in patients refractory to cytostatic agents. Meanwhile, ferroptosis is a novel approach in cancer treatment by triggering cell death and reversing drug resistance. However, the role of selenite in targeted therapy of lung adenocarcinoma (LUAD) and its underlying mechanism to demethylation and ferroptosis are largely unknown. Methods: EGFR- and KRAS-mutant LUAD cells (H1975 EGFR p.L858R and p.T790M and H358 KRAS p.G12C) were treated with selenite for 72 hours to examine its effect on DNA methylation, apoptosis and ferroptosis by western blot, C-11 BODIPY staining, methylation-specific PCR and transcriptome sequencing validated by qPCR and western blot. Cell proliferation and apoptosis of both cells treated with selenite and osimertinib in H1975 or adagrasib in H358 were assessed by MTS assay and western blot. Results: We confirmed selenite to be a dual apoptotic and ferroptotic agent in LUAD, associated with the activation of the p38-ATF4-CHOP axis in the unfolded protein response. This pathway linked ferroptosis with apoptosis by the upregulation of BH3-only proteins. Selenite also altered the DNA methylation machinery by downregulating DNMT1 and upregulation of TET1. We further found that low-dose selenite synergized with adagrasib in KRAS-mutant H358 but only yielded additive interaction at a high dose. Conclusions: Selenite is a dual apoptotic and ferroptotic agent with dose-dependent, oncogenic driver-dependent therapeutic effects in LUAD. These data suggest that low-dose selenite should be a potential drug candidate for the treatment of KRAS mutation-positive lung cancer.
Update to role of the neutrophil lymphocyte ratio in patients with advanced NSCLC undergoing immunotherapy.
Authors: Richardet Eduardo , Acosta Luciana Paola , Magi Ignacio , tello Alfonso Rocio , Peruchin Rita Vanessa , Perea Pablo , Molina Matias , Richardet Martin 
Published: June 2022

e21041 Background: The tumor microenvironment TME is a heterogeneous mixture of different tumor cells, necrotic cells and immune infíltrate.Furthermore nerves and vasculature immersed in the surrounding stroma. The TME cells have different immunological phenotypes. The infiltrating lymphocytes of the tumor stroma (tils) and neutrophil lymphocyte ratio (NLR) are a reflection of the state of “inflammation” in the TME and his systemic repercussion. In our institution we have carried out several research studies studying different markers of inflammation, such as BMI, TILs and NLR in different solid tumors. We conclude that these markers of inflammation have a role in tumor behavior, prognosis and response to treatment. The main objective was investigated the relationship between as NLR and progression-free survival (PFS).in patients with NSCLC who received immunotherapy. The secondary objective was to analyze if there is a relationship between ORR and NLR in patients with NSCLC. Methods: Retrospective and analytical study of patients of Instituto Oncológico de Córdoba. Patients with stage IV NSCLC were analyzed. Were included patient who performed IT alone or in combination with another immunomodulator or platinum-based chemotherapy. The cut-off value for NLR > or < 3 was taken. ORR was evaluated by RECIST criteria. For the statistical analysis of survival, Chi-Square test and Kaplan-Meyer test were used. Results: 52 pts with NSCLC were selected, the average age was 67 years. Of the total number of subjects analyzed, 75% (39) presented non-squamous histology and 25% (13) presented squamous histology. All performed IT (anti PD1) alone or in combination with another immunomodulator (Ipilimumab) or platinum-based CT. Of total patients analized, 27 pts had a NLR < 3; and 25 pts NLR > 3. The median overall survival (OS)was 8.5 months for general population. Patients with an NLR < 3, the median PFS was 14.9 months and those with an NLR > 3 was 5.5 months (p: 0.01). When analyzed the ORR in pts with NLR < 3 it was 21% and those with NLR > 3 the ORR was 4% with statistically significant differences (p:0.02). All patients had follow-up of at least 1 year4 patients (8%)with NLR < 3 had disease progression at 6 months in differencies with patients with NLR > 3 that had progression 13 pts (25%)(p:0.01) and these differences were maintained when we evaluated the PFS at year. Conclusions: Patients with NLR < 3 had better progression-free survival and ORR. It is possible that NLR is a very useful and easily accessible predictive factor in patients with NSCLC undergoing immunotherapy.
Signature based on B cells-related gene pairs could predict prognosis and immunotherapeutic response in NSCLC.
Authors: Li Xuanzong , Fan Xinyu , Wang Linlin 
Published: June 2022

e21051 Background: Tumor-infiltrating B cells accompanying several widely used B cell-related biomarkers, such as CD19 and CD20, have inconsistent clinical prognostic values in non-small-cell lung cancer (NSCLC) patients. Considering only one B cell-related biomarker could not distinguish the anti-tumor and pro-tumor B cell subsets in tumor, we aimed to construct a more accurate B-cells related gene pairs (BRGPs) prognostic model and evaluate its potential predictive ability to immunotherapy in NSCLC patients. Methods: Using public single-cell RNA sequencing data, the B cells-related genes (BRGs) in NSCLC samples were identified. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were utilized to construct the BRGPs model which was not affected by the technical bias of different platforms. With no dependence upon specific gene expression levels, a novel signature based on BRGPs was established in this study. In addition, the prognostic value and immunotherapeutic response for this signature with regard to the TME components and potential molecular mechanism were explored. Results: Based on the TCGA database, we built a novel prognostic signature of 23 BRGPs comprising 28 unique BRGs. This risk model showed significant power in distinguishing good or poor prognosis and could serve as an independent prognostic factor for NSCLC patients in the TCGA cohort. The prognostic accuracy of the model was further verified in the GSE31210 dataset from the GEO database. Likewise, the prognostic value of the risk score for the BRGPs model was demonstrated in the GEO cohorts by the univariate and multivariate cox regression analysis. In addition, the risk model was significantly associated with sex, TNM stage, immune score, tumor purity and various tumor-infiltrating immune cells. GSEA analysis indicated that low-risk group enriched with several immune-related pathways, such as activation of immune response, antigen receptor mediated signaling pathway, B cell activation and B cell mediated immunity, whereas several proliferation-related pathways, such as nuclear chromosome segregation, sister chromatid segregation and mitotic sister chromatid segregation were most enriched in high-risk group. Besides, the tumor mutational burden (TMB) score rather than CD274(PD-L1 mRNA) expression was positively correlated with the risk score (P＜0.001; P = 0.94, respectively). NSCLC patients with high-risk exhibited significantly higher TMB score compared with low-risk patients (P < 0.001). Correspondingly, we demonstrated that immune checkpoint blockade therapy may be more efficacious in high-risk group NSCLC patients according to TIDE method (P＜0.01). Conclusions: This novel BRGPs model can assess the prognosis of patients with NSCLC, and may be helpful to guide immune checkpoint inhibitors treatment in our clinical practice.
Weight loss affects outcome in KrasG12C non-small cell lung cancer first line treated patients.
Authors: Fancelli Sara , Caliman Enrico , Pillozzi Serena , Napolitano Brunella , Pieroni Edoardo , Mazzoni Francesca , Paglialunga Luca , Gatta Michelet Marta Rita , Roviello Giandomenico , Castiglione Francesca , Bartoli Caterina , Antonuzzo Lorenzo 
Published: June 2022

e21054 Background: Cachexia is a syndrome characterized by weight loss (WL), reduction of muscle mass, systemic inflammation and is an independent criteria of worse clinical outcomes in cancer. Patients with KRASmut non-small cell lung cancer (NSCLC) experience a higher rate of WL than KRASwt patients. However no data about the prognostic value of each Kras mutation subtype for WL and/or BMI status are available. Methods: We reviewed the clinicopathological data of 110 NSCLC patients harboring KRAS G12 mutation who were treated at Clinical Oncology Unit, Careggi University Hospital in Florence, from March 2016 to March 2020. Patients received either chemotherapy or anti-PD1 pembrolizumab or a combination of chemo-immunotherapy as first-line treatment. The prognostic value of basal BMI and WL (< and > 5%) was analyzed according to each mutation subtype. Results: In the study population, 49.1% of patients harbor the KRAS G12C mutation, 20.9% G12V, 18.2% G12D and 11.2% of patients have other subtypes of KRAS mutations. Overall, our data confirm the better prognostic value of G12C mutation. At a median follow-up of 18 months, median OS for G12C patients was 17.5 months, longer compared to any other mutation subtype ( p = 0.113), whereas G12V mutation was associated with significantly worse outcomes than in the whole population (mOS 9.5 months IC 95% 6.0-17.0, p = 0.018). WL within 6 months of first-line therapy was observed in 29.7% and 35.3% of G12C and G12V-mutated patients, respectively. WL statistically decreased survival outcomes both in G12C (mPFS 4.0 months vs NR, p < 0.001; mOS 12.0 months vs NR, p = 0.009) and in G12V patients (mPFS 3.0 months vs NR, p = 0.073; mOS 8.0 vs 12.0 months, p = 0.994), compared to patients who do not lose weight during treatment. Conclusions: WL significantly worsens clinical outcomes in G12C patients, with a similar trend in G12V. Further analyses in a larger population including a representative sample of less frequent mutations are needed.
ICI in combination with chemotherapy or anti-angiogenic agents as second-line or beyond treatment for advanced non-small cell lung cancer: A retrospective study.
Authors: Wu Lin , chen bolin , Wang Jingyi , Pu Xingxiang , Li Jia , Wang Qianzhi , Liu Liyu , Xu Yan , Xu Li , Kong Yi , Li Kang , Xu Fang , Liang Shuzhi 
Published: June 2022

e21057 Background: Immune checkpoint inhibitors (ICIs), which are currently used in the standard second-line treatment for non-small cell lung cancer (NSCLC), have largely improved the prognosis of advanced NSCLC. However, patients treated with ICI monotherapy have low response rates; hence, there is an urgent need to expand the population responding to immunotherapy treatment. This study aimed to explore the efficacy and safety of the combination of ICI with chemotherapy or anti-angiogenic therapy compared to ICI monotherapy in patients previously treated for advanced NSCLC. Methods: Data was collected from previously treated patients with NSCLC who further received ICI monotherapy or combination therapy. The distribution of clinical variables was assessed using the chi-square test or Fisher's exact test. The relationship between descriptive variables and survival was described using Kaplan–Meier curves and compared by log-rank test. Cox proportional-hazards models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) to confirm survival differences. Results: A total of 145 patients were included in this study, of which 63 were in the ICI monotherapy group, 57 were in the ICI with chemotherapy group, and 25 were in the ICI with anti-angiogenic therapy group. Compared with the ICI monotherapy group, the ICI with chemotherapy group had significantly higher ORR (31.6% vs. 11.1%, P = 0.006), DCR (84.2% vs. 61.9%, P= 0.006), PFS (mPFS: 6.37 vs. 3.47 months, P< 0.0001; HR = 0.42, 95% CI: 0.29–0.63, P< 0.0001), and OS (mOS: 18.60 vs. 8.47 months, P< 0.0001; HR = 0.40, 95% CI: 0.25–0.64, P= 0.0001). In addition, the ICI with anti-angiogenic therapy group also had significantly elevated DCR (88% vs. 61.9%, P= 0.02), PFS (mPFS: 8.17 vs. 3.47 months, P< 0.0001; HR = 0.30, 95% CI: 0.17–0.53, P< 0.0001), and OS (mOS: 19.20 vs. 8.47 months, P= 0.006; HR = 0.44, 95% CI: 0.24–0.80, P= 0.007) compared with the ICI monotherapy group. There was no significant difference between the ICI with chemotherapy group and the ICI with anti-angiogenic therapy group. Meanwhile, the addition of chemotherapy or anti-angiogenics did not increase immune-related adverse events and had a good safety profile. Conclusions: For previously treated patients with advanced NSCLC, treatment with ICI in combination with chemotherapy led to enhanced ORR, DCR, PFS, and OS compared to treatment with ICI monotherapy. Moreover, treatment with ICI combined with anti-angiogenic therapy led to enhanced DCR, PFS, and OS compared to treatment with ICI monotherapy. The combination of immunotherapies is a promising second-line treatment option for some of the patients in this study, and the findings of this study necessitate the need for further exploration.