bluuebunny/crossref_metadata_2025_split huggingface dataset:
Non-invasive diagnosis of nature of pulmonary nodules using the whole genome methylation sequencing of circulating cell-free DNA.
Authors: Dong Baiqiang , Zhu Xuan , Chen Runzhe , Chen Baoqing , Chen Kelly , Chen Ming 
Published: June 2024

e20038 Background: The frequent false-positive results of lung cancer screening of low-dose computed tomography (LDCT) remains a challenge. In this study, we aimed to establish a novel panel of cancer-specific methylated regions detected from circulating cell-free DNA (cfDNA) for differentiating malignant pulmonary nodules (PNs) from benign lesions in high-risk patients. Methods: We performed DNA methylation profiling by high throughput DNA bisulfite sequencing in tissue samples (nodule size < 3 cm in diameter) to learn methylation patterns that differentiate cancerous tumors from benign lesions. Then we filtered out differential methylation patterns in circulating cfDNA that are consistent with tissue expression patterns and built an assay for plasma sample classification. Area under the curve was computed for each receiving operation curve, and 95% confidence intervals were also estimated by bootstrapping with 1,000 iterations. Results: We first performed the whole genome methylation sequencing of 100 tissue samples from PNs to learn cancer-specific methylation patterns, and obtained 2,406 differential hypermethylated regions and 16,028 differential hypomethylated regions. These tissue-derived DNA methylation markers were further filtered using a training set of 42 plasma samples and 11 markers were ultimately identified to build a diagnostic prediction model. This methylation panel provided promising results in an independent validation set of additional 17 plasma samples, with a sensitivity of 66.67% (95% CI: 0.25–1.00) and a specificity of 79.17% for differentiating patients with malignant tumor (N = 12) from patients with benign lesions (n = 5). A further validation study of this methylation panel in the cancer genome atlas data set demonstrated significant discriminatory performance in distinguishing patients with lung cancer from subjects without malignancy (area under the curve = 0.88). Conclusions: Our model based on the measurement of circulating cfDNA methylation provide a minimally invasive procedure for differentiation of early-stage lung cancer and nonmalignant pulmonary nodules, and may guide management of positive LDCT screening results. Additional clinical studies with larger sample size are needed to establish the robustness of this model.
Landscape of gene fusions and METex14 skipping in non-small cell lung carcinoma among the Chinese population: Insights from targeted RNA sequencing.
Authors: Song Yang , Zhu Yongjun , Wu Ning , Xu Fei , Ma Ting , Chen Zhiming 
Published: June 2024

e20041 Background: Targeted RNA Sequencing is crucial for detecting gene fusions and exon-skipping mutations in non-small cell lung carcinoma (NSCLC). This study delineates the landscape of RNA-based fusion and METex14 skipping in the Chinese NSCLC population, compares the consistency with DNA-based fusion detection, and further explores the relationship between fusion-positive cases and immune markers. Methods: We profiled 294 NSCLC tumor tissues using targeted RNA sequencing, focusing on 29 fusion genes and 6 reference genes. Of these, 229 samples were concurrently assessed for fusions using a DNA panel. Patients with gene fusions or METex14 skipping were categorized as 'FUSION-POS'. Additionally, the expression of PD-L1 was evaluated. Results: In 294 NSCLC patients, 33 types of fusions and METex14 skipping were detected from 45 patients based on RNA detection. Actionable gene fusions/METex14 skipping were present in 11.22% (33/294) of patients, with the most prevalent being ALK (4.4%), METex14 skipping (2.7%), ROS1 (1.4%), and RET (1.0%). The partners of ALK, RET and ROS1 were EML4 (n= 12)/ LCLAT1(n=1), KIF5B (n=3) /PARD3(n=1) and CD74(n=2)/LRIG3(n=1)/EZR (n=1), respectively. Notably, we also identified two patients harboring FGFR2-ATE1 fusion and CD74-NRG1 fusion, respectively. Except for MET 14skipping, ST7-MET fusion was detected in 2 patients. Comparing the consistency of actionable fusions/METex14 skipping between RNA and DNA assessments in 229 NSCLC patients, RNA detection yielded a higher number of cases (24 patients vs 15 patients, 10.5% vs 6.5%), with all 15 fusions/ METex14 skipping detected by DNA also identified by RNA. Furthermore, we observed that PD-L1 expression was significantly elevated in the FUSION-POS group within lung adenocarcinoma patients (TPS: P=0.015). Conclusions: Our findings indicate that 11.22% of Chinese LUAD patients possess actionable fusions and METex14 skipping. The detection rate of fusions/ METex14 skipping via RNA is higher than that via DNA, with RNA detection fully encompassing all fusions/ METex14 skipping identified by DNA. Meanwhile, the association between fusions and PD-L1 expression suggests potential synergies for combining targeted therapy and immunotherapy in NSCLC.
Country-specific differences in the lung tumour microbiome.
Authors: Stafford Amanda , Lam Jie (James) Min , Basgaran Amedra , Lymberopoulos Eva , Tanweer Mohammad , Hobbs Michael , Arney James , Korovilas Dionisios , Delanoue David , Moore Stephen , Alomari Muhannad , Sharma Nikhil 
Published: June 2024

e20044 Background: Sputum examination for the early detection of lung cancer continues to be explored ( Thunnissen 2003 ), however has so far resulted in a low diagnostic yield. An increasing number of studies have evidenced a mechanistic role of the lung microbiome in the induction of lung cancer ( Liu et al., 2020 ), and the presence of bacterial biomarkers in bronchoalveolar lavage and sputum have been proposed ( Cheng et al., 2020 ). It is currently unknown whether the sputum microbiome can appropriately capture the lung tumour microbiome. Given that the lung microbiome may vary by geography, this analysis was considered over two populations: China and Italy. Methods: Microbiome analysis was performed using BioCorteX’s industry-leading knowledge graph and integrated proprietary engines v20240126_153156. Data from 9 studies was used. In total, 461 samples from lung cancer patients in China (250 sputum, 211 tumour) and 60 from Italy (34 sputum, 26 tumour) were considered. Shannon’s diversity was used to consider within-sample diversity, and dimensional scaling based (MDS) on Bray-Curtis diversity was used to consider between-sample diversity. Results: All sample were checked to have a library size greater than 100, and more than 10 unique species. Only those species present in over 1% of samples were considered to reduce noise. In both China and Italy, tumour samples had a lower diversity than sputum samples (p = 0.00016 and p < 2.2e-16, respectively). Samples from Italy had a lower diversity than samples from China (p < 2.22e-16). In the MDS analysis, the tumour samples from China and Italy formed two distinct, non-overlapping clusters. A third cluster was formed from the union of sputum samples from both countries. These results were independent of any study-specific effects. Conclusions: These results indicate that the sputum microbiome is not representative of the tumour microbiome, and that the divergence of the tumour microbiome away from the sputum microbiome is country specific. The results of this analysis highlight that further work into differences in the lung tumour microbiome by country is warranted, especially in light of the growing body of evidence suggesting a causative role of the microbiome in lung cancer. It is also possible that lung cancer treatments may be impacted by the country-specific nature of the lung tumour microbiome.
Characterization of DNA damage repair mutations in lung cancer in an underserved urban patient population.
Authors: Kao Jeremy , Pasquinelli Mary , Nguyen Ryan Huu-Tuan , Feldman Lawrence Eric , Weinberg Frank 
Published: June 2024

e20058 Background: DNA-damage repair (DDR) mutations in lung cancer have shown potential for use as therapeutic targets and predictive biomarkers. However, the relationship between DDR mutations and socioeconomic factors remains largely unknown. In this study, we characterize the distribution of DDR gene mutations in lung cancer patients at a single academic medical center serving a unique population consisting of primarily underserved, underinsured patients. Methods: All lung cancer patients seen at the University of Illinois Chicago (UIC) between 11/2/2015 and 9/11/2023 with TEMPUS genetic data available were included in the study (N = 235). DDR mutations of interest were ARID1A, ATM, ATR, ATRX, BAP1, BRCA1, BRCA2, BRIP1, CHEK2, ERCC3, FANCA, FANCC, MLH3, MRE11, MSH6, MUTYH, NBN, PALB2, and RAD50. The population was subdivided into a DDR mutation positive group and a DDR mutation negative group. Each group was compared with respect to lung cancer type, tumor mutational burden (TMB), and socioeconomic factors including sex, race, insurance category, and zip code. Results: The overall frequency of DDR mutations in the population was 28.5% (n = 67). The most common DDR mutations were ARID1A (20.7%), CHEK2 (12.8%), ATM (9.9%), BRCA2 (9.9%), ATRX (7.9%), and MUTYH (7.9%). The histological distribution of the DDR mutation positive group was adenocarcinoma (76.1%), squamous cell carcinoma (4.4%), adenosquamous carcinoma (2.9%), neuroendocrine carcinoma (5.9%), and other (10.4%). The histological distribution of the DDR negative group was adenocarcinoma (60.1%), squamous cell carcinoma (22.0%), adenosquamous carcinoma (1.1%), neuroendocrine carcinoma (4.1%), and other (12.5%). There was a significant effect in TMB, t(55) = 2.97, p = 0.004, with a higher mean TMB in the DDR positive group (M = 14.4, SD = 11.1) compared to the DDR negative group (M = 9.4, SD = 5.1). The most common zip codes in the DDR positive groupwere 60608 (9.0%), 60629 (9.0%), and 60616 (7.5%) compared to 60616 (8.3%), 60609 (5.3%), and 60624 (4.7%) in the DDR negative group. Demographic factors of the two groups are compared below. Conclusions: The frequency and distribution of DDR mutations in lung cancer at UIC appears similar to what has been previously reported in the literature. There is a higher tumor mutational burden in lung cancers with DDR mutations, which may suggest greater susceptibility to immunotherapy. There may be a correlation between the presence of DDR mutations and lung cancer type, insurance category, and patient geographic distribution. Future work will include obtaining further geographic data for the study population such as average income, pollution exposure, and smoking rate by neighborhood. [Table: see text]
Cardiac substructure radiation dose study of conventional radiotherapy for stage N2-3 non-small cell lung cancer.
Authors: Zhu Yiying , Ouyang Weiwei , Su Shengfa , Ma Zhu , Li Qingsong , Yang Wengang , Lu Bing 
Published: June 2024

e20071 Background: There has been widespread reporting on predictive dose parameters for cardiac substructures in radiotherapy for non-small cell lung cancer (NSCLC). However, most advanced NSCLC patients are staged as N2-3, and there is a lack of research on the dose distribution, dose contribution and prognosis of the heart in conventional radiotherapy for N2-3 stage NSCLC. Methods: Retrospective analysis of 274 patients of stage N2-3 NSCLC treated with radiotherapy (RT) of prescription dose from 60Gy to 70Gy. Experienced radiation oncologists delineated the cardiac substructures. All patients were categorized according to different lymph node irradiation and tumor spatial locations. Spearman and linear regression were used for variation of dose-volume parameters, as well as the impact of different primary tumor locations and irradiated lymph nodes on the parameters of the entire heart and substructures. Receiver operating characteristic (ROC) curves, Kaplan-Meier, and Cox regression were performed on the influencing factors of adverse cardiac events after radiotherapy and prognosis analysis. Results: There are significant differences in the dose-volume parameters of the whole heart and its substructures. Mean heart doses (MHD),and the mean doses (Dmean) for the left atrium, right atrium, right ventricle, left ventricle and the left anterior descending coronary artery (LAD) were 15.7Gy (range 0.2-30.0Gy), 19.7Gy (range 0.3-55.0Gy), 9.7Gy (range 0.3-59.8Gy), 7.9Gy (range 0.1-48.2Gy), 6.4Gy (range 0.1-52.6Gy) and 5.2Gy (range 0.1-45.0Gy), respectively. The left atrium Dmean has the most significant impact on MHD compared to other substructures (B = 0.418, P < 0.05). Dose-volume parameters of the whole heart and the left atrium were positively correlated with the irradiation of the 7th lymph node region (P < 0.05). MHD and left atrium Dmean for tumors located in the lower region were significantly higher than those in the upper region (P < 0.001). Patients with LAD V30 ≥ 26.9% had a significantly higher risk of mortality compared to those with LAD V30 < 26.9% (P = 0.003, HR = 2.883, 95% CI = 1.436-5.788). Conclusions: With the dose distribution differences among the whole heart and its substructures. We observed the base of the heart received the highest dose, the dose to the left atrium is particularly required attention. The irradiation of different lymph nodes and different primary lesions has an impact on the dose variations of different cardiac structures. LAD V30 is an independent influencing factor of overall survival (OS) for N2-3 stage NSCLC. This study provides considerable information for the dose optimization of cardiac substructure in radiotherapy planning for N2-3 stage NSCLC.
Tracheal cancer epidemiology and survival trends: A SEER database analysis.
Authors: Shah Princy , Kela Kashyap , Hegde Upendra P. 
Published: June 2024

e20078 Background: Tracheal cancer is one of the rarest malignancies of the respiratory system and, hence one of the least studied ones. It has a poor prognosis and understanding its epidemiology can help with effective diagnosis and management. Here we present the Surveillance, Epidemiology, and End Results (SEER) analysis of tracheal cancer. Methods: Information was obtained from the SEER database November 2022 with 17 registries for years 2000-2022. Case selection was done for the Primary labeled site Trachea C 33.9. Only patients with age >20 years and with one primary cancer were included. A total of 537 Patients were analyzed for incidence and survival based on Histology, Age, Gender, Race, Household Income, Area of residence, and treatment received. Results: The most common histology was squamous cell carcinoma (34%),followed by adenoid cystic carcinoma (23%) and Small cell carcinoma (4%). Other histologies (39%) included but were not limited to Large cell carcinoma, adenoid carcinoma, mucoepidermoid carcinoma, etc. The age group studied was 15 years and above. The most common age group affected was 65-69 years (12.3%), closely followed by 60-64 years (12.1%). The mean age of population was 62.5 +/- 14.7 years. Out of the total,56% were males and 44% were females (P value (P) < 0.002). 68.7% of cases were observed in Non-Hispanic Whites, (P <0.0001) followed by Blacks (11.4%), Hispanics (9.3%), Asian/Pacific Islanders (9.9%). 83% of the population was residing in metropolitan versus 17% in non-metropolitan regions (P<0.0001). 38% cases were observed in Annual household Income of >75,000 US dollars (USD) versus 62% in <75,000 USD (P <0.0006). Overall 5-year survival of tracheal cancer was noted to be 27%. Surgery was done in 40% of the cases. Poor 5-year survival was observed in those who did not have surgery compared to those who did(Hazard ratio (HR)=1.45, Confidence Interval (CI) 1.23-1.71, P <0.0001). Radiation was done in 28.1% of cases. Patients who received no radiation therapy had poor outcome compared to those who did. (HR=1.214, CI 1.066-1.383, P <0.0001). White race had worse outcomes compared to other races (HR 1.14, CI 1.003-1.289, P<0.023). The risk of death at 5 years in Males was slightly higher than in females but not statistically significant (HR 1.067, CI 0.96-1.18). Difference was also not significant in those with Household income <75,000 USD compared to those with more than >75,000 USD (HR 0.92 CI 0.83-1.01), Metropolitan versus non-metropolitan areas of residence (P=0.14). Conclusions: Statistically significant improvement in survival has been noted in patients who received the treatments including surgery or radiation in tracheal cancer versus patients who didn’t. Our study suggests that less than half of the patients received surgery and less than one-third of the patients received radiation therapy. Efforts should be made to emphasize the continued utilization of these therapy options for better outcomes.
Enhancing non-small cell lung cancer treatment utilizing natural killer cell-derived extracellular vesicles (NKEVs) as a novel adoptive cellular therapeutic.
Authors: Palade Joanna , Tang Nanyun , Alsop Eric , Antone Jerry , Paredes Dorothy , Whitsett Timothy , Berens Michael E. , Schwartz Gary , Finholt Jennifer P. , Snipes George J. , Van Keuren Jensen Kendall , Kelly Ronan Joseph 
Published: June 2024

e20079 Background: An established mechanism contributing to immune checkpoint inhibitor (ICI) therapy failure is tumor evasion of T-cell responses via downregulation of human leukocyte antigen (HLA). Conversely, the effector function of Natural Killer (NK) cells is enhanced in the absence of HLA expression, making NK-based cellular therapies an attractive option for ICI resistant tumors. NK-derived extracellular vesicles (NKEVs) have the potential to become a personalized adoptive cellular therapeutic that may overcome challenges associated with traditional NK cell-based therapies failing to deliver adequate numbers of cells to the tumor. We sought to investigate the preclinical efficacy of an approach using selective isolation of NK cells and harvesting of NKEVs in NSCLC. Methods: From 10 NSCLC patients, tumor tissue was collected, and blood mononuclear cells (PBMCs) were retrieved pre- and -post surgery. Single-cell RNAseq (scRNAseq) was used to examine the cellular landscape in PBMCs and tumor tissue. NK cells were isolated from PBMCs, expanded in vitro, and NK-derived EVs (NKEV) were collected and the EV RNA and protein cargo was characterized using proteomics and transcriptomics. The functional capabilities of patient derived NKEVs were assayed with patient derived organoids. Results: scRNAseq highlighted significant cellular heterogeneity, particularly in the cancer cell population. Within the tumor, infiltrating immune cells were lymphoid and myeloid in origin. Over 200,000 PBMCs were analyzed with scRNAseq, revealing differences associated with cancer subtype, tumor mutation burden and experimental time point. Exposure to patient NKEV treatment resulted in a 40-45% decrease in organoid viability, significantly lowering the cisplatin dose required to elicit a cytotoxic response. NKEVs derived from healthy controls were less efficient. In Nivolumab-treated PBMC organoid co-culture experiments, NKEV addition increased the proportion of infiltrating CD8+ T cells and CD56+ NK cells compared to PD-1 inhibitors alone, particularly from the pre-tumor resection PBMCs. Conclusions: This work demonstrated that NKEVs can be successfully harvested from patient derived, expanded NK cells, and highlighted their anti-tumor properties in combination with standard-of-care therapies. Additional in-depth immune analysis will be presented. [Table: see text]
Use of cell-free tumor DNA in early detection of lung cancer.
Authors: White Larissa Lee , Feigelson Heather S , Maiyani Mahesh , Quintana LeeAnn M , Nichols Lindsay E , Dollar Blythe , Bedoy Ruth , Elias Martinez America , Raymond Victoria M. , Lefterova Martina 
Published: June 2024

e20088 Background: USPSTF recommends annual screening for lung cancer with low-dose computed tomography (LDCT) in adults 50-80 years with 20 pack-year smoking history or current/former smoking in the past 15 years. This prospective study evaluated whether we could detect lung cancer at the time of LDCT screening from cell-free tumor DNA using Guardant Health’s LUNAR-2 assay. Methods: Kaiser Permanente Colorado (KPCO) members with upcoming LDCT screenings were invited via email/phone and recruited into two groups, (1) suspicious lung nodules or (2) no lung nodules. We limited enrollment to patients whose LDCT results were classified under the Lung-RADS (version 1.0) categories of 1-3 (recommended follow-up at 12-month intervals) or category 4 (“suspicious”; recommended follow-up at 3-month intervals). We excluded members with lung nodules > 30mm, those with a history of any hematologic malignancy, history of invasive malignancy within the past 5 years, currently pregnant, or known dementia or cognitive impairment. After informed consent, Guardant Health LUNAR test collection kits were mailed to the participant with sample collection instructions provided. Participants were asked to have their blood drawn on the day of their LDCT visit, or no more than 14 days of the scan. We also collected survey and EHR data on smoking history, LDCT, and other associated factors. The KPCO tumor registry confirmed all reported cancers. Results: The study initiated in September 2020 and ended in 08/2022 with 982 individuals consented and blood samples collected. Participants were on average 68 years old, 56% female, 58% former smokers, and 85% had no personal history of cancer. A total of 15 lung cancer cases and 22 other cancer cases were diagnosed. Data analysis is ongoing and expected to be completed early 2024. Conclusions: This study will demonstrate sensitivity and specificity of the LUNAR-2 assay to detect lung cancer relative to standard of care screening modalities in high-risk populations. We will also evaluate whether factors such as comorbidities, pack year history, or medications affect assay accuracy. The impact of this research can inform blood-based early detection of lung cancer.