bluuebunny/crossref_metadata_2025 huggingface dataset:
Noncanonical RET fusions in Chinese patients with non-small cell lung cancer from DNA-based next-generation sequencing.
Authors: Lin Hao , Liu Yujie , Zhou Ruitao , Feng Yutao , Cao Huiya , Suo Peisu , Guo JIA , Chen Shifu
Published: June 2024

e20000

Background: The FDA has approved selpercatinib and pralsetinib for the treatment of metastatic RET fusion-positive non-small cell lung cancer in adult patients. Although the overall response rate is high and the response is durable, the outcomes may vary due to different fusion types of the same driver gene. Methods: We retrospectively collected and analyzed 14062 samples (tumour tissue or plasma) from Chinese lung cancer patients who underwent tissue-based or ctDNA-based next-generation sequencing (NGS) assays at HaploX Genomic Sequencing Center from May 18, 2020, to January 11, 2024. All samples with a RET gene fusion were included and classified based on the fusion partner gene and breakpoint position. Results: A total of 157 (1.1%) samples with DNA-based NGS harbored a RET gene fusion. Among the samples with a RET gene fusion, the most common RET fusion partners at the DNA level were KIF5B (73.2%) and CCDC6 (21.0%). We categorized RET fusions into canonical fusions and noncanonical fusions based on fusion partner and breakpoint position, and the proportions of canonical fusions and noncanonical fusions were 88.5% (139/157) and 11.5% (18/157) respectively. Among the samples with a noncanonical RET fusion, 5 samples harbored a RET fusion with an uncommon fusion partner, it remains unclear whether these fusions lead to RET activation. Conclusions: In this retrospective study, we identify different types of RET fusions in Chinese lung cancer patients. The majority are canonical fusions, which can benefit from tyrosine kinase inhibitors in clinical, the rest are noncanonical fusions, and their role in precision therapy needs further verification by RNA-based NGS or other assays. All in all, our research helps guide precision therapy in clinical settings. [Table: see text]
PM 2.5 and risk of lung cancer and associated mortality: An umbrella meta-analysis.
Authors: Gupta Ashima , Singh Abhishek , Tarimci Baris , Sindhu Alamjeet Kaur , Bathvar Pinank , Bedi Simranjeet , Theik Nyein Wint Yee , Shah Vedant , Malhotra Saarthak , Khealani Milan , Obulareddy Sri Usha Jeevani , Kukreja Geetika , Kanitkar Amaraja
Published: June 2024

e20012

Background: PM 2.5, particulate matter with a diameter of 2.5 micrometers or less, is a major contributor to lung cancer and associated mortality. Epidemiological studies reveal a concerning trend, with each 10 micrograms per cubic meter increase in PM 2.5 associated with a 15% higher risk of lung cancer and a 13% increase in mortality rates, underscoring the significant burden it imposes on public health systems globally. We aimed to evaluate the odds of association between environmental exposure to PM 2.5 and the risk of lung cancer and associated mortality. Methods: We performed a systematic review and umbrella meta-analysis using studies containing quantitative data on PM 2.5 and lung cancer. We used PRISMA guidelines and the MOOSE protocol using PubMed and MeSH terms like PM 2.5, non-small cell cancer, lung cancer, pollutants, particulate matter 2.5, and environmental factors. We had excluded non-full-length articles, non-meta-analysis studies, and non-human studies. RavMan 5.4 was used, and generic inverse variance methods with mixed effect models were applied to identify a pooled risk ratio with a 95% confidence interval. Forest plots were obtained, and sensitivity analysis was performed based on funnel plots and I2 (heterogeneity) values. Results: Of the 245,529 articles evaluated for the quality of the data, 99 met the inclusion and exclusion criteria. Out of 99, we used six articles to derive the quantitative data. In umbrella meta-analysis, PM 2.5 exposure was associated with a 1.16 times higher risk (95%CI: 1.1-1.22, p<0.00001, I2=0%) of lung cancer and a 1.22 times higher risk of non-lung cancers (95%CI: 1.15-1.30, p<0.00001, I2=0%). PM 2.5 was associated with non-significant higher mortality (RR: 1.06, 95%CI: 0.99-1.13, p=0.09, I2=97%) with leave-on-out analysis (excluding Chen et al.) significant association between mortality and PM 2.5 (RR: 1.08, 95%CI: 1.06-1.10, p<0.00001, I2=0%). Conclusions: Our umbrella meta-analysis shows a significant risk of lung cancer and mortality from PM 2.5 exposure. Further investigation and increased consciousness are necessary to mitigate the risk of lung cancer associated with this pollutant.
Early-stage lung adenocarcinoma with a micropapillary pattern showing a distinct immunogenic tumor microenvironment.
Authors: Han Yun , Yu Yue , Xu Chongyuan , He Qianru , Zhang Qin , Duan Qianqian , Chen Dongsheng
Published: June 2024

e20016

Background: Lung adenocarcinomas with a micropapillary pattern (MPP) have been suggested to be associated with prognosis. Immune microenvironment plays a critical role in cancer from onset to relapse. However, it is unclear whether MPP can reflect the tumor immune microenvironment (TIME). Methods: A total of 44 stage I lung cancer patients who underwent surgery at Shengjing Hospital of China Medical University were included (with micropapillary pattern, n = 16; without micropapillary pattern, n = 28). Using NanoString nCounter, the gene expression patterns (GEPs) of 289 tumour immune-related genes were examined. Differentially expressed genes(DEGs), estimation of TIME cell infiltration, and TIME signatures between micropapillary and non-micropapillary were assessed. Results: Significant immunological differences were seen between histological subtypes. Differential gene expression analysis showed that KIR2DL3, MAGEA4, MELK, CD244, and 26 other genes were significantly upregulated in the micropapillary group compared with the non-micropapillary group, while PDGFA, RORC, CCL22, and other seven genes were down-regulated in the micropapillary group. These DEGs were mostly enriched in “leukocyte cell-cell adhesion”, “T cell activation”, “cellular response to chemokine”, and “T cell proliferation” pathways according to GO enrichment analysis. The results of the KEGG analysis revealed that genes were significantly enriched in “Cytokine-cytokine receptor interaction”, “Cell adhesion molecules (CAMs)”, “Chemokine signaling pathway”, and so on. Immune analyses revealed that micropapillary group had a better TIME cell infiltration which are associated with increased CD45, CD8+ T cells, Exhausted CD8, and NK CD56dim cells. Furthermore, the immune signature scores for chemokines, total TILs, and GEP scores were higher in the micropapillary group, indicating increased immune cytotoxic activity. Conclusions: Lung adenocarcinomas with micropapillary pattern were identified as a subtype with enhanced immunogenic tumor microenvironment. According to these results, patients with lung adenocarcinomas that have micropapillary pattern may be a prospective select group who will benefit from adjuvant immunotherapy.
A novel strategy for detecting mutations from circulating tumor DNA with blood tissue only.
Authors: Wen Jiale , Zheng Zhi
Published: June 2024

e20031

Background: Molecular Residual Disease (MRD) test detects tumor-specific mutations in circulating tumor DNA (ctDNA), which can indicate the risk of tumor recurrence. However, without tumor-specific mutations, detecting mutations in blood tissue alone is extremely challenging due to the low concentration of ctDNA in blood. To address this challenge, we proposed an innovative mutation filtering and calling strategy by simulating noise’s distribution and quality assessment to greatly boost the performance. Methods: We performed 406 pairs of MRD tests on both tumor and blood tissue of postoperative patients with mixed cancer types, including lung, gastrointestinal (GI), hepatobiliary, and pancreatic. Patients that possess one or more tumor-specific mutations in their blood tissue were classified as recurrence high-risk (n = 66), others were classified as recurrence low-risk (n = 340). All sequence data were analyzed using both traditional and proposed method. In the traditional method, VAF threshold, end-reads, multiple-align reads and population frequencies were used as filtering criteria. While in the proposed method, VAF threshold was excluded and two new parameters were introduced: The distribution of variant allele frequency (VAF) of sequencing noise, which simulated 42 healthy individuals’ background noise with conf > 0.995; The normalized proportion of supported unique and total variants, to assess the likelihood of mutations originated from ctDNA. Results: Among 406 patients of mixed tumor types, the traditional approach barely reached a sensitivity of 39.4% and a specificity of 89.1%, while our strategy achieved a sensitivity of 71.2% and a specificity of 80.9%. Particularly among the 92 patients with gastrointestinal tumor, by filtering specific noise caused by the MRD panel (e.g. multi-alignment error of MUC gene family), we further boost the sensitivity from 47.1% to 82.4% with a loss of specificity from 93.3% to 90.7%. Moreover, among 248 patients with lung tumors, the sensitivity and specificity between traditional approach and proposed method were 15.8%, 93.9%, and 52.6%, 90.0% respectively, which might be caused by the low recurrence rate in the patient cohort (19 out of 248). Conclusions: The novel strategy based on simulated noise distribution and read quality assessment surpasses the traditional threshold-based approaches in mutation detection, especially in deep sequencing like MRD tests. The findings of the study indicate that the recurrence monitoring strategy is applicable across various tumor types and exhibits superior performance in GI tumor, albeit with certain limitations. In conclusion, this study boosts the feasibility of MRD as a non-invasive alternative for tissue biopsy by providing a novel mutation filtering strategy, which further strengthen the potential of MRD testing in enhancing cancer patients’ long-term prognosis and treatment.
ViTR-SP: A CT-based vision transformer model for prediction of pneumonitis in patients with non-small cell lung cancer who received thoracic radiotherapy and immunotherapy.
Authors: Yang Linlin , Li Butuo , Dong Taotao , Wang Linlin
Published: June 2024

e20034

Background: The combination of thoracic radiotherapy (TRT) and immunotherapy accompanied by the accumulation of pulmonary toxicity. This study aimed to construct a deep radiomics model based on sequential computed tomography (CT) images for radioimmune-associated pneumonitis prediction in non-small cell lung cancer (NSCLC) patients treated with TRT and immune checkpoint inhibitors (ICIs). Methods: Three models were constructed based on a vision transformer (ViT) network using sequential chest CT images, tumor-mask and lung-mask as inputs, respectively. NSCLC patients treated with TRT and ICIs at Shandong Cancer Hospital and Qilu Hospital were included for model training and external validation, respectively. The image-level model was trained based on ViT to identify predictive images, and the image-level probability distribution were performed. Then, a ViT-Recursive Neural Network (ViT-RNN) model framework was constructed at the patient-level to integrate the image-level information to derive the final prediction, which was evaluated in an independent validation cohort. Results: A total of 230 NSCLC patients from Shandong Cancer Hospital were randomly assigned in a 7:3 ratio for model training and validation, respectively. Another 42 patients from Qilu Hospital were used as an independent external validation cohort. The ViT-RNN model for symptomatic pneumonitis (ViTR-SP) based on sequential CT images achieved better area under curve (AUC), sensitivity, and specificity of 0.725, 0.750, and 0.886 than lung-mask based model (0.575, 0.625, and 0.705) and tumor-mask based model (0.658, 0.667, and 0.773) in the internal validation set. In the external validation set, the proposed model achieved the AUC, sensitivity, and specificity of 0.654, 0.818, 0.727, while the lung-mask and tumor-mask based models had the AUC, sensitivity, and specificity of 0.540, 0.545, 0.677, and 0.630, 0.545, 0.742, respectively. The performance of the model was improved after integrating clinical features, with internal and external validation AUC of 0.782 and 0.672, respectively. Conclusions: In conclusion, the clinical combined ViTR-SP neural network risk prediction model based on sequential chest CT images can be used for predicting the risk of developing radioimmune-associated pneumonitis in NSCLC patients.
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.
Neoadjuvant toripalimab plus chemotherapy for resectable stage II-IIIB non-squamous non-small cell lung cancer with EGFR mutations: A multi-center, multi-cohort, exploratory study.
Authors: Cheng Sida , Wei Zihan , Li Hecheng , Li Mingru , Liao Yongde , Xu Song , Yan Xiaolong , Yang Desong , Yue Dongsheng , Zhong Wenzhao , Zhou Lixin , Chang Geyun , Yan Xiang , Yang Fan
Published: June 2024

TPS8120

Background: Neoadjuvant immunotherapy has been widely applied in the treatment of resectable stage II-IIIB NSCLC patients without driver gene mutation. However, as for the EGFR-positive patients, the therapeutic effect of neoadjuvant treatment, either TKI or chemotherapy, is far from satisfied and the outcome of neoadjuvant immunotherapy plus chemotherapy in these patients remains an unanswered but crucial question. Herein, we conducted a phase 2 prospective trial (NCT05962021). Methods: This is a multicenter, multi-cohort prospective phase 2 study in the treatment-naïve patients with resectable stage II-IIIB (N2) (AJCC 8th edition) non-squamous NSCLC harboring EGFR mutations (19DEL or L858R). Enrolled patients will be divided into two cohorts according to EGFR status and receive neoadjuvant toripalimab (240mg, q3w) plus platinum-based doublet chemotherapy (pemetrexed 500mg/m2 plus carboplatin AUC 5, q3w) for 3 cycles. Surgery will be performed after completion of neoadjuvant therapy based on the multidisciplinary discussion, while local radiotherapy will be considered if the patient cannot undergo surgery due to disease progression. Key inclusion criteria: non-squamous NSCLC, resectable stage II-IIIB (N2), EGFR mutations (19DEL or L858R), age≥18 years, ECOG PS 0-1 and adequate cardiopulmonary function. Exclusion criteria: prior systemic anticancer treatment, contraindication to immunotherapy, active autoimmune disease. Adequate pre-treatment tissue samples are required for RT-PCR or next-generation sequencing to determine the EGFR mutation status and PD-L1 expression immunohistochemical detection. The primary study endpoint is complete pathological response (pCR) rate, per blinded independent pathologist review. Simon's optimal two-stage design will be used to test the null hypothesis of pCR rate ≤5% and alternative hypothesis of pCR rate ≥15%, and 5 or more pCRs among 56 patients per arm are needed for the primary endpoint to be met. Secondary endpoints include major pathological response (MPR) rate, pCR/MPR rate in different EGFR mutation subgroups (19DEL or L858R) and different PD-L1 expression subgroups (TPS < 1% and ≥ 1%), event-free survival and safety and tolerability. Peripheral blood, stool and tissue samples will be obtained longitudinally at baseline, during perioperation and at follow-ups for exploratory analysis. Clinical trial information: NCT05962021 .
A phase II exploratory trial of adebrelimab in combination with chemotherapy and concurrent radiotherapy as a first-line treatment for oligo-metastatic extensive-stage small-cell lung cancer.
Authors: Dong Zhong-Yi , Wei Wei , Ruan Yingchen , Bai Xue , Li Qisheng
Published: June 2024

TPS8131

Background: Oligometastasis of extensive-stage small-cell lung cancer (ES-SCLC) is an intermediate state between local and extensive metastasis, characterized by reduced metastatic potential and a limited number of metastatic sites, which makes local treatment of each lesion possible. Multiple clinical studies have shown that adding local therapy to standard systemic therapy can improve the prognosis of patients with oligometastatic disease. The PD-L1 inhibitor adebrelimab combined with chemotherapy has become one of the standard regimens for first-line treatment of ES-SCLC. Based on these, we hypothesize that in patients with oligometastatic ES-SCLC at risk of early progression, the early addition of chest radiotherapy and stereotactic radiotherapy (SBRT) for metastatic lesions to first-line treatment with adebrelimab combined with chemotherapy may be expected to achieve local control, thereby improving survival benefits. Methods: This is a prospective, single-arm, multicenter, phase II exploratory trial. Patients will be eligible if they are 18 to 75 years of age; have histopathologically or cytologically confirmed ES-SCLC with the number of metastatic lesions of ≤ 5 and organ metastasis of ≤ 3 (i.e. oligometastases); have an ECOG PS of 0-1; and have no previous systemic treatment. The treatment period in this trial is subdivided into induction therapy, concurrent chemoradiotherapy, and consolidation and maintenance therapy. In the induction setting, patients will receive two 3-week cycles of adebrelimab (20 mg/kg on day 1), carboplatin (AUC of 5 mg/mL per min on day 1)/cisplatin (75 mg/m2 on day 1), and etoposide (100 mg/m2 on days 1-3). Patients who achieve partial response or stable disease after induction therapy will then receive concurrent chemoradiotherapy, of which chemotherapy regimen is the same as the induction setting. Radical IMRT radiotherapy (2.5-3 Gy/f, total dose 45-55 Gy) will be performed for the primary tumor in the chest and lymph node region, and SBRT radiotherapy will be given to metastatic lesions. Prophylactic cranial irradiation is optional. After the end of chemoradiotherapy, patients will receive 1-2 cycles of consolidation treatment with the same regimen as induction treatment, followed by adebrelimab monotherapy (20 mg/kg on day 1, q3w) as maintenance treatment until disease progression, intolerance toxicity, or up to 2 years of adebrelimab. The total cycle number of chemotherapy is 4-6. The primary endpoint is progression-free survival (PFS), and secondary endpoints are objective response rate, duration of response, overall survival (OS), 6-month and 1-year PFS rates, 1-year and 2-year OS rates, and safety. The trial is under recruitment, and a total of 62 patients are planned to be enrolled. Clinical trial information: NCT06177925 .
«Είναι ένα μικρόβιο... και έρχεται από έναν πράσινο πλανήτη»
Authors: Χρηστίδου Βασιλεία , Μπονώτη Φωτεινή , Παπαδοπούλου Πηνελόπη , Δούμπαλα Πολυξένη
Published: June 2024

Η έρευνα εξετάζει πώς τα παιδιά νοηματοδοτούν τον νέο κορωνοϊό και αν οι νοηματοδοτήσεις τους διαφοροποιούνται με την ηλικία και τον τρόπο έκφρασης. Ζητήθηκε από 460 παιδιά ηλικίας 4-6 ετών να περιγράψουν και να σχεδιάσουν τον κορωνοϊό. Η ανάλυση περιεχόμενου των δεδομένων ανέδειξε το πώς τα παιδιά αντιλαμβάνονται τον κορωνοϊό, καθώς και 3 επιπλέον θέματα σχετικά με τις Υγειονομικές, τις Ψυχολογικές και τις Κοινωνικές διαστάσεις της πανδημίας. Τα αποτελέσματα αντανακλούν την αξιοσημείωτη ενημερότητα των συμμετεχόντων για τον SARS-COV-2 και την COVID-19 και την πολυπλοκότητα των νοηματοδοτήσεών τους. Η ηλικία των παιδιών διαφοροποιεί τις λεκτικές περιγραφές του κορωνοϊού, ενώ ο τρόπος έκφρασης διαφοροποιεί την έμφαση σε διαφορετικές διαστάσεις της πανδημίας. Η δημοσιότητα του νέου κορωνοϊού και της πανδημίας μπορεί να προσφέρει το κατάλληλο πλαίσιο για το σχεδιασμό και την υλοποίηση εκπαιδευτικού υλικού και παρεμβάσεων σχετικά με τους ιούς και την ενδυνάμωση των παιδιών προκειμένου να συμμετέχουν στη διαχείριση παρόμοιων μελλοντικών κρίσεων.
The genome sequence of the slender mouse-tail moss, Isothecium myosuroides Brid., 1827 (Lembophyllaceae)
Authors: Bell David , Kungu Liz ,   Royal Botanic Garden Edinburgh Genome Acquisition Lab,   Plant Genome Sizing Collective,   Darwin Tree of Life Barcoding collective,   Wellcome Sanger Institute Tree of Life Management, Samples and Laboratory team,   Wellcome Sanger Institute Scientific Operations: Sequencing Operations,   Wellcome Sanger Institute Tree of Life Core Informatics team,   Tree of Life Core Informatics collective,   Darwin Tree of Life Consortium
Published: June 2024

We present a genome assembly from an individual Isothecium myosuroides gametophyte (the slender mouse-tail moss; Bryophyta; Bryopsida; Hypnales; Lembophyllaceae). The genome sequence is 388.3 megabases in span. Most of the assembly is scaffolded into 11 chromosomal pseudomolecules. The mitochondrial and plastid genome assemblies have lengths of 104.59 kilobases and 125.02 kilobases in length, respectively.
Participants in the Leasing Market in Russian Federation
Authors: Oreshkin M. , Garnov Andrey
Published: June 2024

The main participants in the leasing market are lessors, lessees, and sellers. For them, the main advantages and disadvantages of leasing operations are analyzed. The structure of the leasing market is formed by lessors represented by leasing companies. For the ten largest leasing companies by volume of new business, the main indicators of their activities and the difficulties they face are analyzed.
Features of Regulation of Financial Markets in the Context of Digitalization
Authors: Staroverova O.
Published: June 2024

The article is devoted to the peculiarities of financial market regulation in the context of digitalization, as well as the peculiarities of the influence of digital instruments on various segments of the financial market. The paper examines new trends and transformations in the credit, monetary, stock and insurance markets; provides examples of indicators for analyzing the effectiveness of its regulation, as well as examines in detail the impact of digitalization on the insurance market and the banking system (within the credit market) and the main risks arising in digital financial services. To assess the effectiveness of financial market regulation, the author proposed to apply an individual and comprehensive approach.
Trabajadores de plataformas digitales de reparto: un estudio de derecho comparado y análisis concreto en la ciudad de Tunja
Authors: Fonseca Alfonso Yair Leonardo
Published: June 2024

El trabajo realizado por domiciliarios vinculados con plataformas digitales de reparto ha tenido un crecimiento exponencial en el último lustro, tanto a nivel mundial como a nivel local. Lo anterior, representa retos y desafíos para la regulación y garantía de derechos laborales de las personas que dependen de esta actividad como su principal fuente de ingresos. Por tal motivo, este artículo realiza un estudio de las plataformas digitales de reparto en el contexto internacional, nacional y en particular, en la ciudad de Tunja (Colombia). A través de un proceso de investigación mixto, este escrito recolectó y analizó datos cuantitativos y cualitativos, con el objetivo de plantear como hipótesis de investigación, la necesidad de formalizar los servicios ejecutados por repartidores a través de un contrato de trabajo.
Una fundamentación contrahegemónica de los derechos
Authors: Pacheco Rodríguez Miguel Ángel
Published: June 2024

El título de nuestro trabajo incorpora tres elementos que vienen siendo objeto de debate desde hace mucho tiempo. Podríamos afirmar, por tanto, que de alguna manera son conceptos (mejor concepciones) esencialmente controvertidos. Además, el objeto principal de este estudio, la fundamentación (contrahegemónica) de los derechos, se presenta de forma indeterminada (una), de modo que se asume que hay, o puede haber, otras. Esta última cuestión, la del carácter contrahegemónico de la fundamentación de los derechos que se propone, quedará explicitada en los siguientes apartados. Del mismo modo, como podrá comprobarse unas líneas más abajo, también hemos intentado definir cuál es la teoría ética que consideramos más apropiada a tal fin: el constructivismo ético (con los matices que se apuntarán). Sin embargo, aún nos quedaría un elemento por aclarar: nuestra concepción de lo que sea el “derecho”. A este respecto, nos adherimos a una concepción positivista del derecho y, de forma más concreta, al denominado positivismo metodológico.
Estado y gobernanza ambiental. Paradigmas alternativos
Authors: Narváez Quiñónez Iván
Published: June 2024

La sinopsis teórica de los tópicos Estado-sociedad, crisis ambiental y gobernanza ambiental coadyuva a dilucidarlos en clave de gobernanza sociopolítica y complejidad ambiental, contribuyendo al debate sobre aquella crisis denominada “crisis de nuestro tiempo” y atribuida a la crisis civilizatoria o del conocimiento1.
Marco sancionatorio ambiental en Colombia: contexto y desafíos
Authors: Salas-Pérez Yuliana , Acosta Jurado Alexánder
Published: June 2024

Este documento constituye un capítulo de revisión cuyo objetivo es caracterizar los elementos que se requieren abordar para robustecer la aplicación del marco legal sancionatorio en Colombia, para ello se desarrolla el contexto previo, la descripción de las incorporaciones de la Ley 1333 de 2009, y la relación y desarrollo de las observaciones y vacíos necesarios de abordar en la aplicación de las sanciones, finalmente se concluye con las propuestas de fortalecimiento a la ley, todo lo anterior con miras a que sirva a las autoridades ambientales, reguladas y definidoras de políticas para enmarcar el deber ser de la norma en cuanto a su función protectora de los recursos naturales.