bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrated analysis of genomic and microenvironment characteristics associated with pathology and radiology features in patients with early multifocal lung nodules.
Authors: Jiang Ben-Yuan , Zhou Wenhao , Luo Haitao 
Published: June 2022

e20519 Background: Pulmonary nodules are distinct clinical entities, and patients with different pulmonary nodules have different rates of progression to lung cancer. However, the genomic and microenvironment features of different pulmonary nodules are still unclear. Methods: 2 to 3 pulmonary nodules and matched paracancerous tissue were collected from 10 patients. Whole-exome sequencing and RNA sequencing were performed for each sample. The genomic and microenvironment characteristics were analyzed based on pathology (AIS/MIA/IA) and radiology (pGGO/mGGO/solid) features. Results: At genomic level, tumor mutational burden (TMB) and tumor neoantigen burden (TNB) were significantly increased with the development of the nodules. The most frequent mutation genes EGRF and KRAS were mutated exclusively. TMB and TNB in nodules with EGFR or KRAS mutation were significantly increased compared with nodules without these mutations and paracancerous. Transcriptome analysis revealed that energy metabolism signal pathways was upregulated in early stages (pGGO/AIS), while immune-related signal pathways were upregulated in latter stages (mGGO/IA). And in EGFR mutated nodules, cytokine-cytokine-receptor signal pathways were upregulated. Furter, tumor microenvironment was analyzed, and it was found that DCs, B cells and CD4+ T cells were significantly increased while endothelial and myocytes were significantly decreased with the development of the nodules. In addition, DCs were found to be significantly increased in EGFR mutated nodules when compared with KRAS mutated nodules. Conclusions: In this study, some genomic and tumor microenvironment biomarkers in different developmental stages of lung nodules were found, which may provide basis for the development of accurate diagnosis and classification of pulmonary nodules.
Assessment of antitumor effect of 2-(6,8-dimethyl-5-nitro-4-chloroquinoline-2-yl)-5,6,7-trichloro-1,3-tropolone in subcutaneous xenografts of A-549 tumor cell culture.
Authors: Lukbanova Ekaterina A. , Dzhenkova Elena A. , Engibaryan Marina A. , Ulianova Yulia V. , Goncharova Elena G. , Volkova Viktoriya L. , Komarova Ekaterina Fedorovna , Bauzhadze Mamuka V. , Komarova Elizaveta , Pustovaya Irina V. , Chertova Natalia A. , Gvaramiya Astanda K. , Cherkes Maria A. , Maldonado Mary L. , Shevchenko Nataliya , Mindar Maria V. 
Published: June 2022

e20520 Background: The aim of the study was an assessment of antitumor effect of 2-(6,8-dimethyl-5-nitro-4-chloroquinoline-2-yl)-5,6,7-trichloro-1,3-tropolone for subcutaneous xenografts of A-549 lung tumor cells in immunodeficient Balb/c Nude mice. Methods: 2-(6,8-dimethyl-5-nitro-4-chloroquinoline-2-yl)-5,6,7-trichloro-1,3-tropolone is a new compound in the series of 2-quinoline-2-yl-1,3-tropolone derivatives. The study included 50 immunodeficient Balb/c Nude mice divided into 5 groups depending on the dosage of the studied substance (0.0055; 0.055; 0.55 and 2.75 mg/g). The A-549 cells of lung cancer were used as the xenograft. Antitumor effect of tropolone was evaluated by the inhibition of tumor growth (ITG%) and the index of tumor growth (I). The experiment lasted for 36 days starting from the first administration of substances. Results: Indicators of the average tumor volume on day 36 of the experiment in experimental groups 1, 2, 3 and 4 and in the control group were 678.9; 952.3; 1746.4; 2150.8 and 2729.5 mm3, respectively. The indices of tumor growth in groups 1, 2, 3 and 4 were statistically significantly lower than in group 5 (controls) starting from days 15, 21, 21 and 24, respectively, and until the end of the experiment. Maximal differences between groups 1 and 5 were observed on days 33 and 36 – by 3.7 (p = 0.01) and 4.1 (p = 0.003) times, respectively. Antitumor effect of 2-(6,8-dimethyl-5-nitro-4-chloroquinoline-2-yl)-5,6,7-trichloro-1,3-tropolone demonstrated by the study could be associated with various mechanisms. For example, its closely related compound – hinoktiol, according to numerous studies, has a cytotoxic effect associated with stopping the cell cycle, induction of apoptosis, DNA damage, and autophagic death of tumor cells. Conclusions: The study demonstrated statistically significant differences in xenograft volumes between all experimental groups and the control group. 2.75 mg/g of mouse weight was the most effective dosage of the studied compound leading to a slow decrease in tumor growth rates and a decrease in the volumes of subcutaneous xenografts.
Establishment of multiplex IHC staining panel and immune subpopulation quantificationsystem for cancer prognosis.
Authors: Ye Chih-Hung , Peng Guan - Ru , Hu Sui Yun , Yu Wei - Chieh , Theng Patrick , Yi Yap Kah , Yu Wei - Chen , Yu Shu-Han 
Published: June 2022

e20525 Background: Tumor microenvironment (TME) is now an important direction for cancer prognosis research. For analyzing the immune component within TME, illustrating the distribution of the immune cells in patient tissue samples by immunohistochemistry (IHC) and image quantification analysis are now been applied in many cancer types. However, most of the TME studies only used the tumor microarray to investigate the composition of immune cells in TME, in which the views of immune component are restricted. In addition, with single biomarker staining to stratify therapy strategy shows limited efficacy in treatment since the complicated interactions of the immune components in TME. Based on these shortages, to increase the efficiency and identify the scarce immune subsets, a more systemic analysis approach for immune subpopulations quantification is now imperative. Methods: In this study, we first established an immune cell multiplex IHC staining panel (Opal Polaris, Akoya Bioscience) in non-small cell lung cancer (NSCLC) to investigate the immune components in all the tumor blocks of each patient. In this panel, we applied markers of infiltrating immune cells (CD8, CD68), regulatory markers (PD-1, PD-L1,CD163), and tumor marker (pan-cytokeratin) to explore the TME landscape in NSCLC. Then, with an in-house built quantitative software: SIMPiE, we could analyze the staining signal intensity of each cell markers generated from in Form software to define each lymphocytic immune subsets by phenotyping and quantifying. In addition, SIMPiE (Spatial Image cytometry Multiplex IHC analysis by phyton and in Form based Elements) software allowed us to generate image cytometry data to further explore the spatial context to map the organization and interactions of immune and tumor cells in the TME, and we can define thresholds for the graph to distribute the plurality of the mark points into a plurality of quadrants. Finally, we performed the survival analysis according to the clinicopathological and immune parameters of the patients, and to examine the prognostic significance of each immune subtypes. Results: We have built up an automation quantitative image analysis software to efficiently quantity the signal density and spatial context of all the immune subpopulations in all the tissue sections of each patient, and we further performed the integrative survival analysis to explore the prognostic significance of infiltrating immune cells and immunoregulatory molecules within the TME in NSCLC. Finally, in our study, we found that M1 macrophage patamars showed the most significantly regulatory effect to the patient’s overall survival rate, and M2 macrophage showed less effect compared with M1 macrophage. Conclusions: By this way, we can generate image cytometry data to further explore the spatial context to map the organization of immune and tumor cells in the TME for prognosis analysis.
High specificity lung cancer test to rule out cancer in non-malignant lung nodules found at LDCT.
Authors: Tsai Tung-Ming , Pamart Dorian , Hardat Nathalie , Herzog Marielle , Chen Jin-Shing 
Published: June 2022

e20533 Background: Lung Cancer (LC) is the leading cause of cancer death worldwide and smoking is the leading risk factor. Only 15% of patients with LC are still alive 5 years after diagnosis due to advanced diseases stage at diagnosis. Low-Dose Computed Tomography (LDCT) is the widely accepted standard for screening of individuals at high risk of lung cancer. However, LDCT has several limitations including the high prevalence of non-malignant pulmonary nodules detected leading to overdiagnosis, the potential harms of cumulative radiation dose and poor adherence to recommended follow-up. Therefore, novel blood-based tests could offer a simple follow confirmation approach and this test is designed to find those patients who DO NOT have cancer. Methods: We measured levels of nucleosomes, CEA and CYFRA21-1in a cohort of 912 subjects and report data relating to 184 smoker subjects referred for CT scan at National Taiwan University Hospital. The smoker patients were later confirmed to have either a LC (n = 129, including 59 patients at early stage (stage 0-I), 15 at stage II, 47 at late stage (III and IV) and 8 with unknown stage), or non-malignant nodules (n = 41), or control with no-nodules (n = 14). Whole blood was collected in EDTA plasma tubes for analysis by six different Nu.Q chemiluminescent magnetic microparticle immunoassays (Belgian Volition, Belgium) targeting H3.1-nucleosomes or different histone modifications (H3K9Me3-, H3K27Me3-, H3K36Me3-, H3K9Ac-, H3K14Ac-nucleosomes). CEA was analyzed on the Abbott ARCHITECT analyzer. CYFRA21-1 was analyzed on the Roche Cobas E411 analyzer. We evaluated each biomarker levels individually and in a combinatorial approach by logistic regression for their performance in discriminating subject with a LC vs non-malignant nodules. Results: Among the eight individual markers evaluated, the best area under the curve (AUC) in discriminating LC vs non-malignant nodule were observed for CEA, H3K9Ac-nucleosomes and CYFRA21-1 with an AUC of 0.68, 0.69 and 0.74, respectively and a specificity at 95% sensitivity of 9.5%, 7.3% and 21.4%, respectively. A logistic regression approach defined H3K9Ac-nucleosomes, CEA and CYFRA21-1 as the best panel of biomarkers tested to improve the discrimination between LC and non-malignant nodules relatives to the markers alone, achieving a specificity of 34.1% at 95% sensitivity and an AUC of 0.80. 55 out of the 59 stage 0-I, 25/26 stage III and 20/21 stage IV LC were detected by this combination of markers while 34.1 % of the patients with benign nodules are found negative and not sent to unnecessary biopsy to ascertain the nodule status. Conclusions: Results of our proof-of-concept study indicate that a blood test combining H3K9Ac-nucleosome levels with CEA and CYFRA21-1 levels could help to rule-out patients with a non-malignant nodule offering a non-invasive tool as an aid to the decision-making process of the malignancy status of nodules detected by LDCT.
Association between TP53, PAR1 and CCR5 gene polymorphisms and non-small cell lung cancer susceptibility in the Amazon.
Authors: Pereira Esdras Edgar Batista , Barra Williams Fernandes , Fernades Marianne Rodrigues , Rodrigues Juliana Carla Gomes , Modesto Antônio André Conde , Fernandes Bruno Melo , Pastana Lucas Favacho , Burbano Rommel Mario Rodriguez , Assumpção Paulo Pimentel , Guerreiro João Farias , Santos Sidney Emanuel Batista dos , Santos Ney Pereira Carneiro dos 
Published: June 2022

e20538 Background: Lung cancer is one of the most frequent neoplasms in the world, representing 11.4% of all registered cancers, and is responsible for 18% of cancer deaths. It is divided into two categories, small cell lung cancer, responsible for 15% of cases; and non-small cell lung cancer (NSCLC), which represents 85% of cases. The most well-known risk factor for the development of lung cancer is smoking, due to substances contained in tobacco associated with inflammation and carcinogenesis. Pulmonary carcinogenesis is a complex and gradual process, with synergistic and complex interactions between environmental risk factors and individual genetic susceptibility. The aim of this study was to investigate possible associations between TP53, PAR1, and CCR5 gene polymorphism for susceptibility to NSCLC in the Amazon. Methods: This is a pilot, case-control study, which included 263 subjects, 67 patients with NSCLC and 196 healthy subjects. The samples were analyzed for TP53 (rs17880560), PAR1 (rs11267092), and CCR5 (rs333) gene polymorphism, genotyped in PCR, followed by fragment analysis. To avoid misinterpretation due to population substructure, we applied a previously developed set of 61 informative ancestral markers that were genotyped by multiplex PCR. We used logistic regression to identify differences in genotypic frequencies between individuals with and without lung cancer. Results: We observed that some genotypes were associated with protection for NSCLC: TP53 gene LED/DEL genotype (p = 0.041, OR: 0.510, 95%CI: 0.267-0.974); DEL/DEL genotype of the PAR1 gene (p = 0.023, OR: 0.471, 95%CI: 0.247-0.971); and also the INS/INS genotype of the CCR5 gene (p = 0.033, OR: 0.331, 95%CI: 0.120-0.917). Conclusions: TP53 (rs17880560), PAR1 (rs11267092) and CCR5 (rs333) gene variants were significantly associated with NSCLC in patients from the Amazon. The validation of these findings may favor, in the future, the screening of individuals, facilitating the institution of preventive measures personalized, early diagnosis, consequently reducing the cost for health services and mortality from this malignant neoplasm. Keywords: Genetic Polymorphism; TP53; PAR1; CCR5; Biomarker; Non-Small Cell Lung Cancer.
Heterogeneity of tumor immune microenvironment and real-world analysis of immunotherapy efficacy in lung adenosquamous carcinoma.
Authors: Zheng Xiaobin , Lin Gen , Zheng Xinlong , Long Feng , Jiang Kan , Mok Tony S. K. 
Published: June 2022

e20546 Background: Lung adenosquamous carcinoma (ASC) is an uncommon histological subtype. We aimed to characterize the tumor immune microenvironment (TIME) in lung ASC and estimate patient response to immune checkpoint inhibitors (ICIs), which have never been systematically investigated. Methods: In cohort I, we collected 30 ASCs from a single center for analysis of TIME characteristics, including immuno-phenotyping, tumor mutation burden (TMB), T cell receptor (TCR) repertoires, tumor-infiltrating lymphocytes (TILs), and immune checkpoint expression. In cohort II, the efficacy of ICI-based therapy were estimated using a real-world data of 46 ASCs from 11 centers. Results: In cohort I, 22 (73.3%) patients were EGFR-positive. The TIME were defined by immune-excluded (60%) and immune-desert phenotype (40%). Strikingly, PD-L1 and PD-1 were predominantly expressed in SCCC versus ACC, where enhanced CD4+ FOXP3+ regulatory T cell and attenuated CD57+ natural killer cell infiltration was present, consistent with a landscape of fewer innate immune cells, more immunosuppressive cells. SCCC had higher TMB, higher TCR clonality, and lower TCR diversity than ACC. In cohort II, majority of 46 patients were driver genes negative and unknown mutation status, 18 (39%) and 18 (39%), respectively. Overall objective response rate of 28%, median progression-free survival of 6.0 months (95% CI 4.3-7.7), and median overall survival of 24.7 months (95% CI 7.2-42.2) were observed in the ICI-based treatment. Conclusions: This work ascertains suppressive TIME in lung ASC and genetic and immuno-heterogeneity between ACC and SCCC. Lung ASC patients have a moderate response to ICI-based immunotherapy.
The utility of liquid biopsies for management of stage IV non-small cell lung cancer (NSCLC) in an academic community medical center.
Authors: Maity Alisha Paro , Gangireddy Mounika , Dessain Scott K. , Evans Tracey L. 
Published: June 2022

e20577 Background: The management of stage 4 non-squamous non-small cell lung cancer (NSCLC) relies heavily on the use of tumor genotyping that allows for the preferential use of targeted therapies as first-line treatment to eligible patients. Recently, the “liquid biopsy”, a non-invasive genomic analysis of circulating tumor DNA, has been deemed a suitable complementary method to identify actionable mutations and guide therapy in NSCLC patients. At our community-based academic medical system in suburban Philadelphia, liquid biopsies began to be used more regularly for these patients in 2018. All patients in the study received tissue biopsies with molecular testing. Our study compared patients who also underwent liquid biopsy with patients who did not, in order to determine whether performance of this biopsy affected their treatment. Methods: This retrospective cohort study used a bank of Main Line Health patients diagnosed with Stage 4 non-squamous NSCLC from 2014-2020. Chart review was used to extract variables from these patients regarding dates of tissue biopsies and treatments, information on liquid biopsies, and demographic information. The primary objective was to compare the rate of detection of actionable mutations in the liquid biopsy vs. non-liquid biopsy cohorts. A secondary objective was to assess the time interval between the identification of a potential lung cancer by imaging and the initiation of first line therapy. Results: 152 patients met inclusion criteria and of these 68 patients underwent liquid biopsy testing and 84 patients did not. Of the 68 patients who underwent liquid biopsy testing, 34 patients (50% patients) did not have sufficient tissue on their tissue biopsy for a molecular diagnosis. Of these 34 patients, 15 patients (44%) had an actionable mutation detected with liquid biopsy. Thus, 28 patients (41%) of the liquid biopsy group had actionable mutations detected. In comparison, only 18 patients (21%) in the cohort without liquid biopsy testing had actionable mutations detected. The initiation of first line treatment occurred sooner for the group undergoing liquid biopsies, an average of 48.3 days (median 40.5 days, range 13-317) compared to 72.7 days (median 50.5 days, range 14-534), p = 0.012 by two-tailed T-test. Conclusions: In our community academic medical center, patients with stage IV non-squamous, NSCLC who underwent a liquid biopsy as part of their initial diagnostic workup had a higher rate of detection of actionable mutations and initiated first line therapy sooner than patients who received only tissue-based molecular diagnostic testing.
Meta-analysis of rates and causes of local recurrence in surgically-resected NSCLC and differences in recurrence and survival between Asian and non-Asian populations.
Authors: Varlotto John M. , Bosetti Cristina , Bronson Dwight , Santucci Claudia , Chiaruttini Maria Vittoria , Scardapane Marco , Hodgkinson Gerald 
Published: June 2022

e20579 Background: Recently, the PORT-C (China) and Lung ART (Europe) trials have been reported for non-small cell lung cancer patients (NSCLC) with surgically resected N2 nodal disease subsequently randomized to post-operative radiation (PORT). The two studies noted widely different locoregional relapse (LR) rates in the control arms, 18.3% in PORT-C and 28.1%(46% of recurrences) in Lung ART. We performed a meta-analysis of patients with N0-N2 disease to better understand risk factors for LR, and the possible differences in risk and rates between Asian (AP) vs. non-Asian populations (NAP). Methods: The present systematic review and meta-analysis identified all original studies of curative NSCLC surgical resections which reported risk and rates of LR between January 1st, 2000 and January 10th, 2021. Studies were excluded if patient number was less than 10, if metastatic disease was present, or if any neo-adjuvant chemotherapy and/or radiation was given. Eighty-seven studies were included; of these, 56 were of high quality (HQ) based on the Newcastle-Ottawa Scale (ratings 7-9). For each risk factor, we derived pooled relative risk (RR) and rate estimates using random-effects models. Results: Overall, the three highest pooled RRs for LR were N2 vs. N0 (RR 3.01), lymphovascular invasion (LVI; 1.92), and advanced T stage (T3-T4) vs. T1 (1.86). For HQ studies, the highest RRs for LR were LVI (1.94), sublobar vs. lobar resection (1.86), and N1 vs. N0 (1.84), but N2 vs N0 was no longer significant (RR 3.0 (95% confidence interval 0.57 -15.61) based on only 2 studies. The RRs for LR were consistent for most factors across geographic areas, although the RRs for male vs. female sex were higher in AP (1.44) than in NAP (1.09). The pooled rate of LR at 5-years was lower in the AP 12.00% (6.92-17.09) vs. NAP 22.66% (17.06 - 28.26), despite similar overall recurrence rates (both LR and distal) at 5 years in both populations: 38.03% (25.15-50.90) in AP and 37.30% (32.44-42.17) in NAP. However, a lower 5-year mortality rate was noted in AP (24.30%, 15.56 -33.03) than in NAP (45.87%, 41.23-50.50). Conclusions: Our meta-analysis found that N2 nodal disease is not a risk factor for LR when considering HQ studies based upon scant data, and confirmed that LR is lower in AP. We propose that prospective evaluation of LR risk factors and rates should be undertaken prior to any other prospective evaluation of PORT because LR may not be dependent upon N2 node status and because LR rates may differ in AP.