bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immune subtypes in LUAD identify novel tumor microenvironment profiles with prognostic and therapeutic implications.
Authors: Liu Shuoyan , Wang Feng , Gao Xuan , Wang Peiyuan , Chen Yujie , Chen Peng , He Hao , Chen Xiaofeng , Zhang Derong 
Published: June 2021

e20512 Background: The incidence of lung adenocarcinoma (LUAD) is increasing year by year worldwide. Thorsson et al. identified six immune subtypes (ISs) (C1 - C6) in 33 diverse cancer types, including LUAD. The tumor microenvironment and lung cancer cells of 6 ISs have complex and different interplay, and the consequence of the interplay determines the growth of tumor cells and the prognosis of patients. Methods: Clinical and molecular information of TCGA LUAD patients were downloaded from The Cancer Genome Atlas (TCGA) (N = 457). Kaplan-Meier survival analysis and Cox proportional-hazard analyses were performed in 4 independent GEO LUAD data sets (GSE31210, GSE37745, GSE50081, and GSE68465) and, where five immune subtypes C1-C4, C6 were stratified according to Thorsson et al.’s immune classification method. Results: Only 5 ISs were identified in the TCGA NSCLC cohort; the proportion of the C3 inflammatory IS (39.2%) was the most common IS observed in the TCGA LUAD cohort, whereas C1 was particularly dominant in LUSC (57.1%). The proportion of C3 was also the most common IS observed in GEO LUAD cohorts (GSE37745, GSE50081, GSE68465), except for one stage I-II lung adenocarcinomas cohort (GSE31210). The prognostic relevance of the C3 IS was associated with significantly longer overall survival and progression-free interval time of LUAD in the TCGA cohort. In contrast, the association was not significant in the TCGA LUSC cohort. C3 was also associated with significantly longer overall survival (p < 0.001) and disease-free interval time (p < 0.001) in the 4 GEO LUAD cohorts by multivariate analyses. To further evaluate prediction accuracies of C3, we compared the C3 model with the other 3 reported immune-related signatures. For all comparisons in these 4 GEO cohorts, C3 outperformed the other 3 signatures with superior overall survival and DFS predictive performances according to the time-dependent Concordance index. C3 presented higher levels of CD8 T, follicular helper T, M1 macrophage, CD4 memory resting, myeloid dendritic, neutrophils, and endothelial cells by using CIBERSORT and MCP counter. Low levels of M2 macrophages and cancer-associated fibroblast cells were also found in the C3 subtype. GSEA pathway analysis showed that the C3 subtype had a heightened activation in the antigen process and presenting pathway, interferon-gamma response pathway, T cell receptor signaling pathway, and neural killer cell-mediated cytotoxicity pathway than C1/C2. In contrast, the C1/C2 presented greater activation of pathways related to the cell cycles, MMR repair DNA repair, and p53 signaling pathways than the C3 subtype. Conclusions: The robust prognostic relevance of the C3 IS allows a more precise categorization of patients with relevant clinical and biological implications, which may be valuable tools to improve tailored therapeutic interventions in LUAD patients.
Large cell neuroendocrine carcinoma of the lung: Prognostic factors to predict clinical outcomes.
Authors: Andrini Elisa , Tateo Valentina , De Biase Dario , Campana Davide , Lamberti Giuseppe 
Published: June 2021

e20515 Background: Large cell neuroendocrine carcinoma of the lung (LCNEC) is a rare tumor, with clinical and molecular features between non-small cell and small-cell lung cancer (NSCLC and SCLC, respectively). To date, little is known about factors able to predict clinical outcome of these patients. We sought to identify prognostic factors in LCNEC. Methods: We retrospectively collected pathologically-confirmed LCNEC patients treated at the S. Orsola Malpighi Hospital of Bologna between 01/01/2009 and 31/12/2020. LCNEC was defined as tumor with neuroendocrine morphology, expression of ≥2 neuroendocrine markers (including chromogranin A, synaptophysin, or CD56) at immunohistochemistry and high tumor grade (defined as necrosis and high Ki67 ≥ 50% or high mitotic rate, ≥ 10 mitoses per 2 mm2). Clinical features, pathological features, and blood test values (including neuron-specific enolase [NSE], carcinoembryonic antigen [CEA], cytokeratin 19 fragment [cyfra 21-1]) were correlated with progression-free survival to first-line chemotherapy (PFS) and overall survival from the diagnosis of extensive disease (OS). Results: Eighty-one LCNEC patients (median age 69 years, range 63-76) were identified. Twenty-seven (33.3%) had limited-stage disease and 52 patients (67.5%) had Eastern cooperative oncology group performance status (ECOG PS) ≥ 1 at diagnosis. When extensive disease was found (ED-LCNEC, N = 67), 23 patients (34.3%) had liver metastases, 10 (14.9%) had brain metastases and 24 (35.8%) had bone metastases. Treatment in ED-LCNEC was platinum plus etoposide in 45 patients (81.9%) and platinum plus paclitaxel in 10 patients (18.1%). Among 55 patients treated with platinum-based chemotherapy, 5 patients (9.1%) received cisplatin, while 50 (90.9%) received carboplatin. Overall, OS was 9.17 months (95% confidence interval [95%CI]7.17-13.87), PFS was 4.87 months (95%CI 4.21-6.02) and ORR was 38.2% (95%CI 25.4-42.3, N = 21/56). At univariate analysis, ECOG PS ≥ 1 (P = 0.049), presence of liver (P = 0.004) and bone metastases (P = 0.009), ≥ 2 non-nodal metastatic sites (P < 0.001), elevated NSE (P = 0.009) and CEA level at diagnosis (P = 0.011) were associated with increased risk of death. At multivariate analysis, ECOG PS ≥ 1 (P = 0.020), ≥ 2 metastatic sites (P = 0.002), and elevated NSE level at diagnosis (P = 0.009) were independently associated with the risk of death. At univariate analysis brain metastases (P = 0.017), ≥2 metastatic sites (P = 0.006) and elevated value of CEA at baseline (P = 0.026) were associated with increased risk of progression. At multivariate analysis, only the presence of brain metastases (P = 0.043) retained its association with the risk of progression. Conclusions: In ED-LCNEC of the lung, ECOG PS, number of non-nodal sites of metastases and NSE at baseline are associated with worse survival, while the presence of brain metastases is associated with shorter PFS.
Analysis of genetic mutations associated with immune-activated microenvironment in lung adenocarcinoma.
Authors: Liang Zhen , Zhao Shuhua , Liu Danni , Mu Tianhao , Chen Jinfeng 
Published: June 2021

e20520 Background: Tumor microenvironment plays an important role in suppressing or enhancing immune response. However, the relationship between genetic mutation and prognosis of lung adenocarcinoma (LUAD) patients, and the molecular mechanism of immune microenvironment are not completely clear. Methods: Expression matrix and somatic mutations of TCGA LUAD (n = 509) were downloaded from UCSC Xena. Immune-related gene list was downloaded from ImmPort. We applied R packages ESTIMATE and CIBERSORT to calculate the proportion of tumor-infiltrating immune cell by mRNA data. Samples were divided into ImmuneScore-High or ImmuneScore-Low depending on upper or lower quartiles of ESTIMATE immune infiltration score. Differential expression analysis between ImmuneScore-High and ImmuneScore-Low was performed with R package DESeq2. Results: Samples were divided into ImmuneScore-High (n = 127) and ImmuneScore-Low (n = 128). The immune cell components of these two groups presented different patterns. 10 most frequently mutated immune-related genes were significantly different between two groups (Chi-Squared test, p value < 0.05). 4,139 differentially expressed genes were obtained (|log2FC| > 1, FDR < 0.05). IL-7R, PIK3R5, TRBC2 and VCAM1 were identified with differential mutation frequency and presented differential expression between two groups. Kaplan-Meier plot in UALCAN cancer database showed IL-7R had a significant influence on the prognosis of patients (log rank test, p value = 0.045). Conclusions: ImmuneScore-High and ImmunScore-Low groups presented different genetic mutation frequency and gene expression. Moreover, mutation and different expression of IL-7R may be used as a potential biomarker in the treatment of patients with lung adenocarcinoma.
Real-world concordance between tumor mutational burden (TMB) from blood (circulating tumor DNA) and tissue in lung cancer.
Authors: Park Inae , Hwang Jin Young , Bae William , Lee Grace , Kim Leeseul , Choi Yoonhee , Jung Hojung , Chae Young Kwang 
Published: June 2021

e20522 Background: Tumor mutational burden (TMB) level is associated with response to immunotherapy in lung cancer. However, tissue TMB can be difficult to obtain, as tissue samples obtained from biopsies may be insufficient. Circulating tumor DNA-based TMB has been developed in order to complement or replace tissue TMB, but there is limited real-world data on their concordance. Here, we investigate the landscape and concordance between blood and tissue TMB, along with clinical traits of the concordant and discordant groups. Methods: Tumor mutational burden (TMB) was calculated using Tempus (tissue) and Guardant Health (blood) next generation sequencing (NGS) platforms from October 2020 to January 2021. There were 33 patients who had both Tempus and Guardant TMB data. Under the assumption that tissue TMB (tTMB) correlates with blood TMB (bTMB) at a ratio of 1:1.6, the patients were divided into concordant and discordant groups. The concordant group patients had bTMB/tTMB ratios between 1.3 and 1.9. The discordant group was divided into two subgroups: over 1.9 (Group B) and less than 1.3 (Group C). Among the 33 patients, 9 patients were excluded due to their non-evaluable bTMB levels. Treatment response was evaluated using RECIST criteria. Results: Of the remaining 24 patients, 7 patients in the concordant group and 21 patients in the discordant group were analyzed according to their clinical manifestations [Blood TMB (n = 24): range [1.46, 44.01], median = 9.57], [Tissue TMB (n = 24), range [1.3, 18.4], median = 4.5]. We compared the clinical presentations (number of metastatic organs and metastatic sites) between the two discordant groups (Groups B and C). Among the 24 patients, 13% (n = 3) had small cell lung cancer, 50% (n = 12) had adenocarcinoma, and 29% (n = 7) had squamous cell lung carcinoma. Patients with higher bTMB than tTMB (Group B) had more squamous cell carcinoma cases (71%, n = 5) compared to remaining groups (Groups A and C) (29%, n = 2). Among the discordant group, 6% of the patients (n = 1) had small cell lung cancer, 47% (n = 8) had adenocarcinoma, and 35% (n = 6) had squamous cell carcinoma. Further, 58% (n = 14) of the patients had higher bTMB than tTMB levels. Among the concordant and discordant groups, tumor burden as reflected by the number of metastatic sites and metastatic lesions and the sum of the largest diameters of tumor lesions using RECIST had no significant difference (p = 0.10, 0.68, 0.54, respectively). The concordant and discordant groups showed no significant difference in objective response (33% vs. 20%, p = 0.60) or clinical benefit rate (100% vs. 60%, p = 0.33). Conclusions: The majority of the patients had higher blood TMB than tissue TMB (Group A), with a concordance rate as low as 28%. Further studies are warranted to understand the biology behind the difference between blood and tissue TMB, including intertumoral heterogeneity.
Dose-painting radiation with concurrent chemotherapy for locally advanced non-small cell lung cancer: A single-center observational study.
Authors: Lv Jiahua , Wang Junchao , Jia Hongyuan , Liang Long , Wu Lei , Wang Yi , Wang Qifeng , Li Tao 
Published: June 2021

e20529 Background: Dose-painting radiotherapy is a promising technique which enables different dose distribution to different areas within the lung cancer. However, the efficacy and safety of this irradiation technique are still uncertain. In this study, we observed and analyzed the outcomes of dose-painting radiotherapy with chemotherapy for the locally advanced non-small cell lung cancer. Methods: Patients with stage III non-small cell lung cancer undergoing chemoradiotherapy were enrolled in this study. The dose-painting target was defined according to the distance between the tumor and the mediastinum (GTVwithin 2cm and GTVout-of 2cm). Doses of 60-80 Gy( 3-4Gy/fraction, bid) and 40-60 Gy (2-3Gy/fraction, bid) were prescribed to the GTVwithin 2cm and GTVout-of 2cm, respectively, in 20 fractions, using simultaneous integrated boost. All the patients received 2-4 cycles of chemotherapy using cisplatin plus paclitaxel or pemetrexed. Results: In total, 65 patients were included in this study. Median follow-up was 66.1 months (range 8.0-117.3months). The incidence of ≥Grade 2 radiation pneumonitis and esophagitis were was 30.8% and 38.5%, respectively. The 1, 3, 5-year OS and PFS were 78.4% and 58.5%, 32.3% and 26.1%, 18.5% and 13.8%, respectively. Late radiation esophagitis were seen in 3 patients and 2 patients were observed severe pulmonary fibrosis. None of the patients experienced fatal bronchopulmonary hemorrhage or tracheal fistula. Conclusions: Radiation dose painting with concurrent chemotherapy is feasible and well tolerated for locally advanced non-small cell lung cancer. It needs to be further confirmed by large randomized controlled clinical studies.
Neoadjuvant prehabilitation therapy for locally advanced non-small-cell lung cancer: Optimizing outcomes throughout the trajectory of care.
Authors: Schmid Severin , Minnella Enrico Maria , Najmeh Sara , Cools-Lartigue Jonathan , Ferri Lorenzo , Mulder David , Sirois Christian , Owen Scott Peter , Carli Francesco , Spicer Jonathan 
Published: June 2021

e20545 Background: Prehabilitation is well established for improving outcomes in cancer surgery. Combining prehabilitation with neoadjuvant treatments may provide an opportunity to rapidly initiate cancer-directed therapy while improving functional status in preparation for local consolidation. In this proof-of-concept study, we analyzed non-small-cell lung cancer patients who underwent simultaneous prehabilitation and neoadjuvant therapy. Methods: We retrospectively analyzed all patients who underwent neoadjuvant treatment for non-small-cell lung cancer followed by curative intent surgery at the McGill University Health Center between 2015-2020. Patients who were screened for the prehabilitation program were identified. Screening included assessment of physical performance, nutritional status and signs for anxiety and depression. 6-minute-walk test was used as a functional outcome parameter of prehabilitation. Results: We identified a total of 93 patients who underwent neoadjuvant therapy. Of these, 12 patients were screened to undergo a prehabilitation program. For 1 patient surgical intervention was too soon to complete the program, 1 patient dropped out after the first and another patient was deemed fit to undergo surgery without intervention. Thus, 9 patients completed full neoadjuvant prehabilitation therapy. Postoperative median length of stay was 2 days (IQR 1-5) and there were no mortalities. We found major complications in 1 patient and minor complications (prolonged air leak) in 2 cases. Patients improved their 6-minute-walk test despite undergoing neoadjuvant treatment by a mean of 35 meters (SD 39). Conclusions: Neoadjuvant prehabilitation therapy is feasible and associated with encouraging results. The performance of all measures remains a logistic challenge. With multimodal strategies for lung cancer treatment becoming key to optimal outcomes, neoadjuvant prehabilitation therapy is a concept worthy of prospective multi-center evaluation.
Assessing tumor metabolic heterogeneity of non-small cell lung cancer with total body PET-CT imaging on the uExplorer: Analysis of dynamic changes of 18F-FDG uptake.
Authors: Liu Hui , Zhang Xu , Liu Hui , Qiu Bo , Wang DaQuan , Zhou Yin , Li QiWen , Chu Chu , Liu FangJie , Chen NaiBin , Hu Nan , Ai XinLei , Guo JinYu , Fan Wei 
Published: June 2021

e20549 Background: Total body positron emission tomography (PET) of uExplorer enables imaging of highly quantitative parameters beyond the standardized uptake value (SUV). The aim of this prospective study is to assess the dynamic changes of 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) uptake in characterizing tumor heterogeneity of non-small cell lung cancer (NSCLC). Methods: Sixteen NSCLC patients were prospectively enrolled in a prospective study (NCT04654234, GASTO-1067) between September 2020 and December 2020. All patients underwent a dynamic total-body 18F-FDG PET/CT scan before any treatment. The primary lung tumor, metastatic regional lymph node and inflammatory lymph node were manually delineated by a nuclear medicine physician and a radiation oncologist. Total Body PET was acquired between 0 – 60 mins after the injection of FDG from the subject’s feet. We compared lesion heterogeneity and different image-derived PET metrics including the SUV-mean, Patlak-derived influx rate constant (Ki) and distribution volume (DV). Results: The SUV-mean and Ki-mean of primary lung tumor and metastatic lymph node were significantly higher than inflammatory lymph node (p < 0.001), while there was no significantly different of DV(p > 0.05). By the scatter plot of SUV-mean and Ki-mean of primary lung tumor, 9 patients had been separated into high dynamic FDG metabolic (H-DFM) group and 7 in low DFM(L-DFM) group. The SUV-mean(p = 0.0002) and Ki-mean(p = 0.0002) of primary lung tumor were significantly higher in H-DFM group, whereas there is no difference in metastatic lymph node of both group. Interestingly, the SUV-mean and Ki-mean of primary lung tumor were higher than that of metastatic lymph node(p = 0.0002) in H-DFM group. On the contrast, the SUV-mean and Ki-mean of primary lung tumor were lower than that of metastatic lymph node(p = 0.05) in L-DFM group. There is no significant difference of DV-mean among primary lung tumor, metastatic lymph node and inflammatory lymph node in both arms. Conclusions: The results demonstrated that dynamic parameters from total body PET scan has the potential of providing complementary information of tumor heterogeneity in NSCLC than conventional static SUV imaging. The characteristics of H-DFM and L-DFM group could be taken into account for evaluation of further treatment response.
Construction and validation of an eight-gene risk prediction model for stage II-IIIA lung adenocarcinoma.
Authors: Duan Jianchun , Bai Hua , Sun Yiting , Gai Fei , Tian Shenya , Xu Wenfang 
Published: June 2021

e20553 Background: Clinical characters cannot precisely evaluate long-term survival of patients with resectable lung adenocarcinoma. Genomics studies of lung adenocarcinoma (LUAD) have advanced our understanding of LUAD's biology. Thus, genomics-based robust models predicting survival outcome for patients with operatable LUAD needs to be investigated. Here, we aimed to identify new gene signatures to construct a risk prediction model via integrating Omics data from The Cancer Genome Atlas (TCGA) to better evaluate the long-term clinical outcome of LUAD patients. Methods: A cohort of one hundred and eighty-nine stage II-IIIA lung adenocarcinoma cases receiving tumor resection were screened out and downloaded from TCGA database. Tumor samples without survival information and genes with low or no expression were removed. Genes associated with cancer and immune were further narrowed down using a Master Panel Gene Set (Amoydx). Lasso-Cox regression analysis was used to screen gene-survival outcome, and then a risk prediction model was established. LUAD cases were divided into high-risk or low-risk groups as per the scores, to assess differential expressed genes and pathways. Results: A total of 8 most survival outcome related genes (CLEC7A, PAX5, XCR1, KRT7, PLCG1, DKK1, CLEC10A, IKZF3) were identified after Lasso-Cox regression analysis and used for model construction. The overall survival (OS), progression-free survival (PFS) and disease-free survival (DFS) from the subgroups within the high- and low-risk groups were assessed and showed significant prolonged in low-risk group, the hazard ratio (HR) of OS was 2.72 (95%CI: 2.04-3.61, P = 5.91e-12) in high-risk group. Hierarchical clustering analysis, gene ontology (GO) analysis, gene set enrichment analysis (GSEA), and gene set variation analysis (GSVA) revealed that genes involved in immune responses were significantly suppressed in high-risk group, while as genes involved in antioxidative metabolism were activated, which gave us a hint that immune-metabolism interaction might play a vital role in determining the distal survival outcome of LUAD. Conclusions: Our risk prediction model enables precise evaluation of long-term survival for patients with LUAD. Further, it provides a novel and comprehensive understanding of biological impacts on LUAD prognosis, which offers new insights for future development of precise diagnostic and therapeutic approaches.[Table: see text]
Using predictive models to determine the presence of non-small cell lung cancer metastasis to N2 and N3 regions.
Authors: Hauptmann Edward , Batra Kiran , Kandathil Asha , Canan Arzu , Alvarado Sergio , Li Qiubai , Kukkar Vishal , Xi Yin , Kernstine Kemp H. 
Published: June 2021

e20560 Background: Accurate assessment of non-small cell lung cancer (NSCLC) mediastinal involvement is key to developing treatment plans and determining prognosis. To date, there is no reliable imaging-based means to determine the presence or absence of mediastinal involvement. Current computed tomogram (CT) and fluorodeoxyglucose-positron emission tomography/ computed tomogram (PET-CT) technologies provide numerous derived automated variables have not been sufficiently evaluated to determine the presence of metastasis to the mediastinum. We have developed predictive models to determine the presence or lack of metastatic NSCLC in N2 and N3 regions. Methods: Consecutive patients from 2012-2017 with biopsy-proven NSCLC who had CT and PET-CT, as well as biopsy of the mediastinum had their images reread by a team of blinded specialty radiologists and nuclear medicine specialists. Patients with no mediastinal malignancy on biopsy were followed for 6 months from the initial evaluation to confirm lack of mediastinal malignancy.278 regions (N2 and N3) from 139 patients were included. Logistic regression models were used to build a baseline model, as well as models with additional nodal station maximum standard uptake valuve (SUVm) measurements (SUVm, SUVm-SUVmeanbloodpool and SUV lymph node/tumor (LN/T)) for N2 and N3 regions, respectively. When nodal station SUVm was not measured, SUVmeanbloodpool was used. The SUVm within each region was used. Stepwise selection was used to select variables in the baseline model. Cross-validated ROC curve and area under the curve (AUC) were reported. All analyses were done in SAS 9.4 (SAS Institute, Inc., Cary, NC). Results: 40/139 N2 regions had malignancy, 4/139 N3 regions had malignancy. Baseline models for N2 regions selected lung laterality (OR right vs left: 4.84 (1.79, 13.05)) and nodal station short-axis diameter > 1 cm (OR yes vs no: 5.49 (1.71, 17.54)) while no variables were selected for the baseline model for N3 regions due to lack of statistical power. We used the same variables for the N3 baseline model. Conclusions: We have identified models that use a more advanced analysis of predicting the presence or absence of metastatic NSCLC in both N2 and N3 regions with respect to the primary lesion. All models perform better with SUVm related measurements. From this information, we are developing a clinical application to provide practitioners a better means of assessing the presence of mediastinal involvement of NSCLC. [Table: see text]