bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predictive value of TGFβ1/TGFBR2 ratio for evaluating the effectiveness of treatment in patients with diffuse large B-cell lymphoma (DLBCL).
Authors: Bandovkina Valeria A. , Frantsiyants Elena M. , Kushtova Luiza B. , Kozel Yuliya Yu. , Snezhko Aleksandr V. , Dmitrieva Viktoria V. , Kozyuk Olga V. , Malinin Sergey A. , Chalkhakhyan Lusegen Kh. , Kaminskiy Gennadiy V. , Lysenko Irina B. , Nikolaeva Nadezhda V. , Kit Oleg I. 
Published: June 2022

e19559 Background: About 30-40% of patients with diffuse large B-cell lymphoma (DLBCL) do not respond to treatment, they subsequently relapse or remain refractory, so the search for predictive factors for the treatment effectiveness is relevant. TGF-β is a pleiotropic regulator of many pathophysiological processes, including carcinogenesis and immune responses, and its signals are initiated via its binding with proteins, including TGF-β receptor type 1 and type 2 (TGFBR2). The purpose of this study was to analyze the TGFβ1 and TGFBR2 blood levels and their ratio in patients with DLBCL depending on the treatment efficacy. Methods: The study included 63 patients (32 men and 31 women aged 23-88 years, median age 55.6 years) diagnosed with DLBCL. Blood levels of TGFβ1 and TGFBR2 were determined by ELISA before and after treatment. Stage I DLBCL was registered in 6 (9.5%) patients, stage II in 25 (39.7%), stage III in 5 (7.9%), stage IV in 27 (42.9%). All patients received standard treatment with R-CHOP, R-CHOEP, R-EPOCH. Direct results of the treatment were assessed by Cheson’s criteria. By their response to the therapy, patients were divided into 3 groups: group 1 (25.4%) – relapsed disease, group 2 (25.4%) – refractory disease, and group 3 (49.2%) – remission. A group of healthy donors included 20 men and women. All patients gave their informed consent to the study. Results: Blood levels of TGF-β1 in all patients before the treatment were higher than in donors by 2.1 times, and after the treatment by 2.4, 1.9 and 1.9 times, respectively, in groups 1, 2 and 3. The values between the groups did not differ significantly. Levels of TGFBR2, on the contrary, were lower in patients before treatment than in donors by 3 times, and after treatment by 3.5 in group 1, by 4 times in group 2, and similar to the norm in group 3. The TGFβ1/TGFBR2 ratios in patients before treatment were 6.1 times higher than the norm. After treatment, the ratio in patients of groups 1 and 2 were 8.6 and 7.2 times higher than in healthy donors. The ratio in patients of group 3 was 2.3 times higher than in healthy donors, and the value differed significantly from the values in groups 1 (3.8 times lower) and 2 (3.2 times lower). Conclusions: Monitoring the TGFβ1/TGFBR2 ratio in DLBCL patients before and during the treatment will allow promptly determination of adverse outcomes and changing the treatment regimen.
Observational study evaluating wait time and clinical outcomes in patients (pts) with diffuse large B-cell lymphoma (DLBCL) who received chimeric antigen receptor (CAR) T-cell therapy (T-CT).
Authors: Chun Danielle , Yin Yu , Bernhardt Alf , Sanders Lynn , Brouwer Emily 
Published: June 2022

e19577 Background: 5-year survival rates for DLBCL pts in the first-line setting range from 60% to 70%. Up to 50% of pts become refractory to or relapse (r/r) after treatment. Autologous CAR T-CT has shown efficacy in r/r DLBCL in ≥2 lines of treatment but faces significant challenges with cell collection and manufacturing that may delay pt treatment. This study assessed the impact of wait time for CAR T-CT (time between apheresis and CAR T-CT administration) on progression-free survival (PFS) in DLBCL pts. Methods: Data from pts in the electronic health record-derived de-identified US-based Flatiron Health database, who had a DLBCL diagnosis after Jan 1, 2011, and a documented CAR T-CT administration date, were included. Pts missing a documented apheresis date were excluded. Demographic and clinical characteristics were assessed within 6 months (mos) prior to index date (CAR T-CT administration). Pts were followed from index date to the first of pt death or end of data availability. Given no established clinically relevant cut points, short wait time was defined as < median time between apheresis and index date. Long wait time was defined as ≥ median time. 3-, 6-, and 12-mo PFS probabilities (95% confidence intervals [CIs]) by wait time were reported. Results: 91 DLBCL pts received CAR T-CT; 78 had a documented apheresis date. Median time from apheresis to index date was 37 days (interquartile range: 25, 116). 55% of pts experienced longer wait times (≥37 days). 45% experienced shorter times (<37 days). Pts were mostly white (80%–84%), male (57%–65%), and older (median: 60–67 years), with similar median follow-up time from index (4.0–4.7 mos). More pts with short wait times had stage 4 disease than those with long wait times (51% vs 28%). 71% of pts with shorter wait times received axicabtagene ciloleucel. Among those with long wait times, 72% received tisaggenlecleucel. More pts with long wait times received bridging therapy (66% vs 74%). Pts with short wait times had a higher 3-mo PFS probability than pts with long wait times. The 6- and 12-mo PFS probabilities were lower in those with shorter wait times (Table). No statistical comparisons were made due to small sample size. Conclusions: This real-world study showed no meaningful differences in PFS between wait times in DLBCL pts in the United States. Results from this study show evidence of channeling bias which is an important consideration for evaluating real-world data to construct external control arms. Future studies are needed to further evaluate the impact of delayed treatment in pts with r/r DLBCL. Funding: Takeda Development Center Americas, Inc.[Table: see text]
Economic evaluations of adjunctive osimertinib treatment in surgically resected epidermal growth factor receptor positive (EGFR+) non-small cell lung cancer (NSCLC): Analysis for stage 1B disease.
Authors: Choi Briana M , Abraham Rachel B , Aqel Osama , Agu Uche S , Gregory Kristen C. , Obeng-Kusi Mavis , Calamia Matthias , Halawah Hala , Tugay Deniz , Alamer Ahmad , McBride Ali , Abraham Ivo 
Published: June 2022

e20502 Background: Patients with stage 1B non-small cell lung cancer (NSCLC) who receive surgical resection are at continued risk of disease recurrence and death after the surgery. Osimertinib, a tyrosine kinase inhibitor indicated for epidermal growth factor receptor positive (EGFR+) NSCLC, has been used post-operatively as adjunctive therapy to improve clinical outcomes in surgically resected EGFR+ stage 1B NSCLC. We evaluated the cost effectiveness/utility of adjunctive osimertinib treatment post-surgically in stage 1B. Methods: A two state partitioned survival model with disease free survival (DFS) and disease recurrence or death was specified (US payer perspective). Kaplan-Meier DFS curves were fitted to parametric functions. A 5 year time horizon was adopted and a 3% discount rate was applied to costs and utilities after year 1. Wholesale acquisition costs for treatments were sourced from Redbook, adverse event costs (grade 3/4; all grades for immunotherapy related AEs) utilized published data, and monitoring costs were based on Physician Fee Schedules (US $2021). We estimated incremental costs, DFS life years (DFSLY), and DFS quality adjusted life years (DFSQALY). Based on DFSLY and DFSQALY gained (g), incremental cost effectiveness/utility ratios (ICER/ICUR) were determined in base case analyses (BCA) and probabilistic sensitivity analyses (PSA). Results: Exponential regression was utilized to extrapolate the osimertinib DFS Kaplan-Meier curve, while Weibull regression was applied for extrapolation of the placebo DFS curve. Shown in the table below, the BCA (PSA) revealed incremental cost of $774,710 ($775,941) and ncremental DFSLY of 0.813 (0.954), yielding an ICER of $952,797/DFSLYg ($813,162/DFSLYg); and incremental DFSQALY of 0.576 (0.676), yielding an ICUR of $1,345,340/DFSQALYg (1,147,793/DFSQALYg). Conclusions: In surgically resected stage 1B EGFR+ NSCLC, the model estimated incremental benefits of 0.813 (0.954) LYg and 0.576 (0.676) QALYg, however at marked incremental cost. As adjunctive osimertinib treatment is indicated in EGFR+ NSCLC disease stages 2 and 3A, the present stage 1B cost effectiveness/utility results should be compared to those for stages 2 and 3A.[Table: see text]
A survey on gene mutations of PD-1/PD-L1 treatment in Chinese lung cancer patients.
Authors: Long Fang Fang , Huang Wen Chuang , Peng Bo , Zhang Jing , Peisu Suo , Chen Shifu , Wu Fa Sheng 
Published: June 2022

e20503 Background: The expression of PD-L1 is closely related to the curative effect. Here, we want to study the details of gene mutation in expression and dig out some relevant information from Chinese LC patients. Methods: LC patients with both genomic information and PD-L1 expression status were screened from HapLab database. PD-L1 expression was detected by immunochemistry. R packages ClusterProfiler was used for gene enrichment analysis. Results: LC Patients were divided into two groups by tumor proportion score (TPS):1039 PD-L1 negative patients (TPS < 1%) and 1669 PD-L1 positive patients (TPS > = 1%). The overall mutation frequency of 51 genes were significantly different between PD-L1 negative patients and PD-L1 positive patients (Chi-Squared test, Pvalue < 0.05). 6 genes were mutated at high frequencies in patients with high TPS, and 45 genes were mutated at high frequencies in patients with low TPS. Among these genes, FGFR3, MDM2 and SKT11 have been reported to be associated with HPD, showing significantly higher mutation frequencies in PD-L1 negative patients (Pvalue < = 0.001). Two sets of genes were enriched respectively, both of which were enriched in MAPK and PI3K-Akt related pathways, while the enrichment results of EGFR tyrosine kinase inhibitor resistance only existed in PD-L1 negative. Conclusions: Our study investigated the genomic alterations associated with PD-L1 expression status in Chinese LC patients. From the data of Chinese lung cancer patients, we found 55 genes related to PD-1/PD-L1 treatment. These genes contain HPD related genes. Perhaps PD-L1 expression is associated with HPD.
Intratumor heterogeneity analysis in lung adenocarcinoma by single-cell RNA sequencing and construction of a prognostic gene signature.
Authors: Huang Haifu , Wang Weiyu , Mu Tianhao , Fu Biqian 
Published: June 2022

e20521 Background: Lung adenocarcinoma (LUAD), at the cellular level, has a high degree of intratumor heterogeneity. Advanced single-cell sequencing technologies have offered tools to analyze intratumor heterogeneity and identify the biomarkers, thereby aiding cancer diagnosis and prediction of the patient prognosis. Methods: From the Gene Expression Omnibus (GEO) (www.ncbi.nlm.nih.gov/geo) database, the single-cell RNA sequencing (scRNA-seq) data from two LUAD and two para-cancerous tissue samples were obtained. We performed a dimensionality reduction and unsupervised clustering to identify the different cell clusters within the tumor tissues. To identify the most relevant modules and important cell subpopulations (clusters) in LUAD tissues, a weighted gene co-expression network analysis (WGCNA) was performed. Subsequently, we classified the LUAD molecular subtypes according to the marker genes of these clusters. The Limma package ( www.bioconductor.org/packages/release/bioc/html/limma ) was used to screen for the differentially expressed genes (DEGs) between the subtypes. Using univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses, the gene signature most significantly associated with the prognosis of LUAD patients was determined. Results: A total of 14 cell clusters belonging to 10 cell types in LUAD was identified. The turquoise module was found to be the most relevant to LUAD among all the modules; cluster 10 (C10) was found to be the most strongly associated with the turquoise module. In The Cancer Genome Atlas (TCGA), patients with LUAD were divided into two groups of distinct molecular subtypes. Based on the 165 shared genes between the turquoise module and C10, 511 DEGs between the two molecular subtypes were obtained, and five of them were selected to construct the gene signature, which was validated to be an independent prognostic marker of LUAD. Conclusions: 14 cell clusters co-existed in LUAD, which contributed to its intratumor heterogeneity. In addition, two molecular subtypes of LUAD were identified and a five-gene signature was developed and validated to be significantly associated with prognostic and clinical characteristics of LUAD patients. Keywords: single-cell RNA sequencing, lung adenocarcinoma, intratumor heterogeneity, molecular subtypes, prognosis, five-gene signature.
Construction of a diagnostic model through the gene expression profile of the patients’ peripheral blood mononuclear cells and clinical characteristics for malignant lung nodules diagnosis.
Authors: Cai Yi , Li Zhuoqi 
Published: June 2022

e20527 Background: Low dose computed tomography (LDCT) is widely accepted for detecting early-stage lung cancer. However, it remains a great challenge for it to distinguish malignant lung tumors from benign lung nodules because of the high false positive rate. Therefore, a better non-invasive diagnostic tool is needed to improve the specificity. Methods: Two GEO datasets of expression profiling by array of peripheral blood mononuclear cells (PBMC) from patients with malignant lung nodules or non-malignant lung conditions, as well as relevant clinical information were downloaded and disposed. R package edgeR was applied to screen out the differentially expressed genes with |log2-fold change (FC)| ≥ 0.25 and p≤0.05. Logistic regression model was constructed based on GSE135304 dataset in order to find which factors contribute to the distinguishing of malignant lung nodules from non-malignant lung conditions, and this model was then validated in GSE108375 dataset. Results: 23 differentially expressed genes from the PBMC between patients with lung cancer and non-malignant lung conditions, and the patients’ lung nodule size and age were included in the diagnostic model through the logistic regression analysis. And in the training dataset GSE135304, the ROC curve shows the specificity of the model is 0.866 and sensitivity is 0.848, and the AUC value is 0.857. In the meantime, the specificity and sensitivity of the validation dataset GSE108375 are 0.865 and 0.893 respectively, and the AUC value comes to 0.879. Conclusions: This diagnostic model shows high sensitivity and specificity in both training group and validation group, so it may be a good tool for the mini-invasive diagnosis of malignant lung nodules.
Systematic analysis the genomic and microenvironment characteristics with the status of human leukocyte antigen (HLA) and the integration of HLA LOH, TMB and PD-L1 could further distinguish the responders to immunotherapy.
Authors: Zhang Xiaotao , Wang Jun , Chen Jun , Zhang Linlin , Guan Yaping , Chu Huili , Yu Haiming , Yu Lan , Lu Huiping , Jin Haoxuan , Gu Tiantian , Wang Xiuyan 
Published: June 2022

e20529 Background: Although studies have shown that loss of heterozygosity (LOH) at the human leukocyte antigen (HLA) locus is one of the mechanisms of immune escape, the effect of HLA LOH on the immune checkpoint inhibitors (ICIs) treatment is still need to be further investigated, especially for the patients with positive programmed cell death-Ligand 1 (PD-L1) expression and high tumor mutation burden (TMB). Methods: 425 sample of Chinese lung cancer patients who received PD-L1 immunotherapy were performed with targeted panel sequencing to analyzed the genomic characteristics with HLA status. 994 non-small cell lung cancer (NSCLC) sample from The Cancer Genome Atlas (TCGA) were used to analyze the impact of HLA LOH on the tumor microenvironment. In addition, 89 samples from previous study were used to analyze the association of HLA status with the ICIs treatment in NSCLC. Results: The genomic characteristics from 425 sample of Chinese lung cancer patients who received PD-L1 immunotherapy were analyzed. We found that mutation frequency of driver genes and TMB in the HLA LOH high group were significantly increased. Transcriptome analysis revealed HLA LOH played a critical role in the tumor immune microenvironment in PD-L1+/TMB-H population and the impact on lung adenocarcinoma was greater than that on lung squamous cell carcinoma. Progression-free survival of PD-L1+/TMB-H population was significantly decreased in HLA LOH group which suggest that comprehensive considering HLA LOH as a biomarker may improve clinical response to immunotherapy. Conclusions: This work showed the genomic and immune microenvironment characteristics of HLA LOH and demonstrated HLA LOH as a significant negative predictor of outcomes after ICIs treatment, especially in PD-L1+/TMB-H population. These data suggested that comprehensive considering HLA LOH as a biomarker may improve clinical response to immunotherapy.
Characterization of MET exon 14 skipping in pancancer.
Authors: Li Fei , Chen Jing , Zhang Xiaoyan , Yang Dongxiao , Xia Liang , Wang Dazhong , Jin Kai , Zhu Jianhua , Fang Yu , Wang Chunyang , Ma Tonghui , Pu Xingxiang 
Published: June 2022

e20530 Background: MET exon 14 skipping ( METex14) is characterized oncogenic that possesses susceptibility to targeted inhibitors. We retrospectively investigated a Chinese Pan-cancer cohort to characterize METex14 alterations and co-mutation. Methods: We screened tumor tissues or body fluids of a pan-cancer patients by DNA-based next-generation sequencing assay (Genetron Health) from 2017 to 2020. And distribution of co-mutation with METex14 was analyzed. Results: 233 samples from 187 patients (190 tissues and 43 circulating tumor DNA) were identified with METex14. Average age of these METex14 patients was 67.84 ± 12.19 years old, indicating they were characterized by advanced age. The cancer distribution involved METex14 was 95.72% of lung cancer (179 cases), 3.21% of brain tumors (4 glioma blastoma, 1 anaplastic astrocytoma and 1 ependymoma), 0.535% of gastrointestinal stromal tumor (1 case) and 0.535% of sarcoma (1 case). Referring to different transcripts (NM_001127500.1/2 or NM_000245.2), a total of 68 distinct sequence variants of METex14 were identified spanning functional regions: 31 forms in splice donor site (SD, 148 cases, including 1 case of D1010H), 5 in splice acceptor site (SA, 5 cases), 13 in poly-pyrimidine tract (PPT, 15 cases), 19 cover PPT and SA (19 cases). In non-lung cancers, 5 of 8 cases were detected of METex14 variation in SD site. Among the driver coexisting cases of lung cancer, METex14 samples mainly coexisted with MET amplification, EGFR driver mutations and functional fusions. Co-mutation cases with MET amplification (13) and SEMA3D-MET fusion (1) may benefit from MET inhibitors, which may be the same as the samples of METex14 alone. 13 of METex14 cases occurred with MDM2 and 9 of CDK4 amplification, respectively. There were 2 of METex14 cases coexisted with EGFR 19del or L858R, which may benefit from combination or sequential therapies of MET inhibitor and EGFR TKIs. In addition, 2 of METex14 cases were detected with functional fusions (1 ALK-EML4, 1 KIFI5B-RET), resulting in potential benefit from combination of corresponding targeted agents. Among non-lung cancer cases, 2 of 8 case had coexistence of METex14 and MET amplification, 6 of 8 patients had coexistence of METex14 and TP53, similar phenomenon was also observed in lung cancer samples. Conclusions: Here we reported diverse METex14 alterations in a Chinese pan-cancer cohort that contribute to oncogenic transformation. METex14 mutations of pan-cancer mainly occurred in SD site. TP53 was its main co-mutant gene among pan-cancers, and MET amplification was also observed.
Characterization of patients with lung adenocarcinoma treated at a reference oncology center in northeastern Brazil and submitted to EGFR gene mutation research.
Authors: Silva-Fernandes Isabelle Joyce de Lima , Andrade Letícia Macedo Nicácio , Lima Arthur Ernani Saldanha e Oliveira , Bezerra Maria Júlia Barbosa , Luciano Maria Claudia dos Santos , Lima Valeska Portela , Neto José de Brito Vieira , Soares Bruno Marques , Rodrigues Aline Kimberly Almeida , Oliveira Samara Regia , Cunha Maria do Perpétuo Socorro Saldanha , Hirth Carlos Gustavo , Bitencourt Flávio da Silveira , Sant'Ana Rosane Oliveira , Silva Paulo Goberlânio de Barros 
Published: June 2022

e20548 Background: Lung cancer has the highest incidence and mortality worldwide. In Brazil, it is the second most common, and individualized therapy, although more efficient than traditional chemotherapy, is still a challenge for health services, especially in developing countries, as socioeconomic disparities make access to genetic testing difficult or treatment. Thus, it is understood that greater knowledge about the genetic profile and therapeutic response of different populations can contribute to policy changes that guarantee expanded access to individualized therapy. Methods: the EGFR gene mutation status was correlated with clinical-epidemiological, socioeconomic, treatment, and survival parameters of patients with lung adenocarcinoma treated from 2014 to 2021 at an oncology referral center in northeastern Brazil. Data were obtained retrospectively from the patient's charts at the Hospital Haroldo Juaçaba/Instituto do Câncer do Ceará. The X²/Fisher and Log-Rank Mantel-Cox tests were used to associate clinical variables and overall survival curves. The Research Ethics Committee approved the research under protocol number 3.544.754. Results: 586 patients tested, 157 (26.8%) had an EGFR mutation, with exon 19 deletion (n = 83, 52.9%). the most frequent followed by L858R (n = 54, 34.4%) and others (n = 30, 12.8%). The EGFR mutation was inversely associated with smoking history (p < 0.001) and previous use of carboplatin plus paclitaxel (p < 0.001). The median overall survival was 33 (95%CI = 25-41) months, and the presence of a mutation was not associated with a worse outcome (p = 0.146). Interestingly, patients with sensitivity mutation who used gefitinib (64.1%) did not show a significant difference in overall survival (p = 0.218). However, when stratifying analyzes according to mutation type, it was observed that patients with exon 19 deletion treated with gefitinib had greater median overall survival (32, 95%CI = 27-37 months) than patients with this mutation not treated with gefitinib (median = 15, 95%CI = 2-25 months) (p < 0.001). Patients with the L858R type sensitivity mutation (p = 0.523) or other mutations (p = 0.439) did not experience significant benefits from gefitinib use. Conclusions: In the population studied, the exon 19 deletion was the most frequent and the only one associated with a substantial benefit from using gefitinib.