bluuebunny/crossref_metadata_2025_split huggingface dataset:
Real-world treatment patterns in stages IA-IIIB non-small cell lung cancer.
Authors: Lee Jay M. , Wang Rongrong , Abbass Ibrahim M. , Sheinson Daniel , Kent Matthew , Johnson Ann , Lee Janet 
Published: June 2021

e20528 Background: Given the rising number of immunotherapy or targeted therapy trials, a call for real-world treatment (Tx) data among resectable non-small cell lung cancer (NSCLC) patients is needed. We describe Tx patterns and timelines to Tx. Methods: Retrospective data were collected from the SEER Medicare database. Patient inclusion criteria: newly diagnosed NSCLC stages IA to IIIB between 2010 and 2015, ≥65 years of age, and continuously enrolled in Medicare Part A and B and no HMO enrollment for ≥7 months prior to diagnosis (Dx) date. A subset of patients with a follow-up of ≥12 months after Dx or ≥6 months after surgery were evaluated for Tx patterns. Results: Among 31,921 NSCLC patients identified, the mean (SD) age was 76 (7) years and 51% were female. AJCC (7th edition) stages included IA (25%), IB (21%), II (8%), IIIA (17%), and IIIB (30%). Among the 6,559 (21%) patients identified with a solitary pulmonary nodule (SPN) prior to Dx, the median [IQR] time from SPN to Dx was 29 [13, 67] days. Among the 24,952 (78%) patients who received Tx, the median [IQR] time from Dx to Tx was 31 [14, 54] days. Among 19,304 patients included in the Tx pattern analysis, 63% did not undergo surgery. Among resected patients with lymph node metastasis, only 64% (stage II), 74% (stage IIIA), and 52% (stage IIIB) of patients received chemotherapy (CT) before or after surgery (Table). Median [IQR] time in days between Dx and neoadjuvant or adjuvant CT was 29 [14, 48] and 84 [56, 119], respectively. Median [IQR] time in days between Dx and surgery was longer for patients with neoadjuvant Tx (Table). Median [IQR] time between surgery to adjuvant CT was 46 [33, 63] days, with 59% of patients receiving their adjuvant CT ≥ 6 weeks after surgery and 33% of patients receiving their adjuvant CT ≥ 8 weeks after surgery. Conclusions: A significant proportion of lymph node positive stage II or III NSCLC patients did not receive perioperative systemic therapy despite standard of care guidelines. This finding suggests a patient population with unmet need notwithstanding recommendations for systemic therapy. [Table: see text]
Spatial analysis of the T-cell repertoire in non-small cell lung cancer reveals a clonality gradient from the tumor to the distal lung.
Authors: Frank Meredith , Yu Fenglei , Reuben Alexandre , Peng Muyun , Yang Gao , Chen Xiaofeng , Ji Liyan , Li Pansong , Xia Xuefeng , Guan Yan-Fang , Zhang Jianjun 
Published: June 2021

e20544 Background: The immunomodulatory effects of the tumor microenvironment (TME) significantly impact the T cell repertoire resulting in different anti-tumor immune responses. Previous work by our group and others has highlighted intratumor heterogeneity in T cell clonality, spatial distribution, and diversity, as well as infiltration of bystander T cells in early-stage non-small cell lung cancer (NSCLC). However, little is known about how the TME impacts the T cell repertoire in distant or surrounding adjacent uninvolved lung tissue. Methods: We investigated the interplay between tumor and surrounding lung tissues by investigating the T cell repertoire at the tumor site, tumor margin, and 1cm, 2cm, 5cm, and 10cm away from the tumor as well as in peripheral blood in 21 NSCLC patients with a total of 123 samples undergoing T cell receptor (TCR) CDR3b sequencing using the Geneplus technology. Differences in regional T cell repertoires were analyzed based on clonality, diversity, and Morisita Overlap Index (MOI). GLIPH was utilized to identify motifs associated with pathogen specificity in each region. Results: Clonality was lowest within the tumor and progressively increases from tumor margin to tumor adjacent lung toward distant lung with “hot spot” regions of T cell expansion located in adjacent lung tissue proximal to the tumor, namely 2cm away (p = 0.0025). Dominant T cell populations were better conserved between the tumor margins and “hot regions” of high clonality compared to the tumors (p = 0.0009) highlighting the differences between these environments and possible T cell exclusion in immunosuppressive TME. GLIPH analysis revealed an inverse correlation between clonality and the proportion of pathogen-associated TCR motifs (r = -0.83, p = 0.0195). Interestingly, tumor tissue contained the highest proportion of predicted pathogen TCRs whereas regions of high clonality contained the lowest (p < 0.0001), suggesting the antigen-independent nature of T cell trafficking. Conclusions: Combined, these results highlight isolated pockets of T cell expansion in the lungs outside the tumor and potential immune evasion mechanisms in NSCLC.
The genomic and transcriptomic characteristics of early recurrence patients in stage IA non-small cell lung cancer.
Authors: Zhang Shirong , Jiang Hong , Chen Xueqin , Zhu XiuLi , Bai Jing , Wu Qiong , Hu Runlei , Zhu Chenchen , Xia Xuefeng , Xun Yanping , Zhang Jing , Ma Shenglin 
Published: June 2021

e20547 Background: Lung cancer is the leading cause of cancer-related death worldwide. The mortality risk is still high in early stage because of the high relapse rates about 30–45% within 5 years after surgery. The main purpose of this study was to depict the genomic and transcriptomic characteristics in stage IA non-small cell lung cancer (NSCLC) patients and elucidate the recurrence risk factors for providing more postoperative intervention management and treatment. Methods: We prospectively enrolled 60 patients with stage IA NSCLC from 2012 to 2018 including 29 non-relapse patients and 31 early-relapse patients within 5 years. A total of 60 primary tumor specimens and 10 relapse tumor specimens were obtained. The paired adjacent non-tumor tissues for each patient were collected as negative control. DNA and RNA were co-extracted and performed with whole exon and transcriptome sequencing. The immune cell infiltration scores were estimated using ssGSEA algorithm. Results: The most frequently mutated genes in our cohort were EGFR (46.4%), TP53 (38.0%), TTN (35.2%) and USH2A (21.1%). Notably, USHA was enriched in relapse patients (32.3% vs 3.4%, p = 0.006). The median tumor mutation burden of the post-relapse group was 6.14/Mb, significantly higher than the pre-relapse group (Median: 2.63/Mb, p = 0.047) and the non-relapse group (1.91/Mb, p = 0.025). Among the early-relapse patients, copy number amplification at 2q31.1 was prevalent in the pre-relapse group (p < 0.05). Two patterns of clonal evolution were identified during the recurrence, including autonomous clonal evolution and acquired clonal evolution. Compared with non-tumor tissues, differentially expressed genes in pre-relapse affected the metabolism-associated pathways. Furthermore, post-relapse samples down-regulated antigen processing and presentation signaling pathway compared to non-relapse group. Interestingly, lower plasma dendritic cell infiltration was detected in post-relapse (p = 0.0078), indicating the defect of antigen presentation in recurrence. Concentrating on the primary tumor specimens, samples from relapse patients showed higher infiltration of CD8+T cell (p = 0.019), Helper T cells (p = 0.0036) and Treg cells (p = 0.0071) than that from non-relapse patients. Conclusions: This study elucidated the recurrence risk molecular and immune microenvironment in stage IA NSCLC patients. Findings in our research may help find out the subset of patients with early stage at high risk for recurrence who have the urgent need for postoperative intervention and guide therapeutic strategies.
Single institution toxicity of definitive chemoradiation and maintenance durvalumab in locally advanced non-small cell lung cancer.
Authors: Prodduturvar Pranitha , Leventakos Konstantinos , Potter Ashley , Gao Robert W. , Dimou Anastasios , Marks Randolph , Garces Yolanda I. , Olivier Kenneth R. , Molina Julian R. , Merrell Kenneth , Mansfield Aaron Scott , Adjei Alex A. , Schwecke Anna , Hocum Craig , Moffett Jenesse Nicole , Park Sean Sunghun , Owen Dawn 
Published: June 2021

e20554 Background: The paradigm for locally advanced non-small cell lung cancer has been markedly altered to include maintenance durvalumab (D) post completion of definitive chemoradiation (CRT) following the publication of the Pacific trial in 2018. The toxicity of this treatment has not been well evaluated in the real-world setting. Methods: We identified 42 patients (pts) with Stage IIB-IIIC NSCLC treated at Mayo Clinic Rochester between 6/1/2018 and 10/1/2020 who received definitive CRT followed by maintenance D. Data were abstracted by retrospective chart review under an IRB approved protocol. Results: Median age was 66 yrs (range 47-90) and 62% were women. Primary lung cancer histology included 19 adenocarcinoma, 20 squamous cell, and 3 adenosquamous. The distribution of stages was: IIB (4/42), IIIA (15/42), IIIB (19/42), IIIC (4/42). Approximately half of patients had PDL1 expression > 25% (20/42). With a median follow up of 12.2 months (calculated from first cycle of D; range 4.2-30.5 months), 14 had completed one year of maintenance D, 16 were receiving ongoing D, and 10 stopped D early with 6/12 discontinuing due to disease progression (4/6 local progression, 2/6 distant progression). Other reasons for discontinuation (5/10) included grade 3 colitis, grade 2 hepatitis, aspergillus lung infection, and flare of autoimmune disorders. One quarter of patients experienced grade 2 radiation pneumonitis (RP; 10/42) with median time to development of RP 78 days from end of CRT and 45 days from start of D. RP was determined by multidisciplinary review of imaging and treatment fields. 17/42 patients developed immune related adverse events (see Table for details). There was minimal overlap between the patients who experienced pneumonitis and immune related toxicity; 2/17 had both pneumonitis and immune related toxicity (hepatitis, thyroiditis). Conclusions: In our early experience with the Pacific regimen, 29% of patients did not complete D due to either toxicity or progression during D administration. Pneumonitis was common (10/42 patients) although there were no grade 3 events. Nearly half of the patients developed an immune-related adverse event. Further analysis is needed to evaluate the real-world toxicity of this treatment as well as oncologic outcomes.[Table: see text]
Validation of National Comprehensive Cancer Network Guidelines (NCCN) at a single institution.
Authors: Dolan Daniel Powell , Polhemus Emily , Lee Daniel N. , Gentilella Chris , Tsukada Hisashi , Bueno Raphael , Khalil Hassan , White Abby , Swanson Scott James 
Published: June 2021

e20556 Background: Invasive mediastinal staging is necessary to identify locally advanced non-small cell lung cancer (NSCLC). We sought to validate NCCN guidelines for invasive mediastinal staging. Methods: We retrospectively reviewed all patients who had curative lung resection for pathologically confirmed NSCLC from October 2018 to December 2019. We excluded patients who had induction therapy without undergoing invasive mediastinal staging first. We evaluated methods of mediastinal staging, staging results, and final pathology. Indications for staging were one or more of the following; mediastinal lymph nodes > 1.0cm in short axis, Standardized Uptake Value of > 3.0 on Positron Emission Tomography, > 50% of tumor on medial side of mid-clavicular line (central vs peripheral), or peripheral lesion > 3.0cm in diameter. Staging methods were mediastinoscopy, endobronchial ultrasound (EBUS), and video-assisted thoracoscopic surgery (VATS) ipsilateral mediastinal staging before resection of main tumor. Results: In total, 457 lung resections were performed. Staging was done in 144/275 indicated cases (52.4%). Mediastinoscopy was completed in 49 patients, with 20.4% (n = 10) N2-positive. The false negative rate of mediastinoscopy was 4.1% (n = 2 at station 7). EBUS was performed in 64 patients and 21.9% (n = 14) were N2 positive. The false negative rate for EBUS was 3.1% (n = 2 at station 7). Two mediastinoscopy and 9 EBUS patients had 0 N2 stations sampled. None of the patients were ultimately N2 positive. Staging of three mediastinal stations (4L, 4R, and 7) was done in 26/49 mediastinoscopies and 15/64 EBUS. Of 20 patients who had VATS ipsilateral mediastinal staging, none were N2 positive and there were 0 false negatives. This left 131 patients who did not received indicated staging. The most common indication in this group was central location, 83.2% (n = 109). Four of these unstaged patients were N2 positive at resection (3.1%). The sole indication for these 4 patients was a centrally located tumor. Clinical tumor sizes were 1.2 cm, 1.3 cm, 1.5 cm, and 1.9 cm. Overall, the N2-positive rate of the staged group was 24/144 (16.7%) vs 4/131 (3.1%) N2 positive in the unstaged group, p < 0.001. Conclusions: The current NCCN staging guidelines accurately reflect the risk of N2 disease for NSCLC. The indication of central location for tumors may benefit from being reevaluated in a larger cohort, particularly given efficacy of adjuvant therapy.
Analysis of chemotherapy efficacy according to histology in malignant pleural mesothelioma (MPM) patients (p).
Authors: Cedres Perez Susana , Assaf Pastrana Juan David , Iranzo Patricia , Callejo Ana , Pardo Nuria , Navarro Alejandro , Martinez-Marti Alex , Marmolejo Castañeda David Humberto , Lostes Julia , Gonzalo Javier , Frigola Joan , Carbonell Caterina , Amat Ramon , Pedrola Anna , Dienstmann Rodrigo , Felip Enriqueta 
Published: June 2021

e20563 Background: MPM is a highly aggressive pleural tumor associated with asbestos exposure and with limited survival despite systemic therapy. Histology is a prognostic factor and recently CheckMate 743 trial demonstrated survival benefit of immunotherapy in first line with some differences in the efficacy of chemotherapy according to histology. However, randomized trials who led to the approval of antifolate in mesothelioma did not include analysis of outcomes by histology. The objective of this study is to characterize the impact of chemotherapy according to histology in p with MPM at our institution. Methods: We review 189 MPM p diagnosed at Vall d´Hebron University Hospital between November 2002 and April 2020. Associations between clinical variables and outcome were assessed with Cox regression models and survival data were calculated by the Kaplan-Meier method. Results: Patient’s characteristics: median age 68 years (y) (45-88 y), males: 70%, performance status (PS)1: 69%, asbestos exposure: 75%, epithelioid subtype: 76%. First line chemotherapy was offered to 85% of p (66% cisplatin-pemetrexed and 27% carboplatin-pemetrexed). Median overall survival (OS) in overall population was 21.3 m (95%CI17.2-24.3). Epithelioid histology, PS 0, neutrophil-lymphocyte ratio <5 and treatment with cisplatin vs carboplatin were associated with significant improvements in OS (p<0.001). When we analyzed the survival of patients who received first line chemotherapy according to histology, we found that patients with epithelioid tumors had better PFS and OS. Median PFS for p with epithelioid tumors treated with chemotherapy in first line was 4.8 m versus 3.6 months non-epithelioid (HR1.5 CI95% 1.1-2.3; p=0.03). OS of epithelioid p treated with first line chemotherapy was 26.7 m versus 15.0 m non-epithelioid patients (HR2.25 CI95% 1.4-3.4; p<0.001). We analyzed if the differences in survival according to histology were due to type of systemic treatment received (Table). Conclusions: In our series, p with non-epithelioid tumors presented worse prognosis. We confirmed histology is a prognostic factor with better OS for p with epithelioid tumors. Moreover, we demonstrated better efficacy of chemotherapy in epithelioid tumors, although histology is not a predictive factor for the platinum agent sensitivity (p of interaction PFS=0.09, p of interaction OS= 0.65).[Table: see text]
Multivalent state transitions regulate the intratumoral composition of small cell lung carcinoma.
Authors: Gopal Priyanka , Petty Aaron , Bareja Rohan , Bera Titas , Rogacki Kevin , Patel Jyoti D. , Peacock Craig , Abazeed Mohamed E. 
Published: June 2021

e20587 Background: Small cell lung carcinoma (SCLC) is an aggressive, tobacco-associated tumor with neuroendocrine features characterized by rapid growth, metastatic progression, and initial response followed by almost invariable resistance to therapy. Studies to date have not resolved the extent that diverse transcriptional programs drive SCLC and contribute to its lethality. Methods: We combined one of the largest and most diverse inventories of patient-derived xenograft models of SCLC with an ex vivo culture system that maintains transcriptional fidelity with matched primary SCLC tumor to identify transcriptional state heterogeneity. Using the expression of the Ascl1, NeuroD1, and Yap1 as markers of well-conserved SCLC states, we developed a state-of-the-art fluorescent platform that can directly measure single-cell state transitions in a multi-layered ecosystem using tandemly integrated reporters. We modeled population dynamics using a discrete time Markov chain and directly measure single-cell state transitions. Results: We show significant cell-state heterogeneity in several SCLC primary tumors, patient-derived xenografts (PDX), and ex vivo cultures. These states comprise distinct subpopulations marked by the master regulatory transcription factors (TFs) Ascl1, NeuroD1, and Yap1. Ex vivo, the 3 TFs are associated with suspension aggregates of small neuroendocrine cells, pre-suspension (loosely adherent) aggregates, and large mesenchymal cells with visible cytoplasm and spindle-like membrane extensions, respectively. We have observed equilibria in cell-state proportions in SCLC tumors both in vivo (PDX) and ex vivo. In addition, we have shown that the “elasticity” of SCLC responses, measured as the extent of clinical response during chemotherapy followed by the time to relapse from the end of therapy, is dependent on tumor TF levels. These observations suggest that mechanistic modeling of intra-tumoral state dynamics is of high clinical relevance. Conclusions: Our integrative approach is poised to formulate and validate a unified model of cellular states and program diversity in SCLC. If successful, the characterization of malignant cell ontogenic programs, their plasticity, and the advancement of new therapies designed to combat plasticity by epigenetic reprogramming will create a new scientific canvas for the study of this highly lethal disease.
Exploring the applicability of immunotherapy in different EGFR mutation subgroups based on data analysis of 9,659 Chinese patients with NSCLC.
Authors: Peng Hao , Zhang Hushan , Zhang Libin , Wang Yang , Shen Xudong , Huang Depei , Xu Zheyuan , Wang Han 
Published: June 2021

e21020 Background: Here we assessed TMB level, PD-L1 expression, and their correlation in 9649 Chinese NSCLC patients with or without EGFR mutation, and different subtypes of EGFR mutations, to find out the underlying mechanisms that different outcomes of ICI for EGFR wild type and EGFR mutation NSCLC patients, and the possibility of ICI therapy for NSCLC patients of different EGFR mutation subtypes. Methods: Tumor tissue samples of 9649 NSCLC patients were collected from Janary 2018, expression of PD-L1 were detected by using Dako PD-L1 IHC 22C3 pharmDx, Tumor Proportion Score (TPS) was used to determine expression of PD-L1. Gene mutation was detected by means of next generation sequencing (NGS). Performed Whole-Exome Sequencing (WES) on 70 tissue samples and corresponding White Blood Cells (WBCs) as matched control. Other samples were detected with panel covering whole exon regions of 733 cancer related genes. All these detections were performed in a College of American Pathologists (CAP)-certified and Clinical Laboratory Improvement Amendments (CLIA)-accredited lab for gene mutation analysis (3D Medicines Inc.,Shanghai, China). Statistical analysis was performed using GraphPad Prism (version 7.01) and SPSS version 21.0 (SPSS,Inc.). Results: Results showed that the proportion of EGFR mutation in Chinese patients with NSCLC was 51.3%, and the proportion of EGFR mutation subtypes were 42.6% L858R, 39.5% exon 19del, 2.3% exon 20in, 4.3% T790M. These samples were divided into different groups according to EGFR mutation, both WES based and panel-based results showed that EGFR wild type group displayed higher TMB level than EGFR mutation group (P < 0.05). However, except for exon 19del, L858R, exon 20in, no significant differences were found between wild type and other EGFR mutation subtypes. Furthermore, results of IHC revealed that, higher proportion of strong positive PD-L1 expression (TPS≥50) were found in EGFR wild type than exon 19del, L858R and exon 20in, no significant correlation was found between TMB level and PD-L1 expression. Conclusions: EGFR mutations account for half of Chinese NSCLC patients. The biomarkers of immune checkpoint inhibitors (such as TMB and PD-L1) are different in various EGFR mutation subtypes, which may indicate that for some NSCLC patients with EGFR mutation subtypes, they may also respond to ICI treatment as wild-type.