bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prospective evaluation of cell-free DNA fragmentation profiles for lung cancer detection.
Authors: Wong Kwok-Kin , Mazzone Peter J. , Tsay Jun-Chieh , Pass Harvey I. , Vachani Anil , Thompson Jeffrey C. , Ryan Allison , Carey Jacob , Jakubowski Debbie , Wu Tony , Zong Yuhua , Portwood Carter , Lumbard Keith , Catallini Joseph , Arjungi Kavita , Birch Ashley , Leal Alessandro , Bach Peter Brian , Scharpf Robert B. , Velculescu Victor E. 
Published: June 2023

e20521 Background: Annual lung cancer screening can save lives, but fewer than 10% of eligible persons participate each year. More widespread screening is hindered by cost, inaccessibility, and uncertainty over individual-level benefit vs risk. Screening rates could be raised by a simple, inexpensive initial blood test, if it were sensitive for cancer detection. The DELFI (DNA evaluation of fragments for early interception) technology uses low-coverage, whole-genome sequencing and machine learning to identify patterns of cell-free DNA (cfDNA) fragmentation associated with cancer. Here we report preliminary cfDNA analysis results from DELFI-L101 (NCT04825834), a prospective, observational, multistate case-control study to train and test DELFI classifiers for lung cancer detection. Methods: Enrollees were ≥50 years old with current or previous smoking histories of ≥20 pack-years and recent or planned chest CT imaging. Medical history was recorded at enrollment, and blood samples were collected for DELFI analysis. Repeated 10-fold cross-validation was used to develop a classifier for lung cancer detection. A split study approach is planned for independent validation of the classifier. Results: At this time, 242 individuals with lung cancer and 652 without cancer have enrolled. Most participants were ≥65 years old, and the proportions of men and women were similar. Lung cancer risk factors were present among both cases and controls. Like the lung cancer screening population, approximately half of lung cancer cases were stage I. Median DELFI scores were higher among individuals with lung cancer than no cancer, overall and across groups stratified by age or body mass index (BMI). Cross-validated area under the receiver operator characteristic curve was 0.81 for lung cancer detection. Clinically meaningful sensitivity to detect lung cancer was attained across all disease stages, with sensitivity increasing stepwise with stage. Conclusions: We developed a classifier based on cfDNA fragmentome patterns analyzed using DELFI that could differentiate between lung cancer cases and controls with cross-validated performance across age groups, BMI categories, and cancer stages. A blood-based DELFI fragmentome test could serve as a low-cost, high-performance blood test with potential to improve lung cancer screening efficiency. Clinical trial information: NCT04825834 .
CD73/adenosine pathway-related gene signature for intratumor heterogeneity and immune infiltration in prognosis of lung adenocarcinoma.
Authors: Luo Wang , Zhang Shuhua 
Published: June 2023

e20524 Background: Adenosine is an immunosuppressive molecule that can inhibit the activity of immune cells, particularly T cells, and promote tumor growth. CD73, also known as ecto-5'-nucleotidase, is a cell-surface enzyme that plays a role in the adenosine pathway can catalyzes the conversion of AMP to adenosine. Establish and evaluate a prognosis model based on CD73/ Adenosine pathway will help to understanding of the biological mechanisms in lung adenocarcinoma (LUAD) and providing more accurate predictions for patients' treatment. Methods: The RNA sequencing (RNA-seq), whole exome sequencing (WES) and clinical data were obtained from LUAD cohorts of the Cancer Genome Atlas (TCGA). CD73/ Adenosine pathway-related genes were identified by screening for genes that were in both the CD73 STRING network (confidence = 0.9, 1st shell ≤50 interactors) and the KEGG purine metabolism pathway gene list(map00230). Least absolute shrinkage and selection operator (LASSO) regression was conducted to develop a CD73/ Adenosine pathway-related risk score (CD73RS). Time-dependent ROC curve and survival analysis were conducted in LUAD-TCGA cohort to verify the predictive performance of CD73RS. The MATH (Mutant-Allele Tumor Heterogeneity) ITH scores were calculated to evaluate intratumor heterogeneity (ITH) in LUAD-TCGA WES "maf" files using the R package "maftools" and the "math.score" function. TIMER 2.0 database(http://timer.cistrome.org/) was conducted to estimation of tumor microenvironment to further understand the molecular features of CD73RS. An independent cohort (GSE72094) was used to verify the prognostic effect of CD73RS. Results: A prognosis prediction model based on 21 CD73/ Adenosine pathway-related genes was established using LASSO regression. Kaplan-Meier survival analysis of the risk model from LUAD-TCGA cohort showed that the high-risk group had a significantly worse prognosis (HR = 3.298, P = 1.26e-08). The area under the curve (AUC) in time-dependent ROC curve at 1, 3 and 5 years were turn out to be 0.794, 0.722 and 0.686, respectively. The validation set also showed worse prognosis in high-risk group(HR = 1.473,p = 0.0403). In the high-risk group, there was a higher ITH score compared to the low-risk group (p = 0.0094), along with lower infiltration levels of B cells(p = 7.23e-15), CD4+ T cells(p = 0.003), macrophage cells(p = 0.016), and myeloid dendritic cells(p = 0.037). Conclusions: We established and validated a CD73/ Adenosine pathway risk model that exhibits a robust predictive performance for the outcome of patients with LUAD. The CD73/Adenosine pathway has been shown to play a role in both self-driven genomic changes, such as intra-tumor heterogeneity (ITH), as well as non-autonomous processes, such as immune microenvironment adaptation, which contribute to tumor plasticity and development.
Use of immune checkpoint gene (ICG) signatures to identify selective enrichment of FGL1 and CEACAM1 in histologic subtypes of lung cancer.
Authors: Puthanmadhom Narayanan Susrutha , Huang Yufei , Owonikoko Taofeek K. 
Published: June 2023

e20527 Background: Immune checkpoint blockade has changed the management paradigm for lung cancer. Identification of vulnerable subsets using reliable predictive biomarkers is an area of unmet need. We systematically compared the pattern of expression of validated mediators of adaptive and innate immune response in clinical and histologic subsets of lung cancer using publicly available datasets. Methods: Gene expression data for lung adenocarcinoma (LUAD, N = 501) and and lung squamous cell carcinoma (LUSC, N = 491) was obtained from The Cancer Genome Atlas. We compared the expression of ICGs between LUSC and LUAD using DESeq2 and estimated the proportion of different immune cells in the tumor microenvironment by CIBERSORT. An expanded panel of ICG signatures from MSigDB was compared between LUSC and LUAD using gene set variation analysis (GSVA). Weighted gene co-expression network analysis (WGCNA) identified modules of immune checkpoint inhibitor genes with significant correlation with histology, which were further investigated for biologic pathway involvement and survival analysis using Ingenuity Pathway Analysis and Gene Expression Profiling Interactive Analysis (GEPIA2), respectively. Results: Majority of the ICGs had a higher expression in LUAD than LUSC with the strongest differential expression recorded for FGL1 (LogFC = 6.2, FDR = 1.2E-239) and CEACAM1 (LogFC = 1.4, FDR = 2E-71). Treg cells and monocytes were higher in LUAD while NK cells and macrophages were higher in LUSC. There was no difference in CD8(+) T cell population by histology. Genesets related to PD1 signaling from MSigDB had significantly higher GSVA scores in LUAD than LUSC. WGCNA identified 2 modules containing immune checkpoint genes – one module containing 15 of the 23 ICGs involved in allograft rejection, interferon gamma response, interferon alpha response, IL6-signaling, IL2-signaling and TNF-alpha signaling showed moderate correlation with LUAD (module-trait correlation = 0.3, P = 8e-26). A second module with 4 ICGs ( FGL1, LGALS3, CEACAM1, PVRL2) enriched in pathways related to carbohydrate and lipid metabolism (galactose degradation, gamma-linolenate biosynthesis) showed very strong correlation with LUAD (module-trait correlation = 0.85, P = 5e-278). Additional comparison by gender and smoking status along with external validation using independent dataset is ongoing. Conclusions: ICG expression profile differs between LUAD and LUSC with a stronger expression profile in LUAD than LUSC.
Influence of increase in hospital costs on mortality for pleural mesothelioma in teaching hospitals: A nationwide analysis.
Authors: Guevara Nehemias , Francis-Morel Garry , Perez Esmirna , Bustamante Alvarez Jean Gabriel 
Published: June 2023

e20533 Background: Rural and non-teaching hospitals are known to have a lower budget compared to urban-teaching hospitals. Pleural mesothelioma is an aggressive and rare malignancy, and it remains unknown whether treatment in institutions with higher revenue or reimbursement rates impacts outcomes. This study sought to elucidate if such a difference in outcomes exists. Methods: A retrospective cohort analysis of adults admitted from 2016 to 2020 with the primary diagnosis of pleural mesothelioma was conducted. Data was extracted from the National Inpatient Sample Database. We compared outcomes such as mortality, length of stay (LoS), and total charges in teaching versus non-teaching hospitals. Results: We identified 7,320 patients that met inclusion criteria; 84% were admitted to teaching hospitals, and the remaining 16% to non-teaching facilities ( p < 0.001). Elderly patients were the most afflicted group, with a mean age of 72 to 74 years ( p 0.009). No differences in sex, race, or primary insurance distribution were noted ( p 0.067; p 0.731; p 0.801, respectively). The mean hospital LoS was 6.4 days in non-teaching hospitals compared to 7.7 days in teaching hospitals ( p 0.0061). In addition, Asians ( p 0.016), those with a median household income of 65,000 to 85,999 ( p 0.021), higher Charlson index ( p < 0.001), and those admitted to large to medium size hospitals ( p 0.011; p 0.001, respectively) had a positive linear relation to LoS. Moreover, total hospital charges were greater in teaching hospitals (120,100 USD) in comparison to non-teaching hospitals (73,883 USD) ( p < 0.001). Mortality did not differ based on teaching status ( p 0.643). However, Native Americans and those with higher Charlson comorbidity index were more likely to die ( aOR 21, p 0.004; aOR 1.32, p < 0.001, respectively). Conclusions: Hospital teaching status does not impact mortality in patients admitted with malignant pleural mesothelioma, even though teaching hospitals incur higher expenses on average. It does not come as a surprise due to this condition's known high mortality rate, late presentation in advanced stages, and resistance to current therapies. Prevention is key in a deadly disease, and more research is needed to offer a better prognosis; even though current regimens have shown improvement in survival, curative therapies are still unavailable. Even though asbestos is subject to strict regulations in the United States, it is not banned. We should revisit the idea of a complete ban; those most affected tend to have the least access to healthcare and need a safer work environment. Decreasing exposure to known carcinogens should also be a priority, as there is no better medicine than preventive medicine. Interestingly, mortality was greater in Native Americans compared to other races; the underlying causes are broad and need more research and better characterization of MM.
Management of tumor treating fields (TTFields) therapy-related skin adverse events in pleural mesothelioma: A single center experience of TTFields therapy concomitant with chemotherapy.
Authors: Grosso Federica , Delfanti Sara , Gallizzi Giulia , Marengo Francesca , Megna Iacopo , Bertolina Carlotta , Ceresoli Giovanni Luca 
Published: June 2023

e20542 Background: Tumor Treating Fields (TTFields) therapy is a noninvasive, locoregional modality comprised of electric fields which disrupt critical cellular processes necessary for cancer cell viability and tumor progression. TTFields therapy is FDA approved and CE-marked for glioblastoma, and pleural mesothelioma. Approval for the latter was based on results from the phase 2 STELLAR study (EF-23, NCT02397928), in which the median OS was 18.2 months (95% CI 12.1–25.8) and median PFS was 7.6 months (95% CI 6.7–8.6). As the electrical fields are delivered non-invasively via skin-adhered arrays, the most common adverse events (AEs) are mild-moderate skin reactions which can be effectively managed with appropriate prophylaxis and timely intervention. Here we report a single-center experience of treating and managing TTFields therapy-related AEs in the STELLAR study, based on a center-specific protocol. Methods: The STELLAR study was a multicenter, single-arm, non-randomized, phase 2 study, whereby patients received TTFields therapy (150 kHz, 18 h/day) concomitant with pemetrexed (500 mg/m2) and platinum-based chemotherapy (75 mg/m2). TTFields-therapy AEs were managed and treated using a center-specific protocol (Table). Results: In this single center, 23 patients were treated using the predefined protocol to prevent skin AEs; all were included in the safety analysis. n = 15 (65%) reported a mild-moderate skin AE (n = 12 [52%] medical device site reaction [skin AE], n = 1 [4%] had mild-moderate rash, rash erythematous and skin irritation) in the single center, vs n = 54 (68%) in the overall STELLAR population. n = 2 (9%) in the single site had a severe medical device site reaction, which was comparable with the overall STELLAR study population. Conclusions: A predefined multidisciplinary approach was successful to help prevent mild-moderate skin AEs. Timely and appropriate management of mild/moderate skin AEs can prevent exacerbations. Skin management may support usage, thus optimizing outcomes for patients. Guidelines on preventing skin AEs when using TTFields therapy are available and should be incorporated in a clinical setting. Clinical trial information: NCT02397928 . [Table: see text]
Characteristics and trends of globally registered malignant pleural mesothelioma clinical trials in the past 27 years.
Authors: Guo Chenguang , Li Congsen , Shen Guoping , Zhou HaiYu 
Published: June 2023

e20544 Background: Malignant pleural mesothelioma (MPM), arising from the serosal lining of the thoracic cavity, is a rare malignancy with limited treatment options and very poor prognosis. Recent progress in immunotherapy and innovative devices have advanced treatment fields of MPM. To help investigators understand the landscape of MPM clinical research, characteristic and trends of globally registered trials in the past decades were analyzed in our study. Methods: This is a cross-sectional analysis of MPM trials registered on ClinicalTrials.gov between January 1996 and December 2022. Characteristics pertaining to trail phase, enrollment number, study design, type, funding source, age of population, trial purpose, and participating country were extracted, and chronological shifts were analyzed. Clinical trial variables were enumerated using descriptive statistics and categorical data were presented as frequencies and percentages. Chi-square trend analysis (Cochran–Armitage trend test) was used to evaluate the trend of MPM trials. Results: 267 registered MPM trials were analyzed involving 40 participating countries among which the United States, the United Kingdom, and Italy were top 3. 8.2% trials were phase 3 and 18.7% were randomized. 74 trials had publications by the December 2022. The trial purposes concerning surgery, radiotherapy, chemotherapy, target therapy, immunotherapy, photodynamic therapy, cryotherapy, tumor treating fields （TTF）and non-anticancer research accounted for 2.6%, 5.2%, 20.2%, 25.5%, 31.1%, 1.1%, 0.7%, 0.7% and 12.7% respectively. In the past 27 years, the numbers of chemotherapy and targeted therapy trials declined while immunotherapy trails steadily escalated (all above ptrend < 0.05). There are no significant changes for the trends of each trial phase. 205 drug therapy trials involved 26 cytotoxic drugs, 44 targeted drugs and 11 immune checkpoint inhibitors and 34 other drugs. Pemetrexed-cisplatin with TTF and ipilimumab-nivolumab have changed the frontline treatment space while improvement for regulatory approvals has been far slower in salvage treatment, with the median overall survival all less than 11 months in phase 3 trials. There are no definitive trials that justify the use of predictive biomarkers for systemic therapy in MPM. Conclusions: Immunotherapy and TTF have reshaped the standard of care landscape over the past 27 years. With the enhanced understanding of molecular characteristics and mechanism of MPM, it is anticipated that ongoing immunotherapy combined with target therapy, chemotherapy or other novel treatment can improve the frontline and post-line therapeutic effect.
Association of neutrophil-lymphocyte ratio with survival in peripheral early-stage non–small-cell lung cancer after stereotactic body radiation therapy.
Authors: Huang Karen , Prasad Sharan , Ma Sung Jun , Yu Han , Iovoli Austin , Farrugia Mark , Dexter Elisabeth , Demmy Todd L. , Malik Nadia Karen , Singh Anurag K. 
Published: June 2023

e20547 Background: Prior studies have demonstrated that neutrophil-lymphocyte ratio (NLR) can predict overall survival in patients undergoing stereotactic body radiation therapy (SBRT) for multiple types of cancer. The role of neutrophil-lymphocyte ratio (NLR) as a predictor for survival in single fraction SBRT-treated non-small cell lung cancer (NSCLC) patients remains unclear. Methods: A single-institution database of peripheral early-stage NSCLC patients treated with SBRT from February 2007 to May 2022 was queried. Consecutive patients with peripheral early-stage NSCLC (T1-2N0M0) and a complete blood count within six months of the start of SBRT treatment were included. Patients treated with SBRT regimens of more than 3 fractions were excluded as these regimens were reserved for patients with centrally located lesions with higher risk of toxicity which could affect survival. Optimal threshold of neutrophil-lymphocyte ratio (NLR) was defined based on maximally selected rank statistics. Cox multivariable analysis (MVA), Kaplan-Meier, and propensity score matching were performed to evaluate outcomes. Results: A total of 286 patients (164 female [57.3%]; median [IQR] age 76 [69-81] years) were included for analysis with median follow up of 19.7 months. The median NLR was 3.06 ([IQR] 2.21-4.33). There were 15 local failures, 27 nodal failures, and 50 distant failures. On Cox multivariate analysis, as a continuous variable, NLR was shown to be an independent predictor of OS (adjusted hazards ratio [aHR] 1.06, 95% CI 1.02-1.10, p = 0.005; Figure 1) and PFS (aHR 1.05, 95% CI 1.01-1.09, p = 0.013; Figure 1). In addition, NLR was associated with DF (aHR 1.11, 95% CI 1.05-1.18, p < 0.001; Figure 1). Maximally selected rank statistics determined 3.28 as the cutoff point of high NLR versus low NLR. These findings were confirmed upon propensity matching. Conclusions: Pretreatment NLR is an independent predictor for survival outcomes of peripheral early-stage NSCLC patients after SBRT. High NLR is associated with worse overall survival, progression-free survival, and distant metastasis. Pretreatment NLR levels should be tracked on trials for early-stage NSCLC patients.
Blood-based DNA methylation panel for the early diagnosis of lung cancer.
Authors: Yang Rongxi , Di Feifei , Li Mengxia , Yang Yining , Yuan Hongli , Jin Jialie 
Published: June 2023

e20551 Background: Early detection of lung cancer (LC) is vital for reducing of LC-related mortality. Although the screening of persons at high risk for LC by low-dose computed tomographic (LDCT) has showed an inspiring 20.0% decrease in mortality, it also comes along with a dramatically high false positive rate for distinguishing the malignant nodules from the benign nodules. Thus, it is necessary to develop a diagnostic tool with high discriminant ability for identifying malignant nodules. Methods: The methylation levels of five candidate genes were quantitatively measured via mass spectrometry. A diagnostic model was developed by blood-based methylation levels in training cohort (650 LC cases vs. 114 benign lung nodules), and further validated the performance in validation cohort (195 LC cases vs. 39 benign lung nodules) by binary logistic regression. Notably, 91.8% LC cases were collected at Stage I. Results: The methylation model of 35 CpG sites was developed and validated for LC diagnosis. This model achieved a sensitivity of 85.4% and a specificity of 92.5% in training cohort [Area Under the Curve (AUC): 0.945], and a sensitivity of 84.1% and a specificity of 97.2% in validation cohort (AUC: 0.932). The performance was well maintained in (a) Stage I subgroup (n = 447), with a sensitivity of 82.6% and a specificity of 81.6%; (b) nodule diameter ≤ 1 cm (n = 113), with a sensitivity of 80.6% and a specificity of 81.6% in validation cohort. Conclusions: This study suggests that the blood-based DNA methylation panel may provide the potential utility for early diagnosis of LC cases, which would promote early diagnosis and benefit more LC patients.