bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sensitive detection of CSF-derived cell-free DNA at the CNV level by shallow whole-genome sequencing for diagnosis and characterization of CNS metastases.
Authors: Yubin Li , Shi Zongkun , An Juan , Xu Weiran , Hua Yichun , Zheng Xixi , Ding Xiaosheng , Shi Hui , Nie Yanli , Zhou Lili , Cao Dandan , Li Xiaoyan 
Published: June 2023

e21185 Background: The cfDNA targeted capture sequencing technology has been gradually applied to research central nervous system (CNS) metastases. But targeted sequencing usually requires at least 5 ng of cfDNA. Due to the limited amount of cerebrospinal fluid (CSF) that can be collected there are not many samples that can meet the requirements of targeted sequencing. Methods: This study assessed the use of shallow whole-genomic sequencing (sWGS) of blood and CSF samples obtained from 35 patients with lung cancer to identify tumor-derived cfDNA. Among them, 6 cases had no intracranial metastasis, 22 had only PMs, and 7 had LMs. Some of these cases underwent irregular follow-up. For blood samples, 5 ng cfDNA was used for library preparation. For CSF samples, try to use trace DNA to prepare libraries, regardless of whether the Qubit assays can quantify the concentration. Cytologic analysis was also performed on CSF samples from the LM cases. A total of 35 peripheral blood samples and 31 cerebrospinal fluid samples were subjected to sWGS tests, and the arm-level CNV and tumor proportion were analyzed.Cytologic analysis was also performed on CSF samples from the LMs. Results: The lowest concentration of cfDNA in 35 plasma samples was 2.20 ng/mL. But when the cfDNA was extracted from the CSF, 50% (6/12) of the LM samples and 70.59% (12/17) of the samples with only PMs could not be quantified by Qubit assays. All libraries were all successfully prepared from the samples that could not quantify cfDNA. For CSF samples from LM cases, the sensitivity of detecting tumor signals by the sWGS test was 90.9% (10/11), higher than 81.8% (9/11) by CSF cytologic analysis. For samples from PM cases, the sensitivity of detecting tumor signals by the sWGS test was 75% (21/28); among them, the detection sensitivity of samples with a total amount of cfDNA not less than 5 ng was 90% (9/10), while the detection sensitivity of samples with the total amount of cfDNA less than 5 ng was 66.67% (12/18). Three patients underwent multiple CSF cfDNA tests, of which one case with RANO evaluation as PR had a decrease in the tumor fraction in CSF cfDNA, while only one of the two cases with RANO SD evaluation had stable tumor fraction in CSF cfDNA. Conclusions: We established a method for detecting CNVs by sWGS using trace amounts of cfDNA. Using the sWGS test improves the sensitivity of the detection of LMs. Compared with targeted capture sequencing, our method reduces the requirement for the amount of cfDNA, which can be more widely used in the detection of CNS metastases, especially in PM-only patients with extremely low CSF cfDNA concentrations.
Real-world healthcare costs amongst non-small cell lung cancer (NSCLC) patients tested with a host immune classifier (HIC).
Authors: Iams Wade Thomas , Le Kimberly , Princic Nicole , Marlin Taylor 
Published: June 2023

e21187 Background: The HIC is a proteomic test that measures immune response in patients diagnosed with NSCLC. The blood based HIC stratifies patients into two groups, HIC-H and HIC-C which helps evaluate the patient’s prognosis and response to treatment. Currently, no real-world studies have described healthcare costs amongst patients tested with the HIC. This subset analysis of HIC claims examined costs among patients with NSCLC prior to and after using the HIC proteomic test. Methods: HIC test results were retrospectively queried using MarketScan Commercial and Medicare Supplemental Databases using data between January 1, 2016 to June 30, 2021 linked to Biodesix data files. Patients were included if they were age 18 and older on index date (date of HIC testing), underwent a HIC proteomic test, were continuously enrolled in the MarketScan database for the 6-months before index (pre-index period) and one month post-index, and had at least one non-diagnostic medical claim of lung cancer during the pre-index period. Healthcare costs were measured per patient per month (PPPM) during the pre-index and post-index period and compared between HIC-H and HIC-C cohorts. All-cause healthcare costs analyzed included inpatient costs, outpatient costs, outpatient pharmacy costs, total medical costs (inpatient + outpatient), and total costs (total medical + outpatient pharmacy). Results: Of the 328 included patients, 260 patients were HIC-H and 68 were HIC-C. On index, 178 patients had non-metastatic lung cancer and 150 patients had metastatic lung cancer. When examining healthcare costs prior to HIC testing, total costs and inpatient costs were higher amongst HIC-C patients ($10,299 vs $9,689 and $4,032 vs $3,218, respectively) although not statistically significant. HIC-C patients had significantly higher biopsy costs compared to HIC-H patients ($1,285 vs $400, P < 0.05) even though less HIC-C patients underwent a lung biopsy (41% vs 53%, P = 0.091). When assessing healthcare costs post HIC testing, total medical costs were significantly higher in the HIC-C patients ($25,255 vs $17,210, P < 0.05). Although not statistically significant, HIC-C patients had higher inpatient costs and total costs ($9,903 vs $5,583 and $26,237 vs $18,652, respectively). Amongst the patients had significantly higher inpatient costs ($18,580 vs $4,278, P < 0.05), total medical costs ($29,574 vs $12,446, P < 0.05) and total costs ($31,316 vs $13,500, P < 0.05). Conclusions: Patients with NSCLC who are identified as HIC-C have higher healthcare costs, including lung cancer diagnostic and total costs, prior to and post HIC testing. Utilization of the HIC test may help to identify patients who may benefit from additional health system navigation support to mitigate their anticipated increased health care costs.
CD57+CD8+ T cells and response to PD-1/PD-L1 blockade in patients with NSCLC.
Authors: Zhou Jianya , Sun Wenjia , Zeng Xun , Zheng Jing , Qu Jingjing , Jiang Nan , Zhou Jianying 
Published: June 2023

e21189 Background: Immune checkpoint inhibitors (ICIs) are currently widely used and have made significant advances in the treatment of patients with advanced non-small cell lung cancer (NSCLC). Despite available biomarker stratification, clinical responses vary. Thus, potential biomarkers for identifying patients who will benefit from the immunotherapy are urgently needed. Methods: We applied mass cytometry (CyTOF) to deeply analyze the association of cell subpopulations in PBMC before and after single-agent immunotherapy with clinical outcomes in advanced NSCLC. We then performed flow cytometry of peripheral blood and multiplex immunohistochemistry/immunofluorescence (mIHC/IF) of tumor samples to validate our conclusion. In addition, RNA sequencing (RNA-seq) was performed to explore the mechanism of the ICIs treatment efficacy of NSCLC. Results: In a prospective cohort (n = 20), high CD57+ CD8+ T cell proportion in PBMC detected by CyTOF was associated with good response ( p= 0.014) in advanced NSCLC patients. The result was confirmed in an independent, prospective cohort (n = 30) using flow cytometry, and the specificity and sensitivity of flow cytometry was then assessed in this cohort. CD57+CD8+ T cell proportion, as determined by flow cytometry, successfully stratified responders and non-responders to ICIs ( P< 0.001). We also confirmed this result in FFPE samples (n = 31) ( p= 0.004). In addition, transcriptomic differences between CD57+CD8+ T cells and CD57-CD8+ T cells were found performed by RNA sequencing (RNA-seq). Conclusions: Our results suggest that CD57+CD8+ T cell proportion may serve as a predictive value of response to PD-1/PD-L1 checkpoint blockade. Further validation in additional NSCLC cohorts is warranted.
Combining plasma and tissue next-generation sequencing provides optimal treatment selection for metastatic NSCLC: A comparative study.
Authors: Samol Jens , Bharwani Lavina D. , Chia Puey Ling , Chia Yee hong , Gehlot Pritish , Heah Kai Xin , Heong Valerie , Kulendran Lavenia , Lim Jianri , Muthu Vaishnavi , Teo Hui Lin , Vong Elise , Yeo Chong Ming , Rajah Lisa , Tan Min-Han 
Published: June 2023

e21193 Background: 64% of all NSCLC patients in the USA with targetable mutations do not receive therapy due to clinical practice gaps around biomarker identification, including guideline-recommended alterations. Similar diagnostic and access challenges are also seen in Asia, but the scope of these challenges may differ due to the different mutation profiles of NSCLC. To determine the biomarker gaps involved, we conducted a study evaluating 38 metastatic NSCLC patients who received 3 diagnostic molecular workflows, and compared all 3 results to determine potential practice gaps. This is the first study to our knowledge that evaluates 3 different diagnostic workflows for one cohort to determine relative performance. Methods: 386 newly diagnosed and pathologically confirmed patients with metastatic lung cancer were managed at our hospital over Aug 21 - Sep 22. 38 metastatic non-squamous NSCLC patients were recruited prospectively. The patients received 1 plasma NGS tests (LiquidHALLMARK, Lucence, Singapore), 1 tissue comprehensive genomic profiling (CGP) test, and a panel of single-gene molecular tests (Idylla EGFR, ALK-IHC, ROS1-FISH, PD-L1 IHC). Results: Of the 38 patients recruited for the prospective trial, liquid biopsy identified 24 actionable alterations (TAT 3-13 days), tissue NGS identified 23 actionable alterations (TAT 11-27 days) and single gene testing approach provided 17 actionable alterations (TAT variable). 6 patients did not have available tissue reports. In terms of patient numbers, liquid biopsy detected at least one G9 biomarker in 21/38 patients and tissue NGS detected at least one G9 biomarker in 22/32 patients. Combining tissue NGS and liquid biopsy provided 26/38 (68.4%) patients with targeted treatment options. Single gene testing identified at least one G9 biomarker in 16/38 (42.1%) patients. Combining tissue NGS, liquid biopsy and single gene test improved sensitivity to 73.7% (28/38 patients). Overall, an estimated 1 in 4 NSCLC patients (26.4%) would have been identified with a diagnostic strategy using combined tissue and liquid NGS, over current conventional single gene testing approaches. Conclusions: Combining tissue and liquid NGS profiling provides the best treatment selection outcomes for patients with metastatic NSCLC. Our study highlighted that a quarter of NSCLC patients in Singapore would be identified for eligible targeted treatments from adopting a nationwide NGS testing approach, ideally tissue and liquid combined, to improve cancer services.
Comparison of response from RECIST1.1 and abstraction in real-world patients with lung cancer.
Authors: Chen Lu , Davis Ryan , Lee Joe , Weberpals Janick , Wyatt Shelby , Ounadjela Souhila , Trinh Huong , Fruechtenicht Charlotta , Reyes Adriana , Huntley Melanie 
Published: June 2023

e21194 Background: Treatment response in clinical trials with solid tumors is measured by applying RECIST1.1 to radiographic images. However, response in real-world data (RWD) studies is based on information abstracted from clinician's notes. Differences in these two approaches can lead to bias when comparing response in trials to RWD. This study investigates the relationship between response from (1) certified radiologists applying RECIST1.1 to images from routine care and (2) electronic health records (EHR) notes-abstraction in the same patients. Methods: The nationwide Flatiron Health (FH) EHR-derived de-identified database was used to identify patients diagnosed with advanced non-small-cell lung cancer (aNSCLC) on/after Jan 1, 2011, with a visit in the FH network within 90 days of diagnosis, first line treatment (1L), and ≥1 radiographic image both at baseline (8 weeks before or at 1L start) and during 1L. RECIST1.1 and response abstraction were applied retrospectively to images and EHR notes obtained from routine care, respectively. For each patient, time-point responses were determined by RECIST1.1 (rwRECIST) and abstraction (rwR) and dichotomized as unconfirmed best overall response (BOR, complete+partial response = responder, all others = non-responder), and confirmed BOR if patients had an additional assessment. Results: We included 157 patients (59% on chemotherapy, 15%/12% on cancer immunotherapy combination/alone, 10% on targeted therapies). Patients had an image taken every 11 weeks (median). All images were readable and 75% were optimal quality. Response rate was lower by rwRECIST than rwR (unconfirmed: 48% vs 59%; confirmed: 34% vs 55%). Concordance in BOR between rwRECIST and rwR was 68%/60% for unconfirmed/confirmed response. Disagreement between rwRECIST and rwR was higher than inter-reader variability between radiologists and was mainly in one direction (rwR higher, Table). The disagreement was driven by patients deemed responders by abstraction who did not meet the -30% target lesion size cutoff specified by RECIST1.1 or presence of new lesions. Conclusions: RECIST1.1 can be applied to images from aNSCLC routine oncology care, although limited by image availability and less frequent assessment than trials. Differences were observed in response measured by rwRECIST and by abstraction. [Table: see text]
Docetaxel as a subsequent line after progression to platinum-based chemotherapy and immunotherapy.
Authors: Garitaonaindia Yago , Calvo Virginia , Redondo Isabel , Uribarren Maria , Ospina Serrano Aylen Vanessa , Collazo Ana , Blanco Mariola , Lozano Carla , Martinez Cutillas Marta , Manso Marta , TRASEIRA CRISTINA , Aguado Ramon , Sanchez del Corral Maria Matilde , Provencio Mariano 
Published: June 2023

e21197 Background: Docetaxel was the standard of care for patients with non-small cell lung cancer (NSCLC) after platinum-based chemotherapy failure. The introduction of immune checkpoint inhibitors (ICIs) has radically altered the first-line treatment for advanced/metastatic NSCLC without driver mutations. However, limited clinical data are known after failure of chemotherapy and immunotherapy. Efficacy of docetaxel after progressing to platinum-based chemotherapy and checkpoint inhibitors are scarce. The aim of this study is to evaluate docetaxel in patients with advanced NSCLC after chemotherapy and ICIs failure in a real-world scenario. Methods: Retrospective, single centre study, including patients treated with docetaxel after progression to platinum-based chemotherapy and immunotherapy. We analysed demographic characteristics, treatments received and survival. Long survivors to Docetaxel were defined as those who lived more than 12 months after initiating Docetaxel. Results: 65 patients were included in this study. Median age was 67.0 years and 67.7% were male. 63.1% were adenocarcinoma, 24.6% squamous-cell carcinoma and 12.3% other histologies. Objective response rate (ORR) for docetaxel was 21.0%, with a control disease rate of 42.1%. 55.7% experienced toxicity from the treatment. Median progression-free survival (PFS) and overall survival (OS) were respectively 2.0 months (1.3-2.7, IQ 95%) and 6.0 months (4.6-7.4, IQ 95%). 16 patients (24.6%) were long survivors. Differential characteristics of long survivors are shown in Table. Conclusions: Docetaxel displayed poor survival results in our study after progression to platinum-based chemotherapy and ICIs, arising the necessity of developing new therapies for this scenario. Despite these results, almost 25% of the patients lived more than one year. Objective response to docetaxel was significantly associated with surviving more than one year, and better ECOG and lacking hepatic metastases showed a non-significant trend. Clinical biomarkers predicting benefit of Docetaxel in this scenario are lacking. [Table: see text]
Using cell-free DNA to predict response to immunotherapy in non-small cell lung cancer pre- and post-treatment.
Authors: Rao Satyanarayan , Zukowski Alexis , Weirich Abigail , Kabos Peter , Stensland Elin Marie , Eide Inger Johanne Zwicky , Brustugun Odd Terje , Ramachandran Srinivas 
Published: June 2023

e21198 Background: Despite revolutionizing cancer therapy, immune checkpoint inhibitors (ICI) still do not benefit a significant proportion of patients. The risks associated with ICI-related adverse events, mixed performance of PD-L1 staining in predicting treatment response and its high cost, present a clinical need for more precise methods to define disease states in the context of ICI treatment. ICI response is thought to depend on the phenotype of the tumor and the associated immune response, especially functional state of CD8+ T cells in the tumor microenvironment (TME). Methods: Here we show that the CD8+ T cell signatures from plasma cell-free DNA (cfDNA) could be used to predict response of patients to anti-PD-1 therapy, using samples collected before and shortly after start of treatment. Blood samples were drawn just before the first dose, 1 day to 1 week before the start of treatment and 45-60 days since start of treatment. The treatment duration varied depending on response. Response was evaluated by CT scans every 8-12 weeks. 11 of the samples are from patients with no or minor response ( < 6 months of treatment), and 12 are from patients with prolonged benefit of the medication ( > 1 year of treatment). Exhausted CD8+ T cells, one of the targets of immunotherapy treatment are epigenetically regulated. So, we utilized naïve and PD-1high CD8+ T cell ATAC-seq data to define the repertoire of accessible chromatin specific to these cell types. We found an enrichment of short cfDNA fragments at a significant fraction of these sites, enabling us to define responder-specific and non-responder-specific accessible PD-1high regions from cfDNA. Results: We used the enrichment of short- versus long-cfDNA fragments (reflecting transcription factor-nucleosome dynamics in tissue of origin of cfDNA) as a scoring function, and repeated-cross-validation as a classifier model to identify differentially enriched features between responders and non-responders. Our model accurately predicts the two classes of response both pre-treatment (mean test AUC = 0.86; SD = 0.14). Conclusions: Notably, in addition to generating an accurate classifier, our analysis enabled us to identify predominant transcription factor motifs from predictive ATAC-seq peaks that characterize both response and lack of response, paving the way for further understanding the mechanistic basis of patient-specific response to ICI. Our results suggest the possibility of personalized prediction of treatment response that is independent of specific tumor genotype.
Time to treatment initiation in a retrospective cohort of patients with advanced lung cancer treated with an immune checkpoint inhibitor.
Authors: Quattlebaum Alexander M. , Faucheux Andrew T. , Russell Greg B. , Duckworth Christopher , Hunting John , Elko Catherine A. , Khoury Lara M. , Bloomer Chance H. , Ruiz Jimmy , Lycan Thomas William 
Published: June 2023

e21199 Background: Advanced lung cancer is diagnosed by imaging through screening, incidental findings, or during the workup of symptoms. Historically, there was no apparent benefit in expediting the times to biopsy, staging, and chemotherapy initiation. However, the widespread first-line use of immune checkpoint inhibitors (ICIs) can introduce delays such as biomarker testing and financial approval. We aimed to test whether the time to ICI treatment initiation was associated with worse clinical outcomes. Methods: We created a retrospective registry of all patients with advanced lung cancer who received at least one dose of an ICI for any first-line indication between 2/1/2011 and 4/7/2022 at a comprehensive cancer center and its outreach clinics and made a validated database. We defined the time to biopsy as the interval between the initial diagnostic imaging of the index cancer and the biopsy. We defined time to treatment initiation (TTI) as the interval between initial imaging and the first dose of ICI. Overall survival was the interval from the biopsy date to death. We used a Cox multivariate regression to model the continuous association of each additional month of TTI with survival. Confidence intervals (CI) were calculated to 95%, and p-values < 0.05 were considered significant. The study had institutional IRB approval. Results: Our cohort consisted of 472 patients diagnosed with advanced lung cancer and treated with first-line ICI. The median time to biopsy was 15.5 days with an interquartile range (IQR) of 5-29 days, median TTI was 51 days (IQR 35-79), and median overall survival was 14.3 months (CI 11.5-16.6). TTI was not associated with survival by unadjusted or multivariate analysis (HR 0.98, CI 0.95-1.01 and HR 1.02, CI 1.00-1.05, respectively). Smoking history (HR 1.011, CI 1.00-1.02 per pack-year) and higher pre-treatment ECOG performance scores (p < 0.01) were associated with worse survival. Tumor histologic subtype, autoimmune comorbidities, and toxic dust exposure were not associated with survival. The time to biopsy was not associated with survival by unadjusted or multivariate analysis (HR 0.97, CI 0.95-1.01, and HR 1.02, CI 0.97-1.07, for each additional week). Among the subset of patients with a symptomatic presentation of cancer (n = 363, 77%), longer TTI was associated with improved survival, but this effect became non-significant in multivariate analysis (HR 0.94, CI 0.89-0.99 and HR 0.96, CI 0.86-1.08, respectively). Conclusions: We did not find evidence that a shorter TTI is associated with improved survival among patients with advanced lung cancer starting first-line ICI. Additional studies are needed to test if baseline disease burden or other clinical factors can identify patients who would benefit from expedited initiation of treatment.