bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic characteristics of cerebrospinal fluid-derived circulating tumor DNA in brain metastases of lung adenocarcinoma.
Authors: Tao Rongjie , Zhang Hui , Xu Shaohua , Li Tao , Tang Xiaoyong , Wu Jiayan , Sun Xuejiao , Zhang Chunmei , Shangguan Hong 
Published: July 2024

e20503 Background: Brain metastases (BM), encompassing parenchymal metastases (PM) and leptomeningeal metastases (LM), are a common and fatal complication of advanced lung adenocarcinoma (LUAD). However, the genomic disparities between PM and LM, as determined by cerebrospinal fluid (CSF)-derived circulating tumor DNA (ctDNA), and its clinical utility as a liquid biopsy medium remain unclear. Methods: We conducted a retrospective study involving 33 patients diagnosed with BM from LUAD, comprising 16 cases with PM and 17 cases with LM, at Shandong Cancer Hospital between March 2018 and June 2021. CSF and matched peripheral blood lymphocyte samples were collected from all patients, and plasma samples were collected from 25 of them. Genomic profiles of CSF and plasma in patients with PM and LM were compared. CSF-ctDNA, plasma-ctDNA, and DNA from matched peripheral blood lymphocytes underwent next-generation sequencing (NGS) based on a 769 cancer-related gene panel. Results: A total of 363 mutations were detected in CSF-ctDNA, with 90.9% (30/33) of all LUAD patients with PM or LM showing mutations. EGFR mutations were the most common, occurring in PM samples from 56.3% (9/16) of patients and in LM samples from 76.5% (13/17) of patients, followed by other frequently mutated driver genes, including TP53 in 19 (57.6%) patients, MLH1 in 9 (27.3%) patients, and KMT2C in 8 (24.2%). Notably, EGFR 19del was more prevalent as a driver mutation in patients with LM compared to those with PM in our study, particularly the p.E746_A750del mutated subtype. Furthermore, the frequency of mutations in the mismatch repair (MMR) pathway was significantly higher in patients with LM than in those with PM. Additionally, CSF exhibited a more comprehensive profile of driver genomic mutations than matched plasma in patients with any form of BM, accompanied by a higher variation burden and detection of druggable mutations. Conclusions: CSF-ctDNA sequencing revealed distinct genomic patterns in patients with BM, particularly in LM, and could potentially enhance the management of BM patients compared to plasma.
Ultra-short circulating tumor DNA (usctDNA): A new paradigm for ctDNA liquid biopsy.
Authors: Wong David T. , Wei Fang , Lin Chien-Chung , Huang Wei-Lun , Tang Cheuk Ying , He Hua-Jun , Kim Yong , Li Feng 
Published: July 2024

e20510 Background: Mononucleosomal ctDNA (mnctDNA, 157-bp, double-stranded) spearheads liquid biopsy (LB) for cancer detection, treatment and clinical care. The bottleneck of mnctDNA LB are low copy number of ctDNA and limit of detection of platform technologies. Recent discovery of ultra-short ctDNA (usctDNA, 52-54 nt, single-stranded) that harbors somatic mutations prompted us to explore the quantification and stoichiometry of usctDNA to mnctDNA in plasma and saliva of NSCLC patients. Methods: Paired plasma and saliva from 20 advanced NSCLC patients with tissue genotyped positive for L858R were processed for cfDNA extraction and quantification with Qubit and Tape Station. Digital PCR assays targeting L858R somatic mutation to generate amplicons of 57-bp (usctDNA) and 100-bp (mnctDNA) were performed by UCLA and independently by NIST. Results: Results in Table 1 revealed that three findings of usctDNA that will have potential to impact ctDNA liquid biopsy. First, the somatic mutation (L858R) is present in usctDNA. Second, The stoichiometric ratio of usctDNA to mnctDNA is similar in plasma and saliva at 1.6X. For the wild-type counterpart, the ratio is 1.1X for plasma and 0.6X for saliva. Third, the copy number of usctDNA and mnctDNA in saliva to plasma is 7.8X and 7.7X. Conclusions: Detection of tumor-associated/specific EGFR L858R somatic mutations in uscfDNA is translationally impactful, adding 1.6X of the ctDNA targets for molecular detection, effectively cumulating 2.6X of total ctDNA targets, permitting earlier cancer detection, treatment monitoring and therapy prognostication. The finding that saliva harbors 7X of the us- and mnctDNA further raises the prospect of advancing saliva ctDNA liquid biopsy for NSCLC detection as it may effectively allow 15.5X (7.8X+7.7X) ability to detect malignancy-associated ctDNA. [Table: see text]
What is a bad ALK? A scoping review of molecular markers of poor prognosis.
Authors: Chan Sze Wah Samuel , Zeng Joy , Liu Geoffrey , Jao Kevin , Juergens Rosalyn A. 
Published: July 2024

e20530 Background: Patients with non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase ( ALK) rearrangements derive a significant and durable clinical benefit from tyrosine kinase inhibitors (TKI). However, a portion of patients have progressive disease as their best response and progress to death much earlier than expected which is termed primary resistance. This scoping review aims to summarize the known molecular mechanisms that underlie this lethal ALK phenotype. Methods: We performed a systematic scoping review from scientific databases such as Ovid Medline, Ovid Embase, and Cochrane Central Register of Controlled Trials. Data was extracted from the database inception to March 13, 2023. Studies included molecular markers of poor prognosis, with a focus on TP53, variant 3 re-arrangements, and reports of poor clinical response to TKIs (defined as progression-free survival less than 3 months on 1st line TKI or overall survival less than 2 years from exposure to 1st line TKI). 2nd generation and 3rd generation ALK TKI clinical trial data were also included. Results: A total of 4360 studies were screened and 136 studies were included. Numerous studies implicated the negative prognostic role of variant 3 likely mediated through the acquisition of on-target resistance mutations compared to other variants. TP53 mutations were also associated with a worse prognosis and implicated with greater chromosomal instability and mutational burden. Furthermore, reports of both variant 3 and TP53 mutations together were associated with even worse survival suggesting both molecular mechanisms combined can confer primary resistance phenotype. Other mediators of primary resistance included aberrations in cell cycle regulators such as CDKN2A/B loss, mutations in cell signalling pathways such as the PI3K/ AKT/mTOR pathway, deficiencies in DNA repair mechanisms, and uncommon fusion partners. Consistent with these prior studies, comprehensive genomic analysis from clinical trial data of 2nd generation and 3rd generation TKIs was unable to identify a singular genomic signature that underlies this lethal phenotype. However, a general trend from the literature suggested that the combination of multiple aberrations is likely necessary to confer a primary resistance phenotype, though the relative contribution of each somatic mutation likely will vary. Conclusions: This scoping review highlights that in NSCLC, the lethal ALK phenotype is likely composed of a heterogeneous population of various combinations of poor prognostic factors including variant 3, mutations in cell cycle regulators and other aberrations in cell signalling pathways. There remains an unmet need for a genomic assay to integrate all these various molecular markers to predict the lethal ALK phenotype.
Impact of concomitant H1 antihistamine administered during initiation of immune checkpoint inhibitor therapy on survival outcome and safety in patients with advanced primary lung cancer.
Authors: Zhang Weihong , Li Bingxue , Liu Liang , Ren Xiubao 
Published: July 2024

e20532 Background: Antihistamines alleviate the side effects of antitumor drugs and have some antitumor effects. However, they have rarely been tested in combination with other antitumor therapies, especially immunotherapy. Methods: We compared the progression-free survival (PFS) and overall survival (OS) of patients with advanced primary lung cancer (stage III or IV) receiving immunotherapy with H1 antihistamine diphenhydramine alone (n = 40) or in combination with H2 antihistamine cimetidine (n = 69) [experimental group] to those receiving immunotherapy alone (n = 75) or with a H2 antihistamine cimetidine (n = 27) [control group]. We used the inverse probability of treatment weights (IPTW) to balance the two groups. Kaplan Meier curves were used to compare OS and PFS between the two groups. Cox regression analyses were used to describe the association between patient characteristics and OS or PFS. Results: The experimental group comprised 109 patients, while the control group comprised 102. The median PFS (mPFS) was 12.7 months in the experimental group and 4.3 months in the control group (HR 0.46, 95% CI 0.35-0.63, P < 0.001). The median OS (mOS) was 32.8 months in the experimental group and 18.1 months in the control group (HR 0.63, 95% CI 0.44-0.91, P = 0.038). In the experimental group, patients treated with only H1 antihistamine had longer mPFS and mOS as compared with those who received H1 plus H2 antihistamines (mPFS: 18.0 months vs. 6.8 months, HR 1.40, 95% CI 0.26-0.63, P < 0.001; mOS: not reached vs. 26.6 months, HR 0.55, 95% CI 0.32-0.94, P = 0.030). In the control group, patients who received no antihistamine had longer mPFS and mOS compared to those who received only H2 antihistamines (mPFS: 5.8 months vs. 4.1 months, HR 0.44, 95% CI 0.29-0.67, P < 0.001; mOS: 25.5 vs. 16.9 months, HR 0.61, 95% CI 0.37-1.00, P = 0.049). After multivariate analyses, H1 antihistamine was the independent good prognostic factor for PFS and OS (PFS: HR 0.44, 95% CI 0.31-0.65, P < 0.001; OS: HR 0.62, 95% CI 0.39-0.99, P = 0.047). Conversely, H2 antihistamine was the independent poor prognostic factor for PFS and OS (PFS: HR 2.44, 95% CI 1.67-3.57, P < 0.001; OS: HR 2.38, 95% CI 1.49-3.70, P < 0.001). After IPTW, the rate of any grade of irAEs in the experimental group was 52.4%, while that of the control group was 69.2% ( P = 0.015), including 4.5% for irAEs grades ≥3 in the experimental group and 25.9% for irAEs grades ≥3 in the control group ( P = 0.003). Conclusions: Concomitant H1 antihistamines can not only improve immunotherapy efficacy but also reduce irAEs. Concomitant use of H2 antihistamines may shorten PFS and OS time.
Single-cell transcriptome in the examination of the molecular characteristics of macrophages in lung cancer brain metastasis.
Authors: Zhao Jixing , Yan Wu , Huang Wencong , Li Yongsheng , Jing Zhang , Li Yingqiang , Guo Jia 
Published: July 2024

e20546 Background: Brain metastasis is one of the most common distant metastasis types in lung cancer patients. Its mechanism involves multiple factors, including cell-cell interactions, immune evasion, and the influence of the microenvironment. Single-cell RNA sequencing technology has significantly advanced our understanding of tumors at a single-cell resolution. It enables an in-depth understanding of the expression profiles of metastatic cells in brain tissue, providing potential predictive biomarkers for future monitoring, diagnosis, and effective treatment. Methods: We collected 50 samples from the GEO database, including 17 normal lung samples, 17 lung cancer samples, and 16 brain metastasis samples. We used the MNN method for batch correction and performed differential analysis using findAllMarkers and FindMarkers. Additionally, we conducted enrichment analysis using ClusterProfiler. Results: After batch correction and re-clustering of the macrophages, we identified 9 clusters. Based on their biological functions, they were classified into 5 macrophage subtypes: RTM_macro, Angio_macro, SEPP1_macro, Prolif_macro, and Mono_like. The angiogenic macrophages (Angio_macro) were most prominent in lung cancer brain metastasis samples (52%), followed by lung cancer (25%), and least present in normal samples (17%). Enrichment analysis revealed that iron death, antigen processing and presentation, and endoplasmic reticulum protein processing were more enriched in brain metastasis. This correlates with the high proportion of angiogenic macrophages present in the brain. The SEPP1_macro subtype showed high expression of SEPP1 and VCAN, genes associated with angiogenesis. Studies suggest that SEPP1 is associated with poor prognosis as it promotes neovascularization and tumor invasion. This subtype was highly expressed in brain metastasis (40%) and lung cancer (45%), but rare in normal samples (4%). In the SEPP1_macro subtype, brain metastasis samples were enriched in signaling pathways such as tumor necrosis factor, PI3K-AKT, NF-kB, and Mitogen-activated protein kinase (MAPK), focusing mainly on the interaction of cytokines and cytokine receptors. Conclusions: In lung cancer and lung cancer brain metastasis, there is a significant presence of macrophages that promote angiogenesis and subpopulations of tumor-promoting cells associated with poor prognosis. The existence of these two cell subsets may indicate their activation during tumor metastasis and their regulatory role in the formation of new blood vessels, thereby promoting tumor growth.
Interchangeability of anti-PD1 antibodies in patients (pts) with metastatic NSCLC.
Authors: Kravchuk Darya , Fedyanin Mikhail , Ivan Borovkov , Moiseenko Fedor Vladimirovich , Zhukova Lyudmila , Pokataev Ilya , Rays Anastasia , Chubenko Viacheslav , Volkov Nikita , Ivanilov Kirill , Glazkova Elena 
Published: July 2024

e20553 Background: PD-(L)1 inhibitors are approved immunotherapy agents in treatment for mNSCLC, however, limited data exists about switching between different anti-PD1 antibodies. Our study aimed to evaluate the safety and efficacy of the interchangeability of nivolumab, pembrolizumab, and atezolizumab in patients (pts) with mNSCLC in the 2nd and 3rd line. Methods: We retrospectively evaluated data of pts with mNSCLC treated in four oncology centers in Moscow and SaintPetersburg (Russia). Inclusion criteria were as follows: histologically confirmed mNSCLC with no driver mutations, performance status ECOG 0-2, monotherapy of anti-PD(L)1 antibody, and switching to another PD(L)1 inhibitor for any reason except progression disease or toxicity after initiating of immunotherapy. The primary end-point was progression-free survival (PFS), and secondary end-points were the rate of all grades and grade 3-4 adverse events (CTC AE 5.0). A sample size of 83 achieves 80% power to detect an equivalence difference of 15% in 3-months PFS after the change of anti-PD1 antibody with a one-sided significance level of 0,05. Results: A total of 103 patients (27% female) were included with a mean age of 66 years (33-93). 0-1, 2, and ≥3 organs with metastases have 70 (68%), 17 (17%), and 16 (16%) pts, respectively. Performance status ECOG 0, 1, and 2 was in 16 (16%), 70 (68%), and 17 (17%) pts, respectively. 50 (48%) patients received pembrolizumab, 40 (39%) pts received nivolumab, and 13 (13%) pts – atezolizumab. 48 (47%) pts were switched to atezolizumab, 28 (27%) pts were switched to nivolumab, 26 (25%) pts – to pembrolizumab. The median duration of treatment with the first anti-PD(L)1 antibody was 6 months (1-53 months), with the second PD(L)1-inhibitor was 3 months (1-41 months). Within 3 months after 1 replacement of the drug, there were 77 (74,7%) pts without progression. With the median follow-up of 8 months (1-41), the estimated 3-month PFS was 79,3%. The efficacy of switching was not associated with the agent (HR 0,97, 95CI 0,68-1,38, p = 0,9). There were 2 cases of AEs of 3-4 grades when switching to the second drug. Conclusions: Switching from one anti-PD(L)1 antibody to another in pts with mNSCLC is possible in case of limited access to PD(L)1 inhibitors.
Current status of PD-(L)1 inhibitor usage in advanced or metastatic non-small cell lung cancer: A national survey of oncologists in China.
Authors: Wang Baocheng , Zhou Caicun , Wang Jun , Hu Jie , Duan Jianchun , Yao Yu , Li Guohui , Fan Yun , Huang Cheng , Chu Qian , Liu Chunling , Liu Lihua , Ma Zhiyong , Pan Yueyin , Su ChunXia , Shu Yongqian , Wang Yongsheng , Zhou Chengzhi , Zhao Mingfang , Zhang Xiaotao 
Published: July 2024

e20559 Background: The aim of the present study conducted by Chinese Society of Clinical Oncology Expert Committee on Immunotherapy was to obtain real-world information on the use of PD-(L)1 inhibitors for non-small cell lung cancer (NSCLC) in different regions of China via a national questionnaire survey for oncologists. Methods: This survey was distributed online to cancer-related medical departments in 202 first-tier to fourth-tier cities of China between March to April 2023. The national survey consisted of four sections regarding oncologists’ concerns about immunotherapy as follows: treatment choice, response assessment, treatment duration, and management of immune-related adverse events (irAEs). Results: A total of 2,018 oncologists completed this survey. For advanced squamous (SQ) and non-squamous (NSQ) NSCLC without targetable genetic alterations, PD-(L)1 inhibitor-based regimens were the most widely used first-line treatment regimen (SQ: 52%, NSQ: 46%), followed by chemotherapy alone (SQ: 37%, NSQ: 37%) and other regimens (SQ: 11%, NSQ: 17%). The average treatment duration of 1L PD-(L)1 inhibitor-based regimens in SQ NSCLC and NSQ NSCLC were 6.4 and 6.2 cycles, respectively. 67% of oncologists may discontinue immunotherapy or change regimens when the first radiographic tumor assessment was SD per RECIST 1.1. Other reasons for early discontinuation of PD-(L)1 inhibitors before PD or unacceptable toxicity included economic reasons (78%) and patients’ low willingness to continue immunotherapy even they reached CR/PR (62%). Oncologists in the second-tier cities and below were more likely to discontinue immunotherapy when the tumors were stable, with shorter treatment duration of 5.7 cycles versus 7.1 cycles in the first-tier cities. The most common irAEs included dermatologic, endocrine, pulmonary, gastrointestinal, and hepatic toxicities. Conclusions: PD-(L)1 inhibitor-based regimens have become the priority choice for advanced NSCLC in China, however, the status of standardized continuous use of immunotherapy is obviously insufficient. There is a gap between clinical practice and clinical trials regarding PD-(L)1 inhibitor usage, which need more attention. [Table: see text]
Impact of race and gender on outcomes from patients with stage IV non-small cell lung cancer receiving immunotherapy: A retrospective study performed at Mitchell Cancer Institute, Mobile, AL.
Authors: Escobar Daisy E. , Muthyala Krithika , Ashfaq Muhammmad Areeb , Persing Brian Edward , Mulekar Madhuri S. , Prodduturvar Pranitha 
Published: July 2024

e20562 Background: The use of immunotherapy is associated with improved survival among patients with Non-Small Cell Lung Cancer (NSCLC). The impact of race and gender on survival with immunotherapy is limited and conflicting. Our study sought to examine the influence of race and gender on the outcomes of patients with stage IV NSCLC treated with first line immunotherapy. Methods: A retrospective review of 91 patients with stage IV NSCLC was performed. Patients with confirmed NSCLC who received first line immunotherapy between January 2018 to December 2022 identified from Mitchell Cancer Institute (MCI) Cancer Registry were analyzed for clinical outcomes. Disease-specific survival was evaluated and compared among patients across racial/ethnic categories using mean, standard deviation, median, and interquartile range. Mean outcomes for numerical factors were compared using a t-test, while median outcomes were compared using a median test. The association between categorical factors was assessed using Fisher’s test, with a significance level of 0.05. Results: A total of 91 patients (45 [49.5%] male) were included in the analysis, with 61 White (67.0%; mean [SD] age, 70.2 [10.1] years) and 30 African American [AA] (32.9%; mean [SD] age, 65.9 [9.2] years). Based on histological analysis 71(77.8%) were adenocarcinoma, 18 (19.8%) squamous cell carcinoma, and 2 (2.2%) adenosquamous carcinoma. Mean progression free survival (PFS) was greater in Whites (315 vs 178 days; p = 0.041). Mean overall survival (OS) was longest in Whites (397 vs 218 days; p = 0.016). No significant differences were observed in age at diagnosis (p = 0.096), mean cycles given (p = 0.406) and PD-L1 status (p = 0.077) between Whites and AA’s. No significant differences were observed in age at diagnosis (p = 0.184), mean cycles given (p = 0.729) and time to progression (p = 0.769) or death (p = 0.938) between genders. PD-L1 distribution differed between males and females (p = 0.021) with a higher percentage of females having PD-L1 ≥1% (63% vs 38%). Conclusions: Our study showed longer PFS and OS in White patients receiving first line immunotherapy in stage IV NSCLC regardless of age at diagnosis or PD-L1 status. No differences in PFS or OS were seen between genders irrespective of age at diagnosis, mean cycles of treatment or PD-L1 status. These findings demonstrate the importance of integrating race, ethnicity, and gender as prognostic variables in the evaluation of patients with NSCLC in the incorporation of social determinants of health. This inclusion is crucial to obtain a more comprehensive understanding of how these factors influence patient outcomes.