tbuckley/cabot-search huggingface dataset:
Non-invasive diagnosis of nature of pulmonary nodules using the whole genome methylation sequencing of circulating cell-free DNA.
Authors: Baiqiang Dong, Xuan Zhu, Runzhe Chen, Baoqing Chen, Kelly Chen, Ming Chen
Journal: Journal of Clinical Oncology (2024)

e20038 Background: The frequent false-positive results of lung cancer screening of low-dose computed tomography (LDCT) remains a challenge. In this study, we aimed to establish a novel panel of cancer-specific methylated regions detected from circulating cell-free DNA (cfDNA) for differentiating malignant pulmonary nodules (PNs) from benign lesions in high-risk patients. Methods: We performed DNA methylation profiling by high throughput DNA bisulfite sequencing in tissue samples (nodule size &lt; 3 cm in diameter) to learn methylation patterns that differentiate cancerous tumors from benign lesions. Then we filtered out differential methylation patterns in circulating cfDNA that are consistent with tissue expression patterns and built an assay for plasma sample classification. Area under the curve was computed for each receiving operation curve, and 95% confidence intervals were also estimated by bootstrapping with 1,000 iterations. Results: We first performed the whole genome methylation sequencing of 100 tissue samples from PNs to learn cancer-specific methylation patterns, and obtained 2,406 differential hypermethylated regions and 16,028 differential hypomethylated regions. These tissue-derived DNA methylation markers were further filtered using a training set of 42 plasma samples and 11 markers were ultimately identified to build a diagnostic prediction model. This methylation panel provided promising results in an independent validation set of additional 17 plasma samples, with a sensitivity of 66.67% (95% CI: 0.25–1.00) and a specificity of 79.17% for differentiating patients with malignant tumor (N = 12) from patients with benign lesions (n = 5). A further validation study of this methylation panel in the cancer genome atlas data set demonstrated significant discriminatory performance in distinguishing patients with lung cancer from subjects without malignancy (area under the curve = 0.88). Conclusions: Our model based on the measurement of circulating cfDNA methylation provide a minimally invasive procedure for differentiation of early-stage lung cancer and nonmalignant pulmonary nodules, and may guide management of positive LDCT screening results. Additional clinical studies with larger sample size are needed to establish the robustness of this model.
Application of ctDNA sequencing in patients with metastasized lung cancer.
Authors: Zhi Zheng, Jiale Wen, Yaru Chen, Wei Guo, Yanqing Zhou
Journal: Journal of Clinical Oncology (2024)

e20033 Background: Circulating tumor DNA (ctDNA) is a form of cell-free DNA (cfDNA) found in blood that originates from tumor cells, which has emerged as a promising non-invasive biomarker in monitoring cancer prognosis and precision medicine with the advancement of deep sequencing. Here we compared the mutational landscape between solid tumor and cfDNA in metastasis-free and metastasized lung cancer patients using targeted NGS to investigate the feasibility of ctDNA sequencing in monitoring cancer prognosis. Methods: Blood-derived cfDNA samples and formalin-fixed paraffin embedded tissue were collected from 217 Chinese patients with metastatic lung cancer (n = 39) or metastasis-free lung cancer (n = 178). Blood samples were collected after surgery. Panel sequencing targeting 680 cancer-related genes was performed on both samples. Somatic single nucleotide variations and indels were analyzed. Results: Among the 178 metastasis-free patients, 89.3% of the patients have at least one mutation both detected in tumor and blood samples. On average, 50.4% of tumor mutations were detected in blood for each patients. EGFR, TP53, CSMD3, LRP1B and SYNE1 were the top five most frequently mutated genes, with the proportion of tumor mutation found in blood of 89.1%, 80.2%, 70.0%, 61.3% and 64.3% respectively. In the metastasized cohort, all 39 individuals have at least one tumor mutations found in blood, achieving a concordance of 100%. On average, 59.9% of tumor mutations were detected in blood for each patients. Notably, the proportion of tumor mutations detected in blood for each patients is significantly higher than the metastasis-free cohort (unpaired T-test, p = 0.0167). EGFR, TP53, RBM10, PIK3CA and CSMD3 were the top five most frequently mutated genes, with the proportion of tumor mutation found in blood of 93.5%, 80.8%, 57.1%, 83.3% and 42.9% respectively. Moreover, the proportion of patients having EGFR p.L858R mutation in metastasized cohort was higher than the metastasis-free cohort (54.3% vs 32.8%). While within the metastasized cohort, blood samples detected a higher proportion of EGFR p.T790M (12.9% vs 7.69%) but a lower proportion of EGFR exon19 deletion (p.E746_A750del, 19.4% vs 27.7%) comparing to tumor sample, which can indicate drug resistance. Conclusions: We demonstrated a high mutation detection concordance between tumor and blood using targeted NGS, with an exceptional performance especially in driver oncogenes like EGFR and TP53. Our findings showed that metastasized lung cancer patients exhibit a higher positive concordance rate compared to metastasis-free cohort using ctDNA. We also showed a varied mutational landscape between ctDNA and tumor sequencing in metastasized lung cancer patients. Overall, this study not only reaffirms the viability of using blood as an alternative of tissue biopsy, but also provides new insights on application of ctDNA monitoring lung cancer metastasis and its clinically targetable mutations.
Multi-omics profiling the genomic origin and adeno-squamous transdifferentiation mechanism in adenosquamous carcinoma.
Authors: Xinlong Zheng, Chao Li, Kan Jiang, Zhipeng Zhou, Jing Bai, Feng Long, Jianfeng Yan, Gen Lin
Journal: Journal of Clinical Oncology (2024)

e20032 Background: Adenosquamous carcinoma (ASC) represents a rare subtype (0.4-4%) of non-small-cell lung cancer (NSCLC), with its multi-omic landscape yet to be fully elucidated. This study aims to explore the genomic origins and molecular mechanisms of adeno-squamous transdifferentiation in lung ASC through comprehensive multi-omics. Methods: We analyzed 69 samples from 31 lung ASC patients, including 16 FFPE samples with microdissected paired adenocarcinoma (AC) and squamous cell carcinoma (SCC) components, and additionally, incorporated pure Lung Adenocarcinoma (LUAD, n = 51) and pure Squamous Cell Carcinoma (LUSC, n = 28) for comparative analysis. Techniques included whole-exome sequencing, whole-genome methylation profiling, transcriptomics, single-cell RNA sequencing, and spatial transcriptomics. Results: AC and SCC exhibited similar genomic mutation landscapes, indicating a common genomic origin for AD and SCC. The SCC component in ASC displayed higher homologous recombination repair deficiency (HRD) and a notable 16p13.3 deletion in 31% of ASC transformations. Differential methylation analysis highlighted TP63's lower methylation in SCC, correlating negatively with RNA expression (P &lt; 0.001), indicative of methylation-driven regulation. DMR binding motif analysis revealed hypo-methylation in p63, p53, and AP-1 motifs, and hyper-methylation in MKX2-1, FOXA1/2 motifs (P &lt; 0.05). The transition from AC to SCC in ASC was marked by upregulated MYC signaling, proliferation, and DNA repair, with EMT changes not methylation-driven. Metabolic pathways were upregulated, and EMT/KRAS pathways downregulated in SCC compared to LUSC. Immune infiltration in LUAD-AC-ASC transformation showed an initial increase and subsequent decrease, transitioning from immune-infiltrated and immune-excluded to immune-desert phenotypes. IL36G of the IL1 family was highly expressed in the SCC component and strongly correlated with the squamous marker P63 (Pearson r = 0.72, P &lt; 0.001). Single-cell RNA-seq data demonstrated a significant increase in IL36G in squamous cells of lung ASC. In vivo models showed adeno-squamous differentiation in adenocarcinoma cells expressing IL36G. Conclusions: This study provides a comprehensive multi-omic insight into the complex genomic and epigenomic landscape of ASC, highlighting a shared genomic origin and distinct molecular mechanisms in the adeno-squamous transdifferentiation process. The findings, particularly the role of TP63 methylation and IL36G expression in the SCC component, offer novel insights into the molecular heterogeneity of ASC. These results not only deepen our understanding of ASC but also pave the way for future investigations into targeted therapies that could potentially exploit these molecular distinctions for more effective treatment strategies in ASC.
Predicting spread through air space and immune status in lung adenocarcinoma by CT-based deep learning model.
Authors: HaiYu Zhou, Qiaxuan Li, Linghan Cai, Daipeng Xie, Lintong Yao, Yu Lei, Canjia Cai, Qi Zhang
Journal: Journal of Clinical Oncology (2024)

e20043 Background: Tumor spread through air space (STAS) is a novel histologic pattern of invasion related to high recurrence and poor prognosis. Meanwhile, there is a potential relationship between STAS status and the tumor immune microenvironment. The aim of this study was to predict STAS status in lung adenocarcinoma (LUAD) using a CT-based 3D-CNN deep learning model and explore the tumor immune microenvironment in the GSE58661 cohort. Methods: We retrospectively collected data from 368 patients with lung adenocarcinoma and STAS status from Guangdong Province General Hospital between 2021 and 2023. We performed propensity score matching (PSM) based on gender, year, BMI, and smoking status to obtain a cohort of 368 patients without STAS status. A 3D-Resnet-Resnetearning model was developed to identify the STAS status of lung adenocarcinoma, and the performance of the models was evaluated using the area under the curve (AUC), accuracy, sensitivity, and specificity. Meanwhile, bule RNA sequencing and baseline CT of LUAD from 41 patients in the GSE58661 cohort and the TCIA dataset were used to investigate the potential biological mechanism in the patients with STAS status. Results: We included 584 and 152 patients in the training and testing sets, respectively. The 3D-Resnet algorithm was used in the 3D patch with voxel sizes of 128*128*128, 96*96*96, and 64*64*64 to construct the DL-STAS model. With the training set's AUC of 0.899, the results showed that the model achieved an AUC, sensitivity, specificity, and accuracy of 0.884, 0.831, 0.838, and 0.835 in the testing cohort, respectively. According to our model, we divided the patients in GSE58661 into STAS and non-STAS. By identifying and analyzing the differentially expressed genes between the STAS and non-STAS groups, we found that several immune-related pathways, such as the T cell receptor signaling pathway, the PD-1/PD-L1 expression pathway, the natural killer cell-mediated cytotoxicity pathway, and the macrophage activation pathway, were enriched in the group with STAS status. Conclusions: The DL-STAS model we developed has great potential for accurately predicting STAS status in lung adenocarcinoma. In the meanwhile, the prognosis of patients with STAS status may be impacted by their particular tumor immune microenvironment.
The treatment modalities and radiotherapy pattern in patients with primary lung cancer in Japan.
Authors: Qingqing Hu, Titan Huang, Ko Nakajo, Yongjing Zhang, Hong Qiu
Journal: Journal of Clinical Oncology (2024)

e20070 Background: In Japan, lung cancer has high incidence and mortality among all cancers. The study is to understand the existing status of the treatment modalities in Japan, especially for radiotherapy (RT). Methods: This was a retrospective cohort study using the Japan Medical Data Center (JMDC) database. A cohort of adult patients with at least two diagnosis codes of primary lung cancer (ICD-10-CM: C34) during January 1 st , 2015-March 31 st , 2023, and initiated lung cancer treatment was included in the study. The initial treatment episode was defined as a period with the first single or multiple treatments before a 90-day gap. Patients were followed up until a record of death, or the last enrollment in JMDC. The cohort was stratified into four exclusive groups: Group A: ≥1 record of distant metastasis; Group B-1: ≥1 record of regional metastasis; Group B-2: no record of surgery and no metastasis; Group C: ≥1 record of surgery and no metastasis. The characteristics, initial treatment episode and RT patterns were described across the four groups. Results: A total of 9,373 patients were included, with Group A 1,625 (17.3%), Group B-1 527 (5.6%), Group B-2 2084 (22.2%), and Group C 5137 (54.8%). The median follow-up was 21.2 months of the cohort. The median (IQR) time to initial treatment episode from the initial diagnosis was 27 (27), 35 (40), 34 (47) and 38 (36) days for the four groups, respectively. Most of patients in group A (74.1%), B-1 (70.8%), and B-2 (67.6%) had a &gt;3 months duration of initial treatment, and only 32.7% in group C. For treatment involved in the initial treatment episode, RT was accounted for 59.2%, 29.8%, 43.4%, and 4.7% in four groups respectively. For treatment categories in Groups A, B-1, and B-2, RT only was performed in 15.5%, 2.2% and 6.9% of patients with single treatment; and RT was commonly performed with chemotherapy in multiple treatments, with proportions of 83.6%, 95.3% and 95.6% among no surgery. For RT with chemotherapy group, the median RT fractions are 22, 36 and 42, covering a median duration of 35, 43 and 43 days of RT. Conclusions: In Japan, the initial treatment episode usually starts in 30 days and lasts more than 3 months for metastasis and unresectable primary lung cancer. RT only is not commonly performed, and RT with chemotherapy is commonly performed in initial treatment episode. [Table: see text]
Biomarkers in a phase 1b study of investigational microbiome therapeutic SER-155 in adults undergoing allogeneic hematopoietic cell transplantation (allo-HCT).
Authors: Doris M. Ponce, Swarna Pandian, Marcel R. M. van den Brink, Satyajit Kosuri, Nandita Khera, Zachariah Michael DeFilipp, Bindu Tejura, David I Lichter, Meghan Chafee, Kankana Bardhan, Nathan D Hicks, Emily Walsh, Mary-Jane Lombardo, Christopher B. Ford, Lisa von Moltke, Matthew R. Henn, Jonathan U. Peled
Journal: Journal of Clinical Oncology (2024)

6554 Background: Acute graft- versus-host disease (aGvHD) is a life-threatening complication following allo-HCT. Microbiome dysfunction and associated GI barrier disruption may contribute to aGvHD via activation of inflammatory immune responses. Circulating biomarkers in the peri-transplant period are correlated with risk of severe aGvHD, including suppression of tumorigenicity 2 (ST2), regenerating islet-derived 3-alpha (Reg3a) and inflammatory cytokines (IL6, IFNϒγ &amp; TNFα). SER-155 is an investigational cultivated oral microbiome therapeutic designed to restructure the GI microbiome, improve GI barrier integrity and reduce GI inflammation and is being assessed in a 2-part Phase 1b study in adults undergoing allo-HCT. We present preliminary safety, GvHD, PK, and exploratory biomarker data from the completed open-label Cohort 1 through Day 100 post-HCT. Methods: Adult recipients of allo-HCT were eligible. HCT conditioning and aGvHD prophylaxis were per investigator discretion. Patients received 2 courses of SER-155 (pre-HCT and post-neutrophil engraftment, each comprised of 4 days of microbiome conditioning with oral vancomycin followed by 10 days oral SER-155. The primary endpoint was safety. Strain engraftment (PK) and biomarkers were assessed in stool and plasma samples. Results: Fifteen adults enrolled; 13 received at least 1 course of study drug (median age 67; 54% male), and 11 underwent allo-HCT. Following each course, the majority of the 16 SER-155 strains were detected in stool. Treatment-emergent adverse events (AEs) were reported in all patients with GI AEs the most common. No serious AEs (SAEs) were deemed related to SER-155. Most SAEs and AEs of special interest (ie, BSIs, invasive or GI infections) occurred between HCT and the 2nd SER-155 course. There were no deaths before Day 100. No BSIs were attributable to SER-155 strains. The rate of grade 2-4 aGvHD based on MAGIC criteria through Day 100 was 45.5%; no severe grade 3-4 aGvHD was observed. Median levels of plasma biomarkers REG3α, ST2 and inflammatory cytokines were not elevated relative to a reference range (Table). Conclusions: In this small open-label cohort, SER-155 was generally well-tolerated through Day 100 without drug-related SAEs and no severe aGvHD. Plasma biomarkers were not elevated at HCT Day 0 or neutrophil recovery. These preliminary observations align with the design and preclinical evaluation of SER-155. Clinical trial information: NCT04995653 . [Table: see text]
Thiotepa/cyclophosphamide (TT/Cy) preparative regimen for patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic stem cell transplantation.
Authors: Cydney Nichols, Kirsten Ervin, Caitlin Schmidt, Jennifer E. Schwartz, Mohammad Issam Abu Zaid, Michael J. Robertson, Rafat Abonour, Meagan Grove, Teresa Thakrar, Sherif Farag
Journal: Journal of Clinical Oncology (2024)

6556 Background: Total body irradiation (TBI)-based preparative regimens have been standard for patients with ALL undergoing allogeneic stem cell transplant (SCT). It is unclear if chemotherapy-only regimens are equally efficacious. Here, we present the largest reported experience with myeloablative TT/Cy in patients with ALL undergoing allogeneic SCT and compare outcomes with TBI-based regimens. Methods: Patients with ALL receiving myeloablative allogeneic SCT at Indiana University from 2007-2020 were included. TT/Cy consisted of TT 15 mg/kg and Cy 120 mg/kg. TBI/Cy consisted of 13.2 Gy in 8 fractions and Cy 3600 mg/m 2 or etoposide 60 mg/kg. The primary endpoint was overall survival (OS). Secondary endpoints included relapse-free survival (RFS), engraftment, and toxicities within the first 100 days. Median follow up for surviving patients is 2,532 (range 599-4,762) days. Results: 80 patients with ALL of median age 40 (range 22-59 years) received conditioning with TT/Cy (n=25) versus TBI/Cy or TBI/etoposide (n=55). Baseline characteristics were similar. For patients receiving TT/Cy, the median OS was not reached, and the 4-year OS was 54.5% (95% confidence interval [CI], 34.3-74.7%), compared with a median OS of 1,491 days and a 4-year OS of 50.9% (95% CI, 37.8-64.2%) for those receiving TBI-based conditioning (p=.75). Similarly, for TT/Cy patients, the median RFS was 847 days and 4-year RFS was 43.2% (95% CI, 23.4-63%), not significantly different from median RFS of 1491 days and 4-year RFS 50.2% (95% CI 36.9-63.5; p=.232) for recipients of TBI regimens. On multivariable analysis, only a higher disease risk index was associated with significantly worse OS (p&lt;.001), while conditioning regimen was not predictive of OS. Similarly, there was no significant difference in RFS between TT/Cy and TBI-based regimens on either univariable or multivariable analysis. Secondary endpoints are summarized in the table. As shown, TT/Cy was associated with significantly lower incidence of mucositis, TPN usage, bacterial infection, sinusoidal obstruction syndrome (SOS), and longer length of stay of primary transplant admission. Conclusions: While there was no significant difference in OS or RFS for patients receiving either TT/Cy or TBI-based conditioning, TBI was associated with greater toxicity. Our data suggests that TT/Cy is an acceptable alternative to TBI-based conditioning for ALL patients undergoing myeloablative allogeneic SCT. [Table: see text]
Exploring the role of UMP as a molecular marker in the tumor microenvironment of lung adenocarcinoma.
Authors: Yiran Meng, Yang Liu, Liuqing Zheng, Li Wang
Journal: Journal of Clinical Oncology (2024)

e20064 Background: Currently, there is a relatively extensive research emphasis on tumor microenvironment based on single-cell transcriptomics. However, the investigation of the metabolic aspects of tumor microenvironment is relatively rare due to technological limitations. To address this gap, our study employes scFEA and MEBOCOST, which are metabolic level prediction tools based on single-cell transcriptomics, to explore the metabolic landscape of tumor microenvironment in lung adenocarcinoma(LUAD). Methods: This study utilized four single-cell sequencing (scRNA-seq) datasets, two targeted metabolomics datasets, and the TCGA-LUAD RNA sequencing dataset obtained from the Cancer Genomics Data Portal. To perform dimensionality reduction, the Seurat package was employed. Cell annotation was carried out using scType, followed by manual correction using the FindAllMarkers function. Tumor cell clusters were identified by utilizing tumor marker genes and the R package inferCNV. Single-cell metabolic levels were inferred using scFEA. The TCGA-LUAD datasets underwent analysis to estimate and analyze immune levels using estimate and cibersort algorithms. Additionally, scFEA was used for metabolic level analysis, and survival analysis was conducted. UMP differential expression analysis was performed on the targeted metabolomics datasets. Results: Across all four single-cell sequence datasets, metabolites such as (GlcNAc)4 (Man)3 (Asn)1[G00015], B-Alanine[C00099], and UMP[C00105] exhibited significantly higher levels in immune cells compared to tumor cells (P &lt; 0.05). These findings were further validated using the TCGA-LUAD datasets. Cox regression analysis was performed using immune scores and tumor purity scores and based on the median value of risk scores, high and low-risk groups were distinguished. it was observed that UMP levels were higher in the low-risk group. Moreover, higher UMP levels were associated with elevated immune levels and decreased tumor purity. Analysis of targeted metabolomics datasets from various pan-cancer cell lines revealed that UMP expression level in tumor cells was lower than that in B and T cells. Furthermore, in different subtypes of LUAD, including AAH, AIS, MIA, and IAC, UMP expression in tissues gradually decreased as the severity of the subtype increased (P &lt; 0.05). Conclusions: The study revealed that UMP metabolites are expressed at higher levels in immune cells compared to tumor cells within LUAD. Moreover, UMP expression levels showed significant variations among different disease severities of LUAD. These findings indicate that UMP has the potential to serve as a molecular marker for distinguishing between different disease severities. Further research is needed to investigate the underlying mechanisms and validate the diagnostic usefulness of UMP in LUAD.