tbuckley/cabot-search huggingface dataset:
Pulmonary blastoma: An NCDB analysis of demographic and socioeconomic factors.
Authors: Brianna Eillen Ramos, Yanick Tade, Rawaan Khatib, Assal Sadighian, Peter T. Silberstein, Craig Heise, Beau Hsia
Journal: Journal of Clinical Oncology (2024)

e20069 Background: Pulmonary blastoma (PB) is a rare sarcomatoid carcinoma classified as a non-small cell lung cancer with a poor prognosis and no standard treatment. This malignancy exhibits glandular proliferation with a morular component resembling embryonic development. Leading PB treatment favors surgical resection with concurrent chemotherapy. However, radiation is recommended for inoperable tumors. Further analysis of diagnostic trends may provide information about the epidemiology of PB. The National Cancer Database (NCDB) was analyzed to establish the demographic factors in diagnosed patients. Methods: A retrospective cohort study from 2004 to 2020 was conducted using the NCDB. 146 patients were identified with a histologically confirmed diagnosis of PB (ICD-O-3 code 8972). Race, gender, Hispanic origin, urban/rural residence, insurance coverage, treatment approaches, and mean survival rates were analyzed via descriptive statistics. Regression analysis was performed to examine incidence trends. Results: 146 patients diagnosed with PB were identified in the NCDB, where the incidence rate of diagnoses strongly declined annually (R² = 0.079). The average age of diagnosis was 50 years (SD = 26, range = 1-90 years), with women (56%) more likely to be affected than men (44%). The majority of patients identified as White (80%) and non-Hispanic (88%), lived in metropolitan counties with a population greater than 1 million (58%), and were privately insured (45%). The top primary sites of diagnoses were the upper (38%) and lower (28%) lobe of the bronchus or lung. For patients who did not receive palliative care (93%), many received surgery (75%) as their primary treatment. Within this group, chemotherapy and radiation therapy were also chosen as treatment options (48% and 27%, respectively). The majority of individuals (66%) had a Charlson-Deyo comorbidity score of 0. The survival rates were 58% at two years, 49% at five years, and 34% at ten years. The mean survival was also found to be 86 months. Conclusions: To the best of our knowledge, this is the first NCDB analysis on pulmonary blastoma and helps provide insight on a previously understudied topic. Results demonstrated that the majority of PB patients are non-Hispanic White females, who were primarily diagnosed at the upper lobe of the bronchus or lung. These findings confirmed similar descriptions from other databases and earlier case reports. This is the first time the socioeconomic factors of PB patients have been described in the literature: PB patients typically do not receive palliative care and choose to undergo surgery as their primary treatment. Further research is indicated to provide a greater insight on the effects of demographic/socioeconomic factors on diagnostic criteria, chosen treatments, and overall survival rates of patients with PB.
Enhancing non-small cell lung cancer treatment utilizing natural killer cell-derived extracellular vesicles (NKEVs) as a novel adoptive cellular therapeutic.
Authors: Joanna Palade, Nanyun Tang, Eric Alsop, Jerry Antone, Dorothy Paredes, Timothy Whitsett, Michael E. Berens, Gary Schwartz, Jennifer P. Finholt, George J. Snipes, Kendall Van Keuren Jensen, Ronan Joseph Kelly
Journal: Journal of Clinical Oncology (2024)

e20079 Background: An established mechanism contributing to immune checkpoint inhibitor (ICI) therapy failure is tumor evasion of T-cell responses via downregulation of human leukocyte antigen (HLA). Conversely, the effector function of Natural Killer (NK) cells is enhanced in the absence of HLA expression, making NK-based cellular therapies an attractive option for ICI resistant tumors. NK-derived extracellular vesicles (NKEVs) have the potential to become a personalized adoptive cellular therapeutic that may overcome challenges associated with traditional NK cell-based therapies failing to deliver adequate numbers of cells to the tumor. We sought to investigate the preclinical efficacy of an approach using selective isolation of NK cells and harvesting of NKEVs in NSCLC. Methods: From 10 NSCLC patients, tumor tissue was collected, and blood mononuclear cells (PBMCs) were retrieved pre- and -post surgery. Single-cell RNAseq (scRNAseq) was used to examine the cellular landscape in PBMCs and tumor tissue. NK cells were isolated from PBMCs, expanded in vitro, and NK-derived EVs (NKEV) were collected and the EV RNA and protein cargo was characterized using proteomics and transcriptomics. The functional capabilities of patient derived NKEVs were assayed with patient derived organoids. Results: scRNAseq highlighted significant cellular heterogeneity, particularly in the cancer cell population. Within the tumor, infiltrating immune cells were lymphoid and myeloid in origin. Over 200,000 PBMCs were analyzed with scRNAseq, revealing differences associated with cancer subtype, tumor mutation burden and experimental time point. Exposure to patient NKEV treatment resulted in a 40-45% decrease in organoid viability, significantly lowering the cisplatin dose required to elicit a cytotoxic response. NKEVs derived from healthy controls were less efficient. In Nivolumab-treated PBMC organoid co-culture experiments, NKEV addition increased the proportion of infiltrating CD8+ T cells and CD56+ NK cells compared to PD-1 inhibitors alone, particularly from the pre-tumor resection PBMCs. Conclusions: This work demonstrated that NKEVs can be successfully harvested from patient derived, expanded NK cells, and highlighted their anti-tumor properties in combination with standard-of-care therapies. Additional in-depth immune analysis will be presented. [Table: see text]
Dynamic network biomarker of treg cells differentiation critical state with neoadjuvant treatment in LUSC.
Authors: Yiran Meng, Hai Lin, Liuqing Zheng, Li Wang
Journal: Journal of Clinical Oncology (2024)

e20063 Background: Regulatory T cells (Tregs) suppress immune responses and can promote tumor growth and metastasis during cancer progression. Studies have shown that tumor-infiltrating Tregs upregulate inhibitory gene programs after immune checkpoint blockade therapy. Targeting Tregs is believed to be a valuable approach to enhance the effectiveness of immunotherapy. However, the precise role of Tregs in the tumor microenvironment, their connection to treatment resistance mechanisms, and how changes in their immune activity impact tumor treatment are still not well understood. Methods: Single-cell data and clinical information were obtained from the Gene Expression Omnibus database with the accession number GSE176021 for 4 patients diagnosed with lung squamous cell carcinoma (LUSC) who received neoadjuvant anti-PD-1 therapy, including 2 patients with major pathologic response (MPR) and 2 patients with non-MPR. BioTIP was employed to identify critical transition signals of the Treg cell differentiation trajectory constructed by Monocle2. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and gene set variation analysis were performed to understand biological processes and pathways. Additionally, potential transcription factors were identified using Single-Cell rEgulatory Network Inference and Clustering, and CellChat analysis was conducted to evaluate possible interactions among cell populations. Results: The study constructed a pseudo-temporal differentiation trajectory of Tregs in LUSC patients, and Treg subpopulations during the critical transition period were identified based on the dynamic network biomarker method. Notably, subpopulations of Treg cells clustering MPR or non-MPR samples were located at different ends of the differentiation trajectory, showing variations in Treg-related pathways and transcription factor regulation. The critical transition subpopulation exhibited high expression of glycolysis, TCA cycle, and natural killer cell receptors, along with upregulation of the CEBPB transcription factor activity and downregulation of ARNTL activity. SELPLG-SELL, CD99-CD99, and MHC-II-CD4 were identified as potential key signals that may affect therapeutic effect, primarily influencing cell adhesion, the immune suppressive activity of Treg cells, and T cell response. Conclusions: In conclusion, this study utilized single-cell data analysis to uncover the dynamic regulation of Treg cells in LUSC, identifying critical transition Treg subpopulations. Notably, our findings suggest the involvement of the transcription factors CEBPB and ARNTL in regulating Treg activity. These novel insights shed light on potential strategies for targeted therapies and provide valuable information regarding resistance mechanisms associated with Treg cells.
Depletion of histone H3K27 demethylase exerts anti-tumor activity as a monotherapy and in combination therapy with ceralasertib in non-small cell lung carcinoma.
Authors: Pony Yu-Ling Lee, Kun-Yuan Lin, Chao-Di Chang, Shan-Yun Cheng, Ya-Wen Hung, Chih-Chieh Yang, Yu-Hsien Chang, Chien-Chang Shen, Lin-Wen Yeh, Marvin Angelo Esteban Aberin, Shu-Ping Wang
Journal: Journal of Clinical Oncology (2024)

e20035 Background: Lung cancer is one of the most frequently diagnosed cancers and is the leading cause of cancer-related death worldwide. Non-small cell lung carcinoma (NSCLC) represents 85% of lung cancers and is the most common type with poor prognosis. The lysine-specific demethylase UTX (gene name KDM6A) demethylates H3K27me2/3 at genes and enhancers and have been shown to support oncogenic transcription factors. We hypothesize that UTX is a highly pleiotropic factor in tumorigenesis and may plays a critical role in controlling DNA replication-associated gene activation as well as in replication stress-related DNA damage repair. Methods: To evaluate the role of UTX in tumorigenesis, shRNA-mediated UTX knockdown was employed in NCI-H1975 cells followed by cell cycle and cell proliferation assays. In the UTX-knocked down NCI-H1975 cells, target genes involved in DNA replication and DNA damage repair were discovered by RNA sequencing and further validated with RT-qPCR. Effects of UTX depletion on DNA replication and radiation-induced DNA repair were analyzed by immunofluorescence. Effects of UTX depletion on cell cycle arrest and the ATR–CHK1 checkpoint signaling pathway were analyzed by flow cytometry and immunoblotting. In vivo response to UTX inhibition monotherapy (UTX knockdown) and combination therapy of UTX knockdown with ceralasertib, a selective ATR kinase inhibitor, was evaluated in dox-inducible UTX knockdown NCI-H1975 xenografts. Results: Induction of UTX knockdown significantly reduced the NCI-H1975 tumor volume compared to the control group, showing anti-tumor activity. Furthermore, loss of UTX induced hyperactivation of ATR–CHK1 checkpoint signaling pathway, suggesting the UTX-depleted tumor cells attempt to alleviate replication stress to escape from apoptosis. To inhibit the UTX-depletion induced ATR–CHK1 pathway, ceralasertib (formerly AZD6738), an oral potent selective inhibitor of ATR, was combined with UTX-knockdown for in vitro and in vivo evaluation. Consistent with in vitro cell-based assay, combination therapy of ceralasertib with UTX depletion showed enhanced tumor growth inhibition and regression in the NCI-H1975 xenograft model. Conclusions: Our findings provide new insights into a pro-oncogenic role of UTX in supporting tumor maintenance via engaging DNA replication and repair pathway. Depletion of UTX alone may serve as a new therapeutic target in non-small cell lung carcinoma; and further combination with ceralasertib enhances the anti-tumor activity of UTX knockdown by inhibiting the ATR–CHK1 checkpoint signaling pathway.
Landscape of gene fusions and METex14 skipping in non-small cell lung carcinoma among the Chinese population: Insights from targeted RNA sequencing.
Authors: Yang Song, Yongjun Zhu, Ning Wu, Fei Xu, Ting Ma, Zhiming Chen
Journal: Journal of Clinical Oncology (2024)

e20041 Background: Targeted RNA Sequencing is crucial for detecting gene fusions and exon-skipping mutations in non-small cell lung carcinoma (NSCLC). This study delineates the landscape of RNA-based fusion and METex14 skipping in the Chinese NSCLC population, compares the consistency with DNA-based fusion detection, and further explores the relationship between fusion-positive cases and immune markers. Methods: We profiled 294 NSCLC tumor tissues using targeted RNA sequencing, focusing on 29 fusion genes and 6 reference genes. Of these, 229 samples were concurrently assessed for fusions using a DNA panel. Patients with gene fusions or METex14 skipping were categorized as 'FUSION-POS'. Additionally, the expression of PD-L1 was evaluated. Results: In 294 NSCLC patients, 33 types of fusions and METex14 skipping were detected from 45 patients based on RNA detection. Actionable gene fusions/METex14 skipping were present in 11.22% (33/294) of patients, with the most prevalent being ALK (4.4%), METex14 skipping (2.7%), ROS1 (1.4%), and RET (1.0%). The partners of ALK, RET and ROS1 were EML4 (n= 12)/ LCLAT1(n=1), KIF5B (n=3) /PARD3(n=1) and CD74(n=2)/LRIG3(n=1)/EZR (n=1), respectively. Notably, we also identified two patients harboring FGFR2-ATE1 fusion and CD74-NRG1 fusion, respectively. Except for MET 14skipping, ST7-MET fusion was detected in 2 patients. Comparing the consistency of actionable fusions/METex14 skipping between RNA and DNA assessments in 229 NSCLC patients, RNA detection yielded a higher number of cases (24 patients vs 15 patients, 10.5% vs 6.5%), with all 15 fusions/ METex14 skipping detected by DNA also identified by RNA. Furthermore, we observed that PD-L1 expression was significantly elevated in the FUSION-POS group within lung adenocarcinoma patients (TPS: P=0.015). Conclusions: Our findings indicate that 11.22% of Chinese LUAD patients possess actionable fusions and METex14 skipping. The detection rate of fusions/ METex14 skipping via RNA is higher than that via DNA, with RNA detection fully encompassing all fusions/ METex14 skipping identified by DNA. Meanwhile, the association between fusions and PD-L1 expression suggests potential synergies for combining targeted therapy and immunotherapy in NSCLC.
Comparative genomic landscape of patients with lung cancer with high-load versus low-load Epstein-Barr virus infection.
Authors: Ming Liu, Yingxiang Li, Shifu Chen, Tianhao Mu
Journal: Journal of Clinical Oncology (2024)

e20017 Background: As the first known oncogenic virus, Epstein–Barr virus (EBV) has been proven to be associated with nasopharyngeal carcinoma, gastric cancer, and lymphomas. Its relationship with lung cancer, however, remains ambiguous. Given that over 90% of adults globally harbor EBV infections and that EBV can be detected in the tumor cells of lung cancer patients, we hypothesize that lung cancer may be associated with high-load EBV infection, whereas low-load infection is less likely. Here, we compared the genomic landscapes of lung cancer patients with high-load and low-load EBV infections. Methods: We conducted a study on 2,268 Chinese lung cancer patients, collecting tumor tissue samples for analysis. Targeted sequencing of 680 cancer-related genes and EBV genome was performed using the HapOnco StarPanel NGS Assay (HaploX Biotechnology, Shenzhen). The EBV infection load was evaluated based on the proportion of reads aligned to the EBV reference genome in the total sequenced reads for each patient. 99% of these samples could be detected with at least two EBV reads. From them, we selected a total of 32 high-load EBV cases (2.1% - 64.3%) and 35 low-load EBV cases (0.1% - 1.7%). Their genomic profiles and altered signaling pathways were subsequently analyzed. Results: In the high-load EBV group, we identified 122 somatic mutations with no recurrent mutations between cases. As for genes, the most frequently mutated were TP53 (25.0%), LRP1B (15.6%), NFKBIA (12.5%), ERBB4 (9.4%), and CNTNAP5 (9.4%), with these mutations being notably enriched in EBV infection pathways according to KEGG, and IL−7 Signal Transduction pathways as per BioCarta. The most common copy number variation events were FGFR3 (12.5%), CDKN2A (12.5%) and FOXP1 (12.5%) gene deletions. In contrast, the low-load EBV group presented with 316 somatic mutations, with the most recurrent mutations being EGFR L858R (17.1%) and E746_A750del (17.1%). The top frequently mutated genes were TP53 (55.3%), EGFR (44.7%), ARID1A (10.5%) and KRAS (10.5%). Conclusions: The genomic profiles of lung cancer patients with high-load EBV infection differ significantly from those with low-load infection. Notably, the genomic mutations in the high-load EBV group are closely associated with EBV infection, suggesting that high-load EBV infection may be linked to lung cancer, unlike low-load infection.
Early-stage lung adenocarcinoma with a micropapillary pattern showing a distinct immunogenic tumor microenvironment.
Authors: Yun Han, Yue Yu, Chongyuan Xu, Qianru He, Qin Zhang, Qianqian Duan, Dongsheng Chen
Journal: Journal of Clinical Oncology (2024)

e20016 Background: Lung adenocarcinomas with a micropapillary pattern (MPP) have been suggested to be associated with prognosis. Immune microenvironment plays a critical role in cancer from onset to relapse. However, it is unclear whether MPP can reflect the tumor immune microenvironment (TIME). Methods: A total of 44 stage I lung cancer patients who underwent surgery at Shengjing Hospital of China Medical University were included (with micropapillary pattern, n = 16; without micropapillary pattern, n = 28). Using NanoString nCounter, the gene expression patterns (GEPs) of 289 tumour immune-related genes were examined. Differentially expressed genes(DEGs), estimation of TIME cell infiltration, and TIME signatures between micropapillary and non-micropapillary were assessed. Results: Significant immunological differences were seen between histological subtypes. Differential gene expression analysis showed that KIR2DL3, MAGEA4, MELK, CD244, and 26 other genes were significantly upregulated in the micropapillary group compared with the non-micropapillary group, while PDGFA, RORC, CCL22, and other seven genes were down-regulated in the micropapillary group. These DEGs were mostly enriched in “leukocyte cell-cell adhesion”, “T cell activation”, “cellular response to chemokine”, and “T cell proliferation” pathways according to GO enrichment analysis. The results of the KEGG analysis revealed that genes were significantly enriched in “Cytokine-cytokine receptor interaction”, “Cell adhesion molecules (CAMs)”, “Chemokine signaling pathway”, and so on. Immune analyses revealed that micropapillary group had a better TIME cell infiltration which are associated with increased CD45, CD8+ T cells, Exhausted CD8, and NK CD56dim cells. Furthermore, the immune signature scores for chemokines, total TILs, and GEP scores were higher in the micropapillary group, indicating increased immune cytotoxic activity. Conclusions: Lung adenocarcinomas with micropapillary pattern were identified as a subtype with enhanced immunogenic tumor microenvironment. According to these results, patients with lung adenocarcinomas that have micropapillary pattern may be a prospective select group who will benefit from adjuvant immunotherapy.
Improved survival for myeloid malignancy patients receiving thiotepa/cyclophosphamide (TT/Cy) versus total body irradiation/cyclophosphamide (TBI/Cy) conditioning and 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)

6555 Background: TBI/Cy is a commonly used conditioning regimen prior to allogeneic stem cell transplant (SCT). Chemotherapy only regimens, mostly containing busulfan, have been shown to be effective and less toxic in patients with myeloid malignancies. Here, we present the largest reported experience with a non-busulfan myeloablative chemotherapy regimen of TT/Cy in myeloid malignancy patients undergoing allogeneic SCT and compare outcomes with TBI/Cy. Methods: Patients with myeloid malignancies receiving 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 . 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 2,046 (range 816-5,572) days. Results: 225 patients with AML (n=160), CML (n=45), and MDS (n=30) of median age 44 (range 19-59 years) received conditioning with TT/Cy (n=159) or TBI/Cy (n=66). Baseline characteristics were similar. For TT/Cy patients, the median OS was not reached, and 4-year OS was 57.2% (95% confidence interval [CI], 49.2-65.2%), which was significantly better than with TBI/Cy, with median OS 373 days and 4-year OS 33.9% (95% CI, 22.3-45.5%; p&lt;.001). Similarly, for TT/Cy patients, the median RFS was not reached and 4-year RFS was 59.2% (95% CI, 52-67.2%), significantly better than median RFS of 341 days and 4-year RFS 35.2% (95% CI, 23.7-46.9%; p&lt;.001) for recipients of TBI/Cy. On multivariable analysis adjusting for age, sex, diagnosis, disease risk, comorbidity index (HCI), and degree of stem cell source, TT/Cy had significantly lower risk of death (HR 0.44, 95% CI, 0.30-0.65; p&lt;.001) together with female sex (p=.03) and lower HCI (p=.046). As shown in the Table summarizing secondary endpoints, TBI/Cy was associated with significantly higher rates of mucositis, sinusoidal obstruction syndrome (SOS), TPN usage, multiorgan failure, and length of stay of primary admission. Conclusions: TT/Cy is an efficacious regimen for patients with myeloid malignancies undergoing myeloablative allogeneic SCT with less toxicity and improved RFS and OS compared with TBI/Cy. TT/Cy should be compared to other non-TBI containing busulfan-based regimens. [Table: see text]