bluuebunny/crossref_metadata_2025_split huggingface dataset:
FISH abnormalities in Agent Orange–associated multiple myeloma.
Authors: Kort Jeries , O'Brien Timothy 
Published: June 2023

e20056 Background: Multiple myeloma (MM) is a plasma cell neoplasm that accounts for approximately 10% of all hematologic malignancies. Molecular investigations have identified a wide heterogeneity in MM at the genomic and epigenomic levels, often with IgH translocations and trisomies seen early in the pathogenesis. Etiological factors, though, are still not well characterized. Agent Orange (AO) was a herbicide widely used as a defoliant by the U.S. military during the Vietnam War. Studies have indicated a probable causative link between exposure to AO and the development of multiple myeloma; in fact, MM is now recognized by the VA as a service-connected diagnosis. However, there have been few small studies addressing whether there are any unique molecular findings in AO associated MM. We sought to determine if there were any specific myeloma FISH abnormalities seen in AO associated MM and if there were any differences in their respective survival. Methods: We included all patients diagnosed with MM from 2010-2022 at Louis Stokes VA Medical Center (Cleveland, OH). Data collected included: age, sex, race, year of diagnosis, AO exposure, bone marrow biopsy results and myeloma FISH panel results. We defined high risk MM based on the presence of t(14;16), t(14;20), del 17p/TP53 or gain 1q. Overall survival (OS) was calculated from date of diagnosis to death. Results: We included 162 patients with MM, among them 32 had AO exposure. There was no significant difference in age or race between exposed and non-exposed patients. MM FISH results were available for 137 patients. Overall, 20% of patients had high risk group cytogenetics and there was no significant difference based on AO exposure. However, there was a trend for increased TP53 mutations in those exposed to AO, although this did not reach statistical significance (8% vs. 3.6%, p = 0.3). Median OS was 72 months for non-exposed patients and 98 months for exposed patients, with no significant difference observed (p = 0.18). Conclusions: In this single institution, retrospective study, AO exposure was not associated with a higher incidence of high-risk cytogenetics by FISH in MM. There was a trend for increased TP53 mutation with AO exposure, but the cohort was small and did not reach statistical significance. In addition, AO exposure was not associated with a worse survival. Further studies are needed to clarify the effects of AO on the development of MM, including genomic and transcriptomic analysis to elucidate the pathobiology of this disease. [Table: see text]
Estimating the impact of adjuvant atezolizumab in preventing recurrences and reducing costs in resectable early PD-L1 high non-small cell lung cancer in Europe.
Authors: Arnold Melina , Jovanoski Nick , Tomar Akanksha , Dubey Akansha , Yim Yeun Mi , Napalkov Pavel 
Published: June 2023

e20501 Background: Recurrences of non-small cell lung cancer (NSCLC) after surgery remain common and are associated with significant morbidity and mortality. Loco-regional or metastatic disease recurrence can lead to a substantial health care resource use and economic burden. The aim of this study was to estimate the effect of treating patients with early-stage NSCLC with adjuvant atezolizumab (ATZ) on the number of recurrences and direct healthcare costs in Germany, Spain, France Italy and the UK, together referred to as EU5. Methods: Using an epidemiological model, we estimated the reduction in loco-regional (LR) recurrences or distant metastases (DM) after adjuvant ATZ treatment following chemotherapy in operable NSCLC patients with PDL-1 expression of ≥ 50% on tumor cells (PD-L1 high), stage II-IIIA (AJCC 7th edition staging), without EFGR or ALK alterations. We used data from cancer registries, published literature sources, and market research to obtain incidence rates, staging distribution, biomarker status data, and adjuvant treatment rates. Moreover, we used evidence on the disease-free survival (DFS) of patients on adjuvant ATZ from the IMpower010 (NCT02486718) clinical trial to calculate the projected reduction in the number of LR recurrences or DM over a 10-year period post-ATZ launch relative to best supportive care (BSC). The model considers the costs associated with treatment, management of adverse events, monitoring of the disease, and follow-up healthcare. Results: We project that between 2023 and 2033, 20,483 patients with resected PD-L1 high stage II-IIIA NSCLC would experience recurrence (LR, or DM, or both) in the EU5 if they were treated with BSC (adjuvant platinum-based chemotherapy) alone (Table 1). Assuming peak ATZ uptake of 75%, the model estimates that following adjuvant ATZ and chemotherapy, a total of 4,665 recurrences would be prevented in this patient population in the EU5 over 10 years, representing a 23% decrease in recurrence relative to BSC. These avoided recurrences in EU5 could translate into a considerable reduction in direct healthcare costs. Conclusions: Adjuvant ATZ following chemotherapy results in a considerable population-level reduction of loco-regional recurrence or distant metastasis in resected PD-L1 high stage II-IIIA NSCLC patients. This could translate into a substantial decrease in the economic and societal burden caused by the disease. [Table: see text]
A survey on the detection of HPD-related genes by liquid biopsy in patients with lung cancer in China.
Authors: Zhang Peng , Peng Bo , Jing Zhang , Cheng Shaochen 
Published: June 2023

e20502 Background: he prognosis for lung cancer patients receiving immunotherapy is impacted by hyper-progression disease (HPD). Assays for HPD-associated gene mutations were anticipated to be crucial for immunotherapy. Although easy and non-invasive, the liquid biopsy technique is not widely employed in immunotherapy. Here, we want to study details of HPD-related gene mutations in the detection of tissue and liquid biopsy and dig out some relevant information from Chinese Lung Cancer (CLC) patients. Methods: 10 genes with HPD-associated mutation were collected by literature, like SNV ( EGFR, KEAP1, STK11, DNMT3A, PTEN), CNV ( ALK fusion, amplification of MDM2, MDM4, FGF3, FGF4). 3540 cell-free DNA (cfDNA) samples and 6553 tumor tissue samples of LC patients download from Haplab database (HaploX, Shenzhen, China). Genetic alterations were sequenced by NGS platform and microsatellite instability status was calculated through msisensor analysis. The chi-square test was used for statistical hypothesis test. Results: In general, all mutation genes tested except EGFR were detected significantly differently between tissue and cfDNA samples (p < 0.05). 193 samples (156 tDNA, 37cfDNA) with microsatellite instability (MSI) were screened to test HPD-related gene consistency. Results showed no significant difference in 10 HPD-related genes between MSI tissue and blood samples (p > 0.05). Microsatellite stable (MSS) samples of 4499 tumor DNA and 1173 cfDNA were also performed on consistency test. EGFR and the other 4 genes ( FGF3, FGF4, KEAP1, PTEN) were found consistency in tDNA and cfDNA, and ALK (p 0.0051), MDM2 (p 0.0004), MDM4 (p 0.0052), STK11 (p 0.0344), DNMT3A (p < 0.0001) showed significant difference of two type of samples. Conclusions: In overall samples and subtypes tested, only EGFR had no significant differences between tissue and cfDNA, which might make EGFR a perfect biomarker candidate in HPD detection and prognosis. Our outcomes also proved that liquid biopsy has some limitations in monitoring HPD-related genes of CLC compared with tissue biopsy. MSS patients presented more reliable results than MSI patients. When monitoring HPD-related genes except for EGFR using cfDNA, appropriate patients should be considered.
Comparison of gene alterations detected with tumor tissue and plasma in a Chinese population with advanced lung adenocarcinoma.
Authors: Zhang Yong , Li Si , Xi Wenjing , Zhu Chan , Song Yunjie , Deng Wanglong , Qi Chuang 
Published: June 2023

e20511 Background: Currently, plasma cell-free DNA has been recommended as an alternative biomarker for guiding precision treatment in lung cancer. In this study, we retrospectively reviewed gene alterations detected by matched plasma and tumor tissue to investigate the concordance and sample-specific observations. Methods: The inclusion criterions included 1) samples collected between January and October 2022, 2) clinical stage IV, lung adenocarcinoma, 3) plasma taken within 4 weeks of tumor biopsy, 4) cell-free DNA and tumor DNA were extracted for next-generation sequencing (sequencing depth, 4000X for tissue and 10000X for plasma), with a pan-cancer 539-gene panel in a CAP-certificated laboratory. Alterations including mutations (SNV, indel), fusion and CNV of driver genes, including EGFR, ALK, ROS1, RET, MET, NTRK, BRAF, ERBB2, KRAS (9-gene), were emphatically reviewed and compared. Concordance was defined as tissue and plasma reported alterations within the same gene, or both negative. Tumor mutation burden (TMB) was calculated as ratio between total number of non-synonymous variants and total size of coding region. Results: After reviewing 630 patients with matched plasma and tumor samples, 121 patients diagnosed with stage IV lung adenocarcinoma were included. The top five altered genes in tissue were TP53 (71.07%), EGFR (57.86%), MYC (33.88%), MUC16 (23.97%), CDK6(23.97%), those in plasma were TP53 (52.89%), EGFR (40.5%), DNMT3A (28.93%%), MUC16 (18.18%), LRP1B (15.7%). The detection rates of driver gene (9-gene) alterations were 92.56% (112/121) for tissue and 69.42% (84/121) for plasma. The overall concordance of 9-gene alteration was 69.42%, it increased to 74.38% excluding fusions and CNVs. Among mutations, EGFR (61/121), KRAS (14/121), ERBB2 (9/121) and BRAF (3/121) were more often reported in tissue or plasma. The concordances were 71.13% ( EGFR), 66.67% ( BRAF), 55.56% ( ERBB2) and 42.86% ( KRAS) respectively. We also observed five mutations ( EGFR G719A/S768I, KRAS G12A/Q61L/A146P) that were only detected in plasma in four patients. One patient was detected with STRN-ALK only in plasma. These plasma-only mutations might provide extra efficacy predicting (sensitive or resistance) for EGFR/KRAS/ALK inhibitors. TMB of plasma and tissue showed strong correlation (Pearson’s Correlation Coefficient of 0.74). 14 and 13 patients were divided into TMB-H ( > 10 mutations/Mb) in tissue and plasma respectively, the concordance rate was 94.21% (114/121). Among qualified samples for MSI evaluations, non MSI-H was detected, the concordance rate was 100%. Conclusions: The sequencing results of matched plasma and tissue presented good concordance of driver gene alterations (especially for EGFR mutations), TMB-H and MSI-H. These suggested ctDNA testing might be a reliable commentary approach to tissue to guide target and immunotherapy in advanced lung adenocarcinoma.
High frequency of germline mutations in DDR associated genes SLX4, MSH6, CDK4, TSC2, and BRCA2 might contribute to the occurrence of MPLC.
Authors: Gu Weiquan , Zhao Ning , Ye Jun , Wang Fei , Xiao Ye , Xiao Mingzhe 
Published: June 2023

e20514 Background: Multiple primary lung cancer (MPLC) is the presence of two or more distinct and separate lung tumors in a single patient. Each is considered a primary tumor rather than a metastasis from another site. This phenomenon has been the subject of several studies in recent years due to its increasing incidence and potential implications for patient management and prognosis. The underlying causes of MPLCs are not fully understood. Still, several factors have been proposed to contribute, including the genetic predisposition of carcinogens, such as those in the TP53, BRCA1, and BRCA2 genes, which are associated with an increased risk of developing MPLCs, as well as other cancers. Whether the presence of germline genetic mutations can increase an individual's susceptibility and contribute to the development of MPLCs is not clear yet. Here we reported the landscape of germline mutations of 77 MPLC patients. Methods: We retrospectively analyzed the somatic and germline mutations from 77 MPLC patients by NGS analysis. The GO and KEGG analyses were performed based on the top 30 most frequent germline mutations. Results: Among the 77 patients, 21 (27.27%) were male, and 56 (72.73%) were female. The median age was 60 (26-82) years old. The top 5 frequent germline mutated genes were SLX4 (34.92%), MSH6 (39.68%), CDK4 (26.98%), TSC2 (25.4%), and BRCA2 (25.4%). The top 5 frequent somatic mutated genes were EGFR (80.95%), CDK4 (26.98%), MCL1 (23.81%), SOCS1 (19.05%), and TP53 (19.05%). GO analysis of germline mutations revealed enrichment in ontologies such as response to radiation and UV, cell cycle regulation, a series of DNA damage repair associated ontologies, and telomere organization. KEGG analysis indicated that these germline mutations were enriched in the PI3K-Akt pathway, microRNAs in cancer, TP53 pathway, Fanconi anemia pathway, cellular senescence, and many other cancer-associated pathways. Conclusions: Germline alterations in many genes coding for proteins regulating DNA repair and DNA damage response (DDR) to DNA double-strand breaks (DDSB) have been recognized as pathogenic factors in hereditary cancer predisposition. In our analysis, the MPLC patients contained widespread germline mutations in SLX4, MSH6, CDK4, TSC2, and BRCA2, which were all associated with DNA damage repair. Besides, GO analysis and KEGG analysis also revealed enrichment in DDR-associated ontologies or pathways (e.g., TP53 pathway, Fanconi anemia pathway, cellular senescence pathways). To our knowledge, an underlying hallmark of cancers is their genomic instability, which is associated with a greater propensity to accumulate DNA damage. The widespread of germline mutations in DDR-associated genes, including SLX4, MSH6, CDK4, TSC2, and BRCA2, might contribute to the gene instability and promote the development of MPLC.
Multicenter evaluation of AI-based CT radiomics for EGFR mutation prediction in NSCLC.
Authors: Liu Yan , Bodard Sylvain , Felfli Mehdi , Zerka Fadila , Voyton Charles , Thinnes Alexandre , Jacques Sebastien , Iannessi Antoine 
Published: June 2023

e20515 Background: Tyrosine kinase inhibitors targeting the epidermal growth factor receptor (EGFR) were the first targeted therapy to enter clinical use for non-small cell lung cancer (NSCLC), thanks to its significant improvement on treatment response and patient survival. Today, tissue sampling is the standard to collect material for testing EGFR mutation status in advanced NSCLC, but has known sampling limitations due to intra-tumoral heterogeneity leading to false negative results. Computed tomography (CT) image based radiomics models offer a non-invasive solution, allowing comprehensive analysis of the entire tumor and surrounding tissue. Radiomics could provide insights during patient longitudinal follow up, or when tissue sample is not accessible is suboptimal. During the past decade, predicting EGFR mutation status using CT radiomics was widely investigated, with promising results. Nevertheless, most studies were single center retrospective studies, without external validation. Therefore, our study aims to investigate the performance of a CT radiomics EGFR mutation prediction model in a multicentral setting with an external cohort. Methods: CT images were collected from multicenter institutions and open source databases (https://www.cancerimagingarchive.net/), including a total of 1047 patients with advanced stage NSCLC with at least one measurable lung lesion (≥10mm). Each lung lesions was segmented semi-automatically followed by the validation of an experienced radiologist with > 20 years of experience. The dataset was divided to 2:1 for training and testing, with the test set originating from centers unique from the training cohort. A total of 1246 radiomics features were extracted using the Pyradiomics package. The 10 most robust features were selected first, by removing all features with variances near zero, then by applying Maximum Relevance — Minimum Redundancy (MRMR) to the remaining features. All selected features were standardized before modelling. A support vector machines (SVM) classifier was trained using a five-fold cross validation to classify EGFR mutations status (Wild type vs Mutant). Results: The SVM model trained with the radiomics features achieved mean area under curve (AUC) of 0.83 (95% CI, ±0.03) on the cross validation and an AUC of 0.76 (95% CI, ±0.03) on the test set. Conclusions: Our multicentric study demonstrated the potential of CT radiomics models in predicting EGFR mutation status in advanced NSCLC, with results similar to those found in current literature. We are optimizing the radiomics model by combining deep learning and clinical features, to improve the accurate, reliable and reproducible performance. AI powered medical image analysis has a bright future as an non-invasive and easy-to-use alternative to identify the expression status of common oncologic genes, serving as predictive biomarker for guiding the targeted therapies of the future.
Impact of CLEC3B mRNA expression on genetic landscape and immune tumor-microenvironment in NSCLC.
Authors: Zimmer Kai , Kocher Florian , Tymoszuk Piotr , Martowicz Agnieszka , Daum Sophia , Pircher Andreas , Horvath Lena , Baca Yasmine , Puri Sonam , Owonikoko Taofeek K. , Oliver Trudy G. , Uprety Dipesh , Kulkarni Amit , Lopes Gilberto , Halmos Balazs , Borghaei Hossein , Liu Stephen V. , Ma Patrick C. , Wolf Dominik , Seeber Andreas 
Published: June 2023

e20517 Background: Downregulation of C-type lectin domain family 3 member B (CLEC3B) is observed in non-small cell lung cancer (NSCLC), but its role remains largely unclear. Thus, we conducted this large scale genomic and transcriptomic analysis to gain novel insights into molecular and immunological functions of CLEC3B mRNA expression in NSCLC. Methods: Five publicly available WTS/WES NSCLC datasets (TCGA LUAD/LUSC, GSE41271, GSE66863, GSE81089, BATTLE) and the lung cancer single-cell atlas (Salcher, Cancer Cell 2022) were re-analyzed to decipher various molecular and biological aspects of CLEC3B in NSCLC. Findings were validated in a cohort of 19,982 NSCLC samples, which were centrally profiled (Caris Life Sciences, Phoenix, AZ) using WES/WTS. The cohort was stratified in quartiles according to CLEC3B mRNA expression status, with CLEC3Bhigh ( CLEC3BH) and CLEC3Blow ( CLEC3BL) expression defined as top and bottom quartile of transcripts per million (TPM) for further comparison. Immune cell fractions were calculated using QuantiSeq. Real-world overall survival (OS) was calculated using data from insurance claims. Results: CLEC3B mRNA expression was diminished in NSCLC compared to matched normal tissue (p < 0.001). Adenomatous histology was associated with higher CLEC3B expression compared to squamous/large-cell carcinomas (p < 0.005). In CLEC3B H tumors we observed lower rates of somatic mutations in TP53 (44.1 vs 81.7%), TTN (54.1 vs 79%), CDKN2A (5.2 vs 15%), but higher rates in KRAS (24 vs 7.8%) and STK11 (15.8 vs 2.69%) (all, q < 0.01), which we corroborated in our validation cohort (TP53 (52.4 vs 74.7%), CDKN2A (8.3 vs 13%), RB1 (9.2 vs 13.5%), KMT2D (3.8 vs 7.3%), KRAS (31.8 vs 25.6%), EGFR (17.2 vs 8.1%) and STK11 (15.9 vs 11.3%, all q < 0.05)). Further, CLEC3BH tumors were characterized by an immunosuppressive phenotype reflected by lower TMB and lower rates of MSI-H/dMMR, lower PD-L1 IHC expression and abundance of M2 macrophages and regulatory T-cells. Analysis of bulk and single cell transcriptomic datasets revealed that CLEC3BH was linked to endothelium-specific signaling and higher expression levels in endothelial cells. Finally, increased CLEC3B expression was associated with improved OS in the exploratory and validation cohorts. Conclusions: We herein described the molecular landscape of NSCLCs according to CLEC3B mRNA expression. We speculate that CLEC3B is mainly expressed by endothelial cells, and observed that CLEC3BH was associated with a distinct genetic profile and an immunosuppressive tumor-microenvironment. Thus, CLEC3B expression warrants further investigation as a stratification marker for NSCLC patients undergoing immune checkpoint therapy.
Clinical characteristics of patients with non-small cell lung cancer eligible for biology-guided radiotherapy.
Authors: Olaechea Santiago , Song Tidie , Gilmore Linda , Infante Rodney E. , Westover Kenneth D. , Zhang Yuanyuan , Desai Neil B. , Dan Tu , Timmerman Robert D. , Oz Orhan K. , Iyengar Puneeth , Garant Aurelie 
Published: June 2023

e20523 Background: Biology-guided radiotherapy (BgRT) is a novel radiotherapy modality that uses real-time positron emission tomography (PET) to guide radiotherapy beamlets. BgRT recently received FDA clearance for clinical use using the 18F FDG radiotracer for the treatment of tumors in lung and bone. We sought to identify non-small cell lung cancer (NSCLC) patients who may be candidates for BgRT based on diagnostic FDG PET/CT imaging. Methods: We conducted an IRB-approved retrospective assessment of NSCLC patients diagnosed between 01/01/2006 and 12/31/2013 at a tertiary care center in the United States. Patient and tumor characteristics were verified by an institutional data repository team and through electronic medical record review. Patients were excluded from analysis when documentation of clinical/ imaging findings was insufficient. Frequency of characteristics were interpreted with and without tumor diameter and maximum standardized uptake value (SUVMax) parameters, to confirm eligibility for BgRT on this novel radiotherapy device. Results: Of the 686 patients eligible for analysis, 523 presented with tumor SUVMax of ≥6 on diagnostic PET imaging and 360 presented with tumor diameters of at least 2 cm and below 5 cm. Of the 277 patients who met both SUVMax and size parameters, respectively, 75 (27.1%), 145 (52.3%), and 57 (20.6%) presented with squamous, adenocarcinoma, or other/unknown histology, and 77 (27.9%), 29 (10.5%), 92 (33.3%), and 78 (28.3%) presented with stage I, II, III, or IV tumors (AJCC 7th edition). Conclusions: Theoretical applicability of biology-guided radiotherapy was observed in our NSCLC patient cohort. Therefore, despite current limitations of radiotracer uptake thresholds and tumor size restrictions, there is broad potential applicability of this treatment modality, either as a single modality treatment or in conjunction with active systemic therapy. [Table: see text]