bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparing implementation of Telemedicine compliance and feasibility among oncology patients across countries during the COVID 19 pandemic.
Authors: Pelles Sharon , Peleg Hasson Shira , Waissengrin Barliz , Hasid Lior , Deutsch Irad , Safra Tamar , Wolf Ido , Geva Ravit 
Published: June 2021

e13622 Background: COVID19 pandemic expedited the use of telemedicine across nations. Oncology patients as at risk population especially needed the use of telemedicine to continue patient care. Evaluating patients' compliance and satisfaction with telemedicine is needed and might vary across nations and cultures. Experience from telemedicine during COVID might help shape oncology care in the future. Methods: A questionnaire that was locally validated in the Tel-Aviv Sourasky Oncology Division was distributed internationally using the BELONG.life digital health platform, a free and anonymous application (app) for cancer pts and caregivers. Results were compared between US pts replied through the app and Israeli patients. Results: The questionnaire was distributed to 232 Israeli patients and to 362 BELONG users in the US. The compliance was 74% and 35% pts respectively. Majority of users in Israel were male (54%) versus female in the US (77%). In the US 75% were Caucasian. More Israeli patients had a family member present in the call then in the corresponding US group (47% vs 64%). Both Israeli and US pts felt satisfied with the meeting and reported the willingness to continue with the same approach in the future regardless of the pandemic situation (84.9%, 63%, respectively). 95.9% of Israeli patients were attended by their regular doctor as opposed to 71% in the US. Call time duration was prolonging to 30-60 min and willingness to repeat the calls dropped to 47% when performed with a different doctor. In the US 76% of patients reported the telemedicine call saved them precious time. Conclusions: Patients' response to telemedicine meetings across countries was positive with oncology care visits being maintained successfully despite the ongoing COID19 pandemic. Most patients regardless of country of origin showed willingness to continue with telemedicine however maintaining the care with the patient's regular physician is important for the continued use of telemedicine in reducing visits time and improving the pts interaction and satisfaction. Clinical trial information: 0227-20.
The analysis of EGFR variants in Chinese adult glioblastoma patients.
Authors: Li Qiao , Sun Weijie , Lu Yi , Guo Didi , Han Tiantian , Lu Guanghua , Li Xiaomin , Ding Ran , Bu Fanfeng 
Published: June 2021

e14020 Background: Glioblastoma multiforme (GBM) is the most common primary brain tumor with complex genetic alterations and genomic profiles. EGFR amplification occurs in approximately 40% of primary GBM，EGFR mutation is also a prevalent genetic abnormality in GBM. A series of potential therapies targeting EGFR variants are currently in development, such as tyrosine kinase inhibitors (TKIs), monoclonal antibodies, vaccines, etc. However, to date, EGFR-targeted therapy continues to face significant challenges. A deeper understanding of EGFR variant profiles and pathobiology of GBM will be required. Methods: Next-generation sequencing of 131-gene profiling was performed to analyze EGFR activating mutations from 891 Chinese glioma patients in 2019-2020. Somatic mutations and copy number variations were detected following the standard operating procedure (SOP). We screened out the EGFR activating mutation and calculated the mutation frequency and the tumor location. Results: 51 GBM patients had activating mutations. The average age was 49 years (range,25-73 years). Most of the tumors occurred in the cerebral hemisphere (56.9%), followed by ventricles (3.9%) and thalamus (3.9%), etc. 43/51 (84.3%) were accompanied by high-fold EGFR amplification. 9/12 (75%) were EGFR intracellular mutation occurs with EGFR amplification, 31/35 (88.6%) were EGFR extracellular mutation occurs with EGFR amplification. Moreover, 4 patients carried EGFR intracellular and extracellular mutation occurs with EGFR amplification. There was no significant difference between the ratio of intracellular mutations and extracellular mutations with EGFR amplification (P=0.3496). Conclusions: In our GBM patients, EGFR activating mutations were accompanied by high-fold EGFR amplification. As we know that, GBM benefit from EGFR-TKIs may be limited. Therefore, multi-targeted combination therapy research could be considered in the future.
MAPK pathway alteration may be a new integrated diagnosis term.
Authors: Cheng Chuandong , Ji Ying , Han Tiantian , Li Xiaomin , Huang Yahui , Sun Weijie , Lu Guanghua , Deng Wanglong , Ding Ran , Bu Fanfeng 
Published: June 2021

e14022 Background: The 2016 CNS WHO classification is the first to include molecular factors to classify in glioma. We are in the age of glioma subgroups, in which the category depended on the histological and molecular composition, providing more clinical behavior, prognosis, and therapeutic targets hints. The most well-known molecular modifications are IDH1/2 mutation, ATRX variant, TP53 variant, BRAF mutation or fusion, 1p/19q co-deletions. However, there is a diagnostic term“NOS” in the 2016 CNS WHO classification，which indicates that a tumor could not be placed into a more specific WHO category. Here, our analysis of the MAPK pathway may suggest a new subtype. Methods: Targeted next-generation DNA sequence of the 131-genes panel was performed on gliomas in 119 patients. We measured the somatic variations in the MAPK pathway after filtering known driver mutations. The analysis of genomic alterations was performed using a two-sided Fisher exact test. Results: 90/119（75.6%）were excluded due to known driver mutations. 29/119(24.4%) were classified in NOS with a typical “single MAPK pathway alteration” and different histological characteristics and WHO grade. The median age at diagnosis was 35 years (4-79) in our gliomas. The most frequent mutations were NF1(10/29), FGFR1(7/29), KRAS (6/29), BRAF (3/29), PTPN11(2/29), although there are other gene mutations like FGFR2, FGFR3, AKT1, MAP2K1. According to cIMPACT-NOW update 4, our pediatric gliomas ( < 30 years, n = 14) could be identified as “diffuse glioma, other MAPK pathway alteration.” Our adult gliomas have a higher frequency of NF1 mutations（8/15 vs. 2/14, p = 0.05), a lower KRAS (1/15 vs. 5/14) and FGFR1 (2/15 vs. 5/14) mutations than children. Conclusions: Our result suggests that MAPK pathway alteration may be a new integrated diagnosis term in all ages of glioma. Moreover, KRAS and FGFR1 may be associated with pediatric gliomas. NF1 is more common in adult gliomas.
RBM8A promotes growth and invasion through the Notch/STAT3 pathway in glioblastoma.
Authors: Lin Yan , Zhang Jinyan , Hu Beiquan , Qin Gang , Liang Rong , Lin Yingying , Wei Jiazhang , Qian Zhongrun , Zou Donghua 
Published: June 2021

e14038 Background: Glioblastoma (GBM) is a prevalent brain malignance with an extremely poor prognosis, which is attributable to its invasive biological behaviors. The RNA-binding motif protein 8A (RBM8A) has different effects on various human cancers. However, the implication of RBM8A in glioblastoma progression remains unclear. Methods: Glioblastoma (GBM) data set was downloaded from the Cancer Genome Atlas (TCGA). Differential expression analysis was used to screen the differentially expressed genes (DEGs) between GBM and control, RBM8A high and low expression samples, Gene Ontology (GO) analysis and Kyoto Encyclopedia of Gene Genomes (KEGG) analysis were performed on the co-upregulated DEGs. Additionally, We investigated the expression levels of RBM8A in 94 glioblastoma patients and explored the correlation between the RBM8A expressions with prognosis. Using in vitro and in vivo assays, we addressed the functional impacts of RBM8A on and the underlying mechanisms through which RBM8A contribute to glioblastoma progression. In addition, a comprehensive regulatory network of RBM8A regulation was constructed based on STRING database. Molecular docking model was used to predict the possibility of RBM8A binding to target genes. Combined with TCGA and Chinese glioma genome map (CGGA), gene set variance analysis (GSVA) was used to calculate the GSVA scores of the genes involved in the mechanism. Receiver operator characteristic curve (ROC) curve analysis and survival analysis were performed to explore the prognostic and diagnostic ability of GSVA score for GBM. Results: Our results indicate that higher RBM8A expression in glioblastoma tissues was associated with a poor prognosis. In addition, functional enrichment analysis based on genes related to RBM8A expression showed that RBM8A was related to cell cycle and Notch signaling pathway. RBM8A may promote glioblastoma cell proliferation and migration by activating Notch/STAT3 pathway in glioblastoma cells. In vitro and in vivo assays confirmed that knocking down RBM8A inhibited glioblastoma progression and invasion ability. We also observed that the pro-oncogenic effects of RBM8A in glioblastoma tissues were mediated by activation of the Notch/STAT3 pathway. Finally, it was concluded that the GSVA score has good diagnostic and prognostic value for GBM. Conclusions: RBM8A may promote glioblastoma cell proliferation and migration by activating Notch/STAT3 pathway in glioblastoma cells, suggesting that RBM8A may serve as a potential therapeutic target for the treatment of glioblastoma.
Local progenitor cells shape the neoplastic vasculature and promote brain tumor growth.
Authors: Kälin Roland , Cai Linzhi , Zhao Dongxu , Zhang Huabin , Zhang Wenlong , Kirchleitner Sabrina , Siller Sebastian , Enard Wolfgang , Schiemann Matthias , Andrä Immanuel , Giachino Claudio , Taylor Verdon , Synowitz Michael , Tonn Joerg , Baumgarten Louisa von , Hellmann Ines , Glass Rainer 
Published: June 2021

e14044 Background: Aggressive brain tumors like glioblastoma depend on support by their local environment. While the role of tumor-associated myeloid cells on glioblastoma progression is well-documented, we have only partial knowledge of the pathological impact of glioblastoma -parenchymal progenitor cells. Methods: We investigated the glioblastoma microenvironment with transgenic lineage-tracing models ( nestin-creER2, R26-tdTomato and sox2-creER2,R26-tdTomato), intravital imaging, single-cell transcriptomics, immunofluorescence and flow-cytometry as well as histopathology and characterized a previously unknown tumor-associated progenitor cell. In functional experiments, we studied the knockout of the transcription factor SOX2 in these tumor-associated cells. Results: Lineage-traced cells from mouse glioblastoma were obtained by flow-cytometry and single cell transcriptomes compared to established gene expression data from brain tumor parenchymal cells. The traced tumor-associated cells had a transcriptomic profile largely resembling myeloid cells and expressed microglia-/macrophage-markers on the protein-level. However, transgenic models and bone-marrow chimera revealed that the traced cells were clearly distinct from microglia or macrophages. The traced tumor associated cells with a myeloid expression profile derived from a SOX2-dependent progenitor cell. Consequently, conditional Sox2-knockout ablated the entire myeloid-like cell population. Remarkably, this tumor-associated cell population had a large impact on disease-progression causing significant reduction of glioblastoma –vascularization to 53%, changing vascular function and leading to a decrease in tumor volume to 42% as compared to controls. The myeloid-like progenitor cells were identified in human brain tumors by immunofluorescence and in scRNA-seq data. Conclusions: We identified a previously unacknowledged population of tumor-associated progenitor cells with a myeloid-like expression profile that transiently appeared during glioblastoma growth. These progenitors have strong impact on glioblastoma progression and point towards a new and promising therapeutic target in order to support anti-angiogenic regimen in glioblastoma.
Activating chimeric receptor on IL-15 armored NK cells to improve in vitro and in vivo tumor response within the liver following regional delivery.
Authors: Tan Joanne , Guha Prajna , Wadsworth Sarah , Ghosh Chandra C. , Chai Louis F. , Katz Steven C. , Trager James 
Published: June 2021

e14517 Background: Colorectal cancer liver metastases (CRCLM) are a major source of morbidity and mortality. Historically, curative therapy has been limited to surgical resection, but only a small fraction of patients are eligible. Cellular immunotherapy has shown promise in hematologic cancers, but challenges to solid tumor therapy remain, including lymphocyte trafficking, elevated interstitial fluid pressures, and immunosuppression. Regional intravascular infusion is a non-surgical, minimally invasive procedure commonly used in liver cancer to deliver therapeutics, which can be augmented by Pressure Enabled Drug Delivery (PEDD). We hypothesized that utilizing established regional delivery strategies to administer natural killer (NK) cells engineered to express a natural killer group 2, member D (NKG2D) activating chimeric receptor and membrane bound IL-15 (CAR NKG2D cells) could increase anti-tumor activity against liver cancer. Methods: In vitro cytotoxicity of CAR NKG2D NK cells was determined in co-culture systems. CRCLM-bearing NSG mice were treated with either CAR NKG2D, non-transduced NK cells (NT-NK), or vehicle via portal vein (PV) for regional PEDD or tail vein (TV) for systemic delivery (SD). Tumor burden was measured via tumor bioluminescence. Mann-Whitney tests were performed for statistical comparisons. Correlation of NKG2D ligand expression in tissue and serum was measured by CODEX and Luminex. Results: Multiple NKG2D ligands are highly expressed in hepatocellular and colorectal carcinoma cell lines (HCC and CRC respectively). As such, these cells lines are highly susceptible to NKG2D-mediated cytotoxicity. CAR NKG2D NK cells were 3- to 4-fold more potent in vitro than NT-NK cells against multiple HCC and CRC cell lines, including those bearing Ras pathway mutations. Using a mouse model of locoregional delivery under high pressure (10 mL/minute), we show that significant tumor reduction (p < 0.05) is only achieved when CAR NKG2D NK cells, but not vehicle or NT-NK cells, were delivered via PV and not via TV. Recovery of CAR NKG2D NK cells in hepatic tissues was on average 2-fold higher after administration via PV than that observed after TV delivery (p = 0.0001). PV delivery of NT-NK cells did not result in appreciable liver engraftment or tumor growth inhibition. Conclusions: CAR NKG2D NK cells demonstrate enhanced in vitro and in vivo cytotoxicity against CRC and HCC cell lines. Significant tumor control using regional delivery in initial studies support continued clinical development. NKX101 is an investigational agent comprised of CAR NKG2D NK cells being evaluated in a phase 1 clinical study for treatment of relapsed/refractory acute myeloid leukemia or higher risk myelodysplastic syndrome. Studies are ongoing to understand NKX101 kinetics, role of delivery pressure, and activity in combination in preclinical models of CRCLM.
A pan-cancer profiling of somatic mutations and tumor microenvironment to reveal mutation dependent immunophenotypic signature differences in KRAS.
Authors: McDaniel Lee , Abbott Charles , Pyke Rachel , Levy Eric , Zhang Simo V. , Wang Jing , McClory Rena , Chen Richard , Boyle Sean Michael 
Published: June 2021

e14526 Background: The ubiquity of tumor genotyping has identified hundreds of clinically actionable somatic mutations such as KRAS mutations predicting anti-EGFR response in colorectal cancer. Here, we describe an integrative pan-cancer study leveraging the Personalis NeXT Platform across 13 tumor types to reveal a broad portrait of clinically relevant mutations across 36 genes. Given the ascendance of tumor immunotherapy, there is an urgent need to better elucidate associations between clinically relevant gene mutations, patient demographics, and tumor immunobiology. Methods: Paired tumor-normals (n > 450) were sequenced on the Personalis NeXT Platform, a diagnostic platform which simultaneously profiles tumor and immune microenvironments via exome and transcriptome sequencing. Samples were evaluated for the presence of KRAS variants at the G12, G13, and Q61 positions, requiring a minor allele frequency of more than 2%. Additionally, more than 200 clinically relevant amino acid changes were considered across 36 genes. DNA sequencing data was harnessed to profile MSI status, oncovirus status, HLA allele-specific LOH, SNVs, and neoantigens. RNA sequencing data furnished profiles for gene expression, TILs, TCR, BCR, and immune signatures. Statistical tests compared both the presence of clinically relevant mutations, and specific amino acid changes, to each of these DNA and RNA derived features. Results: Immunogenomic analysis with the Personalis NeXT Platform identified KRAS mutations at the G12, G13, and Q61 positions in 6 of the 13 tumor types, including bladder, CRC, liver, NSCLC, pancreatic, and uterine cancers, consistent with known KRAS allelic incidence. 11 different KRAS amino acid substitutions were identified in this cohort, including G12(A/C/D/R/S/V), G13(C/D), and Q61(H/K/L), with 14% of samples positive for KRAS variants across our pan-cancer cohort, including malignancies not associated with KRAS. Immune signatures, including TCRB clones, mutational burden, and TILs signatures demonstrated variability in a KRAS allele-dependent manner. Pancreatic cancers demonstrated a statistically significant increase in macrophage enrichment score (p < 0.001) in KRAS-mutant tumors. Conclusions: Utilizing the Personalis NeXT Platform, our analysis characterized the tumor microenvironment of over 460 samples across 13 tumor types, 36 genes, and over 200 clinically relevant amino acid substitutions. This comprehensive characterization demonstrated significant differences in immune cell signatures in pancreatic cancer, suggestive of an association between the presence of KRAS mutations and immune cell infiltrate composition.
Investigating the impact of immune related adverse events, glucocorticoids use and immunotherapy interruption on long-term survival outcomes.
Authors: Lafayolle de la Bruyère Charline , Peron Julien , Souquet Pierre Jean 
Published: June 2021

e14551 Background: It remains unclear whether immune related adverse events (irAEs) and glucocorticoids use could impact long term-outcomes in patients treated for solid tumors with immune checkpoint inhibitors (ICI). Methods: All patients treated with a single-agent ICI for any advanced cancer were included in this retrospective multicentric study. Objectives were to assess the impact of grade 3+ irAEs, glucocorticoids use and interruption of immunotherapy on progression free survival (PFS) and overall survival (OS). Data collection was performed retrospectively using a standardized data collection form. Adverse events were categorized as irAEs based on the judgement of the treating physicians, based on the common Terminology Criteria for Adverse Events, version 4.0. Only grade 3 and more irAEs were considered in this study. As irAEs might happen late during the follow-up and progression event or death might happen early, an immortal-time bias might occur as patients responding to ICI will receive the ICI and then be exposed to irAE for a longer period of time. The first occurrence of an irAE was then included in Cox models, as a time-varying covariate. Similar methods were used to evaluate the impact of glucocorticoids introduction or ICI interruption. Results: In this 828 patients’ cohort, 78 patients presented at least one grade 3+ irAE. The first occurrence of grade 3+ irAEs had no significant impact on PFS (HR 0,94; 95%CI 0.7-1.26; p = 0,70) or OS (HR 0.82; 95%CI 0.6-1,12; p = 0,21). 65% of patients with anti CTLA4 and 55% of patients with anti PD(L)1 requested glucocorticoids, which was associated with a significant shorter PFS (adjusted HR 3.0; 95%CI 1.6-5.4; p = 0.00040) and a trend toward shorter OS. Grade 3+ irAEs led to interruption of the ICI in 82 % of patients, which was associated with a significant shorter PFS (adjusted HR 3.5; 95%CI 1.7-6.0; p < 0.00043) and shorter OS (HR 4.5; 95%CI 1.7-12.1; p = 0.0027). The use of glucocorticoids was statistically associated with immunotherapy interruption. Conclusions: In our population of patients treated with single agent ICI, grade 3+ irAEs did not impact long-term outcomes. However, the need for glucocorticoids and the interruption of immunotherapy resulted in poorer long-term outcomes. The impact of grade 3+ irAEs reported in other studies might then be explained by the management of the irAEs.
CARG-2020, an oncolytic artificial virus co-delivering three immunomodulators, to regress and cure established tumors in mice.
Authors: Almassian Bijan , Madina Bhaskara R , Chen Ju , Krady Marie M , Ma Xianyong , Yarovinsky Timur O , Nakaar Valerian , Wang Kepeng 
Published: June 2021

e14560 Background: Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in humans. Treatment of late-stage CRC remains ineffective, even with the use of latest immunotherapies. Oncolytic viruses have shown limited use for the treatment of cancers, and further improvement of these agents with immune-modulating activities may prove crucial for patients with CRC and other malignancies. To this end, we developed CARG-2020 as an artificial virus for infectious diseases and immuno-oncology (AVIDIO) that employs virus-like vesicles (VLV). VLVs, which are membrane-encapsulated RNA replicons, are oncolytic and can deliver multiple genes resulting in the modulation of several independent immune pathways. Methods: The AVIDIO platform is comprised of in vitro evolved RNA-dependent RNA polymerase from an alphavirus, Semliki Forest virus, and envelope glycoproteins from vesicular stomatitis virus, which together form VLVs. Unarmed or empty vector (VLV), VLV armed with IL-12 (VLV-IL-12) and a VLV that simultaneously expresses IL-12, a dominant-negative form of IL-17 receptor A (dn-1L17RA) and shRNAs targeting PD-L1 (CARG-2020), were given intratumorally to test their therapeutic potential against established (500-600mm3) MC38 tumors in mice. We used tumor growth measurements and analyses of tumor-infiltrating cells after consecutive treatments with these agents to monitor their antitumor and immunomodulatory activities, respectively. Results: Both VLV-IL-12 and CARG-2020 regressed the tumors to undetectable levels in most mice harboring syngeneic MC38 tumors when given intratumorally. CARG-2020, carrying IL-12, dn-IL17RA and PD-L1 shRNA, exerts broader spectrum of immuno-responses and higher number of complete response rates compared with VLV-IL-12. Treatment of primary tumors with VLV-IL-12 or CARG-2020 also significantly repressed the growth of secondary tumors on the other flank of mouse’s body, suggesting an effective systemic immunity elicited by these two agents against the same type of tumors. In addition to the marked local and systemic activation of Th1 cells and CD8+ T cells by both vectors, CARG-2020 also downregulated PD-L1 expression in tumors, and suppressed expression of IL-17A-activated chemokines CXCL1 and CXCL2 that are known to promote cancer development and therapy resistance. Conclusions: As an oncolytic RNA replicon, AVIDIO platform-derived CARG-2020 encodes IL-12, dn-IL-17RA and PD-L1 shRNAs which are expressed concurrently within the same vector. CARG-2020 modulates IL-12, IL-17RA and PD-L1 signaling, and exerts broad immune modulation in tumor microenvironment. Treatment with CARG-2020 eliminates the majority of grafted large tumors in mice, and is effective against both primary and distal tumors. Based on this impressive efficacy results, further development of CARG-2020 in colorectal patients is warranted.