tbuckley/cabot-search huggingface dataset:
STEM-16. IGF1/N-CADHERIN/b-CATENIN/CLUSTERIN SIGNALING AXIS MEDIATES ADAPTIVE RADIORESISTANCE IN GLIOBLASTOMA
Authors: Satoru Osuka, Dan Zhu, Zhaobin Zhang, Oltea Sampetrean, Jeffrey Olson, Hideyuki Saya, Erwin Van Meir
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma (GBM) is composed of heterogeneous tumor cell populations including those with stem cell properties, termed glioma stem cells (GSCs). GSCs are innately less radiation sensitive than the tumor bulk and are believed to drive GBM formation and recurrence after repeated irradiation. However, it is unclear how GSCs adapt to escape the toxicity of repeated irradiation used in clinical practice. To identify important mediators of adaptive radioresistance, we generated radioresistant human and mouse GSCs by exposing them to repeat cycles of irradiation. Surviving subpopulations acquired strong radioresistance in vivo, which was accompanied by increased cell-cell adhesion, slower proliferation, an elevation of stemness properties and N-cadherin expression. Increasing N-cadherin expression rendered parental GSCs radioresistant, reduced their proliferation, and increased their stemness and intercellular adhesive properties. Conversely, radioresistant GSCs lost their acquired phenotypes upon CRISPR/Cas9-mediated knockout of N-cadherin. Mechanistically, elevated N-cadherin expression resulted in the accumulation of b-catenin at the cell surface, which suppressed Wnt/ b-catenin proliferative signaling, reduced neural differentiation, and protected against apoptosis through Clusterin secretion. Restoration of wild type N-cadherin, but not mutant N-cad lacking b-catenin binding region, led to induce radioresistance in N-cadherin knockout GSCs, indicating the importance of the binding between N-cadherin and b-catenin. We also demonstrated that N-cadherin upregulation was induced by radiation-induced IGF1 secretion, and the radiation resistance phenotype could be reverted with picropodophyllin (PPP), a clinically applicable blood-brain-barrier permeable IGF1 receptor inhibitor, supporting clinical translation. Moreover, the elevation of N-cad and Clusterin are related to prognosis of GBM in the TCGA dataset. In conclusion, our data indicate that IGF1R inhibitor can block the N-cadherin-mediated resistance pathway. Our study deepens our understanding of adaptive radioresistance during repeated irradiation in GBM, and validates the IGF1/N-cadherin/b-catenin/Clusterin signaling axis as a novel target for radio-sensitization, which has direct therapeutic applicability.
PATH-28. EXTENT AND PROGNOSTIC VALUE OF MGMT PROMOTOR METHYLATION DEPEND ON IDH MUTATION AND 1p19q CO-DELETION IN GLIOMA WHO GRADE II
Authors: Philipp Karschnia, Nico Teske, Sebastian Siller, Mario M Dorostkar, Jonathan Weller, Jochen Herms, Joachim M Baehring, Louisa von Baumgarten, Joerg-Christian Tonn, Niklas Thon
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Methylation of the promotor region of the O6-methylguanin-DNA-methyltransferase (MGMT) gene is associated with increased survival in low- and high-grade glioma. It is unknown whether this association also applies to the 2016 WHO categories of glioma WHO grade II. MATERIAL AND METHODS We retrospectively searched the institutional database of the Center for Neuro-Oncology for patients with glioma WHO grade II. Patients were assigned to one of three groups according to the 2016 WHO classification system: 1. 1p19q co-deleted oligodendroglioma, IDH mutant; 2. 1p19q non-codeleted astrocytoma, IDH mutant; 3. 1p19q non-codeleted astrocytoma, IDH wild-type. MGMT methylation status was analysed using Sanger sequencing of the CpG sites 74-98 within the MGMT promotor region. The total number of methylated CpG sites was calculated for each patient. RESULTS 155 patients with glioma WHO grade II were encountered, including 81 1p19q co-deleted, IDH mutant oligodendrogliomas; 54 IDH mutant astrocytomas; and 20 IDH wild-type astrocytomas. The mean number of methylated CpG sites among oligodendrogliomas was significantly higher when compared to IDH mutant astrocytomas (18.9 ± 0.4 vs. 16.3 ± 0.6; p = 0.001). In turn, the number of methylated CpG sites among IDH mutant astrocytomas was higher when compared to IDH wild-type astrocytomas (16.3 ± 0.6 vs. 12.3 ± 1.9; p = 0.007). Median follow-up was estimated at 35 months. Median time to malignant progression was 87 months for all patients, and median overall survival was not reached. In the entire cohort, a larger number of methylated CpG sites was prognostic of overall survival and time to malignant progression. When analysed separately for the three WHO subgroups, a similar association was only retained in IDH wild-type astrocytoma. CONCLUSION In our series of WHO II gliomas, MGMT promotor methylation appeared strongly associated with 1p19q codeletion and IDH mutations. MGMT promotor methylation was only prognostic in IDH wild-type astrocytoma.
EPID-05. COMPARATIVE EFFICACY OF FIRST-LINE ALK-INHIBITORS IN ALK+ LUNG CANCER BRAIN METASTASES: A NETWORK META-ANALYSIS
Authors: Philip Haddad, Dalia Hammoud, Kevin Gallagher
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Lung cancer has been the leading cause of cancer death for both men and women worldwide. Non-small-cell lung cancer (NSCLC) displays an array of molecular abnormalities most commonly involving ALK and EGFR pathways. NSCLC with ALK rearrangements comprises close to 5% of cases. Several ALK inhibitors (ALKI) have been approved with activity in brain metastases. However, there have been limited comparative studies exploring their relative efficacies. This meta-analysis was conducted to compare the relative efficacy of ALKIs against ALKI-naïve ALK+ lung cancer brain metastases. METHODS A review of the medical literature was conducted using online databases. Inclusion criteria consisted of English language; diagnosis of ALKI-naïve ALK+ lung cancer trials with brain metastases; treatment with Crizotinib (CRZ), Alectinib (ALC), Brigatinib (BRG), and Ceritinib (CER); and comparative studies reporting brain metastases specific responses/events. A Bayesian and a frequentists network meta-analysis were conducted using netmeta package and the random-effects model. RESULTS Eight studies comprising a total of 665 participants with ALKI-naive ALK+ lung cancer brain metastases were included. When compared pair-wise to CRZ, ALC (RR=0.49;95%CI:0.36–0.66), BRG (RR=0.39;95%CI:0.24–0.64), and CER (RR=0.36;95%CI:0.19–0.68) demonstrated significantly superior response rates in patients with untreated or previously treated lung cancer brain metastases. When the efficacy of each ALKI was compared to each other, BRG and CER were ranked the highest, followed by ALC and CRZ in decreasing order. CONCLUSIONS This network meta-analysis is the first to compare and rank approved ALKIs used in treating metastatic ALK+ lung cancer. It indicates that BRG, CER, and ALC are better therapeutic options for patients with ALK-naive ALK+ lung cancer brain metastases when compared to CRZ.
Three-dimensional Imaging Coupled with Topological Quantification Uncovers Retinal Vascular Plexuses Undergoing Obliteration
Authors: Chih-Chiang Chang, Alison Chu, Scott Meyer, Yichen Ding, Michel M. Sun, Parinaz Abiri, Kyung In Baek, Varun Gudapati, Xili Ding, Pierre Guihard, Kristina I. Bostrom, Song Li, Lynn K. Gordon, Jie J. Zheng, Tzung K. Hsiai
Journal: Theranostics (2020)

Murine models provide microvascular insights into the 3-D network disarray seen in retinopathy and cardiovascular diseases. Light-sheet fluorescence microscopy (LSFM) has emerged to capture retinal vasculature in 3-D, allowing for assessment of the progression of retinopathy and the potential to screen new therapeutic targets in mice. We hereby coupled LSFM, also known as selective plane illumination microscopy, with topological quantification, to characterize the retinal vascular plexuses undergoing preferential obliteration.
BIOM-48. PTEN MUTATIONS PREDICT BENEFIT FROM TUMOR-TREATING FIELDS THERAPY IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Antonio Dono, Sonali Mitra, Takeshi Takayasu, Jay-Jiguang Zhu, Nitin Tandon, Yoshua Esquenazi, Leomar Y Ballester
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Glioblastoma IDH-wildtype (GBM-IDH-WT) recurs despite the standard of care which includes surgical resection and concurrent chemoradiotherapy. Optimal treatment for recurrent GBM-IDH-WT (rGBM) is not standardized and multiple therapeutic approaches are utilized. Clinical trials have shown that Tumor-Treating Fields (TTF) provide equal benefits compared to physician’s chemotherapy choice for patients with rGBM. However, not all rGBM patients respond equally to TTF and understanding which patients will benefit from TTF therapy is critical. METHODS We reviewed clinical, molecular, and outcome characteristics of rGBM patients between 09/2009 to 2/2019 in our institution. Patients who received TTF-treatment at the time of 1st recurrence were selected for analysis. Tumors were analyzed for mutations in 315 cancer-related genes by next-generation sequencing. Post-progression survival (PPS) defined as the interval from 1st recurrence to death or the time of analysis, was examined using the Log-rank test and multivariable Cox-regression model. RESULTS 149 rGBM patients were identified of which 29 (19%) were treated with TTF. Overall, no significant difference in survival was observed in rGBM patients who received TTF therapy (13.9-months vs 10.9-months, p= 0.06). However, among TTF-treated patients (n= 29), there was improved survival in PTEN-mutant (n= 14) patients compared to PTEN-wt (n= 15), (22.2-months vs 11.6- months, p= 0.017). No differences in TTF usage were observed between groups. Within the PTEN-mutant patients (70/149, 47%), those treated with TTF (n= 14) had longer PPS (22.2-months vs 9.3-months, p= 0.005). No survival benefit with TTF-treatment was observed in PTEN-wt patients (79/149, 53%). CONCLUSIONS Patients with GBM-PTEN-mutant tumors show a significant improvement in survival when treated with TTF at recurrence. Understanding the molecular mechanism underpinning the differences in response to TTF therapy could help elucidate the mechanism of action of TTF and identify patients that will benefit the most from this therapeutic option.
Molybdenum-based hetero-nanocomposites for cancer therapy, diagnosis and biosensing application: Current advancement and future breakthroughs
Authors: Namdev Dhas, Ritu Kudarha, Atul Garkal, Vivek Ghate, Shilpa Sharma, Prabhakar Panzade, Shubham Khot, Pinal Chaudhari, Ashutosh Singh, Mitali Paryani, Shaila Lewis, Neha Garg, Narinder Singh, Priyanka Bangar, Tejal Mehta
Journal: Journal of Controlled Release (2020)
IMMU-20. EVALUATION OF CAR T CELLS IN EPENDYMOMA
Authors: Anandani Nellan, Andrew Donson, Jacob Calhoun, Andrea Griesinger, Terry Fry, Nicholas Foreman
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Ependymoma is the third most common pediatric brain tumor and current treatment still results in a 10-year relapse rate of over 70% in the highest risk groups. The treatment refractory nature of ependymoma to standard therapies strongly supports the development of novel interventions. Ependymoma tumor cells express HER2 and there are active clinical trials treating children with ependymoma using local delivery of second-generation HER2 CAR T cells. METHODS Two high-risk patient-derived ependymoma cell lines, MAF811 and MAF928, that display HER2 surface expression are used for testing. We tested second-generation HER2-BBz CAR T cells in vitro and in vivo. RESULTS HER2 CAR T cells effectively kill ependymoma tumor cells in culture, but this strategy cannot eradicate the same tumor cells in mice when implanted in the fourth ventricle of the brain. HER2 CAR T cells proliferate and traffic into the tumor, but this causes a dramatic influx of immune cells, tumor swelling and lethal toxicity in a subset of mice. Mice that survive this initial tumor swelling, display significant tumor shrinkage but all tumors eventually start growing again. Ependymoma tumor cells release high amounts of inflammatory chemokines that strongly attract neutrophils and monocytes to the tumor, compared to other brain tumors, and can downregulate HER2 expression to escape recognition by CAR T cells. CONCLUSION The immunosuppressive microenvironment as well as tumor heterogeneity make HER2 CAR T cells ineffective in ependymoma. Studying these two hurdles in CAR T cell therapy is critical to effectively treat brain tumors with CAR T cells.
Abstract 10725: Computed Tomography Evaluation of LV Outflow Tract: Impact on Survival in Aortic Stenosis
Authors: Marie-Annick Clavel, Joseph Malouf, Phillip Araoz, Hector I Michelena, Maurice Enriquez-Sarano
Journal: Circulation (2013)

Background: It is well established that LV outflow tract (LVOT) is not circular and that 2D echocardiography annular measurement may not accurately assess LVOT area. However, the impact of this pot...
COVD-23. PLANNED-USE GLUCARPIDASE FOR OUTPATIENT HIGH DOSE METHOTREXATE (HD-MTX) ADMINISTRATION IN PATIENTS WITH CNS LYMPHOMA (CNSL) DURING THE COVID-19 PANDEMIC
Authors: Lauren Schaff, Mina Lobbous, Alexis Bozza, Dean Carlow, Louis Nabors, Christian Grommes
Journal: Neuro-Oncology (2020)

Abstract Infection with SARS CoV-2 virus has resulted in a global pandemic of COVID-19, a respiratory illness with a crude mortality rate of 3–4%. Risk of death is higher in the elderly and in patients with underlying comorbid conditions. When local incidence of COVID-19 is high, hospital resources are scarce and elective admissions and procedures are placed on hold. Patients with CNSL receiving first-line HD-MTX require admission for monitoring and aggressive hydration to prevent toxicity. This study explores the feasibility of planned-use glucarpidase, a recombinant bacterial enzyme that rapidly reduces serum MTX levels, to facilitate outpatient administration of HD-MTX. Eligible adult patients had isolated CNSL and had previously tolerated inpatient HD-MTX. MTX 3.5 g/m2 was administered in the outpatient setting with hydration. Patients returned 24 hours after MTX administration for glucarpidase 2000u and additional hydration. MTX level was determined by high pressure liquid chromatography (HPLC) 48 hours following MTX administration. To date, seven outpatient HD-MTX treatments have been administered to a total of three patients. In all cases, MTX levels were reduced to &amp;lt; 100 nmol/L at 48 hours. Three treatments resulted in grade 1 elevation of AST/ALT (two patients). One treatment resulted in a grade 2 creatinine increase. Creatinine returned to baseline following additional outpatient hydration. No patients required hospital admission. This study demonstrates feasibility of outpatient HD-MTX administration with planned-use glucarpidase during the COVID-19 pandemic. We are currently enrolling to a larger study of planned-use glucarpidase for repeated doses of outpatient HD-MTX.
EPCO-30. A RADIOMICS BASED REGRESSION MODEL TO PREDICT GLIOBLASTOMA CELL MOTILITY
Authors: Kellen Mulford, Mariah McMahon, David Odde, Christopher Wilke
Journal: Neuro-Oncology (2020)

Abstract PURPOSE Radiomics has shown considerable success as a diagnostic tool in the classification of tumor grade, stage, and prognosis. The purpose of this work is to examine the potential for radiomics techniques to accurately predict the motility properties of glioblastoma cells. METHODS Tissues specimens were obtained from a total of 31 patients undergoing surgical resection of glioblastoma. Mean tumor cell motility was calculated from time-lapse videos using previously described methods (Bangasser et al. Nat Comm 2017). Preoperative, post-contrast T1-weighted MR images with 1 mm voxels were obtained from the medical records for each patient. Manual segmentation was used to define the border of the enhancing tumor and 108 radiomics features were extracted from the normalized image volumes using the PyRadiomics software package. Imaging features that correlated strongly with cellular motility were selected in a stepwise manner by p-value. The four features most strongly correlated with cellular motility were included in a regression model using the adaptive lasso technique with leave-one-out cross validation (LOOCV). RESULTS Two first order and two gray-level run length matrix features were selected for the model. The R-squared value for the predictive model was 0.60 with p-values for each individual parameter estimate less than 0.0001. An analysis of the residual values of the predicted model did not show any evidence of bias in the estimate. The average root mean squared error between the predicted and actual motility from the LOOCV for the model was 0.75. CONCLUSION The results of this work suggest that it is possible for a quantitative image feature-based model to predict the cellular motility of glioblastomas. Further work will prospectively test the model and explore the role of cellular motility in clinical outcomes such as time to recurrence and patterns of failure.
LINC-18. FOLLOW-UP EVALUATION OF A WEB-BASED PEDIATRIC BRAIN TUMOR BOARD IN LATIN AMERICA
Authors: Mariel Rosabal Obando, Diana S Osorio, Alvaro Lassaletta, Andrés Morales La Madrid, Ute Bartels, Jonathan L Finlay, Ibrahim Qaddoumi, Stefan Rutkowski, Martin Mynarek
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Since 2013, pediatric oncologists from Latin America have discussed neuro-oncology cases with experts from North America and Europe in a web-based “Latin American Tumor Board” (LATB). This descriptive study evaluates the feasibility of the recommendations rendered during the Board. METHODS An electronic questionnaire was distributed to physicians who received recommendations between October 2017 and October 2018, two months after their case presentation on the LATB. Physicians were asked regarding the feasibility of each recommendation given during the Board. Baseline case characteristics of all presented cases were obtained from anonymized minutes prepared after the presentations. RESULTS 36 physicians from 15 countries answered 103 of 142 questionnaires (72.5%), containing 283 recommendations. Physicians followed 60% of diagnostic procedural recommendations and 70% of therapeutic recommendations. Overall, 96% of respondents considered the recommendations applicable and useful. The most difficult recommendations to follow were genetic and molecular testing, pathology review, locally adapted chemotherapy protocols administration, neurosurgical interventions and access to molecular targeted therapies. The most cited reasons for not implementing the recommendations were lack of resources, inapplicable recommendations to that low-to-middle income country (LMIC) setting, and lack of parental consent. CONCLUSION The recommendations given on the LATB are frequently applicable and helpful for physicians in LMIC. Nevertheless, limitations in availability of both diagnostic procedures and treatment modalities affected the feasibility of some recommendations. Virtual tumor boards offer physicians from LMIC access to real time, high-level subspecialist expertise and provide a valuable platform for information exchange among physicians worldwide.
Abnormally activated OPN/integrin αVβ3/FAK signalling is responsible for EGFR-TKI resistance in EGFR mutant non-small-cell lung cancer
Authors: Yulong Fu, Yang Zhang, Zhe Lei, Ting Liu, Tingting Cai, Anqi Wang, Wenwen Du, Yuanyuan Zeng, Jianjie Zhu, Zeyi Liu, Jian-an Huang
Journal: Journal of Hematology & Oncology (2020)

Acquired epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance limits the long-term clinical efficacy of tyrosine kinase-targeting drugs. Although most of the mechanisms of acquired EGFR-TKI resistance have been revealed, the mechanism of ~ 15% of cases has not yet been elucidated. Cell viability was analysed using the Cell Counting Kit-8 (CCK-8) assay. Proteome profiler array analysis was performed to find proteins contributing to acquired EGFR-TKI resistance. Secreted OPN was detected by ELISA. Immunohistochemical analysis was conducted to detect expression of integrin αV in NSCLC tissue. The effect of VS-6063 on apoptosis and proliferation of PC9 gefitinib-resistant cells was detected by fluorescence-activated cell sorting (FACS) and clonogenic assays. A mouse xenograft model was used to assess the effect of VS-6063 on the sensitivity of PC9 gefitinib-resistant cells to gefitinib. OPN was overexpressed in acquired EGFR-TKI-resistant NSCLCs. Secreted OPN contributed to acquired EGFR-TKI resistance by activating the integrin αVβ3/FAK pathway. Inhibition of FAK signalling increased sensitivity to EGFR-TKIs in PC9 gefitinib-resistant cells both in vitro and in vivo. OPN contributes to acquired EGFR-TKI resistance by up-regulating expression of integrin αVβ3, which activates the downstream FAK/AKT and ERK signalling pathways to promote cell proliferation in NSCLC.
EPEN-22. SINGLE-CELL RNA SEQUENCING IDENTIFIES UPREGULATION OF IKZF1 IN PFA2 MYELOID SUBPOPULATION DRIVING AN ANTI-TUMOR PHENOTYPE
Authors: Andrea Griesinger, Eric Prince, Andrew Donson, Kent Riemondy, Timothy Ritzman, Faith Harris, Vladimir Amani, Michael Handler, Todd Hankinson, Richard Grundy, Andrew Jackson, Nicholas Foreman
Journal: Neuro-Oncology (2020)

Abstract We have previously shown immune gene phenotype variations between posterior fossa ependymoma subgroups. PFA1 tumors chronically secrete IL-6, which pushes the infiltrating myeloid cells to an immune suppressive function. In contrast, PFA2 tumors have a more immune activated phenotype and have a better prognosis. The objective of this study was to use single-cell(sc) RNAseq to descriptively characterize the infiltrating myeloid cells. We analyzed approximately 8500 cells from 21 PFA patient samples and used advanced machine learning techniques to identify distinct myeloid and lymphoid subpopulations. The myeloid compartment was difficult to interrupt as the data shows a continuum of gene expression profiles exist within PFA1 and PFA2. Through lineage tracing, we were able to tease out that PFA2 myeloid cells expressed more genes associated with an anti-viral response (MHC II, TNF-a, interferon-gamma signaling); while PFA1 myeloid cells had genes associated with an immune suppressive phenotype (angiogenesis, wound healing, IL-10). Specifically, we found expression of IKZF1 was upregulated in PFA2 myeloid cells. IKZF1 regulates differentiation of myeloid cells toward M1 or M2 phenotype through upregulation of either IRF5 or IRF4 respectively. IRF5 expression correlated with IKZF1, being predominately expressed in the PFA2 myeloid cell subset. IKZF1 is also involved in T-cell activation. While we have not completed our characterization of the T-cell subpopulation, we did find significantly more T-cell infiltration in PFA2 than PFA1. Moving forward these studies will provide us with valuable information regarding the molecular switches involved in the tumor-immune microenvironment and to better develop immunotherapy for PFA ependymoma.