tbuckley/cabot-search huggingface dataset:
LGG-09. CORRELATING GENETIC SIGNATURE OF PILOMYXOID ASTROCYTOMAS AND PILOCYTIC ASTROCYTOMAS WITH QUALITATIVE AND QUANTITATIVE MR IMAGING CHARACTERISTICS
Authors: Sandra Abi Fadel, Zeynep Erson Omay, Armine Darbinyan, Richard Bronen, Robert Fulbright, Amit Mahajan, Mariam Aboian
Journal: Neuro-Oncology (2020)

Abstract PURPOSE Pilomyxoid astrocytomas are predominantly located in supra-chiasmatic region and are more clinically aggressive than pilocytic astrocytomas, although recent WHO 2016 classification placed them into the grade I/II category. In our study, we describe imaging correlation of PMA to their genetic signature. MATERIALS AND METHODS We identified 12 pediatric patients with pathologically proven PMA, PA, and PA with myxoid features in an IRB approved study. Three of the tumors had whole exome somatic and germline sequencing. Qualitative MRI characteristics of location, size, enhancement, edema, T2 and T1 intensity, and multifocality were assessed. RESULTS Among the PMA, 3 cases were found to have KIAA1549-BRAF fusion, 1 case BRAF V600E mutation, and 2 cases had wildtype BRAF. The BRAF wildtype tumors had atypical imaging features with intraventricular extension of tumor, involvement of frontal lobe parenchyma and one tumor demonstrating increase in size and development of enhancement at 5 years. Whole exome sequencing of BRAF wildtype tumors identified somatic truncation mutations in NF1 R1534X and R1513X with wildtype germline NF1 and missense mutations in KMT2C and GLTSCR1. Among PAM, one was BRAF wildtype with mutations i PTCH1 M956V and PTPN1 (A72V) and demonstrated atypical features of intratumoral hemorrhage on presentation. Among PA, one was positive for KIAA1549-BRAF, one was BRAF wildtype. CONCLUSIONS BRAF wildtype PMA and PA demonstrate atypical tumor localization and are associated with atypical genetic mutations on whole exome sequencing. On the contrary, presence of KIAA1549-BRAF fusion or BRAF V600E mutation within PMA and PA correlates with classic qualitative imaging characteristics.
CBIO-16. SUPPRESSION OF HISTONE H3.3 MITOTIC PHOSPHORYLATION DRIVES DEVELOPMENT OF H3K27M-MUTANT DIFFUSE MIDLINE GLIOMAS
Authors: Charles Day, Alyssa Langfald, Florina Grigore, Leslie Sepaniac, Jason Stumpff, Kevin Vaughan, James Robinson, Edward Hinchcliffe
Journal: Neuro-Oncology (2020)

Abstract Pediatric midline gliomas – including DIPG – are lethal brain tumors in children, with poor prognosis and limited treatment options that provide only short-term benefits. The majority have a lysine-to-methionine substitution at residue 27 (H3K27M) in genes expressing histone H3 – predominantly in the H3.3 variant. This causes a global reduction in H3 Lys27 tri-methylation (H3K27Me3), comprehensive epigenetic reprogramming, and is a key driver in gliomagenesis. We show that the H3.3K27M mutation also induces chromosome segregation defects, which in high-grade tumors, results in extensive copy number alterations (CNAs). Ser31 is one of five amino acid substitutions differentiating H3.3 from canonical H3.1. Mitotic phosphorylation of H3.3 Ser31 by Chk1 kinase is restricted to pericentromeric heterochromatin, where it plays a role in chromosome segregation. We show that the K27M mutation affects neighboring Ser31 phosphorylation and pericentromeric heterochromatin organization. We demonstrate that (i) H3.3 K27M protein is defective for Ser31 phosphorylation by Chk1 kinase in vitro; (ii) DIPG cell lines have significantly decreased mitotic Ser31 phosphorylation, and are chromosomally unstable; and (iii) CRISPR-reversion of H3.3K27M to Lys27 restores phospho-Ser31 (and Lys27 tri-methylation) and significantly decreases chromosome instability. Expression of H3.3K27M or non-phosphorylatable H3.3S31A mutants in WT cells results in chromosome missegregation; this is suppressed by co-expression of phospho-mimetic H3.3K27M/S31E. In normal cells, chromosome missegregation stimulates p53-dependent cell cycle arrest in G1 to prevent the proliferation of aneuploid daughters. However, cells expressing H3.3 K27M or S31A failed to arrest following missegregation - despite having WT p53. Finally, in a novel mouse model of glioma, mean survival of mice with tumors induced with H3.3K27M and H3.3S31A was 81 and 68 days: 100% of H3.3S31A mice developed high-grade tumors. H3.3 WT controls developed only low-grade tumors and all survived 100 days. H3.3S31A is WT for Lys27 tri-methylation and thus, loss of Ser31 phosphorylation alone is oncogenic.
NIMG-68. MATHEMATICAL MODELING OF THERMAL DAMAGE ESTIMATE VOLUMES IN MAGNETIC RESONANCE-GUIDED LASER INTERSTITIAL THERMAL THERAPY
Authors: Allison Liang, Sean Munier, Shabbar Danish
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Magnetic resonance-guided laser interstitial thermal therapy is a minimally invasive procedure that produces real-time thermal damage estimates of ablation (TDE). Orthogonal TDE-MRI slices provides an opportunity to mathematically estimate ablation volume. OBJECTIVE To mathematically model TDE volumes and validate with post-24 hours MRI ablation volumes. METHODS Ablations were performed with the Visualase Laser Ablation System (Medtronic). Using ellipsoidal parameters determined for dual-TDEs from orthogonal MRI planes, TDE volumes were calculated by two definite integral methods (A and B) implemented in Matlab (MathWorks). Post 24-hours MRI ablative volumes were measured in OsiriX (Pixmeo) by two-blinded raters and compared to TDE volumes via paired t-tests and Pearson’s correlations. RESULTS Twenty-two ablations for 20 patients with various intracranial pathologies were included. Average TDE volumes calculated with Method A was 3.44 ± 1.96 cm3 and with Method B was 4.83 ± 1.53 cm3. Method A TDE volumes were significantly different than post-24 hours volumes (P &amp;lt; 0.001). Method B TDE volumes were not significantly different than post-24 hours volumes (P = 0.39) and strongly correlated with each other (r = 0.85, R2 = 0.72, P &amp;lt; 0.0001). A total of 8/22 (36%) method A versus 17/22 (77%) method B TDE volumes were within 25% of the post 24-hours ablative volume. CONCLUSION We present the first iteration of a viable mathematical method that integrates dual-plane TDEs to calculate volumes resembling 24 hours post-operative volumes. Future iterations of our algorithm will need to determine additional calculated variables that improve the performance of volumetric calculations.
EPEN-41. C11orf95-RELA FUSION REGULATES ABERRANT GENE EXPRESSION THROUGH THE UNIQUE GENOMIC BINDING SITES FOR EPENDYMOMA FORMATION
Authors: Tatsuya Ozawa, Syuzo Kaneko, Mutsumi Takadera, Eric Holland, Ryuji Hamamoto, Koichi Ichimura
Journal: Neuro-Oncology (2020)

Abstract A majority of supratentorial ependymoma is associated with recurrent C11orf95-RELA fusion (RELAFUS). The presence of RELA as one component of the RELAFUS leads to the suggestion that NF-kB activity is involved in the ependymoma formation, thus being a viable therapeutic target in these tumors. However, the oncogenic role of another C11orf95 component in the tumorigenesis is not still determined. In this study, to clarify the molecular mechanism underlying tumorigenesis of RELAFUS, we performed RELAFUS-ChIP-Seq analysis in cultured cells expressing the RELAFUS protein. Genomic profiling of RELAFUS binding sites pinpointed the transcriptional target genes directly regulated by RELAFUS. We then identified a unique DNA binding motif of the RELAFUS different from the canonical NF-kB motif in de novo motif discovery analysis. Significant responsiveness of RELAFUS but not RELA to the motif was confirmed in the reporter assay. An N-terminal portion of C11orf95 was sufficient to localize in the nucleus and recognizes the unique motif. Interestingly, the RELAFUS peaks concomitant with the unique motif were identified around the transcription start site in the RELAFUS target genes as previously reported. These observations suggested that C11orf95 might have served as a key determinant for the DNA binding sites of RELAFUS, thereby induced aberrant gene expression necessary for ependymoma formation. Our results will give insights into the development of new ependymoma therapy.
Bonanza of New Treatment Regimens for Multiple Myeloma: What Is Right for My Patient?
Authors: Shaji K. Kumar
Journal: Journal of the National Comprehensive Cancer Network (2020)

Although recent advances in the treatment of multiple myeloma have improved survival, it remains a chronic disease that requires a long-term treatment strategy. The key to achieving the best outcomes for patients is delivering the best “package” of treatment at a given stage. This means using optimal combinations that maximize benefit based on what patients have received previously and minimize treatment-related toxicity. Sequencing of regimens also plays an important role. As new agents and new classes of drugs continue to be approved for multiple myeloma, future strategies will use more individualized approaches to treatment.
Abstract 17404: Leisure Time Physical Activity and High-Density Lipoprotein Subspecies: Results From the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil)
Authors: Xiaochen Lin, Isabela M Bensenor, Margery A Connely, Raul Santos, James D Otvos, Simin Liu, Paulo A Lotufo
Journal: Circulation (2017)

Introduction: Leisure time physical activity (LTPA) has been associated with high-density lipoprotein (HDL) cholesterol and cardiometabolic health, but whether it is related to HDL subspecies remai...
NCOG-07. FEATURES OF EPILEPTOGENIC BRAIN METASTASES AND THEIR TREATMENT
Authors: Nicholas Musgrave, Kristin Huntoon, Joshua Wang, Douglas Hardesty, Daniel Prevedello, Russell Lonser, Bradley Elder
Journal: Neuro-Oncology (2020)

Abstract Patients with brain metastases (BM) may experience seizures at diagnosis or during their treatment. Seizures are associated with decreased overall survival (OS) and poorer quality of life. Therapeutic options may include surgical resection of epileptogenic BM. This study evaluated features of epileptogenic BM and whether surgical resection of these tumors improved seizure control and OS. A retrospective single-center review between 2006-2016 identified 1581 patients with BM. Data analyzed included demographics, primary cancer, systemic treatments, radiographic features of BM, BM treatment modalities, anti-epileptic drugs (AEDs), and seizure characteristics before and after intervention for BM. Chi-squared tests were used for categorical variables. Kaplan-Meier curves and Breslow values were used to assess OS following seizure. Of 1581 patients with BM, 136 (9%) experienced one or more seizures. Seizure was the presenting symptom of BM in 74 (54.4%) patients. Melanoma metastases were most epileptogenic, causing seizure in 38 of 216 (17.6%) patients (p&amp;lt; 0.001). Frontal lobe metastases were most common in patients with seizures (100, 73.5% p=0.033). After median follow-up of 23 months, 48 of 80 (60%) surgical patients were seizure free compared with 27 of 56 (48.2%) non-surgical patients. OS from first seizure was improved in surgical patients versus non-surgical patients (735±133 vs 447±74 days, p=0.043). Frontal lobe tumor resection (n=61) conferred improved survival compared with non-frontal lobe tumor resections (n=19) (698±323 vs 344±132 days, p=0.044). Variables such as demographics, number of BM, tumor histology, and dose of AED were not significantly different between surgical and non-surgical groups. Seizures due to BM cause significant morbidity and mortality. Frontal lobe location and melanoma histology increase seizure risk. Resection of BM was associated with improved seizure control and prolonged OS from the time of first seizure. Further studies should delineate the impact of surgery and determine if a specific constellation of variables warrants prophylactic AEDs.
CTIM-33. THE REMIND TRIAL: MULTI-ANTIGEN TARGETED T CELLS FOR PEDIATRIC CNS TUMORS
Authors: Melanie Grant, Maria Fernanda Fortiz, Jennifer (Lu) Wang, Haili Lang, Anushree Datar, Emily Reynolds, Madeline Terpilowski, Christopher Lazarski, Jay Tanna, Adriana Pitino, Nan Zhang, Fahmida Hoq, Patrick Hanley, Lindsay Kilburn, Roger Packer, Brian Rood, Catherine Bollard, Eugene Hwang
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Patients with relapsed CNS malignancies or DIPG face terrible prognoses. We hypothesized that T cells specific for 3 tumor-associated antigens (TAA), WT1, PRAME and survivin, would be safe and elicit anti-tumor immunity. METHODS Patients (n=15) received autologous tumor antigen-associated T cells (TAAT) (up to 4x107/m2) for newly diagnosed DIPG (Group A) or recurrent CNS malignancies (Group B) on a Phase I dose-escalation study (NCT03652545) and were monitored for safety and response. RESULTS/DISCUSSION 15/15 patients who received TAAT completed the 45-day safety monitoring phase with no dose-limiting toxicities. Adverse events were minimal despite multiple pretreatments in Group B. Infused cells were predominantly CD3+ T cells (median 96%; range: 87–99%), with CD4+ and CD8+ comprising 16% (range: 5–87%) and 40% (range: 4–67%) respectively. Specificity for 1–3 TAAs was demonstrated in 13/15 TAAT by a-IFN-γ ELISPOT. Plasma cytokine and proteomic analyses are ongoing but have demonstrated dynamic post-infusion immune cytokine and protein responses. Increases in the inflammatory and immune-stimulatory cytokines IL-1b, IL-6, IL-2 and IL-7 were observed post-infusion in most patients evaluated. Infusion-related increases in regulatory cytokines IL-10 and IL-13 were also observed in 4/7 patients. These results are consistent with an infusion-mediated immune response in vivo. Of 9 patients who have been tested thus far, 29/92 plasma proteins showed significant differences between dose levels 1 and 2, including increased IL-7 (p &amp;lt; 0.0004) and CD40L (p &amp;lt; 0.046) and reduced IL-4 (p &amp;lt; 0.0004). T cell receptor sequencing data on in vivo TAAT persistence is pending. In summary, TAAT have thus far been safe and elicit immune responses in vivo. Clinical and immunologic response assessments are ongoing.
EPEN-45. NORMALIZING AND FACILITATING GENOMIC TESTING AT DIAGNOSIS IN PEDIATRIC EPENDYMOMA
Authors: Emily Owens Pickle, Ana Aguilar-Bonilla, Amy Smith
Journal: Neuro-Oncology (2020)

Abstract The current consensus is that diagnosis and treatment of ependymoma should be based upon clinical and molecular classification. As we move into this paradigm, it is important all ependymoma cases undergo tumor collection, preservation, and molecular profiling at diagnosis. Our group of 6 sites gathered data on a cohort of 72 ependymoma cases. Sites were asked to report known molecular findings; 60/68 eligible cases (88%) did not include genetic findings. The low number of cases with molecular findings was surprising and since cases were diagnosed from as early as 2004, we asked collaborators to share their current practice in profiling (e.g., how frequently; in what setting were ependymomas sent for testing) to try and better understand current practice at sites. Since the publication of ependymoma molecular data, sites with a neuro-oncology program report sending almost all newly diagnosed ependymomas for molecular testing, whereas current practices at sites without dedicated neuro-oncology were less consistent. Profiling in the setting of relapse was more frequently reported at all centers. The implementation of molecular testing at diagnosis may need support at sites without dedicated neuro-oncology. Lead investigators for upcoming ependymoma clinical trials will need to think carefully about the logistics of profiling at centers where this is not standard practice at diagnosis.
NCOG-67. QUANTIFYING THE UTILITY OF A MULTIDISCIPLINARY NEURO-ONCOLOGY TUMOR BOARD
Authors: Adham Khalafallah, Adrian Jimenez, Carlos Romo, David Kamson, Lawrence Kleinberg, Jon Weingart, Henry Brem, Stuart Grossman, Debraj Mukherjee
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND There is limited research attempting to measure the efficacy of tumor boards (MDTBs) in the treatment of patients with tumors affecting the nervous system. OBJECTIVE The objective of the present study was to quantify the utility of a MDTB in providing alternative diagnostic interpretations and treatment plans for this patient population. METHODS A prospective study of patient cases discussed at four hospitals’ MDTBs between July and November 2019 was performed. Demographic data, diagnoses, treatment plans, and eligibility for clinical trials were recorded, among other variables. RESULTS A total of 176 patient cases met eligibility criteria. The majority of patients (53%) were male with a mean age of 52 years. The most frequent diagnosis was glioblastoma (32.4%). Among the evaluable cases, MDTBs led to 38 (21.6%) changes in image interpretation and 103 (58.2%) changes in patient management. Additionally, patients whose cases were discussed at MDTBs had significantly shorter referral times compared to patients whose cases were not discussed (p= 0.024). CONCLUSION MDTB discussions led to a significant number of diagnostic and treatment plan changes as well as shortened referral times, highlighting the potential clinical impact of multidisciplinary care for patients with nervous system tumors.
When Cardiac Function Dangles on a Thread of Conduction: Dyssynchronopathy in Patients With Left Bundle Branch Block⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Frieder Braunschweig
Journal: Journal of the American College of Cardiology (2013)
CTIM-05. COMBINATION OF CONTROLLED INTERLEUKIN-12 GENE THERAPY WITH IMMUNE CHECKPOINT BLOCKADE IN RECURRENT GLIOBLASTOMA: UPDATED RESULTS OF A MULTI-INSTITUTIONAL, OPEN LABEL PHASE 1 TRIAL
Authors: E Antonio Chiocca, Rimas Lukas, Clark Chen, Ganesh Rao, Christina Amidei, Jill Buck, Nira Hadar, Nathan Demars, John Miao, Taylor Estupinan, John Loewy, Yunxia Wang, Arnold Gelb, Laurence Cooper
Journal: Neuro-Oncology (2020)

Abstract A published clinical trial of veledimex (V)-regulatable interleukin-12 (IL-12) gene therapy (“Controlled IL-12”) under the control of a transcriptional switch (RheoSwitch Therapeutic Systemâ, RTSâ) as monotherapy in recurrent glioblastoma (rGBM) showed sustained infiltration of activated T cells within the tumor months after treatment (Sci Transl Med. 2019;11(505)). These T cells demonstrated up-regulation of immune checkpoint signaling, providing a rationale for combination therapy with the PD-1 inhibitor, nivolumab (nivo). We report interim findings following completion of enrollment (with follow-up ongoing) for a multi-institutional, open label, dose-escalation phase 1 trial (NCT03636477) evaluating safety and tolerability of loco-regional Controlled IL-12 in combination with nivo in adults with rGBM. Replication-incompetent adenovirus coding for RTS-IL-12 (Ad) was administered during surgery by free-hand injection into the tumor and periphery (2 x 1011 viral particles, Day 0) accompanied by V (10 or 20 mg) PO QD x 15 (Days 0 to 14) in combination with nivo (1 or 3 mg/kg) IV on Days -7, 15, then Q2W. Twenty-one subjects were treated (Cohort 1: V 10 mg, nivo 1 mg/kg, n=3; Cohort 2: V 10 mg, nivo 3 mg/kg, n=3; and Cohort 3: V 20 mg, nivo 3 mg/kg, n=3 &amp; 12 in expansion). Safety data were comparable to Ad+V monotherapy. Adverse reactions (ARs) during follow-on nivo dosing were consistent with nivo labeling. ARs were manageable and generally reversible with no synergistic toxicities. Updated overall survival findings will be presented. Baseline and post-treatment histochemical staining and multiplex immunofluorescence analyses for a subgroup of subjects will be discussed. The safety of this combination immunotherapy has been established, leading to a currently accruing phase 2 clinical trial of loco-regional Controlled IL-12 gene therapy in combination with the PD-1 inhibitor cemiplimab-rwlc (NCT 04006119).
A Large-Scale Association Study Detects Novel Rare Variants, Risk Genes, Functional Elements, and Polygenic Architecture of Prostate Cancer Susceptibility
Authors: Nima C. Emami, Taylor B. Cavazos, Sara R. Rashkin, Clinton L. Cario, Rebecca E. Graff, Caroline G. Tai, Joel A. Mefford, Linda Kachuri, Eunice Wan, Simon Wong, David Aaronson, Joseph Presti, Laurel A. Habel, Jun Shan, Dilrini K. Ranatunga, Chun R. Chao, Nirupa R. Ghai, Eric Jorgenson, Lori C. Sakoda, Mark N. Kvale, Pui-Yan Kwok, Catherine Schaefer, Neil Risch, Thomas J. Hoffmann, Stephen K. Van Den Eeden, John S. Witte
Journal: Cancer Research (2020)

Abstract To identify rare variants associated with prostate cancer susceptibility and better characterize the mechanisms and cumulative disease risk associated with common risk variants, we conducted an integrated study of prostate cancer genetic etiology in two cohorts using custom genotyping microarrays, large imputation reference panels, and functional annotation approaches. Specifically, 11,984 men (6,196 prostate cancer cases and 5,788 controls) of European ancestry from Northern California Kaiser Permanente were genotyped and meta-analyzed with 196,269 men of European ancestry (7,917 prostate cancer cases and 188,352 controls) from the UK Biobank. Three novel loci, including two rare variants (European ancestry minor allele frequency &amp;lt; 0.01, at 3p21.31 and 8p12), were significant genome wide in a meta-analysis. Gene-based rare variant tests implicated a known prostate cancer gene (HOXB13), as well as a novel candidate gene (ILDR1), which encodes a receptor highly expressed in prostate tissue and is related to the B7/CD28 family of T-cell immune checkpoint markers. Haplotypic patterns of long-range linkage disequilibrium were observed for rare genetic variants at HOXB13 and other loci, reflecting their evolutionary history. In addition, a polygenic risk score (PRS) of 188 prostate cancer variants was strongly associated with risk (90th vs. 40th–60th percentile OR = 2.62, P = 2.55 × 10−191). Many of the 188 variants exhibited functional signatures of gene expression regulation or transcription factor binding, including a 6-fold difference in log-probability of androgen receptor binding at the variant rs2680708 (17q22). Rare variant and PRS associations, with concomitant functional interpretation of risk mechanisms, can help clarify the full genetic architecture of prostate cancer and other complex traits. Significance: This study maps the biological relationships between diverse risk factors for prostate cancer, integrating different functional datasets to interpret and model genome-wide data from over 200,000 men with and without prostate cancer. See related commentary by Lachance, p. 1637