tbuckley/cabot-search huggingface dataset:
CMET-15. WHOLE EXOME SEQUENCING OF BRAIN METASTASES FROM COLORECTAL PRIMARY CANCERS REVEALS CLINICALLY ACTIONABLE MUTATIONS
Authors: Matthew Strickland, Mia Bertalan, Benjamin Kuter, Tareq Juratli, Victoria Melchert, Nancy Higgins, Michelle Toups, Alexander Kaplan, Ivanna Bihun, Naema Nayyar, Maria Martinez-Lage, Darrell Borger, Helen Shih, Theodore Hong, Priscilla Brastianos
Journal: Neuro-Oncology (2018)

Current understanding of the underlying genetic evolution in metastatic colorectal cancer to the central nervous system is lacking. Further, there are no specific treatments for brain metastasis derived from primary gastrointestinal malignancies. Here, we report preliminary data using a next generation sequencing approach to characterize actionable genomic targets in matched colorectal primaries and their associated extra- and intracranial metastases. A growing cohort of metastatic colorectal cancer is being assembled that consists of a primary tumor, at least a single extracranial metastasis, an intracranial metastasis, and a normal tissue control for each patient. Nucleic acid was extracted for use in whole exome sequencing from twelve samples. Somatic variants in the primary tissue were identified relative to the matched control sample and further compared relative to the metastatic samples. Initial analysis has focused on cancer genes that have been established to have clinical implications to identify variants with potential therapeutic value. Complex variant signatures were found across the primary colorectal tumors. At least one clinically actionable variant was identified in each case. Alterations in AKT1, POLE, BRAF and GNAS were detected in the brain metastasis samples and not in the extracranial sites. Alterations in GNAS, ARID1A, RET, and FGFR2 occurred at a higher frequency in metastatic samples (extracranial and brain metastases) compared to primary. KRAS and PIK3CA status was concordant across all tumors while PTEN and BRAF status was variable. CONCLUSIONS: Clinically actionable mutations can be found in brain and extracranial metastases that are not detected in their respective clinically sampled colorectal primary tumor. This provides support for the development of combined targeted therapeutic strategies that may be more successful in the metastatic setting. Further investigation is required in larger cohorts to fully characterize the genetic landscape and potential drivers of brain metastasis from colorectal cancer.
IMMU-35. PSYCHOSOCIAL STRESS NEGATIVELY IMPACTS IMMUNOTHERAPY IN IMMUNOCOMPETENT MODELS OF GLIOBLASTOMA
Authors: Erik Ladomersky, Sebastian Otto-Meyer, Lijie Zhai, Rohan Savoor, Kristen Lauing, Alicia Lenzen, Christina Amidei, Rimas Lukas, Derek Wainwright
Journal: Neuro-Oncology (2018)

Recent Phase III clinical trial findings indicate a failure of anti-PD-1 mAb (nivolumab) monotherapy to increase overall survival (OS) for recurrent glioblastoma (GBM) patients. Supportingly, we previously demonstrated that, while neither mono- nor dual-therapy with anti-PD-1, radiotherapy, or an IDO1 inhibitor, leads to long-term survival, the trimodal combination of all three durably increases survival in ~40% of mice with well-established, intracranial, syngeneic GL261. A concern arose, however, as to why ~60% of subjects always succumb to brain tumor, regardless of treatment. Psychological stress is a well-known modifier of the immune response, although the impact of psychosocial stressors on immunotherapeutic effectiveness have yet to be investigated in GBM. Because single-mouse housing induces chronic stress, we wondered if psychological factors diminish immunotherapeutic efficacy. C57BL/6 mice were housed singly (n=10) or at five mice/cage (normally; n=10) for one week, prior to the intracranial injection (ic.) of 2 × 105 GL261 cells. At fourteen days post-ic., subjects were treated with trimodal immunotherapy as previously reported (Ladomersky et al., 2018; CCR). Trimodal treatment leads to a median OS of 17.5 days in singly-housed subjects, which is significantly decreased as compared to the 29 day OS for normally-housed subjects (P=0.037). Strikingly, long-term survivors were only observed in the normally-housed group. Subjects were treated with RT and PD-1/IDO1 inhibitors, with and without the anxiety inhibiting pharmacologic, propranolol. While there was no difference in OS between subjects treated with IgG control or propranolol, alone, 60% of mice treated with all four agents survived long-term, whereas only 30% survived long-term with trimodal immunotherapy, alone (P=0.001). Given the association between higher anxiety levels, and an increased mortality rate among cancer patients in the U.S., these data suggest that, inhibiting stress-signaling pathways may synergize to improve immunotherapeutic efficacy, specifically improved likelihood of sustained response, for patients with malignant glioma.
Protocol Deviations, Reanalyses, and Corrections to Derivative Studies of the PREDIMED Trial
Authors: Miguel A. Martínez-González
Journal: JAMA Internal Medicine (2018)

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NIMG-54. SPATIAL DISTRIBUTION ATLASES OF POST-TREATMENT MRI SCANS REVEAL DISTINCT HEMISPHERIC DISTRIBUTION OF GLIOBLASTOMA RECURRENCE FROM PSEUDO-PROGRESSION
Authors: Marwa Ismail, Virginia Hill, Volodymyr Statsevych, Raymond Huang, Ramon Correa, Gagandeep Singh, Kaustav Bera, Rajat Thawani, Anant Madabhushi, Manmeet Ahluwalia, Pallavi Tiwari
Journal: Neuro-Oncology (2018)

PURPOSE: A significant challenge in post-treatment assessment of Glioblastoma is differentiating tumor recurrence (TR) from pseudo-progression (PsP), a radiation-induced treatment effect on routine MRI scans. Previous studies on pre-treatment MRI suggested that aggressive GBM lesions are spatially localized in the right hemisphere; and are associated with poor survival. We thus hypothesize that aggressive TR lesions appearing on post-treatment scans, will likely be more localized in the right hemisphere, as compared to benign PsP. 106 post-treatment MRI studies (35 PsP, 71 TR) were collected from 2 institutions. Confirmation for PsP and TR was obtained either from pathologic resection or MRI follow-up using RANO criteria. Scans were registered to T1-weighted brain atlas (MNI152), followed by expert delineation of enhancing lesion on Gd-T1w MRI and peri-lesional hyperintensities on T2/FLAIR. Population atlases quantifying the frequency of occurrence of enhancing lesion and peri-lesional hyperintensities were constructed by averaging voxel intensities across all patients. Analysis of differential involvement (ADIFFI) based on a two-tailed Fisher’s exact test was performed to compute significant differences (p-value<0.05) across PsP and TR voxels. Significant clusters were finally mapped to a structural atlas to provide anatomic localization of TR and PsP lesions. ADIFFI results showed TR prominence in the right parietal lobe with 75% occurrence in enhancing lesion and 61% in peri-lesional T2/FLAIR hyperintensities. PsP lesions were prominent in the left hemisphere, with peri-lesional T2/FLAIR hyperintensities having a multi-focal spatial distribution in the temporal lobe, insula, and putamen, and enhancing lesion being localized at the temporal lobe. TR tends to be lateralized towards the right parietal lobe. PsP tends to be multi-focally distributed in the left hemisphere. Such spatial localization on MRI could serve as a biomarker for differentiating PsP and TR. This could allow for immediate treatment changes in patients with recurrence, while avoiding unnecessary treatment for pseudo-progression.
DIPG-60. PILOT STUDY OF CIRCULATING TUMOR CELLS IN PEDIATRIC HIGH GRADE BRAIN TUMORS
Authors: Wafik Zaky, Long Dao, Dristhi Ragoonanan, Izhar Bath, Sofia Yi, Jonathan Gill, Soumen Khatua, Shulin Li
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Despite its increasing use, circulating tumor cells (CTCs) have not been studied in pediatric brain tumors. METHODS Cell surface vimentin (CSV) is a marker for CTC detection. We developed an automated CSV-based CTC capture method for pediatric brain tumor using the Abnova Cytoquest platform. PBMCs isolated from blood samples from 52 brain tumor patients were processed to isolate CSV+ CTCs. Captured cells were then stained for CSV and CD45 and scanned to determine the number of CTCs. DIPG samples were additionally examined for H3K27M expression on CSV+ cells. Long term cancer survivors were used as a control cohort. RESULTS 86.4% of all the samples exhibited between 1–13 CSV+ CTCs, with a median of 2 CSV+ CTCs per sample. Using a value of ≥ 1 CTC as a positive result, the sensitivity and specificity of this test was 83.05% and 60.0% respectively. 19 DIPG samples were analyzed and 70% (13 samples) were positive for 1–5 CTCs. Five of these 7 positive CSV+ CTCs DIPG samples were also positive for H3K27M mutations by immunohistochemistry (71%). Mean survival in days for the CTC positive and negative DIPG samples were 114 and 211 days, respectively (p= 0.13). CONCLUSION This is the first study of CTCs in pediatric CNS tumors using an automated approach. Patients with brain tumors can exhibit CSV+ CTCs within peripheral blood. The use of specific molecular markers such as H3K27M can improve the diagnostic capability of liquid biopsies and may enable future disease assessment for personalized therapy.
CADD-31. CD97 PERTUBATION BY NOVEL FUSION PROTEIN DAF-FC INHIBITS GBM INVASION AND INDUCES ANTIBODY DEPENDENT CELLULAR CYTOTOXICITY
Authors: Alan Nguyen, Michael Safaee, Ankush Chandra, Keith Wycoff, Manish Aghi
Journal: Neuro-Oncology (2018)

The poor prognosis of GBM reflects its capacity to supplement proliferative programs with pro-tumoral interactions with the microenvironment, including invasion and immunosuppression. There is a need to simultaneously target these processes, as they can be temporally, mutually exclusive phenotypes toggling back and forth. We have shown CD97 to be upregulated in GBM and capable of mediating each of these pro-tumoral functions in GBM by binding three ligands: decay accelerating factor (DAF/CD55), chondroitin sulfate, and integrins. To validate CD97 as a therapeutic target in glioblastoma, we partnered with an industry collaborator to produce a DAF-Fc fusion protein in a plant expression system combining DAF with IgG1 Fc to block CD97. CD97 was targeted with siRNA or DAF-Fc. Scratch and matrigel invasion assays were used to assess migration and invasion, respectively. Antibody dependent cellular cytotoxicity (ADCC) assays used NK-92 human natural killer cells as effector cells and GBM or peripheral blood mononuclear cells (PBMCs) as target cells. Intracranial implantation of glioblastoma cells into athymic mice was followed by DAF-Fc or IgG treatment, with IgG1-Fc detected by immunohistochemistry. CD97 expression was elevated in GBM cells versus astrocytes and lymphocytes, and CD97 knockdown by siRNA reduced migration and invasion by 65–75% (p<0.01). Treatment of human and mouse GBM cells with human and mouse DAF-Fc inhibited migration and invasion by 60–80% (p<0.001). There was increased ADCC against GBM cells with increased DAF-Fc concentration and effector to target ratio (p<0.001), but negligible PBMC toxicity at the highest DAF-Fc dose. Systemically delivered DAF-Fc crossed the blood-brain barrier in orthotopic GBM models with specific tumoral uptake compared to normal brain. Our results validate DAF-as a GBM therapeutic with negligible off-target effects against normal astrocytes or PBMCs. Further preclinical evaluation in invasive murine models ahead of a phase I trial is underway.
NIMG-49. ELECTRIC FIELD INTENSITIES DELIVERED BY TUMOR-TREATING FIELDS (TTFIELDS) TO GLIOBLASTOMA REGIONS: EFFECT ON TREATMENT RESPONSE ASSESSED BY AMINO ACID PET
Authors: Csaba Juhasz, Flora John, Ariel Naveh, Geoffrey Barger, Zeev Bomzon, Sandeep Mittal
Journal: Neuro-Oncology (2018)

The main goal of this study was to evaluate if the magnitude of electric field (EF) intensities delivered to glioblastomas by TTFields was related to interval changes of tumoral amino acid uptake measured by PET. Ten patients (mean age: 55 years) with residual or recurrent glioblastoma underwent alpha[C-11]-methyl-L-tryptophan (AMT)-PET followed by TTFields treatment. The PET scan was repeated 44–90 days later (mean: 69 days). To simulate delivery of TTFields to the tumor, we used the patient’s high-resolution MRI and CT scans to create patient-specific realistic head models comprised of various tissue compartments. Each tissue was assigned appropriate electrical properties. For each direction of treatment (antero-posterior and left-right), two 9-disk transducer arrays were simulated using disks placed according to the patients NovoTAL-planned arrays. To generate TTFields, an alternating voltage difference (200V, 200 KHz) was imposed on the outer surfaces of the disks. The simulations were performed using ZMT’s Sim4Life V3.0 electro-quasi-static solver. The field intensities were then normalized to simulate 2A peak-to-peak current supplied by the device. EF maps were fused with the patients’ PET images, and mean EF intensities were measured in the PET-defined tumor region at baseline and follow-up and correlated with the interval change of the tumoral AMT uptake ratios. A total of 18 distinct tumor regions were evaluated in the 10 patients. The mean EF intensity delivered to the metabolically active tumor region varied widely (1.24–2.56 V/cm, mean: 1.93 V/cm). Out of 16 tumor regions of 9 patients with good compliance with TTFields, AMT uptake ratios showed an interval decrease in 13. Higher mean EF intensity delivered to the tumors was associated with a more robust decrease of tumoral AMT uptake (r=-0.55, p=0.028). CONCLUSIONS: These data suggest that the magnitude of electric field intensities delivered to metabolically active glioblastoma regions may affect treatment responses.
Treatment-Induced Tumor Cell Apoptosis and Secondary Necrosis Drive Tumor Progression in the Residual Tumor Microenvironment through MerTK and IDO1
Authors: Thomas A. Werfel, David L. Elion, Bushra Rahman, Donna J. Hicks, Violeta Sanchez, Paula I. Gonzales-Ericsson, Mellissa J. Nixon, Jamaal L. James, Justin M. Balko, Peggy A. Scherle, Holly K. Koblish, Rebecca S. Cook
Journal: Cancer Research (2018)

Efferocytosis is the process by which apoptotic cells are cleared from tissue by phagocytic cells. The removal of apoptotic cells prevents them from undergoing secondary necrosis and releasing their inflammation-inducing intracellular contents. Efferocytosis also limits tissue damage by increasing immunosuppressive cytokines and leukocytes and maintains tissue homeostasis by promoting tolerance to antigens derived from apoptotic cells. Thus, tumor cell efferocytosis following cytotoxic cancer treatment could impart tolerance to tumor cells evading treatment-induced apoptosis with deleterious consequences in tumor residual disease. We report here that efferocytosis cleared apoptotic tumor cells in residual disease of lapatinib-treated HER2+ mammary tumors in MMTV-Neu mice, increased immunosuppressive cytokines, myeloid-derived suppressor cells (MDSC), and regulatory T cells (Treg). Blockade of efferocytosis induced secondary necrosis of apoptotic cells, but failed to prevent increased tumor MDSCs, Treg, and immunosuppressive cytokines. We found that efferocytosis stimulated expression of IFN-γ, which stimulated the expression of indoleamine-2,3-dioxegenase (IDO) 1, an immune regulator known for driving maternal-fetal antigen tolerance. Combined inhibition of efferocytosis and IDO1 in tumor residual disease decreased apoptotic cell- and necrotic cell-induced immunosuppressive phenotypes, blocked tumor metastasis, and caused tumor regression in 60% of MMTV-Neu mice. This suggests that apoptotic and necrotic tumor cells, via efferocytosis and IDO1, respectively, promote tumor 'homeostasis' and progression. SIGNIFICANCE: These findings show in a model of HER2+ breast cancer that necrosis secondary to impaired efferocytosis activates IDO1 to drive immunosuppression and tumor progression.
NIMG-76. POST-GADOLINIUM 3-DIMENSIONAL SPATIAL, SURFACE, AND STRUCTURAL CHARACTERISTICS OF GLIOBLASTOMAS DIFFERENTIATE PSEUDOPROGRESSION FROM TRUE TUMOR PROGRESSION
Authors: Madison Hansen, Edward Pan, Andrew Wilson, Morgan McCreary, Yeqi Wang, Thomas Stanley, Marco Pinho, Xiaohu Guo, Darin Okuda
Journal: Neuro-Oncology (2018)

PURPOSE: Pseudoprogression is often indistinguishable from true tumor progression on conventional 2-dimensional (2D) MRI in glioblastoma multiforme (GBM) patients. The aim of this study was to determine the association between post-gadolinium 3-dimensional (3D) characteristics and clinical state in GBM patients. Standardized 3D brain MRI studies were performed, and contrast enhancing portions of each tumor were segmented and analyzed blinded to clinical state using principal component analysis (PCA), medial axis transformation (MAT), and coverage analysis. Associations between the 3D characteristics of the post-gadolinium enhanced regions and the clinical status of patients were performed. A total of 15 GBM patients (male: 11 (73%); median age (range): 62 years (36–72 years)) with a median disease duration of 6 months (range: 2–24 months) were studied cross-sectionally with 6 (40%) patients identified with tumor progression. Post-gadolinium features corresponding to the group with progressive disease exhibited a more spherical and symmetric shape relative to their stable counterparts (p<0.005). The predictive value of a more uniformly full post-gadolinium enhanced shell to clinical progression was determined with a sensitivity of 66.7% (95% CI 29.9–92.5), specificity of 100% (54.1–100) and PPV of 100% (p=0.028, 2 tailed Fisher’s exact test). There did not appear to be an association between the thickness of the contrast enhanced shell to clinical state. CONCLUSIONS: The application of 3D technology to MRI studies with post-gadolinium imaging data may inform healthcare providers of GBM patients with new insights into pseudoprogression versus true tumor progression based on 3D spatial, surface, and structural patterns of enhancing lesions.
Abstract IA27: MYC drives molecular and therapeutically distinct subtype of SCLC
Authors: Gurkan Mollaoglu, Matthew R. Guthrie, Stefanie Bohm, Johannes Bragelmann, Milind D. Chalishazar, Abbie S. Ireland, Fang Huang, Zeping Hu, Robert J. Cardnell, Triparna Sen, Jason Gertz, Jane E. Johnson, Adi F. Gazdar, Lauren A. Byers, Ralph J. DeBerardinis, Robert J. Wechsler-Reya, Martin Sos, Trudy G. Oliver
Journal: Clinical Cancer Research (2018)

Abstract Small cell lung cancer (SCLC) has largely been treated in the clinic as a homogeneous disease for the last 40 years. However, it is become increasingly appreciated that SCLC exhibits both intra- and intertumoral heterogeneity. Genetic loss of the tumor suppressors RB1 and TP53 is nearly universal in SCLC, while amplifications in MYC family members including C-, L-, and N-MYC are mutually exclusive. Using genetically engineered mouse models (GEMMs), we show that MycT58A expression cooperates with Rb1 and Trp53 loss in the mouse lung to promote aggressive, highly metastatic tumors that are initially sensitive to chemotherapy followed by relapse, similar to human SCLC. Importantly, MYC drives a neuroendocrine-low ‘‘variant’’ subset of SCLC with low ASCL1 and high NEUROD1 expression corresponding to transcriptional profiles of human SCLC. The MYC-driven subset of SCLC is also low for other clinically relevant biomarkers such as TTF1/NKX2.1 and DLL3. Targeted drug screening reveals that SCLC with high MYC expression is vulnerable to Aurora kinase inhibition, which, combined with chemotherapy, strongly suppresses tumor progression and increases survival. These findings are consistent with the results of recent clinical trials in patients with relapsed SCLC who received paclitaxel with or without the AURKA inhibitor alisertib. Furthermore, recent preclinical studies demonstrate that the MYC-driven subset of SCLC is preferentially sensitive to CHK1 inhibition and other metabolic targets compared to MYCL-driven SCLC. These data identify molecular features for patient stratification and uncover potential targeted treatment approaches for MYC-driven SCLC. Citation Format: Gurkan Mollaoglu, Matthew R. Guthrie, Stefanie Bohm, Johannes Bragelmann, Milind D. Chalishazar, Abbie S. Ireland, Fang Huang, Zeping Hu, Robert J. Cardnell, Triparna Sen, Jason Gertz, Jane E. Johnson, Adi F. Gazdar, Lauren A. Byers, Ralph J. DeBerardinis, Robert J. Wechsler-Reya, Martin Sos, Trudy G. Oliver. MYC drives molecular and therapeutically distinct subtype of SCLC [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr IA27.
Abstract 20216: Irregularity in Size of Mitochondria in Cardiac Myocytes Associates With Prognosis in Patients With Dilated Cardiomyopathy
Authors: Atsushi Shibata, Yasuo Sugano, Hideaki Kanzaki, Keiko Ogo, Yoshihiko Ikeda, Hatsue Ishibashi-Ueda, Satoshi Yasuda, Toshihisa Anzai
Journal: Circulation (2017)

Background: Reactive oxygen species (ROS) play some important roles in the development and progression of heart failure. Mitochondria are a major target for ROS damage, as well as a major source of...