tbuckley/cabot-search huggingface dataset:
TMIC-10. AUTOPSY STUDY ON THE EFFECTS OF TUMOR TREATMENT FIELDS IN RECURRENT GLIOBLASTOMA: PRELIMINARY RESULTS
Authors: Alexander Barrington, Sarah Hurrell, Peter Laviolette
Journal: Neuro-Oncology (2018)

Treatment of recurrent glioblastoma using tumor treatment fields (TTFields) has recently been approved. This resulted from a recent clinical trial that showed better quality of life and comparable overall survival. Low-intensity, alternating frequency electric fields, known as TTFields, have been shown to disrupt cell division and subsequently tumor growth. Apoptosis and cell cycle arrest have been seen in vitro, and shown in mice and rabbit tumor models. Glioblastoma patients who have undergone TTField therapy have not yet been assessed at autopsy to determine both the pathological signature of TTField therapy, and the pattern of failure. Whole brain samples were acquired and analyzed pathologically from six recurrent GBM patients at autopsy. Three patients served as controls and three were considered test patients who had undergone TTField therapy. Tissue samples were acquired from regions suspicious of tumor and treatment effects. Samples were paraffin embedded and hematoxylin and eosin (H&E) stained, and pathologically reviewed by a board certified pathologist. Pathomic features of interest were extracted from each sample, including texture features and cellular morphometrics. Samples were then compared statistically. Regions of necrosis and cellular debris were more prevalent in the patients who underwent TTField therapy. Some pathomic features of interest differed significantly between the two groups. These findings suggest there is increased apoptosis in patients treated with TTFields compared to those on chemoradiation alone. Recruitment is ongoing for expansion of this study.
TMOD-01. THE ROLE OF PERSISTENCE, PROLIFERATION, AND TUMOR CELL KILLING EFFICIENCY IN DETERMINING RESPONSE TO CAR T-CELL THERAPY IN GLIOBLASTOMA: A MATHEMATICAL MODEL AND ANALYSIS
Authors: Prativa Sahoo, Daniel Abler, Vikram Adhikarla, Davide Maestrini, Russell Rockne
Journal: Neuro-Oncology (2018)

Chimeric antigen receptor (CAR) T-cell therapy is a promising emerging area of immunotherapy for the treatment of recurrent glioblastoma. In this therapy, T-cells are genetically modified to target tumor-specific antigens. Efficacy of CAR T-cell therapy depends on several factors, including CAR T-cell proliferation, persistence, and tumor cell killing capacity. Here we use a mathematical model to investigate the role of these three factors in determining response of recurrent GBM to this novel immunotherapy. Additionally, the impact of dosing and scheduling of CAR T-cell infusions on the therapeutic response is explored. We model the interaction between the two cell populations (cancer cells and CAR T-cells) using an ordinary differential equation based formalism. The growth and death of cancer cells are simulated as rates of proliferation and interaction between cancer cells and CAR T-cells, respectively. Biological data was used to parameterize the model. Analysis of the dynamics of interaction between cancer cells and CAR T-cells was performed to determine the maximum efficacy of a single and multiple doses of CAR T-cells. Our mathematical model and analysis shows that a critical parameter for the success of CAR T-cell therapy is the ratio of cancer cell proliferation to the killing capacity of the CAR T-cells. We quantify the dose level of CAR T-cells required to eliminate the cancer cell population. Furthermore, we use the mathematical model to predict the time to progression for specific dose levels, which may help in optimizing and scheduling multiple doses of CAR T-cell monotherapy. We compare the mathematical results with patient data from an ongoing dose-escalation study (NCT02208362) using central memory derived IL13Rα2-targeted CAR T-cell therapy for recurrent glioblastoma.
GENE-09. FUNCTIONAL GENOMIC ELEMENTS DEFINED BY DNA METHYLATION CAN DISTINGUISH MENINGIOMA SUBGROUPS
Authors: Tathiane Malta, James Snyder, Ana deCarvalho, Laila Poisson, Camila Souza, Gelareh Zadeh, Kenneth Aldape, Daniela Tirapelli, Carlos Carlotti, Ian Lee, Steven Kalkanis, Tobias Walbert, Houtan Noushmehr
Journal: Neuro-Oncology (2018)

Despite advances in therapy, treatment of malignant meningioma remains challenging - the tumor usually progresses after treatment. Atypical and anaplastic (malignant) meningiomas (grades II/III) are high-risk meningiomas that are prone to recurrence and unfavorable prognosis. We seek to understand the mechanisms of meningioma progression after initial treatment. Recently, based on DNA methylation, two subgroups of meningioma were described with recurrence-free survival differences. Master regulators at distinct genomic elements define gene activity and tissue identity and deregulation have been shown to be involved in tumorigenesis. We hypothesize that functional genomic elements can contribute to meningioma progression/recurrence. Our aim is to use DNA methylation data to identify candidate noncoding elements and their connection with genes that might explain differences in meningioma prognostic subgroups. Using published DNA methylation markers that define favorable and unfavorable meningioma subgroups, we identified 1,330 differentially methylated probes (p< 0.0001, difference mean-methylation beta-value> 0.25) distributed across CpG islands (13%), shores (34%) and open-sea regions (53%). Focusing on probes within known functional genomics, we identified 18 highly conserved genomic enhancers that can potentially drive meningioma recurrence. We next investigated links between these enhancers and their targeted genes by incorporating GeneHancer annotation. We found that the unfavorable subgroup of meningiomas presented hypomethylation within enhancer regions that have the potential to target PARK7, ARID4B, and FBH1. ARID4B was previously shown to be highly active in high-grade meningiomas. Our preliminary results are the first to suggest that DNA methylation changes can be used to identify noncoding regions associated with meningioma prognosis. We will use additional independent data to confirm our preliminary results. Identification of noncoding regions associated with meningioma progression/recurrence will provide knowledge of the role of epigenomics in the development of malignant meningioma and of opportunities for targeted therapy.
NCMP-30. OUTCOME OF CONCOMITANT CHEMORADIATION WITH TEMOZOLOMIDE FOLLOWED BY TEMOZOLOMIDE IN PATIENTS WITH GLIOBLASTOMA MULTIFORME
Authors: Adeeba Zaki
Journal: Neuro-Oncology (2018)

Glioblastoma is the most common primary brain tumor in adults. The current standard of care is multimodal approach comprising of maximal safe surgical resection, post-operative radiation therapy (RT), and concurrent and adjuvant temozolomide (TMZ). To date, no published data are available for the outcome of this disease treated with standard of care in Pakistan. In this study results of concomitant chemoradiation with 5 days of temozolomide followed by temozolomide has been reported. To determine Progression Free Survival (PFS) and Overall Survival (OS) in patient’s receiving concomitant chemoradiation with 5 days of temozolomide followed by temozolomide in newly diagnosed GBM. Patients with newly diagnosed glioblastoma were assigned to receive concomitant chemoradiation with temozolomide (75mg/m2) 5 days per week on the days of radiation. After a 4-week break, patients then received monthly temozolomide (150-200mg/m2) 5-day schedule every 28 days. From June 2011 to June 2016, 58 patients with newly diagnosed GBM were included in the study. Median age was 54 years, 71% (n=41) were male, whereas 29% (n=17) were female. 57% (n=33) underwent subtotal resection, 33% (n=19) had gross total resection while 10% (n=6) underwent biopsy only. About 64% (n=37) completed standard of care concomitant chemoradiation followed by monthly TMZ.36 % (n=21) completed only concomitant chemoradiation and were lost to follow. At a median follow up of 1 year, median PFS and OS was 8 and 13 months respectively with chemoradiation followed by TMZ. In subgroup analysis median PFS and OS benefit was more in patients who underwent maximal safe resection as compared to biopsy. This study confirmed that PFS and OS benefit was more in patients who completed concomitant chemoradiation followed by monthly TMZ. OS benefit was almost similar with 5 days of TMZ as opposed with 7 days of TMZ as reported in international study.
RDNA-14. IDENTIFICATION OF NOVEL RADIOSENSITIZERS IN GLIOBLASTOMA CANCER STEM-LIKE CELLS
Authors: Elisabeth Anne Adanma Obara, Henriette Pedersen, Diana Aguilar-Morante, Petra Hamerlik
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is the most lethal primary brain malignancy characterized by rampant genomic instability, angiogenesis and intra- as well as inter-tumoral heterogeneity, albeit leading to therapeutic resistance. Substantial evidence has identified glioblastoma stem cells (GSCs), to be the source of therapeutic resistance and tumor recurrence. In comparison to their differentiated counterparts, GSCs exhibit increased DNA damage response (DDR) signaling, which at least in part contributes to their radioresistant phenotype. To identify novel factors that drive the DNA Damage Responses in GSCs and so contribute to their radio-resistance, we performed a medium-throughput siRNA microscopy screen using a library targeting genes involved in chromatin remodelling. The primary screen identified a number of novel players sensitizing GSC population to ionizing radiation. We believe that our findings will contribute to better understanding of the mechanisms employed by GSCs to evade radiotherapy.
CMET-26. PERIOPERATIVE IMAGING OF BRAIN METASTASES: A EUROPEAN ASSOCIATION OF NEURO-ONCOLOGY (EANO) YOUNGSTERS SURVEY
Authors: Barbara Kiesel, Carina M Thomé, Tobias Weiss, Asgeir Jakola, Amelie Darlix, Alessia Pellerino, Julia Furtner, Johannes Kerschbaumer, Michael Weller, Geoffrey Pilkington, Elizabeth Cohen-Jonathan Moyal, Roger Henriksson, Colin Watts, Roberta Rudà, Guido Reifenberger, Ingela Oberg, Jerôme Honnorat, Wolfgang Wick, Matthias Preusser, Georg Widhalm, Anna Berghoff
Journal: Neuro-Oncology (2018)

Neurosurgical resection is an important treatment option in the multimodal therapy of brain metastases (BM). Perioperative imaging is established in primary brain tumors to assess the extent of resection. However, structured guidelines on the use of perioperative imaging for BM patients are so far missing. The European Association of Neuro-Oncology (EANO) Youngsters committee designed a comprehensive questionnaire on the use of perioperative imaging. The survey was distributed to physicians with neuro-oncologic focus via the EANO and the European Association of Neurosurgical Societies (EANS) network. 120 physicians from non-European countries and European countries responded to the survey. 76/120 neurosurgeons, 18/120 radiation oncologists and 17/120 neurologists participated. 89/120 participants worked at academic hospitals and 39/40 participants worked in high patient volume centers as defined by >50 BM cases per year. Local standard operating procedures for perioperative imaging were applied by 94/120 physicians. The preferred preoperative imaging method represented MRI for 112/120 (93.3%) participants. Postsurgical imaging was routinely performed by 106/120 physicians. 77/120 participants indicated MRI as the preferred postoperative imaging method, however, only 71/120 performed postoperative MRI imaging within 72 hours after resection. No correlation of postsurgical MRI and localization at an academic hospital (58/79 [73.4%] vs. 19/27 [70.4%], p>0.05) or patient volume (49/71 [69%] vs 25/40 [62.5%], p>0.05) was evident. The most frequently indicated reason for postsurgical imaging was the assessment of extent of resection as participants indicated to adjust the radiotherapy plan or even considered re-surgery to achieve complete resection. CONCLUSIONS: This EANO survey indicates that preoperative MRI is the preferred imaging technique for the majority of physicians, whereas a high variability of postoperative neuroimaging routines including CT and MRI was observed. International guidelines for perioperative imaging with special focus on postoperative MRI are warranted in order to optimize perioperative treatment modalities for BM patients.
PDTM-26. DUAL THERAPY WITH PI3K INHIBITOR ZSTK-474 AND MEK INHIBITOR TRAMETINIB VIA CONVECTION-ENHANCED DELIVERY IN A GENETICALLY-ENGINEERED MOUSE MODEL OF DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Raymond Chang, Umberto Tosi, Uday Bhanu Maachani, Iuliia Voronina, Melanie Schweitzer, Linda Wu, Mark Souweidane
Journal: Neuro-Oncology (2018)

Diffuse intrinsic pontine glioma (DIPG) is a pediatric brain tumor with a median survival of less than one year. Prior studies have highlighted PI3K/AKT signaling amplifications in DIPG. However, compensatory activation of parallel pathways, e.g. MAPK, may lead to resistance to PI3K inhibition. We evaluated whether dual therapy with PI3K and MEK inhibitors would synergistically inhibit DIPG growth in vitro and prolong survival in a genetically-engineered mouse model. Three patient-derived (SU-DIPG-IV, SU-DIPG-XIII, and SF8628) and one mouse-derived cell line were treated with ZSTK-474 and trametinib. Synergy was analyzed using Chou-Talalay combination index (CI). In vivo experiments introduced H3.3K27M mutations, PDGF-B overexpression, and p53 loss via RCAS-tva in Nestin-tva mice. Animals were treated with local convection-enhanced delivery (CED) of ZSTK-474 and trametinib at IC90 concentrations (both 1.9uM). ZSTK-474 and trametinib reduced cell proliferation across all cell lines (IC50s 0.75uM, 0.77uM, 0.37uM, and 0.12uM for ZSTK-474; 0.09uM, 0.01uM, 0.52uM, and 0.27uM for trametinib). Combination treatments were found to be synergistic (CI<1) across cell lines at tested concentrations, with the exception of SU-DIPG-XIII above 1uM. Western blot analysis of SU-DIPG-XIII demonstrated decreased AKT phosphorylation and increased ERK phosphorylation (downstream targets of PI3K and MEK) when treated with ZSTK-474, increased pAKT and decreased pERK with trametinib, and decreased pAKT and pERK with combined treatment. In vivo experiments revealed a trend towards prolonged survival versus vehicle (median survival 41 versus 31.5 days post-induction, Gehan-Breslow-Wilcoxon χ2 = 2.7, p = 0.10). Importantly, however, no symptoms of neurotoxicity from CED were observed. Dual therapy with ZSTK-474 and trametinib synergistically inhibited DIPG growth in vitro. Preliminary in vivo results demonstrated a trend towards prolonged survival. Novel local CED of ZSTK-474 and trametinib resulted in no short- or long-term neurotoxicity at current dosing, indicating increased dosage or treatment frequency may prolong survival in future work.
MNGI-08. A RARE CASE OF INFANTILE PAPILLARY RHABDOID MENINGIOMA
Authors: Nabanita Bhunia, Jeffrey Mullin, Aimee Carlson, Connor Wathen, William Bingaman, Tanya Tekautz
Journal: Neuro-Oncology (2018)

Infantile meningioma is exceedingly rare, frequently larger and of higher-grade histology than older patients. We describe a case of papillary meningioma with rhabdoid features in a 6-month-old, previously healthy infant. During evaluation for accidental head trauma the patient was found to have a large heterogeneous mass in the right temporal parietal region with midline shift and uncal herniation on cranial Computed Tomography (CT).Magnetic resonance imaging (MRI) of the brain revealed a large extra axial middle cranial fossa lesion with involvement of sphenoid and extraconal space of right orbit. There was no metastatic disease on MRI spine, CT chest, abdomen and CSF studies. A diagnostic cerebral angiogram showed a hyperplastic right middle meningeal artery (MMA) supplying the tumor. Skull base near total resection of tumor was performed after embolization of the right MMA pedicle artery and right ophthalmic artery recurrent branch. Pathology was consistent with papillary meningioma with focal rhabdoid features. Comprehensive genomic profile was positive for Neurofibromatosis (NF) type II. MRI obtained 4 weeks after initial resection revealed local progression. Gross total resection(GTR) of residual tumor was performed. In view of rapid progression, chemotherapy was initiated 12 weeks from diagnosis, as per Dana Farber Protocol 02-294 for ATRT (Atypical Teratoid Rhabdoid Tumor). Therapy related complications included – febrile neutropenia, Candida rugosa fungemia, loss of vision in right eye and right ear sensorineural hearing loss. The patient continues to be in remission 1 year after completion of his therapy. There are no established guidelines for the management of pediatric rhabdoid meningiomas. Multiagent chemotherapy as per DFCI ATRT 02-294 along with GTR should be considered as a potential treatment option for papillary rhabdoid meningioma. Radiation therapy should be excluded in younger patients due to risk of neuro-cognitive sequelae. Patients with meningioma associated with NF II need to have lifelong follow up.
TMOD-20. TRKing DOWN NOVEL THERAPEUTIC TARGETS IN GLIOMAS
Authors: Barbara Oldrini, Massimo Squatrito
Journal: Neuro-Oncology (2018)

The occurrence and importance of gene fusions in glioma has been appreciated only recently, largely due to high-throughput technologies, and gene fusions have been indicated as one of the major genomic abnormalities in glioblastoma (GBM), the most frequent and aggressive glioma subtype. The functional role of the majority of these alterations is completely unexplored. Recurrent gene fusions involving the Tropomyosin Receptor tyrosine Kinases (TRK) receptor family have been recently described in a variety of tumors, including both pediatric and adult low-grade (LGG) and high-grade gliomas (HGG). Strikingly, 40% of non-brain stem pediatric HGGs in infants have been shown to carry TRK gene fusions, making Trk inhibition an important potential therapeutic intervention in patients in which the current treatment modalities have devastating side effects. For the in vivo study of genomic rearrangements, we have recently generated an innovative mouse model that combines the genome editing capability of the CRISPR/Cas9 system with the somatic gene delivery of the RCAS/tv-a system. By searching the scientific literature we have identified approximately 30 different fusion involving NTRK1, NTRK2 and NTRK3 genes. To discriminate those fusions with tumorigenic potential in gliomas we have performed an in vivo gRNA pair screening. Four different RCAS-gRNA library pools have been transduced into p53-null TVA-Cas9 neural stem cells (NSCs) and subsequently transplanted into NOD/SCID mice. So far, half of the mice rapidly developed (1–2 months) quite aggressive tumors. We are currently characterizing those tumors to identify the most potent oncogenic NTRK fusions. NTRK gene rearrangements are emerging as novel targets across multiple tumor types, because of the increasing availability of new drugs with anti-Trk activity. As part of our studies, we are investigating the response and the resistance mechanism to Trk inhibitors that are currently used in different clinical trials.
MEDU-40. MATCHING OF SINGLE CELL TRANSCRIPTOMICS FROM CEREBELLAR DEVELOPMENT IDENTIFIES PUTATIVE SUBGROUP SPECIFIC CELLS OF ORIGIN FOR MEDULLOBLASTOMA
Authors: Ibrahim El-Hamamy, Maria Vladoiu, Laura Donovan, Hamza Farooq, Borja Holgado, Vijay Ramaswamy, Florence Cavalli, Betty Luu, Jennifer Chan, Claudia Kleinman, Alexandra Joyner, Nada Jabado, Lincoln Stein, Michael Taylor
Journal: Neuro-Oncology (2019)

We isolated cells from various points in murine embryonic and early post-ntal cerebellar development (E10 to P14) and undertook single cell RNA sequencing to identify >30 transcriptionally distinct cell populations. Reconstruction of developmental lineages in the developing cerebellum through pseudotemporal analysis demonstrate that a progenitor cell population from the upper rhombic lip gives rise to both the external granule cell layer (EGL) and the previously under-studied unipolar brush cells (UBC). Unipolar brush cells are a glutamatergic interneuron most prevalent in the inferior and lateral cerebellum. Transcriptional matching of bulk human tumor RNA-seq data from human patients demonstrates subgroup specific transcriptional resemblances. As expected, Shh MBs resemble the developing EGL. Fascinatingly, only Shh tumors that transcriptionally mirror earlier, but not later EGL developmental time points were found to be metastatic in human patients. Group 3 tumors have a resemblance to early Nestin +ve stem cells across the entire subgroup, with additional similarities to the EGL, UBC, and GABAergic interneurons. Unexpectedly, Group 4 tumors were vastly most similar to UBCs, and on further analysis to a single known subset of UBCs (Calb2+ve UBCs). Single cell RNA-seq from human medulloblastomas (Shh, Group 3, and Group 4 MB) largely confirms the transcriptional similarities to murine cerebellar developmental lineages observed in the bulk RNA-seq data, but also demonstrates that most medulloblastomas have multiple distinct tumor cell clusters. Distinct single cell expression clusters from an individual MB demonstrate that there is a developmental lineage or hierarchy of cells with most tumors, that this hierarchy is likely hardwired from normal development, and that bulk tumor data in fact reflects a heterogeneous cell population. These data pinpoint possible cells of origin for medulloblastoma subgroups, illustrate a further layer of MB heterogeneity, and allow a comparison of normal and MB transcriptomes to further understand MB biology.
ANGI-13. TENASCIN-C INDUCES VASCULOGENIC MIMICRY FORMATION IN GLIOBLASTOMA THROUGH AKT PATHWAY
Authors: Hai-ping Cai, Yin-sheng Chen, Jing Wang, Xiang-rong Ni, Fu-rong Chen, Zhong-ping Chen
Journal: Neuro-Oncology (2018)

Glioblastoma is a highly invasive and vascularized primary CNS tumor. Although anti-angiogenesis therapy was effective in some tumors but not in GBM. Vasculogenic mimicry (VM), a vessel-like structure formed by highly invasive tumor cells, has been considered responsible for the failure of GBM patients for anti-angiogenesis therapy. Tenascin-c (TNC), an extracellular protein involves in tumor angiogenesis, is overexpressed in GBM. However, how TNC contributes to VM formation remains unclear. We first knocked down the expression of TNC in two glioma cell lines (U251 and A172), which had TNC overexpression. Then the formations of VM were observed by three-dimensional culture. Transwell and wound-healing assay were applied to investigate the role of TNC in cell invasion and migration abilities. The expression of MMP2, MMP9 and the phosphorylation status of AKT were determined by western-blot, RT-qPCR and gelatin zymography. Furthermore, AKT inhibitor, MK-2206 was used to block the AKT/MMP2/MMP9 signaling pathway to investigate its role in TNC regulation at different concentration (0µm, 5µm, 10µm and 20µm) for 24 hours. The knockdown efficiency was detected by western blot and RT-qPCR in U251 and A172 after siRNA transfection for 48 hours. Three-dimensional culture showed that VM-like structure formation decreased in knockdown groups compared to controls dramatically (19.67 ± 6.65 and 46.34 ± 9.10 vs. 125.67 ± 8.34 p<0.01 in U251; 59.67 ± 18.52 and 51 ± 14.97 vs. 100.67 ± 2.87, p<0.01 in A172). The invasion and migration ability of U251 and A172 were also attenuated (p<0.01) by TNC knockdown. TNC knockdown impaired the phosphorylation of AKT at both Ser473 and Thr308, and the expression of MMP2 and MMP9 were downregulated too. Exposure of AKT inhibitor blocked the VM formation as well as the expression of MMP2 and MMP9. Our study demonstrated that TNC upregulated the VM formation via AKT/MMP2/MMP9 pathway in glioma and provided a potential therapeutic target for glioblastoma by anti-angiogenesis therapy.