tbuckley/cabot-search huggingface dataset:
ACTR-29. A PHASE 2 STUDY OF TTFIELDS AND PULSED BEVACIZUMAB IN PATIENTS WITH BEVACIZUMAB-REFRACTORY RECURRENT GLIOBLASTOMA
Authors: David Tran, Ashley Ghiaseddin, Jian Campian, Stephen Staal, Sarah Andrews, Sonisha Warren, George Ansstas
Journal: Neuro-Oncology (2017)

Despite aggressive treatment comprising surgery, radiation therapy and chemotherapy, the median overall survival (OS) for patients with recurrent GBM averages 25 weeks. Our prior experience in 8 bevacizumab-refractory GBM patients initially treated with TTFields monotherapy and re-challenged with bevacizumab on progression suggest that successive cycles of on/off (or pulsed) bevacizumab dosing, will produce peaks and troughs in mitotic activities of glioma cells that render glioma cells more sensitive to the antimitotic activity of TTFields during peak growth rates, thus lowering disease burden and increasing survival.This Phase 2, single arm, open label study [NCT02663271] will investigate whether TTFields combined with pulsed bevacizumab treatment increases overall survival in patients with bevacizumab-refractory GBM compared to historical controls treated with continuous bevacizumab alone or in combination with standard chemotherapy. Twenty-five adult male or female patients with bevacizumab-refractory recurrent GBM (WHO grade IV) aged ≥ 22 years, KPS>60 will be recruited. Patients will undergo 12 months of planned continuous TTFields (200 KHz) (60–75% compliance goal; patients <60% compliance at 2 month withdrawn) followed by pulsed bevacizumab (10mg/kg IV/ 2 weeks) on further progression (RANO), with option of extending treatment to 24 months in patients not progressed and/or have adequate performance status at the 12 month mark. Pulsed bevacizumab dosing is defined by at least one cycle on and at least one cycle off. A cycle is defined as 8 weeks in length. Primary endpoint is progression-free survival between the groups. Secondary endpoints include adverse events, KPS, QoL (Mini-Mental Status Exam) and response rate (RANO). Largest hazard ratio (HR)<1 (or smallest median survival time >3.3 months) that can be detected at 80%, 90%, or 95% power and a 1-tailed significance level of 0.05, by sample size (N=20 to 36, or 10 to 18 months of accrual at 2 patients per month) and shape parameter k=1.50, 2.50.
DRES-10. THE DISTINCT CYTOTOXIC MECHANISM OF DIANHYDROGALACTITOL (VAL-083) OVERCOMES CHEMORESISTANCE AND PROVIDES NEW OPPORTUNITIES FOR COMBINATION THERAPY IN THE TREATMENT OF GLIOBLASTOMA
Authors: Beibei Zhai, Anna Golebiewska, Guangan He, Anne Steino, Jeffrey Bacha, Dennis Brown, Simone Niclou, Zahid Siddik, Mads Daugaard
Journal: Neuro-Oncology (2017)

Treatment of glioblastoma (GBM) includes surgery and chemoradiation with temozolomide. Due to chemoresistance, nearly all tumors recur and 5-year survival is less than 3%. Various treatments, including anti-angiogenic treatment with bevacizumab, nitrosoureas and topoisomerase inhibitors, have failed to improve overall survival in recurrent GBM (rGBM). GBM tumors expressing O6-methylguanine-DNA-methyltransferase (MGMT) are resistant to temozolomide and nitrosourea, and deficient DNA mismatch repair (MMR) confers secondary resistance to temozolomide. Our recent phase I/II trial in rGBM patients previously treated with temozolomide and bevacizumab, suggested that VAL-083 may offer a clinically meaningful survival benefit for rGBM patients. VAL-083 is a first-in-class bi-functional DNA-targeting agent that readily crosses the blood-brain barrier and accumulates in brain tumor tissue. The mechanism-of-action of VAL-083 differs from other alkylating agents and overcomes both MGMT- and MMR-related resistance to temozolomide, in vitro. VAL-083 rapidly induces interstrand cross-links at N7-guanine, causing DNA double-strand breaks and persistent activation of the homologous recombination (HR) DNA repair pathway. Furthermore, VAL-083 potency is increased in HR-deficient cancer cells, suggesting increased cytotoxicity in HR-impaired tumors. Hypoxic GBM cells downregulate HR activity, thus proposing increased VAL-083 potency in hypoxic tumors. Bevacizumab increases intratumor hypoxia, suggesting VAL-083 as a treatment option in HR-deficient or hypoxic cancers following, or as part of combination with, bevacizumab. The potency of VAL-083 as part of a combinatory treatment with bevacizumab was investigated in GBM models under hypoxia both in vitro and in vivo. Separately, we demonstrated that VAL-083 induces irreversible S/G2-phase cell-cycle arrest, thus proposing synergy with S-phase specific chemotherapeutics, including topoisomerase and PARP inhibitors. Here, we investigated cytotoxicity of VAL-083 combinations with various topoisomerase and PARP inhibitors in a range of cancer cells. Our results support the potential of VAL-083 to i) overcome resistance to temozolomide, and ii) display synergy as part of combinatory therapies with topoisomerase or PARP inhibitors.
CBIO-02. AMPLIFIED EGFR DRIVES TUMORIGENESIS IN TP53 WILD TYPE GLIOBLASTOMA THROUGH INHIBITION OF p53 FUNCTION BY DNA-PK/p53 BINDING
Authors: Jie Ding, Xiaolong Li, Amanda Wasylishen, Feng Gao, Yang Zhao, Keith Baggerly, Guillermina Lozano, Dimpy Koul, W K Alfred Yung
Journal: Neuro-Oncology (2017)

Epidermal growth factor receptor (EGFR) amplification/mutation and TP53 mutation are two most frequent genetic events that differentiate molecular subtypes of Glioblastoma. An extensive analysis of the Glioblastoma TCGA database showed a near exclusivity between p53 mutation and EGFR amplification in two groups of patients with a third group that has neither event. To understand the relationship between EFGR amplification and TP53 status in tumorigenesis, we identified a series of glioma stem cell (GSC) lines with EGFR amplification from our GSC bank at MD Anderson Cancer Center. The EGFR amplified group was further divided into two groups based on p53 status: one group with wild type TP53 and the second group with mutant p53. To elucidate the role of EGFR in regulating p53 function in gliomas, we used CRISPR gene editing system to knock out EGFR expression in amplified cells lines. EGFR knockout clones were isolated only from TP53 mutant GSCs, but not in TP53 wild type GSCs. Knocking down of EGFR expression by siRNA, showed that p53 activity was increased in wild type TP53 GSCs as demonstrated by increased p21/WAF1/CDKN1A and BCL2 Associated X (BAX) expression. However, direct binding between EGFR and wild type p53 was not detected in these GSCs. Using co-IP and mass spectrometry, we found that DNA-PK is the linker between EGFR and wild type p53. EGFR knock down decreased the binding between DNA-PK and wild type p53. Furthermore, EGFR knock down resulted in decreased sphere numbers and sizes in wild type TP53 GSCs but not in mutant GSCs. In conclusion, we propose that EGFR functions as the driver of tumorigenesis and progression in EGFR amplified TP53 wild type GSCs by inhibiting wild type p53 function through DNA-PK, while EGFR amplification and TP53 mutation co-regulate the tumorigenesis process in TP53 mutant GSCs.
TMIC-43. STROMAL REACTIVATION BY GLIOBLASTOMA CELLS PROMOTES TUMOR GROWTH AND TRANSCRIPTIONAL REPROGRAMMING OF ASTROCYTES
Authors: Mette Hartmark Nilsen, Lina Wik Leiss, Per Øyvind Enger
Journal: Neuro-Oncology (2017)

Glioblastoma is a highly heterogeneous disease, characterized by high invasion, florid angiogenesis and poor prognosis. Data from recent years introduces the microenvironmental involvement in glioma biology. Still the involvement of astrocytes in Gliomas is not completely understood. We have previously shown that tumor associated astrocytes isolated from mouse models of primary glioblastomas undergo a change in gene expression profile compared to control astrocytes. Suggesting an epigenetic shift of the stroma of glioblastoma. Furthermore, co-implantation of different ratios of normal human astrocytes with a glioma cell line revealed a shortened survival in correlation with increased number of normal astrocytes, suggesting an astrocytic involvement in glioma growth. The aim of the study is therefore to increase our knowledge of how the astrocytic involvement facilitates tumor growth. We have created an in vitro co-culture 3D model system to understand the shift in transcriptional factors of human astrocytes when cultured with primary glioblastoma cell lines created from patient biopsies as well as commercially available cell lines. Using FACS sorting we have been able to separate DsRed normal human astrocytes and glioma cells from the 3D model, thus being able to investigate changes in the two cell types on a transcriptional level using qRT-PCR and microarray. We have found an upregulation in astrocytes of the reprogramming factors SOX2 and POU3F2. This led to establishment of a normal human astrocyte cell line with dual knock down of SOX2 and POU3F2. Current work aims to further understand the expression profile of human glioblastoma-associated astrocytes, and map key factors contributing to the growth promoting effect astrocytes have on glioblastoma cells, potentially leading to a new therapeutic targets.
RTHP-01. SPECTROSCOPIC MRI PREDICTS RECURRENCE PATTERNS IN GLIOBLASTOMA
Authors: Saumya Gurbani, Lawrence Kleinberg, Jim Zhong, Chad A Holder, Jeffrey J Olson, Eric Mellon, Andrew Maudsley, Hui-Kuo Shu, Hyunsuk Shim
Journal: Neuro-Oncology (2017)

Radiation therapy (RT) targeted by conventional MRI may not fully identify the tumor profile of (GBM), which may in part account for high recurrence rates. Identifying the extent of GBM margins remains a challenging task due to the infiltrative nature of these tumors and limitations in current standard imaging methods. Multiple studies have demonstrated that MR spectroscopic imaging, or spectroscopic MRI (sMRI), can detect areas of infiltrating tumor with a high degree of sensitivity, and could be an essential tool in targeting tumor margins. sMRI enables the identification of non-enhancing, infiltrating cells that are marked by increased Choline/N-Acetylaspartate ratio (Cho/NAA), including regions undetected by standard MRI and therefore left untreated. sMRI shows considerable promise for improving the efficacy of RT and may delay recurrence. In this study, we correlated pre-treatment sMRI metabolite maps with recurrence patterns to validate that sMRI could provide coverage for untreated regions that later recurred, and provide support for its adjunctive use in tumor contouring for RT planning. In an ongoing NCI-funded trial (U01CA172027), metabolite and their ratio maps were obtained pre-chemoradiation and normalized to the patient’s normal-appearing contralateral white matter (NAWM) and then compared to contrast-enhancing recurrence patterns with at least 6 months follow-up. A Cho/NAA ratio of twice the NAWM mean was used to identify regions of potential infiltration in our patients, and the resulting planning target volumes were compared with actual treated target volumes based on conventional MRI. For 9 out of 11 cases, the addition of sMRI data expanded RT volumes to better encompass regions of tumor recurrence, which were not completely covered by the CTV60. Thus, RT planning for GBMs augmented by sMRI could reduce recurrence rates. A multi-institutional clinical trial has been initiated to prospectively assess potential for sMRI to guide RT and assess treatment response (R01CA214557).
Long-term Trends in Antidiabetes Drug Usage in the U.S.: Real-world Evidence in Patients Newly Diagnosed With Type 2 Diabetes
Authors: Olga Montvida, Jonathan Shaw, John J. Atherton, Frances Stringer, Sanjoy K. Paul
Journal: Diabetes Care (2017)

To explore temporal trends in antidiabetes drug (ADD) prescribing and intensification patterns, along with glycemic levels and comorbidities, and possible benefits of novel ADDs in delaying the need for insulin initiation in patients diagnosed with type 2 diabetes.Patients with type 2 diabetes aged 18-80 years, who initiated any ADD, were selected (n = 1,023,340) from the U.S. Centricity Electronic Medical Records. Those who initiated second-line ADD after first-line metformin were identified (subcohort 1, n = 357,482); the third-line therapy choices were further explored.From 2005 to 2016, first-line use increased for metformin (60-77%) and decreased for sulfonylureas (20-8%). During a mean follow-up of 3.4 years post metformin, 48% initiated a second ADD at a mean HbA1c of 8.4%. In subcohort 1, although sulfonylurea usage as second-line treatment decreased (60-46%), it remained the most popular second ADD choice. Use increased for insulin (7-17%) and dipeptidyl peptidase-4 inhibitors (DPP-4i) (0.4-21%). The rates of intensification with insulin and sulfonylureas did not decline over the last 10 years. The restricted mean time to insulin initiation was marginally longer in second-line DPP-4i (7.1 years) and in the glucagon-like peptide 1 receptor agonist group (6.6 years) compared with sulfonylurea (6.3 years, P < 0.05).Most patients initiate second-line therapy at elevated HbA1c levels, with highly heterogeneous clinical characteristics across ADD classes. Despite the introduction of newer therapies, sulfonylureas remained the most popular second-line agent, and the rates of intensification with sulfonylureas and insulin remained consistent over time. The incretin-based therapies were associated with a small delay in the need for therapy intensification compared with sulfonylureas.
MA 07.12 Short-Term Culture of Patient Derived Tumor Organoids Identify Neratinib/Trastuzumab as an Effective Combination in HER2 Mutant Lung Cancer
Authors: E. Ivanova, M. Bahcall, A. Aref, T. Chen, L. Taus, F. Avogadri-Connors, R. Cutler, A. Lalani, J. Choi, J. Haworth, E. Chambers, M. Kuraguchi, M. Xu, A. Redig, K. Wong, C. Paweletz, P. Jänne
Journal: Journal of Thoracic Oncology (2017)
Réseaux de sentinelles : une autre piste pour la surveillance des maladies intestinales d’origine infectieuse
Authors: C Gauci, T Melillo Fenech, H Gilles, S O'Brien, I Stabile, N Calleja, F Ruggeri, L Cuschieri, J Mamo
Journal: Eurosurveillance (2007)

Les systemes de surveillance par sentinelles offrent certains avantages par rapport a la surveillance passive qui a montre ses limites lorsque les signalements sont incomplets. Les reseaux de sentinelles destines a collecter des donnees aupres de certaines sources ont ete mis en place pour la premiere fois dans le cadre de la surveillance des maladies intestinales d’origine infectieuse a Malte.
NTOX-03. NEUROLOGIC COMPLICATIONS OF CTLA-4 INHIBITOR IPILIMUMAB
Authors: Michael Ruff, Michelle Mauermann
Journal: Neuro-Oncology (2017)

Neurologic complications are an increasingly recognized complication of the use of the immune checkpoint inhibitors in the treatment of solid tumors. The clinical spectrum of the CTLA-4 immune checkpoint inhibitor ipilimumab associated neurologic complications and optimum treatment approach is not established. To determine the frequency, clinical spectrum and optimum treatment approach to CTLA-4 inhibitor associated neurologic complications. This single center, retrospective cohort study was conducted from the drug’s FDA approval, March 2011 to December, 2016. All patients receiving a CTLA-4 inhibitor were identified using the Mayo Cancer Pharmacy database. Patients who developed neurological symptoms in immediate temporal proximity to Ipilimumab use were included. We excluded patients who developed symptoms after subsequent immune-modulatory or cancer related treatments (e.g. PD-1 inhibitors), or patients with symptoms referable to metastatic disease. 445 patients received ipilimumab at our institution between March 2011 and January 2016. 222 (49.8%) had been evaluated by a staff neurologist at our institution during their care. 3 patients (0.6%) were felt to have neurologic phenomenon in proximity to dosing of ipilimumab which was potentially attributable to the medication while not on another immune checkpoint inhibitors. Two patients (66%) had transient self-limited cranial neuropathies (Bell’s palsy; transient diplopia). One patient (33%) had bilateral phrenic nerve inflammatory neuropathies with diaphragmatic failure and simultaneous pan-hypopituitarism while being treated with ipilimumab. In our cohort multiple patients (n= 13, 2.9%) who had previously received ipilimumab subsequently were treated with PD-1 inhibitors and developed neurologic complications. Neurological adverse events associated with the CTLA-4 inhibitor ipilimumab in our large cohort consisted of transient self-limited cranial neuropathies and one case of inflammatory amyotrophy which responded to discontinuation of ipilimumab and initiation of steroids, with an incidence of 0.6%. Discontinuation and immune rescue may be indicated.
Classifying Fecal Microbiota Transplantation Failure: An Observational Study Examining Timing and Characteristics of Fecal Microbiota Transplantation Failures
Authors: Jessica R. Allegretti, Andrew S. Allegretti, Emmalee Phelps, Huiping Xu, Monika Fischer, Zain Kassam
Journal: Clinical Gastroenterology and Hepatology (2017)
TMOD-37. ENGINEERING 3D HUMAN CORTICAL MICROTISSUES HARBORING PATIENT-DERIVED GLIOBLASTOMAS
Authors: Sarah Fergione, Nikos Tapinos, Jeff Morgan
Journal: Neuro-Oncology (2017)

Human glioblastomas develop within the brain parenchyma in which there is continuous interaction of glioma cells with axon fibers, glial cells and endothelial cells. This cellular interplay cannot be accounted for with the current monolayer in vitro models. Moreover, the development of new therapies against glioblastoma has often failed due to toxicities that were not identified through in vitro studies and animal testing. To mitigate some of these limitations, we have developed an all human ex vivo 3D glioblastoma model. ReNcell CX cells, an immortalized human neural progenitor cell line, were used as the base of the 3D model. ReNcell CX cells were seeded into micromolds to form self-assembled spheroids and subsequently induced to differentiate. After 46 days of differentiation, spheroids were fixed, embedded, and cryosectioned for immunostaining to confirm assembly of polarized cortical microtissues. N-cadherin is essential for maintaining the polarized architecture of neuroepithelial cells in the cerebral cortex through the formation of adherent junctions. We show that our human cortical spheroids express N-cadherin in a polarized pattern close to the apical surface of the spheroids. To verify the presence of neocortical progenitors we stained with Pax6, while the presence of mature cortical neurons was verified with Tuj1 and BF1b staining. To investigate the invasion of glioma cells into the human cortical spheroids, a confrontation assay between cortical and glioma spheroids was implemented. Finally, spheroids were fixed and stained using combinations of glioma cell and cortical neuron specific markers. The proposed model aims to mitigate some of the limitations in current in vitro and in vivo approaches. Our 3D human brain microtissues will be used to gain a more in-depth understanding of the origins of brain cancer, including the migration and invasion of glioblastoma into the brain parenchyma, and serve as drug development platform to test novel cancer therapeutics.
SURG-21. LASER ABLATION IN STEREOTACTIC NEUROSURGERY (LAISE): A MULTI-INSTITUTIONAL RETROSPECTIVE ANALYSIS OF LITT FOR NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMAS (GBMS)
Authors: Andrew Sloan, Steven Tatter, Alireza Mohammadi, Kevin Judy, Sujit S Prabhu, Darren Lovick, Roukoz Chamoun, Veronica Chiang, Eric Leuthardt
Journal: Neuro-Oncology (2017)

Laser Interstitial Thermotherapy (LITT) is a minimally invasive procedure used to treat brain tumors. Here we present a retrospective series of 68 consecutive patients with GBMs treated at 9 centers. Retrospective, De-identified data on 34 primary and 34 recurrent GBMs treated with LITT. The demographics of the patients in both groups were similar with median patient age of 58.4 yrs.; male gender (55.8 %); pre-op KPS (82.7), and ECOG status (1). Other characteristics differed between the two groups however. The indications for LITT in newly diagnosed patients was more commonly “unresectable tumor” than recurrent GBMs treated with LITT (70.6% vs. 41.2%; p = 0.0146). Also, newly diagnosed GBMs treated with LITT were more commonly infratentorial (58.3% vs. 19.4 %; p =0.0021) or deep (63.9% vs. 27.8%; p = 0.0021), with larger median volumes (16.9 cm3 vs. 7.9 cm3; p= 0.0014) than GBMs at recurrence. Interestingly, the increased complexity of the newly diagnosed GBMs did not result in outcomes differences. Median lasing time (57.2 min), days to ambulation (2.3) and total stay (4.1 d) did not differ between the groups. Median ICU stay tended to be shorter in the recurrent group (20.7 hrs vs. 45.7 hrs; p =0.058), and the patients with recurrent GBM were discharged to home more commonly than patients with newly diagnosed GBM (75.8% vs. 51.5%; p = 0.0407). Median overall survival was similar in the two groups at 12 and 24 months (51% and 25.2% months respectively) with median follow-up of 244.6 days. LITT is safe and effective for the treatment of both newly diagnosed and recurrent glioblastomas with similar outcomes and survival. This may be explained in part by the increased complexity of the GBMs treated with LITT at time of diagnosis, which tended to be larger, deeper, and more often “unresectable.”
CBIO-21. DNA HELICASE HELLS MAINTAINS GLIOMA STEM CELLS
Authors: Guoxin Zhang, Zhen Dong, Petra Hamerlik, Jeremy Rich
Journal: Neuro-Oncology (2017)

HELLS (Helicase, Lymphoid-Specific, SMARCA6) is a DNA helicase and a member of SNF2 family that interacts with epigenetic regulators, including BMI1, DNMT3B, and HDACs, which function in the glioma cellular hierarchy. HELLS regulates DNA methylation genome-wide to silence expression of repeat sequences, such as microsatellites and retrotransposons. Using a combination of targeted in silico and expression analysis, we identified HELLS as a potential target gene overexpressed in glioma stem cells (GSCs). Using patient-derived GSC models, we confirmed that HELLS was preferentially expressed in GSCs and neural stem cells (NSCs) compared to the differentiated progeny. Knockdown of HELLS expression in GSCs induced cell cycle arrest, apoptosis and reduced sphere formation associated with increased DNA damage. Interrogating in silico survival data demonstrates that HELLS expression informs poor prognosis for glioma patients. Collectively, our data support a critical role for HELLS in GSC maintenance, likely mediated through genome-wide epigenetic regulation.