tbuckley/cabot-search huggingface dataset:
ATIM-01. A PHASE II, OPEN-LABEL, SINGLE ARM, MULTICENTER STUDY OF AVELUMAB WITH HYPOFRACTIONATED RE-IRRADIATION IN ADULT SUBJECTS WITH TRANSFORMED IDH MUTANT GLIOBLASTOMA
Authors: Andrew S Chi, Sylvia Eisele, Isabel Arrillaga-Romany, Tracy Batchelor, Daniel Cahill, Jennie Taylor, Timothy F Cloughesy, Amie Patel, Malcolm Delara, Sunita Latchman, Dimitris Placantonakis, Donato Pacione, Girish Fatterpekar, Timothy Shepherd, Rajan Jain, Christine Cordova, Jessica Schafrick, Matija Snuderl, David Zagzag, Douglas Kondziolka, John Golfinos, Joshua Silverman
Journal: Neuro-Oncology (2017)

Isocitrate dehydrogenase (IDH) mutant gliomas are relatively indolent, however nearly all IDH mutant gliomas eventually transform to secondary glioblastoma (GBM) for which no effective salvage therapy exists. Transformation to secondary GBM is associated with a high rate of chemotherapy-induced hypermutation phenotype in IDH mutant glioma. Therefore, we aimed to test the safety and efficacy of avelumab, an anti-PD-L1 antibody, and hypofractionated re-irradiation in transformed IDH mutant GBM patients. This is a single arm phase II trial with a 6 patient safety lead-in with the primary objectives of safety and 6-month progression-free survival (PFS6) assessment. 43 patients are planned across 4 sites. Avelumab is given 10 mg/kg intravenously every 2 weeks. RT is given in 5 consecutive daily fractions to a total dose of 25 Gy starting day 8. Major eligibility criteria include prior diagnosis of grade II or III IDH mutant glioma; progression after treatment with temozolomide; CCNU, or BCNU; receipt of prior RT; progressive tumor tissue with either histopathologic diagnosis of GBM or any glioma with evidence of mismatch repair defect, microsatellite instability, or hypermutation phenotype by next-generation sequencing; no prior PD-1/PD-L1 pathway inhibitor treatment. Secondary objectives include estimation of overall survival, PFS, and response rate. Exploratory objectives include association of PFS6 with hypermutation phenotype, proportion of predicted mutation-associated neoantigens among all somatic mutations, tumor PD-L1 expression, baseline and change in circulating regulatory T cell and myeloid-derived suppressor cell levels. Two patients have been enrolled in the safety lead in cohort. No DLTs were observed. Both patients experienced treatment-induced grade 2 neurological symptoms related to brain edema. Both patients are currently on study at cycle 3. Avelumab and hypofractionated RT has been tolerated with no DLTs observed thus far. Enrollment in the Safety Lead-In and collection of safety and preliminary response data is ongoing.
QLIF-01. GLIOMA AND PREGNANCY – CHALLENGES IN CLINICAL PRACTICE
Authors: Anouk van Westrhenen
Journal: Neuro-Oncology (2017)

Gliomas and pregnancy pose many clinical questions that remain unanswered in the current literature, due to rare nature of this phenomenon. The aim of this review is to address these underexposed clinical challenges and to examine the strength of evidence for clinical management suggested in literature. PubMed and Embase databases were systematically searched for studies on glioma and pregnancy. Due to the scarcity of observational studies, articles that expressed an opinion on clinical management were included in addition to case series and case reports. Strength of evidence was categorized as either arguments based on results from observational studies, or consensus in expert opinions, or single export opinions. 27 eligible studies were selected, including 342 patients with newly diagnosed (n=202) and known (n=114) gliomas during pregnancy. The majority of studies were case reports (n=9) or case series (n=15) with a median sample size of 6 (range 1-65, interquartile range 1-9) patients. Few conclusions were based on findings from observational studies, including changes in tumor behavior during pregnancy, safely performed surgery after the first trimester and no benefit of cesarean section over vaginal delivery in stable patients. The remainder of arguments arose from consensus in expert opinions, including the importance of pre-pregnancy counseling, discouragement of chemotherapy during pregnancy and benefit of anticonvulsant treatment over insufficient seizure control. Many clinical questions on pregnancy in glioma patients remain unanswered, due to lack of large observational studies. Multicenter prospective registries are needed that collect granular information on clinical management and related outcomes to provide evidence for clinical decision-making in pregnant glioma patients.
NIMG-18. CREATING ACCURATE COMPUTATIONAL HEAD MODELS OF PATIENTS USING DATASET COMBINING MRI AND CT IMAGES
Authors: Ariel Naveh, Ze’ev Bomzon, Csaba Juhasz, Sandeep Mittal
Journal: Neuro-Oncology (2017)

A 3D model of AC electrical conductivity of the head (or other body part) can be generated by obtaining both CT and MRI images of the head, and combining the CT and MRI images into a composite model that specifies a conductivity at each voxel of the composite model. Voxels in the composite model that correspond to bone (e.g., the skull) are derived from the CT image, and voxels that correspond to the brain (e.g., white matter, gray matter, etc.) are derived from the MRI image. In some embodiments, the 3D model of conductivity is used to determine the positions for the electrodes in TTFields (Tumor Treating Fields) treatment.
RBIO-05. DOWNREGULATION OF H-FERRITIN EXPRESSION USING MULTIVALENT CATIONIC LIPOSOMES RESULTS IN INCREASED RADIATION SENSITIVITY IN PATIENT DERIVED GLIOMA INITIATING CELLS
Authors: Vagisha Ravi, A B Madhankumar, James Connor
Journal: Neuro-Oncology (2017)

Glioblastoma multiforme (GBM) is the most prevalent, lethal, malignant and refractory primary brain tumor with a very dismal survival rate. The glioma initiating cell (GIC) population within GBMs has been associated with treatment resistance and subsequently been implicated in tumor recurrence. Studies from our lab had previously shown that expression of the heavy chain subunit of the iron storage protein ferritin, H-ferritin, is essential for the survival and therapeutic resistance of non-stem glioma cells. Since H-ferritin is overexpressed in GICs, we hypothesized that downregulating its expression in these cells would lead to increased radiosensitivity. We therefore developed a novel strategy to sensitize these recalcitrant GICs to radiation therapy using a multivalent cationic liposome formulation that could efficiently transfect and deliver H-ferritin siRNA to GICs in vitro. Using patient derived T3691 CD133+ GICs we showed that downregulating H-ferritin led to a reduction in cell viability compared to controls upon being radiated at 4Gy and 8Gy dosage. Additionally these cells also showed an increased expression of the DNA damage response protein phospho-ϒH2AX upon radiation over controls. Thus, we have demonstrated that loss of H-ferritin in GICs leads to increased radiation sensitivity. Ongoing studies are focused on delineating the mechanisms through which H-ferritin loss mediates this effect in GICs.
ACTR-64. PHASE 2 STUDY OF SYM004 FOR ADULT PATIENTS WITH RECURRENT GLIOBLASTOMA (GBM)
Authors: Annick Desjardins, Dina Randazzo, Katherine B Peters, Margaret O Johnson, Woody Massey, James E Herndon, Frances McSherry, Eric S Lipp, Paul Nadler, Ivan D Horak, Henry S Friedman
Journal: Neuro-Oncology (2017)

Sym004, a recombinant antibody mixture binding specifically to the epidermal growth factor receptor (EGFR), contains two mouse-human chimeric IgG1 monoclonal antibodies (mAbs) binding to non-overlapping epitopes on the extracellular domain III of EGFR. It induces highly efficient internalization and degradation of EGFR on cancer cells. In solid tumors, the phase 2 Sym004 dose is 18 mg/kg intravenously every 2 weeks. Results of a phase 2 trial in recurrent GBM are reported. Eligible patients are adults with recurrent GBM; EGFR amplified (>15% of cells exhibiting >5 copies of EGFR loci); ≤3 prior progressions; ≥4 weeks after chemotherapy, or study drug; ≥12 weeks after radiation; adequate organ function; and KPS ≥70%. Patients received Sym004 18 mg/kg IV every 2 weeks and imaging every 8 weeks. Bevacizumab naïve (cohort 1) and bevacizumab failure (cohort 2) patients were enrolled. As of 5/26/2017, 24 patients have been treated on study (cohort 1: 17 patients; cohort 2: 7 patients). Grade 3 or higher adverse events (AEs) possibly related to study include: fatigue (grade 3, n=1); skin infection (grade 3, n=1); hypokalemia (grade 3, n=1); and dry skin (grade 3, n=1). Adverse events of special interest are: rash (grade 3, n=3; grade 2, n=7; grade 1, n=12) and hypomagnesemia (grade 1, n=18). Eighteen patients experienced disease progression within 2 months of initiating treatment, but three patients remained stable for at least six months. Because of the low frequency of significant cutaneous toxicity and hypomagnesia observed in our phase 2 trial evaluating GBM patients, AEs generally associated with anti-tumor response to anti-EGFR mAbs, we are increasing the dose administered to 24 mg/kg to evaluate whether increased efficacy may be observed. Data on the new dose will be presented.
TMOD-08. IN VITRO PRE-TREATMENT OF CELL LINES PRODUCES A ROBUST IN VIVO XENOGRAFT MODEL MIMICKING RECURRENT GLIOBLASTOMA
Authors: Mona M Al-Gizawiy, Robert T Wujek, Hisham S Alhajala, Ninh B Doan, Jeffrey Knipstein, Jennifer M Connelly, Shama P Mirza, Christopher R Chitambar, Kathleen M Schmainda
Journal: Neuro-Oncology (2017)

Glioblastoma (GBM) is a devastating cancer of the central nervous system. The prognosis of this most malignant form of brain tumor remains poor, largely due to the inherent resistance of GBM to therapy. Unfortunately, recurrent or progressive GBM (rGBM) frequently has very different molecular characteristics from the original tumor. Moreover, it exhibits a vastly different biological behavior. Thus, rGBM has proven exceedingly difficult to treat. Current preclinical rGBM models primarily reflect treated de novo tumor, and require either a lengthy study period or complicated methodology. Here, we present an entirely novel rat xenograft model of rGBM that is grown from pre-treated tumor cells. Irradiated pediatric (SJ-GBM2) and adult (U87-MG) GBM cells were generated by exposure to a total radiation dose of 10 Gy. The resultant irradiated SJGBM2-10Gy and U87-10Gy cells were tested for cell viability and allowed to reach confluence prior to stereotactic implantation into the right striatum of male athymic rats. In vivo advanced MR imaging at 9.4T was carried out over a three-week time course starting two weeks after implantation. Less than 1% of total cells survived irradiation. In vitro cytotoxicity assays demonstrated that irradiated cells were more resistant to temozolomide than untreated cells, indicating biological differences. Advanced MR imaging of in vivo tumors revealed differences in angiogenic character and blood brain barrier disruption between irradiated and untreated cell tumors. Immunohistochemical analysis identified different invasive and angiogenic phenotypes in rat xenograft tumors formed by irradiated GBM cells. Angiogenic phenotype histology mimicked that observed in GBM xenografts irradiated in vivo. Histological similarities to patient tumor tissues with treatment effect were also noted. To our knowledge, this is the first report of an intracranial rat xenograft model mimicking rGBM using irradiated cell lines. It represents a robust and expedient in vivo model for studying rGBM biology.
Abstract 13237: Placental Growth Factor as a Predictor of Long-term Outcome in Patients With Acute Decompensated Heart Failure
Authors: Yasuki Nakada, Rika Kawakami, Tomoya Ueda, Tomoya Nakano, Hiroyuki Kawata, Hiroyuki Okura, Yoshihiko Saito
Journal: Circulation (2016)

Background: Placental growth factor (PlGF), a member of the vascular endothelial growth factor (VEGF), contribute to atherogenesis through vascular inflammation and plaque destabilization. We reported high PlGF levels (≥14.5 pg/ml) were independent predictor of adverse events in patients with chronic kidney disease, but the significance of PlGF in acute decompensated heart failure (ADHF) patients was not clear. Methods: We have studied consecutive 437 patients with ADHF admitted to our hospital from 2011.4 through 2014.12. Among these patients, 281 patients measured PlGF levels were studied. The primary endpoint was all-cause death. Results: To investigate the impact of PlGF levels on prognosis of ADHF, we divided patients into 2 groups according to previous cutoff levels (14.5 pg/ml). There was no significant differences in age, left ventricular ejection fraction, and estimated glomerular filtration rate between high PlGF group (≥14.5 pg/ml, n=49) and low PlGF group (&lt;14.5 pg/ml, n=232). Kaplan-Meier analysis revealed that the patients with high PlGF group had worse prognosis than those with low PlGF group (p=0.0092) (Figure 1). Multivariate analysis revealed that PlGF was independent predictor of all-cause death (HR 1.026 [1.005-1.045], p=0.0172) (Figure 2). Conclusions: The high placental growth factor levels at acute phase in patients with acute decompensated heart failure predicts the long-term clinical outcome independent from various prognostic factors.
OA 09.02 Osimertinib Resistance Mediated by Loss of EGFR T790M Is Associated with Early Resistance and Competing Resistance Mechanisms
Authors: G. Oxnard, Y. Hu, K. Mileham, P. Tracy, N. Feeney, L. Sholl, C. Paweletz, K. Thress, P. Jänne
Journal: Journal of Thoracic Oncology (2017)
GENE-35. THE ORIGIN OF HUMAN GLIOBLASTOMA: FIREWORK PATTERN GLIOBLASTOMA GENESIS FROM SUBVENTRICULAR ZONE
Authors: Seok-Gu Kang, Joo Ho Lee, Jeong Eun Lee, Seon Jin Yoon, Junseong Park, Se Hoon Kim, Eui Hyun Kim, Jong Hee Chang, Jeong Ho Lee
Journal: Neuro-Oncology (2017)

Glioblastoma (GBM) is an incurable brain tumor, with a median overall survival of 15 months. Identifying the cell of origin that harbors mutations driving GBM could provide a fundamental basis for understanding disease developing novel treatments. Given that the accumulation of somatic mutations is implicated in gliomagenesis, studies have suggested that neural stem cells (NSCs), with their self-renewal and proliferative capacities, in the subventricular zone (SVZ) of the adult human brain may be the cells from which GBM originates. However, there is a lack of direct genetic evidence thereof in human GBM patients. Here, we describe direct molecular genetic evidence from patient brain tissue and genome edited mouse models that show astrocyte-like NSCs in the SVZ to be the cell of origin that harbors the driver mutations of human GBM. First, we performed deep sequencing of triple-matched tissues, consisting of i) radiologically and pathologically normal SVZs away from the tumor mass, ii) the tumor, and iii) normal cortical tissue (or blood), from 17 patients with primary GBM (isocitrate dehydrogenase-wild type) or other types of brain tumors. In doing so, we found that normal SVZ tissue away from the tumor in 46.2% of primary GBM patients contained low-level GBM driver mutations (down to ~1% of the mutational burden; TP53, PTEN, EGFR, PDGRF or TERT variations) that were observed at high levels in their matching tumors. Moreover, via single cell sequencing and laser microdissection analysis of patient’s brain tissues and genome editing of a mouse model (CRISPR-Cas9 system), we discovered that astrocyte-like NSCs (the astrocyte ribbon area) carrying driver mutations (TP53, PTEN, EGFR) migrate from the SVZ and lead to the development of high-grade gliomas in distant brain regions through aberrant growth. Altogether, our results highlight NSCs in human SVZ as the cell of origin that harbors the driver mutations of GBM.
PATH-53. EXPRESSION BASED INTRINSIC GLIOMA SUBTYPES ARE PROGNOSTIC IN LOW GRADE GLIOMAS OF THE EORTC22033-26033 CLINICAL TRIAL
Authors: Pim French, Ya Gao, Bas Weenink, Martin van den Bent, Lale Erdem-Eraslan, Johan Kros, Peter Sillevis Smitt, Thierry Gorlia, Roger Stupp, Monika Hegi, Brigitta Baumert
Journal: Neuro-Oncology (2017)

Medulloblastoma (MB) is a common pediatric malignant primary brain tumor originating in the posterior fossa.MB is generally classified into one of four molecular subgroups: Wnt, Shh, Group 3, and Group 4. Group 3 is the most clinically aggressive of the four and exhibits a molecular signature that includes over-expression of the GABRA5 isoform of the GABA A neurotransmitter receptor.Paradoxically, we previously observed that by administration of a positive modulator of the GABA A neurotransmitter receptor, a benzodiazepine, Group 3 cells with a GABRA5 signature could be arrested.We subsequently reported on use of a novel microdevice to screen a broad range of benzodiazepine compounds that functioned as GABRA5 positive modulators.This study identified a new benzodiazepine compound (KRM-II-08) that was particularly efficacious and thus an attractive candidate as a therapeutic against Group 3 MB.Using KRM-II-08 we have examined how a benzodiazepine can effectively arrest Group 3 MB cells.We report on the mechanism underlying the cell cycle arrest.
Dignity Therapy: a new psychoterapeutic approach for people facing advanced disease
Authors: F. Andreis, E. Gadaldi, F. Meriggi, M. Mirandola, L. Rota, C. Abeni, P. Bertocchi, F. Aroldi, T. Prochilo, B. Di Biasi, C. Ogliosi, M. Libertini, S. Noventa, A. Zaniboni
Journal: Annals of Oncology (2017)
As consequências da onda de calor do verão de 2003 sobre a mortalidade nos Países-Baixos
Authors: J Garssen, C Harmsen, J De Beer
Journal: Eurosurveillance (2005)

Nos Paises-Baixos, durante o verao de 2003, entre 1400 e 2200 obitos poderiam ter sido associados ao calor. O fato das temperaturas maximas terem sido inferiores as de outros paises europeos e de ter ocorrido em areas menos povoadas pode explicar cifras de mortalidade relativamente menos dramaticas. O aumento temporal das taxas de mortalidade e devido so por parte a uma deslocacao da mortalidade. A maior parte dos obitos associados ao calor foi observada em pessoas idosas em lares de terceira idade.
QLIF-08. DETERMINING THE NET CLINICAL BENEFIT IN NEURO-ONCOLOGY CLINICAL TRIALS BY COMBINING SURVIVAL AND TOXICITY DATA
Authors: Jeff Sloan, Brittny Major, Jan C Buckner
Journal: Neuro-Oncology (2017)

Despite new treatment options for glioblastoma, the improvements in survival time have not been groundbreaking. When considering treatment options it is important for the clinician to consider both the quantity as well as the quality of life benefit of the treatment. How can a clinician incorporate efficacy and toxicity information into a single expression of comparative treatment benefit? We have devised a new quality-adjusted effect size (QASES) method that combines efficacy and toxicity information into a single expression of comparative treatment benefit. QASES is a weighted combination of the efficacy and toxicity effect sizes based on differences in efficacy and toxicity using the ½ standard deviation method Results will be presented for the four possible case combinations of significant/non-significant differences in survival and toxicity data using completed randomized clinical trials (RCT) in patients with newly diagnosed glioblastoma. As an example, a phase III RCT of radiotherapy and daily temozolomide followed by bevacizumab in adults who had centrally confirmed glioblastoma found a 3.4 months (10.7 months vs. 6.3 months) increase in PFS compared with radiotherapy and TMZ alone. When equal weights were placed on survival and toxicity, the observed Median PFS difference 3.4 months reduced to a Quality Adjusted PFS Difference of 1.2 months for anemia, 0.9 months for fatigue, -0.1 months for hypertension, 1.1 months for leukopenia and 0.5 months neutropenia. The QASES approach allows for an intuitively appealing and mathematically simple and robust approach to combining efficacy and toxicity data. Clinicians can use QASES to interpret and communicate the findings of clinical trials to patients by weighing both the efficacy and toxicity information into a single quality-adjusted estimate of efficacy.
IMMU-62. OPTICAL BARCODING REVEALS IMMUNOEDITING OF THE CLONAL ARCHITECTURE AND MODULATION OF GENE EXPRESSION SIGNATURES IN A SYNGENEIC GLIOMA MODEL
Authors: Malte Mohme, Cecile Maire, Kristoffer Riecken, Malik Alawi, Lasse Dührsen, Katrin Neumann, Tobias Lange, Antonio Failla, Svenja Zapf, Boris Fehse, Manfred Westphal, Katrin Lamszus
Journal: Neuro-Oncology (2017)

Given the increasing importance of immunotherapeutic treatment strategies in neuro-oncology, the investigation of immune escape mechanisms, which lead to treatment resistance, is crucial. Therefore, studying tumor heterogeneity to understand the clonal dynamics and emergence of immune escape variants during cancer immunoediting can yield valuable insights into the adaptive processes of treatment resistance. We applied a novel multicolor labeling strategy, termed optical barcoding, which makes use of flow-cytometric read-out to compare in-vivo clonality in an immunocompetent versus -deficient environment. The optically barcoded syngeneic GL261 glioma was administered to wildtype and immunodeficient C57BL/6 pfp-/- rag2-/- mice, and tumor growth was monitored. We also analyzed the phenotype of tumor-infiltrating lymphocytes and the gene-expression signatures of explanted tumors using RNAseq. Ex-vivo analysis of individual tumor clones demonstrated that tumors grown in immunocompetent C57BL/6 mice were composed of a significantly different clonal architecture compared to pfp-/- rag2-/- C57BL/6. Whereas pfp-/- rag2-/- mice displayed a homogeneous clonal distribution in all tumors, immunoedited tumors in wildtype mice exhibited reduced clonality with emergence of immune escape clones, independent of proliferation rates. Beyond the expected prolonged survival of wildtype mice, immunoediting was further associated with differences in macroscopic growth patterns, vascularity and invasiveness. Tissue staining, time-course microarray analyses and flow-cytometric phenotyping of tumor-infiltrating immune cells highlighted the exemplary role of PD-L1 as mechanism to adapt to interferon-ɣ and infiltration of T-cells. Furthermore, RNAseq profiling of GL261 tumors grown in wt vs immunodeficient mice allowed the identification of an interferon-ɣ-mediated T-cell-shaped gene expression signature and new pathways potentially involved in the immune escape of glioma. Taken together, using optical barcoding we have demonstrated that the process of cancer immunoediting during tumor evolution not only shapes the gene expression profile and growth pattern, but also has a profound impact on the intratumoral heterogeneity of glioma in the syngeneic GL261 model.