tbuckley/cabot-search huggingface dataset:
GENE-21. THE KETOGENIC DIET ALTERS THE EPIGENETIC LANDSCAPE OF GBM TO POTENTIATE THE EFFECTS OF CHEMO AND RADIOTHERAPY
Authors: Stylianou Tzouliana, Nabil Hajji, Richard Perryman, Kevin O’Neill, Eric C Woolf, Adrienne C Scheck, Nelofer Syed
Journal: Neuro-Oncology (2017)

Glioblastoma Multiforme (GBM) is the most aggressive form of primary brain tumor, with a median survival time of just 14 months. Although a number of targeted therapies have been devised for these tumors, they have proved to be ineffective due to the high degree of inherent heterogeneity exhibited by them. An alternative and more attractive strategy is to exploit their altered metabolism, a feature shared by virtually all tumor cells. This can be accomplished using the therapeutic ketogenic diet (KD) which is a high fat, very low carbohydrate and adequate protein diet. This changes metabolism by increasing blood ketone and decreasing blood glucose and is currently used for the clinical management of refractory paediatric epilepsy. Previous studies have shown the KD to extend survival in a number of animal models of glioma and potentiate the effects of radiotherapy in some of them. The addition of ketones to tumor cells in vitro mimics the effects seen in vivo. In an attempt to unravel the mechanistic basis behind these effects, we carried out small RNA sequencing of tumors from mice fed either a KD or standard diet (SD). Our results highlighted global upregulation of miRNAs with tumor suppressor function, typically downregulated in gliomas, in animals fed a KD verses those fed a SD. These include miR-138-1-5p, miR-204-5p and several members of the mmu-let-7 family members. Furthermore, we observed a corresponding downregulation of many of the target genes of these miRNAs in KD fed animals. These target genes have previously been shown to be important regulators of tumor growth and invasion as well as chemo and radio-resistance. Our results reveal that altering metabolism using the KD changes the epigenetic landscape of GBM tumors and effects the regulation of key genes critical for tumor survival.
HOUT-27. TREATMENT PATTERNS AND SURVIVAL IN PATIENTS WITH GLIOBLASTOMA: A RETROSPECTIVE DATABASE ANALYSIS USING US ELECTRONIC HEALTH RECORDS (EHR)
Authors: Priya Kumthekar, Nawaal Shaikh, Reethi Iyengar, Rajesh Kamalakar, Patrick Bonnet, Kyle D Holen, Maria Guseva, Amir Abushamaa, Karan Dixit
Journal: Neuro-Oncology (2017)

Glioblastoma (GBM) represents 14.9% of all primary brain tumors in the US with ≥12,000 new cases expected in 2017. Current management lacks any curative therapies and remains palliative through the use of surgery, postoperative radiotherapy and concurrent and adjuvant chemotherapy. This study compares guideline-recommended-care to current practice patterns in GBM patients treated in the community, which is largely unknown. A retrospective analysis using geographically and socioeconomically diverse de-identified EHR data from Optum, covering 50M lives, between 2007 and 2015 was conducted. Patients with no prior/other cancers, aged ≥18 years treated at integrated delivery networks and whose treatment began ≤28 days from diagnosis were included. Treatment patterns, demographics and Charlson Co-morbidity Index (CCI) of patients were noted. Descriptive statistics were used to examine survival by treatment regimens and correlational analysis explored association between various factors and survival. Study sample included 540 patients, with men representing 55.0%. Average age was 64.3 years and average CCI at diagnosis was 0.68. Surgery was performed in 44% of patients. 114 patients (21.1%) received surgery+radiotherapy+temozolomide (TMZ) resulting in a 13.3-month median survival. Among these, 47 patients also received bevacizumab with median survival of 20.2 months. An additional 145 patients received only TMZ+radiotherapy, 38 patients received surgery+radiotherapy and 33 patients received surgery+adjuvant TMZ. Median survival for these patients was 8.5, 8.2 and 10.9 months, respectively. The remaining nearly 40% of the patients received diverse combinations of treatment regimens. Younger age and having surgery correlated with longer survival (p<.05). To our knowledge, this is the first study describing US practice patterns in the treatment of GBM indicating variations in practice patterns. As these variations could be explained by tumor heterogeneity, wide tumor location and rapid growth, gaining a better understanding of real-world practice is critical in achieving improved care coordination and better clinical outcomes.
PATH-07. FAMILIAL MELANOMA-ASTROCYTOMA SYNDROME: SYNCHRONOUS DIFFUSE ASTROCYTOMA AND PLEOMORPHIC XANTHOASTROCYTOMA IN A PATIENT WITH GERMLINE CDKN2A/B DELETION AND A SIGNIFICANT FAMILY HISTORY
Authors: Winward Choy, Andrew K Chan, Seunggu J Han, Daniah Beleford, Manish K Aghi, Mitchel S Berger, Joseph T Shieh, Andrew W Bollen, Arie Perry, Joanna J Phillips, Nicholas Butowski, David A Solomon
Journal: Neuro-Oncology (2017)

Familial melanoma-astrocytoma syndrome is a tumor predisposition syndrome caused by inactivating germline alteration of the CDKN2A tumor suppressor gene on chromosome 9p21. While some families with germline CDKN2A mutations are prone to development of just melanomas, other families develop both melanomas, astrocytomas, and occasionally other nervous system neoplasms including peripheral nerve sheath tumors and meningiomas. The histologic spectrum of the astrocytomas that arise as part of this syndrome is not well described, nor are the additional genetic alterations that drive these astrocytomas apart from the germline CDKN2A inactivation. Herein, we report the case of a young man with synchronous development of a pleomorphic xanthoastrocytoma, diffuse astrocytoma, and paraspinal mass radiographically consistent with a peripheral nerve sheath tumor. His paternal family history is significant for melanoma, glioblastoma, and oral squamous cell carcinoma. Genomic profiling revealed that he harbors a heterozygous deletion in the germline of chromosome 9p21.3 encompassing the CDKN2A and CDKN2B tumor suppressor genes. Both the pleomorphic xanthoastrocytoma and diffuse astrocytoma were found to have homozygous deletion of CDKN2A/B due to somatic loss of the other copy of chromosome 9p containing the remaining intact alleles. Additional somatic alterations included BRAF p.V600E mutation in the pleomorphic xanthoastrocytoma and PTPN11, ATRX, and NF1 mutations in the diffuse astrocytoma. The presence of germline CDKN2A/B inactivation together with the presence of multiple anatomically, histologically, and genetically distinct astrocytic neoplasms, both with accompanying somatic loss of heterozygosity for the CDKN2A/B deletion, led to a diagnosis of familial melanoma-astrocytoma syndrome. This remarkable case illustrates the histologic and genetic diversity that astrocytomas arising as part of this rare glioma predisposition syndrome can demonstrate.
Excess mortality among 10‐year survivors of classical Hodgkin lymphoma in adolescents and young adults
Authors: Ana C. Xavier, Narendranath Epperla, Jeffrey W. Taub, Luciano J. Costa
Journal: American Journal of Hematology (2017)

Abstract Adolescents and young adults (AYA) surviving classical Hodgkin lymphoma (cHL) risk long term fatal treatment‐related toxicities. We utilized the Surveillance, Epidemiology and End Results (SEER) program to compare excess mortality rate (EMR‐observed minus expected mortality) for 10‐year survivors of AYA cHL diagnosed in 1973–1992 and 1993–2003 eras. The 15‐year EMR reduced from 4.88% to 2.19% while the 20‐year EMR reduced from 9.46% to 4.07% between eras. Survivors of stages 1–2 had lower EMR than survivors of stages 3–4 cHL in the 1993‐2003 but not in the 1973–1992 era. There was an overall decline in risk of death between 10 and 15 years from diagnosis, driven mostly by second neoplasms and cardiovascular mortality. Despite reduction in fatal second neoplasms and cardiovascular disease with more current therapy, long term survivors of AYA cHL still have a higher risk of death than the general population highlighting the need for safer therapies.
P3.03-024 Real-Life Experience and Clinical Characterization of BRAF V600E Mutation in Austrian NSCLC Patients
Authors: S. Schwab, U. Setinek, D. Krenbek, S. Watzka, S. Gasser, F. Huemer, I. Kapfhammer, H. Fabikan, E. Hauptmann-Repitz, O. Burghuber, M. Hochmair
Journal: Journal of Thoracic Oncology (2017)
OA 13.01 CD38-Mediated Immunometabolic Suppression as a Mechanism of Resistance to PD-1/PD-L1 Axis Blockade
Authors: L. Chen, L. Diao, Y. Yang, X. Yi, B.L. Rodriguez, Y. Li, J. Rodriguez-Canales, X. Liu, A. Huang, Q. Zhao, D. Peng, J. Fradette, P. Tong, C. Ungewiss, Y. Fan, D. Peng, P. Villalobos, E. Dmitrovsky, V. Papadimitrakopoulou, J. Wang, L.A. Byers, J. Heymach, S. Ullrich, I. Wistuba, X. Qin, D. Gibbons
Journal: Journal of Thoracic Oncology (2017)
EXTH-56. EGFR EXTRACELLULAR DOMAIN POINT MUTANT A289V: A THERAPEUTICALLY TARGETABLE DRIVER OF GLIOBLASTOMA INVASION
Authors: Amy Haseley Thorne, Zev A Binder, Spyridon Bakas, E Paul Wileyto, Jennifer J D Morrissette, Hamed Akbari, Saima Rathore, Andrew Scott, Christos Davatzikos, Donald O’Rourke, Frank Furnari
Journal: Neuro-Oncology (2017)

Tumor heterogeneity is a defining hallmark of glioblastoma (GBM), found both inter- and intra-tumoral. Heterogenous Epidermal Growth Factor Receptor (EGFR) mutations typically occur within the extracellular domain (ECD), and single cell transcriptome studies have shed light on both the diversity and frequency of mutations. This study investigates the oncogenic effect of the most common EGFR ECD point-mutations (R108K, A289D/T/V, and G598V) in a retrospective cohort of 270 de novo GBM patients from the University of Pennsylvania. Although no survival differences were identified when comparing EGFR-amplified with non-amplified GBM, extrapolation of each individual point-mutation revealed a significant reduction in patient survival for the EGFR-A289D/T/V mutants (p=0.028). Moreover, quantitative integrative analysis of multiparametric magnetic resonance imaging data, via multivariate machine learning algorithms, revealed radiographic characteristics of increased invasion for patients bearing the A289 mutation. The underlying mechanism of EGFR-A289V in tumor growth was further examined using engineered U87 glioma cells and patient-derived HK281 glioma spheres simulating expression of wild-type-EGFR or point-mutant variations. Corroborating our findings in patients, mice bearing intracranial tumors with EGFR-A289V mutations revealed significantly worse survival and highly invasive tumors, as detected by H&E. Cells expressing EGFR-A289V yielded a highly active EGFR/ERK signaling pathway, resulting in increased expression and functionality of the matrix metalloproteinase MMP1, which can be benefited by the use of ERK pathway inhibitors. Using the in vivo mouse model, we were able to efficiently target tumors bearing the A289V mutations using the monoclonal antibody 806, which led to a reduction in tumor burden and increased survival in mice. Collectively, the findings of this study yield a highly invasive and prognostic indicator in the EGFR-A289V point-mutation in GBM. Moreover, these results postulate the A289V mutation may be a molecular marker for responsiveness to therapy in patients currently enrolled in clinical trials with the antibody-drug conjugate ABT-414.
P3.02-084 FGF9-FGFR Pathway Induce Neuroendocrine Differentiation in Lung Epithelial Cells
Authors: K. Ishioka, H. Yasuda, K. Soejima, D. Arai, O. Keiko, J. Hamamoto, M. Ozaki, K. Masuzawa, I. Kawada, K. Naoki, K. Emoto, Y. Hayashi, H. Watanabe, H. Ahmed, T. Betsuyaku
Journal: Journal of Thoracic Oncology (2017)
MA 01.11 Timing of Thoracic Radiotherapy Is More Important Than Dose Escalation in Patients with Limited-Stage Small Cell Lung Cancer
Authors: X. Hu, B. Xia, Y. Bao, Y. Xu, J. Wang, H. Ma, Y. Jin, M. Fang, H. Tang, M. Chen, B. Dong, X. Fu, M. Chen
Journal: Journal of Thoracic Oncology (2017)
NIMG-17. STRUCTURAL DEFORMATION FIELD ON T1W MRI IN HEALTHY BRAIN PARENCHYMA IS ASSOCIATED WITH OVERALL SURVIVAL IN TREATMENT-NAÏVE GLIOBLASTOMA MULTIFORME
Authors: Prateek Prasanna, Jhimli Mitra, Niha Beig, Sasan Partovi, Gagandeep Singh, Marco Pinho, Anant Madabhushi, Pallavi Tiwari
Journal: Neuro-Oncology (2017)

Infiltrative nature of glioblastoma multiforme (GBM) forces the compression of surrounding brain tissue resulting in increased intracranial pressure and tissue deformation. Here we characterize the systemic nature of GBM by capturing the heterogeneity in tissue deformation in the normal-appearing brain-around-tumor (BAT) regions on treatment-naïve T1w MRI, and employ these deformation features to distinguish long-term (LTS) from short-term (STS) survivors. We hypothesize that BAT regions in STS would have significantly higher heterogeneity of deformation, as compared to LTS. A total of 79 (41 STS, overall survival<240 days and 38 LTS, OS>540 days) 3-Tesla treatment-naive Gadolinium (Gd)-contrast T1w, T2w, and FLAIR MRI GBM studies were obtained from the Cancer Imaging Archive. An expert reader segmented the necrotic core, active tumor and peritumoral brain zone (PBZ). Voxel-wise deformation magnitude was obtained from the deformation orientations after registration to a normal T1w template. Deformation statistics were computed within 5mm annular BAT regions (0<d<60mm where d is the distance from the PBZ). The results demonstrated that the deformation magnitude was positively skewed in STS as compared to LTS. The distributions were found to be statistically different (p<0.05) for 0<d<30mm, implying that structural deformation is, possibly, more unevenly spread in BAT regions right next to PBZ as compared to relatively distal regions. Kaplan-Meier survival analysis and log-rank test yielded a statistically significant p-value of 0.03. A structural deformation field was found to exist in healthy brain parenchyma in treatment-naïve GBM subjects, with statistical significant differences between the two survival cohorts existing up until 30mm outside the PBZ boundary. These deformation distribution measures were also found to be associated with overall patient survival.
Plasticity of PD-L1 expression between nodal metastases and primary tumors in p16 negative squamous cell carcinoma of the oral cavity
Authors: C. Patriarca, C. Gervasoni, A. d’Aiuto, R. Roselli, G. Petracco, A. Laudati, M. Cipolla, P. Ronchi, M. Giordano
Journal: Annals of Oncology (2017)
ACTR-69. PHASE I TRIAL OF TG02 PLUS DOSE-DENSE OR METRONOMIC TEMOZOLOMIDE FOR ADULTS WITH RECURRENT ANAPLASTIC ASTROCYTOMA AND GLIOBLASTOMA
Authors: Jing Wu, Christine Bryla, Ann McCoy, Boris Lisa, Nancy Garren, Christine Siegel, Ewa Grajkowska, Brett Theeler, Deric M Park, Tracy Parrott, Terri S Armstrong, Ying Yuan, Mark R Gilbert
Journal: Neuro-Oncology (2017)

Most therapies for recurrent high grade gliomas have not been successful, largely due to the complexity of the disease. Our preclinical studies have demonstrated the anti-glioma effects of TG02 and the synergy with temozolomide (TMZ) through modulation of transcription and metabolism. We hypothesize that given the multiple mechanisms of TG02 and established efficacy of TMZ, combined treatment may be effective for malignant gliomas. We launched a phase I/II trial and herein report the phase I results. Adults with recurrent high-grade astrocytoma, KPS ≥ 60, normal organ function, no more than 2 prior relapses, and no prior bevacizumab were enrolled. A Bayesian Optimal Interval design was employed to determine the maximum tolerated dose (MTD) and the toxicity profile of the combination of TG02 (starting dose 200mg orally on days 1, 12, 15, and 26) and TMZ, either as a dose-dense (DD; 125mg/m2/d, 7on/7off) or metronomic (MN; 50mg/m2/d) dosing schedule on a 28-day cycle. A total of 15 patients have been enrolled; 80% are male, median age 50.6. Nine patients were enrolled in DD TMZ arm; 1/6 receiving TG02 at 200mg had grade 4 diarrhea, a dose-limiting toxicity (DLT); 1/3 patients receiving TG02 at 250mg in the DD arm had grade 4 neutropenia, a DLT. In MN TMZ arm, 0/3 patients receiving TG02 at 200mg had a DLT. 1/3 patients receiving TG02 at 250mg had a DLT of grade 4 lymphopenia. To date, although not a primary endpoint, 2 partial objective responses have been observed in ongoing patients receiving 200mg TG02 in combination with TMZ. The combination of TG02 at 200mg and DD/MN TMZ is well tolerated. Dose escalation continues in both DD/MN arms (currently at TG02 250mg) with determination of MTD anticipated soon. Additionally, objective responses have been observed suggesting activity for this regimen.
A incidência da bacteriemia por S. aureus nos hospitais da area Centro-Oeste na Irlanda, 2002-2004
Authors: D Whyte, R Monahan, L Boyle, B Slevin, R FitzGerald, D Barron, J De Freitas, K Kelleher
Journal: Eurosurveillance (2005)

A apprehensao frente as infeccoes nosocomiais e o fenomeno mundial de resistencia aos antibioticos, aumentaram o medo do que se chama um “superbug”. Na Irlanda, nao existe indicador que seja considerado como uma medida fiavel du nivel de Staphylococcus aureus resistente a meticilina (SARM) nos hospitais. O objetivo do estudo seguinte era de comparar duas medidas brutas dos SARM – a percentagem de bacteriemias devidas aos SARM e a taxa de incidencia (por 1000 camas occupadas/dia) dos SARM em seis hospitais. Analisamos todas as culturas sanguineas positivas para S aureus (sejam sensiveis ou resistentes a meticilina) de 2002 a 2004, na area Centro-Oeste da Irlanda. Os dados dos registos medicais (Hospital In-Patient Enquiry, HIPE) serviram para avaliar em cada mes a taxa de ocupacao dos leitos. 
Dos 245 episodios de bacteriemia de pacientes, 119 eram SARM. Tem-se comparado as tendencias das percentagems de isoladas de SARM com as taxas de incidencia calculadas. A taxa de incidencia parece ser um indicador de SARM nos hospitais mais fiavel e solido que a percentagem. As dificuldades de interpretacao dos indicadores de SARM nao deveriam impedir a publicacao regular de dados, ao menos ao nivel regional, na Irlanda.
EXTH-18. CT-179 SELECTIVELY TARGETS OLIG2-POSITIVE GLIOMA STEM CELLS AND DEMONSTRATES POTENT ANTI-TUMOR ACTIVITY IN GLIOBLASTOMA
Authors: Gordon Alton, Graham Beaton, Susan Knowles, Adriana Guerrero, Santosh Kesari, Gregory Stein
Journal: Neuro-Oncology (2017)

Olig2 is a lineage-specific bHLH transcription factor in normal brain development and has been shown to be a critical oncogene controlling the tumorigenesis, growth, invasion, differentiation and radiation resistance of gliomas, including glioblastoma (GBM). Importantly, Olig2-positive glioma stem-like cells (GSCs) are responsible for the recurrence of disease that occurs in most of the GBM patients. CT-179 is a small molecule (397 kD) that was designed to bind to the dimerization interface of Olig2. Based on comparison to shOlig2 effects in GSCs, the mechanism of action of CT-179 is through modulation of the transcription of Olig2-targeted genes. CT-179 inhibits cellular growth and induces apoptosis of Olig2-expressing GSCs at low nanomolar concentrations (average GI50=154 nM; n=18). CT-179 also causes mitotic catastrophe and a corresponding G2/M arrest of GSCs. The compound is completely water soluble, is nearly 100% orally bioavailable, demonstrates a long duration of pharmacologic action suitable for once daily dosing, and readily crosses the blood-brain barrier. As such, it achieves therapeutically effective concentrations in the brain. Immunohistochemistry demonstrates a reduction of Olig2-positive cells in tumor bearing animals. CT-179 significantly extends survival of mice implanted orthotopically with patient-derived GSCs. Importantly, CT-179 combined with standard of care temozolomide and radiation dramatically inhibits tumor growth compared to either treatment alone. CT-179 represents a novel agent which selectively targets GSCs with great potential as an adjunctive therapy in the treatment of GBM and other gliomas.
CMET-48. CE7 CANADIAN CLINICAL TRIALS GROUP / ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY. A PHASE III TRIAL OF STEREOTACTIC RADIOSURGERY COMPARED WITH WHOLE BRAIN RADIOTHERAPY (WBRT) FOR 5–15 BRAIN METASTASES
Authors: David Roberge, Paul Brown, Warren Mason, Chris O’Callaghan, Keyue Ding, Anthony Whitton, Michael D Chan
Journal: Neuro-Oncology (2017)

It is now accepted that for patients with 1–4 brain metastases radiosurgery (SRS) provides improved cognitive and quality of life (QoL) outcomes vs. whole-brain radiotherapy (WBRT). It has been our recent finding that SRS also provides overall survival equivalent to WBRT following resection of a brain metastasis, again with improved cognitive and QoL outcomes. A gap in high-level evidence remains for patients with 5 or more brain metastases. We report on the framework of a Phase III trial. The NCI Brain Malignancies Steering Committee approved the trial concept in March 2017. The trial is to be led by the NCIC and endorsed by the NRG and Alliance for Clinical Trials in Oncology. Planned total accrual is 206 patients randomized to either radiosurgery (volume-based dosing) or WBRT (30Gy in 10 daily fractions) and memantine. Eligible patients will have a maximum total tumor volume of 30cm3. They will have 5–15 parenchymal metastases, free of gross leptomeningeal disease and ECOG performance status 0–2. The primary endpoints will be cognitive deterioration free survival and overall survival. Secondary endpoints include those related to: patient/treatment related outcomes (patterns of failure, validation of a nomogram to predict early appearance of new brain metastases, time to (re-)initiation of systemic therapy, etc.), economic endpoints (comparison based on payer rates (Medicare for US / provincial heath authorities in Canadian jurisdictions with activity-based funding) as well as comparison based on "time based activity costing" in selected institutions), dosimetric endpoints, imaging endpoints and quality of life endpoints. Translational endpoints will include analysis of serum samples to elucidate molecular/genomic mechanisms of neurocognitive decline. Additional translational endpoints are contingent on the outcome of applications for supplemental funding. A collaborative effort has been agreed upon to fill the largest evidence gaps in the focal management of brain metastases.