tbuckley/cabot-search huggingface dataset:
EXTH-59. THE IDH1 MUTANT INHIBITOR AG-120 SHOWS STRONG INHIBITION OF 2-HG PRODUCTION IN AN ORTHOTOPIC IDH1 MUTANT GLIOMA MODEL IN VIVO
Authors: Brandon Nicolay, Rohini Narayanaswamy, Elia Aguado, Raj Nagaraja, Josh Murtie, Guowen Liu, Yuko Ishii
Journal: Neuro-Oncology (2017)

Mutations in isocitrate dehydrogenase (IDH) 1 and 2 result in accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), which drives multiple oncogenic processes, including increased histone and DNA methylation, leading to a block in cellular differentiation. IDH1/2 mutations occur in >70% of diffuse low-grade gliomas (LGG). Standard of care treatment for patients with diffuse LGG involves combined modality approaches including surgery, radiation, and chemotherapy. Here we present preclinical data from studies using AG-120, a potent, orally available inhibitor of the mIDH1 protein currently in clinical trials. In an orthotopic mouse xenograft model of a human mIDH1-R132H glioma, strong inhibition of 2-HG production in brain tumor samples (>77% inhibition) was observed when AG-120 was dosed orally at 150 mg/kg twice daily. Pharmacokinetic analysis revealed that AG-120 was detectable in the brain and brain-tumor tissues of the mice, although at much lower exposures than in the plasma, indicating that AG-120 is highly potent against the mIDH1-R132H protein in vivo. Results from ongoing preclinical studies testing the potential activity of AG-120 combined with radiation therapy in an orthotopic human mIDH1-R132H glioma model will also be shared.
Medication-Related Osteonecrosis of JAW (MR-ONJ) After Bisphosphonates, Denosumab and other Drugs in Advanced Cancer Patients: Recent Experience Data from Rete Oncologica Piemonte – Valle D’aosta (North-Western Italy Cancer Network)
Authors: V. Fusco, M. Cabras, A. Gambino, O. Bertetto, G. Numico, I. De Martino, M. Alessio, M. Marinella
Journal: Annals of Oncology (2017)
La rosolia in Danimarca
Authors: S Glismann
Journal: Eurosurveillance (2004)

Fino al 1987 in Danimarca sono stati registrati annualmente una media di 20 000 casi di rosolia. Nel 1989, invece, sono stati registrati solo 1006 casi; l'incidenza reale attualmente non si conosce con esattezza ma si considera essere molto bassa, inferiore a 1 per 100 000 abitanti. Questa significativa diminuzione dell'incidenza di rosolia riflette il successo della vaccinazione delle donne in eta fertile e sieronegative per la rosolia, iniziata in Danimarca nel 1980. Dal 1982 il servizio sanitario nazionale rimborsa la vaccinazione dei bambini e il vaccino MPR e stato introdotto in Danimarca nel programma vaccinale scolastico nel 1987. Questi interventi hanno permesso di mantenere bassa l'incidenza, e dal 1994 la sindrome da rosolia congenita e la rosolia in gravidanza sono state inserite tra le malattie soggette a notifica obbligatoria in Danimarca. Tuttavia, allo scopo di soddisfare l'obiettivo dell'OMS di controllare la rosolia nella Regione, si considera ora di introdurre anche la notifica obbligatoria di tutti i casi di rosolia diagnosticati in laboratorio.
CBIO-19. CHARACTERIZATION OF GPR133 EXPRESSION IN GLIOMA SUBTYPES
Authors: Michael Kader, Joshua Frenster, Benjamin Liechty, Aram Modrek, Aristotelis Tsirigos, John Golfinos, Sylvia Eisele, Rajan Jain, Timothy Shepherd, Girish Fatterpekar, Douglas MacNeil, Nadim Shohdy, Xinyan Huang, Andrew S Chi, Matija Snuderl, David Zagzag, Dimitris Placantonakis
Journal: Neuro-Oncology (2017)

We recently reported that GPR133, an orphan adhesion G protein-coupled receptor, is necessary for tumor initiation and growth in our patient-derived xenograft model for IDH wild-type (IDHwt) glioblastoma (GBM) (Bayin et al., 2016, Oncogenesis). This finding is in accordance with TCGA GBM data that suggest an inverse correlation between GPR133 mRNA expression levels and patient survival. An important and so far unanswered question is the expression profile of GPR133 in glioma molecular subtypes, including IDHwt, IDH mutant 1p/19q co-deleted (IDHmut codel) and IDHmut 1p/19q intact (IDHmut non-codel) gliomas, relative to normal brain tissue. We used a mouse monoclonal antibody against the N-terminal ectodomain of human GPR133 to perform immunohistochemical comparisons of archived human glioma tissue vs. cadaveric cortex and subventricular zone. The fraction of immunopositive cells was determined using a grading scale that we previously utilized (Bayin et al., 2016, Neoplasia): +, <1% positive; ++, 1–10%; +++, 10–50%; ++++, >50%. Cerebral cortex and the subventricular zone, where putative progenitor cells may reside, do not express GPR133 (n=5). 100% (n=9) of IDHwt GBM showed at least +++ staining, with 78% of specimens showing ++++ intensity. IDHmut codel tumors had only moderate staining (++, n=3). IDHmut non-codel tumors showed moderate to intense staining (++ to ++++, n=3). Our findings suggest that GPR133 is expressed throughout the glioma family of tumors but not in normal brain tissue. Within the glioma family, expression seems to be highest in IDHwt GBM and moderate in IDHmut tumors. We are currently collecting additional specimens to perform a thorough characterization of GPR133 expression in both adult and pediatric gliomas.
P3.01-085 A Phase 2 Trial of Apatinib in Advanced Non-Squamous NSCLC: Updated Data and Clinical Benefit of Continuing Apatinib after Initial Progression
Authors: F. Wu, S. Zhang, J. Yu, G. Gao, W. Li, W. Cai, C. Su, X. Chen, S. Ren, C. Zhou
Journal: Journal of Thoracic Oncology (2017)
SCDT-22. ROLE FOR LASER INTERSTITIAL THERMAL THERAPY (LITT) TO MANAGE PROGRESSED GLIOBLASTOMA DURING PREGNANCY
Authors: Na Tosha Gatson, Cameron Brimley, Ganesh Rao, T Linda Chi, Sujit Prabhu, Shiao-Pei Weathers
Journal: Neuro-Oncology (2017)

Glioblastoma (GBM) is the most lethal primary brain tumor in adults and is rarely identified concurrent with pregnancy. Several retrospective reports suggest that pregnancy promotes oncogenicity and ultimately tumor progression, although these mechanisms have not been clearly defined. Despite optimized multimodality treatment, median overall survival in GBM is 14-16 months. Tumor recurrence is inevitable and presents additional treatment challenges due to tumor heterogeneity which confers resistance to therapy and increased tumor oncogenicity. Treatment of recurrent disease in pregnant patients is further complicated by pregnancy-associated host immunosuppression, increased metabolic and vascular demands, restricted use of contrasted imaging modalities, and overall avoidance of risks to the fetus. Here, we offer the first report of a clinical case using laser interstitial thermal therapy (LITT) to manage progressed GBM during pregnancy. This work discusses the unique challenges related to determining the neurosurgical and medical treatment approaches, interpretation of neuroimaging post-LITT procedure, and appropriate multidisciplinary clinical follow-up. LITT was successfully used to offer a minimally invasive neurosurgical approach with reduced time of anesthesia to halt GBM progression and delay use of systemic chemotherapy in a second trimester pregnant patient. Standard temozolomide therapy was re-initiated after the birth of a healthy female singleton. Addition of chemotherapy timed with important post-partum immune profile changes facilitated continued tumor control and avoided risk to the fetus. Ultimately, research in this area offers potential indications and considerations for optimized timing for use of the LITT neurosurgical approach in pregnant GBM patients with progressed disease.
Abstract P257: Between-pedigree Genome-wide Linkage Screen Identifies a Locus on Chromosome 9 Influencing Coronary Artery Calcification in the Family Heart Study
Authors: James E Hicks, Michael A Province
Journal: Circulation (2016)

Coronary artery calcification (CAC) is the buildup of calcium deposits in the arteries leading to the heart, and is an indicator of atherosclerosis. CAC is known to have a genetic component. To identify the genes underlying CAC, a genome-wide linkage screen was performed in the Family Heart Study. There are two established loci influencing CAC identified by genome-wide association scans, at chromosome 9p21 and 6p24. However, there may be rare variants on haplotypes in the population that influence CAC. These would not be able to be identified by genome-wide association scans, but linkage scans could detect them. From the study, 2,687 individuals of European descent from 508 pedigrees with CAC scores were genotyped on the Illumina Human 1M-DuoV3 single nucleotide polymorphisms (SNP) array. CAC scores were determined by cardiac CT scan and adjusted for age, sex, and principal components before analysis. Using 484,358 common SNPs (minor allele frequency greater than 5%), common ancestry across the genome was determined for all pairs of individuals in the study. A segment of the genome was considered to be inherited from a common ancestor (identical-by-descent, IBD) if it contained more than 1,000 matching SNP genotypes over a length of at least one megabase. To test the influence of IBD at a locus on CAC, a linear mixed effects model was fit, including random effects to account for covariance due to relatedness and IBD states at each locus. All pedigrees were considered jointly in the model. Statistical significance was determined by comparing this model to one without IBD covariance via the likelihood ratio test. This model was evaluated approximately every megabase across all 22 pairs of autosomes. Since IBD states are determined solely by dense genotype data, IBD can be detected both within and between pedigrees in the study. This allows the inclusion covariance due to IBD in individuals in different pedigrees. If there is a haplotype shared across pedigrees, power to detect linkage is increased. CAC was found to have a narrow-sense heritability of 37.4% in this sample. Significant evidence of linkage was encountered at rs13293430 (chromosome 9, 31,050,747bp, LOD=3.042). When considering IBD between pedigrees, 914 pairs of individuals from different pedigrees were IBD at this position. This locus is near DDX58. Mutations in DDX58 cause Singleton-Merton syndrome, a disease characterized by calcification of blood vessels, making it an intriguing candidate gene for influence on CAC.
P1.07-033 Differential Expression of Immune Inhibitory Markers in Association with the Immune Microenvironment in Resected Lung Adenocarcinomas
Authors: M. Zhang, M. Kem, M. Mooradian, J. Eliane, T. Huynh, A. Iafrate, J. Gainor, M. Mino-Kenudson
Journal: Journal of Thoracic Oncology (2017)
P1.12-002 Nanoparticle Targeted Folate Receptor 1 Enhanced Photodynamic Therapy for Lung Cancer
Authors: T. Kato, C. Jin, H. Ujiie, D. Lee, F. Kosuke, H. Wada, H. Hu, R. Weersink, J. Chen, M. Kaji, B. Wilson, G. Zheng, K. Kaga, Y. Matsui, K. Yasufuku
Journal: Journal of Thoracic Oncology (2017)
P2.02-043 Multicenter Assessment of PD-L1 Immunohistochemistry: Challenges for Establishing the Concordance Between Four Different Antibodies
Authors: C. Ortiz –Villalón, H.H.n. Pham, A. Yoshikawa, A. Montero, A. Roden, C. Fernandez, L. Kis, L. De Petris, J. Fukuoka
Journal: Journal of Thoracic Oncology (2017)
Aortic rupture involving matrix metalloproteinases 8 and 9 during <i>Staphylococcus aureus</i> pneumonia
Authors: Mitsuo Hashimoto, Saki Kuriiwa, Ayako Kojima, Shunsuke Minagawa, Takanori Numata, Hiromichi Hara, Jun Araya, Yumi Kaneko, Katsutoshi Nakayama, Mamiko Owada, Daisuke Aizawa, Takashi Yorozu, Masafumi Suzuki, Kazuyoshi Kuwano
Journal: Thorax (2017)

An 87-year-old man was admitted to Jikei University Hospital presenting with fever and fatigue. Physical examinations revealed inspiratory coarse crackles on the left lung field. A chest CT detected a tumour-like consolidation around the thoracic aorta (figure 1A). Biochemical examinations found a high number of white blood cells and elevated C-reactive protein level, and a diagnosis of pneumonia was made. Penicillin antibiotics (ampicillin/sulbactam) were administered. Two days later, methicillin-sensitive Staphylococcus aureus (MSSA) was detected in two sets of blood cultures. An echocardiogram showed no vegetation and a urine culture was negative. A sputum culture was unobtainable, but pneumonia was the only focus of infection for the MSSA. Penicillin antibiotics were continued, but the patient suddenly developed cardiopulmonary arrest …
Epidemie trasmesse da alimenti nel nord del Portogallo, 2002
Authors: A M Correia, G Gonçalves, Margarida Saraiva
Journal: Eurosurveillance (2004)

Nell'ottobre 2001 furono incluse nel sistema portoghese di sorveglianza, allerta e risposta, le epidemie trasmesse da alimenti (ETA). Di conseguenza l'autorita sanitaria regionale del nord (Delegado Regional de Saude do Norte - DRSN) inizio un programma di sorveglianza sulle epidemie trasmesse da alimenti. Questo rapporto e una breve descrizione dei dati generati da questo programma nel 2002. Per ciascuna epidemia ad origine alimentare l'autorita sanitaria locale (Delegado de Saude Concelhio - DSC) produsse un rapporto scritto. Il 59% delle 27 ETA studiate dai DSC nel 2002 furono riportate entro 72 ore dalla data di insorgenza. Si ammalarono 577 persone, il 9,6% dei pazienti fu ricoverato in ospedale, e non fu registrato nessun decesso. L'agente eziologico fu identificato dai pazienti nel 63% delle epidemie e negli alimenti nel 18,5% delle situazioni. Responsabile risulto la Salmonella enterica nel 73,7% delle epidemie nelle quali l'agente fu confermato in laboratorio. I pasti implicati nelle epidemie erano stati preparati principalmente in ristoranti e case private (75,0% delle epidemie). I fattori piu spesso riportati dal DSC come maggiori responsabili furono procedimenti, preparazioni o manipolazioni inadeguati. Crediamo che la sorveglianza e il controllo epidemiologici delle ETA dovrebbero essere rinforzati in Portogallo come parte di una piu ampia strategia per promuovere la sicurezza degli alimenti.
GENE-20. USE OF DECITABINE TO ALTER PATTERNS OF TREATMENT-INDUCED MUTAGENESIS IN GLIOBLASTOMA
Authors: Matthew Gallitto, Margaret Pain, Huaien Wang, Gintaras Deikus, Robert Sebra, Raymund Yong
Journal: Neuro-Oncology (2017)

The standard chemoradiation strategy used to treat GBM triggers cell death by inducing overwhelming numbers of DNA double-strand breaks (DSBs). Cancer cells escaping apoptosis activate error-prone DNA damage response mechanisms that have the potential to produce new mutations in critical driver genes, leading to the emergence of treatment-resistant subclones. Decitabine (DAC) is a DNA demethylating agent currently FDA approved for the treatment of higher-risk myelodysplastic syndrome. Early studies of DAC in GBM suggest a possible synergy with temozolomide (TMZ), but the mechanism remains unclear. Because methylated CpG sites are hypermutable and alter the accessibility of DNA to the damage repair machinery, we hypothesized that epigenetic priming with DAC may be used as a novel method to mitigate radiation- and TMZ-induced mutagenesis without sacrificing cytotoxicity. In this study, we examine how DAC alters patterns of treatment-induced DSBs in a region of TP53 particularly susceptible to acquiring deleterious missense mutations. GBM stem cells were isolated from human surgical resections and subjected to conventional GBM treatment with or without pre-treatment with DAC. We used a novel long-read bisulfite-converted DNA sequencing technique to quantify 5-methylcytosine (5mC) levels at CpGs within a 2 kb region coding for a portion of the TP53 DNA-binding domain. After DAC treatment, we observed an average decrease in 5mC levels by 25%. Interestingly, some CpGs at known mutational hotspots exhibited variable demethylation across samples. We developed an inverse PCR method to quantify DNA damage in the same region, and found that DAC pre-treatment resulted in a significant reduction in DSBs. Our preliminary experiments show that demethylation therapy with DAC prior to TMZ may have a protective effect against C:G>T:A transitions at CpG mutational hotpot sites in TP53. Our current follow-up studies are exploring CpG demethylation patterns in a larger region of TP53, and will correlate this with tumor evolutionary outcomes.
IMMU-63. OVERCOMING GLIOBLASTOMA RESISTANCE TO IMMUNE CHECKPOINT BLOCKADE VIA RNA-LOADED NANOPARTICLES
Authors: Elias Sayour, Adam Grippin, Hector Mendez-Gomez, Gabriel De Leon, Duane Mitchell
Journal: Neuro-Oncology (2017)

In a randomized phase III study for recurrent glioblastoma (GBM), checkpoint inhibition with nivolumab failed to improve overall survival outcomes. GBM immune escape through loss of MHC class expression juxtaposed to an immunoregulatory milieu, both local and systemic, remain significant hurdles. To overcome these limitations, we developed tumor mRNA loaded nanocarriers to activate systemic immunity and re-program the regulatory intratumoral microenvironment into an immune activated locale. Since local vaccination strategies are mired with poor immunogenicity, we assessed if intravenous delivery of tumor derived RNA encapsulated in lipophilic NPs could systemically activate peripheral and intratumoral antigen presenting cells (APCs) for induction of therapeutic anti-tumor immunity in pre-clinical murine malignant glioma models Systemic administration of RNA-NPs localized to reticuloendothelial organs (i.e. spleen, liver, bone marrow) inducing a pro-inflammatory phenotype (characterized by co-expression of PD-L1 and CD86) on both parenchymal cells and CD11c+ MHCII+ APCs; this phenotype was strictly dependent on type I interferon. These effects were also observed in the tumor microenvironment, which displayed an increase in PD-L1, CD86 and MHC class I expression. Addition of a checkpoint inhibitor (PD-L1 mAb) to RNA-NPs further increased intratumoral MHC-I expression and precipitated an increase in intratumoral MHC-II expression. Combination therapy with RNA-NPs and immune checkpoint blockers increased intratumoral PD-1 expression on CD4/CD8+ T cells, and mediated synergistic anti-tumor efficacy in settings where PD-1 or PD-L1 did not confer therapeutic benefit. In a radiation and temozolomide resistant murine glioma (resistant to monotherapy with RNA-pulsed dendritic cells or ex vivo activated T-cells), these RNA-NPs elicited significant anti-tumor efficacy. By employing a systemic nanoliposomal formulation that can act as a dual targeted agent to remodel the peripheral and intratumoral microenvironment, RNA-NPs represent a versatile platform to overcome GBM related immune suppression for synergy with immune checkpoint inhibitors.
RBIO-03. CSF-1R INHIBITION AMELIORATES RADIATION-INDUCED MEMORY LOSS IN A RODENT GLIOMA MODEL
Authors: Xi Feng, Katherine Grue, Sharon Liu, Nalin Gupta, Susanna Rosi
Journal: Neuro-Oncology (2017)

Fractionated whole brain irradiation is widely used for the treatment of primary brain tumors and brain metastases. Long-term survival occurs depending on the tumor type, but patients often develop cognitive deficits after radiation. The underlying mechanisms that cause loss of cognitive function after radiotherapy are not clear, and there is no treatment available to prevent the adverse effects. We have previously reported that temporary depletion of microglia by CSF-1R inhibition protects neuronal structures and prevents fractionated whole brain irradiation (WBI) induced memory loss in mice. Here, we established a novel glioma model by engineered rodent glioma cell line GL261 to express diphtheria toxin receptor (DTR) in mice. This model allows restriction of tumor growth/progression after treatment with diphtheria toxin (DT) and assessment of cognitive functions. We simulate the effect of tumor growth with subsequent fractionated radiation treatment, and tested the outcomes of CSF-1R antagonist treatment during radiotherapy on cognitive function. We found that 1) DT treatment significantly prolonged survival of glioma bearing mice; 2) Tumor growth and DT treatment did not affect object recognition memory; 3) Radiotherapy further prolonged survival of glioma bearing mice but resulted in memory deficits; and 4) CSF-1R inhibition during radiotherapy prevented fractionated whole brain irradiation-induced memory loss. These results suggest that 1) WBI, not tumor growth, is the main cause of memory impairment in glioma bearing mice; and 2) transient CSF-1R inhibition during radiotherapy could prevent cognitive decline in patients.
Abstract 16076: Cost-effectiveness of Percutaneous Closure of the Left Atrial Appendage in Atrial Fibrillation Based on Results From PROTECT AF vs. PREVAIL
Authors: James V Freeman, David W Hutton, Geoffrey D Barnes, Ruo P Zhu, Douglas K Owens, Alan M Garber, Alan S Go, Mark A Hlatky, Paul A Heidenreich, Paul J Wang, Amin Al-Ahmad, Mintu P Turakhia
Journal: Circulation (2015)

Introduction: Randomized trials of left atrial appendage (LAA) closure with the Watchman device have shown disparate results, and its cost-effectiveness compared to anticoagulation has not been evaluated using contemporary data. Methods: We used a Markov decision model to estimate lifetime quality-adjusted survival, costs, and cost-effectiveness of LAA closure with Watchman, compared directly with warfarin and indirectly with dabigatran, using data from the long-term (mean 3.8 year) follow-up of PROTECT AF and PREVAIL randomized trials. Results: Using data from PROTECT AF, the incremental cost-effectiveness ratios (ICER) compared to warfarin and dabigatran were $20,140 and $24,400 per quality adjusted life year (QALY), respectively. Using data from PREVAIL, LAA closure was dominated by warfarin and dabigatran, meaning that it was less effective (9.46, 9.59, and 9.64 QALYs, respectively) and more costly. At a willingness-to-pay-threshold of $50,000 per QALY, LAA closure was cost-effective 62% and 35% of the time under PROTECT AF and PREVAIL assumptions, respectively. These results were sensitive to the rates of ischemic stroke and intracranial hemorrhage for LAA closure and medical anticoagulation. Conclusion: The cost-effectiveness of LAA closure with the Watchman device depends largely on the clinical trial used for assigning event rates. Using data from PROTECT AF, Watchman was cost-effective; using PREVAIL data, Watchman was more costly and less effective than warfarin and dabigatran. Results were highly sensitive to the rates of stroke and intracranial hemorrhage in both treatment groups. Post-marketing surveillance of major adverse events will be vital to determining the value of the Watchman in clinical practice.
P2.02-026 Impact of PD-L1 Expression on 18F-FDG-PET in Pulmonary Squamous Cell Carcinoma
Authors: N. Kasahara, K. Kaira, B. Alatan, T. Higuachi, Y. Arisaka, E. Bilguun, N. Sunaga, T. Oyama, T. Yokobori, T. Asao, M. Nishiyama, K. Shimizu, A. Mogi, H. Kuwano
Journal: Journal of Thoracic Oncology (2017)
OA 15.02 Benefits, Harms, and Economic Efficiency of Low-Dose CT Lung Cancer Screening Strategies in a Population-Based Setting
Authors: A. Kuhlmann, M. Treskova, I. Aumann, H. Golpon, J. Vogel-Claussen, T. Welte, J.-. Graf Von Der Schulenburg
Journal: Journal of Thoracic Oncology (2017)