tbuckley/cabot-search huggingface dataset:
IMMU-53. CO-ADMINISTRATION OF DEXAMETHASONE WITH CHECKPOINT BLOCKADE THERAPY INCREASES SURVIVAL IN BRAIN TUMOR MODEL
Authors: Marsha-Kay Hutchinson, Amber Giles, Heather Sonnemann, Caitlin Reid, Deric M Park, Mark R Gilbert
Journal: Neuro-Oncology (2017)

The use of corticosteroids for therapeutic benefit must be weighed against risks of adverse consequences associated with these drugs. Brain tumor patients are routinely prescribed dexamethasone to reduce tumor-associated edema. Checkpoint blockade, a type of immune therapy, is currently being investigated as a potential treatment for brain tumors. Although glucocorticoid signaling has been shown to attenuate the immune response, the effect of glucocorticoids on the anti-tumor immune response during checkpoint blockade remains unclear. Here, we propose that dexamethasone-induced upregulation of a T-cell checkpoint molecule (i.e. CTLA-4) might be an immunosuppressive mechanism, but can be countered with checkpoint blockade therapy. Healthy donor T cells were tested for response to dexamethasone. T cell proliferation, cell cycle analysis, apoptosis, glucose uptake, and protein expression were assessed with flow cytometry and Western blots. Transcriptional changes were assessed with qPCR. CTLA-4 was blocked using monoclonal antibodies in vitro on human PBMCs and in vivo with the GL261 syngeneic glioblastoma model. CTLA-4 was increased by dexamethasone treatment upon T cell stimulation. Unexpectedly, dexamethasone did not elicit a direct lymphotoxic effect on T cells but significantly reduced T cell cell cycle entry, preventing proliferation. Dexamethasone also abated CD28 signaling as shown by reduced AKT phosphorylation and reduced glucose uptake. Blockade of CTLA-4 resulted in a substantial reversal of these effects. In addition, we discovered that antigen-experienced memory T cells were invulnerable to dexamethasone treatment. In vivo, dexamethasone and CTLA-4 blockade provided a survival benefit to tumor bearing mice. These results suggest that mature T cells, which predominate in the tumor microenvironment, are resilient to the negative effects of corticosteroids. Thus, corticosteroids are unlikely to destroy anti-tumor T cells. For patients who have not responded to immune therapy, CTLA-4 blockade may provide protection from corticosteroids to the naïve T cell pool.
EXTH-23. ANTISECRETORY FACTOR-MEDIATED LOWERING OF INTERSTITIAL FLUID PRESSURE PRODUCES ANTI-TUMOR ACTIVITY IN GLIOBLASTOMA
Authors: Hanna Sabelstrom, Shirin IIkhanizadeh, Yekaterina A Miroshnikova, Aaron Frantz, Wen Zhu, Aurora Idilli, David Quigley, Trenten Fenster, Edith Yuan, Supna Saxena, Janna K Mouw, Jason A Burdick, Sergey Magnitsky, Mitchel S Berger, Daniele Arosio, Dandan Sun, Valerie M Weaver, William A Weiss, Anders I Persson
Journal: Neuro-Oncology (2017)

Glioblastoma (GBM) is among the most aggressive cancers. Although high interstitial fluid pressure presents a barrier to drug uptake, how mechanical stresses and osmotic changes impact tumor biology remains unclear. We show that inhibition of the sodium-potassium-chloride co-transporter 1 (NKCC1) hindered proliferation and invasion of GBM cells. Compressive pressures actually promoted proliferation of GBM, an effect antagonized by the NKKC1 inhibitor bumetanide, which penetrates poorly into brain, or antisecretory factor, a protein that readily accumulates in brain, and has been used clinically. Antisecretory factor reduced IFP in patient-derived GBM xenografts. Both antisecretory factor and bumetanide inhibited osmotic adaptation of cultured GBM cells. In vivo, antisecretory factor reduced tumor growth, increased uptake of chemotherapeutics, and promoted temozolomide-sensitivity in therapy-resistant GBM xenografts. Thus, antisecretory factor represents a novel strategy to improve outcome in GBM patients.
OA 09.06 A Phase Ib Trial of Savolitinib plus Gefitinib for Chinese Patients with EGFR-Mutant MET-Amplified Advanced NSCLC
Authors: J.-. Yang, J. Fang, Y. Shu, J. Chang, G. Chen, J. He, W. Li, X. Liu, N. Yang, C. Zhou, J. Huang, L. Yang, A. Handzel, M. Frigault, G. Ahmed, C. Egile, S. Morgan, Y. Wu
Journal: Journal of Thoracic Oncology (2017)
Infecciones humanas por H5N1 : tantos casos - ¿por qué se sabe tan poco?
Authors: A Nicoll
Journal: Eurosurveillance (2006)

La edicion de este mes contiene un informe sobre agrupaciones o clusters de infecciones humanas por H5N1 en Azerbaiyan. Esto es raro por varias razones. La fuente de infeccion parece ser las aves silvestres, hecho descrito por primera vez. La lectura de los hechos es mas tranquilizadora, pues parece ser que las personas infectadas mataron y desplumaron cisnes infectados. Esto indica que no se trato de una exposicion ocasional a aves silvestres, mas bien se parece cualitativamente a una exposicion estrecha a aves domesticas enfermas, lo que sigue siendo el factor de riesgo mas potente (un estudio analitico reciente revelo un odds ratio de 29).
CBIO-27. INCREASE OF MRNA EXPRESSION OF BOTH FATTY ACID SYNTHASE (FASN) AND CARNITINE PALMITOYLTRANSFERASE 1C (CPT1C) IN STARVED HUMAN GLIOMA CELL LINES
Authors: Tatsuya Abe, Tomihiro Wakamiya, Motofumi Kouguchi, Hiroshi Ito, Yukiko Nakahara
Journal: Neuro-Oncology (2017)

In this previous annual meeting, we reported that both of Fatty acid synthase (FASN) and carnitine palmitoyltransferase 1C(CPT1C) immunohistochemically coexpressed in human gliomas, regardless of the genetic status of isocitrate dehydrogenase 1 (IDH1). FASN and carnitine palmitoyltransferase 1(CPT1) are related to fatty acid metabolism. CPT1C is a brain-specific isoform of CPT1. However, CPT1C is normally found only in the microsomal fraction of neurons, and shows a much lower carnitine acyltransferase activity than other CPT1s. Accordingly, we examined the mRNA expression of FASN and CPT1C in starved human glioma cell lines used by a real-time reverse transcription polymerase chain reaction (RT-PCR). After 48 hours from medium change (glucose concentration: 25mM 17.2mM 12.5mM 0mM), the mRNA levels of both FASN and CPT1C remarkably elevated at the glucose free medium. In conclusion, we observed the mRNA expression of both FASN and CPT1C according to the glucose concentration of these mediums in these starved human glioma cell lines.
Hospital Length Of Stay And Hospitalization Costs For Pulmonary Embolism Comparing Patients Receiving Rivaroxaban Or Warfarin
Authors: J. A. Kline, S. Deitelzweig, J. M. Margolis, M. Raut, O. Tran, D. M. Smith, C. Crivera, B. Bookhart, J. Schein, W. Olson
Journal: American Journal of Respiratory and Critical Care Medicine (2016)
Confounding role of tumor necrosis factor in cryopyrin-associated periodic syndromes
Authors: Balaji Banoth, Fayyaz S. Sutterwala
Journal: Journal of Clinical Investigation (2017)

The NLRP3 inflammasome is a critical component of the innate immune system and can be activated in response to microbial and endogenous danger signals. Activation of the NLRP3 inflammasome results in caspase-1-dependent secretion of the proinflammatory cytokines IL-1β and IL-18. Gain-of-function missense mutations in NLRP3 result in a group of autoinflammatory diseases collectively known as the cryopyrin-associated periodic syndromes (CAPS). CAPS patients have traditionally been successfully treated with therapeutics targeting the IL-1 pathway; however, there are a number of identified CAPS patients who show only a partial response to IL-1 blockade. In this issue of the JCI, McGeough et al. demonstrated that TNF-α, in addition to IL-1β, plays an important role in promoting NLRP3 inflammasomopathies.
(Gd-DOTA)2-KRAS PNA-peptide MRI contrast enhancement in AsPC1 pancreatic xenografts
Authors: Nariman V. Amirkhanov, Ivan Dimitrov, Kaijun Zhang, Mohan R. Aruva, Song Lai, Mathew L. Thakur, Eric Wickstrom
Journal: Cancer Research (2006)

416   Pancreas cancer occurs in about 30,000 US residents per year, with 80% mortality at one year. In 90% of pancreas cancers,  KRAS  oncogene is activated by mutation. Imaging of gene expression non-invasively with high sensitivity and specificity could identify cell malignancy at an early stage and provide a more powerful diagnostic tool than available currently. Non-invasive molecular imaging of gene expression by detection of specific messenger RNAs in cells to diagnose cancer and other diseases in living systems can be accomplished with antisense oligonucleotide derivatives. Peptide nucleic acids (PNA) have great potential for these applications because PNA is resistant to biological degradation and binds complementary mRNA with affinity, specificity, and stability exceeding those of corresponding DNA/RNA duplexes. Internalization of PNA into tumorigenic cells that overexpress insulin-like growth factor 1 (IGF1) receptors can be accomplished with a short IGF1 peptide analog at the C-terminus of PNA. We have previously demonstrated Tc-99m and Cu-64 radioimaging of  KRAS  mRNA in xenografts with chelator-PNA-peptides. Chelating Gd to mRNA-specific DOTA-PNA-peptides might enable MRI of these pathogenic mRNAs in cells and living subjects, following Gd-DOTA-PNA-peptide permeation into tissue, endocytosis into the cells, hybridization with the target mRNA, accumulation in the specific cells, and effluxing of unbound probes. Non-hybridized probes must leave cells with little or no expression of the target mRNA in order to permit a specific image in the targeted cells. The aim of this study was to establish whether a (Gd-DOTA) 2 - KRAS  PNA-peptide dendrimer that we synthesized was taken up by tumors, enabling the use of such chimeras for MRI experiments. We injected 0.10 mL of 1.5 mM (Gd-DOTA) 2 - KRAS  PNA-peptide into the tail vein of an immunocompromised mouse bearing a human AsPC1 pancreatic cancer xenograft. The animal was imaged on a Philips 3T Achieva human MRI system fitted with a small animal solenoid coil (diameter = 4 cm) using THRIVE (3D T1-TFE fat suppressed) with resolution of 0.19 x 0.19 x 1 mm. Imaging parameters were: TR/TE 15/4.6 ms, Flip 10°, TSE factor 80, FOV 60 mm. Imaging 12 slices, with NSA 4, took ∼ 2 min. An initial sharp rise was seen in the concentration of the (Gd-DOTA) 2 - KRAS  PNA-peptide in different organs, followed by a slower decrease of the signal to a common background value at 24 h. A 2.5% higher signal was recorded in the tumor vs. normal muscle from 25 min to 200 min. This suggests that administration of higher concentrations of the (Gd-DOTA) 2 - KRAS  PNA-peptide might allow delineation of normal vs. cancerous tissue  in vivo . Supported by NCI CO-27175.
P1.03-052 Comparing EGFR-TKI with EGFR-TKI plus Chemotherapy as 1st Line Treatment in Advanced NSCLC Patients with Both Mutated EGFR and Bim Polymorphism
Authors: Y. He, C. Zhao, X. Li, S. Ren, T. Jiang, J. Zhang, C. Su, X. Chen, W. Cai, G. Gao, W. Li, F. Wu, J. Li, J. Zhao, F. Zhou, Q. Hu, F.R. Hirsch, C. Zhou
Journal: Journal of Thoracic Oncology (2017)
P2.03-037 Osimertinib in Relapsed EGFR-Mutated, T790M-Negative Non-Small Cell Lung Cancer (NSCLC) Patients: Results from the TREM-Study
Authors: I.J. Eide, Å. Helland, S. Borrisova, S. Ekman, S. Cicenas, J. Koivunen, B.H. Grønberg, O.T. Brustugun
Journal: Journal of Thoracic Oncology (2017)
P3.03-008 Organoid Cultures of Lung Squamous Cell Carcinoma for Drug Screening
Authors: R. Shi, N. Radulovich, M. Cabanero, M. Pintille, V. Raghavan, R. Quevedo, L. Tamblyn, C. Ng, V. Stambolic, T. Pugh, N. Moghal, M. Tsao
Journal: Journal of Thoracic Oncology (2017)
P1.03-027 Randomized Phase 2 Study Comparing CBDCA+PTX+BEV and CDDP+PEM+BEV in Treatment-Naïve Advanced Non-Sq NSCLC (CLEAR Study)
Authors: S. Atagi, H. Udagawa, E. Sugiyama, O. Hataji, F. Tanaka, A. Niimi, H. Kida, Y. Kawa, T. Yamanaka, K. Goto
Journal: Journal of Thoracic Oncology (2017)
Quantity versus Quality
Journal: New England Journal of Medicine (1947)

Over	 the	 past	 decade,	 structural	 changes	 is	 the	 way	 public	 art	 museums	 in	 the	
Netherlands	 are	 funded,	 have	 been	 taking	 place.	 This	 has	 forced	 museums	 to	
reconsider	 their	 economic	 strategies.	 This	 thesis	 explores	 the	 role	 of	 blockbuster	
exhibitions	 in	 this	 strategy,	 by	 placing	 blockbusters	 within	 the	 commercialization	
discussion.	 Through	 three	 case	 studies	 of	 large	 Dutch	 art	 museums,	 it	 looks	 at	
whether	due	to	the	recent	changes,	Dutch	art	museums	have	started	to	rely	more	on	
the	income	of	these	temporary	exhibitions	and	if	they	have	changed	their	exhibition	
policies.	The	paper	concludes	that	although	the	shift	towards	commercial	activities	is	
evident,	the	core	values	if	the	museum	remain	intact.	The	subject	matter	remains	at	
the	 center	 of	 the	 exhibition	 strategies,	 and	 money	 is	 a	 resource	 rather	 than	 an	
objective.	 Blockbusters	 are	 profitable	 for	 art	 museums,	 providing	 then	 with	 more	
stability,	autonomy,	and	the	opportunity	to	experiment.
GENE-26. PREDICTIVE SIGNATURE OF MALIGNANT RECURRENCE IN G-CIMP TUMORS
Authors: Camila Souza, Houtan Noushmehr
Journal: Neuro-Oncology (2017)

Histomorphology and grading schemes are unable to predict glioma relapse and malignant tumor progression. We reported IDH-mutant associated Glioma-CpG Island Methylator Phenotype (G-CIMP) can be further divided into two clinically distinct subtypes independent of neuropathological grading (G-CIMP-high and -low) with evidence of tumor progression. Glioma biomarkers that can predict the risk of progression of G-CIMP-high tumors (favorable survival) to G-CIMP-low tumors (unfavorable survival) are lacking. To find molecular markers of G-CIMP progression, we first defined G-CIMP by analyzing genome-wide DNA methylation data of 181 longitudinal glioma fragments derived from 74 (21 from our own cohort) patient biopsies using the HM450 DNA methylation platform, the Random Forest computational method, and supervised analysis of G-CIMP tumors using either Wilcoxon test or Fisher’s exact test (P < 0.05) and a beta-value difference cutoff of 0.2. We found 134 G-CIMPs out of 181 glioma fragments and then we defined a set of candidate biomarker signature composed by seven hypomethylated CpG sites in primary G-CIMP-high gliomas that undergo malignant progression to WHO grade IV recurrent G-CIMP-low gliomas (n=7) when compared to G-CIMP-high primary gliomas that retain the G-CIMP-high epigenetic profiling through tumor recurrence (n=32) (Fisher-test P < 0.05). Our molecular signature was able to predict the risk to progression to G-CIMP-low tumors in an independent set of TCGA and non-TCGA primary CIMP gliomas (n=79 out of 271; 29%) which associates significantly with patient overall survival (log-rank P value = 0.02, hazard ratio = 2.19). Our study provides insights into the tumorigenic events that may drive G-CIMP malignant recurrence and opportunities for further targeted therapy exploitation and clinical trials design.
SURG-12. INTRAOPERATIVE MAGNETIC RESONANCE SPECTROSCOPY (iMRS) FOR GLIOMA SURGERY
Authors: Takashi Sasayama, Masaaki Kohta, Kazuhiro Tanaka, Masahiro Maeyama, Hiroaki Nagashima, Eiji Kohmura
Journal: Neuro-Oncology (2017)

3-T intraoperative MRI (iMRI) detects residual tumor tissue during glioma surgery and that it helps to increase the extent of resection. However, a differential diagnosis between tumoral and nontumoral tissue at the resection border with T2-hyperintense areas in iMRI images may be difficult. The aim of this study is to examine the usefulness of intraoperative MR spectroscopy (iMRS) to detect the residual glioma tissue. Thirty-four patients with low- and high-grade gliomas underwent iMRI-assisted surgery, including pre- and intraoperative MRS measurements. Single- voxel or multi-voxel proton MRS was performed at the resection margin in the T2-hyperintense areas of iMRI images. Peak areas under the major metabolites resonances (N-acetyl-aspartate: NAA; choline: Cho; and creatine: Cr) were estimated, and their ratios entered in the statistical analysis. The regions of high ratio of Cho/NAA>1 and/or Cho/Cr >1 were performed additional resection. Additionally resected tissues were examined pathologically, including Ki-67 positive index, and evaluated the association with MRS data with pathological findings. Histological grade of all cases were 21 cases with grade 4 (glioblastoma), 3 cases with grade 3, 8 cases with grade 2, 2 cases with grade 1. The average ratio of Cho/NAA, Cho/Cr, and Lac/Cr were 1.44 ± 1.63, 1.41 ± 1.02, 0.68 ± 0.96, respectively. There was no significant difference among WHO grades. In 15 cases with high ratios of Cho/NAA (2.01 ± 0.80) and/or Cho/Cr (2.15 ± 1.32), additional resections were performed. All additionally resected tissues with high Cho/NAA or Cho/Cr had residual tumor cells and high Ki-67 index (8.01 ± 5.65). Finally, gross-total or subtotal resections were achieved in 26 cases with no neurological complications except for one patient with hemiparesis. iMRS could be used to detect residual tumor in T2-hyperintense areas around the resection cavity. iMRS may be helpful tool for an extended tumor resection.
Legionelose em turistas Europeus associada a viagens em Espanha
Authors: A Galmés Truyols, J. F. Martinez Navarro
Journal: Eurosurveillance (1997)

A Doenca dos Legionarios associada a viagens tem causado preocupacao entre os paises europeus desde a segunda metade dos anos 80, por causa da morbilidade nos cidadaos da Uniao Europeia e por causa da ameaca que constitui, para as economias dos paises mediterrâneos, a ocorrencia da doenca entre os turistas. Em resultado, o European Working Group for Legionella Infections (EWGLI) (1) criado em 1986 e coordenado pelo National Bacteriology em Estocolmo ate 1993, quando esse papel foi transferido para o Public Health Laboratory Service Communicable Disease Surveillance Centre em Londres. Os casos notificados foram comunicados pelos paises de residencia dos doentes aos paises que eles tinham visitado.
GENE-55. CONSTITUTIONAL MUTATIONS IN TERT AND MENINGIOMA RISK
Authors: Ivo Muskens, Helen Hansen, Ivan Smirnov, Annette Molinaro, Marike Broekman, Margaret Wrensch, Joseph Wiemels, Elizabeth Claus
Journal: Neuro-Oncology (2017)

Telomere-associated constitutional and somatic variants have been associated with etiology and outcome in glioma but have not yet been studied extensively in meningioma. Constitutional DNA from 275 meningioma patients (Grade I and II) and 1142 controls was evaluated for 1258 preselected telomere associated SNPs using a log-additive model. Odds ratios (OR) and 95% Confidence Intervals were calculated with a Bonferroni-correction applied for multiple testing (p=3.98*10-5). SNPs at 4 different loci were significantly associated with increased meningioma risk: 5q23 (rs739719, p=5.75*10-7, OR:2.08), 10q23 (rs9420907; p=3.23*10-6; OR:1.73, rs911547; p=4.31*10-6, OR:1.70), and 12q12 (rs7956602; p=1.85*10-5, OR:1.575, rs1641528; p=2.15*10-6, OR:1.80), and 17p13 (rs4602096; p=1.91*10-5, OR:1.60). SNPS at loci 10q23 (rs2067832; p=2.28*10-5, OR:0.66, rs9325507; p=2.28*10-5; OR:0.66, rs2273698; p=2.28*10-5, OR:0.66, rs11191865; p=3.66*10-5, OR:0.67) were associated with lower incidence of meningioma. These results are the first to identify an association between meningioma risk and TERT and confirm the previously reported association of chr10 with meningioma risk.
Everolimus-exemestane (EE) vs palbociclib-letrozole (PL) or palbociclib-fulvestrant (PF) in the treatment of metastatic HR+, HER2- breast cancer. Indirect comparisons with network meta-analysis for daily clinical practice
Authors: L. Stocchi, L. Gianni, M. Nicolini, C. Santelmo, O. Carminati, V. Arcangeli, M. Papi, C. Cherubini, A. Polselli, D. Tassinari
Journal: Annals of Oncology (2017)
ACTR-82. LASER INTERSTITIAL THERMAL THERAPY (LITT) OF RECURRENT GLIOBLASTOMA (GBM) INDUCES TEMPORARY DISRUPTION OF THE PERITUMORAL BLOOD BRAIN BARRIER (BBB) AND MAY IMPROVE EFFICACY OF CHEMOTHERAPY WITH POOR CNS PENETRATION
Authors: David Tran, Eric Leuthardt, Joshua Shimony, Albert Kim, George Ansstas, Jian Campian
Journal: Neuro-Oncology (2017)

Inadequate drug delivery across the BBB is a major limiting factor in brain cancer therapy. Since most GBM recurrences occur within the peritumoral region where infiltrating glioma cells reside, peritumoral BBB disruption may help improve drug delivery and efficacy. LITT, a minimally invasive cytoreductive treatment for brain tumors, may disrupt the peritumoral BBB as evidenced by post-ablation contrast enhancement. Forty patients with recurrent bevacizumab-naïve GBM will be equally randomized to weekly low-dose doxorubicin, a BBB-impermeant chemotherapy, either immediately (Early Dox) or 6 weeks after LITT (Late Dox). The degree of post-LITT peritumoral BBB disruption was measured by the vascular transfer constant (Ktrans) in dynamic contrast-enhancement brain MRI. Serum levels of brain-specific enolase (BSE) were quantified as an independent measure of BBB disruption. The primary endpoint is 6-month PFS rate (6-PFS). Peritumoral Ktrans levels peaked immediately post-LITT, followed by a gradual decline for the next 4 weeks. Similarly, serum BSE concentrations increased shortly after LITT and peaked in 1–3 weeks before decreasing to baseline by 6 weeks. For the first 28 evaluable patients, 12 and 16 were randomized to Early and Late Doxo, respectively. Demographic and molecular markers were balanced between the two cohorts. As of 5/16/17, four patients in Early and 2 in Late Dox cohorts have neither progressed nor reached the primary endpoint (range 3–5 months). For those who have reached the primary endpoint, 6-PFS was 75% (6/8) (95% CI: 35–97%) vs. 42.9% (6/14) (95% CI: 18–71%) for the Early vs. Late Dox, respectively (Fisher exact, p=0.156). The only grade 3–4 toxicity was neutropenia observed in 2 (8%) patients. LITT induces temporary peritumoral BBB disruption lasting 4–6 weeks. This window provides a rare opportunity to enhance local delivery of potentially efficacious but BBB-impermeant therapeutic agents. Initial results using doxorubicin trend toward support for this hypothesis.