Search

Imaging response assessment is a cornerstone of patient care and drug development in oncology. Clinicians/clinical researchers rely on tumor imaging to estimate the impact of new treatments and guide decision making for patients and candidate therapies. This is important in brain cancer, where associations between tumor size/growth and emerging neurological deficits are strong. Accurately measuring the impact of a new therapy on tumor growth early in clinical development, where patient numbers are small, would be valuable for decision making regarding late-stage development activation. Current attempts to measure the impact of a new therapy have limited influence on clinical development, as determination of progression, stability or response does not currently account for individual tumor growth kinetics prior to the initiation of experimental therapies. Therefore, we posit that imaging-based response assessment, often used as a tool for estimating clinical effect, is incomplete as it does not adequately account for growth trajectories or biological characteristics of tumors prior to the introduction of an investigational agent. Here, we propose modifications to the existing framework for evaluating imaging assessment in primary brain tumors that will provide a more reliable understanding of treatment effects. Measuring tumor growth trajectories prior to a given intervention may allow us to more confidently conclude whether there is an anti-tumor effect. This updated approach to imaging-based tumor response assessment is intended to improve our ability to select candidate therapies for later-stage development, including those that may not meet currently sought thresholds for “response” and ultimately lead to identification of effective treatments.

Chapter 8 focuses on the United Arab Emirates (UAE), led by Mohamed bin Zayed, and its newly assertive power projection strategy that includes establishment naval and military bases on the Red Sea, in the chokepoints of the Bab al-Mandab one of the most important global shipping lanes and the Gulf of Aden and its littoral territory—the arid nations of Djibouti, Eritrea, and Somalia to achieve dual geostrategic and economic goals including the acquisition of operational and management rights over ports and economic zones. The theoretical framework used in this chapter to asses foreign policy change employs simultaneous levels of inquiry taking into account regional and systemic effects, domestic influences, and the role of leadership adding to the literature on international relations and the Middle East in two distinct ways (1) by addressing understudied theoretical questions concerning foreign policy change in small states and (2) exploring the nature and motivations of the emerging trend of securitizing waterspace and shipping lanes in the Middle East.

Middle powers rise at times of instability in the international or regional orders. Two sets of middle powers, namely the traditional and the so-called “emerging” middle powers, came to being during and after the Cold War, respectively. On the one hand, traditional middle powers, such as Australia and Canada, emerged during the Cold War. On the other hand, emerging middle powers ascended after the Cold War, and are not the traditional “good citizens” but controversial reformists with independent foreign policy portfolios, and they are becoming increasingly vocal in world affairs.

BACKGROUND Ivosidenib (AG-120, IVO) is a first-in-class oral inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), and vorasidenib (AG-881, VOR) is an oral, potent, brain-penetrant inhibitor of mIDH1/2. Both have been evaluated in glioma patients in ongoing phase 1 studies. In orthotopic glioma models, IVO and VOR reduced 2-hydroxyglutarate (2-HG) levels by 85% and 98%, respectively, despite different brain-to-plasma ratios (< 0.04 vs 1.33). METHODS Patients with recurrent, nonenhancing, WHO-2016 grade 2/3, mIDH1-R132H oligodendroglioma or astrocytoma undergoing craniotomy were randomized 2:2:1 to IVO 500mg QD, VOR 50mg QD, or no treatment (cohort 1), or 1:1 to IVO 250mg BID or VOR 10mg QD (cohort 2), for 4 weeks preoperatively. Postoperatively, patients continued receiving IVO or VOR (control patients were randomized 1:1 to IVO or VOR). Tumors were assessed for mIDH1 status, cellularity, and 2-HG and drug concentrations. Treated subjects were compared with controls and mIDH1/wild-type banked reference samples. Primary endpoint: tumor 2-HG concentration following IVO or VOR. RESULTS As of March 1, 2019, 27 patients (18 men; 25/2 grade 2/3) were randomized preoperatively in cohort 1 (IVO 10, VOR 12, untreated 5): 27 received drug (IVO 13, VOR 14); 1 discontinued VOR postoperatively due to disease progression. Of 26 tumors analyzed, 22 were evaluable. Mean brain-to-plasma ratios: 0.13 IVO, 1.59 VOR. Relative to untreated samples, IVO and VOR reduced tumor 2-HG by 92.0% (95% CI 73.2, 97.4) and 92.5% (95% CI 78.1, 97.7), respectively. Common (≥ 4 patients) TEAEs (all cohort 1 patients, all grades): diarrhea (37.0%), constipation, hypocalcemia, and nausea (each 18.5%), anemia, hyperglycemia, pruritus, headache, and fatigue (each 14.8%). Cohort 2 has completed accrual, with analyses ongoing. CONCLUSIONS In cohort 1 of this phase 1 perioperative study, IVO and VOR demonstrated brain penetrance and lowered 2-HG compared with controls. Updated data from both cohorts will be presented.

This chapter examines the question of how the ruling family proactively continues to consolidate its own position within Qatari society. The state adopts three primary means to reproduce and stimulate the existing inclusion and exclusion schemes in Qatari society. First, it promotes the dominant Arab social values, culture, traditions, and customs that perpetuate a scheme of inclusion and exclusion and secure the position of the ruling family and Arab tribal social actors at the apex of the social hierarchy of the state. Second, it narrows down the definition of national identity in order to limit vertical social mobility in society only to certain tribal families. Third, through articles of the Constitution, the legal system and implicit family policies related to marriage and nationality, the state has been influencing individuals, insofar as marriage choices are concerned, as a further means of preventing social mobility to wider strata of society.

A precise clinically relevant characterization of glioblastoma (GBM) heterogeneity and underlying genomic variability is urgently needed. To evaluate the true potential of radiogenomics, an emerging field for GBM research, we have tested its scope in a pre-clinical setting. First, glioblastoma stem cells (GSCs) are altered to express decreased levels of Periostin (POSTN), previously identified in a radiogenomic screen as a key pro-invasive gene. Second, orthotopic tumors arising from these GSCs, were scanned and analyzed to identify gene specific MRI texture feature (MRTF) signatures, which can simultaneously predict POSTN status in GBM patients. Doxycycline inducible short hairpin RNA mediated knockdown of POSTN in GSC lines were established. 5X10^6 cells were stereotactically implanted in nude mice frontal cortex and randomized into POSTN knockdown and control groups. Monitored tumor growth longitudinally by MRI (n = 3-4 per group). Region of interest (ROI) methods were applied to the rigid registration images based on axial T1-weighted imaging and corresponding fluid-attenuated inversion recovery sequences. After pre-processing, gray level co-occurrence matrices (GLCMs) were generated in 4 angular directions and 3 invariant measures (mean, range and angular variance) of each texture feature is calculated. A matrix of 3x20 invariant features is generated for each gray level. Mean values of normalized MRTFs from edema T1 post and T2, subgroup tumors arising from independent GSCs (p

BACKGROUND: FMRI maps commonly show multiple areas of false positive activity. We aimed to identify areas of true fMRI activation by using complex MRI texture analysis (TA) of raw EPI data, thus enhancing the identification of true activity. METHODS: 12 right handed healthy volunteers were recruited (IRB approved). All scans were performed on a 3.0T GE MR scanner. FMRI consisted of a high resolution 3D T1 weighted structural scan and a gradient echo EPI functional scan. FMRI data analysis was performed using SPM8 software for a sentence completion block design task. T map for each individual was displayed using xjview toolbox and thresholded individually to optimize visualization of language area. Each activity cluster was selected and saved. Board-certified neuroradiologists and neuroscientists classified different clusters into two separate groups Expected (E) and Non Expected (NE) based on their anatomical locations. TA was performed using the mean EPI volume for each individual, and 20 invariant texture features were obtained. Efficacy of TA in fMRI was assessed by decision tree and validated using a 4 fold cross validation. RESULTS: fMRI areas of activity in individual scans were identified based on their texture features with 95.3% accuracy, sensitivity 95.3% and specificity 95.3%. Sum of Variance, Cluster shade, sum of average and information measure of correlation were the most important texture features. These features had higher texture values in the NE ROIs indicating more homogeneous areas. Texture features were able to significantly differentiate areas of true versus false activity. CONCLUSIONS: Extracted features indicated that true activity has more heterogeneous texture compared to non-expected activity Quantitative TA of functional MRI using texture feature can enhance the accuracy and sensitivity of the test to true activity and help eliminate false activation

Dexamethasone is routinely administered to manage cerebral edema in glioblastoma (GBM). Its impact on molecular mechanisms driving GBM invasion is unknown. Utilizing radiogenomic strategies, we previously introduced Periostin as key mediator of GBM associated edema and cellular invasion. We observed that multiple molecular targets of Dexamethasone are significantly upregulated and overlap with Periostin correlated genes, including CEBPB. We hypothesized that Dexamethasone, by regulating Periostin correlated genes, promotes a mesenchymal program of tumor cells including Glioblastoma Stem Cells (GSCs). A panel of GSCs were profiled for Periostin correlated genes after Dexamethasone treatment, using microarray, qPCR and Western blotting. Tests for self-renewal (limiting dilution assay), differentiation (neural lineage marker analysis), invasion (Boyden chamber) and proliferation (BrdU) were performed after Dexamethasone exposure. Three independent GSC lines were used to generate orthotopic tumors and mice were then treated with Dexamethasone (intraperitoneal). Differentially expressed genes in GSC derived tumors (total RNA from cells of human origin were isolated using human specific Anti- HLA Class I ABC antibody by FACS) upon Dexamethasone exposure were evaluated with connectivity map (cmap) to screen for specific therapeutics. Cells treated with Dexamethasone showed an increased CEBPB expression, indicating a more aggressive mesenchymal gene signature. Histopathologic validation of orthotopic tumors supported this effect of Dexamethasone. Treatment with specific, FDA approved therapeutics in combination with Dexamethasone suppressed Periostin correlated gene levels and subsequently reduced this mesenchymal shift. In this preclinical study we showed that Dexamethasone promotes a molecular mesenchymal shift by elevating CEBPB expression levels in both, in vitro and in vivo. These results warrant an evaluation of Dexamethasone for managing edema in glioblastoma patients. Neutralizing side effects of Dexamethasone by adding our shortlisted drugs may improve GBM patient care.