tbuckley/cabot-search huggingface dataset:
EXTH-48. ORAL GALLIUM MALTOLATE IMPAIRS TUMOR GROWTH AND EXTENDS DISEASE-SPECIFIC SURVIVAL IN A XENOGRAFT MODEL OF RECURRENT GBM
Authors: Mona Al-Gizawiy, Wujek Robert, Hisham Alhajala, Jonathan Cobb, Melissa Prah, Shama Mirza, Christopher Chitambar, Kathleen Schmainda
Journal: Neuro-Oncology (2018)

Recurrent glioblastoma (rGBM) is a distinctly different disease condition than de novo GBM, characterized by chemo- and radioresistance. Consequently, treatment options remain limited. Given our recently published promising results using the novel iron mimetic, gallium maltolate (GaM), in a rat xenograft of de novo GBM, we set out to investigate the effects of oral GaM in an in vivo model of rGBM. Irradiated adult human GBM cells were stereotactically implanted into the right striatum of 12 male athymic rats. Following confirmation of in vivo tumor growth by advanced MRI at 9.4T on day 14 post-implantation, animals received GaM (50 mg/kg/day, n=5) in an oral preparation for voluntary ingestion. Two animals received daily oral GaM continuously throughout the study period, while three underwent a 2-week on, 1-week off treatment cycle. Tumor growth was monitored weekly by MRI, and lesion volume and associated parameter maps were determined using enhancing tumor ROIs. Mean compliance with voluntary ingestion of GaM was 97% (49 mg/kg/day). Complete longitudinal MRI data was available for 5 GaM rats and 5 controls. The mean weekly tumor growth rates of enhancing lesions were 78% and 156% in GaM-treated and control animals, respectively (p=0.006). Median disease-specific survival was 28 days in controls and 49 days in GaM-treated animals, with 3/5 treated animals still alive (p=0.004). Preliminary histological findings in GaM-treated tumor tissue indicate treatment effect (swollen cells, degeneration and/or granulation of cytoplasm) and apoptotic cells throughout the lesions, compared to pseudopalisading necrosis and standard tumor cell size in control tissues. No adverse physiological effects due to treatment were noted. We presented compelling evidence that oral GaM significantly impairs tumor growth and extends disease-specific survival in a xenograft model of rGBM. We propose that GaM shows great promise as a new interventional strategy for GBM therapy.
NIMG-64. A CLINICAL RULE FOR PREOPERATIVE PREDICTION OF BRAF MUTATION STATUS IN CRANIOPHARYNGIOMAS
Authors: Shingo Fujio, Tareq Juratli, Kazunori Arita, Hirofumi Hirano, Yushi Nagano, Tomoko Takajo, William Curry, Pamela Jones, Maria Martinez-Lage, Daniel Cahill, Fred Barker, Priscilla Brastianos
Journal: Neuro-Oncology (2018)

Papillary craniopharyngiomas are characterized by BRAF V600E mutations. Targeted therapy can elicit a dramatic radiographic regression of these tumors. Therefore, prediction of BRAF mutation status before definitive surgery could enable neoadjuvant treatment strategies. The aim of this study was to establish preoperative prediction criteria to identify patients with a BRAF mutant craniopharyngioma. Sixty-four patients with craniopharyngioma were included in this study. We determined BRAF mutation status by targeted sequencing. After scoring inter-observer variability between pre-surgical clinical data and radiographic features, we established a diagnostic rule for BRAF mutation in our discovery cohort. We then validated the rule in an independent cohort. The BRAF V600E mutation was detected in 12 of 42 patients in the discovery cohort. There were no patients under age 18 with BRAF mutation. Calcification was rare in tumors with BRAF mutation (P < .001), and 92% of them were supradiaphragmatic in location. Combining these three features older than 18 years, absence of calcification, and supradiaphragmatic tumor location we established a rule for predicting BRAF mutation. In cases where all three criteria were fulfilled, the sensitivity and specificity for the presence of BRAF mutation was 83% and 93%, respectively. In the validation cohort (n=22), the sensitivity was 100% and specificity was 89%. We propose predictive criteria for a BRAF mutation in craniopharyngioma using preoperative clinical and radiographic data. This rule may be useful in identifying patients who could potentially benefit from neoadjuvant BRAF V600E targeted systemic therapies.
Abstract 20481: Impact of Insurance Type on Eligibility for Advanced Heart Failure Therapies and Survival
Authors: Alanna A Morris, Rachel Patzer, William Schultz, Celena Halladay, Divya Gupta, Duc Nguyen, S. Raja Laskar, J. David Vega, Andrew Smith, Victoria Phillips
Journal: Circulation (2016)

Background: Medicaid patients with advanced heart failure (HF) rarely receive left ventricular assist devices (LVAD) at our center due to significant reimbursement constraints from the Georgia Depa...
GENE-32. ASSOCIATION OF OLIGODENDROGLIAL MORPHOLOGY, MOLECULAR FACTORS AND OVERALL SURVIVAL IN PATIENTS WITH LOWER GRADE GLIOMAS
Authors: Eriel Pareira, Makoto Shibuya, Kentaro Ohara, Yu Nakagawa, Tokunori Kanazawa, Dai Kamamoto, Kazunari Yoshida, Hikaru Sasaki
Journal: Neuro-Oncology (2018)

Presence or absence of 1p/19q codeletion is more closely associated with clinical outcome as well as the biology of tumor than histological diagnosis in lower grade gliomas (LrGGs). Nonetheless, it is still controversial if classic oligodendroglial morphology might be relevant to patients’ prognoses. The subjects were institutionally-diagnosed grade II-III gliomas resected at Keio University Hospital from 1990 through 2016. Biopsy cases were excluded. The tumors were reassessed according to WHO 2007 classification. Presence or absence of the classic oligodendroglial features (classic for oligodendroglioma, CFO) was also assessed. The association between either pure oligodendroglioma diagnosis or presence of CFO and patients’ survival or any of the molecular factors including copy number aberration (CNA) status, IDH mutations, ATRX mutations, and TERT mutation were assessed. 94 LrGGs were included in the study. There was only 36% concordance between the original institutional histological diagnosis and the reassessment. In the IDHmut/Codel tumors, there was no molecular factors that was associated with pure oligodendroglial diagnosis, CFO status or overall survival (OS). Interestingly, we found longer OS in pure oligodendroglial diagnosis (p= 0.023). In the IDHmut/Noncodel tumors, some molecular factors (ATRXmut, TERTmut, gain of 8q) were associated with pure oligodendroglial diagnosis, but not with CFO. In the IDHwild tumors, some CNAs were associated with longer OS, however, there was no molecular factors associated with either pure oligodendroglial diagnosis or CFO. The pure oligodendroglioma histology might be associated with better OS in patients with IDHmut/Codel LrGGs but not in those with IDHmut/Noncodel or IDHwild LrGGs.
CMET-18. RISK FACTORS FOR CEREBRAL EDEMA AFTER STEREOTACTIC RADIOSURGERY FOR BRAIN METASTASES
Authors: Ali Alattar, Brian Hirshman, Rushikesh Joshi, Clark Chen
Journal: Neuro-Oncology (2018)

Adverse radiation effect (ARE) after stereotactic radiosurgery (SRS) for brain metastasis (BM) patients is a dreaded complication that often leads to significant compromise in the patient’s quality of life. Here, we sought to determine risk factors associated with ARE following SRS. We identified 214 BM patients (1,106 BM) treated between 2007 and 2017 at our institution with > 3 months of MRI follow up. We collected pertinent demographic, clinical, and SRS parameters. ARE was defined as the presence of FLAIR hyperintensity in > 25% of the area of any of four axial MRI images defined by 1) the centrum semiovale, 2) third ventricle, 3) temporal horns, and 4) the fourth ventricle. Statistical analysis was carried out using Student’s t-test, Pearson’s chi-squared test, and univariate and multivariate logistic regression. Of the 214 patients, 62 patients (28.97%) suffered ARE following SRS. On univariate logistic regression, the odds of ARE were increased with higher cumulative intracranial tumor volume (CITV) (odds ratio (OR) 1.026 per 1 cm3 increase, 95% CI 1.009 - 1.043, p= 0.003), > 4 rounds of SRS sessions (OR 9.545, 95% CI 1.924 - 47.352, p=0.006), and prior history of whole-brain radiation therapy (WBRT) (OR 4.459, 95% CI 2.233 - 8.907, p< 0.001). On multivariate logistic regression adjusted for length of follow-up, these associations remain robust: CITV (p=0.036), > 4 rounds of SRS (p=0.033), and prior history of WBRT (p< 0.001). Variance analysis indicated that the relative importance of these risk factors in contributing to ARE, in descending order, is: prior history of WBRT, CITV, and > 4 rounds of SRS. In this analysis of our decade-long experience, we discovered three risk factors for ARE, including prior history of WBRT, increasing CITV, and > 4 rounds of SRS. Consideration of these factors should facilitate patient counseling and clinical decision making.
Intravascular Ultrasound Versus Angiography-Guided Drug-Eluting Stent Implantation
Authors: Junjie Zhang, Xiaofei Gao, Jing Kan, Zhen Ge, Leng Han, Shu Lu, Nailiang Tian, Song Lin, Qinghua Lu, Xueming Wu, Qihua Li, Zhizhong Liu, Yan Chen, Xuesong Qian, Juan Wang, Dayang Chai, Chonghao Chen, Xiaolong Li, Bill D. Gogas, Tao Pan, Shoujie Shan, Fei Ye, Shao-Liang Chen
Journal: Journal of the American College of Cardiology (2018)
PATH-29. CLINICAL SIGNIFICANCE OF TEMOZOLOMIDE-INDUCED SOMATIC HYPERMUTATION IN INITIALLY LOW-GRADE IDH-MUTANT DIFFUSE GLIOMAS
Authors: Yao Yu, Stephanie Hilz, Matthew Grimmer, David Solomon, Serah Choi, Michael Wahl, Tali Mazor, Chibo Hong, Anny Shai, Joanna J Phillips, Javier Villanueva-Meyer, Michael McDermott, Daphne Haas-Kogan, Jennie Taylor, Nicholas Butowski, Jennifer Clarke, Mitchel Berger, Annette Molinaro, Susan Chang, Joseph Costello, Nancy Ann Oberheim Bush
Journal: Neuro-Oncology (2018)

Diffuse low-grade gliomas (DLGG) treated with temozolomide (TMZ) can develop somatic hypermutation. We present data on the incidence and prognostic importance of somatic hypermutation in IDH-mutant DLGGs. We analyzed 120 patients treated on a phase II clinical trial of TMZ for sub-totally resected DLGGs to estimate the risk of recurrence and transformation after TMZ. To understand the prognostic significance of somatic hypermutation, we determined hypermutation status by exome or targeted sequencing on tumors from 81 patients with recurrent IDH-mutant DLGGs. 63/81 patients received TMZ before recurrence, including 28 patients treated on-trial. With median follow-up of 8.7 years, 89 patients from the phase II trial progressed, 60 underwent 1 re-operation, and 36 had histologically confirmed transformation. The 8-year freedom from transformation was 48.2% and 59.9% for IDH-mutant astrocytomas and oligodendrogliomas, respectively; risk of transformation increased with pre-TMZ tumor volume (HR 2.5 per 100cc, p<0.001). In the recurrent glioma cohort, 65/81 patients transformed to grade III or IV; hypermutation was identified at transformation in 30/53 (57%) treated with TMZ. Hypermutation occurred in 31 patients all had received TMZ and 30/31 had developed transformed tumors. Analyzing by specimen, hypermutation was associated with transformation (bootstrapped logistic regression p < 0.001). After transformation to grade III disease (n=47), hypermutation was associated with diminished survival (HR 5.6, p=0.007), controlling for molecular subtype and age at diagnosis. Patients with transformation to glioblastoma (n=18) had poor prognosis regardless of hypermutation (p=0.53). Four cases of spinal dissemination were identified, all of whom had hypermutated gliomas. CONCLUSIONS: Somatic hypermutation is common in transformed, initially low grade IDH-mutant diffuse gliomas treated with TMZ. After anaplastic transformation, somatic hypermutation is associated with reduced survival, independent of molecular subtype. These data have implications for the management of newly diagnosed and recurrent DLGG, and indicate a potential role for immunotherapy.
Prognostic Value of Clone Size in Paroxysmal Nocturnal Hemoglobinuria (PNH) for Thrombotic Events in Untreated Patients in the International PNH Registry
Authors: Regis Peffault De Latour, Jaroslaw P. Maciejewski, Austin G. Kulasekararaj, Loree Larratt, Ronald S. Go, David Dingli, Amanda Wilson, Philippe Gustovic, Aleksandr Kulagin
Journal: Blood (2018)
PDCT-12. A PHASE I TRIAL OF TUMOR TREATING FIELDS WITH AND WITHOUT CONCOMITANT TEMOZOLOMIDE AND BEVACIZUMAB IN PEDIATRIC PATIENTS WITH HIGH-GRADE GLIOMA AND EPENDYMOMA
Authors: Derek Hanson
Journal: Neuro-Oncology (2018)

High-grade gliomas (HGG) comprise 8–12% of brain tumors in children and include anaplastic astrocytoma or glioblastoma multiforme (GBM) pathology. Ependymoma is the third most common pediatric brain tumor accounting for 5–10% of all diagnoses. Treatment for these tumors involves surgical resection, adjuvant radiation and chemotherapy. The prognosis for high-grade glioma and recurrent ependymoma is poor and new therapies must be investigated to improve clinical outcomes for these patient populations. Tumor treating Fields (TTFs) is a non-invasive antimitotic treatment comprised of low-intensity alternating electric currents delivered through the Optune device approved for adults with GBM. This phase 1 study [NCT03128047] will include 2 cohorts of pediatric patients (N= 6–12), age ≥1 and <18 years, with histologically-confirmed supratentorial newly-diagnosed or recurrent HGG and recurrent ependymoma. This study will have two safety endpoints to assess the safety and tolerability of TTFs for the treatment of pediatric HGG and ependymoma both alone and in combination with temozolomide (TMZ) and bevacizumab (BEV). Cohort 1 patients with recurrent HGG or ependymoma will receive TTFs (200 kHz 18 hours/day). Cohort 2 patients with newly-diagnosed or recurrent HGG or recurrent ependymoma will receive TTFs plus BEV 10 mg/kg/dose and TMZ 200 mg/m2/day. Safety endpoints will be determined by a standard 3 + 3 phase I study design based on the incidence and severity of adverse events and toxicities (CTCAE V4). There are no primary efficacy endpoints for this study. Patients will be followed to assess their progression-free and overall survival as the efficacy data gained from this study may be useful in designing future phase II/III investigations. The sample size will be determined by the number of observed severe adverse events related to therapy. A minimum of two and a maximum of twelve patients will be needed to complete this study.
Abstract 16185: Ang-(1-7) Corrects CD34+ Endothelial Progenitor Cell (EPC) Dysfunction from Patients with Heart Failure
Authors: Sugata Hazra, Colleen T Cole-Jeffrey, Carl J Pepine, Michael J Katovich, Maria B Grant, Mohan K Raizada
Journal: Circulation (2012)

Introduction: Circulating EPC numbers are reduced in patients with cardiovascular disease (CVD) however, less is known about the functional capabilities and reparative potential of these cells. The...
CBMT-27. PROTEOMIC MAP OF GLIOMA BIOPSIES REVEALS FUNCTIONAL DEFECTS IN ENDOCYTOSIS
Authors: Jean-Louis Boulay, Marie-Françoise Ritz, Gregor Hutter, Cristobal Tostado, Dominik Buser, Martin Spiess, Stephan Frank, Paul Jenö, Luigi Mariani
Journal: Neuro-Oncology (2018)

Decades of molecular genetic analyses have shown that gliomas accumulate genetic alterations that result in the enhanced activity of growth factor receptor tyrosine kinases (RTKs) and mediators of downstream pathways. Among them are gain-of-function of EGFR, PDGFR, PIK3CAor BRAF, and loss-of-function of PTEN or NF1, resulting in exacerbated proliferative responses. We performed deep proteomic analysis of human gliomas of distinct genetic backgrounds, i.e. IDH, TERT statuses in combination with EGFR or PDGFRA amplification. Mass spectrometric analysis confirmed the R132H mutation in the IDH-mutant biopsies. Proteomic quantification not only revealed strikingly high levels of EGFR protein in biopsies carrying EGFR amplification when compared to control biopsies from white matter, but also overexpression of EGFR irrespective of EGFR copy number status, genetic background, tumor histology or grade. Furthermore, proteomic data and Western blot analysis showed a general decrease in the expression of core components of clathrin-mediated endocytosis, like adaptin (AP2), clathrin (CLT) and dynamin (DNM) in tumors of all genotypes, histology or grades. Functional binding assays in two primary cell lines yielded identical binding of transferrin to its receptor, even though one contained much reduced transferrin receptor levels. This clearly shows that reduced endocytosis leads to prolonged residence time of receptors on the plasma membrane. CONCLUSION: These three groups of proteins are indispensable for clathrin-mediated endocytosis and inactivation of growth factor receptors. Thus, loss of endocytosis proteins increases the availability of RTKs at the plasma membrane by prolonging growth factor signaling, leading to a selective advantage in tumorigenesis and progression. We are currently performing electron microscopy to visualize impaired clathrin vesicle formation in glioma cell lines and extending our uptake assay to RTKs like EGFR. Further, we are currently investigating on a general endocytosis gene shut down in gliomas by epigenetic silencing.
The Development of Kraepelin’s Mature Diagnostic Concepts of Paranoia (<i>Die Verrücktheit</i>) and Paranoid Dementia Praecox (<i>Dementia Paranoides</i>)
Authors: Kenneth S. Kendler
Journal: JAMA Psychiatry (2018)

Over 12 years (1887-1899), in his second through sixth editions of his textbook<i>Psychiatrie: Ein Lehrbuch für Studierende und Ärzte</i>, Emil Kraepelin created, through an iterative, self-examining process, his mature concepts of<i>Verrücktheit</i>(paranoia) and<i>Paranoide Formen Dementia Praecox</i>. I seek in this essay to show this skilled nosologist at work. Four themes were prominent. First, Kraepelin used symptoms throughout, but he transitioned from superficial phenomenon (delusional themes) to those he considered more pathognomonic: disorganized fantastical delusions vs organized, nonbizarre delusions. Second, he increasingly emphasized the distinction between delusions arising from misinterpretations of real events vs delusions arising from hallucinations. Third, the putative causes of the disorder became more important as he came to understand<i>Verrücktheit</i>from a psychological and developmental perspective, whereas<i>dementia paranoides</i>(the precursor to<i>paranoide formen dementia praecox</i>) resulted from pathological brain changes. Fourth, Kraepelin appreciated the importance of disease course, but he initially lacked adequate data to elucidate it. As his research program developed, he used the well-recognized disease of general paralysis of the insane as a paradigm and correlated symptoms, modes of delusion formation, and presumed mechanisms of disease with course and outcome. Patients with slowly developing, referential, nonbizarre delusions without hallucinations were typically stable for years with minimal deterioration. Patients with rapidly developing, poorly organized, fantastical delusions emerging from prominent hallucinations tended to deteriorate quickly. Using conceptual tools first proposed by Kahlbaum and Hecker, Kraepelin developed his concepts of<i>Verrücktheit</i>and paranoide formen dementia praecox using an exploratory, conceptual, and data-gathering process in which each syndrome was defined in contrast to the other and, in addition to a core focus on disease course, multiple additional levels of clinical inquiry were included.
EXTH-72. MP-Pt(IV): A MAOB SENSITIVE MITOCHONDRIAL SMART BOMB FOR TREATING GLIOMA
Authors: Martyn Sharpe, David Baskin, Sudhir Raghavan
Journal: Neuro-Oncology (2018)

We have previously demonstrated that monoamine oxidase B (MAOB), highly elevated in glioma, may be used to catalytically convert uncharged methyl-tetrahydropyridine (MP-) groups into the mitochondrial targeted, cationic, methyl-pyridinium (P+-) form. Our first generation mitochondrial ‘smart-bomb’, MP-MUS, used a nitrogen mustard ‘warhead’, and was demonstrated to attach glioma mitochondrial DNA in vitro and in vivo. The development of our lead compound into a clinically used therapeutic was hampered by the reactivity of the nitrogen mustard ‘warhead’ and thus the potential of off-target toxicity. We now report our second generation lead compound, MP-Pt(IV), in which we replaced the reactive nitrogen mustard with an unreactive platinum (IV) group. This new ‘warhead’ was designed to undergo ascorbate-linked reductive activation so as to give rise to cis-platin, DNA-crosslinking chemotherapeutic, that will be able to attack gliomal mitochondrial DNA. MP-Pt(IV) is a very good substrate for MAOB, but not MAOA, and is converted by gliomal MAOB into the cationic, lipophilic mitochondrial targeting P+-Pt(IV). The principle biological reductant capable of converting Pt(IV) into cis-platin is ascorbate. We show that gliomas have high levels of mitochondrial ascorbate, and these elevated levels of ascorbate reflect the elevation of glucose/dehydroxyascorbate transporters, GLUT1, GLUT 3, and GLUT4. Here we show that MP-Pt(IV) is highly effective chemotherapeutic, in in vitro as well as in vivo mouse intracranial mouse models of glioblastoma. In vitro studies show that we can potentiate the toxicity of MP-Pt(IV) by increasing mitochondrial ascorbate levels, by incubating cells with dehydroxyascorbate. In an in vivo model, we see that MP-Pt(IV) potentiates the classical chemotherapeutic agent temozolomide and also temozolomide based chemoradiation. Of note is the ability of MP-Pt(IV), like MP-MUS, to cause an elevation in mitochondrial, MAOB levels in treated cells. Treatment of glioma with MP-Pt(IV) creates the opposite of drug resistance, with treating cells becoming increasingly sensitive to MP-Pt(IV).
Commercialised portable intravenous fluids in sports: placing vulnerable athletes at risk
Authors: Morteza Khodaee, Bradley G Changstrom, Martin D Hoffman
Journal: British Journal of Sports Medicine (2018)

Provision of intravenous fluids outside of medical facilities has become an expanding business in the USA, and for several years has been marketed for pre-event and postevent hydration at various sporting events, including mass events like marathons.1 These ‘for-purchase on-demand’ intravenous services are marketed to enhance performance and postevent recovery. Typically administered in a tent or a mobile station by a nurse under the licensure of a physician, little or no preintervention medical assessment is involved.

Since the composition of intravenous fluids can be easily reproduced in oral solutions, the benefit of intravenous fluids lies in circumventing delays with absorption of oral fluids.2 These delays can be strictly related to intestinal absorption in a healthy athlete or delays related to gastrointestinal distress (eg, vomiting or diarrhoea) in an ill athlete. Intravascular plasma volume expansion with intravenous fluids in a healthy athlete is only transiently increased when compared with oral rehydration and the benefit probably lasts for 35 min or less.2 …