tbuckley/cabot-search huggingface dataset:
CBMT-45. A NOVEL C-CIRCLE ASSAY FOR DETECTING ALTERNATIVE LENGTHENING OF TELOMERES (ALT) MECHANISMS
Authors: Humaira Noor, Robert Rapkins, Jeremy Henson, Kerrie McDonald
Journal: Neuro-Oncology (2018)

Low-grade gliomas, in particular astrocytoma, have been previously reported to harbor Alternative lengthening of telomere (ALT) to maintain their telomeres to aid sustained replication. Targeting genetic pathways specific to ALT mechanism is crucial in developing novel drugs to minimise recurrence and improve prognosis in low grade glioma patients. Herein, we used a novel C-circle assay to identify ALT positivity in a local, retrospective cohort of astrocytoma and oligodendroglioma, where matched primary and recurrent tumors were available. We identified a retrospective cohort of 25 patients with grade II or III astrocytomas (n=17) or oligodendrogliomas (n=8) where matched tissue from recurrences were available. DNA was extracted and a novel C-circle assay was used to determine the ALT status of the primary and recurrent tumors. Approximately 77% (13 out of 17) astrocytomas were positive for ALT. Only 25% (2 out of 8) oligodendrogliomas were ALT positive. LOH 1p/19q was confirmed in these cases. Patients who were ALT positive showed longer overall survival. We found a significant association with ALT and IDH1 mutation status and mutations in TP53. In conclusion, the C-circle assay provides a robust and quantitative measure of ALT and could be incorporated into routine clinical use.
TMIC-02. INTERACTION OF LIGAND CONJUGATED QUANTUM DOTS WITH THE GLIOMA STEM CELL SECRETED EXOSOMES AND SUBSEQUENT UPTAKE BY THE GLIOMA STEM CELLS OF VARIOUS SUBTYPES
Authors: A B Madhankumar, Oliver Mrowczynski, Becky Slagle-Webb, Abraham Thomas, Brad Zacharia, Akiva Mintz, James Connor
Journal: Neuro-Oncology (2018)

Glioblastoma tumors are known to secrete an enormous number of exosomes with various molecular signatures. Some recent studies also demonstrate that the exosomes secreted by the glioma initiating cells or glioma stem cells carry differentially expressed mRNA, miRNA and protein that would impart radiation and chemo-resistance to the adjacent non-stem cancer cells. It is important to investigate the exosome secretion profile by the cancer stem cells and their re-uptake profile by the glioma cells belonging to various subtypes in the vicinity of tumor. In our earlier study we identified that exosomes from glioma stem cells express a tumor associated IL13Rα2 that could bind with interleukin 13 conjugated quantum dots (QD), which can be subsequently profiled by various physico-chemical methods. In our recent investigation we observed that a mutated form of IL-13, TQM13, can be conjugated with QD and can complex with exosomes. These QD-bound exosome can subsequently be monitored by fluorescent microscopy utilizing the intrinsic fluorescence property of the quantum dots. In our present investigation,TQM13-QD was complexed with exosomes that originated from glioma stem cells from mesenchymal (T387) and proneural (T3691) subtypes. Various glioma cell lines such as U87, T3691 and T387, and Jurkat cells, an immortalized T-lymphocyte cells, were then treated with the TQM13-QD:exosome complex. Our investigation revealed that cells had a higher uptake of the TQM13-QD upon complexation with exosomes when compared to quantum dots without exosome complexation. In vivo experiments were subsequently performed by injecting T3691 exosomes complexed with TQM13-QD in U87-Luc cells which were implanted as an orthotopic glioma tumor mouse model. Intravital imaging spectroscopy (IVIS) images confirmed the localization of TQM13-QD: exosome complex in the tumor region as early as 60 minutes post injection. Current studies are investigating the mechanism of uptake of TQM13-QD complexed with fluorescently labeled exosomes and quantifying their uptake.
Abstract 18897: Extracellular Signal-related Kinase Signaling and Smooth Muscle Cell Contractile Gene Expression are Uniformly Enhanced in the Aortic Root and Ascending Aorta in Marfan Syndrome
Authors: Albert J Pedroza, Tiffany K Koyano, Jeffrey Trojan, Itai Palmon, Mamoru Arakawa, Kiril Penov, Michael P Fischbein
Journal: Circulation (2015)

Introduction: Enhanced TGF-β signaling drives aortic root aneurysm development in Marfan syndrome (MFS) via the non-canonical (ERK) pathway in murine models, but ERK not been studied in human tissue. Conversely, blockade of canonical (Smad) TGF-β signaling is detrimental in MFS mice. Recently, TGF-β-induced increases in smooth muscle cell (SMC) contractile genes and collagen I (COL1) expression have been proposed to lead to aortic stiffness and dilatation in MFS. Hypothesis: We hypothesized that ERK signaling is enhanced in human MFS tissue and dictates the predilection of the aortic root to develop aneurysm by altering SMC gene expression. Methods and Results: Western blot of aortic root tissue from MFS patients with root aneurysms (4.67±0.09 cm) revealed 3.1-fold increased ERK activation relative to control aortic root (p=0.03, n=8). When compared to non-dilated MFS ascending (ASC) aorta (2.94±0.14 cm), there was no difference in ERK activation between the two regions. While RT-PCR of MFS root showed increased expression of the contractile gene regulator myocardin (2.4±0.07 fold, p=0.01), and of MYH11 (3.05±0.13 fold, p=0.03) ACTA2 (2.93±0.10 fold, p&lt;0.01), and SM22-α (1.88±0.13 fold, p=0.02) versus controls, these genes were not differentially expressed between MFS root and ASC. COL1 expression was increased in MFS root relative to controls (5.57±0.06 fold, p&lt;0.01) and MFS ASC (2.25±0.06 p&lt;0.01). In vitro treatment of cultured MFS aortic root SMCs (n=5 patients) with TGF-β and Smad-specific inhibitor (SB431542) failed to increase expression of MYOCD, MYH11, ACTA2, SM22-α or COL1, while co-treatment with TGF-β and ERK inhibitor (PD98059) induced significant increases in expression of these genes (5.4-, 2.6-, 2.7-, 1.4-, and 1.4- fold, respectively p&lt;0.05). Conclusions: ERK signaling is uniformly enhanced in MFS aortic root and ASC tissue, indicating that further study into aortic region-specific responses to cellular signals is needed to assess the development of focal aortic root aneurysm in MFS. Increased contractile gene expression is Smad-dependent and non-focal and thus does not clarify focal root aneurysm. COL1, while focally enhanced in the MFS root, is Smad-driven and suppressed by ERK, and may represent a compensatory response.
NCOG-04. EFFECTS OF PROTON RADIATION ON BRAIN STRUCTURE AND FUNCTION IN LOW GRADE GLIOMA
Authors: Michael Parsons, Katharina Hoebel, Ken Chang, Thanakit Pongpitakmetha, Andrew Beers, James Brown, Jayashree Kalpathy-Cramer, Janet Sherman, Helen Shih, Jorg Dietrich
Journal: Neuro-Oncology (2018)

Previous studies have shown progressive global brain volume loss over a 1–2 year period after treatment for glioblastoma with conventional chemoradiation. The pathogenesis of this toxicity is not well understood, though may reflect unintentional exposure of normal brain to photon irradiation. Proton, as compared to photon, irradiation reduces exposure to brain areas outside the target. To explore the possibility that proton radiation therapy limits neurotoxicity seen in our previous studies, we followed a cohort of patients treated with proton radiation over a 2-year period with serial imaging and neuropsychological evaluation, in whom we have previously reported stable cognitive function. 20 patients with low grade glioma (13 male, mean age 37.5y) were treated with proton radiation (54Gy(RBE), 1.8Gy/fx). Volumetric MRI analysis was conducted at baseline and 2 years post-treatment (interval mean/SD=26.4/4 months) on 18 subjects using an automated deep learning algorithm to segment grey and white matter in the hemisphere opposite to brain tumor. Neuropsychological evaluations were conducted on 16/18 subjects at similar timepoints (interval mean/SD=25.7/3.2 mos; 2 subjects did not complete post-treatment evaluations). There was no significant change in grey (t=0.98; p=ns) or white matter t=-1.46; p=ns) volume over the 2-year post-treatment interval. Neuropsychological index scores were chosen to evaluate broad domains that might be sensitive to diffuse volume loss (IQ, processing speed, working memory, delayed recall). There were no significant changes in cognitive performance. Correlations between volumetric and cognitive change were nonsignificant across all domains. CONCLUSIONS: In contrast to our prior studies demonstrating neurotoxic effects on brain volume following standard chemotherapy in combination with photon irradiation, no similar effects were observed following proton irradiation. While tumor biology effects on neurotoxicity and methodological differences are considered, proton irradiation appears to preserve brain structure and function over a comparable 2-year period. HS and JD contributed equally.
INNV-42. COST-EFFECTIVENESS OF INTRAOPERATIVE MRI IN THE TREATMENT OF HIGH-GRADE GLIOMAS
Authors: Peter Abraham, Reith Sarkar, Michael Brandel, Arvin Wali, Robert Rennert, Christian Lopez Ramos, Jennifer Padwal, Jeffrey Steinberg, David Santiago-Dieppa, Vincent Cheung, J Scott Pannell, James Murphy, Alexander Khalessi
Journal: Neuro-Oncology (2018)

OBJECT: High-grade gliomas (HGGs) have poor survival and high treatment costs. Intraoperative MRI (ioMRI) improves gross-total resection (GTR) rates and prolongs progression-free survival (PFS) in HGGs, but questions regarding its cost-effectiveness persist. To date, no clinical decision analysis models assessing ioMRI in the treatment of HGG exist. An integrated 5-state microsimulation model was constructed to follow patients with HGG. Patients treated with ioMRI were compared to those without ioMRI from initial resection/debulking until death. Following surgery and treatment of complications, patients existed in one of 3 health states: PFS, progressive disease, or dead. Patients with recurrence were offered up to two repeat resections. PFS, health utility values, probabilities, and costs were obtained from randomized-controlled trials whenever possible. Otherwise, national databases, registries, and non-randomized trials were used. Uncertainty in model inputs was assessed using deterministic and probabilistic sensitivity analyses. A healthcare perspective was taken for this analysis. A willingness to pay (WTP) threshold of $100,000/QALY gained was used to determine cost-efficacy. IoMRI yielded an incremental benefit of 0.18 QALYs (1.16 QALYs without ioMRI vs. 1.34 with) at an incremental cost of $13,447 ($157,000 without vs. $170,447 with) in microsimulation modeling, resulting in an incremental cost-effectiveness ratio (ICER) of $76,442 per QALY. Given our parameter distributions, probabilistic sensitivity analysis demonstrated that ioMRI had a 99.5% chance of cost-effectiveness at a WTP threshold of $100,000/QALY. Intra-operative MRI is likely a cost-effective modality in the treatment of HGGs.
NIMG-35. TREATMENT RESPONSE ASSESSMENT MAPS (TRAMs) SENSITIVITY TO TUMOR/TREATMENT-EFFECTS AS A FUNCTION OF DATA ACQUISITION PARAMETERS
Authors: David Guez, Leor Zach, Dianne Daniels, Shirley Sharabi, Ouzi Nissim, Roberto Spiegelmann, Arielle Tylim, Alisa Taliansky, Yigal Shoshan, Deborah Blumenthal, Felix Bokstein, Zvi Cohen, Yael Mardor, David Last
Journal: Neuro-Oncology (2018)

INTRODUCTIONTRAMs calculated from delayed-contrast MRI enable reliable (sensitivity/specificity>70%) differentiation between tumor (blue in the TRAMs) and non-tumoral tissues (red). The TRAMs are calculated by subtracting 3D T1-MRIs acquired 5min (early time point) post-contrast injection from those acquired 60-105min (late point) later. Here we studied the sensitivity to tumor/treatment-effects as a function of the early T1-MRI acquisition time.
PDCT-06. PHASE 1 STUDY OF ONC201 IN PEDIATRIC PATIENTS WITH H3 K27M-MUTANT HIGH GRADE GLIOMA OR NEWLY DIAGNOSED DIPG
Authors: Sharon Gardner, Fernando Suarez, James M Stafford, Rohinton S. Tarapore, Krystal Merdinger, Wolfgang Oster, Joshua Allen, Andrew S. Chi, Hope Fuller-Becker, Anna Yaffe, Jeffrey C. Allen
Journal: Neuro-Oncology (2018)

The imipridone ONC201 is the first selective antagonist of DRD2 for clinical oncology. Several Phase 1, Phase 1/2 and Phase 2 studies in patients with advanced cancers have established the single agent recommended Phase 2 dose (RP2D) of 625mg ONC201 administered orally once a week in adults. ONC201 induces p53-independent apoptosis in newly diagnosed and recurrent high-grade glioma in vitro, ex vivo and in vivo. Furthermore, radiographic regressions in adult recurrent H3 K27M-mutant glioblastoma patients in response to single agent ONC201 have been reported. Based on this adult experience and complementary preclinical results demonstrating the increased susceptibility of H3 K27M-mutant gliomas to ONC201, we initiated the first Phase 1 pediatric clinical trial of ONC201 January 30, 2018. This trial will determine the safety and RP2D of ONC201 in pediatric post-radiation H3 K27M-mutant glioma patients as a single agent and in newly diagnosed diffuse intrinsic pontine glioma (DIPG) patients in combination with radiation (NCT03416530). Patients without known H3 K27M-mutation status by a CLIA-lab can enroll with commitment to post-term biopsy. This is a multicenter, open-label, 2 arm, dose-escalation and dose-expansion study. Ten children with H3 K27M-mutant gliomas ages 5–18 years have been treated post-radiation: 3 at dose level 1; 3 at dose level 2; 4 as part of the dose expansion cohort on dose level 2. Patients have received 2–12 doses (median= 5). The ONC201 has been tolerated very well. Grade III/IV events include: decreased neutrophil count grade III (n=1) spontaneously resolved without dose modification and elevated AST grade III (n=1) returned to grade II after holding 1 dose. Additional safety data as well as pharmacokinetics, pharmacodynamics, and progression-free survival results from this trial will be reported.
Can Better Care Coordination Lower Health Care Costs?
Authors: Dhruv Khullar, Dave A. Chokshi
Journal: JAMA Network Open (2018)

Scott A. Berkowitz, MD, MBA; Shriram Parashuram, PhD, MPH; Kathy Rowan, PhD, MPH; Lindsay Andon, MSPH; Eric B. Bass, MD, MPH; Michele Bellantoni, MD; Daniel J. Brotman, MD; Amy Deutschendorf, MS, RN, ACNS-BC; Linda Dunbar, RN, PhD; Samuel C. Durso, MD, MBA; Anita Everett, MD; Katherine D. Giuriceo, PhD; Lindsay Hebert, MSPH; Debra Hickman, MDiv; Douglas E. Hough, PhD; Eric E. Howell, MD; Xuan Huang, MPH; Diane Lepley, RN, MSN; Curtis Leung, MPH; Yanyan Lu, MS; Constantine G. Lyketsos, MD; Shannon M. E. Murphy, MA; Tracy Novak, MHS; Leon Purnell, MEd; Carol Sylvester, RN, MS; Albert W. Wu, MD, MPH; Ray Zollinger, MD; Kevin Koenig, MPP; Roy Ahn, ScD, MPH; Paul B. Rothman, MD; Patricia M. C. Brown, JD; for the Johns Hopkins Community Health Partnership (J-CHiP) Team
MNGI-09. FERTILITY TREATMENT AND MENINGIOMA INCIDENCE
Authors: Maryam Shahin, Stephen Magill, Cecilia Dalle Ore, Pamela Peters, Jennifer Viner, Michael McDermott
Journal: Neuro-Oncology (2018)

Meningiomas are more common in females and 70–80% express the progesterone receptor. They have been reported after gender reassignment therapy, suggesting that high-dose exogenous estrogen/progesterone exposure, such as occurs during fertility treatments, may increase the risk of developing a meningioma. The goal of this study was to report the incidence of prior fertility treatment in a consecutive series of female patients presenting with meningioma. A retrospective review of patients presenting with meningioma from 2015–2018 was conducted. Female patients with prior fertility treatments were compared to those who did not receive fertility treatment using standard statistical methods. Of 206 female patients with meningioma, 26 (12.6%) had a history of fertility treatments. Patients underwent various forms of assisted reproductive technology including: in vitro fertilization (50.0%), clomiphene with or without intrauterine insemination (34.6%), and unspecified (3.8%). One patient (3.8%) received supplemental progesterone during her treatment. The most common presenting symptoms were incidental (57.7%) and headache (26.9%). Median follow up was 1.8 years. Tumors were WHO grade I (78.6%) or grade II (21.4%). Patients who underwent fertility treatments presented at significantly younger mean age compared to those who had not (51.8 vs 57.3 yrs, p = 0.0135, 2-tailed T-test) and were more likely to have multifocal (OR: 4.5, 95% CI: 1.4–14.8, p = 0.0196) and non-skull base meningiomas (OR: 4.4, 95% CI: 1.7–11.4, p = 0.0012). A history of fertility treatment is common in female patients presenting with meningioma. Patients with meningioma and a history of fertility treatment were more likely to present at a younger age and have multifocal and non-skull base tumors. These findings stress the importance of assessing for prior estrogen/progesterone exposure in patients presenting with meningioma. Future large prospective series and laboratory investigations are needed to determine the impact of fertility treatment on meningioma development.
Limited Focus in Evaluation of Vaccine Cost-effectiveness
Authors: Desmond Curran, Désirée Van Oorschot, Philip Buck
Journal: JAMA Internal Medicine (2018)

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Abstract 15114: Paradoxical Association of Ventricular Tachyarrhythmias and All-Cause Mortality in Patients With Renal Impairment: a MADIT-CRT Substudy
Authors: Usama Daimee, Arthur Moss, Ilan Goldenberg, Martin Ruwald, Wojciech Zareba, Bela Merkely, Scott McNitt, Bronislava Polonsky, Valentina Kutyifa
Journal: Circulation (2014)

Background: The risk of ventricular tachyarrhythmias (VTAs) in mild heart failure patients with renal dysfunction receiving cardiac resynchronization therapy plus an implantable cardioverter-defibrillator (CRT-ICD) or an ICD alone is not well understood. Hypothesis: We assessed the hypothesis that baseline renal function affects risk of VTAs and all-cause mortality as well as benefit derived from CRT-ICD during in-trial follow-up. Methods: We evaluated the impact of renal function in 1274 patients with mild heart failure and left-bundle branch block enrolled in MADIT-CRT. Patients with BUN&gt;70 mg/dl or creatinine&gt;3.0 mg/dl were excluded from the trial. Two subgroups were created based on the estimated glomerular filtration rate (GFR): GFR&lt;60 and GFR≥60 ml/min/1.73 m2. Patients were studied over 3.3 years of follow-up for endpoints of ventricular tachycardia ≥200 beats per minute or ventricular fibrillation (fast VT/VF) and all-cause mortality. Results: The 413 patients with GFR&lt;60 ml/min/1.73 m2 (mean 48.1±8.3) experienced lower risk of fast VT/VF (HR: 0.63, 95% CI: 0.44-0.90, p=0.012) but increased risk of death (HR: 2.43, 95% CI: 1.67-3.57, p&lt;0.001), relative to those in the GFR≥60 group (mean 79.6±16.0) [Figure]. For both, CRT-ICD relative to ICD-only treatment was associated with lower likelihood of fast VT/VF (GFR&lt;60: HR=0.46, 95% CI: 0.24-0.86, p=0.016; GFR≥60: HR=0.54, 95% CI: 0.38-0.76, p&lt;0.001) without a significant effect on death (GFR&lt;60: HR=0.62, 95% CI: 0.38-1.04, p=0.065; GFR≥60: HR=0.78, 95% CI: 0.45-1.36, p=0.379). There was no significant treatment interaction for the endpoints (p&gt;0.10). Conclusion: In conclusion, in mild heart failure patients, moderate renal dysfunction is associated with lower risk of VTAs but greater risk of all-cause mortality relative to mildly impaired-to-normal renal function. In both groups, similar benefit from CRT-ICD was found in reducing risk of VTAs.
Public health guidelines on sedentary behaviour are important and needed: a provisional benchmark is better than no benchmark at all
Authors: Jean-Philippe Chaput, Timothy Olds, Mark S Tremblay
Journal: British Journal of Sports Medicine (2018)

The narrative review by Professor Stamatakis and colleagues1 published in the British Journal of Sports Medicine ( BJSM ) challenges the appropriateness of having quantitative public health guidelines on sedentary behaviour at this time. The authors argue that we still know little about the independent health effects of sitting, and the possibility that sitting is merely the inverse of physical activity remains. While we agree that many questions still need to be addressed in the field of sedentary behaviour research, we feel that providing quantitative recommendations on reducing sedentary behaviour is not premature, is needed, is low risk and is important for public health.

Public health approaches to promoting healthy movement should be reconceptualised by considering the full 24-hour period (ie, sleep, sedentary behaviour and all physical activity) rather than focusing on individual behaviours or guidelines. Ignoring the compositional nature of these behaviours (they add up to 24 hours) is misleading, and we need to think in terms of ‘activity mixes’ and healthy ways to compose the day.2–5 In this context, talking about behaviours in isolation of one another is inappropriate, and we should rather think about the optimal mix of behaviours over the whole 24 hours. This integrated approach is supported by recent evidence that used compositional data analysis in their analysis (ie, a statistical approach that deals with the finite nature of the 24-hour …