tbuckley/cabot-search huggingface dataset:
HGG-13. DETERMINING REGIONAL DIFFERENCES IN HIGH-GRADE GLIOMA VASCULATURE PHENOTYPE
Authors: Xin Wei, Rachel Hartley, Heather Bear, Christine Fuller, Timothy N Phoenix
Journal: Neuro-Oncology (2019)

Pediatric high-grade gliomas (pHGG) are among the most common childhood brain tumors. Distinct patterns of genetic alterations and pathological features have been identified based on regional location, including limited disruption of the blood-brain barrier in diffuse intrinsic pontine gliomas (DIPG). To determine the underlying differences in pHGG regional tumor-vascular interactions, we have started to perform histological and molecular analyses of normal and tumor vasculature. By utilizing in utero electroporation to target defined CNS regions, we have generated pHGG mouse models that develop in supratentorial and brainstem regions, and faithfully recapitulate features of the human disease. Preliminary analysis shows that brainstem gliomas display limited vascular abnormalities, and little to no vascular leakage, suggesting maintenance of the BBB. Interestingly, supratentorial pHGG contain core regions that display traditional vascular abnormalities normally associated with glioblastoma, including increased vascular permeability and hemorrhaging. Ongoing studies are being performed to determine underlying molecular differences between normal and tumor associated endothelial cells purified from supratentorial and brainstem regions. Overall, we hope to advance our understanding of vascular heterogeneity within the brain, and define mechanisms utilized by gliomas to modulate BBB function. By determining cell autonomous and non-autonomous differences that drive tumor angiogenesis and BBB disruption, we hope to identify molecularly targeted therapies to enhance drug penetration and responsiveness of pHGGs.
HGG-26. TARGETABLE MOLECULAR ALTERATIONS IN CONGENITAL GLIOBLASTOMA
Authors: Ahmed Gilani, Andrew Donson, Susan Whiteway, John DeSisto, Lindsey Hoffman, Nicholas Foreman, Bette K Kleinschmidt-DeMasters, Adam Green
Journal: Neuro-Oncology (2019)

BACKGROUND: Congenital glioblastomas (cGBM) are uncommon tumors presenting in early infancy (less than six months). Molecular features have not been not sufficiently explored due to the rarity of these tumors. We previously reported that cGBM appears similar to pediatric and adult GBM based on histology and microarray expression analysis but generally has a far more favorable outcome, with good responses to subtotal resection followed by moderate intensity chemotherapy (Neuro Oncol 14(7):931–41, July 2012). We thus explored other modalities of molecular analysis in an attempt to find an etiology for this difference in prognosis. METHODS: We performed molecular testing on a set of six cGBM samples from patients diagnosed at our institutions. We used Archer’s FUSIONPlex Solid Tumor Kit, Illumina RNA-Seq, and next-generation sequencing of a panel of 25+ clinically relevant genes. RESULTS: The six cases represent four males and two females who underwent surgery between one and ten weeks of age. Three of the six cases analyzed showed fusions containing ALK (involving MAP4, MZT2B and EML4 as fusion partners), raising the potential for therapy with FDA-approved drugs lorlatinib or crizotinib. Of the remaining three, one case showed a ROS1 fusion, one had a mutation in heat shock protein gene HSPA1A, and one demonstrated a mutation in the transcriptional repressor gene CIC. None of the cases showed alterations in IDH1/2, histone 3 genes, NTRK, or TERT, alterations which are most commonly associated with pediatric and adult high-grade gliomas (HGG). CONCLUSIONS: These data show that cGBM are genetically heterogeneous and harbor alterations different from pediatric and adult HGG. Actionable fusions can frequently be identified.
THER-13. PEDIATRIC NEURO-ONCOLOGY CLINICAL TRIAL ENROLLMENTS: A 30 YEARS’ EXPERIENCE IN THE STATE OF FLORIDA
Authors: Emily Owens Pickle, Ana Aguilar Bonilla, Amy Smith
Journal: Neuro-Oncology (2019)

BACKGROUND: Currently about 200 newly diagnosed pediatric central nervous system (CNS) cases are reported in the state of Florida each year. In addition to the Florida Cancer Data System (FCDS), Florida has collected data on pediatric cancer cases diagnosed in the state since 1986 through the Statewide Pediatric Incidence Reporting System (SPIRS). SPIRS collects statewide data on pediatric cancer diagnosis, treatment, and clinical trial participation. Follow-up is performed annually at local sites for each case. METHODS: The SPIRS dataset was queried to find the total number of CNS cases diagnosed over a 30-year period in Florida and the annual enrollment on upfront cooperative group study each year. RESULTS: A total of 3,856 pediatric CNS cases were reported from 1986–2016. A range of 3–25 patients were reported as enrolled onto upfront cooperative group studies each year for a total of 419 enrollments over the 30-year period. From 1986–1995, 14.89% of patients enrolled on an upfront trial, from 1996–2005, 14.14% of patients enrolled on an upfront trial, and from 2006–2015, 8.5% of patients enrolled on an upfront trial. CONCLUSIONS: Enrollment onto upfront CNS trials in our state appears to have decreased over the past decade. Factors that may be an influence are an increase in non-cooperative group trials, the prodigious amount of time it takes from study conception to data analysis, increasingly narrow eligibility criteria, underreporting at sites, and perhaps a natural life-cycle of clinical research. Some patients may have been treated on a study out of state. The utility of our current approaches to pediatric oncology clinical trials collaboration might be a relevant topic for discussion if we are to bring forward meaningful advances for this group of rare pediatric diseases. Findings and solutions may be transferable to similar challenges at a national level.
Longitudinal trends of serum IgE and <i>IL5RA</i> expression throughout childhood are associated with asthma but not with persistent wheeze
Authors: Matthias Klös, Loreen Thürmann, Mario Bauer, Joachim Heinrich, Marie Standl, Andrea von Berg, Beate Schaaf, Dieter Weichenhan, Oliver Mücke, Christoph Plass, Stefan Röder, Gunda Herberth, Ulrich Sack, Michael Borte, Gabriele I. Stangl, Roland Eils, Saskia Trump, Irina Lehmann
Journal: Allergy (2019)

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MEDU-39. HIGHLY RECURRENT U1 SMALL NUCLEAR RNA HOTSPOT MUTATIONS DRIVE ALTERNATIVE SPLICING IN SONIC HEDGEHOG MEDULLOBLASTOMA
Authors: Sachin Kumar, Hiromichi Suzuki, Shimin Shuai, Lincoln Stein, Michael Taylor
Journal: Neuro-Oncology (2019)

Recurrent somatic single nucleotide variants (SNVs) in cancer are largely confined to protein-coding genes, and are rare in pediatric cancers. Similar to many pediatric cancers, medulloblastomas harbor few recurrent somatic SNVs except for TERT promoter mutations. To investigate non-coding mutations, we analyzed whole-genome sequencing from 341 medulloblastoma cases. We identified hotspot mutations of the U1-snRNAs in ~50% of Shh-medulloblastomas, which were not present across other medulloblastoma subgroups. U1 spliceosomal small nuclear RNA (snRNA) mutations were further analyzed in an additional 179 sonic hedgehog (Shh) medulloblastoma cases using allele-specific PCR. Mutations were largely absent from infant Shh-medulloblastoma, but were prevalent in 97% of adults (Shhδ), and 25% of adolescents (Shhα). The U1-snRNA mutation was found in most adolescents with TP53 mutations, and represents a higher risk than TP53 mutation. The mutation was assessed in 2,442 cases across 36 tumour types from the ICGC, and hotspot mutations were highly specific to Shh-medulloblastomas. The U1-snRNA mutation occurs in the 5’ splice site binding region (r.3a>g), and snRNA mutant tumors have significantly disrupted RNA splicing with an excess of 5’ cryptic splicing events. Shh pathway genes PTCH1 and GLI2 were aberrantly spliced, generating stop codons induced by novel cassette exons. Consequently, both alternative isoforms translate incomplete mRNAs, which reduce Ptch1 function and increase Gli2 function. U1-snRNA mutations also affected several oncogenes and tumor suppressor genes such as CCND2 and PAX5. Our results provide the first evidence of a hotspot mutation in U1-snRNA, revealing a novel mechanism of aberrant splicing in cancer and implicating splice site targeting mutations in medulloblastoma pathogenesis. As U1 mutations are present in medulloblastoma patients with the highest mortality, it represents an exciting target for novel therapy.
In vivo temperature-sensitive drug release system trigged by cooling using low-melting-point microcrystalline wax
Authors: Kohei Matsumoto, Shin-ichiro Kimura, Shigeru Itai, Hiromu Kondo, Yasunori Iwao
Journal: Journal of Controlled Release (2019)

Temperature-sensitive formulations are attractive controlled-release formulations, which release an incorporated drug by changes in body temperature induced by external temperature stimulation. Recently, it has been reported that wax matrix (WM) particles composed of a low-melting-point microcrystalline wax (MCW) released only a small amount of the drug at 37 °C, whereas faster drug release occurred at 25 °C. In this study, temperature-sensitive formulations composed of low-melting-point MCW that release drugs triggered by cooling, rather than heating, were developed. In an in vitro dissolution test in which the test medium was repeatedly cooled from 37 to 25 °C, control of the promotion and suppression of drug release was achieved. The drug concentration in the plasma of rats administered the particles was significantly increased by cooling compared with non-cooling, indicating that the drug release from the particles was promoted by cooling both in vitro and in vivo. Therefore, particles composed of low-melting-point MCW should be useful for the development of cooling-triggered, temperature-sensitive formulations.
Effect of a behaviour change intervention on the quality of peri-urban sanitation in Lusaka, Zambia: a randomised controlled trial
Authors: James B Tidwell, Jenala Chipungu, Samuel Bosomprah, Robert Aunger, Val Curtis, Roma Chilengi
Journal: The Lancet Planetary Health (2019)

BackgroundPoor sanitation in peri-urban areas is a growing public health problem. We tested a scalable, demand-side behaviour change intervention to motivate landlords to improve the quality of shared toilets within their plots.MethodsWe did a residential plot-randomised controlled trial in a peri-urban community in Lusaka, Zambia. We enrolled adult resident landlords on plots where at least one tenant lived. We allocated landlords 1:1 to intervention and control arms on the basis of a random number sequence. The intervention was developed using the Behaviour Centred Design approach and consisted of a series of group meetings designed to motivate sanitation quality improvement as a way to build wealth and reduce on-plot conflict; no subsidies or materials were provided. The control group received no intervention. The four primary outcomes were having a rotational cleaning system in place (to improve hygiene); having a solid door on the toilet used by tenants with an inside lock (for privacy); having an outside lock (for security); and having a sealed toilet (to reduce smell and contamination). We measured outcomes 1 month before the start of the intervention and 4 months after the end of the intervention. Data collectors measuring outcomes were blinded to group assignment. We analysed outcomes by intention to treat, including all landlords with study-end results. Because the outcomes were assumed to not be independent, we used a family-wise error rate of 0·05 to calculate an adjusted significance level of 0·0253. This study was registered with ClinicalTrials.gov, number NCT03174015.FindingsBetween June 9 and July 6, 2017, 1085 landlords were enrolled and randomly assigned to the intervention (n=543) or the control group (n=542). The intervention was delivered from Aug 1, 2017, and evaluated from Feb 15 to March 5, 2018. Analysis was based on the 474 intervention and 454 control landlords surveyed at study end. The intervention was associated with improvements in the prevalence of cleaning rotas (relative risk 1·16, 95% CI 1·05–1·30; p=0·0011), inside locks (1·34, 1·10–1·64; p=0·00081), outside locks (1·27, 1·06–1·52; p=0·0028), and toilets with simple covers or water seals (1·25, 1·04–1·50; p=0·0063).InterpretationIt is possible to improve the structural quality and cleanliness of shared sanitation by targeting landlords with a scalable, theory-driven behaviour change intervention without subsidy or provision of the relevant infrastructure.FundingSanitation and Hygiene Applied Research for Equity.
THER-04. OLFACTORY ENSHEATHING CELLS TRAVEL THEIR NATURE ROUTE FROM NASAL CAVITY TO CNS AND DELIVER THERAPEUTIC TRANSGENES TO HIGH-GRADE PEDIATRIC GLIOMAS
Authors: Litia Carvalho, Jian Teng, Bakhos Tannous
Journal: Neuro-Oncology (2019)

The olfactory ensheathing cells (OECs) are a unique glial cell type playing a role in promoting the axonal growth of neuronal receptors from the nasal mucosa towards the olfactory bulb during physiological turnover. OECs have the ability to migrate from the peripheral nervous system to the central nervous system, which is critical for the development of the olfactory system. Owing to their ability to guide axonal outgrowth, interact with astrocytes, and their immuno-modulatory and phagocytic properties, OECs showed promising results in regenerative medicine, including spinal cord injury and amyotrophic lateral sclerosis in the clinic, but were never studied in the context of cancer. Here, we evaluated for the first time OEC potential for pediatric gliblastoma gene therapy. We extracted/cultured OECs from mice olfactory bulb and established their phenotype by immunofluorescence microscopy. We first confirmed OEC tropism to intracranial glioblastoma, both at the primary tumor and the infiltrating single stem-like cells and showed that two cytokines, TNFα and IL-6, are responsible for this tropism. We chose the intranasal delivery since this route will bypass the blood-brain barrier, limit systemic side effects, and is the natural migration path of OECs to CNS. We then evaluated the potential of OEC as a delivery vehicle for pediatric glioma gene therapy by genetically engineering these cells to express cytosine deaminase (CD) under the control of CMV promoter. Mice bearing intracranial glioblastoma tumors injected intranasally with OEC-CD and treated with 5-FC showed slower tumor growth and increase in survival compared to controls. Our findings show for the first time OECs tropism to pediatric glioma tumors and their potential for brain cancer gene therapy using intranasal delivery. OECs have the advantage over other typical stem cells in that they can be easily obtained from olfactory bulb, allowing autologous transplantation and overcoming ethical issues.
Abstract 14140: The Weight of the Evidence: Comparison of Operatively Excised Aortic Valve Weights in Patients With High Gradient versus Low Gradient Aortic Stenosis and Overall Survival Following Aortic Valve Replacement
Authors: Sara M Negrotto, Jeremy J Thaden, Rakesh M Suri, Joseph J Maleszewski, Sorin V Pislaru, Mackram F Eleid, Vuyisile T Nkomo
Journal: Circulation (2015)

Introduction: Excised aortic valve weight (AVW) correlates with severity of AS. There is some debate about the true severity of AS in low gradient AS (LGAS) compared to high gradient AS (HGAS). We sought to compare patient characteristics and operatively excised AVW in patients with LGAS vs HGAS vs moderate AS. Methods: 916 patients with EF ≥50% undergoing surgical aortic valve replacement for AS between 2010-2012 were included. Clinical and echocardiographic characteristics of LGAS patients (AVA≤1cm 2 , MnG&lt;40mmHg; N=68) were compared to HGAS patients (AVA≤1cm 2 , MnG≥40mmHg; N=745) and operatively excised AVW were compared to moderate AS (AVA&gt;1cm 2 , MnG&lt;40mmHg; N=102). Results: Compared to HGAS, LGAS patients were older (mean age 77 ± 10 vs 73 ± 10 years; p=0.001), often female (56% vs 38%; p=0.006), but without differences in diabetes (26% vs 29%; p=0.78), hyperlipidemia (85% vs 86%, p=0.86), coronary artery disease (49% vs 44%; p=0.53), or hypertension (81% vs 76%; p=0.38). LGAS patients predominantly had trileaflet aortic valves (91% vs 71%; p&lt;0.001), smaller LVOT diameter (2.16 ± 0.15 vs 2.25 ± 0.20 cm; p=0.002), lower stroke volume index (42.1 ± 7.3 vs 49.0 ± 8.8 cc/m 2 ; p&lt;0.001), lower systemic compliance (0.77 ± 0.30 vs 0.93 ± 0.33 ; p&lt;0.001), but no difference in valvulo-arterial impedance (3.96 ± 0.76 vs. 3.84 ± 0.80, p=0.24) compared to HGAS. Excised AVW were lower in patients with LGAS vs HGAS (1.77 ± 0.76 vs 2.69 ± 1.26 g, p&lt;0.001), but not different from moderate AS (1.77 ± 0.76 vs 2.04 ± 0.94 g; p=0.1). This relationship held true when AVW was indexed to body surface area. Three-year mortality post-valve replacement was significantly higher in LGAS compared to HGAS (22% vs 11%, p=0.02). Conclusions: LGAS occurs mostly in older female patients with trileaflet aortic valves. Excised AVW in LGAS is similar to moderate AS but lower than HGAS. However, systemic compliance is higher in LGAS vs HGAS contributing to increased afterload. Poorer outcomes after surgery in LGAS patients may be attributed to noncompliant vasculature which is not corrected with valve replacement and evaluation of patients with LGAS should include assessment of peripheral resistance.
THER-34. MEK BLOCKADE SYNERGISTICALLY INCREASES THE ANTI-TUMOR EFFECTS OF mTOR INHIBITION IN GLIOMAS
Authors: Jie Zhang, Kevin Liu, Rogier Dik, Xiaodong Yang, Angela Waanders, Adam Resnick, Karen Wright, William Weiss, Daphne Haas-Kogan, Sabine Mueller
Journal: Neuro-Oncology (2019)

Abnormal signaling of the RAS/RAF and mTOR pathways predominates in pediatric low-grade gliomas (PLGGs). MLN0128 is a second-generation pan-mTOR inhibitor (TORC1/2). Rapalink-1, a third-generation bivalent mTOR inhibitor that combines rapamycin with MLN0128 by an inert chemical linker, shows potent anti-tumor effects in preclinical adult glioma models. MEK inhibition with e.g. AZD6244 shows promising anti-tumor effects in PLGGs and the type II generation pan-RAF inhibitor TAK580 is currently under clinical investigation in PLGG. In this study, we evaluate the effects of MLN0128 and Rapalink-1 in preclinical models of PLGGs, for both mono- and combination therapy with AZD6244 and TAK580. These inhibitors were used to treat glioma cell lines carrying wild-type BRAF (SF188 and LN229), and isogenic systems of KIAA1549-BRAF expressing NIH/3T3 cell line. Using CellTiter-Glo Luminescent Cell Viability Assay, we found that mTOR inhibition monotherapy reduces cell viability in a dose dependent manner while Rapalink-1 (IC50 between 3.5–8.2nM) is more effective than MLN0128 (IC50 between 22.9–120.2nM). Combined with AZD6244, both inhibitors synergistically increase the suppression of cell viability (combination index value ndgeneration pan-RAF inhibitor TAK580 in combination with mTOR inhibition.
Abstract 3242: Transient Post-Operative Atrial Fibrillation is Associated with an Increased Rate of All-Cause Mortality
Authors: Matthew C Becker, John M Galla, Ryan P Daly, Femi Philip, Stephen O Chen, Chen H Chow, Peter Zimbwa, Tingfei Hu, Arman T Askari, Richard A Krasuski
Journal: Circulation (2007)

Background : Atrial fibrillation (AF) is the most common arrhythmia observed following coronary artery bypass grafting surgery (CABG) and is associated with increased morbidity and mortality. While the majority of affected patients are discharged in sinus rhythm, little is known about their ultimate outcome. We evaluated the effect of transient post-operative AF (TPAF) on long-term outcome in this population. Methods : The Cleveland Clinic Cardiothoracic Database was used to identify 5,205 consecutive patients who underwent first time, isolated CABG from January 1993 to December 2005. Patients diagnosed with post-operative AF (n=1560, 30%) were separated into two groups: transient AF (confirmed AF with discharge rhythm of sinus; n=1490, 28.6%) and persistent AF (confirmed AF with discharge rhythm of AF; n=70, 1.3%). These groups were compared to those patients that did not develop post-operative AF (n=3645). Endpoints of death, myocardial infarction (MI), and stroke were evaluated using the Chi squared and Fischer Exact tests. Long-term survival was evaluated with multivariate Cox proportional hazards methods to account for baseline differences. Results : Overall rates of 1 year mortality, MI and stroke were 12.5, 2.2, and 3.3 % respectively. TPAF was associated with an increased risk of death at 1 year as compared to patients with persistent AF (6.4 vs 2.9%; p&lt;0.001) or without post-operative AF (6.4 vs 2.7%; p&lt;0.001) but was not associated with increased risk of stroke or MI. Multivariate analysis identified TPAF as an independent predictor of both death (HR 1.93 95% CI [1.45, 2.56]; p&lt;0.001) and the combination of death, MI, or stroke (1.8 [1.37, 2.36]; p&lt;0.001). Use of beta-blockers (0.52 [0.34, 0.80]; p&lt;0.003) and statins (0.26 [0.11, 0.64]; p&lt;0.003), but not antiplatlet agents or warfarin, were associated with a reduced risk of death. Conclusion : In those undergoing first-time, isolated CABG, the presence of TPAF identifies patients at increased risk for all-cause mortality. In addition, the use of post-operative statins and beta-blockers appear to reduce this risk. These data suggest that morbidity unrelated to stroke or MI are responsible for the poor outcome in this population and warrant prospective investigation.