tbuckley/cabot-search huggingface dataset:
IMMU-16. GUADECITABINE (SGI-110) ENHANCES MHC class I AND TUMOR ANTIGEN EXPRESSION ON MURINE C57BL/6-SYNGENEIC GLIOMA AND DIPG MODELS
Authors: Gary Kohanbash, Lauren McCarl, Karsen Shoger, Alberto Broniscer, Katherine E Warren, Ian Pollack
Journal: Neuro-Oncology (2018)

Diffuse intrinsic pontine glioma (DIPG) is one of the most lethal pediatric brain tumors, with a median survival time of less than one year. As DIPG tumors are insensitive to chemotherapy and surgically inaccessible, there is an urgent need for the development of novel therapeutic approaches. Our group and others have been evaluating peptide vaccine immunotherapies that target glioma-associated antigens (GAAs). Enhancing the expression of these immunogenic GAAs and MHC I on tumor cells may promote immune-mediated tumor recognition and killing following peptide vaccine immunotherapy. Accordingly, DNA methyltransferase (DNMT) inhibitors have been shown to augment the expression of MHC, tumor antigens, and other immunosensitizing molecules. Guadecitabine (SGI-110), a next-generation DNMT inhibitor prodrug, has been developed to prolong tumor cell exposure to its active metabolite, decitabine. In the current study, we evaluated whether SGI-110 can immunosensitize murine glioma cells to peptide vaccine immunotherapy by enhancing their surface expression of MHC I and a GAA, EphA2. We developed a novel C57BL/6-syngeneic DIPG model by culturing cells from a Sleeping Beauty de novo glioma-induced in neonatal mice using a K27M-mutated histone 3.3 plasmid and other oncogenic plasmids (SB-DIPG-11). Flow cytometry analysis showed that SB-DIPG-11 cells express both murine MHC I (H-2Kb/H-2Db) and EphA2 on their surface. In vitro, treatment of SB-DIPG-11 and C57BL/6-syngeneic GL261 cells with SGI-110 resulted in a dose-dependent increase of MHC I and EphA2 surface expression. Based on these data, we are evaluating whether SGI-110 can improve the efficacy of peptide vaccine immunotherapy targeting EphA2 in vivo using our new DIPG mouse model. Our current data demonstrate that SGI-110 may promote antigen and MHC I expression to improve peptide vaccine immunotherapy for children with DIPG.
Abstract 17372: Comparison of Resting Energy Expenditure With Energy Intake in Neonates With Hypoplastic Left Heart Syndrome Following Stage 1 Palliation
Authors: Christine L French, Kimberly I Mills, Brian K Walsh, Aditya K Kaza, Alexis Cole, Catherine Baird, Hilary Bond, Nilesh M Mehta, Christopher P Duggan, John N Kheir
Journal: Circulation (2015)

Introduction: Nutrition provision and fluid administration following cardiac surgery in neonates impacts ventilator-dependent days, intensive care unit length of stay and diuretic administration. Resting energy expenditure (REE) in neonates following stage 1 palliation (S1P) for hypoplastic left heart syndrome (HLHS) has been poorly characterized and is essential to the provision of optimal nutrition. Methods: We continuously measured REE from postoperative day (POD) 0 through 7 following S1P in n=22 infants using an in-line, indirect calorimetric device (E-COVX moduleTM, GE Healthcare). Artifactual REE values were identified and filtered according to a predefined algorithm. Energy intake (EI) was abstracted from a detailed nutrition record. Results: There were no complications related to REE measurement, and 7.4% of measurements were found to be artifactual and excluded. Mean REE was 35.9 ± 10.1 kcal/kg/day on POD 0 and increased by an average of 3.1 ± 0.2 kcal/kg/day each day between POD 0 and 7 (A). Current recommended dietary allowance (RDA) estimates propose energy needs to be 108 kcal/kg/day in these patients. From POD 0-1, EI was less than REE by 18.5±4.3 kcal/kg/day, as fluid intake was primarily comprised of blood products (46.8±7.4%) and flushes (24.5±1.9%, B). From POD 2-7, EI exceeded REE by 22.6±4.4 kcal/kg/day (cumulative amount of 111 ± 7.7 kcal/kg/day over a 5 day period, C). EI from carbohydrates was disproportionately high (69.1±6.2%), and that from protein remained low (7.6±1.2% of calories, 1.53±0.3 g/kg/day, C). Conclusions: Following S1P, EI correlates poorly with measured REE, which is significantly lower than RDA estimates. This may result in excessive fluid and calorie administration in this fluid-sensitive population. Continuous measurement of REE is safe to perform and should be considered in neonates following cardiac surgery. A future trial comparing restricted EI to estimated EI in postoperative neonates is necessary.
HOUT-16. THE COST EFFECTIVENESS OF TUMOR TREATING FIELDS TREATMENT FOR PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA BASED ON THE EF-14 TRIAL
Authors: Gregory Guzauskas, Bruce CM Wang, Erqi Pollom, Volker W Stieber, Lou Garrison
Journal: Neuro-Oncology (2018)

With the EF-14 Trial reporting a 5-year survival rate of 13% for newly diagnosed Glioblastoma (GBM) patients treated with TTFields and maintenance temozolomide (TMZ) chemotherapy, a relevant number of patients will become long-term survivors. The impact on resource utilization from a health-economic standpoint is important for all health care decision-makers and therefore cost-effectiveness of TTFields treatment in first line GBM is assessed from a U.S. health system perspective. The incremental cost-effectiveness ratio (ICER) for treatment of newly diagnosed GBM with TTFields and TMZ versus TMZ monotherapy was estimated. We used a 3-state area under the curve model including alive without progression, progressed disease, and death to simulate patient outcomes and a lifetime horizon for survival by integrating the 5-year Kaplan-Meier curves of the EF-14 trial with long-term GBM epidemiology data and U.S. background mortality rates. For the calculation of quality-adjusted life years (QALYs) health utility values reported by Garside et al. were used. Frequency of adverse events (AE) were based on the EF-14 trial. AE and supportive care cost estimates were derived from published literature. We applied a discount of 3% to future survival benefits and costs. Parametrical uncertainty was addressed by one-way and probabilistic sensitivity analyses. We calculated an undiscounted increase in mean survival of 1.8 life years for TTFields plus TMZ versus TMZ alone. After applying the 3% discount rate, the incremental total cost was $188,637. The incremental cost-effectiveness ratio (ICER) was $150,452 per life year gained and $197,336 per QALY gained. Mean lifetime survival and quality-adjusted survival substantially increases by treatment with TTFields plus TMZ compared to treatment with TMZ alone in newly diagnosed GBM patients. Treatment with TTFields for can be considered cost-effective within the reported range of willingness-to-pay thresholds in the United States based on the results of this analysis.
STEM-29. UNSATURATED FATTY ACID (UFA) METABOLISM REGULATES MEMBRANE-ENDOLYSOSOME-NUCLEAR INTER-ORGANELLE COMMUNICATION IN GLIOMA STEM CELLS
Authors: Jian Hu
Journal: Neuro-Oncology (2018)

Stem cells receive the signals from their niches that instruct them to self-renew and prevent them from differentiating through a cascade of inter-organelle communication processes. However, how the inter-organelle communication mechanism functions in the maintenance of stemness in glioma stem cells (GSCs) remains unclear. To identify potential glioma suppressors that affect the interaction of GSCs with their niches, we discovered that the RNA-binding protein Quaking (QKI) is a key regulator of cellular endocytosis. QKI is mutated or deleted in ~34% of human glioblastomas. Consistently, 92% of the Nestin-CreERT2;QkiL/L;PtenL/L;p53L/L (QPP) mice developed glioblastoma with a median survival of 105 days, yet the Nestin-CreERT2;PtenL/L;p53L/L mice did not develop any gliomas. Mechanistically, QKI regulates the RNA stability and alternative splicing of numerous protein and lipid components of endolysosomes, particularly the unsaturated fatty acids (UFAs). Notably, lower levels of QKI, endolysosomes, and stearoyl-CoA desaturase (SCD, the key enzyme for UFA biosynthesis) all correlate with poorer prognosis in glioblastoma patients. Functionally, Qki and UFA loss both decrease endolysosome-mediated receptor degradation, thereby enriching receptors on the cytoplasmic membrane (e.g., Frizzled and Notch1) that are essential for maintaining stemness. This enrichment of receptor signaling enables GSCs to cope with the low ligand levels outside their niches. On the other hand, lower lysosomal activity induced by Qki and/or UFA loss also lead to defective mitophagy, which consequently leads to accumulation of damaged mitochondria, high level of ROS, and genomic instability in Qki-deficient NSCs. We identified that genomic instability induced by Qki deletion led to copy number gains of classical glioblastoma-associated oncogenes such as of PDGFRa and Cyclin D1/D3. Lastly, the heterogeneity of Nestin-CreERT2;QPP tumors also lead to heterogeneous responses to immunocheckpoint blockade inhibitors including anti-CTLA4 and anti-PD1. Taken together, our data suggest that Qki/UFA loss-induced endolysosomal defects promotes gliomagenesis through both reducing receptor degradation and inducing genomic instability.
ACTR-33. A PHASE I STUDY OF CONVECTION-ENHANCED DELIVERY OF LIPOSOMAL-IRINOTECAN USING REAL-TIME IMAGING WITH GADOLINIUM IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMA
Authors: Seunggu Han, Jennie Taylor, Manish Aghi, Susan Chang, Jennifer Clarke, Krystof Bankiewicz, Alastair Martin, Daryl Drummond, Jonathan Fitzgerald, Nicholas Butowski
Journal: Neuro-Oncology (2016)

Local delivery into the central nervous system circumvents the challenges associated with the blood-brain barrier and minimizes systemic toxicity while achieving higher concentrations of therapeutics. Convection enhanced delivery (CED) utilizes fluid convection to distribute macromolecules into the interstitial spaces of brain parenchyma. CED a high-concentration version of liposomal irinotecan (nal-IRI-HC) has been optimized in animal models and showed promising anti-tumor activity. A major recent advance in the application of CED is the development of real time CED (RCD), which utilizes MRI to visualize the CED process with the aid of co-convected contrast agents and thus monitor infusions and ensure precise delivery. A phase I study is ongoing evaluating CED of nal-IRI-HC with real-time MRI for patients with recurrent high grade glioma (HGG). This 3+3 dose escalation trial employs dose levels of 20 mg, 40 mg, 60 mg, and 80 mg of nal-IRI-HC, given via up to 3 catheters surgically placed in an intra-tumoral location. Maximum total volume infused will be 1.0 ml for the two lowest dose groups, 1.5 ml for the third dose group, and 2.0 ml for the highest dose group. To date 7 patients have been enrolled and treated. Median progression free survival was 2.9 months. All radiographic progression was found to be outside the infusion area. One grade 3 adverse event was encountered. The median total volume of distribution (Vd) to volume infused (Vi) ratio was 1.6 - 2.0 for each infusion based on correlations between pre-infusion modeling of drug distribution and post-infusion imaging. Image-guided CED allows for real-time placement and adjustment of cannula and for real time visualization of therapeutics into the brains of patients with recurrent HGG. In this early phase trial, real time CED of nal-IRI-HC appears well tolerated and suggests larger volume infusions warrants clinical evaluation.
Abstract 12012: Relation Between Colchicine and Epicardial Adipose Tissue Volume Surrounding Left Atrium in Atrial Fibrillation Recurrence After Ablation
Authors: Yasuyuki Egami, Masami Nishino, Ryu Shutta, Nomuhiko Makino, Jun Tanouchi
Journal: Circulation (2015)

Background: Immediate recurrence of atrial fibrillation (AF) after AF ablation was related with inflammatory process. Colchicine treatment after AF ablation can reduce AF recurrence by suppression of such inflammatory reactions. The epicardial adipose tissue (EAT) has been shown to release activated pro-inflammatory cytokines and to associate with the development of AF. However, it is unclear whether colchicine treatment affects recurrence of AF according to EAT volume of left atrium (LA-EAT volume). The purpose of this study was to evaluate the relation between reduction of AF recurrence by colchicine treatment after AF ablation and LA-EAT volume. Methods: One hundred twenty two consecutive AF patients who underwent AF ablation and in whom multi-detector computed tomography was performed before ablation were included. Colchicine was prescribed to patients who approved colchicine treatment and was started at 0.5 mg/day for 2 weeks after AF ablation. We divided the study patients into larger LA-EAT group and smaller LA-EAT group according to the median (22.4 cm3) of LA-EAT volume. LA-EAT volume was obtained by semi-automatically tracing axial images from the bifurcation of the pulmonary artery to the coronary sinus and EAT was recognized using threshold attenuation values of -50 to -200 HU. In each group, we compared incidences of AF recurrence (AF &gt; 30 sec) in 3 months and 12 months after ablation between colchicine group and non-colchicine group. Results: Forty-two patients received colchicine. In larger LA-EAT group (&gt; 22.4 cm3) (n=60) incidence of AF recurrence in colchicine group showed lower tendency in 12 months after ablation (10.5% vs. 34.2%, p=0.06) while in smaller LA-EAT group (&lt; 22.4 cm3) (n=62), incidence of AF recurrence was similar between colchicine group and non-colchicine group (Table). Conclusion: Colchicine treatment after AF ablation may reduce mid-term AF recurrence in AF patients with larger LA-EAT volume.
Abstract 17534: The Most Appropriate Number of Personnel Needed for Chest Compressions for In-hospital Cardiac Arrest: A Randomized, Crossover Manikin Study
Authors: Shunsuke Yamanaka, Kei Nishiyama, Hiroyuki Hayashi, Ji Young Huh
Journal: Circulation (2015)

Background: Effective chest compression (CC) is vital in cardiopulmonary resuscitation (CPR), and rescuer’s fatigue negatively affects quality of CPR. However, there is no consensus on the appropriate number of personnel needed for CC to avoid rescuer’s fatigue. Objective: We determined the appropriate number of personnel needed for 30-min CPR in a rescue-team in a hospital. Methods: We conducted a preliminary randomized, crossover, manikin trial on healthcare providers. We divided them into Groups A to D according to the intervals between the 2-min CC and assigned a different interval to each group. Groups A, B, C, and D performed CCs at 2-, 4-, 6-, and 8-min intervals as in 2, 3, 4, and 5 personnel, respectively. All participants performed CCs for 30 min with different intervals depending on the assigned group; participants allocated to Groups A, B, C, and D performed 8, 5, 4, and 3 cycles, respectively. We compared the differences between first cycle and the second to the last cycle Results: We enrolled 42 participants (age: 25.2±4.2, men 47.6%) for the preliminary evaluation. We used Kruskal-Wallis for the analysis. Participants in the less interval Groups A and B performed faster (A: -24.28±15.18, B: -7.90±13.49, C: -11.27±17.01, D: -2.38±3.31, P=0.03) and shallower CCs (A: -4.42±6.92, B: -3.18±5.43, C: -0.18±5.74, D: -1.23±4.10, P=0.62). Women-rescuers performed faster (A: -27.25±12.23, B: -7.00±13.97, C: -8.16±19.26, D: 3.16±4.66, P= 0.05) and shallower CCs (A: -6.25±7.54, B: -3.00±6.89, C: -3.66±3.32, D: -0.16±4.35, P=0.58). However, CCs of men-rescuers were not faster (A: -20.33±20.65, B: -9.00±14.44, C: -15.00±15.11, D: -7.14±16.70, P= 0.60) or shallower (A: -2.00±6.55 B: -3.40±3.78, C: 4.00±5.33, D: -2.14±3.98, P=0.06). Conclusion: At least four rescuers (Group C) may be needed to reduce rescuer’s fatigue for 30-min CPR. If the team only includes women, more personnel would be needed as women experience fatigue faster.
NIMG-20. DIFFUSION-WEIGHTED MAGNETIC RESONANCE IMAGING FINDINGS IN PATIENTS WITH CENTRAL NERVOUS SYSTEM INVOLVEMENT OF SYSTEMIC LYMPHOMA
Authors: Ashley Roque, Daniela Galluzzo, Frank Barbiero, Robert Fulbright, Joachim Baehring
Journal: Neuro-Oncology (2018)

CNS involvement may be seen at any time point in patients with systemic Non-Hodgkin lymphoma (SNHL). The leptomeninges are the most common site of CNS involvement, however parenchymal metastases are seen in up to 1/3 of patients. Given the potentially disabling nature of such lesions, early diagnosis initiation of appropriate therapy are of paramount importance. MRI remains the primary tool for the initial detection of suspected CNS spread of systemic lymphoma. Diffusion-weighted imaging is often used employed in the diagnosis and response of cellular neoplasms. The primary goal of this study was to describe DW-Imaging characteristics in a retrospective cohort of patients with SNHL with nervous system involvement. We identified patients with SNHL and dissemination to the CNS parenchyma diagnosed at our institution between 2010 and 2018. MR data with the following sequences: T1 (with gadolinium administration), T2- FLAIR, DWI and ADC sequences were required for inclusion. Imaging characteristics such as number of lesions, location of lesions, presence of contrast-enhancement, ADC, DWI signal intensity were evaluated. Quantitative ADC analyses were performed within a target lesion, peritumoral edema, and normal white matter. Twenty-six patient fulfilled eligibility criteria. Data for quantitative analysis of ADC signal were available in 25 patients. All patients had enhancing disease. 24 of 26 patients (92%) had lesions with Hyperintense DWI signal and hypointense ADC signal. One-way ANOVA analysis showed significant difference between the mean ADC Lesion, ADC peritumoral region, and ADC white matter (f-statistic 142.79 and p < 0.0001). Post-Hoc analysis showed significant difference between ADC Lesion and ADC peritumoral region, ADC pertimuoral and ADC white matter, but not between ADC lesion and ADC white matter. DW-MRI is a useful adjunct to anatomical MRI sequences in the diagnosis of CNS dissemination of SNHL. In the appropriate clinical setting, comprehensive MRI analysis may obviate the need for biopsy confirmation.
EXTH-18. DEVELOPMENT OF ULTRASOUND-FACILITATED DRUG DELIVERY DEVICE FOR LOCAL DRUG INFUSION AGAINST BRAIN TUMORS
Authors: Ryuta Saito, Aya Sato, Kenji Inoue, Wenting Jia, Saori Okuno, Yuji Ohashi, Kei Kamada, Akira Yoshikawa, Teiji Tominaga
Journal: Neuro-Oncology (2018)

Drug delivery against brain tumors is a challenge. Blood-brain barrier (BBB) and blood-tumor barrier always hinders the entry of therapeutic agents into brain tumors. On the other hand, local drug delivery also faces a major problem: limitations of distribution. Convection-enhanced delivery (CED) is a promising drug delivery method that deliver high-concentration drug directly into the targeted lesion beyond the BBB. We have been working to develop a novel treatment strategy with CED delivering chemotherapeutic agents directly into the tumor. Previously we developed an ultrasound facilitated drug delivery (UFD) system in order to achieve more robust drug distribution (J Neurosurg 124, 2016). In this study, we fabricated a second-generation device by analyzing optimal ultrasound generating condition and tested the intraparenchymal drug distribution using the device. Resonance frequency of the device was determined by measuring the strength of sound field using hydrophone in water. Using the UFD system, applying resonance frequency, evans blue dye was infused into the striatum of Fisher344 rats. Immediately after the infusion, brains were harvested, quickly frozen, and sectioned to evaluate the distributions of the dye. The second-generation device successfully distributed the dye to the volume 1.5~2 times larger than simple CED with using half the driving voltage than first-generation device. Moreover, the distribution instability, which was a major problem with the first-generation device, was resolved achieving smaller standard deviation. Using multiple resonance frequencies of the device, we found the difference in drug distribution; suggesting the existence of optimal frequencies for brain interstitial drug delivery. The second generation UFD device successfully and stably achieved enlarged distribution in the brain parenchyma.
R-CHOEP-14 × 6 Followed by Systemic CNS Prophylaxis for Diffuse Large B-Cell Lymphoma/Follicular Lymphoma Grade 3 with Age Adjusted IPI Score 2–3: Final Results of a Nordic Lymphoma Group Phase 2 Study Including 156 Patients Aged 18–65 Years.
Authors: Harald Holte, Sirpa LeppÃ¤, Magnus Bjorkholm, Øystein Fluge, Sirkku Jyrkkiö, Jan Delabie, Christer Sundstrom, Marja-Liisa Karjalainen-Lindsberg, Martin Erlanson, Arne Kolstad, Alexander Fosså, Bj∅rn Østenstad, Eva Löfvenberg, Marie Nordström, Lars Möller Pedersen, Harald Anderson, Mats Jerkeman, Mikael Eriksson
Journal: Blood (2010)
NCOG-05. INTRA-INDIVIDUAL NEUROCOGNITIVE VARIABILITY IN PATIENTS WITH CANCER: A PREDICTOR AND MARKER OF NEUROTOXICITY ASSOCIATED WITH CHEMOTHERAPY?
Authors: David Sheppard, Kyle Noll, Jeffrey Wefel
Journal: Neuro-Oncology (2018)

There is a growing concern about neurotoxicity involving decreased neurocognitive function (NCF) associated with systemic chemotherapy. Intra-individual variability (IIV) is an index of NCF performance spread within an individual considered to be an indicator of neurocognitive control, and has been shown to worsen on reaction time tasks after chemotherapy in breast cancer. The aim of the current study was to investigate IIV as indexed by dispersion of performances across a battery of NCF tests to determine whether (1) IIV prior to chemotherapy predicts declines in NCF status and (2) whether IIV increases during and shortly after chemotherapy. Forty-two women with breast cancer were administered a standardized neuropsychological battery that included tests of learning and memory, attention, processing speed, and executive function prior to and during/shortly after chemotherapy. To compute covariance of variation (CoV), intra-individual standard deviation across normatively-adjusted z-scores was generated and divided by the mean of these scores. Patients were assessed for depression using the BDI-2. Baseline IIV was higher in patients that declined (mean[SD]= 3.19[3.94]) compared to patients that were stable or improved after chemotherapy (1.43[0.88]) with a medium to large effect size (Hedge’s g=.62, p=.12). Paired samples t-test revealed that IIV did not significantly change on average from before to during/after chemotherapy (Hedge’s g=.18, p=.42). Trends were observed for a correlation between worsened IIV over time and worsened mean-level neuropsychological performance (r =-.29, p=.08), but not with changes in depression (r =.03, p=.87). CONCLUSIONS: Neurocognitive IIV prior to chemotherapy was associated with declines in cognitive performance, although changes in IIV after chemotherapy were not evident. Higher levels of neurocognitive dispersion prior to treatment may serve as an important risk factor for susceptibility to neurotoxic effects of systemic chemotherapies. Confirmation of these results in larger samples and diverse cancer and treatment types are warranted.