tbuckley/cabot-search huggingface dataset:
IMMU-03. TUMOR NECROSIS FACTOR OVERCOMES IMMUNE EVASION IN P53-MUTANT MEDULLOBLASTOMA
Authors: Alexandra Garancher, Hiromichi Suzuki, Svasti Haricharan, Meher Beigi Masihi, Jessica M Rusert, Paula S Norris, Florent Carrette, Megan M Romero, Sorana A Morrissy, Patryk Skowron, Florence M.G. Cavalli, Hamza Farooq, Vijay Ramaswamy, Steven J.M. Jones, Richard A Moore, Andrew J Mungall, Yussanne Ma, Nina Thiessen, Yisu Li, Alaide Morcavallo, Lin Qi, Jacob J Henderson, John R Crawford, Michael L Levy, James M Olson, Yoon-Jae Cho, Ani Deshpande, Xiao-Nan Li, Louis Chesler, Marco A Marra, Oren J Becher, Linda M Bradley, Carl F Ware, Michael D Taylor, Robert J Wechsler-Reya
Journal: Neuro-Oncology (2019)

Many immunotherapies act by enhancing the ability of T cells to kill tumor cells. But T cell killing depends on recognition of antigens presented by Class I MHC (MHC-I) on the tumor cell surface; if a tumor lacks MHC-I, it cannot be recognized by T cells. To study the efficacy of immunotherapy for Group 3 medulloblastoma, we have used mouse models driven by overexpression of Myc and dominant negative p53 ("MP tumors"), or by overexpression of Myc and Gfi1 ("MG tumors"). While MP tumors grow in immunocompetent mice, MG tumors don't grow, due to T-cell rejection. To understand this difference, we analyzed expression of immunoregulatory molecules, and found that MP tumors completely lack surface MHC-I. Mechanistically, this is because two key proteins required for MHC-I trafficking – TAP1 and ERAP1 – are targets of p53; since MP tumors lack functional p53, they also lack TAP1 and ERAP1, and surface MHC-I. These studies suggest that p53 plays a critical role in determining immunogenicity, and that p53-mutant tumors are resistant to immune attack. To overcome this resistance, we treated tumor cells with agents that regulate MHC-1. We found that low doses of tumor necrosis factor alpha (TNF) can rescue expression of ERAP, TAP and MHC-I on MP tumor cells. In vivo, TNF prolongs survival of tumor-bearing mice, and markedly augments the efficacy of immune checkpoint inhibitors. These results raise the possibility that TNF could be used prior to immunotherapy to render tumors more sensitive to T cell attack.
Tracheal Lymphoepithelioma-Like Carcinoma on FDG PET/CT
Authors: Dan Shao, Wenshuang Ding, Siyun Wang, Jiawei Liang, Shuxia Wang
Journal: Clinical Nuclear Medicine (2019)

Lymphoepithelioma-like carcinoma (LELC) in the trachea is an extremely rare disease. We present a case of a 64-year-old man with FDG-avid tracheal LELC on F-FDG PET/CT. Despite its rarity, LELC in the trachea should be considered as one of the possibilities in patients with a hypermetabolic mass in the trachea. If LELC in the trachea is suspected, F-FDG PET/CT is a useful tool for initial staging.
Long-Term Outcomes in Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)
Authors: Naveen Pemmaraju, Hagop M. Kantarjian, Joseph David Khoury, Susan M. O'Brien, Jorge E. Cortes, Guillermo Garcia-Manero, Elias J. Jabbour, Nitin Jain, Yesid Alvarado, Madeleine Duvic, Phyu Aung, Muzaffar H. Qazilbash, C. Cameron Yin, Sergej Naumovich Konoplev, Keyur P. Patel, Sherry Pierce, Mark Brandt, Marina Konopleva
Journal: Blood (2017)
GENE-16. EVALUATING THE UTILITY OF INTEGRATED CLINICAL SEQUENCING FOR CHILDHOOD NEURO-ONCOLOGY PATIENTS: THE TEXAS KIDSCANSEQ STUDY
Authors: Ross Mangum, Frank Y Lin, Adekunle M Adesina, Carrie A Mohila, Guillermo Aldave, Murali M Chintagumpala, Angshumoy Roy, Amy McGuire, Sharon E Plon, D Williams Parsons
Journal: Neuro-Oncology (2019)

Genomic sequencing technologies have facilitated the unbiased examination of cancer genomes, allowing rational prioritization of candidate genes and pathways for biological study and clinical application. Clinical experience with these methods as “precision oncology” strategies for children with central nervous system (CNS) tumors remains unproven. Over the past several years, a number of pilot studies of precision oncology have provided early clues regarding the feasibility, clinical utility, and limitations of genome-scale testing, emphasizing the critical importance of both tumor and germline results for patient care. These studies provide a foundation for incorporation of genomic testing into prospective clinical trials utilizing biomarker-driven treatment assignments in the care of pediatric cancer patients. To more rigorously compare the diagnostic utility of clinical genomic tests, the Texas KidsCanSeq study, an NHGRI and NCI-funded Clinical Sequencing Evidence Generating Research (CSER) Program project, was activated in June 2018. This study, which will enroll 1100 patients from six Texas institutions, aims to compare the diagnostic yield of targeted panel testing (comprehensive pediatric cancer-focused DNA and RNA panels utilized clinically at Texas Children’s Cancer Center) versus more extensive genomic testing (exome sequencing, transcriptome sequencing, copy number array) of formalin-fixed paraffin-embedded tumor and blood samples. Additionally, study oncologists are being surveyed regarding the downstream implications of these tests on decision-making related to the use of molecularly targeted therapies and/or enrollment on clinical trials. Early examples of CNS tumor cases with clinically-actionable mutations include two patients with midline high grade glioma (HGG) harboring activating PIK3CA mutations (15 year old male with thalamic HGG and PIK3CA p.Glu542Lys; 7 year old female with pontine HGG and PIK3CA p.Glu545Gly) that are potentially targetable by PI3K inhibitors or combined PI3K/MTOR inhibitors. These cases highlight the potential utility of molecular testing of pediatric CNS tumors for identification of novel therapies and relevant clinical trials.
MEDU-44. MUSASHI-1 IS A MASTER REGULATOR OF ABERRANT TRANSLATION IN GROUP 3 MEDULLOBLASTOMA
Authors: Michelle Kameda-Smith, Kevin Brown, Helen Zhu, EnChing Luo, Brian Yee, Sansi Xing, Chitra Venugopal, Eric van Nostrand, David Bakhshinyan, Minomi Subapanditha, Ashley Adile, John Provias, Adam Fleming, Kristin Hope, Juri Reimand, Yu Lu, Gene Yeo, Robert Wechsler-Reya, Sheila Singh
Journal: Neuro-Oncology (2019)

Pediatric medulloblastoma (MB) is the most common solid malignant brain neoplasm, with group 3 (G3) MB representing the poorest prognostic subgroup with a remarkable ability to resist upfront multimodal therapy. Despite a low mutational burden of disease and MYC amplification identified as a independent factor associated with poor survivorship, efforts to target MYC or the MYC-MAX complex has met with limited therapeutic success. Consequently alternative mediators associated with the aggressive phenotype of G3 MB continues as a common goal within the MB community. Here we show how the neural stem cell determinant Musashi 1 (MSI1) is a central and vital moderator of G3 MB. Specifically, we employed shRNA inhibition against Msi1 in multiple patient derived cell lines, observing a striking deficit in multiple key stem cell features. Notably, in our MYC amplified G3 MB patient derived xenograft (PDX) models, Msi1 inhibition resulted in a failure of tumor initiation, translating to a significantly prolonged survival, reaffirming the essential role for MSI1 in G3 MB. To determine how MSI1 symphonizes the anarchic post-transcriptional landscape of G3 MB, an unbiased approach using enhanced cross-linking and immunoprecipitation (eCLIP) of both normal neural stem cells and G3 MB provided insight into the aberrant function of MSI1 in G3 MB. To further tease out the functional mechanism of MSI1, a multi-platform study of the 1) eCLIP binding targets, and differential analysis post-Msi1 inhibition at the 2) transcriptome-, and 3) proteome-wide scale was completed to inform targeted drug discovery. MSI1 not only binds and moderates MYC and OTatrt-14 X2 but other key G3 MB associated gene transcripts. Here we propose the neural RNA binding protein MSI1, as a master regulator, hijacked from its normal neural developmental function, orchestrating the aberrant translational landscape of G3 MB.
用于特应性皮炎的 PAC‐14028 乳膏
Authors: Y.W. Lee, C.‐H. Won, K. Jung, H.‐J. Nam, G. Choi, Y.‐H. Park, M. Park, B. Kim
Journal: British Journal of Dermatology (2019)

这项来自韩国的研究显示,一种名为 PAC‐14028 的不含类固醇的乳膏在治疗湿疹症状时与当前市售乳膏一样有效,且副作用更少。湿疹是最常见的皮肤病之一。现有局部(外用于皮肤)治疗在治疗湿疹症状方面可以非常有效。但是,它们可导致不良副作用,如瘙痒和烧灼感,进而使患者中止他们的治疗。对 194 名轻中度湿疹成人进行了这项研究。参与者被分为 4 个组,接受对照乳膏或 3 种不同浓度(0.1%、0.3% 或 1.0%)新治疗 PAC‐14028 乳膏给药。参与者每天两次外用乳膏,共计 8 周。主要使用研究者整体评估 (IGA) 测量结果。这是一个基于典型症状评估患者湿疹严重程度的视觉量表。8 周后,最高浓度 PAC‐14028 乳膏组中有 57.5% 患者的 IGA 评分显示他们的湿疹症状完全根除或降低至几乎清除的水平。对于对照乳膏,第 8 周的 IGA 成功率为 15%,而 0.1%、0.3% 和 1.0% PAC‐14028 乳膏分别为 43%、38% 和 57%。PAC‐14028 乳膏的疗效与常用的名为吡美莫司的非类固醇乳膏相似,但不良副作用的发生率远低于吡美莫司。
TMOD-19. GABRIELLA MILLER KIDS FIRST DATA RESOURCE CENTER: LARGE-SCALE HARMONIZED CLINICAL AND GENOMIC DATA PLATFORM TO SUPPORT CHILDHOOD CANCER AND STRUCTURAL BIRTH DEFECT RESEARCH
Authors: Allison Heath, Pichai Raman, Yuankun Zhu, Jena Lilly, Deanne Taylor, Phillip Storm, Angela Waanders, Vincent Ferretti, Michele Mattioni, Brandi Davis-Dusenbery, Zachary Flamig, Robert Grossman, Samuel Volchenboum, Sabine Mueller, Javad Nazarian, Nicole Vasilevsky, Melissa Haendel, Adam Resnick
Journal: Neuro-Oncology (2019)

Childhood cancers and structural birth defects share a common context of altered developmental biology, but the potential role of shared, genetic alterations and/or pathways across pediatric cancers and birth defects is not well explored. It is increasingly critical that genomic data are paired with high-quality clinical data to drive translational research by elucidating the relationship between genomic alterations, treatments, outcomes, and other phenotypic characteristics. The NIH Common Fund Gabriella Miller Kids First Program represents a first-in-kind national, collaborative initiative focused on large-scale clinical and genomic data sharing for childhood cancers and structural birth defects. As part of this program, the Kids First Data Resource Center (DRC) is charged with empowering collaborative discovery across Kids First datasets. Through newly developed platforms and cloud-based resources, researchers will be able to rapidly and interactively access standardized and harmonized clinical and genomic data. A better understanding of common developmental programs could spur advancements in prevention, detection, and therapeutics that will improve the outcomes of affected children and families. Approximately 8,000 patient samples were available at the launch of the Kids First DRC portal including a data cohort of more than 2000 pediatric brain tumor WGS/RNAseq provided by the Children’s Brain Tumor Tissue Consortium (CBTTC) and the Pacific Pediatric Neuro-Oncology Consortium (PNOC). More than 25,000 WGS are expected to be processed by 2019, making the DRC platform one of the largest pediatric data resources across childhood diseases. The combination of harmonized genomic and clinical data across pediatric cancers and structural birth defect provides a key foundation for exploring and developing new methods to better understand the relationships between germline variants, cancer risk, and associated treatments and outcomes across cancers and especially within pediatric brain tumors.
Abstract 19021: Relationship Between Smoker’s Paradox and P2y12 Receptor Inhibition Therapy in Patients With St-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention: A Novel Insight into a Persisting Paradox
Authors: Pier-Giorgio Masci, Sophie Degrauwe, Olivier Muller, Eric Eeckhout, Dragana Radovanovic, Paul Erne, Juan F. Iglesias
Journal: Circulation (2016)

Introduction: Recent studies have shown that active smokers undergoing primary percutaneous coronary intervention (pPCI) for ST-segment elevation myocardial infarction (STEMI) have lower in-hospita...
Early Binaural Hearing: The Comparison of Temporal Differences at the Two Ears
Authors: Philip X. Joris, Marcel van der Heijden
Journal: Annual Review of Neuroscience (2019)

Many mammals, including humans, are exquisitely sensitive to tiny time differences between sounds at the two ears. These interaural time differences are an important source of information for sound detection, for sound localization in space, and for environmental awareness. Two brainstem circuits are involved in the initial temporal comparisons between the ears, centered on the medial and lateral superior olive. Cells in these nuclei, as well as their afferents, display a large number of striking physiological and anatomical specializations to enable submillisecond sensitivity. As such, they provide an important model system to study temporal processing in the central nervous system. We review the progress that has been made in characterizing these primary binaural circuits as well as the variety of mechanisms that have been proposed to underlie their function.
Single-Fraction Stereotactic vs Conventional Multifraction Radiotherapy for Pain Relief in Patients With Predominantly Nonspine Bone Metastases
Authors: Quynh-Nhu Nguyen, Stephen G. Chun, Edward Chow, Ritsuko Komaki, Zhongxing Liao, Rensi Zacharia, Bill K. Szeto, James W. Welsh, Stephen M. Hahn, C. David Fuller, Bryan S. Moon, Justin E. Bird, Robert Satcher, Patrick P. Lin, Melenda Jeter, Michael S. O’Reilly, Valerae O. Lewis
Journal: JAMA Oncology (2019)

Consensus is lacking as to the optimal radiotherapy dose and fractionation schedule for treating bone metastases.To assess the relative efficacy of high-dose, single-fraction stereotactic body radiotherapy (SBRT) vs standard multifraction radiotherapy (MFRT) for alleviation of pain in patients with mostly nonspine bone metastases.This prospective, randomized, single-institution phase 2 noninferiority trial conducted at a tertiary cancer care center enrolled 160 patients with radiologically confirmed painful bone metastases from September 19, 2014, through June 19, 2018. Patients were randomly assigned in a 1:1 ratio to receive either single-fraction SBRT (12 Gy for ≥4-cm lesions or 16 Gy for <4-cm lesions) or MFRT to 30 Gy in 10 fractions.The primary end point was pain response, defined by international consensus criteria as a combination of pain score and analgesic use (daily morphine-equivalent dose). Pain failure (ie, lack of response) was defined as worsening pain score (≥2 points on a 0-to-10 scale), an increase in morphine-equivalent opioid dose of 50% or more, reirradiation, or pathologic fracture. We hypothesized that SBRT was noninferior to MFRT.In this phase 2 noninferiority trial of 96 men and 64 women (mean [SD] age, 62.4 [10.4] years), 81 patients received SBRT and 79 received MFRT. Among evaluable patients who received treatment per protocol, the single-fraction group had more pain responders than the MFRT group (complete response + partial response) at 2 weeks (34 of 55 [62%] vs 19 of 52 [36%]) (P = .01), 3 months (31 of 43 [72%] vs 17 of 35 [49%]) (P = .03), and 9 months (17 of 22 [77%] vs 12 of 26 [46%]) (P = .03). No differences were found in treatment-related toxic effects or quality-of-life scores after SBRT vs MFRT; local control rates at 1 and 2 years were higher in patients receiving single-fraction SBRT.Delivering high-dose, single-fraction SBRT seems to be an effective treatment option for patients with painful bone metastases. Among evaluable patients, SBRT had higher rates of pain response (complete response + partial response) than did MFRT and thus should be considered for patients expected to have relatively long survival.ClinicalTrials.gov identifier: NCT02163226.
Abstract 19542: A North American Survey of Public Opinion on the Acceptability of Crowdsourcing Basic Life Support for Out-of-hospital Cardiac Arrest
Authors: Katie N Dainty, Steven Brooks
Journal: Circulation (2015)

Introduction: Performance of bystander CPR and early defibrillation following out-of-hospital cardiac arrest (OHCA) have been shown to increase the odds of survival to hospital discharge more than 3-fold. The PulsePoint Respond™ Application (App) is a novel system that can be implemented by EMS to crowdsource basic life support for victims of OHCA. The system sends cardiac arrest notifications to a user’s mobile device which includes the location of the emergency and nearby public access defibrillators to facilitate bystander CPR and AED use while EMS personnel are en route. We conducted a North American survey to evaluate public perceptions of such an application, including acceptability and willingness to respond to alerts. Methods: The web-based survey was conducted in Canada and the USA by an established external polling vendor, Ipsos Reid. Sampling was designed to ensure broad representation of gender, age, geography, and spoken language following recent census statistics. Respondents were presented with a short concept description of cardiac arrest and the Pulsepoint app in text format followed by 6 closed-ended and 4 open-ended questions. Results: A random sample of 2,415 total surveys were collected (1106 from Canada and 1309 from the US). 70% of Canadian respondents but only 47% of US respondents had been trained in CPR at some point. On average, 79.5% of respondents agreed that Pulsepoint is something they would like to see in their community and 59.5% said they would download the App. 80% of Canadians and 77% of Americans were comfortable with receiving help in a public setting (street, office, etc) and 72 and 68% respectively, indicated they would be comfortable with receiving help in a private setting (home). Less than 40% of respondents identified concerns; as expected those identified included training concerns and trust issues. An average of 89% of the sample from both countries felt it was important that responders have up-to-date CPR certification. Conclusions: Overall, the North American public find the concept of the Pulsepoint application and crowdsourcing basic life support for OHCA acceptable and would be willing to respond. This is encouraging insight to support the use of social media to increasing bystander CPR rates in North America.
Assessment of the hygiene-related risks of child illness at selected elementary schools in Nablus city: a cross-sectional survey
Authors: Mohammad Qadi, Lubna Kharraz, Amira Shaheen, Athar Amleh, Fatima Ibrahim, Doaa Abu Saleh, Hanin Rabee, Ro'ya Hamed, Ghassan Shakhshir, Rasha Khayyat
Journal: The Lancet (2019)
BSTM-02. LONGITUDINAL MONITORING OF GD-DTPA FOLLOWING CONVECTION ENHANCED DELIVERY IN THE BRAIN STEM
Authors: Umberto Tosi, Mark Souweidane
Journal: Neuro-Oncology (2019)

Convection-enhanced delivery (CED) for primary CNS tumors has recently been adopted as a mean for bypassing the blood brain barrier, a known obstacle in systemic chemotherapeutic strategies. Appropriate drug distribution, tumor coverage, avoidance of egress, and longitudinal monitoring should logically be integrated into measuring clinical utility. To date, co-infusion of surrogate tracers, most notably Gadolinium-diethylenetriaminepentacetate (Gd-DTPA), has been employed for estimations of dose scaling. Understanding the elimination kinetics of surrogate tracers will be meaningful in understanding the relationship with drug pharmacokinetics and inherent time differences in drug administration and imaging. In this case, a 5-year-old girl with diffuse intrinsic pontine glioma (DIPG) previously treated with conventional radio-chemotherapy was treated with oncolytic adenovirus (ICOVIR-5) therapy using convection enhanced delivery (CED). An infusion volume (Vi) of 2000 microliters was used to deliver a total viral load of 1.00 x 1010 (0.50 x 1010 / target site). Co-infusion with Gd-DTPA (1 mM) was used for dosimetry assessment using serial MR imaging at 1, 6, 12, 24, 48, and 168 hours after infusion (3D SPGR). Segmented gadolinium signal was used to estimate the volume of distribution (Vd) and serial measurements were plotted over time to define elimination kinetics. Vd ranged between 2.92 and 3.06 cm3, with a Vd / Vi ranging between 1.46 and 1.53. There was an increase in Vd over time during the initial 18 hours and by 30 hours no Gd-DTPA signal could be detected. In conclusion, Vd and Vd / Vi measurements using 1mM Gd-DTPA are inconsistent with other measures using higher concentrations of surrogate tracer or direct molecular imaging. Gd-DTPA distribution in the brain stem using CED follows time-dependent changes with a small increase in Vd followed by rapid elimination. Defining the elimination kinetics of Gd-DTPA after CED should assist in the interpretation of post-treatment MR imaging
IMMU-24. OX40 AGONISM AS A POTENT TREATMENT FOR IMMUNE-PRIMED HIGH RISK MEDULLOBLASTOMA
Authors: Jacob Henderson, Matt Wood, Andrew Weinberg, Yoon-Jae Cho
Journal: Neuro-Oncology (2019)

Group 3 medulloblastomas (MB) harboring MYC gene amplification are generally considered a relative immune desert. This is despite often carrying a relatively high mutational burden, which is associated with immune checkpoint inhibitor sensitivity in other cancers. For this reason the use of checkpoint inhibitors has largely been dismissed as a potential treatment strategy in these high risk tumors. However, our work using TGFb receptor small molecule inhibitors (TGFbRi) in MYC-amplified MB has shown that inhibiting the TGFb pathway results in increased antigen presenting machinery and checkpoint ligands. And while TGFb pathway inhibition alone significantly prolongs survival in MB-bearing mice, it was not curative with all animals eventually dying of disease. Therefore, we set out to exploit the tumor intrinsic and extrinsic changes that occur in MB with TGFb pathway inhibition and hypothesized that combining TGFb pathway inhibition with immune checkpoint inhibition would result in meaningful improvements in rates of survival. Indeed, “priming” MBs with a TGFbRi in conjunction with weekly administration of OX40 agonist resulted in tumor rejection and durable overall survival relative to either therapy alone. Intracranial tumors collected at various time points throughout TGFbRi “priming” showed increased cell surface expression of OX40, PD-L1 and MHC class one molecules within 1–2 days of TGFbRi treatment. Concurrently, there was a consistent increase in CD4+ and CD8+ T cells into the tumor, which was potentiated with OX40 agonism. These findings imply that the sequence of TGFb receptor inhibition followed by OX40 agonism could be a potent, synergistic combination that should be actively explored in upcoming clinical trials. LOW GRADE GLIOMA