tbuckley/cabot-search huggingface dataset:
IMG-20. RADIOMIC FEATURES IMPROVE PROGNOSTICATION OVER CONVENTIONAL MR DERIVED QUALITATIVE DESCRIPTORS IN PEDIATRIC SUPRATENTORIAL HIGH GRADE GLIOMA: COMPARISON OF MACHINE LEARNING TECHNIQUES
Authors: John Lucas, Chih-Yang Hsu, Jared Becksfort, Scott Hwang, Zhaohua Lu, Yichuan Wang, Jason Chiang, Christopher Tinkle, Amar Gajjar, Thomas Merchant, Zoltan Patay
Journal: Neuro-Oncology (2020)

Abstract PURPOSE/OBJECTIVES Pediatric supratentorial high-grade glioma (stHGG) is a biologically heterogeneous disease defined by unique mutations, natural history and prognosis. Prior work by our group outlined a role for qualitative imaging features in aiding prognostication. We build on that work by evaluating the prognostic utility of radiomic features (RM) when paired with clinical factors. MATERIALS/ METHODS Ninety-one patients age &amp;lt; 21 years with stHGG treated between 1980–2007 were retrospectively reviewed. Prognostic clinical, qualitative imaging (Visually AcceSAble Rembrandt Images, VASARI), and treatment characteristics were evaluated in concert with manual and automatically segmented (DeepMedic), tumor-derived semi-quantitative radiomic features (Pyradiomics) extracted from MR images. Prognostic RM were limited to stable imaging features which were subsequently selected using bootstrapped least absolute shrinkage and selection operator (LASSO). Nonparametric descriptive statistics and prognostication model evaluation, incorporating RM and clinical variables, were developed using random forest (RF), Cox proportional hazards (CPH), and deep learning (deepsurv) algorithms and assessed for goodness of fit using (c-index). RESULTS A subset (N=80) of 386 intensity, shape, and texture derived RM were stable between pre-treatment MR. 28 RM features were independently predictive of survival when compared to models utilizing combinations of clinical, VASARI and had comparable model fit statistics. CPH, RF and deepsurv showed comparable utility in modelling RM features. Combined modelling of clinical, VASARI and RM features using CPH, RF, and deepsurv resulted in c-indices of 0.68, 0.67, 0.68, respectively. CONCLUSION RM features are stable and independently prognostic. Combined modelling of clinical, VASARI, and RM features improves prognostication in stHGG.
Genome-wide association study of asthma exacerbations despite inhaled corticosteroid use
Authors: Natalia Hernandez-Pacheco, Susanne J. Vijverberg, Esther Herrera-Luis, Jiang Li, Yang Yie Sio, Raquel Granell, Almudena Corrales, Cyrielle Maroteau, Ryan Lethem, Javier Perez-Garcia, Niloufar Farzan, Katja Repnik, Mario Gorenjak, Patricia Soares, Leila Karimi, Maximilian Schieck, Lina Pérez-Méndez, Vojko Berce, Roger Tavendale, Celeste Eng, Olaia Sardon, Inger Kull, Somnath Mukhopadhyay, Munir Pirmohamed, Katia M.C. Verhamme, Esteban G. Burchard, Michael Kabesch, Daniel B. Hawcutt, Erik Melén, Uroš Potočnik, Fook Tim Chew, Kelan G. Tantisira, Steve Turner, Colin N. Palmer, Carlos Flores, Maria Pino-Yanes, Anke H. Maitland-van der Zee
Journal: European Respiratory Journal (2020)

Substantial variability in response to asthma treatment with inhaled corticosteroids (ICS) has been described among individuals and populations, suggesting the contribution of genetic factors. Nonetheless, only a few genes have been identified to date. We aimed to identify genetic variants associated with asthma exacerbations despite ICS use in European children and young adults and to validate the findings in non-Europeans. Moreover, we explored whether a gene-set enrichment analysis could suggest potential novel asthma therapies.A genome-wide association study (GWAS) of asthma exacerbations was tested in 2681 children of European descent treated with ICS from eight studies. Suggestive association signals were followed up for replication in 538 European asthma patients. Further evaluation was performed in 1773 non-Europeans. Variants revealed by published GWAS were assessed for replication. Additionally, gene-set enrichment analysis focused on drugs was performed.10 independent variants were associated with asthma exacerbations despite ICS treatment in the discovery phase (p≤5×10-6). Of those, one variant at the CACNA2D3-WNT5A locus was nominally replicated in Europeans (rs67026078; p=0.010), but this was not validated in non-European populations. Five other genes associated with ICS response in previous studies were replicated. Additionally, an enrichment of associations in genes regulated by trichostatin A treatment was found.The intergenic region of CACNA2D3 and WNT5A was revealed as a novel locus for asthma exacerbations despite ICS treatment in European populations. Genes associated were related to trichostatin A, suggesting that this drug could regulate the molecular mechanisms involved in treatment response.
SWK-05. EDUCATIONAL APPROACH TO GRIEF MANAGEMENT
Authors: Veronica DeRosa, Nina Madrid
Journal: Neuro-Oncology (2020)

Abstract Pediatric neuro-oncology has a high mortality rate compared to other childhood cancers. This project sought to bring Awareness to the Grief and Trauma that families undergo during treatment through end of life. It also sought to create a pool of parent partners to support families receiving palliative care and to mend the healthcare relationship that is severed when a child passes away. The educational series included Grief Workshops for Bereaved Parents using the ATTEND model, a mindfulness-based bereavement model and seminars with traumatic grief experts for providers. This provided a better understanding on how healthcare workers are influential in the “death story” of a child and how this can dictate the family’s lifelong grief journey. Grief workshops consisted of 2 English and 1 Spanish speaking cohort each with 10–12 bereaved parents. The curriculum provided psychoeducation with the goal of creating a safe space to validate, clarify, and understand the events that happened in their child’s life; support for the parent as they explore emotional awareness; relief of emotional tension; support as the parent expresses their perspective of their new world to others that are in their life; and support as the parent finds meaning in their child’s life and untimely death. At the end of each group surveys showed that parents found that the group provided a safe community, a place to say their child’s name, a place to share their story, and a need to advocate for future oncology parents who undergo this journey.
BIOM-49. SERUM microRNA IS A PROGNOSTIC AND POST-OPERATIVE MONITORING BIOMARKER IN GLIOMA
Authors: Jordan Jones, Andrew Morokoff, Kate Drummond
Journal: Neuro-Oncology (2020)

Abstract Although magnetic resonance imaging (MRI) provides accurate anatomical and spatial details regarding gliomas, it is not reliable at predicting biological behaviour and is confounded by problems such as pseudo-progression. A circulating biomarker has potential to improve predictions of glioma outcomes and identify tumor progression post treatment, however no such biomarker is currently available. We aimed to discover a microRNA (miRNA) serum biomarker for longitudinal monitoring of glioma patients as well as identify miRNAs that are predictive of survival outcomes. To investigate this a prospectively collected cohort of 91 gliomas and 17 healthy controls underwent pre- and post-operative serum miRNA profiling using the next-generation sequencing platform Nanostring®. Differentially expressed miRNAs were discovered using a machine learning random forest analysis. Candidate miRNAs were then assessed by droplet digital PCR in 11 patients with multiple follow-up samples and compared to tumor volume based on MRI. A lasso-regression model was used to identify candidate miRNAs from pre-operative serum that were associated with both progression-free and overall survival. We identified a 9-gene miRNA signature that could distinguish between glioma and healthy controls with 99.8% accuracy. From this signature, we identified two miRNAs that demonstrated dynamic changes which correlated closely with tumor volume in both LGG and GBM. Importantly, miRNA levels did not increase in two cases of pseudo-progression, indicating the potential utility of this test in guiding treatment decisions. Additionally, altered expressions of 6 miRNAs were found to be associated with overall and progression-free survival and were incorporated in a predictive model with already known survival factors. In conclusion, we have identified a highly accurate 9-miRNA signature associated with glioma serum and observed specific miRNAs that both correlated with tumor volume over long-term follow up and were predictive of survival. These results support a large prospective validation study of serum miRNA biomarkers in glioma.
Does dose reduction of renally cleared antibiotics in patients with impaired renal function lead to adequate drug exposure? A systematic review
Authors: Suzanne L. de Vroom, Frederike V. van Daalen, Saskia E. Zieck, Ron A.A. Mathôt, Reinier M. van Hest, Suzanne E. Geerlings
Journal: Clinical Microbiology and Infection (2020)

There is inconsistency between many guidelines in the recommended dose reduction of renally cleared antibiotics in patients with impaired renal function.This systematic review summarizes the available evidence on the adequacy of the recommended dose reduction in terms of achieving sufficient antibiotic drug exposure or pharmacokinetic/pharmacodynamic target attainment after treatment with these reduced doses.We systematically searched Ovid Medline and Embase from inception (respectively 1946 and 1947) through July 2019.All studies reporting antibiotic drug exposure and/or pharmacokinetic/pharmacodynamic (PK/PD) target attainment after dose reduction of antibiotics in patients with impaired renal function.Adult patients with or without infections.Administration of reduced doses of antibiotics (orally, intravenously or intramuscularly).The reduced dose was considered adequate when the most relevant parameters of drug exposure or PK/PD target attainment in patients with impaired renal function were within a range of 80% to 125% of that patients with adequate renal function receiving a regular dose (reference) or when PK/PD target attainment was attained in at least 90% of the patients with impaired renal function, regardless of the lack of a reference group.Twenty-seven of the 4202 identified studies were included. The quality of 15 of 27 studies was fair, and most studies were of β-lactams (12/27). Best evidence was available for meropenem: four studies were included, of which two studies were of good quality. Drug exposure for meropenem is 158% to 286% higher in patients with impaired renal function receiving reduced doses compared to patients with adequate renal function receiving regular doses. For all other antibiotics, a maximum of one good-quality study could be identified.No good-quality evidence on the recommended dose reduction of renally cleared antibiotics in patients with impaired renal function is present, with the exception of meropenem.
β1-アドレナリン作動受容体の第2細胞外ループに対する慢性自己免疫は,ウサギにおける早期後脱分極を誘導し,Kチャネル密度を減少させる
Authors: Fukuda Y, Miyoshi S, Tanimoto K, Oota K, Fujikura K, Hagiwara Y, Iwata M, Baba A, Ogawa S
Journal: Circulation (2003)
Association of plasma phospholipid fatty acids with breast cancer risk among postmenopausal cigarette smokers
Authors: Yumie Takata, Irena King, Marian Neuhouser, Matt Barnett, Mark Thornquist, Gary Goodman, Ulrike Peters
Journal: Cancer Research (2008)

1252  Background: Evidence suggests dietary fat may influence breast cancer risk. A recent large randomized clinical trial of a low-fat diet reported a borderline non-significant reduction in breast cancer incidence. In contrast, observational studies using questionnaire data to estimate dietary fat intake have been equivocal. Blood fatty acids have been suggested as a potential biomarker for recent dietary fat intake. In this report, we investigated the association between the plasma phospholipid fatty acid composition and breast cancer risk in female participants of a large cancer prevention trial.  Methods: We analyzed the plasma phospholipid fatty acid composition in 130 incident postmenopausal breast cancer cases and 257 matched controls nested within the β-Carotene and Retinol Efficacy Trial Cohort. Postmenopausal women included in this study were between 50 and 69 years of age at enrollment (1985-94), had smoked at least 20 pack-years, and were active smokers or had quit within 6 years prior to enrollment. Incident breast cancer cases were diagnosed in between 1990 and 1999. For each case, we selected two controls matched for age, study site, race, study cohort, smoking status, and year of enrollment. The fatty acid composition was measured by gas chromatography. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) for the risk of breast cancer by quartiles of fatty acids were estimated using logistic regression, while adjusting for body mass index and alcohol consumption.  Results: There were no associations with breast cancer risk for total saturated fatty acids (p for trend = 0.38), total monounsaturated fatty acids (p for trend = 0.33), total n-3 fatty acids (p for trend = 0.32), and total n-6 fatty acids (p for trend = 0.82). For individual fatty acids, a suggestive decreasing trend was observed for the n-6 fatty acid, γ-linolenic acid (C18: 3n-6; OR for highest versus lowest quintile = 0.61; 95% CI = 0.33-1.12; p for trend = 0.08).  Conclusion: Overall, we observed no significant association between plasma phospholipid fatty acids and breast cancer risk. The suggested non-significant inverse association of γ-linolenic acid with the risk of breast cancer is consistent with experimental data and results from two case-control studies. This finding needs to be further confirmed in larger epidemiologic studies. This study was funded by National Cancer Institute (NCI CA063673).
EPCT-03. A PHASE I TRIAL OF 2-HYDROXYOLEIC ACID IN PEDIATRIC PATIENTS WITH ADVANCED CENTRAL NERVOUS SYSTEM TUMORS
Authors: Derek Hanson
Journal: Neuro-Oncology (2020)

Abstract 2-hydroxyoleic acid (2-OHOA) is the first potential anti-cancer drug to act by modification of cell membrane lipid content. The agent is a derivative of oleic acid, a naturally occurring component of olive oil. Through its unique mechanism of activating sphingomyelin synthase 1, 2-OHOA targets the membrane lipid composition of cancer cells. These lipid changes alter membrane-dependent signaling cascades, such as the Ras/MAPK pathway, that promote tumor cell proliferation. A comprehensive pre-clinical program has characterized the safety and effects of 2-OHOA across a host of animal models. A European phase I/IIa trial of 2-OHOA in adult patients has shown initial promising results with five refractory high-grade glioma patients demonstrating objective clinical benefit by RANO criteria for six or more months. The drug has been very well-tolerated in adult patients with minimal toxicity. This phase I study is the first pediatric investigation of 2-OHOA and focuses on the treatment of relapsed/refractory pediatric central nervous system (CNS) tumors. The trial consists of a dose-escalation phase in up to 18 patients using a standard “3 + 3” design, followed by an expanded safety cohort of up to 10 patients treated at the maximum tolerated dose to confirm the recommended phase II dose. Due to the promising clinical results in adult neuro-oncology patients and the widespread involvement of the Ras/MAPK pathway and other membrane-dependent signaling cascades in the development of pediatric malignancies, we hypothesize that 2-OHOA may be a safe and effective treatment for pediatric patients with several types of advanced CNS tumors.
INNV-18. RECURRENT SHH MEDULLOBLASTOMA EXTRANEURAL METASTASES TO THE BONE MARROW WITHOUT CNS INVOLVEMENT
Authors: Brad Clifton, Mark Anderson
Journal: Neuro-Oncology (2020)

Abstract Medulloblastoma is the most common primary brain tumor in children, but is rare in adults. Because of the scarcity of adult medulloblastoma cases, treatment guidelines in the adult population are not well established, especially regarding surveillance and treatment of recurrent disease. A 47-year-old African American male presented with one month of progressive unsteady gait and dizziness. Imaging revealed a posterior fossa mass and the patient underwent gross total resection. Histology confirmed medulloblastoma and molecular subtyping revealed Sonic Hedgehog (Shh) pathway activation. No metastases were found at the time of diagnosis, and the patient received adjuvant craniospinal radiation therapy. Three years later the patient developed low back pain with severe sciatica affecting his gait and pancytopenia. Imaging revealed diffuse osseous disease without CNS recurrence and bone marrow biopsy confirmed recurrent medulloblastoma. The patient subsequently began reduced chemotherapy consisting of cisplatin and etoposide because of his severe pancytopenia. Due to a lack of response after 4 cycles, the SMO antagonist vismodegib was added. Follow-up imaging revealed improvement/stability of osseous disease, lab work demonstrated resolution of pancytopenia, and repeat bone marrow was without malignancy. Vismodegib was continued as maintenance therapy. Six months after completion of cisplatin/etoposide, follow-up imaging revealed progression of metastatic disease. Shh activated medulloblastomas have demonstrated responses to SMO inhibition. However, these responses are often transient secondary to rapid development of resistance, but may have a role to play in patients who have bone marrow involvement that limits use of cytotoxic therapy or bone marrow transplant. Due to poor survival outcomes associated with bone marrow metastases, aggressive screening for bone marrow metastases at diagnosis and in surveillance should be considered.
PATH-32. CLINICAL AND MUTATIONAL PROFILES OF ADULT MEDULLOBLASTOMA GROUPS
Authors: Gabriel Chun-Hei Wong, Queenie Junqi Huang, Manix Fung Man Poon, Nellie Yuk-Fei Chung, Queenie Hoi-Wing Wong, Zhen-Yu Zhang, Zhi-Feng Shi, Hong Chen, Aden Ka-Yin Chan, Kay Ka-Wai Li, Ho-Keung Ng
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Adult medulloblastomas are clinically and molecularly understudied due to their rarity. METHODS We studied a cohort of 101 adult medulloblastomas grouped by Nanostring assay. We performed targeted sequencing on exonic regions of 69 genes implicated in medulloblastoma, and Sanger sequencing for TERT promoter hotspot mutations. RESULTS Median age was 27 (range 19-63), and 9.5% were metastatic at diagnosis. SHH accounted for 50% of cases. Unlike previous studies, Group 3 comprised a significant proportion (14%) of adult medulloblastomas, comparable to WNT (19%) and Group 4 (18%). Median follow-up was 51.1 months. Median OS and PFS were 102 and 99 months respectively. In contrast to paediatric medulloblastomas, molecular groups had no prognostic impact in adults, for both OS (p=0.956) and PFS (p=0.162). Most frequently mutated genes were TERT (including promoter, mutated in 35% cases), chromatin modifiers KMT2C (32%) and KMT2D (31%), TCF4 (31%), PTCH1 (26%) and DDX3X (24%). Adult WNT patients showed enrichment of TP53 mutations (6/15 WNT cases), and 3/6 TP53-mutant WNT tumours were of large cell/anaplastic histology. 5 WNT cases harboured concurrent CTNNB1 and PTCH1 mutations. Adult SHH medulloblastomas had frequent upstream pathway alterations (PTCH1 and SMO mutations) and seldom downstream alterations (SUFU mutations, MYCN amplifications). TERT promoter mutations were found in 71% of adult SHH patients, and were restricted to this group. Adult Group 3 patients lacked hallmark MYC amplifications, but had recurrent mutations in KBTBD4 and NOTCH1. Adult Group 4 patients had recurrent mutations in TCF4 and chromatin modifier genes. Overall, amplifications of MYC and MYCN were rare (3%) in adult medulloblastomas. CONCLUSIONS We identified distinct clinical and mutational characteristics of adult medulloblastomas that will inform their treatment and risk stratification. Importantly, molecular groups were not prognostic in adult medulloblastoma, TP53 mutations were enriched in adult WNT, and MYC amplifications were absent in adult Group 3.
Apolipoprotein E, low-density lipoprotein receptor, and immune cells control blood-brain barrier penetration by AAV-PHP.eB in mice
Authors: Bao-Shu Xie, Xin Wang, Yao-Hua Pan, Gan Jiang, Jun-Feng Feng, Yong Lin
Journal: Theranostics (2020)

Rationale: The blood-brain barrier (BBB) prevents the effective delivery of therapeutic molecules to the central nervous system (CNS). A recently generated adeno-associated virus (AAV)-based vector, AAV-PHP.eB, has been found to penetrate the BBB more efficiently than other vectors including AAV-PHP.B. However, little is known about the mechanisms. In this study, we investigated how AAV-PHP.eB penetrates the BBB in mice. Methods: We injected AAV-PHP.eB into the bloodstream of wild-type C57BL/6 and BALB/c mice as well as mouse strains carrying genetic mutation in apolipoprotein E gene (Apoe) or low-density lipoprotein receptor gene (Ldlr), or lacking various components of the immune system. Then, we evaluated AAV-PHP.eB transduction to the brain and spinal cord in these mice. Results: We found that the transduction to the CNS of intravenous AAV-PHP.eB was more efficient in C57BL/6 than BALB/c mice, and significantly reduced in Apoe or Ldlr knockout C57BL/6 mice compared to wild-type C57BL/6 mice. Moreover, poor CNS transduction in BALB/c mice was dramatically increased by B-cell or natural killer-cell depletion. Conclusions: Our findings demonstrate that the ApoE-LDLR pathway underlies the CNS tropism of AAV-PHP.eB and that the immune system contributes to the strain specificity of AAV-PHP.eB.
NCMP-14. SKULL BASE OSTEOMYELITIS DUE TO COMMUNITY-ACQUIRED ASPERGILLUS FUMIGATUS MIMICKING RECURRENT CHONDROSARCOMA
Authors: Kevin Lillehei, B K Kleinschmidt-Demasters
Journal: Neuro-Oncology (2020)

Abstract Skull base chondrosarcomas are often low grade tumors that do not metastasize, but are locally invasive and often recur locally. Thus, when patients with these tumors re-present with new onset symptoms, even decades later, recurrent tumor is presumed. A 50 year old woman with skull base chondrosarcoma initially diagnosed 30 years prior developed the subacute onset of worsening confusion and vision, with progressive blindness. Imaging disclosed a bony-erosive skull base mass without associated sinusitis/sinus opacification; additional small cerebral infarcts were identified. She had been on physiologic replacement therapy for panhypopituitarism since the original surgery, but had not received recent radiation therapy or chemotherapy and did not have neutropenia. RESULTS: Biopsy disclosed a chronic inflammation and necrotic debris; only on permanent sections were septated, 45-degree angle-branching fungi identified in one area. These had morphological features of, and were polymerase chain reaction-proven, Aspergillus fumigatus. No recurrent tumor was present. Given the lack of perceived risk factors, further questioning of the patient and her mother disclosed that precisely 1 year prior to surgery she and her family had participated in “cleaning out an old very dirty and dusty barn” in southern Colorado without the use of face masks; only the proband experienced sequelae. Anti-fungal therapy (voriconazole) was recommended although patient use was intermittent and symptoms have progressed. CONCLUSION: Community-acquired Aspergillus infections due to exposure to silage or barn detritus contaminated by fungal hyphae is almost never seen today, in comparison to opportunistic infections due to known risk factors of neutropenia and/or steroid usage. Replacement therapy may have added to this patient’s risk. Infections all too often mimic recurrent tumor.