tbuckley/cabot-search huggingface dataset:
QOL-21. DEVELOPMENT AND UTILISATION OF A NEURO-ONCOLOGY REHABILITATION TEAM: 2018–2019 UPDATE
Authors: Helen Paisley, Helen Hartley, Anna Kearney, Alex Hagan, Joanne Owen, Barry Pizer, Natalie Holman, Ram Kumar
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION A multi-disciplinary Neuro-Oncology Rehabilitation Team (NORT) was established at our institution in 2014. We reviewed NORT inputs, processes and outputs in 2018 to 2019 compared to our previously presented data from 2015, soon after service inception. METHODS Retrospective analysis of patients who received NORT input June 2018 - May 2019 compared to 2015 data. Descriptive analysis of changes to NORT operational processes and structure. Complexity of rehabilitation needs was measured using the Rehabilitation Complexity Scale-Extended V13 (RCS). RESULTS 54 children received NORT input in 2018–2019 (10 children in 2015) with total of 129 outputs. NORT input was highest in children with high grade glioma (median reviews: 3; median RCS: 5) and ependymoma (median reviews: 3; median RCS: 5). Pilocytic astrocytoma formed the largest tumour group (n = 11; median reviews: 2; median RCS: 7). 11% patients were referred to neurologist (9% already known); 17% referred to community services (44% already known); 31% referred to neuropsychology. In 2015, outputs were predominantly referral to occupational therapy and physiotherapy. 6 patients (11% of 54) were discharged in 2018–2019 (40% of 10 patients in 2015). 4 patients died. Between 2015 and 2019, developments included: clarifying referral and discharge pathways, use of screening measures, neuropsychology integration, therapy-led drop-in clinics, use of RCS-E. DISCUSSION: There has been a clear increase in utilisation and scope of work of NORT over last 4 years. The strength of this team is multidisciplinary working and expertise. Further developments planned: multidisciplinary rehabilitation interventions and NORT outcome tools.
RONC-12. TREATMENT AGE AND NEUROCOGNITIVE OUTCOMES FOLLOWING PROTON BEAM RADIOTHERAPY FOR PEDIATRIC LOW GRADE GLIOMA
Authors: Andrew Heitzer, Lisa Kahalley, David Grosshans, M Fatih Okcu, Kimberly Raghubar, Marsha Gragert, Mark McCurdy, Emily Warren, M Douglas Ris, Arnold Paulino, Murali Chintagumpala
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Younger age at radiotherapy increases cognitive risk for patients with pediatric low grade glioma (LGG). We examined the impact of age at treatment on cognitive trajectories in LGG patients treated with proton radiotherapy (PRT) compared to patients treated without radiotherapy (surgery only; SO). METHODS We examined cognitive scores of 48 LGG patients on a prospective, longitudinal study. General linear mixed models evaluated change in cognitive scores over time. RESULTS The sample included 16 patients treated with PRT and 32 with SO (median follow-up=3.1 years, range 0.9–6.1). Median age of PRT patients was 8.2 years at diagnosis (range 1.0–14.4) and 9.4 years at PRT (range 4.2–16.7). 13 PRT patients also received surgery: 53.8% biopsy, 30.8% subtotal resection, 15.4% gross total resection. Tumor sites included: 31.2% hypothalamic/suprasellar, 25.0% optic pathway, 18.8% temporal, 25.0% other. Median age of SO patients was 8.2 years at diagnosis (range 2.9–18.6). Surgical outcomes were: 75.0% gross total resection, 21.9% biopsy/other. There were no group differences in diagnosis age, tumor volume, or shunt history (all p&amp;gt;0.05). Both PRT and SO groups displayed stable cognitive functioning over time (all p&amp;gt;0.1). Slopes (i.e., change in scores over time) did not differ between groups (all p&amp;gt;0.1). Age at treatment was not associated with slope or performance at last follow-up in either group (all p&amp;gt;0.05). CONCLUSIONS We observed stable cognitive functioning, independent of age at treatment, following PRT for LGG. Outcomes were similar to patients receiving surgery only. Further examination in a larger sample is warranted.
MBCL-05. TREATMENT OF CHILDREN WITH MEDULLOBLASTOMA WITHOUT METASTATIC INVOLVEMENT IN THE AGE GROUP OLDER THAN 3 YEARS: RESULTS OF INTERCENTER TRIAL
Authors: Andrey Levashov, Anna Stroganova, Dmitry Khochenkov, Svetlana Zagidullina, Stepan Babelyan, Marina Ryzhova, Sergey Gorelyshev, Shavkat Kadirov, Natalya Subbotina, Vidmante Daylidite, Dmitry Sidelnikov, Georgy Mentkevich, Vasily Grigorenko
Journal: Neuro-Oncology (2020)

Abstract The aim of this study was to identify a group of patients aged 3 to 7 years for whom there is the possibility for reducing of craniospinal radiation dose (CSI). From 2008 to 2018 fifty one pediatric patients with primary diagnosed medulloblastoma in the age group 3 - 18 years were included in trial, 38 in standard risk group, 13 in high risk group. Treatment program consisted of surgical removal of the primary tumor site with subsequent radiation therapy (with CSI of 23,4 Gy or 36 Gy, depending on the risk group) and high-dose chemotherapy (with high-dose cyclophosphamide or thiophosphamide). As a result of this study, sufficiently high rates of overall survival and progression/relapse - free survival (PFS) were achieved in standard and high-risk groups patients, which amounted to 76,0 ± 8,8% and 83,3 ± 10,8% with median follow-up 62,9 ± 6,2 months and 52,2 ± 7,8 months, respectively. There was revealed patients group in the age 3 - 7 years with 100% PFS and median follow-up 66,9 ± 8,9 months. Morphological and molecular biological factors of an unfavorable outcome of the disease (large cell - anaplastic histology, MYC/MYC-N gene amplification, Iso17q and TP53 gene mutation) were absent in this tumor samples. We have also achieved 100% PFS in patients with desmoplastic tumor histology and in patients, who were treated with thiphosphamide - based chemotherapy regimen. Molecular - biological characteristics analysis of tumor cells showed a negative effect on PFS of DNMT - positive status (Score 4 and&amp;gt;, by 3 markers) and presence of MYC-N gene amplification (SHH molecular subgroup).
Cyclin D3 drives inertial cell cycling in dark zone germinal center B cells
Authors: Juhee Pae, Jonatan Ersching, Tiago B.R. Castro, Marta Schips, Luka Mesin, Samuel J. Allon, Jose Ordovas-Montanes, Coraline Mlynarczyk, Ari Melnick, Alejo Efeyan, Alex K. Shalek, Michael Meyer-Hermann, Gabriel D. Victora
Journal: The Journal of Experimental Medicine (2020)

During affinity maturation, germinal center (GC) B cells alternate between proliferation and somatic hypermutation in the dark zone (DZ) and affinity-dependent selection in the light zone (LZ). This anatomical segregation imposes that the vigorous proliferation that allows clonal expansion of positively selected GC B cells takes place ostensibly in the absence of the signals that triggered selection in the LZ, as if by “inertia.” We find that such inertial cycles specifically require the cell cycle regulator cyclin D3. Cyclin D3 dose-dependently controls the extent to which B cells proliferate in the DZ and is essential for effective clonal expansion of GC B cells in response to strong T follicular helper (Tfh) cell help. Introduction into the Ccnd3 gene of a Burkitt lymphoma–associated gain-of-function mutation (T283A) leads to larger GCs with increased DZ proliferation and, in older mice, clonal B cell lymphoproliferation, suggesting that the DZ inertial cell cycle program can be coopted by B cells undergoing malignant transformation.
IMMU-50. BBB CROSSING NANO-IMMUNOMEDICINE COMBINATION THERAPY TO TREAT BRAIN PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA
Authors: Tao Sun, Jiyuan Yang, Maximilian Gamburg, Vladimir Ljubimov, Zachary Grodzinski, Keith Black, Eggehard Holler, Jindřich Kopeček, Julia Ljubimova
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Lack of standard treatment of Primary Central Nervous System Lymphoma (PCNSL) was acknowledged in phase III intergroup study (HOVON 105/ALLG NHL 24). PCNSL incidence is increasing for unknown reasons, particularly among persons over 65 years. One of the major limitations of successful treatment of PCNSL is the blood-brain barrier (BBB), which prevents drug delivery into the brain. METHODS Polymer nanoconjugate based on biodegradable poly(N-(2-hydroxypropyl) methacrylamide) (PHPMA) was used for treatment of BALB/C mice with intracranially inoculated murine A20 lymphoma. PHPMA-based nanoconjugates have defined synthesis strategy for BBB transcytosis, tumor targeting, and cancer cell killing. Nano immunodrug PHPMA/AP-2/Fab’/c-Myc inhibitor/H6 conjugate contains multiple AP-2 peptides for efficient delivery across the BBB and Fab’ fragments of αCD20 mouse Ab for CD20 receptor crosslinking on PCNSL cells. c-Myc inhibitor bound via a disulfide bond is transferred to the cytoplasm followed by cleavage. The therapeutic efficacy and survival were evaluated together with spectral flow cytometry and RNA-seq bioinformatic analysis of tumor tissues. RESULTS Nanoconjugates were able to penetrate BBB and accumulate in brain parenchyma. The best survival results were obtained for the group where nanoconjugate with αCD20 Fab’ causing tumor cell apoptosis and c-Myc antisense inhibitor was combined with αPD-1 checkpoint inhibitor. Survival compared to PBS-treated controls was significant (P=0.0006 by ANOVA). Ex vivo analysis of A20 brain lymphoma tissue after treatment with nanoconjugates demonstrated reduction of Tregs, associated with downregulation of IL-10 and IL-1β in plasma. Spectral flow cytometry revealed activation of tumor infiltrating T lymphocytes and M1 macrophages in lead nanodrug treated groups. RNA-seq data correlated with flow cytometry results indicating the activation of genes linked to IFN-γ pathway important for anti-tumor response and M1 macrophage activation. Immunostaining confirmed a marked increase of M1-specific iNOS expression in the nanodrug-treated tumors. Support: NIH grants: R01 CA188743, R01 CA206220, R01 CA209921
EXTH-32. TARGETED STAT3 INHIBITION IMPAIRS MDSC MOBILIZATION AND RECRUITMENT IN GLIOBLASTOMA
Authors: Christina von Roemeling, Chenglong Li, Duane Mitchell
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Glioblastoma tumors (GBM) are comprised upwards of 30 percent by glioma-associated myeloid cells (GAMs). A large fraction of GAMs are myeloid-derived suppressor cells (MDSC) thought to traffic in from peripheral circulation. MDSCs foster a hospitable environment for cancer cells by regulating immune suppression and driving resistance to immunotherapy. While signal transducer and activator of transcription 3 (STAT3) is considered to be a specific marker for MDSCs and is a known player in their phenotypic polarization in cancer, we sought to closely examine its specific role in MDSC trafficking and tumor recruitment. HYPOTHESIS Targeted inhibition of STAT3 blocks MDSC from the bone marrow, mitigating their accumulation within GBM tumors. METHODS Human and murine GBM samples were analyzed for immune-specific STAT3 phosphorylation (P-STAT3). Immune cell characterization and quantification in peripheral and GBM tissue from syngeneic murine models treated with a novel STAT3 inhibitor (LLL12B) was done. Therapeutic responses to LLL12B alone and in combination with immune checkpoint blockade were evaluated. RESULTS We found P-STAT3 to be predominantly expressed by tumor-associated immune cells in both human and murine GBM, particularly MDSCs. Circulating numbers of MDSCs dramatically increase in response to tumor burden. P-STAT3 is elevated in these cells, indicating that its activation occurs prior to tumor infiltration. LLL12B blockade of STAT3 significantly reduced the number of circulating and tumor-infiltrating MDSCs. As a single agent LLL12B reduced tumor volume and extended the survival of murine GBM models. When combined with anti-PD-1 checkpoint blockade, we observed durable survival in a significant fraction of treated mice. CONCLUSIONS These findings advocate a critically important role for STAT3 in regulating MDSC mobilization and trafficking to GBM tumors. It additionally reveals a new therapeutic mechanism of action for LLL12B that may be relevant for other direct inhibitors of STAT3, influencing their clinical applicability to treat GBM.
A Spatially Explicit Model of Stabilizing Selection for Improving Phylogenetic Inference
Authors: Jeremy M Beaulieu, Brian C O’Meara, Michael A Gilchrist
Journal: Molecular Biology and Evolution (2020)

Ultraconserved elements (UCEs) are stretches of hundreds of nucleotides with highly conserved cores flanked by variable regions. Although the selective forces responsible for the preservation of UCEs are unknown, they are nonetheless believed to contain phylogenetically meaningful information from deep to shallow divergence events. Phylogenetic applications of UCEs assume the same degree of rate heterogeneity applies across the entire locus, including variable flanking regions. We present a Wright-Fisher model of selection on nucleotides (SelON) which includes the effects of mutation, drift, and spatially varying, stabilizing selection for an optimal nucleotide sequence. The SelON model assumes the strength of stabilizing selection follows a position-dependent Gaussian function whose exact shape can vary between UCEs. We evaluate SelON by comparing its performance to a simpler and spatially invariant GTR+Γ model using an empirical data set of 400 vertebrate UCEs used to determine the phylogenetic position of turtles. We observe much improvement in model fit of SelON over the GTR+Γ model, and support for turtles as sister to lepidosaurs. Overall, the UCE-specific parameters SelON estimates provide a compact way of quantifying the strength and variation in selection within and across UCEs. SelON can also be extended to include more realistic mapping functions between sequence and stabilizing selection as well as allow for greater levels of rate heterogeneity. By more explicitly modeling the nature of selection on UCEs, SelON and similar approaches can be used to better understand the biological mechanisms responsible for their preservation across highly divergent taxa and long evolutionary time scales.
NCOG-55. HARMONIZING LANGUAGE TO MAXIMIZE IMPACT: AN UPDATE ON COMMON DATA ELEMENTS FOR MENINGIOMA AND REVIEW OF CLINICAL TRIALS IN MENINGIOMA
Authors: Justin Wang, Farshad Nassiri, Karolyn Au, Kate Drummond, Michael Jenkinson, Thomas Santarius, Jill S Barnholtz-Sloan, Christine Jungk, Francesco DiMeco, Evanthia Galanis, Andrea Saladino, Yueren Zhou, Suganth Suppiah, Jetan Badhiwala, Kenneth Aldape, Laila M Poisson, Gelareh Zadeh
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND With increasing studies reporting on the molecular profiling of meningiomas, there is a need to harmonize language used to capture clinical data across centers to ensure that molecular alterations are appropriately linked to clinical variables of interest. Here the International Consortium on Meningiomas presents a final set of core and supplemental meningioma-specific Common Data Elements (CDEs) to facilitate comparative and pooled analyses. METHODS The generation of CDEs followed the four-phase process similar to other National Institute of Neurological Disorders and Stroke (NINDS) CDE projects: development/discovery based on data from published and ongoing meningioma trials, internal validation, external validation including presentation of our data form at the Society for Neuro-Oncology previously, and distribution. RESULTS We developed a set of CDEs organized into patient- and tumor-level modules. In total, the Consortium identified 16 core CDEs (9 patient-level and 7-tumour-level) e.g. age at index surgery, diagnosis of neurofibromatosis, prior chemotherapy or radiation, tumor location, extent of resection, recurrence, etc. An additional 15 supplemental CDEs were defined and described (8 patient-level and 7 tumour-level) e.g. race, cause of death, multiple tumors, tumor size, Simpson grade, second intervention, etc. These CDES are now made publicly available for dissemination and adoption. We also present a narrative review and analysis of recent and ongoing meningioma trials. CONCLUSIONS These CDEs provide a framework for discussion in the neuro-oncology community that will facilitating data sharing for collaborative research projects and aid in developing a common language for comparative and pooled analyses. The CDEs are intended to be dynamic parameters that evolve with time and The Consortium welcomes international feedback for further refinement and implementation of these CDEs.
BIOM-57. PEDIATRIC TUMOR CLASSIFICATION THROUGH GENOME-WIDE METHYLATION PROFILING OF EXTRACELLULAR VESICLE DNA
Authors: Franz Ricklefs, Cecile Maire, Krys Fita, Friederike Fritzsche, Gertrud Kammler, Manfred Westphal, Katrin Lamszus, Ulrich Schüller
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Genome-wide methylation profiling reliably classifies pediatric central nervous system (CNS) tumors. Extracellular vesicles (EVs) are released by pediatric CNS tumor cells (pCC) and contain high molecular weight tumor DNA, rendering EVs a potential biomarker source to identify tumor subgroups, stratify patients and monitor therapy by liquid biopsy. We investigated whether the DNA in pCC-derived EVs reflects genome-wide tumor methylation profiles and allows tumor subtype classification. METHODS DNA was isolated from EVs secreted by pediatric CNS tumor cells (pCC) as well as from the shortly cultured tumor cells and from the original tumor samples (n=4 patients). Pediatric Fibroblasts and EVs derived thereof were used as a non-tumorous control. EVs were classified by nanoparticle analysis (NTA), immunoblotting, imaging flow cytometry (IFCM and electron microscopy. Genome-wide DNA methylation profiling was performed using an 850k Illumina EPIC array and results were classified according to the DKFZ brain tumor classifier and further analysed by t-SNE and Copy number alteration analysis (CNA). RESULTS The size range of pCC-derived EVs was 120–150 nm, as measured by NTA. The majority of secreted EVs exhibited high expression of common EV markers (i.e. CD9, CD63 and CD81), as characterized by IFCM. Genome-wide DNA methylation profiling of pCC-derived EVs correctly identified the methylation class of the original tumor (i.e. pilocytic astrocytoma, medulloblastoma). In addition, t-SNE analysis and copy number alterations matched the pattern of the parental pCC and original tumor samples. CONCLUSION EV DNA faithfully reflects the tumor methylation class and copy number alterations present in the parental cells and the original tumor. Methylation profiling of circulating tumor EV DNA could become a useful tool to detect and classify pediatric CNS tumors.
The Ca2+-activated chloride channel ANO1/TMEM16A: An emerging therapeutic target for epithelium-originated diseases?
Authors: Yani Liu, Zongtao Liu, KeWei Wang
Journal: Acta Pharmaceutica Sinica B (2020)

Anoctamin 1 (ANO1) or TMEM16A gene encodes a member of Ca2+ activated Cl– channels (CaCCs) that are critical for physiological functions, such as epithelial secretion, smooth muscle contraction and sensory signal transduction. The attraction and interest in ANO1/TMEM16A arise from a decade long investigations that abnormal expression or dysfunction of ANO1 is involved in many pathological phenotypes and diseases, including asthma, neuropathic pain, hypertension and cancer. However, the lack of specific modulators of ANO1 has impeded the efforts to validate ANO1 as a therapeutic target. This review focuses on the recent progress made in understanding of the pathophysiological functions of CaCC ANO1 and the current modulators used as pharmacological tools, hopefully illustrating a broad spectrum of ANO1 channelopathy and a path forward for this target validation.
NCOG-05. MANAGEMENT OF BRAIN METASTASIS IN TRIPLE NEGATIVE BREAST CANCER
Authors: Ravi Medikonda, Siddhartha Srivastava, Timothy Kim, Yuanxuan Xia, Mira Patel, Christopher Jackson, Debebe Theodros, Jennifer Kim, Lawrence Kleinberg, Kristin Redmond, Jon Weingart, Debraj Mukherjee, Chetan Bettegowda, Gary Gallia, Henry Brem, Michael Lim
Journal: Neuro-Oncology (2020)

Abstract Brain metastasis is common in patients with breast cancer, and those with triple negative status have an even higher risk. Stereotactic radiosurgery (SRS) is preferred to whole brain radiation therapy (WBRT) in most patients. However, triple negative status is currently not considered when determining optimal radiation therapy. Given the aggressive nature of triple negative breast cancer, we evaluated a role for WBRT for all patients in this cohort. We conducted a single-institution retrospective cohort study to determine whether triple negative patients with brain metastases have a higher burden of intracranial disease and whether type of initial radiation therapy affects overall survival for this cohort of patients. 85 patients met the inclusion criteria for this study. 25% of patients had triple negative breast cancer, of which 91% received SRS and 53% of patients received WBRT. The average number of new brain metastases from time of initial brain imaging to radiation therapy was 0.67 (St.Dev:1.1) in the non-triple negative status patients and 2.6 (St. Dev:3.7) in the triple negative status patients (p=0.001). Using a cox proportional hazards model, it was found that whole brain radiotherapy does not significantly affect overall survival in patients with triple negative breast cancer (p = 0.96). Our findings highlight the highly aggressive intracranial nature of triple negative breast cancer. Indeed, the rate of increase in brain metastases is significantly higher for triple negative patients compared to non-triple negative patients. As a result, we evaluated whether triple negative patients would benefit from whole brain radiation regardless of findings on initial brain imaging. Despite 53% of patients receiving WBRT, our investigation found that there is no additional benefit to WBRT in triple negative breast cancer patients. These results suggest a need to re-evaluate the role of WBRT in the management of triple negative breast cancer.
Surveillance for Harmful Algal Bloom Events and Associated Human and Animal Illnesses — One Health Harmful Algal Bloom System, United States, 2016–2018
Authors: Virginia A. Roberts, Marissa Vigar, Lorraine Backer, Gabriella E. Veytsel, Elizabeth D. Hilborn, Elizabeth I. Hamelin, Kayla L. Vanden Esschert, Joana Y. Lively, Jennifer R. Cope, Michele C. Hlavsa, Jonathan S. Yoder
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

Harmful algal bloom events can result from the rapid growth, or bloom, of photosynthesizing organisms in natural bodies of fresh, brackish, and salt water. These events can be exacerbated by nutrient pollution (e.g., phosphorus) and warming waters and other climate change effects (1); have a negative impact on the health of humans, animals, and the environment; and damage local economies (2,3). U.S. harmful algal bloom events of public health concern are centered on a subset of phytoplankton: diatoms, dinoflagellates, and cyanobacteria (also called blue-green algae). CDC launched the One Health Harmful Algal Bloom System (OHHABS) in 2016 to inform efforts to prevent human and animal illnesses associated with harmful algal bloom events. A total of 18 states reported 421 harmful algal bloom events, 389 cases of human illness, and 413 cases of animal illness that occurred during 2016-2018. The majority of harmful algal bloom events occurred during May-October (413; 98%) and in freshwater bodies (377; 90%). Human and animal illnesses primarily occurred during June-September (378; 98%) and May-September (410; 100%). Gastrointestinal or generalized illness signs or symptoms were the most frequently reported (>40% of human cases and >50% of animal cases); however, multiple other signs and symptoms were reported. Surveillance data from harmful algal bloom events, exposures, and health effects provide a systematic description of these occurrences and can be used to inform control and prevention of harmful algal bloom-associated illnesses.