tbuckley/cabot-search huggingface dataset:
SURG-33. ROLE OF SURGERY IN TREATING EPSTEIN-BARR VIRUS-ASSOCIATED SMOOTH MUSCLE TUMOR (EBV-SMT) WITH CENTRAL NERVOUS SYSTEM INVASION: A SYSTEMIC REVIEW
Authors: Ko-Ting Chen, Ka-Wei Lau, Yu-Wei Hsu, Yin-Ting Lin
Journal: Neuro-Oncology (2020)

Abstract Epstein-Barr virus-associated smooth muscle tumor (EBV-SMT) is a rare mesenchymal tumor that almost exclusively occurs in immunocompromised hosts. The term unknown malignant potential once used interchangeably to describe EBV-SMT and the less invasive clinical behavior than leiomyosarcoma indicate an indolent growth pattern of EBV-SMT. Nevertheless, an EBV-SMT with CNS invasion would result in neurological deficits which may jeopardize patients’ survival.We provide a systemic review of literature under PRISMA guideline on the clinical features, treatment modalities, role of surgery intervention and outcomes of all 65 reported EBV- SMTs with central nervous system (CNS) invasion. Over 95% of the reported cases were immunocompromised, while human immunodeficiency virus infection and post- organ transplantation being the most commonly associated underlying causes (near 90%). A 76.0% 1-year survival rate and 59.6% 5-year survival rate confirms the indolent and non-deadly nature of EBV-SMT even with CNS invasion. An immune survey and reconstruction should be conducted for every patient with CNS EBV-SMT. Surgical resection is mostly adopted as primary treatment to acquire diagnosis and relieve compressive effect. A total resection of tumor may be beneficial if tumor was symptomatic and had intracranial invasion
EXTH-26. SECONDARY STRUCTURE ANALYSIS OF THE EGFR PRE-mRNA TRANSCRIPT TO IDENTIFY TARGETABLE REGIONS AND OPTIMIZE RNA THERAPY
Authors: Martin Hicks, Ryan Fink, Flobater Gawargi
Journal: Neuro-Oncology (2020)

Abstract Individuals diagnosed with glioblastoma multiforme (GBM) have a short life expectancy of 12–15 months. Current strategies are often limited by the blood-brain barrier. This project is to develop therapies to bypass challenges to effective and continuous drug delivery to the brain, targeting cancer-driving genes. Epidermal growth factor receptor (EGFR) is dysregulated in 57% of all GBM. Our approach uses an adeno-associated virus gene transfer vector encoding RNA therapeutics targeting critical elements of the EGFR pre-mRNA transcript. The ‘pre-mRNA structurome’ can be used to uncover and determine the accessibility of targetable regions. Our approach has the potential to deliver one single dose of gene therapy directly to the GBM tumor environment and block the production of EGFR and activate the expression of a stable therapeutic isoform of EGFR. To advance our therapeutic strategy, we have analyzed the EGFR secondary structure using selective 2’ hydroxyl acylation and primer extension followed by mutational profiling (SHAPE-MaP). SHAPE-MaP reactivity profiles were generated revealing the structure of splicing and cryptic polyadenylation signal (PAS) elements within the targeted region. We identified enhancer binding motifs surrounding the 5’ splice site and hidden elements of the cryptic PAS. Based on these structural profiles, we generated RNA therapies to unravel the hidden PAS to activate expression of the short therapeutic isoform.
Tissue‐Engineered Vascular Grafts: Effects of Braiding Parameters on Tissue Engineered Vascular Graft Development (Adv. Healthcare Mater. 24/2020)
Authors: Jacob C. Zbinden, Kevin M. Blum, Alycia G. Berman, Abhay B. Ramachandra, Jason M. Szafron, Katherine E. Kerr, Jennifer L. Anderson, Gurneet S. Sangha, Conner C. Earl, Noah R. Nigh, Gabriel J. M. Mirhaidari, James W. Reinhardt, Yu‐Chun Chang, Tai Yi, Ryan Smalley, Peter D. Gabriele, Jeremy J. Harris, Jay D. Humphrey, Craig J. Goergen, Christopher K. Breuer
Journal: Advanced Healthcare Materials (2020)

In article number 2001093 by Jacob C. Zbinden, Christopher K. Breuer, and co-workers, tissue engineered arterial grafts are created from braided poly(glycolic acid) fibers at the boundaries of the manufacturable design space with and without a poly(glycerol sebacate) coating and evaluated in a mouse intrarenal aortic model. Implants are followed with 4D ultrasound and explants are evaluated with biaxial mechanical testing and histological analysis.
Response to: ‘ Correspondence on ‘Haemodynamic phenotypes and survival in patients with systemic sclerosis: the impact of the new definition of pulmonary arterial hypertension’’ by Iudici<i>et al</i>
Authors: Ekkehard Grünig, Nicola Benjamin, Panagiota Xanthouli, Suzana Jordan, Nicklas Milde, Alberto Marra, Norbert Blank, Benjamin Egenlauf, Matthias Gorenflo, Satenik Harutyunova, Hanns-Martin Lorenz, Christian Nagel, Vivienne Theobald, Mona Lichtblau, Charlotte Berlier, Silvia Ulrich, Oliver Distler
Journal: Annals of the Rheumatic Diseases (2020)

In their correspondence Iudici et al 1 highlight three important aspects which are to consider in the interpretation of survival data when introducing new thresholds of an early stage of disease.2 They point out, that lead-time bias, length-time bias as well as increasing numbers of patients have to be considered for the new haemodynamic definition of pulmonary arterial hypertension (PAH).

In studies investigating the effect of systematic PAH screening programmes on survival in patients with systemic sclerosis, part of the effect of an increased survival may be attributed to lead-time bias and length-time bias.3 4

We agree with Iudici et al that lead-time bias is an important aspect when introducing a new definition of a disease, which includes patients at a less severe stage. This becomes especially important for screening programmes, as survival of screened patients who are diagnosed at early disease stages may implicitly be better compared with patients with a more severe disease.

In our study we analysed the frequency of PAH in patients with systemic sclerosis when applying the new PAH definition according to the suggestion from the World Symposium on pulmonary hypertension in Nice 2018. According to a large meta-analysis of haemodynamic data of healthy people, a pulmonary vascular resistance (PVR) >2 Wood Units (WU) …
Understanding FLT3 Inhibitor Resistance to Rationalize Combinatorial AML Therapies
Authors: Aditi Shastri, Jesus Gonzalez-Lugo, Amit Verma
Journal: Blood Cancer Discovery (2020)

Patients treated with Fms-like tyrosine kinase 3 (FLT3) inhibitor-based acute myeloid leukemia therapies nearly always develop resistance. In this issue, Alotaibi and colleagues describe the patterns of mutations that emerge upon relapse after FLT3 inhibitor therapy after initial response, as well as in treatment-refractory disease in a single-institution study; the findings offer insights for sequential therapies targeting the dominant clone at the time of relapse. See related article by Alotaibi et al., p. 125.
ETMR-01. TREATMENT OUTCOME OF TWO CASES WITH HIGH-GRADE NEUROEPITHELIAL TUMOR WITH BCOR ALTERATION
Authors: Ines Kristensen, Louise Lindholt Hansen, Torben Stamm Mikkelsen, Louise Tram Henriksen, Benedicte Parm Uldhøi, Gorm von Oettingen, Søren Cortnum, Yasmin Lassen-Ramshad
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION High grade neuroepithelial tumor with BCOR exon 15 internal tandem duplication (HGNET BCOR) is a recently described tumor entity of the central nervous system (CNS) with a distinct methylation profile and characteristic genetic alteration. We report the outcome of two cases after 1st line multimodality therapy. MATERIAL AND METHOD A 7 year old girl with a ventricular tumour and a 6 year old boy with a tumour in the occipital region with infiltration of the transverse and sigmoid sinus were both diagnosed based on histology and methylation with HGNET-BCOR. No spinal or liquor dissemination were found at diagnosis in both cases. Treatment consisted of radical resection of the tumour. In the case of the lesion with sinus infiltration residual tumour in the vessel could not be removed. Both children were postoperatively treated with radiotherapy (craniospinal 36 Gy and boost to 54 Gy), concomitant Vincristin and adjuvant Cisplatin, Lomustine and Vincristine. RESULTS The girl developed a local recurrence at the primary tumour site 18 months after diagnosis. Reoperation showed the same histology. Start of 2nd line chemotherapy with Temozolomid and Irinotecan is being discussed. The boy with sinus infiltration developed seven months after diagnosis multiple liver, lung and bone metastasis. Biopsy of a liver lesion showed HGNET-BCOR. He was treated with Temozolomid, Irinotecan and died nine months after diagnosis. CONCLUSION We report two cases with failure after 1st line treatment for HGNET-BCOR. To our knowledge HGNET-BCOR with development of hematological disease dissemination is a rare finding.
MBRS-44. TIME, PATTERN AND OUTCOME OF MEDULLOBLASTOMA RELAPSE ARE ASSOCIATED WITH TUMOUR BIOLOGY AT DIAGNOSIS AND UPFRONT THERAPY: A COHORT STUDY
Authors: Rebecca Hill, Stacey Richardson, Edward Schwalbe, Debbie Hicks, Janet Lindsey, Stephen Crosier, Gholamreza Rafiee, Yura Grabovska, Stephen Wharton, Thomas Jacques, Anthony Michalski, Abhijit Joshi, Barry Pizer, Daniel Williamson, Simon Bailey, Steven Clifford
Journal: Neuro-Oncology (2020)

Abstract Disease relapse occurs in ~30% of children with medulloblastoma, and is fatal in the majority. We sought to establish whether clinico-molecular characteristics at diagnosis are associated with the nature of relapse, subsequent disease-course, and whether these associations could inform clinical management. We surveyed the clinical features of medulloblastoma relapse (time-to-relapse, pattern-of-relapse, time-to-death and overall outcome) in 247 centrally-reviewed patients who relapsed following standard-upfront-therapies. We related these to clinico-molecular features at diagnosis, prognostic factors, and first-line/relapse treatment. Patients who received upfront craniospinal irradiation (CSI-treated) displayed prolonged time-to-relapse compared to CSI naïve patients (p&amp;lt;0.001). Similarly, in CSI naïve patients, CSI at relapse, alongside re-resection and desmoplastic/nodular histology, were associated with long-term survival. In CSI-treated patients, the nature of relapse was subgroup-dependent. Local-nodular relapse patterns were enriched in relapsed-MBSHH patients (p&amp;lt;0.001), but a notable proportion (65%) also acquired distant-diffuse disease (p=0.010). MBGroup3 relapsed quickly (median 1.3 years), MBGroup4 slowly (median 2.1 years). Distant-disease was prevalent in MBGroup3 and MBGroup4 relapses (90%) but, in contrast to relapsed-MBSHH, nodular and diffuse patterns of distant-disease were observed. Furthermore, nodular disease was associated with a prolonged time-to-death post-relapse (p=0.006). Investigation of second-generation MBGroup3/4 subtypes refined our understanding of heterogeneous relapse characteristics. Subtype VIII had prolonged time-to-relapse; subtype II a rapid time-to-death. Subtypes II/III/VIII developed a significantly higher incidence of distant-disease at relapse, whereas subtypes V/VII did not. The nature of medulloblastoma relapse are biology and therapy-dependent, providing immediate translational opportunities for improved disease management through biology-directed surveillance, post-relapse prognostication and risk-stratified selection of second-line treatment.
PATH-18. A MULTI-CENTER CASE SERIES OF ADULT K27M MUTATED DIFFUSE MIDLINE GLIOMAS REVEALING A POPULATION UNIQUE FROM PAEDIATRIC CASES
Authors: Alexander Yuile, Madhawa De Silva, Marina Kastelan, Veronica Cheung, Joanne Sy, Michael Buckland, Jamie Drummond, Michael Back, Helen Wheeler
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Histone mutations in the K27M gene were first described in 2014, and incorporated into the WHO CNS tumour classification system in 2016. They are typically associated with diffuse midline gliomas (DMG). Presenting symptoms vary greatly, with some experiencing significant delay in diagnosis. Median survival is only 9-12 months for these patients. Biopsy samples are small, and in some due to location, not performed. Although data is predominately based on the paediatric population, DMGs are seen in both adolescence and adults. In this multi-site retrospective study, we describe 11 adult patients with K27M DMG gliomas across two tertiary Neuro-Oncology services in Sydney, Australia. To the authors’ knowledge we present the largest known collection of adult K27M cases in the Asia-Pacific region with correlation of treatment, clinicopathologic and radiologic features with outcomes. METHODS The glioma databases of Royal North Shore Hospital (RNSH) and Royal Prince Alfred Hospital (RPAH) between January 2009 and March 2020 were interrogated to identify patients. Selection criteria included patients aged ≥ 18 years who presented with a DMG, had undergone biopsy, and had confirmed K27M via next generation sequencing. Clinicopathologic, radiologic and treatment outcomes were extracted for correlation. RESULTS Eleven patients fitting the selection criteria were identified and reported. The median age at diagnosis was 30 years and 4 were female. Five presented with hydrocephalus, the most common presenting symptoms were headaches and nausea and/or vomiting (n= 4 and n= 2 respectively). The median progression-free survival was 13 months (4-31 months) and the median overall survival was 23 months (4-59 months). CONCLUSION This case series reports the outcomes of older patients with K27M. The clinical course demonstrated suggests a divergence from paediatric biology. Ongoing studies are required to further characterise the histopathological and clinical differences of these tumours in older patients.
IMMU-25. SEVERE AND MULTIFACETED SYSTEMIC IMMUNOSUPPRESSION CAUSED BY EXPERIMENTAL CANCERS OF THE CENTRAL NERVOUS SYSTEM REQUIRES RELEASE OF NON-STEROID SOLUBLE MEDIATORS
Authors: Katayoun Ayasoufi, Christian Pfaller, Laura Evgin, Roman Khadka, Zachariah Tritz, Emma Goddery, Cori Fain, Lila Yokanovich, Benjamin Himes, Fang Jin, Jiaying Zheng, Matthew Schuelke, Michael Hansen, Wesley Tung, Ian Parney, Latty Pease, Richard Vile, Aaron Johnson
Journal: Neuro-Oncology (2020)

Abstract Immunosuppression of unknown etiology is a hallmark feature of glioblastoma (GBM) and is characterized by decreased CD4 T cell counts and down regulation of MHC class II expression on peripheral blood monocytes in patients. This immunosuppression is a critical barrier to the successful development of immunotherapies for GBM. We recapitulated the immunosuppression observed in GBM patients in the C57BL/6 mouse and investigated the etiology of low CD4 T cell counts. We determined that thymic involution was a hallmark feature of immunosuppression in three distinct models of CNS cancer, including mice harboring GL261 glioma, B16 melanoma, and in a spontaneous model of Diffuse Intrinsic Pontine Glioma (DIPG). In addition to thymic involution, we determined that tumor growth in the brain induced significant splenic involution, reductions in peripheral T cells, reduced MHC class II expression on hematopoietic cells, and a modest increase in bone marrow resident CD4 T cells with a naïve phenotype. Using parabiosis we report that thymic involution, declines in peripheral T cell counts, and reduced MHC class II expression levels were mediated through circulating blood-derived factors. Conversely, T cell sequestration in the bone marrow was not governed through circulating factors. Serum isolated from glioma-bearing mice potently inhibited proliferation and functions of T cells both in vitro and in vivo. Interestingly, the factor responsible for immunosuppression in serum is nonsteroidal and of high molecular weight. Through further analysis of neurological disease models, we determined that the aforementioned immunosuppression was not unique to cancer itself, but rather occurs in response to CNS injury. Noncancerous acute neurological insults also induced significant thymic involution and rendered serum immunosuppressive. Both thymic involution and serum-derived immunosuppression were reversible upon clearance of brain insults. These findings demonstrate that CNS cancers cause multifaceted immunosuppression and pinpoint circulating factors as a target of intervention to restore immunity.
EXTH-24. INCREASING THERAPEUTIC INDUCED NEURAL STEM CELL PERSISTENCE IN THE GLIOBLASTOMA TUMOR RESECTION CAVITY
Authors: Hunter Bomba, Kevin Sheets, Abigial Carey-Ewend, Morgan Goetz, Ingrid Findlay, Juli Bago, Shawn Hingtgen
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Induced neural stem cells (iNSCs) have emerged as a promising therapeutic platform for glioblastoma (GBM). iNSCs have the innate ability to home to tumor foci, making them ideal carriers for anti-tumor payloads. However, iNSC persist for only two weeks in the murine GBM tumor resection cavity. We hypothesized that, by encapsulating iNSCs in a scaffold matrix, we could increase both the persistence of the cells the therapeutic durability. METHODS iNSCs expressing TRAIL were encapsulated in a gelatin-thrombin matrix; fibrinogen was used to polymerize the matrix. SEM was used to explore interactions between iNSCs and the scaffold matrix. To evaluate persistence, iNSCs encapsulated in the matrix were implanted into mock resection cavities of athymic nude mice and followed via BLI. To study the impacts of encapsulation on iNSC efficacy, athymic nude mice were implanted with U87 or GBM8 tumors. Tumors were then resected, and iNSCs encapsulated in the matrix were implanted; tumor volume was monitored via BLI. RESULTS SEM images showed homogeneous distribution of iNSCs throughout the matrix; iNSCs were completed encased in the fibrin clot component of the matrix and did not adhere to gelatin. In vivo, encapsulated iNSCs persisted for nearly 100 days whereas iNSCs directly injected into the brain parenchyma persisted &amp;lt; 20 days. Using mice bearing GBM8 tumors, animals treated with a high dose of therapeutic encapsulated iNSCs survived ~60 days longer than animals treated with non-therapeutic cells. A similar trend was observed in animals inoculated with U87 tumors. While not statistically significant, 25% of mice treated with iNSCs encapsulated in the gelatin-thrombin matrix survived longer than those treated with iNSCs encapsulated in a fibrin-only matrix, suggesting additional benefit due to the gelatin component. FUTURE DIRECTIONS Prospective experiments will explore the impact of the scaffold on iNSC phenotype, including proliferation, differentiation, and migration markers.
Эффективность биорегуляционного подхода в комплексной коррекции эндогенной интоксикации при хроническом поражении панкреатогепатобилиарной системы
Authors: L.S. Babinets, O.I. Kryskiv, O.R. Shaihen, G.O. Khomin
Journal: GASTROENTEROLOGY (2020)

Актуальность. Поиск методов коррекции эндогенной интоксикации (ЭИ) является актуальным, несмотря на большое количество существующих методов терапии заболеваний панкреатогепатобилиарной системы (ПГБС). Цель работы: изучить характер изменений показателей синдрома ЭИ у больных с хроническими поражениями панкреатогепатобилиарной системы в процессе биорегуляционной терапии (БРТ). Материалы и методы. Обследовано 72 больных с хроническим панкреатитом в фазе нестойкой ремиссии в возрасте 18–62 лет, среди которых 15 мужчин и 57 женщин. При наличии сопутствующей патологии ПГБС пациентов разделили на три группы: хронический вирусный гепатит С впервые диагностирован у 26 больных (I группа), хронический бескаменный холецистит — у 25 (II группа), дискинезию желчевыводящих путей — у 21 (III группа). Всем пациентам назначали курс препаратов базовой терапии и одновременно — курс комплексного биорегуляционного корректора внешнесекреторной недостаточности поджелудочной железы и комплексного биорегуляционного гепатотропного препарата. Для оценки эндотоксикоза изучали динамические изменения (до БРТ и после нее) среднемолекулярных пептидов (СМП), циркулирующих иммунных комплексов (ЦИК) и лейкоцитарного индекса интоксикации (ЛИИ). Результаты. После проведенного курса БРТ наряду с исчезновением или уменьшением болевого синдрома, диспептических явлений, нормализацией деятельности кишечника и другими клиническими признаками улучшения состоялось достоверное снижение уровня ЭИ (р &lt; 0,05). Согласно данным определения СМП, ЦИК и ЛИИ после проведенного комплексного лечения с включением курса БРТ, незначительные признаки эндотоксикоза проявлялись лишь у 33,6 % больных. Выводы. Вышеописанные изменения показателей ЭИ можно расценить как физиологические адаптационные процессы, которые проходят в организме человека под воздействием биорегуляционного лечения и способствуют формированию детоксикационного и саногенного эффектов БРТ.
RONC-01. PROTON BEAM THERAPY IN THE MULTIDISCIPLINARY THERAPY FOR PEDIATRIC BRAIN AND SPINAL TUMOR AT KOBE CHILDREN’S HOSPITAL WITH KOBE PROTON CENTER
Authors: Atsufumi Kawamura, Junji Koyama, Nobuyuki Akutsu, Yuske Demizu, Nobuyoshi Fukumitsu, Toshinori Soejima, Yoshiyuki Kosaka
Journal: Neuro-Oncology (2020)

Abstract It could be remarked that Radiotherapy (RT) has the important role for the multidisciplinary therapy to Malignant Pediatric Central Nervous System tumor. And recently among RT, Proton Beam Therapy (PBT) is expected to be effective and decrease serious late effects after RT in malignant pediatric tumor. PBT could be controlled precisely the dose and depth and spare the normal structures outside the target. Thus, PBT becomes applicable for pediatric solid tumor to insurance in April, 2016 in Japan. We have worked in closer cooperation with Hyogo Prefectural Ion Beam Medical Center and started PBT from April 2015. And from December 2017, our PBT has transferred to adjacent new medical center (Kobe Proton Center) which has the only institute that equipped the exclusive gantry for children in our country. The treated cases are 28 boys and 35 girls (age average 8.2 years oid). They are 15 Germ cell tumor, 14 Ependymoma, 13 Medulloblastoma, 4 Chordoma, 4 Atypical teratoid/rhabdoid tumor, 2 Craniopharyngioma and others. We have simulated the applications of not only broad beam but also scanned beam to limit the dose distribution and prepare for the cranio-spinal irradiation. All cases underwent magnetic resonance imaging to evaluate the results at out clinic and also the complications are assessed after treatments. The effect of PBT in this series is similar to our experience of traditional RT. There are a few controllable complications such as conventional RT. Farther more follow up is necessary to evaluate the advantage of PBT which could reduce delayed complications of RT.