tbuckley/cabot-search huggingface dataset:
RONC-16. PROTON BEAM THERAPY FOR PATIENTS WITH INTRACRANIAL EPENDYMOMA UNDER 3 YEARS OLD: INITIAL CLINICAL OUTCOMES
Authors: Takayuki Hashimoto, Shigeru Yamaguchi, Takashi Mori, Akihiro Iguchi, Yukitomo Ishi, Hiroaki Motegi, Rikiya Onimaru, Atsushi Manabe, Shinichi Shimizu, Hidefumi Aoyama
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Proton beam therapy (PBT) provides dosimetric benefits in sparing normal tissue when treating pediatric patients with brain tumors. We report the preliminary clinical outcomes of surgery and adjuvant PBT for patients under 3 years old diagnosed as intracranial ependymoma at our institute. METHODS This is a retrospective review of the medical records for 3 children with ependymoma in the fourth ventricle, diagnosed between March 2013 and September 2019. PBT was performed after tumor resection in all the patients. RESULTS Gross total resection was achieved in 2 males and 1 female patients with fourth ventricle WHO grade II to III ependymoma at 15, 18, and 37 months old. All the patients received adjuvant PBT (54.0 GyE/30 fractions) to the postoperative tumor bed under general anesthesia or sedation. PBT was acutely well tolerated, with mostly mild alopecia and skin reactions at the irradiated sites. At a median follow-up of 54 months (4–59 months) after irradiation, all the patients are alive without recurrence. No serious late adverse events were observed in any of the patients. CONCLUSION The number of patients in this study remains small for drawing any definite conclusion, however our preliminary results are still encouraging. Further studies of a large number of pediatric patients with long term follow-up are needed to more fully assess tumor control and late adverse events.
GCT-57. ARE MELATONIN LEVELS A RELIABLE MARKER FOR INTRACRANIAL GERM CELL TUMORS POST TREATMENT DEFICIENCY?
Authors: Andréa M Cappellano, Alex M M Fujita, Nasjla S Silva, Daniela B Almeida, Fernanda G Amaral
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Pineal is the melatonin-producing gland, with this hormone importantly acting as a central and peripheral chronobiotic, antioxidant and in energy metabolism. The urinary dosage of 6-sulfatoxymelatonin (aMT6s), a melatonin metabolite, is an indirect marker to estimate the total melatonin nocturnal production, ranging in clinically normal individuals from 10–50 micrograms(ug). The purpose of this study was to evaluate aMT6s in patients with diagnosis of intracranial germ cell tumors (iGCT) treated at IOP/GRAACC/UNIFESP. METHODS After an interview to collect data about therapies employed and medications, night urine samples (from 8:00pm to first void in the morning) were collected and analyzed by ELISA. RESULTS Twenty patients between 5–42 years old (mean 20.9 years), all male, were analyzed. Thirteen patients had diagnosis of Germinoma, 1 with Imature Teratoma, 5 NGGCT and 2 Mature Teratoma. The first site was pineal (N=15) and bifocal (N=5). The treatment was surgery/biopsy/2º look surgery in 17 patients associated with chemotherapy/ radiotherapy, except in 2 (pure teratoma-surgery only) and 1 (chemo only). Three patients had diagnosis by tumor markers treated with chemo only (N=1) and chemotherapy/radiotherapy (N=2). The levels of aMT6s were between 0.2–3.2ug in all participants, except in one (14.8ug-biopsy, chemo and RT). CONCLUSION aMT6s levels found in most patients are below the expected for the general population suggesting that this is an appropriate marker for pineal tumors with melatonin deficiency. It may contribute to support future studies in this area and adoption of follow-up protocols, with eventual hormone supplementation and consequently improved quality of life.
Trained immunity, tolerance, priming and differentiation: distinct immunological processes
Authors: Maziar Divangahi, Peter Aaby, Shabaana Abdul Khader, Luis B. Barreiro, Siroon Bekkering, Triantafyllos Chavakis, Reinout van Crevel, Nigel Curtis, Andrew R. DiNardo, Jorge Dominguez-Andres, Raphael Duivenvoorden, Stephanie Fanucchi, Zahi Fayad, Elaine Fuchs, Melanie Hamon, Kate L. Jeffrey, Nargis Khan, Leo A. B. Joosten, Eva Kaufmann, Eicke Latz, Giuseppe Matarese, Jos W. M. van der Meer, Musa Mhlanga, Simone J. C. F. M. Moorlag, Willem J. M. Mulder, Shruti Naik, Boris Novakovic, Luke O’Neill, Jordi Ochando, Keiko Ozato, Niels P. Riksen, Robert Sauerwein, Edward R. Sherwood, Andreas Schlitzer, Joachim L. Schultze, Michael H. Sieweke, Christine Stabell Benn, Henk Stunnenberg, Joseph Sun, Frank L. van de Veerdonk, Sebastian Weis, David L. Williams, Ramnik Xavier, Mihai G. Netea
Journal: Nature Immunology (2020)
RARE-37. NOONAN SYNDROME AND GLIONEURONAL TUMORS: A CENTRAL NERVOUS SYSTEM CANCER PREDISPOSITION ASSOCIATION?
Authors: Margaret Shatara, Elizabeth A Varga, Daniel R Boué, Lisa Martin, Jerome A Rusin, Diana P Rodriguez, Jeremy Jones, Aaron McAllister, Jeffrey R Leonard, Jonathan Pindrik, Kathleen M Schieffer, Kristen M Leraas, Tara M Lichtenberg, Elaine R Mardis, Catherine E Cottrell, Diana S Osorio, Mohamed S AbdelBaki, Jonathan L Finlay
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Noonan syndrome (NS) is associated with germline Ras signaling pathway mutations, RAS overactivation and increased tumorigenesis risk. Rosette-forming glioneuronal tumors (RFGT) are rare indolent tumors. We report the molecular profiling of two patients with NS and RFGT. PATIENT 1: A 22-year-old male with NS was diagnosed with RFGT after partial tumor resection followed by focal irradiation. He was enrolled on a comprehensive genomic profiling study involving paired tumor-normal whole exome sequencing and RNA sequencing of the disease-involved tissue, revealing a germline PTPN11 alteration (p.Gly60Ala) consistent with NS, and a somatic deletion (p.Ile442_Thr454del) in PIK3R1 and a somatic variant (p.Lys656Glu) in FGFR1 with concomitant increased expression of PIK3R1 and FGFR1 by RNA-sequencing. The patient remains without tumor progression now nine months since irradiation. PATIENT 2: A 19-year-old male with persistent headaches, underwent a brain MRI demonstrated multiple abnormal signals in the pineal region and midbrain. He had a stereotactic biopsy revealing RFGT. He was enrolled on the genomic study revealing a germline PTPN11 alteration (p.Asn308Asp) resulting in a new diagnosis of NS. Several family members were subsequently identified with clinical features of NS, including his mother and two siblings, enabling appropriate counseling. Two somatic variants were found in trans in PIK3R1 (p.Thr454_Phe456del and p.Glu451_Asn453delinsAsp), and a somatic variant (p.Val695Met) in FGFR1, with resultant overexpression of PIK3R1. The patient is monitored with surveillance imaging. CONCLUSION We report the molecular profiling of two patients with NS and RFGT; strongly suggesting their connection to RASopathies through the overactivation of the MAPK and PI3K/AKT/mTOR signaling pathways.
The Nuclear Receptor ESRRA Protects from Kidney Disease by Coupling Metabolism and Differentiation
Authors: Poonam Dhillon, Jihwan Park, Carmen Hurtado del Pozo, Lingzhi Li, Tomohito Doke, Shizheng Huang, Juanjuan Zhao, Hyun Mi Kang, Rojesh Shrestra, Michael S. Balzer, Shatakshee Chatterjee, Patricia Prado, Seung Yub Han, Hongbo Liu, Xin Sheng, Pieterjan Dierickx, Kirill Batmanov, Juan P. Romero, Felipe Prósper, Mingyao Li, Liming Pei, Junhyong Kim, Nuria Montserrat, Katalin Susztak
Journal: Cell Metabolism (2020)
ATRT-13. DIFFERENT CELLS OF ORIGIN PAVE THE WAY FOR MOLECULAR HETEROGENEITY IN RHABDOID TUMORS
Authors: Monika Graf, Marta Interlandi, Natalia Moreno, Dörthe Holdhof, Viktoria Melcher, Dennis Kastrati, Gerd Meyer zu Hörste, Martin Dugas, Michael C Frühwald, Thomas K Albert, Ulrich Schüller, Kornelius Kerl
Journal: Neuro-Oncology (2020)

Abstract Rhabdoid tumors (RT) are rare but highly aggressive pediatric neoplasms. These tumors carry homozygous loss-of-function alterations of SMARCB1 in almost all cases with an otherwise low mutational load. RT arise at different intracranial (ATRT) as well as extracranial (MRT) anatomical sites. Three main molecular subgroups (ATRT-SHH, ATRT-TYR, ATRT-MYC) have been characterized for ATRT which are epigenetically and clinically diverse, while MRT show remarkable similarities with ATRT-MYC distinct from ATRT-SHH and ATRT-TYR. Even though there are hypotheses about various cells of origin among RT subgroups, precursor cells of RT have not yet been identified. Previous studies on the temporal control of SMARCB1 knockout in genetically engineered mouse models have unveiled a tight vulnerable time frame during embryogenesis with regard to the susceptibility of precursor cells to result in RT. In this study, we employed single-cell RNA sequencing to describe the intra- and intertumoral heterogeneity of murine ATRT-SHH and -MYC as well as extracranial MYC tumor cells. We defined subgroup-specific tumor markers for all RT classes but also observed a notable overlap of gene expression patterns in all MYC subgroups. By comparing these single-cell transcriptomes with available single-cell maps of early embryogenesis, we gained first insights into the cellular origin of RT. Finally, unsupervised clustering of published human RT methylation data and healthy control tissues confirmed the existence of different cells of origin for intracranial SHH tumors and MYC tumors independent of their anatomical localizations.
Clostridium difficile-ассоциированный колит: обзор литературы, клинический случай
Authors: Y.M. Stepanov, E.V. Simonova, I.Y. Budzak, I.N. Коnonov
Journal: GASTROENTEROLOGY (2020)

В статье приведены современные представления об инфекции Clostridium difficile (C. difficile): приводится современная классификация, разбираются вопросы эпидемиологии, этиологии, патогенеза кишечных нарушений, клинические аспекты этого заболевания, а также лабораторные, эндоскопические, морфологические проявления. Представлены современные международные подходы к лечению C. difficile-инфекции. C. difficile-ассоциированный колит — заболевание, развивающееся при нарушении кишечного микробиома с избыточной колонизацией C. difficile, токсины которой вызывают воспаление и повреждение слизистой оболочки толстой кишки и диарею. Прием антибиотиков приводит к угнетению эндогенной микрофлоры и размножению C. difficilе благодаря плазмидам спорообразования; после отмены препаратов споры переходят в вегетативную форму бактерий и начинают вырабатывать токсины; в результате повреждения эндотелия, обширных воспалительных изменений в слизистой оболочке толстой кишки формируются участки некроза на поверхности эпителия с образованием псевдомембран (экссудативных бляшек). Клостридиальная инфекция приводит к широкому спектру клинических проявлений — от бессимптомного носительства, умеренной, неосложненной диареи до угрожающего жизни псевдомембранозного колита — тяжелой клинической формы C. difficile-ассоциированного колита, вызванной токсигенной формой C. difficile, характерным признаком которого являются фибринозные наложения на слизистой оболочке толстой кишки (псевдомембраны), выявленные при эндоскопическом исследовании. Золотым стандартом и наиболее информативным методом верификации диагноза является обнаружение токсинов C. difficile в кале. В диагностике C. difficile-ассоциированного колита важную роль играют также оценка лабораторных показателей, эндоскопическое и морфологическое исследования. При постановке диагноза псевдомембранозного колита лечение необходимо начинать незамедлительно. Первый шаг — отмена антибиотика, вызвавшего диарею. Неотъемлемой частью стандартной терапии пациентов с C. difficile-ассоциированным колитом является антибактериальная терапия, которая должна ограничить колонизацию кишечника C. difficile и оказать противовоспалительное действие. C. difficile наиболее чувствительны к ванкомицину и метронидазолу. Обязательным условием является энтеральное назначение антибиотиков, так как при парентеральном их введении в кишечнике не всегда создается достаточная их концентрация, в связи с чем может не наступить полная санация от C. difficile. В статье показан и проанализирован клинический случай у пациента с данным заболеванием, проходившего лечение в Институте гастроэнтерологии НАМН Украины.
EXTH-57. INVESTIGATION OF THE TUMORICIDAL EFFECTS OF SONODYNAMIC THERAPY IN MALIGNANT GLIOBLASTOMA BRAIN TUMORS
Authors: Kimball Sheehan, Darrah Sheehan, Mohanad Sulaiman, Frederic Padilla, Jason Sheehan, Zhiyuan Xu
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE Glioblastoma is the most common primary brain tumor; survival is typically 12–18 months after diagnosis. We sought to study the effects of sonodynamic therapy (SDT) using 5-Aminolevulinic acid hydrochloride (5-ALA) and high frequency focused ultrasound (FUS) on 2 glioblastoma cell lines. PROCEDURE Rat C6 and human U87 glioblastoma cells were studied under the following conditions: 1mM 5-ALA (5-ALA); Focused ultrasound (FUS); 5-ALA and focused ultrasound (SDT); control. Studied responses included cell viability using an MTT assay, microscopic changes using phase contract microscopy, apoptotic induction through a caspase-3 assay, and apoptosis staining to quantify cell death. RESULTS SDT led to a marked decrease in cell extension and reduction in cell size. For C6, the MTT assay showed reductions in cell viability for 5-ALA, FUS, and SDT groups of 5%, 16%, and 47%, respectively compared to control (p&amp;lt; 0.05). Caspase 3 induction in C6 cells relative to control showed increases of 109%, 110%, and 278% for 5-ALA, FUS, and SDT groups, respectively (p&amp;lt; 0.05). For the C6 cells, caspase 3 staining positivity was 2.1%, 6.7%, 11.2%, and 39.8% for control, 5-ALA, FUS, and SDT groups, respectively. C6 Parp-1 staining positivity was 1.9%, 6.5%, 9.0%, and 37.8% for control, 5-ALA, FUS, and SDT groups, respectively. U87 cells showed similar responses to the treatments. CONCLUSIONS Sonodynamic therapy resulted in appreciable glioblastoma cell death as compared to 5-ALA or FUS alone. The approach couples two already FDA approved techniques in a novel way to treat the most aggressive and malignant of brain tumors. Further study of this promising technique is planned using glioma and also brain metastasis models.
<i>SPRED1</i> deletion confers resistance to MAPK inhibition in melanoma
Authors: Julien Ablain, Sixue Liu, Gatien Moriceau, Roger S. Lo, Leonard I. Zon
Journal: The Journal of Experimental Medicine (2020)

Functional evaluation of genetic lesions can discover a role in cancer initiation and progression and help develop novel therapeutic strategies. We previously identified the negative MAPK regulator SPRED1 as a novel tumor suppressor in KIT-driven melanoma. Here, we show that SPRED1 is also frequently deleted in human melanoma driven by mutant BRAF. We found that SPRED1 inactivation in human melanoma cell lines and primary zebrafish melanoma conferred resistance to BRAFV600E inhibition in vitro and in vivo. Mechanistically, SPRED1 loss promoted melanoma cell proliferation under mutant BRAF inhibition by reactivating MAPK activity. Consistently, biallelic deletion of SPRED1 was observed in a patient whose melanoma acquired resistance to MAPK-targeted therapy. These studies combining work in human cells and in vivo modeling in zebrafish demonstrate a new mechanism of resistance to BRAFV600E inhibition in melanoma.
Author Correction: Deep learning algorithm predicts diabetic retinopathy progression in individual patients
Authors: Filippo Arcadu, Fethallah Benmansour, Andreas Maunz, Jeff Willis, Zdenka Haskova, Marco Prunotto
Journal: npj Digital Medicine (2020)

A Correction to this paper has been published: https://doi.org/10.1038/s41746-020-00365-5.
LINC-41. TREATMENT OF RECURRENT MEDULLOBLASTOMA IN CHILDREN IN LOW INCOME SETTINGS
Authors: Roman Kizyma, Khrystyna Zapotochna, Bogdan Romanyshyn, Zoryana Kizyma, Roman Sobko
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Children with recurrent medulloblastoma after initial therapy have very poor prognosis due to limited second line treatment options and significant treatment-related morbidity. METHODS A retrospective chart review of 18 children with recurrent or progressive medulloblastoma, treated initially with risk-adapted therapy in Western Ukrainian Specialized Pediatric Medical Centre from 2012 to 2019, was performed. RESULTS All patients received first line multimodal treatment: surgery, distant beam radiotherapy and chemotherapy. Recurrent disease in 11 patients presented with metastatic dissemination and in 7 patients as local relapse. The median time to recurrence was 10 months. The median follow-up after diagnosis of recurrent disease diagnosed was 2 years and 2 months. Second line therapy included re-surgery (5 cases), radiation therapy (10 cases) and various cytostatic agents as monotherapy or combination - carboplatin, cisplatin, cyclophosphamide, etoposide, methotrexate, temozolomide, lomustine. Patients treated with radiotherapy for salvage had prolonged local control compared to those that received chemotherapy only. On follow-up 8 children are currently alive. CONCLUSION Recurrent and progressive medulloblastoma had a poor prognosis with a 2-year overall survival (OS) of 28% on different salvage therapy. The variety in the treatment of all patients experiencing recurrence was observed due to low income country settings. The factors that influenced higher survival after recurrence of medulloblastoma were longer time to relapse, and local pattern of relapse/progression.
ATRT-08. A PHASE II STUDY OF CONTINUOUS LOW DOSE PANOBINOSTAT IN PAEDIATRIC PATIENTS WITH MALIGNANT RHABDOID TUMORS/ATYPICAL TERATOID RHABDOID TUMORS
Authors: Paul Wood, Jayesh Desai, Kelly Waldeck, Jason Cain, Nick Gottardo, Robyn Strong, Kathryn Kinross, Michelle Carr, Janelle Jones, Lily Wong, David Ziegler, Jordan Hansford, Michael Michael, David Ashley
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Panobinostat treatment has been shown to terminally differentiate malignant rhabdoid tumor (MRT)/atypical teratoid rhabdoid tumors (ATRT) in pre-clinical models. This is an open label, phase II study of panobinostat in patients with newly diagnosed or relapsed MRT/ATRT. AIMS: To assess the anti-tumor activity of low dose, continuous panobinostat, its associated toxicities, the biological activity of low dose panobinostat by measuring histone acetylation status in peripheral mononuclear cells (PMNC), and markers of differentiation in fresh tumor tissue specimens. METHODS Following cycles of induction and consolidation chemotherapy and/or radiation treatment, patients were enrolled and commenced on panobinostat as a continuous daily oral dose starting at 10mg/m2 following a three-week wash out period between therapies. Real-time acetylation status, measuring acetylated H4 on PMNC, was performed to determine the pharmacodynamics of panobinostat. Patients were monitored for drug toxicities with the possibility of dose reductions in decrements of 2mg/m2. RESULTS Six patients with newly diagnosed ATRT/MRT and one patient with relapsed MRT have been enrolled to date. The average age at enrollment was 2.5 years. Currently, six patients (85.7%) remain on study with a mean treatment duration of 170 days (range 44–327 days). One patient was removed from study at day 44 due to disease progression. The main dose-limiting toxicity observed to date has been myelosuppression. Panobinostat, at a dose of 10mg/m2, caused significant acetylation of H4 in PMNC. CONCLUSIONS Treatment with panobinostat appears to be well tolerated in infants with MRT/ATRT, with successful real-time pharmacodynamic assessment of H4 acetylation.
Determinants and Trends of Adherence to a Gluten-Free Diet in Adult Celiac Patients on a Long-term Follow-up (2000–2020)
Authors: Annalisa Schiepatti, Stiliano Maimaris, Maria Luisa Nicolardi, Eleonora Alimenti, Marta Vernero, Martina Costetti, Stefania Costa, Federico Biagi
Journal: Clinical Gastroenterology and Hepatology (2020)
CBIO-20. MOLECULAR MECHANISMS OF OLIG2 TRANSCRIPTION FACTOR IN GLIOBLASTOMA
Authors: Norihiko Saito, Sho Sato, Yu Hiramoto, Satoshi Fujita, Haruo Nakayama, Morito Hayashi, Keisuke Ito, Takatoshi Sakurai, Satoshi Iwabuchi
Journal: Neuro-Oncology (2020)

Abstract Oligodendrocyte lineage transcription factor 2 (OLIG2) promotes proliferation of normal neural stem/progenitor cells and glioma cells. However, the mechanisms underlying the regulation of OLIG2 remain largely unknown. Here, we show that a comprehensive analysis of the critical gene regulatory networks involving OLIG2 in glioma initiating cell (GIC) lines. In vitro differentiation studies showed that proneural GIC lines possess the potential to differentiate into astrocytic, neuronal, and oligodendrocytic lineages, whereas mesenchymal GICs exhibited limited potential for neural lineage differentiation following retinoic acid induction. We also showed that CDK2-mediated OLIG2 phosphorylation stabilizes OLIG2 protein from proteasomal degradation. Phosphorylated OLIG2 binds to the E-Box regions of p27 promoter and represses p27 transcription, which in turn activates CDK2 in positive feedback manner. CDK2-mediated OLIG2 phosphorylation promotes cell cycle progression, cell proliferation, and tumorigenesis. OLIG2 inhibition disrupted cell cycle control mechanism by decreasing CDK2 and elevating apoptosis-related molecules. Inhibition of CDK2 activity disrupted OLIG2-CDK2 interactions and attenuated OLIG2 protein stability. In addition, OLIG2-high glioma initiating cells are highly sensitive to CDK2 inhibitor treatment, indicating that OLIG2 can be a biomarker for personalized treatment for glioblastoma patients with CDK2 inhibitors. In conclusion, we have identified OLIG2-CDK2 interactions in glioma stem cells that can be targeted by CDK2 inhibitors and this may allow the selection of patients with high likelihood of responding to this therapy.
COVD-11. THE BRAIN TUMOR AND NOT FOR PROFIT AND CHARITY EXPERIENCE OF COVID 19: REACTING AND ADJUSTING TO AN UNPRECEDENTED GLOBAL PANDEMIC IN THE 21ST CENTURY
Authors: Mary Ellen Maher, Christina Amidei, Jean Arzbaecher, Kathy Oliver, Christine Mungoshi, Rosemary Cashman, Stuart Farrimond, Carol Kruchko, Anita Granero, Chris Tse, Maureen Daniels, Mary Lovely, Sally Payne, Sharon Lamb, Jenifer Baker
Journal: Neuro-Oncology (2020)

Abstract The COVID-19 pandemic has not only affected individuals, but also disease specific not-for-profits and charities. Brain tumor not-for-profit and charitable organizations around the world exist in all shapes and sizes, and address unmet needs of the patients and caregivers they serve. The International Brain Tumor Alliance(IBTA) carried out an international survey to identify organization changes brought about by the virus and the approaches adopted to address operational challenges created by COVID-19. A 37-question survey was sent across the world. In total, 77 organizations from 22 countries responded. Descriptive statistics and content analysis were used to present RESULTS: Responses fell into three categories: 1) organizational characteristics, 2) the impact of COVID-19 on services, and 3) how COVID-19 has affected the financial and human resources in these organizations. Although organizational characteristics vary widely, common concerns reported across organizations were primarily: a) the disruption of activities which impacted organizations’ abilities to offer their usual services and b) challenges to sustaining funding. Although brain tumor organizations have been impacted by the COVID-19 pandemic, organizations quickly adjusted to this unprecedented global healthcare crisis.
Double-counting of effect sizes and inappropriate exclusion of studies in “The influence of vitamin D supplementation on IGF-1 levels in humans: A systematic review and meta-analysis”
Authors: Mojgan Amiri, Hamidreza Raeisi-Dehkordi, Colby J. Vorland, Xiwei Chen, Andrew W. Brown, David B. Allison
Journal: Ageing Research Reviews (2020)