tbuckley/cabot-search huggingface dataset:
STEM-15. SMALL BUT FIERCE: THE ROLE OF EXTRACELLULAR VESICLES IN MESENCHYMAL TRANSITION AND THERAPEUTIC RESISTANCE IN GLIOBLASTOMA
Authors: Markus Schweiger, Mao Li, Renata Fleming, Elie Tabet, Thomas Würdinger, Bakhos Tannous
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma (GBM) is a dismal disease and despite optimal treatment, long-term survival remains uncommon. Molecular classification revealed three distinct GBM subgroups and has helped to shine light on the tumor’s inter/intratumoral heterogeneity. Interestingly, recent evidence shows plasticity between these subtypes in which the proneural (PN) glioma stem-like cells undergo transition into the more aggressive mesenchymal (MES) subtype leading to therapeutic resistance. Extracellular vesicles (EVs) are considered a heterogeneous group of membrane-limited vesicles secreted by nearly every cell. In the context of GBM, these biological nanoparticles act as multifunctional signaling complexes and play an important role in intercellular communication allowing cancer cells to exchange information with each other, the tumor microenvironment, and distant cells. We show that MES cells derived EVs modulate PN cells to increase migratory potential, stemness, invasiveness, aggressiveness, and therapeutic resistance by inducing mesenchymal transition through NF-KB/STAT3 signaling. Furthermore, we shine light on the role of EVs derived from irradiated GBM cells and their potential impact on microglia and resulting treatment resistance.
TAMI-15. THE EFFECT OF INTERSTITIAL FLUID FLOW AND ASTROCYTES / MICROGLIA ON INVASION, PROLIFERATION AND STEMNESS OF PATIENT-DERIVED GLIOMA STEM CELLS
Authors: Naciye Atay, Jessica Yuan, Chase Cornelison, Jennifer Munson
Journal: Neuro-Oncology (2020)

Abstract SIGNIFICANCE Glioblastoma is a highly infiltrative, malignant, and deadly glioma that can be classified into subtypes based on molecular classification. Treatment resistant glioma stem cells (GSCs) depend on the tumor microenvironment (TME) to drive recurrence. Cellular composition and interstitial fluid flow (IFF) are significant aspects of the TME. IFF and astrocyte and microglia (A+M) presence have independently been shown to mediate invasion. This study’s goal is to expand our knowledge of IFF and A+M effects on invasion to proliferation and stemness. METHODS Seven patient-derived GSC lines were tested in an in vitro 3D model, which consists of GSCs ± A+M resuspended in 0.2% hyaluronan / 0.12% rat tail collagen I gel. The gel was applied to an 8um pore 96-well transwell system. Flow and static conditions were modeled with and without a pressure head above the gel, respectively. Cells beyond the transwell membrane after 18 hrs of incubation were considered invaded. Stemness and proliferation were determined via flow cytometry for CD71 and Ki67, respectively. RESULTS/CONCLUSIONS The three mesenchymal GSC lines tested exhibited the largest IFF fold increases in stemness, proliferation, and invasion with averages of 23.9, 19.1, and 2.1, respectively. CD44+ cell populations, highest in mesenchymal cells, had a strong correlation with proliferation (R=0.8439) and stemness (R=0.7829) under flow. Furthermore, depending on the cell line/subtype, the addition of A+M either amplified, reduced, reversed, mitigated, or kept constant the effect of IFF on invasion and proliferation. Incorporating A+M never amplified the effect of IFF on stemness. Adding A+M had a strong effect on the IFF fold change of at least one parameter in six of the cell lines. This is the first presentation showing that IFF, patient-specific, and context-specific factors contribute to both increased proliferation, and maintenance of stem-like phenotypes in glioma.
NCOG-02. PROGNOSTIC VALIDATION OF THE EANO ESMO CLASSIFICATION OF LEPTOMENINGEAL METASTASIS
Authors: Emilie Le Rhun, Patrick Devos, Johannes Weller, Katharina Seystahl, Francesca Mo, Annette Compter, Anna Sophie Berghoff, Joost Jongen, Fabian Wolpert, Roberta Rudà, Dieta Brandsma, Matthias Preusser, Martin van den Bent, Ulrich Herrlinger, Michael Weller
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND The EANO ESMO guidelines have proposed a classification of leptomeningeal metastases (LM) based on clinical (typical/atypical), cytological (positive/negative/equivocal) and MRI (A linear, B nodular, C linear and nodular, D normal or hydrocephalus only) presentation. Type I LM is defined by the presence of tumor cells in the cerebrospinal fluid (CSF) (confirmed LM) whereas type II LM is defined by typical clinical and MRI signs (probable or possible LM). Here we explored the clinical utility of these EANO ESMO LM subtypes for choice of treatment and outcome. PATIENTS AND METHODS We retrospectively assembled data from 254 patients with newly diagnosed LM from different solid tumors, including as main primary tumors breast cancer (n=98, 45%), lung cancer (n=65, 25.5%) and melanoma (n=51, 13.5%). Survival curves were estimated using the Kaplan-Meier method and compared by Log-rank test. RESULTS Median age at LM diagnosis was 56.5 years (range 20-82 years). Typical clinical LM symptoms or signs were noted in 225 patients (88.5%); only 13 patients (5%) were clinically asymptomatic. The most common MRI subtype was A seen in 117 patients (46%). Types B (n=33, 13%), C (n=54, 21%) and D (n=50, 19.5%) were less common. Tumor cells in the CSF were observed in 186 patients (73%) whereas the CSF was equivocal in 24 (9.5%) and negative in 44 (17.5%) patients. Patients with confirmed LM had inferior outcome than patients with probable or possible LM (p=0.0063). Type I patients had inferior outcome than type II patients (p=0.0019). Nodular disease was a negative prognostic factor in type II LM, but not in type I LM (p=0.0138). CONCLUSION The EANO ESMO LM subtypes are highly prognostic and should be considered for stratification and overall design of clinical trials.
IMMU-26. UNRAVELING ANTIGEN PRESENTATION IN CENTRAL NERVOUS SYSTEM ANTI-TUMOR IMMUNITY
Authors: Jay Bowman-Kirigin, Dale Kobayashi, Alexandra Livingstone, Brian Saunders, Max Schaettler, Connor Liu, Vivek Durai, Jay Bowman-Kirigin, Eric Leuthardt, Albert Kim, Gregory Zipfel, Joshua Osbun, Michael Chicoine, Kenneth Murphy, Bernd Zinselmeyer, Tanner Johanns, Gavin Dunn
Journal: Neuro-Oncology (2020)

Abstract The antigen presenting cell that primes T cells in the central nervous system (CNS) remains unknown. Outside the CNS, the conventional dendritic cell 1 (cDC1) subset presents antigen to and primes CD8 T cells. However, the steady-state CNS parenchyma is relatively devoid of all dendritic cell subsets, including cDC1. cDC1 are required for anti-tumor immunity a variety of other tumor types, but their role CNS tumors remains undefined. Using the orthotopic preclinical glioblastoma models, GL261 and CT2A, we characterized the role of cDC1 in the CNS anti-tumor immune response. While cDC1 are absent in the steady state brain, tumor presence drove recruitment of cDC1 into extravascular spaces within the tumor and adjacent brain parenchyma. We further found that while GL261-bearing wildtype mice experienced survival benefit following anti-PDL1 checkpoint blockade treatment, mice with cDC1 genetically deleted experienced no survival benefit. cDC1-deficient mice completely lacked neoantigen-specific CD8 T cells against the endogenously-primed GL261-neoantigen mutant Imp3, and possessed broad CD8 effector T cell defects compared to wild type mice. Furthermore, using a fluorescent tumor-associated reporter, we detected tumor-derived material within dendritic cells from the tumor, the lymphatic vessel-containing dura, and the cervical lymph nodes. We observed the human cDC1-equivalent CD141+ cDC within human brain tumors (not limited to GBM) and dura as well. We used the GBM-specific reporter, 5-aminoilevulinic acid/protoporphyrin IX (PPIX) fluorescent metabolite to resect the tumor, and observed PPIX specifically in conventional dendritic cell subsets that had infiltrated the resected tumor, but not within those same cell subsets in the periphery, nor in T cells within the tumor. These findings comport with the canonical understanding that cDC1 uptake antigen at the effector site and migrate to draining lymph nodes to prime effector CD8 T cells, and highlight the significant role that cDC1 play in CNS anti-tumor immunity in mice and humans.
Defining and Utilizing Surrogates in the Evaluation of Coronary Stents: What Do We Really Want and Need to Know?⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Robert A. Harrington, Vic Hasselblad, Robert M. Califf
Journal: Journal of the American College of Cardiology (2008)
NIMG-36. AUTOMATIC STRATIFICATION OF ENHANCING AND NON-ENHANCING GLIOMAS INTO GENETIC SUBTYPES USING DEEP NEURAL NETWORKS AND DIFFUSION-WEIGHTED IMAGING
Authors: Julia Cluceru, Paula Alcaide-Leon, Yannet Interian, Valentina Pedoia, Joanna Phillips, Devika Nair, Tracy Luks, Javier Villanueva-Meyer, Janine Lupo
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Current WHO guidelines emphasize classification of diffuse gliomas by genetic alterations into three subgroups: 1) IDH-wildtype; 2) IDH-mutant, 1p/19q-codeleted; and 3) IDH-mutant, 1p/19q-non-codeleted. Non-invasive genetic characterization can benefit patients with inoperable lesions or who are administered molecularly-targeted therapy before surgery. Prior studies that use anatomical images and convolutional neural networks (CNNs) to distinguish either IDH-mutant from IDH-wildtype tumors, or 1p/19q-codeleted from non-codeleted tumors have resulted in misclassification of nonenhancing IDH-wildtype and enhancing IDH-mutant tumors. This study investigated the benefit of a priori separation of enhancing from nonenhancing lesions and the inclusion of ADC maps from diffusion MRI to genetic subgroup classification. METHODS 3D T2-weighted, T2-FLAIR, and post-contrast T1-weighted images were acquired preoperatively from 254 patients with newly-diagnosed gliomas. IDH1R132H mutations[VJ1] [CJ2], 1p19q-codeletions, ATRX alterations, and p53 mutations were assessed from the resected tissue to determine subtype stratification: IDH-wildtype (n=95), IDH-mutant, 1p/19q-codeleted (n=62), and IDH-mutant, non-codeleted (n=97). 3-channel input images were constructed for each patient using T2-FLAIR, T1-post-contrast, and either T2-weighted or ADC images. Three VGG-16 CNNs pre-trained on ImageNet were re-trained for: 1) lesions without enhancement, 2) enhancing lesions, and 3) all lesions together[VJ3]. RESULTS A network trained on only enhancing lesions predicted the IDH-wildtype subtype with the highest class accuracy (ADC 94%, T2-weighted 100%) compared to using all lesions combined (ADC 90%, T2-weighted 90%). Models trained using non-enhancing lesions and ADC yielded the highest accuracy classifying 1p/19q-codeleted/non-codeleted subgroups (87%/90% for the non-enhancing network vs 83%/81% for combined network). CONCLUSIONS Our results support a strategy that first considers whether a lesion is enhancing when predicting molecular subgroup and includes ADC if the lesion is non-enhancing. Analysis is underway to test this model framework on independent TCIA data.
John Violet: radiation oncologist and physician scientist who pioneered targeted radionuclide therapy for prostate cancer
Authors: Gavin Yamey
Journal: BMJ (2020)

Photo credit: Imogen Violet

In every hospital—every lucky one, that is—there is a doctor who has a reputation for staying late to talk with patients, giving them as much information and time as they need to absorb and understand their diagnosis and treatment options. At the Peter MacCallum Cancer Centre in Melbourne, Australia, the radiation oncologist John Violet was that doctor. Violet was known as much for his empathy as his tireless quest to develop a new generation of tailored cancer treatments and his profound respect for the autonomy of patients he recruited into trials.

There was also more than a whiff of the Renaissance man about him. An acclaimed photographer with a love of cityscapes, he came to work dressed in purple three piece suits, with a fountain pen and leather briefcase, carrying off what one of his colleagues called a “slightly bonkers magician fashion look” with aplomb. He was an avid traveller, a connoisseur of food, wine, interior design, and 1980s rock music, and a devoted father who was at his happiest when singing along to Queen to the delight of his two young daughters.

Violet was just three years old when his father—a beloved …
QOLP-26. USE OF MEDICAL ASSISTANCE IN DYING (“DEATH WITH DIGNITY”) IN WASHINGTON STATE PATIENTS WITH BRAIN TUMORS.
Authors: Jerome Graber, Kaite Sofie, Lynne Taylor
Journal: Neuro-Oncology (2020)

Abstract Since 2009, Washington State has had a “Death with Dignity” (DWD) process whereby people with a terminal illness may legally obtain a prescription for medications that will end their life. Patients initiate a voluntary request from two physicians certifying they have a prognosis &amp;lt; 6 months, are aware of other palliative care options, and have capacity without the comorbidity of a psychiatric diagnosis. Since 2015, over 200 people annually have used the DWD process in Washington. Other papers have described the characteristics of people using DWD with a diagnosis of cancer or amyotrophic lateral sclerosis (ALS) but none have specifically looked at patients with brain tumors (BT) who used DWD. We describe 20 people with BT who accessed DWD since 2015 at our center. Median age at the time of death was 51 (range 38-79) and 75% were men. Glioblastoma was the diagnosis in 10 (50%), anaplastic glioma in 8 (40%), grade II astrocytoma in 1, and a presumed high-grade glioma by imaging in 1. Median Karnofsky Performance Status (KPS) was 90 at diagnosis (range 50-100) and 70 at DWD request (range 40-90). Standard radiation (RT) and chemotherapy was used by 17 (85%) prior to DWD request, while 3 patients (15%, ages 70-79, KPS 50-90) requested DWD immediately after diagnosis and did not undergo further treatment. Pain was present in 4 patients (20%), 2 using opioids (10%). Six patients (30%) continued tumor treatments after approval for DWD. Median OS was 22 months (range 2-285) and 24 months excluding patients who declined treatment (range 8-285). Most glioma patients in our cohort requested DWD after undergoing chemoradiation, pain was uncommon and rarely severe, and survival from diagnosis was comparable to standard therapy. As access to medical assistance in dying continues, further research is needed on its utilization for people with brain tumors.
IMMU-26. DISEASE CONTROL IN A PEDIATRIC PATIENT WITH NEWLY DIAGNOSED GLIOBLASTOMA MULTIFORME (GBM) AND SOMATIC HIGH MICROSATELLITE INSTABILITY (MSI-H) WITH PD-1 INHIBITOR NIVOLUMAB (NIVO) ONLY AND NO FOCAL RADIOTHERAPY (RT)
Authors: Trisha Larkin, Jason Blatt, Sridharan Gururangan
Journal: Neuro-Oncology (2020)

Abstract Immune checkpoint inhibitors that target programmed death receptor-1 (PD-1) have recently been shown to be a promising option for the management of recurrent mismatch repair (MMR) deficient GBM following radiotherapy. We report a case of a 9-year-old boy who presented with a 6 week history of frontal headaches and was found to have a left frontal lobe mass. Pathology obtained from a gross total resection (GTR) was consistent with classic GBM, WHO Grade IV. Neuroimaging four weeks following initial resection was remarkable for local recurrence. The patient underwent another GTR of the tumor at our center. While pathology again confirmed GBM, GlioSequencing of tumor tissue from second resection showed MSI-H, NF2 mutation p.R338H, NF1 mutations p.R2450* and pI193Yfs*11, TP53 mutations p.R213* and p.R273C, EGFR mutation, and multiple variants of uncertain significance. Germline testing was negative for MMR deficiency or other deleterious mutations. Parents opted to defer radiotherapy and consented to monotherapy treatment with Nivolumab (Opdivo, BMS pharmaceuticals, USA), a PD-1 inhibitor, at a dose of 3 mg/kg administered every two weeks. Our patient is now 22 months post-second resection and continues to receive Nivolumab without evidence of recurrent disease or adverse autoimmune effects from PD-1 blockade. He has remained in school with good academic performance and has exhibited no regression of functional status during the entirety of his treatment course. This case provides evidence of possible efficacy of PD-1 blockade without focal radiotherapy in this child with GBM and somatic MSI instability.
IMMU-36. HIGH AFFINITY CHIMERIC ANTIGEN RECEPTOR WITH CROSS-REACTIVITY TO CLINICALLY-RELEVANT EGFR MUTATED PROTEINS
Authors: Radhika Thokala, Zev Binder, Yibo Yin, Michael Milone, Donald M O’Rourke
Journal: Neuro-Oncology (2020)

Abstract Tumor heterogeneity is one of the key reasons for therapeutic failure in Glioblastoma (GBM). Our chimeric antigen receptor (CAR) T cell clinical trial (NCT02209376) against Epidermal growth factor receptor (EGFR) variant III (EGFRvIII) demonstrated successful trafficking of T cells across the blood brain barrier into GBM active tumor sites. However, CART cell infiltration was associated with a selective loss of EGFRvIII+ tumor cells and upregulation of immunosuppressive molecules. Post-CAR T treated tumor specimens showed continued presence of EGFR amplification and oncogenic EGFR extracellular domain (ECD) missense mutations. To study this further We generated two structurally different CARs by fusing the scFv of mAb806 to 4-1BB and Killer immunoglobulin like receptor (KIR) co-stimulatory domains. Both 4-1BB and KIR based EGFR806 CAR T cells specifically lysed tumor cells and secreted cytokines when co-cultured with U87-MG (expressing low levels of EGFR) and U87-MG EGFR (U87-MG transduced with EGFR wild type for amplified background) cell lines and engineered to ectopically express targeted EGFR-ECD missense mutations and EGFRvIII. Unlike EGFR-specific cetuximab based CAR, EGFR-806CART cells did not kill EGFR wild type expressing fetal brain primary astrocytes and keratinocytes in vitro. We further evaluated the in vivo efficacy of 806-CARs and EGFRvIII CART currently in clinic in NSG mice. While EGFRvIII CART cells cleared EGFRvIII+ tumors alone 806 CART cells controlled EGFRvIII, amplified EGFR and EGFRR108K-mutant bearing tumors. KIR-CAR treated tumors are GVHD free and enhanced survival compared to 4-1BB based CARs. The broad specificity of EGFR806 CART cells to amplified EGFR and its mutant variants gives us the potential to clear various forms of EGFR. The enhanced anti-tumor efficacy by KIR based CAR in vivo setting provides us with additional therapeutic options.
Неалкогольная жировая болезнь печени у лиц с нормальным весом: современные представления и подходы (обзор литературы)
Authors: Yu.M. Stepanov, O.Yu. Zavhorodnia
Journal: GASTROENTEROLOGY (2020)

Неалкогольная жировая болезнь печени (НАЖБП) является самой распространенной причиной хронических заболеваний печени во всем мире. НАЖБП у лиц с нормальным весом представляет собой заболевание, морфологическим субстратом которого выступает стеатоз печени, индуцированный неоднородным спектром этиологических факторов, начиная от пищевых привычек (таких как избыточное содержание фруктозы и жиров в диете), распределения жира в организме (висцеральное ожирение в противовес общему ожирению), состава тела (приобретенная или врожденная липодистрофия, саркопения) и генетических факторов риска, включая редкие врожденные дефекты обмена веществ. У около 20 % таких пациентов диагностируется стеатогепатит, характеризующийся гистопатологической степенью тяжести, подобной состоянию пациентов с классической НАЖБП. Существуют большие пробелы в понимании НАЖБП среди лиц с нормальным весом, поэтому освещению основных аспектов этиологии, патогенеза, диагностической и лечебной тактики посвящен данный обзор литературы.
Low-dose chest CT had 95% sensitivity and 91% specificity for diagnosing COVID-19 in patients with clinical symptoms
Authors: Brit Long
Journal: Annals of Internal Medicine (2020)

Source CitationSchulze-Hagen M, Hübel C, Meier-Schroers M, et al. Low-dose chest CT for the diagnosis of COVID-19. Dtsch Arztebl Int. 2020;117:389-95. https://pubmed.ncbi.nlm.nih.gov/32762834/AbstractClinical Impact RatingsGIM/FP/GP: Emergency Med: Hospitalists: Infectious Disease: Pulmonology:
GCT-17. WHAT IS THE CLINICAL OUTCOME OF PROTON BEAM THERAPY FOR PATIENTS WITH INTRACRANIAL GERM CELL TUMOR IN KOREA?
Authors: Sang Hee Youn, Joo-Young Kim
Journal: Neuro-Oncology (2020)

Abstract PURPOSE To evaluate the clinical outcome of patients with intracranial germ cell tumor treated with proton beam therapy (PBT). MATERIALS AND METHODS Fifty-seven patients with intracranial germ cell tumor treated with PBT between 2009 and 2016 were retrospectively analyzed. RESULTS Median follow-up duration was 63.7 months (range, 5.6–204.5). Thirty-seven patients (64.9%) were pure germinoma and 20 patients (35.1%) were non-germinomatous germ cell tumor (NGGCT). All patients except 2 patients received chemotherapy before PBT. Twenty-one patients (36.8%) of localized germinoma were treated with whole ventricle irradiation (WVI), while 36 (63.2%) patients who were diagnosed as disseminated germinoma or NGGCT received cranio-spinal irradiation (CSI). Two patients with pure germinoma in basal ganglia showed disease relapse at 3.0 and 6.9 years after PBT at the primary site and pituitary gland, respectively. There was one patient with NGGCT who died of chemotherapy-related mortality at 4.7 years after PBT while her disease was complete remission. The 7-year progression-free survival and overall survival were 70.8% and 100% for focal germinoma, 100% and 100% for disseminated germinoma, 100% and 100% for focal NGGCTs, and 100% and 80.0% for disseminated NGGCTs, respectively. CONCLUSIONS PBT of pure germinoma resulted in comparable clinical outcomes to that with photon radiotherapy. Our result for NGGCT is also excellent compared to other reports. Failure patterns of germ cell tumors originating in basal ganglia needs to be assessed in large pooled data.