tbuckley/cabot-search huggingface dataset:
Estimating the false-negative test probability of SARS-CoV-2 by RT-PCR
Authors: Paul S Wikramaratna, Robert S Paton, Mahan Ghafari, José Lourenço
Journal: Eurosurveillance (2020)

Background Reverse-transcription PCR (RT-PCR) assays are used to test for infection with the SARS-CoV-2 virus. RT-PCR tests are highly specific and the probability of false positives is low, but false negatives are possible depending on swab type and time since symptom onset. Aim To determine how the probability of obtaining a false-negative test in infected patients is affected by time since symptom onset and swab type. Methods We used generalised additive mixed models to analyse publicly available data from patients who received multiple RT-PCR tests and were identified as SARS-CoV-2 positive at least once. Results The probability of a positive test decreased with time since symptom onset, with oropharyngeal (OP) samples less likely to yield a positive result than nasopharyngeal (NP) samples. The probability of incorrectly identifying an uninfected individual due to a false-negative test was considerably reduced if negative tests were repeated 24 hours later. For a small false-positive test probability (&lt;0.5%), the true number of infected individuals was larger than the number of positive tests. For a higher false-positive test probability, the true number of infected individuals was smaller than the number of positive tests. Conclusion NP samples are more sensitive than OP samples. The later an infected individual is tested after symptom onset, the less likely they are to test positive. This has implications for identifying infected patients, contact tracing and discharging convalescing patients who are potentially still infectious.
DIPG-68. ALPHA-THALASSEMIA X-LINKED MENTAL RETARDATION PROTEIN (ATRX) LOSS-OF-FUNCTION IN A MOUSE MODEL OF DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Chen Shen, David Picketts, Oren Becher
Journal: Neuro-Oncology (2020)

Abstract Diffuse Intrinsic Potine Glioma (DIPG) is a rare pediatric brain tumor for which no cure or efficacious therapies exist. Previous discoveries have revealed that, DIPG harbors distinct genetic alterations, when compared with adult high-grade glioma (HGG) or even with non-DIPG pediatric HGGs. ATRX alteration is found in 9% of clinical cases of DIPG, and significantly overlaps with H3.3K27M mutation and p53 loss, the two most common genetic changes in DIPG, found in 80% and 77% clinical cases, respectively. Here we developed genetically engineered mouse model of brainstem glioma using the RCAS-Tv-a system by targeting PDGF-B overexpression, p53 loss, H3.3K27M mutation and ATRX loss-of function to Nestin-expression brainstem progenitor cells of the neonatal mouse. Specifically, we used Nestin-Tv-a; p53 floxed; ATRX heterozygous female and Nestin-Tv-a; p53 floxed; ATRX floxed male breeders, generated offsprings with ATRX loss of function (n=18), ATRX heterozygous females (n=6), and ATRX WT (n=10). Median survial of the three groups are 65 days, 88 days and 51 days, respectively. Also, ATRX null mice is lower in tumor incidence (44.4%), compared with ATRX WT (80%). We evaluated the pathological features of DIPG with or without ATRX alteration, RNA-seq is performed to identify differentially expressed genes between ATRX WT and loss-of-function. In conclution, this study generated the first genetically modified mouse model studying ATRX loss-of-function in DIPG, and suggested that ATRX loss-of-function in DIPG may slow down tumorigenesis and decrease tumor incidence.
5P Uncovering the evolution of glioblastoma proteome landscape from primary to the recurrent stage for development of novel diagnostic and predictive biomarkers
Authors: N. Tatari, S. Khan, J. Livingstone, C. Venugopal, J. Chan, C. Hawkins, J. Provias, J.Q. Lu, K. Ask, T. Kislinger, S. Singh
Journal: Annals of Oncology (2020)
Preexisting immunity shapes distinct antibody landscapes after influenza virus infection and vaccination in humans
Authors: Haley L. Dugan, Jenna J. Guthmiller, Philip Arevalo, Min Huang, Yao-Qing Chen, Karlynn E. Neu, Carole Henry, Nai-Ying Zheng, Linda Yu-Ling Lan, Micah E. Tepora, Olivia Stovicek, Dalia Bitar, Anna-Karin E. Palm, Christopher T. Stamper, Siriruk Changrob, Henry A. Utset, Lynda Coughlan, Florian Krammer, Sarah Cobey, Patrick C. Wilson
Journal: Science Translational Medicine (2020)

Antibody immunodominance to conserved influenza virus epitopes is affected by both preexisting B cell memory and route of exposure.
Nitrogen recycling buffers against ammonia toxicity from skeletal muscle breakdown in hibernating arctic ground squirrels
Authors: Sarah A. Rice, Gabriella A. M. Ten Have, Julie A. Reisz, Sarah Gehrke, Davide Stefanoni, Carla Frare, Zeinab Barati, Robert H. Coker, Angelo D’Alessandro, Nicolaas E. P. Deutz, Kelly L. Drew
Journal: Nature Metabolism (2020)
TBIO-05. GENOME-SCALE NUCLEOTIDE-SPECIFIC CHARACTERIZATION OF 5-HYDROXYMETHYLCYTOSINE IN PEDIATRIC CENTRAL NERVOUS SYSTEM TUMORS
Authors: Nasim Azizgolshani, Curtis L Petersen, Lucas Salas, Youdinghuan Chen, Laurent Perreard, Lananh N Nguyen, Brock C Christensen
Journal: Neuro-Oncology (2020)

Abstract Though aberrant cytosine modifications are prevalent in cancer, nucleotide-specific 5-hydroxymethylcytosine (5hmC) modifications remain understudied, including in pediatric CNS tumors. Brain 5-hydroxymethylation is linked with development and differentiation. We measured genome-scale nucleotide-specific 5hmC in patients with diagnoses of glioma, ependymoma, and embryonal tumors under age 18 (n=36), and in non-tumor pediatric brain tissues (n=3). DNA was processed with tandem oxidative (OxBS) and bisulfite (BS) treatments followed by hybridization to the Illumina Methylation EPIC Array that interrogates over 860,000 CpG sites. We used the OxyBS R package to determine levels of 5hmC and 5mC. Mean 5hmC levels were lower in tumors (gliomas 4.1%, ependymomas 3.9%, and embryonal tumors 3.4%) compared to nontumor tissues (5.3%). We subset to the CpGs with the 5% highest 5hmC content for downstream analyses (37,173 CpGs). These sites were enriched among regulatory elements, including TFBS (Odds Ratio 1.14 p-value 3.57E-20) and super-enhancers (OR 1.93, p-value 1.14E-126). Linear mixed-effects models adjusted for age, sex, and cell type proportions tested the CpG-specific differences in 5hmC between tumor and nontumor samples, as well as between tumor subtypes. 5hmC levels were depleted across tumors compared with nontumor brain tissues, including at CpG islands. Model-based clustering (RPMM) results indicated that patients with low 5hmC patterns have poorer overall survival and increased risk of recurrence. Our results indicate that 5hmC localizes to sites in the DNA critical to gene regulation and is associated with patient outcomes. This study offers an opportunity to potentially contribute to classification markers for childhood brain tumors.
RTID-08. A PHASE 1/2 STUDY OF SELINEXOR IN COMBINATION WITH STANDARD OF CARE THERAPY FOR NEWLY DIAGNOSED OR RECURRENT GLIOBLASTOMA (ndGBM OR rGBM)
Authors: Patrick Wen, Yazmin Odia, Minesh Mehta, Samuel Goldlust, Sharon Tamir, Sharon Shacham, Hongwei Wang, Heidi Sheehan, Kai Li
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND GBM is the most common and most aggressive primary brain tumor with poor prognosis and median overall survival (mOS) of patients with ndGBM and rGBM being 15 vs 5-7 months, respectively. Selinexor is a first-in class, oral, selective nuclear export inhibitor which forces nuclear retention and reactivation of many tumor suppressor proteins. Selinexor with low dose dexamethasone was recently approved for patients with triple-class refractory multiple myeloma. Additionally, selinexor monotherapy has demonstrated broad activity in other hematologic and solid malignancies. In a Phase 2 study in rGBM (NCT01986348), selinexor demonstrated encouraging intratumoral penetration and single-agent efficacy at 80 mg once weekly with durable response and disease stabilization in heavily pretreated patients. Preclinical GBM studies showed synergy when combining selinexor with radiation, temozolomide and lomustine. METHOD This is a phase 1 (PH-1) dose finding study followed by a 1:1 randomized phase 2 (PH-2; n= 350) efficacy exploration trial to independently evaluate 3 different combination regimens: Arm A: radiation +/- selinexor in uMGMT ndGBM; Arm B: radiation and temozolomide +/- selinexor in MGMT ndGBM; Arm C:omustine +/- selinexor in first relapse rGBM following frontline radiation and temozolomide. The PH-1 primary endpoint is MTD/RP2D, with secondary endpoints of ORR per modified RANO, duration of response (DOR), PFS, and OS. The PH-2 primary endpoint for Arms A and B in ndGBM is PFS, with key secondary endpoints being OS, PFS6, ORR, DOR. For Arm C, the PH-2 primary endpoint is OS while key secondary endpoints are PFS, PFS6, ORR, DOR. The study has 70% power to detect a hazard ratio of 0.67 between selinexor and control for primary efficacy for arms A &amp; B, and 80% power to detect a hazard ratio of 0.70 for arm C. We are currently enrolling patients nationwide. Clinical trial identifier: NCT04421378
Abstract 14746: A National Level Analysis of Long-term Outcomes in Patients With Carotid Body Tumors
Authors: Edgar Aranda-Michel, Ibrahim Sultan, James Brown, Valentino Bianco, Andreas Habertheuer, Olugbenga T Okusanya
Journal: Circulation (2020)

Introduction: Carotid body tumors represent the most common site for extra-adrenal paragangliomas. Surgical resection is the treatment of choice as a low percentage of these tumors are malignant. Here we present long-term outcomes of a contemporary cohort of patients with a carotid body tumor. Methods: The national cancer database was quired for all cases of a carotid body tumor between 2004-2015. All baseline variables were gathered from the database. Kaplan-Meier curves were generated for the entire cohort to assess overall survival. The group was split into surgical and non-surgical cohorts. Survival was assessed via Kaplan-Meier estimates. Patients that underwent surgery were divided based on isolated surgical therapy or multimodal therapy (surgery with radiation or chemotherapy). Cox multivariable analysis was used to determine independent predictors for mortality. Results: The search returned 130 patients with a carotid body tumor. The average age of this cohort was 47 years and the majority were women (58.5%). A small proportion (9.2%) of the cohort had a metastasis at the time of diagnosis. Most patients underwent surgery (80%) followed by radiation (44.6%). The overall survival of the cohort was 81.5% at 10 years (Figure 1A) . Long-Term survival was higher in the surgical cohort (P=0.001) (Figure 1B) . Patients with multimodal therapy survived longer than those that underwent surgery alone (P=0.007) (Figure 1C). On Cox multivariable analysis (Figure 1D) , only radiation was a predictor for survival (HR 0.25, P=0.008). Having a metastasis on the time of diagnosis was a predictor for worse outcomes (HR 4.45, P=0.03). Conclusions: While surgery had a survival benefit on Kaplan-Meier analysis, when risk adjusting for other variables, radiation was the only treatment that conferred a survival benefit; an interesting finding given the historical standard of surgical management. Despite improvements in therapeutic modalities, metastasis on diagnosis carries an increased mortality, favoring aggressive treatment.
Cuts in cancer research funding due to COVID-19
Authors: Talha Khan Burki
Journal: The Lancet Oncology (2020)

On Dec 8, 2020, Cancer Research UK (CRUK) announced cuts of £45 million to its research budget. The charity has been badly affected by the COVID-19 pandemic, which forced the cancellation of fundraising events and the suspension of trading at the 600 CRUK shops across the country. Earlier this year, CRUK applied £44 million worth of cuts. It expects to make a further set of reductions in April, 2021. "We are planning for a managed decrease in spending on research from pre-COVID levels of £400–450 million to somewhere around £250 million", said Iain Foulkes, CRUK's executive director of research and innovation.
NCOG-69. SEX DIFFERENCES IN GLIOBLASTOMA PATIENT SURVIVAL AS A FUNCTION OF EXTENT OF SURGICAL RESECTION AND CYCLES OF ADJUVANT TEMOZOLOMIDE DURING STANDARD-OF-CARE REGIMENS
Authors: Julia Lorence, Tomas Bencomo, Haylye White, Cassandra Rickertsen, Susan Massey, Kyle Singleton, Andrea Hawkins-Daarud, Sandra Johnston, Alyx Porter, Maciej Mrugala, Bernard Bendok, Leland Hu, Joshua Rubin, Kristin Swanson
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE Glioblastoma (GBM) is the most common malignant primary brain tumor in adults, with males more commonly affected than females(1.6:1). Despite advancements in treatments, prognosis is dismal with a median overall survival of 15 months. Our aim was to investigate sex as a variable in GBM patient survival after receiving incremental levels of standard-of-care treatment regimens – different extents of surgical resection and different numbers of cycles of adjuvant temozolomide chemotherapy. METHODS Drawing from our extensive multi-institutional brain tumor repository, we investigated GBM subjects with overall survival (OS), extent of resection (EOR), number of temozolomide (TMZ) cycles, and sex data (n=620, males: n=387, females: n=233). Cox proportional hazard ratios were computed to investigate the multivariable predictive value of the patient variables with OS. Patients were then divided into groups based on their sex, EOR (either biopsy, subtotal resection (STR) or gross total resection (GTR)), and TMZ cycles (I: &amp;lt; 6 cycles, II: 7-11 cycles and III: &amp;gt;12 cycles). RESULTS We observed that STR was beneficial for females (HR=0.52; CI=0.33-0.83; p-value=0.013), while for males the benefit was not detected (HR=0.73; CI=0.46-1.15; p-value=0.173) for STR but was detectable for GTR (HR=0.58, CI=0.37-0.90; p-value=0.014). Females receiving 7-11 cycles of TMZ showed a survival benefit (HR=0.52; CI=0.12-0.53; p-value=0.048) while males in the same group did not (HR=0.74; CI=0.46-1.19; p-value=0.21), in comparison to those in group I of TMZ cycles. No sex differences were identified in patients receiving &amp;lt; =6 cycles or &amp;gt;=12 cycles. CONCLUSION Together, our results contribute to the growing literature that sex differences exist in GBM patients, even in response to standard-of-care therapies. This should be accounted for when designing clinical trials for GBM so that we may advance our pursuit to deliver personalized medicine.
RTID-09. A RANDOMIZED, DOUBLE-BLINDED, PHASE 3 STUDY OF ENZASTAURIN ADDED TO TEMOZOLOMIDE DURING AND FOLLOWING RADIATION THERAPY IN NEWLY DIAGNOSED GLIOBLASTOMA PATIENTS WHO POSSESS THE NOVEL BIOMARKER, DGM1
Authors: Nicholas Butowski, Ying Mao, Wilson Wu, Wen Luo, Lan Ge, Daniel Pertschuk, Theresa Dewitt, Isabel Han, Thomas Heineman
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Limited progress has been made in improving therapeutic outcomes for glioblastoma (GBM) patients. Enzastaurin (enza) is an oral PKC-β inhibitor that suppresses signaling through the PKC and PI3K/AKT pathways. Although enza did not significantly improve survival in a prior Phase 1/2 study, we have identified a novel genomic biomarker, DGM1, that may predict a response to enza in GBM. PRIMARY OBJECTIVE To assess whether enza added to temozolomide and radiation therapy (RT) improves overall survival (OS) in newly diagnosed GBM patients who possess the DGM1 biomarker. POPULATION Adults with newly diagnosed GBM regardless of DGM1 status who have undergone surgical resection and are candidates for chemoradiation. Approximately 318 patients will be enrolled. DGM1 status will be determined prior to analysis. DESIGN This is a randomized, double-blinded, placebo-controlled study. Patients will be stratified by MGMT and IDH1 status and by geographic region. Treatment will be divided into 3 phases. In the Concurrent Phase (6 weeks), patients will receive RT plus temozolomide and either enzastaurin or placebo. Patients will then enter the Single-Agent Phase and receive either enza or placebo (21-35 days). Then, patients will enter the Adjuvant Phase and receive temozolomide with either enza or placebo (6-12 cycles) followed by enza or placebo alone (to 24 cycles total). ANALYSIS The primary efficacy endpoint of OS will be analyzed using stratified log-rank test for all DGM1-positive randomized patients. The study has approximately 90% power to detect a HR of 0.63 assuming 196 OS events based on a 2.5% one-sided false positive error rate. Statistical significance would be achieved with an estimated observed HR &amp;lt; 0.76. Safety evaluation will include all patients receiving at least one dose of enza or placebo. If OS in DGM1-positive patients is statistically significant, OS in the overall population will be assessed.
32P Low immunogenicity and favorable safety seen with novel regimen of tremelimumab (T) plus durvalumab (D) in patients (pts) with unresectable hepatocellular carcinoma (uHCC)
Authors: R.K. Kelley, A. Negro, C. Chen, S. Ali, N. Standifer, M. Watras, B. Evans, G.K. Abou-Alfa
Journal: Annals of Oncology (2020)
Real Life Data on Clinical Aspects and Treatment of Marginal Zone Lymphoma: An Analysis from the NF10 Project, an International, Prospective, Observational Study of the Fondazione Italiana Linfomi
Authors: Irene Defrancesco, Luigi Marcheselli, Sara Rattotti, Marina Cesaretti, Marco Frigeni, Roberta Sciarra, Federica Cavallo, Alessandra Tedeschi, Maria Giuseppina Cabras, Michele Merli, Angela Ferrari, Francesca Re, Michele Spina, Emanuele Cencini, Ombretta Annibali, Giuseppe Cimino, Marcia Torresan Delamain, Donato Mannina, Gianluca Gaidano, Caterina Stelitano, Daris Ferrari, Carlo Visco, Francesco Angrilli, Vittoria Tarantino, Stefano Luminari, Luca Arcaini
Journal: Blood (2017)
CTNI-47. PHASE II STUDY OF ABEMACICLIB IN RECURRENT GBM PATIENTS WITH CDKN2A/B LOSS AND INTACT RB
Authors: Eudocia Lee, Alona Muzikansky, Isabel Arrillaga-Romany, Ugonma Chukwueke, Timothy Cloughesy, Howard Colman, Mariza Daras, John de Groot, Jose Mcfaline-Figueroa, Lakshmi Nayak, Robert Prins, David Reardon, Jennie Taylor, Keith Ligon, Patrick Wen
Journal: Neuro-Oncology (2020)

Abstract Deregulation of the cyclin-dependent kinases (CDK) 4 and 6 (cdk4/6)–cyclin D-INK4—retinoblastoma protein (Rb) signaling pathway is among the most common aberrations found in glioblastoma (GBM) with more than 80% of patients estimated to be affected. We conducted an open label, multi-center, phase II trial of abemaciclib in participants with recurrent glioblastoma (GBM) at their first relapse and with documented evidence of CDKN2A/B loss and intact RB from archival tissue. A total of 32 patients enrolled on the non-surgical arm of the study with 13 women (40.63%) and median KPS 90 [range 60–100]. The PFS6 rate was 9.37% [95% CI, 2.4%, 22.27%], median PFS 55 days [95% CI, 49, 56], and median OS 384 days [95% CI, 228, 488]. Out of 31 evaluable patients, best response was PR 1 (3.2%), SD 11 (35.5%), and PD 19 (61.3%). The most common grade 3 or higher toxicities at least possibly related to abemaciclib included leukopenia (21.9%), neutropenia (18.6%), lymphopenia (9.4%), and thrombocytopenia (6.3%). Abemaciclib has minimal activity in this preselected recurrent GBM population. Correlative studies from the surgical arm of this study are pending.
TAMI-29. MULTIFACTORIAL UPREGULATION OF ID1 DRIVES DIPG INVASIVENESS AND IS THERAPEUTICALLY TARGETABLE
Authors: Viveka Nand Yadav, Micah K Harris, Stefanie Stallard, Rinette Woo, Robert Siddaway, Tingting Qin, Jessica Cummings, Brendan Mullan, Zachary Miklja, Ruby Siada, Ramya Ravindran, Xuhong Cao, Amy Pasternak, Maria G Castro, Pedro Lowenstein, Rajen Mody, Arul Chinnaiyan, Cynthia Hawkins, Pierre Desprez, Sean McAllister, Sriram Venneti, Carl Koschmann
Journal: Neuro-Oncology (2020)

Abstract Diffuse intrinsic pontine gliomas (DIPGs) are lethal brain tumors with no effective therapies other than radiation. Inhibitor of DNA binding (ID) proteins, key regulators of lineage commitment during embryogenesis, are implicated in tumorigenesis in multiple human cancers. Prior work showed that recurrent H3F3A and ACVR1 mutations increase ID1 expression in cultured astrocytes. However, this has not been validated in human DIPG. The regulation and targetability of ID1 in DIPG has not been explored either. Exome and transcriptome sequencing analysis of multi-focal DIPG tumors and normal brain tissue from autopsy (n=52) revealed that ID1 expression is significantly elevated in DIPG tissues. Higher ID1 expression correlates with reduced survival in DIPG patients and increased regional invasion in multi-focal autopsy samples. Analyses of developing mouse brain RNA/ChiP-Seq data revealed high ID1 expression and H3K27ac promoter binding in prenatal hind brain compared to all other prenatal and postnatal brain regions. ChIP-qPCR for H3K27ac and H3K27me3 revealed that ID1 gene regulatory regions are epigenetically poised for upregulation in DIPG tissues compared to normal brain, regardless of H3/ACVR1 mutational status. These data support that the developing pons is regionally poised for ID1 activation. Genetic (shRNA) ID1 knockdown in primary human H3.3K27M-DIPG cells (DIPG007) resulted in significantly reduced invasion and migration in vitro. Additionally, DIPG-ID1-KO cells showed improved sensitivity to radiation therapy. Phospho-kinase array analysis of DIPG cells revealed that Akt and WNK1 activity were significantly downregulated upon ID1 knockdown, which was previously shown in lung tumors. Treatment of DIPG007 cells with cannabidiol (CBD) reduced ID1 expression levels and viability/proliferation of DIPG cells in vitro. ID1 knockdown and CBD treatment studies in vivo are ongoing. In summary, our findings indicate that multifactorial (genetic and regional) epigenetic upregulation of ID1 drives DIPG invasiveness and targeting ID1 using CBD may be a potential strategy for the treatment of DIPGs.
TAMI-02. ALTERATIONS IN C-X3-C MOTIF CHEMOKINE RECEPTOR 1 (CX3CR1) EXPRESSION INFLUENCE MICROGLIAL AND MACROPHAGE RESPONSE IN DIFFERENT STEPS OF CEREBRAL METASTASIS FORMATION
Authors: Wenlong Zhang, Iven-Alex von Mücke-Heim, Matthias Mulazzani, Philipp Karschnia, Andreas Straube, Louisa von Baumgarten
Journal: Neuro-Oncology (2020)

Abstract Metastasis to the brain is a frequent complication in lung cancer and is still associated with a dismal prognosis. Current treatment strategies not only target tumor cells but also focus on cells of the tumor microenvironment like tumor associated microglia/macrophages (TAMs). The interactions between tumor cells and TAMs during different steps of cerebral metastasis formation of lung cancer brain metastasis are poorly characterized. Moreover, the role of CX3CR1 in this process remains unclear. We established a syngeneic cerebral metastasis mouse model by combining a chronic cranial window and two-photon laser scanning microscopy (TPLSM), which allows the tracking of single fluorescent metastasizing tumor cells and the tumor microenvironment on a cellular resolution in vivoover time for a period of weeks. Transgenic CX3CR1 proficient and deficient mice (CX3CRGFP/wt and CX3CR1GFP/GFP) were injected with red fluorescent Lewis lung carcinoma cells. During different steps of metastasis formation (extravasation, formation of micro- and macrometastasis) the density and cell body volume of TAMs, their interaction with tumor cells and possible influence on the fate of single metastatic tumor cells were investigated using serial TPLSM. We found that during metastasis formation TAM density was significantly lower in CX3CR1 deficient mice. However, activation as assessed by TAM morphology did not differ in the absence of CX3CR1. Strikingly, CX3CR1 deficiency was associated with a significant increase of tumor cells successfully extravasating the cerebral vasculature. However, subsequent steps (mirco- and macrometastasis formation) were observed less frequent in CX3CR1 deficient mice. In summary, our results highlight a complex role of CX3CR1 for TAMs during cerebral metastasis formation, indicating anti-tumorous properties of CX3CR1 at early steps and possible pro-tumorous effects at later stages (micro- and macrometastasis formation).