tbuckley/cabot-search huggingface dataset:
TAMI-06. PRECLINICAL MODELS REVEAL BRAIN-MICROENVIRONMENT SPECIFIC METABOLIC DEPENDENCIES IN GLIOBLASTOMA
Authors: Jenna Minami, Nicholas Bayley, Christopher Tse, Henan Zhu, Danielle Morrow, William Yong, Linda Liau, Timothy Cloughesy, Thomas Graeber, David Nathanson
Journal: Neuro-Oncology (2020)

Abstract Metabolic reprogramming is a hallmark of cancer, and malignant cells must acquire metabolic adaptations to fuel neoplastic progression. Mutations or changes in metabolic gene expression can impose nutrient dependencies in tumors, and even in the absence of metabolic defects, cancer cells can become auxotrophic for particular nutrients or metabolic byproducts generated by other cells in the tumor microenvironment (TME). Conventional cell lines do not recapitulate the metabolic heterogeneity of glioblastoma (GBM), while primary cultured cells do not account for the influences of the microenvironment and the blood brain barrier on tumor biology. Additionally, these systems are under strong selective pressure divergent from that in vivo, leading to reduced heterogeneity between cultured tumor cells. Here, we describe a biobank of direct-from-patient derived orthotopic xenografts (GliomaPDOX) and gliomaspheres that reveal a subset of gliomas that, while able to form in vivo, cannot survive in vitro. RNA sequencing of tumors that can form both in vivo and in vitro (termed “TME-Indifferent”) compared to that of tumors that can only form in vivo (termed “TME-Dependent”) revealed transcriptional changes associated with altered nutrient availability, emphasizing the unique metabolic programs impacted by the tumor microenvironment. Furthermore, TME-dependent tumors lack metabolic signatures associated with nutrient biosynthesis, thus indicating a potential dependency of these tumors on scavenging specific nutrients from the extracellular milieu. Collectively, these data emphasize the metabolic heterogeneity within GBM, and reveal a subset of gliomas that lack metabolic plasticity, indicating a potential brain-microenvironment specific metabolic dependency that can be targeted for therapy.
IMG-04. RESPONSE ASSESSMENT IN PEDIATRIC HIGH-GRADE GLIOMA: RECOMMENDATIONS FROM THE RESPONSE ASSESSMENT IN PEDIATRIC NEURO-ONCOLOGY WORKING GROUP
Authors: Craig Erker, Benita Tamrazi, Tina Y Poussaint, Sabine Mueller, Daddy Mata-Mbemba, Enrico Franceschi, Alba A Brandes, Arvind Rao, Kellie B Haworth, Patrick Y Wen, Stewart Goldman, Gilbert Vezina, Tobey J Macdonald, Ira J Dunkel, Paul S Morgan, Tim Jaspan, Michael D Prados, Katherine E Warren
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Response criteria for pediatric high-grade gliomas (pHGG) have varied historically and across clinical trials. Compared to adult HGG, pHGG response assessment has unique challenges. An international Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group was established to develop pHGG response assessment criteria. METHODS Pediatric and adult neuro-oncologists, neuro-radiologists and experts in imaging informatics developed a consensus statement and established a unified response assessment for biopsy-proven pHGG, excluding DIPG. This was achieved by identifying major challenges, reviewing existing literature and current practices, and finally developing recommendations through an iterative process. RESULTS Categories for response assessment include complete response, partial response, minor response, stable disease and progressive disease. Refractory disease is excluded. Criteria used to determine response assessment include quantitative evaluation of measurable disease, qualitative assessment of diffusion imaging, presence or absence of new lesions, clinical status using performance score, and vascular endothelial growth factor inhibitor and/or corticosteroid use. Response is determined over 2-time points ≥ 8 weeks apart, and when progressive disease is unclear, guidance for repeat MRI imaging and/or utility of repeat biopsy is described. A number of recommendations are also given to standardize response assessment across clinical trials including MRI protocol sequence recommendations for brain and spine, definitions for measurable and non-measurable disease, and imaging time points with post-operative considerations. In addition, guidance is given for differentiating vasogenic edema versus tumor invasion in non-enhancing disease. CONCLUSION Consensus recommendations and response definitions have been established and, similar to other RAPNO recommendations, prospective validation in clinical trials is warranted.
INNV-06. SECOND GENERATION BRAF/MEK INHIBITION IN ANAPLASTIC PLEOMORPHIC XANTHROASTROCYTOMA
Authors: Brian Stocksdale, Yaping Joyce Liao, Gwen Coffey, Seema Nagpal
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Up to 65% of anaplastic pleomorphic xanthoastrocytomas (A-PXA) harbor the BRAFV600E oncogene. Trials and case series have demonstrated that BRAF-mutant gliomas, including A-PXAs, can be responsive to the first generation BRAF inhibitors dabrafenib and vemurafenib, with an ORR ranging from 26–43%. The second generation BRAF/MEK inhibitor combination encorafenib/binimetinib improves systemic outcome in melanoma patients, has better tolerability, and may have better intracranial activity compared to first generation drugs. METHOD We review the three patients with BRAFV600E A-PXA treated with encorafenib/binimetinib in our practice. RESULTS Two patients were diagnosed with A-PXA in 2014 and one in 2013. The presence of BRAFV600E was confirmed by molecular testing. All patients have received prior surgery, chemotherapy, and radiation and were at a recurrence when BRAF/MEK inhibition was initiated. One patient had CR after 2 months on treatment and remains in CR at 1-year. One patient, who is also receiving bevacizumab, has a PR, with continued clinical and imaging improvement at 6 months. Our third patient had a PR at 2 months and remains on therapy, currently 3 months post-initiation. All 3 patients report improvement in symptoms. The patient who has been on treatment for 1 year experienced rapid onset bilateral multifocal sub-retinal fluid collections followed by rapid resolution, without intervention, within days of starting treatment. This patient has also had mild decrease in EF over time. We will present continued follow up. CONCLUSIONS Encorafenib/binimetinib appears feasible, with 3 of out 3 patients with BRAFV600E A-PXA demonstrating radiographic response; 2 of these patients have durable responses. We stress the importance of a clear lab, cardiac, ophthalmologic, and dermatologic monitoring regimen as side effects can be rapid and severe. Prospective studies with encorafenib/binimetinib in BRAF-mutant primary CNS tumors are underway, and we eagerly anticipate their RESULTS:
Comparison of Treatments for Frozen Shoulder
Authors: Dimitris Challoumas, Mairiosa Biddle, Michael McLean, Neal L. Millar
Journal: JAMA Network Open (2020)

<h3>Importance</h3> There are a myriad of available treatment options for patients with frozen shoulder, which can be overwhelming to the treating health care professional. <h3>Objective</h3> To assess and compare the effectiveness of available treatment options for frozen shoulder to guide musculoskeletal practitioners and inform guidelines. <h3>Data Sources</h3> Medline, EMBASE, Scopus, and CINHAL were searched in February 2020. <h3>Study Selection</h3> Studies with a randomized design of any type that compared treatment modalities for frozen shoulder with other modalities, placebo, or no treatment were included. <h3>Data Extraction and Synthesis</h3> Data were independently extracted by 2 individuals. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Random-effects models were used. <h3>Main Outcomes and Measures</h3> Pain and function were the primary outcomes, and external rotation range of movement (ER ROM) was the secondary outcome. Results of pairwise meta-analyses were presented as mean differences (MDs) for pain and ER ROM and standardized mean differences (SMDs) for function. Length of follow-up was divided into short-term (≤12 weeks), mid-term (&gt;12 weeks to ≤12 months), and long-term (&gt;12 months) follow-up. <h3>Results</h3> From a total of 65 eligible studies with 4097 participants that were included in the systematic review, 34 studies with 2402 participants were included in pairwise meta-analyses and 39 studies with 2736 participants in network meta-analyses. Despite several statistically significant results in pairwise meta-analyses, only the administration of intra-articular (IA) corticosteroid was associated with statistical and clinical superiority compared with other interventions in the short-term for pain (vs no treatment or placebo: MD, −1.0 visual analog scale [VAS] point; 95% CI, −1.5 to −0.5 VAS points;<i>P</i> &lt; .001; vs physiotherapy: MD, −1.1 VAS points; 95% CI, −1.7 to −0.5 VAS points;<i>P</i> &lt; .001) and function (vs no treatment or placebo: SMD, 0.6; 95% CI, 0.3 to 0.9;<i>P</i> &lt; .001; vs physiotherapy: SMD 0.5; 95% CI, 0.2 to 0.7;<i>P</i> &lt; .001). Subgroup analyses and the network meta-analysis demonstrated that the addition of a home exercise program with simple exercises and stretches and physiotherapy (electrotherapy and/or mobilizations) to IA corticosteroid may be associated with added benefits in the mid-term (eg, pain for IA coritocosteriod with home exercise vs no treatment or placebo: MD, −1.4 VAS points; 95% CI, −1.8 to −1.1 VAS points;<i>P</i> &lt; .001). <h3>Conclusions and Relevance</h3> The findings of this study suggest that the early use of IA corticosteroid in patients with frozen shoulder of less than 1-year duration is associated with better outcomes. This treatment should be accompanied by a home exercise program to maximize the chance of recovery.
Decreased Expression of the Host Long-Noncoding RNA-GM Facilitates Viral Escape by Inhibiting the Kinase activity TBK1 via S-glutathionylation
Authors: Yujia Wang, Pin Wang, Yunkai Zhang, Junfang Xu, Zhiqing Li, Zemeng Li, Zhongcheng Zhou, Lin Liu, Xuetao Cao
Journal: Immunity (2020)
スタチン類やアスピリン,アンギオテンシンII修飾剤などで処置された患者の高感受性C-反応性蛋白レベルの違い
Authors: Takeda T, Hoshida S, Suna S, Taniike M, Egami Y, Shutta R, Kawabata M, Nishino M, Kamada T
Journal: Circulation (2002)
STEM-11. INTERROGATING INTRATUMORAL TRANSCRIPTOMIC HETEROGENEITY AND PLASTICITY AS RESISTANCE MECHANISMS IN GLIOBLASTOMA
Authors: Yahaya A Yabo, Thais Arns, Anais Oudin, Kamil Grzyb, Suresh Poovathingal, Alessandro Michelucci, Alexander Skupin, Simone P Niclou, Anna Golebiewska
Journal: Neuro-Oncology (2020)

Abstract Intratumoral heterogeneity is one of the major barriers in the treatment of many tumor types. In glioblastoma (GBM) – the most aggressive brain tumor - survival of patients following standard therapy has stagnated to an average of 14 months, largely due to the inherent heterogeneity and phenotypic plasticity. Patient-derived orthotopic xenografts (PDOX) are important tools for preclinical cancer studies. We have shown that they recapitulate histological and molecular features of patient tumors, thus producing more clinically relevant study outcomes when compared to other preclinical models. To understand the impact of treatment on intratumoral heterogeneity and interactions of tumor cells with the microenvironment, we applied single-cell RNA-seq in GBM PDOX models generated from naive and treatment exposed patient tumors. Here we show that PDOX models recapitulate all the major cell types and transcriptional programs reported in GBM patient samples. We demonstrate that GBM tumor cells occur in distinct phenotypic states dictated by microenvironmental cues and treatment-induced pressure. Non-neoplastic cells present within xenografts undergo transcriptomic adaptation similar to the GBM microenvironment in patients. Analysis of treated PDOXs and longitudinal PDOX models derived from patients prior and after treatment allows us to investigate short-term and stable long-term transcriptomic adaptations. We aim to reveal key molecular regulators enhancing tumor cell plasticity and resistance, that could be targeted in combinatory treatments. Our GBM PDOX models provide a platform for high-quality pre-clinical research and an improved clinical relevance in the development and testing of novel therapeutics.
CTNI-04. ACTIVITY OF LAROTRECTINIB IN TROPOMYOSIN RECEPTOR KINASE (TRK) FUSION CANCER PATIENTS WITH CENTRAL NERVOUS SYSTEM (CNS) METASTASES
Authors: Jyoti D Patel, Anna F Farago, David S Hong, Ulrik N Lassen, Serge Leyvraz, Keunchil Park, Davendra P S Sohal, Benjamin Solomon, John A Reeves, Laura Dima, Nicoletta Brega, Alexander Drilon
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND NTRK gene fusions occur in a range of tumor types, including those with CNS metastases. Larotrectinib, a highly selective FDA- and EMA- approved TRK inhibitor, demonstrated an objective response rate (ORR) of 79% across various cancers (Hong et al. Lancet Oncol. 2020). We report data on patients with TRK fusion cancer with CNS metastases treated with larotrectinib. METHODS Patients with solid tumors with CNS metastases at baseline harboring an NTRK gene fusion enrolled in two clinical trials (NCT02122913 and NCT02576431) were identified. Response was assessed by the investigator per RECIST v1.1. RESULTS As of July 15, 2019, 14 patients with CNS-metastases were enrolled: lung cancer (n=7), thyroid cancer (n=4), melanoma (n=2), and non-secretory breast cancer (n=1). Median age was 53 years (range 25–76). Including all sites of disease, the ORR was 71% (95% CI 42–92%): ten patients had a partial response (PR), two had stable disease (SD), and two had progressive disease (lung and melanoma). Of the three patients with measurable intracranial disease at baseline, the best intracranial response was 1 complete response, 1 PR, and 1 SD. Median duration of response for all patients was 14.8 months (range 1.9+ to 17.4+), median progression-free survival was 9.9 months (range 1.4 to 19.3+), and median overall survival was 27.8 months (range 1.4+ to 27.8). Treatment duration ranged from 1.4 to 25.0 months; six patients continued treatment beyond progression (lasting between 0.1+ and 8.5 months). Treatment-emergent adverse events (TEAEs) were mainly Grade 1 and 2; Grade 3 TEAEs occurred in seven patients (50%), with one (myalgia) attributed to larotrectinib (7%). There were no Grade 4 TEAEs. CONCLUSIONS Larotrectinib was highly active and well tolerated in TRK fusion cancer patients with CNS metastases. These results support testing for NTRK gene fusions across all cancers, including in patients with CNS metastases.
Parathyroid Carcinoma With Marked Uptake of 99mTcO4 −
Authors: Elahe Pirayesh, Mehrdad Tavakoli
Journal: Clinical Nuclear Medicine (2020)

A 51-year-old man with a palpable neck mass and elevated parathyroid hormone was referred to our department for parathyroid scintigraphy. After injection of 740 MBq 99mTc-MIBI, a dual-phase scan was obtained, which revealed a persistent and intense focal hyperactivity in the left side of the neck (compatible with the neck mass). Thyroid scan with 99mTcO4- also showed increased uptake of the mass, similar to a hot thyroid nodule. After surgery, parathyroid carcinoma was confirmed pathologically. This case demonstrates a rare presentation of parathyroid carcinoma as a hot nodule in thyroid scan, which has been attributed to hypervascularity of the lesion.
Beyond glucose: alternative sources of energy in glioblastoma
Authors: John L. Caniglia, Anvesh Jalasutram, Swapna Asuthkar, Joseph Sahagun, Simon Park, Aditya Ravindra, Andrew J. Tsung, Maheedhara R. Guda, Kiran K. Velpula
Journal: Theranostics (2020)

Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults.With a designation of WHO Grade IV, it is also the most lethal primary brain tumor with a median survival of just 15 months.This is often despite aggressive treatment that includes surgical resection, radiation therapy, and chemotherapy.Based on the poor outcomes and prevalence of the tumor, the demand for innovative therapies continues to represent a pressing issue for clinicians and researchers.In terms of therapies targeting metabolism, the prevalence of the Warburg effect has led to a focus on targeting glucose metabolism to halt tumor progression.While glucose is the dominant source of growth substrate in GBM, a number of unique metabolic pathways are exploited in GBM to meet the increased demand for replication and progression.In this review we aim to explore how metabolites from fatty acid oxidation, the urea cycle, the glutamate-glutamine cycle, and one-carbon metabolism are shunted toward energy producing pathways to meet the high energy demand in GBM.We will also explore how the process of autophagy provides a reservoir of nutrients to support viable tumor cells.By so doing, we aim to establish a foundation of implicated metabolic mechanisms supporting growth and tumorigenesis of GBM within the literature.With the sparse number of therapeutic interventions specifically targeting metabolic pathways in GBM, we hope that this review expands further insight into the development of novel treatment modalities.
COVD-19. COGNITION, CANCER, AND COVID: DELIVERING DIRECT-TO-HOME TELE-NEUROPSYCHOLOGY SERVICES TO NEURO-ONCOLOGY PATIENTS
Authors: Melissa Gardner, Farah Aslanzadeh, Giuliana Zarrella, Sarah Braun, Ashlee Loughan, Michael Parsons
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND The COVID-19 pandemic altered the delivery of healthcare services globally with a rapid adoption of telemedicine to meet patient’s needs. Telemedicine is critical for neuro-oncology patients who may be at an increased risk of infection, yet require continuity of care. An important aspect of neuro-oncology care includes neuropsychological assessment, which can be challenging to complete outside of a structured testing environment. Teleneuropsychology (TNP) has been explored under proctored conditions and proven feasible and reliable. Conducting TNP visits directly to the patients’ home (DTH-TNP) had minimal study prior to the pandemic, but was implemented to reduce COVID-19 exposure. METHODS We used surveys to examine patient acceptance and clinician feasibility of DTH-TNP at two regionally diverse medical institutions routinely providing neuropsychological assessments services to neuro-oncology patients from April to August 2020, Massachusetts General Hospital (MGH) and Virginia Commonwealth University (VCU). RESULTS 45 patients voluntarily responded (MGH=30, VCU=15) and 98 percent (MGH=100%, VCU=93%) of respondents were satisfied with the DTH-TNP experience. Nine percent (MGH=7%, VCU=13%) reported challenges (e.g., technological issues) during the appointment. Eighty-nine percent (MGH=90%, VCU=87%) would recommend the virtual visit to others. Patients perceived reduced risk of infection (MGH=77%, VCU=87%) and time traveling to clinic (MGH=87%, VCU=80%) as favorable aspects of DTH-TNP. 43 clinician surveys collected at MGH indicated that clinicians were able to achieve the goal of their appointment in 91% of clinical encounters. Common issues reported by clinicians included trouble connecting (7%) to the telemedicine platform and environmental disruptions (12%). DISCUSSION This preliminary data suggests neuro-oncology patients and clinicians find DTH-TNP to be an acceptable and feasible practice, while also recognizing its limitations. This study is limited in that voluntary patient surveys are subject to bias. These results suggest that further study of DTH-TNP (e.g., reliability, validity, and limitations) for neuro-oncology patients is warranted. Future directions are discussed.
HIV infection and COVID-19 death: a population-based cohort analysis of UK primary care data and linked national death registrations within the OpenSAFELY platform
Authors: Krishnan Bhaskaran, Christopher T Rentsch, Brian MacKenna, Anna Schultze, Amir Mehrkar, Chris J Bates, Rosalind M Eggo, Caroline E Morton, Sebastian C J Bacon, Peter Inglesby, Ian J Douglas, Alex J Walker, Helen I McDonald, Jonathan Cockburn, Elizabeth J Williamson, David Evans, Harriet J Forbes, Helen J Curtis, William J Hulme, John Parry, Frank Hester, Sam Harper, Stephen J W Evans, Liam Smeeth, Ben Goldacre
Journal: The Lancet HIV (2020)

SummaryBackgroundWhether HIV infection is associated with risk of death due to COVID-19 is unclear. We aimed to investigate this association in a large-scale population-based study in England.MethodsWe did a retrospective cohort study. Working on behalf of NHS England, we used the OpenSAFELY platform to analyse routinely collected electronic primary care data linked to national death registrations. We included all adults (aged ≥18 years) alive and in follow-up on Feb 1, 2020, and with at least 1 year of continuous registration with a general practitioner before this date. People with a primary care record for HIV infection were compared with people without HIV. The outcome was COVID-19 death, defined as the presence of International Classification of Diseases 10 codes U07.1 or U07.2 anywhere on the death certificate. Cox regression models were used to estimate the association between HIV infection and COVID-19 death; they were initially adjusted for age and sex, then we added adjustment for index of multiple deprivation and ethnicity, and then for a broad range of comorbidities. Interaction terms were added to assess effect modification by age, sex, ethnicity, comorbidities, and calendar time.Results17 282 905 adults were included, of whom 27 480 (0·16%) had HIV recorded. People living with HIV were more likely to be male, of Black ethnicity, and from a more deprived geographical area than the general population. 14 882 COVID-19 deaths occurred during the study period, with 25 among people with HIV. People living with HIV had higher risk of COVID-19 death than those without HIV after adjusting for age and sex: hazard ratio (HR) 2·90 (95% CI 1·96–4·30; p<0·0001). The association was attenuated, but risk remained high, after adjustment for deprivation, ethnicity, smoking and obesity: adjusted HR 2·59 (95% CI 1·74–3·84; p<0·0001). There was some evidence that the association was larger among people of Black ethnicity: HR 4·31 (95% CI 2·42–7·65) versus 1·84 (1·03–3·26) in non-Black individuals (p-interaction=0·044).InterpretationPeople with HIV in the UK seem to be at increased risk of COVID-19 mortality. Targeted policies should be considered to address this raised risk as the pandemic response evolves.FundingWellcome, Royal Society, National Institute for Health Research, National Institute for Health Research Oxford Biomedical Research Centre, UK Medical Research Council, Health Data Research UK.