tbuckley/cabot-search huggingface dataset:
EPID-16. EPIDEMIOLOGICAL TRENDS FOR LONGER TERM GBM SURVIVORS POST STUPP
Authors: Samantha Forner, Omar Al-Salihi, Lucy Brazil, Angela Swampillai
Journal: Neuro-Oncology (2020)

Abstract Patients with Glioblastoma Multiforme (GBM) have a poor prognosis with few long-term survivors (&amp;gt;2 years from diagnosis). This review analyses key characteristics of this cohort. METHODS: Retrospective single-centre review of GBM patients treated with the STUPP protocol at a Regional Neuro-oncology centre, Nov-09–Sept-19. Demographics, histology and treatment details were reviewed, with progression (PFS) and overall survival (OS) analysed. RESULTS: In 282 patients (mean age 55 years;M:F ratio 2:1), 77% of patients underwent de-bulking surgery and 35% were MGMT-methylated. Median OS was 72.1 weeks with a statistically significant survival benefit in patients who underwent debulking surgery (p=0.0001), were methylated for MGMT (P=0.0026) or those less than 50yrs (p=&amp;lt; 0.0001). 14% patients were treated within clinical trials. 66 patients (23%) were alive at 24 months. Baseline characteristics - mean age 52yrs; 53% MGMT-methylated; 88% debulking surgery; 16 (24%) patients with histological low grade components and 1 (1%) was of small cell. 55 (83%) relapsed of which (19) 35% received 2 lines of further treatment,14 (25%) had re do surgery, 32 (80%) received CCNU/PCV with or without surgery (24% vs 56%), 7 (13%) received TMZ-alone and 3 (5%) were not suitable for treatment. 8 (3%) were alive at 5 years. Baseline characteristics - mean age 46 years; MGMT (4 methylated, 2 unmethylated, 2 unknown); 3 (38%) had lower-grade histological components. 6 (75%) relapsed - 1 patient received TMZ (within a clinical trial) and 5 PCV/CCNU (2 within a clinical trial). 3 patients had further progression of which 2 received a further 1 line of treatment and 1 a further 3 lines. 6 (75%) remain alive, 2 (33%) in remission following STUPP. CONCLUSIONS: This real world data demonstrates that despite poor prognosis, features including methylation, younger age and surgical resection assist to predict long-term survivors. This highlights the importance of clinical trials.
Nab-paclitaxel plus gemcitabine versus nab-paclitaxel plus gemcitabine followed by FOLFIRINOX induction chemotherapy in locally advanced pancreatic cancer (NEOLAP-AIO-PAK-0113): a multicentre, randomised, phase 2 trial
Authors: Volker Kunzmann, Jens T Siveke, Hana Algül, Eray Goekkurt, Gabriele Siegler, Uwe Martens, Dirk Waldschmidt, Uwe Pelzer, Martin Fuchs, Frank Kullmann, Stefan Boeck, Thomas J Ettrich, Swantje Held, Ralph Keller, Ingo Klein, Christoph-Thomas Germer, Hubert Stein, Helmut Friess, Marcus Bahra, Ralf Jakobs, Ingo Hartlapp, Volker Heinemann, Elke Hennes, Udo Lindig, Thomas Geer, Michael Stahl, Metin Senkal, Thomas Südhoff, Matthias Egger, Christoph Kahl, Christina Große-Thie, Marcel Reiser, Stefan Mahlmann, Peter Fix, Holger Schulz, Georg Maschmeyer, Wolfgang Blau
Journal: The Lancet. Gastroenterology & hepatology (2020)
DDRE-07. DIPG HARBOUR ALTERATIONS TARGETABLE BY MEK INHIBITORS, WITH ACQUIRED RESISTANCE MECHANISMS OVERCOME BY COMBINATORIAL INHIBITION
Authors: Elisa Izquierdo, Diana Carvalho, Alan Mackay, Sara Temelso, Jessica K R Boult, Valeria Molinari, Mark Stubbs, Yura Grabovska, Lu Yu, Jyoti Choudhary, Sarita Depani, Patricia o’Hare, Simon P Robinson, Michael Hubank, Darren Hargrave, Chris Jones
Journal: Neuro-Oncology (2020)

Abstract The survival of children with diffuse intrinsic pontine glioma (DIPG) remains dismal, with new treatments desperately needed. In the era of precision medicine, targeted therapies represent an exciting treatment opportunity, yet resistance can rapidly emerge, playing an important role in treatment failure. In a prospective biopsy-stratified clinical trial, we combined detailed molecular profiling (methylation BeadArray, exome, RNAseq, phospho-proteomics) linked to drug screening in newly-established patient-derived models of DIPG in vitro and in vivo. We identified a high degree of in vitro sensitivity to the MEK inhibitor trametinib (GI50 16-50nM) in samples, which harboured genetic alterations targeting the MAPK pathway, including the non-canonical BRAF_G469V mutation, and those affecting PIK3R1 and NF1. However, treatment of PDX models and of a patient with trametinib at relapse failed to elicit a significant response. We generated trametinib-resistant clones (62-188-fold, GI50 2.4–5.2µM) in the BRAF_G469V model through continuous drug exposure, and identified acquired mutations in MEK1/2 (MEK1_K57N, MEK1_I141S and MEK2_I115N) with sustained pathway up-regulation. These cells showed the hallmarks of mesenchymal transition, and expression signatures overlapping with inherently trametinib-insensitive primary patient-derived cells that predicted an observed sensitivity to dasatinib. Combinations of trametinib with dasatinib and the downstream ERK inhibitor ulixertinib showed highly synergistic effects in vitro. These data highlight the MAPK pathway as a therapeutic target in DIPG, and show the importance of parallel resistance modelling and rational combinatorial treatments likely to be required for meaningful clinical translation.
Assessment of Trends in Second Primary Cancers in Patients With Metastatic Melanoma From 2005 to 2016
Authors: Weiye Deng, Yifan Wang, Xiangyu Liu, Jieqiong Liu, Liang Wang, Zhaogang Yang, Mingming Yang, Yi An, Chad Tang, Nina N. Sanford, Betty Y. S. Kim, Wen Jiang
Journal: JAMA Network Open (2020)

<h3>Importance</h3> To date, the risk of developing second primary cancers (SPCs) after the first primary melanoma has not been studied in the era of immune checkpoint inhibitors (ICIs). <h3>Objective</h3> To assess differences in the risk of SPCs in patients with primary melanoma before (2005-2010) and after (2011-2016) the introduction and approval of ICIs. <h3>Design, Setting, and Participants</h3> Population-based cohort study using the Surveillance, Epidemiology, and End Results database from January 2005 to December 2016 of patients diagnosed with metastatic melanoma. Data were analyzed from January 4 to June 30, 2020. <h3>Exposures</h3> Receipt of immunotherapy or other anticancer agents. <h3>Main Outcomes and Measures</h3> The primary outcome was the development of second primary cancers in patients with melanoma. Standardized incidence ratios (SIRs) were calculated for the development of SPCs before and after the introduction of ICIs. <h3>Results</h3> Among 5016 patients with diagnosed metastatic melanoma, 2888 (58%) were younger than 65 years at the time of diagnosis, and 3441 (69%) were male. From 2005 to 2010, SIRs were 3.24 (95% CI, 0.08-18.04) for small intestine cancer, 1.93 (95% CI, 1.14-3.05) for lung and bronchus cancer, 2.77 (95% CI, 1.02-6.03) for kidney cancer, and 7.29 (95% CI, 2.93-15.02) for myeloma. From 2011 to 2016, SIRs were 9.23 (95% CI, 1.12-33.35) for small intestine cancer, 1.54 (95% CI, 0.71-2.93) for lung and bronchus cancer, 2.66 (95% CI, 0.73-6.82) for kidney cancer, and 5.90 (95% CI, 1.61-15.10) for myeloma. The overall risk of developing SPCs in individuals who survived the first primary melanoma was 65% higher (SIR, 1.65; 95% CI, 1.35-2.00) in the pre-ICIs period and 98% higher (SIR, 1.98; 95% CI, 1.57-2.45) in the post-ICIs period than the overall cancer incidence rate in the general population. <h3>Conclusions and Relevance</h3> In this study, an increase in the overall risk of second primary cancers after melanoma after the introduction of immune checkpoint inhibitors was observed. The pattern of SPCs has been altered in the era of systemic therapy. Close monitoring and screening for SPCs may be warranted in patients with metastatic melanoma.
TAMI-19. METABOLIC INTERACTIONS BETWEEN TUMOR CELLS AND THE IMMUNE SYSTEM IN GBM: A POTENTIAL ACHILLES HEEL OF GBM FOR NOVEL THERAPEUTICS
Authors: Guimei Tian, Changlin Yang, Michael Andrews, Aida Karachi, Mariana Dajac, Devshri Doshi, Hector Mendez-Gomez, Ginger Moore, Joseph Flores-Toro, Maryam Rahman, Jianping Huang, Elias Sayour, Jeffrey Harrison, Duane Mitchell, Loic Deleyrolle
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Glioblastoma (GBM) contains cell populations with distinct metabolic requirements, with fast-cycling cells harnessing aerobic glycolysis, and treatment-resistant slow-cycling cells (SCCs) preferentially engaging lipid metabolism. How the different tumor cells interact with immune cells and how this metabolic heterogeneity shapes the immune landscape in GBM has yet to be understood. OBJECTIVES The objectives are to unravel the various molecular signals and metabolic link that underlie the interaction of SCCs with the GBM microenvironment, in particular with the suppressive immune compartment, and to effectively target these interactions for better therapeutics. METHODS Multiple murine glioma cell lines were used to establish metabolic heterogeneity and communications, while various genetic and pharmacological approaches were applied to assess the effect of disrupting the metabolic interplay between SCCs and the immune system. RESULTS We determined that SCCs exhibit distinct metabolic dependencies, involving preferential lipid metabolism supported by enhanced fatty acid uptake. We also found that tumor progression is regulated by the interaction of SCCs with the immune system and established that SCCs recruit immune suppressive M2-like macrophages to the tumor microenvironment, which in turn work against tumor immune rejection by inhibiting T cell anti-tumor activity. The immune microenvironment shaped by SCCs is marked by specific metabolic features enhancing lipid exchange capacities that are exploited by SCCs to support their survival and functions. Importantly, disrupting lipid metabolic exchange sensitized tumors to chemotherapy. CONCLUSION Our results reveal that metabolic interactions between SCCs and tumor-associated macrophages within the GBM microenvironment play a critical role in the development of drug and immune resistant tumors. This study delineates these metabolic communications and assesses the potential therapeutic effect of disrupting these interactions to treat GBM. The insights generated from this project uncover fundamental principles of the emerging connections between the tumor microenvironment, cell metabolism, anti-tumor immunity, and associated therapeutic vulnerabilities.
QOLP-20. A FEASIBILITY STUDY UTILIZING MINDFULNESS MEDITATION DURING CONCOMITANT CHEMORADIATION IN MALIGNANT GLIOMA PATIENTS: HEALTH-REPORTED QUALITY OF LIFE (HRQOL) RESULTS
Authors: Dina Randazzo, Evan Buckley, James Herndon, Nicole Cort, Mary Affronti, Eric Lipp, Annick Desjardins, Margaret Johnson, Daniel Landi, David Ashley, Henry Friedman, Oliver Glass, Laura Porter, Katherine Peters
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Primary brain tumor patients experience high levels of distress due to their diagnosis and treatment leading to changes in their health-related quality of life (HRQoL). Even with the standard treatment of 6 weeks of radiation with concurrent temozolomide for malignant gliomas, the prognosis remains poor. We sought to provide a new intervention and coping skill for our patients during chemoradiation to alleviate some of their stress and anxiety. Mindfulness meditation is a mind-body therapy used in many other cancer groups which can alleviate stress and improve fatigue, cognition, and sleep. METHODS 15 newly diagnosed malignant glioma subjects started 1-hour weekly phone mindfulness sessions during the 6 weeks of chemoradiation. They completed an in-person mindfulness session and interview upon return to the clinic with a final follow up survey 2 months later. Patient reported outcomes questionnaires were collected at each time point. RESULTS 0/15 subjects completed their post-chemo/in-person visit, and 9 completed their final follow-up surveys 2 months later. Scores for perceived cognition, fatigue, sleep, anxiety, spiritual-well being and mindfulness improved over these time points. Completed HRQoL patient-reported outcome questionnaires with positive trends noted from the mean (SD) post-chemo/in-person visit change from baseline and the follow-up change from baseline were: FACT-Cog perceived Cognitive Impairments subscale 4.11(13.55), 9.14(16.77); FACT-G total -5.48(16.02), 7.02(13.44); FACT-Br total -3.15(24.76), 13.17(23.37); FACIT-F -5(7.68), 0(7.92); and the FACIT-Sp12 -1.38(7.6), 2.17(4.88). Trail making Part A completion times from baseline to follow up decreased over time in 8/9 subjects and 7/9 subjects in Part B. Per the final follow up survey, 7/9 subjects continued their meditation practices after the training sessions and subjectively noted benefits with their stress and anxiety. Conclusion: Despite this small sample size, this mindfulness meditation intervention did positively impact patient-report outcomes of HRQoL in this patient population, thereby larger randomized studies are warranted.
PLGA-Nanoparticles for Intracellular Delivery of the CRISPR-Complex to Elevate Fetal Globin Expression in Erythroid Cells
Authors: Luis J. Cruz, Thamar van Dijk, Olena Vepris, Tracy M.W.Y. Li, Timo Schomann, Fabio Baldazzi, Ryo Kurita, Yukio Nakamura, Frank Grosveld, Sjaak Philipsen, Christina Eich
Journal: Biomaterials (2020)

Ex vivo gene editing of CD34+ hematopoietic stem and progenitor cells (HSPCs) offers great opportunities to develop new treatments for a number of malignant and non-malignant diseases. Efficient gene-editing in HSPCs has been achieved using electroporation and/or viral transduction to deliver the CRISPR-complex, but cellular toxicity is a drawback of currently used methods. Nanoparticle (NP)-based gene-editing strategies can further enhance the gene-editing potential of HSPCs and provide a delivery system for in vivo application. Here, we developed CRISPR/Cas9-PLGA-NPs efficiently encapsulating Cas9 protein, single gRNA and a fluorescent probe. The initial 'burst' of Cas9 and gRNA release was followed by a sustained release pattern. CRISPR/Cas9-PLGA-NPs were taken up and processed by human HSPCs, without inducing cellular cytotoxicity. Upon escape from the lysosomal compartment, CRISPR/Cas9-PLGA-NPs-mediated gene editing of the γ-globin gene locus resulted in elevated expression of fetal hemoglobin (HbF) in primary erythroid cells. The development of CRISPR/Cas9-PLGA-NPs provides an attractive tool for the delivery of the CRISPR components to target HSPCs, and could provide the basis for in vivo treatment of hemoglobinopathies and other genetic diseases.
TMOD-20. A SWINE MODEL OF GLIOBLASTOMA INDUCED BY SOMATIC GENE MODIFICATION
Authors: Barbara Tschida, Dylan Duerre, Mandy Taisto, Adrienne Watson
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma (GBM) is the most common and malignant primary brain tumor. Novel therapeutic development for GBM is needed since the standard of care universally fails to cure patients and the five-year survival rate remains below 10%. GBM therapeutic development is hampered by the lack of relevant large animal models for preclinical studies. To mitigate this problem, we are developing a model of GBM in outbred, immune-proficient swine which have comparable brain size and anatomy to humans. We developed methods for introducing genome engineering tools to minipig brain cells in vivo by direct injection of gene delivery reagents to the lateral ventricle. Using this technique, we have delivered a combination of expression vectors for oncogenes and targeted nucleases to disrupt tumor suppressor genes commonly altered in human GBM to alter six major human GBM-associated signaling pathways in a cohort of minipigs (Ras, Pi3k, p53, Rb/E2F, Pdgf, and the alternative lengthening of telomeres (ALT) pathways). These minipigs are being monitored for tumorigenesis using a secreted reporter, detectable through a simple luminescence-based blood test. Resulting tumors will be examined molecularly to detect the pathway-associated alterations in tumor tissue and determine the resemblance to human GBM. We hypothesize that this somatic cell gene-modification platform we have developed in the minipig will facilitate the efficient production of brain tumors that histologically and genetically resemble human GBM. It will allow the production of tumors that are genetically heterogeneous, of specified molecular subclasses, containing therapeutic targets of interest, and in the context of genetic backgrounds of interest. This minipig model of GBM will be applied towards preclinical therapeutic studies, imaging studies using human clinical grade equipment, and surgical technique development, to improve clinical trial success rates and patient outcomes. Funding for this study is provided by the National Institutes of Health through SBIR grant # 1R43CA235837-01A1.
TAMI-55. THE EVOLUTIONARY ENIGMA OF FATTY ACID DESATURATION IN GLIOBLASTOMA
Authors: Nicole Oatman, Julie Reisz, Angelo D’Alessandro, Biplab Dasgupta
Journal: Neuro-Oncology (2020)

Abstract Fatty acid desaturation is an enzymatic reaction in which a double bond is introduced into an acyl chain. Of the four functionally distinct desaturase subfamilies, the First Desaturase Family of enzymes introduce the first double bond into a saturated fatty acid, resulting in the synthesis of monounsaturated fatty acids (MUFA). MUFA are essential components of membrane and storage lipids and exert a profound influence on the fluidity of biological membranes. A disequilibrium in saturated to unsaturated fatty acid ratio alters cell growth, differentiation and response to external stimuli, and thus affects a range of pathologies including cancer. The most abundant and key First Desaturase Family enzyme is the delta 9 desaturate called Stearoyl Co-A Desaturase (SCD and SCD5 in humans, and SCD1-4 in mice). SCD desaturates Stearoyl-CoA (C18) and palmitoyl-CoA (C16) to oleoyl-CoA (C18:1) and palmitoyl-CoA (C16:1), respectively. Besides SCD, the only known First Desaturase in mammals with dual function is FADS2 which desaturates palmitate to Sapienate (C16:1, a positional isomer of palmitoleate) in skin cells. A recent study showed that some cancer cells can use FADS2 to bypass the SCD reaction. SCD and SCD5 are by far the most abundant desaturases expressed in the human brain. We made an unexpected discovery that SCD undergoes monoallelic codeletion with PTEN on chromosome 10, and is also highly methylated in glioblastoma (GBM). More surprisingly, all GBM cell lines with SCD codeletion/methylation (that expressed very little SCD protein) are completely resistant to SCD/SCD5 inhibition, yet their phospholipids contained abundant oleic acid. It is unknown if GBMs bypassed SCD, but retained the delta 9 desaturation reaction through a novel enzymatic activity. Our targeted and untargeted metabolomics studies revealed unexpected findings that cannot be explained by conventional wisdom, and may lead to identification of novel lipogenic targets in GBM.
Efficacy of EBL-1003 (apramycin) against Acinetobacter baumannii lung infections in mice
Authors: Katja Becker, Vincent Aranzana-Climent, Sha Cao, Anna Nilsson, Reza Shariatgorji, Klara Haldimann, Björn Platzack, Diarmaid Hughes, Per E. Andrén, Erik C. Böttger, Lena E. Friberg, Sven N. Hobbie
Journal: Clinical Microbiology and Infection (2020)

Novel therapeutics are urgently required for the treatment of carbapenem-resistant Acinetobacter baumannii (CRAB) causing critical infections with high mortality. Here we assessed the therapeutic potential of the clinical-stage drug candidate EBL-1003 (crystalline free base of apramycin) in the treatment of CRAB lung infections.The genotypic and phenotypic susceptibility of CRAB clinical isolates to aminoglycosides and colistin was assessed by database mining and broth microdilution. The therapeutic potential was assessed by target attainment simulations on the basis of time-kill kinetics, a murine lung infection model, comparative pharmacokinetic analysis in plasma, epithelial lining fluid (ELF) and lung tissue, and pharmacokinetic/pharmacodynamic (PKPD) modelling.Resistance gene annotations of 5451 CRAB genomes deposited in the National Database of Antibiotic Resistant Organisms (NDARO) suggested >99.9% of genotypic susceptibility to apramycin. Low susceptibility to standard-of-care aminoglycosides and high susceptibility to EBL-1003 were confirmed by antimicrobial susceptibility testing of 100 A. baumannii isolates. Time-kill experiments and a mouse lung infection model with the extremely drug-resistant CRAB strain AR Bank #0282 resulted in rapid 4-log CFU reduction both in vitro and in vivo. A single dose of 125 mg/kg EBL-1003 in CRAB-infected mice resulted in an AUC of 339 h × μg/mL in plasma and 299 h × μg/mL in ELF, suggesting a lung penetration of 88%. PKPD simulations suggested a previously predicted dose of 30 mg/kg in patients (creatinine clearance (CLCr) = 80 mL/min) to result in >99% probability of -2 log target attainment for MICs up to 16 μg/mL.This study provides proof of concept for the efficacy of EBL-1003 in the treatment of CRAB lung infections. Broad in vitro coverage, rapid killing, potent in vivo efficacy, and a high probability of target attainment render EBL-1003 a strong therapeutic candidate for a priority pathogen for which treatment options are very limited.
EPEN-17. FAVORABLE OUTCOME TO INTENSIVE CHEMOTHERAPY WITHOUT IRRADIATION IN INFANTILE METASTATIC EPENDYMOMA WITH A NOVEL MOLECULAR PROFILE: A CASE REPORT
Authors: Flavia W de Faria, Kathleen M Schieffer, Christopher Pierson, Daniel Boué, Nicholas Zumberge, Jerome Rusin, Stephanie LaHaye, Katherine E Miller, Daniel C Koboldt, Tara Lichtenberg, Kristen Leraas, Patrick Brennan, Benjamin Kelly, Peter White, Vincent Magrini, Richard K Wilson, Elaine R Mardis, Diana S Osorio, Jeffrey Leonard, Jonathan L Finlay
Journal: Neuro-Oncology (2020)

Abstract Metastatic disease at initial presentation of intracranial ependymoma is an uncommon occurrence with only rare reports of survival and is reportedly more prevalent in the youngest of children. Clinical and molecular characteristics associated with metastatic presentation, their prognostic implications, as well as optimal treatment options for such patients, have not been identified. CASE REPORT: A seven months old child presented with posterior fossa anaplastic ependymoma; following sub-total resection of primary tumor, a spine MRI revealed leptomeningeal dissemination along the cervical spinal cord and nerve roots of the cauda equina. The patient was successfully treated with five cycles of intensive induction chemotherapy (as per Head Start with high-dose methotrexate) followed by three sequential cycles of marrow-ablative chemotherapy and autologous hematopoietic progenitor cell rescue (AuHPCR) without irradiation; he is currently without evidence of the disease now 60 months following initial diagnosis. MOLECULAR/GENOMIC RESULTS: The patient was enrolled on a patient-centric comprehensive molecular profiling protocol, which included paired tumor-normal whole-exome sequencing, RNA sequencing of the disease-involved tissue, and DNA methylation classification. The genomic profile of the tumor was relatively unremarkable, revealing only a terminal gain of chromosome 3p and a terminal deletion of chromosome 22q, suggestive of an unbalanced translocation. Using RNA sequencing, we identified a novel SPECC1L-RAF1 gene fusion. The tumor harbors unique transcriptomic and DNA methylation profiles, failing to discretely classify with well-established ependymoma subgroups. CONCLUSION: Use of genomic profiling techniques provides meaningful information for disease characterization allowing for further expansion of the molecular spectrum associated with malignant disease.