tbuckley/cabot-search huggingface dataset:
DIPG-11. A PHASE I DOSE ESCALATION STUDY OF BXQ-350 IN CHILDREN AND YOUNG ADULTS WITH RELAPSED SOLID TUMORS
Authors: Bhuvana Setty, Timothy Cripe, Mariko DeWire- Schottmiller, Richard Curry, Mohamed AdelBaki
Journal: Neuro-Oncology (2020)

Abstract BXQ-350 is a novel agent composed of the multifunctional, lysosomal activator protein Saposin C (SapC) and dioleoyl- phosphatidylserine (DOPS). BXQ-350 demonstrated antitumor effects in vitro and in vivo. Many tumors, including diffuse intrinsic pontine glioma (DIPG), and cells of tumor vasculature have aberrantly-exposed PS-rich domains on the cell surface. BXQ-350 is an anti-tumor agent in development from Bexion Pharmaceuticals, Inc. that selectively targets tumor cell PS, particularly those translocated to the outer leaflet of the plasma membrane in tumor cells. BXQ-350 activates and participates in various cellular processes, including apoptosis and necrosis, and may also exhibit novel mechanisms leading to cell death that require further investigation. An adult Phase I trial with BXQ-350 completed enrollment in 2019 having dosed 86 recurrent solid tumor patients, including glioblastoma, with only one serious infusion-related reaction. The highest planned dose of 2.4 mg/kg was achieved and seven patients remain on study with multiple cases demonstrating an objective response. A Phase I pediatric dose escalation trial in recurrent solid tumors, including central nervous system (CNS) tumors, also completed enrollment in 2019. The highest planned dose of 3.2 mg/kg was achieved and there have been no BXQ-350 related serious adverse events. Eight patients (7 CNS and 1 non-CNS) completed at least one cycle with one DIPG patient completing cycle five. A pediatric Phase I trial in newly diagnosed DIPG and diffuse midline glioma (DMG) is planned for 2nd quarter 2020.
COVD-15. COVIDNEUROONC: A UK MULTI-CENTRE, PROSPECTIVE COHORT STUDY OF THE IMPACT OF THE COVID-19 PANDEMIC ON THE NEURO-ONCOLOGY SERVICE
Authors: Daniel Fountain, Rory Piper, Michael Poon, Georgios Solomou, Paul M Brennan, Yasir Chowdhury, Francesca Colombo, Tarek Elmoslemany, Frederick Ewbank, Paul Grundy, Md Tanvir Hasan, Molly Hilling, Peter Hutchinson, Konstantina Karabatsou, Angelos Kolias, Nathan McSorley, Christopher Millward, Isaac Phang, Puneet Plaha, Stephen Price, Ola Rominiyi, William Sage, Syed Shumon, Ines Silva, Stuart Smith, Surash Surash, Simon Thomson, Jun Yi Lau, Colin Watts, Michael Jenkinson
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND The COVID-19 pandemic has profoundly affected cancer services. Our objective was to determine the effect of the COVID-19 pandemic on decision making and the resulting outcomes for patients with newly diagnosed or recurrent intracranial tumors. METHODS We performed a multi-centre prospective study of all adult patients discussed in weekly neuro-oncology and skull base MDTs who had a newly diagnosed or recurrent intracranial (excluding pituitary) tumor between 01 April and 31 May 2020. All patients had follow-up data at least 30-days after the index MDT date. Descriptive statistical reporting was used. RESULTS There were 1357 referrals for newly diagnosed or recurrent intracranial tumors across fifteen neuro-oncology centres. Of centres with all intracranial tumors, a change in initial MDT management was reported in 8.6% of cases (n=104/1210). Decisions to change the MDT management plan reduced over time from a peak of 19% referrals at the start of the study to 0% by the end of the study period. Changes in management were reported in 16% (n=75/466) of cases previously recommended for surgery and 28% of cases previously recommended for chemotherapy (n=20/72). The reported SARS-CoV-2 infection rate was similar in surgical and non-surgical patients (2.6% vs. 2.4%, p &amp;gt;0.9). CONCLUSIONS Disruption to neuro-oncology services in the UK caused by the COVID-19 pandemic was most marked in the first month, affecting all diagnoses. Patients considered for chemotherapy were most affected. In those recommended surgical treatment this was successfully completed. Longer-term outcome data will evaluate oncological treatments received by these patients and overall survival.
IMMU-09. CONCURRENT DEXAMETHASONE LIMITS THE CLINICAL BENEFIT OF IMMUNE CHECKPOINT BLOCKADE IN GLIOBLASTOMA
Authors: Bryan Iorgulescu, Prafulla Gokhale, Maria Speranza, Benjamin Eschle, Michael Poitras, Margaret Wilkens, Kara Soroko, Chhayheng Chhoeu, Aine Knott, Yang Gao, Mary Jane Lim-Fat, Gregory Baker, Dennis Bonal, Quang-De Nguyen, Gareth Grant, Keith Ligon, Peter Sorger, E Antonio Chiocca, Ana Anderson, Paul Kirschmeier, Arlene Sharpe, Gordon Freeman, David Reardon
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Dexamethasone, a uniquely potent corticosteroid, is frequently administered to brain tumor patients to decrease tumor-associated edema, but limited data exist describing how dexamethasone affects the immune system systemically and intratumorally in glioblastoma patients – particularly in the context of immunotherapy. METHODS We evaluated the dose-dependent effects of dexamethasone when administered with anti-PD-1 and/or radiotherapy in immunocompetent C57BL/6 mice with syngeneic GL261 or CT-2A glioblastoma tumors, including analyses of intracranial tumors, draining lymph nodes, and spleen. Clinically, the effect of dexamethasone on survival was additionally evaluated in 181 consecutive IDH-wildtype glioblastoma patients treated with anti-PD-(L)1, with adjustment for relevant prognostic factors. RESULTS Despite the inherent responsiveness of GL261 to immune checkpoint blockade, concurrent dexamethasone administration with anti-PD-1 therapy decreased survival in a dose-dependent fashion and decreased survival following anti-PD-1 plus radiotherapy in both GL261 and immunoresistant CT-2A models. Dexamethasone quantitatively decreased T lymphocytes by reducing the proliferation while increasing apoptosis. Dexamethasone also decreased lymphocyte functional capacity. Myeloid and NK cell populations were also generally reduced. Thus, dexamethasone negatively affects both the adaptive and innate immune responses. As a clinical correlate, a retrospective analysis of 181 consecutive IDH-wildtype glioblastoma patients treated with PD-(L)1 blockade revealed worse survival among those on baseline dexamethasone. Upon multivariable adjustment with relevant prognostic factors, baseline dexamethasone use – regardless of dose – was the strongest predictor of poor survival (reference no dexamethasone; &amp;lt; 2mg HR 2.28, 95%CI=1.41–3.68, p=0.001; ≥2mg HR 1.97, 95%CI=1.27–3.07, p=0.003). CONCLUSIONS Our preclinical and clinical data indicate that concurrent dexamethasone therapy may be detrimental to immunotherapeutic approaches for glioblastoma patients. Our preclinical analyses also suggest that dexamethasone’s detrimental effects are dose-dependent, suggesting that the lowest possible dose should be used for patients when dexamethasone use is unavoidable. Careful evaluation of dexamethasone use is warranted for neuro-oncology patients undergoing immunotherapy clinical trials.
DDEL-14. SAFETY OF INTERVENTRICULAR METHOTREXATE ADMINISTRATION FOLLOWING RADIATION IN PEDIATRIC PATIENTS WITH MALIGNANT BRAIN TUMORS
Authors: Kristofer Rosales, Ossama Maher, Maggie Fader, Natalie Gallegos, Toba Niazi, John Ragheb, Ziad Khatib
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Methotrexate has been used for intrathecal administration in leukemia as well as embryonal CNS tumors in children. Concerns about neurologic side effects including leukoencephalopathy, demyelination, and seizures have limited the use of methotrexate following exposure to focal radiation. OBJECTIVE To evaluate and determine safety of Intraventricular administration of Methotrexate in pediatric patients with recurrent malignant brain tumors along with systemic Topotecan and Cyclophosphamide after exposure to prior radiation therapy. DESIGN/METHOD: Patients with recurrent cerebellar embryonal tumors after standard treatment that included radiation were enrolled on this IRB approved phase 2 study. An Ommaya reservoir was inserted in the lateral ventricle and used to administer 4 daily doses of methotrexate (2 mg/dose) along with (Topotecan [0.75mg/m2/day] and Cyclophosphamide [250 mg/m2/day]). A neurological evaluation was performed at baseline and daily during the intraventricular administration of the Methotrexate, this evaluation was repeated prior to each subsequent cycle and at completion of the protocol. RESULTS Three patients (age range 3–20) received 2–3 cycles of intra-Ommaya Methotrexate and Topotecan/Cyclophosphamide. No MRI demyelination or white matter changes were seen after completion of the intraventricular Methotrexate therapy. None of the patients enrolled on this trial had adverse effects related to the therapy regimen received. Clinical neurological status was unchanged during the entire course of the treatment and upon completion of the scheduled therapy. CONCLUSION Intraventricular administration of daily low dose Methotrexate is well tolerated in children with recurrent embryonal CNS tumors who had prior exposure to radiation.
PATH-07. SIGNIFICANCE OF H3K4me3 IN PEDIATRIC HIGH-GRADE GLIOMAS
Authors: Rebecca Lewis, Nitin Wadhwani, Barbara Mania-Farnell, Tadanori Tomita, Charles James, Guifa Xi
Journal: Neuro-Oncology (2020)

Abstract Pediatric high-grade gliomas (pHGGs) account for ~20% of childhood brain tumors, are incurable in nearly all instances, and have an average patient survival of less than 15 months. Histone posttranslational modifications (PTMs) are deregulated in pHGGs. There are many gaps in our knowledge regarding the mechanisms by which “normal” PTM is subverted during pHGG development. Preliminary results from our lab show pHGGs are enriched in H3K4me3 and that the extent of this specific PTM is predictive of patient survival length. H3K4me3 levels are controlled by methyltransferase and demethylase activity. Gene expression analysis indicates SETD1A and WDR82, enzymatic subunits of human SETD1A containing methyltransferase complex (referred to as hSETD1A-COMPASS), are responsible for H3K4 methylation. SETD1A and WDR82 are significantly elevated in pHGGs, relative to pediatric low-grade gliomas (pLGGs), and both show a direct association with glioma malignancy. Interestingly, these associations do not exist in adult gliomas. The results suggest that hSETD1A-COMPASS specifically impacts pHGG development and is a potential therapeutic target for these tumors.
PATH-27. CLINICAL, RADIOLOGIC AND PROGNOSTIC PROFILE OF IDH WILD TYPE DIFFUSE ASTROCYTOMA WITH MOLECULAR FEATURES OF GLIOBLASTOMA
Authors: Oluwatosin Akintola, Wesley Samore, Maria Martinez-Lage Alvarez, Elizabeth Gerstner
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND cIMPACT-NOW-3 recommends that IDH-wildtype diffuse astrocytic glioma Grade II or III with EGFR amplification, or combined whole chromosome 7 gain and whole chromosome 10 loss, or TERT promoter mutation should receive an integrated classification: Diffuse astrocytic glioma, IDH-wildtype with molecular features of glioblastoma, WHO grade IV. The aims of this study were: Outline the features of a cohort of patients with molecular glioblastoma according to the above criteria; Assess clinical and molecular factors that may inform prognosis; Determine if cIMPACT-NOW-3 recommendation changed clinical practice and clinical trial enrolment. METHODS 61 patients diagnosed with IDH-wildtype diffuse astrocytic glioma Grade II or III and EGFR amp or mTERT or chromosome (+7/-10) between 2011 and 2019 at MGH were included in this single center retrospective cohort study. Data collected: sex, age, extent of surgery, functional status, histological grade, molecular diagnostics and treatment. Progression was defined using RANO criteria, progression was quantified in terms of months from the initial surgery. Survival was defined in terms of months from initial surgery to date of death or last known visit. RESULTS mOS was 16 months, mPFS was 9 months. 14 patients (23%) survived &amp;gt; 24 months, 7 ≥ 36 months (mOS 32 months; 9 deceased). The probability of survival in patients with markedly enhancing tumors was 0.5 at 3 months versus 0.5 at 11 months in non-enhancing tumors. The probability of survival in patients who underwent biopsy only was 0.5 at 5 months compared to 0.5 at 12 months in patients with maximally resected tumors. 1 patient was enrolled in a clinical trial at diagnosis. 6 were enrolled at time of recurrence. CONCLUSIONS mOS and pFS in the deceased patients was comparable to historical data on survival in IDH wild-type glioblastomas. Inclusion criteria in clinical trials have not reflected the cIMPACT-NOW-3 recommendation so far.
Dissecting the Functional Significance of DNA Polymerase Mutations in Cancer
Authors: Amy J. Wisdom, David G. Kirsch
Journal: Cancer Research (2020)

DNA polymerase mutations can cause hypermutant cancers, but the mechanisms of tumorigenesis and the impact of various DNA polymerase mutations on treatment response is poorly understood. In this issue of Cancer Research, Galati and colleagues investigate the effects of cancer-associated DNA polymerase ϵ (Pole) mutations on tumorigenesis and response to immune checkpoint blockade. They describe novel genetically engineered mouse models harboring cancer-associated Pole mutations and examine the effects of these mutations on tumorigenesis, the tumor mutational landscape, and the tumor immune microenvironment. Integrating this information with an emerging understanding of how different tumor mutations influence the response to immunotherapy may aid in prediction, diagnosis, and treatment of Pole-mutant tumors.See related article by Galati et al., p. 5606.
CTIM-24. AUTOLOGOUS CD34+ ENRICHED HEMATOPOIETIC PROGENITOR CELLS GENETICALLY MODIFIED FOR HUMAN INTERFERON-α2, ARE WELL TOLERATED &amp; RAPIDLY ENGRAFT IN PATIENTS WITH GLIOBLASTOMA MULTIFORME (TEM-GBM_001 STUDY)
Authors: Gaetano Finocchiaro, Bernhard Gentner, Marica Eoli, Farina Francesca, Elena Anghileri, Stefania Girlanda, Matteo Carrabba, Valeria Cuccarini, Francesco DiMeco, Federico Legnani, Bianca Pollo, Maria Grazia Bruzzone, Marco Saini, Paolo Ferroli, Alessia Capotondo, Rosina Paterra, Mariagrazia Garramone, Stefania Mazzoleni, Andrew Zambanini, Carlo Russo, Luigi Naldini, Fabio Ciceri
Journal: Neuro-Oncology (2020)

Abstract GBM with an unmethylated MGMT gene promoter is associated with very poor prognosis. A subset of tumor associated macrophages expressing the angiopoietin receptor Tie2 (TEMs) can be genetically modified for local &amp; tumor restricted release of interferon-α2 (IFN). IFN has antitumor effects, inhibits angiogenesis &amp; modulates the immune system. Temferon consists of autologous HSPCs transduced ex-vivo with an LVV encoding an IFN gene &amp; expression control sequences for TEMs. TEM-GBM is an open-label, Phase I/IIa study (Part A: 3x3x3 dose escalation; Part B: n=12), &amp; Temferon (single dose) is given to patients with first diagnosis of GBM &amp; unmethylated MGMT promoter. Part A 3rd cohort is ongoing &amp; completes dosing in September 2020. Eight patients completed screening; one patient died (disease progression) before Temferon was administered. Six patients received Temferon (3 women, 3 men, mean age 52.3 years). Cohort 1 received Temferon 0.5x106 cells/kg &amp; Cohort 2, 1x106 cells/kg. Neutropenia &amp; thrombocytopenia occurred as expected following conditioning &amp; hematologic recovery (HR) occurred median D+13. Transduced PBMCs were identified by vector copy number (VCN) on myeloid cells at HR &amp; at later timepoints. In general, a dose-ordered increase in VCN was observed (mean VCN D+30 CD14+ Cohort 1: 0.094, cohort 2: 0.125); 1 patient in each cohort had low VCNs. VCN remained detectable up to recent follow up visits (≤ D+180). No dose-limiting toxicities have been reported. Four SAEs occurred in 3 patients who received Temferon (pneumonia, pulmonary embolism, febrile neutropenia, fatigue) but these events were not attributed to Temferon, resolved, &amp; may have been related to the conditioning regimen (carmustine &amp; thiotepa). Disease progression has been confirmed in 3 patients who received Temferon. These preliminary results indicate feasibility of engrafting a pre-determined fraction of Temferon cells in the bone marrow of GBM patients without, so far, causing dose-limiting toxicity.
NCOG-34. AN ASSESSMENT OF OVERALL SURVIVAL AND PALLIATIVE CARE USE AMONG PATIENTS WITH GLIOSARCOMA DIAGNOSED OVER A TWELVE-YEAR SPAN
Authors: Stephanie Boisclair, Shenae Samuels, Luis E Raez, Delia A Wietecha, Alejandro Lopez Cohen, Arjun Khunger, Kelly King, Candice Sareli, Jorges Adames, Jessica Jacques, Mathew Salzberg, Brian Hunis, Michel Vulfovich, Atif M Hussein
Journal: Neuro-Oncology (2020)

Abstract Gliosarcoma (GS), a rare variant of glioblastoma, accounts for less than 5% of CNS tumors. Due to its low incidence and prevalence, very few comprehensive, large-scale studies are reported in the literature that describe prognostic elements and treatment outcomes. The objective of the study was to examine patient and treatment characteristics to identify significant predictors of survival. METHODS: Data on patients with GS, diagnosed between 2004-2016, was extracted from the National Cancer Database (NCDB). Univariate analysis and a multivariate Weibull regression model was used to determine prognostic factors of survival (months). Kaplan-Meier (KM) method with log-rank test was used to compare and estimate overall survival rates between various groups. RESULTS: There was a total of 2,656 GS patients identified in the NCDB between the years of 2004-2016 with median age of 62 years old. In multivariable Weibull regression model, increasing age (HR=1.04, p=0.000) and increasing comorbidities were independent predictors of increased hazard of death. Having 3 or more comorbidities had the strongest association with increased hazard of death (HR=1.44; P=0.001). The OS has minimally improved over the period of 2004-2016; median OS was highest among those diagnosed between 2012 and 2016 at 11.4 months followed by an OS of 10.6 months between 2004 and 2007, and 9.1 months between 2008 and 2011 (P=0.001). Although current clinical guidelines recommend chemotherapy and radiation within 30 days of surgery, there was no statistically significant difference in median OS between patients who had chemotherapy initiated within 30 days, between 30 and 60 days or later than 60 days (P=0.109). There is also no statistically significant difference in OS for time of radiation initiation categories (P=0.752). In a disease with such low OS and limited treatment options, palliative care use was found in only 45 (1.7%) patients.
Providing Neonatal Outcome Estimates as an Intervention—Reply
Authors: André Kidszun, Julia Inthorn
Journal: JAMA Pediatrics (2020)

In Reply We thank Rysavy and Haward for their interest in our study1 and their important comments. They raise 2 critical points: the effects of message framing and the question whether, in general, providing neonatal outcome estimates is a valuable intervention.
EXTH-40. THERAPEUTICALLY TARGETING DE NOVO PURINE BIOSYNTHESIS IN DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Ian Mersich, Biplab Dasgupta
Journal: Neuro-Oncology (2020)

Abstract Diffuse intrinsic pontine glioma (DIPG) is an incurable brainstem malignancy in children with median survival less than 1 year and 5-year overall survival only 2 percent. Little progress has been made in treating this deadly disease due to its inoperable location and treatments aimed at targets defined in adult gliomas. Despite recent advances in genetic characterization of DIPGs there are still no targeted therapies that significantly improve overall survival. We recently generated a metabolic profile for DIPG elucidating an upregulation in purine metabolism, specifically in de novo purine biosynthesis (DNPB). Normally nucleotide salvage maintains cellular purine levels by recycling degraded bases, however DNPB is needed when purine levels are depleted. Purine metabolism provides the basic components of nucleotides needed for tumor proliferation and thus considered a high-priority target in cancer treatment. DNPB is a sequential ten step enzymatic process resulting in the production of inosine monophosphate. The last step in DNPB is carried out by the bifunctional enzyme ATIC which is upregulated in DIPG cell lines, and in patient tumors. Our preliminary data demonstrates DIPG cell lines are sensitive to pharmacological inhibition and genetic ablation of multiple enzymes in the DNPB pathway. Strikingly, cell viability could be rescued by purine supplementation when inhibiting this pathway except when ATIC is inhibited indicating the mechanism of cell death for ATIC inhibition is independent of purine nucleotide levels. Furthermore, there is a therapeutic window for targeting ATIC in DIPG cell lines relative to normal neural stem cells and normal human astrocytes. Metabolic flux experiments have demonstrated DNPB is upregulated in DIPG cell lines and the reason these cells are more sensitive to ATIC inhibition is likely related to the rapid accumulation of a cytotoxic metabolite upstream of ATIC. In vivo studies are currently underway in pre-clinical mouse models for DIPG.
RARE-56. PERITONEAL SEEDING OF A DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR IN A CHILD
Authors: Julie Messiaen, Anne Uyttebroeck, Bart Depreitere, Isabelle Vanden Bempt, Raf Sciot, Sandra A Jacobs
Journal: Neuro-Oncology (2020)

Abstract Diffuse leptomeningeal glioneuronal tumors (DLGNT) are rare neoplasms of the central nervous system and have been included in the 2016 update of the WHO classification. This is the first description of a DLGNT disseminating to the peritoneal cavity via a ventriculoperitoneal shunt (VPS) in a child. We describe an 11-year old girl who received a VPS for a Dandy-Walker malformation at the age of seven, and was diagnosed with a spinal pilocytic astrocytoma with leptomeningeal metastases six months later. She received chemotherapy (SIOP-LGG protocol) with partial response, and had progressive disease eight months after therapy cessation. Following a novel biopsy, the diagnosis was revised to a DLGNT, with a KIAA1549-BRAF fusion and loss of 1p. She received vinblastine, but was clinically progressive and craniospinal radiotherapy was initiated. 13 months later, she suddenly presented with ascites. The inferior vena cava was compressed due to the ascites, and an abdominal drain was placed, with massive fluid release. Abdominal MRI indicated an omental cake and peritoneal contrast enhancement. Bone metastases were suspected in the iliac and femoral bones. Anatomopathological examination of the ascites showed an atypical cell population, with irregular, hyperchromatic and enlarged nuclei resembling the primary tumor. The cells were positive for synaptophysin, MAP2 and weakly positive for S100. Pan-NTRK staining was negative. The diagnosis of a metastatic localization of the DLGNT was made, due to seeding of tumoral cells via the VPS. Treatment with a MEK-inhibitor was initiated, but was stopped due to progressive disease and she died 3 weeks later.