tbuckley/cabot-search huggingface dataset:
QOL-28. NEUROCOGNITIVE PROFILE OF PEDIATRIC MEDULLOBLASTOMA PATIENTS PRIOR TO RADIATION THERAPY
Authors: Muhammad Baig, Ineke Osthoorn, Susan McGovern, David Grosshans, Mary McAleer, Kristina Woodhouse, Arnold Paulino, Grace Yang, Peter Stavinoha, Wafik Zaky
Journal: Neuro-Oncology (2020)

Abstract Neurocognitive late effects are unfortunately common following treatment for pediatric medulloblastoma. While radiation therapy is an essential component of treatment for most pediatric medulloblastoma patients, it is associated with neurocognitive compromise. Effects include deficits in cognitive speed and performance efficiency, aspects of attention, as well as working memory. Yet long after treatment it is difficult to tease apart relative contributions of other risk factors to neurocognitive functioning beyond radiation. We examined neurocognitive functioning in a sample of pediatric medulloblastoma patients prior to radiation therapy, including investigation of neurocognitive risk factors such as hydrocephalus, presence of posterior fossa syndrome, and duration of neurological symptoms prior to diagnosis. Results indicated that the sample functioned in the average range in terms of overall IQ (n=34, X̅=103). Patients also functioned in the normal range in terms of language-based ability (X̅=106), nonverbal ability (X̅=104), and working memory (X̅=103). However, the sample performed statistically significantly lower than the general population in terms of cognitive speed and efficiency (z=-2.026, p=.043). The sample was also rated by parents as exhibiting more attention problems relative to the general population (z=1.988, p=.047). There was no specific association with hydrocephalus, duration of symptoms, or history of posterior fossa syndrome. Results suggest weaknesses in attention and processing speed may exist in some pediatric medulloblastoma patients prior to radiation therapy secondary to tumor and related complications. Implications for future research are presented, along with difficulties inherent to “baseline” assessment with pediatric brain tumor survivors.
MBRS-17. EXAMINING THE ROLE OF LHX9 IN GROUP 3 MEDULLOBLASTOMA
Authors: Sarah Injac, L Frank Huang, Stephen Mack, Frank Braun, Yuchen Du, Mari Kogiso, Holly Lindsay, D William Parsons, Hong Zhao, Ching C Lau, Stephen T C Wong, Xiao-nan Li
Journal: Neuro-Oncology (2020)

Abstract Medulloblastoma (MB) is the most common malignant brain tumor of childhood. Despite major advances in our understanding of the biology of MB, novel treatments remain urgently needed. Using a chemical-genomics driven drug repositioning strategy, we identified the cardiac glycoside family of compounds as potential treatments for Group 3 MB. We subsequently demonstrated that single-agent treatment with digoxin prolongs survival in a patient-derived xenograft model (PDOX) of Group 3 MB to a degree comparable to radiation therapy, a mainstay in the treatment of MB. Finally, we examined the mechanism of digoxin-mediated cell killing using RNA-seq. This work identified LHX9, a member of the LIM homeobox family of transcription factors, as the gene most significantly down-regulated following treatment (Huang and Injac et al, Sci Trans Medicine, 2018). Homologs of LHX9 play key roles in cerebellar development via spatially and temporally restricted expression and LHX9 has been proposed as a core transcription factor (TF) in the regulatory circuitry of Group 3 tumors. Loss of function of other core TFs has been shown to impact MB growth. The role of LHX9 in MB, however, has not been previously experimentally evaluated. We now report that knockdown of LHX9 in MB-derived cell lines results in marked growth inhibition raising the possibility that loss of LHX9 plays a major role in digoxin-mediated cell killing and that LHX9 represents a key dependency required for the growth of Group 3 MB. Clinical targeting of core TFs would represent a novel approach to targeting this devastating disease.
COVD-14. TELEMEDICINE REVIEW IN NEURO-ONCOLOGY: COMPARATIVE EXPERIENTIAL ANALYSIS FOR BARROW NEUROLOGICAL INSTITUTE AND GEISINGER HEALTH DURING THE 2020 COVID-19 PANDEMIC
Authors: Ekokobe Fonkem, Na Tosha Gatson, Ramya Tadipatri, Amir Azadi
Journal: Neuro-Oncology (2020)

Abstract Coronavirus disease 2019 (COVID-19) has grossly impacted how we deliver healthcare and how healthcare institutions derive value from the care provided. at increased infectious risk on immunosuppressive therapies and often have mobility limitations. Adapting to new technologies and reimbursement patterns were challenges that had to be met by the institutions while patients struggled with decisions to prioritize concerns and to identify new pathways to care. With the implementation of social distancing practices, telemedicine plays an increasing role in patient care delivery, particularly in the field of Neurology. This is of particular concern in our cancer patient population given that these patients are often at increased infectious risk on immunosuppressive therapies and often have mobility limitations. We reviewed telemedicine practices in neurology pre-/post-COVID-19 and evaluated the neuro-oncology clinical practice approaches of two large care systems, Barrow Neurological Institute and Geisinger Health. Practice metrics were collected for impact on clinic volumes, institutional recovery techniques, and task force development to address COVID-19 specific issues. Neuro-Oncology divisions reached &amp;gt;67% of pre-pandemic capacity (patient visits and slot utilization) within 3-weeks and returned to &amp;gt;90% capacity within 6-weeks of initial closures due to COVID-19. The two health systems rapidly and effectively implemented telehealth practices to recover patient volumes. While telemedicine will not replace the in-person clinical visit, telemedicine will likely continue to be an integral part of neuro-oncologic care. Telemedicine has potential for expanding access in remote areas and provides a convenient alternative to patients with limited mobility, transportation, or other socioeconomic complexities that otherwise challenge patient visit adherence.
MBCL-41. LYMPHOHEMATOPOIETIC TOXICITY IDENTIFIED IN PATIENTS WITH MEDULLOBLASTOMA RECEIVING CRANIOSPINAL IRRADIATION
Authors: Atsuko Watanabe, Yuuki Shimizu, Atsuhiko Ohta, Takashi Fukushima, Tomonari Suzuki, Ryo Nishikawa, Ryuhei Tanaka
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Medulloblastoma (MB) is the most common malignant brain tumor of childhood. MB easily disseminates through the spinal fluid. Surgery followed by radiotherapy, applied to the entire craniospinal axis (CSI), and adjuvant chemotherapy, represent the treatment of choice for patients aged ≥3 years. Since the bone marrow of the skull and vertebral column are the major hematopoietic organs, we investigated the myelosuppressive effect of irradiation treatment in patients with MB retrospectively. METHODS Medical records of newly diagnosed MB patients treated at our hospital from 2007–2019 were analyzed. Children &amp;lt;3 years old were excluded because they did not receive CSI to avoid potential neurotoxicity. RESULTS Medical records of 18 patients (11 males and 7 females, aged 6–26, median 11 years) were reviewed. Eight patients were stratified as high-risk disease and 10 patients with standard risk. All patients received CSI (dosage range 23.4–39.6 Gy based on disease risk) and posterior fossa boost. All patients developed lymphocytopenia (&amp;lt;0.5×109/L) during irradiation, and for 11 of 18 patients, lymphocytopenia (&amp;lt;0.2×109/L) was severe. Although 13 patients recovered from the lymphocytopenia before the initiation of chemotherapy, five patients underwent chemotherapy without recovery. Conversely, only six patients developed neutropenia (&amp;lt;1.0×109/L), and five of the six patients were &amp;lt;10 years old. CONCLUSION Although infectious episode associated with lymphocytopenia was not observed in this study, CSI treatment in children and adolescents may induce immunodeficient condition particularly in the lymphocytic system. Pediatric oncologists should pay attention to the impaired immunity of patients with MB who receive CSI.
Failed Assignments — Rethinking Sex Designations on Birth Certificates
Authors: Vadim M. Shteyler, Jessica A. Clarke, Eli Y. Adashi
Journal: New England Journal of Medicine (2020)

Sex designations on birth certificates offer no clinical utility, and they can be harmful for intersex and transgender people. Moving such designations below the line of demarcation wouldn't compromise the birth certificate's public health function but could avoid harm.
Abstract 985: Sca-1+ Progenitors Derived from Stem Cells Differentiate into Endothelial Cells: Implications for Stem Cell-Based Therapy in the Injured Artery
Authors: Qingzhong Xiao, Lingfang Zeng, Zhongyi Zhang, Andriana Margariti, Yanhua Hu, Qingbo Xu
Journal: Circulation (2006)

Background: Embryonic stem (ES) cells have the ability to differentiate into somatic cells of all tissue types, which can be used for tissue engineering and repair of damaged organs. However, no su...
MODL-01. SAFETY IN CONCOMITANT USE OF MEK AND BRAF INHIBITORS WITH BEVACIZUMAB
Authors: Shelby Winzent, Ashley Sabus, Molly Hemenway, Anandani Nellan, Jean Mulcahy-Levy
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND MEK and BRAF inhibitors are increasingly common treatments for pediatric nervous system tumors. While effective in blocking Ras/Raf/MEK/ERK pathway activation driving tumor progression, the side effect profile differs from traditional cytotoxic chemotherapies. Little data exists on overlapping toxicities with other targeted agents like bevacizumab despite their potential combined therapeutic benefit. METHODS A retrospective review of patients treated with MEK +/- BRAF inhibitors and bevacizumab from 2015–2019 was conducted. Data collected included demographics, tumor type, neurofibromatosis status, treatment duration, reason for concurrent treatment, and toxicities. RESULTS Fifteen patients aged 3–24 years old (median age 14 years) were identified. Diagnoses included five high-grade gliomas, four low-grade gliomas, four benign nerve sheath tumors, and one ependymoma. Nearly half (46.7%) were positive for neurofibromatosis type 1. Three patients were treated with a BRAF + MEK inhibitor and twelve were treated with a MEK inhibitor combined with bevacizumab. Duration of treatment ranged from 16–420 days (median 119 days). Reasons for concomitant therapy included progressive disease with neurologic decline (46.7%), painful benign nerve sheath tumors (26.7%), and visual loss with optic pathway gliomas (26.7%). Toxicities while on concurrent therapy included one episode of grade 1 left ventricular dysfunction, one grade 1 bleeding episode, and one grade 2 wound complication. There were no episodes of hypertension, thrombosis, GI perforations, or cytopenias. CONCLUSIONS Our preliminary experience suggests bevacizumab in combination with MEK and BRAF inhibitors can be used safely across a variety of pediatric nervous tumors. Larger studies are needed to confirm these findings.
Beyond Osimertinib: The Development of Third-Generation EGFR Tyrosine Kinase Inhibitors For Advanced EGFR+ NSCLC
Authors: Misako Nagasaka, Viola W. Zhu, Sun Min Lim, Michael Greco, Fengying Wu, Sai-Hong Ignatius Ou
Journal: Journal of Thoracic Oncology (2020)

Single-agent osimertinib is the standard of care for the first-line treatment of advancedEGFR+ NSCLC and remained the only marketed third-generation EGFR tyrosine kinase inhibitor (TKI) until March 2020 when almonertinib (HS-10296) was approved in the People's Republic of China for the treatment of advanced EGFR T790M+ NSCLC based on a phase 2 expansion study of a phase 1/2 trial. In this review, we profiled many of the third-generation EGFR TKIs in late-stage clinical development (e.g., almonertinib, lazertinib, alflutinib1, rezivertinib, ASK120069, SH-1028, D-0316, and abivertinib) based on their interim results from phase 1 and phase 2 trials, and included the designs of the phase 3 trials and their chemical structures when publicly available. We also listed other third-generation EGFR TKIs in pipeline development based on the search of clinical trial registration websites. In addition, we summarized the results of clinical trials that previously reported third-generation EGFR TKIs (rociletinib, olmutinib, nazartinib, mavelertinib), including phase 3 results of rociletinib and naquotinib. We further profiled combination clinical trial design of the third-generation EGFR TKIs including FLAURA2 (NCT04035486), MARIPOSA (NCT04487080), ACROSS1 (NCT04500704), and ACROSS2 (NCT04500717) that if positive can potentially usher in the next standard of care for advanced EGFR+ NSCLC.
NIMG-33. CHANGES IN MAGNETIC RESONANCE IMAGING AFTER PROTON BOOST THERAPY FOR GLIOBLASTOMA WITH AND WITHOUT TUMOR TREATING FIELDS THERAPY
Authors: Hanna Goett, Alexandra Jensen, Tobias Struffert, Eberhard Uhl, Marco Stein
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Tumor treating fields (TTFields) are an approved glioblastoma (GBM) treatment modality that demonstrated a significant improved median overall survival in newly diagnosed GBM patients. Data about morphologic changes in serial magnetic resonance imaging (MRI) for patients with a combination therapy of TTFields and proton boost therapy does not exist. METHODS Twenty-two patients were included in this study. All patients were treated with initial tumor resection followed by combined chemo- and radiation therapy. Radiation therapy was performed with 50.0 Gy photons and a proton boost with 10 Gy equivalent (Gy(RBE)). 11 patients were additionally treated with TTFields. RESULTS A new increase in contrast enhancement and/or a progress in the T2 FLAIR hyperintensity was observed in 54.5% (N=12) at 3 months and in 31.8% (N=7) at 6 months. No differences were observed between patients with and without TTFields therapy at 3 months [63.6% (N=7) vs. 45.5% (N=5); P=0.392] and at 6 months [27.3 (N=3) vs. 36.3% (N=4); P=0.647). By the RANO criteria a progressive disease (PD) was observed in 6 patients (27.3%) at 3 months and in 7 patients (31.8%) at 6 months. Pseudoprogression (PP) was observed in in 36.4% (N=8) at months and in 27.3% (N=6) at 6 months. Neither for PD at 3 months [36.4% (N=4) vs. 18.2% (N=2); P=0.338] or at 6 months [36.4% (N=4) vs. 27.3% (N=3); P=0.647), nor for PP at 3 months [45.5% (N=5) vs. 27.2% (N=3); P=0.375] or at 6 months [18.2% (N=2) vs. 36.4% (N=4); P=0.338] differences for patients with and without TTFields therapy were found. CONCLUSION Increased contrast enhancement and/or increased T2 FLAIR MRI hyperintensity after proton boost therapy are common. Furthermore, the rates for new contrast enhancement, PD, and PP after photon therapy with and without additional TTFields therapy are comparable.
LTBK-04. PHASE 2 MULTICENTER STUDY OF THE ONCOLYTIC ADENOVIRUS DNX-2401 (TASADENOTUREV) IN COMBINATION WITH PEMBROLIZUMAB FOR RECURRENT GLIOBLASTOMA; CAPTIVE STUDY (KEYNOTE-192)
Authors: Gelareh Zadeh, Mariza Daras, Timothy F Cloughesy, Howard Colman, Priya U Kumthekar, Clark C Chen, Robert Aiken, Morris D Groves, Shirley Ong, Rohan Ramakrishna, Michael A Vogelbaum, Simon Khagi, Thomas Kaley, Jason M Melear, David M Peereboom, Analiz Rodriguez, Maxim Yankelevich, Suresh G Nair, Vinay K Puduvalli, Farshad Nassiri, Adam M Sonabend, Laura Agensky, Brett Ewald, Matteo Levisetti, Frederick F Lang
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND A Phase 2 multi-center study was conducted to evaluate the replication-competent oncolytic adenovirus, DNX-2401 (tasadenoturev), in combination with the anti-PD-1 antibody, pembrolizumab, in subjects with recurrent glioblastoma. METHODS Subjects ≥ 18 years with glioblastoma at first or second recurrence were treated with a single intratumoral injection of 5e8-5e10 vp DNX-2401 at the time of biopsy, followed by 200 mg pembrolizumab infusions every 3 weeks until progression or toxicity. RESULTS Forty-nine subjects were enrolled at first (79.6%) or second (20.4%) recurrence after prior surgery (89.8%), radiotherapy (100%), and temozolomide (100%). Forty-eight of 49 (98%) were treated with 5e8 vp (n=3), 5e9 vp (n=3), or 5e10 vp (n=42) DNX-2401 and pembrolizumab. Median treatment duration was 7 cycles (range 1–35) with one subject remaining on treatment (cycle 31). Adverse events were primarily mild to moderate, consistent with underlying disease, and manageable. Headache, brain edema, and fatigue are the most common events reported as related to the treatment regimen. Of subjects treated with full dose DNX-2401 and pembrolizumab (n=42), 5 subjects (11.9%) had confirmed responses, including 2 durable ongoing complete responses and 3 partial responses. One subject remains tumor free &amp;gt; 12 months after completing the planned 24 months of pembrolizumab. Median overall survival was 12.5 months; OS-12 and OS-18 were 54.5% and 20.8%, respectively. Four subjects, all of which have survived more than 21 months, continue to be followed for survival. CONCLUSIONS DNX-2401 plus pembrolizumab provides encouraging activity and is safe in patients with recurrent glioblastoma. A global, randomized, controlled Phase 3 study is planned.
Enhanced SARS-CoV-2 neutralization by dimeric IgA
Authors: Zijun Wang, Julio C. C. Lorenzi, Frauke Muecksch, Shlomo Finkin, Charlotte Viant, Christian Gaebler, Melissa Cipolla, Hans-Heinrich Hoffmann, Thiago Y. Oliveira, Deena A. Oren, Victor Ramos, Lilian Nogueira, Eleftherios Michailidis, Davide F. Robbiani, Anna Gazumyan, Charles M. Rice, Theodora Hatziioannou, Paul D. Bieniasz, Marina Caskey, Michel C. Nussenzweig
Journal: Science Translational Medicine (2020)

Human dimeric IgA antibodies are potent neutralizers of SARS-CoV-2.
Impact of scaling up dolutegravir on antiretroviral resistance in South Africa: A modeling study
Authors: Anthony Hauser, Katharina Kusejko, Leigh F. Johnson, Huldrych F. Günthard, Julien Riou, Gilles Wandeler, Matthias Egger, Roger D. Kouyos
Journal: PLoS Medicine (2020)

Background Rising resistance of HIV-1 to non-nucleoside reverse transcriptase inhibitors (NNRTIs) threatens the success of the global scale-up of antiretroviral therapy (ART). The switch to WHO-recommended dolutegravir (DTG)-based regimens could reduce this threat due to DTG’s high genetic barrier to resistance. We used mathematical modeling to predict the impact of the scale-up of DTG-based ART on NNRTI pretreatment drug resistance (PDR) in South Africa, 2020 to 2040. Methods and findings We adapted the Modeling Antiretroviral drug Resistance In South Africa (MARISA) model, an epidemiological model of the transmission of NNRTI resistance in South Africa. We modeled the introduction of DTG in 2020 under 2 scenarios: DTG as first-line regimen for ART initiators, or DTG for all patients, including patients on suppressive NNRTI-based ART. Given the safety concerns related to DTG during pregnancy, we assessed the impact of prescribing DTG to all men and in addition to (1) women beyond reproductive age; (2) women beyond reproductive age or using contraception; and (3) all women. The model projections show that, compared to the continuation of NNRTI-based ART, introducing DTG would lead to a reduction in NNRTI PDR in all scenarios if ART initiators are started on a DTG-based regimen, and those on NNRTI-based regimens are rapidly switched to DTG. NNRTI PDR would continue to increase if DTG-based ART was restricted to men. When given to all men and women, DTG-based ART could reduce the level of NNRTI PDR from 52.4% (without DTG) to 10.4% (with universal DTG) in 2040. If only men and women beyond reproductive age or on contraception are started on or switched to DTG-based ART, NNRTI PDR would reach 25.9% in 2040. Limitations include substantial uncertainty due to the long-term predictions and the current scarcity of knowledge about DTG efficacy in South Africa. Conclusions Our model shows the potential benefit of scaling up DTG-based regimens for halting the rise of NNRTI resistance. Starting or switching all men and women to DTG would lead to a sustained decline in resistance levels, whereas using DTG-based ART in all men, or in men and women beyond childbearing age, would only slow down the increase in levels of NNRTI PDR.
An epoxide hydrolase inhibitor reduces neuroinflammation in a mouse model of Alzheimer’s disease
Authors: Anamitra Ghosh, Michele M. Comerota, Debin Wan, Fading Chen, Nicholas E. Propson, Sung Hee Hwang, Bruce D. Hammock, Hui Zheng
Journal: Science Translational Medicine (2020)

Blocking epoxide hydrolase with a bioavailable small-molecule inhibitor reduces neuropathology in an Alzheimer’s disease mouse model.
Activity and Adverse Events of Actinium-225-PSMA-617 in Advanced Metastatic Castration-resistant Prostate Cancer After Failure of Lutetium-177-PSMA
Authors: Benedikt Feuerecker, Robert Tauber, Karina Knorr, Matthias Heck, Ali Beheshti, Christof Seidl, Frank Bruchertseifer, Anja Pickhard, Andrei Gafita, Clemens Kratochwil, Margitta Retz, Jürgen E. Gschwend, Wolfgang A. Weber, Calogero D’Alessandria, Alfred Morgenstern, Matthias Eiber
Journal: European Urology (2020)
Therapeutic targeting of transcriptional elongation in diffuse intrinsic pontine glioma
Authors: Hiroaki Katagi, Nozomu Takata, Yuki Aoi, Yongzhan Zhang, Emily J Rendleman, Gavin T Blyth, Frank D Eckerdt, Yusuke Tomita, Takahiro Sasaki, Amanda M Saratsis, Akihide Kondo, Stewart Goldman, Oren J Becher, Edwin Smith, Lihua Zou, Ali Shilatifard, Rintaro Hashizume
Journal: Neuro-Oncology (2021)

Diffuse intrinsic pontine glioma (DIPG) is associated with transcriptional dysregulation driven by H3K27 mutation. The super elongation complex (SEC) is required for transcriptional elongation through release of RNA polymerase II (Pol II). Inhibition of transcription elongation by SEC disruption can be an effective therapeutic strategy of H3K27M-mutant DIPG. Here, we tested the effect of pharmacological disruption of the SEC in H3K27M-mutant DIPG to advance understanding of the molecular mechanism and as a new therapeutic strategy for DIPG.Short hairpin RNAs (shRNAs) were used to suppress the expression of AF4/FMR2 4 (AFF4), a central SEC component, in H3K27M-mutant DIPG cells. A peptidomimetic lead compound KL-1 was used to disrupt a functional component of SEC. Cell viability assay, colony formation assay, and apoptosis assay were utilized to analyze the effects of KL-1 treatment. RNA- and ChIP-sequencing were used to determine the effects of KL-1 on gene expression and chromatin occupancy. We treated mice bearing H3K27M-mutant DIPG patient-derived xenografts (PDXs) with KL-1. Intracranial tumor growth was monitored by bioluminescence image and therapeutic response was evaluated by animal survival.Depletion of AFF4 significantly reduced the cell growth of H3K27M-mutant DIPG. KL-1 increased genome-wide Pol II occupancy and suppressed transcription involving multiple cellular processes that promote cell proliferation and differentiation of DIPG. KL-1 treatment suppressed DIPG cell growth, increased apoptosis, and prolonged animal survival with H3K27M-mutant DIPG PDXs.SEC disruption by KL-1 increased therapeutic benefit in vitro and in vivo, supporting a potential therapeutic activity of KL-1 in H3K27M-mutant DIPG.